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WO1993006118A1 - Antibacterial, antimycoplasmal compounds related to mupirocin - Google Patents

Antibacterial, antimycoplasmal compounds related to mupirocin Download PDF

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Publication number
WO1993006118A1
WO1993006118A1 PCT/GB1992/001760 GB9201760W WO9306118A1 WO 1993006118 A1 WO1993006118 A1 WO 1993006118A1 GB 9201760 W GB9201760 W GB 9201760W WO 9306118 A1 WO9306118 A1 WO 9306118A1
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WO
WIPO (PCT)
Prior art keywords
epoxy
hydroxy
tetrahydropyran
methylhexyl
title compound
Prior art date
Application number
PCT/GB1992/001760
Other languages
French (fr)
Inventor
Nigel John Perryman Broom
Peter John O'hanlon
John Stephen Elder
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB919120491A external-priority patent/GB9120491D0/en
Priority claimed from GB929201507A external-priority patent/GB9201507D0/en
Priority claimed from GB929219053A external-priority patent/GB9219053D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP5505935A priority Critical patent/JPH06510781A/en
Priority to EP92919853A priority patent/EP0605524A1/en
Publication of WO1993006118A1 publication Critical patent/WO1993006118A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen

Definitions

  • This invention relates to a novel class of compounds having antibacterial and antimycoplasmal activity, to processes for their preparation and to their use in human and veterinary medicine, and also to intermediates for use in the preparation of such compounds.
  • Mupirocin (formerly known as pseudomonic acid) is rapidly hydrolysed in vivo to monic acid A, the compound of formula (B):
  • the present invention provides a compound of formula (IA), (IB) or (IC):
  • R° denotes a substituted or unsubstituted hydrocarbyl or heterocyclyl group. More specifically R° denotes the term (A) n - (B) m ; wherein n and m are integers having a value of 0 or 1; A is a (C 1 -6 ) alkyl, (C 2-6 ) alkenyl, or (C 2-6 ) alkynyl group; B is a (C 3-7 ) cycloalkyl, (C 4-7 ) cycloalkenyl, aryl, heterocyclyl or heteroaryl group. Both A and B may be optionally substituted as herein below defined.
  • B is a substituted or unsubstituted (C 4-7 ) cycloalkenyl, aryl, heterocyclyl or heteroaryl group.
  • B is preferably an aryl or heteroaryl moiety. More specifically, B is a cyclohexenyl, phenyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazolyl, oxazolyl, or thiazolyl group.
  • A is a (C 1-6 )alkyl moiety.
  • A is preferably a substituted or unsubstituted butyl group.
  • A is a (C 2-6 )alkenyl, (C 2-6 )alkynyl group.
  • B is a substituted or unsubstituted aryl or heteroaryl group, such as a furanyl or phenyl. More preferably A is an ethenyl or acetylenyl (ethynyl) group.
  • B is a substituted or un-substituted aryl or heteroaryl group.
  • (un)substituted refers to both the substituted and unsubstituted derviative.
  • B is a (un)substituted phenyl, (un)substituted pyrimidinyl, (un)substituted thiazolyl, (un)substituted oxazolyl, or (un)substituted pyridyl. More preferably B is an
  • a or B may be optionally substituted
  • Suitable X groups for A, when n is 1, include, cyano, amino,
  • substituents (X 1 ), for B when m is 1, include, for example, (C 1-6 )alkyl, (po-y)halo(C 1-6 )alkyl, cyano, (un)substituted heterocyclyl, amino, (C 1-6 )alkanoylamino, mono- or di-(C 1-6 )alkylamino, substituted mono- or di-(C 1-6 )alkylamino, [also referred to as -NR 2 R 3 ], hydroxy, (C 1-6 )alkoxy, substituted (C 1-6 )alkoxy [also referred to as -O-R 1 ], (C 1-6 )alkenoxy, hydroxy substituted (C 1-6 )alkoxy, (un)substituted heterocyclylthio, arylthio, arylsulphinyl, arylsulphonyl, (C 1-6 )alkylthio,
  • R 1 group may be a (C 2-6 ) alkenyl, (C 1-6 ) alkoxy alkyl, (poly)hydroxy
  • (C 1-6 ) alkyl (poly)halo(C 1-6 ) alkyl, substituted or unsubstituted heteroaryl (C 1-6 ) alkyl, substituted mono- or di- amino (C 1-6 ) alkyl, substituted or unsubstituted heterocyclyl (C 1-6 ) alkyl, or N-(C 1-6 alkyl)- N- heteroaryl-(C 1-6 )alkyl.
  • (poly) refers to the optional substitution of more than one, such as (poly)haloalkyl would allow for more than one halogen, independently on the alkyl moiety, i.e., -CF 3 .
  • the R 1 group is a C 2-3 alkenyl, hydroxy C 1-6 alkyl,
  • the heteroaryl is a pyridyl, or furanyl moiety.
  • the heterocyclyl is a piperidine group.
  • R 1 is ethenyl, 2-ethanol, 3-propanol, -CH 2 -O-CH 3 ,
  • R 2 and R 3 moieties are independently a (C 1-6 ) alkyl group or one of R 2 or R 3 may be a hydroxy (C 1-6 ) alkyl group.
  • R 2 and R 3 are (C 1-6 ) alkyl, more preferably methyl; or one of R 2 R 3 is methyl and the other 2-ethanol.
  • the X 1 substitutents are selected from hydroxy, substituted and unsubstituted (C 1-6 )alkoxy, (C 1-6 )alkyl, oxy(C 1-6 )alkyl, cyano, chloro, fluoro, bromo, nitro, hydroxy(C 1-6 )alkyl, (C 1-6 )alkylthio,
  • X 1 is methoxy, C(O)CH 3 , methyl, cyano, chloro, fluoro, bromo, -CH(OCH 2 CH 3 )2, nitro, -CH(O), N(CH 3 ) 2 , SCH 3 , S(O)CH 3 , S(O) 2 CH 3 , -CH 2 OH, piperidine, O-CF 3 , hydroxy, ethenyloxy, 2- hydroxyethoxy, N-(2-hydroxyethyl)-N-methylamino, 3-hydroxypropyloxy, azidoethoxy, N-methyl-N-pyridylaminoethoxy, piperidinylethoxy, pyridylmethyloxy, nitrofuranyl methyloxy, or furanylmethyloxy.
  • the optional substituents for said groups are independently substituted up to five times, preferably up to three times, from the same group listed herein under the X 1 term.
  • (unsubstituted carbamoyl would allow the nitrogen atom to be mono- or di-substituted with a (C 1-6 )alkyl moiety;
  • the (un)substitued heterocyclic would allow, for example, a piperidine ring to be substituted by a (C 1-6 )alkyl, or hydroxy moiety;
  • an (un)substituted heteroaryl would allow for a furanyl ring to be substituted by a nitro group.
  • Preferred substituent groups (X 1 ) when B is an aryl group include, for example, halogen, cyano, (C 1-6 )alkyl, hydroxy(C 1-6 )-alkyl, oxo(C 1-6 )alkyl, gem di(C 1-6 )alkoxy(C 1-6 )alkyl, (C 1-6 )alkoxy, (C2-g)alkenoxy,
  • (C 1-6 )-alkylsulphonyl sulphamoyl, mono- or di-(C 1-6 )alkylsulphamoyI, carbamoyl, mono- or di-(C 1-6 )alkylcarbamoyl and heterocyclyl.
  • Preferred substituents (X 1 ) when B is a heteroaryl group include, for example, halogen, (C 1-6 )alkyl, (C 1-6 )cycloalkyl, (C 1-6 )alkoxy,
  • Preferred substituent (X 1 ) when B is a heterocyclyl group include, for example, halogen, (C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, (C 1-6 )alkoxy, hydroxy(C 1-6 )alkoxy, halo(C 1-6 )alkyl, hydroxy, amino, mono- or
  • a substituent group preferably in the (B) m term, has an acidic hydrogen arising from the presence in a heteroaryl ring of an NH moiety, for instance, when R° is pyrazolyl, the hydrogen may be replaced by a (X or X 1 ) substituent as hereinbefore defined.
  • the substitutent is a (C 1-6 ) alkyl group.
  • alkyl group or moiety referred to herein may be a straight or branched hydrocarbon chain, and may contain, for example, up to 12 carbon atoms, suitably up to 6 carbon atoms.
  • the alkyl chain may be unsubstituted or substituted.
  • the alkyl group or moiety may be an unsubstituted or substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl or tert-butyl group.
  • suitable optional substituents for any such alkyl group or moiety include the above-listed substituents for the (A) n term.
  • the term 'aryl' includes, unless otherwise defined, phenyl or naphthyl.
  • the term 'heterocyclyl' and 'heterocyclic' includes non-aromatic single or fused rings comprising up to four heteroatoms in each ring selected from oxygen, nitrogen and sulphur.
  • the heterocyclic ring comprises from 4 to 7, preferably from 5 to 6 ring atoms.
  • a fused heterocyclic ring system may include aromatic carbocyclic and heteroaryl rings.
  • the heterocyclic group is piperidinyl.
  • heteroaryl' includes aromatic hetrocyclic containing rings and ring systems as is commonly defined in the art, such as by Katritzky et al., Handbook of Heterocyclic Chemistry, Pergamon Press, Oxford, England (1985).
  • a heteroaromatic structure is based on the 6 ⁇ -electron system. These structure are related to and formally derived from benzene by successive replacement of one or two annular CH groups by trivalent or divalent heteroatom groups respectively. The overall patttern of filled bonding molecular orbitals is retained.
  • heteroaryl ring has 5 to 6 ring atoms in each ring.
  • Prefered heteroaryl groups herein include, pyridyl, pyrim idinyl, furanyl, thienyl, thiazolyl, isoxazolyl, oxazolyl and pyrazolyl.
  • hydrocarbyl may include groups having up to 18 carbon atoms, suitably up to 10 carbon atoms, conveniently up to 6 carbon atoms. Suitable groups include those listed under the (A) n term and the (B) m term groups which do not contain a heteroatom, i.e.
  • cycloalkyl cycloalkenyl and aryl.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • the halogen is fluoro, chloro or bromo.
  • mupirocin i.e. [2S, 3R, 4R, 5S] about the tetrahydropyran ring and [2S, 3S, 4S, 5S] in the 5-(2,3-epoxy-5-hydroxy-4-methylhexyl) sidechain ofthe tetrahydropyran ring.
  • the compounds of the present invention may exist in the forms shown in formulae (IA), (IB) or (IC), the three forms being in equilibrium.
  • the compounds of formula (I) of the present invention are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations ofthe compounds of formula (I) may be used for preparing the more pure forms used in the
  • the compounds of the present invention are obtained in crystalline form.
  • solvent of crystallisation may be present in the crystalline product.
  • This invention includes within its scope such solvates.
  • some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed.
  • This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. Examples of compounds within the scope of this invention include the following:
  • Compounds of the present invention may be prepared by methods known for the preparation of ⁇ -diketones. Some of these processes will be more appropriate than others.
  • compounds of formula (I) may be prepared by a process which
  • Z 1 , Z 2 and Z 3 are the same or different and each is hydrogen or a hydroxyl-protecting group, and R° is as hereinbefore defined; with an oxidising agent which converts a ⁇ -hydroxyketone into a
  • oxidising agents include, for example, activated manganese
  • the oxidation reaction is effected in a organic solvent such as, for example, dioxan, acetonitrile, tetrahydrofuran, ether, carbon
  • a compound of formula (III) may be obtained by treating a ketone compound of formula (V):
  • Z 1 , Z 2 and Z 3 are as hereinbefore defined, with a suitable enolising agent such as, for example, lithium diisopropylamide.
  • the compound of formula (III) may be generated in situ, prior to the treatment thereof with a compound of formula (IV).
  • the present invention provides a second process for preparing a compound of formula (I) as hereinbefore defined, which process comprises treating a compound of formula (VI):
  • Suitable reagents for effecting such a conversion include ozone and osmium tetroxide, each of which forms an intermediate which may then be converted to the compound of formula (I).
  • Alternative reagents useful in the conversion herein may be found in Harrison et al, Compendium of Organic Synthetic Methods, Wiley-Interscience (1971).
  • Ozonolysis may be effected under conditions conventionally used for such a reaction.
  • the reaction may be effected at a low temperature, for instance about -70°, in the presence of a suitable solvent such as dichloromethane.
  • the intermediate ozonide thus formed may be conveniently decomposed by an agent conventionally used for such a task, of which triphenyl phosphine is especially preferred.
  • the compound of formula (VI) may be treated with osmium tetroxide, according to the procedure described by V. Van Rheenen, R.C. Kelly and D.Y. Cha, Tetrahedron Lett, 1976, 1973.
  • osmium tetroxide a catalytic quantity of osmium tetroxide is employed, in the presence of a
  • tertiaryamine oxide catalyst such N-methylmorpholine N-oxide
  • a solvent such as aqueous tetrahydrofuran
  • an oxidising agent such as sodium periodate
  • a further aspect of the invention also provides a compound of formula (VI) as hereinbefore defined.
  • compounds of formula (VI) may be prepared by a process which comprises treating the acid of formula (VII) or an activated derivative thereof:
  • Suitable organometallic reagents include:
  • an organocerium reagent R°Li-CeX 3 in which R° is as defined with respect to formula (I) and X represents chlorine, bromine or iodine.
  • reaction with the organometallic reagent may be conveniently carried out in an ethereal or hydrocarbon solvent, the choice of which is
  • the Grignard reagent is generated and used in diethyl ether or tetrahydrofuran.
  • the reaction is generally carried out in an inert atmosphere such as argon or nitrogen and at ambient temperature or below.
  • the period for which the reaction is allowed to proceed depends upon the particular starting materials employed.
  • the course ofthe reaction may be followed by conventional methods such as thin layer chromatography and the reaction may be terminated when an optimum quantity of product is present in the reaction mixture.
  • Suitable activated derivatives ofthe acid of formula (VII) include
  • a 5- or 6-membered heterocyclic ring which may contain in addition to the nitrogen atom, one or two further heteroatoms selected from oxygen, nitrogen and sulphur and which may be substituted or fused to a benzene ring which may itself be substituted.
  • Preferred thio-esters are of formula (Vllla):
  • Z 1 , Z 2 , and Z 3 are as hereinbefore defined, and R 2 and R 3 are the same or different and each denotes an aryl group, for instance phenyl, or a (C 1-6 )alkoxy group, for instance ethoxy.
  • R 4 and R 5 are the same or different, and each is (C 1 -6 )alkyl, preferably methyl, or the substituents R 4 and R 5 form a (C 2-7 )alkylene chain and; amides of the formula (XII):
  • Z 1 , Z 2 , and Z 3 are as hereinbefore defined and R 6 and R 7 , together with the nitrogen atom to which they are bonded, form an imidazolyl or triazolyl ring.
  • organomanganous reagent of formula R°MnCl, as hereinbefore defined.
  • organolithium reagent of formula R°Li as hereinbefore defined:
  • Suitable organometallic reagents may be prepared according to
  • Suitable organomanganous reagents of the formula R°MnCl may be conveniently prepared by addition of an organolithium reagent R°Li to a solution of manganous chloride and lithium chloride in dry THF, or a suspension of anhydrous manganous chloride in dry THF. An excess of R°MnCl is preferably employed. Alternatively, a Grignard reagent may be used in place ofthe organolithium reagent, to generate the
  • organomanganous reagent R°MnCl organomanganous reagent
  • organomanganous reagents which may be used instead of R°MnCl include:
  • Organocerium reagents may be generated in situ by treatment of an organolithium compound ofthe formula R°Li, in which R° is as
  • cerium (III) halide by analogy with the procedure described by Imamoto el al; J.Chem. Soc. , Chem. Commun, 1982, 1042.
  • the activated derivatives of compounds of formula (VI) may be prepared from the compounds of formula (VI) by standard methodology.
  • Compounds of formula (VII) may be obtained by treating the protected methylester of monic acid with a base such as lithium diisopropylamide, as described by Crimmin et at, J. Chem. Soc. Perkin Trans 1. 1985, 549, followed by ester hydrolysis.
  • a base such as lithium diisopropylamide
  • a compound of formula (VI) may be prepared by treating a compound of formula (XI) in which R 4 and R 5 each is methyl with an organometallic reagent which is preferably an organolithium reagent of the formula R°Li.
  • Z 1 , Z 2 , Z 3 , R 4 and R 5 are as hereinbefore defined, with a strong non-nucleophilic base such as, for example, lithium diisopropylamide, followed by quenching with a mild proton source such as ammonium chloride.
  • a strong non-nucleophilic base such as, for example, lithium diisopropylamide
  • Compounds of formula (XIII) may be prepared from monic acid by initial conversion thereof to an activated derivative, for instance a mixed anhydride such as that formed with iso-butylchloroformate, followed by subsequent treatment with an amine HN(OR 4 )R 5 in which R 4 and R 5 are as hereinbefore defined, or a salt thereof; under standard conditions, for instance, with dichloromethane as the reaction solvent, at about 0°C for 2h; and thereafter and if required, introducing any hydroxyl-protecting groups that may be subsequently required.
  • an activated derivative for instance a mixed anhydride such as that formed with iso-butylchloroformate
  • the present invention provides a third process for preparing a compound of formula (I) which process comprises treating a compound of formula (XlV):
  • a further aspect ofthe invention provides a compound of formula (XEV) as hereinbefore defined.
  • Compounds of formula (XIV) may be prepared from the corresponding acids of formula (XVI):
  • Compounds of formula (XVI) may be prepared from compounds of formula (V), as hereinbefore defined, and in which the hydroxyl groups are protected, preferably as a silylether, by initial conversion thereof to the enol form followed by ozonoloysis and subsequent decomposition of the intermediate ozonide using, for instance, dimethyl sulphide.
  • Compounds of formula (I) may be obtained from other compounds of formula (I) by suitable manipulation ofthe substituents present in the group R° according to conventional methodology.
  • an alkylthio substituent may be converted to an alkyl sulphinyl or an alkylsulphonyl substitutent by treatment thereof with a conventional oxidising agent such as m-chloroperbenzoic acid.
  • the term 'hydroxyl-protecting group' refers to any such group known in the art which may be removed without disruption of the remainder ofthe molecule. Suitable hydroxyl-protecting groups include those described in 'Protective Groups in Organic Synthesis', T.W. Greene, Wiley-Interscience, New York 1981.
  • the hydroxyl groups of the compounds of formulae (II), (III), (V) to (XIV) and (XVI) may be protected at any stage of the above processes, using conventional methods.
  • the hydroxyl-protecting group may be removed by methods known in the art, including enzymatic methods.
  • Particularly suitable hydroxyl-protecting groups are silyl groups since these are readily removed under mild conditions. Such groups are introduced using conventional silylating agents, including halosilanes and silazanes, ofthe formulae below: LgSiO-C-NSiLj
  • a preferred silyating agent is trimethylsilyl chloride.
  • Particularly suitable protecting groups are trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl groups. Preferred protecting groups are trimethylsilyl groups because of their ease of removal.
  • the glycol function ofthe compounds of formulae (II), (III), (V) to (XIV) and (XVI) may be protected by forming a cyclic derivative using a compound of formula (XVII):
  • R 8 is hydrogen or (C 1-6 )alkyl and each of R 9 , R 10 and R 11 is (C 1-6 )alkyl.
  • Z 1 and Z 2 together are a moiety:
  • R 8 is as hereinbefore defined and R 12 is (C 1-6 )alkyl.
  • R 8 is hydrogen, methyl, ethyl, n- or iso-propyl; most suitably it is hydrogen.
  • the groups R 9 , R 10 and R 11 are suitably methyl, ethyl, n- or iso-propyl, or n-, iso-, sec- or t-butyl; most suitably methyl.
  • hydroxyl-protecting groups described above may be removed by mild acid hydrolysis followed by alkaline hydrolysis, for instance, as described by J.P. Clayton, K. Luk and N.H. Rogers, in
  • the compounds of this invention are useful in therapy, in particular for the treatment of bacterial and mycoplasma-induced infections in
  • non-human and human animals such as the treatment of respiratory tract infections, otitis, meningitis, skin and soft tissue infections in human animals, mastitis in cattle, and respiratory infections in non-human animals such as pigs and cattle.
  • the compounds of this invention are active against both Gram negative and Gram positive organisms, including Haemophilus. for instance
  • Streptococci for instance S,pyogrenes CN10 and S.pneumonia PU7; and Staphylococci. for instance S.aureus Oxford, Legrionella. for instance L. pneumophila: and against mycoplasma.
  • compounds of the present invention are active against Staphylococci organisms such as S. aureus and S. epidermis which are resistant, including multiply resistant, to other anti-bacterial agents, for instance macrolides; aminoglycosides; lincosamides; and ⁇ -lactams, such as, for example methicillin.
  • the compoimds of this invention are also active against
  • the present invention provides a method of treating humans infected with M. fermentans. in particular humans also infected with HIV, which method comprises treating humans in need of such therapy with an anti-mycoplasmal effective amount of a compound of formula (II).
  • This invention also provides a pharmaceutical or veterinary composition which comprises a compound of formula (I) (hereinafter referred to as the 'drug') together with a pharmaceutically or veterinarily acceptable carrier or excipient.
  • a pharmaceutical or veterinary composition which comprises a compound of formula (I) (hereinafter referred to as the 'drug') together with a pharmaceutically or veterinarily acceptable carrier or excipient.
  • compositions may be formulated for administration by any route, for instance, by topical, parenteral or oral administration and would depend on the disease being treated.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical or sterile parenteral suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate, or acacia
  • non-aqueous vehicles which may include edible oils
  • preservatives for example methyl or propyl p-hydroxybenzoate or
  • Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics and cosmetics, such as 'Harry's Cosmeticology' published by Longman, and the British Pharmacopoeia.
  • Suppositories will contain conventional suppository bases, e.g.
  • cocoa-butters or other glyceride cocoa-butters or other glyceride.
  • fluid unit dosage forms are prepared utilizing the drug and a sterile vehicle.
  • the drug depending on the vehicle and concentration used, can be suspended in the vehicle.
  • adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition may be frozen after filling into the vial and water removed under vacuum.
  • the dry lypophilized powder is then sealed in the vial.
  • the drug can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the drug.
  • the drug may be made up into a suspension in a suitable liquid carrier, such as water, glycerol, diluted ethanol, propylene glycol, polyethylene glycol or fixed oils.
  • a suitable liquid carrier such as water, glycerol, diluted ethanol, propylene glycol, polyethylene glycol or fixed oils.
  • the drug is formulated as a suspension in a suitable, sterile aqueous or non-aqueous vehicle.
  • Additives for instance buffers such as sodium metabisulphite or disodium edetate;
  • preservatives including bactericidal and fungicidal agents, such as phenylmercuric acetate or nitrate, benzalkonium chloride or
  • compositions administered topically will, of course, depend on the size of the area being treated. For the ears and eyes each dose will typically be in the range from 10 to 100 mg ofthe drug.
  • compositions for intramammary treatment of mammary disorders in animals, especially bovine mastitis will generally contain a suspension ofthe drug in an oily vehicle.
  • the compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, ofthe drug.depending on the method of
  • each dosage unit will preferably contain from 50-500 mg ofthe drug.
  • the dosage as employed for adult human treatment will preferably range from 100 mg to 3 g, per day, for instance 250 mg to 2 g of the drug per day, depending on the route and frequency of administration.
  • the drug may be administered to non-human animals as part ofthe total dietary intake.
  • the amount of drug employed may be less than 1% by weight of the diet and in preferably no more than 0.5% by weight.
  • the diet for animals may consist of normal foodstuffs to which the drug may be added or the drug may be included in a premix for adimxture with the foodstuff.
  • a suitable method of administration of the drug to a non-human animal is to add it to the non-human animal's drinking water. In this case a concentration of the drug in the drinking water of about 5-500 ⁇ g/ml, for example 5-200 ⁇ g/ml, is suitable.
  • the present invention further provides a method for treating the human or non-human animal which method comprises administering a compound of formula (I) as hereinbefore defined, to a human or non-human animal in need of such therapy.
  • compositions as hereinbefore described may be employed in the treatment.
  • the present invention also provides a compound of formula (I) as hereinbefore defined for use in therapy.
  • the present invention also provides a compound of formula (I) as hereinbefore defined for use in the manufacture of a medicament for anti-bacterial therapy or mycoplasma-induced infections.
  • a compound of formula (I) as hereinbefore defined for use in the manufacture of a medicament for anti-bacterial therapy or mycoplasma-induced infections.
  • N,O -dim ethyl hydroxylamine hydrochloride (1.95grams (hereinafter g.), 20milimoles (hereinafter mmoles)) was dissolved in
  • dichloromethane/aqueous sodium hydroxide (20milliters (hereinafter ml: 10ml, 2.5Molar (hereinafter M)).
  • ml 10ml, 2.5Molar (hereinafter M)
  • M 10ml, 2.5Molar
  • the aqueous layer was re- extracted with dichloromethane (10ml) and the combined organic layers washed with saturated brine (5ml).
  • the organic layer was dried (MgS04) and added to monic acid isobutyl carbonic anhydride (10mmol)*.
  • the reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen chloride and brine.
  • the combined aqueous solutions were extracted with ethyl acetate, and the combined organic solutions dried (MgSO 4 ) and concentrated to give the amide, 3.0g.
  • furan-3-carboxaldehyde (0.28ml, 3.2mmol) was reacted to give the title compound (1.3g, 75%); ⁇ H (CDCI 3 ) inier alia 0.90 (3H, d, J 7.1Hz, 17-H 3 ), 1.20 (3H, d, J 6.3Hz, 14-H 3 ), 4.07-4.18 (1H, m, 5-H), 5.05-5.18 (1H, m, 1-H), 6.38-6.42 (1H, m, 4'-H), 7.35-7.44 (2H, m, 2',5'-H 2 ).
  • ⁇ H (CDCI 3 /CD 3 OD) inter alia 0.93 (3H, d, J 7.0Hz, 17-H 3 ), 1.21 (3H, d, J 6.3Hz, 14-H 3 ), 3.19 (6H, s, N(CH 3 ) 2 ), 6.13 (1H, s, 2- H), 6.53 (1H, d, J 9.1Hz, 3'-H), 7.94 (1H, dd, J 2.3 and 9.1Hz, 4'-H), and 8.71 (1H, d, J 2.3Hz, 6'-H); ⁇ C (CDCI 3 /CD 3 OD) 12.6 (C-17), 20.6 (C-14), 31.7 (C-9), 38.1 (N(CH 3 ) 2 ), 39.6 (C-8), 41.8 (C-4), 42.7 (C-12), 55.7 (C-10), 61.2 (C-11), 65.6 (C-16), 68.9 (C-6), 70.2 (C-7), 71.1 (C-13), 74.0 (C-5), 95.6 (C-2
  • 2-Chloropyridine-5-carboxylic acid (1.576g, 10mmol) was dissolved in dry THF (100ml), cooled in an ice-bath, then triethylamine (1.5ml, llmmol) added, followed by iso-butylchloroformate (1.3ml, 10mmol). The mixture was stirred for 3/4h, then N,O-dimethylhydroxylamine (ex hydrochloride salt, 15mmol) in dichloromethane (70ml) was added. After stirring for 13/4h, the mixture was diluted with dichloromethane, washed with water, aqueous sodium hydrogen carbonate, and brine, dried and
  • N-methoxy, N-methyl-2- bromopyridine-5-carboxamide (1.60g, 6.53mmol) was reacted to give the title compound (1.042g, 86%); m.p.103.5-104°C (chloroform/hexane); found C, 38.72; H, 2.09; N, 7.53; Br, 42.62%.
  • C 6 H4BrNO requires C, 38.74; H, 2.17; N, 7.53; Br.
  • Ethyl 2-mercaptoimidazole-4(5)-carboxylate (10.0g, 58mmol) was dissolved in dry DMF (200ml), and sodium hydride (80% in oil, 3.5g, 116mmol) added slowly with cooling. The mixture was stirred for 1h under argon, cooled in an ice bath, and methyl iodide (14.4ml, 232mmol) added. The reaction was then stirred overnight, diluted with water (200ml) and extracted with ethyl acetate (6 x 100ml). The combined organic extracts were washed with brine, dried and evaporated.
  • Ethyl 2-(3-triethylsilyloxyprop-1-oxy)pyridine-5-carboxylate (1.53g, 4.5mmol) was dissolved in dry THF (50ml) under argon, then diisobutylaluminium hydride (1.0M, 5ml, 5mmol) was added slowly. After stirring for 1 ⁇ 2 h, more diisobutylaluminium hydride (5ml) was added, and stirring continued for a further 1h. Methanol (11ml) and saturated sodium sulphate (14ml) were added, and the mixture stirred for l5minutes.
  • 2-Methoxythiazole (contained 25% 2-bromothiazole, 0.50g, 4.3mmol) was dissolved in THF (20ml), cooled to -70%, and treated dropwise with n- butyllithium (1.5M, 3.2ml, 4.8mmol). The mixture was stirred for 75 minutes, then N,N-dimethylformamide (1.16ml, l5mmol) added. Stirred for a further 11 ⁇ 2 h, then quenched with saturated ammonium chloride and ether. The phases were separated, the organic washed with water, dried and reduced to a small volume.
  • diethylazodicarboxylate (1.26ml, 8mmol). After 1 ⁇ 4 hour ice bath removed. After 1 hour reaction mixture evaporated, added ethyl acetate and 5N hydrochloric acid. Acid phase separated, covered with ethyl acetate and basified with saturated sodium hydrogen carbonate. Organic phase separated, dried and evaporated.
  • Furfurylalcohol (0.86ml, 10mmol) was added dropwise to a cold (5°C) mixture of sodium hydride (80%, 300mg, 10mmol) in DMF (40ml). After 1 hour p-fluoro-benzaldehyde (1.07ml, 10mmol) was added. After 3 hours reaction mixture poured into water and extracted with ethyl acetate.
  • MacFarland's barium sulphate opacity standard 0.5 The suspension is further diluted 1:100 in TCM to yield a final inoculum of 4.83 x 106 cfu/ml.
  • Human foetal lung fibroblast (MRC-5) cells are grown to 80% confluency in 6-well plates. The medium is removed and the monolayers washed twice with Dulbecco's PBS and the inoculum added.
  • Dosing Sixteen hours after infection (time Oh), the medium is removed and the inoculated monolayers washed twice to remove any adherent, non-intracellular, organisms. The compounds are prepared to the required concentrations (0.5, 2 and 8 ⁇ g/ml) in TCM, and added to the cells. Erythromycin at 0.5 and 2 ⁇ g/m is used as a control.
  • Stability tests The stability ofthe compounds in TCM is also examined over a 72h period. Solutions of 2 ⁇ g/ml of each ofthe compounds to prepared in TCM and incubated at 37°C or 4°C and aliquots are removed at intervals. The compounds of formula (I) are assayed against Bacillus subtilis ATCC 6633 and erythromycin lactobinate against Sarcina lutea NCTC 8340, using standards prepared in TCM.

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Abstract

This invention relates to a novel class of mupirocin derived compounds of Formula (I) having a modification of the C-1 to C-3 fragment. The β-diketone compounds of Formula (I) are useful as antibacterial and antimycoplasmal agents. The compounds of this invention are represented by formula (I) wherein R0 is a hydrocarbyl or heterocyclic group.

Description

ANTIBACTERIAL,ANTIMYCOPLASMAL COMPOUNDS RELATED TO MUPIROCIN
This invention relates to a novel class of compounds having antibacterial and antimycoplasmal activity, to processes for their preparation and to their use in human and veterinary medicine, and also to intermediates for use in the preparation of such compounds.
Mupirocin, the compound of formula (A):
Figure imgf000003_0001
' exhibits good activity against Gram positive bacteria, H.influenzae.
Legionella and mycoplasma. It is marketed as a. topical formulation by Beecham Group pl.c. under the trade mark BACTROBAN. Mupirocin (formerly known as pseudomonic acid) is rapidly hydrolysed in vivo to monic acid A, the compound of formula (B):
Figure imgf000003_0002
which is inactive. Various proposals have been made to improve the metabolic stability of mupirocin with respect to enzymatic hydrolysis by varying the nature of the C-1 to C-3 fragment, for instance, by modification ofthe C-1 ester functional group. Examples of this strategy include C-1 heterocyclic derivatives (EP-A-O 087 953 and EP-A-O 123 578, Beecham Group p.l.c), C-1 amides (US 4 312 764, Beecham Group Ltd), and C-1 ketones, including inter alia aryl and heterocyclic ketones (US 4 312 874, Beecham Group Ltd, Klein et al, poster presented at the Third Annual Chemical Congress of North America, Toronto, June 1988, and J . Med. Chem. 1989, 3 2, 151). In addition, various modifications elsewhere in the C-1 to C-3 fragment, other than at C-1, have also been made, including β-ketoesters (Klein et al, ibid.), C-2 alkyl and C-2 halo derivatives (Crimmin M. J. et al; J . Chem. So., Perkin Trans.1, 1985, 549), and reduction of the C-2 C-3 double bond (Chain E.B. e t al, J . Chem. Soc. , Perkin Trans.1, 1977, 294). No improvement in the overall biological profile, compared with
mupirocin, was, however, observed. Indeed, the β-ketoester is reported to have shown little if any antibacterial activity.
It has now been surprisingly found that alternative modification ofthe C- 1 to C-3 fragment leads to compounds with an enhanced biological profile.
Accordingly, the present invention provides a compound of formula (IA), (IB) or (IC):
Figure imgf000005_0001
wherein R° denotes a substituted or unsubstituted hydrocarbyl or heterocyclyl group. More specifically R° denotes the term (A)n - (B)m; wherein n and m are integers having a value of 0 or 1; A is a (C1 -6) alkyl, (C2-6) alkenyl, or (C2-6) alkynyl group; B is a (C3-7) cycloalkyl, (C4-7) cycloalkenyl, aryl, heterocyclyl or heteroaryl group. Both A and B may be optionally substituted as herein below defined. In the R° moiety when n is 0 then A represents a bond, and when m is 0 then B represents hydrogen; m and n may not both represent 0 at the same time. Suitably when n is 0 and m is 1, B is a substituted or unsubstituted (C4-7) cycloalkenyl, aryl, heterocyclyl or heteroaryl group. B is preferably an aryl or heteroaryl moiety. More specifically, B is a cyclohexenyl, phenyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazolyl, oxazolyl, or thiazolyl group. Suitably, when n is 1, m is 0, and B is hydrogen, then A is a (C1-6)alkyl moiety. A is preferably a substituted or unsubstituted butyl group. Suitably, when n is 1, and m is 1, then A is a (C2-6)alkenyl, (C2-6)alkynyl group. Preferably, when n is 1, and m is 1, then B is a substituted or unsubstituted aryl or heteroaryl group, such as a furanyl or phenyl. More preferably A is an ethenyl or acetylenyl (ethynyl) group. Suitably B is a substituted or un-substituted aryl or heteroaryl group. As used herein the term "(un)substituted" refers to both the substituted and unsubstituted derviative. Preferably B is a (un)substituted phenyl, (un)substituted pyrimidinyl, (un)substituted thiazolyl, (un)substituted oxazolyl, or (un)substituted pyridyl. More preferably B is an
(un)substituted phenyl, (un)substituted pyridyl, or (un)substituted pyrimidinyl.
As defined herein both A or B may be optionally substituted,
independently, with up to five, preferably up to three substituent groups, hereinafter referred to as X and Xx respectively.
Examples of suitable X groups for A, when n is 1, include, cyano, amino,
(C1-6)alkanoyIamino, mono- or di- (C1-6)alkylamino, hydroxy,
(C1-6)alkoxy, substituted (C1-6)alkoxy [also referred to as -O-R1],
(C1-6) la kylthio, (un)substituted heterocyclylthio, arylthio, (un)substituted sulphamoyl, (un)substituted carbamoyl, amidino, guanidino, nitro, halogen, carboxy and salts and esters thereof, (C1-6)alkanoyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy, and acyl groups. Suitably optional substituents (X1), for B when m is 1, include, for example, (C1-6)alkyl, (po-y)halo(C1-6)alkyl, cyano, (un)substituted heterocyclyl, amino, (C1-6)alkanoylamino, mono- or di-(C1-6)alkylamino, substituted mono- or di-(C1-6)alkylamino, [also referred to as -NR2R3], hydroxy, (C1-6)alkoxy, substituted (C1-6)alkoxy [also referred to as -O-R1], (C1-6)alkenoxy, hydroxy substituted (C1-6)alkoxy, (un)substituted heterocyclylthio, arylthio, arylsulphinyl, arylsulphonyl, (C1-6)alkylthio,
(C1-6)alkylsulphinyl, (C1-6)alkylsulphonyl, (un)substituted sulphamoyl,
(un)substituted carbamoyl, amidino, guanidino, nitro, halogen, carboxy and salts and esters thereof, (C1-6) alkylcarbonyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy, and acyl groups.
When X or Xx is a substituted alkoxy [ -O-R1], as hereinbefore defined, the R1 group may be a (C2-6) alkenyl, (C1-6) alkoxy alkyl, (poly)hydroxy
(C1-6) alkyl, (poly)halo(C1-6) alkyl, substituted or unsubstituted heteroaryl (C1-6) alkyl, substituted mono- or di- amino (C1-6) alkyl, substituted or unsubstituted heterocyclyl (C1-6) alkyl, or N-(C1-6 alkyl)- N- heteroaryl-(C1-6)alkyl.
As used herein, the term "(poly)" refers to the optional substitution of more than one, such as (poly)haloalkyl would allow for more than one halogen, independently on the alkyl moiety, i.e., -CF3. Preferably the R1 group is a C2-3 alkenyl, hydroxy C1-6 alkyl,
(C1-6)alkoxy(C1-6)alkyl, (poly)halo(C1-6) alkyl, (un)substituted (C1-6) alkyl heteroaryl, (un)substituted (C1-6) alkyl heterocyclyl, or N-(C1-6 alkyl)-N- pyridyl-(C1-6)alkyl. Preferably the heteroaryl is a pyridyl, or furanyl moiety. Preferably the heterocyclyl is a piperidine group.
More preferably R1 is ethenyl, 2-ethanol, 3-propanol, -CH2-O-CH3,
CH2-furanyl, CH2-furan-2-yl-5-nitro; CF3, N-methyl-N-2- pyridylaminoethyl, N-piperidinylethyl, or 4-pyridylmethyl. When Xx is NR2R3, the R2 and R3 moieties are independently a (C1-6) alkyl group or one of R2 or R3 may be a hydroxy (C1-6) alkyl group. Preferably, both R2 and R3 are (C1-6) alkyl, more preferably methyl; or one of R2 R3 is methyl and the other 2-ethanol. Preferably the X1 substitutents are selected from hydroxy, substituted and unsubstituted (C1-6)alkoxy, (C1-6)alkyl, oxy(C1-6)alkyl, cyano, chloro, fluoro, bromo, nitro, hydroxy(C1-6)alkyl, (C1-6)alkylthio,
(C1-6)alkylsulphinyl, (C1-6) alkylsulphonyl, NR2R3, or (un)substituted heterocyclyl, or gem di(C1-6)alkoxy(C1-6)alkyl.
More preferably X1 is methoxy, C(O)CH 3, methyl, cyano, chloro, fluoro, bromo, -CH(OCH2CH3)2, nitro, -CH(O), N(CH3)2, SCH3, S(O)CH3, S(O)2CH3, -CH2OH, piperidine, O-CF3, hydroxy, ethenyloxy, 2- hydroxyethoxy, N-(2-hydroxyethyl)-N-methylamino, 3-hydroxypropyloxy, azidoethoxy, N-methyl-N-pyridylaminoethoxy, piperidinylethoxy, pyridylmethyloxy, nitrofuranyl methyloxy, or furanylmethyloxy. For the optional substituent groups X and X1 wherein their respective members are also referred to as (un)substituted group, the optional substituents for said groups are independently substituted up to five times, preferably up to three times, from the same group listed herein under the X1 term. For example, (unsubstituted carbamoyl would allow the nitrogen atom to be mono- or di-substituted with a (C1-6)alkyl moiety; the (un)substitued heterocyclic would allow, for example, a piperidine ring to be substituted by a (C1-6)alkyl, or hydroxy moiety; an (un)substituted heteroaryl would allow for a furanyl ring to be substituted by a nitro group.
Preferred substituent groups (X1) when B is an aryl group include, for example, halogen, cyano, (C1-6)alkyl, hydroxy(C1-6)-alkyl, oxo(C1-6)alkyl, gem di(C1-6)alkoxy(C1-6)alkyl, (C1-6)alkoxy, (C2-g)alkenoxy,
hydroxy(C1-6)alkoxy, (C1-6)alkoxy(C1-6)alkoxy, halo(C1-6)alk yl, hydroxy, a m ino, mono- or di-(C1-6)alkylamino, acylamino, nitro, carboxy,
(C1-6)alkoxycarbonyl, (C1-6)alkoxycarbonyl(C1-6)alkyl,
(C1-6)alkylcarbonyloxy, (C1-6)alkylthio, (C1-6)alkylsulphinyl,
(C1-6)-alkylsulphonyl, sulphamoyl, mono- or di-(C1-6)alkylsulphamoyI, carbamoyl, mono- or di-(C1-6)alkylcarbamoyl and heterocyclyl.
Preferred substituents (X1) when B is a heteroaryl group include, for example, halogen, (C1-6)alkyl, (C1-6)cycloalkyl, (C1-6)alkoxy,
hydroxy(C1-6)alkoxy, halo(C1-6)alkyl, hydroxy, amino, mono- or
di-(C1-6)alkylamino, N-hydroxy(C1-6)alkyl N-(C1-6)alkyl amino, carboxy,
(C1-6)alkoxycarbonyl, (C1-6)alkoxycarbonyl(C1-6)alkyl, aryl, oxo, non-aromatic heterocyclyl, (C1-6)alkylthio, (C1-6)alkylsulphinyl and
(C1-6)alkylsulphonyl.
Preferred substituent (X1) when B is a heterocyclyl group include, for example, halogen, (C1-6)alkyl, hydroxy(C1-6)alkyl, (C1-6)alkoxy, hydroxy(C1-6)alkoxy, halo(C1-6)alkyl, hydroxy, amino, mono- or
di-(C1-6)alk yl amino, carboxy, (C1-6)alkoxycarbonyl,
(C1-6)alkoxycarbonyl(C1-6)alkyl, aryl and oxo. When a substituent group, preferably in the (B)m term, has an acidic hydrogen arising from the presence in a heteroaryl ring of an NH moiety, for instance, when R° is pyrazolyl, the hydrogen may be replaced by a (X or X1) substituent as hereinbefore defined. Preferably the substitutent is a (C1-6) alkyl group.
As used herein, the term "alkyl" group or moiety referred to herein may be a straight or branched hydrocarbon chain, and may contain, for example, up to 12 carbon atoms, suitably up to 6 carbon atoms. The alkyl chain may be unsubstituted or substituted. In particular, the alkyl group or moiety may be an unsubstituted or substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl or tert-butyl group. Examples of suitable optional substituents for any such alkyl group or moiety include the above-listed substituents for the (A)n term.
When used herein, the term 'aryl' includes, unless otherwise defined, phenyl or naphthyl. When used herein, the term 'heterocyclyl' and 'heterocyclic' includes non-aromatic single or fused rings comprising up to four heteroatoms in each ring selected from oxygen, nitrogen and sulphur. Suitably, the heterocyclic ring comprises from 4 to 7, preferably from 5 to 6 ring atoms. A fused heterocyclic ring system may include aromatic carbocyclic and heteroaryl rings. Suitably the heterocyclic group is piperidinyl.
When used herein, the term 'heteroaryl' includes aromatic hetrocyclic containing rings and ring systems as is commonly defined in the art, such as by Katritzky et al., Handbook of Heterocyclic Chemistry, Pergamon Press, Oxford, England (1985). As defined therein, a heteroaromatic structure is based on the 6 π-electron system. These structure are related to and formally derived from benzene by successive replacement of one or two annular CH groups by trivalent or divalent heteroatom groups respectively. The overall patttern of filled bonding molecular orbitals is retained. Thus replacement of one CH group by O+, S+, or N gives the six-membered pyrylium, thiinium or pyridine systems, and replacement of two CH groups by O, S, or NH gives the five-membered furan, thiophene, or pyrrole. Multiple replacements are also possible with up to four heteroatoms in five- and six-membered rings. Suitably the heteroaryl ring has 5 to 6 ring atoms in each ring. Prefered heteroaryl groups herein include, pyridyl, pyrim idinyl, furanyl, thienyl, thiazolyl, isoxazolyl, oxazolyl and pyrazolyl.
When used herein, the term "hydrocarbyl" may include groups having up to 18 carbon atoms, suitably up to 10 carbon atoms, conveniently up to 6 carbon atoms. Suitable groups include those listed under the (A)n term and the (B)m term groups which do not contain a heteroatom, i.e.
cycloalkyl, cycloalkenyl and aryl.
It will be appreciated that another aspect of the present invention is in the many variations which can result from the point of attachment ofthe respective heteroaryl rings, such as in the 2-pyridyl, 3-pyridyl or 4-pyridyI moieties. Further where isomers of a heteroaryl exist, such as in a 1,3- pyrazolyl or 1,2- pyrazolyl, said isomers are also another aspect ofthe present invention.
When used herein, the term 'halogen' refers to fluorine, chlorine, bromine or iodine. Preferably, the halogen is fluoro, chloro or bromo.
It will be further appreciated that in compounds of formula (I), the moiety:
Figure imgf000010_0001
will have the same relative and absolute stereochemistry at each ofthe chiral centres (indicated by *) as that of corresponding moiety in
mupirocin i.e. [2S, 3R, 4R, 5S] about the tetrahydropyran ring and [2S, 3S, 4S, 5S] in the 5-(2,3-epoxy-5-hydroxy-4-methylhexyl) sidechain ofthe tetrahydropyran ring. The compounds of the present invention may exist in the forms shown in formulae (IA), (IB) or (IC), the three forms being in equilibrium. It will be appreciated that the compounds of formulae (IA), (IB), and (IC) are interrelated by keto-enol tautomerism, with formula (IA) representing the keto tautomer and formula (IB) and (IC) representing the two possible enol tautomers. References hereinafter to 'formula (I)' encompass all three forms unless the context requires otherwise.
It will be appreciated that in compounds of formula (I), the group R° may contain one or more chiral centres. The present invention encompasses all such resultant isomeric possibilities.
Since the compounds of formula (I) of the present invention are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations ofthe compounds of formula (I) may be used for preparing the more pure forms used in the
pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I). Preferably, whenever possible, the compounds ofthe present invention are obtained in crystalline form. When some of the compounds of this invention are allowed to crystallise, or are recrystallised, from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. Examples of compounds within the scope of this invention include the following:
3R,4R-Dihydroxy-2S-[2,4-Dioxo-4-(4-methoxyphenyl)-but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-(2,4-dioxo-4-phenyl-but-1-yl)-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methoxypyrid-5-yl)-but-1- yl]-5S-(2S,3S,epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
2S-[4-(4-Acetylphenyl)-2,4-dioxobut-1-yI]-3R,4R-dihydroxy- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[4-(4-dimethylaminophenyl)-2,4-dioxobut-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R-Dihydroxy-2S-(2,4-dioxo-4-(furan-3-yl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(1-methylpyrazol-4-yl)- but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(furan-2-yl)but-1-yl]5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(pyrid-4-yl)but-1-yl]5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(pyrid-3-yl)but-1-yl]5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(pyrid-2-yl)but-1-yl]5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(3-methylisoxazol-5-yl)- but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetra- hydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(3-methoxyphenyl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[4-(4-cyanophenyl)-2,4-dioxobut-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R-Dihydroxy-2S-[4-(4-chlorophenyl)-2,4-dioxo-but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[4-(4-diethoxymethylphenyl)-2,4-dioxobut-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[4-(4-dioxo-4-(4-formylphenyl)-but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-nitrophenyl)-but-1-yl]-
5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran.
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(thien-2-yl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(thien-3-yl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[4-(2-dimethylaminopyrid-5-yl)-2,4- dioxobut-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methyl- hexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methylthiopyrid-5-yl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methylsulphinylpyrid-5-yl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methylsulphonylpyrid-5-yl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)-tetrahydropyran;
3R,4R-Dihydroxy-2S-[4-(2-chloropyrid-5-yl)-2,4-dioxobut-1-yl]-5S-(2S,3S- epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(5-hydroxymethylfuran-2-yl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-nitrothien-4-yl)but-1-yl]-5S-(2S,3S- epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[4-(2-bromopyrid-5-yl)-2,4-dioxobut-1-yl]-5S-(2S,3S- epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(5-methoxyfuran-2-yl)but-1-yl]-5S-
(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-(piperidin-1-yl)-pyrimidin-5-yl)but-1- yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(l-methyl-2-methylthioimidazol-4-yl)- but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methoxyphenyl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methylthiophenyl)but-1- yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methylsulphinyl-phenyl)- but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methyl-hexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methylsulphonyl-phenyl)- but-1-yl)-5S-(2S,3S-epoxy-5S-hydroxy-4S-methyl-hexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(3-cyanophenyl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-trifluoromethoxy-phenyl)- but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-fluorophenyl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-hydroxyphenyl)but-1-yl]-5S-(2S,3S- epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R Dihydroxy-2S-[4-(4-allyloxyphenyl)-2,4-dioxobut-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-bihydroxy-2S-[2,4-dioxo-4-(4-methoxymethyloxophenyl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[4-(but-1-yl)-2,4-dioxobut-1-yl]-5S-(2S,3S-epoxy- 5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{2-hydroxyethoxy}phenyl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(3-fluorophenyl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-fluorophenyl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[4-(3,4-difluorophenyl)-2,4-dioxobut-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran ;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-N-(2-hydroxyethyl)-N- methylaminopyrid-5-yl)but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S- methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-(4-hydroxypiperidin-1-yl)pyrid-5-yl)- but-1-yl]-5S-[2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)-tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-(3-hydroxyprop-1-oxy)pyrid-5-yl)but- 1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methoxythiazol-5-yl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R-Dihydroxy-2S-[4-(cyclohexen-1-yl)-2,4-dioxobut-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[3,5-dioxo-1-(furan-2-yl)hex-1(E)-en-6-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetra-hydropyran;
3R,4R-Dihydroxy-2S-[3,5-dioxo-1-(4-methoxyphenyl)hex-1(E)-en-6-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-(3,5-dioxo-1-phenyIhex-1-yn-6-yl)-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[4-(2-dimethylaminopyrimidin-5-yl)-2,4-dioxobut- 1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methoxypyrimidin-5-yl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{2-azidoethoxy}phenyl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dmydroxy-2S-[2,4-dioxo-4-(4-{2-N-methyl-N-2-pyridylamino- ethoxy}phenyl)but-1-yl-5S-(2S,3S-epoxy-5S-hydroxy-4S- methylhexyl) tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{2-piperidinylethoxy}phenyl)but-1-yl- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{4-pyridylmethyloxy}phenyl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{5-nitrofuran-2-ylmethyloxy}phenyl) but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; and
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{furan-2-ylmethyloxy}phenyl)but-1- yl]-5S-(2S,3S-epoxy-6S-hydroxy-4S-methylhexyl)tetrahydropyran. Preferred compounds of the instant invention are:
3R,4R-Dihydroxy-2S-[2,4-Dioxo-4-(4-methoxyphenyl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dmydroxy-2S-[2,4-dioxo-4-(2-methoxypyrid-5-yl)- but-1-yl]-5S-(2S,3S,epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-nitrophenyl)-but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)-tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methylthiopyrid-5-yl)- but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methylthiophenyl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[4-(2-chloropyrid-5-yl)-2,4-dioxobut-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-_luorophenyl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R Dihydroxy-2S-[4-(4-allyloxyphenyl)-2,4-dioxobut-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methoxymethyloxophenyl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{2-hydroxyethoxy}phenyl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; and
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{2-azidoethoxy}phenyl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran.
Compounds of the present invention may be prepared by methods known for the preparation of β-diketones. Some of these processes will be more appropriate than others.
Suitably, compounds of formula (I) may be prepared by a process which
comprises treating a compound of formula (II):
Figure imgf000018_0001
in which Z1, Z2 and Z3 are the same or different and each is hydrogen or
Figure imgf000018_0002
a hydroxyl-protecting group, and R° is as hereinbefore defined; with an oxidising agent which converts a β-hydroxyketone into a
β-diketone; and thereafter, and if necessary, removing any hydroxyl-protecting
groups.
Suitably such oxidising agents include, for example, activated manganese
dioxide, 2,3-dichloro-5,6- dicyano-1,4-benzoquinone (DDQ), chromium
trioxide, pyridinium dichromate, pyridinium chlorochromate,
dimethylsulphoxide/trifluoroacetic anhydride, dimethylsulphoxide/oxalyl
chloride, ruthenium tetroxide, and tetra-n-propylammonium
perruthenate.
Suitably, the oxidation reaction is effected in a organic solvent such as, for example, dioxan, acetonitrile, tetrahydrofuran, ether, carbon
tetrachloride, chloroform, dichloromethane, benzene or toluene and at a
temperature which is preferably in the range from -20° to 100°C.
Preferably, the compounds of Formula (I) wherein (A)n is an alkenyl or
alkenyl moiety in which the double or triple bond is in a conjugated or
non-conjugated system with the rest ofthe molecule are made according to the process of Formula (II) as noted above. Alternatively, under carefully controlled conditions the process of Formula (VI) as hereinbelow defined, may also be used. Compounds of formula (II) are novel and useful intermediates for the preparation of compounds of formula (I).
Accordingly, a further aspect of the invention also provides a compound of formula (II) as hereinbefore defined.
Compounds of formula (II) may be prepared by a process which comprises treating a compound of formula (III):
Figure imgf000019_0001
in which Z1, Z2 and Z3 are as hereinbefore defined and M+ is a metal such as lithium, with an aldehyde of formula (IV):
R°CHO (IV) in which R° is as hereinbefore defined and thereafter, and if necessary, removing any hydroxyl-protecting groups.
A compound of formula (III) may be obtained by treating a ketone compound of formula (V):
Figure imgf000019_0002
in which Z1, Z2 and Z3 are as hereinbefore defined, with a suitable enolising agent such as, for example, lithium diisopropylamide.
It will be appreciated that in practice, the compound of formula (III) may be generated in situ, prior to the treatment thereof with a compound of formula (IV).
The preparation of a compound of formula (V) is described in GB 1 587 58 (to Beecham Group pic).
In a further aspect, the present invention provides a second process for preparing a compound of formula (I) as hereinbefore defined, which process comprises treating a compound of formula (VI):
Figure imgf000020_0001
in which Z1, Z2, Z3 and R° are as hereinbefore defined, with a reagent capable of converting a terminal methylene-substituent to an oxo- substituent and thereafter, and if necessary, removing any
hydroxyl-protecting groups.
Suitable reagents for effecting such a conversion include ozone and osmium tetroxide, each of which forms an intermediate which may then be converted to the compound of formula (I). Alternative reagents useful in the conversion herein may be found in Harrison et al, Compendium of Organic Synthetic Methods, Wiley-Interscience (1971). Ozonolysis may be effected under conditions conventionally used for such a reaction. Thus the reaction may be effected at a low temperature, for instance about -70°, in the presence of a suitable solvent such as dichloromethane. The intermediate ozonide thus formed may be conveniently decomposed by an agent conventionally used for such a task, of which triphenyl phosphine is especially preferred.
Alternatively, the compound of formula (VI) may be treated with osmium tetroxide, according to the procedure described by V. Van Rheenen, R.C. Kelly and D.Y. Cha, Tetrahedron Lett, 1976, 1973. Preferably a catalytic quantity of osmium tetroxide is employed, in the presence of a
tertiaryamine oxide catalyst such N-methylmorpholine N-oxide, in a solvent such as aqueous tetrahydrofuran, to give an intermediate 1,2-diol which may then be treated with an oxidising agent such as sodium periodate to give the compound of formula (VI).
Compounds of formula (VI) are novel and useful intermediates for preparing of compounds of formula (I).
Accordingly, a further aspect of the invention also provides a compound of formula (VI) as hereinbefore defined.
Suitably, compounds of formula (VI) may be prepared by a process which comprises treating the acid of formula (VII) or an activated derivative thereof:
Figure imgf000021_0001
in which Z1, Z2 and Z3 are the same or different and each is hydrogen or a hydroxyl-protecting group, with an organometallic reagent; and thereafter, and if necessary, removing any hydroxyl-protecting groups. Suitable organometallic reagents include:
(i) a Grignard reagent ofthe formula R°MgX in which R° is as defined with respect to formula (I) and X represents chlorine, bromine or iodine, which reaction may optionally be carried out in the presence of copperd) iodide as catalyst;
(ii) an organolithium reagent of formula R°Li in which R° is as defined with respect to formula (I);
(iii) an organomanganous reagent ofthe formula R°MnCl in which R° is as defined with respect to formula (I); and
(iv) an organocerium reagent R°Li-CeX3, in which R° is as defined with respect to formula (I) and X represents chlorine, bromine or iodine.
The reaction with the organometallic reagent may be conveniently carried out in an ethereal or hydrocarbon solvent, the choice of which is
dependent upon the specific requirements ofthe organometallic reagent. Preferably, the Grignard reagent is generated and used in diethyl ether or tetrahydrofuran.
The reaction is generally carried out in an inert atmosphere such as argon or nitrogen and at ambient temperature or below. The period for which the reaction is allowed to proceed depends upon the particular starting materials employed. The course ofthe reaction may be followed by conventional methods such as thin layer chromatography and the reaction may be terminated when an optimum quantity of product is present in the reaction mixture.
Suitable activated derivatives ofthe acid of formula (VII) include
thio-esters of formula (VIII):
Figure imgf000023_0001
in which Z1, Z2 and Z3 are as hereinbefore defined and the moiety:
Figure imgf000023_0002
represents a 5- or 6-membered heterocyclic ring which may contain in addition to the nitrogen atom, one or two further heteroatoms selected from oxygen, nitrogen and sulphur and which may be substituted or fused to a benzene ring which may itself be substituted.
Preferred thio-esters are of formula (Vllla):
Figure imgf000023_0003
in which Z1, Z2 and Z3 are as hereinbefore defined.
Other suitable activated derivatives of the acid of formula (VII) include mixed anhydrides of the formula (IX):
Figure imgf000024_0001
in which Z1, 7 2, and Z3 are as hereinbefore defined, and R1 is
(C1-6)alkyl; and ofthe formula (X):
Figure imgf000024_0002
in which Z1, Z2, and Z3 are as hereinbefore defined, and R2 and R3 are the same or different and each denotes an aryl group, for instance phenyl, or a (C1-6)alkoxy group, for instance ethoxy.
Further suitable activated derivatives ofthe acid of formula (VII) include amides ofthe formula (XI):
Figure imgf000024_0003
in which Z1, Z2 and Z3 are as hereinbefore defined, R4 and R5 are the same or different, and each is (C1 -6)alkyl, preferably methyl, or the substituents R4 and R5 form a (C2-7)alkylene chain and; amides of the formula (XII):
Figure imgf000025_0001
in which Z1, Z2, and Z3 are as hereinbefore defined and R6 and R7, together with the nitrogen atom to which they are bonded, form an imidazolyl or triazolyl ring.
The reaction of an N-methoxy-N-methylamide compound with an organolithium or a Grignard reagent to form a ketone is described by
Nahm and Weinreb in Tetrahedron Lett, 1981, 3815. The reaction of an α,β-unsaturated acid or its imidazolyl derivative with a Grignard reagent is described in Chem. Ber., 1965, 95 1284. Suitably a thio-ester of formula (VIII) is treated with an
organomanganous reagent of formula R°MnCl, as hereinbefore defined.
Suitably an amide of formula (XI) or (XII) is treated with an
organolithium reagent of formula R°Li as hereinbefore defined:
Suitable organometallic reagents may be prepared according to
conventional procedures.
Suitable organomanganous reagents of the formula R°MnCl may be conveniently prepared by addition of an organolithium reagent R°Li to a solution of manganous chloride and lithium chloride in dry THF, or a suspension of anhydrous manganous chloride in dry THF. An excess of R°MnCl is preferably employed. Alternatively, a Grignard reagent may be used in place ofthe organolithium reagent, to generate the
organomanganous reagent R°MnCl.
Other organomanganous reagents which may be used instead of R°MnCl include:
(i) (R°)3MnLi or (R°)3MnMgX in which X is as hereinbefore defined, as described in Synthetic Communications, 1979, 9, 639; (ii) R°MnI in ether; as described in Synthetic Communications, 1979, l, 639; and
(iii) R°MnBr in ether, as described in Tetrahedron Lett., 1976, 3155. As in the case of R°MnCl, the above organomanganous reagents may be prepared in situ when required.
Organocerium reagents may be generated in situ by treatment of an organolithium compound ofthe formula R°Li, in which R° is as
hereinbefore defined, with cerium (III) halide, by analogy with the procedure described by Imamoto el al; J.Chem. Soc. , Chem. Commun, 1982, 1042.
The activated derivatives of compounds of formula (VI) may be prepared from the compounds of formula (VI) by standard methodology.
Compounds of formula (VII) may be obtained by treating the protected methylester of monic acid with a base such as lithium diisopropylamide, as described by Crimmin et at, J. Chem. Soc. Perkin Trans 1. 1985, 549, followed by ester hydrolysis.
Advantageously, a compound of formula (VI) may be prepared by treating a compound of formula (XI) in which R4 and R5 each is methyl with an organometallic reagent which is preferably an organolithium reagent of the formula R°Li.
Compounds of formula (XI) are novel and useful intermediates in the preparation of compounds of formula (VI). Accordingly, a further aspect ofthe invention provides compounds of formula (XI) as hereinbefore defined. Compounds of formula (XI) may also be obtained by a process which comprises treating a compound of formula (XIII):
Figure imgf000027_0001
in which Z1, Z2, Z3, R4 and R5 are as hereinbefore defined, with a strong non-nucleophilic base such as, for example, lithium diisopropylamide, followed by quenching with a mild proton source such as ammonium chloride.
Compounds of formula (XIII) are novel and useful intermediates for the preparation of compounds of formula (XI). Accordingly, a further aspect ofthe invention provides a compound of formula (XIII) as hereinbefore defined.
Compounds of formula (XIII) may be prepared from monic acid by initial conversion thereof to an activated derivative, for instance a mixed anhydride such as that formed with iso-butylchloroformate, followed by subsequent treatment with an amine HN(OR4)R5 in which R4 and R5 are as hereinbefore defined, or a salt thereof; under standard conditions, for instance, with dichloromethane as the reaction solvent, at about 0°C for 2h; and thereafter and if required, introducing any hydroxyl-protecting groups that may be subsequently required.
In a further aspect, the present invention provides a third process for preparing a compound of formula (I) which process comprises treating a compound of formula (XlV):
Figure imgf000028_0001
in which Z1, Z2, Z3, R4 and R5 are as hereinbefore defined, with a compound of formula (XV):
R°COCH2-
(XV) in which R° is as hereinbefore defined and thereafter, and if necessary, removing any hydroxyl-protecting groups.
Compounds of formula (XEV) are novel and useful intermediates for the preparation of compounds of formula (I).
Accordingly, a further aspect ofthe invention provides a compound of formula (XEV) as hereinbefore defined. Compounds of formula (XIV) may be prepared from the corresponding acids of formula (XVI):
Figure imgf000028_0002
in which Z1, Z2 and Z3 are as hereinbefore defined, by initial conversion thereof to an activated derivative, for instance a mixed anhydride such as that formed with iso-butylchloroformate, followed by subsequent treatment with an amine HN(OR4)R5, in which R4 and R5 are as hereinbefore defined, or a salt thereof, under standard conditions, for instance, with dichloromethane as the reaction solvent, at about 0°C for 2h. Compounds of formula (XVI) are novel and useful intermediates for the preparation of compounds of formula (I).
Accordingly, a further aspect of the invention provides a compound of formula (XVI), as hereinbefore defined.
Compounds of formula (XVI) may be prepared from compounds of formula (V), as hereinbefore defined, and in which the hydroxyl groups are protected, preferably as a silylether, by initial conversion thereof to the enol form followed by ozonoloysis and subsequent decomposition of the intermediate ozonide using, for instance, dimethyl sulphide.
Compounds of formula (I) may be obtained from other compounds of formula (I) by suitable manipulation ofthe substituents present in the group R° according to conventional methodology. For instance, an alkylthio substituent may be converted to an alkyl sulphinyl or an alkylsulphonyl substitutent by treatment thereof with a conventional oxidising agent such as m-chloroperbenzoic acid.
When used herein, the term 'hydroxyl-protecting group' refers to any such group known in the art which may be removed without disruption of the remainder ofthe molecule. Suitable hydroxyl-protecting groups include those described in 'Protective Groups in Organic Synthesis', T.W. Greene, Wiley-Interscience, New York 1981. The hydroxyl groups of the compounds of formulae (II), (III), (V) to (XIV) and (XVI) may be protected at any stage of the above processes, using conventional methods. The hydroxyl-protecting group may be removed by methods known in the art, including enzymatic methods. Particularly suitable hydroxyl-protecting groups are silyl groups since these are readily removed under mild conditions. Such groups are introduced using conventional silylating agents, including halosilanes and silazanes, ofthe formulae below: LgSiO-C-NSiLj
L3SiY
L2SiY2 L
L^SiNL-
L3SiNHSiL3
L3SiNHCOL
L3SiNHCONHSiL3
Figure imgf000030_0001
LNHCO NHSiL 3
tBuMθ2Si-O-SO2-CF2 wherein Me denotes methyl and tBu denotes t-butyl, Y is halogen and each group L is independently selected from hydrogen, (C1-6)alkyl,
(C1-6)alkoxy, aryl or aryl(C1-4)alkyl. A preferred silyating agent is trimethylsilyl chloride. Particularly suitable protecting groups are trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl groups. Preferred protecting groups are trimethylsilyl groups because of their ease of removal. The glycol function ofthe compounds of formulae (II), (III), (V) to (XIV) and (XVI)may be protected by forming a cyclic derivative using a compound of formula (XVII):
Figure imgf000030_0002
wherein R8 is hydrogen or (C1-6)alkyl and each of R9, R10 and R11 is (C1-6)alkyl. In the cyclic derivative Z1 and Z2 together are a moiety:
Figure imgf000031_0001
in which R8 is as hereinbefore defined and R12 is (C1-6)alkyl.
Suitably R8 is hydrogen, methyl, ethyl, n- or iso-propyl; most suitably it is hydrogen. The groups R9, R10 and R11 are suitably methyl, ethyl, n- or iso-propyl, or n-, iso-, sec- or t-butyl; most suitably methyl.
Similarly the hydroxyl groups of a compound of formula (I) may be protected prior to conversion to a further compound of formula (I) as described above.
In each case the hydroxyl-protecting groups described above may be removed by mild acid hydrolysis followed by alkaline hydrolysis, for instance, as described by J.P. Clayton, K. Luk and N.H. Rogers, in
'Chemistry of Pseudomonic Acid, Part II', J.C.S. Perkin Trans. I. 1979, 308.
The compounds of this invention are useful in therapy, in particular for the treatment of bacterial and mycoplasma-induced infections in
non-human and human animals, such as the treatment of respiratory tract infections, otitis, meningitis, skin and soft tissue infections in human animals, mastitis in cattle, and respiratory infections in non-human animals such as pigs and cattle. The compounds of this invention are active against both Gram negative and Gram positive organisms, including Haemophilus. for instance
H.influenzae QI; Branhamella,for instance B.Catarrhalis 1502;
Streptococci, for instance S,pyogrenes CN10 and S.pneumonia PU7; and Staphylococci. for instance S.aureus Oxford, Legrionella. for instance L. pneumophila: and against mycoplasma. In addition, compounds of the present invention are active against Staphylococci organisms such as S. aureus and S. epidermis which are resistant, including multiply resistant, to other anti-bacterial agents, for instance macrolides; aminoglycosides; lincosamides; and β-lactams, such as, for example methicillin. The compoimds of this invention are also active against
mycoplasma-induced infection, in particular Mycoplasma fermentans, which has been implicated as a co-factor in the pathogenesis of AIDS. Accordingly in a further aspect, the present invention provides a method of treating humans infected with M. fermentans. in particular humans also infected with HIV, which method comprises treating humans in need of such therapy with an anti-mycoplasmal effective amount of a compound of formula (II).
This invention also provides a pharmaceutical or veterinary composition which comprises a compound of formula (I) (hereinafter referred to as the 'drug') together with a pharmaceutically or veterinarily acceptable carrier or excipient.
The compositions may be formulated for administration by any route, for instance, by topical, parenteral or oral administration and would depend on the disease being treated. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical or sterile parenteral suspensions.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
For topical application to the skin the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics and cosmetics, such as 'Harry's Cosmeticology' published by Longman, and the British Pharmacopoeia.
Suppositories will contain conventional suppository bases, e.g.
cocoa-butters or other glyceride.
For parenteral administration, fluid unit dosage forms are prepared utilizing the drug and a sterile vehicle. The drug, depending on the vehicle and concentration used, can be suspended in the vehicle.
Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability thereof the composition may be frozen after filling into the vial and water removed under vacuum. The dry lypophilized powder is then sealed in the vial. The drug can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the drug.
For topical application to the ear, the drug may be made up into a suspension in a suitable liquid carrier, such as water, glycerol, diluted ethanol, propylene glycol, polyethylene glycol or fixed oils.
For topical application to the eye, the drug is formulated as a suspension in a suitable, sterile aqueous or non-aqueous vehicle. Additives, for instance buffers such as sodium metabisulphite or disodium edetate;
preservatives including bactericidal and fungicidal agents, such as phenylmercuric acetate or nitrate, benzalkonium chloride or
chlorhexidine, and thickening agents such as hypromellose may also be included. The dosage employed for compositions administered topically will, of course, depend on the size of the area being treated. For the ears and eyes each dose will typically be in the range from 10 to 100 mg ofthe drug.
Veterinary compositions for intramammary treatment of mammary disorders in animals, especially bovine mastitis, will generally contain a suspension ofthe drug in an oily vehicle. The compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, ofthe drug.depending on the method of
administration. Where the compositions are in unit dose form, each dosage unit will preferably contain from 50-500 mg ofthe drug. The dosage as employed for adult human treatment will preferably range from 100 mg to 3 g, per day, for instance 250 mg to 2 g of the drug per day, depending on the route and frequency of administration.
Alternatively, the drug may be administered to non-human animals as part ofthe total dietary intake. In this case the amount of drug employed may be less than 1% by weight of the diet and in preferably no more than 0.5% by weight. The diet for animals may consist of normal foodstuffs to which the drug may be added or the drug may be included in a premix for adimxture with the foodstuff. A suitable method of administration of the drug to a non-human animal is to add it to the non-human animal's drinking water. In this case a concentration of the drug in the drinking water of about 5-500 μg/ml, for example 5-200 μg/ml, is suitable.
The present invention further provides a method for treating the human or non-human animal which method comprises administering a compound of formula (I) as hereinbefore defined, to a human or non-human animal in need of such therapy.
Alternatively, a pharmaceutical composition as hereinbefore described may be employed in the treatment.
In particular aspects ofthe treatment, there are provided methods for treating bacterial infections and mycoplasma-induced infections of human or non-human animals, especially respiratory infections in human or non-human animals.
The present invention also provides a compound of formula (I) as hereinbefore defined for use in therapy.
The present invention also provides a compound of formula (I) as hereinbefore defined for use in the manufacture of a medicament for anti-bacterial therapy or mycoplasma-induced infections. The following Examples illustrate the invention, but are not intended to limit the scope in any way.
The Examples hereinafter are named according to the IUPAC convention. For the H nmr data, however, the numbering system is derived, from monic acid viz:
Preparation of N-methoxy-N-methyl 6,7,13-tris-trimethylsilyl monamide
N,O -dim ethyl hydroxylamine hydrochloride (1.95grams (hereinafter g.), 20milimoles (hereinafter mmoles)) was dissolved in
dichloromethane/aqueous sodium hydroxide (20milliters (hereinafter ml: 10ml, 2.5Molar (hereinafter M)). The aqueous layer was re- extracted with dichloromethane (10ml) and the combined organic layers washed with saturated brine (5ml). The organic layer was dried (MgS04) and added to monic acid isobutyl carbonic anhydride (10mmol)*. After stirring at 20°C for 1 hour (hereinafter h) the reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen chloride and brine. The combined aqueous solutions were extracted with ethyl acetate, and the combined organic solutions dried (MgSO4) and concentrated to give the amide, 3.0g.
This was taken up in tetrahydrofuran (50ml) and treated with
triethylamine (8.4ml, 60mmol) and chlorotrimethyl silane (6.3ml,
50mmol). After 10 minutes a catalytic amount of 4-DMAP was added.
After 2h at room temperature the reaction was diluted with diethyl ether, filtered, and the filtrate evaporated. The residue was taken up in hexane, refiltered, and washed with water and brine. After drying and evaporation the residue was taken up in hexane (20ml) and allowed to crystallise at 0 to -20°C, to give the required product as a colourless crystalline solid, 34.0g, 50%, mp 78-79°C. *Monic acid isobutyl carbonic anhydride was obtained by treating monic acid with iso-butylchloroformate and triethylamine in tetrahydrofuran at from -5 to 20°C for about 30 min.
Example 1 3R,4R-Dihydroxy-2S-[2,4-Dioxo-4-(4-methoxyphenyl)- but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran a) Deconjugation of
N-Methoxy-N-methyl-6,7,13-tristrimethylsilylmonamide
A solution of N-methoxy-N-methyl-6,7,13-tristrimethylsilylmonamide (1.2g, 2mmol) in dry THF (20ml) under argon at -70°C was sequentially treated with diisopropylamine (0.03ml, 0.2mmol) and a solution of
t-butyllithium (1.7M, 1.4ml, 2.4mmol) in hexane. After 30min the reaction mixture was quenched with saturated ammonium chloride. Ethyl acetate was added and the organic phase was washed with water, brine, then dried and evaporated to give a 4:1 mixture ofthe deconjugated+ and conjugated* monamides in quantitative yield, δH (CDCI3) inter alia 4.93 (4/5H, s, 15-H+), 5.03 (4/5H, s, 15-H+) 6.18 (1/5H, s, 2-H*). b) 2-[3R,4R-BistrimethyIsilyloxy-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran-2S- yI]methylprop-2-ene-1-yl 4-methoxyphenyl ketone
A solution of p-bromoanisole (0.75ml, 6mmol) in THF (20ml) at -70°C under argon was treated with a solution of n-butyllithium (1.5M, 4ml, 6mmol) in hexane. After 30min the mixture was treated with a solution of the mixture from la (1.2g, 2mmol) in THF (5ml). After a further 30min saturated ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4),evaporated and chromatographed on silica eluting with ethyl acetate/hexane mixtures to give material containing the title compound (543mg); δH (CDCI3) inter alia 0.93 (3H, d, J 6.9Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, I4-H3), 3.87 (3H, s, Ar-OMe), 4.89 (1H, s, 15-H), 5.06 (1H, s, 15-H), 6.92 (2H, d, J 8.4Hz, 3',5'-H2), 7.97 (2H, d, J 8.7Hz, 2',6'-H2). c) 3R,4R-Bistrimethylsilyloxy-2S-[2.4-Dioxo-4- (4-methoxyphenyl)-but-1-yl]-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydrofuran A solution ofthe ketone from lb (630mg, 0.8mmol) in dichloromethane (25ml) at -70°C was ozonolysed until a blue colour persisted. Argon was then passed through the mixture. Triphenylphosphine (124gmg
0.47mmol) was added and the mixture warmed to room temperature. The mixture was evaporated to low volume and chromatographed on silica eluting with ethyl acetate/hexane mixtures to give the title compound (370mg, 70%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 3.86 (3H, s, OMe), 6.20 (1H, s, 2-H), 6.93 (2H, d, J 8.7Hz, 3',5'-H2), 7.95 (2H, d, J 8.7Hz, 2',6'-Hz). The 1H spectrum
indicated that the title compound was essentially in the enolic form. d) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methoxyphenyl)- but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)
tetrahydropyran A solution ofthe ketone from lc (360mg, 0.54mmol) in methanol (10ml) was treated with dimethylaminopyridine dihydrochloride (3mg). After 30min the reaction mixture was diluted with dichloromethane, washed with sodium hydrogen carbonate solution, dried and evaporated.
Chromatography on silica eluting with dichloromethane/methanol mixtures gave the title compound (175mg, 74%); vmax (KBr) 3435,
1603cm-1; λmax (EtOH) 324nm (εm 18,430); δH (CDCI3) inter alia 0.93 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.1Hz, 14-H3), 3.86 (3H, s,
Ar-OMe), 6.20 (1H, s, 2-H), 6.92 (2H, d, J 9.8Hz, 3',5'-H2), 7.87 (2H, d, J 9.8Hz, 2',6'-H2). δC (CDCI3) 12.7 (C-17), 20.8 (C-14), 31.7 (C-9), 39.7 (C-8), 42.5 (C-4), 42.8 (C-12), 55.5 (OMe), 55.7 (C-10), 61.3 (C-11), 65.6 (C-16), 69.1 (C-6), 70.3 (C-13), 71.3 (C-7), 73.9 (C-5), 96.5 (C-2), 114.0 (C-3'5'), 126.9 (C-1'), 129.3 (C-2',6'), 163.3 (C-4'), 183.0 (C-3), 193.1 (C-1). M/Z
(FAB) MH± 437. The 1H nmr spectrum indicatd that the title compound was essentially in the enolic form.
Example 2 3R,4R-Dihydroxy-2S-(2,4-dioxo-4-phenyl-but-1-yl)- 5S-
(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 2-[3R,4R-Bistrimethylsilyloxy-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran-2S- yl]methylprop-2-en-1-yl phenyl ketone
A solution ofthe products from la (600mg, lmmol) in THF (20ml) under argon at -70°C was treated with a solution of phenyllithium in ether (2M, 1.5ml, 3mmol). After 30min the reaction was worked up as in lb to give material containing the title compound (300mg); δH (CDCI3) inter alia
0.89 (3H, d, J 7.1Hz), 1.19 (3H, d, J 6.3Hz, 14-H3), 4.91 (1H, s, 15-H), 5.08 (1H, s, 15-H), 7.40-7.60 (3H, m), 7.44-8.05 (2H, m). b) 3R,4R-BistrimethyIsilyloxy-2S-(2,4-dioxo-4-phenyl- but-1-yl)-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl) tetrhydropyran
The material from 2a (300mg, 0.47mmol) was converted to the title compund (182mg, 61%) using the method described in lc δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 6.27 (1H, s, 2-H), 7.43-7.60 (3H, m), 7.82-7.95 (2H, m). The 1H spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-(2,4-dioxo-4-phenyl-but-1-yl)- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran
Using the method described in Id, the ketone from 2b (180mg, 0.28mmol) was deprotected to give the title compound (53mg, 47%); νmax (KBr) 3422, 1609, 1570cm-1; λmax (EtOH) 312nm (εm 13,620), 248 (5140); δH
(CDCI3), inter alia 1.06 (3H, d, si 6.9Hz, 17-H3), 1.29 (3H, d, J 6.2Hz,
14-H3), 6.28 (1H, s, 2-H), 7.36-7.64 (3H, m), 7.83-7.98 (2h, m); δC (CDCI3) 12.7 (C-17), 20.8 (C-14), 31.6 (C-9), 39.6 (C-8), 42.8 (C-4), 42.8 (C-12), 55.7 (C-10), 61.3 (C-11), 65.7 (C-16), 69.0 (C-13), 71.3 (C-7), 73.8 (C-5), 97.5 (C-2), 127.1 (C-3'5'), 128.7 (C-2',6'), 132.6 (C-4'), 134.3 (C-1'), 182.3 (C-3), 196.0 (C-1); (Found: M+ 406.1991. C22H30O7 requires M 406.1992). The 1Η. spectrum indicated that the title compound was essentially in the enolic form.
Example 3 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methoxypyrid-5-yl)- but-1-yl]-5S-(2S,3S,epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 2-[3R,4R-Bistrimethylsilyloxy-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran-2S- yrimethylprop-2-ene-1-yI 2-methoxy pyrid-5-yl ketone Using the method described in lb and on the same scale,
2-methoxy-5-bromopyridine (1.13g, 6mmol) was reacted to give material containing the title compound (470mg); δH (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, si 6.3Hz, 14-H3), 4.00 (3H, s, OMe), 4.90 (1H, s, 15-H), 15.08 (1H, s, 15-H), 6.77 (1H, d, J 8.8Hz, 3'-H), 8.16 (1H, dd, J 2.3, 8.6Hz, 4'-H), 8.82 (1H, d, J 2.2Hz, 6'-H). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4- (2-methoxypyrid-5-yl)but-1-yl]-5S-(2S,3S-epoxy-5S- trimethylsiIyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in lc, the material from 3a (470mg,
0.71mmol) was converted to the title compound (330mg, 70%); δH ( CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 4.00 (3H, s, OMe), k6.18 (1H, s, 2-H), 6.79 (1H, d, J 8.7Hz, 3'-H), 8.06 (1H, dd, J 2.3, 8.7Hz, 4'-H), 8.72 (1H, d, J 2.7Hz, 6'-H). The 1H spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methoxypyrid-5- yl)but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran
Using the method described in Id, the material from 3b was deprotected to give the title compound (100mg, 46%); vmax (KBr) 3503, 3428, 1603, 1494cm-1; λmax (EtOH) 315.5nm (εm 17,120); δH (CDCI3) inter alia 0.93 (3H, d, J 7.0Hz, 17-H3), 1.22 (3H, d, J 6.3Hz, 14-H3), 4.00 (3H, s, OMe), 6.19 (1H, s, 2-H), 6.80 (1H, d, 19.8Hz, 3'-H), 8.05 (1H, dd, J 2.4, 9.8Hz, 4'-H), 8.72 (1H, d, J 2.4Hz, 6'-H); δC (CDCI3) 12.7 (C-17), 20.8 (C-14), 31.7 (C-9), 39.7 (C-8), 42.2 (C-4), 42.9 (C-12), 54.3 (C-10), 55.7 (C-11), 61.3 (OMe), 65.7 (C-16), 69.0 (C-6), 70.3 (C-13), 71.4 (C-7), 73.9 (C-5), 96.8 (C-2), 111.0 (C-3'), 124.0 (C-5'), 137.2 (C-4'), 147.6 (C-6'), 166.7 (C-2'), 181.9 (C-3), 194.0 (C-1); (Found: M+ 437.2048. C22H31NO8 requires M+ 437.2050).
Example 4
2S-[4-(4-Acetylphenyl)-2.4-dioxobut-1-yl]-3R,4R- dihydroxy-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran
To a solution ofthe trimethylsilylenol ether of p- bromoacetophenone (1.63g, 6mmol) in THF (20ml) under argon at -70°C was added dropwise a solution of n- butyllithium (1.5M, 4ml, 6mmol) in hexane. After 30min a solution ofthe mixture from la (1.2g, 2mmol) in THF (5ml) was added. After 30min saturated ammonium chloride was added and the mixture extracted with ethyl acetate. The organic phase was washed with brine, dried and evaporated. The residue was filtered through silica eluting with 20% (v/v) ethyl acetate/hexane. The filtrate was evaporated then dissolved in methanol (20ml) and treated with dimethylaminopyridine dihydrochloride (3mg). After 20min the mixture was diluted with ethyl acetate washed with sodium hydrogen carbonate, brine then dried and evaporated.
Chromatography on silica eluting with dichloromethane/methanol mixtures gave material (330mg) which was a 2:1 mixture of deconjugated* and conjugate+ ketones [δH (CDCI3) 5.00 (2/3H, s, 15-H*), 5.18 (2/3H, s, 15-H*), 6.83 (1/3H, s, 2-H+)].
This material was dissolved in dichloromethane (30ml) and ozonolysed at -70°C until a green/blue colour was obtained. Argon was then passed through the solution. Triphenylphosphine (194mg, 0.74mmol) was added and the mixture warmed to room temperature. Evaporation to low volume followed by chromatography on silica eluting with di chloromethane/methanol mixtures gave the title compound (106mg); νmax (KBr) 3436, 1684, 1603cm-1; λmax (EtOH) 256nm (Em 8,550), 324.5 (11,750); δH (CDCI3) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.22 (3H, d, J 6.3Hz, 14-H3), 2.65 (3H, s, COMe), 6.31 (1H, s, 2-H), 7.96 and 8.02 (4H, ABq, J 8.5Hz); δc (CDCI3) 12.7 (C-17), 20.8 (C-14), 26.8 (COMe), 31.6 (C-9), 39.7 (C-8), 42.8 (C-12), 43.0 (C-4), 55.6 (C-10), 61.2 (C-11), 65.5 (C-16), 69.0 (C-6), 70.3 (C-13), 71.3 (C-7), 73.9 (C-5), 98.3 (C-2), 127.2 (C-3'5'), 128.6 (C-2',6'), 138.3 (C-1'), 139.6 (C-4'), 179.8 (C-3), 197.5 (C-1), 197.6 (COMe); (Found: M+ 448.2106. C24H32O8 requires M 448.2097). The 1H spectrum indicated that the title compound was essentially in the enolic form.
Example 5 3R,4R-Dihydroxy-2S-[4-(4-dimethylaminophenyl)-2,4- dioxobut-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-(4-dimethylamino- phenyl)-4-hydroxy-2-oxobut-1-yl]-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
A solution of diisopropylamine (0.48ml, 3.36mmol) in dry THF (25ml) under argon at -30°C was treated dropwise with a solution of
n-butyllithium (1.5M, 2.24ml, 3.36mmol) in hexane. After 15min the mixture was cooled to -70°C and treated dropwise over 5min with a solution of tristrimethylsilylmonone (1.45g, 2.8mmol) in THf (7ml). After 1 hour the mixture was treated with a solution of
p-dimethylaminobenzaldehyde (447mg, 3.2mmol) in THF (2ml). After a further hour saturated ammonium chloride was added. The mixture was extracted with ethyl acetate and the organic phase washed with brine, then dried and evaported. Chromatography on silica eluting with ethyl acetate/hexane mixtures gave the title compound (300mg); δH (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.22 (3H, d, J 6.3Hz, 14-H3), 2.94 (6H, s, NMe2), 4.06-4.19 (1H, m, 5-H), 5.05-5.14 (1H, m, 1-H), 6.65-6.86 (2H, m, 2',6'-H2), 7.25 (2H, d, J 6.5Hz, 3'5'-H2). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-(4-dimethylamino- phenyl)- 2.4-dioxobut-1-yI]-5S-(2S,3S-epoxy-5S-tri- methylsilyloxy-4S-methylhexyI)tetrahydropyran
A solution ofthe product from 5a (300mg, 0.45mmol) in dioxan (15ml) was treated with 2,3-dichloro-5,6- dicyanobenzoquinone (102mg, 0.45mmol). After 5min the mixture was diluted with dichloromethane, filtered through Kieselguhr, washing with dichloromethane, and the filtrate evaporated. Chromatography on silica eluting with ethyl acetate/hexane mixtures gave the title compound (250mg, 83%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.19
(3H, d, J 6.3Hz, M-H3), 3.06 (6H, s, -NMe2), 6.17 (1H, s, 2-H), 6.68 (2H, d, J 9.0Hz, 3'5'-Η2), 7.82 (2H, d, 19.0Hz, 2',6'-H2). The 1H spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[4-(4-dimethylaminophenyl)-2.4- dioxobut-1-yl] -5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran
A solution ofthe product of 5b (100mg, 0.15mmol) in THF (5ml) was treated with 0.4M HCl (1ml). After 2min saturated sodium hydrogen carbonate solution (1ml) was added. The mixture was then extracted with ethyl acetate and the organic phase washed with brine, dried and evaporated. Chromatography on silica eluting dichloromethane/methanol mixtures gave the title compound (64mg, 95%); vmax (KBr) 3424, 1715, 1597, 1524cm-1; λmax (EtOH) 370nm (Em 29,750); δH (CDCI3) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 3.07 (6H, s, -NMe2), 6.16 (1H, s, 2-H), 6.64 (2H, d, 19.0Hz, 3',5'-H2), 7.82 (2H, d, J
9.0Hz, 2',6'-H2); δC (CDCI3) 12.7 (C-17), 20.7 (C-14), 31.7 (C-9), 39.6 (C-8), 39.7 (NMe2), 42.5 (C-4), 42.6 (C-12), 55.6 (C-10), 61.3 (C-11), 65.6 (C-16), 69.3 (C-6), 70.3 (C-13), 71.3 (C-7), 74.0 (C-5), 95.6 (C-2), 111.1 (C-3',5"), 121.1 (C-1"), 129.3 (C-2',6), 153.4 (C-4'), 183.8 (C-3), 192.1 (C-1); (Found: M+, 449.2423. C24H35NO7 requires M 449.2414).
Example 6 3R,4R-Dihydroxy-2S-(2,4-dioxo-4-(furan-3-yl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 3R,4R-Bistri-nethylsilyloxy-2S-r4-(furan-3-yl)-4- hydroxy-2-oxobut-1-yl]-5S-(2S,3S-epoxy-5S-trimethyl- siIyloxy-4S-methylhexyl)tetrahydropyran Using the method described in 5a and on the same scale,
furan-3-carboxaldehyde (0.28ml, 3.2mmol) was reacted to give the title compound (1.3g, 75%); δH (CDCI3) inier alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 4.07-4.18 (1H, m, 5-H), 5.05-5.18 (1H, m, 1-H), 6.38-6.42 (1H, m, 4'-H), 7.35-7.44 (2H, m, 2',5'-H2). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(furan- 3-yl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran The product from 6a (650mg) in benzene (30ml) was treated with manganese dioxide (1.76g) and refluxed with provision for azeotropic removal of water (Dean and Stark apparatus containing molecular sieves 4A) for 4 hours. The mixture was diluted with dioxan filtered through Kieselguhr, washing pad well with dioxan and evaporated.
Chromatography on silica eluting ethyl acetate/hexane mixtures gave the title compound (267mg, 41%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.4Hz, 14-H3), 5.92 (1H, s, 2-H), k6.70 (1H, d, J 1.2Hz, 4'-H), 17.45 (1H, m, 5'-H), and 7.99 (1H, s, 2'-H). The 1H spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(furan-3-yl)but- 1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran Using the method described in 5c, the product from 6b (200mg, 0.33mmol) was deprotected to give the title compound (120mg, 93%); vmax (KBr) 3427, 1718, 1620, 1509cm-1; λmax (EtOH) 303.5nm (Em 11,075); δH (CDCI3) inter alia 0.93 (3H, d, J 7.0Hz, 17-H3), 1.21 (3H, d, J 6.3Hz, 14-H3), 5.93 (1H, s, 2-H), 6.69 (1H, d, J 1.6Hz, 4'-H), 7.46 (1H, s, with further fine coupling, 5'-H), 8.02 (1H, bs, 2'-H); δC (CDCI3) 12.5 (C-17), 20.6 (C-14), 31.4 (C-9), 39.4 (C-8), 41.9 (C-4), 42.6 (C-12), 55.5 (C-10), 61.1 (C-11), 65.4 (C-16), 68.5 (C-6), 70.1 (C-13), 71.1 (C-7), 73.6 (C-5), 98.1 (C-2), 107.8 (C-2"), 123.8 (C-3'), 144.1 (C-4"), 145.6 (C-3'), 178.3 (C-3), 188.1 (C-1); M/Z 396 (M+, 100%) and 95 (100). (Found M+ 396.1788; C20H28O8 requires M 396.1784). The 1H nmr spectrum indicated that the material was essentially in enolic form. Example 7 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(1-methylpyrazol-4-yl)- but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methyIhexyl)- tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-4-(1- methyIpyrazol-4-yl)-2-oxobut-1-yl]-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran Using the method described in 5a, and on the same scale,
1-methylpyrazole-4-carboxaldehyde (352mg, 3.2mmol) was reacted to give the title compound (1.25g, 71%); δH (CDCI3) inter alia 0.90 (3H, d, J
7.1Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 3.87 (3H, s, 1'-Me), 4.07-4.17 (1H, m, 5-H), 5.12-5.22 (1H, m 1-H), 7.36 (1H, s, 5'-H), 7.43 (1H, s, 3'-H). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(1- methylpyrazol-4-yl)-but-1-yl] 5S-(2S,3S-epoxy-5S- trimethylsilyIoxy-4S-methylhexyl)tetrahydropyran Using the method described in 6b, the product from 7a (450mg, 0.7mmol) in benzene (15ml) was reacted with manganese dioxide (1.25g) for 1 1/2 hours to give the title compound (260mg, 58%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H3), 3.94 (3H, s, NMe), 5.92 (1H, s, 2-H), 7.86 (2H, bs, 3',5'-H2). The 1H nmr spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(1-methylpyrazol- 4-yl)but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran
Using the method described in 5c, the product from 7b (250mg, 0.4mmol) was deprotected to give the title compound (125mg, 76%); vmax (KBr) 3424, 1718, 1617, 1546cm-1; λmax (EtOH) 308nm (εm 10,030); δH (CDCl3) inter alia 0.94 (3H, d, J 7.1Hz, 17-H3), 1.22 (3H, d, J 6.3Hz, 14-H3), 3.94 (3H, s, NMe), 5.94 (1H, s, 2-H), 7.87 (2H, s, 3',5'-H2); δC (CDCI3); 12.7 (C-17), 20.7 (C-14), 31.6 (C-9), 39.3 (C-8), 39.6 (1'-Me), 41.5 (C-4), 42.8 (C-12), 55.6 (C-10), 61.1 (C-11), 65.5 (C-16), 68.9 (C-6), 70.3 (C-13), 71.2 (C-7), 73.9 (C-5), 97.6 (C-2), 120.3 (C-4'), 131.7 (C-3'), 139.3 (C-5"), 179.6 (C-3), 191.5 (C-1); MZ (FAB) MNa± 433, MH± 411. The 1H spectrum indicated that the title compound was essentially in the enolic form. Extra signals were observed in the 13C nmr spectrum which were identified as being from the presence of a small amount of the diketone form.
Example 8 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(furan-2-yl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-(furan-2-yl)- 4-hydroxy-2-oxobut-1-yl]-5S-(2S,3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, and on the same scale,
furan-2-carboxaldehyde (0.28ml, 3.36mmol) was reacted to give the title compound (1.196g, 69%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H3), 4.10-4.22 (1H, m, 5-H), 5.15-5.22 (1H, m, 1-H), 6.27 (1H, m, 3'-H), 6.33-6.35 (1H, m, 4'-H), and 7.37 (1H, m, 5'-H); m/z 614 (M+, 1%) and 117 (100). (Found: M+, 614.3136.
C29H54O8Si3 requires M, 614.3127). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(furan- 2-yl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethyIsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 8a (1.176g, 1.9mmol) in benzene (40ml) was reacted with manganese dioxide (4.3g) for 1 1/2 hours to give the title compound (0.601g, 51%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H3), 6.17 (1H, s, 2-H), 6.54 (1H, dd, 3.6 and 1.7Hz, 4'-H), 7.15 (1H, d, 3.7Hz, 3'-H), and 7.57 (1H, m, 5'-H); m/z 612 (M+, 1%), 597 (1), 117 (90), and 73 (100). (Found: M+, 612.2979. C29H52O8Si3 requires M, 612.2970). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(furan-2-yl)but-1- yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyI)tetra- hydropyran
Using the method described in 5c, the product from 8b (0.6g, 0.98mmol) was deprotected to give the title compound (0.289g, 74%); vmax (KBr) 3472, 1627, 1467, 1087, and 1046cm-1; λmax (EtOH) 321.5nm
(εm 20,440); δH (CDCl3) inter alia 0.93 (3H, d, J 7.0Hz, 17-H3), 1.22 (3H, d, J 6.3Hz, 14-H3), 6.17 (1H, s, 2-H), 6.55 (1H, dd, J 3.5 and 1.7Hz, 4'-H), 7.16 (1H, d, J 3.5Hz, 3'-H), and 7.58 (1H, s, with fine coupling, 5'-H); δC (CDCI3/CD3OD); 12.5 (C-17), 20.6 (C-14), 31.6 (C-9), 39.6 (C-8), 41.2 (C-4), 42.6 (C-12), 55.6 (C-10), 61.1 (C-11), 65.6 (C-16), 68.7 (C-6), 70.1 (C-7), 71.0 (C-13), 74.0 (C-5), 96.8 (C-2), 112.5 (C-4'), 116.0 (C-3"), 146.2 (C-5"), 150.1 (C-2'), 175.1 (C-3), and 191.1 (C-1); m/z 396 (M+, 1%) and 137 (100). (Found: M+, 396.1784. C20H28O8 requires M, 396.1784). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 9 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(pyrid-4-yl)but-1-yI]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-(pyrid-4-yl)-
4-hydroxy-2-oxobut-1-yI]-5S-(2S,3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetτahydropyran
Using the method described in 5a, and on the same scale,
pyridine-4-carboxaldehyde (0.32ml, 3.36mmol) was reacted to give the title compound (1.20g, 68%); δH
(CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 5.14-5.22 (1H, m, 1-H), 7.34-7.38 (2H, m, 3' and 5'-H), and
8.56-8.60 (2H, m, 2' and 6'-H); m/z 625 (M+, 3%) and 117 (100). (Found: M+, 625.3288. C30H55NO7Si3 requires M, 625.3286). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(pyrid- 4-yl)but-1-yI]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran Using the method described in 6b, the product from 9a(1.18g, 1.88mmol) in benzene (60ml) was reacted with manganese dioxide (3.3g) for 2 hours to give the title compound (0.556g, 47%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H3), 6.33 (1H, s, 2-H),
7.75-7.79 (2H, m, 3' and 5'-H), and 8.76 (2H, br, 2' and 6'-H); m/z 623 (M+, 4%), 117 (99), and 73 (100). (Found: M+, 623.3131. C30H53NO7Si3 requires M, 623.3130). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(pyrid-4-yl)but-1- yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetra- hydropyran
Using the method described in 5c, the product from 9b (0.535g, 0.86mmol) was deprotected to give the title compound (0.32 lg, 92%); vmax (KBr) 3421, 1595, 1550, 1455, 1111, and 1062cm-1; λmax (EtOH) 316.5nm
(εm 10,786); δH (CDCI3/CD3OD) inter alia 0.93 (3H, d, J 7.1Hz, 17-H3), 1.22 (3H, d, J 6.3Hz, 14-H3), 2.63 (1H, dd, J 15.1 and 8.5Hz, 4-H), 2.73 (1H, dd, J 7.6 and 2.1Hz, 11-H), 2.82 (1H, td, J 5.7 and 2.1Hz, 10-H), 2.98 (1H, dd, J 15.1 and 3.3Hz, 4-H), 6.33 (1H, s, 2-H), 7.69-7.73 (2H, m, 3' and 5'-H), and 8.70-8.75 (2H, m, 2' and 6'-H); δC (CDCI3/CD3OD); 12.5 (C-17), 20.6 (C-14), 31.6 (C-9), 39.8 (C-8), 42.6 (C-12), 43.2 (C-4), 55.6 (C-10), 61.0 (C-11), 65.6 (C-16), 68.5(C-6), 70.1 (C-7), 70.9 (C-13), 73.9 (C-5), 98.6 (C-2), 120.6 (C-3' and 5'), 141.9 (C-4'), 150.2 (C-2' and 6'), 177.1 (C-3), and 198.6 (C-1); m/z 407 (M+, 6%) and 148 (100). (Found: M+, 407.1954.
C21H29NO7 requires M, 407.1944). The 1Η n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 10 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(pyrid-3-yl)but-1-yl ]-
5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-(pyrid-3-yl)- 4-hydroxy-2-oxobut-1-yI]-5S-(2S,3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.34g, 2.58mmol) and pyridine-3-carboxaldehyde (0.29ml, 3.1mmol) were reacted to give the title compound (1.154g, 71%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 5.19-5.27 (1H, m, 1-H), 7.33 (1H, dd, J 7.8 and 4.9Hz 5'-H), 7.77-7.82 (1H, m, 4'-H), 8.54 (1H, dd, J 4.7 and 1.1Hz, 6'-H), and 8.62 (1H, d, si 1.6Hz, 2'-H) (contains
approximately 4% pyridine-3-carboxaldehyde). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(pyrid- 3-yl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 10a(1.10g, 1.76mmol) in benzene (70ml) was reacted with manganese dioxide (4.0g) for 2 1/2 hours to give the title compound (0.513g, 47%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.4Hz, 14-H3), 6.29 (1H, s, 2-H), 7.43 (1H, dd, J 7.9 and 4.9Hz, 5'-H), 8.20 (1H, dt, J 7.9 and 1.7Hz, 4'-H), 8.73 (1H, m, 6 -H), and 9.09 (1H, s with fine coupling, 2'-H); m/z 623 (M+, 75%), and 331 (100). (Found: M+, 623.3118. C30H53NO7Si3 requires M, 623.3130). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(pyrid-3-yl)but-1- yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetra- hydropyran Using the method described in 5c, the product from 10b (0.50g, 0.80mmol) was deprotected to give the title compound (0.262g, 81%); vmax (KBr) 3411, 1597, 1452, 1111, and 1043cm-1; λmax (EtOH) 312nm (εm 12,785); δH (CDCI3) 0.93 (3H, d, J 7.0Hz, 17-H3), 1.22 (3H, d, 16.4Hz, 14-H3), 6.34 (1H, s, 2-H), 7.42 (1H, dd, 18.0 and 4.9Hz, 5'-H), 8.18 (1H, dt, J 8.0 and 1.7Hz, 4'-H), 8.72 (1H, dd, J 4.9 and 1.4Hz, 6'-H), and 9.07 (1H, d, J 1.8Hz, 2' -H); δC (CDCI3) 12.8 (C-17), 20.8 (C-14), 31.6 (C-9), 39.8 (C-8), 42.5 (C-4), 42.8 (C-12), 55.5 (C-10), 61.0 (C-11), 65.5 (C-16), 68.6 (C-6), 70.3 (C-7), 71.2 (C-13), 73.6 (C-5), 97.9 (C-2), 123.6 (C-5'), 130.4 (C-3'), 134.7 (C-4'), 148.1 (C-6'), 152.4 (C-2'), 179.4 (C-3), and 196.4 (C-1); m/z 407 (M+, 17%)
and 106 (100). (Found: M+, 407.1946. C21H29NO7 requires M, 407.1944). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 11 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(pyrid-2-yl)but-1-yl]but- 1-yl]5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-(pyrid-2-yl)- 4-hydroxy-2-oxobut-1-yl]-5S-(2S,3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.04g, 2mmol) and pyridine-2-carboxaldehyde (0.23ml, 2.4mmol) were reacted to give the title compound (0.804g, 64%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, 1 6.3Hz, 14-H3), 5.21-5.27 (1H, m, 1-H), 7.22 (1H, m, 5'-H), 7.51 (1H, d, J 7.8Hz, 3'-H), 7.73 (1H, t with further fine coupling, J 7.7Hz, 4'-H), and 8.54 (1H, d, J 4.7Hz, 6'-H); m/z 625 (M+, 3%), 129 (100), 117 (100), and 73 (100). (Found: M+, 625.3281. C30H55NO7Si3 requires M, 625.3286). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(pyrid- 2-yl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran Using the method described in 6b, the product from lla(0.790g,
1.26mmol) in benzene (35ml) was reacted with manganese dioxide (2.5g) for 2 hours to give the title compound (0.275g, 35%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3),
6.89 (1H, s, 2-H), 7.37-7.44 (1H, m, 5'-H), 7.83 (1H, dt, J 1.7 and 7.8Hz, 4'-H), 8.08 (1H, d, J 7.8Hz, 3'-H), 8.67 (1H, d, J 4.2Hz, 6'-H); m/z 623 (M+, 14%), 148 (75), 117 (82), and 73 (100). (Found: M+, 623.3143.
C30H53NO7Si3 requires M, 623.3130). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(pyrid-2-yl)but-1- yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran
Using the method described in 5c, the product from 11b (0.260g,
0.42mmol) was deprotected to give the title compound (0.042g, 25%); vmax (KBr) 3399, 1607, 1587, 1516, 1449, and 1045cm-1; λmax (EtOH) 314nm (εm 11,010); δH KCD3)2CO] inter alia 0.92 (3H, d, J 7.0Hz, 17-H3), 1.16 (3H, d, J 6.4Hz, 14-H3), 6.98 (1H, s, 2-H), 7.57 (1H, ddd, J 7.4, 4.8, and 1.4Hz, 5'-H), 8.00 (1H, dt, si 7.7 and 1.7Hz, 4'-H), 8.10 (1H, d, J 7.8Hz, 3'-H), and 8.71 (1H, d, with further fine coupling, J 4.8Hz, 6'-H); m/z
(TSP) 408 (MH+, 65%) and 99 (100); m/z 407 (M+, 40%) and 122 (100). (Found: M+, 407.1950. C21H29NO7 requires M, 407.1944).
Example 12 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(3-methylisoxazol-5-yl)
but-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-(3-methyl- isoxazbl-5-yl)-4-hydroxy-2-oxobut-1-yI]-5S-(2S,3S- epoxy-5S-trimethylsiIyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.04g, 2mmol) and 3-methylisoxazole-5-carboxaldehyde (0.267g, 2.4mmol) were reacted to give the title compound (0.834g, 66%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.4Hz, 14-H3), 2.29 (3H, s, 3'-CH3), 5.18-5.27 (1H, m, 1-H), and 6.10 (1H, s, 4'-H); m/z 629 (M+, 8%), 129 (100), 117 (100), and 73 (100). (Found: M+, 629.3260. C29H55NO8Si3 requires M, 629.3236). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(3- methylisoxazol-5-yl)but-1-yl]-5S-(2S,3S-epoxy-5S-tri- methylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 12a(0.815g, 1.29mmol) in benzene (35ml) was reacted with manganese dioxide (2.04g) for 2 hours to give the title compound (0.360g, 42%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.4Hz, 14-H3), 2.37 (3H, s, 3'-CH3), 6.32 (1H, s, 2-H), and 6.69 (1H, s, 4'-H); m/z (TSP) 645 (MNH4 +, 100%) and 628 (MH+, 65); m/z 627 (M+, 10%), 612 (12), 117 (100), and 73 (100). (Found: M+, 627.3104. C29H53NO8Si3 requires M, 627.3079). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(3-methylisoxazol-
5-yl) but-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran
Using the method described in 5c, the product from 12b (0.380g, 0.6mmol) was deprotected to give the title compound (0.167g, 68%); vmax (KBr) 3395, 1617, 1584, 1512, 1457, 1412, and 1055cm-1; λmax (EtOH) 330nm (εm 13,500); δH [(CD3)2SO] inter alia 0.83 (3H, d, J 7.1Hz, 17-H3), 1.07 (3H, d, J 6.4Hz, 14-H3), 2.25 (3H, s, 3'-CH3), 5.83 (1H, s, 2-H), and 6.64 (1H, s, 4'-H); δC (CD3OD) 11.3 (isox-CH3), 12.3 (C-17), 20.4 (C-14), 32.9 (C-9), 41.5 (C-8), 43.7 (C-12), 45.1 (br, C-4), 56.9 (C-10), 61.3 (C-11), 66.5 (C-16), 70.1 (C-6), 70.8 (C-13), 71.6 (C-7), 76.0 (br, C-5), 99.0 (br, C-2), 106.6 (br, C-4'), 161.9 (C-3'), 170.5 (br, C-5'), 171.4 (br, C-3), and 197.0 (br, C-1); m/z (FAB, thioglycerol) 450 (MK+) and 434 (MNa+); m/z 411 (M+, 0.1%), 125 (80), and 43 (100). (Found: M+, 411.1892. C20H29NO8 requires M, 411.1893). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 13 SR,4R-Dihydroxy-2S-[2,4 -dioxo-4-(3-methoxyphenyl)but- 1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-(3-methoxy- phenyl)-4-hydroxy-2-oxobut-1-yI]-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, and on the same scale, 3-methoxybenzaldehyde (0.39ml, 3.2mmol) was reacted to give the title compound (1.06g, 56%);
δH (CDCl3) inter alia 0.89 (3H, d, 17.1Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 3.82 (3H, s, OMe), 4.07-4.20 (1H, m, 5-H), 5.09-5.21 (1H, m, 1-H), 6.78-6.85 (1H, m, 6'-H), 6.90-6.99 (2H, m, 2', 4'-H2), 7.23-7.32 (1H, m, 5'-H); m/z 654 (M+, 0.5%) and 117 (100). (Found: M+, 654.3456.
C32H58O8Si3 requires M, 654.3440). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(3- methoxyphenyl)but-1-yI]-5S-(2S,3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 13a(1.0g, 1.49mmol) in benzene (50ml) was reacted with manganese dioxide (3.0g) for 3 hours to give the title compound (0.610g, 61%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.4Hz, 14-H3), 3.86(3H, s, OMe), 6.25 (1H, s, 2-H), 7.06 (1H, dd, J 1.6, 8.0Hz, 6'-H), 7.35 (1H, dd, J 7.8, 8.0Hz, 5'-H), 7.40-7.51 (2H, m, 2', 4'-H2); m/z 652 (M+ 1%) and 41 (100). (Found: M+, 652.3280. C35H56O8Si3 requires M, 652.3280). c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(3-methoxyphenyl
but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran Using the method described in 5c, the product from 13b (250mg,
0.37mmol) was deprotected to give the title compound (140mg, 87%); vmax (KBr) 3430, 1718, 1576, 1457cm-1; λmax (EtOH) 309nm (εm 15,360); δH (CDCI3) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.21 (3H, d, J 6.4Hz, 14-H3), 3.86 (3H, s, OMe), 6.26 (1H, s, 2-H), 7.08 (1H, d with further fine coupling, J ca.8.0Hz, 6'-H), 7.30-7.52 (3H, m, 2", 4',
5'-H3); δC (d4-MeOH), 12.0 (C-17), 20.0 (C-14), 32.6 (C-9), 41.3 (C-8), 42.6 (C-4), 43.4 (C-12), 55.6 (C-10), 56.5 (OMe). 60.9 (C-11), 66.1 (C-16), 69.5 (C-6), 70.4 (C-13), 71.2 (C-7), 75.1 (C-5), 98.1 (C-2), 113.8 (C-5'), 119.0 (C-4'), 120.1 (C-6'), 130.5 (C-3), 137.1( C-1'), 161.0 (C-3'), 183.1 (C-3), 196.3 (C-1); m/z 436 (M+, 0.2%) and 135 (100). (Found: M+, 436.2105.
C27H32O8 requires M, 436.2097). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. Example 14 3R,4R-Dihydroxy-2S-[4-(4-cyanophenyl)-2,4-dioxobut-1- yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-(4-cvanophenyl)- 4-hydroxy-2-oxobut-1-yI]-5S-(2S,3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, and on the same scale,
4-cyanobenzaldehyde (419mg, 3.2mmol) was reacted to give the title compound (1.25g, 68%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 4.08-4.19 (1H, m, 5-H), 5.16-5.28 (1H, m, 1-H), 7.49 (2H, d, J 8.2Hz, 2", 6'-H2), 7.62 (2H, d, J 8.2Hz, 3', 5'-H2). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-(4-cvanophenyl)- 2,4-dioxobut-1-yl] -5S-(2S,3S-epoxy-5S-trimethylsilyl- oxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 14a(1.25g) in benzene (65ml) was reacted with manganese dioxide (3.5g) for 1 hour to give the title compound (625mg, 50%); δH (CDCI3) 0.90 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 1.31-1.45 (1H, m, 8-H), 1.50-1.66 (2H, m,
9-H), 1.80-1.90 (1H, m, 12-H), 2.39 (1H, dd, J 10.2, 14.8Hz, 4-H), 2.62-2.75 (2H, m, 10, 11-H2), 2.86 (1H, dd, J 2.6, 14.7Hz, 4-H), 3.46 (1H, dd, J 2.4, 9.2Hz, 6-H), 3.57 (1H, d, J 11.3Hz, 16-H), 3.77-3.92 (2H, m, 7, 13-H2), 3.96 (1H, d, J 11.3Hz, 16-H), 4.07-4.20 (1H, m, 5-H), 6.28 (1H, s, 2-H), 7.74 (2H, d, J 8.5Hz, 3', 5'-H2), 7.97 (2H, d, J 8.5Hz, 2', 6'-H2). The 1H spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[4-(4-cyanophenyl)-2,4-dioxo- but-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran
Using the method described in 5c, the product from 14b (200mg, 0.31m mol) was deprotected to give the title compound (95mg, 71%); vmax (KBr) 3431, 2230, 1597, 1558cm-1; λmax (EtOH) 321.5nm (εm 16,280); δH (CDCI3) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.22 (3H, d, J 6.3Hz, 14-H3), 6.29 (1H, s, 2-H), 7.75 (2H, d, J 8.4Hz, 3', 5'-H2), 7.97 (2H, d, J 8.4Hz, 2', 6'-H2); δC (CDCI3) 13.1 (C-17), 21.2 (C-14), 31.9 (C-9), 40.1 (C-8), 43.2 (C-12), 43.3 (C-4), 56.0 (C-10), 61.6 (C-11), 66.0 (C-16), 69.2 (C-6), 70.6 (C-13), 71.7 (C-7), 74.2 (C-5), 98.8 (C-2), 115.8 (C-1'), 118.4 (C-4'), 127.8 (C-2', 6'), 132.8 (C-3', 5'), 138.7(CN),179.1 (C-3), 198.1 (C-1); m/z (FAB) 454 (M Na+). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 15 3R,4R-Dihydroxy-2S-[4-(4-chlorophenyl)-2.4-dioxo-but-1- yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-(4-chlorophenyl)- 4-hydroxy-2-oxobut-1-yI]-5S-(2S,3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, and on the same scale,
4-chlorobenzaldehyde (450mg, 3.2mmol) was reacted to give the title compound (1.4g, 76%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.18 (3H, d, J 6.4Hz, 14-H3), 4.07-4.18 (1H, m, 5-H), 5.08-5.20 (1H, m, 1-H), 7.28-7.32 (4H, m, Ar); m/z 658 (M+, 0.01%) and 117 (100). (Found: M+, 658.2947. C31H55O7CISi3 requires M, 658.2944). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-(4-chlorophenyl)- 2,4-dioxobut-1-yI]-5S-(2S,3S-epoxy-5S-trimethylsilyl- oxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 15a(700mg,
1.06mmol) in benzene (30ml) was reacted with manganese dioxide (1.75g) for 2 hours to give the title compound (296mg, 42%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.10 (3H, d, J 6.3Hz, 14-H3), 3.94-4.08 (1H, m, 5-H), 6.23 (1H, s, 2-H), 7.41 (2H, d, J 8.6Hz, 3', 5'-H2), 7.82 (2H, d, J 8.6Hz, 2', 6'-H2); m/z, 656 (M+, 5%) and 117 (100). (Found: M+, 656.2803. C31H53O7ClSi3 requires M, 656.2788). c) 3R,4R-Dihydroxy-2S-[4-(4-chlorophenyl)-2,4-dioxo- but-1-vI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)=
tetrahydropyran
Using the method described in 5c, the product from 15b (296mg,
0.45mmol) was deprotected to give the title compound (160mg, 80%); vmax (KBr) 3424, 1718, 1595, 1486, 1451, 1380cm-1; λmax (EtOH) 313nm
(εm 17,760) and 255 (7,460); δH (CDCI3) inter alia 0.93 (3H, d, J 7.0Hz, 17-H3), 1.22 (3H, d, J 6.3Hz, 14-H3), 6.20 (1H, s, 2-H), 7.43 (2H, d, J
8.6Hz, 3', 5'-H2), 7.82 (2H, d, J 8.6Hz, 2', 6'-H2); δC (CDCI3) 12.7 (C-17), 20.8 (C-14), 31.6 (C-9), 39.7 (C-8), 42.7 (C-4), 42.8 (C-12), 55.7 (C-10), 61.3 (C-11), 65.6 (C-16), 69.0 (C-6), 70.3 (C-13), 71.3 (C-7), 73.9 (C-5), 97.4 (C-2), 128.4 (C-3', C-5'), 129.0 (C-2', C-6'), 134.6 (C-1'), 140.4 (C-4'), 181.1 (C-3), 196.0 (C-1); m/z 441 (MH+, 2%) and 139 (100). (Found: M+,
441.1680. C22H30O7CI requires M, 441.1680). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. Example 16 3R,4R-Dihydroxy-2S-[4-(4-diethoxymethylphenyl)-2,4- dioxobut-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-(4-diethoxy- methy-phenyl)-4-hydroxy-2-oxobut-1-yl]-5S-(2S,3S-epoxy- 5S-trimethylsilyloxy-4S-methylhexyl)tetrahydropyran Using the method described in 5a, and on the same scale,
terephthalaldehyde-mono, diethyl acetal (666mg, 3.2mmol) was reacted to give the title compound (1.52g, 75%); δH (d4-MeOH) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 4.02-4.16 (1H, m, 5-H), 5.10-5.19 (1H, m, 1-H), 5.47 (1H, s, ArCH-(OEt)2), 7.36 and 7.42 (4H, ABq, J 8.4Hz); m/z (FAB) 749 (MNa+). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-(4-diethoxy
methylphenyl)-2,4-dioxobut-1-yl]-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 16a(1.0g, 1.38mmol) in benzene (50ml) was reacted with manganese dioxide (2.5g) for 2 hours to give the title compound (535mg, 53%); δH (d4-MeOH) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 1.22 (6H, t, J 7.1Hz, -(OEt)2), 4.07-4.17 (1H, m, 5-H), 5.55 (1H, s, Ar-CH-(OEt)2), 6.41 (1H, s, 2-H), 7.56 (2H, d, 18.3Hz, 3', 5'-H2), 7.92 (2H, d, J 8.3Hz, 2', 6'-H2); m/z 724 (M+, 0.1%) and 432 (100). (Found: M+, 724.3860. C36H64O9Si3 requires M, 724.3858). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[4-(4-diethoxymethylphenyl)- 2,4-dioxobut-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S- methyIhexyl)tetrahydropyran
Using the method described in Id, the product from 16b (150mg,
0.21mmol) in ethanol (5ml) was deprotected to give the title compound (60mg, 57%); λ max (EtOH) 315nm (εm 18,870) and 252 (7,350); δH
(dg-acetone) inter alia 0.92 (3H, d, J 7.0Hz, 17-H3), 1.10-1.30 (9H, m,
17-H3, 2 x OEt), 5.58 (1H, s, -CH-(OEt)2), 6.52 (1H, s, 2-H), 7.59 (2H, d, J 8.4Hz, 3", 5'-H2), 7.99 (2H, d, J 8.4Hz, 2', 6'-H2); δC (d6-acetone) 12.3 (C-17), 15.5 (-CH2Me ), 20.8 (C-14), 32.7 (C-9), 41.3 (C-8), 43.0 (C-4), 43.3 (C-12), 55.8 (C-10), 60.4 (C-11), 61.6 (-CH2Me), 66.0 (C-16), 69.4 (C-6), 70.1 (C-7), 71.1 (C-13), 75.1 (C-5), 98.0 (C-2), 101.6 (CH(-OEt)2), 1-27.6 and 127.7 (C-2', 6', 3', 5'), 135.5 (C-4'), 144.9 (C-1'), 183.0 (C-1), 197.2 (C-3). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. Example 17 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-formylphenyl)-but-1- yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(4- formylphenyl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethyl- sOyyloxy-4S-methylhexyI)tetrahydropyran The product from 16b (110mg) was dissolved in acidic chloroform (10ml) [standard solution: chloroform (100ml):concentrated hydrochloric acid (1 drop)]. After 1 1/2 hours the mixture was evaporated and
chromatographed on silica eluting with ethyl acetate/
hexane mixtures to give the title compound (60mg, 60%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.2Hz, 14-H3), 4.08-4.22 (1H, m, 5-H), 6.33 (1H, s, 2-H), 7.95 and 8.04 (4H, ABq, J 8.4Hz, Ar), 10.09 (1H, s, -CHO); m/z (FAB) 673 (MNa+). b) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-formylphenyl)- but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran Using the method described in 5c, the product from 17a (50mg, 0.08mmol) was deprotected to give the title compound (33mg, 100%); vmax (KBr) 3427, 1701, 1602, 1564cm-1; λmax (EtOH) 322.5nm (εm 16,240) and 258 (9,430); δH (CDCI3) inter alia 0.93 (3H, d, J 7.0Hz, 17-H3), 1.21 (3H, d, J 6.3Hz, 14-H3), 6.33 (1H, s, 2-H), 7.94 and 8.01 (4H, ABq, J 8.3Hz, Ar), 10.06 (1H, s, -CHO); δC (CDCI3) 12.8 (C-17), 20.9 (C-14), 31.6 (C-9), 39.8 (C-8), 42.9 (C-12), 43.2 (C-4), 55.7 (C-10), 61.3 (C-11), 65.7 (C-16), 69.0 (C-6), 70.3 (C-7), 71.4 (C-13), 73.9 (C-5), 98.2 (C-2), 127.6 (C-3', 5'), 129.8 (C-2', 6'), 138.6 (C-4'), 139.5 (C-1'), 179.3 (C-1), 191.6 (CHO), 197.9 (C-3); m/z 434 (M+, 2%) and 133 (100); (Found: M+, 434.1944. C23H30O8 requires M, 434.1941). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 18 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-nitrophenyl)-but-1-yI]-
5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)-tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-4-(4- nitrophenyl)-2-oxobut-1-yI]-5S-(2S,3S-epoxy-5S-tri- methylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, and on the same scale,
4-nitrobenzaldehyde (483mg, 3.2mmol) was reacted to give the title compqund (1.42g, 76%); δH (CDCl3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 4.08-4.17 (1H, m, 5-H), 5.22-5.33 (1H, m, 1-H), 7.55 (2H, dd, J 1.5, 8.7Hz, 2', 6'-H2), 8.21 (2H, d, J 8.7Hz, 3', 5'-H2); m/z 669 (M+, 5%) and 117 (100). (Found: M+, 669.3198.
C31H55NO9Si3 requires M, 669.3185). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(4- nitrophenyl)but-1-yI]-5S-(2S,3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 18a(1.0g, 1.49mmol) in benzene (50ml) was reacted with manganese dioxide (2.5g) for 45 minutes to give the title compound (618mg, 68%); δH (CDCI3) inter alia
0.90 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 4.08-4.22 (1H, m, 5-H), 6.32 (1H, s, 2-H), 8.04 (2H, d, 18.8Hz, 2', 6'-H2), 8.30 (2H, d, J
8.8Hz, 3', 5'-H2); m/z 667 (M+, 5%) and 117 (100). (Found: M+, 667:3043.
C31H53NO9Si3 requires M, 667.3043). The 1H spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-nitrophenyl)- but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran
Using the method described in 5c, the product from 18b (200mg, 0.3mmol) was deprotected to give the title compound (83mg, 61%); vmax (KBr)
3112, 1588, 1488, 1451, 1346cm-1; λmax (EtOH) 331.5nm (εm 13,490) and 253.5 (9,430); δH (CDCI3) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.22 (3H, d, J 6.2Hz, 14-H3), 6.32 (1H, s, 2-H), 8.03 (2H, d, J 8.9Hz, 2', 6'-H2), 8.30 (2H, d, J 8.9Hz, 3', 5'-H2); δC (CDCI3) 12.8 (C-17), 20.9 (C-14), 31.6 (C-9), 39.8 (C-8), 42.9 (C-12), 43.1 (C-4), 55.7 (C-10), 61.3 (C-11), 65.6 (C-16), 68.9 (C-7), 70.4 (C-6), 71.4 (C-13), 73.9 (C-5), 98.8 (C-2), 123.8 (C-2', 6'), 128.0 (C-3', 5'), 140.0 (C-1'), 149.9 (C-4'), 178.2 (C-1), 198.1 (C-3); m/z (FAB) 469 (MNH4 +) and 452 (MH+). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 19 3 R,4R-Dihydroxy-2S-[2,4-dioxo-4-(thien-2-yl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-r4-(thien-2-yl)-4- hydroxy-2-oxobut-1-yI]-5S-(2S,3S-epoxy-5S-trimethylsilyl- oxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.15g, 2.22mmol) and thiophene-2-carboxaldehyde (0.24ml, 2.6mmol) were reacted to give the title compound (1.086g, 78%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H3), 5.36-5.46 (1H, m, 1-H), 6.94-7.00 (2H, m, 3' and 4'-H), and 7.22-7.28 (1H, m, 5'-H); m/z 630 (M+, 4%) and 117 (100). (Found: M+, 630.2909. C29H54O7SSi3 requires M, 630.2898). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(thien-2- yl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 19a (1.05g, 1.66mmol) in benzene (40ml) was reacted with manganese dioxide (2.6g) for 1 3/4h to give the title compound (0.684g, 66%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 6.13 (1H, s, 2-H), 7.12 (1H, dd, J 3.9 and 4.9Hz, 4'-H), 7.59 (1H, dd, J 0.9 and 4.9Hz, 3'-H), and 7.70 (1H, dd, J 0.9 and 3.9Hz, 5'-H); m/z 628 (M+, 2%), 336 (90), 117 (100), and 73 (99). (Found: M+, 628.2759. C29H52O7SSi3 requires M, 628.2742). The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(thien-2-yl)but-1- yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5c, the product from 19b (0.670g, l.Oβmmol) was deprotected to give the title compound (0.367g, 84%); νmax (KBr) 3421, 1611, 1412, 1272, 1110, and 1043cm-1; λmax (EtOH) 325nm (εm 15,308); δH (CDCI3) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.21 (3H, d, J 6.3Hz, 14-H3), 6.13 (1H, s, 2-H), 7.14 (1H, dd, J 3.9 and 4.9Hz, 4'-H), 7.62 (1H, dd, J 4.9 and 0.9Hz, 3'-H), and 7.72 (1H, dd, J 3.9 and 0.9Hz, 5'- H); δC (CDCI3) 12.7 (C-17), 20.7 (C-14), 31.6 (C-9), 39.6 (C-8), 40.8 (C-4), 42.8 (C-12), 55.6 (C-10), 61.2 (C-11), 65.6 (C-16), 68.8 (C-6), 70.3 (C-7), 71.3 (C-13), 74.0 (C-5), 97.3 (C-2), 128.3, 130.6 and 132.6 (C-3', 4', 5'), 140.9 (C-2'), 180.7 (C-3), and 189.3 (C-1); m/z 412 (M+, 1%) and 111 (100). (Found: M+, 412.1559. C20H28O7S requires M, 412.1556). The Η n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 20 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(thien-3-yl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-4-(thien- 3-yl)- 2-oxobut-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy- 4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.15g, 2.22mmol) and thiophene-3-carboxaldehyde (0.23ml, 2.6mmol) were reacted to give the title compound (0.953g, 68%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 5.21-5.29 (1H, m, 1-H), 7.04-7.09 (1H, m, 4'-H), 7.22-7.24 (1H, m, 2'-H), and 7.28-7.32 (1H, m, 5'-H); m/z 630 (M+, 0.1%), 226 (65), 129 (92), 117 (88), and 73 (100). (Found: M+, 630.2897. C29H54O7SSi3 requires M, 630.2898). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(thien- 3-yl)but-1-yl)-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 20a (0.93g, 1.47mmol) in benzene (40ml) was reacted with manganese dioxide (2.5g) for 1 3/4h to give the title compound (0.537g, 58%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 6.10 (1H, s, 2-H), 7.34 (1H, dd, J 3.0 and 5.1Hz, 4'-H), 7.46 (1H, dd, J 1.1 and 5.1Hz, 5'-H), and 8.01 (1H, dd, J 1.1 and 3.0Hz, 2'-H); m/z 628 (M+, 2%), 336 (78), 117 (85), and 73 (100). (Found: M+, 628.2753. C29H52O7SSi3 requires M, 628.2742). The Η n.m.r. spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(thien-3-yl)but-1- yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydro
pyran Using the method described in 6c, the product from 20b (0.53g, 0.84mmol) was deprotected to give the title compound (0.309g, 89%); νmax (KBr) 3417, 1609, 1508, 1258, 1109, and 1054cm-1; λmax (EtOH) 313nm
(εm 16,375); δH (CDCI3) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.21 (3H, d, J 6.2Hz, 14-H3), 7.36 (1H, dd, J 2.9 and 5.1Hz, 4'-H), 7.45 (1H, dd, J 1.2 and 5.1Hz, 5'-H), and 8.04 (1H, dd, J 1.2 and 2.9Hz, 2'-H); δH (CDCI3)
12.6 (C-17), 20.7 (C-14), 31.6 (C-9), 39.6 (C-8), 42.3 (C-4), 42.7 (C-12), 55.6 (C-10), 61.2 (C-11), 65.6 (C-16), 68.9 (C-6), 70.2 (C-7), 71.2 (C-13), 73.8 (C-5), 98.0 (C-2), 125.8, 126.6 and 129.9 (C-2', 4' and 5'), 138.1 (C-3'), 177.9 (C-3), and 194.9 (C-1); m/z 412 (M+, 2%), 394 (7), 153 (70), and 111 (100). (Found: M+, 412.1563. C20H28O7S requires M, 412.1556). The Η n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 21 3R,4R-Dihydroxy-2S-[4-(2-dimethylaminopyrid-5-yl)-2,4- dioxobut-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methyl- hexyl)tetrahydropyran a) 2-Dimethylaminopyridine-5-carboxaldehyde
5-Bromo-2-dimethylaminopyridine (1.005g, 5.0mmol) was dissolved in dry THF (25ml), cooled to -70°C, and treated dropwise with nbutyllithium (1.5M, 3.67ml, 5.5mmol). The mixture was stirred at -70°c for lh, then N,N-dimethyl-formamide (1.16ml, l5mmol) added. Stirring was continued for a further hour, then the reaction quenched with saturated ammonium chloride. Water was added, and the mixture extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried and evaporated. The crude product was purified by column chromatography, on silica (36g), eluting with 20, 40 and 60% ethyl acetate in hexane, to give the title compound as white crystals (0.617g, 82%); m.p.55-55.5°C; δH (CDCI3) 3.22 (6H, s, N(CH3)2), 6.56 (1H, d, J 9.0Hz, 3'-H), 7.92 (1H, dd, J 9.0 and 2.3Hz, 4'-H), 8.56 (1H, d, J 2.3Hz, 6'-H), and 9.77 (1H, s, CHO); m/z 150 (M+, 100%), 135 (83), 121 (88), and 44 (86). (Found: M+,
150.0795. C8H10N2O requires M, 150.0793). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-(2-dimethylamino- pyrid-5-yl)-4-hydroxy-2-oxobut-1-yl]-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and 2-diιnethylaminopyridine-5-carboxaldehyde (0.330g,
2.2mmol) were reacted to give the title compound (1.04g, 78%); δH
(CDCl3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14- H3), 3.09 (6H, s, N(CH3)2), 5.04-5.11 (1H, m, 1-H), 6.52 (1H, d, J 8.8Hz, 3'-H), 7.52 (1H, dt, 18.8 and 2.8Hz, 4'-H), and 8.13 (1H, d, J 2.3Hz, 6'-H); m/z 668 (M+, 3%), 226 (100), 129 (90), 117 (80), and 73 (70). (Found: M+, 668.3724. C22H60N2O7Si3 requires M, 668.3708). c) 3R,4R-Bistrimethylsilyloxy-2S-[4-(2-dimethylamino- pyrid-5-yl)-2,4-dioxobut-1-yl]-5S-(2S,3S-epoxy-5S-trimethyl
silyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 21b (1.01g, 1.51mmol) in benzene (35ml) was reacted with manganese dioxide (2.6g) for 3h to give the title compoimd (0.440g, 44%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 3.18 (6H, s, N(CH3)2), 6.13 (1H, s, 2-H), 6.51 (1H, d, J 9.1Hz, 3'-H), 7.96 (1H, dd, J 9.1 and 2.4Hz, 4'- H), and 8.72 (1H, d, J 2.4Hz, 6'-H); m/z 666 (M+, 11%), 651 (3), and 149 (100). (Found: M+, 666.355l. C32H58N2O7Si3 requires M, 666.3552). The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. d) 3R,4R-Dihydroxy-2S-[4-(2-dimethyIaminopyrid-5-yl)- 2,4-dioxobut-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methyl- hexyl)tetrahydropyran Using the method described in 5c, the product from 21c (0.420g,
0.63mmol) was deprotected to give the title compound (0.238g, 84%); νmax (KBr) 3371, 1624, 1554, 1401, HO5, 1059, and 785cm-1; λmax (EtOH) 355nm (εm 35,913);. δH (CDCI3/CD3OD) inter alia 0.93 (3H, d, J 7.0Hz, 17-H3), 1.21 (3H, d, J 6.3Hz, 14-H3), 3.19 (6H, s, N(CH3)2), 6.13 (1H, s, 2- H), 6.53 (1H, d, J 9.1Hz, 3'-H), 7.94 (1H, dd, J 2.3 and 9.1Hz, 4'-H), and 8.71 (1H, d, J 2.3Hz, 6'-H); δC (CDCI3/CD3OD) 12.6 (C-17), 20.6 (C-14), 31.7 (C-9), 38.1 (N(CH3)2), 39.6 (C-8), 41.8 (C-4), 42.7 (C-12), 55.7 (C-10), 61.2 (C-11), 65.6 (C-16), 68.9 (C-6), 70.2 (C-7), 71.1 (C-13), 74.0 (C-5), 95.6 (C-2), 105.1 (C-4'), 118.0 (C-5'), 135.9 (C-3'), 149.1 (C-6'), 160.6 (C-2'), 183.3 (C-3), and 191.5 (C-1); m/z 450 (M+, 5%) and 149 (100). (Found: M+, 450.2372. C23H34N2O7 requires M, 450.2366). The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 22 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methylthiopyrid-5-yl)- but-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 2-Methylthiopyridine-5-carboxaldehyde
Using the method described in 21a, 5-bromo-2-methylthio-pyridine
(1.020g, 5mmol) was converted to the title compound (0.650g, 85%);
m.p.43-45°C; δH (CDCI3) 2.64 (3H, s, SCH3), 7.31 (1H, d, J 8.5Hz, 3'-H), 7.94 (1H, dd, J 2.1 and 8.5Hz, 4'-H), 8.84 (1H, d, J 2.1Hz, 6'-H), and 10.00 (1H, s, CHO); m/z 153 (M+, 100%), 152 (60), 124 (10), and 107 (48).
(Found: M+, 153.0247. C7H7NOS requires M, 153.0248). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-(2-methylthiopyrid- 5-yl)-4-hydroxy-2-oxobut-1-yI]-5S-(2S,3S-epoxy-5S-tri
methylsilyIoxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (2.750g, 5.3mmol) and 2-methylthiopyridine-5-carboxaldehyde (0.890g, 5.8mmol) were reacted to give the title compound (2.840g, 80%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.4Hz, 14-H3), 2.59 (3H, s, SCH3), 5.11-5.19 (1H, m, 1-H), 7.20 (1H, d, J 8.3Hz, 3'-H), 7.58 (1H, dt, J 8.3 and 2.8Hz, 4'-H), and 8.43 (1H, d, J 2.0Hz, 6'-H); m/z 671 (M+, 2%), 129 (65), 117 (85), and 73 (100). (Found: M+, 671.3187. C31H57NO7SSi3 requires M, 671.3164). c) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(2- methylthiopyrid-5-yl)but-1-yl]-5S-(2S,3S-epoxy-5S- trimethyl-silyloxy-4S-methyIhexyl)tetrahydropyran
Using the method described in 6b, the product from 22b (2.09g, 3.11mmol) in benzene (150ml) was reacted with manganese dioxide (2.8g) for 24h to give the title compoimd (1.340g, 64%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 2.61 (3H, s, SCH3), 6.23 (1H, s, 2-H), 7.24 (1H, d, J 8.5Hz, 3'-H), 7.95 (1H, dd, J 2.2 and 8.5Hz, 4'-H), and 8.91 (1H, d, J 2.2Hz, 6'-H); m/z 669 (M+, 3%), 152 (45), 117 (95), 75 (56), and 73 (100). (Found: M+, 669.3018. C31H55NO7SSi3 requires M, 669.3007). The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. d) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methylthiopyrid- 5-yl)but-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran
Using the method described in 5c, the product from 22c (0.648g,
0.97mmol) was deprotected to give the title compound (0.341g, 78%);
m.p.l35.5-136°C; found C, 57.91; H, 6.88; N, 3.09; S, 7.10%. C22H31NO7S requires C, 58.26; H, 6.89; N, 3.09; S, 7.07%; νmax (KBr) 3483, 3392, 1583, 1298, 1120, 1106, and 1061cm-1; λmax (EtOH) 336nm (εm 29,695); δH (CDCI3/CD3OD) inter alia 0.93 (3H, d, J 7.0Hz, 17-H3), 1.22 (3H, d, J 6.4Hz, 14-H3), 2.61 (3H, s, SCH3), 6.26 (1H, s, 2-H), 7.27 (1H, d, J 8.5Hz, 3'-H), 7.98 (1H, dd, J 8.5 and 2.3Hz, 4'-H), and 8.89 (1H, d, J 2.3Hz, 6 -H); δC (CDCI3/CD3OD) 12.3 (C-17), 13.2 (SCH3), 20.3 (C-14), 31.6 (C-9), 39.7 (C-8), 42.0 (C-4), 42.5 (C-12), 55.6 (C-10), 60.9 (C-11), 65.6 (C-16), 68.4 (C- 6), 70.0 (C-7), 70.6 (C-13), 73.9 (C-5), 97.0 (C-2), 120.8 (C-4"), 125.9 (C-5'), 133.9 (C-3'), 148.1 (C-6'), 165.2 (C-2'), 180.5 (C-3), and 194.6 (C-1); m/z 453 (M+, 1%) , 167 (100) and 152 (65). (Found: M+, 453.1825. C22H31NO7S requires M, 453.1821). The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 23 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methylsulphinylpyrid-
5-yl)but-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran The product from 22c (0.215g, 0.32mmol) was dissolved in
dichloromethane (9ml), cooled in an ice bath, saturated sodium hydrogen carbonate (0.5ml) and water (1.5ml) were then added, followed by 3- chloroperbenzoic acid (ca.95%, 0.064g, 0.35mmol). The mixture was stirred for 3/4h, then separated, and the aqueous extracted with
dichloromethane (x2). The combined organic phases were washed with brine, dried and evaporated. The product was purified by column chromatography, on silica (10g), eluting with 30-40% ethyl acetate in hexane, to give the pure product (0.152g, 69%).
This material was dissolved in THF (7ml), water (0.7ml) added, followed by glacial acetic acid (0.7ml). Further portions of glacial acetic acid
(5 x 0.4ml) were added over the following 28h. After this the solution was evaporated to dryness, and purified by column chromatography to give the title compound (0.064g, 62%); νmax (KBr) 3405, 1602, 1451, 1109, 1084, and 1042cm-1; λmax (EtOH) 322nm (εm 15,550); δH (CDCI3) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.23 (3H, d, J 6.3Hz, 14-H3), 2.90 (3H, s, SOCH3), 6.33 and 6.35 (1H, 2s, 2-H), 8.13 (1H, d, J 8.2Hz, 3'-H), 8.39 (1H, br d, 4'-H), and 9.06 (1H, s, 6'-H); δC (CDCI3) 12.8 (C-17), 20.9 (C-14), 31.7 (C-9), 39.9 (C-8), 41.1, 42.7 and 42.8 (C-4, C-12 and SOCH3), 55.6 (C-10), 61.1 (C-11), 65.6 (C-16), 68.8 (C-6), 70.4 (C-7), 71.3 (C-13), 73.9 (C-5), 98.5 (C-2), 119.4 (C-4'), 131.5 (C-5'), 136.5 (C-3'), 148.3 (C-6'), 169.0 (C-2'), 178.3 (C-3), and 197.2 (C-1); m/z (FAB, thioglycerol) 491 (MNa+) and 470 (MH+). The spectra indicated that the compound was a mixture of sulphoxide isomers, and essentially in the enolic form.
Example 24 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methylsulphonylpyrid- 5-yl)but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran
The product from 22c (0.235g, 0.35mmol) was dissolved in
dichloromethane (15ml), saturated sodium hydrogen carbonate (1.5ml) and water (3ml) added, and the mixture stirred while 3-chloroperbenzoic acid (ca.95%, 0.140g, 0.77mmol) was added. Stirring was continued for seven hours, then water added and the mixture extracted with dichloromethane (x3). The combined organic extracts were dried and evaporated. The crude material was purified by column chromatography, on silica (10g), eluting with 25-40% ethyl acetate in hexane, to give the pure product (0.097g, 40%).
This material was deprotected using the method described in 5c, to give the title compound (0.037g, 57%); νmax (KBr) 3490, 1623, 1307, 1163, 1103, 1060, and 778cm-1; λmax (EtOH) 320nm (εm 14,012); δH
(CDCI3/CD3OD) inter alia 0.94 (3H, d, 17.1Hz, 17-H3), 1.22 (3H, d, J
6.4Hz, 14-H3), 3.29 (3H, S, SO2CH3), 6.38 (1H, S, 2-H), 8.18 (1H, d, J
8.2Hz, 3'-H), 8.45 (1H, dd, J 8.2 and 2.0Hz, 4'-H), and 9.16 (1H, d, J 2.0Hz, 6'-H); m/z 485 (M+, 0.1%), 135 (70), and 122 (100); m/z (FAB, thioglycerol) 498 (MNa+) and 486 (MH+). The Η n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 25 3R,4R-Dihydroxy-2S-[4-(2-chloropyrid-5-yl)-2,4-dioxobut-1-yI]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) N-Methoxy,N-methyl-2-chloropyridine-δ-carboxamide
2-Chloropyridine-5-carboxylic acid (1.576g, 10mmol) was dissolved in dry THF (100ml), cooled in an ice-bath, then triethylamine (1.5ml, llmmol) added, followed by iso-butylchloroformate (1.3ml, 10mmol). The mixture was stirred for 3/4h, then N,O-dimethylhydroxylamine (ex hydrochloride salt, 15mmol) in dichloromethane (70ml) was added. After stirring for 13/4h, the mixture was diluted with dichloromethane, washed with water, aqueous sodium hydrogen carbonate, and brine, dried and
evaporated. The crude product was purified by column chromatography, on silica (25g), eluting with 40% ethyl acetate in hexane, to give the title compound (1.280g, 64%); δH (CDCI3) 3.35 and 3.55 (6H, 2s, 2 x CH3), 7.35 (1H, d, J 8Hz, 3'-H), 8.0 (1H, dd, J 8 and 2Hz, 4'-H), and 8.7 (1H, d, J 2Hz, 6'-H). b) 2-Chloropyridine-5-carboxaldehyde
The product from 25a (1.25g, 6.23mmol) was dissolved in dry dichloromethane (25ml), cooled to -70°C, and treated dropwise with diisobutylalu minium hydride (1.0M in toluene, 9.3ml, 9.3mmol). After stirring for lh at -70°C, the reaction was quenched with methanol and saturated sodium sulphate solution. The mixture was filtered, the phases separated, the organic washed with brine, dried and evaporated. The crude product was purified by column chromatography, on silica (18g), eluting with 20% ethyl acetate in hexane, to give the title compound (0.743g, 84%); m.p.80-81°C; found C, 50.86; H, 2.60; N, 9.85; Cl, 24.83%. C6H4C.NO requires C, 5θ.91; H, 2.85; N, 9.89; Cl, 25.05%; νmax
(CH2CI2) 1713, 1584, 1560, 1349, 1102, and 837cm-1; δH (CDCI3) 7.52 (1H, d, J 8.3Hz, 3'-H), 8.15 (1H, dd, J 2.3 and 8.3Hz, 4'-H), 8.87 (1H, d, J 2.3Hz, 6'-H), and 10.11 (1H, s, CHO); m/z 141/143 (M+, 75 and 25%), 140/142 (100 and 37), and 112/114 (54 and 18). (Found: M+, 140.9981. C6H4ClNO requires M, 140.9981). c) 3R,4R-Bistrimethylsilyloxy-2S-[4-(2-chloropyrid- 5-yl)-4-hydroxy-2-oxobut-1-yI]-5S-(2S,3S-epoxy-5S-tri- methyl-silyloxy-4S-methylhexyl)tetrahydropyran Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and 2-chloropyridine-5-carboxaldehyde (0.311g, 2.2mmol) were reacted to give the title compound (0.910g, 69%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 5.16-5.24 (1H, m, 1-H), 7.32 (1H, d, J 8.3Hz, 3'-H), 7.71 (1H, dt, J 8.3 and 2.3Hz, 4'-H), and 8.37 (1H, d, J 2.3Hz, 6'-H); m/z 660 (MH+, 3%), 129 (45), 117 (77), and 73 (100); m/z (FAB, 3-NOBA/Na) 682 (MNa+) and 660 (MH+). (Found: MH+, 660.2967. C30H55ClNO7Si3 requires M, 660.2978). d) 3R,4R-Bistrimethylsilyloxy-2S-[4-(2-chloropyrid- δ-yl)-2,4-dioxobut-1-yl]-5S-(2S,3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 25c (0.880g,
1.33mmol) in benzene (40ml) was reacted with manganese dioxide (1.5g) for 3h, to give the title compound (0.442g, 50%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 6.24 (1H, s, 2- H), 7.42 (1H, d, J 8.4Hz, 3'-H), 8.13 (1H, d, J 8.4 and 2.4Hz, 4'-H), and 8.85 (1H, d, J 2.4Hz, 6'-H); m/z 657 (M+, 0.3%), 117 (70), and 73 (100). (Found: M+, 657.2747. C30H52ClNO7Si3 requires M, 657.2740). The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. e) 3R,4R-Dihydroxy-2S-[4-(2-chloropyrid-5-yl)-2,4- dioxobut-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran
Using the method described in 5c, the product from 25d (0.420g,
0.64mmol) was deprotected to give the title compound (0.223g, 79%); vmax (KBr) 3443, l589, 1452, 1303, 1110, 1057, and 1015cm-1; λmax (EtOH) 316nm (εm l5,694); δH (CDCI3/CD3OD) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.22 (3H, d, J 6.4Hz, 14-H3), 6.33 (s, 2-H, partly exchanged), 7.50 (1H, d, J 8.4Hz, 3'-H), 8.20 (1H, dd, J 8.4 and 2.4Hz, 4'-H), and 8.86 (1H, d, J 2.4Hz, 6'-H); δC (CDCI3/CD3OD) 11.3 (C-17), 19.2 (C-14), 31.0 (C-9), 39.4 (C-8), 41.5 (C-4), 41.8 (C-12), 55.0 (C-10), 59.9 (C-11), 64.8 (C-16), 67.7 (C-6), 69.4 (C-13), 73.3 (C-7), 76.9 (C-5), 97.2 (C-2), 123.9 (C-3'), 129.1 (C-5'), 136.8 (C-4'), 147.7 (C-6'), 153.8 (C-2'), 177.8 (C-3), and 195.2 (C-1); m/z 441 (M+, 3%), 140/142 (100/35), and 69 (94). (Found: M+, 441.1559. C21H28CINO7 requires M, 441.1554). The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 26 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(5-hydroxymethyIfuran-2- yl)but-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran a) 5-Triethyls-Iyloxymethylfuran-2-carboxaldehyde 5-Hydroxymethylfuran-2-carboxaldehyde (0.63 lg, 5mmol) was dissolved in dry dichloromethane (10ml), cooled in an ice-bath, and triethylamine (1.0ml, 7mmol) added followed by triethylchlorosilane (1.0ml, 6mmol). After stirring for 3/4h, the mixture was evaporated. The residue was purified by column chromatography, on silica (17 g), eluting with 10% ethyl acetate in hexane, to give the title compound (1.194g, 99%); δH (CDCI3) 0.55-0.8 (6H, m, 3 x CH2), 0.85-1.15 (9H, m, 3 x CH3), 4.65 (2H, s, CH2O), 6.4 and 7.1 (2H, 2d, J 4Hz, 3 and 4-H), and 9.5 (1H, s, CHO). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-2-oxo-4-(5- triethylsiIyloxymethylfuran-2-yl)but-1-yl]-5S-(2S,3S-epoxy- 5S-trimethylsilyloxy-4S-methyIhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and 5-triethylsilyloxymethylfuran-2-carboxaldehyde (0.529g, 2.2mmol) were reacted to give the title compound (1.000g, 66%); δH
(CDCl3) inter alia 0.62 (6H, br q, 3 x CH2), 0.86-1.0 (12H, m, 17-H3 and 3 x CH3), 1.20 (3H, d, J 6.3Hz, 14-H3), 4.61 (2H, s, OCH2), 5.l3-5.20 (1H, m, 1-H), 6.19 and 6.21 (2H, 2d, J 3.2Hz, 3' and 4'-H); m/z (FAB, 3- NOBA/Na) 781 (MNa+). c) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(δ-tri- ethylsilyloxymethylfuran-2-yl)but-1-yl]-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 26b (0.975g,
1.28mmol) in benzene (70ml) was reacted with manganese dioxide (4.1g) for 3 1/2h to give the title compound (0.395g, 41%); δH (CDCI3) inter alia 0.65 (6H, br q, 3 x CH2), 0.86-1.01 (12H, m, 17-H3 and 3 x CH3), 1.20 (3H, d, J 6.4Hz, 14-H3), 4.70 (2H, s, OCH2), 6.14 (1H, s, 2-H), 6.41 (1H, d, J
3.5Hz, 4'-H), and 7.10 (1H, d, J 3.5Hz, 3'-H); m/z 756 (M+, 2%), 117 (100), and 73 (98). (Found: M+, 756.3949. C36H68O9Si4 requires M, 756.3940). The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. d) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(5-hydroxymethyl- furan-2-yl)but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methyl- hexyl)tetrahydropyran
Using the method described in 5c, the product from 26c (0.386g, 0.5mmol) was completely deprotected to give the title compound (0.153g, 72%);
νmax (KBr) 3411, 1618, 1209, 1101, and 1020cm-1; λmax (EtOH) 330nm (εm 19,562); δH (CDCI3/CD3OD) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.22 (3H, d, J 6.4Hz, 14-H3), 4.62 (2H, s, OCH2), 6.18 (s, 2-H, partly exchanged), 6.47 (1H, d, J 3.5Hz, 4'-H), and 7.16 (1H, d, J 3.5Hz, 3'-H); δC (CDCI3/CD3OD) 12.3 (C-17), 20.4 (C-14), 31.5 (C-9), 39.6 (C-8), 40.7 (C-4), 42.5 (C-12), 55.6 (C-10), 56.9 (OCH2), 60.9 (C-11), 65.4 (C-16), 68.4 (C-6), 70.1 (C-7), 70.7 (C-13), 73.9 (C-5), 96.7 (C-2), 110.0 (C-4'), 117.1 (C-3'), 149.4 (C-2'), l58.9 (C-5'), 175.4 (C-3), and 190.0 (C-1); m/z 426 (M+, 1%), 140 (100), 125 (92), and 69 (90). (Found: M+, 426.1900. C21H30O9 requires M, 426.1890). The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 27 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-nitrothien-4-yl)but-1- yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetra- hvdropvran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-4-(2-nitro- thien-4-yl)-2-oxobut-1-yI]-5S-(2S,3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and 2-nitrothiophene-4-carboxaldehyde (0.346g, 2.2mmol) were reacted to give the title compound (0.390g, 69%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 5.11-5.21 (1H, m, 1-H), 7.46-7.50 and 7.87-7.91 (2H, m, 3' and 5'-H); m/z (FAB, 3- NOBA/Na) 698 (MNa+). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(2- nitrothien-4-yl)but-1-yI]-5S-(2S,3S-epoxy-5S-tri-methyl- silyIoxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 27a (0.500g,
0.74mmol) in benzene (35ml) was reacted with manganese dioxide (1.0g) for 4 1/2h to give the title compound (0.186g, 37%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H3), 6.08 (1H, s, 2-H), 8.14 and 8.23 (2H, 2d, 1 1.7Hz, 3' and 5'-H); m/z (FAB, thioglycerol) 674 (MH+); m/z (FAB, 3-NOBA/Na) 718 (M + 2Na-H+). The Η n.m.r.
spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-nitrothien-4-yl) hut-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)
tetrahydropyran
Using the method described in 5c, the product from 27b (0.170g,
0.25mmol) was deprotected to give the title compound (0.095g, 83%); νmax (KBr) 3423, 1604, l534, 1506, 1336, 1111, and 1052cm-1; λmax (EtOH) 311nm (εm 20,545); δH (CDCI3) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.22 (3H, d, J 6.3Hz, 14-H3), 6.09 (1H, s, 2-H), 8.16 and 8.22 (2H, 2d, J 1.7Hz, 3' and 5'-H); δC (CDCI3/CD3OD) 12.4 (C-17), 20.4 (C-14), 31.9 (C- 9), 40.1 (C-8), 42.1 (C-4), 42.7 (C-12), 55.9 (C-10), 61.0 (C-11), 65.8 (C-16), 68.6 (C-6), 70.2 (C-7), 70.6 (C-13), 74.2 (C-5), 98.1 (C-2), 126.7 and 134.5 (C-3' and 5'), 137.8 (C-4'), 152.7 (C-2'), 175.8 (C-3), and 195.1 (C-1); m/z (FAB, thioglycerol) 475 (MNH4 +) and 458 (MH+); m/z (FAB, 3-NOBA/Na) 502 (M + 2Na-H+) and 480 (MNa+).
Example 28 3R,4R-Dihydroxy-2S-[4-(2-bromopyrid-5-yl)-2.4-dioxobut-1- yl] -5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetra- hydropyran a) N-Methoxy, N-methyl-2-bromopyridine-5-carboxamide
Using the method described in 25a, 2-bromopyridine-5-carboxylic acid (2.02g, 10mmol) was reacted to give the title compound (1.637g, 67%); δH (CDCI3) 3.35 and 3.55 (6H, 2s, 2 x CH3), 7.55 (1H, d, J 8Hz, 3'-H), 7.9 (1H, dd, J 8 and 2Hz, 4'-H), and 8.7 (1H, d, J 2Hz, 6'-H). b) 2-Bromopyridine-5-carboxaldehyde
Using the method described in 25b, N-methoxy, N-methyl-2- bromopyridine-5-carboxamide (1.60g, 6.53mmol) was reacted to give the title compound (1.042g, 86%); m.p.103.5-104°C (chloroform/hexane); found C, 38.72; H, 2.09; N, 7.53; Br, 42.62%. C6H4BrNO requires C, 38.74; H, 2.17; N, 7.53; Br. 42.96%; δH [(CD3)2CO] 7.8 (1H, d, J 8Hz, 3'-H), 8.15 (1H, dd, J 8 and 2Hz, 4'-H), 8.85 (1H, d, J 2Hz, 6'-H), and 10.15 (1H, s, CHO). c) 3R,4R-BistrimethylsilyIoxy-2S-[4-(2-bromopyrid-5- yl)-4-hydroxy-2-oxobut-1-yl]-5S-(2S,3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahydropyran Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and 2-bromopyridine-5-carboxaldehyde (0.409g, 2.2mmol) were reacted to give the title compound (0.729g, 52%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 5.l3-5.22 (1H, m, 1-H), 7.47 (1H, d, J 8.2Hz, 3'-H), 7.58-7.64 (1H, m, 4'-H), and 8.35 (1H, d, J 2.3Hz, 6'-H); m/z (NH3, DCI) 706/704 (MH+, 10%), 186/188 (50), 108 (50), and 90 (100). d) 3R,4R-BistrimethylsiIyloxy-2S-[4-(2-bromopyrid-5- yl)-2,4-dioxobut-1-yI]-5S-(2S,3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 28c (0.721g,
1.02mmol) in benzene (40ml) was reacted with manganese dioxide (1.44g) for2½ hours to give the title compound (0.320g, 45%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 6.24 (1H, s, 2-H), 7.59 (1H, d, J 8.3Hz, 3'-H), 8.01 (1H, dd, J 8.3 and 2.5Hz, 4'-H), and 8.82 (1H, d, J 2.5Hz, 6'-H); m /z 701/703 (M+, 1%), 409/411 (5), 117 (100), and 73 (97). (Found: M+, 701.2232. C30H52BrNO7Si3 requires M,
701.2235). The 1H n.m.r. spectrum indicated that the compound was essentially in the enolic form. e) 3R,4R-Dihydroxy-2S-[4-(2-bromopyrid-5-yl)-2.4-dioxo
but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran
Using the method described in 5c, the product from 28d (0.310g,
0.44mmol) was deprotected to give the title compound (0.090g, 42%);
m.p.133-134°C; found C, 5l.53; H, 5.85; N, 2.94%; C21H28BrNO7 requires C, 51.86; H, 5.80; N, 2.88%; νmax (KBr) 3435, l576, 1452, 1096, 1057, and 1013cm-1; λmax (EtOH) 313 (εm 18,198) and 248nm (8,079); δH (CD3OD) inter alia 0.94 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.4Hz, 14-H3).6.47 (1H, s, 2-H), 7.73 (1H, d, J 8.5Hz, 3'-H), 8.16 (1H, dd, J 8.5 and 2.4Hz, 4'-H), and 8.86 (1H, d, J 2.4Hz, 6'-H); δC (CD3OD) 12.3 (C-17), 20.3 (C-14), 33.0 (C-9), 41.8 (C-8), 43.2 (C-4), 43.7 (C-12), 56.9 (C-10), 61.2 (C-11), 66.4 (C-16), 69.8 (C-6), 70.7 (C-13), 71.5 (C-7), 75.4 (C-5), 99.1 (C-2), 129.6 (C-3'), 131.5 (C-5'), 138.4 (C-4'), 146.4 (C-2'), 149.8 (C-6'), 179.7 (C-1), and 197.8 (C-3); m/z (NH3 DCI) 486/488 (MH+, 30%), 200/202 (35), and 122 (100); m/z 485/487 (M+, 2%), 226/228 (48), 200/202 (70),
184/186 (80), 71 (85), and 69 (100). (Found: M+, 485.1022. C21H28BrNO7 requires M, 485.1049). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. Example 29 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(5-methoxyfuran-2-yl)but-1- yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetra- hydropyran a) 5-Methoxyfuran-2-carboxaldehyde n-Butyllithium (1.5M, 7.3ml, 11mmol) was added slowly to
diisopropylamine (1.5ml, 10.5mmol) in THF (20ml) at -30°C. Stirred for 10 mins, cooled to -70°C, and 2-methoxyfuran (0.98 lg, 10mmol) in THF (8ml) added slowly. After stirring for ½ h dimethylformamide (2.4ml, 30mmol) was added, and the mixture stirred for a further 1h. After quenching with saturated aqueous ammonium chloride, the mixture was extracted with dichloromethane (x2). The combined organic extracts were washed with brine, dried and carefully evaporated. The residue was purified twice by flash chromatography, eluting with ether/hexane mixtures, to give the title compound (0.463g, 37%); δH (CDCI3) 4.05 (3H, s, OCH3), 5.55 (1H, d, J 4Hz, 4-H), 7.3 (1H, d, J 4Hz, 3-H), and 9.35 (1H, s, CHO). b) 3R,4R-BistrimethylsiIyloxy-2S-[4-hydroxy-4-(5- methoxyfuran-2-yl)-2-oxobut-1-yI]-δS-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and 5-methoxyfuran-2-carboxaldehyde (0.29g, 2.2mmol) were reacted to give the title compound (1.055g, 82%); δH (CDCI3) inter alia 0.9 (3H, d, J 7Hz, 17-H3), 1.2 (3H, d, J 6Hz, 14-H3), 3.8 (OCH3), 4.9-5.15 (2H, m, 1-H and 4'-H), and 6.1 (1H, d, J 4Hz, 3'-H). The product was unstable, and readily dehydrated. c) 3R,4R-Bistrimethylsylyloxy-2S-[2,4-dioxo-4-(methoxy- furan-2-yl)but-1-yI]-δS-(2S,3S-epoxy-5S-trimethylsilyloxy-
4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 29b (1.01g, 1.57mmol) in benzene (40ml) was reacted with manganese dioxide (3.0g) for 4 hours to give the title compound (0.159g, 16%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 3.96 and 3.97 (OCH3), 5.39 (0.8H, d, J 3.6Hz) and 5.41 (0.2H, d, J 3.8Hz, 4'-H), 5.98 (0.8H, s, 2-H), and 7.14 (0.8H, d, J 3.6Hz) and 7.23 (0.2H, d, J 3.8Hz, 3'-H); m/z (NH3 DCI) 643 (MH+, 22%) and 90 (100); m/z 643 (MH+, 3%), 125 (50), 117 (100), and 73 (72). (Found: MH+, 643.3140. C30H55O9Si3 requires MH+ 643.3154). d) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(5-methyoxyfuran-2- yl)but-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran
Using the method described in 5c, the product from 29c (0.146g,
0.23mmol) was deprotected to give the title compound (0.080g, 82%); νmax (KBr) 3432, 1718, 1627, 1523, 1426, and 1042cm-1; λmax (EtOH) 347nm (εm 16,692); δH (CD3OD) inter alia 0.94 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H3), 3.97 (OCH3), 5.59 (1H, d, J 3.7Hz, 4'-H), 6.01 (1H, s, 2-H), and 7.29 (1H, d, J 3.7Hz, 3'-H); δC (CD3OD) 12.3 (C-17), 20.4 (C-14), 33.0 (C-9), 40.6 (C-4), 41.7 (C-8), 43.8 (C-12), 56.9 (C-10), 58.9 (OCH3), 61.3 (C-11), 66.5 (C-16), 69.7 (C-6), 70.8 (C-13), 71.5 (C-7), 74.4 and 75.5 (C-5), 85.6 (C-4'), 96.7 (C-2), 122.3 (C-3'), 142.2 (C-2'), 166.4 (C-5'), 178.2 (C-1), and 187.0 (C-3); m/z (NH3 DCI) 427 (MH+, 100%); m/z 426 (M+, 3%), 140 (60), and 125 (100). (Found: M+, 426.1892. C21H30O9 requires M, 426.1890). The n.m.r. spectra indicated that the title compound was mainly in the enolic form, but contained 20-40% ofthe diketone.
Example 30 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-(piperidin-1-yl)- pyrimidin-5-yl)but-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S- methylhexyl)tetrahydropyran a) 2-(l)iperidin-1-yl)pyrimidine-5-carboxaldehyde 5-Bromo-2-chloropyrimidine was converted to 5-bromo-2-(piperidin-1- yl)pyrimidine using the method of Nasielski et al (Tetrahedron 1972, 28., 3767). Using the method described in 21a, 5-bromo-2-(piperidin-1- yl)pyrimidine (3.63g, 15mmol) was converted to the title compound (1.23g, 43%); δH (CDCI3) 1.5-1.8 (6H, m, 3',4',5'-CH2), 3.8-4.1 (4H, m, 2 x NCH2), 8.65 (2H, s, 4' and 6'-H), and 9.7 (1H, s, CHO). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-2-oxo-4-(2- (piperidin-1-yl)pyrimidin-5-yl)but-1-yl]-δS-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and 2-(piperidin-1-yl)pyrimidine-5-carboxaldehyde (0.421g,
2.2mmol) were reacted to give the title compoimd (1.140g, 80%); δH
(CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.4Hz, 14-H3), 1.48-1.90 (9H, m, 9-H2, 8-H, 3 x CH2), 3.72-3.98 (7H, m,
16,13,7-H and 2 x NCH2), 4.98-5.08 (1H, m, 1-H), and 8.30 (2H, s, 4' and 6'-H); m/z (NH3 DCI) 710 (MH+, 20%), 192 (100), and 91 (82); m/z 710 (MH+, 3%), 709 (M+, 2), 191 (70), 129 (82), and 117 (100). (Found: M+, 709.3981. C34H63N3O7Si3 requires M, 709.3974). c) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(2- (piperidin-1-yl)pyrimidin-5-yl)but-1-yI]-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 30b (1.12g, 1.58mmol) in benzene (70ml) was reacted with manganese dioxide (3.0g) for 4 hours to give the title compound (0.681g, 61%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 1.5-1.9. (9H, m, 9-H2, 8-H, 3 x CH2), 3.7-3.95 (7H, m, 16,13,7-H and 2 x NCH2), 6.06 (1H, s, 2-H), and 8.77 (2H, s, 4' and 6'-H); m/z (NH3 DCI) 708 (MH+, 7%), 147 (97), 91 . (100), and 74 (95); m/z 707 (M+, 1%), 190 (98), and 73 (100). (Found: M+, 707.3820. C34H61N3O7Si3 requires M, 707.3817). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. d) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-fpiperidin-1-yl)- pyrimidine-5-yl)but-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S- methylhexyl)tetrahydropyran
Using the method described in 5c, the product from 30c (0.655g,
0.92mmol) was deprotected to give the title compound (0.388g, 85%);
found C, 60.72; H, 7.75; N, 8.49%. C25H37N3O7 requires C, 61.08; H, 7.59; N, 8.55%; vmax (KBr) 3466, 1609, 1641, 1269, 1254, and 803cm-1; λmax (EtOH) 348nm (εm 33,937); δH (CDCI3/CD3OD) inter alia 0.93 (3H, d, J 7.1Hz, 17-H3), 1.22 (3H, d, J 6.3Hz, 14-H3), 1.58-1.90 (8H, m, 9-H2 and 3 x CH2), 3.74-4.0 (8H, m, 5,7,13,16-H and 2 x NCH2), 6.08 (1H, s, 2-H), and 8.77 (2H, s, 4' and 6'-H); δC (CDCI3/CD3OD) 12.4 (C-17), 20.4 (C-14), 24.8 (C-4"), 26.0 (C-3" and 5"), 31.9 (C-9), 40.0 (C-8), 41.3 (C-4), 42.7 (C-12), 45.4 (C-2" and 6"), 55.9 (C-10), 61.1 (C-11), 65.8 (C-16), 68.7 (C-6), 70.2 (C-7), 70.6 (C-13), 74.3 (C-5), 95.6 (C-2), 116.3 (C-5'), 168.0 (C-4' and 6'), 161.9 (C-2'), 182.1 (C-1), and 190.8 (C-3); m/z 491 (M+, 7%), 232 (36), 206 (54), 204 (56), and 190 (100). (Found: M+, 491.2602.
C25H37N3O7 requires M, 491.2630). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 31 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(1-methyl-2-methylthio- imidazol-4-yl)but-1-yl]-6S-(2S,3S-epoxy-6S-hydroxy-4S- methylhexyl)tetrahydropyran a) Ethyl 1-methyI-2-methylthioimidazole-4-carboxylate
Ethyl 2-mercaptoimidazole-4(5)-carboxylate (10.0g, 58mmol) was dissolved in dry DMF (200ml), and sodium hydride (80% in oil, 3.5g, 116mmol) added slowly with cooling. The mixture was stirred for 1h under argon, cooled in an ice bath, and methyl iodide (14.4ml, 232mmol) added. The reaction was then stirred overnight, diluted with water (200ml) and extracted with ethyl acetate (6 x 100ml). The combined organic extracts were washed with brine, dried and evaporated. The crude product was separated by flash chromatography eluting with 32-44% ethyl acetate in hexane, to give (a) the 1,2,5-isomer (3.742g, 32%), and (b) the title compound (4.261g, 37%); δH (CDCI3) 1.35 (3H, t, J 7Hz, CH3). 2.6 (3H, s, SCH3), 3.6 (3H, s, NCH3), 4.3 (2H, q, J 7Hz, CH2), and 7.55 (1H, s, 5-H). The assignments of the structures were confirmed by n.O.e. studies. b) 1-Methyl-2-methylthioimidazole-4-carboxaldehyde
Ethyl 1-methyl-2-methylthioimidazole-4-carboxylate (1.97g, 9.8mmol) was dissolved in dry THF (80ml) under argon, then diisobutylaluminium hydride (1.0M in toluene, 22ml, 22mmol) was added slowly. The mixture was stirred at room temperature for 1½ h, and at reflux for ½ h. The reaction was cooled, quenched with methanol (25ml) and saturated sodium sulphate (31ml), and stirred for l5 minutes. The mixture was then filtered, washing well with ethyl acetate, and the filtrate extracted with ethyl acetate (x4). The combined organic extracts were dried and evaporated to give crude 4-hydroxymethyl-1-methyl-2- methylthioimidazole (1.43g, 92%). This material was dissolved in dry chloroform (70ml), activated
manganese dioxide (1.5g) added and the mixture stirred for 30 minutes. Only a little reaction had occurred, so 4A sieves (4g) were added, followed portionwise by more manganese dioxide (3.5g). After stirring overnight the reaction was complete. The mixture was filtered, washing the manganese dioxide thoroughly with chloroform and dichloromethane, and the filtrate evaporated. The residue was purified by column
chromatography on silica (38g), eluting with 90-100% ethyl acetate in hexane, to give the title compound as a white solid (1.183g, 84%; 77% overall); νmax (CH2Cl2) 1680, 1640, 1320, and 1130cm-1; δH (CDCI3) 2.68 (3H, s, SCH3), 3.66 (3H, s, NCH3), 7.68 (1H, s, 5-H), and 9.7 (1H, s, CHO). c) 3R,4R-Bistrimethylsilyloxy-2-[4-hydroxy-4-(1-methyl-2- methylthioimidazol-4-yl)-2-oxobut-1-yI]-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and 1-methyl-2-methylthioimidazole-4-carboxaldehyde were reacted to give the title compound (1.050g, 78%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.4Hz, 14-H3), 2.67 (3H, s, SCH3), 3.58 (3H, s, NCH3), 5.10-6.18 (1H, m, 1-H), and 6.88 (1H, s, 5'-H); m/z (NH3 DCI) 675 (MH+, 40%) and 157 (100); m/z 674 (M+, 1%), 156 (50), 129 (62), and 117 (100). (Found: M+, 674.3267. C30H58N2O7SSi3 requires M, 674.3273). d) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(1- methyl-2-methyIthioimidazol-4-yl)but-1-yl]-5S-(2S,3S- epoxy-5S-trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 31c (1.03g, 1.50mmol) in benzene (70ml) was reacted with manganese dioxide (2.0g) for 2 hours to give the title compound (0.656g, 64%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 2.66 (3H, s, SCH3), 3.62 (3H, s, NCH3), 6.44 (1H, s, 2-H), and 7.55 (1H, s, 5'-H); m/z (NH3 DCI) 673 (MH+ 100%); m/z 673 (MH+, 2%), 672 (M+, 1%), 197 (30), 155 (53), 117 (50), and 73 (100). (Found: M+, 672.3125. C30H56N2O7SSi3 requires M, 672.3116). e) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(1-methyl-2-methyl- thioimidazol-4-yl)but-1-yl]-5S-(2S,3S-epoxy-6S-hydroxy-4S- methylhexyl)tetrahydropyran Using the method described in 5c, the product from 31d (0.240g,
0.36mmol) was deprotected to give the title compound (0.140g, 85%); νmax (KBr) 3426, 1616, 1451, 1379, 1332, 1135, 1108, and 1055cm-1; λmax (EtOH) 328nm (εm 17,229); δH (CDCI3) inter alia 0.93 (3H, d, J 7.1Hz, 17-H3), 1.22 (3H, d, J 6.3Hz, 14-H3), 2.66 (3H, s, SCH3), 3.64 (3H, s, NCH3), 6.44 (1H, s, 2-H), and 7.58 (1H, s, 5'-H); δC (CDCI3) 12.6 (C-17),
16.1 (SCH3), 20.7 (C-14), 31.6 (C-9), 33.6 (NCH3), 39.5 (C-8), 42.2 (C-4), 42.8 (C-12), 55.7 (C-10), 61.3 (C-11), 65.6 (C-16), 69.1 (C-6), 70.3 (C-7),
71.2 (C-13), 73.9 (C-5), 96.9 (C-2), 126.3 (C-5"), 137.9 (C-4'), 146.7 (C-2"), 178.5 (C-1), and 193.2 (C-3); m/z (NH3 DCI) 457 (MH+, 100%); m/z 456 (M+, 2%), 170 (75) and 155 (100). (Found: M+, 456.1922. C21H32N2O7S requires M, 656.1930). The 1H n.m.r. spectrum indicated that the title compound was mainly in the enolic form (17% ofthe diketone present). Example 32 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methoxyphenyl)but-1-yI]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-(2-methoxyphenyl)- 4-hydroxy-2-oxobut-1-yI]-5S-(2S,3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahydropyran Using the method described in 5a, tristrimethylsilylmonone (0.725g,
1.4mmol) and 2-methoxybenzaldehyde (218mg, 1.68mmol) were reacted to give the title compound (600mg, 65%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 3.83 (3H, s, OMe), 4.08-4.19 (1H, m, H-5), 5.36-5.60 (1H, m, H-1), 6.85 (1H, d, J 8.1Hz, H-3'), 6.98 (1H, t, J 7.2Hz, H-5'), 7.24 (1H, dt, J 1.6 and 8.0Hz, H-4'), 7.48 (1H, d, J 7.4Hz, H-6'). (Found: M+, 664.3456. C32H58O8Si3 requires M, 654.3440). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(2- methoxyphenyl)but-1-yI]-5S-(2S,3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 32a (600mg,
0.92mmol) in benzene (50ml) was reacted with manganese dioxide (1.5g) for 3 hours to give the title compound (260mg, 43%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 3.92 (3H, s, OMe), 6.53 (1H, s, 2-H), 6.96 (1H, d, J 8.3Hz, 3'-H), 7.02 (1H, t, J 7.7Hz, 5'-H), 7.43 (1H, dt, J 1.8 and 8.3Hz, 4'-H), 7.88 (1H, dd, J 1.8 and 7.8Hz, 6'-H). (Found: M+, 652.3293. C32H5608Si3 requires M, 652.3283). c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methoxyphenyl)- but-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetra- hydropyran
Using the method described in 5c, the product from 32b (250mg,
0.38mmol) was deprotected to give the title compound (142mg, 85%); νmax (KBr) 3431, 1718, 1603, 1489cm-1; λmax (EtOH) 326.5nm (εm 12,445), 306 (11,456), 253.5 (4,740); δH (CDCI3) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 3.92 (3H, s, OMe), 6.58 (1H, s, 2-H), 6.97 (1H, d, J 8.3Hz, 3'-H), 7.04 (1H, t, J 7.7Hz, 5'-H), 7.45 (1H, dt, J 1.8 and 8.3Hz, 4'-H), 7.91 (1H, dd, J 1.8 and 7.8Hz, 6'-H); δC (CDCl3) 12.7 (C-17), 20.7 (C-14), 31.6 (C-9), 39.5 (C-8), 42.8 (C-12), 43.3 (C-4), 55.7 (C-10), 55.7 (ArOMe), 61.3 (C-11), 65.6 (C-16), 69.3 (C-7), 70.3 (C-6), 71.3 (C-13), 73.7 (C-5), 102.4 (C-2), 111.7 (C-5'), 123.4 (C-1') , 130.2 (C-3'), 133.2 (C-6"), 168.6 (C-2'), 180.1 (C-1), 196.7 (C-3). (Found: M+, 437.2164.
C23H33O8 requires M, 437.2175). The IH n.m.r. spectrum indicated that the title compound was essentially in the enolic form. Example 33 3R,4R-Dihydroxy-2S-r2.4-dioxo-4-(4-methylthiophenyl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-(4-methylthio- phenyl)-4-hydroxy-2-oxobut-1-yI]-5S-(2S,3S-epoxy-6S- trimethyl-siIyIoxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (2.175g, 4.2mmol) and 4-methylthiobenzaldehyde (0.64ml, 4.8mmol) were reacted to give the title compound (2.12g, 75%); δH (CDCl3) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, si 6.3Hz, 14-H3), 2.48 (3H, s, ArSMe), 4.05- 4.18 (IH, m, 5-H), 5.08-5.20 (1H, m, l-H), 7.20-7.34 (4H, m, Ar); m/z (FAB) 693 (_yTNa+). b) 3R,4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(4- methyIthiophenyl)but-1-yl1-5S-(2S,3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahydropyran Using the method described in 6b, the product from 33a (2.12g, 3.16mmol) in benzene (150ml) was reacted with manganese dioxide (4.2g) for 2 hours to give the title compound (1.3g, 62%); δH (CDCI3) inter alia 0.89 (3H, d, s∑ 7.1Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 2.52 (3H, s, ArSMe), 6.23 (1H, s, 2-H), 7.26 (2H, d, 18.6Hz, 3',5'-H2), 7.80 (2H, d, J 8.6Hz, 2',6'-H2).
(Found: M+, 668.3060. C32H56O2SSi requires M, 668.3055). c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methylthio- phenyl)but-1-yl] -5S-(2S,3S-epoxy-5S-hydroxy-4S-methyl- hexyl)t etrahydropyran
Using the method described in 5c, the product from 33b (250mg,
0.37mmol) was deprotected to give the title compound (144mg, 85%); νmax (KBr) 3425, 1591, 1488, 1436, 1267cm-1; λmax (EtOH) 337nm
(εm 27,090), 239 (5,680); δH (CDCl3) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.21 (3H, d, J 6.3Hz, 14-H3), 2.35 (3H, s, ArSMe), 6.23 (1H, s, 2-H), 7.26 (2H, d, J 8.6Hz, 3',5'-H2), 7.80 (2H, d, J 8.6Hz, 2',6'-H2); δC (CDCI3) 11.9 (C-17), 14.5 (ArSMe), 20.0 (C-14), 31.5 (C-9), 39.6 (C-8), 41.9 (C-4), 42.3 (C-12), 55.5 (C-10), 60.7 (C-11), 66.4 (C-16), 68.3 (C-7), 69.9 (C-6), 70.3 (C-13), 73.8 (C-5), 96.6 (C-2), 125.1 (C-3',5'), 127.2 (C-2',6'), 130.5 (C-1'), 144.9 (C-4'), 181.9 (C-1), 194.1 (C-3). (Found: M+, 452.1867. C23H32O7S requires M 452.1869). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 34 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methylsulphinyl-phenyl)- but-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methyl-hexyl)- tetrahydropyran
Using the method described in 23, the product from 33c (200mg, 0.3mmol) was reacted to give the pure product (175mg, 85%). This material was deprotected using the method described in 5c to give the title compound (154mg, 45%); νmax (KBr) 3417, 1600, 1560, 1451, 1292cm-1; λmax
(EtOH) 317nm (εm 17,420), 225 (7,480); δH (CDCI3) inter alia, 0.90 (3H, d, J 7.1Hz, 17-H3), 1.22 (3H, d, J 6.3Hz, 14-H3), 2.77 (3H, s, ArS(O)Me), 6.30 (1H, s, 2-H), 7.72 (2H, d, J 8.4Hz, 3',5'-H2), 8.03 (2H, d, J 8.4Hz, 2',6'-H2); δC (CDCI3) 12.7 (C-17), 20.6 (C-14), 31.6 (C-9), 39.6 (C-8), 42.8 (C-12 and C-4), 43.6 (ArS(O)Me), 65.6 (C-10), 61.1 (C-11), 65.6 (C-16), 66.8 (C-7), 70.3 (C-6), 71.2 (C-13), 73.7 (C-5), 98.0 (C-2), 123.9 (C-3',5'), 128.0 (C-2',6'), 137.2 (C-1'), 149.5 (C-4'), 180.1 (C-1), 196.7 (C-3); m/z (FAB) 491 (MNa+), 469 (MH+). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 35 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methylsulphonyl-phenyl)- but-1-yl)-6S-(2S,3S-epoxy-5S-hydroxy-4S-methyl-hexyl)- tetrahydropyran
Using the method described in 24, the product from 34c (200mg, 0.3mmol) was reacted to give the pure product (l55mg, 74%). This material was deprotected using the method described in 5c to give the title compound (90mg, 92%); νmax (KBr) 3496, 3438, 1622, 1602cm-1; λmax (EtOH) 317.5nm (εm 14,610), 239 (8,540); δH (CD3OD) inter alia 0.94 (3H, d, J 7.1Hz, 17-H3), 1.21 (3H, d, J 6.3Hz, 14-H3), 3.13 (3H, s, ArSO2Me), 6.37 (approx. 1H, s, exch, 2-H), 7.92-8.17 (4H, m, Ar); m/z (FAB) 485 (MH+). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 36 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(3-cyanophenyl)but-1-yl- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-r4-(3-cyanophenyl)-4- hydroxy-2-oxobut-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy- 4S-methylhexyl)tetrahydropyran
Using the method described in 5a, and on the same scale, 3- cyanobenzaldehyde (4.19mg, 3.2mmol) was reacted to give the title compound (1.46g, 80%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 5.13-5.26 (1H, m, 1-H), 7.48-7.62 (3H, m), 7.70 (1H, s, 2'-H); m/z (NH3 DCI), 667 (MNH4 +, 50%), 650 (MH+, 10%), 536 (100). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(3- cyanophenyl)but-1-yI]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy- 4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 36a (1.45g, 2.23mmol) in benzene (120ml) was reacted with manganese dioxide (2.18g) for 3½ h to give the title compound (574mg, 40%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H3), 6.26 (1H, s, 2-H), 7.68 (1H, t, J 7.8Hz, 5'-H), 7.79 (1H, dd, J 1.2 and 7.7Hz, 4'-H), 8.10 (1H, dd, J 1.0 and 6.7Hz, 6'-H), 8.16 (1H, d, J 1.4Hz, 2'-H); m/z 648 (MH+). c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(3-cyanophenyl)but- 1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetra- hydropyran
Using the method decribed in 5c, the product from 36b (550mg, 0.55mmol) was deprotected to give the title compound (315mg, 86%); νmax (KBr) 3439, 2232, 1610, 1670, 1452cm-1; λmax (EtOH) 312.5nm (εm 14,620), 239.5 (9,990); δH (CDCl3) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3) 1.22 (3H, d, J 6.3Hz, 14-H3), 6.27 (1H, s, 2-H), 7.60 (1H, t, J 7.8Hz, 5'-H), 7.80 (1H, d, with further fine coupling, J 7.8Hz, 4'-H), 8.10 (1H, d, with further fine coupling, J 8.0Hz, 6'-H), 8.16 (1H, d, J 1.2Hz, 2'-H); δC (CDCI3) 12.9 (C-17), 21.0 (C-14), 31.8 (C-9), 39.9 (C-8), 42.9 (C-4), 43.0 (C-12), 65.8 (C-10), 61.4 (C-11), 65.8 (C-16), 69.0 (C-6), 70.5 (C-13), 71.5 (C-7), 74.1 (C-5), 98.0 (C-2), 113.3 (C-1'), 118.2 (C-3'), 129.8 (C-2'), 130.9 (C-4'), 131.3 (C-6'), 135.4 (C-5'), 136.0 (CN), 179.6 (C-3), 196.9 (C-1). (Found: M+ 431.1949. C23H29NO7 requires M 431.1944). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 37 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-trifluoromethoxy- phenyl)but-1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methyl- hexyl)-tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-r4-(4-trifluoro- methoxyphenyl)-4-hydroxy-2-oxobut-1-yI]-5S-(2S,3S-epoxy-
5S-trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilymonone (1.45mg, 2.8mmol) and 4-trifluoromethoxybenzaldehyde (608mg, 3.2mmol) were reacted to give the title compound (1.52g, 76%); δH (CDCI3) inter alia 0.93 (3H, d, J 7.1Hz, 17-H3), 1.23 (3H, d, J 6.4Hz, 14-H3), 4.07-4.18 (1H, m, 5-H), 5.10-5.22 (1H, m, 1-H), 7.18-7.28 (2H, m, 3',5'-H2), 7.38-7.49 (2H, m, 2',6'-H2); m/z (NH3 DCI) 726 (MNH4 +, 30%), 90 (100%). [Found: MH+, 709.3239. C31H55O8F3Si3 requires MH, 709.3235.] b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(4- trifluoromethoxyphenyl)but-1-yl]-5S-(2S,3S-epoxy-5S-tri- methylsilyIoxy-4S-methylhexyl)tetrahydropyran Using the method described in 6b, the product from 37a (1.5g, 2.15mmol) in benzene (120ml) was reacted with manganese dioxide (3g) for 1½ hours to give the title compound (772mg, 51%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, 16.4Hz, 14-H3), 4.08-4.20 (1H, m, 5-H), 6.24 (1H, s, 2-H), 7.22-7.34 (2H, m, 3',5'-H2), 7.93 (2H, d, J 8.8Hz,
2',6'-H2); m/z 707 (MH+, 8%), 73 (100). [Found: MH, 707.3072.
C31H59O8F3Si3 requires MH, 707.3079.] c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-trifluoro- methoxyphenyl)but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S- methylhexyl)tetrahydropyran
Using the method described in 5c, the product from 37b (750mg,
1.06mmol) was deprotected to give the title compound (350mg, 74%); νmax (KBr) 3496, 1624, 1583, 1506, 1441cm-1; λmax (EtOH) 311nm
(εm 16,860), 243.5 (6730); δH (CDCI3) inter alia 0.93 (3H, d, J 7.0Hz,
17-H3), 1.21 (3H, d, J 6.3Hz, 14-H3), 6.24 (1H, s, 2-H), 7.24-7.35 (2H, m, 3',5'-B2), 7.92 (2H, d, J 8.8Hz, 2',6'-H2); δC (CDCI3) 12.7 (C-17), 20.8 (C-14), 31.6 (C-9), 39.7 (C-8), 42.7 (C-4), 42.9 (C-12), 55.7 (C-10), 65.7 (C-16), 69.0 (C-7), 70.3 (C-6), 71.4 (C-13), 73.9 (C-5), 97.5 (C-2), 120.6 (C-3',5'), 129.0 (C-2',6'), 132.9 (C-1'), 152.2 (C-4'), 180.9 (C-1), 196.0 (C-3); m/z 491 (MH+, 30%), 189 (100). [Found: MH+, 491.1893. C23H30O8F3 requires MH, 491.1893.] The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. Example 38
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-fluorophenyl)but-1-yI]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-(4-fluorophenyl)-4- hydroxy-2-oxobut-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy- 4S-methylhexyl)tetrahydropyran Using the method described in 5a, tristrimethylsilylmonone (1.45g, 2.8mmol) and 4-fluorobenzaldehyde (0.34ml, 3.2mmol) were reacted to give the title compound (l.5g, 83%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 4.08-4.17 (1H, m, 5-H), 5.11- 5.22 (1H, m, 1-H), 7.03 (2H, t, J 8.7Hz, 3',5'-H2), 7.30-7.41 (2H, m,
2,,6'-H2); m/z (NH3 DCI) 660 (MNH4 +, 52%), 643 (MH+, 15), 90 (100). [Found: MH+, 643.3811. C31H55O7FSi3 requires MH, 643.3318.] b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(4-fluorophenyl)but-1- yl]-5S-(2S,3S-epoxy-6S-trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 38a (l.5g, 2.34mmol) in benzene (70ml) was reacted with manganese dioxide (3.0g) for 1½ hours to give the title compound (890mg, 69%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H3), 4.06-4.18 (1H, m, 5-H), 6.22 (1H, s, 2-H), 7.13 (2H, t, J 8.7Hz, 3',5'-H2), 7.91 (2H, dd, J 5.4 and 8.7Hz, 2',6'-H2); m/z (NH3 DCI) 641 (MH+). [Found: MH+, 641.3167. C31H54O7FSi3 requires MH, 641.3161.] c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-fluorophenyl)but-1-yl] -5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5c, the product from 38b (400mg,
0.625mmol) was deprotected to give the title compound (215mg, 81%); νmax (KBr) 3427, 1603, 1605, 1452cm-1; λmax (EtOH) 310nm
(εm 15,800), 248.5 (5,785); δH (CDCI3) inter alia 0.93 (3H, d, J 7.1Hz, 17-H3), 1.21 (3H, d, J 6.3Hz, 14-H3), 6.22 (1H, s, 2-H), 7.13 (2H, t, J
8.7Hz, 3',5'-H2), 7.90 (2H, dd, J 5.4 and 8.7Hz, 2',6'-H2); δC (CDCI3) 12.8 (C-17), 20.8 (C-14), 31.6 (C-9), 39.7 (C-8), 42.6 (C-4), 42.9 (C-12), 55.7 (C-10), 61.3 (C-11), 65.7 (C-16), 69.0 (C-7), 70.3 (C-6), 71.4 (C-13), 73.9 (C-5), 97.2 (C-2), 115.8 (d, J 23Hz, C-3',5'), 129.6 (d, J 9Hz, C-2',6'), 130.7 (d, J 3Hz, C-1'), 165.4 (d, J 252Hz, C-4'), 181.8 (C-1), 195.1 (C-3); m/z
(NH3 DCI) 425 (MH+, 15%), 79 (100). [Found: MH+, 425.1968.
C22H30O7F requires MH, 425.1976.] The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
EXAMPLE 39 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-hydroxyphenyl)but-1 -yl] -5S-(2S,3S- epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 4-Triethylsilyloxybenzaldehyde
A suspension of 4-hydroxybenzaldehyde (610mg, 5mmol) in
dichloromethane (30ml) at 5° under argon was treated with triethylamine (0.84ml, 6mmol) followed by triethylsilyl chloride (1ml, 6mmol). After 30 minutes ether was added and the mixture filtered through Kieselguhr. The filtrate was washed with brine, dried (MgS04) and evaporated to give the title aldehyde (1.1g) as an orange oil; δ(CDCl3) 0.65-1.42 (15H, m), 6.96 (2H, d, J 9Hz), 7.83 (2H, d, J 9Hz), 9.95 (1H, s). This material was sufficiently pure for further synthetic manipulations. b) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-2-oxo-4-(4-triethyl- silyloxyphenyl)but-1-yI]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 5a, 4-triethylsilyloxy-benzaldehyde
(520mg, 2mmol) and tris trimethylsilylmonone (1.04g, 2mmol) were reacted to give the title compound (1.2g, 80%); δH (CDCI3) inter alia 0.66- 0.82 (6H, m, Si(CH2CH3)3), 0.89 (3H, d, J 7.0Hz, 17-H3), 0.99 (9H, t, J
7.4Hz, Si(CH2CH3)3), 4.08-4.17 (1H, m, 5-H), 5.05-5.16 (1H, m, 1-H), 6.84
(2H, d, J 8.5Hz, 3',5'-H2), 7.18-7.27 (2H, m, 2',6'-H2); m/z (FAB; 3- NOBA/Na) 777 (MNa+, 100%). c) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(4-triethylsilyroxy- phenyl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethyIsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 39b (1.2g) in benzene (70ml) was reacted with manganese dioxide (3.4g) for 3 hours to give the title compoimd (598mg, 50%); δH (CDCI3) inter alia 0.68-0.82 (6H, m, Si(CH2CH3)3), 0.90 (3H, d, J 7.0Hz, 17-H3), 1.00 (9H, t, J 7.4Hz,
Si(CH2CH3)3), 1.20 (3H, d, J 6.4Hz, 14-H3), 6.20 (1H, s, 2-H), 6.88 (2H, d, J 8.7Hz, 3',5'-H2), 7.81 (2H, d, 8.7Hz, 2',6'-H2); m/z (FAB; 3-NOBA/Na) 775 (MNa+, 40%), 235 (100%). d ) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-hydro xyphenyl)hut-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5c the product from 39c (598mg, 0.8mmol) was deprotected to give the triethylsilylated title compound (264mg). This material was dissolved in tetrahydrofuran (THF) (5ml) and treated with acetic acid (30μl, 0.5mmol) and a solution of tetrabutylammonium fluoride trihydrate in THF (1M, 0.5ml, 0.5mmol). After 20 minutes the mixture was diluted with ethyl acetate and washed with brine, dried, evaporated and chromatographed on silica eluting with dichloromethane/ methanol mixtures to give the title compound containing 25% tetrabutyl ammonium acetate (234mg). This mixture was treated with ethyl acetate (10ml), water (5ml) and nonafluorobutane sulphonate (76mg). The organic phase was separated, washed with brine, dried and evaporated.
Chromatography eluting with dichloromethane/methanol mixtures gave the title compound (168mg) as a solid; vmax (KBr) 3385, 1604, 1508, 1455cm-1; λmax (EtOH) 326nm (εm 21,460); δH (d6-acetone) inter alia0.92 (3H, d, J 7.1Hz, 17-H3), 1.16 (3H, d, J 6.4Hz, 14-H3), 6.39 (1H, s, 2- H), 6.95 (2H, d, J 8.8Hz, 3',5'-H2), 7.90 (2H, d, J 8.8Hz, 2',6'-H2); δc (d6- acetone) 12.3 (C-17), 20.8 (C-14), 32.6 (C-9), 41.2 (C-8), 42.3 (C-4), 43.3 (C- 12), 55.6 (C-10), 60.4 (C-11), 66.0 (C-16), 69.4 (C-7), 70.1 (C-6), 71.1 (C-13),75.1 (C-5), 96.7 (C-2), 116.3 (C-3',5'), 127.3 (C-1'), 130.2 (C-2',6'), 162.5 (C- 4'), 184.9 (C-1), 194.1 (C-3); m/z 440 (MNH4 +, 12%), 423 (MH+, 15%), 181(100%).
EXAMPLE 40 3R,4R Dihydroxy-2S-[4-(4-aI]yloxyphenyl)-2,4-dioxobut-1-yl]-5S-(2S,3S- epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 4-Allyloxybenzaldehyde
A solution Of 4-allyloxybromobenzene (K. Mino et al. Synthesis. 1979, 688) (1.5g, 7.5mmol) in THF (25ml) at -70° under argon was treated with a solution of n-butyllithium in hexane (1.5M, 5ml, 7.5mmol). After 30 minutes the reaction mixture was treated with dimethylformamide
(0.88ml, 11.25mmol). After 10 minutes saturated ammonium chloride wass added and the mixture extracted with ethyl acetate. The organic phase was washed with brine, dried, evaporated and chromatographed on silica eluting with ethyl acetate/hexane mixtures to give the title compound (784mg) contaminated with ethyl acetate (16%); δH (CDCI3) inter alia 4.61 (1H, dd, J 2,6Hz), 4.93 (1H, dd, J 2,14Hz), 6.71 (1H, dd, J 6,14Hz), 7.12 (2H, d, J 9Hz), 7.88 (2H, d, J 9Hz), 9.93 (1H, s). This material was used in further synthetic transformations. b) 3R,4R-Bistrimethylsilyloxy-2S-[4-(4-allyloxyphenyl)-4-hydroxy-2- oxobut-1-yI]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 5a, and on the same scale, the product from 40a was reacted to give the title compound (815mg, 43%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 4.08- 4.17 (1H, m, 5-H), 4.42 (1H, d, J 6.0Hz, 2"-H), 4.75 (1H, d, J 13.7Hz, 2"-H), 6.63 (1H, dd, J 6.0, 13.7Hz, 1"-H), 6.98 (2H, d, J 8.6Hz, 3',5'-H2), 7.32 (2H, dd, J 8.6Hz, 2',6'-H2); m/z (NH3DCI) 684 (MNH4 +, 10%), 90 (100%). c) 3R,4R-Bistrimethylsilyloxy-2S-[4-(4-allyloxyphenyl)-2,4-dioxobut-1- yI]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 40b (800mg, 1.2mmol) in benzene (50ml) was reacted with manganese dioxide (1.2g) for 3 hours to give the title compound (437mg, 55%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.2Hz, 14-H3), 4.08-4.17 (1H, m, 5-H), 4.56 (1H, d, J 6.0Hz, 2''-H), 4.89 (1H, d, J 13.6Hz, 2"-H), 6.21 (1H, s, 2-H), 6.68 (1H, dd, J 6.0, 13.6Hz, 1"-H), 7.09 (2H, d, 18.7Hz, 3',5'-H2), 7.88 (2H, d, J 8.7Hz, 2',6'-H2); m/z (FAB; 3-NOBA/Na) 687 (MNa+, 18%), 117
(100%). d ) 3R,4R-Dihydroxy-2S-[4-(4-allyIoxyphenyl)-2,4-dioxobut-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran Using the method described in 5c, the product from 40c (370mg,
0.56mmol) was deprotected to give the title compound (218mg, 87%); vmax (KBr) 3436, 1600, 1502, 1440cm-1; λmax (EtOH) 323nm (εm 22620); δH (CDCI3) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.21 (3H, d, J 6.3Hz, 14- H3), 4.59 (1H, dd, J 1.8, 6.1Hz, 2"-H), 4.91 (1H, dd, J 1-8, 13.6Hz, 2"-H), 6.22 (1H, s, 2-H), 6.69 (1H, dd, J 6.0, 13.6Hz, 1"-H), 7.05 (2H, d, J 8.8Hz, 3',5'-H2), 7.88 (2H, d, J 8.8Hz, 2',6'-H2); δC (CDCl3) 12.7 (C-17), 20.8 (C- 14), 31.6 (C-9), 39.7 (C-8), 42.5 (C-4), 42.6 (C-12), 55.7 (C-10), 61.3 (C-11), 65.7 (C-16), 69.1 (C-7), 70.3 (C-6), 71.3 (C-13), 73.9 (C-5), 96.7 (C-2), 97.4 (C-2"), 116.5 (C-3',5'), 129.0 (C-1'), 129.3 (C-2',6'), 146.7 (C-1"), 160.2 (C-4'), 182.3 (C-1), 194.7 (C-3). [Found: M+ 448.2119. C24H32O8 requires M 448.2097]. The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
EXAMPLE 41 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methoxymethyloxophenyl)but-1-yl] - 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-2-oxo-4-(4- methoxymethyloxyphenyl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy- 4S-methylhexyl)t etrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and 4-methoxymethyloxobenzaldehyde (J.P. Yardley et al,
Synthesis, 1976, 244) (365mg, 2.2mmol) was reacted to give the title compound (1.25g, 91%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, 17- H3), 1.19 (3H, d, J 6.4Hz, 14-H3), 3.47 (3H, s, OMe), 4.02-4.18 (1H, m, 5- H), 5.03-5.15 (1H, m, 1-H), 5.17 (2H, s, OCH2O), 7.02 (2H, d, J 8.7 Hz, 3',5'-H2), 7.22-7.32 (2H, m, 2',6'-H2); m/z (NH3, DCI), 702 (MNH4 +, 8%), 239 (100%). b) 3R,4R-Bistrimethylsilyloxy-2S[2,4-dioxo-4-(4-methoxymethyl- oxyphenyl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 41a (1.2g, 1.75mmol) in benzene (50ml) was reacted with manganese dioxide (1.8g) for 3½ hours to give the title compound (750mg, 62%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 3.49 (3H, s, OMe), 5.23 (2H, s, OCH2O), 6.21 (1H, s, 2-H), 7.07 (2H, d, J 8.9Hz, 3',5'-H2), 7.86 (2H, d, J 8.9Hz, 2',6'-H2); m/z (NH3, DCI) 683 (MNH4 +, 16%), 90 (100%). c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methoxymethyloxyphenyl)but- 1-yI]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyI)tetrahydropyran
Using the method described in 5c, the product from 41b (750mg) was deprotected to give the title compound (400mg, 78%); vmax (KBr) 3421, 1602, 1507, 1454cm-l; λmax (EtOH) 321.5nm (εm 20,160); δH (CDCl3) inter alia 0.94 (3H, d, J 7.1Hz, 17-H3), 1.21 (3H, d, J 6.3Hz, 14-H3), 3.49 (3H, s, OMe), 5.24 (2H, s, OCH2O), 6.21 (1H, s, 2-H), 7.08 (2H, d, J 8.9Hz, 3',5'-H2), 7.56 (2H, d, si 8.9Hz, 2',6'-H2); δc (CDCI3) 12.8 (C-17), 20.8 (C- 14), 31.7 (C-9), 39.7 (C-8), 42.7 (C-4), 42.9 (C-12), 55.8 (C-10), 56.3 (OMe), 65.7 (C-11), 69.2 (C-7), 70.3 (C-6), 71.4 (C-13), 73.7 (C-5), 94.2 (OCH2O), 96.7 (C-2), 116.1 (C-3',5'), 127.9 (C-1') , 129.2 (C-2',6'), 160.9 (C-4'), 182.7 (C-1), 194.4 (C-3); (Found: M+ 466.2198. C24H34O9 requires M
466.2203). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
EXAMPLE 42 3R,4R-Dihydroxy-2S-[4-(but-1-yl)-2.4-dioxobut-1-yl]-5S-(2S,3S-epoxy-5S- hydroxy-4S-methylhexyl)tetrahydropyran al 2-[3R,4R-Bistrimethylsilyloxy-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran-2S-yl1methylprop-2- ene-1-yl but-1-yl ketone
A 1.75:1 mixture ofthe product from la (900mg, 1.5mmol) in THF (20ml) under argon at -70° was treated dropwise with a solution of n- butyllithium in hexane (1.5M, 2ml, 3mmol). After 30 minutes the mixture was worked-up and purified as in lb to give material containing the title compound (320mg); δH (CDCI3) inter alia 3.16 (2H, s, 2-H2), 4.90 (1H, s, 15-H), 5.03 (1H, s, 15-H). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-(but-1-yl)-2,4-dioxobut-1-yl]-5S- (2S,3S-epoxy-5S-trimethyl-silyIoxy-4S-methylhexyl]tetrahydropyran The material from 41a (300mg) in dichloromethane (20ml) was ozonolysed and then purified as described in 1c to give the title compound (93mg, 50%); δH (CDCl3) inter alia 1.20 (3H, d, J 6.3Hz, 14-H3), 5.59 (1H, s, 2-H). c) 3R,4R-Dihydroxy-2S[4-(but-1-yl)-2,4-dioxobut-1-yl] -6S-(2S,3S- epoxy-5S-hydroxy-4S-methylhexyl)tetra-hydropyran
Using the method described in 5c, the product from 41b (85mg, 0.14mmol) was deprotected to give the title compound (43mg, 78%); vmax (KBr) 3460, 1622, 1459cm-1; λmaχ (EtOH) 276nm (εm 9,295); δH (CDCI3) inter alia 1.20 (3H, d, J 6.3Hz, 14-H3), 5.60 (1H, s, 2-H); m/z (NH3, DCI) 387 (MH+, 100%). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. EXAMPLE 43 3R,4R-Dihydroxy-2S-r2.4-dioxo-4-(4-{2-hydroxyethoχy}phenyl)but-1-yl] - 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 4-(2-Triethylsilyloxyethoxy)benzaldehyde
A solution of 4-(2-hydroxyethoxy)benzaldehyde (J. Bernstein et al. JACS, 1951, 73, 906) (996mg, 6mmol) in dichloromethane (20ml) under argon at 5° was treated with triethylamine (1.17ml, 8.4mmol) followed by
triethylsilyl chloride (1.21ml, 7.2mmol). After 30 minutes the mixture warmed to room temperature and after a further 30 minutes ether was added and the mixture was washed with 5% citric acid, saturated sodium bicarbonate and brine then dried and evaporated to give the crude title compound (1.53g, 91%); δH (CDCI3) 0.64 (6H, q, J 7.8Hz), 0.98 (9H, t, J 7.8Hz), 4.00 (2H, t, J 5.1Hz), 4.14 (2H, t, J 5.1Hz), 7.02 (2H, d, J 8.7Hz), 7.83 (2H, d, J 8.7Hz), 9.90 (1H, s). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-2-oxo-4-(4-{2- triethylsiIyloxyethoxy}phenyl)bu_-1-yl]-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.04g, 2mmol) and the product from 43a (560mg, 2mmol) were reacted to give the title compound (1.33g, 83%); δH (CDCI3) 0.64 (6H, q, J 8.0Hz, SiCH2), 0.90 (3H, d, J 7.0Hz, 17-H3), 0.98 (9H, t, J 8.0Hz, SiCH2Me ), 1-18 (3H, d, J 6.3Hz, 14-H3), 5.07-5.18 (1H, m, 1-H), 6.89 (2H, d, J 8.6Hz, 3,,5'-H2), 7.28 (2H, d, J 8.6Hz, 2',6'-H2); m/z (NH3.DCI) 816 (MNH4 +, 5%), 90 (100%). c) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(4-{2-triethyl- silyloxyethoxy}phenyl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 43b (1.3g, 1.63mmol) in benzene (70ml) was reacted with manganese dioxide (2.7g) for 3½ hours to give the title compoimd (713mg, 55%); δH (CDCI3) inter alia 0.65 (6H, q, J 7.9Hz, Si(CH2Me)3), 0.90 (3H, d, J 7.0Hz, 17-H3), 0.98 (9H, t, J 8.0Hz, Si(CH2Me)3), 1.20 (3H, d, J 6.3Hz, 14-H3), 4.12 (2H, t, 14.9Hz, 1''- H2), 6.20 (1H, s, 2-H), 6.95 (2H, d, J 8.7Hz, 3',5'-H2), 7.87 (2H, d, J 8.7Hz, 2',6'-H2); m/z (FAB: thioglycerol) 797 (MH+ , 1-0%), 167 (100%). d) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{2-hydroxyethoxy}phenyl)buty- 1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5c, the product from 43c (700mg,
0.88mmol) was deprotected to give the title compound (294mg, 72%); vmax (KBr) 3421, 1603, 1506, 1451cm-1; λmax (EtOH) 324.5nm (εm 20,790); δH (CDCl3/d4-MeOH) inter alia 0.93 (3H, d, J 7.1Hz, 17-H3), 1.21 (3H, d, J 6.3Hz, M-H3), 4.14 (2H, t, J 4.8Hz, 1"-H2), 6.23 (approx. 1H, s, 2-H), 6.98 (2H, d, J 8.9Hz, 3',5'-H2), 7.86 (2H, d, J 8.9Hz, 2',6'-H2); δc (CDCI3/d4- MeOH) 12.3 (C-17), 20.3 (C-14), 31.5 (C-9), 39.6 (C-8), 41.7 (C-4), 42.5 (C- 12), 55.6 (C-10), 60.9 (C-11), 65.4 (C-2"), 68.6 (C-7), 69.5 (C-1"), 70.1 (C-6), 70.7 (C-13), 73.9 (C-5), 96.4 (C-2), 114.4 (C-3',5'), 127.1 (C-1'), 129.1 (C- 2',6'), 162.3 (C-4'), 182.7 (C-1), 193.5 (C-3); m/z (FAB: Glycerol) 467 (MH+, 30%), 185 (100%). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. EXAMPLE 44 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(3-fluorophenyl)but-1-yI]-5S-[2S,3S- epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-(3-fluorophenyl)-4-hydroxy-2- oxobut-1-yl]-5S-(2S-3S-epoxy-5S-trimethylsilyloxy-4S-methyl- hexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.04g, 2mmol) and 3-fluorobenzaldehyde (0.23ml, 2.2mmol) were reacted to give the title compound (0.998g, 78%); δH (CDCI3) inter alia 0.90 (3H, d, J
7Hz, 17-H3), 1.19 (3H, d, J 6.4Hz, 14-H3), 5.08-5.24 (1H, m, 1-H), 6.91- 7.37 (4H, m, 2',4',5',6'-H4); (Found M+ 642.3237. C31H55O3FSi3 requires 642.3240). b ) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(3-fluorophenyl)but-1- yI]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 44a (0.99g, l.5mmol) in benzene (70ml) was reacted with manganese dioxide (2.0g) for 3½ hours to give the title compound (439mg, 49%); δH (CDCI3) inter alia 0.91 (3H, d, J 7.0Hz, 17-H3), 1.21 (3H, d, J 6.4Hz, 14-H3), 6.24 (1H, s, 2-H), 7.16-7.26 (1H, m, 3'-H), 7.37-7.48 (1H, m, 4'-H), 7.58-7.71 (2H, m, 2',6'- H2); m/z (NH3.DCI) 641 (MH+, 30%), 90 (100%). c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(3-fluorophenyl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methyIhexyl)tetrahydropyran
Using the method described in 5c, the product from 44b (480mg) was deprotected to give the title compound (229mg, 76%); νmax (KBr) 3423, 1581, 1455, 1380cm-1; λmax (EtOH) 312nm (εm 15,735); δH (CDCI3) inter alia 0.94 (3H, d, J 6.9Hz, 17-H3), 1.22 (3H, d, J 6.3Hz, 14-H3), 6.24 (1H, s, 2-H), 7.17-7.69 (4H, m, 2',4',5',6'-H4); δc (CDCI3) 12.7 (C-17), 20.8 (C-14), 31.6 (C-9), 39.6 (C-8), 42.7 (C-4), 42.8 (C-12), 55.6 (C-10), 61.2 (C-11), 65.6 (C-16), 68.9 (C-6), 70.2 (C-7), 71.3 (C-13), 73.8 (C-5), 97.7 (C-2), 113.8 (d, J 43.3Hz, C-4'), 119.3 (d, J 21.2Hz, C-2'), 122.7 (C-6'), 130.2 (d, 7.9Hz, C-5'), 136.6 (d, J 7.1Hz, C-1'), 162.8 (d, J247.3Hz, C-3"), 180:6 (C-1), 191.3 (C-3). (Found: M+ 424.1898. C22H29O7F requires M 424.1897). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. EXAMPLE 46 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-fluorophenyl)but-1-yl]-5S-(2S,3S- epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran al 3R,4R-Bistrimethylsilyloxy-2S-[4-(2-fluorophenyl)-4-hydroxy-2- oxobut-1-yI]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran Using the method described in 5a, tristrimethylsilylmonone (1.04g,
2mmol) and 2-fluorobenzaldehyde (0.23ml, 2.2mmol) were reacted to give the title compound (850mg, 66%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, 16.3Hz, 14-H3), 4.06-4.19 (1H, m, 5-H), 5.40- 5.60 (1H, m, l-H), 6.87-7.06 (1H, m, 5'-H), 7.14-7.32 (2H, m, 4',6'-H2), 7.62-7.60 (1H, m, 3'-H); m/z (NH3.DCI) 660 (MMH4 +, 15%), 90 (100%). b ) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(2-fluorophenyl)but-1- yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S-methylhexyl)tetrahydropyran Using the method described in 6b, the product from 45a (730mg) in benzene (50ml) was reacted with manganese dioxide (1.65g) for 3½ hours to give the title compound (480mg, 67%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 6.35 (1H, d, J 1.2Hz, 2- H), 7.07-7.18 (1H, m, Ar-H), 7.20-7.26 (1H, m, Ar-H), 7.42-7.63 (1H, m, Ar- H), and 7.90-7.99 (1H, m, Ar-H); m/z 640 (M+, 0.6%), 625(1), 165(63), 117(92), and 73(100). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-fluorophenyl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5c, the product from 45b (0.110g,
0.17mmol) was deprotected to give the title compound (0.053g, 67%); vmax (KBr) 1610, 1587, 1459, 1112, 1043, and 771cm-1; λmax (EtOH) 312nm (εm 15,920); δH (CDCI3) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.21 (3H, d, J 6.3Hz, 14-H3), 6.39 (1H, s, 2-H), 7.08-7.30 (2H, m, 2Ar-H), 7.42-7.56 (1H, m, Ar-H), and 7.87-7.99 (1H, m, Ar-H); m/z (NH3DCI) 442 (MNH4 + 10%), 425 (MH+, 18), and 156 (100); m/z (FAB, 3-NOBA/Na) 447 (MNa+). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
EXAMPLE 46 3R,4R-Dihydroxy-2S-[4-(3,4-difluorophenyl)-2,4-dioxobut-1-yl]-5S-(2S,3S- epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-(3,4-difluorophenyl)-4-hydroxy-2- oxobut-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.04g, 2mmol) and 3,4-difluorobenzaldehyde (0.24ml, 2.2mmol) were reacted to give the title compound (0.880g, 66%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H3), 5.07-6.17 (1H, m, 1-H), and 7.01-7.30 (3H, m, Ar-H); m/z 660 (M+, 0.5%), 129 (46), 117 (85), and 73 (100). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-(3,4-difluorophenyl)-2,4-dioxobut- 1-yn-6S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 46a (1.39g) in benzene (100ml) was reacted with manganese dioxide (2.5g) for 3½ hours to give the title compound (780mg, 57%); δH (CDCI3) inter alia 0.90 (3H, d, J
7.1Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H3), 6.20 (1H, s, 2-H), 7.17-7.29 (1H, m, Ar-H), and 7.61-7.73 (2H, m, Ar-H); m/z 658 (M+, 0.6%), 643(1), 117(73), and 73(100); m/z (FAB 3-NOBA/Na) 703 (M-H+2Na+) and 681 (MNa+). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[4-(3,4-difluorophenyl)-2,4-dioxo-but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5c, the product from 46b (385mg,
0.58mmol) was deprotected to give the title compound (226mg, 87%); vmax (KBr) 1612, 1594, 1516, 12δ0, 1118, 1090, and 1043cm-1; λmax (EtOH) 311.5nm (εm 14,940); δH (CDCI3) inter alia 0.94 (3H, d, si 7.0Hz, 17-H3), 1.22 (3H, d, J 6.3Hz, 14-H3), 6.19 (1H, s, 2-H), 7.19-7.31 (1H, m, Ar-H), and 7.61-7.78 (2H, m, Ar-H); δc (CDCI3) 12.2 (C-17) 20.2 (C-14), 31.6 (C- 9), 39.8 (C-8), 41.9 (C-4), 42.5 (C-12), 55.7 (C-10), 60.9 (C-11), 65.6 (C-16), 68.6 (C-6), 70.0 (C-7), 70.5 (C-13), 74.0 (C-5), 97.2 (C-2), 116.3 (J 19Hz) and 117.5 (J 18Hz) (C-2' and 5'), 123.8 (C-6'), 131.3 (C-1'), 149.8 and 153.0 (two overlapping dd, J 253 and 13Hz, C-3' and 4'), 130.4 (C-1), and 194.5 (C-3); m/z (FAB 3-NOBA/Na) 437 (M-H+2Na+) and 465 (MNa+); m/z (FAB Thioglycerol) 460 (MNH4 + ) and 443 (MH+). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
EXAMPLE 47 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-N-(2-hydroxyethyl)-N- methyIaminopyrid-5-yl)but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S- methylhexyl)tetrahydropyran a) 5-Bromo-2-N-(2-hydroxyethyl)-N-methylaminopyridine 2,5-Dibromopyridine (4.74g, 20mmol) in 2-(methylamino)ethanol (5ml, 62mmol) was heated at 95-110°C for 6h, and stirred at RT for 16h. The viscous oil was then diluted with water (30ml) and extracted with ethyl acetate (3 x 50ml). The combined organic extracts were washed with brine, dried and evaporated to give a pale yellow viscous oil (4.565g, 99%); δH (CDCI3) 3.05 (3H, s, NCH3), 3.70 (2H, t, J 4.7Hz, CH2), 3.34 (2H, t, J 4.7Hz, CH2), 4.27 (1H, br, OH, xch + D2O), 6.45 (1H, d, J 9.0Hz, 3-H), 7.52 (1H, dd, J 9.0 and 2.5Hz, 4-H), and 8.08 (1H, d, J 2.4Hz, 6-H); m/z 232/230 (M+, 18%) and 201/199 (100). (Found: M+, 230.0056.
C8H11BrN2O requires M, 230.0055). b) 5-Bromo-2-N-methyl-N-(2-triethylsilyloxyethyl)amino pyridine
5-Bromo-2-N-(2-hydroxyethyl)-N-methylaminopyridine (4.53g, 19.6mmol) was dissolved in dry dichloromethane (70ml), cooled in an ice bath, and treated with triethylamine (3.8ml, 27mmol) and chlorotrietbylsilane (3.95ml, 23.5mmol). After five minutes the mixture was diluted with ether, filtered and evaporated. The residue was purified by column chromatography on silica (47g), eluting with 3-5% ethyl acetate in hexane, to give the pure product as a colourless oil (6.510g, 96%); δH (CDCI3) 0.5- 0.62 (6H, m, 3xSiCH2), 0.88-0.96 (9H, m, 3xCH3), 3.08 (3H, s, NCH3), 3.64 (2H, d, J 5.8Hz, CH2), 3.78 (2H, d, J 5.7Hz, CH2), 6.42 (1H, d, J
9.1Hz, 3-H), 7.47 (1H, dd, J 9.1 and 2.5Hz, 4-H), and δ.13 (1H, d, J 2.5Hz, 6-H); m/z 347/346 (MH+, 40%), 346/344 (M+, 50), and 201/199(100).
(Found: M+, 344.0919. C14 H2 5BrN2OSi requires M, 344.0920). c ) 2-N-Methyl-N-(2-triethylsilyloxyethyl)aminopyridine-5- carboxaldehyde
5-Bromo-2-N-methyl-N-(2-triethylsilyloxyethyl)aminopyridine (1.727g, δmmol) was dissolved in dry THF (30ml), cooled to -90°C, and treated dropwise with n-butyllithium (1.5M, 3.67ml, 5.5mmol). The mixture was stirred at -95°C for five minutes, then N,N-dimethylformamide (1.16ml, 15mmol) added. Stirring was continued for 3/4h at -90°C, then the reaction was quenched with saturated ammonium chloride. Water was added, and the mixture extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried and evaporated. The crude product was purified by column chromatography, eluting with 10- 15% ethyl acetate in hexane, to give the title compound as a pale yellow oil (1.354g, 92%); δH (CDCI3) 0.56 (6H, q, J 7.9Hz, 3xSiCH2), 0.92 (9H, t, J 7.9Hz, 3-H), 3.21 (3H, s, NCH3), 3.72-3.88 (4H, m, 2 x CH2), 6.58 (1H, d, J 9.0Hz, 3-H), 7.90 (1H, dd, J 9.0 and 2.2Hz, 4-H), 8.53 (1H, d, J 2.2Hz, 6- H), and 9.76 (1H, s, CHO); m/z 295 (MH+, 60%), 294 (M+, 55), 163 (70), and 136 (100). (Found: M+, 294.1767. C15H26N2O2Si requires M, 294.1764). d) 3R,4R-BistrimethylsiIyloxy-2S-[4-hydroxy-4-(2-N-methyl-N-(2- triethylsilyloxyethyl)aminopyrid-5-yl)-2-oxobut-1-yl]-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and 2-N-methyl-N-(2-triethylsilyloxyethyl)aminopyridine-5- carboxaldehyde (0.647g, 2.2mmol) were reacted to give the title compound (1.353g, 83%); δH (CDCI3) inter alia 0.52-0.64 (6H, m, 3xSiCH2), 0.88- 0.98 (12H, m, 4xCH3), 3.11 (3H, s, NCH3), 5.01-5.12 (1H, m, 1-H), 6.53 (1H, br d, 3'-H), 7.50 (1H, br d, 4'-H), and 8.09 (1H, d, J 2.2Hz, 6'-H); m/z (FAB, 3NOBA/Na) 835 (MNa+) and 813 (MH+). e) 3R,4R-Bristrimethylsilyloxy-2S-[2,4-dioxo-4-(2-N-methyl(2- triethylsilyloxyethyl)aminopyrid-5-yl)but-1-yl]-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 47d (1.331g,
1.64mmol) in benzene (70ml) was reacted with manganese dioxide (4.1g) for 5h to give the title compound (0.631g, 48%); δH (CDCI3) inter alia 0.5- 0.63 (6H, m, 3xSiCH2), 0.87-0.97 (12H, m, 4xCH3), 1.20 (3H, d, J 6.3Hz, 14-H3), 3.19 (3H, s, NCH3), 6.13 (1H, s, 2-H), 6.55 (1H, br d, 3'-H), 7.95 (1H, dd, J 9-1 and 2.1Hz, 4'-H), and 8.70 (1H, d, J 2.2Hz, 6'-H); m/z 810 (M+, 1%) 293(40), 135(46), 117(73), and 73(100). (Found: M+, 810.4524. C39H74N2O8Si4 requires M, 810.4522). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. f) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-N-(2-hydroxyethyl)-N- methylaminopyrid-5-yl)but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S- methyIhexyl)tetrahydropyran Using the method described in 5c, the product from 47e (0.610g,
0.75mmol) was completely deprotected to give the title compound (0.325g, 90%); vmax (KBr) 3423, 1603, 1521, 1403, 1279, 1111, and 1054cm-1; λmax (EtOH) 356nm (εm 32,162); δH (CDCI3/CD3OD) inter alia 0.92 (3H, d, J 7.1Hz, 17-H3), 1.21 (3H, d, J 6.3Hz, 14-H3), 3.16 (3H, s, NCH3), 6.14 (1H, s, 2-H), 6.58 (1H, d, si 9.1Hz, 3'-H), 7.96 (1H, dd, J 9.1 and 2.4Hz, 4'- H), and 8.63 (1H, d, J 2.4Hz, 6'-H); δC (CDCI3/CD3OD) 12.5 (C-17), 20.5 (C-14), 31.8 (C-9), 37.9 (NCH3), 39.8 (C-3), 41.5 (C-4), 42.7 (C-12), 53.4 (NCH3), 55.8 (C-10), 61.1 (C-11), 61.2 (OCH2), 66.7 (C-16), 68.7 (C-6), 70.2 (C-7), 70.8 (C-13), 74.2 (C-5), 95.8 (C-2), 105.9 (C-4'), 119.0 (C-5'), 148.7 (C-6'), 160.3 (C-2'), 183.1 (C-1), and 191.4 (C-3); m/z 480 (M+, 2%) and 163 (100). (Found: M+, 430.2471. C24H36N2O8 requires M, 480.2472). The n.m.r. spectra indicated that the title compound was mainly in the enolic form. EXAMPLE 48 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-(4-hydroxypiperidin-1-yl)pyrid-5- yl)but-1-vn-5S-[2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 5-Bromo-2-(4-hydroxypiperidin-1-yl)pyridine
2,5-Dibromopyridine (3.554g, 15mmol) and 4-hydroxypiperidine (4.552g, 45mmol) were heated at 100-110°C for 1h. The mixture was diluted with water and extracted with ethyl acetate (3x40ml). The combined organic extracts were dried and evaporated to give a white solid, which was recrystallised from chloroform/ hexane to give the title compound as white crystals (3.058g, 79%); m.p. 98.5-99.5°C; found C, 46.66; H, 5.10; N, 10.69%. C10H13BrN2O requires C, 46.71; H, 5.10; N, 10.89%; δH
(CDCI3) 1.48-1.66 (3H, m, 3'-H, 5'-H, OH), 1.90-2.05 (2H, m, 3'-H, 5'-H), 3.10-3.26 (2H, m, 2'-H, 6'-H), 3.87-4.06 (3H, m, 2'-H, 4'-H, 6'-H), 6.58 (1H, d, J 9.1Hz, 3-H), 7.52 (1H, dd, J 9.1 and 2.5Hz, 4-H), and 8.17 (1H, d, J 2.4Hz, 6'-H; m/z 268/256, 213/211 (90), 201/199 (80), 187/185 (85), and 157/169 (69). (Found: (M+, 256.0216. C10H13BrN2O requires M,
256.0211).
___ 5-Bromo-2-(4-trimethylsilyloxypiperidin-1-yl)pyridine 5-Bromo-2-(4-hydroxypiperidin-1-yl)pyridine (2.985g, 11.6mmol) was dissolved in dry dichloromethane (40ml), coled in an ice bath, and treated with triethylamine (2.1ml, l5mmol) and chlorotrimethylsilane (1.76ml, 14mmol). After ½h the mixture was diluted with ether, filtered and evaporated. The residue was redissolved in ether, filtered and evaporated to give an off-white crystalline solid (3.797g, 99%); δH (CDCI3) 0.14 (9H, s, Si(CH3)3), 1.49-1.66 (2H, m, 3'-H, 5'-H), 1.76-1.90 (2H, m, 3'-H, 5'-H), 3.11-3.26 (2H, m, 2'-H, 6'-H), 3.82-3.99 (3H, m, 2'-H, 4'-H, 6'-H), 6.57 (1H, d, J 9.1Hz, 3-H), 7.50 (1H, dd, J 9.1 and 2.5Hz, 4-H), and 8.17 (1H, d, J 2.4Hz, 6-H); m/z 330/328 (M+, 80%), 211/213 (100), and 73(74). (Found: M+, 328.0606. C13H21BrN2OSi requires M, 328.0607). c) 2-(4-Trimethylsilyloxypiperidin-1-yl)pyridine-5-carboxaldehyde
Using the method described in 47c, 5-bromo-2-(4-trimethylsilyloxy- piperidin-1-yl)pyridine (1.647g, 5mmol) was reacted to give the title compound as yellow crystals (0.932g, 67%); δH (CDCI3) 0.15 (9H, s, Si(CH3)3), 1.51-1.69 (2H, m, 3'-H, 5'-H), 1.77-1.92 (2H, m, 3'-H, 5'-H), 3.44-3.63 (2H, m, 2'-H, 6'-H), 3.92-4.13 (3H, m, 2'-H, 4'-H, 6'-H), 6.68 (1H, d, J 9.1Hz, 3-H), 7.91 (1H, dd, J 9.1 and 2.3Hz, 4-H), 8.54 (1H, d, J 2.3Hz, 6-H), and 9.76 (1H, s, CHO); m/z 278 (M+, 60%), 263 (38), 209 (78), 161 (100), and 107 (69). (Found: M+, 278.1454. C14H22N2O2Si requires M, 278.1451). dl 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-4-(2-(4-trimethyl- silyloxypiperidin-1-yl)pyrid-5-yl)-2-oxobut-1-yl]-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran Using the method described in 5a, tristrimethylsilylmonone (1.038g,
2mmol) and 2-(4-trimethylsilyloxypiperidin-l-yl)pyridine-5-carboxaldehye (0.613g, 2.2mmol) were reacted to give the title compound (1.135g, 71%); δH (CDCI3) inter alia 0.90 (3H, d, 17.1Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 5.02-5.16 (1H, m, 1-H), 6.68 (1H, br d, 3'-H), 7.53 (1H, br d, 4'-H), and 8.13 (1H, d, J 2.2Hz, 6'-H); m/z (NH3, DCI) 797 (MH+, 15%) and 279 (100); m/z 796 (M+, 0.2%), 278(31), 129(74), and 73(100). (Found: M+, 796.4364. C38H72N2O8Si4 requires M, 796.4366). e ) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(2-(4-trimethyl- silyloxypiperidin-1-yl)pyrid-5-yl)but-1-yI]-6S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 48d (1.120g, 1.4mmol) in benzene (70ml) was reacted with manganese dioxide (2.9g) for 3h to give the title compound (0.633g, 57%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 6.13 (1H, s, 2-H), 6.6-6.72 (1H, m, 3'-H), 7.95 (1H, br d, 4"-H), and 3.70 (1H, d, J 2.3Hz, 6'-H); m/z (NH3 DCI) 795 (MH+ , 15%), 251(32), 92(52), and 90(100); m/z 794 (M+, 0.5%), 277 (100), 117 (76), and 73 (96). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. f) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-(4-hydroxypiperidin-1-yl)pyrid-
5-yl)but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran
Using the method described in 5c, the product from 48e (0.600g,
0.75mmol) was completely deprotected to give the title compound (0.240g, 63%); m.p. 137-133°C (chloroform/ethyl acetate/hexane); vmax (KBr) 3453, 1608, 1500, 1440, 1357, 1250, and 1075cm-1; λmax (EtOH) 358nm (εm 33,099); δH (CD3OD) inter alia 0.94 (3H, d, J 7.2Hz, 17-H3), 1.19 (3H, d, J 6.4Hz, 14-H3), 1.34-1.68 (3H, m, 12-H, 3"-H, 5"-H), 1.86-2.02 (3H, m, 8-H, 3"-H, 5"-H), 4.16-4.28 (2H, m, 2"-H), 6"-H), 6.26 (1H, s, 2-H), 6.85 (1H, d, J 9.2Hz, 3'-H), 7.99 (1H, dd, J 9.2 and 2.4Hz, 4'-H), and 8.67 (1H, d, J 2.3Hz, 6'-H); δC (CD3OD) 12.2 (C-17), 20.2 (C-14), 32.9 (C-9), 34.7 (C- 3" and 5"), 41.6 (C-8), 42.0 (C-4), 43.6 (C-2" and 6"), 43.7 (C-12), 56.8 (C- 10), 61.2 (C-11), 66.3 (C-16), 68.3 (C-4"), 69.8 (C-6), 70.6 (C-13), 71.5 (C-7), 75.6 (C-5), 96.6 (C-2), 107.1 (C-4'), 120.1 (C-5'), 137.4 (C-3'), 149.9 (C-6'), 161.6 (C-2'), 184.4 (C-1), and 192.4 (C-3); m/z 506 (M+, 5%), 247(20),
220(29), and 206(100). (Found: M+, 506.2624. C26H38N2O8 requires M, 506.2628). A further quantity of the title compound (0.096g, 25%) was obtained after chromatography of the mother liquors. The n.m.r. spectra indicated that the compound was essentially in the enolic form.
EXAMPLE 49 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-(3-hydroxyprop-1-oxy)pyrid-5-yl)but- 1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 3-Iodo-1-triethylsilyloxypropane
3-Bromopropan-1-ol (1.81ml, 20mmol) and sodium iodide (6.75g, 45mmol) in acetone (15ml) were refluxed for 1½h. The mixture was cooled, filtered and reduced in volume. Water was added and the mixture extracted with ether. The combined organic extracts were washed with sodium metabisulphite solution and brine, dried and evaporated. The residue was distilled, using a water pump (15mm Hg), to give 3- iodopropan-1-ol (2.885g, 78%) b.p. 96-100°C; δH (CDCI3) 2.04 (2H, q, J 7Hz, 2-H2), 3.15 (1H, s, OH), 3.3 (2H, t, J 7Hz, 1-H2), and 3.7 (2H, t, J 7Hz, 3-H2).
3-Iodopropan-1-ol (2.79g, l5mmol) was dissolved in dry dichloromethane (30ml), cooled in an ice bath, and treated with triethylamine (2.3ml, 20mmol) and chlorotriethylsilane (3ml, 17.8mmol). After ½h the mixture was diluted with ether, filtered and carefully evaporated to give the title compound, which was used without further purification. b) Ethyl 2-(3-triethylsilyloxyprop-1-oxy)pyridine-5-carboxylate
A suspension of ethyl 2-hydroxypyridine-5-carboxylate (1.170g, 7mmol) and silver carbonate (1.930g, 7mmol) in benzene (30ml) was stirred with 3-iodo-1-triethylsilyloxypropane (15mmol) for 23h. T.l.c. showed little or no reaction, so more benzene was added and the mixture gently refluxed for 48h, then stirred at room temperature for a further 48h. The mixture was then filtered and evaporated. The crude product was separated by column chromatography, eluting with 0-20% ethyl acetate in hexane, to give: (a) recovered 3-iodo-1-triethylsilyloxypropane (1.33g, 4.4mmol); (b) the title compound (contaminated with a little of (a)) (1.55g, ca.65%); δH (CDCI3) 0.63-0.69 (6H, m, 3xSiCH2), 0.39-1.01 (9H, m, 3xCH3), 1.39 (3H, t, J 7.1Hz, CH3), 2.01 (2H, q, J 6.2Hz, 2'-H2), 3.79 (2H, t, J 6.2Hz, 3'- CH2), 4.37 (2H, q, J 7.1Hz, CO2CH2), 4.46 (2H, t, J 6.2Hz, 1'-H2), 6.74 (1H, d, J δ.9Hz, 3-H), 8.15 (1H, dd, J 8.8 and 2.4Hz, 4-H), and 8.82 (1H, d, J 2.4Hz, 67-H); m/z (NH3 DCI) 340 (MH+, 100%); m/z 339 (M+, 0.5%), 310(91), 252(100), and 224(45). (Found: M+, 339.1863. C17H24NO4Si requires M, 339.1866); and (c) the N-alkylated compound (0.56g, 24%). c) 2-(3-Triethylsilyloxyprop-1-oxy)pyridine-5-carboxaldehyde
Ethyl 2-(3-triethylsilyloxyprop-1-oxy)pyridine-5-carboxylate (1.53g, 4.5mmol) was dissolved in dry THF (50ml) under argon, then diisobutylaluminium hydride (1.0M, 5ml, 5mmol) was added slowly. After stirring for ½ h, more diisobutylaluminium hydride (5ml) was added, and stirring continued for a further 1h. Methanol (11ml) and saturated sodium sulphate (14ml) were added, and the mixture stirred for l5minutes. The salts were filtered off through celite, the filtrate dried and evaporated to give the hydroxymethyl compound as a colourless oil (1.36g, 100%). This material was dissolved in dichloromethane (50ml), activated manganese dioxide (2.7g) added, and the mixture stirred for 16h. After filtering, the filtrate was evaporated to give a colourless oil. This residue was purified by column chromatography, eluting with 10% ethyl acetate in hexane, to give the title compound (0.958g, 72%); δH (CDCI3) 0.64-0.66 (6H, m, 3xSiCH2), 0.39-1.0 (9H, m, 3xCH3), 2.02 (2H, q, J 6.2Hz, 2'-H2), 3.80 (2H, t, J 6 .2Hz, 3'-H2), 4.51 (2H, t, J 6.3Hz, 1'-H2), 6.82 (1H, d, J 8.8Hz, 3-H), 8.06 (1H, dd, J 8.7 and 2.4Hz, 4-H), 8.62 (1H, d, J 2.4Hz, 6-H), and 9.95 (1H, s, CHO); m/z (NH3 DCI) 296 (MH+, 100%); m/z 296 (MH+, 1%), 266 (M-Et+, 68), 208 (100), and 124 (70). (Found: MH+, 296.1681.
C15H26NO3Si requires M, 296.1682. Found M-Et+, 266.1203.
C13H20NO3Si requires M, 266.1212). d) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-4-(2-(3-triethyl- silyloxyprop-1-oxy)pyrid-5-yl)-2-oxobut-1-yl]-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and 2-(3-triethylsilyloxyprop-1-oxy)pyridine-5-carboxaldehyde
(0.650g, 2.2mmol) were reacted to give the title compound (1.454g, 89%); δH (CDCl3) inter alia 0.64-0.65 (6H, m, 3xSiCH2), 0.86-1.00 (12H, m,
4xCH3), 1.19 (3H, d, J 6.4Hz, 14-H3), 1.94-2.05 (2H, m, 2"-H2), 4.12 (1H, dt, J 9.6 and 2.9Hz, 5-H), 4.33 (2H, t, J 6.2Hz, 1"-H2), 5.09-5.16 (1H, m, 1- H), 6.73 (1H, d, J 8.5Hz, 3'-H), 7.60-7.68 (1H, m, 4'-H), and 8.11 (1H, d, J
2.2Hz, 6'-H); m/z 813 (M+, 0.4%), 266(56), 208(72), 117(61), and 73(100).
(Found: M+, 813.4509. C39H75NO9Si4 requires M, 813.4519). e) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-4-(2-(3-triethyl- silvloxyprop-1-oxy)pyrid-5-yl)-2-oxobut-1-yl1-5S-(2S,3S-epoxy-6S- trimethyIsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and 2-(3-triethylsilyloxyprop-1-oxy)pyridine-5-carboxaldehyde (0.650g, 2.2mmol) were reacted to give the title compound (1.454g, 89%); δH (CDCI3) inter alia 0.54-0.66 (6H, m, 3xSiCH2), 0.86-1.00 (12H, m, 4xCH3), 1.19 (3H, d, J 6.4Hz, 14-H3), 1.94-2.05 (2H, m, 2"-H2), 4.12 (1H, dt, J 9.6 and 2.9Hz, 5-H), 4.38 (2H, t, J 6.2Hz, 1"-H2), 5.09-5.18 (1H, m, 1- H), 6.73 (1H, d, J 8.5Hz, 3'-H), 7.60-7.68 (1H, m, 4'-H), and 8.11 (1H, d, J 2.2Hz, 6'-H); m/z 813 (M+, 0.4%), 266(66), 203(72), 117(61), and 73(100). (Found: M+, 813.4509. C39H75NO9Si4 requires M, 813.4519). ej 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(2-(3-triethyl- silyloxyprop-1-oxy)pyrid-5-yl)but-1-yl]-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 49d (1.426g,
1.75mmol) in benzene (70ml) was reacted with manganese dioxide (3.5g) for 3h to give the title compound (0.770g, 54%); δH (CDCI3) inter alia
0.55-0.66 (6H, m, 3xSiCH2), 0.87-1.0 (12H, m, 4xCH3), 1.20 (3H, d, J
6.4Hz, M-H3), 1.95-2.06 (2H, m, 2"-H2), 4.46 (2H, t, J 6.3Hz, 1"-H2), 6.19 (1H, s, 2-H), 6.77 (1H, d, J 8.8Hz, 3'-H), 3.06 (1H, dd, J 8.7 and 2.5Hz, 4'- H), and 8.70 (1H, d, J 2.3Hz, 6'-H); m/z 811 (M+, 0.1%), 782(2), 117(68), and 73(100); m/z (NH3 DCI) 812 (MH+, 1%), 191(25), 132(45), and
90(100). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. f) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-(3-hydroxyρrop-1-oxy)pyrid-5- yl)but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5c, the product from 49e (0.740g,
O.θlmmol) was completely deprotected to give the title compound (0.286g, 65%); vmax (KBr) 3437, 1604, 1493, 1313, 1293, and 1058cm-1; λmax (EtOH) 319nm (εm 20,731); δH (CD3OD) inter alia 0.94 (3H, d, J 7.2Hz, 17-H3), 1.19 (3H, d, J 6.4Hz, 14-H3), 1.91-2.03 (3H, m, 8-H, 2"-H2), 3.73 (2H, t, J 6.3Hz, 3"-H2), 4.46 (2H, t, J 6.3Hz, 1"-H2), 6.36 (1H, s, 2-H), 6.86 (1H, d, J 8.8Hz, 3'-H), 8.17 (1H, dd, J 8.8 and 2.5Hz, 4'-H), and 8.72 (1H, d, J 2.3Hz, 6'-H); δC (CD3OD) 12.3 (C-17), 20.3 (C-14), 33.0 (C-9 and 2"), 41.7 (C-δ), 42.5 (C-4), 43.7 (C-12), 56.7 (C-10), 59.5 (C-3"), 61.2 (C-11), 64.8 (C-1"), 66.4 (C-16), 69.8 (C-6), 70.7 (C-13), 71.5 (C-7), 75.5 (C-5), 97.7 (C- 2), 112.0 (C-3'), 125.6 (C-5'), 133.7 (C-4'), 148.5 (C-6'), 167.8 (C-2'), 163.0 (C-1), and 194.9 (C-3); m/z 481 (M+, 0.5%), 138(60), and 122(100). (Found: M+, 481.2313. C24H35NO9 requires M, 481.2312). A further quantity of the title compound (0.122g, 28%) was obtained after chromatography of the mother liquors. The n.m.r. spectra indicated that the compound was essentially in the enolic form. EXAMPLE 50 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methoxythiazol-5-yl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 2-Methoxythiazole-5-carboxaldehyde
2-Methoxythiazole (contained 25% 2-bromothiazole, 0.50g, 4.3mmol) was dissolved in THF (20ml), cooled to -70%, and treated dropwise with n- butyllithium (1.5M, 3.2ml, 4.8mmol). The mixture was stirred for 75 minutes, then N,N-dimethylformamide (1.16ml, l5mmol) added. Stirred for a further 1½ h, then quenched with saturated ammonium chloride and ether. The phases were separated, the organic washed with water, dried and reduced to a small volume. The crude product was purified by flash chromatography, eluting with 60% ether in pentane, to give the title compound as an orange oil (1.08g); δH (CDCI3) 4.18 (3H, s, OCH3), 7.86
(1H, s, 4-H), and 9.83 (1H, s, CHO), signals were also observed for solvents and a few minor impurities. b) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-4-(2-methoxythiazol-5- yl)-2-oxobut-1-yl]-6S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran Using the method described in 5a, tristrimethylsilylmonone (1.038g,
2mmol) and the product from 50a (max. 3.2mmol) were reacted to give the title compound (1.032g, 78%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 4.05 (3H, s, OCH3), 5.21-5.32 (1H, m, 1-H), and 6.93 (1H, s, 4'-H); m/z 661 (M+, 1%), 226 (20), 143 (39), 129 (46), 117 (72), and 73 (100). (Found: M+, 661.2968. C29H55NO8SSi3 requires M, 661.2956). c) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(2-methoxythiazol-5- yl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 50b (1.000g,
1.51mmol) in benzene (70ml) was reacted with manganese dioxide (3.0g) for 3h to give the title compound (0.43 lg, 43%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 4.13 (3H, s, OCH3), 5.96 (1H, s, 2-H), and 7.75 (1H, s, 4'-H); m/z 659 (M+, 0.1%), 644 (0.2), 164(29), 142(40), 117(89), and 73(100); m/z (NH3 DCI) 660 (MH+, 22%) and 90(100). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. dl 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methoxythiazol-5-yl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran Using the method described in 5c, the product from 50c (0.415g,
0.63mmol) was deprotected to give the title compound (0.243g, 87%); vmax
(KBr) 3424, 1616, 1488, 1401, 1277, 1109, and 1048cm-1; λmax (EtOH) 325nm (εm 15,668); δH (CD3OD) 0.94 (3H, d, J 7.2Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H3), 4.13 (3H, s, OCH3), 6.17 (1H, s, 2-H), and 7.93 (1H, s, 4'- H); δC (CD3OD) 12.3 (C-17), 20.3 (C-14), 33.0 (C-9), 40.3 (C-4), 41.8 (C-8),
43.6 (C-12), 56.9 (C-10), 59.9 (OCH3), 61.3 (C-11), 66.4 (C-16), 69.8 (C-6),
70.7 (C-13), 71.6 (C-7), 75.5 (C-5), 97.9 (C-2), 132.0 (C-5"), 143.3 (C-4'), 160.9 (C-2'), 183.9 (C-1), and 188.1 (C-3); m/z (NH3 DCI) 444 (MH+,
100%), 158(33), 91(79), and 74(36); m/z 443 (M+, 0.5%), 157(51), and 142(100). (Found: M+, 443.1665. C20H29NO8S requires M, 433.1614).
The n.m.r. spectra indicated that the title compound was mainly in the enolic form.
EXAMPLE 51 3R,4R-Dihydroxy-2S-[4-(cyclohexen-1-yl)-2,4-dioxobut-1-yl]-5S-(2S,3S- epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran al 3R,4R-Bistrimethylsilyloxy-2S-[4-(cyclohexen-1-yl)-4-hydroxy-2- oxobut-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran Using the method described in 5a, tristrimethylsilylmonone (1.038g,
2mmol) and cyclohexene-1-carboxaldehyde (2.2mmol) were reacted to give the title compound (0.593g, 47%); δH (CDCI3) inter alia 0.89 (3H, d, J
7.1Hz, 17-H3), 1.19 (3H, d, 16.4Hz, U-H3), 4.13 (1H, td, J 9.5 and 3.0Hz, 5-H), 4.37-4.48 (1H, m, 1-H), and 5.72 (1H, br s, 2'-H); m/z (NH3 DCI) 646 (MNH+4, 15%), 629 (MH+, 3), 536(50), 519 (18), 128(100), and 90(83). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-(cyclohexen-1-yl)-2,4-dioxobut-1- yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S-methylhexyl)tetrahydropyran Using the method described in 6b, the product from 5la (0.58g, 0.92mmol) in benzene (70ml) was reacted with manganese dioxide (1.8g) for 3½ h to give the title compound (0.224g, 39%); δH (CDCI3) inter alia 0.39 (3H, d, J 7.0Hz, 17-H3). 1.19 (3H, d, si 6.3Hz, 14-H3), 5.76 (1H, s, 2-H), and 6.90
(1H, br s, 2'-H); m/z 626 (M+, 2%), 611 (0.6), 334 (13), 151 (33)„ 117 (72), and 73 (100). (Fouind: M+, 626.3492. C31H58O7Si3 requires M,
626.3491). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[4-(cyclohexen-1-yl)-2,4-dioxobut-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran Using the method described in 5c, the product from 5lb (0.212g,
0.34mmol) was deprotected to give the title compound (0.134g, 97%); νmax
(KBr) 3423, 2927, 1640, 1588, 1450, 1110, and 1080cm-1; λmax (EtOH) 307nm (εm 12,570); δH (CD3OD) inter alia 0.94 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, si 6.5Hz, 14-H3), 1.66-1.73 (6H, m, 9-H2, 4'-H2, 5'-H2), 2.14- 2.33 (4H, m, 3'-H2, 6'-H2), 5.86 (1H, s, 2-H), and 6.92 (1H, br s, 2'-H); δC (CD3OD) 12.3 (C-17), 20.3 (C-14), 22.7, 23.2, 24.5 and 27.0 (C-3', 4', 5' and
6'), 33.0 (C-9), 41.7 (C-8), 43.3 (C-4), 43.7 (C-12), 66.9 (C-10), 61.2 (C-11), 66.4 (C-16), 69.8 (C-6), 70.7 (C-13), 71.5 (C-7), 75.4 (C-5), 97.3 (C-2), 134.8 (C-1') , 137.7 (C-2'), 182.9 (C-1), 199.2 (C-3); m/z 410 (M+, 2%), 151 (52), and 109 (100). (Found: M+, 410.2307. C22H34O7 requires M, 410.2305).
The n.m.r. spectra indicated that the title compound was essentially in the enolic form.
EXAMPLE 52 3R,4R-Dihydroxy-2S-[3,5-dioxo-1-(furan-2-yl)hex-1(E)-en-6-yl]-5S-(2S,3S- epoxy-5S-hydroxy-4S-methylhexyl)tetra-hydropyran al 3R,4R-Bistrimethylsilyloxy-2S-[1-(furan-2-yl)-3-hydroxy-5-oxohex- 1(E)-en-6-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and 3-(furan-2-yl)propenal (0.269g, 2.2mmol) were reacted to give the title compound (1.207g, 94%); δH (CDCI3) inter alia 0.90 (3H, d, J
7.0Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H3), 4.7-4.8 (1H, m, 1-H), 6.14 (1H, dd, J 15.8 and 5.4Hz, 1'-H), 6.23 (1H, d, J 3.3Hz, 3"-H), 6.36 (1H, dd, J 3.3 and 1.8Hz, 4"-H), 6.49 (1H, dd, J 15.8 and 1.0Hz, 2'-H), and 7.34 (1H, d, J 1.4Hz, 5"-H); m/z 640 (M+, 0.4%), 622 (0.4), 129 (54), 117 (100), and 73 (98). (Found: M+, 640.3267. C31H56O8Si3 requires M, 640.3283). b) 3R,4R-Bistrimethylsilyloxy-2S-[3,5-dioxo-1-(furan-2-yl)hex-1(E)-en-
6-yl] -5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran Using the method described in 6b, the product from 52a (1.187g,
1.85mmol) in benzene (70ml) was reacted with manganese dioxide (3.0g) for 2h to give the title compound (0.320g, 69%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 5.71 (1H, s, 2-H), 6.38 (1H, d, J l5.6Hz, 1'-H), 6.47 (1H, dd, J 3.4 and 1.9Hz, 4"-H), 6.57 (1H, d, J 3.4Hz, 3"-H), 7.34 (1H, d, J 15.6Hz, 2'-H), and 7.48 (1H, d, J 1.5Hz, 5"- H); m/z 638 (M+, 1%), 623(1), 121(67), 117(89), and 73(100). (Found: M+, 638.3140. C31H54O8Si3 requires M, 638.3127). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. c ) 3R,4R-Dihydroxy-2S-[3,5-dioxo-1-(furan-2-yl)hex-1(E)-en-6-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetraydropyran
Using the method described in 5c, the product from 52b (0.78 lg,
1.22mmol) was deprotected to give the title compound (0.477g, 93%); m.p. 150-151°C; vmax (KBr) 1632, 1594, 1458, 1115, 1017, and 756cm-1; λmax (EtOH) 358nm (εm 33,626); δH (CD3OD) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H3), 5.82 (1H, s, 2-H), 6.43 (1H, d, J
15.7Hz, 1'-H), 6.54 (1H, dd, 13.4 and 1.9Hz, 4"-H), 6.71 (1H, d, J 3.4Hz, 3"-H), 7.36 (1H, d, J l5.7Hz, 2'-H), and 7.62 (1H, d, J 1.4Hz, 5"-H); δc (CD3OD) 12.2 (C-17), 20.3 (C-14), 33.0 (C-9), 41.7 (C-8), 43.7 (C-12), 44.1 (C-4), 66.8 (C-10), 61.3 (C-11), 66.4 (C-16), 69.8 (C-6), 70.7 (C-13), 71.5 (C- 7), 75.3 (C-5), 102.6 (C-2), 113.6, ll5.4, 121.3, 127.2, and 146.2 (C-1', 2', 3", 4" and 5"), 163.1 (C-2'') (C-3 and 1 not visible); m/z 422 (M+, 4%), 163 (40), and 121(100); (Found: M+, 422.1946. C22H30O8 requires M,
422.1941). The spectra indicated that the title compound was essentially in the enolic form.
EXAMPLE 53 3R,4R-Dihydroxy-2S-[3,5-dioxo-1-(4-methoxyphenyl)hex-1(E)-en-6-yl] -5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran al 3R,4R-Bistrimethylsilyloxy-2S-[3-hydroxy-1-(4-methoxyphenyl)-5- oxohex-1(E)-en-6-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 5a, tristimethylsilylmonone (1.038g, 2mmol) and 4-methoxycinnamaldehyde (0.357g, 2.2mmol) were reacted to give the title compound (1.200g, 88%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H3), 3.81 (3H, s, OCH3), 4.68-4.78 (1H, m, l-H), 6.07 (1H, dd, J 15.9 and 6.1Hz, 1'-H), 6.58 (1H, d, J 15.9Hz, 2'-H), 6.85 (2H, d, J 8.7Hz, 2"-H, 6"-H), and 7.31 (2H, d, J 8.7Hz, 3"-H, 5"- H); m/z (NH3 DCI) 698 (MNH4+, 5%), 680 (MH+, 1), 180(38), 163(100), and 90(52). b) 3R,4R-Bistrimethylsilyloxy-2S-[3,5-dioxo-1-(4-methoxyphenyl)hex- 1(E)-en-6-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 53a (1.157g,
1.70mmol) in benzene (70ml) was reacted with manganese dioxide (3.0g) for 2h to give the title compound (0.840g, 73%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 3.84 (3H, s, OCH3), 5.71 (1H, s, 2-H), 6.36 (1H, d, J 15.9Hz, 1'-H), 6.90 (2H, d, J 8.8Hz, 2"-H, 6"-H), 7.47 (2H, d, J 8.8Hz, 3"-H, 5"-H), and 7.56 (1H, d, J 15.9Hz, 2'-H); m/z 678 (M+, 0.4%), 663 (0.7), 161(82), 117(63), and 73(100). (Found: M+, 678.3461. C34H58O8Si3 requires M, 678.3440). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-[3,5-dioxo-1-(4-methoxyphenyl)hex-l(E)-en-6- yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran Using the method described in 5c, the product from 51b (0.815g, 1.2mmol) was deprotected to give the title compound (0.46δg, 84%); m.p. 130-132°C; νmax (KBr) 3495, 1636, 1588, 1511, 1251, 1174, and 1114cm-1; λmax (EtOH) 359nm (εm 35,962); δH (CD3OD) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.5Hz, 14-H3), 3.82 (3H, s, OCH3), 5.82 (1H, s, 2-H), 6.51 (1H, d, J 15.9Hz, 1'-H), 6.95 (2H, d, J 8.8Hz, 2"-H, 6"-H), and 7.54 (3H, 2d, J 15.9 and 8.8Hz, 2"-H, 3"-H, 5"-H); δC (CD3OD/CDCI3) 12.2 (C- 17), 20.3 (C-14), 32.6 (C-9), 41.1 (C-8), 43.3 (C-12), 43.7 (C-4), 56.8
(OCH3), 56.6 (C-10), 61.1 (C-11), 66.2 (C-16), 69.4 (C-6), 70.5 (C-13), 71.1 (C-7), 75.0 (C-5), 101.8 (C-2), 115.1 (C-2" and 6"), 121.0 (C-2'), 128.7 (C-1"), 130.4 (C-3" and 5"), 140.6 (C-1'), 162.3 (C-4"), 178.1 (C-1), and 199.4 (C-3); m/z 462 (M+, 0.6%) and 161(100). (Found: M+, 462.2270. C25H34O8 requires M, 462.2254). The n.m.r. spectra indicated that the title
compound was essentially in the enolic form.
EXAMPLE 54 3R,4R-Dihydroxy-2S-(3,5-dioxo-1-phenylhex-1-yn-6-yl)-6S-(2S,3S-epoxy- 6S-hydroxy-4S-methylhexyl)tetrahydropyran al 3R,4R-BistrimethylsilyIoxy-2S-(3-hydroxy-5-oxo-1-phenylhex-1-yn-
6-yl)-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and phenylpropynal (0.27ml, 2.2mmol) were reacted to give the title compound (1.139g, 36%); δH (CDCI3) inter alia 0.90 (3H, d, si 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 5.00-5.10 (1H, m, 1-H), and 7.27-7.49 (5H, m, Ar-H); m/z 648 (M+, 6%), 117(80), and 73(100). (Found: M+, 648.3346. C33H56O7Si3 rquires M, 648.334). hi 3R,4R-Bistrimethylsilyloxy-2S-(3,5-dioxo-1-phenylhex-1-yn-6-yl)- 5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
The product from 52a (0.660g, lmmol) in dichloromethane (60ml) was stirred with manganese dioxide (active black, 1.38g) at room temperature for 75 minutes. After this time the mixture was filtered and the filtrate evaporated. The crude product was purified by column chromatography, eluting with 3-10% ethyl acetate in hexane, to give the title compound (0.328g, 50%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, 16.3Hz, 14-H3), 5.95 (1H, s, 2-H), and 7.32-7.60 (5H, m, Ar-H); m/z 646 (M+, 0.2%), 631 (0.6), 258(28), 186(41), 117(46), and 73(100). (Found: M+, 646.3164. C33H54O7Si3 requires M, 646.3177). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. c) 3R,4R-Dihydroxy-2S-(3.5-dioxo-1-phenyl(hex-1-yn-6-yl))-5S-(2S,3S- epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5c, the product from 54b (0.320g,
0.49mmol) was deprotected to give the title compound (0.117mg, 55%); νmax (KBr) 3419, 2203, 1602, 1443, 1110, 1043, and 758cm-1; λmax
(EtOH) 328nm (εm 20,521); δH (CD3OD) inter alia 0.94 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H3), 5.98 (1H, s, 2-H, exchanging rapidly), and 7.38-7.61 (5H, m, Ar-H); δC (CDCI3) 12.7 (C-17), 20.6 (C-14), 31.6 (C-9), 36.4 (C-4), 39.7 (C-8), 42.8 (C-12), 55.7 (C-10), 61.3 (C-11), 65.7 (C-16), 68.7 (C-6), 70.1 (C-7), 71.2 (C-13), 73.7 (C-5), 85.1 and 94.3 (C=C), 105.6 (C-2), 120.3 (C-1'), 126.0-132.6 (C-Ar), C-1 and C-3 assignments uncertain as all forms rapidly interconverting; m/z 430 (M+, 18%), 412(5), 200(30), 186(100), and 110(66). (Found: M+, 430.1984. C24H30O7 requires M, 430.1992). The spectra indicated that the title compound was mainly in the enolic form.
EXAMPLE 55 3R,4R-Dihydroxy-2S-[4-(2-dimethylaminopyrimidin-5-yl)-2,4-dioxobut-1- yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 2-Dimethylaminopyrimidine-5-carboxaldehyde 5-Bromo-2-chloropyrimidine was converted, using the methods described in 30a, to the title compound (0.495g, 62%); δH (CDCI3) 3.31 (6H, s, N(CH3)2), 8.73 (2H, s, 4-H, 6-H), and 9.77 (1H, s, CHO); m/z 151 (M+, 100%), 136(55), 122(74), and 95(45). (Found: M+, 151.0747. C9H9N3O requires M, 151.0746). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-(2-dimethylaminopyrimidin-5-yl)- 4-hydroxy-2-oxobut-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and 2-dimethylaminopyrimidine-5-carboxaldehyde (0.333g, 2.2mmol) were reacted to give the title compound (0.997g, 74%); δH
(CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.4Hz, 14- H3), 3.20 (6H, s, N(CH3)2), 4.95-5.05 (1H, m, 1-H), and 3.33 (2H, s, 4'-H, 6'-H); m/z669 (M+, 1%), 176(46), 151(42), 129(72), 117(93), and 73(100). (Found: M+, 669.3645. C32H59N3 O7Si3 requires M, 669.3661). s) 3R,4R-BistrimethyIsilyloxy-2S-[4-(2-dimethylaminopyrimidine-5- yl)-2,4-dioxobut-1-yl] -5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 53b (0.949g,
1.42mmol) in benzene (70ml) was reacted with manganese dioxide (3g) for 3h to give the title compound (0.421g, 45%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.4Hz, 14-H3), 3.28 (6H, s,
N(CH3)2), 6.07 (1H, s, 2-H), and 8.80 (2H, s, 4'-H, 6'-H); m/z 667 (M+, 1%), 652(2), 192(50), 150(74), and 73(100). The 1H n.m.r. spectrum indicated that the titie compound was essentially in the enolic form. dl 3R,4R-Dihydroxy-2S-[4-(2-dimethylaminopyrimidin-5-yl)-2,4- dioxobut-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S- methylhexyl)tetrahydropyran Using the method described in 5c, the product from 53c (0.387g,
0.58mmol) was deprotected to give the title compound (0.253g, 97%); vmax (KBr) 3478, 1604, 1559, 1412, 1326, 1284, 1109, and 1059cm-1; λmax (EtOH) 344nm (εm 29,85δ); δH (CD3OD) inter alia 0.94 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, 16.4Hz, 14-H3), 3.26 (6H, s, N(CH3)2), 6.26 (1H, s, 2- H), and 8.81 (2H, s, 4'-H, 6'-H); δC (CD3OD/CDCI3) 12.2 (C-17), 20.2 (C- 14), 32.6 (C-9), 37.6 (N(CH3)2), 41.2 (C-8), 41.6 (C-4), 43.3 (C-12), 56.6 (C- 10), 61.1 (C-11), 66.2 (C-16), 69.4 (C-6), 70.5 (C-13), 71.1 (C-7), 75.1 (C-5), 96 (C-2), 117.3 (C-5*), 158.4 (C-4' and 6'), 163.4 (C-2'), 183.1 (C-1), and 191.6 (C-3); m/z 451 (M+, 2%), 166(30), and 150(100). (Found: M+,
451.2343. C22H33N3O7 requires M, 451.2319). The n.m.r. spectra indicated that the title compound was essentially in the enolic form.
EXAMPLE 56 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methoxypyrimidin-5-yl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran al 2-Methoxypyrimidine-5-carboxaldehyde
Using the method described in 21a, 5-bromo-2-methyoxypyrimidine (0.58g, 3.07mmol) was converted to the title compound (0.185g, 44%); δH (CDCl3) 4.14 (3H, s, OCH3), 9.00 (2H, s, 4-H, 6-H), and 10.03 (1H, s, CHO); m/z 133 (M+, 100%), 123(20), and 108(80). (Found: M+, 138.0433. C6H6N2O2 requires M, 138.0429). hi 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-4-(2-methoxypyrimidin- 5-yl)-2-oxobut-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methyIhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (0.50g, 0.97mmol) and 2-methoxypyrimidine-5-carboxaldehyde (0.134g,
0.97mmol) were reacted to give the title compound (0.384g, 61%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H3), 4.02 (3H, s, OCH3), 5.11-5.21 (1H, m, 1-H), and 8.53 (2H, s, 4'-H, 6'- H); m/z (NH3 DCI) 657 (MH+, 70%), 536(31), and 139(100). c) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(2-methoxypyrimidin-5- yl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S-methyl- hexyl)tetrahydropyran
Using the method described in 6b, the product from 54b (0.373g,
0.57mmol) in benzene (50ml) was reacted with manganese dioxide (1.0g) for 3h to give the title compound (0.160g, 43%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, si 6.3Hz, 14-H3), 4.09 (3H, s, OCH3), 6.17 (1H, s, 2-H), and 8.98 (2H, s, 4'-H, 6'-H); m/z 654 (M+, 2%), 639(1), 117(98), and 73(100). (Found: M+, 654.3186. C30H54N2O8Si3 requires M, 654.3186). dl 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methyoxypyrimidin-5-yl)but-1- yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran Using the method described in 5c, the product from 54c (0.15g, 0.23minol) was deprotected to give the title compound (0.045g, 45%); δH (CD3OD) 0.94 (3H, d, J 7.0Hz, 17-H3), 1.19 (3H, d, J 6.5Hz, 14-H3), 1.30-1.48 (1H, m, 12-H), 1.64-1.74 (2H, m, 9-H2), 1.91-2.03 (1H, m, 8-H), 2.52 (1H, dd, J 14.8 and 9.4Hz, 4-H), 2.70 (1H, dd, J 7.5 and 2.2Hz, 11-H), 2.81 (1H, dt, J 5.7 and 2.2Hz, 10-H), 2.92 (1H, dd, J 14.8 and 2.9Hz, 4-H), 3.44 (1H, dd, J 9.2 and 3.0Hz, 6-H), 3.57 (1H, d, J 11.3Hz, 16-H), 3.73-3.84 (1H, m, 13-H), 3.87-3.95 (2H, m, 7-H, 16-H), 4.03 (1H, dt, J 3.0 and 9.4Hz, 5-H), 4.09 (3H, s, OCH3), 6.42 (1H, s, 2-H), and 9.08 (2H, s, 4'-H, 6'-H); m/z 438 (M+, 3%), 153(71), and 137(100). (Found: M+, 438.2007. C21H30N2O8 requires M, 438.2002). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 57 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{2-azidoethoxy)phenyl)but-1-yI]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methyIhexyl)tetrahydropyran a) 4-(2-Azidoethoxy)benzaIdehyde
A solution of 4-(2-hydroxyethoxy)benzaldehyde (1.328g, 8mmol) in dichloromethane (30ml) was treated with triethylamine (1.34mmol, 9.6mmol) and methane sulphonyl chloride (0.7ml, 9mmol). After 1 hour the reaction mixture was diluted with dichloromethane, washed with dilute citric acid, saturated sodium hydrogen carbonate and brine then dried and evaporated.
The residue was dissolved in dichloromethane (30ml) and treated with tetramethyl guanidinium azide (1.42g, 9mmol). After 24 hours more tetramethyl guanidinium azide (1.42g, 9mmol) was added and the mixture was heated at 40°C. After 48 hours at 40°C followed by 2 days at room temperature the reaction mixture was washed with water, dilute citric acid, saturated sodium hydrogen carbonate and brine then dried and evaporated. Chromatography on silica eluting with ethyl acetate hexane mixtures gave the title compound (1.17g, 76%); νmax (CH2CI2) 2105, 1675, 1600cm-1; δH (CDCI3) 3.65 (2H, t, J 5.0Hz), 4.24 (2H, t, J 5.0Hz), 7.06 (2H, d, J 8.8Hz), 7.88 (2H, d, J 8.8Hz), 9.91 (1H, s). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-2-oxo-4-(4-{2- azidoethoxy)phenyl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran Using the method described in 5a, tristrimethylsilylmonone (2.076g,
4mmol) and the product from 57a (764mg, 4mmol) were reacted to give the title compound (2.31g, 81%); δH (CDCI3) inter alia 0.88 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 3.59 (2H, t, J 5.0Hz, ArOCH2), 5.06- 5.18 (1H, m, 1.H), 6.90 (2H, d, J 8.6Hz, 3',5'-H2), 7.25-7.38 (2H, m, 2',6'- H2). c) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(4-{2- azidoethoxy)phenyl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 57b (2.25g, 3.17mmol) in benzene (140ml) was reacted with manganese dioxide (4.5 lg), for 3 hours to give the title compound (1.35g, 60%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 3.63 (2H, t, J 5.0Hz, 1"-H2), 4.22 (2H, t, J 5.0Hz, 2"-H2), 6.22 (1H, s, 2-H), 6.96 (2H, d, J 8.8Hz, 3',5'-H2), 7.88 (2H, d, J 8.8Hz, 2',6'-H2); (Found M+, 707.3439.
C33H57N3O8Si3 requires M 707.3454). d) 3R,4R-Dihydroxy-2S-[2,4-dioxo-2-oxo-4-(4-{2-azidoethoxy}phenyl)but- 1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5c, the product from 57c (120mg, 0.17mmol) was deprotected to give the title compound (70mg, 90%); νmax (KBr) 3424, 2112, 1604, 1507cm-1; λmax (EtOH) 324.5nm (εm 21,260); δH (CDCI3) inter alia 0.94 (3H, d, J 7.1Hz, 17-H3), 1.21 (3H, d, J 6.3Hz, 14-H3), 4.21 (2H, t, J 5.2Hz, 2"-H2), 6.21 (1H, s, 2-H), 6.93 (2H, d, J 8.9Hz, 3'5'-H2), 7.86 (2H, d, J 8.9Hz, 2'6'-H2); δC (CDCI3) 12.7 (C-17), 20.8 (C-14), 31.6 (C- 9), 39.6 (C-8), 42.8 (C-4), 42.8 (C-12), 50.0 (C-1"), 56.7 (C-10), 61.3 (C-11), 65.6 (C-16), 67.2 (C-2"), 69.0 (C-7), 70.3 (C-6), 171.3 (C-13), 73.9 (C-5), 96.7 (C-2), 114.5 (C-3',5'), 127.5 (C-1'), 129.3 (C-2'6'), 161.8 (C-4'), 182.7 (C-1), 194.3 (C-3); m/z (NH3DCI) 492 (MH+, 100%). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. Example 58
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{2-N-methyl-N-2- pyridylaminoethoxy}phenyl)but-1-yl-5S-(2S,3S-epoxy-5S-hydroxy-4S- methylhexyl)tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-2-oxo-4-(4-{2-N-methyl-
N-2-pyridylaminoethoxylphenyl)but-1-yl]-5S-(2S,3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (518mg, lmmol) and 4-(2-N-methyl-N-2 pyridylaminoethoxy)benzaldehyde (256mg, lmmol) were reacted to give the title compound (580mg, 75%); δH (CDCl3) inter alia 0.90 (3H, d, 7.0Hz, 17-H3), 1.20 (3H, d, 6.3Hz, 14-H3), 3.15 (3H, s, N-Me), 5.06-6.16 (1H, m, 1-H), 6.48-6.59 (2H, m, Ar-H), 6.88 (2H, d, J8.8Hz, 3",5'-H2), 7.21-7.30 (2H, m, Ar-H), 7.41-7.62 (1H, m, Ar- H), .8.03-8.19 (1H, m, Ar-H); m/z (NH2 DCI) 775 (MH+, 5%), 257 (100%). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(4-{2-N-methyI-N-2- pyridylaminoethoxy)phenyl)but-1-yl-5S-(2S,3S-epoxy-5S- trimethylsiIyloxy-4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 58a (560mg,
0.72mmol) in benzene (60ml) was reacted with manganese dioxide (1.12g) for 4 hours to give the title compound (277mg, 49%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 3.16 (3H, s, N- Me), 4.26 (2H, t, J 5.6Hz, 1'-H2), 6.20 (1H, s, 2-H), 6.48-6.62 (2H, m, 3"',5'"-H2), 6.94 (2H, d, J 8.8Hz, 3',5'-H2), 7.47 (1H, dd, J 1.9, 7.1Hz, 5'"- H), 7.84 (2H, d, J8.8Hz, 3',6'-H2), 8.18 (1H, dd, J 1.4, 4.8Hz, 6"'-H2); (Found: M+, 772.3983. C39H64N2O8Si3 requires M 772.3971). c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-(2-N-methyl-N-2- pyridylaminoethoxyιphenyl)but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S- methylhexyl)tetrahydropyran
Using the method described in 5c, the product from 58b (250mg,
0.32mmol) was deprotected to give the title compound (180mg, 94%); νmax (KBr) 3423, 1599, 1558, 1499, 1452cm-1; λmax (EtOH) 324.5nm (εm 25,150), 248.5 (18,630); δH (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17- H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 3.13 (3H, s, N-Me), 4.27 (2H, t, J 5.6Hz, 1"-H2), 6.21 (1H, s, 2-H), 6.53 (1H, d, J 8.7Hz, 3"'-H), 6.58 (1H, dd, J 5.0, 6.8Hz, 5"'-H), 6.95 (2H, d, J 8.8Hz, 3',5'-H2), 7.48 (1H, dd, J 1.9, 7.1Hz, 4"'-H), 7.86 (2H, d, J 8.8Hz, 3',6'-H2), 6.17 (1H, d, J 4.9Hz, with further fine coupling, 6'"-H); δC (CDCI3) 12.7 (C-17), 20.7 (C-14), 31.6 (C-9), 37.6 (N-Me), 39.6 (C-8), 42.7 (C-4), 42.8 (C-12), 49.3 (C-1"), 55.7 (C-10), 61.2 (C- 11), 65.6 (C-16), 66.7 (C-2"), 69.2 (C-7), 70.3 (C-6), 71.3 (C-13), 73.8 (C-5), 96.4 (C-2), 105.7 (C-2"'), 111.9 (C-5'"), 114.5 (C-3'5'), 126.7 (C-D, 129.2 (C- 2',6"), 137.3 (C-4'''), 147.8 (C-6'"), l5δ.2 (C-4'), 162.6 (C-2"'), 182.8 (C-1), 193.9 (C-3); m/z (NH3 DCI) 556 (M+, 55%), 121 (100%). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. Example 59
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-(2-piperidinylethoxy)phenyl)but-1-yl- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-2-oxo-4-(4-(2- piperidinylethoxy}phenyl)but-1-yl]-5S-(2S,3S-epoxy-6S-trimethylsilyloxy- 4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.0388g, 2mmol) and 4(2-piperidinylethoxy)benzaldehyde (466mg, 2mmol) (HD Cossey et al, JCS, 1963, 4322) were reacted to give the title compound (1.0g, 66%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, U-H3), 5.08-5.18 (1H, m, 5-H), 6.δ7 (2H, d, J 8.7Hz, 3',5'-H2), 7.23-7.34 (2H, m, 2',6'-H2). b) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(4-{2- piperidinylethoxy}phenyl)but-1-yl]-5S-(2S,3S-epoxy-6S-trimethylsilyloxy-
4S-methylhexyl)tetrahydropyran Using the method described in 6b, the product from 59a (1.0g, 1.3mmol) in benzene (70ml) was reacted with manganese dioxide (l.5g) for 3 hours to give the title compound (454mg, 45%); δH (CDCI3) inter alia 0.69 (3H, d, J 7.0Hz, 17-H3), 1.21 (3H, d, J 6.4Hz, 14-H3), 6.20 (1H, s, 2-H), 6.93 (2H, d, J 8.8Hz, 3',5'-H2), 7.87 (2H, d, J 8.8Hz, 2',6'-H2); (Found: M+, 749.4181. C38H67NO8Si3 requires M 749.4176). c) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{2- piperidinylethoxy)phenyl)but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S- methylhexyl)tetrahydropyran
Using the method described in 5c, the product from 59b (450mg, 0.6mmol) was deprotected to give the title compound (180mg, 66%); νmax (KBr) 3425, 2933, 1602, 1509, 1453cm-1; λmax (EtOH) 326nm (εm 2000); δH (CDCl3) inter alia 0.93 (3H, d, J 7.1Hz, 17-H3), 1.22 (3H, d, J 6.3Hz, 14- H3), 6.20 (1H, s, 2-H), 6.96 (2H, d, J 8.8Hz, 3',5'-H2), 7.85 (2H, d, J 8.8Hz, 2',6'-H2); δC (CDCI3) 12.8 (C-17), 20.9 (C-14), 24.2 (C-4'''), 25.9 (C-3"',5'"), 31.8 (C-9), 42.7 (C-4), 43.0 (C-12), 65.2 (C-2'",6'"), 55.8 (C-10), 57.8 (C-2"), 61.3 (C-11), 65.7 (C-16), 66.3 (C-1"), 69.2 (C-7), 70.5 (C-6), 71.9 (C-13), 74.0 (C-5), 96.6 (C-2), 114.7 (C-3',5'), 127.0 (C-1'), 129.3 (C-2'6'), 162.7 (C-4'), 183.0 (C-1), 194.0 (C-3); (Found: M+, 533.3001. C29H43NO8 requires M 533.2989). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 60
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{4-pyridylmethyloxy)phenyl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 4-(4-Pyridylmethyloxy)benzaldehyde
A solution of p-hydroxybenzaldehyde (436mg, 4mmol) in THF (50ml) and 0°C under argon was sequentially treated with triphenylphosphine (2.1g, 8mmol), 4-hydroxymethylpyridine (976mg, 8mmol) and
diethylazodicarboxylate (1.26ml, 8mmol). After ¼ hour ice bath removed. After 1 hour reaction mixture evaporated, added ethyl acetate and 5N hydrochloric acid. Acid phase separated, covered with ethyl acetate and basified with saturated sodium hydrogen carbonate. Organic phase separated, dried and evaporated. The residue was chromatographed on silica eluting diochloromethane/ethyl acetate mixtures to give the title compound (440mg, 52%); δH (CD3OD) 5.21 (2H, s, 1'-H2), 7.04 (2H, d, J 8.7Hz, 3.5-H2), 7.51 (2H, d, J 6.1Hz, 3',5'-H2), 7.89 (2H, d, J 8.7Hz, 2,6- H2), 8.60 (2H, d, J 6.1Hz, 2',6'-H2), 9.92 (1H, s, -CHO). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-2-oxo-4-(4-(4- pyridylmethyloxy}phenyl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy- 4S-methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and the product from 60a (426mg, 2mmol) were reacted to give the title compound (1.07g, 73%); δH (CDCI3) inter alia 0.92 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 4.06-4.18 (1H, m, 5-H), 5.10 (2H, s, 1"-H2), 5.10-6.18 (1H, m, 1-H), 6.93 (2H, d, J 8.7Hz, 3',5'-H2), 7.23-7.39 (4H, m, Ar-H), δ.62 (2H, d, J 5,9Hz, 2"',6'"-H2); m/z (NH3 DCI) 732 (MH+, 80%) 94 (100%). c) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(4-(4- pyridylmethyloxy)phenyl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy- 4S-methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 60b (1.0g, 1.37mmol) in benzene (70ml) was reacted with manganese dioxide (2.25g) for 3 hours to give the title compound (600mg, 60%);a δH (CDCI3) 0.90 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 5.16 (2H, s, 1"-H2), 6.22 (1H, s, 2-H), 7.02 (2H, d, J 8.6Hz, 3',5'-H2), 7.37 (2H, d, J 5.8Hz, 3"",5'"-H2), 7.39 (2H, d, J 8.6Hz, 2',6'-H2), 8.65 (2H, d, J 5.8Hz, 2"',6'"-H2); (Found: M+, 729.3546. C37H59NO8Sio3 requires M 729.3549. d) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{4- pyridylmethyloxy}phenyl)but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S- methylhexyl)tetrahydropyran
Using the method described in 5c, the product from 60c (40mg,
0.055mmol) was deprotected to give the title compound (22mg, 78%); νmax
(KBr) 3418, 1715, 1602, 1507, 1450cm-1; λmax (EtOH) 325nm (εm 21140); δH (CDCI3) inter alia 0:92 (3H, d, J 7.0Hz, 17-H3), 1.23 (3H, d, J 6.3Hz, 14-H3), 5.15 (2H, s, 1"-H2), 6.20 (2H, s, 2-H), 7.00 (2H, d, J 8.8Hz, 3',5'-
H2), 7.37 (2H, d, J 5.8Hz, 3'",5'''-H2), 7.88 (2H, d, J 8.8Hz, 2',6'-H2), 8.63
(2H, d, J 5.8Hz, 2",5"-H2); m/z (NH3 DCI) 514 (MH+, 55%), 94 (100%).
The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 61 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{5-nitrofuran-2-ylmethyloxy}phenyl) but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran a) 4-(5-Nitrofuran-2-ylmethyloxy)benzaIdehyde A solution of 2-hydroxymethyl-5-nitrofuran (S. Brokerman and
T. Globerman, Tet, 1974, 30, 3873) (1.22g, 10mmol) in THF (100ml) under argon at 5°C was sequentially treated with triphenylphosphine (2.62g, 10mmol), p-hydroxybenzaldehyde (1.14g, 8mmol) and
dimethylazodicarboxylate (1.46g, 10mmol). After 2 hours reaction mixture diluted with ethyl acetate, washed with water then dried and evaporated. The residue was chromatographed on silica eluting with
hexane/dichloromethane mixtures to give the title compound (1.6g, 81%); δH (CDCl3) 5.19 (2H, s, 1'-H2), 6.68 (1H, d, J 3.7Hz, 3"-H), 7.08 (2H, d, J 8.7Hz, 3,5-H2), 7.34 (1H, d, J 3.7Hz, 4"-H), 7.90 (2H, d, J 8.7Hz, 2,6-H2). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-2-oxo-4-(4-{5-nitrofuran- 2-ylmethyloxy}phenyl)but-1-yl] -5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran Using the method described in 5a, tristrimethylsilylmonone (1.038g,
2mmol) and the product from 61a (494mg, 2mmol) were reacted to give the title compound (1.16g, 76%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H3), 5.06 (2H, s, 1"-H2), 5.07-5.12 (1H, m, 1-H), 6.62 (1H, d, J 3.3Hz, 3'''-H), 6.92 (2H, d, J 8.7Hz, 3',5'-H2), 7.26-7.48 (3H, m). c) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(4-(5-nitrofuran-2- ylmethyloxy}phenyl)but-1-yl]-6S-(2S,3S-epoxy-5S-trimethyIsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 6b, the product from 61b (1.16g, 1.52mmol) in benzene (60ml) was reacted with manganese dioxide (3.02g) for 5 hours to give the title compound (270mg, 23%); δH (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, 17-H3), 1.18 (3H, d, J 6.4Hz, 14-H3), 5.13 (2H, s, 1"-H2), 6.20 (1H, s, 2-H), 6.63 (1H, d, J 3.6Hz, 3"'-H), 6.96 (2H, d, J 9.0Hz, 3,5-H2), 7.32 (1H, d, J 3.6Hz, 4"'-H), 7.90 (2H, d, J 8.9Hz, 2',6'-H2); m/z (NH3 DCI) 781 (MNH4 +, 20%), 764 (MH+, 50%), 112 (100%). d) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-(5-nitrofuran-2- ylmethyloxy}phenyl)but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S- methylhexyl)tetrahydropyran Using the method described in 5c, the product from 61c (250mg,
0.33mmol) was deprotected to give the title compound (126mg, 70%); νmax (KBr) 3463, 1604, 1507, 1468cm- 1; λmax (EtOH) 319.5nm (εm 30,504); δH (d4-MeOH) inter alia 0.96 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, U-H3), 5.23 (2H, s, 1"-H2), 6.36 (1H, s, 2-H), 6.85 (1H, d, J 3.6Hz, 3"'-H), 7.11 (2H, d, J 6.8Hz, 3',5'-H2), 7.44 (1H, d, J 3.6Hz, 4"'-H), 7.93 (2H, d, J 8.8Hz, 2',6'-H2); δC (CD3OD) 12.4(C-17), 20.5 (C-14), 33.1 (C-9), 41.8 (C- 8), 42.7 (C-4), 43.9 (C-12), 57.0 (C-10), 61.4 (C-11), 63.2 (C-16), 66.7 (C-2"), 70.0 (C-7), 70.9 (C-6), 71.1 (C-13), 75.7 (C-5), 97.7 (C-2), 113.4 (C-2"'), 114.3 (C-3'"), 116.0 (C-3',5'), 129.6 (C-1'), 130.4 (C-2',6'), 154.9 (C-1"'), 162.9 (C-4'), 184.1 (C-1), 195.1 (C-3); m/z (NH3 DCI) 565 (MNH4 +, 8%), 548 (MH+, 20%), 112 (100%). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Example 62
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{furan-2-ylmethyloxy}phenyl)but-1- yl]-5S-(2S,3S-epoxy-6S-hydroxy-4S-methylhexyl)tetrahydropyran a) 4-(Furan-2-ylmethyloxy)benzaldehyde
Furfurylalcohol (0.86ml, 10mmol) was added dropwise to a cold (5°C) mixture of sodium hydride (80%, 300mg, 10mmol) in DMF (40ml). After 1 hour p-fluoro-benzaldehyde (1.07ml, 10mmol) was added. After 3 hours reaction mixture poured into water and extracted with ethyl acetate.
Organic phase washed with dilute sodium carbonate and brine then dried and evaporated. Chromatography on silica eluting ethyl acetate/hexane mixtures gave the title compound (700mg, 35%); δH (CDCI3) inter alia 5.10 (2H, s, 1'-H2), 6.38 (1H, dd, J 1.9, 3.2Hz, 4"-H), 6.46 (1H, d, J 3.1Hz, 5" -H), 7.04 (2H, d, J 8.7Hz, 3,5-H2), 7,41 (1H, bs, 3"-H), 7.86 (2H, d, J δ.7Hz, 2,6-H2), 9.92 (1H, s, CHO). b) 3R,4R-Bistrimethylsilyloxy-2S-[4-hydroxy-2-oxo-4-(4-(furan-2- ylmethyloxy)phenyl)but-1-vl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran
Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and the product from 62a (400mg, 2mmol) were reacted to give the title compound (686mg, 43%); δH (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H3), 1.21 (3H, d, J 6.3Hz, 14-H3), 4.98 (2H, s, 1"-H2), 5.06-5.17 (1H, m, 5-H), 6.39 (1H, dd, J 1.9, 3.2Hz, 4"'-H), 6.41 (1H, d, J 3.2Hz, 3'"-H), 6.96 (2H, d, J 8.6Hz, 3',5'-H2), 7.24-7.35 (2H, m, 2',6'-H2), 7.45 (1H, d, J 1.7Hz, 5'"-H); m/z (NH3 DCI) 738 (MNH4 + , 25%), 203 (100%). c) 3R,4R-Bistrimethylsilyloxy-2S-[2,4-dioxo-4-(4-{furan-2- ylmethyloxy)phenyl)but-1-yl]-5S-(2S,3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl)tetrahydropyran Using the method described in 6b, the product from 62b (650mg, 0.9mmol) in benzene (60ml) was reacted with manganese dioxide (1.3g) for 3 hours to give the title compound (293mg, 43%); δH (CDCI3) 0.89 (3H, d, J 7.1Hz, 17-H3), 1.20 (3H, d, J 6.2Hz, 14-H3), 4.07-4.16 (1H, m, 5-H), 5.07 (2H, s, 1''-H), 6.20 (1H, s, 2-H), 6.41 (1H, dd, J 1.9, 3.2Hz, 4'"-H), 6.47 (1H, d, J 3.4Hz, 3'''-H), 7.02 (2H, d, J 8.9Hz, 3',5'-H2), 7.45 (1H, d, J 2.0Hz, 5"'-H), 7.88 (2H, d, J 8.9Hz, 3',6'-H2); m/z (NH3 DCI) 719 (MH+, 40%), 90 (100%). d) 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{furan- 2y]methyloxy)phenyl)but-1-yl] -5S-(2S,3S-epoxy-5S-hydroxy-4S- methylhexyl)tetrahydropyran
Using the method described in 5c, the product from 62c (260mg,
0.36mmol) was deprotected to give the title compound (15δmg, 87%); νmax (KBr) 3424, 1716, 1603, 1507, 1452cm-1; λmax (EtOH) 324.5nm (εm
22,418); δH (CDCI3) inter alia 0.92 (3H, d, 7.1Hz, 17-H3), 1.22 (3H, d, J 6.3Hz, 14-H3), 5.09 (2H, s, 1"-H), 6.20 (1H, s, 2-H), 6.40 (1H, dd, J 1.9, 3.1Hz, 4"'-H), 6.47 (1H, d, J 3.1Hz, 3"'-H), 7.04 (2H, d, J 8.9Hz, 3',5'-H2), 7.88 (2H, d, J 8.9Hz, 2',6'-H2); δC (CDCI3) 12.7 (C-17), 20.8 (C-14), 31.6 (C-9), 39.6 (C-8), 42.5 (C-4), 42.8 (C-12), 64.2 (C-10), 61.3 (C-11), 62.4 (C- 16), 65.6 (C-1"), 69.1 (C-7), 70.3 (C-6), 71.3 (C-13), 73.9 (C-5), 96.6 (C-2), 110.4 (C-3'"), 110.6 (C-4'"), 127.3 (C-1'), 129.2 (C-2',6'), 143.6 (C-5'"), 149.5 (C-2""), 162.0 (C-4'), 182.7 (C-1), 194.2 (C-3); m/z (NH3 DCI) 503 (MH+, 85%), 83 (100%). The 1H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.
Biological Data
The activity ofthe Examples 1 to 62 against various bacteria* which are important in the diseases of humans was assayed in vitro using serial dilutions in nutrient agar with 5% chocolated horse blood. The MIC's were determined after incubation for 18h at 37°C and values in the range 0.03 to 128 mg/ml-1 were observed.
* H. influenzae Q1:
B. catarrhalis 1502;
S. pyogenes CN10;
S. pneumoniae PU7; and
S. aureus Oxford.
The antibacterial activity of compounds of the instant invention against Legionella organisms are assayed in the following manner:
All compounds to be tested are dissolved in distilled water. Organism: L.pneumophila 1624, serogroup 1. The culture is thawed from frozen skim milk stocks and streaked onto supplemented buffered charcoal yeast extract agar (BCYEα, Oxoid). Three days later, colonies are suspended into tissue culture medium (TCM=Eagle's Minimal
Essential Medium + Earles' salts supplemented with 10% foetal calf serum, 2mM L-glutamine and 1% non-essential amino acids) to
MacFarland's barium sulphate opacity standard 0.5. The suspension is further diluted 1:100 in TCM to yield a final inoculum of 4.83 x 106 cfu/ml.
Inoculation of cells: Human foetal lung fibroblast (MRC-5) cells are grown to 80% confluency in 6-well plates. The medium is removed and the monolayers washed twice with Dulbecco's PBS and the inoculum added.
Dosing: Sixteen hours after infection (time Oh), the medium is removed and the inoculated monolayers washed twice to remove any adherent, non-intracellular, organisms. The compounds are prepared to the required concentrations (0.5, 2 and 8μg/ml) in TCM, and added to the cells. Erythromycin at 0.5 and 2μg/m is used as a control.
Sampling: At 0, 3, 12, 24, 36, 48 and 72h after the dose, the medium is removed from one well/treatment, and the monolayers washed twice.
Sterile distilled water is added and left for 30 min to lyse the cells. After vigorous trituration, the lysate is serially diluted in Mueller Hinton brother and plated onto BYCEα and 6% horse blood agars. Colonies of L.pneumophila are counted after 72h incubation at 37°C.
Stability tests: The stability ofthe compounds in TCM is also examined over a 72h period. Solutions of 2 μg/ml of each ofthe compounds to prepared in TCM and incubated at 37°C or 4°C and aliquots are removed at intervals. The compounds of formula (I) are assayed against Bacillus subtilis ATCC 6633 and erythromycin lactobinate against Sarcina lutea NCTC 8340, using standards prepared in TCM.

Claims

Claim Set A:
What is claimed is:
A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000125_0001
wherein
RO is (A)n - (B)m;
n and m are integers having a value of 0 or 1; provided that m and n may not both represent 0; and that when n is 0 then A represents a bond; and when m is 0 then B represents hydrogen;
A is an optionally substituted (C1-6) alkyl, (C2-6) alkenyl, or (C2-6) alkynyl group; and
B is an optionally substituted (C3-7) cycloalkyl, (C4-7) cycloalkenyl, aryl,
heterocyclyl or heteroaryl group.
2. A compound according to Claim 1 wherein n is 0 and m is 1, and B is a substituted or unsubstituted (C4-7) cycloalkenyl, aryl, heterocyclyl or
heteroaryl group.
3. A compound according to Claim 1 or 2 wherein B is an optionally substituted cyclohexenyl, phenyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazolyl, oxazolyl, or thiazolyl group.
4. A compound according to any one of Claims 1 to 3 wherein the
optional substituents are independently selected up to five times by
(C1-6)alkyl, (poly)halo(C1 -6)alkyl, cyano, (un)substituted heterocyclyl, amino, (C1-6)alkanoylamino, (un)substituted mono- or di-(C1 -6)alkylamino, hydroxy, (C1 -6)alkoxy, -O-R1, (C1-6)alkenoxy, hydroxy substituted
(C1 -6)alkoxy, (un)substituted heterocyclylthio, arylthio, arylsulphinyl,
arylsulphonyl, (C1 -6)alkylthio, (C1-6)alkylsulphinyl, (C1-6)alkylsulphonyl, (un)substituted sulphamoyl, (un)substituted carbamoyl, amidino, guanidino, nitro, halogen, carboxy and salts and esters thereof, (C1-6) alkylcarbonyloxy, arylcarbonyloxy,
heterocyclylcarbonyloxy, or acyl groups.
5. A compound according to Claim 4 wherein R1 is selected from
(C2-6) alkenyl, (C1-6) alkoxy alkyl, (poly)hydroxy (C1-6) alkyl,
(poly)halo(C1-6) alkyl, (un)substituted heteroaryl (C1-6) alkyl,
(un)substituted mono- or di- amino (C1-6) alkyl, (un)substituted
heterocyclyl (C1-6) alkyl, or N-(C1-6 alkyl)-N- heteroaryl-(C1-6)alkyl.
6. A compound according to Claim 4 wherein the optional substituents are selected from methoxy, C(O)CH3, methyl, cyano, chloro, fluoro, bromo,
-CH(OCH2CH3)2, nitro, -CH(O), N(CH3)2, SCH3, S(O)CH3, S(O)2CH3, -CH2OH, piperidine, O-CF3, hydroxy, ethenyloxy, 2-hydroxyethoxy, N-(2- hydroxyethyI)-N-methylamino, 3-hydroxypropyloxy, azidoethoxy, N- methyl-N-pyridylaminoethoxy, piperidinylethoxy, pyridylmethyloxy, nitrofuranyl methyloxy, or furanylmethyloxy.
7. A compound according to Claim 1 or 3 wherein n is 1, m is 0 and B is hydrogen.
8. A compound according to Claim 1 or 3 wherein n and m are both 1.
9. A compound according to Claim 1 which is:
3R,4R-Dihydroxy-2S-[2,4-Dioxo-4-(4-methoxyphenyl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-D_hydroxy-2S-[2,4-dioxo-4-(2-methoxypyrid-5-yl)- but-1-yl]-5S-(2S,3S,epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-nitrophenyl)-but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)-tetrahydropyran; 3R,4R-Dihydroxy-2S-[2,4-dibxo-4-(2-methylthiopyrid-5-yl)- but-1-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methylthiophenyl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[4-(2-chloropyrid-5-yl)-2,4-dioxobut-1-yl]- 6S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-fluorophenyl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; 3R,4R Dihydroxy-2S-[4-(4-allyloxyphenyl)-2,4-dioxobut-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methoxymethyloxophenyl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{2-hydroxyethoxy}phenyl)but-1-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; or
3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{2-azidoethoxy}phenyl)but-1-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran.
10. A compound according to claim 1 substantially as hereinbefore defined with reference to any one ofthe Examples.
11. A pharmaceutical composition comprising a compound according to anyone of claims 1 to 9, and a pharmaceutically acceptable carrier thereof.
12. A compound acccording to any one of claims 1 to 9 for use as an active therapeutic substance.
13. A compound according to any one of claims 1 to 9 for use in treating bacterial and mycoplasmal infections.
14. Use of a compound according to any one of claims 1 to 9 in the manufacture of a medicament for use in the treatment of baceterial and mycoplasmal infections.
PCT/GB1992/001760 1991-09-26 1992-09-24 Antibacterial, antimycoplasmal compounds related to mupirocin WO1993006118A1 (en)

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GB9201507.2 1992-01-24
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GB9219053.7 1992-09-09

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GB2282536A (en) * 1993-10-06 1995-04-12 Zeneca Ltd Herbicidal compositions
US6534037B1 (en) 1998-01-21 2003-03-18 Neorx Corporation Non-steroidal compounds for steroid receptors and uses relating thereto
US6291514B1 (en) 1998-02-09 2001-09-18 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines, preparation thereof, and use thereof as protease inhibitors
US6403633B2 (en) 1998-02-09 2002-06-11 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines, and use thereof as protease inhibitors
US6562840B1 (en) 1998-02-09 2003-05-13 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines, and the use thereof as protease inhibitors
US7425557B2 (en) 1998-06-19 2008-09-16 Novartis Vaccines And Diagnostics, Inc. Inhibitors of glycogen synthase kinase 3
US7045519B2 (en) 1998-06-19 2006-05-16 Chiron Corporation Inhibitors of glycogen synthase kinase 3
US7528157B2 (en) 2003-01-29 2009-05-05 Asterand Uk Limited EP4 receptor antagonists
US7858644B2 (en) 2003-01-29 2010-12-28 Asterand Uk Limited EP4 receptor antagonists
US7507754B2 (en) 2003-01-29 2009-03-24 Asterand Uk Limited EP4 receptor antagonists
US7196089B2 (en) 2003-01-29 2007-03-27 Asterand Uk Limited EP4 receptor antagonists
US7569602B2 (en) 2003-10-16 2009-08-04 Asterand Uk Limited Furan derivatives as EP4 receptor antagonists
US7417068B2 (en) 2003-10-16 2008-08-26 Asterand Uk Limited EP4 receptor antagonists
US7649098B2 (en) 2006-02-24 2010-01-19 Lexicon Pharmaceuticals, Inc. Imidazole-based compounds, compositions comprising them and methods of their use
US8093267B2 (en) 2006-02-24 2012-01-10 Lexicon Pharmaceuticals, Inc. Methods of treating rheumatoid arthritis
US7825150B2 (en) 2007-09-06 2010-11-02 Lexicon Pharmaceuticals, Inc. Compositions and methods for treating immunological and inflammatory diseases and disorders
WO2017038650A1 (en) * 2015-08-28 2017-03-09 積水メディカル株式会社 Benzyl compound
JP2018002700A (en) * 2015-08-28 2018-01-11 積水メディカル株式会社 Benzyl compound
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US10822357B2 (en) 2015-08-28 2020-11-03 Sekisui Medical Co., Ltd. Benzyl compound
US11591351B2 (en) 2015-08-28 2023-02-28 Sekisui Medical Co., Ltd. Benzyl compound

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