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WO2004018487A1 - Hydrures de composes organosilicium chiraux - Google Patents

Hydrures de composes organosilicium chiraux Download PDF

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Publication number
WO2004018487A1
WO2004018487A1 PCT/AU2003/001069 AU0301069W WO2004018487A1 WO 2004018487 A1 WO2004018487 A1 WO 2004018487A1 AU 0301069 W AU0301069 W AU 0301069W WO 2004018487 A1 WO2004018487 A1 WO 2004018487A1
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group
atom
chiral
lewis
prochiral
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Carl Schiesser
Dainis Dakternieks
Tamara Perchyonok
Jens Beckmann
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Chirogen Pty Ltd
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Chirogen Pty Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0896—Compounds with a Si-H linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6596—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having atoms other than oxygen, sulfur, selenium, tellurium, nitrogen or phosphorus as ring hetero atoms

Definitions

  • the present invention relates generally to reductive methods useful in chemical synthesis.
  • the present invention relates to enantioselective reductive methods using chiral organosilicon hydrides, and to the novel class of chiral organosilicon hydrides.
  • the enantioselective reducing capacity of chiral non-racemic stannanes is limited.
  • inherently high hydrogen transfer rate constants preclude such stannanes from reducing several classes of prochiral radicals with acceptable chiral discrimination.
  • the chiral recognition of the stannane reducing agents is limited due to the inability for such reagents to sustain chirality at the tin atom.
  • the present invention provides a method for enantioselectively reducing a prochiral carbon centred radical having one or more electron donor groups attached directly to the central prochiral carbon atom of the radical, and/or attached to a carbon atom within 1 to 4 atoms of the central prochiral carbon atom, comprising treating said radical with an activated chiral non-racemic organosilicon hydride in the presence of a Lewis acid.
  • the electron donor group is attached directly to the central prochiral carbon atom or to a carbon atom within 1 or 2 atoms of the central prochiral carbon atom.
  • the present invention provides an activated chiral non-racemic organosilicon hydride of general formula (I):
  • Li, L 2 and L are organic substituents which may be the same or different, and where at least two of Li , L 2 and L 3 each contain an activating group which is attached directly to the silicon atom.
  • Li, L 2 , and L each contain an activating group which is attached directly to the silicon atom.
  • the first aspect of the invention relates to the use of any suitable chiral non-racemic organosilicon hydride reagents, even those which may have been described in the prior art.
  • the invention is directed towards a method of preparing optically enhanced a or ⁇ - amino acids by treatment of a prochiral amino acid carbon centred radical with an activated chiral non-racemic organosilicon hydride in the presence of a Lewis acid, wherein the central prochiral carbon atom is an a- carbon atom of an ⁇ - amino acid or a ⁇ - carbon atom of an ⁇ -amino acid.
  • silanes Chiral silicon hydride reagents
  • silanes have been prepared in the past, however, such reagents have not been used to make chiral compounds through free-radical reduction chemistry.
  • silanes are renowned for their limited ability to act as effective reducing agents due to inherently unfavourable hydrogen transfer rate constants.
  • chiral non-racemic organosilicon hydride reagents bearing activating groups on the silicon atom, can be used to enantioselectively prepare chiral compounds.
  • Such activated silicon reagents demonstrate accelerated hydrogen transfer rate constants relative to ordinary non-activated silanes and reduced hydrogen transfer rate constants relative to their organostannane counterparts.
  • This coupled with the ability to vary the hydrogen transfer rate constants by altering the nature of the activating groups provides the silicon reagents with superior kinetic control over the reduction chemistry.
  • the superior kinetic control can enable the range of suitable prochiral substrates to be extended beyond that available to stannane analogues.
  • the silane reagents are able to sustain chirality at the silicon atom bearing the transferable hydrogen and therefore demonstrate the potential to provide enhanced chiral recognition.
  • the structural integrity of the silane reagents should be sufficiently stable so as not to racemise during the reduction reaction.
  • the activated silanes are capable of enantioselectively reducing prochiral carbon centred radicals at significantly higher temperatures relative to their organostannane counterparts.
  • the silanes have been found to be capable of enantioselectively reducing prochiral carbon centred radicals at temperatures as high as 0°C.
  • prochiral carbon centred radical is a radical of formula R ⁇ R 2 R 3 C", wherein each R residue is different and is not hydrogen. Accordingly, the central prochiral carbon atom is the carbon atom to which the R residues are attached. Reduction of the prochiral carbon centred radical with a hydrogen atom donor affords the chiral compound R)R 2 R 3 CH.
  • the present invention thus relates to the enantioselective preparation of chiral compounds.
  • the prochiral carbon centred radical can be generated from any suitable radical precursor using methods known in the art.
  • exemplary radical precursors include aryl, eg phenyl, selenides; aryl, eg phenyl, sulfides; aryl, eg phenyl, tellurides; xanthates; thionoformates and Barton esters (see for example B. Giese, Radicals in Organic Synthesis - Formation of C-C Bonds (1986) Pergamon Press, Oxford, the contents of which are incorporated herein by reference).
  • Particularly suitable radical precursors for generating the prochiral carbon centred radicals for use in the invention are tertiary chiral halosubstrates, ie R ⁇ R 2 R 3 C- halogen, where R 1 -R 3 are different and not hydrogen and halogen is chlorine, bromine or iodine, preferably bromine.
  • the prochiral carbon centred radicals which can be reduced by the methods of the invention include radicals which bear one or more electron donator groups directly on the prochiral central carbon atom and/or attached to a carbon atom ⁇ , ⁇ , ⁇ , or ⁇ to the central prochiral carbon atom, ie, within 1, 2, 3 or 4 atoms, preferably within 1 or 2 atoms.
  • Suitable electron donator groups include those containing an electron donator atom such as oxygen, nitrogen, and/or sulfur and which will not be affected by the organosilicon hydride.
  • Other electron donator groups include, thioalkyl groups, amines (unsubstituted or substituted once or twice by, for example, a group selected from alkyl, acyl and aryl), hydroxy groups and ethers (eg alkyl and aryl).
  • a preferred electron donator is a carbonyl group.
  • the carbonyl group is adjacent to, ie ⁇ - to the chiral carbon to be reduced.
  • the prochiral carbon centred radical has at least one electron donator atom within 5 atoms (ie 1, 2, 3, 4, or 5) of the central prochiral carbon atom. It will be recognised that some electron donator groups may contain one or more electron donating atoms, eg carboxy acid, carboxy ester, thioester, carboxy amide. A prochiral carbon centred radical may also contain more than one electron donating group attached to the central prochiral atom.
  • prochiral carbon centred radicals include those of the formula R ⁇ R 2 R 3 C, wherein R ⁇ -R are different (and not hydrogen) and are independently selected from alkyl, alkenyl, alkynyl, aryl, heterocyclyl, acyl, amino, substituted amino, carboxy, anhydride, carboxy ester, carboxy amide, lactone, lactam, thioester, formyl, optionally protected hydroxy, thioalkyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heterocyclyloxy; or alternatively, any two of R1-R 3 can together, with the central prochiral carbon atom, form a mono- or poly- cyclic group or fused polycyclic group including as cycloalkyl, cycloalkenyl, cycloalkynyl, a lactone, a lactam, cyclic anhydride, or heterocyclyl and bi-, tri- and tetracycl
  • At least one of R 1 -R 3 contains an electron donator atom within 1 to 5 atoms of the prochiral central carbon atom to be reduced. It will be understood that a radical precursor may contain more than one prochiral radical precursor sites and that reduction may therefore occur at one or more of these sites.
  • at least one of R1-R 3 is an optionally substituted aryl or heteroaryl group.
  • at least one of R 1 -R 3 is an optionally substituted alkyl, alkenyl, or alkynyl group.
  • At least one of R 1 -R 3 is a ketone, aldehyde, carboxy acid, carboxy ester, carboxy amide, anhydride, lactone, lactam or thioester, or two of R 1 -R 3 together with the central prochiral carbon atom form a cyclic anhydride, lactam or lactone.
  • Preferred "ketones" have the formula -C(O)-R wherein R can be any residue, having a carbon atom covalently bonded to the carbonyl group, such as alkyl, alkenyl, alkynyl and aryl.
  • R group may have one or more carbon atoms optionally replaced with one or more heteroatoms to form, for example, heterocyclyl.
  • Preferred "carboxy esters” have the formula -CO 2 R wherein R can be any residue, having a carbon atom covalently bonded to the non-carbonyl oxygen atom, for example, alkyl, alkenyl, alkynyl or aryl.
  • R group may have one or more carbon atoms optionally replaced with one or more heteroatoms, such that R is for example heterocyclyl.
  • Preferred "carboxy amides” have the formula -CO 2 NRR' wherein R and R' are independently selected from hydrogen and any residue having a carbon atom covalently bonded to the nitrogen atom such as alkyl, alkenyl, alkynyl or aryl.
  • R or R' group may have one or more carbon atoms optionally replaced with one or more heteroatoms to form, for example, heterocyclyl.
  • Preferred "thioesters" have the formula -C(O)SR wherein R can be any residue having a carbon atom covalently bonded to the sulfur atom, such as alkyl, alkenyl, alkynyl or aryl.
  • R group may have one or more carbon atoms optionally replaced with one or more heteroatoms to form, for example, heterocyclyl.
  • Preferred anhydrides contain the moiety -C(O)-OC(O)- and may be cyclic or acyclic.
  • Preferred acyclic anhydrides contain the moiety -C(O)-O-C(O)-R wherein R can be any residue, such as alkyl, alkenyl, alkynyl or aryl.
  • An R group may have one or more carbon atoms optionally replaced with one or more heteroatoms to form, for example, heterocyclyl.
  • Preferred cyclic anhydrides contain the moiety -C(O)-O-C(O)-(CH 2 ) n - wherein n is >1, eg. 1, 2, 3, 4, 5 or 6.
  • Lactones are cyclic residues containing the moiety -C(O)O-.
  • Preferred lactones have the formula -C(O)O-R- wherein-R-can be any residue, having a carbon atom covalently bonded to the non-carbonyl oxygen atom, eg alkylene, alkenylene, alkynylene.
  • An R group may have one or more carbon atoms optionally replaced by one or more heteroatoms.
  • Preferred lactones contain the moiety -C(O)-O- (CH 2 ) n - wherein n is >2, eg., 2, 3, 4, 5 or 6.
  • Lactams are cyclic residues containing the moiety -C(O)-N(R')-R- wherein R' can be hydrogen or any hydrocarbon residue such as alkyl, acyl, aryl or alkenyl. -R- can be any hydrocarbon residue having a carbon atom covalently bonded to the nitrogen atom such as alkylene, alkenylene or alkynylene. An R' or R group may have one or more carbon atoms optionally replaced by one or more heteroatoms.
  • Preferred lactams contain the moiety - C(O)-N(R * )-(CH 2 ) n - wherein n is ⁇ 2, eg., 2, 3, 4, 5 or 6.
  • alkyl denotes straight chain, branched or cyclic hydrocarbon residues, preferably C
  • straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1 ,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3- dimethylbutyl, 1 ,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2,-trimethylpropyl, 1,1,2- trimethylpropyl, heptyl, 5-me
  • cyclic alkyl examples include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. Where an alkyl group is referred to generally as "propyl", “butyl” etc, it will be understood that this can refer to any of straight, branched and cyclic isomers. An alkyl group may be optionally substituted by one or more optional substituents as herein defined. Accordingly, "alkyl” as used herein is taken to refer to optionally substituted alkyl. Cyclic alkyl may refer to monocyclic alkyl or, polycyclic fused or non-fused carbocyclic groups.
  • alkenyl denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon to carbon double bond including ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined, preferably C ⁇ - 20 alkenyl (eg C ⁇ - ⁇ 0 or C ⁇ - 6 ).
  • alkenyl examples include vinyl, allyl, 1 -methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3- decenyl, 1,3-butadienyl, 1 -4,pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4- hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5- cycl
  • alkenyl group may be optionally substituted by one or more optional substitutents as herein defined. Accordingly, “alkenyl” as used herein is taken to refer to optionally substituted alkenyl. Cyclic alkenyl may refer to monocyclic alkenyl or, polycyclic fused or non-fused alkenyl carbocyclic groups.
  • alkynyl denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon-carbon triple bond including ethynically mono-, di- or poly- unsaturated alkyl or cycloalkyl groups as previously defined. Unless the number of carbon atoms is specified the term preferably refers to C ⁇ - 20 alkynyl. Examples include ethynyl, 1-propynyl, 2-propynyl, and butynyl isomers, and pentynyl isomers. An alkynyl group may be optionally substituted by one or more optional substitutents as herein defined.
  • alkynyl as used herein is taken to refer to optionally substituted alkynyl.
  • Cyclic alkynyl may refer to monocyclic alkynyl or, polycyclic fused or non-fused alkynyl carbocyclic groups.
  • alkoxy alkenoxy
  • alkynoxy alkynoxy
  • halogen denotes chlorine, bromine or iodine.
  • aryl denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbon ring systems.
  • aryl include phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, idenyl, azulenyl, chrysenyl.
  • Aryl may be optionally substituted as herein defined and thus "aryl" as used herein is taken to refer to optionally substituted aryl.
  • heterocychc denotes mono- or polycarbocyclic groups, which may be fused or conjugated, aromatic (heteroaryl) or non-aromatic, wherein at least one carbon atom is replaced by a heteroatom, preferably selected from nitrogen, sulphur and oxygen.
  • Suitable heterocychc groups include N-containing heterocychc groups, such as: unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolmyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl or piperazinyl; condensed saturated or unsaturated heterocychc groups containing 1 to 5 nitrogen atoms, such as, indolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoindolizinyl,
  • 1 to 3 nitrogen atoms such as, oxazolyl, oxazolinyl, isoxazolyl, furazanyl or oxadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, morpholinyl; unsaturated condensed heterocychc group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, benzoxazolyl or benzoxadiazolyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and
  • 1 to 3 nitrogen atoms such as, thiazolyl, thiazolinyl or thiadiazoyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolidinyl, thiomorphinyl; and unsaturated condensed heterocychc group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, benzothiazolyl or benzothiadiazolyl.
  • a heterocychc group may be optionally substituted by an optional substituent as described herein.
  • Preferred acyl includes C(O)-R, wherein R is hydrogen or an alkyl, alkenyl, alkynyl, aryl or heterocyclyl, residue, preferably a C ⁇ - 2 o residue.
  • acyl examples include formyl; straight chain or branched alkanoyl such as, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; aroyl such as benzoyl, tolu
  • phenylacetyl phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenylhexanoyl
  • naphthylalkanoyl e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl]
  • aralkenoyl such as phenylalkenoyl (e.g.
  • phenylpropenoyl e.g., phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g.
  • aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl
  • arylthiocarbamoyl such as phenylthiocarbamoyl
  • arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl
  • arylsulfonyl such as phenylsulfonyl and napthylsulfonyl
  • heterocycliccarbonyl heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl
  • acyloxy refers to acyl, as herein before defined, when linked by oxygen.
  • a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, hydroxy, alkoxy, alkenyloxy, aryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, acyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, heterocycloxy, heterocyclamino, carboalkoxy, carboaryloxy, alkylthio, arylthio, acylthio, cyano
  • Preferred optional substitutents include alkyl, (eg C ⁇ . 6 alkyl such as methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxyalkyl (eg hydroxymethyl, hydroxyethyl, hydroxypropyl), alkoxyalkyl (eg methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl etc) alkoxy (eg C ⁇ - 6 alkoxy such as methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy), halo, trifluoromethyl, trichloromethyl, tribromomethyl.
  • alkyl eg C ⁇ . 6 alkyl such as methyl, ethyl, propyl, butyl, cyclopropyl,
  • benzyl (wherein benzyl itself may be further substituted), phenoxy (wherein phenyl itself may be further substituted), benzyloxy (wherein benzyl itself may be further substituted), amino, alkylamino (eg C ⁇ - () alkyl, such as methylamino, ethyl amino, propylamino etc), dialkylamino (eg C ⁇ - 6 alkyl, such as dimethylamino, diethylamino, dipropylamino), acylamino (eg NHC(O)CH 3 ), phenylamino (wherein phenyl itself may be further substituted), nitro, formyl, -C(O)-alkyl (eg C .
  • alkylamino eg C ⁇ - () alkyl, such as methylamino, ethyl amino, propylamino etc
  • dialkylamino eg C ⁇ - 6 alkyl, such as di
  • - 6 alkyl such as acetyl
  • O-C(O)-alkyl eg - 6 alkyl, such as acetyloxy
  • benzoyl wherein the phenyl group of the benzoyl may itself be further substituted
  • heteroatom refers to any atom other than a carbon atom which may be a ring-member of a cyclic organic compound.
  • suitable heteroatoms include nitrogen, oxygen, sulfur, phosphorous, boron, silicon, arsenic, sellenium and tellurium.
  • the reductive method of the invention is typically carried out for a time and under conditions sufficient to effect enantioselective reduction of a suitable prochiral radical precursor by hydrogen.
  • Suitable reaction temperatures, solvents and quantities of reducing agent and initiator for free radical reductions are known in the art (see for example V.T. Perchyonok et al, Tetrahedron. Lett., 1998, 39, 5437 and references cited therein).
  • Preferred solvents include hydrocarbon solvents, eg toluene.
  • the reduction is preferably carried out at temperature of 0°C or less, preferably at about -30°C or less.
  • the reagents used and the reaction conditions employed are substantially anhydrous.
  • the activated silanes in accordance with the present invention can enantioselectively reduce prochiral carbon centred radicals at temperatures as high as 0°C.
  • the method of the present invention is preferably conducted in the presence of a Lewis base.
  • the Lewis base is believed to form a complex with the organosilane, the resulting structure of which affords a more highly activated organosilane compound.
  • the method of the invention by pre-complexing the Lewis base with the organosilane before the prochiral carbon centred radical is treated with the organosilane.
  • the Lewis base is preferably used in an amount of about 1 to about 3 molar equivalents per mole of organosilane compound used.
  • Lewis bases for use with the method are compounds which are able to donate an electron pair, i.e. co-ordinate with an electron acceptor, in this case the silicon atom bearing the transferable hydrogen.
  • suitable Lewis bases include, but are not limited to, tetraalkylammonium fluoride, such as tetrabutylammonium fluoride, and trialkyl or triaryl phosphine, such as triphenyl phosphine.
  • the term "activated" chiral non-racemic organosilane hydride (silane) is intended to denote a silane which has a hydrogen transfer rate constant that is sufficiently fast to enable the silane to function as a free radical reducing agent.
  • the term "activating group” is used herein to denote a group or atom which is directly attached to the silicon atom bearing the transferable hydrogen which promotes the transfer rate constant of the transferable hydrogen such that the silane can function as a free radical reducing agent.
  • Exemplary activated chiral non-racemic organosilicon hydrides for use in accordance with the method of the invention have the general formula L ⁇ L 2 L 3 SiH, wherein Li, L 2 and L 3 are substituents, preferably organic, that are different (ie. Li ⁇ (L 2 or L 3 ) and L 2 ⁇ L 3 ).
  • -L 3 can be substituents, preferably organic, which are the same or different wherein at least one of L
  • chiral non-racemic organosilicon hydrides suitable for use in the method of the invention may derive their chirality from a chiral silicon atom bearing the transferable hydrogen, and/or from at least one chiral organic substituent attached to the silicon atom bearing the transferable hydrogen.
  • at least two of L1-L 3 should contain an activating group (eg. silicon-, phosphorus-, sulfur-containing substituent) in which an activating element (ie. the silicon, sulfur, phosphorus or other atom known to those skilled in the art) is attached directly to the silicon atom bearing the transferable hydrogen.
  • each L 1 -L 3 contains an activating group in which the activating element is attached directly to the silicon atom bearing the transferable hydrogen.
  • suitable L 1 -L 3 substituents include, but are not limited to, chiral and achiral optionally substituted aryl (eg. phenyl, and naphthyl), and chiral and achiral optionally substituted alkyl (eg. methyl, butyl), where "alkyl” and "aryl” are as previously defined.
  • Suitable chiral groups also include, but are not limited to, those derived from a- and ⁇ -pinene (through hydrosilation chemistry), fused polycyclics such as 3 ⁇ -cholestane and those derived from cholic acid, eg. 3 ⁇ -24- norcholanyl and 7 ⁇ -24-norcholanyl (Schiesser et al, Aust. J. Chem., 2001).
  • any one of L 1 -L 3 can conveniently be represented as Ri-X-, where Ri is preferably an organic group and X is an activating group or element which is directly attached to the silicon atom bearing the transferable hydrogen.
  • Suitable organic groups Ri include, but are not limited to, chiral and achiral optionally substituted aryl (e.g. phenyl, and naphthyl), chiral and achiral optionally substituted silyl (e.g. trialkylsilyl, and triarylsilyl) and chiral and achiral optionally substituted alkyl (e.g. methyl, and butyl), where "alkyl" and "aryl" are as previously defined.
  • Suitable chiral organic groups Ri also include, but are not limited to, those derived from - and ⁇ -pinene (through hydrosilation chemistry), fused polycyclics such as 3ocholestane and those derived from cholic acid, eg. 3 ⁇ -24-norcholanyl and 7c--24-norcholanyl (Schiesser et al, Aust. J. Chem., 2001) as well as 1,1 'thiobinaphthol and binap.
  • Suitable activating groups or elements, X include, but are not limited to, -Si(R 4 R 5 )-, -S- and -P(R 6 )-, where R -R 6 are as defined for R
  • Other activating groups or elements, X known to those skilled in the art can also be used.
  • Ri-X- groups include, but are not limited to, trialkylsilyl, alkylthiyl and dialkylphosphonyl.
  • chiral silicon atom or “chiral atom” denotes an atom which has different substituents attached to it, and which can form part of a molecule to render the molecule non-superimposable on its mirror image.
  • non-chiral silicon atom denotes a silicon atom that has at least two substituents attached to it which are the same. Accordingly, a non-chiral silicon atom may form part of a molecule that can be superimposed on its mirror image.
  • chiral substituents or “chiral organic substituent” denotes an organic molecule that is not superimposable on its mirror image.
  • activated chiral non-racemic organosilanes include but are not limited to, those derived from 1,1 'thiobinaphthol (a) and those derived from binap (and their enantiomers) (b), in which the groups R' and R" are independently selected from optionally substituted alkyl, and optionally substituted aryl as defined previously, and Y is independently selected from optionally substituted alkyl and trialkylsilyl.
  • Further examples include (R)- and (S)-(t ⁇ methylsilylphenyltriphenylsilyl) silanes (c) and (d) (and related compounds), 3 ⁇ -bis(trimethylsilyl)silyl-5 ⁇ -24-norcl.olane (e) (and the 3 ⁇ analogue), tris[(lS,2S,5S)-myrtanyldimethyl] silane (f) and its enantiomer tris[(lR,2R,5R)- myrtanyldimethyl] silane (f), tris[(l S,2R,5S)-myrtanyldimethyl] silane (h) and its enantiomer tris[(lR,2S,5R)-myrtanyldimethyl] silane (h'), as well as the two enantiomeric tris(triorgano)silylsilanes of general structure (g) in which each R a , R b and R c
  • each of the three R a groups attached to its silicon atom may be the same or different, and each (SiR a 3 ) group can be the same or different to each other (SiR a 3 ) group.
  • R b and R c provided the result is a chiral non-racemic organosilane.
  • Lewis acids for use with the method of the present invention are compounds which are able to accept an electron pair, ie. co-ordinate with an electron donor.
  • Suitable Lewis acidic compounds include transition metal complexes, alkaline earth metal compounds and other metal based compounds wherein the metal centre can accept an electron pair.
  • Lewis acids examples include A1C1 3 , Me 3 Al, MeAl(OPh) 2 , MAD (methyl aluminum bis(2-6-di-tert-butyl-4-mthyl phenoxide)), BF 3 , BBr 3 , BCI 3 , Ln(OTf) 3 , Yb(OTf) 3 , TiCl 4 , FeCh, ZnC ⁇ , zinc silicate, calcium silicate, aluminium silicate, zirconocene dichloride (herein after referred to as (i)), trialkylborates (RO 3 B, wherein each R is an alkyl group which can be the same or different), (S,S)- and (R,R)-(+)-N,N'-bis(3,5- di-tert-butylsalycidene)-l,2-diaminocyclohexamanganese (III) chloride (hereinafter referred to as, (ii) and (iii) respectively
  • the Lewis acid has a solubility, under the reaction conditions employed, of at least about 0.1 molar equivalents, more preferably at least about 0.5 molar equivalents, still more preferably at least about 1.0 molar equivalent, most preferably about 2.0 molar equivalents, per mole of prochiral carbon centred radicals to be reduced.
  • Preferred Lewis acids are those which are alkaline earth metal compounds.
  • the alkaline earth metal compound is a Lewis acidic magnesium compound.
  • suitable Lewis acidic magnesium compounds include MgBr 2 , Mgl 2 , Mg(OAc) 2 and Mg(OTf) 2 . It will be appreciated that the above list of magnesium compounds is not exhaustive and that the invention encompasses the use of other Lewis acidic magnesium compounds or combinations thereof.
  • MgBr 2 as a Lewis acid in accordance with the present invention has a particular advantage in that it is cheap and readily available.
  • the Lewis acid used in accordance with the method of the present invention is a Lewis acidic magnesium compound
  • the Lewis acidic magnesium compound is preferably MgBr 2 .
  • Lewis acids can often be conveniently provided in the form of a Lewis adduct, that is an adduct formed from a Lewis acid and a Lewis base.
  • a Lewis adduct can be used as a convenient source for providing a Lewis acid to a reaction.
  • Lewis acids used in accordance with the present invention may also be provided in the form of a Lewis adduct.
  • Lewis acids such as BF 3 , ZnCl 2 , and MgBr 2 may be provided and used in the form of their diethylether adducts BF 3 Et 2 O, ZnCl 2 -(Et 2 O)2 and MgBr 2 (Et 2 O) 2 , respectively.
  • the activated silane is preferably used in an amount of about 0.5-1.5 molar equivalents, more preferably about 1.1 molar equivalents per mole of reductive sites on the substrate, ie central prochiral carbon atoms, to effect optimum reductive conversion.
  • the Lewis acid is preferably used in an amount of about 0.9 to about 2.0 molar equivalents, more preferably in an amount of about 0.9 to about 1.1 molar equivalents, per mole of reductive sites on the substrate, ie central prochiral carbon atoms.
  • the Lewis acid is preferably used in an amount of about 1.5 molar equivalents, most preferably about 1.0 molar equivalents, per mole of reductive sites on the substrate, ie central prochiral carbon atoms.
  • Lesser amounts can be used such as 0.1 or 0.5 molar equivalents although lower enantiomeric excesses (ees) are usually observed.
  • the addition of higher amounts of Lewis acid can also be used, although this does generally not result in an increase in observed ees.
  • the Lewis acid is an alkaline earth metal compound
  • it is preferable that the Lewis acid is used in an amount of about 1.5 molar equivalents, more preferably about 2.0 molar equivalents, per mole of prochiral carbon centred radicals to be reduced.
  • the Lewis acid is a magnesium compound
  • it is preferable that the Lewis acid is used in an amount of about 1.5 molar equivalents, more preferably about 2.0 molar equivalents, per molecule of prochiral carbon centred radicals to be reduced.
  • the stereochemistry of the reduced prochiral carbon centre in the resulting compound can be R or S.
  • the methods of the invention may be particularly useful in preparing optically enhanced amino acids.
  • a- or -carbon centred radicals derived from a- or / ⁇ -substituted amino acids may be reduced by the methods of the invention to produce optically enhanced amino acids which may be natural or unnatural, including alanine, asparagine, cysteine, glutamine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, aspartic acid, glutamic acid, arginine, histidine, lysine and their homo derivatives.
  • the activated chiral silanes contemplated by the present invention may also be immobilized onto a solid support, eg a polymeric support, such as pins, beads or wells, for use in the methods of the invention, eg used in combinatorial techniques known in the art.
  • a solid support eg a polymeric support, such as pins, beads or wells
  • the present invention provides for a novel class of activated chiral non-racemic organosilicon hydrides of general formula (I):
  • Li, L 2 and L 3 are organic substituents which may be the same or different, and where at least two of Li, L 2 and L 3 contain and activating group which is directly attached to the silicon atom.
  • each Li, L 2 and L 3 of general formula (I) contains an activating group which is directly attached to the silicon atom.
  • the activating group which is directly attached to the silicon atom includes another silicon atom, a phosphorous atom or a sulfur atom.
  • Other activating groups known to those skilled in the art may also be used.
  • the activated chiral non-racemic organosilicon hydrides of general formula (I) have a non-chiral silicon atom bearing the transferable hydrogen and therefore derive their chirality from at least one chiral organic substituent.
  • the organic substituent(s) derives its chirality, although it is preferred that the chirality is derived from a chiral atom, such as a chiral carbon atom, which forms part of the molecular structure of the substituent.
  • suitable L1-L 3 substituents include, but are not limited to, chiral and achiral optionally substituted aryl (eg. phenyl, and naphthyl) and chiral and achiral optionally substituted alkyl (eg. methyl, and butyl), as defined previously.
  • any one of L 1 -L 3 can conveniently be represented as R . -X-, where R 1 is an organic group and X is an activating group which is directly attached to the silicon atom bearing the transferable hydrogen.
  • Suitable organic groups Ri include, but are not limited to, chiral and achiral optionally substituted aryl (e.g. phenyl, and naphthyl), chiral and achiral optionally substituted silyl (e.g. trialkylsilyl, and triarylsilyl) and chiral and achiral optionally substituted alkyl (e.g. methyl, and butyl), as previously defined.
  • Suitable activating groups X include, but are not limited to, Si(R 4 R 5 ), -S- and -P(R 6 )-, where -R -R 6 are as defined for R ⁇ .
  • Other activating groups or elements, X known to those skilled in the art can also be used.
  • each Li, L 2 and L 3 forms a single covalent bond with the silicon atom of general formula (I).
  • Li, L 2 and L 3 may form part of a bidentate or tridentate ligand in which case general formula (I) may be represented as L ⁇ - 2 L 3 SiH or L ⁇ - - SiH, respectively.
  • the chiral substituent (group) is preferably selected from the group of naturally occurring chiral organic compounds, or the so called chiral pool.
  • naturally occurring chiral organic compounds is meant those chiral compounds which have been identified as occurring in nature. Reference to naturally occurring chiral organic compounds is however not intended to limit such compounds to those which are obtained from a natural source.
  • the natural chiral compounds may be prepared by a synthetic process.
  • Suitable classes of chiral organic compounds from which Li, L 2 and L 3 (or Ri) may be selected include, but are not limited to, terpenes and their derivatives (eg. menthol, fenchenol, pinene etc.), steroids and their derivatives (eg. cholestanol, cholane, cortisone etc.), carbohydrates and their derivatives, including mono, di, tri and polysaccharides, as well as cyclodextrins, amino acids, peptides, proteins and their derivatives, as well as alkaloids and their derivatives as well as numerous biological metabolites and their derivatives. Some of these compounds may form part of the chiral pool.
  • terpenes and their derivatives eg. menthol, fenchenol, pinene etc.
  • steroids and their derivatives eg. cholestanol, cholane, cortisone etc.
  • carbohydrates and their derivatives including mono, di, tri and polysaccharides, as well as
  • Exemplary chiral organic compounds include, but are not limited to, myrtanyl, menthyl, 3 ⁇ -cholestanyl, 3 ⁇ -24-norcholanyl, 7 ⁇ -24-norcholanyl, tetra-O-acetylglucosyl, tetra-O- benzylgalactosyl, gamma-cyclodextrinyl, phenylglycinyl, leucinyl and mo ⁇ hinyl. Some of these compounds may also form part of the chiral pool.
  • a preferred chiral organic compound is myrtanyl
  • preferred organosilicon hydride reagents of general formula (I) are tris[(lS,2S,5S)-myrtanyl dimethyl] si lane (f) and its enantiomer tris[(lR,2R,5R)-myrtanyl dimethyl] silane (f '), and tris[(lS,2R,5S)-myrtanyl dimethyljsilane (h) and its enantiomer tris[(lR,2S,5R)-myrtanyl dimethyl]silane (h').
  • carbon tetrachloride (5ml) 1 equiv
  • N-bromosuccinimide (NBS) 1 equiv
  • the mixture was irradiated (under reflux) by a 250W tungsten lamp for 45 minutes.
  • N-bromosuccinimide (0.33g, 1.85mmol) was added to a solution of the previously- prepared racemic naproxen ethyl ester (0.470g, 1.85mmol) in carbon tetrachloride (5.0mL) and the reaction mixture irradiated (under reflux) by a 250W tungsten lamp for 15 minutes. After cooling in ice, the solid was removed by filtration and the solvent removed in vacuo to afford the title racemic bromoester in quantitative yield and of sufficient purity for further use.
  • NBS N-bromosuccinimide
  • Reductions were carried out in toluene at a variety of temperatures.
  • the reaction solution typically comprised the substrate at a concentration of approximately 0.1M, about 1.1 molar equivalents, relative to the substrate, of the required silane, and if present, a Lewis acid of choice in either about 1.0 or 2.0 molar equivalents, relative to the substrate, depending on the Lewis acid chosen (see Table 1).
  • a Lewis base such as Bu NF
  • the silane was typically precomplexed with about 1 to 3 molar equivalents of the Lewis base.
  • Reactions were initiated with Et 3 B/O 2 . Reactions were carried out until TLC analysis indicated no change in the reaction (ca.
  • Triethyl amine (1.1 eq) was added to a stirred solution of the amino acid methyl ester hydrochloride and methyl trifluoroacetate (1.5 equivalents) in dry methanol (10 ml). The reaction was heated under reflux for 12 hours, after which the solvent was removed and resulting residue redissolved in ether (20ml). The solution was washed with sat. ammonium chloride, dried (MgSO ) and the ether removed in vacuo to obtain the corresponding required N-trifluoroacetyl amino acid methyl ester of sufficient purity for further use.
  • Enantioselectivities observed for reactions involving tris[(lS, 2S, 5S)- mertynyldimethyl]silane (f) at various temperatures in toluene MgBr 2 -(Et 2 O) 2 was used in about 2 molar equivalents and all other Lewis acids were used in about 1 molar equivalents, relative to the substrate. When present, the Lewis base (Bu 4 NF) was used in about 3 molar equivalents, relative to the silane.
  • Magnesium bromide etherate (MgBr 2 .Et 2 O) (0.075g, 0.291mmol) was added to dry toluene (0.2mL) and the mixture allowed to stir for 20 min under N 2 after which reaction mixture was cooled to -30°C.
  • the bromoester (0.05g, 0.146 mmol) in dry toluene (0.1 mL) was added slowly to a reaction mixture.
  • (-)-(lS2S5S)-MyrMe 2 SiCl was prepared by a H 2 PtCl 6 catalyzed hydrosilylation of commercially available (-)-(lS,5S)-/?-pinene with HSiMe 2 Cl according to a literature procedure (Wang, D.; Chan, T. H. Tetrahedron Lett. 1983, 24, 1573).
  • (+)-(lR,5R)- ?-pinene and (+)-(lR,5R)-o:-pinene was prepared by a borane-assisted isomerization from commercially available (+)-(lR,5R)-c.-pinene (optical purity 91 % ee) according to a literature procedure (Brown, H. C, Joshi, N. N. J. Org. Chem. 1988, 53, 4059).
  • (+)-(lR,2R,5R)-MyrMe 2 SiCl A suspension of H 2 PtCl 6 (50 mg) in HSiMe 2 Cl (19.9 g, 0.210 mol) was cooled at 0°C and a 5:1 mixture of (+)-(lR,5R)- ?-pinene and (+)-(lR,5R)- ⁇ -pinene (27.2 g, 0.200 mol; weight based on (+)-(lR,5R)- ?-pinene) was slowly added within 1 h. The reaction mixture was stirred at r. t. for 2 h and was heated to 35°C for 10 h.
  • (-)-(lS2R,5S)-myrtanyl chloride was prepared by hydroboration / oxidation of (-)- (lS,5S)- ?-pinene and subsequent chlorination of the resulting (-)-(lS,2R,5S)-c/-s-myrtanol with CC1 4 / PPI1 3 according to a literature procedure (Marinetti, A.; Buzin, F.-X.; Ricard, L. J. Org. Chem. 1997, 62, 297.

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Abstract

L'invention concerne un procédé de réduction énantiosélective d'un radical à atome de carbone prochiral central présentant au moins un groupe donneur d'électrons attaché directement à l'atome de carbone prochiral central et/ou attaché à un atome de carbone dans 1 à 4 atomes de l'atome de carbone prochiral central. Ledit procédé consiste à traiter ledit radical avec un hydrure de composé organosilicium non racémique chiral activé en présence d'un acide de Lewis. L'invention concerne également une nouvelle classe d'hydrures de composés organosilicium non racémiques chiraux activés.
PCT/AU2003/001069 2002-08-21 2003-08-21 Hydrures de composes organosilicium chiraux Ceased WO2004018487A1 (fr)

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CN111203276A (zh) * 2020-02-27 2020-05-29 郑州大学 手性双齿亚磷酸酯配体的应用、硅氢化反应催化剂及其应用和手性硅烷的制备方法
CN115385814A (zh) * 2022-08-30 2022-11-25 南通宝凯药业有限公司 一种3-甲基-n-(三氟乙酰基)-l-缬氨酸的制备方法

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Publication number Priority date Publication date Assignee Title
CN111203276A (zh) * 2020-02-27 2020-05-29 郑州大学 手性双齿亚磷酸酯配体的应用、硅氢化反应催化剂及其应用和手性硅烷的制备方法
CN111203276B (zh) * 2020-02-27 2022-11-18 郑州大学 手性双齿亚磷酸酯配体的应用、硅氢化反应催化剂及其应用和手性硅烷的制备方法
CN115385814A (zh) * 2022-08-30 2022-11-25 南通宝凯药业有限公司 一种3-甲基-n-(三氟乙酰基)-l-缬氨酸的制备方法

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