[go: up one dir, main page]

WO1998030535A1 - Composes aminoacides - Google Patents

Composes aminoacides Download PDF

Info

Publication number
WO1998030535A1
WO1998030535A1 PCT/GB1998/000029 GB9800029W WO9830535A1 WO 1998030535 A1 WO1998030535 A1 WO 1998030535A1 GB 9800029 W GB9800029 W GB 9800029W WO 9830535 A1 WO9830535 A1 WO 9830535A1
Authority
WO
WIPO (PCT)
Prior art keywords
mhz
nmr
mmol
dimethoxy
dihydro
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/GB1998/000029
Other languages
English (en)
Inventor
Kjell Undheim
Kristin Hammer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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 GBGB9700255.4A external-priority patent/GB9700255D0/en
Application filed by Individual filed Critical Individual
Priority to AU54908/98A priority Critical patent/AU5490898A/en
Publication of WO1998030535A1 publication Critical patent/WO1998030535A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

  • This invention relates to novel compounds useful in place of natural amino acids in the preparation of peptidic materials.
  • Peptidic compounds ie. compounds having or incorporating a peptide structure, eg. proteins, glycopeptides, phosphopeptides and oligopeptides, have an enormously important role in many biological processes . Many such compounds are produced commerically as therapeutic or diagnostic agents. Where naturally occurring amino acids are used however, eg. in the production of a therapeutic agent designed to prevent or provoke the effect of a naturally occurring peptidic compound, the resultant peptidic product may have less than optimal properties, eg. in terms of efficacy or stability, and thus it is well known to substitute synthetic (ie. non naturally occurring) amino acids for various natural amino acids in the preparation of biologically active peptidic compounds.
  • D is a bridging group which together with the carbon atom to which it is attached forms a four to ten, especially 5 to 7 , membered carbocyclic ring which is optionally but preferably substituted and/or saturated, eg. optionally substituted by at least one hydroxy, oxo, amino, or carboxy group or by one or more optionally substituted C ⁇ alkyl or alkenyl groups
  • D is a bridging group which together with the carbon atom to which it is attached forms a four to ten, especially 5 to 7 , membered carbocyclic ring which is optionally but preferably substituted and/or saturated, eg. optionally substituted by at least one hydroxy, oxo, amino, or carboxy group or by one or more optionally substituted C ⁇ alkyl or alkenyl groups
  • the bridging group D in the compounds of formula I is preferably substituted, eg. by a hydroxy or hydroxylated group, by a C ⁇ alkenyl group, by a C xschreib 4 alkyl group or by an oxo group .
  • substituents are or contain hydroxy, amino or carboxy groups, these may if desired be esterified or amidated, eg. with C ⁇ _ 4 alkyl or acyl groups.
  • the invention provides the use of an optionally protected compound of formula I (either a ring or side-chain hydroxylated compound or a deshydroxyl analog) for the manufacture of a peptidic compound, eg. a therapeutic or diagnostic agent.
  • an optionally protected compound of formula I either a ring or side-chain hydroxylated compound or a deshydroxyl analog
  • peptide building techniques eg. solid state peptide syntheses, may be used.
  • the compounds of formula I provide rigidified analogs of the natural hydroxylated side chain -amino acids which are suitable for incorporation into small peptides and peptidomimetic compounds and which can provide stabilizing conformational restrictions in conformations such as ⁇ -turns, -helical and extended conformations.
  • the compounds may be used as substitutes for serine or threonine, for example at the last C-terminal turn of an ⁇ -helix, or at an O- glycosylation or O-phosphonation site, eg. in an artifical enzyme, growth factor, growth factor receptor, immunosuppressant , immunostimulant , blood clotting agent, etc.
  • the blood clot formation reducing agents which act to inhibit one or more of the cascade of reactions involved in blood clot formation.
  • the compounds of the invention may be used in place of serine in the low molecular weight hemoregulatory peptides of Bhatnagar et al. (see J. Med. Chem. 3_9: 3814-3819 (1996)).
  • the hydroxy-containing amino acid in the immuno depressant cyclosporin may conveniently be replaced by one of the amino acids of formula I .
  • D carries a single hydroxyl at the 2- or 3- position (the 1 position being the attachment point of D itself and of the amino and carboxy groups) . It is also preferred that the carbocyclic ring be unsaturated, preferably mono-unsaturated at a bond other than the bonds to the 1 and 2 positions.
  • amino acids of the invention may be of formula II
  • the amino acids may be of formula III
  • a and b are as defined above, one, two or three of the ring carbon atoms, preferably at positions 2, 3, 3+b and 4+b, carry hydroxyl or amino groups and one or more of the ring carbons is optionally substituted by an optionally substituted C ⁇ alkyl or alkenyl group or an oxo or carboxyl group .
  • carbocyclic ring in the amino acid compounds of the invention carries an alkyl substituent
  • this may for example be an optionally hydroxylated methyl, ethyl, n-propyl, isopropyl, n-butyl or t-butyl group.
  • the ring atoms of the D chain may be substituted by hydroxy, amino, oxo, CHO and carboxyl groups (which may be esterified or amidated or otherwise protected) or by alkyl or alkenyl groups which themselves may carry substituents such as hydroxy, amino, carboxyl and oxo groups - which again may be esterified or amidated or otherwise protected.
  • the ring atoms have at least one hydroxy, amino or carboxy substituent, especially preferably at least one hydroxy substituent.
  • carbocyclic ring in the amino acid compounds of the invention carries an alkenyl substituent
  • Unsaturated side chains can be produced by a catalysed ring closing reaction as described below in which one of the unsaturated ring forming groups is an alkynyl group. Such unsaturated side chains can then be substituted, eg. to introduce hydroxyl groups into the side chain. Examples of unsaturated side chains include methylene, ethenyl and propenyl .
  • hydroxy, carboxy and amino groups in the compounds of the invention may be protected before they are used to construct a peptidic compound of interest.
  • conventional hydroxyl, carboxy and amine protecting groups may be used and they may be removed when appropriate by conventional deprotection reactions (see for example McOmie “Protective groups in organic chemistry", Plenum, 1973, and Greene “Protective groups in organic synthesis", Wiley- Interscience, 1981).
  • Such singly or multiply protected amino acids fall within the scope of the present invention.
  • hydroxy protection may be by an alkyl (eg. C ⁇ _ 4 alkyl) or acyl (eg. C ⁇ acyl) group.
  • amino acids of the invention may be used in the synthesis of peptidic compounds in which they will be bound by peptide bonds (amide linkages) . Accordingly the resulting peptidic compounds will be amides of compounds of formula I and thus fall within the scope of the present invention.
  • the amino acids of the invention will be used in place of natural amino acids such as serine or threonine or even lysine or glutamic acid.
  • the ring-hydroxylated compounds will be used in place of serine or threonine and the ring- aminated or ring-carboxylated compound, will be used in place of lysine or glutamic acid.
  • the compounds of formula I may be prepared by cyclization of an -amino acid disubstituted at the ⁇ position by unsaturated groups, eg. alkenyl or alkynyl groups, followed if desired by reduction or substitution of the resulting unsaturated bond in the carbocyclic ring. Such a process forms a further aspect of the invention.
  • unsaturated groups eg. alkenyl or alkynyl groups
  • the cyclization is conveniently metal catalysed, eg. with ruthenium, and can be carried out before or after introduction of the ring hydroxyl substituent.
  • the amino acid compounds of the invention may be prepared with desired stereoselectivity if the carboxy and amino groups are held in a cyclic structure which is selectively substituted with the unsaturated groups before the ring closure is effected.
  • This technique for producing cyclic 1-amino-1-carboxylic acids forms a further aspect of the present invention.
  • the invention provides a process for the preparation of a cyclic 1-amino-1-carboxylic acid (preferably a compound of formula I) having a 4 to 10 membered, preferably carbocyclic, ring, which process involves the steps of (i) bisalkenylating (or alkenylating and alkynylating, etc.) a compound of formula IV
  • step (ii) cyclizing the product of step (i) , optionally after removal of group E, to yield an optionally protected bisalkenylated ⁇ -amino acid; (iii) if required removing group E to yield an optionally protected cyclic 1-amino-l-carboxylic acid; (iv) if required deprotecting the resulting product; and (v) optionally reducing or substituting the ring double bond and any side chain double bonds in the product of any one of steps (ii) to (iv) .
  • E is preferably such that the two hydrogens at the substitution site in the starting compound are not sterically equivalent.
  • the compound of formula IV may be
  • Such compounds may be stereoselectively substituted and so stepwise bisalkenylation according to step (i) will allow stereoselective preparation of the final cyclic 1- amino-1-carboxylic acid.
  • step (i) stepwise bisalkenylation according to step (i) will allow stereoselective preparation of the final cyclic 1- amino-1-carboxylic acid.
  • single isomers, as well as isomer mixtures, of the compounds of formula I are deemed to fall within the scope of the invention.
  • the ring closing reaction of step (ii) is preferably catalyzed by a transition metal, such as for example ruthenium, molybdenum or tungsten, especially ruthenium (see Grubbs et al . Ace. Chem. Res. 28.: 446-452 (1995), JACS 118: 100-112 (1996), Angew. Chem. Int. Ed. Engl . 3_4: 2039-2041 (1995), JACS 1T7: 5855-5856 (1995), J. Org. Chem. 59: 4029-4031 (1994), JACS 114.: 5426-5427 (1992) , and JACS 115: 9856-9857 (1993) , and Schuster et al. Angew. Chem. Int. Ed. Engl. 35.: 1979-1980 (1996)).
  • a transition metal such as for example ruthenium, molybdenum or tungsten, especially ruthenium
  • step (v) may be for example to simply reduce the bond (ie. add in hydrogens), to add one or more C x . 4 alkyl substituents, to add one or more hydroxyl substituents or to add alkyl and hydroxyl substituents. Conventional reduction or substitution techniques may be used.
  • the cyclized structure contains a hydroxyl precursor, eg. a carbonyl group
  • this may be converted to a hydroxyl group by standard technique (eg. reduction, or carbometallation by an organic reagent) .
  • the compounds according to the invention in which the ring carbons of bridging group D are amino substituted or carry amino substituted substituents may be produced for example by:
  • epoxidation of a cycloalkenyl or alkenyl precursor followed by epoxide ring opening, eg. with an azide (for example a metal azide or a TMS azide) followed by reduction, or with a cyanide followed by hydrolysis, or with an amine;
  • a cycloalkenyl or alkenyl precursor eg. compound 4 below
  • epoxide ring opening eg. with an azide (for example a metal azide or a TMS azide) followed by reduction, or with a cyanide followed by hydrolysis, or with an amine
  • the compounds in which the ring atoms of D are carboxy substituted or carry carboxy-substituted substituents may be prepared for example by: (i) oxidation of a primary alcohol (eg. a hydroxymethyl substituent) , for example by Swern reaction to an aldehyde followed by standard mild oxidation; or
  • hydrolytic opening of the pyrazine ring ie. A to B or C to D
  • hydrolytic opening of the pyrazine may be effected before or after the RCM reaction. Where the pyrazine opening is effected first the amine should be N- protected (group NHY in intermediate N) .
  • the spiro compounds produced by the RCM reaction in the schemes above are particularly useful as intermediates for stereoselective substitution of the ring double bond due to the steric control exerted by the pyrazine chiral auxiliary.
  • the acyclic precursors can be constructed by alkylation with an ⁇ -halo oxo derivative as in the formation of Y; subsequent RCM reaction yield a spiro-ketone Z as a target molecule.
  • the latter provides secondary hydroxy derivatives on reduction with a metal hydride, " or tertiary hydroxy derivatives on reaction with organometallics ; epimeric hydroxy isomers are conveniently separated by flash chromatography.
  • Epoxides provide an alternative approach.
  • the metallated substrate opens the epoxide ring at the least substituted carbon to form the ⁇ -hydroxy derivatives AA; the latter are substrates for subsequent RCM reactions.
  • This scheme shows hydrolytic reactions leading to target amino acid esters as the oxo derivatives AC or the hydroxy derivatives AD.
  • Hydrolysis can be effected before ring closure as shown for the preparation of AC; similarly the hydrolyzed ester product AE is N-protected and subjected to RCM reaction to furnish AD.
  • Saturated hydroxylated cyclic amino acids may be produced by hydroxylation of spiro-structures AF.
  • Acid or base can be used to produce a trans derivative AK.
  • cis-Derivatives are alternative products using appropriate hydroxylating reagents. Stereochemical control may be achieved. Flash chromatography may be used for stereoisomer separations. Hydroxylated compounds from the scheme above may be hydrolyzed under conventional conditions working with weak TFA solution. In case of problems caused by the OH-groups, the latter have to be protected, e.g. by acylation. Alternatively, hydroxylation reactions can be effected as shown below on cyclic amino ester AS after initial ⁇ -protection.
  • Tri- or dihydroxy derivatives may be prepared from spiro structures A' :
  • the scheme above shows an important series of hydroxylation reactions from the ⁇ -hydroxy derivatives A 1 .
  • the latter represent substrates well suited for Sharpless asymmetric epoxidation to furnish AV which can be reductively opened to a hydroxy derivative, i.e. the dihydroxy derivative AY.
  • Acid or base can be used for to form a vicinal trans diol, i.e. the trihydroxy derivative AZ.
  • Sharpless asymmetric dihydroxylation may yield the triols AX and AY.
  • Acid or base catalyzed hydroxyl ring opening of epoxide Tri or dihydroxy derivatives can also be prepared by analogous hydroxylation reactions as shown below:
  • Hydrolytic cleavage of the pyrazine ring in the ⁇ -oxy series in the desired fashion may be effected conventionally using mild conditions with dilute TFA.
  • R 5 is H or C ⁇ ,, alkyl
  • the RCM reaction can also be effected in the presence of a triple bond.
  • the reaction takes a different course, however, in that the product arises through a cyclic rearrangement to form a product with the same number of carbons.
  • the product is a cyclic unsaturated structure with an additional exocyclic conjugated double bond.
  • Hydroxy derived structures may be formed from alkyne reagents as shown in the scheme above yielding cyclic hydroxylated conjugated dienes, and finally the target amino acid ester (BS) .
  • the substrates for the ring closing metathesis (RCM) reactions discussed in the Examples below were ⁇ , ⁇ - disubstituted glycine derivatives with the desired stereochemistry already built into the stereogenic center.
  • Carbenoid ruthenium (II) complexes are excellent catalysts in RCM reactions. More reactive, but less selective molybdenum complexes can be used. Tungsten complexes also effect RCM reactions.
  • the substrates for the RCM reaction were geminal diolefins 3 derived from (2R) -2 , 5-dihydro-3, 6-dimethoxy- 2-isopropylpyrazine 1.
  • Bisalkylation of the latter was effected in a stepwise manner which allowed for the introduction of two different alkenes .
  • the first alkylation step was effected by lithiation at -78°C using allyl, 4-bromo-l-butene and 5-bromo-1-pentene .
  • the yields of the monoalkylated products 2 were in the range 80-92%, the diastereomeric excess (d.e.)in the range 75-96%.
  • the minor isomer can be removed and isolated by flash chromatography, but separation is not necessary since the overall stereochemistry in the reaction sequence is determined during the second alkylation step.
  • the lithiation of the monalkylated products is slower than before the first alkylation, and was effected at -50°C.
  • the lithiated species were subsequently cooled to -78°C and the second alkylating agent added. Once lithiated the second time, the stereochemistry at the initial alkylating site is lost.
  • the new alkylating agent will approach the reactive carbanionic center at the 5-position from the side of the ring opposite to the isopropyl group.
  • the d.e. of the product 3 after the second alkylation step was excellent, as seen when different alkylating agents were used in the two steps (3b, 3c, 3e) , in excess of 95%; the chemical yields were in the range 65-87%.
  • the RCM reactions were effected by adding catalytic amounts of bis (tricyclohexylphosphine) -benzylidine ruthenium dichloride, usually 2%, to a solution of the bis-olefin 3 in benzene or toluene (Scheme B below) .
  • the progress of the reaction was monitored by GLC or TLC.
  • the time and temperature varied for the reaction to go to completion; the rate was monitored by the disappearance of the substrate.
  • the results from the RCM experiments are shown in Table 1.
  • the catalyst complex seems sensitive to steric interaction from the isopropyl group of the substrate.
  • the bisallyl derivative 3a was hydrolyzed under mild acid conditions with trifluoroacetic acid in acetonitrile at room temperature over 5 days. Mild conditions were necessary to avoid alternative reaction paths which lead to dipeptides . Prior to the RCM reaction the amino group was protected by acetylation. There was a very significant change in the ease of the RCM reaction for the acyclic amino acid 6 and its precursor 3a; the RCM reaction for 3a gave 89% of the cyclic amino acid 7 after 4 hours at ambient temperature .
  • the bislactim ethers are generally hydrolyzed by acid under mild conditions, 0.25-0.50M HCl, to furnish their respective amino acid methyl esters.
  • hydrolysis was slow under these conditions and the formation of dipeptides was a problem.
  • Better results were obtained using slow 0.2M trifluoroacetic acid in acetonitrile allowing the reaction to proceed at ambient temperature for several days .
  • the RCM products 4b, 4c and 4e were diastereomerically pure. Accordingly the specific rotations of the enantiomeric pairs 8b and 8c after acid hydrolysis were found to be approximately the same with opposite rotational sign (see Scheme D below) . Only one of the enantiomeric seven-membered rings, viz 8e, was prepared. The other enantiomer would be available by changing the order of the stepwise alkylation used in the preparation of the intermediate substrate 3, or by using the chiral auxiliary 1 with the opposite (2S) - configuration and retaining the order of the stepwise alkylation.
  • the substrate 1 as its lithiated species was monalkylated with allyl, 4-bromo-l-butene and 5-bromo-l- pentene at -78°C as described above.
  • the diastereomeric excess (d.e.) is in the range 75-95%, but separation of the isomers was not effected since the overall stereochemistry in the reaction is determined during the subsequent aldol reaction.
  • Acrolein used in the present work was exclusively involved in 1,2 -addition to form the aldols 9 and 10.
  • the lithiated bislactam ethers 2 formed exclusively trans-aldols relatively to the 2- isopropyl group (GLC, NMR) .
  • the ⁇ - (S) isomers 9 are characterised by H-bonding from the OH-group to the nearby 6-methoxy group; the hydrogen bonding was not seen in the ⁇ - (R) isomers. With lithium as counterion the isomer ratio 9:10 was about 1:2. After exchange of the metal ion from lithium to tri- iso ropoxytitanium, formation of the ⁇ - (R) -isomer 10 was favoured but the yield in the reaction was markedly reduced because of competing polymerization reactions of the acrolein.
  • the RCM reactions were effected according to Scheme F below in refluxing benzene solution using 2% bis (tricyclohexylphosphine) benzylidine ruthenium dichloride [Ru(II)] without protection of the hydroxyl group to yield the six-membered ring structures lib and 12b in yields 89 and 88%, respectively.
  • the reaction time for the conversion of the ⁇ - (S) -isomer 9b to the RCM product lib was 14 hours, for the (R) -isomer 10b to 12b 3 days.
  • the steric crowding is such that the desired hydrolysis was not effected; instead the dipeptide was formed in 61% yield after 8 days under the standard hydrolytic conditions. The latter was protected as the N-acetyl derivative before cyclization was attempted.
  • the RCM reaction proceeded smoothly by reflux in dichloromethane to yield the five-membered serine analogue as a dipeptide 19.
  • the enyne substrates for the RCM reactions were prepared in a stereoselective manner by alkylation reactions of the Sch ⁇ llkopf chiral auxiliary, the bislactim ether 1. (See Goodman et al . Pure Appl. Chem __8: 1303-1308 (1996) and Degrado in Adv. Protein Chem. 3_9: 51-124 (1988)) .
  • the alkylating agent was either an alkenyl or an alkynyl halide.
  • the diastereomeric excess (d.e.) in the first alkylation step was variable.
  • the stereochemical yield in this step is of little importance in this context since the stereochemistry at C-5 in the initial products 2 or 25 is lost when the monoalkylated species are metallated again for the second alkylation.
  • the d.e. in the second alkylation was invariably very high using propargyl bromide for the formation of the enyne 21.
  • the isomer with the propargyl group in a trans- relationship to the isopropyl group was obtained.
  • the enynes formed have the opposite stereochemistry at C-5 allowing for the synthesis of enantiomeric target compounds without changing the configuration of the chiral auxiliary used in the reaction.
  • a methyl group was introduced indirectly on the acetylenic carbon by using l-bromo-2-butyne for the alkylation of 2b, the product being the enyne 24a.
  • Its isomer 24b with the opposite stereochemistry at C-5 was available by initial alkynylation of the bislactim ether 1 with l-bromo-2-butyne to give 25 in high yield, but the d.e. was low (79%). The stereochemistry at C-5, however, is lost on lithiation. After the subsequent alkylation with 4-bromo-l-butene, the stereoisomer 24b was obtained (70% yield) .
  • an acidic and readily removable proton is situated on the terminal actylenic carbon.
  • substitution on the terminal alkyne carbon in the enyne 21 can be effected by lithiation and treatment with an electrophile; formaldehyde from paraformaldehyde was the reagent used for hydroxymethylation of the lithiated species of 21c with formation of the alcohol 26.
  • the hydroxyl group in 26 was protected as the acetyl derivative 27 before the subsequent metathesis rearrangement .
  • the amino acid products include compounds of formula
  • R x is hydroxyl or an ester or amide forming group (eg. CH 3 0 or an amino acid residue for example a valine residue) and R y is H, CH 3 or H0CH 2 or an acylated hydroxymethyl group.
  • the spirane metathesis products 28 were all cleaved to the desired amino acid methyl esters 29 under mild acid conditions (Scheme L) .
  • 0.2 M trifluoroacetic acid in acetonitrile effected the hydrolysis.
  • the five-membered ring derivative 28a was most difficult to hydrolyze; the yield of the amino acid ester 29a was 42%.
  • An additional product (8% yield) from this reaction was identified as the partially hydrolyzed dipeptidic valine derivative 30.
  • Hydrolysis of the acetyl derivative 28e gave the amino acid ester 29e in 65% yield.
  • the stereoisomers 29c and 29d showed approximately the same figures for the optical rotations which were of opposite sign.
  • the hydroxymethyl derivatives 33a and 33b have also been cyclized using Ru (II) -catalysis producing the spiro compounds 40 and 41 in good yields.
  • the former viz . 40, is a tricyclic structure. It is formed by an exchange of two alcoholic groups, ie. by displacement of the 5-methoxy group with insertion of the 2 -hydroxymethyl function.
  • the cyclization is rationalized as due to ruthenium catalysis under the conditions used to effect RCM.
  • the stereochemistry of the hydroxymethyl group must be such that five-membered ring formation is favourable. In the other isomer there was no exchange of alcoholic functions.
  • the tricyclic structure 40 gave the dipeptide 42 as the major product in which the cyclic amino acid is the ⁇ -terminal in the dipeptide with valine .
  • Dipeptides can be cleaved by acid hydrolysis to their respective amino acids.
  • the two dipeptides 43 and 44 were formed.
  • the former arises by opening of the bislactim ring at the 3,4-imino bond, the latter at the 5,6-imino bond, the former pathway being favoured.
  • D may carry an oxygen function.
  • This oxygen function can either be a hydroxy functionality or an oxo group.
  • the oxo derivative is either a target molecule in itself or acts as an intermediate for hydroxylation by a reductive process, by organometal additions, or is suitable for aminations.
  • hydroxylation may be achieved by epoxide formation (eg. effected by peracid oxidation) and subsequent ring opening, or by vicinal bishydroxylation, eg. by osmium tetroxide glycolation.
  • nBuLi (5.30 ml, 11.13 mmol, 2.1 M in hexane) was added to a solution of (R) -2, 5-dihydro-3 , 6-dimethoxy-2- isopropylpyrazine (2.00 g, 10.86 mmol) in THF (20 ml) under argon at -78°C. After 25 min, 4-bromo-l-butene (1.10 ml, 11.00 mmol) in THF (5 ml) was added dropwise over 20 minutes. The mixture was left to reach ambient temperature overnight before the reaction was quenched by addition of 0.1 M phosphate buffer (pH 7, 15 ml) .
  • nBuLi (2.7 ml, 5.94 mmol, 2.2 M in hexane) was added to a solution of (R) -2, 5-dihydro-3 , 6-dimethoxy-2- isopropylpyrazine (1.00 g, 5.43 mmol) in dry THF (10 ml) under nitrogen at -78°C. After 20 minutes, a solution of allyl bromide (0.51 ml, 5.97 mmol) in THF (2 ml) was added dropwise with stirring. The reaction mixture was left overnight to reach ambient temperature. The mixture was subsequently cooled to -78°C, and nBuLi (2.7 ml, 5.94 mmol, 2.2 M in hexane) was added.
  • nBuLi (1.10 ml, 2.31 mmol, 2.1 M in hexane) was added to a solution of (2R, 5S) -5-allyl-2 , 5-dihydro-3 , 6-dimethoxy- 2-isopropylpyrazine (514 mg, 2.29 mmol) in dry THF (15 ml) under argon at -50°C. After 30 minutes, the mixture was cooled to -78°C and 4-bromo-l-butene (0.25 ml, 2.40 mmol) in THF (1 ml) added dropwise.
  • MS(EI) 292(1, M + ) , 277(14) , 249(10) , 237(36) , 196(13) , 195(100) , 153(14) .
  • MS(EI) M 292.2163. Calc. for C 17 H 28 N 2 0 2 : 292.2151
  • MS(EI) 292(10, M + ) , 252(19) , 251(100) , 209(62) , 195(20) .
  • MS(EI) M: 292.2152. Calc. for C 17 H 28 N 2 0 2 : 292.2151.
  • Bis (tricyclohexylphosphine)benzylidine ruthenium dichloride (24 mg, 0.029 mmol) in dry toluene (1 ml) was added to a solution of (2R) -5, 5-diallyl-2, 5-dihydro-3 , 6- dimethoxy-2 -isopropylpyrazine (193 mg, 0.73 mmol) in dry toluene (10 ml) under argon, the mixture was heated at 100°C for 4 hours, and another portion of bis (tricyclohexylphosphine)benzylidine ruthenium dichloride (24 mg, 0.029 mmol) in dry toluene (1 ml) was added.
  • MS(EI) 264(21, M + ) , 249(11) , 222(17) , 221(100) , 207(12) , 196(26) .
  • MS(EI) M 264.1823. Calc. for C 15 H 24 N 2 0 2 : 264.1838.
  • nBuLi (3.90 ml, 8.61 mmol, 2.2 M in hexane) was added dropwise to a solution of (2R, 5S/R) -allyl-2 , 5-dihydro- 3 , 6-dimethoxy-2-isopropylpyrazine (1.76 g 7.83 mmol) in dry THF (10 ml) at -50°C under argon.
  • Acrolein (0.80 ml, 11.74 mmol) in THF (3 ml) was added dropwise after 1 hour. The mixture was left to slowly reach ambient temperature overnight.
  • nBuLi (1.90 ml, 3.99 mmol, 2.1 M in hexane) was added dropwise to a solution of (2R, 5R/S) -5- (3-butenyl) -2 , 5- dihydro-3 , 6-dimethoxy-2 -isopropylpyrazine (788 mg, 3.31 mmol) in dry THF (10 ml) at -50°C under argon.
  • Acrolein (0.33 ml, 4.87 mmol) in THF (2 ml) was added dropwise after 45 minutes. The temperature was kept at -50°C for 30 minutes, and the reaction mixture was then left to slowly reach ambient temperature overnight.
  • nBuLi (2.00 ml, 4.40 mmol, 2.2 M in hexane) was added to a solution of (2R, 5R/S) -2 , 5-dihydro-3 , 6-dimethoxy-2- isopropyl-5- (4-pentenyl) pyrazine (1.00 g, 3.98 mmol) in THF (10 ml) at -50°C under argon.
  • Acrolein (0.40 ml, 6.03 mmol) in THF (3 ml) was added dropwise after 1 hour. The mixture was left to slowly reach ambient temperature overnight.
  • MS(EI) 308 (1.4, AT) , 252 (15) , 251 (56) , 250 (14) , 210 (14) , 209 (100) , 196 (47) , 195 (14) .
  • MS(EI) M 308.2103. Calc. f or C 17 H 28 N 2 0 3 : 308.2100.
  • Acetic anhydride 35 ⁇ l, 0.37 mmol was added dropwise to a solution of (2R, l'S, 2 ' 'R) Methyl N- [1-allyl-l- amino-1- (2-hydroxy-3-butene) -carbonyl] valinate (87 mg, 0.31 mmol) in dry dichloromethane (3 ml) at ambient temperature, the mixture stirred under argon for 2.5 h, the solution evaporated to dryness at reduced pressure and the product isolated by flash chromatography using 3% methanol in dichloromethane as eluent; yield 79 mg (80%) of a white crystalline mateial, mp. 107-109°C.
  • nBuLi (2.20 ml, 4.84 mmol, 2.2 M in hexane) was added to a solution of (2R, 5R/S) -5- (3-butenyl) -2 , 5-dihydro-3 , 6- dimethoxy-2 -isopropylpyrazine (1.06g, 4.44 mmol) in THF (15 ml) at -50°C under argon. The mixture was stirred for 45 minutes and cooled to -78°C.
  • nBuLi (4.40 mmol, 2.2 M in hexane) was added to a solution of (2R, 5S) -5-alkenyl- 2 , 5-dihydro-3 , 6- dimethoxy-2 -isopropylpyrazine (4.00 mmol) in dry THF (15 ml) under argon at -50°C. The mixture was stirred for 45 min and cooled to -78°C.
  • MS(EI) 262(0.7, M + ) , 223(54) , 222 (11) , 221(42) , 219(25) , 181(100) , 179(72), 164(22), 149(46) .
  • MS(EI) M 262.1676. Calc. for C 15 N 22 N 2 0 2 : 262.1681.
  • nBuLi(1.62 ml, 3.73 mmol, 2.3 M in heptane) was added to a solution of (2R, 5R/S) -5- (3-butenyl) -2, 5-dihydro-3 , 6- dimethoxy-2-isopropylpyrazine (807 mg, 3.37 mmol) in dry THF (15 ml) under argon at -50°C.
  • the solution was cooled to -78°C after 45 min and l-bromo-2-butyne (see Marson et al . J. Org. Chem 59: 284-290 (1994)) (585 mg, 4.40 mmol) in THF (0.5 ml) added dropwise.
  • nBuLi (1.33 ml, 3.08 mmol, 2.3 N in heptane) was added to a solution of (2R, 5S) -5- (2-butynyl) -2, 5-dihydro-3 , 6- dimethoxy-2-isopropylpyrazine (661 mg, 2.80 mmol) in dry THF (10 ml) under argon at -50°C. The solution was cooled to -78°C after 45 min and 4-bromo-l-butene (0.35 ml, 3.36 mmol) in THF (0.5 ml) was added dropwise. The mixture was left to slowly reach ambient temperature overnight.
  • nBuLi (2.00 ml, 4.60 mmol, 2.3 M in heptane) was added to a solution of (2R, 5S) -5- (3-butenyl) -2 , 5-dihydro-3 , 6- dimethoxy-2 -isopropyl-5- (2-propynyl) pyrazine (1.16 g, 4.18 mmol) in dry THF (10 ml) at -78°C under argon. The solution was transferred after 30 min via a Teflon ® tubing to a suspension of paraformaldehyde (188 mg, corresponding to 6.27 mmol of monomer) in THF (5 ml) . The mixture was allowed to slowly reach ambient temperature overnight, 0.1 M phosphate buffer solution
  • Acetic anhydride (0.10 ml, 1.02 mmol) was added dropwise to a solution of (2R, 5S) -5- (3-butenyl) -2, 5-dihydro-3 , 6- dimethoxy-5- (4-hydroxy-2-butynyl) -2 -isopropylpyrazine (285 mg, 0.93 mmol) and 4-dimethylaminopyridine (125 mg, 1.02 mmol) in dichloromethane (10 nml) at ambient temperature under argon. The solvent was evaporated after 30 min and the product isolated by flash chromatography using hexane/ethyl acetate (4:1) as eluent; yield 299 mg (92%) of a colourless oily material.
  • (2R.5S) -2.5-Dihydro-3.6-dimethoxy-2-isopropylpyrazine-5- spiro (3-vinyl-3-cyclopentene) (28a) was obtained from (2R,5S) -5-allyl-2,5-dihydro-3, 6-dimethoxy-2 -isopropyl -5 - (2 -propynyl) pyrazine in 73% yield as a colourless oily material.
  • (2R.5S) -2.5-Dihydro-3 6-dimethoxy-2-isopropylpyrazine-5- spiro (3 -vinyl-3 -cyclohexene) (28b) was obtained from (2R,5S) -5- (3-butenyl) -2 , 5-dihydro-3 , 6-dimethoxy-2 - isopropyl-5- (2 -propynyl) pyrazine in 81% yield as a white solid material, m.p. 68°C. Found: C, 69.00; H, 8.74. Calc. for C 16 H 24 N 2 0 2 : C, 69.53; H, 8.75%.
  • MS(EI) 290(53, M + ) , 249(14) , 247(69) , 195(30) , 153(100) .
  • MS(EI) M 290.1981. Calc. for C 17 H 26 N 2 0 2 : 290.1994.
  • (2R.5R) -2.5-Dihydro-3.6-dimethoxy-2-isopropylpyrazine-5- spiro (3 -isopropenyl-3 -cyclohexene) (28d) was obtained from (2R,5R) -5- (3-butenyl) -5- (2-butynyl) -2 , 5-dihydro- 3 , 6-dimethoxy-2 -isopropylpyrazine in 86% yield as a colourless oil.
  • MS(EI) 290(100, M + ) , 247(100) , 153(83) .
  • MS(EI) M 290.1985. Calc. for C 17 H 26 N 2 0 2 : 290.1994.
  • Methyl (S) -l-amino-3-vinyl-3-cyclopentene-l-carboxylate (29a) was obtained from (2R, 5S) -2 , 5-dihydro-3 , 6- dimethoxy-2-isopropylpyrazine-5-spiro (3 -vinyl-3 - cyclopentene) in 42% yield as a colourless oily material.
  • Methyl (S) -l-amino-3-vinyl-3-cyclohexene-l-carboxylate (29b) was obtained from (2R, 5S) -2 , 5-dihydro-3 , 6- dimethoxy-2 -iso ropylpyrazine-5-spiro (3 -vinyl-3 - cyclohexene) in 83% yield as a colourless oily material.
  • Methyl (S) -l-amino-3-isopropenyl-3-cyclohexene-l- carboxylate (29c) was obtained from (2R,5S)-2,5- dihydro-3 , 6-dimethoxy-2-isopropylpyrazine-5-spiro (3- isopropenyl-3 -cyclohexene) in 80% yield as a colourless oil .
  • Methyl (R) -1 -amino-3 -isopropenyl-3 -cyclohexene-1- carboxylate (29d) was obtained from (2R,5R)-2,5- dihydro-3 , 6-dimethoxy-2-isopropylpyrazine-5-spiro (3- isopropenyl-3 -cyclohexene) in 73% yield as a colourless oil.
  • nBuLi (0.75 ml, 1.80 mmol, 2.4 M in heptane) was added dropwise to a solution of (2R, 5S) -5- (3-butenyl) -2 , 5- dihydro-3 , 6-dimethoxy-2 -isopropylpyrazine (385 mg, 1.62 mmol) in dry THF (10 ml) under argon at -50°C.
  • the solution was cooled to -78°C, stirred at this temperature for 45 min before vinyloxirane (0.145 ml, 1.80 mmol) in THF (2 ml) was added dropwise. The mixture was allowed to slowly reach ambient temperature overnight.
  • nBuLi (2.80 ml, 6.72 mmol, 2.4 M in heptane) was added dropwise to a solution of (2R, 5S) -5- (3-butenyl) -2, 5- dihydro-3, 6-dimethoxy-2 -isopropylpyrazine (1.52 g, 6.39 mmol) in dry THF (15 ml) under argon at -50°C.
  • the solution was cooled to -78°C, stirred at this temperature for 45 min before an excess of ethylene oxide was introduced through a syringe needle by condensing the gas on the glass wall of the reaction vessel .
  • the condensed gas was subsequently washed into the mixture using dry THF (1 ml) in a syringe. Boron trifluoride ethyl etherate (0.84 ml, 6.72 mmol) was then added dropwise. Acetic acid (1 ml) was added after 3 h at -78°C, the cold bath removed, and 0.1 M phosphate buffer (pH 7, 10 ml) added. The aqueous layer was extracted with dichloromethane (3 x 20 ml) . The combined organic layers were dried (MgS0 4 ) and evaporated. The residue was purified by flash chromatography using hexane/ethyl acetate 2 : 1 and 1:1 as eluents.
  • Acetic anhydride (0.23 ml, 2.46 mmol) was added dropwise to a solution of (2R, 5S, 2 'R) -5- (3-butenyl) -2, 5-dihydro- 3 , 6-dimethoxy-5- (2 -hydroxy-3 -butenyl) -2- isopropylpyrazine (689 mg, 2.23 mmol) and 4-dimethylaminopyridine
  • Acetic anhydride (67 ⁇ l, 0.71 mmol) was added to a solution of (2R,5S,2 'S) -5- (3-butenyl) -2 , 5-dihydro-3 , 6- dimethoxy-5- (2-hydroxy-3-butenyl) -2-isopropyl-pyrazine (200 mg, 0.65 mmol) and 4-dimethylaminopyridine (87 mg, 0.71 mmol) in dichloromethane (10 ml) at ambient temperature under argon. The solvent was evaporated after 2 h and the product isolated by flash chromatography using hexane/ethyl acetate 9:1 as eluent. Yield 160 mg (70%); colourless oil.
  • the aqueous phase was extracted with dichloromethane (2 x 20 ml) , the organic phases combined, dried (MgS0 4 ) and evaporated.
  • the products were isolated by flash chromatography using 3% and 10% methanol in dichloromethane.
  • the product first eluated was methyl N ⁇ (IS.2R) -1-amino- 2-hydroxymethyl-3-cyclohexene-l-carbonyll - (R) -valinate
  • the second product eluated was methyl (lS.2R)-2- hydroxymethyl-1- ⁇ (R) -valinylaminol -3-cyclohexene-l- carboxylate (44) ; yield 28 mg (18%) .
  • MS(EI) 252(43, M + ) , 251(15) , 210(16) , 209(69) , 196(67) , 180(45) , 167(30) , 154 (67) , 153 (100) .
  • Osmium tetroxide (0.15 ml, 0.011 mmol, 2.5% in tBuOH) was added to a solution of (2R) -2, 5-dihydro-3 , 6- dimethoxy-2 -isopropylpyrazine-5-spiro (3 -cyclopentene) (267 mg, 1.13 mmol) and 4-methylmorpholine-4-oxide monohydrate (168 mg, 1.24 mmol) in acetone (20 ml) and water (5 ml) at 0°C. Sodium bisulphite (125 mg, 1.24 mmol) was added after 6 h and the mixture stirred for 15 min.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des analogues d'aminoacides, en particulier à des analogues pouvant être utilisés à la place de la sérine ou de la thréonine dans la préparation de composés peptidiques. Les analogues sont des composés de la formule (I) (dans laquelle D est un groupe formant un pont qui constitue avec l'atome de carbone auquel il est relié un composé carbocyclique saturé et/ou substitué ayant entre 4 et 10 chaînons). L'invention concerne en outre des stéréoisomères, des mélanges de stéréoisomères, des sels, des esters, des amides et des protégés dérivés desdits composés.
PCT/GB1998/000029 1997-01-08 1998-01-07 Composes aminoacides Ceased WO1998030535A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU54908/98A AU5490898A (en) 1997-01-08 1998-01-07 Amino acid compounds

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9700255.4 1997-01-08
GBGB9700255.4A GB9700255D0 (en) 1997-01-08 1997-01-08 Compounds
US92157697A 1997-09-02 1997-09-02

Publications (1)

Publication Number Publication Date
WO1998030535A1 true WO1998030535A1 (fr) 1998-07-16

Family

ID=26310765

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1998/000029 Ceased WO1998030535A1 (fr) 1997-01-08 1998-01-07 Composes aminoacides

Country Status (1)

Country Link
WO (1) WO1998030535A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003018618A3 (fr) * 2001-08-20 2004-03-11 Max Planck Gesellschaft Catalyse de l'isomerisation cis/trans de composes secondaires d'amides et de peptides

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0439426A1 (fr) * 1990-01-24 1991-07-31 Ciba-Geigy Ag Agents microbicides
WO1997017092A1 (fr) * 1995-11-09 1997-05-15 Emory University Analogues d'acides amines pour l'imagerie des tumeurs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0439426A1 (fr) * 1990-01-24 1991-07-31 Ciba-Geigy Ag Agents microbicides
WO1997017092A1 (fr) * 1995-11-09 1997-05-15 Emory University Analogues d'acides amines pour l'imagerie des tumeurs

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
AVENOZA, ALBERTO ET AL: "Synthesis of a new enantiomerically pure constrained homoserine", TETRAHEDRON: ASYMMETRY (1996), 7(3), 721-8 CODEN: TASYE3;ISSN: 0957-4166, XP002061591 *
D. MENDEL ET AL.: "Protein biosynthesis with conformational restricted amino acids", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 115, 1993, DC US, pages 4359 - 4360, XP002061719 *
F. ARCHER ET AL.: "Resolution and regiospecific protection of glutamic acid analogues. I- Resolution of diastereomeric alpha-borooxazolidone derivatives", TETRAHEDRON: ASYMMETRY, vol. 5, no. 4, 1994, OXFORD GB, pages 731 - 744, XP002061590 *
FAIRBANKS, ANTONY J. ET AL: "Polyhydroxlated cyclohexane and cyclopentane.alpha.-amino acids from cyclizations of an azidolactone", TETRAHEDRON LETT. (1994), 35(47), 8891-4 CODEN: TELEAY;ISSN: 0040-4039, XP002061589 *
GAITANOPOULOS, DIMITRI E. ET AL: "Racemic diastereoisomers of 1-amino-2-hydroxycyclopentanecarboxylic acid", J. MED. CHEM. (1976), 19(2), 342-4 CODEN: JMCMAR, XP002061588 *
HAMMER, KRISTIN ET AL: "Ruthenium(II) in ring closing metathesis for the stereoselective preparation of cyclic 1-amino-1-carboxylic acids", TETRAHEDRON (1997), 53(6), 2309-2322 CODEN: TETRAB;ISSN: 0040-4020, XP002061592 *
HAMMER, KRISTIN ET AL: "Ruthenium-catalyzed enyne metathesis in stereoselective preparation of cyclic 1-amino-1-carboxylic acids", TETRAHEDRON (1997), 53(30), 10603-10614 CODEN: TETRAB;ISSN: 0040-4020, XP002061593 *
HAMMER, KRISTIN ET AL: "Synthesis of conformationally restricted serine derivatives through ruthenium(II)-catalyzed ring closing metathesis", TETRAHEDRON (1997), 53(16), 5925-5936 CODEN: TETRAB;ISSN: 0040-4020, XP002061594 *
S.P. WALFORD ET AL.: "Preparation of dipeptoid mimetics for the tetrapeptide cholecystokinin, CCK(30-33)", J. PHARM.PHARMACOL., vol. 48, 1996, pages 188 - 191, XP002061629 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003018618A3 (fr) * 2001-08-20 2004-03-11 Max Planck Gesellschaft Catalyse de l'isomerisation cis/trans de composes secondaires d'amides et de peptides
US7589065B2 (en) 2001-08-20 2009-09-15 Max-Planck Gesellschaft Zur Forderung Der Wissenschaften, C.V. Catalysis of the cis/trans-isomerisation of secondary amide peptide compounds

Similar Documents

Publication Publication Date Title
Sakai et al. Total synthesis of galantin I. Acid-catalyzed cyclization of galantinic acid
US4396542A (en) Method for the total synthesis of cyclosporins, novel cyclosporins and novel intermediates and methods for their production
EP0098457B1 (fr) (1S,2R,3R)-et (1R,2S,3S)-Nitrilo-1-carbonyl-3-méthyl-2-oxy-heptanes et-hept-5-ènes utiles dans la synthèse totale de cyclosporines et procédé pour leur préparation
Cardillo et al. Asymmetric synthesis of ß-amino acids and α-substituted β-amino acids
US4978744A (en) Synthesis of dolastatin 10
von Wartburg et al. 1 cyclosporins, fungal metabolites with immunosuppressive activities
Oguri et al. Amino Acids and Peptides. XXIX. A New Efficient Asymmetric Synthesis of α-Amino Acid Derivatives with Recycle of a Chiral Reagent-Asymmetric Alkylation of a Chiral Schiff Base from Glycine
Lubell et al. N-(9-phenylfluoren-9-yl)-. alpha.-amino ketones and N-(9-phenylfluoren-9-yl)-. alpha.-amino aldehydes as chiral educts for the synthesis of optically pure 4-alkyl-3-hydroxy-2-amino acids. Synthesis of the C-9 amino acid MeBmt present in cyclosporin
US20110040087A1 (en) Peptide turn mimetics
Hammer et al. Ruthenium-catalyzed enyne metathesis in stereoselective preparation of cyclic 1-amino-1-carboxylic acids
Wild Enantioselective total synthesis of the antifungal natural products chlorotetaine, bacilysin, and anticapsin and of related compounds: revision of the relative configuration
EP0581429B1 (fr) Procédé de préparation des depsipeptides cycliques
Hammer et al. Ru (II)-catalyzed ring closing metathesis in stereoselective syntheses of constrained homoserine analogues
CA2575280C (fr) Nouveaux procedes de synthese stereoselective d'un compose isa<sb>tx</sb>247 trans
Janusz et al. High potency dipeptide sweeteners. 1. L-aspartyl-D-phenylglycine esters
WO1998030535A1 (fr) Composes aminoacides
Sepe et al. Concise synthesis of AHMHA unit in perthamide C. Structural and stereochemical revision of perthamide C
Gil et al. Synthesis of enantiopure 7-azanorbornane proline–α-amino acid chimeras by highly efficient HPLC resolution of a phenylalanine analogue
Sun et al. Synthesis, conformation, and immunosuppressive activity of cyclosporines that contain. epsilon.-oxygen (4R)-4-[(E)-butenyl]-4, N-dimethyl-L-threonine analogs in the 1-position
AU742747B2 (en) Peptide turn mimetics
Abdelhamid et al. Cyclic Depsipeptides, Callipeltins
US20090275727A1 (en) Peptide turn mimetics
US4535169A (en) 5H-6-oxo-2,3,4,4a,7,7a-hexahydropyrano[2,3-b]pyrrole and the preparation thereof
Niroula Total Syntheses, Absolute Stereochemistry and Evaluation of Natural Products Hortonone C, Cystargolides and Analogs
Choi et al. Preparation of Orthogonally-Protected 3-Methoxy-4-Phosphonomethyl-LPhenylalanine, a New Reagent for the Synthesis of Phosphotyrosyl Mimetic-Containing Peptides

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 1998530633

Format of ref document f/p: F

122 Ep: pct application non-entry in european phase