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Chiral Heterospirocyclic 2H-Azirin-3-amines as Synthons for 3-Amino-2,3,4,5-tetrahydrofuran-3-carboxylic Acid and Their Use in Peptide Synthesis


Stamm, Simon; Linden, Anthony; Heimgartner, Heinz (2003). Chiral Heterospirocyclic 2H-Azirin-3-amines as Synthons for 3-Amino-2,3,4,5-tetrahydrofuran-3-carboxylic Acid and Their Use in Peptide Synthesis. Helvetica Chimica Acta, 86:1371-1396.

Abstract

The heterospirocyclic N-methyl-N-phenyl-5-oxa-1-azaspiro[2.4]hept-1-en-2-amine (6) and N-(5-oxa-1-azaspiro[2.4]hept-1-en-2-yl)-(S)-proline methyl ester (7) were synthesized from the corresponding heterocyclic thiocarboxamides 12 and 10, respectively, by consecutive treatment with COCl2, 1,4-diazabicyclo[2.2.2]octane, and NaN3 (Schemes 1 and 2). The reaction of these 2H-azirin-3-amines with thiobenzoic and benzoic acid gave the racemic benzamides 13 and 14, and the diastereoisomeric mixtures of the N-benzoyl dipeptides 15 and 16, respectively (Scheme 3). The latter were separated chromatographically. The configurations and solid-state conformations of all six benzamides were determined by X-ray crystallography. With the aim of examining the use of the new synthons in peptide synthesis, the reactions of 7 with Z-Leu-Aib-OH to yield a tetrapeptide 17 (Scheme4), and of 6 with Z-Ala-OH to give a dipeptide 18 (Scheme 5) were performed. The resulting diastereoisomers were separated by means of MPLC or HPLC. NMR Studies of the solvent dependence of the chemical shifts of the NH resonances indicate the presence of an intramolecular H-bond in 17. The dipeptides (S,R)-18 and (S,S)-18 were deprotected at the N-terminus and were converted to the crystalline derivatives (S,R)-19 and (S,S)-19, respectively, by reaction with 4-bromobenzoyl chloride (Scheme 5). Selective hydrolysis of (S,R)-18 and (S,S)-18 gave the dipeptide acids (R,S)-20 and (S,S)-20, respectively. Coupling of a diastereoisomeric mixture of 20 with H-Phe-OtBu led to the tripeptides 21 (Scheme 5). X-Ray crystal-structure determinations of (S,R)-19 and (S,S)-19 allowed the determination of the absolute configurations of all diastereoisomers isolated in this series.

The heterospirocyclic N-methyl-N-phenyl-5-oxa-1-azaspiro[2.4]hept-1-en-2-amine (6) and N-(5-oxa-1-azaspiro[2.4]hept-1-en-2-yl)-(S)-proline methyl ester (7) were synthesized from the corresponding heterocyclic thiocarboxamides 12 and 10, respectively, by consecutive treatment with COCl2, 1,4-diazabicyclo[2.2.2]octane, and NaN3 (Schemes 1 and 2). The reaction of these 2H-azirin-3-amines with thiobenzoic and benzoic acid gave the racemic benzamides 13 and 14, and the diastereoisomeric mixtures of the N-benzoyl dipeptides 15 and 16, respectively (Scheme 3). The latter were separated chromatographically. The configurations and solid-state conformations of all six benzamides were determined by X-ray crystallography. With the aim of examining the use of the new synthons in peptide synthesis, the reactions of 7 with Z-Leu-Aib-OH to yield a tetrapeptide 17 (Scheme4), and of 6 with Z-Ala-OH to give a dipeptide 18 (Scheme 5) were performed. The resulting diastereoisomers were separated by means of MPLC or HPLC. NMR Studies of the solvent dependence of the chemical shifts of the NH resonances indicate the presence of an intramolecular H-bond in 17. The dipeptides (S,R)-18 and (S,S)-18 were deprotected at the N-terminus and were converted to the crystalline derivatives (S,R)-19 and (S,S)-19, respectively, by reaction with 4-bromobenzoyl chloride (Scheme 5). Selective hydrolysis of (S,R)-18 and (S,S)-18 gave the dipeptide acids (R,S)-20 and (S,S)-20, respectively. Coupling of a diastereoisomeric mixture of 20 with H-Phe-OtBu led to the tripeptides 21 (Scheme 5). X-Ray crystal-structure determinations of (S,R)-19 and (S,S)-19 allowed the determination of the absolute configurations of all diastereoisomers isolated in this series.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2003
Deposited On:11 Sep 2013 14:24
Last Modified:05 Apr 2016 16:58
Publisher:Wiley-Blackwell
ISSN:0018-019X
Funders:Swiss National Science Foundation, F. Hoffmann-La roche AG, Basel
Publisher DOI:https://doi.org/10.1002/hlca.200390124
Permanent URL: https://doi.org/10.5167/uzh-80791

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