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3-Amino-2H-azirines, equivalents of alpha,alpha-disubstituted alpha-amino acids in the synthesis of heterocycles and peptides


Heimgartner, Heinz (1990). 3-Amino-2H-azirines, equivalents of alpha,alpha-disubstituted alpha-amino acids in the synthesis of heterocycles and peptides. In: Lubec, G; Rosenthal, G A. Amino Acids: Chemistry, Biology and Medicine. Leiden: ESCOM Science Publishers B. V., Leiden, 29-38.

Abstract

The easily available 2,2-disubstituted 3-amino-2H-azirines 1 react with a variety of acidic compounds, e.g. NH-acidic heterocycles, to give novel heterocycles containing alpha,alpha-disubstituted alpha-amino acids. These reactions proceed via formation of an intermediate aziridine, which is rearranged to a bicyclic zwitterion. The zwitterion is the key intermediate in all reactions proceeding via cleavage of the C=N bond of 1. The reaction of 1 with carboxylic acids leads to the formation of diamides, e.g. acyl-amino isobutyric acids. The general character of this reaction has been demonstrated in particular with amino acids and oligopeptides. Together with the selective hydrolysis of the C-terminal amide group, this reaction sequence (‘Azirine/Oxazolone-Method’) represents a new and efficient strategy for the synthesis of peptides with alpha,alpha-disubstituted alpha-amino acids.
The scope of the ‘Azirine/Oxazolone-Method’ for the synthesis of linear and cyclic peptides and depsipeptides is demonstrated by the synthesis of segments of the peptaibols Alamethicin F-30 and Trichotoxin A-50 as well as of model peptides, used for studies of the influence of alpha,alpha-disubstitution on the conformation of the peptide. Via an analogous approach, the synthesis of cyclo[Gly-Phe(2Me)-Aib-Aib-Gly] is achieved by the pentafluorophenol/DCC cyclization of H-Gly-Phe(2Me)-Aib-Aib-Gly-OH. In the case of cyclic depsipeptides, the linear precursos can be cyclised directly by treatment with HCl-gas in a non-nucleophilic solvent (‘Direct Amide-Cyclization’).

Abstract

The easily available 2,2-disubstituted 3-amino-2H-azirines 1 react with a variety of acidic compounds, e.g. NH-acidic heterocycles, to give novel heterocycles containing alpha,alpha-disubstituted alpha-amino acids. These reactions proceed via formation of an intermediate aziridine, which is rearranged to a bicyclic zwitterion. The zwitterion is the key intermediate in all reactions proceeding via cleavage of the C=N bond of 1. The reaction of 1 with carboxylic acids leads to the formation of diamides, e.g. acyl-amino isobutyric acids. The general character of this reaction has been demonstrated in particular with amino acids and oligopeptides. Together with the selective hydrolysis of the C-terminal amide group, this reaction sequence (‘Azirine/Oxazolone-Method’) represents a new and efficient strategy for the synthesis of peptides with alpha,alpha-disubstituted alpha-amino acids.
The scope of the ‘Azirine/Oxazolone-Method’ for the synthesis of linear and cyclic peptides and depsipeptides is demonstrated by the synthesis of segments of the peptaibols Alamethicin F-30 and Trichotoxin A-50 as well as of model peptides, used for studies of the influence of alpha,alpha-disubstitution on the conformation of the peptide. Via an analogous approach, the synthesis of cyclo[Gly-Phe(2Me)-Aib-Aib-Gly] is achieved by the pentafluorophenol/DCC cyclization of H-Gly-Phe(2Me)-Aib-Aib-Gly-OH. In the case of cyclic depsipeptides, the linear precursos can be cyclised directly by treatment with HCl-gas in a non-nucleophilic solvent (‘Direct Amide-Cyclization’).

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Additional indexing

Item Type:Book Section, refereed, further contribution
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:1990
Deposited On:26 Mar 2014 17:27
Last Modified:08 Dec 2017 04:54
Publisher:ESCOM Science Publishers B. V., Leiden
Funders:Swiss National Science Foundation, F. Hoffmann-La Roche AG, Basel

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