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Beilstein J Org Chem. 2017 Nov 15;13:2428-2441. doi: 10.3762/bjoc.13.240. eCollection 2017.

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics.

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1
Organic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Universitätsstraße 25, D-33615 Bielefeld, Germany.

Abstract

The amide moiety of peptides can be replaced for example by a triazole moiety, which is considered to be bioisosteric. Therefore, the carbonyl moiety of an amino acid has to be replaced by an alkyne in order to provide a precursor of such peptidomimetics. As most amino acids have a chiral center at Cα, such amide bond surrogates need a chiral moiety. Here the asymmetric synthesis of a set of 24 N-sulfinyl propargylamines is presented. The condensation of various aldehydes with Ellman's chiral sulfinamide provides chiral N-sulfinylimines, which were reacted with (trimethylsilyl)ethynyllithium to afford diastereomerically pure N-sulfinyl propargylamines. Diverse functional groups present in the propargylic position resemble the side chain present at the Cα of amino acids. Whereas propargylamines with (cyclo)alkyl substituents can be prepared in a direct manner, residues with polar functional groups require suitable protective groups. The presence of particular functional groups in the side chain in some cases leads to remarkable side reactions of the alkyne moiety. Thus, electron-withdrawing substituents in the Cα-position facilitate a base induced rearrangement to α,β-unsaturated imines, while azide-substituted propargylamines form triazoles under surprisingly mild conditions. A panel of propargylamines bearing fluoro or chloro substituents, polar functional groups, or basic and acidic functional groups is accessible for the use as precursors of peptidomimetics.

KEYWORDS:

Ellman’s chiral sulfinamide; amino acid analogous side chains; desilylation; intramolecular Huisgen reaction; peptidomimetics; propargylamines; rearrangement to α,β-unsaturated imines

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