α,β-Dehydroamino Acid Synthesis through Proline-Catalyzed Aldol Condensation with a Glycine Schiff Base

Abstract

A general protocol for the synthesis of α,β-dehydroamino acids and their peptides was developed. Proline efficiently catalyzed an aldol condensation reaction of a glycine Schiff base with a variety of aldehydes. The hydroxy group on the benzophenone imine was crucial for high Z/E selectivity and further transimination for protecting group-free α,β-dehydroamino esters. Peptide elongation of both the C- and N-terminals highlighted the usefulness of our present protocol.

Efficient synthetic methods for α,β-dehydroamino acids as useful and environmentally benign building blocks in biological and materials science

“…The synthetic utility of α,β-dehydroamino acid derivatives prepared by aldol condensations of a glycine Schiff base was demonstrated in peptide synthesis (Scheme 17). 33 An α,β-dehydroamino acid product was converted to a seven-membered compound via intramolecular esterification with a phenolic hydroxy group. The resulting seven-membered compound, containing an α,β-dehydroamino acid structure, was treated with amino acid esters to provide dipeptide products in high yields.…”

“…Catalytic carbon-carbon bond formation approaches in the synthesis of α,β-dehydroamino acid derivatives were reported by Yazaki, Ohshima, and co-workers in 2024 (Scheme 16). 33 They employed aldol condensation of a glycine derivative for the preparation of a wide variety of α,β-dehydroamino acids. By changing the substituents of aldehydes, various types of Scheme 13 Enzymatic approach for the preparation of peptides containing α,β-dehydroamino acid units from serine and threonine derivatives.…”

“…Yazaki and Ohshima also reported an additional approach for the synthesis of peptides containing an α,β-dehydroamino acid moiety (Scheme 17). 33 N-Unprotected α,β-dehydroamino esters were obtained in good yields under optimized conditions using hydrazine. It should be noted that hydrolysis under acidic conditions led to the production of undesired α-keto esters from α,β-dehydroamino esters due to the inherent Scheme 15 Late-stage installation of a dehydroalanine unit in a cyclosporin A analogue.…”