Enantioselective Synthesis of D-α-Amino Amides from Aliphatic Aldehydes

Chemical Science
Kenneth E Schwieter, Jeffrey N Johnston

Abstract

Peptides consisting of D-amino amides are highly represented among both biologically active natural products and non-natural small molecules used in therapeutic development. Chemical synthesis of D-amino amides most often involves approaches based on enzymatic resolution or fractional recrystallization of their diastereomeric amine salts, techniques that produce an equal amount of the L-amino acid. Enantioselective synthesis, however, promises selective and general access to a specific α-amino amide, and may enable efficient peptide synthesis regardless of the availability of the corresponding α-amino acid. This report describes the use of a cinchona alkaloid-catalyzed aza-Henry reaction using bromonitromethane, and the integration of its product with Umpolung Amide Synthesis. The result is a straightforward 3-step protocol beginning from aliphatic aldehydes that provides homologated peptides bearing an aliphatic side chain at the resulting D-α-amino amide.

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Citations

Oct 28, 2015·Chemical Communications : Chem Comm·Kenneth E Schwieter, Jeffrey N Johnston
Jan 6, 2015·Social Science & Medicine·Jennifer Karas Montez, Esther M Friedman
Sep 28, 2016·Chemical Reviews·Renata Marcia de FigueiredoJean-Marc Campagne
Oct 18, 2016·Journal of the American Chemical Society·Brandon A Vara, Jeffrey N Johnston
Dec 30, 2016·The Journal of Organic Chemistry·Ransheng DingChristian Wolf
May 17, 2017·Chemical Science·Kazuyuki Tokumaru, Jeffrey N Johnston
Aug 10, 2017·Organic & Biomolecular Chemistry·Ryosuke TakedaVadim A Soloshonok
Dec 31, 2021·Organic Letters·Luana CardinaleAxel Jacobi von Wangelin

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Methods Mentioned

BETA
column chromatography

Software Mentioned

UmAS

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