Non‐Enzymatic Hybrid Catalysis for Stereoconversion of l‐Amino Acid Derivatives to d‐Isomers

Abstract

A catalytic transformation of N‐unprotected l‐amino esters to N‐protected d‐amino esters was developed. The combined use of a heteroaromatic aldehyde, Lewis acid, palladium complex, and chiral Brønsted acid was a key factor for the successful operation of this catalytic system. The synergistic cooperation of an appropriate aldehyde and Lewis acid was crucial for promoting an efficient racemization of l‐amino esters, while the combination of a palladium complex and chiral phosphoric acid enabled dynamic kinetic resolution through asymmetric N‐allylation, providing N‐protected d‐amino esters in good yields with up to 97 : 3 er. Following appropriate deprotection processes, d‐amino acids were obtained without loss of enantiomeric purity.

New pharmaceuticals approved by FDA in 2020: Small‐molecule drugs derived from amino acids and related compounds

“…In this regard, we would like to stress the growing need in availability and affordability of various tactual types of AAs. Indeed, the interest in the development of synthetic approaches for the preparation of tailor‐made AAs in enantiomerically pure form is currently at an all‐time high 82–135 . Some impressive developments have been made in the area of dynamic kinetic resolution of unprotected AAs, 136–139 a methodology which is best suited for large‐scale production and can rival biocatalytic approaches in affordability and low‐cost structure.…”

Picolinaldehyde‐Zinc(II)‐Palladium(0) Catalytic System for the Asymmetric α‐Allylation of N‐Unprotected Amino Esters

“…[11] Recently, Ooi and coworkers reported the asymmetric N-allylation of amino esters catalyzed by achiral 8-quinolinecarboxaldehyde, Zn(II) salts, achiral palladium complex and chiral phosphoric acid, accessing D-amino acids from L-amino acids (Scheme 1d). [12] The addition of chiral phosphoric acid might play an important role in the control of selectivity, promoting N-allylation faster than αallylation. These trigger us that the combination of appropriate chiral palladium complex and achiral aldehyde with Zn(II) salts enables an efficient α-allylation of N-unprotected amino esters.…”

“…Feng and coworkers have developed a new co‐catalytic system of picolinaldehyde and chiral Yb III ‐ N,N’ ‐dioxides for the direct Mannich/condensation cascade reaction of glycine ester with aromatic aldimines [11] . Recently, Ooi and coworkers reported the asymmetric N ‐allylation of amino esters catalyzed by achiral 8‐quinolinecarboxaldehyde, Zn(II) salts, achiral palladium complex and chiral phosphoric acid, accessing D‐amino acids from L‐amino acids (Scheme 1d) [12] . The addition of chiral phosphoric acid might play an important role in the control of selectivity, promoting N ‐allylation faster than α‐ allylation.…”

Tailor‐Made Amino Acids in Pharmaceutical Industry: Synthetic Approaches to Aza‐Tryptophan Derivatives

“…Even far greater role AAs play in bio‐pharmaceuticals such as peptides, peptidomimetics and proteins [3] . Accordingly, interest in the development of synthetic approaches for the preparation of tailor‐made AAs and their derivatives is currently at an all‐time high [4–21] …”