Enantioselective synthesis of indole‐based unnaturalβ‐Alkynylα‐amino acid derivatives via chiral phosphoric acid catalysis

Abstract

The synthesis of unnatural α‐amino acid derivatives has attracted considerable interest in recent years, as they are ubiquitous in protein synthesis and peptide‐based drug discovery. Herein, we reported the chiral phosphoric acid catalyzed asymmetric reaction of indoles with β,γ‐alkynyl‐α‐imino esters for the enantioselective synthesis of unnatural indole‐based α‐amino acid derivatives. This asymmetric organocatalysis protocol enables efficient synthesis of unnatural α‐amino acid derivatives with a tetrasubstituted stereogenic center and an alkyne moiety with up to 99% yield and 98% ee, resulting in operationally simple conditions, short reaction time, and broad substrate scope.

Accessing unnatural α-amino acids with tetrasubstituted stereogenic centersviacatalytic enantioselective reactions of ketimine-type α-iminoesters/α-iminoamides

“…122 In 2022, they also reported similar chemistry using indoles as nucleophiles (Scheme 75, middle). 123 Zhang and co-workers used 5-aminoisoxazoles as nucleophiles in aza-FC reaction of alkynyl-substituted ketimines 47a catalyzed by CPA 161e to afford α-isoxazole-substituted ATAAs 184 (Scheme 75, bottom). 124 All reactions proceeded to afford good yields, diastereoselectivities, and enantioselectivities, and were broadly substrate-tolerant.…”

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

“…The indole’s NH performed as the H-bond donor whereas the imine nitrogen of 95 was the H-bond acceptor towards the catalyst enabling a face-selective attack by the π-nucleophile to the electrophile C=N plane (see transition state 98 ). The substrate scope comprised mainly varying aryl or heteroaryl-substituents at the alkyne moiety that imparted high degrees of enantioselectivities to the products ( Scheme 22b ) [ 52 ].…”