Enantioselective Synthesis of Pyroglutamic Acid Esters from Glycinate via Carbonyl Catalysis

• Published in: Angewandte Chemie International Edition 2021-05, Vol.60 (19), p.10588-10592
• Main Authors: Ma, Jiguo, Zhou, Qinghai, Song, Guanshui, Song, Yongchang, Zhao, Guoqing, Ding, Kuiling, Zhao, Baoguo
• Format: Article
• Language: English
• Subjects: Absolute configuration; Alzheimer's disease; asymmetric Michael addition; carbonyl catalysis; Carbonyl compounds; Carbonyls; Catalysis; Catalysts; chiral pyridoxal; Decarboxylation; Diastereoisomers; Enantiomers; Esters; Neurodegenerative diseases; Pyroglutamic acid; Rolipram; vitamin B6; α-functionalization of amines
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202017306

Direct α‐functionalization of NH2‐free glycinates with relatively weak electrophiles such as α,β‐unsaturated esters still remains a big challenge in organic synthesis. With chiral pyridoxal 5 d as a carbonyl catalyst, direct asymmetric conjugated addition at the α‐C of glycinate 1 a with α,β‐unsaturated esters 2 has been successfully realized, to produce various chiral pyroglutamic acid esters 4 in 14–96 % yields with 81–97 % ee's after in situ lactamization. The trans and cis diastereomers can be obtained at the same time by chromatography and both of them can be easily converted into chiral 4‐substituted pyrrolidin‐2‐ones such as Alzheimer's drug Rolipram (11) with the same absolute configuration via tert‐butyl group removal and subsequent Barton decarboxylation. In the presence of chiral pyridoxal 5 d as a carbonyl catalyst, asymmetric 1,4‐conjugated addition at the α‐position of NH2‐unprotected glycinate to α,β‐unsaturated esters and subsequent in situ lactamization formed chiral pyroglutamic acid esters 4 in 43–96 % yields with 81–97 % enantioselectivities, providing an interesting and straightforward way to make chemically and biologically significant pyroglutamic acid derivatives.