Enantioselective Synthesis of Pyroglutamic Acid Esters from Glycinate via Carbonyl Catalysis

摘要

Direct alpha-functionalization of NH2-free glycinates with relatively weak electrophiles such as alpha,beta-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 alpha-C of glycinate 1 a with alpha,beta-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.