An efficient approach to asymmetric synthesis of dipeptide β-turn mimetics: indolizidinone amino acids

Abstract

Azabicyclo[ XY0] alkane amino acids are rigid dipeptide β-turn mimetics with great potential applications for drug discovery. The lack of efficient methods to synthesize these compounds is a major bottleneck in this field. Herein we report an efficient approach to the enantiopure synthesis of (3 S,6 S,9 S) and (3 R,6 R,9 R) methyl 2-oxo-3-[ N-(Boc/Cbz)amino]-1-azabicyclo[4.3.0]nonane-9-carboxylates 1 . In this approach, the key intermediates 5a and 5b with different stereochemical configurations were efficiently constructed from the same precursor in high stereoselectivity via asymmetric hydrogenations using ( S, S) or ( R, R) Et-DUPHOS, Rh(I)-based catalysts. The process, starting from inexpensive diethyl 1,3-acetonedicarboxylate 2 , can allow for the practical synthesis of this class of compounds.