Asymmetric synthesis of 2-azabicyclo[3.1.0]hexane-3-carboxylic acid

2-Azabicyclo[3.1.0]hexane-3-carboxylic acids were obtained via amino protection, 4-dimethylaminopyridine (DMAP) catalytic cyclization, reduction-dehydration into alkene, asymmetric Simmons-Smith reaction and hydrolysis reaction from glutamic acid. The intermediates and target products were characterized by ¹H NMR and ¹³C NMR. (1R,3S,5R)- 2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid and (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo- [3.1.0]hexane-3-carboxylic acid were analyzed by X-ray diffraction as well. The process conditions about DMAP catalytic cyclization reaction, Simmons-Smith reaction and hydrolyzation were discussed. The results show that the yield of (R)-1,2-di-tert-butyl 5-oxopyrrolidine- 1,2-dicarboxyate was 82% at the ratio of n(DMAP):n(di-tert-butyl dicarbonate): n(pyridine)=0.40:4.0:1.0. The ratio of cis/trans-form varied with the reaction time in Simmons-Smith reaction, which gave a best ratio of 6:1 at 19.5 h. The total yield is 30%, and the de value is 72%.