New route to trans-fused bicycloprolines and bicyclopipecolic acids precursors

Abstract

Conformationally restricted bicyclic unnatural amino acids are compounds with broad spectrum of application. Due to extensive usage in medicinal chemistry (especially chemistry of peptidomimetics) as well as organocatalysis new synthetic strategies for their preparation are strongly desired. Herein, we report new strategy for the preparation of trans-fused bicycloprolines and bicyclopipecolic acids precursors from commercially available β-ketoesters. Desired trans-stereochemistry was set up in the second step by Strecker reaction of readily 2-allylcycloalkanones producing corresponding α-aminonitriles which, after tosylation, undergo PhI(OAc)2 promoted electrophilic cyclization. Cyclization step can be carried out in 5-exo or 6-endo mode, depending on reaction conditions, yielding bicycloprolines or bicyclopipecolic acid precursors, respectively.