Cyclic sulfamidates as versatile lactam precursors. An evaluation of synthetic strategies towards (−)-aphanorphine

Abstract

A full account of studies which led to the efficient asymmetric synthesis of (−)-aphanorphine 1 is reported. Two routes to the key cyclic sulfamidate intermediate 5 are described, the first was based on a chiral auxiliary approach and the second utilised asymmetric hydrogenation methodology. A range of C(3)-substituted lactams (4, 22 and 25) were synthesised and evaluated as precursors for Pd(0) catalysed entries (based on (i) α-arylation of a lactam enolate and (ii) reductive Heck reaction) to the 3-benzazepine core of 1. These approaches were less effective than an aryl radical cyclisation which allowed the completion of a synthesis of 1 in 12 steps from anisaldehyde.