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

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) alpha-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.