Synthesis of (+)-Methyl Dihydropalustramate and of the Pyrido[1,2-a]azepine Core of Stemona Alkaloids

Abstract

Starting from a readily available, enantiomerically pure 2,6disubstituted piperidine the synthesis of pyrido[1,2-a]azepines was accomplished. Key reactions for the ring closure were a photochemically induced acyl radical addition or a SmI 2 -promoted ketyl radical addition to an α,β-unsaturated ester. En route to the cyclization precursor an epoxidiation/ring opening sequence led to an undesired oxazolidinone which turned out to be useful for the configuration assignment. The compound was successfully converted into (+)-methyl dihydropalustramate.

Synthetic Studies towards Pyrido[1,2-a]azepine Stemona Alkaloids

“…In their first contribution on the topic, com- Figure 2 Structure 3 of stemocurtisine (pyridostemin) 15 and structures 4 and 5 of synthetic intermediates towards 3 prepared by Pyne and co-workers 16,17 Synthetic efforts in our group towards pyrido[1,2-a]azepine Stemona alkaloids had previously centered on a concomitant formation of the azepane and the -lactone ring by a Michael type addition of a suitable nucleophile with d 1 -polarity. 19 The central piperidine ring with its two stereogenic centers was obtained in enantiopure form from a meso-diol by an enantioselective lipase-catalyzed acetylation. 20 Elongation of the carbon chain at both sides led in ten steps to intermediate 6 (Scheme 1; HMPA = hexamethylphosphoramide; MEM = 2-methoxyethoxyethyl).…”