Calyciphylline F (1) was isolated from the leaves of Daphniphyllum calycinum as a novel class of daphniphyllum alkaloids by Kobayashi and co-workers in 2007. The structural features of 1 include unique fused-pentacyclic skeleton containing a 8-azatricyclo[4.2.1.0.]nonane system that consists of a tropane skeleton, three quaternary carbon centers, and seven contiguous stereogenic carbon centers. The bioactivities of 1 have not been elucidated yet because of its scarce supply. Thus we aim for the first total synthesis of 1 and establishing efficient processes for bioactivity study. We started this project from development of concise [4+3] cycloaddition reaction of 2-oxyally cations with pyrroles to furnish tropane skeleton, a platform for complex framework of 1 (Scheme 1). During the course of total synthesis of 1, we planed the late-stage bridgehead radical reaction for the introduction of side chain and efficient intramolecular [4+3] cycloaddition reaction for construction of tricyclic tropinone 7, a key intermediate of 1 (Scheme 2). First, we obtained the desired tricyclic tropinone 7 as major product via intramolecular [4+3] cycloaddition reaction from a precursor 8, containing pyrrole and 2-silyloxy-allylalcohol moieties (Scheme 3). Next, 7 was converted to methylester 15' which was subjected to the cyclization reaction in the presence of KHMDS and TMSCl to afford the desired cycloadduct 16 as a single stereoisomer (Scheme 4). Then we successfully synthesized pentacyclic skeleton 22 through radical cyclization of iodoalkane 21 (Scheme 5). Finally we examined the bridgehead radical reaction with model xanthate 23. Protonation of tertiary amine was found to be crucial for this radical reaction (Scheme 6).Treatment of 23 with V-40, (TMS)3SiH and methyl acrylate in the presence of Tf2NH gave the desired product 24. The attempt to synthesize 1 by using this protocol is currently underway.
