2 INTERRELATED STRATEGIES FOR CEPHALOTAXINE SYNTHESIS

Studies of two interrelated strategies for the synthesis of members of the cephalotaxus alkaloid family have culminated in a concise route f or the preparation of the parent member cephalotaxine (1). As part of efforts exploring the use of an SET-promoted photocyclization reaction of aryl-substituted silylallyliminium salts to generate the spirocycl ic DE unit of the target, we noted that attempts to generate the penta cyclic amino ketone 23 by deacylation of the enol ester 20 led to prod uction of a mixture of 23 and the macrocyclic amino enone 24. A rapid equilibrium was shown to exist between 23 and 24, favoring the latter ring-opened form. This contrasts with the behavior of desmethylcephalo taxinone (22), a key late intermediate in several earlier cephalotaxin e syntheses, which is known to exist in a ring-closed form. These obse rvations led to the design of a second generation strategy which relie s on transannular cyclization of the macrocyclic amino enedione 28. In practice, the sequence following this design transforms the known iod opiperonylethanol derivative 4 to 22 in 13 steps and a 12% overall yie ld and, thus, corresponds to an efficient formal synthesis of cepahalo taxine.