Studies of two interrelated strategies for the synthesis of members of the cephalotaxus alkaloid family have culminated in a concise route for 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 spirocyclic DE unit of the target, we noted that attempts to generate the pentacyclic amino ketone 23 by deacylation of the enol ester 20 led to production 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 desmethylcephalotaxinone (22), a key late intermediate in several earlier cephalotaxine syntheses, which is known to exist in a ring-closed form. These observations led to the design of a second generation strategy which relies on transannular cyclization of the macrocyclic amino enedione 28. In practice, the sequence following this design transforms the known iodopiperonylethanol derivative 4 to 22 in 13 steps and a 12% overall yield and, thus, corresponds to an efficient formal synthesis of cepahalotaxine.

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