DAPHNIPHYLLUM ALKALOIDS .14. TOTAL SYNTHESIS OF (+/-)-BUKITTINGGINE

The unique heptacyclic Daphniphyllum alkaloid bukittinggine (1) has been prepared by total synthesis. The basic secodaphnane nucleus was fashioned in one step by application of the tetracyclization process to dihydroxy diether 5. The pyrrolidine ring in 1 was formed by a Pd(II)-catalyzed oxidative cyclization of 19 to give hexacyclic amine 32. Hydrogenation of 32 proceeded with little diastereoselectivity in establishing the final stereocenter in 1. However, when 32 was treated to the sequence of hydroboration/oxidation, tosylation, and reduction, excellent control of stereochemistry was observed in the formation of 33. Debenzylation of 33 (Na-liquid NH3), followed by regiospecific oxidative lactonization of diol 36 (Fetizon's reagent), afforded (+/-)-bukittinggine (1). The synthesis required 18 steps (9 --> 10 --> 11 --> 12 --> 13 --> 14 --> 15 --> 8 --> 16 --> 17 --> 18 --> 5 --> 19 --> 32 --> 35 --> 33 --> 36 --> 1) and delivered racemic bukittinggine in 3% overall yield.