DAPHNIPHYLLUM ALKALOIDS .16. TOTAL SYNTHESIS OF (-CODAPHNIPHYLLINE())

A total synthesis of (+)-codaphniphylline (3) has been developed. The synthesis begins with Noyori asymmetric reduction of methyl 2-oxocyclo pentanecarboxylate (15), which gives the trans-P-hydroxy ester 16 (93% ee). Frater-Seebach alkylation of this material with homogeranyl iodi de gives hydroxy esters 18 and 19 in a ratio of 15:1. This mixture is oxidized to keto ester 29, which is converted into acetal 34. Reductio n of the ester function gives primary alcohol 35, which is esterified by treatment with 2-bromo-4-chlorobutanoyl chloride. The resulting ket o ester, 33, is treated with unactivated zinc dust in the presence of 2 equiv of ZnCl2 to obtain lactone ether 36, which is reduced by lithi um aluminum hydride to diol 9. Serial treatment of this material with Swern oxidant, methylamine, and warm acetic acid provides the hexacycl ic amino ether 10 in 63% overall yield. Reductive fragmentation to 11 results when 10 is treated with excess diisobutylaluminum hydride in h ot toluene. Ring closure to the daphnane skeleton (12) occurs when the N,O-bis(phenylcarbamoyl) derivative 41 is treated with hot acetic aci d, followed by KOH in methanol. Displacement of the tosyl group gives sulfide 50, which is oxidized to sulfone 13. This material is metalate d and coupled with enantiomerically-pure aldehyde 46 to secure the cod aphniphylline skeleton, as a mixture of four diastereomeric beta-hydro xy sulfones (51). Oxidation gives a mixture of diastereomeric beta-ket o sulfones (52), which is desulfonated to obtain (+)-codaphniphylline (3). The synthesis requires 12 steps from homogeranyl iodide, the more precious starting material, and provides the enantiomerically pure al kaloid in 9% overall yield.