Daphniphyllum Alkaloids. 16. Total Synthesis of (+)-Codaphniphylline

Article abstract of DOI:10.1021/jo00110a013

A total synthesis of (+)-codaphniphylline (3) has been developed.The synthesis begins with Noyori asymmetric reduction of methyl 2-oxocyclopentanecarboxylate (15), which gives the trans-β-hydroxy ester 16 (93percent ee).Frater-Seebach alkylation of this material with homogeranyl iodide 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.Reduction of the ester function gives primary alcohol 35, which is esterified by treatment with 2-bromo-4-chlorobutanoyl chloride.The resulting keto 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 lithium aluminum hydride to diol 9.Serial treatment of this material with Swern oxidant, methylamine, and warm acetic acid provides the hexacyclic amino ether 10 in 63percent overall yield.Reductive fragmentation to 11 results when 10 is treated with excess diisobutylaluminum hydride in hot toluene.Ring closure to the daphnane skeleton (12) occurs when the N,O-bis(phenylcarbamoyl) derivative 41 is treated with hot acetic acid, followed by KOH in methanol.Displacement of the tosyl group gives sulfide 50, which is oxidized to sulfone 13.This material is metalated and coupled with enantiomerically-pure aldehyde 46 to secure the codaphniphylline skeleton, as a mixture of four diastereomeric β-hydroxy sulfones (51).Oxidation gives a mixture of diastereomeric β-keto 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 alkaloid in 9percent overall yield.