Total Syntheses of the Cytotoxic Marine Natural Product, Aplysiapyranoid C1

The first total syntheses of the cytotoxic marine natural product, aplysiapyranoid C, 1c, are reported. The Wittig reaction of 4-methyl-3-pentenyltriphenylphosphorane with the THP ether of hydroxyacetone gave in 88% yield the Z -alkene 4 which was hydrolyzed to the alcohol 5 in 72% yield. Sharpless asymmetric epoxidation of 5 afforded the epoxy alcohol 6 in 91% yield and 81% ee. Opening of the epoxide of 6 with ammonium chloride in DMSO gave in 76% yield the chloro diol 7 which was converted to the primary TBS ether 8 in 95% yield. Opening of the epoxy alcohol 6 with HCl and Ti(OiPr) 4 afforded the desired chloro diol 7 as the minor product along with the rearranged chloromethyl diol 9 . This compound is presumably formed by opening of the protonated epoxide to give a butenyl cation which rearranges to the cyclopropylcarbinyl cation and is then trapped by chloride ion at the unsubstituted cyclopropyl carbon, regenerating the alkene. Cyclization of the TBS ether 8 with tetrabromocyclohexadienone (TBCO) afforded a mixture of all four possible cyclization products, the desired tetrahydropyrans 11a,b and the tetrahydrofurans 12a,b with the former being isolated in 70% yield. Hydrolysis of the TBS ether afforded the primary alcohols from which the desired isomer, 13, could be isolated (24% overall from 8 ). Swern oxidation furnished the aldehyde 14 which was subjected to the Takai chlorovinylation to give a mixture of aplysiapyranoid C 1c and the reduced product, dechloroaplysiapyranoid C 15 . This dechlorination under these conditions is quite unusual. A second synthesis of aplysiapyranoid C avoided this problem. Selective protection of the more hindered tertiary alcohol of the chloro diol 7 afforded the primary alcohol 16 in which the tertiary alcohol was protected as the triethylsilyl ether. Swern oxidation, Takai reaction, and desilylation gave the dichloro alkenol 17 in 52% overall yield. In this case, only a small amount of the corresponding dechlorinated product was obtained. Final cyclization of 17 with TBCO afforded aplysiapyranoid C 1c as the major product in an isolated yield of 43%. Thus we have completed two total syntheses of aplysiapyranoid C 1c from the simple bromide 2 in eight or nine steps and good overall yield.