摘要：

Frondosin A, a sesquiterpene natural product isolated from marine sponge Dysidea frondosa collected in pohnpei, Federated States of Micronesia, has been shown to be a potent antagonist toward the IL-8 receptor and inhibitor of PKC.1 Recently, we reported that Rh2(S-TCPTTL)4(2) is highly effective catalyst for enantioselective tandem carbonyl ylide formation-cyclization reactions of a-diazo-b-ketoesters with phenylacetylene, ethyl ethynyl ether, styrene and arylallene dipolarophiles, providing cycloadducts with enantioselectivity up to 99% ee as well as perfect exo diastereoselectivity for arylallenes.4,5 In conjunction with our continuing interest in the carbonyl ylide cycloaddition strategy for the synthesis of natural products, we addressed the enantioselective total synthesis of Frondosin A (1). The 1,3-dipolar cycloaddition of carbonyl ylide derived from a-diazo-b-ketoester 3a with 2 equiv of arylallene 4a using 1 mol % of Rh2(S-TCPTTL)4 afforded the exo-cycloadduct 5a in 65% yield with 82% ee. Sequential reduction of ketone and tert-butyl ester followed by selective iodination of secondary alcohol and cleavage of oxygen-bridge with Zn afforded 7-membered carbocycle 6, which was converted to carbonate 15. Deoxygenation of 15 under Tsuji conditions9using Pd(acac)2 and PBu3 followed by deprotection of TIPS ether afforded alcohol 7 and its diastereomer in a 5.5:1 ratio and 88% combined yield. Dess-Martin oxidation of 7 and subsequent addition of cyclopropyl litium reagent10 followed by pinacol-type ring expansion and K-selectride reduction of carbonyl group furnished cyclobutanol 8. [1,3]-sigmatropic rearrangement of 8 with KH11 afforded alcohol 19, which, upon Dess-Martin oxidation and isomerization with basic alumina, gave bicyclo[5.4.0]undecen-8-one 9. Further efforts toward the total synthesis of 1 are currently underway.

展开