A Second-Generation Total Synthesis of(+)-Discodermolide:The Development of a Practical Route Using Solely Substrate-Based Stereocontrol

摘要

A novel total synthesis of the complex polyketide(+)-discodermolide,a promising anticancer agent of sponge origin,has been completed in 7.8% overall yield over 24 linear steps,with 35 steps altogether.This second-generation approach was designed to rely solely on substrate control for introduction of the required stereochemistry,eliminating the use of all chiral reagents or auxiliaries.The common l,2-anti-2,3-syn stereotriad found in each of three subunits,aldehyde 9(C_1-C_5),ester 40(C_9-C_(16)),and aldehyde 13(C_(17)-C_(24)),was established via a boron-mediated aldol reaction of ethyl ketone 15 and formaldehyde,followed by hydroxyl-directed reduction to give 1,3-diol 14.Alternatively,a surrogate aldehyde 22 was employed for formaldehyde in this aldol reaction,leading to the beta-hydroxy aldehyde 20 as a common building block,corresponding to the discodermolide stereotriad.Key fragment unions were achieved by a lithium-mediated anti aldol reaction of ester 40 and aldehyde 13 under Felkin-Anh control to provide(16S,17S)-adduct 51 and a boron-mediated aldol reaction between enone 10 and aldehyde 9,exploiting unprecedented remote 1,6-stereoin-duction,to give the(5S)-adduct 57.