Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 5:  Linkage of Fragments C₁_-₆ and C₇_-₂₄ and Finale

Abstract

The finale of the large-scale preparation of 60 g of the highly complex marine natural product, (+)-discodermolide ( 1 ), using a hybridized Novartis−Smith−Paterson synthetic route is presented. This contribution, which is the concluding part of a five-part series, highlights a reagent-controlled stereoselective boron enolate aldol reaction between 2 and 3 forming the C7 hydroxyl-bearing stereocenter, selective reduction of 4a to generate the 1,3- anti -diol 5, and a global deprotection and concomitant lactonization leading to (+)-discodermolide ( 1 ). A novel procedure for converting the minor epimeric aldol adduct 4b into discodermolide using a five-step sequence is also described. This large-scale synthesis of discodermolide involved 39 steps (26 steps in the longest linear sequence) and several chromatographic purifications and delivered sufficient material for early-stage human clinical trials.