Web Release Date: December 4,
Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 5: Linkage of Fragments C1-6 and C7-24 and Finale
Chemical and Analytical Development, Novartis Pharma AG, CH 4002 Basel, Switzerland
, and
Novartis Institutes for Biomedical Research, One Health Plaza, East Hanover, New Jersey 07936, U.S.A.
University of Cambridge, Chemical Laboratories Lensfield Road, Cambridge CB2 1EW, UK
Received for review September 16, 2003.
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.
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