Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 5: Linkage of Fragments C1-6 and C7-24 and Finale

Stuart J Mickel, Daniel Niederer, Robert Daeffler, Adnan Osmani, Ernst Kuesters, Emil Schmid, Karl Schaer, Remo Gamboni, Weichun Chen, Eric Loeser, Frederick R. Kinder Jr, Kurt Konigsburger, Kapa Prasad, Timothy M. Ramsey, Oljan Repic, Run-Ming Wang, Gordon John Florence, Isabelle Lyothier, Ian Paterson

Research output: Contribution to journalArticlepeer-review

153 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)122-130
Number of pages9
JournalOrganic Process Research & Development
Volume8
Issue number1
DOIs
Publication statusPublished - Jan 2004

Keywords

  • MEDIATED ALDOL REACTIONS
  • KETONES

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