A Practical Synthesis of (+)-Discodermolide and Analogues: Fragment Union by Complex Aldol Reactions

Ian Paterson, Gordon John Florence, Kai Gerlach, Jeremy P. Scott, Natascha Sereinig

Research output: Contribution to journalArticlepeer-review

214 Citations (Scopus)

Abstract

A practical stereocontrolled synthesis of (+)-discodermolide (1) has been completed in 10.3% overall yield (23 steps longest linear sequence). The absolute stereochemistry of the C-1-C-6 (7), C-9-C-16 (8), and C-17-C-24 (9) subunits was established via substrate-controlled, boron-mediated, aldol reactions of the chiral ethyl ketones 10, 11, and 12. Key fragment coupling reactions were a lithium-mediated, anti-selective, aldol reaction of aryl ester 8 (under Felkin-Anh induction from the aldehyde component 9), followed by in situ reduction to produce the 1,3-diol 40, and a (+)-diisopinocampheylboron chloride-mediated aldol reaction of methyl ketone 7 (overturning the inherent substrate induction from the aldehyde component 52) to give the (7S)-adduct 58. The flexibility of our overall strategy is illustrated by the synthesis of a number of diastereomers and structural analogues of discodermolide, which should serve as valuable probes for structure-activity studies.

Original languageEnglish
Pages (from-to)9535-9544
Number of pages10
JournalJournal of the American Chemical Society
Volume123
Issue number39
DOIs
Publication statusPublished - 3 Oct 2001

Keywords

  • MARINE MACROLIDE SYNTHESIS
  • LACTATE-DERIVED KETONES
  • PI-FACE SELECTIVITY
  • MICROTUBULE-STABILIZING AGENTS
  • SPONGISTATIN-1 ALTOHYRTIN-A
  • BETA-HYDROXY KETONES
  • GRAM-SCALE SYNTHESIS
  • MEDIUM RING ETHERS
  • STEREOCONTROLLED SYNTHESIS
  • POLYPROPIONATE SYNTHESIS

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