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

Ian Paterson, Oscar Delgado, Gordon John Florence, Isabelle Lyothier, Matthew O'Brien, Jeremy P. Scott, Natascha Sereinig

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)

Abstract

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 1,2-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-stereoinduction, to give the (5S)-adduct 57.

Original languageEnglish
Pages (from-to)150-160
Number of pages11
JournalThe Journal of Organic Chemistry
Volume70
Issue number1
DOIs
Publication statusPublished - 7 Jan 2005

Keywords

  • LARGE-SCALE SYNTHESIS
  • NATURAL-PRODUCT (+)-DISCODERMOLIDE
  • STABILIZING AGENT (+)-DISCODERMOLIDE
  • MEDIATED ALDOL REACTIONS
  • STEREOSELECTIVE-SYNTHESIS
  • ASYMMETRIC-SYNTHESIS
  • IMMUNOSUPPRESSANT DISCODERMOLIDE
  • POLYPROPIONATE SYNTHESIS
  • BETA-HYDROXYKETONES
  • STEREOGENIC CENTERS

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