Synthetic studies toward the brasilinolides: controlled assembly of a protected C1-C38 polyol based on fragment union by complex aldol reactions

Org Biomol Chem. 2015 May 28;13(20):5716-33. doi: 10.1039/c5ob00498e. Epub 2015 Apr 22.

Abstract

The brasilinolides are an architecturally complex family of 32-membered macrolides, characterised by potent immunosuppressant and antifungal properties, which represent challenging synthetic targets. By adopting a highly convergent strategy, a range of asymmetric aldol/reduction sequences and catalytic protocols were employed to assemble a series of increasingly elaborate fragments. The controlled preparation of suitable C1-C19 and C20-C38 acyclic fragments 5 and 6, containing seven and 12 stereocentres respectively, was first achieved. An adventurous C19-C20 fragment union was then explored to construct the entire carbon chain of the brasilinolides. This pivotal coupling step could be performed in a complex boron-mediated aldol reaction to install the required C19 hydroxyl stereocentre when alternative Mukaiyama-type aldol protocols proved unrewarding. A protected C1-C38 polyol 93 was subsequently prepared, setting the stage for future late-stage diversification toward the various brasilinolide congeners. Throughout this work, asymmetric boron-mediated aldol reactions of chiral ketones with aldehydes proved effective both for controlled fragment assembly and coupling with predictable stereoinduction from the enolate component.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / chemistry*
  • Carbon / chemistry*
  • Catalysis
  • Ketones / chemistry*
  • Macrolides / chemical synthesis*
  • Molecular Structure
  • Polymers / chemistry*
  • Stereoisomerism

Substances

  • Aldehydes
  • Ketones
  • Macrolides
  • Polymers
  • polyol
  • Carbon
  • 3-hydroxybutanal