Synthesis of the C1−C16 Polyol‐Containing Macrolactone of 13‐Desmethyl Lyngbouilloside, an Unnatural Analog of the Originally Assigned Structure of (−)‐Lyngbouilloside

Abstract

AbstractThe synthesis of the C1−C16 polyol‐containing macrolactone of 13‐desmethyl lyngbouilloside, an unnatural analog of the originally assigned structure of (−)‐lyngbouilloside is reported. Synthesis of the C1−C16 acyclic backbone is achieved via iterative use of a phosphate tether‐mediated one‐pot sequential, RCM/CM/chemoselective diimide reduction, with concomitant use of a regio‐ and diastereoselective cuprate addition using Me2Zn/CuCN ⋅ 2LiCl or Pd‐catalyzed reductive allylic transposition, respectively on bicyclo[4.3.1]phosphate‐containing subunits. Subsequent oxidative cleavage and Roskamp homologation completes the pathway to the C1−C16 acyclic fragment. Two routes to the macrocyclic core were explored with mixed success, (i) a Boeckman‐type acylketene trapping of the C13 secondary carbinol and (ii) an alternative route employing acid‐catalyzed pyran‐mixed ketal formation via reaction of the C7 secondary carbinol with the β‐keto ester using trimethylorthoformate, and subsequent Yamaguchi cyclization.