Towards the synthesis of the squalestatins/zaragozic acids: Synthesis of an advanced intermediate and introduction of the C-1 sidechain

Abstract

A highly convergent synthesis of a squalestatin/zaragozic acid A C-4-decarboxydeoxy intermediate has been achieved. The key step involves the construction of the C-1–C-1′ bond by the addition of a fully functionalized C-1 sidechain anion (derived from iodide 34) to a bicyclic core precursor lactone 24 which provides the lactols 35. Mild acid-induced deprotection and ring closure gives the 2,8-dioxabicyclo[3.2.1]octane 36 as a 3∶1 mixture of C-3 epimers. Two-step oxidation of the C-3 alcohol to the acid followed by esterification then gives the ester 37 as the only diastereoisomer. The C-1 sidechain 34 has been synthesized in 11 steps from butane-1,4-diol while lactone 24 has been synthesized in 13 steps from the D-mannose-derived alcohol 14.