Natural Product Synthesis Special Feature: Studies of stereocontrolled allylation reactions for the total synthesis of phorboxazole A

摘要

A highly convergent total synthesis of the potent anticancer agent (+)-phorboxazole A () is accomplished. Four components (–) are assembled with considerations for control of absolute and relative stereochemistry. Iterative asymmetric allylation methodology addresses key stereochemical features in the preparation of the 2,6-cis- and 2,6-trans-tetrahydropyranyl rings of the C3–C19 component (). The stereocontrolled asymmetric allylation process is also used for development of the C28–C41 fragment (). Novel Barbier coupling reactions of α-iodomethyl oxazoles and related thiazoles are described with samarium iodide. The convergent assembly of components 4 and 5 features formation of the fully substituted C22–C26 pyran by intramolecular capture of an allyl cation intermediate with high facial selectivity, and further efforts lead to E-C19/C20 olefination. The synthesis culminates with use of a modified Julia olefination for attachment of the C42–C46 segment and subsequent late-stage macrocyclization by installation of the (Z)-C2/C3 α,β-unsaturated lactone.