Polymer-Supported Synthesis of Aigialomycin D

Significance

The solid-phase synthesis of Aigialomycin D was demonstrated. The polymer-bound thioether 2 was prepared from Merrifield resin-supported thiophenol and ester 1. Alkylation of the thioether 2 with a variety of alkyl bromides yielded the metathesis precursors 3a-e. Polymer-supported macrocycles 4a-e were prepared by ring-closing metathesis of 3a-e. The macrocyclic molecules were released from the resin by oxidation (H₂O₂, HFIP)-elimination or free-radical cleavage (Bu₃SnH, AIBN). The crude products were treated with acidic methanol using sulfonic acid resin to give aigialomycin D (5b) and its analogues 5a,c-e as well as dihydroaigialomycin and its analogues 6a-d.