Demethylative Lactonization Provides a Shortcut to High-Yielding Syntheses of Lamellarins.

Abstract

Modular gram-scale syntheses of the trimethyl ethers of lamellarins G (6) and D (7) were achieved from readily accessible precursors in the highest overall yields reported to date (6, six steps, 82%; 7, seven steps, 86%). A novel demethylative lactonization between an aryl methyl ether and a neighboring carboxylic acid was developed for creating the chromenone unit of the targets to avoid the need for additional protection and deprotection steps. The central pyrrole core was constructed in a late-stage [4 + 1] condensation between ethyl bromoacetate and an enaminone possessing the remaining components of the lamellarin skeleton. Exhaustive demethylation of both permethyl ethers 6 and 7 gave the polyphenolic natural lamellarins A4 (3) and H (5), respectively.