A General Synthetic Approach for the Laurencia Family of Natural Products Empowered by a Potentially Biomimetic Ring Expansion

The Laurencia family of C15-acetogenins is Nature’s largest collection of halogenated natural products, with many of its members possessing a brominated 8-membered cyclic ether among other distinct structural elements. Herein, we demonstrate that a bromonium-induced ring expansion, starting from a common tetrahydrofuran-containing bicyclic intermediate and using the highly reactive bromenium source BDSB (Et2SBr•SbCl5Br), can lead to concise asymmetric total syntheses of microcladallenes A and B, desepilaurallene, laurallene, and prelaureatin. Key advances in this work include: 1) the first demonstration that the core bromonium-induced cyclization/ring-expansion can be initiated using an enyne with an internal ether oxygen nucleophile, 2) that reasonable levels of stereocontrol in such processes can be achieved both with and without appended ring systems and stereogenic centers, 3) that several other unique chemoselective transformations essential to building their polyfunctional cores can be achieved, and...