Total Synthesis of the Potent Antibiotic Platensimycin

Abstract

The pursuit and discovery of new antibiotics that prevent bacterial spread and growth in new ways without causing drug-resistance has met limited success since the early 1960s. In May 2006, scientists at Merck disclosed their finding of platensimycin, a broad-spectrum antibiotic extracted from a Streptomyces platensis broth that originated from a soil sample in South Africa. This natural product exerts potent Gram-positive antibacterial activity with no cross-resistance by selectively inhibiting Type II fatty acid biosynthesis through targeting the fatty acid condensing enzyme FabF. The confluence of interesting biological activity and structural complexity has made platensimycin an attractive target for chemical synthesis (Chapter 1). Whilst encountering several dead ends and detours in our earlier carbonyl ylide cycloaddition strategies to the unprecedented tetracyclic core of platensimycin (Chapters 2 and 3), we eventually succeeded a new and high-yielding enantioselective formal synthesis of this natural product (Chapters 4 and 5) from commercially available eugenol in 16 steps and 18% overall yield. The culmination of our synthesis efforts advanced three key methods: (1) a new Bi(OTf)3-LiClO4 combination to catalyze a Marson-type, Friedel-Crafts cyclization of an unactivated lactol with complete stereo- and regiocontrol; (2) a facile TBAF-promoted intramolecular alkylative dearomatization without undue silyl activation; and (3) a chemo-, regio-, and diastereoselective conjugate reduction of a cyclic dienone, inspired by iminium-based organocatalysis to reverse substrate steric control, and transfer hydrogenation with Hantzsch esters. The unusual aromatic domain of platensimycin was synthesized from 2-nitroresorcinol by a unique and concise four-step sequence, with an overall 57% yield, through the development of a new Lieben-haloform condition to directly convert aryl methyl ketones to the aryl methyl esters in a practical fashion (Chapter 5). Upon installation of the propionate side-arm via a Michael addition approach, the amide coupling of the C-17 tetracyclic enone acid with the anilide unit was achieved by treatment with HATU, and a final hydrolysis subsequently completed the total synthesis of platensimycin. The exploration of C2-symmetrical amine-based organocatalysts to further improve the desired chemo- and stereoselectivity of the conjugate reduction step is currently ongoing in our laboratory.