Total synthesis of (-)-platensimycin by advancing oxocarbenium- and iminium-mediated catalytic methods.

Abstract

(-)-Platensimycin is a potent inhibitor of fatty acid synthase that holds promise in the treatment of metabolic disorders (e.g., diabetes and "fatty liver") and pathogenic infections (e.g., those caused by drug-resistant bacteria). Herein, we describe its total synthesis through a four-step preparation of the aromatic amine fragment and an improved stereocontrolled assembly of the ketolide fragment, (-)-platensic acid. Key synthetic advances include 1) a modified Lieben haloform reaction to directly convert an aryl methyl ketone into its methyl ester within 30 seconds, 2) an experimentally improved dialkylation protocol to form platensic acid, 3) a sterically controlled chemo- and diastereoselective organocatalytic conjugate reduction of a spiro-cyclized cyclohexadienone by using the trifluoroacetic acid salt of α-amino di-tert-butyl malonate, 4) a tetrabutylammonium fluoride promoted spiro-alkylative para dearomatization of a free phenol to assemble the cagelike ketolide core with the moderate leaving-group ability of an early tosylate intermediate, and 5) a bismuth(III)-catalyzed Friedel-Crafts cyclization of a free lactol, with LiClO4 as an additive to liberate a more active oxocarbenium perchlorate species and suppress the Lewis basicity of the sulfonyloxy group. The longest linear sequence is 21 steps with an overall yield of 3.8 % from commercially available eugenol.

• Authors: Stanley T-C Eey, Martin J Lear
• Journal: Chemistry (Weinheim an der Bergstrasse, Germany) (Chemistry) Vol. 20 Issue 36 Pg. 11556-73 (Sep 01 2014) ISSN: 1521-3765 [Electronic] Germany
• PMID: 25047997 (Publication Type: Journal Article)
• Copyright: © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.