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

Eey, Stanley T.-C. and Lear, Martin J. (2014) Total synthesis of (−)-platensimycin by advancing oxocarbenium- and iminium-mediated catalytic methods. Chemistry - A European Journal, 20 (36). pp. 11556-11573. ISSN 0947-6539

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

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Abstract

(-)-Platensimycin is a potent inhibitor of fatty acid synthase (FAS) that holds promise in the treatment of metabolic disorders (e.g., diabetes, “fatty liver”) and pathogenic infections (e.g., against 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: (i) a modified Lieben-haloform reaction to directly convert an aryl methyl ketone to its methyl ester within 30 seconds; (ii) an experimentally improved dialkylation protocol to platensic acid; (iii) a sterically-controlled chemo- and diastereoselective organocatalytic conjugate reduction of a spiro-cyclized cyclohexadienone using the TFA salt of α-amino di-tert-butyl malonate; (iv) a TBAF-promoted spiro-alkylative para-dearomatization of a free phenol to assemble the cage-like ketolide core with the moderate leaving group ability of an early tosylate intermediate; (v) a Bi(OTf)3-catalyzed Friedel-Crafts cyclization of a free lactol, supplemented by LiClO4 to liberate a more active oxocarbenium perchlorate species and suppress the Lewis basicity of a sulfonyloxy group. The longest linear sequence is 21-steps, i.e., 3.8% total yield from commercial eugenol.

Keywords:total synthesis, organocatalysis, conjugate reduction, bismuth, Friedel-Crafts, NotOAChecked
Subjects:F Physical Sciences > F160 Organic Chemistry
Divisions:College of Science > School of Chemistry
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ID Code:17097
Deposited On:17 Apr 2015 10:55

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