Total Synthesis of (−)‐Platensimycin by Advancing Oxocarbenium‐ and Iminium‐Mediated Catalytic Methods |
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| Authors: | Dr Stanley T‐C Eey Prof Dr Martin J Lear |
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| Affiliation: | 1. Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543 (Singapore);2. Department of Chemistry, Graduate School of Science, Tohoku University, Aza Aramaki, Aoba‐ku, Sendai 980‐8578 (Japan), Fax: (+81)?22‐795‐6566 |
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| 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. |
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| Keywords: | bismuth conjugate reduction Friedel– Crafts reactions organocatalysis total synthesis |
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