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Total Synthesis of Ripostatin B and Structure-Activity Relationship Studies on Ripostatin Analogs

Glaus, Florian and Dedic, Darija and Tare, Priyanka and Nagaraja, Valakunja and Rodrigues, Liliana and Antonio Ainsa, Jose and Kunze, Jens and Schneider, Gisbert and Hartkoorn, Ruben C and Cole, ST and Altmann, Karl-Heinz (2018) Total Synthesis of Ripostatin B and Structure-Activity Relationship Studies on Ripostatin Analogs. In: JOURNAL OF ORGANIC CHEMISTRY, 83 (13). pp. 7150-7172.

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Official URL: https://dx.doi.org/10.1021/acs.joc.8b00193

Abstract

Described is the total synthesis of the myxobacterial natural product ripostatin B and of a small number of analogs. Ripostatin B is a polyketide-derived 14-membered macrolide that acts as an inhibitor of bacterial RNA-polymerase, but is mechanistically distinct from rifamycin-derived RNA-polymerase inhibitors that are in use for tuberculosis treatment. The macrolactone ring of ripostatin B features two stereocenters and a synthetically challenging doubly skipped triene motif, with one of the double bonds being in conjugation with the ester carbonyl. Appended to the macrolactone core are an extended hydroxy-bearing phenylalkyl side chain at C13 and a carboxymethyl group at C3. The triene motif was established with high efficiency by ring-closing olefin metathesis, which proceeded in almost 80% yield. The side chain-bearing stereocenter alpha to the ester oxygen was formed in a Paterson aldol reaction between a methyl ketone and a beta-chiral beta-hydroxy aldehyde with excellent syn selectivity (dr > 10:1). The total synthesis provided a blueprint for the synthesis of analogs with modifications in the C3 and C13 side chains. The C3-modified analogs showed good antibacterial activity against efflux-deficient Escherichia coli but, as ripostatin B, were inactive against Mycobacterium tuberculosis, in spite of significant in vitro inhibition of M. tuberculosis RNA-polymerase.

Item Type: Journal Article
Additional Information: Copyright of this article belong to AMER CHEMICAL SOC, 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Depositing User: Id for Latest eprints
Date Deposited: 31 Jul 2018 15:28
Last Modified: 05 Mar 2019 05:08
URI: http://eprints.iisc.ac.in/id/eprint/60330

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