Journal
JOURNAL OF ORGANIC CHEMISTRY
Volume 83, Issue 13, Pages 7150-7172Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.joc.8b00193
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Funding
- European Community Framework Programme 7, More Medicines For Tuberculosis (MM4TB) grant [260872]
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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.
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