1376331-01-9Relevant academic research and scientific papers
Total Synthesis of Ripostatin B and Structure-Activity Relationship Studies on Ripostatin Analogs
Glaus, Florian,Dedi?, Darija,Tare, Priyanka,Nagaraja, Valakunja,Rodrigues, Liliana,Aínsa, José Antonio,Kunze, Jens,Schneider, Gisbert,Hartkoorn, Ruben C.,Cole, Stewart T.,Altmann, Karl-Heinz
, p. 7150 - 7172 (2018/07/15)
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 α to the ester oxygen was formed in a Paterson aldol reaction between a methyl ketone and a β-chiral β-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.
Total synthesis of the myxobacterial macrolide ripostatin b?
Glaus, Florian,Altmann, Karl-Heinz
, p. 227 - 230 (2013/07/25)
This article describes the total synthesis of ripostatin B, which is a 14-membered macrolide of myxobacterial origin that inhibits E. coli RNA polymerase by a different mechanism of action than the first-line anti-tuberculosis drug rifampicin. Structurally, ripostatin B features a labile and synthetically challenging doubly skipped triene motif embedded in the macrolactone ring. Key steps in the synthesis were a Paterson aldol reaction, a low-temperature Yamaguchi esterification and an alkene metathesis reaction to close the macrolide ring. The natural product was synthesized in a longest linear sequence of 21 steps and 3.6% overall yield. Schweizerische Chemische Gesellschaft.
Total synthesis of the bacterial RNA polymerase inhibitor ripostatin B
Glaus, Florian,Altmann, Karl-Heinz
supporting information; experimental part, p. 3405 - 3409 (2012/06/29)
A modular and highly stereoselective synthesis of the title compound was developed. Key steps in the assembly of the carbon framework of ripostatin B (1; see scheme) were a stereoselective Paterson aldol reaction and a high-yielding ring-closing metathesis mediated by Grubbs first generation catalyst. The C15 hydroxy group was established through Tishchenko-Evans reduction in excellent yield and selectivity. Copyright
