12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubstituted Olefinic Bonds from Methyl Ketones and Heteroaromatic Phosphonates and Design, Synthesis, and Biological Evaluation of Potent Antitumor Agents

Journal of the American Chemical Society
K C NicolaouJulia Gavrilyuk

Abstract

The synthesis and biological evaluation of a series of 12,13-aziridinyl epothilone B analogues is described. These compounds were accessed by a practical, general process that involved a 12,13-olefinic methyl ketone as a starting material obtained by ozonolytic cleavage of epothilone B followed by tungsten-induced deoxygenation of the epoxide moiety. The attachment of the aziridine structural motif was achieved by application of the Ess-Kürti-Falck aziridination, while the heterocyclic side chains were introduced via stereoselective phosphonate-based olefinations. In order to ensure high (E) selectivities for the latter reaction for electron-rich heterocycles, it became necessary to develop and apply an unprecedented modification of the venerable Horner-Wadsworth-Emmons reaction, employing 2-fluoroethoxyphosphonates that may prove to be of general value in organic synthesis. These studies resulted in the discovery of some of the most potent epothilones reported to date. Equipped with functional groups to accommodate modern drug delivery technologies, some of these compounds exhibited picomolar potencies that qualify them as payloads for antibody drug conjugates (ADCs), while a number of them revealed impressive activities again...Continue Reading

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Citations

Apr 13, 2018·Organic & Biomolecular Chemistry·Shekh SabirJawahar L Jat
Apr 13, 2021·New Journal of Chemistry = Nouveau Journal De Chimie·Rawan AlnufaieMohammad A Alam
Nov 21, 2018·Journal of the American Chemical Society·Barry M TrostJullien Rey
Dec 24, 2018·Accounts of Chemical Research·Kyriacos C Nicolaou, Stephan Rigol
Apr 4, 2020·ACS Applied Materials & Interfaces·Xuelin XiaDeyue Yan

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