The Nazarov reaction is one of the most versatile methods for the synthesis of five-membered carbocycles in organic chemistry. This electrocyclic process converts a divinyl ketone to a cyclopentenone moiety under acidic conditions. The reaction is compatible with a wide range of substituents in the starting reagent and is actively used for the synthesis of various biologically active substances and natural compounds. However, the Nazarov reaction often does not proceed selectively and leads to a complex mixture of products that are difficult to separate, and also requires a stoichiometric amount of Lewis acid. Therefore, one of the most pressing issues of the modern development of the Nazarov reaction is the development of simple, versatile, regio- and stereoselective approaches to the synthesis of a wide range of organic substances.
Scientists from Laboratory № 3 of the Zelinsky Institute succeeded in developing an effective method for cyclization of polarized triaryldivinyl ketones according to an environmentally friendly 'on-water' protocol. The observed transformations proceed under mild conditions and in high yields. It was shown for the first time that the amphiphilicity of the substrate and the low energy barrier of the reaction were the defining factors for the occurrence of electrophilic and concerted processes in aqueous conditions. The obtained compounds are analogs of combretastatin A-4 and may be of great interest for medicinal chemistry and oncology, since such structures are capable of binding to the colchicine site of tubulin and suppressing the proliferation of cancer cells.
Anton V. Yadykov, Liana V. Yaminova, Mikhail M. Krayushkin,Valerii Z. Shirinian Cyclization of Polarized Divinyl Ketones under Aqueous and Ambient Conditions Adv. Synth. Catal., 2021, 363, 251-258. DOI: 10.1002/adsc.202000956.