Highly diastereoselective cascade [5 + 1] double Michael reaction, a route for the synthesis of spiro(thio)oxindoles

Abstract

The first diastereoselective synthesis of spirothiooxindoles is reported via the Michael reaction between thiooxindoles and dibenzalacetones. The reaction was conducted without any catalyst or additive under green conditions, i.e., ethanol as the solvent and at room temperature. In addition, the described robust method benefits from scalability, simple work-up, and column chromatography-free purification. This work demonstrates the art of governing regio- and stereoselectivity, which has been discussed in the light of Density Functional Theory calculations. Our method represents the first synthesis of spiro[cyclohexanone-thiooxindoles] with the relative configuration of the aryl moieties at the cyclohexanone ring as cis. The obtained cis-spirothiooxindoles, can be used to afford cis-spirooxindoles, which their synthesis had not been explored before. According to our molecular docking studies, cis-spirooxindoles demonstrate higher binding affinities than corresponding trans-spirooxindoles for the OPRT domain of the Leishmania donovani uridine 5′-monophosphate synthase (LdUMPS). Thus, the reported method may eventually be utilized to develop new hit compounds for leishmaniasis treatment.

Metabolic Pathways of Leishmania Parasite: Source of Pertinent Drug Targets and Potent Drug Candidates

“…The orotate phosphoribosyltransferase (OPRT) domain catalyzes the creation of UMP from scratch. The cis-spirooxindoles also show a strong binding affinity for the OPRT domain of the L. donovani uridine 5 -monophosphate synthase (LdUMPS) [26]. However, extensive research is warranted to understand the exact mode of action of spirooxindoles against leishmaniasis.…”

Domino Reactions through Recursive Anionic Cascades: The Advantageous Use of Nitronates

“…Domino RAC is a tandem process, in which anionic cascades originate and recur from the same reaction center, hence recursive , cf. anionic steps 1 & 2 in Scheme 1a [4a] . These reactions typically proceed via a domino rebound mechanism, wherein the reaction cascade reverts to the original carbon through a carbanion rebound ( C→D ).…”