Organocatalytic Synthesis of Highly Functionalized Heterocycles by Enantioselective aza-Morita–Baylis–Hillman-Type Domino Reactions

Abstract

Organocatalytic enantioselective domino reactions are an extremely attractive methodology, as their use enables the construction of complex chiral skeletons from readily available starting materials in two or more steps by a single operation under mild reaction conditions. Thus, these reactions can save both the quantity of chemicals and length of time typically required for the isolation and/or purification of synthetic intermediates. Additionally, no metal contamination of the products occurs, given that organocatalysts include no expensive or toxic metals. The aza-Morita-Baylis-Hillman (aza-MBH) reaction is an atom-economical carbon-carbon bond-forming reaction between α,β-unsaturated carbonyl compounds and imines mediated by Lewis base (LB) catalysts, such as nucleophilic phosphines and amines. aza-MBH products are functionalized chiral β-amino acid derivatives that are highly valuable as pharmaceutical raw materials. Although various enantioselective aza-MBH processes have been investigated, very few studies of aza-MBH-type domino reactions have been reported due to the complexity of the aza-MBH process, which involves a Michael/ Mannich/H-transfer/β-elimination sequence. Accordingly, in this review article, our recent efforts in the development of enantioselective domino reactions initiated by MBH processes are described. In the domino reactions, chiral organocatalysts bearing Brønsted acid (BA) and/or LB units impart synergistic activation to substrates, leading to the easy synthesis of highly functionalized heterocycles (some of which have tetrasubstituted and/or quaternary carbon stereocenters) in high yield and enantioselectivity.

Recent progress and prospects in the organocatalytic Morita–Baylis–Hillman reaction

“… 15 Several reviews subsequently appeared that focused on the biocatalytic asymmetric MBH reaction, 16 application of DABCO as a catalyst for the MBH reaction, 17 and an organocatalytic MBH-type domino reaction. 18 Because of the wide importance and applicability of this reaction, we have summarized the recent advancements in the organocatalytic MBH reaction, from 2018 to 2023. For additional clarity, this review has been organized based on the organocatalyst utilized.…”

Metal-free C(aryl)–P bond cleavage: experimental and computational studies of the Michael addition/aryl migration of triarylphosphines to alkynyl esters

“…Here, an alkynyl ester is employed, and the resulting zwitterionic species can react with nucleophiles or electrophiles to afford structurally diverse products. 19 As part of our continuous effort to develop Lewis-base-mediated reactions, 22,23 we envisioned that by using water as both a nucleophile and an electrophile, phosphonium intermediate I and a hydroxide ion would be generated in situ (Scheme 1C). Owing to the high oxophilicity of the phosphonium and neighboring α,β-unsaturated carbonyl moiety (a Michael acceptor) in intermediate I, the hydroxide ion could attack the phosphonium, and, thus, C(aryl)-P bond cleavage would be enhanced and induce the 1,2-rearrangement of the aryl group to the Michael acceptor via a hydroxyl-λ 5 -phosphane 24 intermediate II (Scheme 1C, path a), thus providing 3-(diarylphosphoryl)-3-aryl propanoic acid derivatives.…”

A New MBH Adduct as an Efficient Ligand in the Synthesis of Metallodrugs: Characterization, Geometrical Optimization, XRD, Biological Activities, and Molecular Docking Studies

“…It involves a reaction of C-C bond formation between sp 2 carbons of an aldehyde as well as an electron-deficient unsaturated hydrocarbon. Under specific reaction conditions, and by using nucleophilic amines or phosphines as catalysts, a powerful multifunctional adduct is achieved [ 6 , 7 ]. Moreover, in the presence of more than one similar position, C-C bond construction at the selective site of the requisite compound is another major challenge for chemists [ 8 ].…”