Isothiourea-catalyzed enantioselective reactions of imines with α,β-unsaturated esters employing α,β- unsaturated acyl ammonium intermediates

The use of isothioureas as Lewis base organocatalysts has been widely studied by the Smith group and shown to be effective in various Michael addition and annulation reactions, which is associated with the formation of the reactive α,β-unsaturated acyl ammonium intermediates. To further explore the reactivity of these reactive intermediates, this research project focuses on employing α,β-unsaturated acyl ammonium intermediates to perform various reactions such as (i) aza-Michael addition reactions, (ii) Michael addition reactions, and (iii) a Michael- addition-cyclisation-lactonisation cascade reactions using imines and other imine derivatives as nucleophiles to access a range of chiral compounds with important structural motifs (e.g. β-amino acids, γ-imino esters and amides, γ-lactam compounds, and pyrrolidine compounds) in high enantio- and diastereoselectivity. In this work, successful protocols for the highly selective aza-Michael addition reaction and Michael addition reaction of imine nucleophiles to α,β-unsaturated ester substrates were established to obtain various β-imino esters, β-imino amides, various γ-imino amide and ester products via the access of the reactive α,β-unsaturated acyl ammonium intermediate using an enantiopure isothiourea organocatalyst showing moderate to excellent yield (20% – 81%) and enantio- and diastereoselectivity ((99:1 dr). The reaction was deduced to follow a highly stereoselective Michael addition, followed by a 5-endo-trig cyclization reaction to generate the pyrrolidine core, and a subsequent lactonization reaction to form the chromeno-pyrrolidine product in excellent enantio- and diastereoselectivity

Synthesis of novel 3\u27-spirocyclic-oxindole derivatives and assessment of their cytostatic activities

The synthesis of some novel 3′-spirocyclic-oxindole compounds, based on the spiro[indole-3,5′-isoxazolidin]-2(1H)-one, the 2′H-spiro[indole-3,6′-[1,3]oxazinane]-2,2′(1H)-dione and the 2′H-spiro[indoline-3,3′-pyrrolo[1,2-c][1,3′]oxazine]-1′,2(1H)-dione heterocyclic structures, is described. These compounds were prepared from methyl α-(2-nitrophenyl)acrylate via [1,3]-dipolar cycloaddition reactions with two acyclic nitrones and one cyclic nitrone followed by reduction of the cycloadducts and then treatment with triphosgene. Two of these compounds showed significant cytostatic activity on three cancer cell lines with GI50 values of 2.6–4.1 μM on the human breast cancer cell line, MCF-7

Organocatalytic Asymmetric Michael/Friedel–Crafts Cascade Reaction of 3‑Pyrrolyl-oxindoles and α<i>,</i>β‑Unsaturated Aldehydes for the Construction of Chiral Spiro[5,6-dihydropyrido[1,2‑<i>a</i>]pyrrole-3,3′-oxindoles]

An efficient and unprecedented organocatalytic asymmetric reaction of 3-pyrrolyl-oxindoles with α,β-unsaturated aldehydes to generate spirocyclic oxindole compounds was developed. The reactions were catalyzed by diphenylprolinol silyl ether and 2-fluorobenzoic acid via an asymmetric Michael/Friedel–Crafts cascade process, followed by dehydration with <i>p</i>-toluenesulfonic acid to afford a wide variety of structurally diverse spiro­[5,6-dihydropyrido­[1,2-<i>a</i>]­pyrrole-3,3′-oxindole] derivatives in high yields (up to 93%) and with high to excellent diastereo- and enantioselectivities (up to >99:1 dr and 97% ee)

Synthesis of novel 3′-spirocyclic-oxindole derivatives and assessment of their cytostatic activities

The synthesis of some novel 3′-spirocyclic-oxindole compounds, based on the spiro[indole-3,5′-isoxazolidin]-2(1H)-one, the 2′H-spiro[indole-3,6′-[1,3]oxazinane]-2,2′(1H)-dione and the 2′H-spiro[indoline-3,3′-pyrrolo[1,2-c][1,3′]oxazine]-1′,2(1H)-dione heterocyclic structures, is described. These compounds were prepared from methyl α-(2-nitrophenyl)acrylate via [1,3]-dipolar cycloaddition reactions with two acyclic nitrones and one cyclic nitrone followed by reduction of the cycloadducts and then treatment with triphosgene. Two of these compounds showed significant cytostatic activity on three cancer cell lines with GI50 values of 2.6-4.1 μM on the human breast cancer cell line, MCF-7. Crown Copyright © 2007

Enantioselective [4 + 1] Annulation Reactions of α‑Substituted Ammonium Ylides To Construct Spirocyclic Oxindoles

Ammonium ylides have a long history in organic synthesis, but their application in asymmetric catalysis is still underdeveloped in regard to both substrate scope and reaction pathways compared with phosphorus and sulfur ylides. Here a previously unreported asymmetric [4 + 1] annulation reaction of 3-bromooxindoles and electron-deficient 1-azadienes has been developed through ammonium ylide catalysis of a newly designed 2′-methyl α-isocupreine (α-MeIC), efficiently delivering spirocyclic oxindole compounds incorporating a dihydropyrrole motif in excellent enantioselectivity (up to 99% ee). To the best of our knowledge, this work represents the first example of asymmetric catalysis of ammonium ylides bearing α-substitutions, and the catalytic [4 + 1] annulation pathway of ammonium ylides is also unprecedented. Moreover, ¹H NMR, mass spectroscopy, and computational calculation studies were conducted, and the catalytic cycle and a tentative explanation of the enantioselective mechanism have been successfully elucidated

Enantioselective [4 + 1] Annulation Reactions of α‑Substituted Ammonium Ylides To Construct Spirocyclic Oxindoles

Ammonium ylides have a long history in organic synthesis, but their application in asymmetric catalysis is still underdeveloped in regard to both substrate scope and reaction pathways compared with phosphorus and sulfur ylides. Here a previously unreported asymmetric [4 + 1] annulation reaction of 3-bromooxindoles and electron-deficient 1-azadienes has been developed through ammonium ylide catalysis of a newly designed 2′-methyl α-isocupreine (α-MeIC), efficiently delivering spirocyclic oxindole compounds incorporating a dihydropyrrole motif in excellent enantioselectivity (up to 99% ee). To the best of our knowledge, this work represents the first example of asymmetric catalysis of ammonium ylides bearing α-substitutions, and the catalytic [4 + 1] annulation pathway of ammonium ylides is also unprecedented. Moreover, ¹H NMR, mass spectroscopy, and computational calculation studies were conducted, and the catalytic cycle and a tentative explanation of the enantioselective mechanism have been successfully elucidated