Asymmetric synthesis of drug-like spiro[chroman-3,3′-indolin]-2′-ones through aminal-catalysis

Abstract

Asymmetric synthesis of drug-like functionalized spiro[chroman-3,3'-indolin]-2'-ones 5 containing three contiguous stereocenters with high diastereo- and enantioselectivities was achieved using the reflexive-Michael (r-M) reaction of unmodified hydroxyenals 1 with various (E)-3-alkylideneindolin-2-ones 2 in the presence of (R)-DPPOTMS/AcOH (R)-3/4b as a catalyst at room temperature. Chiral spiro[chroman-3,3'-indolin]-2'-ones 5 were transformed into the functionalized spiranes 7, 9, and 10 in good yields with high selectivity through Wittig, TCRA, acetal protection and reduction reactions, respectively. Supporting evidence for the reaction pathway through the formation of the important catalytic species of "aminals" was observed through NMR and ESI-HRMS analysis of an ongoing reaction between 1 and (R)-3 in CDCl3 and also shown by the structural requirement in hydroxyenals 1 to generate the “aminals” with (R)-3 through controlled experiments.

Diversified Synthesis of Chiral Chromane-Containing Polyheterocyclic Compounds via Asymmetric Organocatalytic Cascade Reactions

“…All of the 2-hydroxy cinnamaldehydes 2 are synthesized from the corresponding salicylaldehydes via the Wittig reaction. 9 The substituted cyclic 1-azadienes 1 were prepared from 3-methylbenzo[ d ]isothiazole 1,1-dioxide and the corresponding aldehyde. 4…”

“…The catalysts ( S )- and ( R )-diphenylprolinol silyl ether are commercially available from Daicel Chiral Technologies. All of the 2-hydroxy cinnamaldehydes 2 are synthesized from the corresponding salicylaldehydes via the Wittig reaction . The substituted cyclic 1-azadienes 1 were prepared from 3-methylbenzo­[ d ]­isothiazole 1,1-dioxide and the corresponding aldehyde …”

“…7 Although 2-hydroxy cinnamaldehyde could serve as the valuable precursor of chroman-2-ol under iminium-catalyzed reduction conditions, this feature opens the possibility of discovering the new application of 2-hydroxy cinnamaldehyde for the preparation of structurally diverse polyheterocyclic molecules via sequential cascade procedures. 8 Indeed, there are other two reported examples of iminium-catalyzed enantioselective oxa-Michael-initiated cascade reactions, where the 2-hydroxy cinnamaldehyde was used to react with electron-deficient olefins, 9 such as nitroolefins and methyleneindolinones, for the preparation of polysubstituted chromane derivatives with good results. However, despite the wide applicability of 1-aza-1,3-butadienes in the sequential cascade synthesis of chiral polycyclic compounds, to the best of our knowledge, there is no report of asymmetric synthesis of highly functionalized chromane derivatives via [4 + 2] cycloaddition of 2-hydroxy cinnamaldehydes with 1-aza-1,3-butadienes as a two-carbon unit, leading to the products with the remaining ketimine moiety of 1-aza-1,3-butadienes, which offers ample opportunity for further transformations to provide diversified polyheterocyclic frameworks with high molecular and stereogenic complexity.…”

Racemic drug resolution: a comprehensive guide

“…Asymmetric synthesis is a widely used technique for obtaining drug-like molecules, alkaloids, as well as pharmaceutical drugs and intermediates. [37][38][39] The application of chiral catalysts in enantiopure drug synthesis are reported in the literature. 35,40 2.2.3.…”

The Quinary Catalyst–Substrate Complex Induced Construction of Spiro-Bridged or Cagelike Polyheterocyclic Compounds via a Substrate-Controlled Cascade Process

“…When 2-hydroxycinnamaldehydes were involved in asymmetric iminium catalysis (Scheme , top), the formed iminium ion intermediate A would quickly transform into the relatively stable aminal B and potentially in equilibrium with the zwitterionic intermediate C , which could be used as oxygen nucleophiles in oxa-Michael reactions under basic conditions . It was surmised that, in the presence of carboxylic acid (RCOOH), the phenoxide anion in zwitterion C would be protonated to afford the iminium/carboxylate ion pair D .…”