Cinchona Squaramide‐Catalyzed Intermolecular Desymmetrization of 1,3‐Diketones Leading to Chiral 1,4‐Dihydropyridines

Abstract

Addition of prochiral cyclic 1,3‐diketones to Michael acceptors applying bifunctional Cinchona‐derived squaramides resulted in chiral adducts with stereoselectivities of up to 99% ee and allowed for desymmetrization of the nucleophile. These labile hemiacetal intermediates were transformed to new 1,4‐dihydropyridines with high diastereoselectivities and no erosion of optical purity. Their further oxidation to pyridine followed by Fisher indolization provided chiral pyridine‐indoles.

Squaramide Catalyzed Asymmetric Synthesis of Five‐ and Six‐Membered Rings

“…Kowalcyzyk and co‐workers demonstrated a novel desymmetrisation study of prochiral 5‐substituted‐1,3‐cyclohexandiones 175 in course of six‐membered cyclic hemiacetal formation facilitated by H‐bonding squaramide catalyst E′ [69] . Michael/hemiacetalization cascade between 175 and α ‐keto‐ β , γ ‐unsaturated esters 77 would form the fused bicyclic products 176 as a mixture of epimeric hemiacetals along with open chain form.…”

“…Kowalcyzyk and co-workers demonstrated a novel desymmetrisation study of prochiral 5-substituted-1,3-cyclohexandiones 175 in course of six-membered cyclic hemiacetal formation facilitated by H-bonding squaramide catalyst E'. [69] Michael/hemiacetalization cascade between 175 and α-ketoβ,γ-unsaturated esters 77 would form the fused bicyclic products 176 as a mixture of epimeric hemiacetals along with open chain form. The complicacy in separating mixture would direct them for aminolysis of the products in situ to produce chiral dihydropyridines 177 without any significant loss in enantioselectivities.…”

Efficacy of Selenourea Organocatalysts in Asymmetric Michael Reactions under Standard and Solvent-Free Conditions

“…Thereby, Michael addition/hemiacetalization of diketones to the benzylidene pyruvate esters, leading to bicyclic compounds with two stereogenic centers, were studied. Particularly, the reaction of dimedone 11 with benzylidene pyruvate 10 has been successfully carried out with the use of various types of catalysts [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. An asymmetric Michael–hemiacetalization cascade reaction ( Scheme 3 ) was used for the screening of chiral selenoureas’ performance under standard and solvent-less conditions.…”

Further developments of β,γ-unsaturated α-ketoesters as versatile synthons in asymmetric catalysis

“…Recently, Kowalczyk et al. applied this [3 + 3] strategy to the catalytic asymmetric desymmetrization of prochiral cyclic 1,3-diketones 92 ( Scheme 13 C) ( Dajek et al., 2020 ). The unprecedented desymmetrization of the parent C- and O-centered dinucleophiles led to hemiacetals 94 with high stereoselectivities (91–99% ee), which were readily transformed to 1,4-dihydropyridines without erosion of optical purity.…”