Enantiodivergent Reaction of Ketimines with Malononitriles Using Single Cinchona Alkaloid Sulfonamide Catalysts

Abstract

We report the enantiodivergent reaction of ketimines derived from α‐ketoesters with malononitriles using a single chiral source. The reactions using an 8‐quinolinesulfonyl cinchona alkaloid catalyst in the presence and absence of Et2Zn gave both enantiomers in high yields with high enantioselectivities (53∼99% yield, 99:1∼3:97 er). The obtained malononitrile‐derived α‐amino acids were converted into various optically active compounds. A reaction mechanism is proposed to explain the observed enantiodivergency.

Accessing unnatural α-amino acids with tetrasubstituted stereogenic centersviacatalytic enantioselective reactions of ketimine-type α-iminoesters/α-iminoamides

“…In 2022, Nakamura and co-workers also reported enantioselective Mannich-type reactions of malononitrile with acyclic ketimines 1l and 47a using their original catalyst system (Scheme 44). 74 This reaction is catalyzed by cinchonidine-derived 8-quinolinesulfonamide 74b to afford the ( S )-isomers ( S - 110 ) in good yields and high enantioselectivities. Interestingly, the addition of a catalytic amount of diethylzinc inverted the absolute configuration of the product to afford R - 110 instead.…”

Bifunctional Sulfonamide as Hydrogen Bonding Catalyst in Catalytic Asymmetric Reactions: Concept and Application in the Past Decade

“…In a recent research in Nakamura's group, malononitriles were chosen as strong nucleophiles reacting with Boc‐protected ketiminoesters (Scheme 25). [69] ( S )‐ 36 could still apply as effective catalyst with excellent activity and stereoselectivity. Interestingly, the configuration of Mannich products conducted by ( S )‐ 36 would turn over in the presence of Et 2 Zn, which had the same enantiomeric control as ( R )‐ 36 .…”

“…Nakamura's group studied organocatalytic Mannich reaction of imine derivates using cinchona alkaloid sulfonamides as the optimal catalysts. [68][69] N-sulfonyl ketimines, which had difficulty in enantiofacial control, were mixed with malonic acid half thioesters and 10 mol% of cinchonine-based (R)-36 (Scheme 25). [68] With the addition of p-nitrophenol, Mannich adducts could be obtained in excellent yield with high ee values.…”

“…Bifunctional organocatalysts with sulfonamide moiety have proven to be useful in asymmetric Mannich reaction with numerous reports. Sulfonamides derived from various chiral scaffolds, including 1,1'-binaphthyl-2,2'-diamine, [63][64][65][66] cinchona alkaloid, [67][68][69][70][71][72][73] L-proline, [74] are commonly applied in research of Mannich process after 2011.…”

Rapid Construction of Tricyclic Furanobenzodihydropyrans by Asymmetric Tandem Reaction

“…In 2021, Chen and our group found the tandem reactions of 1-(2-hydroxyaryl)-1,3-diketones and α,β-unsaturated aldehydes by iminium catalysis could efficiently provide tricyclic chromanone derivatives . As part of our continuous research in the enantioselective synthesis of benzopyran core through organocatalytic tandem reactions, , we envisioned that the asymmetric catalytic Mannich/ketalization/transesterification tandem reaction of β,γ-alkynyl α-imino esters and 1,3-diketones would allow ready access to the tricyclic chromanone-propargylamine derivatives with multiple stereogenic centers (Scheme e).…”