Enantioselective Michael Addition of α‐Substituted Cyanoacetates to Vinyl Ketones Catalyzed by Bifunctional Organocatalysts

Abstract

A highly enantioselective Michael addition of α‐substituted cyanoacetates to vinyl ketones was accomplished in the presence of simple bifunctional thiourea/tertiary amine organocatalysts. A number of α‐aryl or alkyl cyanoacetates have been successfully applied to give multifunctional compounds with an all‐carbon‐substituted quaternary stereocenter in excellent enantioselectivities (82–97 % ee) and yields (61–99 %). The optical pure adducts could be smoothly converted to variously structured β2,2‐amino acid esters. Moreover, an interesting reaction model involving multiple hydrogen‐bonding interactions amongst the thiourea/tertiary amine catalyst and the reactants has been proposed based on the absolute configuration of the adduct and computational studies.

Quantum Mechanical Investigations of Organocatalysis: Mechanisms, Reactivities, and Selectivities

“…The mechanism involving the coordinated nucleophile was calculated to be favored, in agreement with the activation mode reported by Pápai and co-workers for the cyclohexanediamine-thiourea-catalyzed Michael addition reaction. 256b The approximately 3 kcal/mol difference between the major R and minor S transition structures agrees well with the experimental enantioselectivities.…”

Asymmetric catalysis with bifunctional cinchona alkaloid-based urea and thiourea organocatalysts

“…After Soos' seminal work in this area, bifunctional thiourea-catalysed additions of thioacetic acid and a-substituted cyanoacetates to chalcone and methyl vinyl ketone, respectively were reported by the groups led by Wang 35 and Chen 36 (Scheme 12). The latter case is of interest as stereoselectivity comes not from the formation of an sp 3 -stereogenic centre on the addition of a nucleophile to a internal activated olefin, but rather from the attack of the Michael acceptor at a single enolate face of the conjugate base of the pronucleophile.…”

Cinchona‐Catalyzed Nucleophilic Conjugate Addition to Electron‐Deficient CC Double Bonds

“…By employing this methodology, enantioenriched (R)-rolipram (86) was concisely prepared from the reaction of nitromethane and a,b-unsaturated N-acylpyrrole 85 (Scheme 9. 30 Soon afterward, a broad spectrum of Michael donors and Michael acceptors were successfully employed in the thiourea-catalyzed Michael addition [24][25][26][27]. Selected examples are outlined in Schemes 9.31-9.…”

“…In contrast to the results obtained with thiourea catalysts, the natural quinidine catalyst afforded only the racemic product (Scheme 9.31). The cyano acetates 91 were also examined as nucleophilic partners by Chen and coworkers [25,26]. In the presence of the cinchona-based thiourea catalyst 81a and 81b (10 mol%), ethyl cyanoacetate 91 reacted with various chalcones 92 to afford the Michael adducts 93 in high yields (80-95%) and with high to excellent enantioselectivities for both syn/anti-diastereomers (83-95% ee) (Scheme 9.32) [26], while the reaction of the a-substituted cyanoacetate (94) with methyl vinyl ketone (MVK) gave only modest enantioselectivity (up to 62% ee) [25].…”