Asymmetric Conjugate Addition of Benzofuran‐2‐ones to Alkyl 2‐Phthalimidoacrylates: Modeling Structure–Stereoselectivity Relationships with Steric and Electronic Parameters

Abstract

A highly predictive model to correlate the steric and electronic parameters of tertiary amine thiourea catalysts with the stereoselectivity of Michael reactions of 3-substituted benzofuranones and alkyl 2-phthalimidoacrylates is described. As predicted, new 3,5-bis(trifluoromethyl)benzyl- and methyl-substituted tertiary amine thioureas turned out to be highly suitable catalysts for this reaction and enabled the synthesis of enantioenriched α-amino acid derivatives with 1,3-nonadjacent stereogenic centers.

Study on the Catalytic Behavior of Bifunctional Hydrogen‐Bonding Catalysts Guided by Free Energy Relationship Analysis of Steric Parameters

“…found that benzyl diaminocyclohexane‐based squaramide catalysts without electronic perturbation can also lead to excellent enantioinduction in the reaction of acetylacetone and nitrostyrene . Recently, in the Michael addition of 3‐substituted benzofuranones to alkyl 2‐phthalimidoacrylates, we found that the methyl thiourea catalyst, which has the smallest alkyl substituent, can induce stereoselectivities as high as those of 3,5‐bis(trifluoromethyl)benzyl thiourea . These new findings prompted us to revisit the role of the steric hindrance of bifunctional thioureas/squaramides in the stereocontrol of the Michael addition.…”

“…Intensive efforts have been made to elucidate mechanisms in this context by using experimental or computational approaches. However, investigations of the links between the stereoselectivity of a reaction and the performance of the catalyst remain elusive till now, and due to their great potential in guiding the design of new catalysts, they warrant immediate exploration –,. In particular, given that 3,5‐bis(trifluoromethyl)phenyl, 3,5‐bis(trifluoromethyl)benzyl, fluorinated ethyl, benzyl, and methyl groups occur in numerous privileged bifunctional hydrogen‐bonding catalysts (Figure ), the reasons behind these phenomena need more rational explanations.…”

“…Increased research attention in this area is also reflected by a number of recent investigations . However, cases focused on organocatalysis are still limited ,,,–,…”

Facile Chemoselective synthesis of 2‐(2‐(Methoxycarbonyl)‐3‐oxo‐2,3‐dihydrobenzofuran‐2‐yl)benzoic acids and 3H,3’H‐Spiro[benzofuran‐2,1′‐isobenzofuran]‐3,3′‐dione derivatives

“…Benzofurans are naturally widespread molecules which have drawn considerable attention over the last few years due to their extensive physiological and pharmacological properties. They display potent biological activites including antihyperglycemic, analgesic, antiparasitic, antimicrobial, antitumor, kinase inhibitor . In addition, various natural and synthetic benzofuran derivatives, known as effective drugs, are used routinely in the treatment of different diseases (Figure ).…”

Multidimensional Correlations in Asymmetric Catalysis through Parameterization of Uncatalyzed Transition States

“…[1] Using this technique, a polynomial equation that correlates the reaction outcome with the chemical descriptors of a catalyst and/or substrate set can be derived. The resultant mathematical model can be used to extrapolate better catalysts through virtual screening thus improving the reaction performance.…”