C₂‐symmetric sulfonamides as homogeneous and heterogeneous organocatalysts that mimic enzymes in enantioselective Michael additions

Abstract

Herein, we report the synthesis of C -symmetric sulfonamides as homogeneous and heterogeneous organocatalysts and their application in the enantioselective conjugate 1,4-Michael addition of carbonylic nucleophiles to β-nitrostyrene. Organocatalysts hydrogen bond to β-nitrostyrene and enamine in the transition state, mimicking an enzyme leading to final products in high yields (up to 98%) and good enantioselectivities (up to 96%). In addition, these results were supported by density functional calculations.

Chiral C2‐symmetric bis‐thioureas as enzyme mimics in enantioselective Michael addition

“…We expected bis-C 2 -symmetry primary aminethiourea catalysts 1 and 2 to behave like the previously reported bis-1,3-bis-C 2 -symmetry primary amine sulfonamide catalysts, where the reaction takes place within the cleft, with multiple hydrogen bonding mimicking an enzyme. 4 Organocatalysts 1 and 2 gave good to moderate enantioselectivities and yields in the conjugate Michael addition of aldehyde/ketones to β-nitrostyrene (Table 1).…”

“…For several decades, tremendous effort has been devoted to the development of chiral organocatalyst to achieve high enantioselectivity. Types of enantiopure bifunctional organocatalysts utilized for the conjugate 1,4‐Michael addition of aldehyde/ketone to nitroalkenes are thioureas, proline derivatives, cinchona alkaloids, and sulfonamides, which all gave addition products in good enantioselectivities and yields 4–6 …”

“…Types of enantiopure bifunctional organocatalysts utilized for the conjugate 1,4-Michael addition of aldehyde/ketone to nitroalkenes are thioureas, proline derivatives, cinchona alkaloids, and sulfonamides, which all gave addition products in good enantioselectivities and yields. [4][5][6] Most bifunctional organocatalysts used in the 1,4-Michael addition were designed to noncovalently activate multiple reactants: The proton donor group activates the electrophile, and the amine activates the nucleophile. In attempting to get better enantioselectivities and yields in the 1,4-Michael addition, we explored the synthesis of new multifunctional organocatalysts to increase the noncovalent supramolecular interactions between the reactants and the catalyst, thereby increasing the stability and lowering the transition state energy.…”

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

“… [46–48] For example, halogenated sulfonamide 23 [46] derived from (1 R ,2 R )‐cyclohexanediamine, reported by Somanathan and coworkers, revealed excellent catalytic activity (99 %) and good enantioselectivity (88 % ee) in Michael process of acetone and nitroolefins due to a special interaction between o ‐chlorine substituent and the nitro group O‐atom of Michael acceptor, while over 5 days of reaction time was needed for this protocol. 24 reported in 2018 showed highest stereoselectivity (94 % ee) among these sulfonamide catalysts, however, low catalytic activity (33 %) was demonstrated [48] . For all that, Somanathan's studies are still running ahead of other research of sulfonamide catalysts in asymmetric Michael addition of acetone and nitrostyrenes.…”

“…For solving these drawbacks in sulfonamide-catalyzed asymmetric process, Somanathan's group developed a series of novel sulfonamide catalysts with a diamine structure (Scheme 15). [46][47][48] For example, halogenated sulfonamide 23 [46] derived from (1R,2R)-cyclohexanediamine, reported by Somanathan and coworkers, revealed excellent catalytic activity (99 %) and good enantioselectivity (88 % ee) in Michael process of acetone and nitroolefins due to a special interaction between o-chlorine substituent and the nitro group O-atom of Michael acceptor, while over 5 days of reaction time was needed for this protocol. 24 reported in 2018 showed highest stereoselectivity (94 % ee) among these sulfonamide catalysts, however, low catalytic activity (33 %) was demonstrated.…”