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

• Published in: Chirality (New York, N.Y.) Vol. 34; no. 6; pp. 877 - 886
• Main Authors: Cruz, Harold, Servín, Felipe A., Aguirre, Gerardo, Pérez, Sergio, Madrigal, Domingo, Chávez, Daniel, Cooksy, Andrew L., Somanathan, Ratnasamy
• Format: Journal Article
• Language: English
• Published: HOBOKEN Wiley 01.06.2022; Wiley Subscription Services, Inc
• Subjects: 3‐bis‐thiourea; C2‐symmetric 1; Carbonyl compounds; Carbonyls; Catalysts; Chemical bonds; Chemistry; Chemistry, Analytical; Chemistry, Medicinal; Chemistry, Organic; Enantiomers; enantioselective Michael addition; Enzymes; heterogeneous; homogeneous; Hydrogen bonding; Life Sciences & Biomedicine; mimicking enzyme; Mimicry; Nucleophiles; organocatalysts; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Substrates; supramolecular hydrogen bonding; Thioureas; homogeneous; enantioselective Michael addition; SQUARAMIDE; 3-bis-thiourea; mimicking enzyme; supramolecular hydrogen bonding; organocatalysts; C-2-symmetric 1; heterogeneous
• ISSN: 0899-0042; 1520-636X
• DOI: 10.1002/chir.23438

We report herein the synthesis and application of enantiopure C2‐symmetric primary amine‐1,3‐bis‐thiourea organocatalysts in enantioselective conjugate 1,4‐Michael addition of carbonyl containing nucleophiles, to nitroalkenes and N‐phenylmaleimide, leading to final products in good enantioselectivities (up to 99%) and yields (up to 99%). We propose supramolecular noncovalent interactions within the organocatalyst's cleft between the substrate and the catalyst, via hydrogen bonding. Supramolecular interaction thus lowers the transition state energy mimicking an enzyme. Mechanism underlying our experimental results is supported by theorical calculations.