Stereoselectivity Enhancement During the Generation of Three Contiguous Stereocenters in Tetrahydrothiophenes

• Published in: ChemCatChem Vol. 13; no. 2; pp. 574 - 580
• Main Authors: Mała, Żaneta A., Janicki, Mikołaj J., Niedźwiecka, Natalia H., Góra, Robert W., Konieczny, Krzysztof A., Kowalczyk, Rafał
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 20.01.2021
• Subjects: Aldehydes; Asymmetric catalysis; Bonding strength; Cascade chemical reactions; Chirality; Density functional calculations; Density functional theory; Enantiomers; Hydrogen bonding; Organocatalysis; Squaramides; Stereoselectivity; Tetrahydrothiophenes
• ISSN: 1867-3880; 1867-3899
• DOI: 10.1002/cctc.202001583

Application of carefully designed Cinchona alkaloid based squaramides resulted in the formation of three contiguous stereocenters in enantio‐ and diastereoselective Sulfa‐Michael/intramolecular aldol reactions cascade. Increase of the temperature to 333 K in reaction of mercaptoacetic aldehyde and various en‐ynones allowed the rise of the reaction rate while not affecting the enantioselectivity nor diastereoselectivity. Stereoselectivity was dependent on the structure of the hydrogen‐bonding unit, thus revealing the importance of weak interactions in the formation of the multifunctional tetrahydrothiophenes. Kohn‐Sham Density Functional Theory results suggest that a perfect fit of the electrophile and squaramide via tailored (+)N−H hydrogen bonding and π–π stacking interactions were the main factors of the chirality transfer. Asymmetric catalysis: Tetrahydrothiophenes with three contiguous stereocenters containing three reactive functionalities were formed with high stereoselectivities through a sulfa‐Michael/intramolecular aldol reaction cascade.