NMR chiral recognition of lipoic acid by cinchonidine CSA: A stereocenter beyond the organic function

• Published in: Chirality (New York, N.Y.) Vol. 35; no. 1; pp. 40 - 48
• Main Authors: Marta, Talia Behnen, Argondizzo, Augusto Cardozo, Silva Oliboni, Robson, Silva, Márcio Santos
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2023
• Subjects: Asymmetry; chiral solvent agent; Chloroform; Cinchona Alkaloids - chemistry; cinchonidine; Density functional theory; Design optimization; Deuteration; Fatty acids; Lipoic acid; Magnetic Resonance Spectroscopy - methods; Natural products; NMR; NMR chiral discrimination; Nuclear magnetic resonance; Recognition; Solvation; Stereoisomerism; Thioctic Acid; NMR chiral discrimination; lipoic acid; chiral solvent agent; cinchonidine
• ISSN: 0899-0042; 1520-636X
• DOI: 10.1002/chir.23514

Alpha‐lipoic acid is a natural product that possesses distinct pharmacological properties. Lipoic acid is a short‐chain fatty acid containing an asymmetric carbon at five bonds of distance to the organic function. Herein, we developed a nuclear magnetic resonance protocol to access the chiral recognition of lipoic acid in a simple and rapid procedure employing cinchonidine as a cheap chiral solvation agent in deuterated chloroform. To optimize this method, a statistical design of the experimental model was performed to produce a clear understanding of the optimal concentration, temperature, and molar ratio parameters. Based on the obtained spectra, the cinchonidine H8‐H9 scalar coupling indicated a conformational preference in the chiral discrimination procedure. Density functional theory calculations established a proximity between the asymmetric center of lipoic acid and the aromatic moiety of cinchonidine, clarifying possible conformations in this ion‐pair interaction. The described protocol demonstrates how far is far enough to chiral discrimination using a chiral solvation agent, expanding the method to compounds that contain a remote stereocenter. Herein, we developed an NMR protocol to access the chiral recognition of lipoic acid, which demonstrates a remote stereocenter, in a simple and rapid procedure employing cinchonidine in CDCl3.