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

Abstract

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 H 8 -H 9 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.

Enantiospecific Analysis of Carboxylic Acids Using Cinchona Alkaloid Dimers as Chiral Solvating Agents

“…Furthermore, many structural modifications of the alkaloids enhance these interactions, making chiral recognition more effective. 64,65 These effects contribute to their application in the discrimination and separation of enantiomers. In this work, we center on 1 H NMR spectroscopy and the use of commercially available dimers derived from Cinchona alkaloid (Figure 2), such as monomer dihydroquinine (DHQ) based on natural products and artificial dimers with a nitrogen linker, (DHQ) 2 PYR (hydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether), (DHQ) 2 AQN (hydroquinine anthraquinone-1,4-diyl diether), (DHQ) 2 PHAL (hydroquinine 1,4-phthalazinediyl diether), and its pseudoenantiomer (DHQD) 2 PHAL (hydroquinidine 1,4-phthalazinediyl diether), as potential CSAs to induce enantiospecificity for enantiomeric discrimination and quantification of mandelate derivatives in 1 H NMR spectros- copy; efficient chiral recognition of racemic chiral phosphoric acid was also demonstrated by 31 P NMR spectroscopy.…”