Chiral NMR analysis of phosphines and phosphoric acids, and plasma carboxylic acid analysis via fluorine labeling

Abstract

Herein, efficient chiral recognition of phosphine oxides with octahedral indium complexes was demonstrated. Direct chiral analysis of in situ-prepared phosphine oxides formed using phosphines and hydrogen peroxide was conducted effectively via 31P nuclear magnetic resonance spectroscopy (NMR). Sufficient peak resolution of chiral phosphines was obtained consistently, thereby enabling the reliable determination of absolute chirality. Rational 1:1 binding models based on experiments and density functional theory calculations have been proposed. In addition, we present a novel approach for the chiral recognition of phosphates using cationic octahedral cobalt complexes. By utilizing $^{31}P$ NMR spectroscopy, we were able to accurately measure the enantiopurities of chiral phosphoric acids after forming ion pairs with the cobalt complexes. Furthermore, we were able to achieve an optical resolution of a phosphoric acid with an enantiomeric excess of greater than $99%$. Moreover, we present a novel $^{19}F$ labeling protocol for $^{19}F$ NMR spectroscopy based carboxylic acid containing metabolite analysis. The amide coupling reagent, pivaloyl chloride, exhibited substantial reactivity with thiol, amine, alcohol, and carboxylic acid groups. Particularly noteworthy was its selective activation of carboxylic acids, effectively deactivating the other functional groups, and ultimately enabling the specific $^{19}F$ labeling of carboxylic acids using 2-fluoroaniline. Utilizing this newly developed $^{19}F$ labeling method, we identified and quantified carboxylic acid metabolites in human plasma. This novel analysis method can be a valuable tool, providing invaluable insights into the metabolic status of living organisms. In addition, a chiral imidazoline ligand library was constructed to study the reactivity and selectivity in several transition metal catalyzed reactions. In the palladium-catalyzed amine addition reaction of 3-cyclopentene-1-methanol, the imidazoline-type ligands showed superior reactivity and enantioselectivity compared to the oxazoline-containing ligands. Finally, we developed a visible-light-driven hydroacylation reaction for unactivated alkenes using readily available acyl chlorides as radical precursors. By using cyclohexene as a solvent and hydrogen donor along with an alkene substrate, it was shown that about 20 ketones could be successfully synthesized under mild reaction conditions.