Phosphorylation as a method of tuning the enantiodiscrimination potency of quinine—An NMR study

Abstract

Quinines phosphorylated at the C-9 hydroxyl group (diphenyl and diethyl phosphates) were synthesized and validated as novel effective chiral solvating agents in two alternative methods based on (1)H and (31)P NMR spectroscopy. Tested with a representative set of racemic analytes, the title compounds induced shift nonequivalence effects in (1)H NMR signals with values up to 0.1-0.2 ppm for 3,5-dinitrobenzoyl-substituted amino acids. In terms of enantiodifferentiation extent and application range, introduction of a phosphate group was proven to be superior compared to the action of nonmodified quinine. Interestingly, a temperature decrease to reach the slow exchange conditions also produced nonequivalences in the (31)P NMR spectra of the selectors. Comprehensive NMR analysis showed the existence of two conformations (closed 1 and 2) for both quinines in their free forms and the open 3 arrangement for the protonated ones. The crystal structure of diethylphosphorylquinine hydrochloride dichloromethane hemisolvate revealed a similar conformation to that observed in solution. Structures of complexes of phosphorylated quinines with selected ligands were determined with the use of NMR-based molecular modeling studies.

Zwitterionic Phosphorylated Quinines as Chiral Solvating Agents for NMR Spectroscopy

“…18 Racemic compounds 3-8 were synthesized according to standard methods. Compounds 9-20 and the amino acids were commercially available (Aldrich).…”

“…[10][11][12][13][14][15][16][17] In particular, C9-carbamoylated quinines revealed complementary enantiodiscriminating properties with respect to native quinine toward a range of chiral substrates, such as amines, acids, amides, and N-protected amino acids. 18 These compound were tested with a set of ligands possessing different functional groups, including N-protected amino acids and their methyl esters, carboxylic acids, free and protected amines, and alcohols. 1) as effective chiral solvating agents in 1 H NMR and 31 P NMR spectroscopy.…”

“…1). To understand the role of the modification on the enantiodiscrimination ability, we compared the results obtained for the same set of ligands to those acquired for the diphenyl analog in its free tertiary amine form 1c (results published earlier 18 ) and the protonated quaternary ammonium salt 1c × HCl. Quinine-based mixed phosphate diesters are zwitterionic and possess two charged functions (i.e., the quaternary ammonium cation and the phosphate anion) that offer the possibility of novel specific interactions.…”

Addition of H-phosphonates to quinine-derived carbonyl compounds. An unexpected C9 phosphonate–phosphate rearrangement and tandem intramolecular piperidine elimination

“…Surprisingly, phosphorus compounds chemistry, particularity that avoiding an expansion of the core carbon skeleton [10–13], is poorly recognized and mainly involves esterification of different phosphorus acids with the O -9-hydroxy group [14–21]. These phosphorus esters were consecutively applied in organo- and metal-assisted catalysis [14,17–20] and NMR-monitored enantiodiscrimination [21]. According to our knowledge no example of formation of a direct C–P linkage between the quinine backbone and a phosphorus atom has been reported in the literature.…”

Dithiophosphorylation of quinine

“…Promising synthons in the design of biologically active compounds are hydroxy-containing chiral alkaloids, such as quinine and cinchonine. Accessibility of these alkaloids has underlain their use as chiral P,N-bidentate ligands for metal complexes, catalysts for asymmetric syntheses, chromatographic selectors, and chiral NMR reagents [1][2][3][4]. Wide potential of their application for various purposes is determined by specific features of the molecular structure of quinine and cinchonine as major components of cinchona alkaloids, which consist of a quinoline fragment and vinyl-substituted bicyclic quinuclidine moiety with a tertiary nitrogen atom.…”