Asymmetric induction by the cholestanic moiety on tropos species: synthesis and stereochemical characterization of bile acid-based biphenyl phosphites.

Three different bile acid-derived biphenyl phosphites were synthesized, starting from cholic and deoxycholic acids and biphenol, and their stereochemical features were checked by CD and NMR spectroscopies. On the basis of the spectroscopic results, the capability of the cholestanic system to induce a prevalent sense of twist on the biphenyl moiety of the bile acid-derived phosphites as well as their tropos nature was inferred.

[PtCl3(C2H4)]-[AmH]+ complexes containing chiral secondary amines: use as chiral derivatizing agents for the enantiodiscrimination of unsaturated compounds by 195Pt NMR spectroscopy and NMR stereochemical investigation.

Ionic complexes [PtCl3(C2H4)]-[AmH]+, containing chiral secondary amines, constitute a versatile class of chiral derivatizing agents (CDAs) for the enantiomeric purity determination of chiral unsaturated compounds via 195Pt NMR spectroscopy. The NMR conformational analysis allows us to search for the stereochemical basis of their enhanced versatility.

195Pt NMR determination of the enantiomeric purity and absolute configuration of trisubstituted allenes by using [PtCl3(C2H4)]-[(S,S)-(1-NpMeCH)2NH2]+ as CDA.

[figure: see text] The ionic CDA [PtCl3(C2H4)]-[(S,S)-(1-NpMeCH)2NH2]+ produces, on exchange of its coordinated ethylene by chiral trisubstituted allenes, diastereoisomeric mixtures originating distinct 195Pt NMR resonances for the complexed enantiomers, thus allowing the determination of the enantiomeric purity. A reproducible correlation between relative positions of platinum signals due to the complexed enantiomers and their absolute configuration has been found.

[PtCl]

The ionic complex [PtCl(3)(C(2)H(4))](-)[(S,S)-(PhMeCH)(2)NH(2)](+) containing a chiral secondary amine is a new and versatile chiral derivatizing agent (CDA) for the determination of the enantiomeric composition of several unsaturated compounds including simple olefins: the diastereoisomeric mixtures arising from the exchange of ethylene by the unsaturated analytes are easily detected by (195)Pt NMR spectroscopy.

Different enantioselective interaction pathways induced by derivatized quinines.

The stereochemistries in solution of the diastereoisomeric complexes formed by quinines modified at the hydroxyl site (9-O-acetylquinine; 9-O-(3,5-dimethoxyphenylcarbamate)quinine) or quinuclidine nitrogen (N-benzylquininium chloride) and each enantiomer of 2-(3', 5'-dinitrobenzamido)-1-phenylethanol have been compared to those of the free compounds by (1)H NMR investigations. Completely different interaction models, also involving changes of the free state conformations, have been obtained.

Direct resolution, characterization, and stereospecific binding properties of an atropisomeric 1,4-benzodiazepine.

The chromatographic resolution of 7-chloro-1,3-dihydro-1-(1,1-dimethylethyl)-5- (2-fluorophenyl)-2H-1,4-benzodiazepin-2-on (7), the 2'-fluoro, N1-tertbutyl analogue of diazepam, was attained on both analytical and preparative (mgs) scales, by using several chiral stationary phases (CSPs). The stereochemistry of this compound was characterized by means of 1H-NMR Nuclear Overhauser Effect (NOE) analysis. The single enantiomers of 7 were tested for their configuration and stereochemical stability by circular dichroism (CD), and their interaction with the central nervous system (CNS) benzodiazepine receptor was assayed, showing a significant difference in their binding affinities. Protein binding studies with human serum albumin (HSA, the main benzodiazepine carrier in human plasma) immobilized on a silica stationary phase revealed that HSA also preferentially binds one stereoisomer of 7. However, both on line CD detection and stereospecific interaction with other common drugs clearly demonstrated that the stereoselectivity of immobilized HSA for 7 is opposite to that for all the other studied benzodiazepines. In addition, HSA stereoselectivity for 7 is opposite to CNS receptor binding stereoselectivity for the same compound. Such HSA anomalous stereoselectivity for 7 was also confirmed in aqueous buffer solution by competitive displacement studies. Compared to other chiral 1,4-benzodiazepines, compound 7 thus shows several anomalous binding properties: HSA and the CNS receptor demonstrated opposite enantioselective discrimination; HSA has reversed enantioselectivity for compound 7; and HSA stereospecifically binds the low-affinity enantiomer.

Different NMR approaches to the chiral analysis of trisubstituted allenes devoid of polar functional groups and aromatic hydrocarbons.

The use of permethylated beta-cyclodextrin as chiral solvating agent for NMR spectroscopy allowed us to determine the enantiomeric purity of chiral aromatic hydrocarbons as well as the enantiomeric purity and absolute configuration of chiral trisubstituted allenes devoid of polar functional groups. The enantiomeric excesses of the trisubstituted allenes have been also determined by 195Pt NMR spectroscopy of the diastereoisomeric trans-dichloro[(S)-alpha-phenylethyl-amine](allene)Pt(II) complexes.

The binding of 5-fluorouracil to native and modified human serum albumin: UV, CD, and 1H and 19F NMR investigation.

5-Fluorouracil (FU) is an important and widely used antineoplastic drug that is carried in the serum by plasma proteins. Protein binding studies of this drug to human serum albumin (HSA) have been carried out by several spectroscopic techniques. Difference circular dichroism and UV studies provided information on the class of binding sites involved in the interaction. In particular, displacement experiments showed that FU has at least one secondary binding site in the coumarin binding area, but does not interact with the benzodiazepine binding area. Binding was also investigated by difference 1H NMR and by measuring the increase in the 19F NMR signal of FU when bound to HSA. Finally, evidence was obtained that chemical acetylation of Lys199 results in a decreased apparent binding affinity constant (nK) for FU. Such a modification is induced under physiological conditions by aspirin.

Stereochemistry and dynamics of the inclusion complex of (S)-(+)-fenoprofen with cyclomaltoheptaose (beta-cyclodextrin).

The inclusion complex of the calcium salt of (S)-2-(3-phenoxyphenyl)propionic acid with cyclomaltoheptaose (beta-cyclodextrin) was investigated by 1H NMR spectroscopy. The stoichiometry of the complex was determined by the continuous variation method and the association constant by the Benesi-Hildebrand procedure. Measurements of proton selective relaxation rates allowed the dynamics of the complex to be investigated and the determination of intermolecular 1H(1H)-NOE enhancements revealed the stereochemistry in solution.