Chiral N-heterocyclic carbene catalysts generated from triazolium salts promote the cyclopentene-forming annulation of α,β-unsaturated aldehydes and 4-oxoenoates with excellent levels of enantioinduction and preference for the cis-1,3,4-trisubstituted cyclopentene diastereomer. Although the observed products could arise by conjugate additions of catalytically generated homoenolates, our mechanistic and stereochemical investigations strongly support a novel reaction manifold featuring an intermolecular crossed-benzoin reaction and an NHC-catalyzed oxy-Cope rearrangement.

Enantioselective, cyclopentene-forming annulations via NHC-catalyzed benzoin-oxy-cope reactions.

The biological activity and chemistry of the southern African Combretaceae

The improved multigram-scale syntheses of the important 8-styrylxanthine A(2A) adenosine receptor antagonist MSX-2 (8), its water-soluble prodrug MXS-3 (9), and KW-6002 (16) are described. N-Alkylation reactions at different positions of uracil derivatives were optimized. Two different methods for xanthine formation from 6-amino-5-cinnamoylaminouracil precursors were investigated, (a) the elimination of water by alkaline catalysis and (b) hexamethyldisilazane as a condensing agent; the latter was found to be superior. The photosensitivity of 8-styrylxanthines was studied. The (E)-configurated stryrylxanthine MSX-2 (8) isomerized in diluted solution, and the resulting (Z)-isomer (10a) was isolated and characterized. Furthermore, we describe for the first time that solid 8-styrylxanthines can dimerize upon exposition to daylight or irradiation with UV light. The resulting cyclobutane derivatives with head-to-tail (syn) configuration exhibited a considerably lower A(2A) adenosine receptor affinity than their parent compounds. The dimerization product of MSX-2 was a moderately potent nonselective A(1) and A(2A) antagonist (K(i)(A(1)) = 273 nM, K(i) (A(2A)) = 175 nM) while the dimer of the related compound KW-6002 was inactive at A(1) and only weakly active at A(2A) adenosine receptors (K(i) = 1.57 microM). The light sensitivity of 8-styrylxanthine derivatives, not only in solution, but also in the solid state, has to be considered when using those compounds as pharmacological tools or drugs.

Multigram-Scale Syntheses, Stability, and Photoreactions of A2A Adenosine Receptor Antagonists with 8-Styrylxanthine Structure: Potential Drugs for Parkinson's Disease

Enthalpy–entropy compensations are a consequence of weak associations where the binding enthalpy is much lower than typical covalent bond strengths. The general form of an enthalpy–entropy curve is presented based upon theoretical considerations and justified on the basis of experimental data for associations in the gas phase and for monatomic sublimation. The intrinsic curvature of the enthalpy vs. entropy plot provides the basis for a description of co-operativity and binding phenomena in solution. In the case of cooperativity, we divide the mutual aiding of two interactions into two distinct parts, one of which is entropic in origin and related to the classical chelate enhancement of binding of Jencks; the other is an enthalpic benefit due to improved electrostatic bonding. Since the experimental Gibbs energy for all weak associations in solution is a consequence of competing solute–solvent, solvent–solvent and solute–solute interactions, the summation of these interactions can be usefully described by a vector analysis using the enthalpy–entropy curve. We illustrate the utility of this approach by presenting a qualitative description of the various contributions to binding in the following examples: (i) one-point associations in non-polar solvents, (ii) entropy-driven association of two large discs involving the release of multiple solvent molecules and (iii) enthalpy driven associations involving metal chelation by polyamines. By considering the curvature of the enthalpy–entropy plot for a given interaction, in combination with the possibility of making or breaking multiple interactions on one template, net enthalpies and entropies of association in solution can be explored in an approximate manner.

Application of a generalised enthalpy–entropy relationship to binding co-operativity and weak associations in solution

The 1H-decoupled 13C-NMR. spectra of 35 all-trans, 17 mono-cis vitamin A compounds (acetates, alcohols, aldehydes, acids and esters) and of one 11, 13-di-cis compound (11, 13-di-cis retinol) are reported. Included in this investigation are desmethyl-, desmethylethyl, and aryl-vitamin A analogues and others as well as 30 reference compounds of smaller molecular weight. Furthermore, the 13C-NMR. spectra of 23 β-apo- and other carotenoids were studied. A complete assignment of the signals of all 106 compounds to the specific carbon atoms was achieved by extensive application of lanthanide shift reagents, mainly Yb(dpm)3, by CW-offset and selective 1H-decoupling experiments, by comparison of the shifts of related compounds, and in three cases by utilization of specifically deuteriated compounds (11, 12-D2-retinol and retinyl acetate, 15, 15′-D2-β-carotene). The chemical shift differences between the cis- and trans-vitamin A compounds and the applicability of the shift reagents for the assignment of the 13C-NMR. spectra are discussed.

A 13C-NMR. Study of cis-trans isomeric vitamins A, carotenoids and related compounds.

Conformational analysis by lanthanide induced shifts. I. Applications to .alpha.,.beta.-unsaturated aldehydes, ketones, esters, and amides

1H NMR spectra of photodimers of cinnamic acid, chalcone and related compounds were analysed, and the spectral parameters and all the coupling constants were obtained A clear differentiation among the head-to-head and head-to-tail stereoisomers can be obtained by considering the values of K, L, M and N parameters The different types of hh and ht isomers can be immediately assigned by considering the relative values of the three-bond couplings An authentic example of an A2B2 spin system is reported

S. Caccamese

Papers

Conformational analysis by lanthanide induced shifts. I. Applications to .alpha.,.beta.-unsaturated aldehydes, ketones, esters, and amides

Photodimers of cinnamic acid and related compounds. A stereochemical study by NMR

Self-association in lactams as a function of the ring size

Structural analysis by lanthanide shift reagents: IV. Conformation of the amide group as a function of the ring size in lactams