Comparative 3D QSAR study on β1-, β2-, and β3-adrenoceptor agonists

A quantitative structure–activity relationship study of tryptamine-based derivatives of β1-, β2-, and β3-adrenoceptor agonists was conducted using comparative molecular field analysis (CoMFA). Correlation coefficients (cross-validated r2) of 0.578, 0.595, and 0.558 were obtained for the three subtypes, respectively, in three different CoMFA models. All three CoMFA models have different steric and electrostatic contributions, implying different requirements inside the binding cavity. The CoMFA coefficient contour plots of the three models and comparisons among these plots provide clues regarding the main chemical features responsible for the biological activity variations and also result in predictions which correlate very well with the observed biological activity. Based on the analysis, a summary regeospecific description of the requirements for improving β-adrenoceptor subtype selectivity is given

Acyl radicals: Functionalized free radicals for the construction of carbocyclic compounds

Primary alkyl-, vinyl- and aryl-substituted acyl radicals generated by Bu\sb3SnH treatment of the corresponding phenyl selenoesters participate cleanly in intermolecular addition reactions with alkenes bearing electron-withdrawing or radical-stabilizing substituents, at rates that exceed those of the potentially competitive decarbonylation or intermolecular hydrogen abstraction from Bu\sb3SnH (reduction). The intermolecular addition reactions of secondary alkyl-substituted acyl radicals with alkenes provided substantially lower adduct yields, presumably as a result of competitive decarbonylation of the intermediate acyl radicals. Similarly, the intramolecular additions of acyl radicals to electron-deficient or unactivated alkenes proceed without significant competitive reduction. Consistent with their behavior in intermolecular addition reactions, the 5-exo-trig cyclizations of secondary and tertiary alkyl-substituted acyl radicals to an unactivated olefin acceptor may be accompanied by varying degrees of decarbonylation. Studies demonstrated the effective participation of acyl radicals in each of the fundamental types of tandem free radical-alkene addition reaction, permitting stereoselective formation of 6-5 and 6-6 fused bicyclic carbocycles possessing varying degrees of functionality. Tandem cyclization of several 5-alkyl substituted 6-hexenoyl radicals bearing $\omega$-alkynyl substituents at C-6 proved to be a conceptually novel tandem radical cyclization sequence initiated by six-membered ring formation. Subsequent investigations into the mechanistic course of these polycyclization reactions not only led to the development of a relatively direct route to 7-5 and 8-5 fused carbocyclic systems based on a tandem free radical rearrangement-5-exo-dig 5-hexynyl cyclization process, but also established that the intramolecular additions of acyl radicals to alkenes under the conditions detailed herein are irreversible, kinetically-controlled processes. A range of phenyl selenoesters possessing a $\beta$-unsubstituted acrylate acceptor were observed to undergo effective endo cyclizations to form macrocyclic lactones. Examination of the cyclizations of substrates containing additional sites of unsaturation in the tethering chain revealed that the 16-endo acyl radical-acrylate addition reaction proceeds at a rate which exceeds that of 6-exo-trig acyl radical addition to an unactivated alkene and which is roughly comparable to 5-exo acyl radical addition to an unsubstituted alkene. Such acyl radical macrocyclization reactions permit the high-yield preparation of functionalized macrocyclic lactones under mild conditions. (Abstract shortened with permission of author.

Photochemistry of 1-phenyl-tetrazolone isolated in solid argon

The molecular structure, vibrational spectra, tautomerism and photochemistry of the derivative of tetrazole, 1-phenyl-tetrazolone (C7H6N4O; PT) have been studied by FT-IR matrix isolation spectroscopy and DFT/B3LYP/6-311++G(d,p) calculations. Among the five structures in which PT could be expected to exist (two keto tautomers, one mesoionic olate-form and two different conformers of the hydroxyl tautomer), only the most stable species, 1-phenyl-1,4-dihydro-5H-tetrazol-5-one, could be experimentally observed in low temperature argon matrices. Monomers of this tautomer give rise to an IR spectrum that fits nicely the calculated spectrum obtained at the DFT/B3LYP/6-311++G(d,p) level of theory. In situ UV irradiation (λ > 235 nm) of the matrix-isolated PT induces three main photochemical processes, all of them involving cleavage of the tetrazole ring: e.g. (1) molecular nitrogen loss, with production of 1-phenyl-diaziridin-3-one; this compound reacts subsequently to form 1-aza-1,2,4,6-cycloheptatetraene and isocyanic acid (eventually, also to form CO plus phenyldiazene); (2) cleavage of the C(5)–N(1) and N(3)–N(4) tetrazole-ring bonds, with production of phenylazide and isocyanic acid, with phenylazide then losing N2 to yield as final product 1-aza-1,2,4,6-cycloheptatetraene; and (3) cleavage of the N(1)–N(2) and N(4)–C(5) tetrazole-ring bonds, to yield phenylisocyanate and azide. The observed photochemical processes are distinct from the preferred thermal fragmentation channel, where CO is produced together with a weak IR absorbant species