The equilibrium constant for the thermal isomerization of the diastereomeric alpha- and beta-(cyanomethyl)cobinamides (NCCH(2)Cbi(+)'s) has been measured over the temperature range 70-95 degrees C. Although the beta diastereomer is the thermodynamically more stable isomer, it is favored by the entropy change, but disfavored by the enthalpy change. In the presence of >/=5 x 10(-)(3) M concentration of the radical trap 4-hydroxy-2,2,6,6,-tetramethylpiperidinyloxy (4-HTEMPO), thermolysis of either isomer leads to cob(II)inamide and the trapped NCCH(2)(*) radical (NCCH(2)-4-HTEMPO) in high yield and no isomerization can be detected. The kinetics of the 4-HTEMPO-trapped thermal homolysis of alpha- and beta-NCCH(2)Cbi(+) have been studied in anaerobic glycerol/water mixtures of varying viscosity. The observed first-order rate constants for thermolysis show the expected inverse dependence on viscosity indicating that the process is at least partially diffusion controlled. From these data, the primary rate constant, k(1), for carbon-cobalt bond homolysis and the ratio of the rate constants for in-cage recombination and diffusional separation (k(c)/k(d)) can be extracted. The enthalpies of activation for Co-C bond homolysis are identical (29.0 +/- 0.3 kcal mol(-)(1)) while the entropy of activation is 2-fold higher for the alpha diastereomer. In water, the fractional cage efficiencies, F(c), are quite small (0.12 +/- 0.01, alpha; 0.049 +/- 0.008, beta) and invariant for each complex in the temperature range 75-95 degrees C. Assuming that the rate constant for diffusional separation of the caged radical pairs is the same for both isomers, the ratio of the in-cage recombination rate constants, k(c)(alpha)/k(c)(beta), can be calculated to be 2.6 +/- 0.6. This surprising kinetic preference for the alpha diastereomer results from enthalpic stabilization of the recombination transition state for the alpha diastereomer, since the beta diastereomer is entropically favored.

Six macrocyclic bis(indolyl)maleimides 1-6 bearing a fluorine label on the aliphatic portion of the macrocycle have been prepared as potential fluorine NMR probes for the catalytic domain of protein kinase C. The macrocyclic bis(indolyl)maleimides such as LY333531 are reversible, ATP competitive, and isoform-selective inhibitors of protein kinase C and may thus serve to probe for subtle differences between protein kinase catalytic domains. The key stereochemical elements were put in place by a Welch aldol condensation between ethyl fluoroacetate and (R)-cyclohexylidene glyceraldehyde, which was followed by allylation of the secondary alcohol, elaboration of the alkene and ester to alcohols, and mesylation. The macrocycle was formed by slow addition of a mixture of the fluorinelabeled aliphatic dimesylate and N-methyl 2,3-bis[1H-indol-3-yl]maleimide to a suspension of cesium carbonate. Adjusting the functionality led to the six fluorine-labeled macrocyclic bis(indolyl)maleimides. These compounds retain the high potency of the parent compounds, with IC 50 values below 5 nM for the 14-membered ring compounds 1-3 and 13-90 nM for the 15-membered ring compounds 5-6. Vicinal proton-fluorine coupling constants provide an experimental parameter for determining the local macrocycle conformation.

In this study, a nickel‐catalyzed decarboxylative cyclization of isatoic anhydrides with carbodiimides was developed. This protocol realized the direct introduction of carbodiimides into heterocyclic compounds under an in situ generated Ni(0) complex. Synthetically, this methodology provides a simplified and secure new approach for the preparation of 2‐imino‐2,3‐dihydroquinazolin‐4(1H)‐ones. The control experiments and DFT theoretical calculations indicated that the Ni(0)‐catalyzed process is of central importance to the entire transformation.magnified image

No abstract

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.