Enzymatic kinetic resolution of piperidine atropisomers: synthesis of a key intermediate of the farnesyl protein transferase inhibitor, SCH66336

The resolution of secondary amines via enzyme-catalyzed acylation is a relatively rare process. The kinetic resolution of a series of intermediates of SCH66336 (1), by either enzymatic acylation of the pendant piperidine (4, 5) or hydrolysis of the corresponding carbamate 3, was investigated. In the case of 4, the molecule exists as a pair of enantiomers due to atropisomerism about the exocyclic double bond. The enzymatic acylation of (+/-)-4 was optimized in terms of acylating agent, solvent, and moisture content. The use of lipase, Toyobo LIP-300, and trifluoroethyl isobutyrate as acylating agent resulted in isobutyrylation of the (+)-enantiomer, which is easily separated from the unwanted (-)-4. Hydrolysis of the isobutyramide 6c yielded the desired (+)-4 in high enantiomeric excess. (-)-4 may be recovered from the resolution step, racemized, and resubjected to enzymatic acylation to increase material throughput.     

2H NMR measurements of the molecular orientational ordering in a reentrant liquid-crystalline mixture

Deuterium NMR measurements of the molecular orientational ordering (nematic order) are reported for a reentrant binary mixture of some alkoxy-eyanobiphenyls (nOCB) to which small amounts of perdeuterated p-xylene have been added. The results indicate that the degree of orientational order is enhanced at the smectic A to reentrant nematic phase transition. This effect is shown to be in agreement with the predictions of a Landau-type theory of the reentrant phase transition where-by this phase transition is explained as the result of a coupling between the smectic and the nematic order parameters.     

A universal scaling theory for complexity of analog computation

We discuss the computational complexity of solving linear programming problems by means of an analog computer. The latter is modeled by a dynamical system which converges to the optimal vertex solution. We analyze various probability ensembles of linear programming problems. For each one of these we obtain numerically the probability distribution functions of certain quantities which measure the complexity. Remarkably, in the asymptotic limit of very large problems, each of these probability distribution functions reduces to a universal scaling function, depending on a single scaling variable and independent of the details of its parent probability ensemble. These functions are reminiscent of the scaling functions familiar in the theory of phase transitions. The results reported here extend analytical and numerical results obtained recently for the Gaussian ensemble.     

Acyclic edge colorings of graphs

A proper coloring of the edges of a graph G is called acyclic if there is no 2‐colored cycle in G. The acyclic edge chromatic number of G, denoted by a′(G), is the least number of colors in an acyclic edge coloring of G. For certain graphs G, a′(G) ≥ Δ(G) + 2 where Δ(G) is the maximum degree in G. It is known that a′(G) ≤ 16 Δ(G) for any graph G. We prove that there exists a constant c such that a′(G) ≤ Δ(G) + 2 for any graph G whose girth is at least cΔ(G) log Δ(G), and conjecture that this upper bound for a′(G) holds for all graphs G. We also show that a′(G) ≤ Δ + 2 for almost all Δ‐regular graphs. © 2001 John Wiley & Sons, Inc. J Graph Theory 37: 157–167, 2001     

Identification of firearms handling by the [Fe(PDT)(3)](2+) complex: Chemical and time-dependent factors

Handling of a gun results in the formation of invisible impressions, caused by transfer of iron traces to the skin surface. Visualization of these impressions is possible by spraying the palms with a solution of 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine (PDT), which forms a magenta complex with iron(II) residues. Hence, mark intensity is directly related to the amounts of iron transferred to the palm. Palmar sweat plays a major role in iron transfer from the firearm to the hand. More factors, however, are involved in this process. Three time-dependent factors have been studied with relation to their effect on the developed mark: the gripping duration of the weapon; the time elapsed from the contact; and the rate of iron dissolution in aqueous solutions containing sweat components in physiological concentrations.We found that the amounts of iron transferred to the palm depend on both, the gripping period and the levels of palmar moisture. Thus, only a few seconds of gripping were required for developing good marks (corresponding to 80 ng cm⁻² of iron) on highly-moistured hands, much longer gripping periods were necessary for developing marks of similar intensity on relatively dry hands. Experiments that aimed at studying the effect of sweat components on metallic iron dissolution were carried out in aqueous solutions. It was found that chloride ions in physiological concentrations remarkably enhanced the dissolution, while l-serine, the major amino acid in palmar sweat, had a detrimental effect on this process. Urea, another sweat component, had only a minor effect on the dissolution rate.     

Extending Kotzig’s theorem

The weight of a graphG is the minimum sum of the two degrees of the end points of edges ofG. Kotzig proved that every graph triangulating the sphere has weight at most 13, and Grünbaum and Shephard proved that every graph triangulating the torus has weight at most 15. We extend these results for graphs, multigraphs and pseudographs “triangulating” the sphere withg handlesS _g ,g≧1, showing that the corresponding weights are at most about and 24g−9, respectively; if a (multi, pseudo) graph triangulatesS _g and it is big enough, then its weight is at most 15.     

Structural changes in glutamate cell swelling followed by multiparametric q-space diffusion MR of excised rat spinal cord

Diffusion in the extracellular and intracellular spaces (ECS and ICS, respectively) was evaluated in excised spinal cords, before and after cell swelling induced by glutamate, by high b-value q-space diffusion MR of specific markers and water. The signal decays of deuterated tetramethylammonium (TMA-d(12)) chloride, an exogenous marker of the ECS, and N-acetyl aspartate (NAA), an endogenous marker of the ICS, were found to be non-mono-exponential at all diffusion times. The signal decays of these markers were found to depend on the diffusion time and the cell swelling induced by the glutamate. It was found, for example, that the mean displacements of the apparent fast and slow diffusion components of TMA-d(12) are 7.21 +/- 0.11 and 1.16 +/- 0.05 microm, respectively at a diffusion time of 496 ms. After exposure of the spinal cords to 10 mM of glutamate, these values decreased to 6.62 +/- 0.13 and 1.01 +/- 0.05 microm, respectively. The mean displacement of NAA, however, showed a less pronounced opposite trend and increased after cell swelling induced by exposure to glutamate. q-Space diffusion MR of water was found to be sensitive to exposure to glutamate, and q-space diffusion MRI showed that a more pronounced decrease in the apparent diffusion coefficient and the mean displacement of water is observed in the gray matter (GM) of the spinal cord. All these changes demonstrate that diffusion MR is indeed sensitive to structural changes caused by cell swelling induced by glutamate. Multiparametric high b-value q-space diffusion MR is useful for obtaining microstructural information in neuronal tissues.     

Phase transitions of p-type (Pb,Sn,Ge)Te-based alloys for thermoelectric applications

p-type (Pb,Sn,Ge)Te-based alloys for thermoelectric applications were prepared using Bridgman technique. Second-order, rhombohedral to cubic phase transitions are involved, as evaluated from anomalies in the temperature dependence values of Seebeck coefficient, electrical conductivity, heat flow and the elongation, in the vicinity of the phase transition temperature, T_c. The correlation between these anomalies in both the electronic and thermodynamic properties was interpreted by means of the relationship of Fermi energy to the chemical potential (or to the molar Gibbs free energy).