Stereoselective aza Diels-Alder reaction on solid phase: a facile synthesis of hexahydrocinnoline derivatives

As part of our continuing studies of polymer-supported pericyclic reactions for preparing biologically interesting heterocyclic compounds, we have introduced a traceless solid-phase synthesis of hexahydrocinnolines. We developed a method in which mild reaction conditions can be used for the hetero-Diels-Alder reactions on a polymeric support. The dienoic 3-vinyl-2-cyclohexenol attached to a Wang resin through an ether linkage undergoes [4 + 2] cycloaddition reaction with several azadienophiles. The highly stereoselective Diels-Alder reaction showed preferential formation of a single cycloadduct resulting from an anti attack of the dienophile on the polymer-bound diene. Trifluoroacetic acid-mediated cleavage of the polymer-bound cycloadducts yields fused nonaromatic hexahydrocinnolines in moderate yields in three steps.     

Approximating protein flexibility through dynamic pharmacophore models: application to fatty acid amide hydrolase (FAAH)

A structure-based drug discovery method is described that incorporates target flexibility through the use of an ensemble of protein conformations. The approach was applied to fatty acid amide hydrolase (FAAH), a key deactivating enzyme in the endocannabinoid system. The resultant dynamic pharmacophore models are rapidly able to identify known FAAH inhibitors over drug-like decoys. Different sources of FAAH conformational ensembles were explored, with both snapshots from molecular dynamics simulations and a group of X-ray structures performing well. Results were compared to those from docking and pharmacophore models generated from a single X-ray structure. Increasing conformational sampling consistently improved the pharmacophore models, emphasizing the importance of incorporating target flexibility in structure-based drug design.     

Using the idea of expanded core for the exact solution of bi-objective multi-dimensional knapsack problems

We propose a methodology for obtaining the exact Pareto set of Bi-Objective Multi-Dimensional Knapsack Problems, exploiting the concept of core expansion. The core concept is effectively used in single objective multi-dimensional knapsack problems and it is based on the “divide and conquer” principle. Namely, instead of solving one problem with n variables we solve several sub-problems with a fraction of n variables (core variables). In the multi-objective case, the general idea is that we start from an approximation of the Pareto set (produced with the Multi-Criteria Branch and Bound algorithm, using also the core concept) and we enrich this approximation iteratively. Every time an approximation is generated, we solve a series of appropriate single objective Integer Programming (IP) problems exploring the criterion space for possibly undiscovered, new Pareto Optimal Solutions (POS). If one or more new POS are found, we appropriately expand the already found cores and solve the new core problems. This process is repeated until no new POS are found from the IP problems. The paper includes an educational example and some experiments.     

Reactivity of the Mitsunobu reagent toward 3-formylchromones: a strategy for the one-pot synthesis of chromeno[2,3-c]pyrazolines and chromeno[2,3-e]tetrazepines

The zwitterionic intermediates generated from dialkyl azodicarboxylates and triphenylphosphine displayed excellent reactivity toward 3-formylchromones to afford chromeno[2,3-c]pyrazolines and chromeno[2,3-e]tetrazepines.     

Structural,electronic, and magnetoresponsive properties of triangular lanthanide clusters and their free‐standing nitrides

The molecular and electronic structures, stabilities, bonding features, and magnetoresponsive properties of three‐membered [c‐Ln₃]^+/0/? (Ln = La, Ce, Pr, Nd, Gd, Lu) and heterocyclic six‐membered [c‐Ln₃E₃]^q (Ln = La, Ce, Pr, Nd, Gd, Lu; E = C, N; q = 0 or 1) rings have been investigated by means of electronic structure calculation methods at the DFT level. The [c‐Ln₃]^+/0/? clusters are predicted to be bound with respect to dissociation to their constituent atoms, the estimated binding energies ranging from 45.8 to 2056.4 kJ/mol. The [c‐Ln₃] rings capture easily a planar three‐coordinated nitrogen atom at the center or above the center of the ring yielding the lanthanide nitride clusters [c‐Ln₃(μ₃‐N)] adopting a planar geometry, except [c‐La₃(μ₃‐N)] which exhibits pyramidal geometry. The [c‐Ln₃(μ₃‐N)] clusters are predicted to be bound, with respect to dissociation to N (⁴S) atom and [c‐Ln₃] clusters in their ground states, the binding energies ranging from 53.9 to 257.9 kcal/mol. The six‐membered [c‐Ln₃E₃]^q rings are predicted to be bound with respect to dissociation to LnE^q monomers in their ground states with dissociation energies in the range of 173.8 to 318.0 kcal/mol. Calculation of the NICS_zz‐scan curves of the clusters predicted a “hermaphrodic” magnetic response of the [c‐Ln₃]^+/0/? and heterocyclic six‐membered [c‐Ln₃E₃]^q rings, manifested by the coexistence of successive diatropic (aromatic) and paratropic (antiaromatic) zones. The [c‐La₃]^+/0/? and [c‐Lu₃]^? are predicted to be weakly antiaromatic, the [c‐Lu₃]^0/+, [c‐Lu₃C₃]⁺, and [c‐Lu₃N₃] double (σ+π) aromatic, and the [c‐Gd₃C₃] and [c‐Gd₃N₃]⁺ rings (σ+δ)‐aromatic systems. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011     

Dynamics in coarse-grained models for oligomer-grafted silica nanoparticles

Coarse-grained models of poly(ethylene oxide) oligomer-grafted nanoparticles are established by matching their structural distribution functions to atomistic simulation data. Coarse-grained force fields for bulk oligomer chains show excellent transferability with respect to chain lengths and temperature, but structure and dynamics of grafted nanoparticle systems exhibit a strong dependence on the core-core interactions. This leads to poor transferability of the core potential to conditions different from the state point at which the potential was optimized. Remarkably, coarse graining of grafted nanoparticles can either accelerate or slowdown the core motions, depending on the length of the grafted chains. This stands in sharp contrast to linear polymer systems, for which coarse graining always accelerates the dynamics. Diffusivity data suggest that the grafting topology is one cause of slower motions of the cores for short-chain oligomer-grafted nanoparticles; an estimation based on transition-state theory shows the coarse-grained core-core potential also has a slowing-down effect on the nanoparticle organic hybrid materials motions; both effects diminish as grafted chains become longer.     

Enantioselective synthesis of (10S)- and (10R)-methyl-anandamides

For the development of novel endocannabinoid templates with potential resistance to hydrolytic and oxidative metabolism, we are targeting the bis-allylic carbons of the arachidonoyl skeleton. Toward this end, we recently disclosed the synthesis and preliminary biological data for the (13S)-methyl-anandamide. We report now the total synthesis of the (10S)- and (10R)-methyl-counterparts. Our synthetic approach is stereospecific, efficient, and provides the analogs without the need for resolution. Peptide coupling, P-2 nickel partial hydrogenation, and cis-selective Wittig olefination are the key steps.     

Numerical Simulation of Turbulent Flow and Heat Transfer in a Three-Dimensional Channel Coupled with Flow Through Porous Structures

This study investigates numerically the turbulent flow and heat transfer characteristics of a T-junction mixing, where a porous media flow is vertically discharged in a 3D fully developed channel flow. The fluid equations for the porous medium are solved in a pore structure level using an Speziale, Sarkar and Gatski turbulence model and validated with open literature data. Overall, two types of porous structures, consisted of square pores, are investigated over a wide range of Reynolds numbers: an in-line and a staggered pore structure arrangement. The flow patterns, including the reattachment length in the channel, the velocity field inside the porous medium as well as the fluctuation velocity at the interface, are found to be strongly affected by the velocity ratio between the transversely interacting flow streams. In addition, the heat transfer examination of the flow domain reveals that the temperature distribution in the porous structure is more uniform for the staggered array. The local heat transfer distributions inside the porous structure are also studied, and the general heat transfer rates are correlated in terms of area-averaged Nusselt number accounting for the effects of Reynolds number, velocity ratio as well as the geometrical arrangement of the porous structures.     

Statics and dynamics of 2D colloidal crystals in a random pinning potential

We report the first experimental study of a model system of a two-dimensional colloidal crystal in a random pinning potential. The colloidal crystal consists of monodispersed charged polystyrene microspheres suspended in deionized aqueous media and confined near a rough charged surface. It is found that the static orientational correlation function g6(r) decays exponentially for intermediate and strong pinning, in agreement with theories. The driven depinning is dominated by thermally activated creep motion along 1D-like channels between regions with short-range order. A coexistence model is proposed for describing the observations.     

A chiral phosphazane reagent strategy for the determination of enantiomeric excess of amines

Methods for measuring enantiomeric excess (ee) of organic molecules by NMR spectroscopy provide rapid analysis using a standard technique that is readily available. Commonly this is accomplished by chiral derivatisation of the detector molecule (producing a chiral derivatisation agent, CDA), which is reacted with the mixture of enantiomers under investigation. However, these CDAs have almost exclusively been based on carbon frameworks, which are generally costly and/or difficult to prepare. In this work, a methodology based on the readily prepared inorganic cyclodiphosph(iii)azane CDA ClP(μ-N^tBu)₂POBorn (Born = endo-(1S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) is shown to be highly effective in the measurement of ee’s of chiral amines, involving in situ reaction of the chiral amines (R*NH₂) with the P–Cl bond of the CDA followed by quaternization of the phosphorus framework with methyl iodide. This results in sharp ³¹P NMR signals with distinct chemical shift differences between the diastereomers that are formed, which can be used to obtain the ee directly by integration. Spectroscopic, X-ray structural and DFT studies suggest that the NMR chemical shift differences between diastereomers is steric in origin, with the sharpness of these signals resulting from conformational locking of the bornyl group relative to the P₂N₂ ring induced by the presence of the P(v)-bonded amino group (R*NH). This study showcases cheap inorganic phosphazane CDAs as simple alternatives to organic variants for the rapid determination of ee.

The simple inorganic cyclodiphosph(iii)azane chiral derivatisation agent ClP(μ-^tBuN)₂POBorn (Born = endo-(1S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) is shown to be effective in the measurement of ee’s of chiral amines using ³¹P NMR spectroscopy.