W. Clark Still

Direct synthesis of Z-unsaturated esters. A useful modification of the horner-emmons olefination.

Abstract New phosphonoester reagents and reaction conditions are described which yield Z-alpha, beta-unsaturated esters stereoselectively and in high yield from aliphatic and aromatic aldehydes.

Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO)

A fast analytical formula was derived for the calculation of approximate atomic and molecular van der Waals (vdWSA), and solvent‐accessible surface areas (SASAs), as well as the first and second derivatives of these quantities with respect to atomic coordinates. This method makes use of linear combinations of terms composed from pairwise overlaps of hard spheres; therefore, we term this the LCPO method for linear combination of pairwise overlaps. For higher performance, neighbor‐list reduction (NLR) was applied as a preprocessing step. Eighteen compounds of different sizes (8–2366 atoms) and classes (organic, proteins, DNA, and various complexes) were chosen as representative test cases. LCPO/NLR computed the SASA and first derivatives of penicillopepsin, a protein with 2366 atoms, in 0.87 s (0.22 s for the creation of the neighbor list, 0.35 s for NLR, and 0.30 s for SASA and first derivatives) on an SGI R10000/194 Mhz processor. This appears comparable to or better than timings reported previously for other algorithms. The vdWSAs were in good agreement with the numerical results: relative errors for total molecular surface areas ranged from 0.1 to 2.0% and average absolute atomic surface area deviations from 0.3 to 0.7 Å2. For SASAs without NLR, the LCPO method exhibited relative errors in the range of 0.4–9.2% for total molecular surface areas and average absolute atomic surface area deviations of 2.0–2.7 Å2; with NLR the relative molecular errors ranged from 0.1 to 7.8% and the average absolute atomic surface area deviation from 1.6 to 3.0 Å2. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 217–230, 1999

Parallel Synthesis and Screening of a Solid Phase Carbohydrate Library

A solid phase carbohydrate library was synthesized and screened against Bauhinia purpurea lectin. The library, which contains approximately 1300 di- and trisaccharides, was synthesized with chemical encoding on TentaGel resin so that each bead contained a single carbohydrate. Two ligands that bind more tightly to the lectin than Gal-β-1,3-GalNAc (the known ligand) have been identified. The strategy outlined can be used to identify carbohydrate-based ligands for any receptor; however, because the derivatized beads mimic the polyvalent presentation of cell surface carbohydrates, the screen may prove especially valuable for discovering new compounds that bind to proteins participating in cell adhesion.

Chemical consequences of conformation in macrocyclic compounds : An effective approach to remote asymmetric induction

Abstract In this paper we show that the conformational properties of medium- and large-ring organic molecules have profound consequences on the stereochemical course of their chemical reactions. Kinetic enolate alkylations, dimethylcuprate additions and catalytic hydrogenations were examined on a variety of monosubstituted 8- to 12-membered macrocyclic ketones and lactones, and the diastereomeric composition of the products was determined. In many systems a single Me substituent provided enough conformational bias to allow highly stereoselective formation of new asymmetric centers. The diastereoselection exhibited by the reactions investigated appears to be intimately associated with the conformational properties of the macrocyclic substrates employed since simple molecular mechanics calculations allowed semiquantitative prediction of the product distributions in every case.

A rapid approximation to the solvent accessible surface areas of atoms

An analytical expression for approximate atomic and molecular van der Waals and solvent accessible surface areas is described. The treatment is based on the probabilistic method of Wodak and Janin1 but with modifications which allow it to be applied to the calculation of atomic surface areas. The calculation is a pairwise function of atomic positions and radii and is therefore quite rapid. We compare the results of this method with exact areas, list the first and second derivatives of the function and provide a FORTRAN subroutine on disk which calculates the approximate atomic areas from atomic coordinates and connectivity. We also provide some standard test molecules on disk.

Chelation-controlled nucleophilic additions. 1. A highly effective system for asymmetric induction in the reaction of organometallics with α-alkoxyketones.☆

Abstract Organocuprates have been found to be highly stereoselective reagents for the addition of carbanionic nucleophiles to α-asymmetric aldehydes bearing β-oxygen substituents. The major products are those predicted by a chelation-controlled transition state and have diastereomeric purities ranging from -15-30:1.

AMBER torsional parameters for the peptide backbone

A new set of torsional parameters for peptides in the AMBER force field is described which reproduces ab initio calculations on the conformational preferences of simple peptides better than the original set. We designate the new parameter set as AMBER and show how it compares with the performance of AMBER in reproducing the x-ray structure of the small protein crambin.

A rapidly convergent simulation method: mixed Monte Carlo/stochastic dynamics

Although Monte Carlo and molecular dynamics are the primary methods used for free energy simulations of molecular systems, their application to molecules that have multiple conformations separated by energy barriers of ≥ 3 kcal/mol is problematic because of slow rates of convergence. In this article we introduce a hybrid simulation method termed MC‐SD which mixes Monte Carlo (MC) and stochastic dynamics (SD). This new method generates a canonical ensemble via alternating MC and SD steps and combines the local exploration strengths of dynamics with the barrier‐crossing ability of large‐step Monte Carlo. Using calculations on double‐well potentials and long simulations (108 steps of MC and 1 μs of SD) of the simple, conformationally flexible molecule n‐pentane, we find that MC‐SD simulations converage faster than either MC or SD alone and generate ensembles which are equivalent to those created by classical MC or SD. Using pure SD at 300 K, the conformational populations of n‐pentane are shown to be poorly converged even after a full microsecond of simulation.

Combinatorial approach to the development of fluorescent sensors for nanomolar aqueous copper

Abstract New fluorescent sensors for aqueous copper ions were developed via screening of metal ligand libraries. Identified ionophores were linked to a dansyl fluorophore reporter, affording copper ion sensors based on fluorescence quenching. Simple chemical modification of identified ionophores generated sensors responsive to a broad range of copper ion concentrations (10 nM–35 μM).

Highly selective binding of diverse neutral donor/acceptor substrates by a C3 macrotricyclic receptor

Abstract The synthetic receptor 1 binds a variety of peptides and glycosides with high selectivity for functionality and stereochemistry. Depending upon peptide mainchain substitutents, either the C- or the N-terminus of a peptide may be directed into the binding pocket of 1 .