Solvent effects on stereoselectivity: more than just an environment.

Stereoselectivity is a major topic in organic synthesis. Intensive investigations into the role of solvents on diastereo- and enantioselective reactions, as well as temperature-dependent measurements of diastereomeric and enantiomeric ratios, have shed light on the existence of dynamic solvation effects. In this tutorial review, several examples of non-linear Eyring plots in stereoselective nucleophilic additions, cycloadditions, photochemical and enzymatic reactions are reported.

New polyphenolic beta-lactams with antioxidant activity.

Novel 4-alkylidene-beta-lactams with a polyphenolic side chain were synthesized and evaluated as radical scavengers. We have undertaken a detailed study of the antioxidant activity in vitro with chemical and biological testing of the new beta-lactams and of the corresponding methyl polyhydroxy benzoates. Antioxidant activity of beta-lactams and methyl benzoates was measured with the Briggs-Rauscher oscillating reaction, the TEAC (Trolox( Equivalent Antioxidant Capacity) assay, and as ability to inhibit ROS (=Reactive Oxygen Species) production on myoblast H9c2 cells.

Inhibitory effect by new monocyclic 4-alkyliden-beta-lactam compounds on human platelet activation.

In the present study some new beta-lactam compounds were screened for their ability to inhibit human platelet activation. In particular four compounds differing in the group on the nitrogen atom of the azetidinone ring were investigated. A beta-lactam having an ethyl 2-carboxyethanoate N-bound group was demonstrated to inhibit, in the micromolar range, both the Ca(2+) release from endoplasmic reticulum, induced either by thrombin or by the ATPase inhibitor thapsigargin, and the Ca(2+) entry in platelets driven by emptying the endoplasmic reticulum.

Design, synthesis, and biological evaluation of 4-alkyliden-beta lactams: new products with promising antibiotic activity against resistant bacteria.

The design, synthesis, and antibacterial activity of 4-alkyliden-azetidin-2-ones as new antimicrobial agents against multidrug-resistant pathogens is reported. 4-Alkyliden-azetidin-2-ones were easily obtained using an original protocol starting from 4-acetoxy-azetidinones and diazoesters. Parent compounds were further elaborated to obtain a small library of 4-alkylidene derivatives.

Engineered phenylalanine dehydrogenase in organic solvents: homogeneous and biphasic enzymatic reactions.

The use of engineered phenylalanine dehydrogenase N145A supported on Celite for the reductive amination of phenylpyruvic acid in homogeneous and biphasic aqueous-organic solvents is reported. The results indicate that the immobilised biocatalyst is remarkably robust, even in the presence of high concentrations of polar or non-polar organic solvents such as acetone, methanol, n-hexane, toluene and methylene chloride. Cofactor regeneration with alcohol dehydrogenase from Saccharomyces cerevisiae and ethanol was successfully explored.

4-Alkyliden-beta-lactams conjugated to polyphenols: synthesis and inhibitory activity.

A series of compounds combining the beta-lactam and polyphenol scaffold have been prepared and evaluated for inhibition of human leukocyte elastase and matrix metallo-proteases MMP-2 and MMP-9. The design of these compounds has been based on the 'overlapping-type' strategy where two pharmacophores are linked in a single molecule. The most powerful compound against elastase was an N-galloyl-4-alkyliden beta-lactam, [3-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-4-oxo-1-(3,4,5-tris-benzyloxy-benzoyl)-azetidin-2-ylidene]-acetic acid ethylester, with an IC50 of 0.

Can the pi-facial selectivity of solvation be predicted by atomistic simulation?

This work is concerned with the rationalization and prediction of solvent and temperature effects in nucleophilic addition to alpha-chiral carbonyl compounds leading to facial diastereoselectivity. We study, using molecular dynamics simulations, the facial solvation of (R)-2-phenyl-propionaldehyde in n-pentane and n-octane at a number of temperatures and compare it with experimental selectivity data for the nBuLi addition leading to syn- and anti-(2R)-2-phenyl-3-heptanol, which give nonlinear Eyring plots with the presence of inversion temperatures. We have found from simulations that the facial solvation changes with temperature and alkane.

4-alkylidene-azetidin-2-ones: novel inhibitors of leukocyte elastase and gelatinase.

In addition to their antibiotic potency, beta-lactams have recently been investigated as inhibitors of serine proteinase such as leukocyte elastase (LE), released by inflammatory cells. We describe the synthesis of a series of 4-alkylidene-beta-lactams, and investigate how substitutions on C-3, C-4, and N-1 of the beta-lactam ring affect the activity of human LE and gelatinases MMP-2 and MMP-9. LE activity was measured using a chromogenic substrate, while gelatin-zymography assay was used to evaluate gelatinase activity.

Chiral aldehydes in hydrocarbons: diastereoselective nucleophilic addition, NMR, and CD spectroscopy reveal dynamic solvation effects.

Temperature-dependent studies on the diastereoselective nucleophilic addition of n- BuLi to alpha-chiral aldehydes as (S)-O-(t-butyl-dimethylsilyl)lactal, (S)-O-(t-butyl-dimethylsilyl) mandelic aldehyde, and (R)-2-phenylpropanal in n-decane and n-dodecane reveal dynamic solvation phenomena with the presence of inversion temperatures (T(inv)) in the Eyring plots of ln (anti/syn) vs. 1/ T. These dynamic solvent effects were disclosed by temperature-dependent studies of the (13)C NMR, CD, and UV spectra of the starting aldehydes in solution of n-decane and n-dodecane.