Yuri L. Khmelnitsky

Microwave-assisted synthesis of substituted imidazoles on a solid support under solvent-free conditions

Abstract The solvent-free microwave-assisted synthesis of 2,4,5-substituted and 1,2,4,5-substituted imidazoles is reported. Imidazoles are obtained as a result of the condensation of a 1,2-dicarbonyl compound with an aldehyde and an amine using acidic alumina impregnated with ammonium acetate as the solid support.

Biocatalysis in nonaqueous solvents

Biotransformation technologies have enjoyed a renewed interest from researchers and industry because of the progress made in the discovery and design of new, efficient biocatalysts for synthetic applications. Biocatalysis in nonaqueous media, which offers unique capabilities and thus plays a major role in biotransformation technologies, has made tremendous progress in recent years. On average, at least one paper dealing with biocatalysis in organic solvents is published every day. New, remarkable developments have taken place in several key areas of this exciting field during the past year.

Oxidative enzymes possess catalytic activity in systems with ionic liquids

Oxidative enzymes, laccase C from Trametes sp. and horseradish and soybean peroxidases, catalyzed oxidation reactions in systems with ionic liquids whose content varied from several volume percent to almost total non-aqueous ionic liquids. Similar to the effects produced by standard organic solvents used in non-aqueous enzymology, catalytic activity of the enzymes was decreased by adding a water-miscible ionic liquid, 4-methyl-N-butylpyridinium tetrafluoroborate, or by suspending the enzyme in a water-immiscible ionic liquid, 1-butyl-3-methylimdizaolium hexafluorophosphate. For the oxidation of anthracene, catalyzed by laccase C and assisted by a number of mediators, addition of 4-methyl-N-butylpyridinium tetrafluoroborate, instead of tert-butanol, increased the yield of the oxidation product several-fold.

Microwave assisted combinatorial chemistry synthesis of substituted pyridines

Abstract A new highly efficient MICROCOS technology (Microwave-assisted Combinatorial Synthesis) for generating combinatorial libraries is described. The technology is applied to the high throughput, automated, one-step, parallel synthesis of diverse substituted pyridines using the Hantzsch synthesis. The advantages of microwave-assisted chemistry for combinatorial synthesis include a broad range of available chemistries, simple reaction setup and product recovery readily amenable to automation, extremely short reaction times, and high product yields.

Combinatorial biocatalysis: a natural approach to drug discovery

Natures most potent molecules are produced by enzyme-catalysed reactions, coupled with the natural selection of those products that possess optimal biological activity. Combinatorial biocatalysis harnesses the natural diversity of enzymatic reactions for the iterative synthesis of organic libraries. Iterative reactions can be performed using isolated enzymes or whole cells, in natural and unnatural environments, and on substrates in solution or on a solid phase. Combinatorial biocatalysis is a powerful addition to the expanding array of combinatorial methods for the generation and optimization of lead compounds in drug discovery and development.

Relationship between surface hydrophilicity of a protein and its stability against denaturation by organic solvents

The stability of α‐chymotrypsin covalently modified with a strongly hydrophilic modifier, pyromellitic dianhydride, against solvent‐induced denaturation in water—organic solvent binary mixtures has been studied. It was found that the hydrophilization results in a strong stabilization of the enzyme against denaturation by organic solvents. The stabilizing effect is explained in terms of the enhanced ability of the hydrophilized enzyme to keep its hydration shell, which is indispensable for supporting the native protein conformation, from denaturing stripping by organic solvents

Regioselective enzymatic acylation as a tool for producing solution-phase combinatorial libraries

Abstract A simple combinatorial strategy for sequential regioselective enzymatic acylation of multifunctional lead compounds has been developed and demonstrated using a polyhydroxylated flavonoid, bergenin, as a model. The approach is based on the ability of different enzymes to regioselectively acylate different sites on a lead molecule without affecting other similar functional groups. In sharp contrast to enzymatic acylation, conventional chemical acylation methods showed almost complete lack of regioselectivity. The enzymatic strategy was applied successfully to produce a solution phase combinatorial library of 167 distinct selectively acylated derivatives of bergenin on a robotic workstation in a 96-well plate format. General applicability of the automated combinatorial biocatalysis strategy is discussed.

Lipase-catalyzed transamidation of non-activated amides in organic solvent

A novel biocatalytic reaction of transamidation of non-activated amides with amines is reported. Among 45 different lipolytic and proteolytic enzymes tested, only the lipase from Candida antarcticawas able to catalyze this reaction. The reaction proceeded with up to ca. 80% conversion in anhydrous methyl tert-butyl ether and worked with both N-substituted and unsubstituted amides. The biocatalytic transamidation is an equilibrium process and, therefore, higher conversions to the desired amide were achieved by using increased concentrations of the amine nucleophile.

The evolution of biotransformation technologies.

Biotransformation is a broad and growing field of biotechnology and encompasses both enzymatic and microbial biocatalysis. Progress has been made in research on the key drivers of biotransformations, including the isolation and characterization of microbes and their enzymes from, and their utilization in, extreme environments, the manipulation, alteration, and augmentation of metabolic pathways, and the use of combinatorial biosynthesis and biocatalytic methodologies for new compound development.

Phospholipase D-catalyzed transphosphatidylation in anhydrous organic solvents

A new reaction system suitable for phospholipase D (PLD)-catalyzed transphosphatidylation of alcohols with phosphatidylcholine under anhydrous conditions is reported. The key innovation of the reaction system is a cation-exchange resin serving as a scavenger for choline that forms as a byproduct in the transphosphatidylation reaction. Due to the absence of water in this system, the reaction path dramatically shifts in favor of the target transphosphatidylated product, whereas the undesirable side hydrolysis of phosphatidylcholine is completely suppressed, in contrast to commonly used biphasic water-organic systems. In addition, a salt activation technique is successfully applied to increase the catalytic activity of PLD in this anhydrous system. The new reaction system is successfully used for transphosphatidylation of a wide range of primary, secondary, and aromatic alcohols catalyzed by PLD from Streptomyces sp.