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Oxidation reactions are probably the most contaminant reactions among the different types of chemical reactions. The asymmetric epoxidation of unfunctionalized olefins is a fundamental for the preparation of valuable oxirane intermediates which have tremendous versatility for the preparation of a large number of compounds. Indene oxide is an important intermediate for the large scale synthesis of 2aminoindanol present in the protease inhibitor anti?HIV agent Crixivan. Currently, this reaction is carried out with an expensive chiral metal catalyst in a toxic halogenated solvent. Our ultimate goal is to develop an asymmetric oxidation that meets the principles of Green Chemistry.

We have developed a chemo?enzymatic oxidation of unfunctionalyzed olefins. The reaction is atom efficient because it employs stoichiometric amount of a small oxidant and it is carried out in a green solvent, and it is catalyzed by a biocatalyst. However, there are still some drawbacks for this green oxidation. The kinetics depends on the nature of the olefin and it can be very slow in some cases, and it produces racemic oxiranes. The purpose of our research is to solve these problems.

Microwave technology has been employed to accelerate many reactions. We investigated the use of this technology to accelerate the reaction rate in our chemo?enzymatic process. There are two reactions that occur in the chemo?enzymatic oxidation. Initially, the green solvent, ethyl acetate, reacts with a lipase, C. Antarctica lipase?B. An acetyl?enzyme complex is formed, which is attacked by the oxidant, hydrogen peroxide, and peoxyacetic acid is formed. The second reaction is the rate?limiting step, and it is the chemical oxidation of the olefin by the peroxyacetic acid formed in situ. We investigated the effect of microwaves and compared the reaction rates with conventional heat. We run the reaction at room temperature, and peroxyacetic acid is rapidly formed assisted by the enzyme. We, then heat up the reaction and observed an acceleration of the chemical oxidation, solving the problem of the kinetics of the reaction.

We have investigated the lipase?assisted asymmetric epoxidation of styrenes. We employed chiral N2,4?dinitrophenyl?proline and also (2R,3S,4R,5S)?(?)?2,3:4,6?di?O?isopropylidiene?2?keto?L?gulonic acid. These two chiral acids were reported by Goswami (Tetrahedron 2007, 63, 8735 and Tetrahedron: Asymmetry 2009, 20, 1295) to be able to react with a lipase and form chiral peroxycarboxylic acids capable to enantioselectively oxidize styrenes. These two acids did not react with any available lipase in our hands. We then, decided to prepare the corresponding chiral peroxycarboxylic acids employing a chemical way. We employed Miller’s conditions (J. Am. Chem. Soc. 2007, 129, 8710) to prepare these chiral acids. Indeed, we obtained styrene oxides using these Miller’s conditions and the chiral acids, but the styrene oxides obtained did not show any enantioselectivity.

We have also continued our work on the environmentally benign preparation of enantiomerically enriched caprolactones. The racemic caprolactones were prepared by the chemo?enzymatic oxidation of mono?substituted cyclohexanones via enzymatic perhydrolysis of ethyl acetate (Green Chem. 2007, 9, 459). Analytical methods were developed to analyze each caprolactone and hydroxyester derivative. These methods will be valuable to analyze results of enzymatic resolution.

We are very grateful to the PRF?ACS?GCI grant for supporting this research. We are collecting final data to write manuscripts which will be submitted promptly.