Biocatalytic Approaches for the Stereoselective Synthesis of Chiral Building Blocks

This thesis presents a selection of the scientific activity gained by the candidate over the course of the last 14 years, including exclusively scientific results obtained after the public defence of her PhD thesis, as well as the brief description of some maine future research directions. The abilitation thesis contains 5 chapters. After the first introduction chapter, in the second (Enantiotope selective biotransformations) and in the third (Enantiomer selective processes) chapters, the main achieved scientific results are presented. In the chapter 4 some applicative results are described.The fifth chapter contains new approaches regarding biocatalysis. Chapter 2 presents the synthesis of heteroaryl-ethanols and ethanediols with Saccharomyces cerevisiae cells, under the action of the present dehydrogenases (Y-ADHs) and hydrolases. While the reduction of methyl-heteroaryl prochiral ketones undergoes selectively, resulting in the substituted (S)-ethanols, by an appropriate α-derivatization and subsequent biotransformation with baker’s yeast cells, both enantiomers of heteroaryl-ethane diols were prepared. With the aim to synthesized the opposite enantiomer of the biocatalytically obtained enantiopure ethanols, the Mitsunobu reaction was used as a tool to perform a controled stereoinversion, whithout significant loss in enantiomeric excess and with high yields. Chapter 3 contains selected results obtained in the field of enzymatic kinetic resolution of racemic heteroaryl-ethanols, -hydroxy acids and -amines. As target compounds, important structures in drug synthesis like phenothiazin, (benzo)furan and (benzo)thiophene, as well as thiazole based chiral building blocks, were used. To develope efficient procedures several optimization procedures were investigated. The effects of the biocatalyst, reaction temperature, type of solvent and acylating reagent upon the efficacy of each developed procedure was studied. In our first attempt, both enantiomerically enriched stereoisomers of various heteroaryl-1ethanols were prepared by lipase mediated kinetic resolutions of the racemic mixtures. The optimal conditions (enzyme, solvent, acylating agent, ratio, etc) were found in each case and used succesfully also in preparative scale scale biotransformations. Mechanism-based competition between the (R)-acetate (enzymatic acylation product), vinyl acetate (added acylating reagent) and acetic acid (enzymatic hydrolysis product) toward CAL-B, together with the residual water of the lipase were shown to be potential reasons for side reactions, which affected the course of the kinetic resolution of various furan-2-yl-ethanols. The versatility of β-hydroxycarboxylic acids and their esters make them valuable intermediates for the synthesis of many bioactive compounds. Multienzymatic procedures were developed for the synthesis of both enantiomers of some new optically pure heteroaryl-3hydroxypropanoic acids with N-substituted phenothiazinyl-, benzofuranyl and benzothiophenyl moyeties. As an important theoretical approach, the enantiopreference of lipases A and B from Candida antarctica in the kinetic resolutions of these derivatives was also presented. Next, the enzymatic resolution of some racemic heteroaryl-ethane amines was is presented.