Combinatorial and Evolution-Based Methods in the Creation of Enantioselective Catalysts

Abstract

Combinatorial methods in the development of enantioselective homogeneous catalysts constitute a new branch of catalysis research. The goal is to prepare libraries of potential asymmetric catalysts, rather than choosing the traditional one-catalyst-at-a-time approach. Several conceptional advancements have been reported in the parallel preparation of chiral ligands. Currently the most meaningful systems constitute modularly constructed ligands on solid supports, which allow high degrees of structural diversity and thus the maximum probability of finding enantioselective catalysts or even new types of ligands for asymmetric catalysis. Search strategies have been developed which amongst other things, lead to catalysts not likely to have been discovered by traditional methods. Genuine application of such strategies involve thousands of catalysts and require high-throughput screening systems capable of assaying enantioselectivity. The first high-throughput ee-screening systems were in fact developed for use in the directed evolution of enantioselective enzymes, a process based on "evolution in the test tube" in which the appropriate methods of random mutagenesis, gene expression, and ee assays are combined. Since no screening system is likely to be universal, different approaches are necessary. Thus far these include assays based on UV/Vis, fluorescence, circular dichroism, mass spectrometry, and even modified gas chromatography as well as special forms of capillary electrophoresis. One of the most efficient systems involves the concept of the mass-spectrometric detection of deuterium-labeled pseudo-enantiomers and pseudo-prochiral compounds with which about 1000 exact ee determinations can be achieved per day, although the assay is restricted to kinetic resolution and/or reactions of prochiral compounds bearing enantiotopic groups. Super-high-throughput screening for enantioselectivity is possible in many cases by making use of chirally modified capillary array electrophoresis in a parallel step. Accordingly, 7000 to 30 000 ee determinations can be carried out per day. These and other analytical developments are expected to stimulate further research in the combinatorial search for asymmetric homogeneous catalysts and in the directed evolution of enantioselective enzymes for use in organic chemistry.

Metagenomic approach for the isolation of a novel low-temperature-active lipase from uncultured bacteria of marine sediment

“…Whereas carboxylesterases preferentially hydrolyse water-soluble esters and triacylglycerols with fatty acids shorter than C 6 , lipases prefer water-insoluble substrates, typically triacylglycerols with medium-to long-chain fatty acids (Z10 carbon atoms) Pandey et al, 1999;Jaeger & Eggert, 2002). Features such as enantio-/stereoselectivity, discriminating between enantiomers in racemic pairs (Reetz, 2001), broad substrate specificity, and activity in organic solvents (Gupta et al, 2004) make lipases useful in synthetic organic chemistry and in other industrial processes, such as the production of pharmaceuticals (Reetz, 2001). Features such as enantio-/stereoselectivity, discriminating between enantiomers in racemic pairs (Reetz, 2001), broad substrate specificity, and activity in organic solvents (Gupta et al, 2004) make lipases useful in synthetic organic chemistry and in other industrial processes, such as the production of pharmaceuticals (Reetz, 2001).…”

Engineering Novel and Improved Biocatalysts by Cell Surface Display

“…Thus, linking high enantioselectivity of a beneficial mutant to the cell expressing that mutant is difficult. 106 A number of studies have been devoted to the development of high-throughput screening systems with the ability to elucidate the relationship between enzyme mutations and the resulting product selectivity 107–112 (Table 2). One of the more promising studies regarding enantioselectivity engineering was performed by developing a novel, high-throughput screening system called enzyme screening by covalent attachment of products via enzyme display (ES-CAPED).…”

Supramolecular Host-Guest Asymmetric Induction In Organic Synthesis

“…As a solution to this problem, many researchers [42][43][44] have introduced alternatives to the classical bidentate-ligand synthesis by the self-assembly of monodentate to bidentate ligands through complementary hydrogen bonding. Breit and co-workers [45] reported the development of the first library of self-assembled ligands based on new heterocyclic platforms analogous to the A-T base pair (Scheme 13) [46].…”