Catalytic asymmetric synthesis enzyme selection

In a catalytic asymmetric reaction, a small amount of an enantio-merically pure catalyst, either an enzyme or a synthetic, soluble transition metal complex, is used to produce large quantities of an optically active compound from a precursor that may be chiral or achiral. In recent years, synthetic chemists have developed numerous catalytic asymmetric reaction processes that transform prochiral substrates into chiral products with impressive margins of enantio-selectivity, feats that were once the exclusive domain of enzymes.56 These developments have had an enormous impact on academic and industrial organic synthesis. In the pharmaceutical industry, where there is a great emphasis on the production of enantiomeri-cally pure compounds, effective catalytic asymmetric reactions are particularly valuable because one molecule of an enantiomerically pure catalyst can, in principle, direct the stereoselective formation of millions of chiral product molecules. Such reactions are thus highly productive and economical, and, when applicable, they make the wasteful practice of racemate resolution obsolete. 

Naturally occurring redox enzymes have been successfully exploited for asymmetric synthesis for some years.1 Although impressive chemo-, regio-, and enantioselectivities have been achieved in some cases, these biocatalysts have prescribed selectivity and often require expensive cofactors that must be recycled for preparative work. Catalytic antibodies offer an attractive alternative, since they are not limited a priori by Nature s choices. Thus the need for cofactor recycling can be circumvented through the use of inexpensive oxidants and reductants, and, as we have seen above, selectivity can be tailored through appropriate hapten design. 

Sih CJ, Chen C-S (1984) Microbial asymmetric catalysis - Enantio-selective reduction of ketones. Angew Chem Int Ed Engl 23 570-578 Slama J, Oruganti SR, Kaiser ET (1981) Semisynthetic enzymes Synthesis of a new flavopapain with high catalytic efficiency. J Am Chem Soc 103 6211-6213... 

Examples of this kind of enantiomorphic or chiral selectivity are now being found in organic synthesis. Asymmetric synthesis, for example, has been demonstrated with stereo-controlled Michael addition in the synthesis of beta-lactams using chiral catalysts, where an acyl ligand such as acetyl is bound to cyclo-pentadiene carbonyl triphenylphosphine. Essentially complete enantiomorphic selectivity has been achieved in this Michael addition synthesis. Another case is enantio-morhic ketone reduction in ethylbenzene reduction in the ethylation of benzaldehyde. Using chiral catalysts, 97% selectivity has been achieved. Closely related research involves the making of catalytic antibodies and hybrid enzymes. ... 

In order to generate more structurally relevant biomimetics for dinuclear metallohydrolases much effort has been devoted to the synthesis of asymmetric ligands. These ligands are considered to be more suitable models for the asymmetric coordination environment found in enzymatic systems. Nordlander et al. proposed that asymmetric complexes are not only more appropriate functional models for the active site of phosphoesterase enzymes, but also that they exhibit enhanced catalytic rates compared with their symmetric counterparts [1-3]. A selection of ligands used to generate purple acid phosphatase [1, 4, 5, 6-10], phosphoesterase [11], urease [12, 13], catechol oxidase [14] and manganese catalase biomimetics [15, 16] is displayed in Fig. 7.1. 

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