Enzyme catalyzed asymmetrization

Enzyme-Catalyzed Asymmetric Synthesis. The extent of kinetic resolution of racemates is determined by differences in the reaction rates for the two enantiomers. At the end of the reaction the faster reacting enantiomer is transformed, leaving the slower reacting enantiomer unchanged. It is apparent that the maximum product yield of any kinetic resolution caimot exceed 50%. 

Figure 10.36 Enzyme-catalyzed asymmetric synthesis of a pancratistatin analog using a naphthalene dioxygenase and RhuA-catalyzed aldolization for the creation of four contiguous stereocenters.

Chapters 2 through 6 introduced many asymmetric organic reactions catalyzed by small molecules, such as C-C bond formation, reduction, and oxidation reactions. Chapter 7 provided further examples of how asymmetric reactions are used in organic synthesis. This chapter starts with a general introduction to enzyme-catalyzed asymmetric organic reactions. 

This final chapter summarizes the enzyme-catalyzed asymmetric reactions and introduces some new developments in the area of asymmetric synthesis. Among the new developments, cooperative asymmetric catalysis is an important theme because it is commonly observed in enzymatic reactions. Understanding cooperative asymmetric catalysis not only makes it possible to design more enan-tioselective asymmetric synthesis reactions but also helps us to understand how mother nature contributes to the world. 

H. J. Gais, G. Btilow, A. Zatorski, M. Jentsch, P. Maidonis, H. Hemmerle, Enzyme-Catalyzed Asymmetric Synthesis. 8. Enantioselectivity of Pig Liver Esterase Catalyzed Hydrolyses of 4-Substituted meso Cyclopentane 1,2-Diesters , /. Org. Chem. 1989,54,5115 - 5122. 

Enantiomerically pure sulfoxides play an important role in asymmetric synthesis either as chiral building blocks or stereodirecting groups [156]. In the last years, metal- and enzyme-catalyzed asymmetric sulfoxidations have been developed for the preparation of optically active sulfoxides. Among the metal-catalyzed processes, the Kagan sulfoxidation [157] is the most efficient, in which the sulfide is enantioselectively oxidized by Ti(OzPr)4/tBuOOH in the presence of tartrate as chirality source. However, only alkyl aryl sulfides may be oxidized by this system in high enantiomeric excesses, and poor enantioselectivities were observed for dialkyl sulfides. 

En/ymes catalyze a broad spectrum of reactions. They often require such coen/yincs as the nicotinamides NADPH and NADH or a nucleoside triphosphate like ATP together with cofactors, usually metal ions. Hydrolases, including PLE, are exceptions in this regard. They complete their tasks without the need for coenzymes. Enzyme-catalyzed asymmetric syntheses can be conducted either with cell-free enzymes or with microbial systems (i.e., enzymes included within cells).14... 

Fn/ymes display a number of characteristic features 17 They catalyze cnanlioselective reactions, are usually substrate specific, usually display their gieatest catalytic activity in aqueous systems, and are generated in nature in only one asymmetric form. The greatest advantage of enzyme-catalyzed asymmetric synthesis is that the availability of the correct enzyme makes it possible to prepare large amounts of an enantiomericaJly pure compound with relatively little effort... 

An appropriate precursor molecule 13 is accessible by condensation of the three components quinoline 11, the aldehyde 2, and cyanoa-cetamide (3). The stereogenic center at C-20 is introduced in the form of aldehyde 2 very early in the process by an enzyme-catalyzed asymmetric hydrolysis with pig liver esterase. 

Adam W, Hoch U, Saha-Moller CR, Schreier P (1995) Enzyme-catalyzed asymmetric synthesis kinetic resolution of racemic hydroperoxides by enantioselective reduction to alcohols with horseradish peroxidase and guiacol. J Am Chem Soc 117 11898-11901... 

Two approaches were studied to obtain (R)-l,3-BDO. The first was based on an enzyme-catalyzed asymmetric reduction of 4-hydroxy-2-butanone, and the second was based on enantioselective oxidation of the undesirable (S)-l,3-BDO in the racemate. As a result of screening for yeasts, fungi, and bacteria, the enzymatic resolution of racemic 1,3-BDO by Candida parapsilosis IFO 1396, which showed differential rates of oxidation for two enantiomers, was found to be the most practical process to produce (R)-l,3-BDO with high enantiomeric excess and yield. 

Enzyme-catalyzed asymmetric syntheses involve two types of reactions (1) the asymmetric reduction of a prochiral center and (2) the resolution of a racemic material by selective reaction of one enantiomer. Both types arc demonstrated in the syntheses of chiral insect phermones reviewed by Sonnet (1988). Enzymes that have broad substrate specificity and still retain other selectivity features can be versatile and powerful catalysts. In addition, enzyme catalysis is applicable not only in aqueous media but also in nonaqueous solvents, including supercritical fluids (20-22), In all cases, however, enzymes require water to function as catalysts. A small amount of water, corresponding to a monolayer on the enzyme molecule, is usually sufficient (20),... 

A.l. Humphrey, S.F. Parsons, M.E.B. Smith, N.l. Turner, Synthesis of a novel N-hydroxypyrro-lidine using enzyme catalyzed asymmetric carhon-carhon bond synthesis. Tetrahedron Lett. 41 (2000) 4481-4485. 

H. Groger, S. Borchert, M. Krausser, W. Hummel, Enzyme-catalyzed asymmetric reduction of ketones, in M. C. Flickinger (Ed.) Encyclopedia of Industrial Biotechnology, Bioprocess, Bioseparation, and Cell Technology, John Wiley Sons, Inc., Hoboken, 2010, pp. 2094-2110. 

Historically, enzyme catalysis has played a highly prominent role, with the first enzyme-catalyzed asymmetric addition of HCN to aldehydes dating back to 1908 [167]. A wide range of both aromatic and aliphatic ketones are suitable substrates and produce cyanohydrins of high optical purity. The most readily available and hence most commonly employed enzyme for asymmetric cyanohydrin formation is (R)-hydroxynitrile lyase isolated from almonds. Recent cloning and over-expression techniques have also made a number of (S)-hydroxynitrile lyases available for organic synthesis [164, 165]. This was utilized in Griengl s synthesis of coriolic acid (255), a natural product that displays calcium ionophoric activity and acts as a prostacyclin mimic (Scheme 2.32) [168]. Thus, an (S)-hydroxynitrile lyase was cloned from rubber trees (Hevea brasiliensis), overexpressed in Pichia pastoris, and used to provide cyanohydrin 254 in 99 % ee. 

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