Asymmetric synthesis enzymatic reactions

The practice and theory of enantioselective CGC was comprehensively reviewed. Racemic oxygen-, nitrogen- and sulfur-containing selectands can be separated without prior derivatization into enantiomers by CGC on optically active metal(II) bis[3-(perfluoro-acyl)-(lR)-camphorate] (61) selectors. Peak inversion is obtained when the selectors with opposite configuration are employed. Applications pertain to chiral analysis in asymmetric synthesis, enzymatic reactions, pheromone and flavor chemistry. ... 

In an asymmetric synthesis, the enantiomeric composition of the product remains constant as the reaction proceeds. In practice, ho vever, many enzymatic desymmetrizations undergo a subsequent kinetic resolution as illustrated in Figure 6.5. For instance, hydrolysis of a prochiral diacetate first gives the chiral monoalcohol monoester, but this product is also a substrate for the hydrolase, resulting in the production of... 

A classical approach to driving the unfavorable equilibrium of an enzymatic process is to couple it to another, irreversible enzymatic process. Griengl and coworkers have applied this concept to asymmetric synthesis of 1,2-amino alcohols with a threonine aldolase [24] (Figure 6.7). While the equilibrium in threonine aldolase reactions typically does not favor the synthetic direction, and the bond formation leads to nearly equal amounts of two diastereomers, coupling the aldolase reaction with a selective tyrosine decarboxylase leads to irreversible formation of aryl amino alcohols in reasonable enantiomeric excess via a dynamic kinetic asymmetric transformation. A one-pot, two-enzyme asymmetric synthesis of amino alcohols, including noradrenaline and octopamine, from readily available starting materials was developed [25]. 

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. 

Reactions catalyzed by enzymes or enzyme systems exhibit far greater specificities than more conventional organic reactions. Among these specificities which enzymatic reactions possess, stereospecificity is one of the most excellent. To overcome the disadvantage of a conventional synthetic process, i.e., the troublesome resolution of a racemic mixture, microbial transformation with enzymes possessing stereospecificities has been appHed to the asymmetric synthesis of optically active substances [1-10]. C3- and C4-synthetic units (synthons, building blocks), such as epichlorohydrin (EP), 2,3-dichloro-l-propanol (2,3-DCP), glycidol (GLD), 3-chloro-l,2-propanediol (3-CPD), 4-chloro-... 

Oxidoreductases are, after lipases, the second most-used kinds of biocatalysts in organic synthesis. Two main processes have been reported using this type of enzymes-bioreduction of carbonyl groups [39] and biohydroxylation of non-activated substrates [40]. However, in recent few years other processes such as deracemization of amines or alcohols [41] and enzymatic Baeyer-Villiger reactions of ketones and aldehydes [42] are being used with great utility in asymmetric synthesis. 

Desymmetrization of an achiral, symmetrical molecule through a catalytic process is a potentially powerful but relatively unexplored concept for asymmetric synthesis. Whereas the ability of enzymes to differentiate enantiotopic functional groups is well-known [27], little has been explored on a similar ability of non-enzymatic catalysts, particularly for C-C bond-forming processes. The asymmetric desymmetrization through the catalytic glyoxylate-ene reaction of prochiral ene substrates with planar symmetry provides an efficient access to remote [28] and internal [29] asymmetric induction (Scheme 8C.10) [30]. The (2/ ,5S)-s> i-product is obtained with >99% ee and >99% diastereoselectivity. The diene thus obtained can be transformed to a more functionalized compound in a regioselective and diastereoselective manner. 

The facile asymmetric synthesis of a-amino acids usually inaccessible by enzymatic processes becomes feasible by employing appropriate electrophiles such as ortho-disubstituted benzyl bromides. In the reaction with simple alkyl halides such as ethyl iodide, the use of aqueous cesium hydroxide (CsOH) as a basic phase at a lower reaction temperature is generally recommended [7e]. 

Simons, C., Hanefeld, U., Arends, I., Sheldon, R. A. and Maschmeyer, T. Towards genuine cascade reactions asymmetric synthesis using combined chemo-enzymatic catalysts, Top. Catal., in press. 

The enzymatic reduction of a thiocarbonyl compound has been investigated [159] for the first time, in order to provide a new route for enan-tiopure thiols, molecules which are currently needed for asymmetric synthesis. Reaction of easily available /1-thioxoesters with baker s yeast under classical conditions did furnish the expected thiols, but with lower enantiomeric purity and moderate conversion rate, due to the competitive hydrolysis of the thioxo group into a carbonyl leading to an alcohol. However, conditions (ethyl acrylate, dry yeast) were found to improve the production of (S)-ethyl 3-mercaptobutanoate. Cyclic thioxo esters led to high stereoselectivity of cis (1S,2S) products, but with moderate chemical yields. 

The application of asymmetric peptides is much less frequently described (Cai et al., 2001). The production of asymmetric RhllO-labeled to-substituted peptides is much more difficult because the synthesis requires significantly more steps than required for symmetrically to-substituted peptides. The critical step is the synthesis of the mono-substituted intermediate product RhllO-ZYX with low yield in most cases (personal communication). However, due to the fact that a strong fluorescence increase is only observed after the fluorophore has been cleaved off from both peptide chains of the symmetrically to-substituted substrate (two-step proteolysis), the kinetics of the enzymatic reaction can be followed more accurately and easily with peptides comprising only one copy of the scissile bond. 

This collection begins with a series of three procedures illustrating important new methods for preparation of enantiomerically pure substances via asymmetric catalysis. The preparation of 3-[(1S)-1,2-DIHYDROXYETHYL]-1,5-DIHYDRO-3H-2.4-BENZODIOXEPINE describes, in detail, the use of dihydroquinidine 9-0-(9 -phenanthryl) ether as a chiral ligand in the asymmetric dihydroxylation reaction which is broadly applicable for the preparation of chiral dlols from monosubstituted olefins. The product, an acetal of (S)-glyceralcfehyde, is itself a potentially valuable synthetic intermediate. The assembly of a chiral rhodium catalyst from methyl 2-pyrrolidone 5(R)-carboxylate and its use in the intramolecular asymmetric cyclopropanation of an allyl diazoacetate is illustrated in the preparation of (1R.5S)-()-6,6-DIMETHYL-3-OXABICYCLO[3.1. OJHEXAN-2-ONE. Another important general method for asymmetric synthesis involves the desymmetrization of bifunctional meso compounds as is described for the enantioselective enzymatic hydrolysis of cis-3,5-diacetoxycyclopentene to (1R,4S)-(+)-4-HYDROXY-2-CYCLOPENTENYL ACETATE. This intermediate is especially valuable as a precursor of both antipodes (4R) (+)- and (4S)-(-)-tert-BUTYLDIMETHYLSILOXY-2-CYCLOPENTEN-1-ONE, important intermediates in the synthesis of enantiomerically pure prostanoid derivatives and other classes of natural substances, whose preparation is detailed in accompanying procedures. 

Catalytic aldol reactions are among the most useful synthetic methods for highly stereo-controlled asymmetric synthesis. In this account we discuss the recent development of a novel synthetic technique which uses tandem enzyme catalysis for the bi-directional chain elongation of simple dialdehydes and related multi-step procedures. The scope and the limitations of multiple one-pot enzymatic C-C bond formations is evaluated for the synthesis of unique and structurally complex carbohydrate-related compounds that may be regarded as metabolically stable mimetics of oligosaccharides and that are thus of interest because of their potential bioactivity. 

Asymmetric synthesis is the chemical or biochemical conversion of a prochiral substrate to a chiral product. In general, this involves reaction at an unsaturated site having prochiral faces (C=C, C=N, C=0, etc.) to give one product enantiomer in excess over another. The reagents effecting the asymmetric synthesis are used either catalytically or stoichiometrically. Oearly, the former is to be preferred, for economic reasons, when applicable. The reagents can be either chemical or enzymatic. 

Enzymatic reduction, oxidation, ligase, or lyase reactions, especially, provide us with numerous examples in which prochiral precursor molecules are stereo-selectively functionalized. Ajinomoto s S-tyrosinase-catalyzed L-dopa process [112], the formation of L-camitine from butyro- or crotonobetaine invented by Lonza [113], and the IBIS naproxen route oxidizing an isopropylnaphthalene to an (S)-2-arylpropionic acid are representative, classic examples for many successful applications of enzymatic asymmetric synthesis on an industrial scale. A selection of recent industrial contributions in this field are summarized below. 

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