Microbial asymmetric reductions

Optically Active PO. The synthesis of optically pure PO has been accompHshed by microbial asymmetric reduction of chloroacetone [78-95-5] (90). (3)-2-Meth5loxirane [16088-62-3] (PO) can be prepared in 90% optical purity from ethyl (3)-lactate in 44% overall yield (91). This method gives good optical purity from inexpensive reagents without the need for chromatography or a fermentation step. (3)-PO is available from Aldrich Chemical Company, having a specific rotation [0 ] ° 7.2 (c = 1, CHCl ). 

Production of Chiral 4-Chloro-3-Hydroxybutanoate Ethyl Ester by Microbial Asymmetric Reduction of 4-Chloroacetoacetate... 

The development of a novel production system for D-pantoyl lactone (which is a lactone compound carrying a chiral hydroxy group and a chiral intermediate for the commercial production of D-pantothenate) by microbial asymmetric reduction has been undertaken. D-pantothenate is mainly used in various pharmaceutical products and as an animal feed additive, the current world production of calcium pantothenate being about 6,000 tons per year. Conventional commercial production of D-pantoyl lactone has depended exclusively on chemical synthesis involving optical resolution of a chemically synthesized racemic pantoyl lactone, which is the most troublesome step of the pantothenate synthesis process. 

Shimizu, S., Kataoka, M., Morishita, A., Katoh, M., Morikawa, T., Miyoshi, T., and Yamada, H. 1990b. Microbial asymmetric reduction of ethyl 4-chloro-3-oxobutanoate to optically active ethyl 4-chloro-3-hydroxybutanoate. Biotechnol. Lett., 72,593-596. 

R. A. Holt, Microbial asymmetric reduction in the synthesis of a drug intermediate, Chimica Oggi 1996, 9, 17-20. 

Yeast contains a variety of enzymes, and in some cases use of a single purified enzyme is preferable. These arc divided into oxidorcductases, transferases, hydrolases, lyases, isomerases, and lipases. Many of these are commercially available (but expensive). Purified reductases usually require expensive cofactors. In addition individual microbes can be used as biocatalysts. A general review of microbial asymmetric reductions is available.5 These reductions can be the opposite of those of yeast. 

Li, Y.-N., Shi, X.-A., Zong, M.-H. et al. (2007) Asymmetric reduction of 2-octanone in water/organic solvent biphasic system with baker s yeast FD-12. Enzyme and Microbial Technology, 40, 1305-1311. 

Sih, C.J., Chen, C.S. Microbial asymmetric catalysis - enantioselection reduction of ketones. Angew. Chem. Int. Ed. Engl. 1984, 23 570-578. 

Microbial Asymmetric Catalysis - Enantioselective Reduction of Ketones"... 

The most popular methods of preparing optically active l-octyn-3-ol involve asymmetric reduction of l-octyn-3-one with optlcally-active alcohol complexes of lithium aluminum hydride or aluminum hydride. These methods give optical purities and chemical yields similar to the method reported above. A disadvantage of these metal-hydride methods is that some require exotic chiral alcohols that are not readily available in both enantiomeric forms. Other methods include optical resolution of the racemic propargyl alcohol (100 ee) (and Note 11) and microbial asymmetric hydrolysis of the propargyl acetates (-15% ee for l-heptyn-3-ol)... 

Chiral alcohols are some of the most important chiral building blocks for the production of pharmaceuticals. The creation of chiral alcohols through the asymmetric reduction of prochiral carbonyl compounds using biocatalysts, such as microbial cells and commercially available oxidoreductases, has been... 

Although these microbial reactions may substitute for chemical resolution methods, they likewise have the inherent disadvantage that only one half of the material is theoretically utilizable, for the substrate is already chiral. It is therefore preferable to design substrates with pro-chiral centers suitable for microbial asymmetric inductions. Examples that have been applied in the prostaglandin area follow. Reduction of triketone 40 with Dipodascus uninucleatus and Mucor rommanianus furnished the (R) and (S) alcohols (41 and 42) respectively. 6 The (R) alcohol (41) was then chemically converted into 43, a key synthon for prostaglandin synthesis via conjugate addition. 

Enzymes from various sources have been used for asymmetric reductions in organic synthesis. Microorganisms are the most important sources. There are a huge number of species (mostly in soil), containing a variety of enzymes. Commercially available microbial dehydrogenases are alcohol dehydrogenases from yeast, Ther-moanaerobium brockii (TBADH), and the hydroxysteroid dehydrogenase from Pseudomonas testosteroni. 

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... 

Kawai, Y, Saitou, K., Hida, K., Dao, D.H., and Ohno, A. (1996) Stereochemical control in microbial reduction. XXVlll. Asymmetric reduction of a, 3-unsaturated ketones with bakers yeast. Bull. Chem. 

A 2 1 (- )-90-LAH reagent was employed in the asymmetric synthesis of a cij-diol (91) by reduction of c/j-2-acetoxy-6-phenylcyclohexanone (99,100). Diol 91 is of interest as the tetrahydro derivative of a metabolite obtained from the microbial oxidation of biphenyl. Diol 91 was obtained in 46% e.e. as determined by NMR in the presence of a chiral shift reagent. It was shown to have the absolute stereochemistry (lS,2/ )-dihydroxy-3(S)-phenylcyclohexane by oxidation to ( + )-2-(S)-phenyladipic acid of known absolute stereochemistry. 

Microbial reduction has been recognized for decades as a laboratory method of preparing alcohols from ketones with exquisite enantioselectivity. The baker s yeast system represents one of the better known examples of biocatalysis, taught on many undergraduate chemistry courses. Numerous other microorganisms also produce the ADH enzymes (KREDs) responsible for asymmetric ketone reduction, and so suitable biocatalysts have traditionally been identified by extensive microbial screening. Homann et have... 

Gelo-Pujic, M., Le Guyader, F. and Schlama, T., Microbial and homogenous asymmetric catalysis in the reduction of l-[3,5-bis(trifluoromethyl)phenyl]ethanone. Tetrahedron Asymm. 2006, 17, 2000-2005. 

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