Enantioselective microbial oxidations

An enzymatic reaction of some synthetic importance is the enantioselective oxidation of meso diols by horse liver alcohol dehydrogenase HLADH.t i] Some representative examples follow  

There are two interesting features to the reactiori. First, HLADH accomplishes two oxidations, to the hemiacetal and thence to the lactone. Second, as in the natural system (a horse), the four hydrogens from the substrate end up on the flavin mononucleotide cofactor (FMN). The NAD is recycled, and is therefore only needed in catalytic amount. 

The enantiomerically pure lactones which result from HLADH oxidations can be transformed by standard chemistry into valuable chiral units such as (90). 

The humble soil bacteria of Pseudomonas species are capable of effecting a variety of enantiospecific cw-dihydroxylations of alkenes and aromatics, some of which have no equivalent in ordinary organic 

The product from Pseudomonas oxidation of toluene can be converted in only three steps to a prostaglandin intermediate (91). 

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Many further important natural product syntheses are covered by the aforementioned review. Particularly noteworthy amongst them are Hudlicky s syntheses of conduramines [522] and (+)-lycoricidine [523] since they employ enantioselective microbial oxidations of halobenzenes as source of chirality. Racemic lycoricidine has also been prepared by Martin et al. this synthesis exhibits an interesting Heck cyclisation as key step in addition to the hetero Diels-... 

The catalyst efficiency of these hydroalumination varies from a turnover number (TON) of 20-91. It is possible that the catalyst is deactivated by the presence of oxygen and water. Examination of the 31P NMR spectrum of the catalyst indicates that the phosphine monoxide and dioxide are formed in the presence of nickel prior to the addition of the substrate. Rigorous exclusion of oxygen and water is necessary in all these reactions. The enantioselective nickel-catalyzed hydroalumination route to dihydronaphthalenols may prove to be particularly important. Only one other method has been reported for the enantioselective syntheses of these compounds microbial oxidation of dihydronaphthalene by Pseudomonas putida UV4 generates the dihydronaphthalenol in 60% yield and >95% ee.1... 

Cyclohexanone and cyclopentanone monooxygenases have been used in the microbial BV oxidation of prochiral bicycloketones. A significant difference in behaviour of [3.3.0] and [4.3.0] substrates has been analysed by high-level DFT calculations.345 Al-BINOL complexes catalyse the enantioselective BV oxidation of cyclobutanones to give the corresponding y-butyrolactones in up to 84% ee.346 Advances in the enantioselective metal-catalysed reaction have been reviewed, especially for lactone preparation.347... 

T. Hudlicky, H. Luna, G. Barbieri, and L. D. Kwart, Enantioselective synthesis through microbial oxidation of arenes. 

Hudlicky, T. Reed, J. W. An Evolutionary Rerspective of Microbial Oxidations of Aromatic Compounds in Enantioselective Synthesis History, Current Status, and Rerspectives,... 

Use of the chiral pool typically requires a series of subsequent transformations to achieve the substitution pattern desired and sometimes may be limited by the availability of only one enantiomer. Microbial oxidations of benzene derivatives have provided an excellent route to cyclohexadienediols in enantiomerically pure form. Although this provides only one enantiomer, synthetic methods have been devised to circumvent this problem [36]. Far fewer methods exist for the enantioselective synthesis of cycloheptenes for which there exists no reaction analagous to the Diels-Alder process [37,38,39,40,41,42]. The enantioselective hydroalumination route to dihydronapthalenols may prove to be particularly important. Only one other method has been reported for the enantioselective synthesis of these compounds microbial oxidation of dihydronaphthalene by P. putida generates the dihydronaphthalenol in >95% ee and 60% yield... 

Hudlicky, T., H. Luna, G. Barbieri, and L.D. Kwart. 1988. Enantioselective synthesis through microbial oxidation of arenes. 1. Efficient preparation of terpene and prostanoid synthons. /. Am. Chem. Soc. 110 4735-4741... 

Oxidation of Meso Diols. Asymmetric induction of meso and prochiral diols by lipases is very successful in the field of organic synthesis. Also it is well known that selective oxidation of prochiral or meso diols by HLADH provides oxidized products with a significant degree of enantioselectivity. However, it has not been reported that alcohol oxidases were applied to such types of oxidation. The microbial oxidation of meso diols by Candida boidinii SA051 was carried out and gave optically active hydroxy ketones (Figure 8). 

Bicyclic haloketones, which were used for the synthesis of antiviral 6 -fluoro-carbocyclic nucleoside analogs, were resolved by using the same technique [1222] (Scheme 2.163). Both enantiomers were obtained with >95% optical purity. The exquisite enantioselectivity of the microbial oxidation is due to the presence of the halogen atoms since the dehalogenated bicyclo[2.2.1]heptan-2-one was... 

The oxidations accomplished by enzymes or microorganisms excel in regiospecificity, stereospecificity and enantioselectivity. The optical purity (enantiomeric excess) is usually very high nearing 100%. An unbelievably large number of enzymatic (or microbial) oxidations have been accomplished. 

This procedure describes an efficient method for the synthesis of >99% enantiomerically pure ethyl glycidate from L-serine. Although preparation of potassium glycidate via cyclization of 3-bromo-2-hydroxypropionic acid,2 and from 3-chloro-2-hydroxypropionic acid (obtained by microbial reduction of chloropyruvic acid)3 was previously reported, the corresponding ethyl ester was never described. An enantioselective synthesis of the 2,3-epoxy acid by oxidation of 2,3-epoxypropanol has also been reported.4... 

Active hits were found for every type of substrate screened, including those for which other known microbial epoxide hydrolases were ineffective. For example, hydrolysis of m-stilbenc oxide was not successful with several microbial EHs tested previously.4243 By contrast, several of our new enzymes actively hydrolyzed this substrate and exhibited excellent enantioselectivities (>99% ee). It is important to note that these enzymes were found to be capable of selectively hydrolyzing a wide range of mc.vo-cpoxidcs, including cyclic and acyclic alkyl- and aryl-substituted substrates. 

The oxidations accomplished by microorganisms or enzymes excel in regiospecificity, stereospecificity, and enantioselectivity. Although the yields of such oxidations are sometimes fair and even low, optical purity (enantiomeric excess) is usually very high and frequently 100%. The spectrum of microbial and enzymatic oxidations is unbelievably broad many different positions in steroidal rings can be hydroxylated by different microorganisms, and usually, only one diastereomer is formed. From achiral molecules, optically active compounds are generated. 

For the enantioselective preparations of chiral synthons, the most interesting oxidations are the hydroxylations of unactivated saturated carbons or carbon-carbon double bonds in alkene and arene systems, together with the oxidative transformations of various chemical functions. Of special interest is the enzymatic generation of enantiopure epoxides. This can be achieved by epoxidation of double bonds with cytochrome P450 mono-oxygenases, w-hydroxylases, or biotransformation with whole micro-organisms. Alternative approaches include the microbial reduction of a-haloketones, or the use of haloperoxi-dases and halohydrine epoxidases [128]. The enantioselective hydrolysis of several types of epoxides can be achieved with epoxide hydrolases (a relatively new class of enzymes). These enzymes give access to enantiopure epoxides and chiral diols by enantioselective hydrolysis of racemic epoxides or by stereoselective hydrolysis of meso-epoxides [128,129]. 

An enantioselective synthesis of (-)-nonactic acid and (+)-8-epi-nonactic acid using a microbial reduction step (baker s yeast) was reported <97SL159>. A highly enantiotopic-plane selective C-H oxidation of cyclic ethers (up to 82% ee) was achieved by using a (R.R)-(salen)manganese(Hl) complex as a catalyst <97SL836>. 

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