Substrate-product stereoselectivity

Substrate-product stereoselectivity the enantiomers of a drug which possess both asymmetrical and prochiral characteristics can undergo stereoselective metabolism, whereby a second chiral centre is introduced. Examples are the hydroxylation of perhexiline and the keto-reduction of warfarin. 

Dehydrogenases also represent a class of interesting enzymes since enantiose-lective reduction of ketones can lead to the production of enantiomerically pure secondary alcohols for the fine chemicals industry. Compared to liquid systems, in which the cofactor is often eliminated by the circulating phase in continuous systems, solid/gas catalysis can be highly suitable since it has been demonstrated that the cofactor is stable and its regeneration effective by addition of a second substrate. Also, stereoselective oxidation of secondary alcohols by these systems can help in the resolution of racemic mixtures. 

Oxidatively generated oxocarbenium ions have been used for intramolecular epoxide activation. Cascade reactions to form oligotetrahydrofuran products that demonstrated a strong preference for the exo-cyclization pathway were achieved in good yields when disubstituted epoxides were used as substrates. High stereoselectivity was observed in these reactions, with complementary diastereomers being formed from diastereomeric (g) epoxides.257... 

A number of families consisting of one or more distinct proteins comprise this enzyme group. Many xenobiotics are preferentially metabolized by a particular CYP or CYP family however, they may also be substrates for other CYPs. In these instances, the differences in enzyme activity are in the rate at which the oxidation occurs, the site of the modification on the parent compound (regioselectivity), and the steric configuration of the product (stereoselectivity). 

Mechanistical studies, for example, on the stereochemistry of the I -hydroxylation of (R)- and (S)-r-deuterated-phenylelhane by purified cytochrome P450lm2 have demonstrated that the product stereoselectivity most probably results from constraints of the substrate binding site provided by the protein environment, rather than the intrinsic hydroxylation mechanism of cytochrome P450 (White et al., 1986). 

Testa, B. (1988). Substrate and Product Stereoselectivity in Monooxygenase-Mediated Drug Activation and Inactivation, Biochem. Pharmacol., 37 85-92. 

There is good, if somewhat substrate-dependent, stereoselectivity when there is a substituent at the end of the alkene in the starting material. The E-ether 90 gives almost exclusively (98%) the stereochemistry shown in the product.13 The transition state has a half-chair conformation.14... 

Chirality may feature in one of the following ways (a) substrate stereoselectivity (b) product stereoselectivity (c) inversion of configuration (d) loss of chirality. 

Product stereoselectivity occurs when ste-reoisomeric metabolites are generated (l)dif-ferently (in quantitative and/or qualitative terms) and (2) from a single substrate with a suitable prochiral center or face. Examples of metabolic pathways producing new centers of chirality in substrate molecules include ketone reduction, reduction of carbon-carbon double bonds, hydroxylation of prochiral methylenes, oxygenationof tertiary amines to N-oxides, and oxygenation of sulfides to sulfoxides. Product stereoselectivity may be a re-... 

All the nitrile hydrolyzing enzymes described so far are intracellular and differ considerably with respect to substrate specificity, stereoselectivity, molecular mass and substrate and product inhibition characteristics. 

Substrate-controlled stereoselective codimerizations of unsubstituted and substituted methylenecyclopropanes with electron-deficient olefins have been described. Thus, as depicted in the following scheme, (diphenylmethylene)cyclopropane and isopropylidenecyclopropane undergo clean product A formation (distal C—C cleavage) with 2-substituted cyclopcntcnones under palladium(O) mediation63. 

In addition to the physicochemical factors that affect xenobiotic metabolism, stereochemical factors play an important role in the biotransformation of drugs. This involvement is not unexpected, because the xenobiotic-metabolizing enzymes also are the same enzymes that metabolize certain endogenous substrates, which for the most part are chiral molecules. Most of these enzymes show stereoselectivity but not stereospecificity in other words, one stereoisomer enters into biotransformation pathways preferentially but not exclusively. Metabolic stereochemical reactions can be categorized as follows substrate stereoselectivity, in which two enantiomers of a chiral substrate are metabolized at different rates product stereoselectivity, in which a new chiral center is created in a symmetric molecule and one enantiomer is metabolized preferentially and substrate-product stereoelectivity, in which a new chiral center of a chiral molecule is metabolized preferentially to one of two possible diastereomers (87). An example of substrate stereoselectivity is the preferred decarboxylation of S-a-methyIdopa to S-a-methyIdopamine, with almost no reaction for R-a-methyIdopa. The reduction of ketones to stereoisomeric... 

Stereoselective allylation of secondary radicals is possible when a suitable steric bias is present. For example, the thiocarbonyl compound 41 reacts to give exclusively the exo allylated product 42, in which allyl tributylstannane approaches from the less-hindered convex face of the cyclic radical (4.40). In acyclic substrates high stereoselectivity can be achieved by chelation with a Lewis acid. For example, allylation of the selenide 43 is much more stereoselective in the presence of trimethylaluminium, in which the aluminium alkoxide chelates to the carbonyl group to give the species 44, such that the approach of the allyl stannane is directed to the less hindered face (4.41). 

Substrate-controlled stereoselective dearomatizations provide cycloheptatriene derivatives in high diastereomeric excess, and the reaction has been used to prepare 7-membered ring systems found in several natural products. Scheme 15.27a illustrates the Rh(II)-catalyzed conversion of diazo derivative 72 to polycyclic cycloheptatriene 73, which was subsequently converted to har-ringtonolide [78]. Note that the initial cycloheptatriene product of the Buchner reaction is converted to a more stable isomer by the action of DBU. In some instances, intramolecular Buchner reactions afford norcaradiene products that are not in equilibrium with the corresponding cycloheptatrienes. These examples arise as a consequence of conformational constraints inherent in the substrates. Cu-catalyzed Buchner reactions have been anployed to access derivatives of stable norcaradiene fragments found in several natural products (e.g., gibberellin GA j and (-r)-salvileucalin B, Scheme 15.27b and c, respectively) [79]. 

Typical applications of the DHAP aldolases indude the synthesis of monosaccharides and derivatives of sugars from suitable functionalized aldehyde precursors. High conversion rates and yields are usually achieved with 2- or 3-hydroxyaldehydes, because for these compounds reaction equilibria benefit from the cyclization of the products in aqueous solution to give more stable fiiranose or pyranose isomers (Figure 5.32). For example, enantiomers of glyceraldehyde are good substrates, and stereoselective addition of dihydroxyacetone phosphate produces enantiomerically pure ketohexose... 

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