Reduction of keto group

The method of choice for the reduction of keto groups to methylenes remains the WolfT-Kishner reaction (2) or its modification discovered by Huang-Minlon (5). Originally, the hydrazone formation was carried out in a separate step, followed by... 

Hydrolysis reactions are illustrated by the deacylation of colchicine (10) (amide hydrolysis), olivomycin A (29), Rifamycin B (46) or thymoxamine (52) (ester hydrolysis). The reduction of pentoxyfylline (32), zearalenone (56) or warfarin (65) are examples of the common reduction of keto groups, generally affording, with a high stereospecificity, one of the alcohol stereoisomers. 

Stereospecific reductases are involved in the reduction of keto groups to secondary alcohols the desired endproducts of a deoxysugar biosynthesis. This has been shown for the biosynthesis of L-rhamnose and CDP-ascarylose (see Sect. 3.1.4). The reduction of keto groups at C-4 have been proposed to be catalyzed by DnrV (daunorubicin 29), EryBIV (erythromycin 14), and StrL (streptomycin 24) [21]. 

The main use of hydrazine in steroid chemistry has been in the reduction of keto-groups to give unsubstituted methylene groups by the Wolff-Kishner process, particularly as modified by Huang-Minion fij. Hydrazones of simple ketones react rapidly at 200° in hydroxylic solvents such as "diethylene glycol containing strong alkali. 

Many experimental procedures have been developed in order to influence the enantioselectivity and the stereochemistry of the products use of organic media, the addition of various compounds to the incubation mixture, or enclosure in a dialysis tube can be helpful. Immobilized BY can be used in water or in organic solvents for the same purpose. Slight modifications of the substrate can obtain the same result and many examples are available. Several other groups can be present in the carbonyl-containing substrate. For instance, the asymmetric reduction of keto groups in compounds containing a cyclopropyl moiety has been achieved (eq 5). ... 

The lower reactivity of Raney Ni towards sulfones allows the chemoselective desulfurization of (4) with Raney W-2, but an appreciable amount of reduction of keto groups was observed. Raney Ni W-2 also tolerates sulfonamides in this work an ionic mechanism was suggested in order to explain the substitution reaction observed. Lactones,keto lactones," and unsaturated lactoneswere tolerated during the desulfurization of sulfide or dithioketal" groups, but deactivated (e.g. by acetone) Raney Ni was generally used. In contrast, carbon-halide bonds are cleaved where the desulfurization is stereoselective only because the product is the thermodynamically more stable d5-lactone (equation 2)." e-" f... 

Yamamura, S., Hirata, Y. Zinc reductions of keto groups to methylene groups. J. Chem. Soc. C1968, 2887-2889. 

The Archetypal Poly-p-keto Chain Structural Variations Produced by Reduction of Keto Groups... 

The polyketides are a family of natural products containing many important pharmaceutical agents that are synthesized through the multienzyme complex, polyketide synthase, which can display substantial molecular diversity with respect to chain length, monomer incorporated, reduction of keto groups, and stereochemistry at chiral centers (189). This variability, together with the existence of several discrete forms of polyketide synthase, allows the generation of diverse structures like erythromycin, avermectin, and rapamycin. This biochemical diversity has been considerably expanded by the introduction of new sub strate species that were used by the enzymes to produce new or unnatural polyketides (190). 

A selective reduction of keto groups is possible in the presence of epoxides using triisobutyl-aluminum at low7 temperatures153. Thus, 2,3-epoxy-4,4-dimethylcyclohexanone is reduced with good stereoselectivity [d.r. (cis/trans) 5 95] to fr[Pg.822]

Many stereo- and regioselective redox reactions have been carried out on a preparative scale by the catalysis of enzymes or microorganisms. The majority of these reactions involves the reduction of keto groups to chiral secondary alcohols or derivatives thereof Not only the reductions of CX-double bonds, but also selective dehydrogenations are of interest. A well-known example of a regioselective biocatalytic dehydrogenation is the formation of L-sorbose from D-sorbitol which is actually the key step in the synthesis of vitamin C. 

Modular Polyketide Synthases (Type I). In contrast to iterative PKSs, modular PKSs consist of one or more large proteins composed of synthase units called modules (Donadio et al. 1991). Each module performs an elongation step of the synthesis of the polyketide chain. In all the modules are present the enzymes necessary for the condensation of an extension unit of the growing chain acylketosynthase (KS), acyltransferase (AT), and acyl carrier protein (ACP). In some modules, also present may be some or all of the enzymes devoted in fatty acid synthesis to the stepwise reduction of keto groups ketoreductase... 

Other reactions described, with varying degrees of success, have been chiral epoxidation, chiral hydrogenation, chiral iodination, and chiral reduction of keto-groups. One of the last reactions is especially interesting in using a chiral phase-transfer catalyst. Finally, Johnson and his co-workers have reported in full the asymmetric induction in their steroid synthesis via polyene cyclization [e.g. (46) (47) with ca. 90 % optical purity]. ... 

Sodium tetrahgdridoborate Selective and preferential reduction of keto groups... 

Asymmetric reduction of ketones. Pioneering work by Ohno et al. (6, 36 7, 15) has established that l-benzyl-l,4-dihydronicotinamide is a useful NADH model for reduction of carbonyl groups, but only low enantioselectivity obtains with chiral derivatives of this NADH model. In contrast, this chiral 1,4-dihydropyridine derivative (1) reduces a-keto esters in the presence of Mg(II) or Zn(II) salts in >90% ee (equation I).1 This high stereoselectivity of 1 results from the beneficial effect... 

Selective reduction of carbonyl groups in the presence of an ester group. Selective reduction of various keto esters to hydroxy esters is possible in fair yield with LiAlH4 in the presence of a small amount of silica gel (equation I).1... 

The method is said to be more reproducible than a direct vanillin acylation as uncontrolled losses of this volatile intermediate product are obviated. Esselman and Clagett [187] determined the position of the oxygen atom in the chain of polyfunctional fatty acids. The method is based on the reduction of keto, hydroperoxy, epoxy and carboxyl groups to the corresponding alcohols with LiAlH4, subsequent silylation with BSA and the analysis by GC—MS using OV-1 at 225°C. 

Stereoselective reduction of -keto sulfoxides. The reduction of the P-keto sulfoxide 1 with NaBH, in CH,OH/aq. NH, (9 1) proceeds with efficient 1,3-asymmetric induction and epimerization at C, (equation 1). Only slight stereoselectivity obtains in a neutral medium. The chirality of the sulfinyl group has no effect. 

Microbial reduction of carbonyl groups is another possible side reaction, with a 3-keto group seemingly most susceptible to this reaction, but again the nature of the substrate and microorganism can have a major effect on the extent of this side reaction. In the hydioxylation of 5a-androstan-3-one (66) the results shown in Table 4 were obtained. ... 

Various groups on the aromatic nucleus including halo, hydroxyl, alkoxyl, and amino groups are stable during reduction of the carbonyl group by one or more of the above procedures. The Clem-mensen reduction of keto acids is treated in method 269. 

Preparation of acids by the reduction of keto acids is possible when the carbonyl group is in the alpha or gamma positions or further removed from the carboxyl group. The a-keto acid, phthalonic acid, is reduced to o-car-boxyphenylacetic acid (homophthalic acid) in excellent yield by phosphorus and potassium iodide in phosphoric acid " or by constant-boiling hydriodic acid." ... 

The reduction proved to be chemoselective for aldehyde functions even in the presence of keto groups. The yield in homogeneous reactions varies between 9% and 30%. When aminated polystyrene is used as the basic component, the active anionic species [Rh6(CO)i5H] is immobilized via interaction with the supported ammonium eations and leads to an increase in the yields up to 91-99% [22, 23], while the catalyst can be recovered by simple filtration from the product. 

The reduction of keto-cyclohexane compounds, including some inososes,i has been widely studied and it has been found that hindered keto groups afford axial hydroxyl groups, and that the proportion of axial to equatorial hydroxyl groups formed is dependent on the type of reduction. It was found that the results with the keto-pyran compounds (the keto-D-gluco-pyranosides) were rather similar to those obtained with the related keto-cyclohexane compounds (the inososes). 

The use of other complex hydrides, such as LiBD4 and NaBD4, seems so far to play only a minor role for reduction of carbonyl bonds. Catalytic methods for reduction of carbonyl groups also have little importance. However, syntheses of labeled amino acids have been effected by reductive amination of oc-keto acids on suitable catalysts.40... 

The scope of the use of lithium in amines as a reducing agent has been extended recently (3) to include the reduction of functional groups, such as keto and nitrile groups. The following reactions illustrate the courses of the reductions ... 

Reduction of aldehydes. This borane reduces aldehydes and a, 8-enals to the corresponding alcohols in 55-90% yield (isolated). The reaction is chemosclective in the presence of keto groups. 

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