STEREOCHEMICAL COURSE OF THE REDUCTION

The reduction of a,a-difluoroacetophenone by a cyanobacterium proceeded both under light and in the dark, and the poor enantioselectivities (20-30% ee) observed in the dark were improved by irradiation. Thus, the enantioselectivities increased according to the lightness (70% ee under light (1000 lux)). The use of DCMU, a photosynthetic inhibitor, decreased the enantioselectivity of the reduction even under light conditions. The stereochemical course of the reduction is controlled by illumination or by adding DCMU. ... 

For further contributions on the dia-stereoselectivity in electropinacolizations, see Ref. [286-295]. Reduction in DMF at a Fig cathode can lead to improved yield and selectivity upon addition of catalytic amounts of tetraalkylammonium salts to the electrolyte. On the basis of preparative scale electrolyses and cyclic voltammetry for that behavior, a mechanism is proposed that involves an initial reduction of the tetraalkylammonium cation with the participation of the electrode material to form a catalyst that favors le reduction routes [296, 297]. Stoichiometric amounts of ytterbium(II), generated by reduction of Yb(III), support the stereospecific coupling of 1,3-dibenzoylpropane to cis-cyclopentane-l,2-diol. However, Yb(III) remains bounded to the pinacol and cannot be released to act as a catalyst. This leads to a loss of stereoselectivity in the course of the reaction [298]. Also, with the addition of a Ce( IV)-complex the stereochemical course of the reduction can be altered [299]. In a weakly acidic solution, the meso/rac ratio in the EHD (electrohy-drodimerization) of acetophenone could be influenced by ultrasonication [300]. Besides phenyl ketone compounds, examples with other aromatic groups have also been published [294, 295, 301, 302]. 

In addition, the use of enzyme selective inhibitors has turned out to be very effective. Reductions were performed by adding l,l,l-trifluoro-2,4-pentane-dione 1 to a yeast-water suspension with selected additives such as methylvinyl-ketone, allyl alcohol, alkanoic acids, ethyl chloroacetate or allyl bromide, all of them reported to affect the stereochemical course of baker s yeast reduction. In some cases, both the influence of the yeast/substrate ratio and the influence of the presence of glucose were considered. In the presence of alkanoic acids (acetic, fumaric, or oleic acid), no significant effect was observed. However, addition of methylvinyl-ketone, allyl alcohol, ethyl chloroacetate and allyl bromide to the reaction system affected the stereochemical course of the reduction of 1. In particular, (R)-(+)-2 was produced in the presence of ethyl chloroacetate and allyl bromide as additive. 

Early investigations of reactions catalyzed by Saccharomvces cerevi-siae revealed that the stereochemical course of the reduction of 3-oxoacids is influenced by the chain lengths of the substrates ... 

The effect of halogen on the stereochemical course of the reduction is in the same order as that observed on metallic surfaces. The optical purity of the hydrocarbon 49 using a 4 m solution of sodium in liquid ammonia, decreases in going from chloride (58 %) to bromide (43%) to iodide (17%). 

SCHEME 10.91 Sugar-derived auxiliaries can influence the stereochemical course of the reduction of carbonyls. 

The stereochemical course of the reduction of sugar olefins is primarily governed by the neighboring groups. This step proved to be highly stereoselective in the pyranose series, as shown in the synthesis of the thromboxane B2 by Hanessian [106]. As shown in Scheme 11.33, ketone 127,... 

Other substituents in the vicinity of the ketone group can also influence the stereochemical course of the reduction. An OMe group or a fluorine atom at the... 

The enantioselectivity of a biocatalytic reduction can be controlled by modifying the substrate because the enantioselectivity of the reduction reaction is profoundly affected by the structure of substrates. For example, in the reduction of 4-chloro-3-oxobutanoate by bakers yeast, the ester moiety can be used to control the stereochemical course of the reduction 161 531. When the ester moiety was smaller than a butyl group, then (Sj-alcohols were obtained, and when it was larger than a pentyl group then (R)-alcohols were obtained as shown in Fig. 15-9. 

With other less-rigid cyclohexanones, the stereochemical course of the reduction is less easy to predict. In general, a mixture of products is obtained in which, with comparatively unhindered ketones, the more stable equatorial alcohol predominates with hindered ketones, the axial alcohol is often the main product. Thus, reduction of 4-tert-butylcyclohexanone 84 with lithium aluminium hydride gives predominantly the equatorial trans-4-/ crt-butylcyclohexanol, whereas the hindered 3,3,5-trimethylcyclohexanone 85 gives a mixture containing mainly the axial alcohol 86 (7.69,7.70). The latter is almost the only product when a more hindered and hence more selective reducing agent such as L-selectride [LiBH( Bu)3] or lithium hydrido-tri-tert-butoxyaluminate [LiAlH(0 Bu)3] is employed. 

NaBlLt does not seem to be the best reagent for the stereoselective reduction of chiral unfunctionalized acyclic ketones. Bulky complex hydrides such as Li(s-Bu)3BH usually afford better results. When a heteroatom is present in the a- or fi-position, the stereochemical course of the reduction depends also on the possible intervention of a cychc chelated transition state. Also, in this case other complex hydrides are often better suited for favoring chelation (see Zinc Borohydride). Nevertheless, cases are known where excellent degrees of stereoselection have been achieved with the simpler and less expensive NaBUj. Some... 

The second stereochemical problem, enantioselective reduction of the keto-group in the w-side-chain, was solved by Corey already in 1987. The reduction was successful with borane-THF in presence of 10 mole% of the (H)-prolme-derived (H)-oxazaborolidine (Corey-Bakshi-Shibata reduction). If the enone was reduced in presence of the corresponding (S)-oxazaborolidine, the inverse product distribution resulted. Obviously, the other stereocentres in the educt have no impact on the stereochemical course of the reduction at C-15. 

In THF the lithium aluminium hydride reduction of (162) gave 82% axial alcohol as compared to 62% axial alcohol from (163), the difference being ascribed to the influence of equatorial phenyl a to the carbonyl. Reductions of (164) and (160) under the same conditions both resulted in ca. 60% of trans-alcohol. In these cases, where substrates could exist in two eonformations equally accessible to hydride, the results indicated the small influence of the double bond on the stereochemical course of the reduction. Similar results were displayed in a comparison of (162) and (157),where,... 

Studies on the asymmetric reduction with 1,4-dihydronicotinamide derivatives that contain chiral centers within their amide moieties have been widely extended after the first report on this subject COhnishi et al. 1975a,b). To improve the optical yield and to obtain further insights into the stereochemical course of the reduction, a variety of model compounds have been synthesized and subjected to the reduction. Table 4 lists the optical yields from the reduction of methyl or ethyl benzoylformate which has frequently been used as a substrate for these 1,4-dihydropyridine derivatives. 

It has been found that the stereochemical course of the reduction of methyl or ethyl benzoylformate by a 1,4-dihydropyridine derivative is controlled by a variety of factors. First of all, the optical yield is influenced by a variation of the atom connecting the carbonyl and a-methylbenzyl groups as shown in Scheme 17 (Ohno et al. 1976). It is concluded that the basicity of the carbonyl oxygen affects the optical yield because the change.in the basicity is directly correlated with the ability to coordinate onto Mg(II). 

Stereoselective reduction of terpene ketones via hydrosilylation [36] exhibited significant difference in stereochemistry from other reduction by metal hydrides. Results of the reduction of camphor and menthone via hydrosilylation are listed in Table 6. Included also in the Table are reported selectivities obtained by using conventional reducing agents. It is seen in the Table that the bulkiness of silanes exerts remarkable influence on the stereochemical course of the reduction, i.e., a bulky hydrosilane favors the production of the more stable alcohols. This trend is quite... 

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