Catalyzed ketone reduction

A possible solution to overcome these thermodynamic limitations is the use of an in situ product removal (ISPR) technique [42]. This approach can be easily appHed when the co-substrate and the co-product have significantly different physical properties. For example, in the case of the IPA/acetone system used in several ADH-catalyzed ketone reductions, the co-product acetone is the most volatile compound in the reaction mixture. Therefore, it can be removed by a simple stripping process, such as by passing a continuous air stream (previously saturated with water and IPA) through the reaction mixture (Figure 2.1). 

In addition, metal-catalyzed carbon-carbon bond formation and subsequent enzymatic transformations turned out to be compatible. This has been demonstrated by the Groger and Hummel groups [59], combining the Suzuki reaction as an example for a paUadium-catalyzed cross<oupling reaction with an asymmetric ADH-catalyzed ketone reduction in an aqueous reaction medium (Scheme 19.24). In such a one-pot process, the amount of boronic acid turned out to be critical because of strong inhibition of the enzyme. Thus, a two-step one-pot strategy was developed which was based on the use of 1 equiv of boronic acid in the Suzuki reaction, and addition of the enzyme directly to the reaction mixture after consumption... 

Schemell.5 Electronic effect of CF3 group in the 2c-catalyzed ketone reduction.

Figure 1.2 Prelog s rule stereospedfic product formation by alcohol dehydrogenase-catalyzed ketone reduction, assuming the large group having higher priority in CIP rules than the small group.

Enzyme-catalyzed ketone reduction proceeds by a well-established mechanism that involves hydride transfer from a nicotinamide cofactor. The cofactor NAD(P)H can either be regenerated by the same CRED or by a second enzyme such as glucose dehydrogenase (GDH) as shown in Figure 6.1 [4]. 

Baker s yeast has been widely used for the reduction of ketones. The substrate specificity and enantioselectivity of the carbonyl reductase from baker s yeast, which is known to catalyze the reduction of P-keto ester to L-hydroxyester (L2-enzyme) [15], was investigated, and the enzyme was found to reduce chloro-, acetoxy ketones with high enantioselectivity (Figure 8.32) [24aj. 

Silanes And Base. In the presence of bases, certain silanes can selectively reduce carbonyls. Epoxy-ketones are reduced to epoxy-alcohols, for example with (MeO)3SiH and LiOMe. ° Controlling temperature and solvent leads to different ratios of syn- and anti- products.Silanes reduce ketones in the presence of BF3-OEt2 ° and transition metal compounds catalyze this reduction. ... 

The use of chiral ruthenium catalysts can hydrogenate ketones asymmetrically in water. The introduction of surfactants into a water-soluble Ru(II)-catalyzed asymmetric transfer hydrogenation of ketones led to an increase of the catalytic activity and reusability compared to the catalytic systems without surfactants.8 Water-soluble chiral ruthenium complexes with a (i-cyclodextrin unit can catalyze the reduction of aliphatic ketones with high enantiomeric excess and in good-to-excellent yields in the presence of sodium formate (Eq. 8.3).9 The high level of enantioselectivity observed was attributed to the preorganization of the substrates in the hydrophobic cavity of (t-cyclodextrin. 

Two interesting yeast carbonyl reductases, one from Candida magnoliae (CMCR) [33,54] and the other from Sporobolomyces salmonicolor (SSCR) [55], were found to catalyze the reduction of ethyl 4-chloro-3-oxobutanoate to give ethyl (5)-4-chloro-3-hydroxybutanoate, a useful chiral building block. In an effort to search for carbonyl reductases with anti-Prelog enantioselectivity, the activity and enantioselectivity of CMCR and SSCR have been evaluated toward the reduction of various ketones, including a- and /3-ketoesters, and their application potential in the synthesis of pharmaceutically important chiral alcohol intermediates have been explored [56-58]. 

Cyclohexyl ethyl ether [TMSI-catalyzed ketone-unsymmetrical ether reduction], 124... 

Queen substance (140) was synthesized from the same telomer 137 (127). The PdCl2-catalyzed oxidation of the terminal double bond produced the methyl ketone. Reduction of the internal double bond was followed by partial hydrolysis and the displacement of the carboxyl group with phenylselenyl group, which was removed to produce queen substance (140) ... 

Finally, the group of Zhou has recently published the first Pd-catalyzed enantiomeric reduction of ketones using Me-DuPhos [197]. By performing the reaction in TFE, a series of a-phthalimido ketones 140 were reduced in high yield and 75-92% ee, albeit at high catalyst loadings (SCR 50), reaction times (12 h) and pressures (13.7 atm). This procedure was extended to include ketones 134 (R=Ph, R = Et), 139 (Ar=Ph), and 141. 

Far more ruthenium-complex-catalyzed enantioselective hydrogenation has been directed towards ketone reduction rather than alkene reduction. Recent studies carried out on the mechanism of C=C hydrogenation has been rather limited. 

Addition of triethylamine to the oxazaborolidine reaction system can significantly increase the enantioselectivity, especially in dialkyl ketone reductions.79 In 1987, Corey et al.80 reported that the diphenyl derivatives of 79a afford excellent enantioselectivity (>95%) in the asymmetric catalytic reduction of various ketones. This oxazaborolidine-type catalyst was named the CBS system based on the authors names (Corey, Bakshi, and Shibata). Soon after, Corey s group81 reported that another fi-methyl oxazaborolidine 79b (Fig. 6-6) was easier to prepare and to handle. The enantioselectivity of the 79b-catalyzed reaction is comparable with that of the reaction mediated by 79a (Scheme 6-36).81 The -naphthyl derivative 82 also affords high enantioselectivity.78 As a general procedure, oxazaborolidine catalysts may be used in 5-10 mol%... 

Scheme 18. Ru-catalyzed asymmetric ketone reduction used by Schreiber in the total syntheses of immunosuppressive agents FK506 and rapamycin (1990, 1993).

This observation has led to the preparation of more effective bicyclic oxaza-borolidines such as 1, prepared from (S)-(-)-2-(diphenylhydroxymethyl)pyrrolidine and BH3 (la) or methylboronic acid (lb). Both reagents catalyze borane reduction of alkyl aryl ketones to furnish (R)-alcohols in > 95% ee, by face-selective hydride transfer within a complex such as B. Catalyst lb is somewhat more effective than... 

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