Kinetic resolution racemic ketones

The ability to catalyze the asymmetric hydrogenation of aliphatic ketones provides an opportunity to extend the scope of these reactions to the dynamic kinetic resolution of ketones that contain a stereocenter in the enolizable a-position. The catalysts containing bisphosphine and diamine ligands are activated by base, and the base used to activate the metal catalyst can also catalyze the racemization of the ketone. An example of such a process is shown in Equation 15.76. ... 

A kinetic resolution was also observed in the reduction of racemic a-ketosulphoxides 277 by fermenting yeast337 (equation 153). Both the starting ketones 277 and the corresponding /1-hydroxysulphoxides 278 formed have been recovered in almost enan-tiomerically pure form. 

CHMO is known to catalyze a number of enantioselective BV reactions, including the kinetic resolution of certain racemic ketones and desymmetrization of prochiral substrates [84—87]. An example is the desymmetrization of 4-methylcyclohexanone, which affords the (S)-configurated seven-membered lactone with 98% ee [84,87]. Of course, many ketones fail to react with acceptable levels of enantioselectivity, or are not even accepted by the enzyme. 

Dynamic kinetic resolution of racemic ketones proceeds through asymmetric reduction when the substrate does racemize and the product does not under the applied experimental conditions. Dynamic kinetic resolution of a-alkyl P-keto ester has been performed through enzymatic reduction. One isomer, out of the four possible products for the unselective reduction (Figure 8.38), can be selectively synthesized using biocatalyst, and by changing the biocatalyst or conditions, all of the isomers can be selectively synthesized [29]. 

In the case of the ketone (12), a racemic mixture was converted to an optically active mixture (optical yield 46%) by treatment with the chiral base (13). This happened beeause 13 reacted with one enantiomer of 12 faster than with the other (an example of kinetic resolution). The enolate (14) must remain coordinated with the chiral amine, and it is the amine that reprotonates 14, not an added proton donor. 

Enantioselective enolate formation can also be achieved by kinetic resolution through preferential reaction of one of the enantiomers of a racemic chiral ketone such as 2-(f-butyl)cyclohcxanone (see Section 2.1.8 of Part A to review the principles of kinetic resolution). 

Chiral amines can also be produced using aminotransferases, either by kinetic resolution of the racemic amine or by asymmetric synthesis from the corresponding prochiral ketone. The reaction involves the transfer of an amino group, a proton and two electrons from a primary amine to a ketone, and proceeds via an intermediate imine adduct. A variety of chiral amines can be obtained with high to very high ee-values. Several transformations have been developed and can be carried out on a 100-kg scale [94]. 

Bolm et al. (130) reported the asymmetric Baeyer-Villiger reaction catalyzed by Cu(II) complexes. Aerobic oxidation of racemic cyclic ketones in the presence of pivalaldehyde effects a kinetic resolution to afford lactones in moderate enan-tioselectivity. Aryloxide oxazolines are the most effective ligands among those examined. Sterically demanding substituents ortho to the phenoxide are necessary for high yields. Several neutral bis(oxazolines) provide poor selectivities and yields in this reaction. Cycloheptanones and cyclohexanones lacking an aryl group on the a carbon do not react under these conditions. 

Rodriguez, C., de Gonzalo, G., Eraaije, M.W. and Gotor, V., Enzymatic kinetic resolution of racemic ketones catalyzed by Baeyer-Villiger monooxygenases. Tetrahedron Asymm., 2007, 18, 1338. 

Kinetic resolution of racemic secondary hydroperoxides rac-16 can be effected by selective reduction of one enantiomer with employing either chiral metal complexes or enzymes (equation 10). In this way hydroperoxides 16 and the opposite enantiomer of the corresponding alcohols 19 can be produced in enantiomerically enriched form. As side products sometimes the corresponding ketones 20 are produced. 

SCHEME 169. Chiral Pt complexes 231 employed as asymmetric inductors in the kinetic resolution of racemic cyclic ketones formed by enantioselective Baeyer-VilUger oxidation... 

Even more interesting is the oxidative kinetic resolution of alcohols under aerobic conditions. The system Pd(lI)/sparteine/02 was reported to convert a racemic alcohol with high selectivity into the ketone and the alcohol [97-99]. This has also been shown to work with palladium carbene complexes (Scheme 16). 

Kinetic Resolution of a Racemic Ketone. Kinetic resolution is a process by which one of the enantiomeric constituents of a racemate is more readily transformed into a product than the other (63b). For example, in the presence of an (/ )-BINAP-Ru catalyst, the S enantiomer of the a-hydroxy ketone is hydrogenated 64 times faster than R enantiomer, and, after 50.5% conversion, both the syn 1,2-diol and unreacted R hydroxy ketone are obtained in high ee (Scheme 61). 

SCHEME 61. Kinetic resolution of a racemic hydroxy ketone by BINAP-Ru-catalyzed hydrogenation. 

Dynamic Resolution of Chirally Labile Racemic Compounds. In ordinary kinetic resolution processes, however, the maximum yield of one enantiomer is 50%, and the ee value is affected by the extent of conversion. On the other hand, racemic compounds with a chirally labile stereogenic center may, under certain conditions, be converted to one major stereoisomer, for which the chemical yield may be 100% and the ee independent of conversion. As shown in Scheme 62, asymmetric hydrogenation of 2-substituted 3-oxo carboxylic esters provides the opportunity to produce one stereoisomer among four possible isomers in a diastereoselective and enantioselective manner. To accomplish this ideal second-order stereoselective synthesis, three conditions must be satisfied (1) racemization of the ketonic substrates must be sufficiently fast with respect to hydrogenation, (2) stereochemical control by chiral metal catalysts must be efficient, and (3) the C(2) stereogenic center must clearly differentiate between the syn and anti transition states. Systematic study has revealed that the efficiency of the dynamic kinetic resolution in the BINAP-Ru(H)-catalyzed hydrogenation is markedly influenced by the structures of the substrates and the reaction conditions, including choice of solvents. 

As described above, the catalyst comprising RuC12 complex with a strong base is effective for the asymmetric hydrogenation through dynamic kinetic resolution. However, it is not suitable for static kinetic resolution of racemic a-substi-tuted ketones because of the basic conditions. The newly devised frans-RuHfri1-BH4)[(R)-XylBINAP][(S,S)-DPEN] without any additional base allows one to... 

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