Metal-catalyzed hydrogenations stereoselective hydrogenation

The ability to interconvert one functional group into another is of fundamental importance in organic synthesis. Often, these interconversions involve reduction or oxidation of a functional group, and such transformations also may either create or destroy a stereogenic center. The first part of Section 12-1 will explore transition metal-catalyzed hydrogenations of C=C and C=0 bonds, which can exhibit a high degree of stereoselectivity. The second part will consider oxidation reactions that are also catalyzed by transition metal complexes, which can lead to enantioenriched products. 

For recent work on the stereoselective transition metal-catalyzed hydrogenation of alkynes to /i-alkenes, see B. M. Trost, Z. T. Ball, and T. Joge, J. Am. Chem. Soc., 2002,124,7922 and A. Fiirstner and K. Radkowski, Chem. Commun, 2002, 2182. 

Some researchers have begun to explore the possibihty of combining transition metal catalysts with a protein to generate novel synthetic chemzymes . The transition metal can potentially provide access to novel reaction chemistry with the protein providing the asymmetric environment required for stereoselective transformations. In a recent example from Reetz s group, directed evolution techniques were used to improve the enantioselectivity of a biotinylated metal catalyst linked to streptavidin (Scheme 2.19). The Asn49Val mutant of streptavidin was shown to catalyze the enantioselective hydrogenation of a-acetamidoacrylic acid ester 46 with moderate enantiomeric excess [21]. 

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. 

Before illustrating the concept for a mass spectrometric distinction of stereoisomers, let us refer to some of the problems associated with the stereoselective hydrogenation of benzene to cyclohexane this may serve as a simple and illustrative example. Metal-catalyzed hydrogenation is known to proceed with a large syn-selectivity, and the reaction involves at least three separate steps in the case of benzene cyclohexane (Scheme 3). 

The Pd-catalyzed hydrogenation of alkyl-substituted 1-alkoxycyclohexenes is stereoselective. The axial/equatorial stereoisomer predominates no matter where the alkyl substituent is located on the ring. Nishimura suggested that the result indicates that the product-controlling step involves the reductive elimination of the most stable alkyl intermediate which is attached to the metal at the carbon atom that bears the alkoxy group (equation 21). 

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