Enamides, asymmetric catalytic hydrogenation

L-dopa, used in the treatment of Parkinson s disease, is best prepared by asymmetric catalytic hydrogenation (15) of the enamide [6]. The hydrogenation, performed with a soluble rhodium catalyst modified with the... 

In addition, as discussed above, oxidation reactions and reactions which use CO2 as a reagent as well as a solvent are worth investigating. Examples of both are discussed below. Finally, electrophilic processes may be advantageously transferred to supercritical CO2, as demonstrated by the improved isomerization of C4-C12 paraffins catalyzed by aluminum bromide. 2,44) Below, we describe three catalytic reactions which appear promising by these criteria asymmetric catalytic hydrogenation of enamides, ruthenium-catalyzed two-phase oxidation of cyclohexene, and the catalytic copolymerization of CO2 with epoxides. 

Asymmetric catalytic reduction reactions represent one of the most efficient and convenient methods to prepare a wide range of enantiomerically pure compounds (i.e. a-amino acids can be prepared from a-enamides, alcohols from ketones and amines from oximes or imines). The chirality transfer can be accomplished by different types of chiral catalysts metallic catalysts are very efficient for the hydrogenation of olefins, some ketones and oximes, while nonmetallic catalysts provide a complementary method for ketone and oxime hydrogenation. 

Enantioselective catalytic hydrogenation. The ruthenium(II) complexes of (R)- and (S)-l, bearing a chiral BINAP ligand, catalyze asymmetric hydrogenation of N-acyl-l-alkylidenetetrahydroisoquinolines to give (1R)- or (lS)-tetrahydroiso-quinolines in 95-100% ee.1 Thus the (Z)-enamide (2), prepared by acylation of 3,4-dihydropapaverine, is hydrogenated in the presence of (R)-l to (1R)-tetrahydroisoquinolines (3). The enantiomeric (lS)-3 is obtained on use of (S)-l as catalyst. 

The efficiency of an asymmetric catalytic reaction is characterized either by excess of the predominantly formed enantiomer [61], for example of the R-configuration and its optical yield (%), P = ([./ ]-[ S])/([/ ]+[ S]), or by the value of the enantioselectivity, E = [/ ]/[5], Thus, among the amino acids (prochiral enamides) with higher optically active products, the yield (for example, 2-aceta-midoacrylic acid) reaches 67%. The same is true of the asymmetric hydrogenation of prochiral ketones. 

Recent work by several research groups has shown that supercritical fluids can be superior to other solvents for several chemical processes. For example, DeSimone has demonstrated the ability of supercritical CO2 to replace Freons in the free radical polymerization of fluorinatkl acrylate monomers. 34) Noyori has shown that significant rate enhancements can be achieved in supercritical carbon dioxide relative to other solvents for the homogeneous catalytic hydrogenation of carbon dioxide to either formic acid or its derivatives in the presence of triethylamine or triethylamine/methanol respectively, (equation 1). (55-57) As discussed below, we have recently demonstrated that improved enantioselectivities can be achieved in supercritical carbon dioxide for the catalytic asymmetric hydrogenation of several enamides. 5 8)... 

The results clearly show that these novel ligands are able to form a suitable asymmetric enviromnent around the metal resulting in high asymmetric induction. Their catalytic potential has been demonstrated in the highly enantioselective Rh-catalyzed hydrogenation of itaconates and a-enamides and Ru-catalyzed hydrogenation of p-functionalized ketone. 

Asymmetry in metal-alkene coordination plays a critical role in asymmetric catalysis, with implications far beyond the scope of the present treatment. An instructive example is provided by catalytic asymmetric hydrogenation of enamides,... 

Prior to the beginning of our work on sitagliptin, there had been some reports in the literature of catalytic asymmetric hydrogenation of enamines to access chiral secondary amines [19]. The synthesis of P-amino acids had also been established by catalytic asymmetric hydrogenation of enamides [20]. All these reports relied on N-acylenamines as substrates, since it was believed that the N-acyl group was required in order to achieve good reactivity and selectivity [21]. 

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