Asymmetric hydrogenation of enamides

Enamides, in addition to the acrylates shown above, are also asymmetrically hydrogenated with many of the same systems that prove useful for the acetamidoacrylate reductions. The Rh(I)/BICP (2(/J)-2/(i)-bis(dipenylphosphino)-1(R),] (R)-dicyclopenlane) 132 and Rh(I)/DuPHOS systems work well ( 90% ee) for the asymmetric hydrogenation of /3-acctamidovinyl methoxymethyl ethers 

The Rh(I)/136 or Rh(I)/137 combination can be used in the asymmetric hydrogenation of 1-arylenamides in 90-99% ee, with Rh(I)/137 being the better of the two.676 Me-DuPHOS and related ligands with rhodium reduce 1-aryl-2-alkylenamides in 90% ee677 whereas the Rh(I)/DIOP combination carries this out in 97.3-99% ee selectivity.678 Finally, the Rh(I)/138 system reduces /3-substituted-a-arylenamides in 95-99% ee, and a-substituted acetamidoethylenes in 75.7-90% ee.674 

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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,... 

Wink reported the use of bisphosphite ligands in the asymmetric hydrogenation of enamides (2-10% ee) [114]. In 1998, Selke synthesized a series of analogues based on 98a. Of these compounds, 147 (Fig. 27.14) was selected as ligand for the Rh-catalyzed hydrogenation of methyl (Z)-2-ace tamidocinnamate, though it induced only low enantioselectivity (13% ee) [115]. 

Scheme 6-16. Asymmetric hydrogenation of enamide using 25 or 26 as the chiral ligand.

BINAP-ruthenium dicarboxylate complexes are also efficient catalysts for asymmetric hydrogenation of enamides, a,p- and p,y-unsatu rated carboxylic acids, a-amino ketones, and a-acylaminoacrylic acids.1 2 3 4 5... 

Chiral monodentate phosphites and phosphoramidites are also effective ligands for Rh-catalyzed asymmetric hydrogenation of enamide substrates. As seen in the structure of MonoPhos illustrated in Figure 1.2, combination of the mod-ihed BINOF backbone and the amine part gives a structural variety to this type of ligand. Combinatorial methods are effective for optimization of the chiral structures.Elucidation of the hydrogenation mechanism catalyzed by the MonoPhos-Rh complex is in progress." ... 

With this system, we finally succeeded in characterizing the first rhodium dihydride species in the asymmetric hydrogenation of enamides. Additionally, we succeeded afterwards in the characterization of all the possible catalyst dihydride species [39]. In subsequent work, now knowing what to look for and where to look, all transient complexes in the asymmetric enamide hydrogenation with the Rh(PHA-NEPHOS) catalyst could also be observed with classical NMR techniques [37]. 

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]. 

The reaction pathway for rhodium-catalyzed asymmetric hydrogenation of enamides is described and intermediates are defined in solution by P-31, C-13, and H-l NMR. The stereochemical relationship of bound enamide to rhodium alkyl and to the product of hydrogenation is demonstrated. Experiments involving the addition of HD to a variety of olefins in the presence of rhodium biphosphine catalysts suggest that a concerted addition of hydrogen to olefin and metal may occur in appropriate cases. 

Rhodium and palladium catalysts that contain 4 display high enantioselectivities for the asymmetric hydrogenation of enamides, itaconates, P-keto esters, asymmetric hydroboration, and asymmetric allylic alkylation,80 82 but this ligand system distinguishes itself from other chiral bisphos-phines in the asymmetric reduction of tetrahydropyrazines and tetrasubstituted olefins (see also Chapter 15). The reduction of tetrahydropyrazines produces the piperazine-2-carboxylate core,... 

A novel series of atropisomeric ligands uses a paracyclophane backbone. Rhodium and ruthe-nium-PhanePhos catalysts have performed well in the asymmetric hydrogenation of enamide esters, (3-keto esters, and especially arylketones with JST catalysts (Duloxetine). 

Gridnev, I. D., Yasutake, M., Higashi, N., Imamoto, T. Asymmetric Hydrogenation of Enamides with Rh-BisP and Rh-MiniPHOS Catalysts. Scope, Limitations, and Mechanism. J. Am. Chem. Soc. 2001,123, 5268-5276. 

Asymmetric hydrogenation of enamides CO2 Cationic rhodium complex... 

The asymmetric hydrogenations of N acetyl, N carbamate, and N sufonyl indoles are asymmetric hydrogenations of enamides. not imines, and will therefore not be covered here. For reports of this reaction, see (a) Kuwano, R. and Kashiwabara. M., (2006) Org. Lett., 8,... 

Scheme 8.1 Rh DIOP catalyzed asymmetric hydrogenation of enamides.

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