Enamide Hydrogenation with Rhodium Catalysts

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]. 

In order for these rhodium DuPHOS catalysts to achieve the desired reactivity and selectivity, the hydrogenation substrate must contain certain features to facilitate the highly diastereoselective transition state required for the reaction. All the substrates to which rhodium DuPHOS hydrogenation catalysts have been successfully applied thus far possess a donor atom y to the olefin (Fig. 2). Within the constraint of this geometric requirement a wide array of prochiral olefins have been demonstrated as suitable substrates for asymmetric hydrogenation with rhodium DuPHOS catalysts. Examples include enamides 2 [1, 2], vinylacetic acid derivatives 3 [3], and enol acetates 4 [4]. 

In the studies conducted by Reetz, rhodium catalysts based on mixtures of monodentate phosphites, monodentate phosphonites and combinations of the two were screened in the enantioselective hydrogenation of a- and /9-N-acetyl-de-hydroamino acid esters, enamides and dimethyl itaconate [40], and a number of the more striking positive results are listed in Table 36.3. An enhanced ee-value was found mostly with combinations of two phosphonites, or one phosphonite and one phosphite, in particular when one of the ligands carries a bulky substituent and the other a small one. 

A class of chiral bisphosphines based on 3,4-bis(diphenylphosphino)pyrrolidines (9) has been developed by Degussa and the University of Munich. Rhodium-bisphosphine catalysts of this class can reduce a variety of enamides to chiral amino acid precursors with high enantioselectivities. These catalysts are extremely rapid and can operate with high S/C ratios (10,000-50,000) under moderately high hydrogen pressure (150-750 psig). Contrary to other rhodium catalysts that contain... 

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). 

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 all enantioselective hydrogenations the ability of the substrate to form a chelate ring with the catalyst is extremely important. For this reason the enantioselective reductive ami-nation of ketones is always particularly difficult, because these compounds usually do not have a structure suitable for the required chelation. Burk et al. circumvent this problem by reversible derivatization. The ketones are converted into A -acetylhydrazones, whose structures resemble those of enamides. [11] The C-N double bond can then be hydrogenated by nPr-DuPHOS-rhodium with ee values almost as high as those for C-C double bonds of enamides. The A-acetylhydrazines obtained thus can either be transformed into... 

The mechanism of hydrogenation of enamides by rhodium catalysts with monoden-tate phosphorous ligands was investigated computationally by means of the functional M05-2X taking into account the role of trans intermediates. Since the study suggested that cis intermediates played the major role in the mechanism of the reaction, the results with monodentate phosphorous ligands needed interpretation without involvement of structures with rrun -phosphine arrangements. ... 

The rhodium-catalyzed asymmetric hydrogenation of prochiral enamides was investigated by Feldgus and Landis [691, 692]. They demonstrated that computational methods reproduce the ot-substituent effect in enamide hydrogenation catalysis and probe how the interaction of the enamide C=C bond and the catalyst varies with the structure of the substrate. The picture that emerges emphasizes the complex interaction of both electronic (i.e. those effects that do not depend on the size of the model system) and steric effects in controlling the stereochemistry of enamide hydrogenation reactions [691, 692]. 

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