Rh/josiphos

Recently, Merck chemists reported the Rh-josiphos-catalyzed hydrogenation of unprotected dehydro / -amino acids with ee-values up to 97%, but relatively low activity [23]. It was also shown that not only simple derivatives but also the complex intermediate for MK-0431 depicted in Scheme 25.2 can be hydrogenated successfully, and this has been produced on a > 50 kg scale with ee-values up to 98%, albeit with low to medium TONs and TOFs [24]. 

Rhodium diphosphine catalysts can be easily prepared from [Rh(nbd)Cl]2 and a chiral diphosphine, and are suitable for the hydrogenation of imines and N-acyl hydrazones. However, with most imine substrates they exhibit lower activities than the analogous Ir catalysts. The most selective diphosphine ligand is bdppsuif, which is not easily available. Rh-duphos is very selective for the hydrogenation of N-acyl hydrazones and with TOFs up to 1000 h-1 would be active enough for a technical application. Rh-josiphos complexes are the catalysts of choice for the hydrogenation of phosphinyl imines. Recently developed (penta-methylcyclopentyl) Rh-tosylated diamine or amino alcohol complexes are active for the transfer hydrogenation for a variety of C = N functions, and can be an attractive alternative for specific applications. 

A Ru-Josiphos catalyst was highly selective for the hydrogenation of an intermediate for an anthrax lethal factor inhibitor with a tetra-substituted C=C bond, as depicted in Figure 37.8 (Merck [44]). Rh-Josiphos (Lonza [42]) and Rh-Bo-Phoz (Eastman [45]) catalysts were effective for the hydrogenation of an exocy-clic and a cyclopropyl-substituted C=C bond. 

During the course of the development of a new technical synthesis at Lonza for biotin (a water-soluble vitamin), the Rh-Josiphos-catalyzed diastereoselective hydrogenation of a tetrasubstituted C=C bond turned out to be a key step [40, 42, 81] (Fig. 37.19). 

Besides Ir-diphosphines, two more catalyst systems have shown promise for industrial application. As mentioned in Section 37.5.2, the Rh-Josiphos-cata-lyzed hydrogenation of unprotected /1-dehydro amino acid derivatives by Merck actually involves the hydrogenation of a C=N and not a C=C bond (see Fig. 37.10) [3, 51]. Noyori s Ru-PP-NN catalyst system seems also suitable for C=N hydrogenation [129], and was successfully applied in a feasibility study by Dow/Chirotech for the hydrogenation of a sulfonyl amidine [130]. Avecia also showed the viability of its CATHy catalyst for the transfer hydrogenation of phosphinyl imines [115] (see Fig. 37.34). 

Rh complexes of ferrocene-based ligands are very effective for the hydrogenation of several types of dehydroamino (2,3,29,41,42,44) and itaconic acid derivatives (4,5,28) as well as for enamide 45, enol acetate 26, and a tetrasubstituted C = C-COOH 21. Of particular interest are substrates that have unusual substituents (41,42,44) at the C = C moiety or are more sterically hindered than the usual model compounds (21,42). Table 15.10 lists typical examples with very high ee s and often respectable TONs and TOFs. Several industrial applications have already been reported using Rh-Josiphos and Ru-Josiphos (see Figure 15.7) as well as Rh-Walphos (Scheme 15.8). 

Only very low catalyst concentrations down to 5 x 10-5 kmol/m3 are consumed that keeps also the catalyst inventory very small [266], Only 0.08 mg of Rh and about 0.2 mg-13 pg of the very expensive chiral ligands (about 300-1000 /g), depending on their molecular weight, are consumed. Finally, a performance comparison for three different reactors was made for the substrate methylacetamidocinnamate and the two rhodium diphosphine complexes Rh/Josiphos and Rh/Diop (see Figure 4.57). The first reactor was a commercial Caroussel reactor (Radleys... 

Figure 4.57 Reaction performance comparison of three reactors with the most active catalysts Rh/Josiphos and Rh/Diop. Caroussel (car), helical falling-film microreactor (p) and Parr (batch) reactor (by courtesy of Elsevier) [266]. 9% conv. and 46% conv. denote a fixed conversion of 9 and 46%, respectively, which have to be achieved.

Enantioselectivity was roughly the same for the three reactors, being 80-90 and 62-65% for the Rh/Josiphos and Rh/Diop catalysts, respectively [266]. Conversion was very different. For fixed reaction time, the batch reactor and the falling-film microreactor had higher conversions than the Caroussel reactor. This was indicative of operation under mass transfer regime in the latter. On the basis of these data, it was concluded that the mass transfer coefficients kya of the helical falling-film microreactor are in between the boundaries given by the known kta values of 1-2 s 1 for small batch reactors and about 0.01 s-1 for the Caroussel reactor. 

Piperazinecarboxylic acid derivatives are interesting intermediates, e.g., for Crixivan, the well-known HIV protease inhibitor of Merck. The Rh/josiphos-catalyzed hydrogenation of a substituted cyclic enamide was used by Lonza [38] to produce >200 kg of the piperazine intermediate depicted in Scheme 11. A related catalyst was successfully employed by Merck [39] to pilot the hydrogenation of... 

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