Rh/duphos

Based upon the above-mentioned assumptions, the reaction scheme in Figure 3.1 is reduced to the scheme shown in Figure 3.2A. It should be noted that active catalyst is used in the reaction scheme in Figure 3.1 while most asymmetric hydrogenation processes use a pre-catalyst (11). Hence, the relationship between the precatalyst and active catalyst needs to be established for the kinetic model. The precatalyst used in this study is [Et-Rh(DuPhos)(COD)]BF4 where COD is cyclooctadiene. The active catalyst (Xq) in Figure 3.2A is formed by removal of COD via hydrogenation, which is irreversible. We assume that the precatalyst is completely converted to the active catalyst Xq before the start of catalytic reaction. Hence, the kinetic model derived here does not include the formation of the active catalyst from precatalyst. 

Manufacture of rhodium precatalysts for asymmetric hydrogenation. Established literature methods used to make the Rh-DuPhos complexes consisted of converting (1,5-cyclooctadiene) acetylacetonato Rh(l) into the sparingly soluble bis(l,5-cyclooctadiene) Rh(l) tetrafluoroborate complex which then reacts with the diphosphine ligand to provide the precatalyst complex in solution. Addition of an anti-solvent results in precipitation of the desired product. Although this method worked well with a variety of diphosphines, yields were modest and more importantly the product form was variable. The different physical forms performed equally as well in hydrogenation reactions but had different shelf-life and air stability. 

It is well known that acrylates undergo transition metal catalyzed reductive aldol reaction, the silanes R3SiH first reacting in a 1,4 manner and the enolsilanes then participating in the actual aldol addition.57,58 A catalytic diastereoselective version was discovered by arrayed catalyst evaluation in which 192 independent catalytic systems were screened on 96-well microtiter plates.59 Conventional GC was used as the assay. A Rh-DuPhos catalyst turned out to be highly diastereoselective, but enantioselectivity was poor.59... 

In the early 1990s, Burk introduced a new series of efficient chiral bisphospholane ligands BPE and DuPhos.55,55a-55c The invention of these ligands has expanded the scope of substrates in Rh-catalyzed enantioselective hydrogenation. For example, with Rh-DuPhos or Rh-BPE as catalysts, extremely high efficiencies have been observed in the asymmetric hydrogenation of a-(acylamino)acrylic acids, enamides, enol acetates, /3-keto esters, unsaturated carboxylic acids, and itaconic acids. 

Less-common types of C=N derivatives can also be reduced enantioselectively. An interesting example is the hydrogenation of the aromatic N-acyl hydrazones 13 with the Rh-duphos catalyst (Table 34.6 entry 6.1). This reaction was devel-... 

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. 

Dow/Chirotech [35, 36], Topcro Pharma [37] as well as by Solvias [38] using Rh-DuPhos catalysts (Fig. 37.6). Besides these successful examples, a process using Rh-DuPhos was abandoned because of reproducibility problems due to impurities carried over from the preceding step, and because of concerns about the toxicity of 2-nitropropane, even though ee-values of 99% were achieved [39]. 

The hydrogenation of enamides and enol acetates without acid function is often more demanding, and at present is not applied widely. Besides a bench-scale application by Roche with a Ru-biphep catalyst [55], two examples are of interest a pilot process for a cyclic enol acetate by Roche [55], and a feasibility study by Bristol-Myers Squibb [56], both using Rh-DuPhos catalysts (Fig. 37.11). In the latter case, despite very good ee-values, a chiral pool route was finally chosen. Chiral Quests Rh-f-KetalPhos (see Fig. 37.9) has been shown to hydrogenate a variety of substituted aryl enamide model substrates at r.t., 1 bar, with very promising catalyst performance (ee 98-99%, TON 10000) [47]. 

The hydrogenation was carried out on 12-kg scale for Pfizer by Dow/Chirotech, using a cationic Rh-DuPhos catalyst [79] and on 250-kg scale by PPG-Sipsy with a Ru-biphep complex [80]. Both catalysts achieved very high enantioselectivities and medium activities. 

Fig. 44.3 Comparison of hydrogenation rates using various Rh-DuPhos-complexes containing different spectator ...

While Rh-DuPhos mediated asymmetric hydrogenation of acyclic enol esters shows high levels of enantioselectivity, it does not provide the same high... 

We calculate only a 0.7 kcal/mol difference between R-DIHY-B and S-DIHY-B, with nearly identical migratory insertion barriers, so we would predict only modest enantioselectivity if a DuPHOS-ligated catalyst reacted along the hydride route. However, we are not aware of any evidence that a solvated Rh-DuPHOS catalyst reacts with hydrogen to form dihydrides. 

Chiral rhodium-DuPHOS complexes are highly efficient catalyst for the enantioselective hydrogenation of enamides. One drawback of these catalysts is that they are easily oxidised and inert conditions are required for optimal results. The methyl- and ethyl substituted Rh-DuPHOS compounds, 3a and 3b, have been successfully applied in the reduction of a-acetamidocinnamic acids in [C4Ciim][PF6], Scheme 3.7.[7,39] While activities and selectivities are slightly lower compared to the homogeneous reaction in 2-propanol, the ionic liquid-immobilised catalyst is less prone to oxidation and recycling is feasible at least three times. 

Simple a-substituted styrenes are reduced in the presence of RuCl2(DuPhos)(DMF) . The reactivity of the ruthenium catalyst is enhanced by the addition of potassium te/t-butoxide, which may facilitate generation of a ruthenium hydride. The products are obtained under low hydrogen pressures and selectivities obtained are up to 89% ee (eq 8). Neutral Rh-DuPhos complexes catalyze the hydrogenation of a,3-unsaturated acids such as tiglic acid (eq 9). The product is obtained in quantitative yield and good enantioselectivity. ... 

Rh/DuPHOS ee 96 % TON 50000 TOF 5200 pilot process, kg scale Ciba-Geigy/Solvias [16]... 

Preliminary investigations revealed that cationic rhodium complexes [(COD)Rh(-DuPHOS)] OTf bearing the Et-DuPHOS or Pr-DuPHOS ligands [2,5-substitu-ents on phospholanes (1) R = Et or Pr, respectively] were effective catalyst precursors for highly enantioselective hydrogenation of a broad range of A-acetyl a-enamide esters and acids (5 R = Me) (Scheme 2) [4]. 

Scheme 12.14 Rh-duphos complex adsorbed onto the inner surface of MCM-41.

Scheme 8.3 Rh DuPHOS/BPE catalyzed asymmetric hydrogenation of enamides.

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