Catalyst DuPhos

The use of enzyme technology has also been exemplified in a Chirotech process for the synthesis of both enantiomers of the hydrogenation catalyst DuPHOS (80) [2,86]. A hexanediol mixture consisting of 50% meso and 50% racemic diol 77 was acylated with the aid of immobilized CAL-B (Scheme 23). Only the (i )-configured alcohol was converted by the enzyme and led to the monobutyrate (RyS)-7S and the bisbutyrate RyR)-79. The unchanged (S,S)-diol 77 could be removed by extraction with water and was purified by crystallization from ethyl acetate, to reach an optical purity of 98% ee and 88% de. The mesylate of alcohol (RyS)-7S could be inverted with potassium acetate, and saponification of this acetate and of compound RyR)-79 followed by a crystallization step provided the enantiopure diol (RyR)-77 in 48% yield. Although this procedure was used to produce approximately 30 kg of DuPHOS, it has not been used further for commercial catalyst production. 

It was assumed that pyridine derivative 181 yielded pyrido[l,2-c]pyrimidine betaine 182 under catalytic hydrogenation conditions over (5,S)-Et-DuPHoS-Ph catalyst (99TL1211). 6,7-Dehydro derivative 184 of trequinsin (3) was obtained from pyrimidinone 183 by heating in an 1 1 mixture of MeOH and cone. HCl under reflux (97IJC(B)349). 

An iron complex-catalyzed asymmetric hydrosilylation of ketones was achieved by using chiral phosphoms ligands [68]. Among various ligands, the best enantios-electivities (up to 99% ee) were obtained using a combination of Fe(OAc)2/(5,5)-Me-Duphos in THF. This hydrosilylation works smoothly in other solvents (diethylether, n-hexane, dichloromethane, and toluene), but other iron sources are not effective. Surprisingly, this Fe catalyst (45% ee) was more efficient in the asymmetric hydrosilylation of cyclohexylmethylketone, a substrate that proved to be problematic in hydrosilylations using Ru [69] or Ti [70] catalysts (43 and 23% ee, respectively). 

Dupont s DuPhOS catalyst A.symmetric hydrogenation for making S-metolachlor Blaser and Spindler... 

Eastman Chem. Co. has utilized a Ru(I) (R,R)-dimethyl-DuPhOS catalyst, based on singleisomer 2,5-dialkylphospholane ligands, to hydrogenate an enol ester such as 4-phenyl-1,3-butadien-2-yl acetate, to give 4-phenyl-3-buten-(2R)-yl acetate in 94% ee (Stinson, 1999). 

The pharmaceutical industry has been giving increased attention to homogeneous asymmetric hydrogenation for the synthesis of chiral molecules due to significant improvements in this technology (1). We recendy synthesized a chiral a-amino acid intermediate using Et-DuPhos-Rh catalyst, obtaining enantiomeric pmities (EP) of... 

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. 

It should be noted that the reaetion using Et-DuPhos-Rh catalyst is not limited by hydrogen mass transfer sinee the hydrogen mass transfer rate is at least 5 times as fast as the initial reaction rate. Furthermore, the overall reaction time, 700 minutes, remained the same regardless of the size of the reactor. 

Catalyst Decay. Asymmetric hydrogenation of the SM using the Et-DuPhos-Rh catalyst exhibits a catalyst threshold behavior. When the initial charge of the catalyst is below this threshold value, the reaction is not completed. This indicates that the catalyst may become deactivated. 

The results from the kinetic study using Et-DuPhos-Rh catalyst lead to the following snggestions for reactivity improvement ... 

Figure 3.8 Impact of MSA Addition on Figure 3.9 Reactivity of Et-FerroTane-Rh Induction Time and Reactivity. Catalyst vs. Et-DuPhos-Rh Catalyst.

Table 3.n Criteria for Commercially Viable Process Et-DuPhos-Rh Catalyst... 

Search for More Active Catalyst. An extensive screening effort was undertaken to find a catalyst more active than Et-DuPhos-Rh. As a result of this effort, Et-FerroTane-Rh and some other competitive catalysts were found. The reactivity of Et-FerroTane-Rh and Et-DuPhos-Rh, is presented in Figure 3.9. The reaction rate with Et-FerroTane-Rh catalyst is very high with a small induction period, and the total time for reaction completion is drastically less than with Et-DuPhos-Rh. 

The use of rhodium catalysts for the synthesis of a-amino acids by asymmetric hydrogenation of V-acyl dehydro amino acids, frequently in combination with the use of a biocatalyst to upgrade the enantioselectivity and cleave the acyl group which acts as a secondary binding site for the catalyst, has been well-documented. While DuPhos and BPE derived catalysts are suitable for a broad array of dehydroamino acid substrates, a particular challenge posed by a hydrogenation approach to 3,3-diphenylalanine is that the olefin substrate is tetra-substituted and therefore would be expected to have a much lower activity compared to substrates which have been previously examined. 

Catalyst screen at 90 psi hydrogen at r.t. and 60 °C for 20 h - No product detected Pfaltz-lr-BARF-cat, (Et-Duphos)Rh(COD)BF4,(BINAP)Ru(ll)CI2, Phanephos/(COD)2RhBF4, Josiphos SL-J009-1/(COD)RhCI,... 

The carbon supported AHC catalysts, (Rh(COD)(Me-Duphos)/PTA/C (AHC-1) and Rh(COD)(BoPhoz)/PTA/C, (AHC-2) were prepared using the general procedure described previously (1-3). The catalysts contained about 0.9% Rh which corresponds to about an 8.5% load of the anchored complex. The hydrogenations were run using the low pressure apparatus previously described (11) under the conditions listed in the discussion. 

Using this technique, Brandts et al. (24-26) have successfully anchored two homogeneous catalysts, that is [(AyR)-(Me-DuPHOS)Rh(COD)]BF4 and the non-chiral [Rh(DiPFc)(COD)BF4],... 

Complex 7-AI2O3/PTA/ (/< ./< )-(Mc-DuPHOS)Rh(COD) 1 (1) was prepared and tested in the hydrogenation of the prochiral substrate methyl-2-acetamidoacrylate (MAA). After full conversion, the products were separated from the catalyst and analyzed for Rh and W content and product selectivity. The catalyst was re-used three times. Analytical results show no rhodium leaching is observed. Complex 1 maintains its activity and selectivity in each successive run. The first three runs show tungsten (W) leaching but after that no more W is detectable. The leached W comes from the excess of PTA on alumina. The selectivity of both tethered and non-tethered forms gave the product in 94% ee. 

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... 

Using unmodified Ru-BINAP and Rh-Et-DUPHOS catalysts Jacobs et al. performed hydrogenation reactions of dimethylitaconate (DMI) and methyl-2-acetamidoacrylate (MAA), respectively. [11,47] The continuous hydrogenation reaction was performed in a 100 mL stirred autoclave containing an MPF-60 membrane at the bottom, which also acts as a dead-end membrane reactor. The hydrogenation reactions will be discussed in paragraph 4.6.1. 

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. 

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