DuPhos asymmetric hydrogenations

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. 

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. 

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. 

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. 

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... 

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. 

Halide impurities may have a negative effect on the rate of a hydrogenation reaction, as was observed by Cobley et al. These authors studied the asymmetric hydrogenation of 2-methylenesuccinamic acid using [(S,S)-(Et-DuPHOS)Rh-(COD)]BF4 as catalyst [76]. They were able to obtain a 30-fold acceleration upon removal of a chloride impurity from the substrate (Scheme 44.9). 

Burk et al. reported an asymmetric hydrogenation catalyzed by [(Et-DuPhos)Rh]+ catalyst. Very high enantioselectivity was obtained. When R = z -Pr, the minor enantiomer could not be detected by chiral GC methods. The results are shown in Scheme 6-6.24... 

Allylic alcohol derivatives are quite useful in organic synthesis, so the asymmetric synthesis of such compounds via asymmetric hydrogenation of dienyl (especially enynyl) esters is desirable. The olefin functionality preserves diverse synthetic potential by either direct or remote functionalization. Boaz33 reported that enynyl ester and dienyl ester were preferred substrates for asymmetric hydrogenation using Rh-(Me-DuPhos) catalyst [Rh(I)-(R,R)-14], and products with extremely high enantioselectivity (>97%) were obtained (Schemes 6-11 and 6-12). 

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

Chirality transfer in catalytic asymmetric hydrogenation can be achieved not only by using powerful chiral ligands such as BINAP or DuPhos but also by the formation of a dynamic conformational isomer. The availability of many enantiomerically pure diols allows the production of electron-deficient, bi-dentate phosphate in the form of 27. The backbone O-R -O can define the chirality of the 0-R2-0 in complex 28, hence realizing the chirality transfer.44... 

Chiral ligand 78, bearing structural features similar to those of DuPhos, has also been synthesized and gives moderate to high enantioselectivity in the catalytic asymmetric hydrogenation of functionalized carbonyl groups. High levels... 

---