Asymmetric hydrogenations with DuPHOS

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... 

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]. 

Examples of a-amino acid precursors that have been reduced by asymmetric hydrogenation with a rhodium-DuPhos catalyst in commercial processes. Data from references 224-226. 

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. 

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. 

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). 

The asymmetric hydrogenation of the E- or Z-isomer of y9-(acetylamino)-y9-methyl-a-dehydroamino acids with Me-DuPhos-Rh catalyst provides either diastereomer of the N,N-protected 2,3-diaminobutanoic acid derivatives with excellent enantioselectivity (Eqs. 3 and 4) [95]. 

Although enol esters have a similar structure to enamides, they have proven more difficult substrates for asymmetric hydrogenation, which is evident from the significantly fewer number of examples. One possible explanation is the weaker coordinating ability of the enol ester to the metal center, as compared to the corresponding enamide. Some rhodium complexes associated with chiral phosphorous ligands such as DIPAMP [100, 101] and DuPhos [102] are effective for asymmetric hydrogenation of a-(acyloxy)acrylates. 

For example, a wide range of a-(acyloxy)acrylates have been hydrogenated with excellent enantioselectivity using the Et-DuPhos-Rh catalyst. High selectivities are also obtained for the asymmetric hydrogenation of the B/Z-isomeric mixtures of yS-substituted derivatives (Eq. 12). Asymmetric hydrogenation of enol phosphates with either Du-Phos-Rh or BPE-Rh catalyst provides moderate to excellent enantioselectivity (Eq. 13)... 

Only one paper has reported on catalytic asymmetric hydrogenation. In this study by Corma et al., the neutral dimeric duphos-gold(I)complex 332 was used to catalyze the asymmetric hydrogenation of alkenes and imines. The use of the gold complex increased the enantioselectivity achieved with other platinum or iridium catalysts and activity was very high in the reaction tested [195] (Figure 8.5). 

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