Asymmetric Hydrogenation of Acrylic Acids

By these procedures, the anti-inflammatory drugs (S)-ibuprofen and (S)-naproxen (Equation 15.41) can be synthesized by asymmetric hydrogenation. Again, one challenging aspect of this route to naproxen is the synthesis of the substrate, and for this reason, asymmetric hydrogenation has not become the major commercial route to this compound. 

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Only limited successful examples of asymmetric hydrogenation of acrylic acids derivatives have included the use of chiral Rh complexes (Scheme 1.17). The diamino phosphine (28) utilizes selective ligation of the amino unit to a Rh center and also exerts electrostatic interaction with a substrate. Its Rh complex catalyzes enantioselective hydrogenation of 2-methylcinnamic acid in 92% optical yield [116], Certain cationic Rh complexes can attain highly enantioselective hydrogenation of trisubstituted acrylic acids [ 1171. 2-(6 -Methoxynaphth-2 -yl)acrylic acid is hydrogenated by an (.S ..S )-BIPNOR- Rh complex in methanol at 4 atm to give (.S)-naproxen with 98% ee but only in 30% yield [26]. 

Enantioselective catalytic hydrogenation. Hoffmann-LaRoche chemists have examined the efficiency of DIOP (1) and a number of related phosphines as ligands for asymmetric hydrogenation of acrylic acids for synthesis of (R)-6-methyl-tryptophan (6), of potential value as a non-nutritive sweetening agent. Of these, 2 and the less available 3 showed the most promise. Thus catalytic hydrogenation of 4... 

Enzymatic hydrogenations generate optically pure isomers attempts to initiate such processes are made on metal-catalyzed hydrogenations. Asymmetric hydrogenation can fill the need for asymmetric compounds of which only one enantiomorph is active, e.g., amino acids such as L-lysine, 1 (indispensable in animal feeds), L-phenylalanine, 2 (a sweet peptide component), L-dopa 3 (a drug for Parkinsonism), are required in the L-form for human or animal consumption. Consequently, most of the examples investigated are related to the asymmetric hydrogenation of acrylic acid or cinnamic acid derivatives. 

Hydrogenation Easily prepared monodentate phosphoramidite ligands containing a BINOL residue are employed in conjunction with (cod)2RhBp4 in asymmetric hydrogenation of dehydroamino acid derivatives and a-substituted acrylic esters (ee > 99% reachable). 

In recent years, the catalytic asymmetric hydrogenation of a-acylamino acrylic or cinnamic acid derivatives has been widely investigated as a method for preparing chiral a-amino acids, and considerable efforts have been devoted for developing new chiral ligands and complexes to this end. In this context, simple chiral phosphinous amides as well as chiral bis(aminophosphanes) have found notorious applications as ligands in Rh(I) complexes, which have been used in the asymmetric hydrogenation of a-acylamino acrylic acid derivatives (Scheme 43). 

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. 

Table 1 Asymmetric hydrogenation of (Z)-2-(acetamido) cinnamic acid, 2-(acetamido) acrylic acid and their methyl esters...

Compared with 3-alkyl-3-(acylamino)acrylic acid derivatives, much less success has been obtained in the asymmetric hydrogenation of 3-aryl-3-(acylamino)acrylic acid derivatives. An Et-FerroTANE-Rh catalyst has provided up to 99% ee for the hydrogenation of a series of (E)-3-aryl-3-(acylamino)acrylates.95 Since (E)-3-aryl-3-(acylamino)-acrylic acid derivatives are difficult to obtain in large scales compared to (Z)-3-aryl-3-(acylamino)acrylic acid... 

The effects of added C02 on mass transfer properties and solubility were assessed in some detail for the catalytic asymmetric hydrogenation of 2-(6 -meth-oxy-2 -naphthyl) acrylic acid to (Sj-naproxen using Ru-(S)-BINAP-type catalysts in methanolic solution. The catalytic studies showed that a higher reaction rate was observed under a total C02/H2 pressure of ca. 100 bar (pH2 = 50bar) than under a pressure of 50 bar H2 alone. Upon further increase of the C02 pressure, the catalyst could be precipitated and solvent and product were removed, at least partly by supercritical extraction. Unfortunately, attempts to re-use the catalyst were hampered by its deactivation during the recycling process [11]. 

TABLE 6-1. Asymmetric Hydrogenation of Trisubstituted Acrylic Acids Catalyzed by Chiral Ferrocenylphosphine-Rhodium Complexes... 

Table 12.4 Rh-Catalyzed asymmetric hydrogenation of a-(acylamino)acrylic acids and esters.

Furthermore FERRIPHOS ligands bearing alkyl groups instead of dimethy-lamino substituents proved to be excellent ligands in the asymmetric hydrogenation of a-acetamidoacrylic acids[34] and acetoxy acrylic esters[35l Their air stability and the easy modification of their structure make the FERRIPHOS ligands particularly useful tools for asymmetric catalysis. 

BINAP core-functionalized dendrimers were synthesized by Fan et al. (36), via condensation of Frechet s polybenzyl ether dendritic wedges to 5,5 -diamino-BINAP (26—28). The various generations of BINAP core-functionalized dendrimers were tested in the ruthenium-catalyzed asymmetric hydrogenation of 2-[p-(2-methyl-propyl)phenyl]acrylic acid in the presence of 80 bar H2 pressure and in a 1 1 (v/v) methanol/toluene mixture. As later generations of the in situ prepared cymeneruthe-nium chloride dendritic catalysts were used, higher activities were observed (TOF values were 6.5, 8.3, and 214 h respectively). Relative to those of the BINAP... 

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