Enantioselective Hydrogenation of a,P-Unsaturated Acids or Esters

The enantioselective hydrogenation of a,p-unsaturated acids or esters, using 5wt% Pt/Al203 or Pd/Al203 commercial catalysts doped with cinchonidine (CD), was deeply investigated to evidence the specific activity of Pd or Pt and the role of the reaction parameters and solvent polarity. Finally, the steric and electronic effects of different substituent groups were also studied. 

The enantioselective hydrogenation of oc,p-unsaturated acids (or their esters) and a-ketoesters, mainly pyruvates, (Figure 1) is a subject of high industrial relevance in the pharmaceutical and agrochemical areas, considering the very different activity of pure enantiomers (1,2). However, the former reaction has been up to today less investigated, evidencing a lower enantioselectivity (maximum ee 38% in comparison to 90% for the ethyl pymvate) (3,4). 

Asymmetric hydride reduction using Hantzsch ester has recently been extensively explored in organocatalysis using iminium-based catalysts or Brpnsted acid catalysts [72a-c], As an advance to their asymmetric conterion-directed catalysis (ACDC), List and coworkers found that the combination of simple primary amino acids such as L-valine with a chiral phosphoric acid led to an effective primary aminocatalyst for asymmetric transfer hydrogenation of a,P-unsaturated ketones (Scheme 5.43) [72d]. The catalysis could be applied to a range of substrates with good yields and excellent enantioselectivity. 

One of the standard methods for preparing enantiomerically pure compounds is the enantioselective hydrogenation of olefins, a,/3-unsaturated amino acids (esters, amides), a,/3-unsaturated carboxylic acid esters, enol esters, enamides, /3- and y-keto esters etc. catalyzed by chiral cationic rhodium, ruthenium and iridium complexes ". In isotope chemistry, it has only been exploited for the synthesis of e.p. natural and nonnatural H-, C-, C-, and F-labeled a-amino acids and small peptides from TV-protected a-(acylamino)acrylates or cinnamates and unsaturated peptides, respectively (Figure 11.9). This methodology has seen only hmited use, perhaps because of perceived radiation safety issues with the use of hydrogenation procedures on radioactive substrates. Also, versatile alternatives are available, including enantioselective metal hydride/tritide reductions, chiral auxiliary-controlled and biochemical procedures (see this chapter. Sections 11.2.2 and 11.3 and Chapter 12). 

Hydrogenation of -substituted ( )-p-(acylamino)acrylates catalyzed by the BINAP-Ru es P-amino acid derivatives with high enantiopurities (Scheme 1.9) [8S]. The Z double-bond isomers that have an intramolecular hydrogen bond between amide and ester groups are more reactive but are hydrogenated with poor enantioselectivity. The sodium or triethylammonium salts of the unsaturated acid are hydrogenated in water containing a sulfonated p-Ibl-MeO-BIPHEP-Ru ditrifluoroacetate complex with an S/C of KKX)-10,000 and an up to 99% optical... 

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