A concise synthesis of both enantiomers of ligand 2 and rhodium complex 5 is presented. The crux of the synthesis is a chiral HPLC separation of the enantiomers of 4. Rhodium complex 5 possesses three hindered quadrants in the steric environment within which a substrate binds. Evidence is presented that this configuration leads to high enantioselectivity (>99% ee) for rhodium-catalyzed asymmetric hydrogenation of alpha-acetamido dehydroamino acids, 6a-e. High enantioselectivities are also reported for the hydrogenation of a substrate precursor, 8, of pharmaceutical candidate, pregabalin. Advantages for large-scale hydrogenation of 8 using catalyst 5a vs Rh-Me-DuPhos are discussed.

A concise enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (1, Pregabalin) has been developed. The key step is the asymmetric hydrogenation of a 3-cyano-5-methylhex-3-enoic acid salt 2 with a rhodium Me-DuPHOS catalyst, providing the desired (S)-3-cyano-5-methylhexanoate 3 in very high ee. Subsequent hydrogenation of the nitrile 3 with a heterogeneous nickel catalyst provides Pregabalin 1 in excellent overall yield and purity.

The rhodium complex of (R)-(tert-butylmethylphosphino)(di-tert-butylphosphino)methane used in Rh-catalyzed asymmetric hydrogenation of representative substrates 3-14 demonstrated high catalytic activity coupled with wide scope and nearly perfect enantioselectivity. Mechanistic studies (NMR and DFT computations) were carried out in order to investigate the mechanism of the enantioselection in the asymmetric hydrogenation of (Z)-alpha-acetamidocinnamate (3). Although catalyst-substrate complexes 15a,b with the double bond coordinated near the non-"chiral" phosphorus atom were formed as kinetic products upon the addition of 3 to solvate complex 2 at -100 degrees C, they rapidly rearranged to more stable isomers 15c,d with the double bond coordinated near the "chiral" phosphorus atom. The thermodynamic and kinetic parameters of the interconversion between 15c and 15d were determined by NMR; mainly, the interconversion occurred intramolecularly via nonchelating catalyst-substrate complexes 16. The equilibrium between 15d and 16d was directly observed from NMR line shape changes at temperatures ranging from -100 to -40 degrees C, whereas no such equilibrium was observed for 15c. This result was accounted for computationally by determining the corresponding transition states for the methanol insertion into 15c,d. Three sets of experiments of the low-temperature hydrogenation of different catalyst-substrate complexes gave the same order and sense of enantioselectivity (97% ee (R)) even in the case when 15c, having Re-coordinated double bond, was hydrogenated under the conditions precluding its isomerization to 15d. It was concluded that the hydrogenation of 15c,d does not occur directly, but is preceded by the dissociation of the double bond to result in the more reactive species 16. This indicates that enantioselection must occur at a later step of the catalytic cycle. DFT computations of association and migratory insertion steps suggest that enantioselection takes place during the association step when chelating dihydride 19d.MeOH is formed from nonchelating dihydride 18d.