The enantioselective hydrogenation of the aromatic β-ketoesters, methyl 3-phenyl-3-oxypropanoate (1) and its p-methoxy-analogue (2), was studied over tartaric acid-modified Raney nickel catalysts. A competitive hydrogenation approach was used to clarify the catalytic behaviors of the enantio-differentiating hydrogenation of aromatic β-ketoesters over tartaric acid-modified Raney nickel, malic acid-modified Raney nickel, and unmodified Raney nickel in comparison with aliphatic one, represented by methyl acetoacetate. We found that the enantioselectivity could be elucidated by the interaction modes between the surface modifier, Ni metal surface, and the substrate as well as the keto/enol ratio of the substrate. We suggest that the moderate enantioselectivity of 1 over tartaric acid-modified Raney nickel is the result of distorted, weak two-point hydrogen bond interactions with surface tartrate due to unfavorable phenyl–Ni metal surface interactions. The p-methoxy group of 2 suppresses the phenyl–Ni metal surface interactions, resulting in an increase in the enantioselectivity of 2 over tartaric acid-modified Raney nickel. Ligand acceleration effects were observed with methyl acetoacetate and 2 but not with 1.Methyl (R)-3-hydroxybutyrateC5H10O386%ee[α]D20 = −19.7 (neat)Source of chirality: (R,R)-tartaric acid modifiedRaney nickel catalystAbsolute configuration (R)Methyl (S)-3-phenyl-3-oxypropanoateC10H12O352%ee[α]D20 = −8.5 (c 1.0, ethanol)Source of chirality: (R,R)-tartaric acid modifiedRaney nickel catalystAbsolute configuration (S)Methyl (S)-3-p-methoxyphenyl-3-oxypropanoateC11H14O472%ee[α]D20 = −27.7 (c 0.5, CHCl3)Source of chirality: (R,R)-tartaric acid modifiedRaney nickel catalystAbsolute configuration (S)

The effects of the pretreatment and Pd-distribution on the enantioselective hydrogenation of α-phenylcinnamic acid over cinchonidine-modified Pd/C and Pd/Al2O3 were studied by use of EXAFS techniques combined with thiol adsorption. It is suggested that the enhanced performance by the H2-pretreatment at 353 K is ascribed to the elimination of contaminants and/or H2O from Pd/C. The Pd–S CN is related to the Pd dispersion and the reactivity and diffusivity of thiols used.

Enantioselective hydrogenation of α-phenylcinnamic acid (PCA) and p,p′-dimethoxyphenylcinnamic acid (DMPCA) was studied over a variety of commercial 5 % Pd/C catalysts to reveal catalyst properties suitable for obtaining high enantioselectivity. The catalysts were characterized by CO adsorption, X-ray photoelectron spectroscopy (XPS), and transmission electron microscopy (TEM). It is confirmed that pretreatment at 353 K under atmospheric pressure of H2 before modification with cinchonidine is very effective for all the Pd/C catalysts used here to improve the selectivity and reaction rate. It is suggested that the distribution of Pd metal particles is crucial to attain high selectivity (ee% = 79 ± 1 for PCA, 89 ± 2 for DMPCA): a uniform or eggshell-type distribution of Pd is more suitable than an egg-white or egg-yolk-type distribution. It is also suggested that the dispersion of Pd metal particles controls the enantioselectivity over cinchonidine (CD)-modified Pd/C catalysts. XPS techniques are proposed to provide a convenient method to find desirable catalysts. The choice of such Pd/C catalysts could facilitate high-throughput guided study on highly enantioselective hydrogenation of α,β-unsaturated carboxylic acids.

The enantioselective hydrogenation of α-phenylcinnamic acid (PCA) was performed using a cinchonidine (CD)-modified Pd/C catalyst, and the conversion and enantiomeric excess (ee) of the product were monitored during the reaction. Low ee values were observed only during the initial stages of the reaction (<20 % conversion) in the presence of benzylamine as reported, and the use of the 3-ethyl-analogue instead of 3-vinyl natural CD as a modifier resulted in no decline in ee despite the presence of amine. Because the 3-ethyl moiety was generated in situ during the modification process prior to the reaction of PCA, the role of the 3-substituent was unclear, as is the case with Pt/ketone hydrogenation systems. To determine the reasons for the induction, the initial stage of the reaction was mimicked using a very small amount of substrate (stoichiometric catalysis). During this study, a minimum quantity of benzylamine additive was found to be necessary to increase the ee and the reaction rate, indicating that benzylamine functioned during the induction period.

The hydrogenation of 5-alkylidene-2,4-thiazolidiones was studied using Pd/C to establish an alternative process for pioglitazone synthesis. The reportedly sluggish reactivity was due to the high reaction temperature in formic acid. The conditions were improved to 1 atm at 296 K, which results in a quantitative product with a smaller amount of the catalyst.

Optically active (2S,4R)-2-hydroxy-4-pentyl enol ether was prepared for the first time and subjected to hydroxy-directed oxidations at the olefinic group. Treatment with m-chloroperbenzoic acid and tert-butyl hydroperoxide/vanadium acetylacetonate resulted in the same stereoface differentiation at the olefin, with diastereomeric excesses as high as 79% and 92%, respectively, whereas the stereochemistry of the products of subsequent nucleophilic additions of the hydroxy group was opposite.(2S,4R)-4-(Cyclohex-1-en-1-yloxy)pentan-2-olC11H20O2[α]D23=+51.0 (c 0.52, CH2Cl2)Absolute configuration: (2S,4R)Source of chirality: (2R,4R)-2,4-pentanediolC19H26O4(2S,4R)-4-(Cyclohex-1-en-1-yloxy)pentan-2-yl 4-methoxybenzoate[α]D23=+23.0 (c 1.02, CH2Cl2)Absolute configuration: (2S,4R)Source of chirality: (2R,4R)-2,4-pentanediol

Intramolecular cyclization of an α-carbon radical of ester carrying a chiral 2,4-pentanediol tether shows low stereoselectivity when the radical carbon has an alkyl substituent, while the selectivity becomes high to give a single stereoisomer (>99% pure) when the substituent is an aryl group. The difference in the selectivity is attributable to the change in the rate-determining step from the conformational process to the cyclization.

Cinchonidine-modified Pd/C applicable for the high-throughput-guided study was developed. Commercial Pd/C catalysts were employed for the enantioselective hydrogenation of phenylcinnamic acid after the pretreatment, and some of the catalysts were found to result in the sufficient enantioselectivity. The Pd/C catalysts suitable for the cinchonidine modification were characterized by TEM and XAFS to have highly dispersed metal, 2.2 nm of the mean particles size for the best catalyst. The pre-modified Pd/C could be stored in a suspension accompanying with gradual decease in the product ee. The pre-modified catalyst was applicable for the high-throughput screening by using a parallel reactor in the 1/5-scale reactions.

Enantioselective hydrogenation of methyl 4-(4-biphenylyl)-3-oxobutanoate over a tartaric acid-modified Raney nickel catalyst gave the title compound in 82% ee, which was enantiomerically enriched by recrystallizations. The product was converted to an (R)-3-acetoxyglutaric acid half ester via a ruthenium-catalyzed oxidation.(3R)-Methyl 4-(4-phenyl)phenyl-3-hydroxybutanoateC17H18O3Ee = 96%[α]D20=+18.1 (c 0.4, methanol)Source of chirality: enantioselective hydrogenationAbsolute configuration: (3R)(3R)-Methyl hydrogen 3-acetoxypentanedionateC8H12O6Ee = 96%[α]D20=+7.8 (c 0.3, CH2Cl2)Source of chirality: chemical conversionAbsolute configuration: (3R)