Phase-transfer catalysis is one of the most useful methodologies for practical syntheses given its operational simplicity and mild reaction conditions that enable its application in industrial processes. Cinchona alkaloids have been a popular, natural source of practical organocatalysts due largely to their excellent commercial availability and low cost. Since the first Cinchona alkaloid-derived phase-transfer catalysts was disclosed in 1981, diverse generations of Cinchona-derived phase-transfer catalysts have been developed and successfully applied to various asymmetric syntheses. In this feature article, we describe the generation of Cinchona-derived chiral phase-transfer catalysts according to the development stages and our efforts toward the design of polymeric Cinchona phase-transfer catalysts, the effects of the electronic functional group incorporated in the catalysts, and their application in asymmetric organic reactions.

Aims: Increased hepatic oxidative stress and inflammation is the main cause of exacerbating nonalcoholic steatohepatitis (NASH). Retinoic acid-related orphan receptor a (RORa) regulates diverse target genes associated with lipid metabolism, and its expression level is low in the liver of patients with NASH. Here, we investigated the role of RORa in regulating hepatic oxidative stress and inflammation. Results: First, cholesterol sulfate (CS), an agonist of RORa, lowered oxidative stress that was induced by 1.5 mM oleic acid in the primary cultures of hepatocytes. Second, exogenously introduced RORa or CS treatment induced the mRNA level of antioxidant enzymes, superoxide dismutase 2 (SOD2) and glutathione peroxidase 1 (GPx1), through the RORa response elements located in the upstream promoters of Sod2 and Gpx1. Third, RORa significantly decreased reactive oxygen species levels and mRNA levels of tumor necrosis factor a (TNFa) and interleukin-1b that were induced by lipopolysaccharide or TNFa in Kupffer cells. Finally, the administration of JC1-40 decreased the signs of liver injury, lipid peroxidation, and inflammation in the MCD diet-induced NASH mice. Innovation and Conclusion: We showed for the first time that RORa and its ligands protect NASH in mice by reducing hepatic oxidative stress and inflammation. Further, the molecular mechanism of the protective function of RORa against oxidative stress in the liver was revealed. These findings may offer a rationale for developing therapeutic strategies against NASH using RORa ligands.

[structure: see text] Various N-benzylcinchonidinium salts were prepared to study electronic factors in the catalytic enantioselective phase-transfer alkylation of glycine anion equivalent. An ortho-fluoro substituent on the benzyl group in the quaternary ammonium salt dramatically increased the enantioselectivity in the alkylation. O(9)-Allyl-N-2',3',4'-trifluorobenzylhydrocinchonidinium bromide (27), which gave the highest enantioselectivity of the catalysts studied, was used to prepare 12 alpha-alkylated amino acid derivatives in 94 approximately >99% ee.

A novel enantioselective synthetic method for the construction of a quaternary carbon center from malonates via phase-transfer catalytic (PTC) alkylation has been developed. The asymmetric α-alkylation of diphenylmethyl tert-butyl α-alkylmalonates with alkylating agents under phase-transfer catalysis conditions (aq 50% KOH, toluene, 0°C) in the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide (8) as PTC catalyst afforded the corresponding α,α-dialkylmalonates in high chemical (up to 99%) and optical yields (up to 97% ee) which could be readily converted to versatile chiral intermediates. Notably, the direct double α-alkylations of diphenylmethyl tert-butyl malonate also provided the corresponding α,α-dialkylmalonates without loss of enantioselectivity. The synthetic potential of this method has been demonstrated by the preparation of α,α-dialkylamino acid and oxindole systems.