In the presence of catalytic amounts of CeCl 3.7H 2O, [RuCl(benzene)(S)-SunPhos]Cl is a highly effective catalyst for the asymmetric hydrogenation of aromatic alpha-ketoesters. A variety of ethyl alpha-hydroxy-alpha-arylacetates have been prepared in up to 98.3% ee with a TON up to 10,000. Challenging aromatic alpha-ketoesters with ortho substituents are also hydrogenated with high enantioselectivities. The addition of CeCl 3.7H 2O not only improves the enantioselectivity but also enhances the stability of the catalyst. The ratio of CeCl 3.7H 2O to [RuCl(benzene)(S)-SunPhos]Cl plays an important role in the hydrogenation reaction with a large substrate/catalyst ratio.

A novel series of biaryl amides was identified as RORγt inhibitors through core replacement of a starting hit 1. Structure−activity relationship exploration on the biaryl moiety led to discovery of potent RORγt inhibitors with good oral bioavailability and CNS penetration. Compounds 9a and 9g demonstrated excellent in vivo efficacy in EAE mice dose dependently with once daily oral administration. KEYWORDS: RORγt inhibitor, Th17 cell differentiation, biaryl amides, EAE, multiple sclerosis T helper (Th) 17 cells, a lineage of CD4 + effector T cells characterized by the production of IL-17A and IL-17F, are pathogenic in human autoimmune inflammatory diseases including multiple sclerosis (MS). 1−4 The presence of IL-17 was detected in MS lesions, and Th17 cells were observed in the infiltrations of mouse experimental autoimmune encephalomyelitis (EAE) central nervous system (CNS). 5,6 Differentiation and function of Th17 cells are controlled by the transcription factor retinoic acid receptor-related orphan receptor-gamma-t (RORγt). 7−9,11 It has been shown that the genetic deficiency of RORγt in mice severely impaired Th17 cell differentiation and conferred resistance to EAE. 10 RORγt inhibitors has potential utility in reducing the activity of Th17 cells and therefore can be developed as therapeutic agents for the treatment of Th17 cell mediated autoimmune diseases. 12−18 A few small molecule RORγt inhibitors have been reported in literature. 19 Digoxin, 20 SR1001, 21 and ursolic acid 22 were first reported to inhibit RORγt and ameliorate EAE in mice via intraperitoneal administration. Other small molecular RORγt inhibitors 23−31 were later disclosed. Recently, we reported discovery of thiazole ketone amides (e.g., 2) and thiophene ketone amides (e.g., 3) as novel RORγt inhibitors based on a high throughput screening (HTS) hit 1 (Figure 1). 32 These ketones, especially the thiophene ketones, showed good RORγt activities but were poorly orally bioavailable and lack of CNS penetration that is believed to be important for developing an effective oral MS drug. In this Letter, we report the discovery of novel biaryl amides as first potent, orally bioavailable, and CNS penetrant RORγt inhibitors, which demonstrated EAE in vivo efficacy dose dependently via oral administration.The lack of CNS penetration of thiazole/thiophene ketones was attributed to their ketone moiety as the nonketone thiazole amide 1 is CNS penetrant with a brain-to-blood ratio (Br/Bl) of 1.5 in a mouse CNS study (i.p., 2 mg/kg). 33 Encouraged by

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An integrated carbon-sulfur (CSG/PC) membrane with dual shuttle-inhibiting layers was prepared by inserting graphene "nets" and a porous carbon (PC) skin, and the membrane achieved an extraordinary cycling stability up to 1000 cycles with an average Coulombic efficiency of ∼100%.