Highly enantioselective transfer hydrogenation of β-keto sulfonamides was developed via dynamic kinetic resolution using a chiral Ru(ii) catalyst with an azeotropic solution of HCO2H/Et3N as a hydrogen donor, affording α-substituted β-hydroxyl sulfonamides in good yields with excellent diastereo- and enantioselectivities. This method is featured with mild conditions, easy operation, and a broad substrate scope, which make it possible to find wide applications in the synthesis of natural products and biologically active compounds containing the α-substituted β-hydroxyl sulfonamide core.

Pregnane glycoside P57 is known as an active component of Hoodia gordonii, which has long been used as a diet with appetite suppressant property. Chemical synthesis of P57 demands installation of β-cymarosyl linkage onto the steroid aglycone. The stereoselective formation of this special 2-deoxy-β-glycosidic linkage has previously been proven to be difficult and thus a limiting step in the synthesis of P57 and its congeners. Herein, we report the glycosylation reactions with glycals as donors and TPHB (triphenylphosphine hydrobromide) as promoter and a convergent synthesis of P57 via a β-selective glycosylation with a trisaccharide glycal donor.Scheme 1 Prepartion of cymarosyl glycals 5-7 www.cjc.wiley-vch.de

Hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hibernation-like or torpor state in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in rodents. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly recuperated in the mice with knockout of PDXK in medial preoptic area (MPA). We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and both directly activate MPA neurons to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hibernation-like state in rodents.

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