ABSTRACT
A novel reactivity of sulfonylhydrazones under Pd catalysis is described, where SO2 and N2 are formally extruded to afford the product of an apparent internal coupling reaction. The reaction is effective with both carbocyclic and heterocyclic aromatic precursors.
Subject(s)
Alkenes/chemistry , Heterocyclic Compounds/chemistry , Hydrazones/chemistry , Palladium/chemistry , Sulfhydryl Compounds/chemistry , Catalysis , Molecular Structure , Oxidation-ReductionABSTRACT
A general, transition-metal-free, highly stereoselective cross-coupling reaction between glycosyl bromides and various arylzinc reagents leading to ß-arylated glycosides is reported. The stereoselectivity of the reaction is explained by invoking anchimeric assistance via a bicyclic intermediate. Stereochemical probes confirm the participation of the 2-pivaloyloxy group. Finally, this new method was applied to a short and efficient stereoselective synthesis of Dapagliflozin and Canagliflozin.
Subject(s)
Glucosides/chemical synthesis , Benzhydryl Compounds , Glucosides/chemistry , Indicators and Reagents/chemistry , Molecular Structure , StereoisomerismABSTRACT
Cortisol and the glucocorticoid receptor (GR) signaling pathway has been linked to the development of diabetes and metabolic syndrome. In vivo, 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyzes the conversion of inactive cortisone to its active form, cortisol. Existing clinical data have supported 11ß-HSD1 as a valid therapeutic target for type 2 diabetes. In our research program, (R)-1,1,1-trifluoro-2-(3-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)propan-2-ol (HSD-016) was discovered to be a potent, selective, and efficacious 11ß-HSD1 inhibitor and advanced as a clinical candidate. Herein, a reliable and scalable synthesis of HSD-016 is described. Key transformations include an asymmetric synthesis of a chiral tertiary alcohol via Sharpless dihydroxylation, epoxide formation, and subsequent mild reduction. This route ensured multikilogram quantities of HSD-016 necessary for clinical studies.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/chemical synthesis , Piperazines/chemical synthesis , Propanols/chemical synthesis , 11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , Administration, Oral , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Molecular Structure , Piperazines/chemistry , Piperazines/pharmacology , Propanols/chemistry , Propanols/pharmacologyABSTRACT
Diastereoselective hydrogenation of 2'-deoxy-2'-exo-methyleneuridine was carried out under homogeneous conditions using a low loading of a chiral Rh catalyst. This, coupled with improvements in the synthesis of the substrate, allowed the smooth pilot plant preparation of the title compound on >10 kg scale.
Subject(s)
Uridine/analogs & derivatives , Catalysis , Hydrogenation , Magnetic Resonance Spectroscopy , Molecular Structure , Stereoisomerism , Uridine/chemical synthesis , Uridine/chemistryABSTRACT
The carboxylic acid anion moiety has been used as a tunable directing group in the cross-coupling reaction of 2,6-dichloronicotinic acid and 2,5-dibromo-1,2,4-triazole derivatives producing selectively the 2- or 6-substituted nicotinic acids, while only the 5-substituted triazoles were obtained under a variety of conditions.
Subject(s)
Boronic Acids/chemistry , Heterocyclic Compounds/chemistry , Nicotinic Acids/chemical synthesis , Organometallic Compounds/chemistry , Triazoles/chemical synthesis , Catalysis , Molecular Structure , Nicotinic Acids/chemistry , Stereoisomerism , Triazoles/chemistryABSTRACT
[structure: see text] The first enantioselective total synthesis of (-)-tejedine (1) is reported. Tejedine is a seco-bisbenzyltetrahydroisoquinoline isolated in 1998 as a minor component from Berberis vulgaris. The synthesis was achieved using a strategy employing four key steps, including a chiral auxiliary-assisted diastereoselective Bischler-Napieralski cyclization.
