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Two approaches to the synthesis of an oxabicyclic pyrrolidine‐6‐one are described using enzymatic resolution and gold‐mediated catalysis as key steps toward enantiopure compounds previously reported as racemic mixtures. Addition of Grignard reagents to the ketone afforded a variety of diversified tertiary alcohols of interest for their reported pharmacological activities. [ABSTRACT FROM AUTHOR]

Identification of a common Diels–Alder pattern in three classes of bioactive natural products led us to study the synthesis and cycloaddition of a new class of cyclic dienes readily available from β,γ‐unsaturated lactams. A practical and readily scalable route to the parent p‐methoxybenzyl‐protected 6‐ and 7‐membered β,γ‐unsaturated lactams was developed. These were readily transformed into the corresponding O‐silylated dienes, which were reacted with dimethyl and diethyl fumarate to yield stereoselectively highly functionalized bicyclic adducts. These exhibited unexpected and versatile transformations upon acid hydrolysis depending on the nature of the dienophile substituents and the acid catalyst. All reactions have been performed on multigram quantities. These transformations provide a convenient, economical, and easily scalable pathway for the rapid construction of functionally and stereochemically dense privileged scaffolds for the construction of libraries of natural products‐inspired molecules of pharmacological relevance. [ABSTRACT FROM AUTHOR]

Background and Purpose Small-molecule glucokinase activators ( GKAs) are currently being investigated as therapeutic options for the treatment of type 2 diabetes ( T2D). Because liver overexpression of glucokinase is thought to be associated with altered lipid profiles, this study aimed at assessing the potential lipogenic risks linked to oral GKA administration. Experimental Approach Nine GKA candidates were qualified for their ability to activate recombinant glucokinase and to stimulate glycogen synthesis in rat hepatocytes and insulin secretion in rat INS-1E cells. In vivo activity was monitored by plasma glucose and HbA1c measurements after oral administration in rodents. Risk-associated effects were assessed by measuring hepatic and plasma triglycerides and free fatty acids, as well as plasma aminotransferases, and alkaline phosphatase. Key Results GKAs, while efficiently decreasing glycaemia in acute conditions and HbA1c levels after chronic administration in hyperglycemic db/db mice, were potent inducers of hepatic steatosis. This adverse outcome appeared as soon as 4 days after daily oral administration at pharmacological doses and was not transient. GKA treatment similarly increased hepatic triglycerides in diabetic and normoglycaemic rats, together with a pattern of metabolic phenotypes including different combinations of increased plasma triglycerides, free fatty acids, alanine and aspartyl aminotransferases, and alkaline phosphatase. GKAs belonging to three distinct structural families induced hepatic steatosis in db/db mice, arguing in favour of a target-mediated, rather than a chemical class-mediated, effect. Conclusion and Implications Given the risks associated with fatty liver disease in the general population and furthermore in patients with T2D, these findings represent a serious warning for the use of GKAs in humans. Linked Article This article is commented on by Rees and Gloyn, pp. 335-338 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02201.x [ABSTRACT FROM AUTHOR]