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The chemoselective borylation of bromoiodoarenes under continuous flow conditions is described. Bromoarylboronic acids were synthesized in high yields using iPrMgCl•LiCl as the halogen-metal exchange reagent, with 5.7–86 s residence time at room temperature. The process is compatible with a variety of functional groups, including carbanion-reactive moieties, enabling post-product functionalization. A gram-scale reaction, including a continuous-flow work-up, afforded the desired product in a highly efficient manner. Successful telescoping with a Suzuki coupling has also been performed, converting 1-bromo-3-iodobenzene to 3-bromo-1,1′-biphenyl on a gram-scale in a good yield. Highlights: • Bromoarylboronic acids were synthesized in high yields using iPrMgCl•LiCl. • The reactions were performed at room temperature in commercial PFA tubing. • The short residence time enables a high degree of functional group compatibility. • Telescoped synthesis of the corresponding bromobiaryl compound was performed by coupling the boronic acid formation reaction to a Suzuki coupling. Graphical abstract [ABSTRACT FROM AUTHOR]

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]

Under photocatalytic reductive conditions, trifluoromethyl radical addition onto an ynamide followed by cyclization on a benzoyl moiety produces diverse isoindolinone platforms with good yields. The selectivity of the radical cyclization, N-benzoyl vs. N-benzyl as radical acceptor and the E/Z ratio of isomers have been rationalized by modeling. [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]

Efficient four- and five-step routes to access functionalized bicyclo[3.2.1]oct-2-ene and bicyclo[3.3.1]nonadiene via indium-mediated cycloisomerization of 1,6-enynes has been developed. This atom-economical catalytic process was optimized and relied on the efficiency of InCl3 leading to the preparation of functionalized bicyclic adducts in up to 99% isolated yield. The cyclization occurred on two different processes (5-exo versus 6-endo pathway) and were influenced by the substitution of the alkynyl moiety. The exo process was favored for non-substituted alkynes whereas the endo pathway was generally observed for substituted alkynes. Then, the presence of electron-withdrawing groups on the aryl substituted alkyne increased the ratio of the exo isomer. DFT calculations were performed on stability of intermediates and corroborated the intervention of InCl3. [ABSTRACT FROM AUTHOR]