No abstract

Hydrogen borrowing provides an efficient and atom economical method for carbon−nitrogen and carbon− carbon bond formation from alcohol precursors. Glycerol is a renewable nontoxic polyol and a potential precursor to small functional organic molecules. We here report the direct amination of solketal, a 1,2-hydroxy-protected derivative of glycerol, via ruthenium-catalyzed hydrogen borrowing, affording up to 99% conversion and 92% isolated yield using [Ru(pcymene)Cl 2 ] 2 as the catalyst precursor. The synthesis of an antitussive agent in 86% overall yield from solketal was also demonstrated using this methodology.

Thiazolidinedione PPARγ agonists such as rosiglitazone and pioglitazone are effective antidiabetic drugs, but side effects have limited their use. It has been posited that their positive antidiabetic effects are mainly mediated by the inhibition of the CDK5-mediated Ser273 phosphorylation of PPARγ, whereas the side effects are linked to classical PPARγ agonism. Thus compounds that inhibit PPARγ Ser273 phosphorylation but lack classical PPARγ agonism have been sought as safer antidiabetic therapies. Herein we report the discovery by virtual screening of 10, which is a potent PPARγ binder and in vitro inhibitor of the CDK5-mediated phosphorylation of PPARγ Ser273 and displays negligible PPARγ agonism in a reporter gene assay. The pharmacokinetic properties of 10 are compatible with oral dosing, enabling preclinical in vivo testing, and a 7 day treatment demonstrated an improvement in insulin sensitivity in the ob/ob diabetic mouse model.

The treatment of the TBS-protected p-toluenesulfonimidamide with HCl exclusively affords the deprotected product. However, when HCl was replaced with formic acid, and the reaction mixture was left for an extended time or treated at high temperature, a mixture of oligomers was obtained as main products. The relevant N,N′-capped oligomers were prepared through carbamoylation with p-chlorophenyl isocyanate. The key to dicarbamoylation is to remove formic acid from the reaction mixture. For comparison, methylsulfonimidamide (as the representative of alkyl sulfonimidamides) was tested under sim-[a] Dr.