Intramolecular Vinylation of Secondary and Tertiary Organolithiums

Deprotonation of benzylic ureas, carbamates, and thiocarbamates bearing <i>N</i>′-alkenyl substituents generates carbanions which undergo intramolecular migration of the alkenyl group to the carbanionic center. Solvolysis of the urea products generates α-alkenylated amines. With an enantiomerically pure starting urea, migration proceeds stereospecifically, generating in enantiomerically enriched form products containing allylic quaternary stereogenic centers bearing N. Computational and <i>in situ</i> IR studies suggest that the reaction, formally a nucleophilic substitution at an sp² carbon atom, proceeds by a concerted addition-elimination pathway

Amines Bearing Tertiary Substituents by Tandem Enantioselective Carbolithiation–Rearrangement of Vinylureas

In the presence of (−)-sparteine or a (+)-sparteine surrogate, organolithiums add to <i>N</i>-alkenyl<i>-N</i>′-arylureas to give benzylic organolithiums in an enantioselective manner. Under the influence of DMPU, these organolithiums undergo rearrangement with migration of the <i>N</i>′-aryl ring from N to C, leading to the urea derivatives of enantiomerically enriched amines bearing tertiary substituents. Basic hydrolysis returns the functionalized amine, providing a new synthetic route to compounds with quaternary stereogenic centers bearing nitrogen

Discovery of BAY-985, a Highly Selective TBK1/IKK epsilon Inhibitor

The serine/threonine kinase TBK1 (TANK-binding kinase 1) and its homologue IKKϵ are noncanonical members of the inhibitor of the nuclear factor κB (IκB) kinase family. These kinases play important roles in multiple cellular pathways and, in particular, in inflammation. Herein, we describe our investigations on a family of benzimidazoles and the identification of the potent and highly selective TBK1/IKKϵ inhibitor BAY-985. BAY-985 inhibits the cellular phosphorylation of interferon regulatory factor 3 and displays antiproliferative efficacy in the melanoma cell line SK-MEL-2 but showed only weak antitumor activity in the SK-MEL-2 human melanoma xenograft model