Electrochemical Aminoxyl-Mediated α-Cyanation of Secondary Piperidines for Pharmaceutical Building Block Diversification

Secondary piperidines are ideal pharmaceutical building blocks owing to the prevalence of piperidines in commercial drugs. Here, we report an electrochemical method for cyanation of the heterocycle adjacent to nitrogen without requiring protection or substitution of the N–H bond. The reaction utilizes ABNO (9-azabicyclononane N-oxyl) as a catalytic mediator. Electrochemical oxidation of ABNO generates the corresponding oxoammonium species, which promotes dehydrogenation of the 2° piperidine to the cyclic imine, followed by addition of cyanide. The low-potential, mediated electrolysis process is compatible with a wide range of heterocyclic and oxidatively sensitive substituents on the piperidine ring and enables synthesis of unnatural amino acids

Electrochemical Oxidation of Alcohols and Aldehydes to Carboxylic Acids Catalyzed by 4‑Acetamido-TEMPO: An Alternative to “Anelli” and “Pinnick” Oxidations

An electrocatalytic method has been developed to oxidize primary alcohols and aldehydes to the corresponding carboxylic acids using 4-acetamido-2,2,6,6-tetramethyl­piperidin-1-oxyl (ACT) as a mediator. The method successfully converts benzylic, aliphatic, heterocyclic, and other hetero­atom-containing substrates to the corresponding carboxylic acids in aqueous solution at room temperature. The mild conditions enable retention of stereochemistry adjacent to the site of oxidation, as demonstrated in a 40 g-scale synthesis of a precursor to levetiracetam, a medication used to treat epilepsy

The European Federation for Medicinal Chemistry and Chemical Biology (EFMC) Best Practice Initiative: Phenotypic Drug Discovery

Phenotypic Drug Discovery has a long track record of delivering innovative drugs and has received renewed attention in the last few years. The promise of this approach, however, comes with several challenges which should be addressed to avoid wasting time and resources on drugs with undesired modes of action or, worse, false positive hits. In this set of best practices, we go over the essential steps of phenotypic drug discovery and provide guidance on how to increase the chance of success of identifying validated and relevant chemical starting points for optimization: selecting the right assay, selecting the right compound screening library and developing appropriate hit validation assays. Then, we highlight the importance of initiating studies to determine the mode of action of the identified hits early and present the current state-of-the-art

The European Federation for Medicinal Chemistry and Chemical Biology (EFMC) Best Practice Initiative: Hit Generation

: Hit generation is a crucial step in drug discovery that will determine the speed and chance of success of identifying drug candidates. Many strategies are now available to identify chemical starting points, or hits, and each biological target warrants a tailored approach. In this set of best practices, we detail the essential approaches for target centric hit generation and the opportunities and challenges they come with. We then provide guidance on how to validate hits to ensure medicinal chemistry is only performed on compounds and scaffolds that engage the target of interest and have the desired mode of action. Finally, we discuss the design of integrated hit generation strategies that combine several approaches to maximize the chance of identifying high quality starting points to ensure a successful drug discovery campaign