The direct transformation of C−H bonds into C−X bonds (with X being oxygen, nitrogen, halogen or carbon) has attracted considerable attention due to its potential to streamline synthesis through novel disconnections and strategies for the diversification of pre-assembled scaffolds. Over the past five years we have collaborated with Professors Christina White and Jin-Quan Yu to test the value of these new methods for medicinal chemistry applications, such as the late-stage functionalization of lead molecules and the development of alternative routes into drug-like chemical space. This work established protocols for the C−H functionalization of aromatic sulfonamide and phenol moieties which were subsequently applied to the modification of the celecoxib,1 clofibrate2 and penicillin3 pharmacophores. We have also developed a tandem C–H amination/vinylic C–H arylation reaction sequence to access a range of α- and β-homophenylalanine precursors from commodity α-olefins.4 This presentation will discuss key outcomes and lessons learned from these collaborations, as well as in-house applications resulting from our close interaction with these two academic groups. The intent is to highlight the utility and strengths of these new methodologies as well as the importance of collaborations between industry and academia to develop chemistries suitable for broad applications in drug discovery. References: 1. ‘Divergent C–H Functionalizations Directed by Sulfonamide Pharmacophores: Late-stage Diversification as a Tool for Drug Discovery’ Hui-Xiong Dai, Antonia F. Stepan, Mark S. Plummer, Yang-Hui Zhang, Jin-Quan Yu J. Am. Chem. Soc. 2011133, 7222. 2. ‘Pd(II)-Catalyzed ortho- or meta-C–H Olefination of Phenol Derivatives’ Hui-Xiong Dai, Gang Li, Xing-Guo Zhang, Antonia F. Stepan, Jin-Quan Yu J. Am. Chem. Soc. 2013, 135, 7567. 3. ‘Diversification of a β-​lactam pharmacophore via allylic C–​H amination: accelerating effect of Lewis acid co-​catalyst.’ Xiangbing Qi, Grant T. Rice, Manjinder S. Lall, Mark S. Plummer, M. Christina White Tetrahedron 2010, 66, 4816. 4. ‘Sequential Allylic C–H Amination/Vinylic C–H Arylation: A Strategy for Unnatural Amino Acid Synthesis from α-Olefins’ Chao Jiang, Dustin J. Covell, Antonia F. Stepan, Mark S. Plummer, M. Christina White Org. Lett. 2012, 14, 1386.

C−H functionalization: Can we leverage cutting-edge synthetic methods to enhance drug discovery?

249th National Meeting (2015)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.