Research Program

Inspired by small molecule natural products, the Roizen laboratories has initiated research with a long-term vision to access improved antibiotics, and selective ion channel inhibitors, with implications for the study and treatment of cancer, heart disease, and neurological disorders. This program has begun with the development of novel reaction methods, and where appropriate these methodologies will be advanced through mechanistic investigations. New reactions have been designed to streamline access to challenging natural products, such as the guaianolide sesquiterpenes. Access to these small molecules will enable us to collaborate with colleagues to probe the biological activity of these molecular architectures.

Sulfamate Esters Guide C-H Functionalization Processes

Late-stage alkyl C-H functionalization technologies could accelerate access to biomedically important probe molecules and lead compounds for drug discovery. Nevertheless, the scope and synthetic utility of these reactions is constrained by incomplete control over the site of reaction. It is challenging to achieve site-selective C–H functionalization because unactivated alkyl C-H bonds have high bond dissociation energies (BDE ~ 90-105 kcal/mol) and low acidities (pKa ≥ 50), and lack co-localized polarizable and electronically accessible π-orbitals. To address these constraints, efficient atom-transfer processes can rely on differences in BDE or steric accessibility to enable innately selective intermolecular C-H abstraction processes at distal sites. Alternatively, position-selectivity may be controlled kinetically by a directing group. In this manuscript, we disclose a new and general directing group strategy for aliphatic γ-C-H functionalization that relies on a masked alcohol to achieve position-selectivity. Specifically, we determine that sulfamate ester-derived nitrogen-centered radicals mediate 1,6-hydrogen-atom transfer (HAT) processes to guide γ-C-H chlorination. This reaction proceeds through a light-initiated radical chain-propagation process and is capable of installing chlorine atoms at primary, secondary, and tertiary centers.