The utility of chemical synthesis in health-related research is closely tied to efficient access to therapeutic agents. The synthesis of these compounds using standard approaches often involves lengthy, inefficient synthetic routes, hindering the discovery and development of new drugs. Synthetic transformations that selectively functionalize aliphatic C?H bonds hold significant promise in streamlining drug synthesis and providing access to novel analogs of biologically relevant compounds that would otherwise be challenging to obtain. Despite the potential for site-selective C?H functionalization, few intermolecular processes of preparative value exist. This gap in reaction development fundamentally limits the use of C?H functionalization in the synthesis of medicinally valuable, functionalized small molecules. The long-term goal of this research is the development of practical, intermolecular aliphatic C?H functionalizations that introduce diverse chemical functionality and proceed with high levels of selectivity. The overall objective of this application is to develop a new C?H functionalization that unlocks a diverse set of currently inaccessible, valuable C?H transformations, and to further enhance the site selectivities and chemoselectivities of our approach using heteroatom-centered radicals. We will also develop catalytic variants, offering new opportunities in both reagent design and reaction development. Our research is based on the central hypothesis that radical-mediated intermolecular C?H functionalizations offer superior site selectivities and chemoselectivities and will enable the development of new transformations that are inaccessible via metal-catalyzed approaches. The rationale of the proposed research is that these practical and selective reactions will facilitate access to diverse synthetically and medicinally valuable small molecules. This work involves three specific aims: (1) to develop an aliphatic C?H xanthylation (dithiocarbonation) as a platform technology for C?H functionalization; (2) to increase the site selectivity and chemoselectivity of intermolecular C?H functionalizations using heteroatom-centered radicals; and (3) to develop catalytic variants of the radical-mediated C?H functionalizations. Under the first aim, we will develop a practical, efficient method for aliphatic C?H xanthylation. In the second aim, we will enhance both the site selectivity and chemoselectivity of our platform using heteroatom-centered radicals. Under the third aim, we will develop catalytic, intermolecular aliphatic C?H functionalizations. Our proposed research is innovative because it will establish the unique capabilities of intermolecular aliphatic C?H functionalization using tuned radical species in unlocking new, practical transformations of aliphatic C?H bonds with superior levels of site selectivity and chemoselectivity. These contributions are significant because they will offer a range of practical and predictable aliphatic C?H transformations for late-stage functionalizations, catalyzing the discovery and development of next generation biologically active natural products and medicinal agents.
The proposed research is relevant to public health because it is expected to deliver new transformations that will increase the efficiency of drug synthesis and enable access to unique analogs of broad classes of biologically relevant small molecules. Thus, we expect these synthetic tools to facilitate the development of next generation small molecule therapeutics.
| Na, Christina G; Alexanian, Erik J (2018) A General Approach to Site-Specific, Intramolecular C-H Functionalization Using Dithiocarbamates. Angew Chem Int Ed Engl 57:13106-13109 |
| Carestia, Anthony M; Ravelli, Davide; Alexanian, Erik J (2018) Reagent-dictated site selectivity in intermolecular aliphatic C-H functionalizations using nitrogen-centered radicals. Chem Sci 9:5360-5365 |
| Margrey, Kaila A; Czaplyski, William L; Nicewicz, David A et al. (2018) A General Strategy for Aliphatic C-H Functionalization Enabled by Organic Photoredox Catalysis. J Am Chem Soc 140:4213-4217 |
| Czaplyski, William L; Na, Christina G; Alexanian, Erik J (2016) C-H Xanthylation: A Synthetic Platform for Alkane Functionalization. J Am Chem Soc : |
