Design of Phosphoranyl Radical α-scisson Reactions Enabled by Photoredox Catalysis and 1,5-Hydrogen

About This Grant

New methodologies to construct C–C, C–N, C–O, and other C–heteroatom bonds are crucial for the continued development of new pharmaceutical candidates. Photoredox catalysis has emerged as a powerful field of organic chemistry for this purpose; however, while many organic functional groups are within the oxidation and reduction potentials of the growing library of photocatalysts, several important groups remain inaccessible either due to their redox potentials or chemoselectivity challenges. In-situ phosphoranyl radical generation by photoredox catalysis has emerged as a promising alternative to activate such desirable functional groups. There are two major scission pathways from the phosphoranyl radical: 𝛼- and 𝛽-scisson. The reversibility of phosphoranyl radical 𝛼-scission has precluded its application toward generation of highly desirable oxygen- centered radicals from alcohols. This proposal details the application of phosphoranyl radical 𝛼-scisson on sulfonamide and alcohol substrates able to undergo a rapid intramolecular 1,5-hydrogen atom transfer (HAT) step after the 𝛼-scisson event. In the first aim, the catalytic phosphine/photoredox system will be evaluated with secondary sulfonamide substrates, which were unable to engage in productive reactivity in the previous hydroamination work. Distal functionalization, pyrrolidine synthesis, and distal multifunctionalizations will be accomplished under similar sets of reaction conditions. The second aim focuses on engaging a more challenging class of substrates in phosphoranyl radical 𝛼-scisson: alcohols. Through the use of conformationally-strained phosphetanes and by again coupling 𝛼-scisson to 1,5-HAT, we will activate aliphatic alcohols through phosphine/photoredox catalysis in a net-oxidative reaction to form substituted tetrahydrofurans. This catalyst design will then be applied to the first catalytic in phosphine 𝛽-scisson of alcohols for deoxygenation, a valuable medicinal reaction that has remained inaccessible through phosphoranyl radical scission because it results in P(V). Through redox-cycling the strained phosphetane, complex scaffolds such as steroids and carbohydrates can be deoxygenated under catalytic conditions. In both aims, DFT calculations will be utilized to calculate the potential energy surfaces of the key scission events of the phosphoranyl radical, as well as the 1,5-HAT step and possible back-electron transfer of the heteroatom radical with the photocatalyst. In aim 2, a free-energy relationship between the computed conformational strain of synthesized phosphetanes and the scission events will be established. Development of these strategies provide new applications of photoredox-enabled phosphoranyl radical 𝛼- scisson, allowing access to valuable, medicinally-relevant scaffolds including complex sulfonamides, pyrrolidines, tetrahydrofurans, and deuterated compounds. By understanding the factors that influence the energetics of the key mechanistic steps, this work will enable future reaction development in this area.