PROJECT SUMMARY/ABSTRACT Human health is inextricably linked to our ability to rapidly develop novel medicines and agrochemicals to address global needs. However, the development of such bioactive compounds requires extensive synthesis campaigns to access late-stage analogs of lead molecules for fine-tuning of bioactivity. The scope of accessible analogs is limited by current methods for late-stage diversification, which mostly change the periphery of molecules. The development of single-atom skeletal editing methods, particularly for saturated heterocycles ubiquitous in bioactive compounds, would expedite this process by enabling facile, precise changes to molecular cores, circumventing lengthy de novo synthesis and expanding accessible chemical space. The photomediated ring contraction of saturated heterocycles has been reported as a novel skeletal editing method that accomplishes an endo-to-exocyclic migration of a heteroatom in a ring upon blue LED irradiation. However, limitations in scope and unpredictable variance in enantioselectivity preclude the successful application of this reaction to diverse bioactive compounds of interest. Moreover, rational optimization of this ring contraction is challenging due to a lack of mechanistic and photophysical understanding. This proposal will accomplish: 1) expansion of the ring contraction scope to include unfunctionalized, electron-rich, and drug-like azacycles, 2) investigation of mechanism and wavelength-dependence of rate and quantum yield, and 3) parametrization of non-covalent interactions between substrates and chiral catalysts to optimize enantioselectivity. Expansion of the method will be pursued through execution of various synthetic strategies to install the requisite photoreactive handle onto N–Ar azacycles, and the yields and diastereoselectivities of the resulting substrates will be quantified. In addition to demonstrating the ring contraction on novel, larger rings, heterocyclic cores, and drug fragments, strategies to remove the photoreactive handle will be explored for enhanced synthetic utility. Wavelength-dependent reactivity will be investigated by quantifying rates and quantum yields with a range of different wavelengths, while kinetic experiments in combination with quantum yield determination will elucidate mechanistic details. Finally, an enantioselective data set will be generated and analyzed through data science driven computational approaches to rationalize and optimize enantioselectivity. Ultimately, this research will not only improve fundamental understanding of photochemical reactions, but also generalize the application of this skeletal edit to late-stage derivatization in an asymmetric fashion.