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.