Deconstructive Molecular Editing Technology Involving C-C Bond Scission

PROJECT SUMMARY The overarching goal of this project is to harness the untapped reactivity of abundant feedstock materials and renewable natural products to enable the production of useful synthetic intermediates and the late-stage functionalization of biomedically relevant molecules. In particular, we have recently formulated new approaches

for selective C(sp3)–C(sp2) bond functionalization of alkenes, using a combination of O3-mediated oxidation and Fe(II)-mediated reductive fragmentation–radical capture. The net result has been replacement of the alkene C(sp3)–C(sp2) bond with C(sp3)–H, C(sp3)–S, C(sp3)–O, C=O, and C(sp3)–C(sp2) bonds. This redox-based

dealkenylative radical chemistry has allowed us to employ readily available natural products (e.g., terpenoids) as starting materials to streamline the chemical synthesis of biologically active natural product targets and active pharmaceutical ingredients (APIs). While many synthetic methods rely on the functionalization of C(sp2)–C(sp2)

double bonds, generalized methods for functionalizing alkene C(sp3)–C(sp2) linkages remain elusive. Our reaction is the first generalized functionalization of the C(sp3)–C(sp2) single bond; therefore, we envisioned that it would have broad impact on total synthesis, the late-stage diversification of pharmaceuticals, and the

preparation of value-added compounds from abundant starting materials. Going forward, we propose to develop Fe(II)- or Cu(I)-catalyzed functionalization of alkene C(sp3)–C(sp2) bonds for the construction of C(sp3)–C and C(sp3)–heteroatom bonds. Our inspiration for these transition metal–catalyzed dealkenylative cross-coupling

strategies originated from the bio-pathway for H2O2 decomposition catalyzed by Cu- and Fe-containing peroxygenases. Furthermore, Cu possesses exceptional capacity for both the radical capture and reductive elimination steps necessary for radical cross-couplings. We have used these catalytic strategies for modular

construction of C(sp3)–N bonds within terpenes and terpenoids, affording artificial terpenoid alkaloids, and to provide a new vision for the editing of all-carbon frameworks. We will expand this strategy to C(sp3)–C bond- forming processes related to, for example, Suzuki–Miyaura coupling, the Sonogashira reaction,

trifluoromethylation, and cyanation. We will expand the source of alkyl radicals to include carbonyls and phenols, both of which can be converted into α-alkoxy hydroperoxides—the pivotal reaction intermediates. Finally, leveraging the power of well-established enantioselective allylation, we will seek to establish a divergent route

to access a wide variety of enantiopure molecules featuring chiral quaternary centers. Realization of these proposed aims would substantially impact the sustainable synthesis of fine chemicals. These studies will also provide new visions and strategies for the editing of alkenes and other natural products. While our program does

not target a specific disease, collectively it could impact a variety of therapeutic areas by producing valuable synthetic intermediates for and facilitating divergent modification of biomedically relevant molecules.