Friday, May 9, 2025
5/9/2025
Artificial Metalloenzymes Containing Uranyl Cofactors for Photocatalytic C-H Bond Functionalization - Project Summary/Abstract: The selective transformation of unactivated C–H bonds into C–C bonds has been a longstanding challenge for synthetic chemists, and the uranyl cation (UO22+) has been shown to catalyze these transformations on a variety of substrates14-20. The uranyl cation is the most common form of uranium in the environment, existing in sea water at a concentration of about 3.3 ppb10. Early studies on the photochemistry of the uranyl ion have shown that photoexcitation with visible light will populate a highly oxidizing (+2.6 eV vs SHE) triplet excited state of the uranyl unit, which has a lifetime of microseconds with free radical character on the oxo groups and the uranium center11-13. This oxyl radical abstracts H atoms to form an O-H bond that is sufficiently strong to enable abstrac- tion from unactivated C–H bonds. Recent publications on photocatalysis of the uranyl ion have reported the functionalization of a variety of C–H bonds to form C–F bonds, C–C bonds, and C–O bonds17-20. Due to the ubiquity of C–H bonds in organic molecules, site-selectivity transformations are often difficult to achieve. Fur- thermore, stereoselective reactions would require chiral ligands that have not yet been incorporated into uranyl complexes. Nature has developed a variety of metalloenzymes that functionalize unactivated C–H bonds with exquisite selectivities imparted by the enzymatic scaffold22-29. In many of these enzymes, the reactive metal-oxo intermediate abstracts a hydrogen atom from a C–H bond to generate a carbon-centered radical. Functionaliza- tion of the generated radical, however, is largely limited by the rapid rebound of the radical onto the metal hy- droxide, providing hydroxylated, halogenated, or pseudohalogenated products35-42. Abstraction of a C-H bond by the uranyl ion, however, is not followed by transfer of the hydroxyl radical, due to the strong U–O bonds, thereby enabling functionalization of the radical intermediate in different ways. Thus, one should be able to achieve site- selective and stereoselective C–H bond functionalization with the uranyl ion by incorporating a photocatalytically active uranyl ion in place of a natural ion in the active site of an enzyme. The Hartwig group has experience in creating and developing artificial metalloenzymes (ArMs) with non-native metallocofactors for abiotic chemistry and catalysis51-61, and the Arnold group has extensive experience studying the uranyl ion and the photochemistry of this unit14-16,21. Through a collaboration between these two groups, I propose to develop novel ArMs containing an unnatural uranyl cofactor for the site- and stereoselective functionalization of C–H bonds to form C–C bonds. This will be accomplished by following two complementary strategies: 1) design of a photocatalytically active uranyl complex and bioconjugation of this complex into an enzyme scaffold; 2) incorporation of the unnatural amino acid phosphotyrosine or phosphosyrine into an enzyme active site and binding the uranyl ion within the unnatural site containing a phosphate group. These metalloproteins will then be used for intra and intermolecular Giese-type reactions initiated by hydrogen-atom abstraction, followed by addition to electron-poor alkenes.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).