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.