Development of small molecule inhibitors of natural killer group 2D receptor (NKG2D).

Natural killer group 2D (NKG2D) is a homodimeric activating immunoreceptor whose function is to detect and eliminate compromised cells upon binding to the NKG2D ligands (NKG2DL) major histocompatibility complex (MHC) molecules class I-related chain A (MICA) and B (MICB) and UL16 binding proteins (ULBP1-6). While typically present at low levels in healthy cells and tissue, NKG2DL expression can be induced by viral infection, cellular stress or transformation. Aberrant activity along the NKG2D/NKG2DL axis has been associated with autoimmune diseases due to the increased expression of NKG2D ligands in human disease tissue, making NKG2D inhibitors an attractive target for immunomodulation.

Enantioselective radical C-H amination for the synthesis of β-amino alcohols.

Asymmetric, radical C-H functionalizations are rare but powerful tools for solving modern synthetic challenges. Specifically, the enantio- and regioselective C-H amination of alcohols to access medicinally valuable chiral β-amino alcohols remains elusive. To solve this challenge, a radical relay chaperone strategy was designed, wherein an alcohol was transiently converted to an imidate radical that underwent intramolecular H-atom transfer (HAT).

Radical cascade synthesis of azoles tandem hydrogen atom transfer.

A radical cascade strategy for the modular synthesis of five-membered heteroarenes ( oxazoles, imidazoles) from feedstock reagents ( alcohols, amines, nitriles) has been developed. This double C-H oxidation is enabled by generated imidate and acyloxy radicals, which afford regio- and chemo-selective β C-H bis-functionalization. The broad synthetic utility of this tandem hydrogen atom transfer (HAT) approach to access azoles is included, along with experiments and computations that provide insight into the selectivity and mechanism of both HAT events.

Development of an Imine Chaperone for Selective C-H Functionalization of Alcohols via Radical Relay.

The design of a radical relay chaperone to promote selective C-H functionalizations is described. A saccharin-based imine was found to be uniquely suited to effect C-H amination of alcohols via an generated hemiaminal. This radical chaperone facilitates the mild generation of an N-centered radical while also directing its regioselective H atom transfer (HAT) to the β carbon of an alcohol.

Catalytic β C-H amination an imidate radical relay.

The first catalytic strategy to harness imidate radicals for C-H functionalization has been developed. This iodine-catalyzed approach enables β C-H amination of alcohols by an imidate-mediated radical relay. In contrast to our first-generation, (super)stoichiometric protocol, this catalytic method enables faster and more efficient reactivity.

Catalytic Alkene Difunctionalization via Imidate Radicals.

The first catalytic strategy to harness imidate radicals has been developed. This approach enables alkene difunctionalization of allyl alcohols by photocatalytic reduction of their oxime imidates. The ensuing imidate radicals undergo consecutive intra- and intermolecular reactions to afford (i) hydroamination, (ii) aminoalkylation, or (iii) aminoarylation, via three distinct radical mechanisms.

Remote C-H Functionalization via Selective Hydrogen Atom Transfer.

The selective functionalization of remote C-H bonds via intramolecular hydrogen atom transfer (HAT) is transformative for organic synthesis. This radical-mediated strategy provides access to novel reactivity that is complementary to closed-shell pathways. As modern methods for mild generation of radicals are continually developed, inherent selectivity paradigms of HAT mechanisms offer unparalleled opportunities for developing new strategies for C-H functionalization.

Directed β C-H Amination of Alcohols via Radical Relay Chaperones.

A radical-mediated strategy for β C-H amination of alcohols has been developed. This approach employs a radical relay chaperone, which serves as a traceless director that facilitates selective C-H functionalization via 1,5-hydrogen atom transfer (HAT) and enables net incorporation of ammonia at the β carbon of alcohols. The chaperones presented herein enable direct access to imidate radicals, allowing their first use for H atom abstraction.