Reactions that directly install nitrogen into C-H bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Although selective intramolecular C-H amination reactions are known, achieving high levels of reactivity while maintaining excellent site selectivity and functional-group tolerance remains a challenge for intermolecular C-H amination. Here, we report a manganese perchlorophthalocyanine catalyst [MnIII(ClPc)] for intermolecular benzylic C-H amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site selectivity. In the presence of a Bronsted or Lewis acid, the [MnIII(ClPc)]-catalysed C-H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies suggest that C-H amination likely proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C-H cleavage is the rate-determining step of the reaction. Collectively, these mechanistic features contrast with previous base-metal-catalysed C-H aminations and provide new opportunities for tunable selectivities.

Manganese-catalysed benzylic C(sp 3)-H amination for late-stage functionalization

Retinoic Acid Signaling Is Essential for Embryonic Hematopoietic Stem Cell Development

Membrane-perturbing effect of fatty acids and lysolipids

Enzyme-Responsive Liposomes for the Delivery of Anticancer Drugs

The conversion of unactivated carbon-hydrogen (C-H) bonds to carbon-nitrogen (C-N) bonds is a highly valued transformation. Existing strategies typically accomplish such reactions at only a single C-H site because the first derivatization diminishes the reactivity of surrounding C-H bonds. Here, we show that alkylated arenes can undergo vicinal C-H diamination reactions to form 1,2-diamine derivatives through an electrophotocatalytic strategy, using acetonitrile as both solvent and nitrogen source. The reaction is catalyzed by a trisaminocyclopropenium (TAC) ion, which undergoes anodic oxidation to furnish a stable radical dication while the cathodic reaction reduces protons to molecular hydrogen. Irradiation of the TAC radical dication (wavelength of maximum absorption of 450 to 550 nanometers) with a white-light compact fluorescent light generates a strongly oxidizing photoexcited intermediate. Depending on the electrolyte used, either 3,4-dihydroimidazole or aziridine products are obtained.

Electrophotocatalytic diamination of vicinal C–H bonds

4‘-Octyl-4-biphenylcarboxylic acid (1g, AC-55649) was identified as a highly isoform-selective agonist at the human RARβ2 receptor in a functional intact cell-based screening assay. The subsequent hit to lead optimization transformed the lipophilic, poorly soluble hit into a more potent and orally available compound (2, AC-261066) with retained β2 selectivity and greatly improved physiochemical properties. Being an isoform-selective RARβ2 receptor agonist that discriminates between nuclear receptor isoforms having identical ligand binding domains, 2 will be useful as a pharmacological research tool but also a valuable starting point for drug development.

Discovery of a Potent, Orally Available, and Isoform-Selective Retinoic Acid β2 Receptor Agonist

Identification of novel subtype selective RAR agonists.

We recently discovered the isoform selective RAR beta 2 ligand 4'-octyl-4-biphenylcarboxylic acid (3, AC-55649). Although 3 is highly potent at RAR beta 2 and displays excellent selectivity, solubility issues make it unsuitable for drug development. Herein we describe the exploration of the SAR in a biphenyl and a phenylthiazole series of analogues of 3. This ultimately led to the design of 28, a novel, orally available ligand with excellent isoform selectivity for the RAR beta 2.

Natalie K Gauthier

Papers

Discovery of a Potent, Orally Available, and Isoform-Selective Retinoic Acid β2 Receptor Agonist

Identification of novel subtype selective RAR agonists.

Design, Synthesis, and Structure−Activity Analysis of Isoform-Selective Retinoic Acid Receptor β Ligands