A small ring phosphacycle (1,2,2,3,4,4-hexamethylphosphetane) is found to catalyze deoxygenative N-N bond-forming Cadogan heterocyclization of o-nitrobenzaldimines, o-nitroazobenzenes and related substrates in the presence of hydrosilane terminal reductant. The reaction provides a chemoselective catalytic synthesis of 2H-indazoles, 2H-benzotriazoles, and related fused heterocyclic systems with good functional group compatibility. On the basis of both stoichiometric and catalytic mechanistic experiments, the reaction is proposed to proceed via catalytic PIII/PV=O cycling, where DFT modelling suggests a turnover limiting (3+1) cheletropic addition between the phosphetane catalyst and nitroarene substrate. Strain/distortion analysis of the (3+1) transition structure highlights the controlling role of frontier orbital effects underpinning the catalytic performance of the phosphetane.

Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1− DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure-and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1−DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.

This highlight presents advances in transition metal-catalysed alkene and alkyne hydroacylation over the past three years.