Catalytic amounts of Co(SaltBu,tBu)Cl and organosilane irreversibly isomerize terminal alkenes by one position. The same catalysts effect cycloisomerization of dienes and retrocycloisomerization of strained rings. Strong Lewis bases like amines and imidazoles, and labile functionalities like epoxides, are tolerated.

A gold-catalyzed synthesis of fused carbocycles via a regioselective 6-endo dig process is reported. The selectivity can be modulated by the steric and electronic properties of gold(I) complexes. The ligands can influence the pathway selectivity for the first bond formation rather than through a common intermediate generated after an initial bond formation. This gold(I)-catalyzed transformation provides access to synthetically useful carbocyclic motifs that are found in numerous diterpenoid natural products.

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DNA polymerase theta (Polθ) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor of human Polθ (encoded by POLQ). A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods. Structure-based drug design efforts along with optimization of cellular potency and ADME ultimately led to the identification of RP-6685: a potent, selective, and orally bioavailable Polθ inhibitor that showed in vivo efficacy in an HCT116 BRCA2–/– mouse tumor xenograft model.