Experiment and theory favour a model of C–H borylation where significant proton transfer character exists in the transition state.

The NHBoc group affords ortho selective C–H borylations in arenes and alkenes. Experimental and computational studies support an outer sphere mechanism where the N–H proton hydrogen bonds to a boryl ligand oxygen. The regioselectivities are unique and complement those of directed ortho metalations.

7,20-Diisocyanoadociane (DICA) is a potent antimalarial isocyanoterpene endowed with a fascinating tetracyclic structure composed of fused chair cyclohexanes. We report a highly stereocontrolled synthesis of a late-stage intermediate, the "Corey dione", from which DICA has been made previously. This formal synthesis features a rapid buildup of much of the complexity of the target through a sequence of enone tandem vicinal difunctionalization, Friedel-Crafts cyclodehydration, and sequential stereocontrolled reductions. Most importantly, this success establishes the broader feasibility of our previously developed general synthesis approach to the isocyanoterpene family and provides a blueprint for a very direct synthesis of DICA and related natural products.

An anionic oxy-Cope/transannular conjugate addition approach to the potent antimalarial 7,20-diisocyanoadociane is presented. The unexpected formation of undesired diastereomers in the key reaction led to the structural reassignment of previous products of this type of cascade and a reevaluation of the reversibility of the transannular ring closure. During efforts to coax the reaction toward the desired product, a transannular ene reaction provided tricyclic compounds relevant to the kempane diterpenoids.

The development of a factory process to manufacture the novel cardiac myosin activator omecamtiv mecarbil (1) is described. Omecamtiv mecarbil is prepared via the convergent synthesis and coupling of two key fragments, aniline 2 and carbamate 4-HCl, which serves as a masked isocyanate. To enable practical access to aniline 2, reduction of the corresponding nitroaromatic was designed to control potential mutagenic impurities. Key to the efficient preparation of 2 was the benzylic bromination of 8 followed by selective debromination of a gem-dibromide byproduct and subsequent alkylation with 5phosphate. Overall, the longest linear sequence consists of six steps, including a final salt formation step to afford the drug substance in 55% overall yield. Because of poor performance of the original free-base form of the drug substance in modifiedrelease formulations, an improved dihydrochloride hydrate form was developed to aid drug product performance and manufacturability.