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.

The flagship member of the antiplasmodial isocyanoterpenes,7,20-diisocyanoadociane (DICA), was synthesized from dehydrocryptone in 10 steps,a nd in 13 steps from commercially available material. Our previous formal synthesis was reengineered, leveraging only productive transformations to deliver DICA in fewer than half the number of steps of our original effort. Important contributions,i n addition to the particularly concise strategy,include asolution to the problem of axial nucleophilic methylation of alate-stage cyclohexanone,a nd the first selective synthesis and antiplasmodial evaluation of the DICA stereoisomer with both isonitriles equatorial.

An anionic oxy-Cope/transannular Michael addition cascade converts a spirocyclic architecturereadily available by Diels− Alder cycloadditioninto the hydrophenalene carbon skeleton of the pseudopterosin aglycones. Oxidation of the resulting cyclohexenone ring to the phenol that is characteristic of the targets completes a short formal synthesis.Letter pubs.acs.org/OrgLett

Since their discovery in the 1970s, the striking architectures and the unusual isonitrile functional groups of the isocyanoterpenes have attracted the interest of many organic chemists. The more recent revelation of their potent in vitro antiplasmodial activity sparked new endeavors to synthesize members of this family of secondary metabolites. In this Synopsis, we discuss three distinct strategies that each address multiple structurally different members of the isocyanoterpenes, ending with some of our group's recent contributions in this area.