[n.1.1]Propellanes are key precursors to bicyclo[n.1.1]alkanes, rigid small-ring hydrocarbons that have emerged as important building blocks in contemporary drug design as bioisosteres for disubstituted benzene rings. [n.1.1]Propellanes featuring heterocyclic rings could enable the direct synthesis of a wide diversity of bridged bicyclic heterocycles, which should exhibit superior physicochemical profiles compared to their established carbocyclic analogues. Here we report the unified synthesis of a family of heterocyclic [3.1.1]propellanes featuring oxygen, nitrogen and sulfur heteroatoms in the three-carbon bridge. The approaches we have developed are necessarily distinct from the established routes to carbocyclic propellanes, and utilize a common precursor that is conveniently assembled on a multigram scale via rhodium-catalysed cyclopropanation. These hetero[3.1.1]propellanes undergo a range of radical ring-opening reactions, affording bridged heterocycles that are of high utility in drug-discovery programmes.

Transition metal-catalyzed "cut-and-sew" reactions offer an efficient approach to construct bridged and fused scaffolds; however, the substrates have been primarily restricted to cyclic ketones and activated cyclopropanes. Here we report the first cut-and-sew transformation between β-lactams and alkenes/alkynes via C-C bond activation. Diverse bridged and fused nitrogen-heterocycles are prepared using this method with good functional group tolerance. The synthetic utility is demonstrated in the unified and streamlined preparation of norbenzomorphan-containing bioactive compounds.

Interfacial chemistry of molecular baskets remains poorly understood despite their promise for supramolecular applications of detection and sequestration of toxic molecules including those of illicit drugs, organophosphorus compounds, and anticancer agents. We present a fundamental investigation of the interfacial behavior of three amphiphilic supramolecular baskets (ASB 4, 8, and 12), having increasingly longer yet linear alkyl chains at the top of their bowl-shaped cavity. The studies were completed at the air−water interface to elucidate surface activity, interfacial stability, self-assembly, and monolayer organization that drive inverted monolayer formation, in which the molecular arms orient toward the aqueous phase in a configuration opposite to that typically observed for lipids. Herein, surface pressure−area isotherms of ASB 4, 8, 12, deposited on a water surface, were performed in tandem with nonequilibrium relaxation experiments to quantify surface activity, thermodynamic stability, and monolayer compressibility of the baskets’ monolayer assembly. Brewster angle microscopy enabled direct visualization of morphological evolution, aggregation, and packing at the interface. We show that systematic extension of the hydrocarbon arms, from four to 12 methylene groups, progressively modifies intermolecular packing, drives distinct two-dimensional aggregation pathways, and increases number densities at the air−water interface. Atomistic molecular dynamics simulations corrob

The capture of chloride from water by the tetraprotonated form of the spherical macrotricyclic molecule SC24 was studied using molecular dynamics simulation methods. This model ionophore represents a broad class of molecules which remove ions from water. Two binding sites for the chloride were found, one inside and one outside the ligand. These sites are separated by a potential energy barrier of approximately 20 kcal mol-1. The major contribution to this barrier comes from dehydration of the chloride. The large, unfavorable dehydration effect is compensated for by an increase in electrostatic attraction between the oppositely charged chloride and cryptand, and by energetically favorable rearrangements of water structure. Additional assistance in crossing the barrier and completing the dehydration of the ion is provided by the shift of three positively charged hydrogen atoms of the cryptand towards the chloride. This structural rigidity is partially responsible for its selectivity.