A Shapeshifting Roadmap for Polycyclic Skeletal Evolution

Abstract

Polycyclic ring systems are ubiquitous three-dimensional (3D) structural motifs central to the function of many biologically active small molecules and organic materials. Indeed, subtle changes to the overall molecular shape and connectivity of atoms in a polycyclic framework (i.e., isomerism) can drastically alter its function and properties. Unfortunately, direct evaluation of these structure−function relationships typically requires the development of distinct synthetic strategies toward a specific isomer. Dynamic, "shapeshifting" carbon cages present a promising approach for sampling isomeric chemical space but are often difficult to control and are largely limited to thermodynamic mixtures of positional isomers about a single core scaffold. Here, we describe the development of a new shapeshifting C9-chemotype and a chemical blueprint for its evolution into structurally and energetically diverse isomeric ring systems. By leveraging the unique molecular topology of π-orbitals interacting through-space (homoconjugation), a common skeletal ancestor evolved into a complex network of valence isomers. This unusual system represents an exceedingly rare small molecule capable of undergoing controllable and continuous isomerization processes through the iterative use of just two chemical steps (light and organic base). Computational and photophysical studies of the isomer network provide fundamental insight into the reactivity, mechanism, and role of homoconjugative interactions. Importantly, these insights may inform the rational design and synthesis of new dynamic, shapeshifting systems. We anticipate this process could be a powerful tool for the synthesis of structurally diverse, isomeric polycycles central to many bioactive small molecules and functional organic materials.

Quantum Chemical Interrogation of Reactions Promoted by Dirhodium Tetracarboxylate Catalysts─Mechanism, Selectivity, and Nonstatistical Dynamic Effects

“…We have observed similar behavior in a variety of other Rh 2 L 2 catalyzed reactions with pericyclic product-forming steps (Scheme ). In work with the Shaw group, the results of our calculations indicated that [Rh] dissociated from the ammonium ylide shown before Stevens rearrangement occurred (concerted in this case, even though formally forbidden based on orbital symmetry, likely due to the presence of the ester); in that case, we were unable to locate a [Rh]-bound transition structure. In a study with the Tambar group involving the oxonium ylide shown, we again predicted a preference for [Rh]-free rearrangement, and again no competing [Rh]-bound transition structure was found.…”

Gd(III)-Catalyzed Regio-, Diastereo-, and Enantioselective [4 + 2] Photocycloaddition of Naphthalene Derivatives

“…Chiral polycycles are ubiquitous in natural products, biologically active molecules, and pharmaceutical candidates . In the past two decades, the catalytic asymmetric dearomatization (CADA) reaction proved to be one of the most promising methods for the construction of chiral polycyclic backbones in a rapid and economical fashion .…”

Modular, Enantioselective Entry into Polysubstituted Shapeshifting Molecules

“…We next sought to investigate the photochemical isomerization of bicyclo[3.2.2]nonanes ( 14 ) en route to 1,3-disubstituted barbaralones. Given our experience with the photochemistry of related bicyclo[3.2.2]nonanes bearing mixed chromophores, we hypothesized that direct photoirradiation (in the absence of a sensitizer) using a 390 nm violet LED light source would lead to rapid valence reorganization. We anticipated that these mild reaction conditions would greatly expand the functional group tolerance typical of DPM-type rearrangements employed in the synthesis of other shapeshifting molecules.…”

“…Inspired by our previous work on shapeshifting anions, , we hypothesized that we could more efficiently access the barbaralone nucleus via an anion derived from an isomeric bicyclo[3.2.2]­nonane (Figure c). Importantly, we recognized that the known enantioenriched α-halo bicyclo[3.2.2]­nonane 12 could serve as a modular, chiral building block for evaluation of this strategy (Scheme ).…”

“… Following hydrolysis of the corresponding diethyl acetal, we reasoned that base-initiated rearrangement and shape-selective capture of the barbaralone-enolate with a triflating agent would provide enantioenriched 3,4-disubstituted barbaralone enol triflates. Similarly, we hypothesized that photochemical isomerization of homoconjugated bicyclo[3.2.2]­nonanes via a di-π-methane (DPM)-type rearrangement could afford enantioenriched tricyclo­[3.3.1.0 2,8 ]­nonanes en route to barbaralones. ,, Subsequent deprotonation and capture with a triflyl-donating reagent would provide complementary access to isomeric 1,3-disubstituted barbaralone enol triflates.…”