Rapid Access to Chiral and Tripodal Cavitands from β‐Pinene

Abstract

We report Pd‐catalyzed cyclotrimerization of (+)‐α‐bromoenone, obtained from monoterpene β‐pinene, into an enantiopure cyclotrimer. This C3 symmetric compound has three bicyclo[3.1.1]heptane rings fused to its central benzene with each ring carrying a carbonyl group. The cyclotrimer undergoes diastereoselective threefold alkynylation with the lithium salts of five terminal alkynes (41–63 %, de=4–83 %). The addition enabled a rapid synthesis of a small library of novel chiral cavitands that, in shape, resemble a tripod stand. These molecular tripods include a tris‐bicycloannelated benzene head attached to three alkyne legs twisted in one direction to form a nonpolar cavity with polar groups as feet. Tripods with methylpyridinium and methylisoquinolinium legs, respectively, form inclusion complexes with anti‐inflammatory and chiral drugs (R)/(S)‐ibuprofen and (R)/(S)‐naproxen. The mode of binding shows drug molecules docked in the cavity of the host through ion‐ion, cation‐π, and C−H−π contacts that, in addition of desolvation, give rise to complexes having millimolar to micromolar stability in water. Our findings open the door to creating a myriad of enantiopure tripods with tunable functions that, in the future, might give novel chemosensors, catalysts or sequestering agents.