Selective Macrocycle Formation in Cavitands

TLDR

Macrocyclization of long‑chain linear precursors is challenging due to unfavorable entropy and competing intermolecular reactions, but cavitands reverse conventional template roles, acting as hosts that facilitate intramolecular reactions akin to biological catalysis. The study applies cavitands to selectively catalyze intramolecular aldol/dehydration of long‑chain α,ω‑dialdehydes in aqueous solution. Hydrophobic interactions fold the dialdehydes inside cavitands, promoting macrocyclization over competing intermolecular reactions. Macrocyclic aldol products were obtained in 30–85 % yields across 11‑ to 17‑membered rings.

Abstract

The traditional end-to-end cyclization of long-chain linear precursors is difficult and often unpredictable because the unfavorable entropy of macrocyclic closure allows undesired intermolecular reactions to compete. Here, we apply cavitands to the selective intramolecular aldol/dehydration reaction of long-chain α,ω-dialdehydes in aqueous solution. Hydrophobic forces drive the dialdehydes into the cavitands in folded conformations and favor macrocyclization reactions over intermolecular reactions observed in bulk solution. The macrocyclic aldol reaction products are isolated in good yields (30–85%) over a wide range (11 to 17-membered rings). Unlike conventional templates that become guests inside their assembled hosts, cavitands reverse the roles and resemble the situation in biological catalysis—the templates are hosts for guests undergoing the assisted reaction processes.