Macrocyclization of Folded Diamines in Cavitands

Area of Science:

• Supramolecular Chemistry
• Organic Synthesis
• Host-Guest Chemistry

Background:

• Synthetic host molecules like cavitands facilitate chemical reactions in aqueous environments.
• Controlling the conformation of flexible guests is crucial for selective functionalization.

Purpose of the Study:

• To investigate the binding and reactivity of long-chain α,ω-diamines within water-soluble cavitand hosts.
• To develop improved synthetic routes for macrocyclic dilactams using cavitand-mediated reactions.

Main Methods:

• Binding of C11-C18 diamines in cavitand hosts, inducing folded conformations.
• Acylation of bound diamines with succinic anhydride.
• Cyclization of cavitand-bound amino acids to dilactams using water-soluble carbodiimide in D2O.
• Direct reaction of bound diamines with activated diesters.

Main Results:

• Cavitands bind diamines in conformations exposing amino groups to water.
• Improved yields of monofunctionalized products after acylation.
• Successful cyclization to macrocyclic dilactams (17- to 25-membered) with 54-96% yields.
• 3- to 10-fold yield improvement compared to bulk solution reactions.

Conclusions:

• Cavitand hosts effectively control guest conformation and reactivity in aqueous media.
• Cavitand-chaperoned synthesis offers an efficient alternative to high dilution methods for macrocycle synthesis.
• This approach enables improbable reaction pathways for flexible molecules.