A General Method for Synthesis of Unclosed Cryptands via H‑Bond Templated Macrocyclization and Subsequent Mild Postfunctionalization

A practical four-step synthesis of
a model 26-membered N-Boc-protected
macrocycle, starting from commercially available and inexpensive materials,
is reported. The crucial macrocyclization step does not require high-dilution
conditions and is completed in a short time (8 h). The high yield
of macrocyclization (61%) is achieved owing to templation by intramolecular
H-bonds and a chloride anion, which both help to adopt a favorable
folded conformation of the open-chain intermediate. Finally, mild,
selective, and efficient incorporation of intraannular amide function
leading to five diversely functionalized unclosed cryptands (UCs)
is described.