An Indirect Synthetic Approach toward Conformationally Constrained 20-Membered Unclosed Cryptands via Late-Stage Installation of Intraannular Substituents

A new protocol for
PTC-mediated O-alkylation of the intraannular
position of 20-membered unclosed cryptands (UCs) is reported. In contrast
to the classical, “direct” strategy, which requires
functionalization of the lariat arm at the beginning of synthesis,
this “indirect” approach enables the late-stage introduction
of various benzylic substituents after an unfavorable macrocyclization
step (11 examples, yields up to 98%). Notably, this method permits
preparation of, previously inaccessible, crowded UCs bearing 1-acetylpyrene
substituent and dimer joined by p-xylene linker.