Strained Cyclophane Macrocycles: Impact of Progressive Ring Size Reduction on Synthesis and Structure

The synthesis, X-ray crystal structures, and calculated strain energies are reported for a homologous series of 11- to 14-membered
drug-like cyclophane macrocycles, representing an unusual region of
chemical space that can be difficult to access synthetically. The
ratio of macrocycle to dimer, generated via a copper
catalyzed azide–alkyne cycloaddition macrocyclization in flow
at elevated temperature, could be rationalized in terms of the strain
energy in the macrocyclic product. The progressive increase in strain
resulting from reduction in macrocycle ring size, or the introduction
of additional conformational constraints, results in marked deviations
from typical geometries. These strained cyclophane macrocyclic systems
provide access to spatial orientations of functionality that would
not be readily available in unstrained or acyclic analogs. The most
strained system prepared represents the first report of an 11-membered
cyclophane containing a 1,4-disubstituted 1,2,3-triazole ring and
establishes a limit to the ring strain that can be generated using
this macrocycle synthesis methodology.