Medium Rings Bearing Bitriazolyls: Easily Accessible Structures with Superior Performance as Cu Catalyst Ligands

Benefiting from their unique properties,
the development of structurally
novel and easily accessible medium rings is of significant interest
in the pharmaceutical industry and academic research. However, synthetic
access to medium-ring scaffolds is very difficult due to their rigid
skeleton and large-angle strains. In this paper, a new class of medium
rings bearing bitriazolyls (MRBTs) was designed, synthesized, identified
as a promising new skeleton ligand for the Cu­(I)-catalyzed click reaction,
and used in site-special modification of protein. One of the MRBTs, 3aa, exhibited a turnover number (TON) as high as 55 000
and dramatic accelerating effects (kobs = 1.95 M–1 s–1) and ranked among
the most efficient ligands for copper-catalyzed alkyne and azide cycloaddition.
Unlike the difficult access to other known medium rings, these 7–12-membered
MRBTs can be prepared in straightforward, one-step manner from structurally
diverse linear terminal diynes and azides. The unique accessibility
and intriguing properties therefore imply their broad application
perspectives.