Synthesis and Reactivity of a Bis-Strained Alkyne Derived from 1,1′-Biphenyl-2,2′,6,6′-tetrol

The novel “double strained alkyne” 3 has been prepared and evaluated in strain-promoted azide-alkyne cycloaddition reactions with azides. The X-ray crystallographic structure of 3, which was prepared in one step from 1,1′-biphenyl-2,2′,6,6′-tetrol 4, reveals the strained nature of the alkynes. Dialkyne 3 undergoes cycloaddition reactions with a number of azides, giving mixtures of regiosiomeric products in excellent yields. The monoaddition products were not observed or isolated from the reactions, suggesting that the second cycloaddition proceeds at a faster rate than the first, and this is supported by molecular modeling studies. Dialkyne 3 was successfully employed for “peptide stapling” of a p53-based diazido peptide, whereby two azides are bridged to give a product with a stabilized conformation.