Computation-Guided Development of the "Click" ortho-Quinone Methide Cycloaddition with Improved Kinetics.

We report here a deep mechanistic study of the "click" ortho-quinone methide (oQM) cycloaddition between ortho-quinolinone quinone methide (oQQM) and thio-vinyl ether (TV), named as TQ-ligation. DFT calculations revealed the unexpected fact that dehydration of oQQM precursors is the rate-determining step of this transformation, and two highly reactive oQQM precursors were predicted. Guided by the calculations, a new "click" oQM cycloaddition which shows significantly improved kinetics and remarkable efficiency on protein labeling was developed.