Computation-Guided Development of the “Click” ortho-Quinone Methide Cycloaddition with Improved Kinetics

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