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

Xiaoyun Zhang, Shuo-Qing Zhang, Qiang Li, Fan Xiao, Zongwei Yue, Xin Hong,* and Xiaoguang Lei*
Org. Lett. 2020, 22, 8, 2920-2924

We report here a deep mechanistic study of the “click” ortho-quinone methide (oQM) cycloaddition between orthoquinolinone 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.

Xiaoyun Zhang, Shuo-Qing Zhang, Qiang Li, Fan Xiao, Zongwei Yue, Xin Hong,* and Xiaoguang Lei*

Org. Lett. 2020, 22, 8, 2920-2924

We report here a deep mechanistic study of the “click” ortho-quinone methide (oQM) cycloaddition between orthoquinolinone 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.