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; Xiaoguang Lei

doi:10.1021/acs.orglett.0c00578

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

Org Lett. 2020 Apr 17;22(8):2920-2924. doi: 10.1021/acs.orglett.0c00578. Epub 2020 Apr 7.

Authors

Xiaoyun Zhang¹, Shuo-Qing Zhang², Qiang Li¹, Fan Xiao¹, Zongwei Yue¹, Xin Hong², Xiaoguang Lei¹

Affiliations

¹ Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
² Department of Chemistry, Zhejiang University, 38 Zheda Road, Hangzhou 310027, China.

PMID: 32255637
DOI: 10.1021/acs.orglett.0c00578

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't