gem-Difluoromethylene Alkyne-Enabled Diverse C-H Functionalization and Application to the on-DNA Synthesis of Difluorinated Isocoumarins

Hui Gao; Shuang Lin; Shuning Zhang; Weijie Chen; Xiawen Liu; Guang Yang; Richard A Lerner; Hongtao Xu; Zhi Zhou; Wei Yi

doi:10.1002/anie.202013052

gem-Difluoromethylene Alkyne-Enabled Diverse C-H Functionalization and Application to the on-DNA Synthesis of Difluorinated Isocoumarins

Angew Chem Int Ed Engl. 2021 Jan 25;60(4):1959-1966. doi: 10.1002/anie.202013052. Epub 2020 Nov 20.

Authors

Hui Gao¹, Shuang Lin¹, Shuning Zhang², Weijie Chen¹, Xiawen Liu¹, Guang Yang², Richard A Lerner³, Hongtao Xu², Zhi Zhou¹, Wei Yi¹

Affiliations

¹ Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology, the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University Guangzhou, Guangdong, 511436, P. R. China.
² Shanghai Institute for Advanced Immunochemical Studies & School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, P. R. China.
³ Department of Chemistry, Scripps Research Institute, La Jolla, CA, 92037, USA.

PMID: 33022872
DOI: 10.1002/anie.202013052

Abstract

Using gem-difluoromethylene alkynes as effectors, unprecedented diverse C-H activation/[4+2] annulations of simple benzoic acids are reported. The chemodivergent reaction outcomes are well-tuned by Rh/Ir-catalyzed system; in the Rh^III catalysis, 3-alkenyl-1H-isochromen-1-one and 3,4-dialkylideneisochroman-1-one skeletons are afforded in a solvent-dependent manner whereas difluoromethylene-substituted 1H-isochromen-1-ones are generated under the Ir^III -catalyzed system. Mechanistic studies revealed that unusually double β-F eliminations and fluorine effect-induced regioselective reductive elimination are independently involved to enable distinct reaction modes for divergent product formations. Besides, synthetic application in both the derivatization of obtained diene products and the on-DNA synthesis of DNA-tagged difluorinated isocoumarin have been demonstrated, which manifested great potential for synthetic utility of the developed protocols.

Keywords: C−H functionalization; DNA-encoded libraries; Rh/Ir catalysis; chemodivergence; gem-difluoromethylene alkynes.

Publication types

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