期刊
ACS CATALYSIS
卷 12, 期 23, 页码 14507-14516出版社
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.2c04511
关键词
cyclopropanes; fluorination; hypervalent iodine; isosteres; stereoelectronic effects
资金
- WWU Munster
- European Research Council (ERC ) [RECON 818949]
- Alexander von Humboldt Foundation
This study developed an operationally simple strategy to access cis-configured derivatives with high levels of stereoselectivity. By leveraging an organocatalysis platform, cis-alpha,alpha-difluorinated cyclopropanes were synthesized in a highly stereoselective manner. The importance of this compound as an isostere of the 1,4-dicarbonyl moiety suggests potential applications in focused molecular design.
The clinical success of alpha,alpha-difluorocyclopropanes, combined with limitations in the existing synthesis portfolio, inspired the development of an operationally simple, organocatalysis-based strategy to access cis-configured derivatives with high levels of stereoselectivity (up to >20:1 cis:trans). Leveraging an I(I)/I(III)-catalysis platform in the presence of an inexpensive HF source, it has been possible to exploit disubstituted bicyclobutanes (BCBs) as masked cyclobutene equivalents for this purpose. In situ generation of this strained alkene, enabled by Bronsted acid activation, facilitates an unprecedented 4 -> 3 fluorinative ring contraction, to furnish cis-alpha,alpha-difluorinated cyclopropanes in a highly stereoselective manner (up to 88% yield). Mechanistic studies are disclosed together with conformational analysis (X-ray crystallography and NMR) to validate cis-alpha,alpha-difluorocyclopropanes as isosteres of the 1,4-dicarbonyl moiety. Given the importance of this unit in biology and the foundational n(o) -> pi* interactions that manifest themselves in this conformation (e.g., collagen), it is envisaged that the title motif will find application in focused molecular design.
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