Catalytic asymmetric synthesis of CF3-substituted tertiary propargylic alcohols via direct aldol reaction of α-N3 amide

Hidetoshi Noda, Fuyuki Amemiya, Karin Weidner, Naoya Kumagai, Masakatsu Shibasaki

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)

Abstract

Organofluorine compounds are found in several important classes of chemicals, such as pharmaceuticals, agrochemicals, and functional materials. Chemists have been immensely interested in the development of methodologies for expeditious access to fluorine containing building blocks. In this study, we report a new method for the catalytic asymmetric synthesis of CF3-substituted tertiary propargylic alcohols with two contiguous stereogenic centers via the direct aldol reaction of an α-N3 amide to trifluoromethyl ketones. The key to the success of this method is the identification of a catalyst comprising Cu(ii)/chiral hydroxamic acid to promote the desired aldol reaction, constructing a tetrasubstituted carbon in a highly stereoselective fashion. Despite substantial prior advances in asymmetric catalysis, this class of catalysts has not been utilized for the formation of carbon-carbon bond-forming reactions. Our mechanistic study sheds light on the unique profile of this catalytic system, where the Cu(ii) complex plays a bifunctional role of serving as a Lewis acid and a Brønsted base. Furthermore, the densely functionalized aldol adducts undergo chemoselective transformations, affording a series of fluorine containing chiral building blocks with widespread application.

Original languageEnglish
Pages (from-to)3260-3269
Number of pages10
JournalChemical Science
Volume8
Issue number4
DOIs
Publication statusPublished - 2017
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)

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