Catalytic asymmetric trifluoromethylthiolation via enantioselective [2,3]-sigmatropic rearrangement of sulfonium ylides

Abstract

The trifluoromethylthio (SCF) functional group has been of increasing importance in drug design and development as a consequence of its unique electronic properties and high stability coupled with its high lipophilicity. As a result, methods to introduce this highly electronegative functional group have attracted considerable attention in recent years. Although significant progress has been made in the introduction of SCF functionality into a variety of molecules, there remain significant challenges regarding the enantioselective synthesis of SCF-containing compounds. Here, an asymmetric trifluoromethylthiolation that proceeds through the enantioselective [2,3]-sigmatropic rearrangement of a sulfonium ylide generated from a metal carbene and sulfide (Doyle-Kirmse reaction) has been developed using chiral Rh(II) and Cu(I) catalysts. This transformation features mild reaction conditions and excellent enantioselectivities (up to 98% yield and 98% e.e.), thus providing a unique, highly efficient and enantioselective method for the construction of C(sp)-SCF bonds bearing chiral centres.

Photochemical ring expansion reactions: synthesis of tetrahydrofuran derivatives and mechanism studies

“…Ylides are important reaction intermediates in sigmatropic rearrangement reactions and serve as highly versatile synthons for the construction of complex molecular scaffolds. 1 Despite signicant advances over the past decades, 2,3 the basic understanding of the rearrangement process of oxygen or sulfur ylides is still limited and currently available synthesis methods underpin a substantial difference of the reaction mechanism of sulfur vs. oxygen ylides. 3,4 Both are typically accessed from unsymmetrically substituted (thio)ethers in the presence of a metal catalyst.…”

“…1 Despite signicant advances over the past decades, 2,3 the basic understanding of the rearrangement process of oxygen or sulfur ylides is still limited and currently available synthesis methods underpin a substantial difference of the reaction mechanism of sulfur vs. oxygen ylides. 3,4 Both are typically accessed from unsymmetrically substituted (thio)ethers in the presence of a metal catalyst. The inuence of the ether substitution pattern and the catalyst environment on the stereochemical outcome of the rearrangement step can thus not be completely ruled out and both metal-bound or free ylide reaction mechanisms are currently under discussion.…”

Recent Advances and Perspectives of Transition Metal‐Catalyzed Asymmetric Fluorination Reactions

“…[44] Thus, introducing a suitable chiral ligand into the palladium catalysts might realize the asymmetric trifluoromethoxylation reactions. [45] In addition, Wang and coworkers recently reported a novel enantioselective transition metal-catalyzed [2,3]sigmatropic rearrangement reaction of sulfonium ylides forming a sp 3 C-SCF 3 bond (Scheme 14), [46] which provides a highly efficient method for the synthesis of chiral trifluoromethylthiolated compounds.…”

Enantioselective Vinylogous Mannich‐Type Reactions to Construct CF3S‐Containing Stereocenters Catalysed by Chiral Quaternary Phosphonium Salts

“…In 2017, Wang et al. developed an efficient approach for the enantioselective construction of the chiral C(sp 3 )−SCF 3 bond via Rh(II)‐ and Cu(I)‐catalysed [2,3]‐sigmatropic rearrangements of sulfonium ylide (Scheme , a) . Our group has also reported the enantioselective Mannich‐type reactions using cyano‐substituted benzyl trifluoromethyl sulphides to construct tetrasubstituted carbon stereocenters via asymmetric dual‐reagent catalysis (Scheme , b) .…”