Copper-Catalyzed Asymmetric Functionalization of Vinyl Radicals for the Access to Vinylarene Atropisomers

Abstract

A novel asymmetric radical strategy for the straightforward synthesis of atropisomerically chiral vinyl arenes has been established herein, proceeding through copper-catalyzed atroposelective cyanation/azidation of aryl-substituted vinyl radicals. Critical to the success of the radical relay process is the atroposelective capture of the highly reactive vinyl radicals with chiral L*Cu(II) cyanide or azide species. Moreover, these axially chiral vinylarene products can be easily transformed into atropisomerically enriched amides and amines, enantiomerically enriched benzyl nitriles via an axis-to-center chirality transfer process, and an atropisomerically pure organocatalyst for the chemo-, diastereo-, and enantioselective (4 + 2) cyclization reaction.

Rhodium(I)‐Catalyzed Asymmetric Hydroarylative Cyclization of 1,6‐Diynes to Access Atropisomerically Labile Chiral Dienes

“…Variation of the anion of the rhodium catalyst verified the superiority of the triflate anion (entries 4-8). THF was identified as the optimal solvent, and lower reactivity or enantioselectivity was realized for other oxygenated solvents (entries [9][10][11][12][13][14]. In contrast to activity of the Rh(I) catalyst, no desired coupling was observed when a typical Ir(I) or Rh(III) catalyst was used (entry 15).…”

“…Axially chiral open-chained olefins constitute a large family of atropisomers that also fall into this challenging category in that distortion of the four bonds around the C=C unit decreases the racemization barrier (Scheme 1a). [8][9][10][11][12][13][14][15][16] Catalytic functionalization of alkynes represents a straightforward approach to access axially chiral olefins. Recently, Zhu and co-workers realized Ni-catalyzed reductive arylation of internal alkynes.…”

Transition-metal-catalyzed atroposelective synthesis of axially chiral styrenes

“…72 Very recently, on the foundation of their previously developed Cu-catalyzed asymmetric radical functionalization reactions, 73 the Liu group demonstrated the synthesis of axially chiral styrenes 127 through atroposelective functionalization of vinyl radicals formed from terminal alkynes (Scheme 25). 74 Via an analogous enantiocontrol process with Zhang's work mentioned above, both cyanation and azidation were carried on with Int4 , which was acquired from radical trifluoromethylation of alkynes 125 bearing acyloxy (X = O), acylamino (X = NH) or alkyl (X = CH 2 ) groups. Compound 128b was further decorated into 129 , which was a more efficient organocatalyst in asymmetric [4+2] cycloaddition of 132 and 133 compared with traditional thioureas 130 and 131 .…”

Copper-Catalyzed Fluoroalkylphosphorothiolation of Alkynes for the Synthesis of (E)-β-Fluoroalkyl Vinyl Phosphorothioates

“…However, the synthesis of controllable Z/E stereoselective multisubstituted olefins is still very challenging. Considering the low cost and easy commercial availability of copper salts, and the widespread structural unit of alkynes in natural products and drugs, copper-catalyzed radical 1,2-difunctionalization of alkynes provide inexpensive, simple, and convenient access to β-fluoroalkyl multisubstituted olefins. − Thus, far, numerous copper-catalyzed radical β-fluoroalkyl 1,2-difunctionalization of alkynes, such as fluoroalkyl-halogenation, fluoroalkyl-cyanation, fluoroalkyl-azidylation, , fluoroalkyl-hydrogenation, fluoroalkyl-sulfonation, fluoroalkyl-amination, and so on, have been successfully demonstrated (Scheme a, right). Given the importance of phosphorothioates and the admirable “fluorine effect”, we were particularly intrigued to simultaneously introduce fluoroalkyl motifs and the (RO) 2 P­(O)­S– group into alkynes to access the stereoselective and regioselective fluoroalkyl vinyl phosphorothioates for improving their potential bioactivities to enrich drug candidate libraries.…”