Rhodium‐Catalyzed Atroposelective Access to Axially Chiral Olefins via C−H Bond Activation and Directing Group Migration

Abstract

Axially chiral open‐chain olefins represent an underexplored class of chiral platform. In this report, two classes of tetrasubstituted axially chiral acyclic olefins have been accessed in excellent enantioselectivity and regioselectivity via C−H activation of (hetero)arenes assisted by a migratable directing group en route to coupling with sterically hindered alkynes. The coupling of indoles bearing an N‐aminocarbonyl directing group afforded C–N axially chiral acrylamides with the assistance of a racemic zinc carboxylate additive. DFT studies suggest a β‐nitrogen elimination–reinsertion pathway for the directing group migration. Meanwhile, the employment of N‐phenoxycarboxamide delivered C−C axially chiral enamides via migration of the oxidizing directing group. Experiments suggest that in both cases the (hetero)arene substrate adopts a well‐defined orientation during the C−H activation, which in turn determines the disposition of the alkyne in migratory insertion. Synthetic applications of representative chiral olefins are demonstrated.

Atroposelective desymmetrization of 2-arylresorcinols via Tsuji-Trost allylation

“…Strategies to control a stereogenic axis are generally classified into several categories [16][17][18][19][20][21][22][23] , such as direct cross-coupling, dynamic kinetic resolution, ring formation, and desymmetrization (Fig. 1a) [24][25][26][27][28][29][30][31] . As each strategy inherently possesses its own strengths and weaknesses, they are necessarily complementary to each other depending on a target molecule.…”

Chiral Trifluoromethylated Enamides: Synthesis and Applicability

“…Nevertheless, such compounds seem to be of interest as demonstrated by recent examples for the syntheses of axially chiral enamides. [58][59][60] Additionally, the construction of CF3-substituted chiral sp 3 -carbon centers remains a difficult synthetic task despite the high potential of fluorinated motifs in medicinal chemistry. 61,62 Thus, efficient asymmetric methodologies to access such…”

Axially chiral alkenes: Atroposelective synthesis and applications

“…While organocatalytic functionalization of alkynes usually involves trans addition, Li [57] recently devised an approach to cis addition products via rhodium-catalyzed C-H activation and directing group migration (Scheme 14a). The coupling of N-phenoxyacetamides 88 with 1-alkynylnaphthalenes 89 afforded tetrasubstituted enamides 90 in Scheme 12.…”