Enantioselective Synthesis of Biaryl Atropisomers by Pd‐Catalyzed C−H Olefination using Chiral Spiro Phosphoric Acid Ligands

Abstract

The discovery of proper ligands to simultaneously modulate the reactivity and effectively control the stereoselectivity is a central topic in the field of enantioselective C−H activation. Herein, we reported the synthesis of axially chiral biaryls by Pd‐catalyzed atroposelective C−H olefination. A novel chiral spiro phosphoric acid, STRIP, was identified as a superior ligand for this transformation. A broad range of axially chiral quinoline derivatives were synthesized in good yields with excellent enantioselectivities (up to 98 % ee). Density functional theory was used to gain a theoretical understanding of the enantioselectivities in this reaction.

Atroposelective Synthesis of Axially Chiral Styrenes via an Asymmetric C–H Functionalization Strategy

“…This is in sharp contrast to Pd-catalyzed atroposelective CÀH alkenyaltion of biaryls using chiral spiro phosphoric acid ligands, in which the high enantioselectivity originated from a dramatic ligand acceleration effect. 47 LDE-induced highly enantioselective asymmetric synthesis is significantly more challenging than the accelerated scenario. 56 We rationalized that the high ee resulted from the suppression of background reaction by a highly favorable ligand exchange of L-pGlu-OH with Pd(OAc) 2 to form a chiral Pd(L-pGlu-O)(OAc)-type catalyst.…”

“…Although asymmetric CÀH functionalization has emerged as a powerful synthetic tool for the rapid generation of axially chiral biaryl skeletons, 11,14,[34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] construction of axially chiral styrenes bearing an open-chained alkene with more flexibility via catalytic asymmetric CÀH functionalization remains elusive. At least two main difficulties needed to be addressed: first, the reaction has to be conducted under mild conditions in order to preserve enantiomeric purity of the resulting products because of the relatively lower conformational stability.…”

“…Second, the judicious choice of a proper ligand and directing group (DG), which could cooperatively act to modulate the reactivity and effectively induce the enantioselectivity, is extremely challenging. Continuing with our long-standing efforts in construction of axial chirality via enantioselective CÀH activation, [43][44][45][46][47][48] we decided to tackle this synthetic challenge. Herein, we describe the highly atroposelective synthesis of axially chiral styrenes with open-chained alkene by Pd(II)-catalyzed atroposelective CÀH alkenylation and alkynylation by using readily available L-pyroglutamic acid as a chiral ligand.…”

Synthesis of Axially Chiral Biaryl‐2‐amines by PdII‐Catalyzed Free‐Amine‐Directed Atroposelective C−H Olefination

“…[4][5][6][7][8][9][10][11] In particular, chelation-assisted catalytic asymmetric C À H activation offers great opportunities to provide diverse chiral biaryl compounds by changing different directing groups (DGs). To date, two types of DGs, namely N-heteroarenes and their derivatives [5][6][7] and phosphine oxides, [8] have been employed to act as both coordinating groups to enable the reactivity and bulky ortho-substituents to enhance enantiocontrol (Scheme 1 b). [4] In 2000, Murai and co-workers reported a Rh I -catalyzed pyridine-directed atroposelective C À H alkylation, albeit in low yield with moderate stereoinduction (37 % yield, 49 % ee).…”

“…[6d] Our group reported a Pd II -catalyzed atroposelective C À H olefination with quinoline as the DG. [7] The use of phosphine oxide as a DG has been achieved by Yang and co-workers in Pd II -catalyzed asymmetric CÀH olefination. [8a] Meanwhile, the synthesis of axially chiral biaryl compounds by diastereoselective CÀH functionalization using chiral sulfoxide and menthyl phenylphosphate as DGs has been reported by Wencel-Delord and Colobert [9] and Yang [8b] and co-workers, respectively.…”