Catalytic atroposelective synthesis of axially chiral benzonitriles via chirality control during bond dissociation and CN group formation

Abstract

The applications of axially chiral benzonitriles and their derivatives remain mostly unexplored due to their synthetic difficulties. Here we disclose an unusual strategy for atroposelective access to benzonitriles via formation of the nitrile unit on biaryl scaffolds pre-installed with stereogenic axes in racemic forms. Our method starts with racemic 2-arylbenzaldehydes and sulfonamides as the substrates and N-heterocyclic carbenes as the organocatalysts to afford axially chiral benzonitriles in good to excellent yields and enantioselectivities. DFT calculations suggest that the loss of p-toluenesulfinate group is both the rate-determining and stereo-determining step. The axial chirality is controlled during the bond dissociation and CN group formation. The reaction features a dynamic kinetic resolution process modulated by both covalent and non-covalent catalytic interactions. The axially chiral benzonitriles from our method can be easily converted to a large set of functional molecules that show promising catalytic activities for chemical syntheses and anti-bacterial activities for plant protections.

Chalcogen bond-guided conformational isomerization enables catalytic dynamic kinetic resolution of sulfoxides

“…For instance, the hydrogen of aldehyde could be deuterated 61 catalyzed by achiral NHC in the presence of D 2 O to afford 100% deuterated 4a in 77% yield and without the loss of optical purity. Moreover, the formyl group could be cyanation 62 and thioesterification catalyzed by achiral NHC with high er values ( 4b , 4c ). Enantioenriched terminal alkyne 4d and alkene 4e were synthesized efficiently by means of Seyferth–Gilbert reaction 63 and Wittig reaction 64 , respectively.…”

N-Heterocyclic Carbene-Mediated Carbon–Sulfur Bond-Forming Reactions

“…Intermediate 95 can react with electrophiles to give the related products. Meanwhile, intermediate 96 can be transformed into PhCN , and liberate the free NHC additional catalytic cycles.…”

Simultaneous Processing of Antagonistic Chemical Events (SPACE): An Atroposelective Dynamic Kinetic Resolution of MRTX1719

“…Moreover, axially chiral benzonitriles are known to be particularly challenging substrates. 9 Fortunately, a late-stage stereoselective crystallization was developed but a serious drawback was low yield (37%) at the end of the synthesis. Perhaps one might consider a dynamic kinetic resolution to solve this issue.…”