Phosphoric acid-catalyzed atroposelective construction of axially chiral arylpyrroles

Abstract

Axially chiral arylpyrroles are key components of pharmaceuticals and natural products as well as chiral catalysts and ligands for asymmetric transformations. However, the catalytic enantioselective construction of optically active arylpyrroles remains a formidable challenge. Here we disclose a highly efficient strategy to access enantioenriched axially chiral arylpyrroles by means of organocatalytic atroposelective desymmetrization and kinetic resolution. Depending on the remote control of chiral catalyst, the arylpyrroles were obtained in high yields and excellent enantioselectivities under mild reaction conditions. This strategy tolerates a wide range of functional groups, providing a facile avenue to approach axially chiral arylpyrroles from simple and readily available starting materials. Selected arylpyrrole products proved to be efficient chiral ligands in asymmetric catalysis and also important precursors for further synthetic transformations into highly functionalized pyrroles with potential bioactivity, especially the axially chiral fully substituted arylpyrroles.

Fig. 1

Representative molecules containing axially chiral arylpyrrole frameworks. a Bioactive natural products. b Resolving agent. c Chiral ligands and catalysts

Fig. 2

Background and project synopsis. a Aminocatalytic enantioselective synthesis of atropisomeric succinimides via remote control strategy (Bencivenni’s work). b Our strategy for the remote enantiocontrol of axially chiral arylpyrroles. Black circle, sterically bulky substituent

Fig. 3

Versatile synthetic transformations. a Synthetic transformations of compound 3a. Ts, p-toluenesulfonyl. b Synthetic transformations of compound 3h

Fig. 4

Applications in asymmetric catalysis and plausible mechanism. a Asymmetric catalysis applications. b Proposed reaction mechanism