Torsional Strain‐Independent Catalytic Enantioselective Synthesis of Biaryl Atropisomers

Abstract

Catalytic asymmetric dynamic kinetic resolution of configurationally labile bridged biaryls is emerging as a powerful strategy for atropisomer synthesis. However, the reported examples suffer from an inherent challenge as the reactivity is highly dependent on the torsional strain of the biaryl substrates, which significantly narrows down the scope and hampers the application. Herein, we report our discovery and development of a torsional strain-independent reaction between biaryl thionolactones and activated isocyanides. By employing auto-tandem silver catalysis, a universal synthesis of both tri-and tetra-ortho-substituted thiazole-containing biaryls was realized in high yields with high enantioselectivities. In addition, these products could be facilely converted to a novel type of bridged biaryls bearing an eight-membered lactone. Mechanistic studies were carried out to elucidate the cause of this unusual torsional strain-independent reactivity.

Enantioselective Access to Triaryl-2-pyrones with Monoaxial or Contiguous C–C Diaxes via Oxidative NHC Catalysis

“…Axially chiral compounds have played an essential role as chiral ligands and catalysts in asymmetric synthesis. , This class of molecules is widely found in numerous pharmaceutical agents and natural products . Out of different axially chiral structures, substituted biaryls ( A and B , Scheme a) have been extensively developed and applied. − More recently, other atropisomers including alkenes and aryl amides ( C and D , Scheme a) have also been under active investigation. − However, these studies mainly focused on the preparation of atropisomers with a single stereogenic axis. Methods to assemble axially chiral molecules with more than one stereogenic axis ( E and F , Scheme a) have rarely been reported, owing to the formidable challenges involved in the assembly of multiple stereogenic axes with high enantiocontrol.…”

Stereodynamic Strategies to Induce and Enrich Chirality of Atropisomers at a Late Stage

“…Derivatives of 60.3 were studied, and lower yields and enantioselectivity were observed when one or both hydrogen donors were protected, highlighting the importance of these hydrogen-bond donors for substrate activation and enantiocontrol. The authors also applied a similar approach to less highly substituted biaryls lacking torsional strain …”

Assembly of iodinated indolo[1,2-c]quinazoline amines via I2/CHP-promoted cascade annulation of isocyanides and diarylalkynes

“…7 In addition, isocyanides are valuable synthons with extensive applications in organic synthesis and play a significant role in the construction of nitrogen-containing heterocycles. 8 In the past few decades, transition metal-catalyzed cascade reactions based on isocyanide insertion have been extensively investigated, producing a great many high-value chemicals. 9 Cascade reactions have attracted great attention for their applications in the construction of complex molecules, and have undeniable advantages such as having only a single workup procedure and purification step without the isolation of the intermediates, and are looked upon as an atom- and step-economical, environmentally benign strategy for the construction of complex molecules.…”