Synthesis of Axially Chiral Compounds via Transition Metal-Catalyzed Atroposelective C-H Functionalization.

Abstract

ConspectusAxially chiral skeletons are prevalent in natural products and biologically important compounds, and they are widely utilized as privileged scaffolds in enantioselective catalysis. Consequently, the catalytic atroposelective synthesis of enantiopure atropisomers has garnered considerable attention. A variety of synthetic strategies involving metal catalysis or organocatalysis have been developed. Among these elegant approaches, transition metal-catalyzed enantioselective C-H activation has emerged as an atom- and step-economical strategy to streamline the construction of axially chiral compounds in recent years.In this Account, we discuss our efforts in the atroposelective synthesis of different types of axially chiral compounds, including biaryls, atropisomeric styrenes, and C-N atropisomers, via transition metal-catalyzed enantioselective C-H activation strategies. To this end, we have developed several approaches, including the chiral transient directing group (cTDG) strategy using catalytic Pd(OAc)₂ and tert-leucine (Tle), as well as catalytic enantioselective systems involving Pd(II)/chiral phosphoric acid (CPA), Pd(II)/l-pyroglutamic acid (pGlu), Pd(0)/norbornene cooperative catalysis with a chiral biimidazoline (BiIM) ligand, and Co(II)/salicyloxazoline (Salox).At the outset, we successfully applied the cTDG strategy to access axially chiral biaryl aldehydes through Pd-catalyzed atroposelective C-H olefination, alkynylation, allylation, naphthylation, and alkylation. The efficacy of these methods has been demonstrated in the enantioselective synthesis of chiral aldehyde catalysts and natural products, such as TAN-1085, (+)-isochizandrin, and (+)-steganone. To facilitate the synthesis of biaryl atropisomers with diverse functionalities, we developed a novel Pd(II)/CPA catalytic system, which enables the preparation of various axially chiral quinolines, biaryl-2-amines, and atropisomeric biaryls bearing chalcogenoether units with high enantioselectivities. The Pd(II)/CPA system also allows for the synthesis of more challenging conjugated diene-based axially chiral styrenes.Nonbiaryl atropisomers, such as axially chiral styrenes and anilides, present synthetic challenges due to their conformational instability and higher degree of rotational freedom compared to their biaryl counterparts. We have addressed these challenges and achieved the highly efficient synthesis of atropisomeric styrenes and anilides using Pd(II)/pGlu and Pd(0)/norbornene/BiIM catalysis. In addition to palladium catalysis, cobalt(II)/Salox catalysis has also been developed for the construction of chiral biaryls, atropisomers with vicinal C-N and C-C stereogenic axes, remote distinct C-N diaxes, and chiral calix[4]arenes featuring both inherent and axial chirality. We anticipate that the enantioselective C-H activation strategy will find broad applications in the construction of synthetically useful axially chiral compounds.