Enantioselective Synthesis of Atropisomers via Vinylidene ortho-Quinone Methides (VQMs)

Abstract

Conspectus Atropisomers, arising from conformational restriction, are inherently chiral due to the intersecting dissymmetric planes. Since there are numerous applications of enantiopure atropisomers in catalyst design, drug discovery, and material science, the asymmetric preparation of these highly prized molecules has become a flourishing field in synthetic chemistry. A number of catalysts, synthetic procedures, and novel concepts have been developed for the manufacture of the atropisomeric molecules. However, due to the intrinsic properties of different types of atropisomers featuring biaryl, hetero-biaryl, or non-biaryl architectures, only very few methods pass the rigorous inspection and are considered generally applicable. The development of a broadly applicable synthetic strategy for various atropisomers is a challenge. In this Account, we summarize our recent studies on the enantioselective synthesis of atropisomers using the vinylidene ortho-quinone methides (VQMs) as pluripotent intermediates. The most appealing features of VQMs are the disturbed aromaticity and axial chirality of the allene fragment. At the outset, the applications of VQMs in organic synthesis have been neglected due to their principal liabilities: ephemeral nature, extraordinary reactivity, and multireaction sites. The domestication of this transient intermediate was demonstrated by in situ catalytic asymmetric generation of VQMs, and the reactivity and selectivity were fully explored by judiciously modifying precursors and tuning catalytic systems. A variety of axially chiral heterocycles were achieved through five-, six-, seven- and nine-membered ring formation of VQM intermediates with different kinds of branched nucleophilic functional groups. The axially chiral C–N axis could be constructed from VQM intermediates via N-annulation or desymmetrization of preformed C–N scaffolds. We take advantage of the high electrophilicity of VQMs toward a series of sulfur and carbon based nucleophiles leading to atropisomeric vinyl arenes. Furthermore, chiral helical compounds were realized by cycloaddition or consecutive annulation of VQM intermediates. These achievements demonstrated that the VQMs could work as a nuclear parent for the collective synthesis of distinct and complex optically active atropisomers. Recently, we have realized the isolation and structural characterization of the elusive VQMs, which were questioned as putative intermediates for decades. The successful isolation of VQMs provided direct evidence for their existence and an unprecedented opportunity to directly investigate their reactivity. The good thermal stability and reserved reactivity of the isolated VQMs demonstrated their great potential as synthetic reagents and expanded the border of VQM chemistry.

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.…”

Organocatalytic Nazarov-type cyclization of 3-alkynyl-2-indolylmethanols: construction of axially chiral cyclopenta[b]indole scaffolds

“…The selection of 2-naphthols as suitable nucleophiles is based on the consideration that 2-naphthols [75][76][77] are easily activated by Brønsted acids through the interaction of hydrogen bonding. It is noteworthy that 2-naphthols with a planar structure and the effect of steric congestion should lead to the formation of a C-C bond as a chiral axis [78][79][80] , thus endowing the constructed cyclopenta[b]indole frameworks with axial chirality [81][82][83][84][85][86][87][88][89] . Therefore, the significance of this work is threefold:…”

Brønsted acid–catalyzed asymmetric dearomatization for synthesis of chiral fused polycyclic enone and indoline scaffolds

“…Compared with the well-established transition metalcatalyzed transformations, asymmetric organocatalysis based on the activation of inert alkynes has been relatively less exploited (16,17). Recently, vinylidene-quinone methides (VQMs) derived from 2-alkynylnaphthols under organocatalysis, a well-known variant of ortho-QMs (18), have been widely used in such organocatalytic enantioselective alkyne transformations (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). The VQMs were first used to asymmetric synthesis by Irie and colleagues in 2013 (19) and later were extensively exploited by the same group (20) and Yan and colleagues (21)(22)(23)(24)(25)(26)(27)(28).…”

“…Recently, vinylidene-quinone methides (VQMs) derived from 2-alkynylnaphthols under organocatalysis, a well-known variant of ortho-QMs (18), have been widely used in such organocatalytic enantioselective alkyne transformations (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). The VQMs were first used to asymmetric synthesis by Irie and colleagues in 2013 (19) and later were extensively exploited by the same group (20) and Yan and colleagues (21)(22)(23)(24)(25)(26)(27)(28). However, these protocols always rely on the use of the tertiary amine-derived organocatalyst as chiral catalyst and are typically applied into the assembly of axially chiral scaffolds (Fig.…”