Design and Organocatalytic Asymmetric Synthesis of Indolyl-Pyrroloindoles Bearing Both Axial and Central Chirality

Abstract

An axially chiral indolyl-pyrroloindole scaffold, a new member of axially chiral indole-based scaffolds, has been designed, and the catalytic asymmetric construction of this scaffold has been established by the strategy of organocatalytic asymmetric (2 + 3) cycloaddition of 3,3′-bisindoles with isoindolinone-based propargylic alcohols. By this approach, a series of indolyl-pyrroloindole derivatives bearing both axial chirality and central chirality were synthesized in high yields with excellent diastereo- and enantioselectivities (up to 95% yield, 91:9 dr, 99% ee). This reaction not only realizes the first catalytic asymmetric (2 + n) cycloaddition of 3,3′-bisindoles as 1,2-dinucleophiles but also provides a new strategy for atroposelective construction of axially chiral indole-based scaffolds bearing five–five-membered rings, thus solving the challenges in constructing this class of axially chiral indole-based scaffolds.

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

“…In 2022, Shi and co-workers expanded on this protocol by developing a chiral phosphoric acid (CPA)catalyzed (2 + 3)-cycloaddition between 47.1 and propargylic alcohol 47.5 using chiral phosphoric acid 47.6. 208 Under these conditions, spirocyclic 47.7 was afforded in 95% yield and 97% ee with 80:20 dr. In 2019, Zhang, Shi, and their colleagues reported on a chiral phosphoric acid (CPA)-catalyzed dynamic kinetic resolution of axially chiral naphthyl-indoles via nucleophilic addition of indoles (Figure 48).…”

“… A reaction between 2-substituted 3,3′-bisindole 47.1 and isatin-derived 3-indolylmethanol 47.2 afforded the 3,3′-bisindole product 47.3 in 93% yield, >95:5 dr, and 97% ee when conducted in the presence of 5 mol % of CPA catalyst ( R )- 47.4 in toluene. In 2022, Shi and co-workers expanded on this protocol by developing a chiral phosphoric acid (CPA)-catalyzed (2 + 3)-cycloaddition between 47.1 and propargylic alcohol 47.5 using chiral phosphoric acid 47.6 . Under these conditions, spirocyclic 47.7 was afforded in 95% yield and 97% ee with 80:20 dr.…”

The rapid construction and biological evaluation of densely substituted pyrrolo[1,2-a]indoles via a BF3·OEt2-assisted cascade approach

“…Moreover, indolyl-pyrroloindole scaffolds are one of the most important components of certain chiral ligands or catalysts with axial chirality. 19,20 Due to the excellent biological activity of pyrrolo[1,2- a ]indole-containing natural products and the demand for their synthesis in synthetic chemistry, the development of a novel cascade of reactions that can achieve complexity in a one-pot reaction along with the generation of several chiral centres would be of considerable valuable. 21 To date, several useful methods have been developed towards the synthesis of the pyrrolo[1,2- a ]indole skeleton and natural products containing it.…”

Atroposelective Access to Dihydropyridinones with C–N Axial and Point Chirality via NHC-Catalyzed [3 + 3] Annulation

“…Enantiopure axially chiral compounds are important motifs that are widely present in natural products, pharmaceuticals, bioactive compounds, advanced functional materials, and chiral catalysts/ligands . Among them, atropisomers bearing both axial and point chirality have displayed unique applications in pharmaceutical science and asymmetric synthesis . It has been proven that the superposition of a point chiral element with an axial backbone in an organocatalyst or ligand could largely enhance chirality transfer in various enantioselective transformations .…”