Construction of Axially Chiral Indoles by Cycloaddition–Isomerization via Atroposelective Phosphoric Acid and Silver Sequential Catalysis

Abstract

Axially chiral indole-based frameworks occur in natural products, bioactive molecules, and chiral ligands. Thus, the development of catalytic asymmetric atroposelective approaches for de novo construction of these frameworks is highly valuable. Here, the atroposelective organo/metal combined dual catalysis strategy for de novo construction of valuable axially chiral indole frameworks has been developed. This protocol utilized a catalyst system of two chiral phosphoric acids (1 mol %) in combination with AgNO3 (1 mol %) and was based on the unreported intermolecular cycloaddition–isomerization reaction of our recently introduced C-alkynyl N,O-acetals and 2-naphthylamines. An important class of hitherto inaccessible axially chiral indoles with a C–N axis were obtained in good yields and enantioselectivities. The axially chiral indoles obtained also provided a platform for the catalyst-controlled atroposelective synthesis of axially chiral indoles bearing two C–N axes, which are difficult to access by the existing methods. This work is also an example of 2-naphthylamines used as 1,3-dinucleophiles and three-atom (CCN) synthons in cycloadditions.

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

“…In fact, in recent years, the catalytic asymmetric construction of axially chiral indole-based scaffolds has become an emerging area of study [8,78] due to the importance of such scaffolds in many natural products [90][91][92] , bioactive molecules [93,94] and chiral catalysts or ligands [95][96][97][98][99][100][101] . Although a number of axially chiral indole-based scaffolds, such as N-arylindoles [102][103][104][105][106][107][108][109][110] , 3-arylindoles [111][112][113][114][115][116][117][118][119][120] , 2-arylindoles [121][122][123][124][125][126][127] , 3quinonylindoles [128,129] , isochromenone-indoles [130] , bisindoles [131][132][133][134]…”

Advances in Atroposelectively De Novo Synthesis of Axially Chiral Heterobiaryl Scaffolds

“…In sharp contrast, there are rarely reports on the construction of axially chiral indoles via dual catalysis. In 2022, Shao’s group utilized organic catalysts ( L8 and the L9 )/transition-metal (AgNO 3 ) combined dual catalytic system for de novo synthesis of the axially chiral indole-based scaffold 29 with good yields and excellent enantioselectivities, by employing 2-naphthylamines 28 and N, O-acetals 27 as the starting materials ( Scheme 8 ) [ 71 ]. This transformation offered a rare example of the combination of two chiral phosphoric acids with a metal catalyst in a single reaction to enable inaccessible molecules through intermolecular cycloaddition-isomerization.…”

Silver-Catalyzed Direct Nucleophilic Cyclization: Enantioselective De Novo Synthesis of C–C Axially Chiral 2-Arylindoles

“…As far as we know, there has been no report of this kind of Ag-catalyzed direct nucleophilic cyclization when we initiated our research. Until very recently, Shao and Peng reported the relay catalysis of CPA­(1) and Ag- CPA­(2) at 50 °C to prepare polycyclic indoles bearing a C–N axis . Different from our design of one-step 5- endo - dig cyclization with rigid 2-alkynylanilines, it is proposed as a stepwise reaction involving flexible chiral propargylamine intermediates, which was generated by intermolecular asymmetric propargylation and then performed 5- exo cyclization.…”

“…Until very recently, Shao and Peng reported the relay catalysis of CPA(1) and Ag-CPA(2) at 50 °C to prepare polycyclic indoles bearing a C−N axis. 17 Different from our design of one-step 5-endo-dig cyclization with rigid 2-alkynylanilines, it is proposed as a stepwise reaction involving flexible chiral propargylamine intermediates, which was generated by intermolecular asymmetric propargylation and then performed 5-exo cyclization. Herein, inspired by previous reports and our recent work on CPAs, 18 we report a chiral silver phosphate (Ag-CPA)-catalyzed direct 5-endo-dig nucleophilic cyclization for enantioselective de novo synthesis of C−C axially chiral atropisomeric 2-arylindoles in good to excellent yields and enantioselectivities.…”