Issue 43, 2023

Organocatalytic atroposelective synthesis of axially chiral N,N′-pyrrolylindoles via de novo indole formation

Abstract

The first organocatalytic atroposelective synthesis of axially chiral N,N′-pyrrolylindoles based on o-alkynylanilines was successfully established via de novo indole formation catalyzed by chiral phosphoric acid (CPA). This new synthetic strategy introduced CPA-catalyzed asymmetric 5-endo-dig cyclization of new well-designed o-alkynylanilines containing a pyrrolyl unit, resulting in a wide range of axially chiral N,N′-pyrrolylindoles in high yields with exclusive regioselectivity and excellent enantioselectivity (up to 99% yield, >20 : 1 rr, 95 : 5 er). Considering the potential biological significance of N–N atropisomers, preliminary biological activity studies were performed and revealed that these structurally important N,N′-pyrrolylindoles had a low IC50 value with promising impressive cytotoxicity against several kinds of cancer cell lines. DFT studies reveal that the N-nucleophilic cyclization mediated by CPA is the rate- and stereo-determining step, in which ligand–substrate dispersion interactions facilitate the axial chirality of the target products.

Graphical abstract: Organocatalytic atroposelective synthesis of axially chiral N,N′-pyrrolylindoles via de novo indole formation

Supplementary files

Article information

Article type
Edge Article
Submitted
17 Jul 2023
Accepted
04 Oct 2023
First published
11 Oct 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2023,14, 12091-12097

Organocatalytic atroposelective synthesis of axially chiral N,N′-pyrrolylindoles via de novo indole formation

C. Wang, Q. Xiong, H. Xu, H. Yang, Y. Dang, X. Dong and C. Wang, Chem. Sci., 2023, 14, 12091 DOI: 10.1039/D3SC03686C

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