Enantioselective Organocatalytic Indole Alkylations. Design of a New and Highly Effective Chiral Amine for Iminium Catalysis

TLDR

The indole scaffold is a privileged structure found in over 3000 natural products and 40 drugs across diverse therapeutic areas. The study aims to develop a new chiral amine catalyst that improves reactivity and selectivity for iminium‑catalyzed alkylation of indoles with α,β‑unsaturated aldehydes. The authors designed a (2S,5S)-5‑benzyl‑2‑tert‑butyl‑imidazolidinone catalyst that facilitates conjugate addition of indoles to α,β‑unsaturated aldehydes. The catalyst delivers high yields (70–97%) and excellent enantiomeric excesses (84–97%) across diverse indole substrates, and its utility is demonstrated in the enantioselective synthesis of an indolobutyric acid COX‑2 inhibitor.

Abstract

The indole framework has become widely identified as a "privileged" structure with representation in over 3000 natural isolates and 40 medicinal agents of diverse therapeutic action. A new strategy for asymmetric access to this important pharmacaphore has been accomplished that involves the amine catalyzed alkylation of indoles with α,β-unsaturated aldehydes. Central to these studies has been the design of a new chiral amine catalyst that exhibits improved reactivity and selectivity for iminium catalysis. This new (2S,5S)-5-benzyl-2-tert-butyl-imidazolidinone catalyst has enabled the conjugate addition of a variety of indole systems to a diverse range of α,β-unsaturated aldehydes in high yield and with excellent levels of enantiocontrol (70−97% yield, 84−97% ee). A demonstration of the utility of this new organocatalytic alkylation for the rapid construction of biomedically relevant molecules is presented in the enantioselective synthesis of an indolobutyric acid COX-2 inhibitor.