Enantioselective Organocatalytic Indole Alkylations. Design of a New and Highly Effective Chiral Amine for Iminium Catalysis
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.
Additional Information© 2002 American Chemical Society. Received October 7, 2001. Publication Date (Web): January 26, 2002. Financial support was provided by kind gifts from Astra-Zeneca, Dupont, GlaxoSmithKline, Johnson and Johnson, Materia, Merck Research Laboratories and Roche Biosciences. We also thank Great Lakes for their generous donation of (S)-phenylalanine.
Supplemental Material - ja017255c_s1.pdf