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 alpha,beta-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 alpha,beta-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.
Austin
Joel F
JF
Division of Chemistry and Chemical Engineering,California Institute of Technology, Pasadena, California 91125, USA.
MacMillan
David W C
DW
D000478:Alkylation; D000588:Amines / Q000737:chemistry*; D002384:Catalysis; D007097:Imines / Q000737:chemistry*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D000588:Amines; D007097:Imines; D007211:Indoles