Scalable total syntheses of N-linked tryptamine dimers by direct indole-aniline coupling: psychotrimine and kapakahines B and F.
This report details the invention of a method to enable syntheses of psychotrimine (1) and the kapakahines F and B (2, 3) on a gram scale and in a minimum number of steps. Mechanistic inquiries are presented for the key enabling quaternization of indole at the C3 position by electrophilic attack of an activated aniline species. Excellent chemo-, regio-, and diastereoselectivities are observed for reactions with o-iodoaniline, an indole cation equivalent. Additionally, the scope of this reaction is broad with respect to the tryptamine and aniline components. The anti-cancer profiles of 1-3 have also been evaluated.
Newhouse
Timothy
T
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Lewis
Chad A
CA
Eastman
Kyle J
KJ
Baran
Phil S
PS
D000814:Aniline Compounds / Q000737:chemistry*; D045744:Cell Line, Tumor; D019281:Dimerization; D006801:Humans; D026121:Indole Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D009584:Nitrogen / Q000737:chemistry*; D010084:Oxidation-Reduction; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013379:Substrate Specificity; D014363:Tryptamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000814:Aniline Compounds; D026121:Indole Alkaloids; D007211:Indoles; D010456:Peptides, Cyclic; D014363:Tryptamines; C541864:kapakahine B; C476160:kapakahine F; C503380:psychotrimine; C030820:tryptamine; D009584:Nitrogen; C023650:aniline