Open AccessA General Approach to Indoles: Practical Applications for the Synthesis of Highly Functionalized Pharmacophores
Author(s) -
Jeffrey T. Kuethe
Publication year - 2006
Publication title -
chimia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.387
H-Index - 55
eISSN - 2673-2424
pISSN - 0009-4293
DOI - 10.2533/chimia.2006.543
Subject(s) - pharmacophore , combinatorial chemistry , chemistry , aldehyde , indole test , yield (engineering) , stereochemistry , organic chemistry , catalysis , materials science , metallurgy
The development of a long-term manufacturing route to a potent and selective KDR kinase inhibitor has led to the discovery of several novel methodologies for the general synthesis of indoles. The key transformations involved addition of a trimethylsilylnitro benzene to an aromatic aldehyde which afforded the key nitroalcohol intermediate. Oxidation of the nitroalcohol intermediate led to a nitroketone; whereas, elimination afforded exclusively a trans-nitrostyrene. Reductive cyclization gave the target compounds in excellent overall yield from readily available bulk chemicals. Application of this methodology has led to the synthesis of highly functionalized pharmacophores including other KDR kinase inhibitors, biindoles and tjipanazole natural products, indolo[2,3-a]pyrrolo [3,4-c]carbazoles, indole-4-carboxylic amides, N-hydroxyindoles, and 2,3-dihydrobenzofurans.