SYNTHETIC APPROACHES FOR THE PREPARATION OF ANTIMALARIAL QUINDOLINE VIA AROMATIC LITHIATION REACTION
D. S. BASTOS*1, A. C. SILVA1, A. L. M. ALBERT1, W. M. R. BARROS1, G. B. C. SLANA1, J. N. CARDOSO1, R. S. C. LOPES1, C. C. LOPES1
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1Universidade Federal do Rio de Janeiro, Instituto de Química
Several research groups have developed alternative syntheses for preparation of the natural product quindoline and its derivatives through synthetic approaches involving the crossed coupling reactions catalyzed by palladium, reductive cyclization mediated by transition metals, photochemical reactions, among others. Such synthetic routes require a great number of steps or additionally, starting reagents that need previous preparation. Indol (3) is an important heterocyclic compound, largely used as an important starting material in the preparation of polyheteroaromatics with relevant biological activity. Frequently, reactions involving abstraction of the hydrogen atom from position C2 in 3,use an organolithium reagent as protective and directing group, linked to the indolic nitrogen, a group which must be easily removed subsequently. In the case of aromatic or heteroaromatic lithiation reactions, some of these groups can be very useful in a range of regioselective functionalization types as orto-metallation directing agents. One of the most elegant methods to promote lithiation with a view to obtaining indol compounds substituted at C2 was developed by Katritzky, using carbon dioxide as the N-protecting group. In this procedure, the N-protecting group is inserted in situ and removed at the end of the reaction, eliminating deprotecting steps. We describe two approaches for the preparation of natural alkaloid quindoline (1) from indol (3) through a very direct synthetic strategy. Several successive heteroaromatic lithiation reaction steps were performed in the same medium producing bis benzylic alcohol (7) in excellent yield. The alcohol was submitted to catalytic reduction, undergoing simultaneous cyclization and aromatization, yielding quindoline (1) in 55% overall yield.
Financial Support: FAPERJ, CAPES and CNPq; Area: Chemistry.
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