title: Diastereoselective Synthesis of Biologically Active Cyclopenta[b]indoles.
abstract: The cyclopenta[b]indole motif is present in several natural and synthetic biologically active compounds, being directly responsible for the biological effects some of them present. We described herein a three step sequence for the synthesis of cyclopenta[b]indoles with a great structural diversity. The method is based on an oxidative Michael addition of suitable indoles on the double bond of Morita-Baylis-Hillman adducts mediated by a hypervalent iodine reagent (IBX) to form β-ketoesters, which were chemoselectively reduced with NaBH4 in THF to give the corresponding β-hydroxy-esters. The diastereoisomeric mixture was then treated with a catalytic amount of triflic acid (20 mol %) to give cyclopenta[b]indoles with overall yields ranging from 8 to 73% (for 2 steps). The acid-catalyzed cyclization step gave the required heterocycles, via an intramolecular Friedel-Crafts reaction, with high diastereoselectivity, where only the trans product was observed. A mechanistic study monitored by ESI-(+)-MS was also conducted to collect evidence about the mechanism of this reaction. The new molecules herein synthesized were also evaluated against a panel of human cancer cells demonstrating a promising antitumoral profile.
authors.forename: Marilia S
authors.initials: MS
authors.lastname: Santos
authors.affiliation: Instituto Federal de Educação, Ciência e Tecnologia de São Paulo , Campus Matão, 15991-502 Matão, SP, Brazil.
authors.forename: Daniara C
authors.initials: DC
authors.lastname: Fernandes
authors.forename: Manoel T
authors.initials: MT
authors.lastname: Rodrigues
authors.forename: Thais
authors.initials: T
authors.lastname: Regiani
authors.affiliation: Laboratório de Química Medicinal e Computacional, Instituto de Física da USP - São Carlos , 13563-120 São Carlos, SP, Brazil.
authors.forename: Adriano D
authors.initials: AD
authors.lastname: Andricopulo
authors.affiliation: Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas, UNICAMP , PO Box 6171, 13083-970 Paulínia, SP, Brazil.
authors.forename: Ana Lúcia T G
authors.initials: AL
authors.lastname: Ruiz
authors.affiliation: Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas, UNICAMP , PO Box 6171, 13083-970 Paulínia, SP, Brazil.
authors.forename: Débora B
authors.initials: DB
authors.lastname: Vendramini-Costa
authors.affiliation: Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas, UNICAMP , PO Box 6171, 13083-970 Paulínia, SP, Brazil.
authors.forename: João E
authors.initials: JE
authors.lastname: de Carvalho
authors.forename: Marcos N
authors.initials: MN
authors.lastname: Eberlin
authors.forename: Fernando
authors.initials: F
authors.lastname: Coelho
mesh_terms: D020816:Amino Acid Motifs; D002384:Catalysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003500:Cyclization; D019281:Dimerization; D004354:Drug Screening Assays, Antitumor; D004952:Esters / Q000737:chemistry; D019073:HT29 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis*; D007455:Iodine / Q000737:chemistry; D020014:K562 Cells; D008670:Metals / Q000737:chemistry; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism
chemical_list: D004952:Esters; D007211:Indoles; D008670:Metals; D007455:Iodine; D010100:Oxygen