One-pot organocatalyzed synthesis of tricyclic indolizines.

Indolizines and their saturated derivatives are important structural motifs present in several biologically active compounds of both natural and synthetic origin. We describe herein a one-pot approach for the synthesis of tricyclic indolizines catalyzed by a bicyclic imidazole-alcohol. The protocol is based on an aqueous Morita-Baylis-Hillman reaction between pyridine-2-carboxaldehydes and six- or seven-membered cyclic enones, followed by sequential intramolecular cyclization and dehydration. So, in a single operational step two new bonds (C-C and C-N) are formed in an organocatalyzed process that takes place in simple conditions (stirring in water at 60 °C for 12 h) and with great atom economy (water as the sole byproduct), affording the purified compounds in yields ranging from 19 to 70%. The facility of the cyclization strongly depends on the size of the cycloalkenone ring: while MBH adducts derived from six-, seven- or eight-membered cycloenones are readily transformed into the corresponding indolizines, cyclopentenone-derived MBH adducts do not cyclize. A competition experiment revealed that cycloheptenone-derived MBH adducts cyclize faster than cyclohexenone-derived adducts. Model DFT calculations have been performed to rationalize these reactivity trends.

Discovery of highly potent and selective antiparasitic new oxadiazole and hydroxy-oxindole small molecule hybrids.

A series of highly active hybrids were discovered as novel antiparasitic agents. Two heterocyclic scaffolds (1,2,4-oxadiazole and 3-hydroxy-2-oxindole) were linked, and the resulting compounds showed in vitro activities against intracellular amastigotes of two protozoan parasites, Trypanosoma cruzi and Leishmania infantum. Their cytotoxicity was assessed using HFF-1 fibroblasts and HepG2 hepatocytes. Compounds 5b, 5d, 8h and 8o showed selectivity against L. infantum (IC50 values of 3.89, 2.38, 2.50 and 2.85 µM, respectively). Compounds 4c, 4q, 8a and 8k were the most potent against T. cruzi, exhibiting IC50 values of 6.20, 2.20, 2.30 and 2.20 µM, respectively. Additionally, the most potent anti-T. cruzi compounds showed in vitro efficacies comparable or superior to that of benznidazole. These easy-to-synthesize molecules represent novel chemotypes for the design of potent and selective lead compounds for Chagas disease and leishmaniasis drug discovery.

Palladium-Mediated Oxidative Annulation of δ-Indolyl-α,ß-Unsaturated Compounds toward the Synthesis of Cyclopenta[ b]indoles and Heterogeneous Hydrogenation To Access Fused Indolines.

The cyclopenta[ b]indole moiety represents a key skeletal unit in several natural and synthetic compounds that exhibit diverse biological properties. We described herein a two-step sequence for synthesizing cyclopenta[ b]indoles with great structural diversity in overall yields up to 37%. The key step was a palladium-catalyzed oxidative annulation of 3-alkylindoles (Fujiwara-Moritani reaction). The obtained cyclopenta[ b]indoles were used as substrates in heterogeneous hydrogenation reactions to afford new fused indolines in moderate yields. An acid-catalyzed intramolecular cyclization of three such indolines gave tetracyclic lactams in 89, 90, and 61% yields.

Vinyl-1,2,4-oxadiazoles Behave as Nucleophilic Partners in Morita-Baylis-Hillman Reactions.

We describe that vinyl-oxadiazoles function as a new and efficient nucleophilic partner for the Morita-Baylis-Hillman (MBH) reaction. The reaction between 5-vinyl-3-aryl-1,2,4-oxadiazoles and aromatic and aliphatic aldehydes, catalyzed by DABCO in the absence of solvent, showed high efficiency to afford a new class of heterocyclic MBH adducts with potential biological activity on yields up to 99% and short reaction times. These synthetically attractive adducts bear a heterocyclic scaffold of large pharmaceutical and commercial interest associated with a plethora of biological effects and technological applications. We also demonstrate their synthetic usefulness by a photoinduced addition reaction to a polyfunctionalized amino alcohol.

Diastereoselective Synthesis of Biologically Active Cyclopenta[b]indoles.

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 ß-ketoesters, which were chemoselectively reduced with NaBH4 in THF to give the corresponding ß-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.

Crystal structure of 3-(3,4,5-tri-meth-oxy-phen-yl)-1,2,3,4-tetra-hydro-cyclo-penta[b]indole-2-carb-oxy-lic acid.

In the title compound, C21H21NO5, obtained from a Morita-Baylis-Hillman adduct, the hydrogenated five-membered ring adopts a shallow envelope conformation, with the C atom bearing the carb-oxy-lic acid substituent deviating by 0.237 (1) Šfrom the mean plane of the other four atoms (r.m.s. deviation = 0.007 Å). The dihedral angle between the fused ring system (all atoms; r.m.s. deviation = 0.057 Å) and the pendant trimeth-oxy benzene ring is 66.65 (3)°. The C atoms of the meta-meth-oxy groups lie close to the plane of the benzene ring [deviations = 0.052 (1) and -0.083 (1) Å], whereas the C atom of the para-meth-oxy group is significantly displaced [deviation = -1.289 (1) Å]. In the crystal, carb-oxy-lic acid inversion dimers generate R 2 (2)(8) loops. The dimers are connected by N-H⋯O hydrogen bonds, forming [011] chains. A C-H⋯O inter-action is also observed.

Aqueous Morita-Baylis-Hillman reaction of unprotected isatins with cyclic enones.

The readily available bicyclic imidazolyl alcohol 1 is a unique catalyst for the aqueous Morita-Baylis-Hillman (MBH) reaction between unprotected isatins and cyclic enones that gives access to a variety of potentially very useful 3-substituted 3-hydroxy-2-oxindoles in an operationally simple, efficient, and environmentally friendly way. The hydroxyl group of the catalyst is believed to stabilize the betaine intermediate formed in the first step of the MBH reaction.

The antinociceptive activity of harmicine on chemical-induced neurogenic and inflammatory pain models in mice.

Harmicine is a ß-carboline alkaloid isolated and identified as a major active compound present in many plant species and marine invertebrates. This alkaloid exhibits a wide spectrum of pharmacological activities, including antispasmodic, antipyretic, and anticancer properties. This report described the antinociceptive properties of harmicine by means of chemical experimental models in order to evaluate the use for pain relief. The results demonstrating the potential analgesic properties of harmicine administered intraperitoneally were shown with the writhing test, reducing writhes around 60% (1 mg/kg), and in the formalin test, where harmicine was more effective toward neurogenic (reducing reaction time around 60%, 1 mg/kg) than inflammatory (68% reduction, 10 mg/kg) pain responses. Furthermore, these effects may operate via vanilloid receptors as revealed by the capsaicin test (41% reduction, with 3 mg/kg), as well as via peripheral glutamate receptors as shown by the glutamate test (50% reduction, with 1 mg/kg). Moreover, the opioid antagonist naloxone hydrochloride did not interfere in the antinociceptive properties of harmicine in the writhing test, revealing that this effect may not have a relationship with the opioid systems. Concluding, this report highlights harmicine as a new candidate to be used as analgesic in the future. Therefore, further studies are being undertaken in order to understand the exact mechanisms involved with the antinociceptive properties of harmicine.

Novel supramolecular palladium catalyst for the asymmetric reduction of imines in aqueous media.

A novel approach to the asymmetric reduction of dihydro-beta-carboline derivatives to the corresponding tetrahydro-beta-carbolines is described based on the supramolecular lyophilized complex formed from beta-cyclodextrin/imines as an enzyme mimetic and palladium hydride as the reducing agent. The methodology allowed us to develop a short and efficient preparation of (R)-harmicine and (R)-deplancheine alkaloids in high overall yields and ee of 89 and 90%, respectively.