Electrochemical methods are considered useful tools for simulations of biological redox reactions. The activities of quinones depend on their bioreduction. Biologically active pterocarpanquinones LQB-149 (nitroderivative), 150 and 151 (bromo and chloroderivatives, respectively) were electrochemically investigated by cyclic voltammetry, differential pulse voltammetry, and in situ UV-Vis spectroelectrochemistry, in aprotic media (N,N-dimethylformamide (DMF) + tetra-N-butylammonium (TBAPF6)). The data obtained regarding their reduction mechanisms, positive reactivity with oxygen and analysis of the electrogenerated intermediates were useful in explaining their biological outcomes. The appearance of bands at 397 and 480 nm, for the halogenated compounds, suggests the generation of transient quinonemethides (QM), electrophilic intermediates related to their activity. As an additional proof for the intermediacy of QM, in the redox processes, chemical reduction of LQB-150, in the presence of hexanethiol was performed and led to a thioalkylated quinone. For the nitroderivative, a broad band appeared at 432 nm, corresponding to the generation of the nitroradical anion, giving rise to a dianion diradical, after reduction at the second wave potential. Computational data correlate well with electrochemical experiments. Homogeneous electron transfer to oxygen, yielding reactive oxygen species, the generation of electrophilic species and the radical reactivity, explain partially the mechanism of biological action.

Abstract Background: Despite the development of new therapies for leishmaniasis, among the 200 countries or territories reporting to the WHO, 87 were identified as endemic for Tegumentary Leishmaniasis and 75 as endemic for Visceral Leishmaniasis. The identification of antileishmanial drug candidates is essential to fill the drug discovery pipeline for leishmaniasis. In the hit molecule LQB-118 selected, the first generation of pterocarpanquinones was effective and safe against experimental visceral and cutaneous leishmaniasis via oral delivery. In this paper, we report the synthesis and antileishmanial activity of the second generation of pterocarpanoquinones. Methods: The second generation of pterocarpanquinones 2a-f was prepared through a palladium-catalyzed oxyarylation of dihydronaphtalen and chromens with iodolawsone, easily prepared by iodination of lawsone. The spectrum of antileishmanial activity was evaluated in promastigotes and intracellular amastigotes of L. amazonensis, L. braziliensis, and L. infantum. Toxicity was assessed in peritoneal macrophages and selective index calculated by CC50/IC50. Oxidative stress was measured by intracellular ROS levels and mitochondrial membrane potential in treated cells. Results: In this work, we answered two pertinent questions about the structure of the first-generation pterocarpanquinones: the configuration and positions of rings B (pyran) and C (furan) and the presence of oxygen in the B ring. When rings B and C are exchanged, we noted an improvement of the activity against promastigotes and amastigotes of L. amazonensis and promastigotes of L. infantum. As to the oxygen in ring B of the new generation, we observed that the oxygenated compound 2b is approximately twice as active against L. braziliensis promastigotes than its deoxy derivative 2a. Another modification that improved the activity was the addition of the methylenedioxy group. A variation in the susceptibility among species was evident in the clinically relevant form of the parasite, the intracellular amastigote. L. amazonensis was the species most susceptible to novel derivatives, whilst L. infantum was resistant to most of them. The pterocarpanoquinones (2b and 2c) that possess the oxygen atom in ring B showed induction of increased ROS production. Conclusions: The data presented indicate that the pterocarpanoquinones are promising compounds for the development of new leishmanicidal agents.

A series of 2-hydroxy-3-arylnaphthalene-1,4-diones (3-aryllawsones) were synthesized by Suzuki-Miyaura cross coupling reaction of 3-iodolawsone with arylboronic acids/esters. The hydroxylated resulting products were transformed into their corresponding N,N-diethyl carbamates. The antineoplastic and antileishmanial activities of the compounds were evaluated and compared with lapachol and its carbamate, providing promising results.

A reação de Heck entre enoatos de configuração Z e E e o iodobenzeno foi estudada na presença de Pd(OAc)2. A estereoquímica nos adutos formados foi dependente da geometria do enoato (reação estereoespecífica). Os melhores rendimentos foram obtidos a partir de enoatos Z, em acetona, utilizando Ag2CO3 como base. Os principais intermediários catiônicos de paládio possivelmente envolvidos no ciclo catalítico puderam ser interceptados e caracterizados por espectrometria de massas com ionização electrospray (ESI-MS). A estereosseletividade observada pôde ser racionalizada através do mecanismo clássico da reação de Heck.

The Heck reaction between E- and Z-enoates and iodobenzene was studied in the presence of Pd(OAc)2. The stereochemistry in resulting adducts was dependent on the enoate geometry (stereospecific reaction). Best yields were obtained from Z-isomers in acetone using Ag2CO3 as base. The main cationic palladium intermediates possibly involved in the catalytic cycle could be intercepted and characterized by electrospray ionization mass spectrometry (ESI-MS). The stereoselectivity observed was rationalized through the classic mechanism of the Heck reaction.

Benzoato de metila e p-clorofenil acetato de metila reagem com benzilamina e pirrolidina levando às correspondentes amidas. Estas reações são mais rápidas na presença de 20 mol% de DBU, fornecendo os produtos com rendimentos levemente superiores. Quando um diéster derivado do ácido L-aspártico foi usado como substrato, a reação com benzilamina e pirrolidina foi quimiosseletiva para o éster metílico, levando às correspondentes amidas em bons rendimentos. Reação do monoéster metílico do ácido aspártico com estas aminas conduziu a amidas com um grupo ácido livre em C1. Anilina, menos básica e menos nucleofílica, não formou os produtos esperados tanto na ausência quanto na presença de DBU. Através do monitoramento da reação por ESI-MS, foi possível interceptar os intermediários-chave catiônicos formados nas reações entre o benzoato de metila e o p-clorofenil acetato de metila com a benzilamina, os quais foram caracterizados por ESI-MS/MS.

Methyl benzoate and methyl p-chlorophenyl acetate react with neat benzylamine and pyrrolidine to form the corresponding amides. These reactions are faster in the presence of 20 mol% of DBU providing slight better yields. When a diester derived from L-aspartic acid was used as substrate, the reaction with benzylamine and pyrrolidine in the presence of DBU was chemoselective and led to the corresponding amides in good yields. Reaction of aspartic acid monomethyl ester with these amines led to amides having a free carboxy group (at C1). Less nucleophilic and less basic aniline failed to form the expected products in both absence and presence of DBU. By monitoring the course of reaction by ESI-MS, key charged intermediates formed by the reactions of methyl benzoate and methyl p-chlorophenyl acetate with benzylamine were intercepted and further characterized by ESI-MS/MS.

O a-aminoácido (S)-5 foi sintetizado usando na etapa chave uma reação de substituição nucleofílica quimiosseletiva entre um diéster derivado do ácido L-aspártico e a 2-lítio piridina. O rendimento global (13%, 5 etapas) foi semelhante ao previamente descrito por nosso grupo (12%, 10 etapas) para obtenção do isômero R (o primeiro agonista pleno exógeno de receptores do sub-tipo NMDA) a partir do D-manitol e ao da síntese racêmica relatada por Lovey e Copper (17%, 5 etapas).

The a-amino acid (S)-5 was synthesized using in the key step a chemoselective nucleophilic substitution between a diester derived from L-aspartic acid and 2-lithium pyridine. The overall yield (13%, 5 steps) was similar to those previously described by our group for the R isomer (the first exogen full agonist of the NMDA receptors) from D-mannitol (12%, 10 steps) and by Lovey and Copper for the racemic synthesis (17%, 5 steps).

A reação entre o iodo e a N-metil-piperazina ou a tiomorfolina em água, na presença de KI, levou a formação de complexos amina-iodo estáveis e de fácil manipulação, tal qual o complexo morfolina-iodo, previamente descrito na literatura. Entretanto, o complexo formado entre o iodo e a N,N-tetrametiletilenodiamina mostrou-se pouco estável, enquanto que nenhum complexo foi isolado quando a piperidina foi usada como base. Estes resultados mostram que a presença do segundo heteroátomo na estrutura das aminas é fundamental para a formação e estabilidade desses complexos. Neste trabalho descrevemos, pela primeira vez, o emprego dos complexos morfolina-iodo, N-metil-piperazina-iodo e tiomorfolina-iodo como agentes de iodação de vários fenóis substituídos, conduzindo a uma série de produtos iodados em rendimentos variando de bons a excelentes.

The reaction between iodo and N-methyl-piperazine or thiomorpholine in water, in the presence of KI, led to the formation of stable and easy to handle amine-iodine complexes, as the complex morpholine-iodo previously reported in the literature. However, the complex obtained using N,N-tetrametylethylenediamine proved less stable, while no complex was formed when piperidine was used as base. These results show that the presence of a second heteroatom in the structure of amines is of fundamental importance for the formation and stability of these complexes. In this work we describe, for the first time, the use of complexes morpholine-iodo, N-methyl-piperazine-iodo and thiomorpholine-iodo as iodinating reagents of several substituted phenols, leading to iodinated products in good to excellent yields.

A tandem syn-selective conjugate addition - Nef reaction was observed when phenylnitromethane and oxygenated derivatives were allowed to react with an enoate derived from D-mannitol at rt in the presence of TBAF or DBU. While nitro-adducts predominate after 4h of reaction, the corresponding ketones were the main products after 12-24h of reaction. The Nef reaction occurred without racemization of the stereogenic center generated in the conjugate addition step.

Apresentamos a primeira síntese do (±)-3,4-diidroxi-8,9-metilenodioxipterocarpano, um isoflavonóide natural que apresenta atividade antitumoral. A etapa chave envolveu uma arilação de Heck entre o 7,8-dibenziloxicromeno e o organomercurial derivado do sesamol, seguido de reação de desbenzilação. O aduto de Heck foi também empregado na síntese do correspondente derivado cumestano, utilizando DDQ como agente oxidante.

We report the first synthesis of (±)-3,4-dihydroxy-8,9-methylenedioxypterocarpan, a natural isoflavonoid that shows antitumoral activity. The key step involved the Heck reaction between the 7,8-dibenzyloxychromen and the organomercurial derived from sesamol, followed by debenzylation. The Heck adduct was also employed in the synthesis of the corresponding coumestan derivative, using DDQ as oxidant agent.

An overview of the developments that occurred in the field of organic chemistry in Brazil in the last 25 years is presented. These developments are briefly compared to those observed worldwide, including some modern trends. The main source of information was the annual meeting of the Brazilian Chemical Society (RASBQ) covering the period 1979-2001 and the biennial Brazilian Meeting on Organic Synthesis (BMOS). All the contributions presented at these two meetings were classified according to six main indicatives, to permit a discussion about the past, present and future activities of Organic Chemistry in Brazil.

Um procedimento otimizado para a preparação de catecóis através da reação de quebra da ponte metilenodioxílica de derivados do safrol com cloreto de alumínio é descrito. Em substratos com grupos substituintes atraentes de elétrons (carboxaldeído e nitro) observou-se a formação regiosseletiva de éteres clorometílicos facilmente isoláveis. A partir desses intermediários foram sintetizados os fenóis mono O-metilados (3-hidroxi-4-metoxibenzaldeído, 2-bromo-4-metoxi-5-hidroxibenzaldeído, 2-nitro-4-metoxi-5-hidroxibenzaldeído, e 2-metoxi-4-(2-oxoprop-1-il)-5-nitrofenol). Com base nesses dados experimentais e em cálculos semi-empíricos (MNDO) de orbitais moleculares foi proposta uma racionalização mecanística para explicar as regiosseletividades observadas.

An improved procedure for the "one-pot" preparation of cathecols from methylenedioxy-ring cleavage reaction of safrole derivatives with aluminum chloride is described. In substrates substituted by conjugated electron-withdrawing groups (carboxyaldehyde or nitro groups) the regioselective formation of the easily isolable chloromethyl ether intermediates was observed. From these intermediates the syntheses of mono-O-methylated phenols (3-hydroxy-4-methoxybenzaldehyde, 2-bromo-4-methoxy-5-hydroxybenzaldehyde, 2-nitro-4-methoxy-5-hydroxybenzaldehyde and 2-methoxy-4-(2-oxoprop-1-yl)-5-nitrophenol) were accomplished. Based on these experimental data and semi-empirical (MNDO) molecular orbital calculations, a mechanistic rationale that explains the observed regioselectivities was also proposed.

The chemical reactivity of safrole, eugenol, piperonal, vanillin and derivates toward ozone, aluminium chloride, brominating agents and butyl lithium was investigated. The synthesis of naturally occuring anthraquinones, furonaphthoquinones, naphthoquinones, lignans and pterocarpans from these easily available staring materials is also discussed.

Os acrilatos 3-O-acriloil-4,5-di-O-benzoil-1,2- O-isopropilideno-beta-D-frutopiranose (6) e 3-O-benzil-5-O-acriloil-1,2-O -isopropilideno-alfa-D-xilofuranose (8) foram sintetizados em poucas etapas a partir dos respectivos monossacarídeos para utilização como auxiliares quirais em reações de Diels-Alder assimétricas com o ciclopentadieno, sob condições térmicas e promovidas por Et2AlCl. Os resultados indicaram que, embora tenham sido obtidas relações endo/exo de moderadas a excelentes, foram observadas baixas diastereosseletividades pi-faciais para os cicloadutos 3-O-[(1'R,4'R)-biciclo-[2.2.1]hept-2'-eno-5'-formil] -4,5-di- O-benzoil-1,2-O-isopropilideno-beta-D-frutopiranose (21a) e 3-O-benzil-5-O-[(1'S, 4'S)-biciclo-[2.2.1]hept-2'-eno-5'-formil]-1,2- O-isopropilideno-alfa-D-xilofuranose (22b), indicando que as conformações tipo do "pi-stacked" desejadas nos complexos formados entre os acrilatos e o ácido de Lewis não foram estabelecidas.

Acrylates 3-O-acryloyl-4,5-di-O-benzoyl-1,2- O-isopropylidene-beta-D-fructopyranose (6) and 3-O-benzyl-5-O-acryloyl-1,2-O -isopropylidene-alpha-D-xylofuranose (8) were synthesized in few steps from carbohydrates to construct chiral dienophiles for asymmetric Diels-Alder reaction with cyclopentadiene under thermal and Et2AlCl-promoted conditions. Although from moderate to excellent endo/exo ratios were obtained, low p-facial diastereoselectivities were observed for the cycloadducts 3-O-[(1'R, 4'R)-bicyclo-[2.2.1]hept-2'-ene-5'-formyl]-4,5-di- O-benzoyl-1,2-O-isopropylidene-beta-D-fructopyranose (21a) and 3-O-benzyl-5-O-[(1'S, 4'S)-bicyclo-[2.2.1]hept-2'-ene-5'-formyl]-1,2- O-isopropylideno-alpha-D-yilofuranose (22b) indicating that pi-stacked conformations in the Lewis acid-acrylates complex were not effective.

The thalidomide disaster, in the 60,s, is the most painful reminder of the importance of chirality for biological activity. After this episode, much attention has been devoted to study the correlations between toxicological and pharmacological properties and chirality. Actualy, to get a licence for a new chiral drug in EUA, European community and Japan, it is necessary to study the biological properties of each enatiomer independently. This article presents an overview about the importance of the chirality of organic compounds and its relationships with biological activity, asymmetric synthetic methodologies and market.