Ayres G. Dias

Selective conjugate addition of nitromethane to enoates derived from D-mannitol and L-tartaric acid

The conjugate addition of nitromethane to enoates prepared from D-(+)-mannitol, substituted at the alpha-position by a methyl or a benzyl group, was investigated. While excellent syn-selectivity (d.e. >90%) was obtained from a-benzyl enoates (used as a mixture of epimers, E/Z=1.8:1), for alpha-methyl enoates the selectivity depended on the stereochemistry of the double bond in the acceptor (d.e. >90% for the (Z)-enoate and 50% for the (E)-enoate). In all cases, a mixture of epimers was formed at the newly generated stereocenter at the a-position. The epimeric syn-adducts were transformed into the corresponding pure alpha,beta,gamma-trisubstituted gamma-butyrolactones by cyclization in acid medium followed by epimerization of the stereocenter at the a-position in DBU/CH2Cl2. When enoates derived from L-tartaric acid were used as acceptors, syn-selective conjugate additions were also observed (d.e. >90% for the (Z)-isomer and 50% for the (E)-isomer). The configuration at the newly generated stereogenic centers were assigned based on X-ray analyses, H-1-H-1 coupling constants and NOE experiments in NMR spectroscopy

DBU as a catalyst for the synthesis of amides via aminolysis of methyl esters

Benzoato de metila e p-clorofenil acetato de metila reagem com benzilamina e pirrolidina levando as correspondentes amidas. Estas reacoes sao mais rapidas na presenca de 20 mol% de DBU, fornecendo os produtos com rendimentos levemente superiores. Quando um diester derivado do acido L-aspartico foi usado como substrato, a reacao com benzilamina e pirrolidina foi quimiosseletiva para o ester metilico, levando as correspondentes amidas em bons rendimentos. Reacao do monoester metilico do acido aspartico com estas aminas conduziu a amidas com um grupo acido livre em C1. Anilina, menos basica e menos nucleofilica, nao formou os produtos esperados tanto na ausencia quanto na presenca de DBU. Atraves do monitoramento da reacao por ESI-MS, foi possivel interceptar os intermediarios-chave cationicos formados nas reacoes 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.

Synthesis of N-methylarylnitrones derived from alkyloxybenzaldehydes and antineoplastic effect on human cancer cell lines.

New O-isoprenylated-N-methylarylnitrones derived from isomeric o, m and p-hydroxybenzaldehydes have been prepared and the antineoplastic effects on human cancer cell lines were evaluated. The O-geranylated nitrone LQB-278 (1b) and its isomers 2b and 3b inhibited the NO production, but the anti-leukemic activity was drastically dependent on nitrone isomer, with the 1b being the most effective one (IC₅₀ of 6.7 μM) on Jurkat leukemia cell, by MTT assay. In addition, 1b up-regulated p21CIP1/WAF1/Sdi1 protein expression (flow cytometry), a cell cycle inhibitor, reduced cell growth, and induced DNA fragmentation (increased sub-G1 phase cells) and phosphatidylserine externalization in plasmatic membrane (increased annexin V positive cells). Finally, the 1b up-regulation of p21 expression and apoptosis induction seem to be the mechanisms by which it promotes its anti-leukemic effects, making this new molecular architecture a promising prototype for leukemia intervention.

Crude D‐(+)‐Glyceraldehyde Obtained from D‐Mannitol‐Diacetonide by Oxidative Cleavage with Sodium Periodate: Its Reactions with Nucleophilic Species

Abstract The oxidative cleavage of D‐(+)‐mannitol‐diacetonide with sodium periodate lead to a mixture of D‐(+)‐glyceraldehyde, its hydrate and oligomeric derivatives. In spite of the low concentration of free glyceraldehyde (estimated in ∼20%, by NMR), good yields were obtained in nucleophilic additions involving this mixture and a variety of nucleophiles (amines, phosphonates, phosphoranes, nitronates, organometallic compounds).

A green synthesis of α,β-unsaturated carbonyl compounds from glyceraldehyde acetonide

The catalytic behavior of Cs-exchanged and Cs-impregnated zeolites (X and Y) was studied using the Knoevenagel condensation between glyceraldehyde acetonide and ethyl acetoacetate in order to produce the corresponding α,β-unsaturated carbonyl compound that is an important intermediate for fine chemicals. The influence of reaction temperature, type of zeolite, and basicity of the sites on the catalytic behavior of the samples was evaluated. All zeolites were active for the studied reaction. The formation of the main condensation product was favored at lower reaction temperatures. Products of further condensations were also observed especially for samples that were only dried before catalytic test.

Reação entre fenilnitrometanos e enoato derivado do D-manitol na presença de TBAF ou DBU: adição conjugada sin-seletiva e reação de NEF consecutiva

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.

Identification of Ethyl and t-Butyl Glyceryl Ethers Using Gas Chromatography Coupled with Mass Spectrometry

The ethers produced through the etherification reaction of glycerol with ethanol or t-butanol are used as oxygenated fuel additives, intermediates in the pharmaceutical industry, and non-ionic surfactants. However, the identification of these ethers has not been accurately done, because only some mass spectra of these compounds are available in the libraries. Moreover, there is a lack of discussion on their identification in the literature. In this work, a detailed identification of all ethers produced in the etherification of glycerol with ethanol or t-butanol was performed considering the mass spectra of isolated products and the comparison of the retention times. The elution order of the products was: tri-alkyl, 1,3-dialkyl, 2,3-dialkyl, 3-monoalkyl and 2-monoalkyl. In all mass spectra of the ethyl ethers, the base peak was m/z 61, while in the case of t-butyl ethers it was m/z 57.

Mutagenic and Cytotoxicity LQB 123 Profile: Safety and Tripanocidal Effect of a Phenyl-t-Butylnitrone Derivative

The therapeutic options for Chagas disease are limited and its treatment presents a number of drawbacks including toxicity, drug resistance, and insufficient effectiveness against the chronic stage of the disease. Therefore, new therapeutical options are mandatory. In the present work, we evaluated the effect of a phenyl-tert-butylnitrone (PBN) derivate, LQB 123, against Trypanosoma cruzi forms. LQB 123 presented a trypanocidal effect against bloodstream trypomastigotes (IC50 = 259.4 ± 6.1 μM) and intracellular amastigotes infecting peritoneal macrophages (IC50 = 188.2 ± 47.5 μM), with no harmful effects upon the mammalian cells (CC50 values greater than 4 mM), resulting in a high selectivity index (CC50/IC50 > 20). Additionally, metacyclic trypomastigotes submitted to LQB 123 presented an IC50 of about 191.8 ± 10.5 μM and epimastigotes forms incubated with different concentrations of LQB 123 presented an inhibition of parasite growth with an IC50 of 255.1 ± 3.6 μM. Finally, we investigated the mutagenic potential of the nitrone by the Salmonella/microsome assay and observed no induction of mutagenicity even in concentrations as high as 33000 μM. Taken together, these results present a nonmutagenic compound, with trypanocidal activity against all relevant forms of T. cruzi, offering new insights into CD treatment suggesting additional in vivo tests.

Synthesis of Azapterocarpan Analogues by Intramolecular 1,3-dipolar Cycloaddition

The imines type 12 were obtained by Kurth methodology 2 (75%) and employed in 1,3-IDC preliminary experiments. The metallo-azomethine ylides, generated by reaction of imine with DBU in combination with LiBr, 3 were studied in thermal and microwave-assisted experiments to obtained 2a. The allylic sulphone 15 was most conveniently obtained from S-alkylation/bromination of allyl bromide followed by dehydrobromination using TEA, Scheme 2. This bromide will be use in 1,3 IDC reactions to prepare 3 analogues. Work is now in progress to establish the relative configuration in 11 and accomplish others 1,3-DC reactions. CONCLUSION The 1,3-IDC reaction is a rapid and practical approach to Aza-pterocarpan and analogues skeletons. ACKNOWLEDGEMENTS FAPERJ, CNPq, CAPES. REFERENCES

A new and concise strategy to the enantioselective synthesis of (S)-2-amino-4-oxo-4-(pyridine-2-yl) butanoic acid from aspartic acid

O a-aminoacido (S)-5 foi sintetizado usando na etapa chave uma reacao de substituicao nucleofilica quimiosseletiva entre um diester derivado do acido L-aspartico e a 2-litio piridina. O rendimento global (13%, 5 etapas) foi semelhante ao previamente descrito por nosso grupo (12%, 10 etapas) para obtencao do isomero R (o primeiro agonista pleno exogeno de receptores do sub-tipo NMDA) a partir do D-manitol e ao da sintese racemica 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).