Letters in Organic Chemistry - Volume 14, Issue 4, 2017

Background: Fungi can play an important role in environmental remediation. A key class of pollutants is the aromatic amines (AA) comprising dyes, drugs, pesticides and products originated from combustion and other industrial residues. The microbial N-acetylation is known to be a chief detoxifying mechanism for noxious AA. However, this transformation is not widely reported for fungi. Methods: The filamentous soil fungus Aspergillus japonicus (UFMS 48.136) when cultivated with six structurally different AA led to selective N-acetylation of all tested compounds in only 24 h of incubation. Culture medium and mycelia were both separated by filtration over celite and extracted with EtOAc. The solvent was evaporated and the crude extract was purified by column chromatography. Results: Six acetylated AA were obtained with yields between 15.9 to 76.1 %. The products were characterized by IR, 1H NMR, 13C NMR spectra and mass spectrometry. Conclusion: Considering that reports on fungal N-acetylation of xenobiotic AA are scarce, our discovery can contribute for new investigations in this important research field and open opportunities for new methods of environmental detoxification.

Background: Ease of preparation and alkaline stability of methoxymethyl (MOM) makes it an important hydroxyl protecting group. A number of methods are available for the deprotection of MOM. Though the methods are good in general, they use solvents, require prolonged reaction time and tedious work up. A solvent free, solid phase, fast deprotection of MOM has been developed and is the major theme of this paper. Methods: A mixture of MOM protected compounds and pTSA is triturated in a mortar (5 min) and left at room temperature for 30 min. On addition of water (4oC), pTSA, methanol and formaldehyde dissolved leaving the products as precipitates. Results: A series of different MOM ethers were deprotected by this method in good to excellent yield (85-98%). The compatibility of MOM in the presence of other protections such as methoxyl, benzyl, ester, amide, allyl and lactone was also established. Acetate protection is not stable under these conditions. Conclusion: An efficient, selective and high yielding deprotection MOM groups by pTSA under solvent free condition is described. The process is environment friendly since no solvent was used in the deprotection process. The reaction conditions are mild and should be useful for the deprotection of MOM derivatives of complex and labile molecules.

Background: The present study is an effort to extend the utility of the α,β-ditosyloxy chalcone derivatives in establishing the reaction patterns of these compounds which at once was thought that they might behave similar to α,β-dibromo ketones but the results obtained were quite different and interesting in nature. Methods: In the present methodology, the α,β-chalcone ditosylates containing pyrazoles were prepared from corresponding chalcone derivatives on treatment with [hydroxyl(tosyloxy)iodo]benzene in dichloromethane at room temperature and that were further allowed to react with potassium hydroxide in methanol. Results: A new series of acetylenic ketones were obtained in the present case in excellent yield. The analytical data of the compounds fully satisfy the structures of the compounds. Conclusions: In the present case, the α,β-chalcone ditosylates lead to the elimination of ditosyloxy groups and the products isolated are acetylenic ketones which are stable under the reaction conditions. Hence, it offers a facile and convenient route for the synthesis of acetylenic ketones which are difficult to synthesize otherwise.

Background: Geminal diboryl reagents have attracted considerable attention due to their unique reactivities. Double hydroboration of alkynes is a convenient and useful method for the synthesis of diborylalkanes. However, the double hydroboration is applied mainly to terminal alkynes. Methods: Ethyl propiolate was treated with B2pin2 and methanol in the presence of various copper catalysts and ligands. The reaction of several internal conjugated alkynes was also investigated under the optimized reaction conditions. Results: Geminal diboryl compounds were obtained in high yields. While 1,10-phenanthroline was more effective for the reaction of methyl propiolate than tri-n-butylphosphine, the divided addition of B2pin2 and the use of tri-n-butylphosphine were necessary for the reaction of several alkynes, for which second hydroboration was slower. Conclusion: We have found that the copper-catalyzed double hydroboration of conjugated internal alkynes was a useful method for the synthesis of internal gem-diborylalkanes.

Background: Marine sponges have produced a large number of secondary metabolites and become a potent source of anti-cancer agents for drugs discovery. Screening results indicated that methanol extract of the sponge Ircinia echinata significantly induced in vitro antiproliferative effect against human cancer cell strains HepG-2, KB, and MCF-7. Therefore, this study aims to isolate, identify chemical structure, and evaluate antiproliferative activity of constituents from the sponge I. echinata. Methods: Frozen samples of the sponge I. echinata were ultrasonically extracted in methanol. The methanol extract was fractionated and purified using chromatographic methods to obtain pure compounds. Chemical structures of isolated compounds were elucidated by HR-ESI-MS, 1D-, 2D-NMR spectral data, and as well as comparison with reported literature. In addition, antiproliferative effects of isolated compounds on six human cancer cell strains (HepG-2, HL-60, KB, LU-1, MCF-7, and LNCaP) were evaluated by Sulforhodamine B assay. Results: A new furanosesterterpene, 8-hydroxyisovariabilin (1), together with eleven known ones, including four furanoterpenes (2-5), a fatty acid (6), and six sterols (7-12) were isolated from methanol extract of the sponge I. echinata. Antiproliferative evaluation revealed that furanosesterterpene 3 and sterols 7, 9-12 are promising anticancer agents. Among them, sterols 11 and 12 exhibited anti-proliferative effect on tested cancer cell strains with IC50 values in range of 4.53-9.74 μg/mL. Conclusion: The sponge I. echinata found at the sea of Vietnam is a good source for the isolation of furanoterpenoids and sterols. Isolated furanosterterpene (3) and sterols (7, 9-12) are promising antiproliferative agents which could be useful in anticancer drugs discovery.

Background: The oxidation of benzylic alcohols to carbonyl compounds is a fundamental reaction in organic synthesis. In traditional oxidation processes, a large amount of toxic and volatile organic solvents and metal oxidants are used. Thus, developing environmentally benign oxidation processes is an important goal. N-Bromosuccinimide (NBS) is an inexpensive and convenient oxidant widely used in a variety of oxidative reactions under acidic or alkaline conditions. Methods: In this paper, we developed a simple, mild, and efficient oxidation of benzylic alcohols in the presence of N-bromosuccinimide (NBS)/KOAc in aqueous solution (H2O/CH2Cl2 = 3:1). Results: A series of benzylic alcohols were oxidized selectively to the corresponding ketones in moderate to excellent yields at room temperature. Conclusion: This reaction was carried out using a wide variety of substrates, required no metal catalyst, and proved to be tolerant towards a variety of different functional groups.

Background: The synthesis of biologically active model compounds represents a valuable tool for medicinal chemistry. In this regard, the synthesis of MSVII-19, a structurally simplified model compound of Dysiherbaine, developed by the group of Sasaki, was synthesized with the intention of preparing a powerful agonist or antagonist of glutamate receptor. Therefore, the synthesis of an advanced intermediate in the Sasaki’s synthesis of MSVIII-19 is reported. Methods: Taking advantage of the furanose ring of the diacetone-D-glucose (DAG), the cis-fused hexahydrofuro[3,2-b]pyran ring system of the title compound was constructed by featuring two protocols: SHOWO (sequential hydrolysis-oxidation-Wittig olefination) and RCM (ring closing metathesis). Then, by applying a combined allylation at the anomeric position and a Pd-catalyzed double bond isomerization reaction, the methyl ester group in 1b was installed. Results: The synthesis of an advanced intermediate of MSVIII-19 involves three key procedures: a) SHOWO (sequential hydrolysis-oxidation-Wittig olefination) protocol; b) RCM (ring closing metathesis) reaction; y c) the nucleophilic substitution at the anomeric position. Additionally, with the use of a cheaper starting material (DAG) than that used in the previous synthesis (tri-O-acetyl-D-glucal). The current synthesis is truly competitive with that reported by the Sasaki group. Conclusion: A concise formal total synthesis of the advanced intermediate of MSVIII-19 was achieved. (Current synthesis: 14 steps; previous synthesis 20 steps).

Background: During the last years, condensed pyridine compounds have received much attention because of their immense biological properties. In this article, a practical and efficient synthesis of their novel series pyrido[1,2-b][1,2,4]triazine-2,6-dione and pyrido[1,2-b][1,2,4]triazepine-2,7-dione derivatives has been developed. Method: Different epoxides and substituted 1,6-diaminopyridone have been used. The reaction occurred preferentially with the regioselective opening of the epoxides by the N-amino group (N-NH2) of 1,6-diaminopyridone to form the instable intermediates cyanohydrins, which loses hydrogen cyanide giving intermediate acylcyanide or α-keto esters which underwent a cycloaddition reaction between the other amino group at (C-NH2) and the second elecrophilic carbon of the epoxide affording the target pyrido[1,2-b][1,2,4]triazine-2,6-diones and pyrido[1,2-b][1,2,4]triazepine-2,7-diones respectively. The structural assignments of these compounds were made on the basis of spectroscopic data (IR, 1H NMR, 13C NMR and Mass) and elemental analysis. The synthesized compounds were evaluated for their antioxidant (DPPH, FRAP and ABTS assays). Result: The synthesized compounds with different substituent’s were obtained in good yields. Most of the compounds were found to be more active in DPPH, FRAP and ABTS assays. Conclusion: We have successfully synthesized two series of novel fused nitrogen heterocyclic systems such as pyrido[1,2-b][1,2,4]triazine-2,6-diones and pyrido[1,2b][1,2,4] triazepine-2,7-diones. This process offers several advantages: shorter time, operational simplicity, mild reaction conditions and ease of products isolation. A series of compounds showed significant antioxidant activity and seem to be of interest for industrial and medical uses and results from this study suggest their incorporation in toxicological and pharmacological studies.

Background: The synthesis of effective drugs is very important for the scientist. Due to the beneficial pharmacological properties of certain molecules containing the 1,2,4-oxadiazole moiety, the aim of this manuscript is to develop a one pot three component reaction for the synthesis of bis (3, 5- disubstituted 1,2,4-oxadiazoles) bridged by polyoxyethylene chain from bis(β-hydroxynitrile) of polyethylene glycols under neutral and organic solvent-free reaction conditions. These compounds have gained too much interest as proven by large number of reviews and research articles published in the current years. The synthesis of a series of bis (3, 5-disubstituted 1,2,4-oxadiazoles) has initially been stimulated by their known antimalaria properties. Methods: A one-pot two-step synthesis of a new bis (3, 5-disubstituted 1,2,4-oxadiazoles) linked with polyoxyethylene chain was realized starting from the reaction of aqueous hydroxylamine with bis (β- hydroxynitrile) polyoxyethylene obtained in turn by ring opening of oligoethylene diglycidyl ethers under mild conditions. The identity and purity of the products were confirmed by IR, 1H NMR, 13C NMR and HRMS. Results: The synthesized compounds with different chain lengths were obtained in satisfactory to good yields (41-74%).This methodology presented the advantage of being relatively eco-friendly, short reaction times, versatile and avoid the use of organic solvent. Conclusion: This work presents simple direct route to the important structure containing two oxadiazole groups bridged by a polyoxyethylene chain 3(a-d), which would facilitate relevant studies on the pharmacological properties of these oxadiazole derivatives.

Background: Marine algal-derived endophytic fungi have attracted considerable attention in the recent decade due to their prolific production of structurally diverse secondary metabolites with various biological activities. In this study, the potential inhibition of endophytic fungi isolated from Red Sea brown alga Sargassum subrepandum was examined against HCV protease enzyme. Methods: An in vitro HCV NS3-4A protease assay was used to evaluate the HCV protease inhibition activity of the fungi. The fungus with a high-level inhibition was identified based on 18S rDNA and further subjected to chemical and biological investigations on its secondary metabolites. Results: The endophytic fungal strains, Aspergillus parasiticus, Aspergillus terreus and Geotrichum candidum were isolated from Red Sea brown alga Sargassum subrepandum. Of the three fungi, Aspergillus terreus had the highest HCV protease inhibition activity (IC50 10 μg/mL). From that fungus, eleven compounds were isolated and their structures were elucidated on the basis of NMR and MS spectroscopic analysis. Moreover, sophisticated 2-dimensional NMR spectroscopy of the isolated symmetric diketopiperazine bisdethiodi(methylthio)acetylaranotin has been recorded. Of the compounds in the A. terreus extract, only bisdethiodi(methylthio)acetylaranotin and cyclo(L-Tyr-L-Pro) were shown to have a potent HCV PR inhibition with IC50 13.0 and 18.2 μM, respectively. Conclusion: The present study shows that the organic extract of A. terreus has a potential HCV protease inhibition activity. These preliminary results are of great interest and can be proposed for new candidate of anti-HCV agents.

Background: 1,4 Dihydropyridines (1,4 DHPs), chromeno[4,3-b] quinolines and pyrimido [4,5-b]quinolines are biologically and pharmaceutically important heterocycles. They are also present in many natural products. Many methods have been applied for their synthesis but each method has its own advantages as well as disadvantages. So, there is a scope to develop a new green and sustainable protocol for their synthesis. Methods: In this context, our aim was to develop an alternative platform for the synthesis of a collection of the small molecules with high scaffold diversity. Our methods based on Lewis acid catalyzed one-pot synthesis of 1,4-DHP, pyrimido[4,5-b]quinoline and chromeno[4,3-b]quinoline derivatives under room temperature stirring or refluxing condition. Results: We have standardized a protocol for the synthesis of a library of heterocycles such as 1,4- DHP, pyrimido[4,5-b]quinoline and chromeno[4,3-b]quinoline derivatives representing a collection of skeletally diverse simple molecules decorated with the combination of building blocks by an easy, inexpensive and simple reaction technique. With an optimized reaction condition we prepare the 1,4- DHPs and pyrimido[4,5-b]quinolines exclusively by iodine but interestingly we failed to prepare the chromeno[4,3-b]quinolones using iodine but it was successfully synthesized by Sc(OTf)3. 1,4-DHPs were synthesized by using 2 molecules of 4-aminocoumarin and 1 molecule of aromatic aldehydes and pyrimido[4,5-b]quinolines from one molecule each of 6-amino-1,3-dimethyl uracil, aromatic aldehydes, and dimedone by using iodine as a catalyst. Interestingly in the presence of iodine,4-aminocoumarin, aromatic aldehydes, and dimedone results in the formation of 1,4-DHP whereas catalytic amount of Sc(OTf)3 produces the chromeno[4,3-b]quinoline derivatives in a good to excellent yield. Conclusion: In conclusion, we have developed a mild, easy and simple way for the synthesis of 1,4- DHPs, chromeno[4,3-b]quinoline derivatives and pyrimido[4,5-b]quinolines combinatorially with a highly optimized reaction condition.The entire optimization protocol reflects the unique catalytic activity of non-metallic Lewis acid catalyst iodine with rare earth-transition metal catalyst Sc(OTf)3. We were able to generate skeletal diversity with the use of different building block via one synthesis-one skeleton approach. The advantages of our methodology lie in high yields, operational simplicity and chromatographic free separation with high skeleton diversity of the compound.

Background: Azocalix[4] arene derivative based on 2,6-diamino pyridine has been synthesized from diazo-coupling reaction between tetradiazonium salt of calix[4]arene and 2,6-diaminopyridine, and characterized by various spectroscopic methods such as IR, 1HNMR, 13CNMR and Mass spectroscopy. Antibacterial behavior of the product was studied based on reference Gram-positive and Gramnegative bacteria, Disk diffusion assay method and macrodilution experiment. Antibacterial activities were evaluated both in solid and liquid phases. Methods: At 0°C an aqueous HCl solution (3%) was added to a solution of 5, 11, 17, 23-tetraamino- 25, 26, 27, 28-tetrapropoxycalix[4]arene (76.4 mg, 0.12 mmol in 4 ml THF. Then, a solution of NaNO2 (43 mg, 0.61 mmol in 3 ml H2O) was added slowly at 0°C. The reaction mixture was stirred at room temperature for 1h. Then, a solution of 2, 6-diamino pyridine (133.14 mg, 1.22 mmol) in 2 ml pyridine and 4 ml THF was added dropwise. After 12 h at room temperature, the reaction mixture was poured slowly into H2O (100ml). The precipitate was filtered, washed with water and dried. Results: In this work 5, 11, 17, 23-tetrakis [3-(2,6-diaminopyridine)azo]-25, 26, 27, 28-tetrapropoxy calix [4]arene 5 has been prepared by diazo coupling of calixarene at the upper rim. It has been preferred to have the calix[4]arene scaffold preorganized in cone conformation. The structure of Azo-calixarene derivative 5 was identified by 1H NMR & 13C NMR, FT-IR and UV-vis spectroscopy. The UV absorption spectra of 5 was measured in the wavelength range of 250-600 nm in DMSO against DMSO blank, which gave absorption maxima peak at 427 nm arising from π to π* transition of the –N=N-bond. The cone conformation of 5 was confirmed by its NMR spectra that exhibits two pairs of doublets at 3.35 and 4.45 ppm for the bridge methylene protons of ArCH2Ar in 1H NMR spectra and singlet at 31 ppm for the ArCH2Ar bridge carbons in the 13C NMR spectra. Antibacterial test of 5 was carried out in comparison with phenazopyridine 6 which is a well-known anitibacterial azo compound against two gram negative reference strains Pseudomonas aeruginosa and Escherichia coli two gram-positive reference strains, Staphylococcus aureus and Bacillus cereus Bacteria. Antibacterial activities were evaluated in solid phase. Disk diffusion assay method was performed on Mueller-Hinton agar with sterile 6 mm diameter disk impregnated with different quantities of compounds 5 and 6. The petridishes were incubated at 37°C, and the diameters of the zone inhibition were measured at 24h of incubation, according to Finegold and Baron Method. Conclusion: In summary, the present paper reports the synthesis of new azocalixarene derivative 5 by diazo-coupling. Antibacterial activities were evaluated on Mueller-Hinton agar by using disk diffusion assay. The results showed strong activities towards the Gram- Positive bacteria Bacillus cereus. The resistance shown by P.aeruginosa to the compound 5 showed mild activities against Escherichia coli.