Letters in Organic Chemistry - Volume 15, Issue 3, 2018

In the current research, a facile and green one pot synthesis of new gabapentin-lactams (G2-G8) has been achieved by reacting gabapentin (G1) with a variety of sulfonyl chlorides. The new lactamization protocol is furnished under the green solvent i.e., water and reaction was completed in a short period of time by just stirring at room temperature. Whereas in some cases, annulation could not happen and furnished un-cyclized sulfonamide products (G9-G12). The structures of the targeted compounds were established by elemental analysis, FT-IR, 1H-NMR and mass spectrometry. The crystals of some new lactams (G2, G3, G4, and G8) were also evaluated by single crystal X-ray diffraction.

Background: Chiral three-membered heterocycles occupy a special place in medicinal and pharmaceutical chemistry related to their diversity of biological activities due to the strain incorporated in their skeletons. This review covers developments reported in the last thirteen years in asymmetric epoxidation, aziridination, azirination and thiirination applied to the synthesis of biologically relevant or natural three-membered heterocycles. Results: This short review includes 63 references dedicated to the synthesis of natural and/or biologically relevant three-membered heterocycles based on asymmetric epoxidation in a first section, aziridination in a second section, azirination in a third section and thiirination in a fourth section. Conclusion: This review demonstrates that in the past thirteen years, a number of biologically relevant three-membered heterocycles, including chiral epoxides, aziridines, azirines, and even thiiranes, have been synthesized on the basis of asymmetric epoxidation, aziridination, azirination, and thiirination methodologies. The multipurpose synthetic applicability and biologically activity of three-membered heterocycles will facilitate the medicinal chemists to plan, design and implement new approaches towards the discovery of novel drugs.

Background: The continued resistance of the body to antimicrobial drugs has led to the urgent need of preparing new heterogeneous compounds that are active antibacterial and antifungal. Methods: Two series of [1,2,4]triazolo[4,3-a]pyrimidines 8 and pyrido[3,2-f][1,4]thiazepines 12 were prepared in moderate to excellent yields through the reaction of pyrimidinethione 4 and pyridinethione 10 with the appropriate hydrazonoyl halides 5. Results: The elemental and spectral data of the newly synthesized compounds assured their structures. Also, the antimicrobial activity of the products was estimated and several derivatives exhibited promising activity. Conclusion: Two new series of triazolopyrimidine and pyridothiazepine have been synthesized via reaction of pyrimidinethione and pyridinethione with hydrazonoyl chlorides using triethylamine as basic reagent. The studied reaction was proved to be site selective since only one isolable product was obtained in each case. Moreover, the biological activity of the newly synthesized compounds was estimated against some microorganisms (bacteria and fungi) and the results gave promising activity compared with the standard compounds used.

Background: A number of protective groups for hydroxyl functional groups have been developed to date. Alcohols are most commonly protected as ethers and esters, where in alkyl and benzyl ethers are strong protective groups while others, like THP, TBS, TPS and MEM/MOM ethers are acid labile. Among all other hydroxyl protecting groups, Silyl ethers are the most frequently used protecting groups because they are easily and efficiently installed and are stable to a variety of useful reagents and reaction conditions. Among the silyl ethers, triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), and tert-butyldiphenylsilyl (TBDPS) moieties are the frequently used hydroxyl protecting groups in multi step organic syntheses. Methods: A mild, efficient and selective method for the deprotection of variety of silyl ethers developed in high yields by using 20 mol % of Zinc (II) trifluoromethanesulfonate (Zn(OTf)2) at room temperature in methanol as a solvent without affecting both the acid and base sensitive protecting groups was reported. Results: To study the generality of this methodology, several silyl ethers were prepared from a variety of substrates having different protecting groups and subjected to desilylation using Zn(OTf)2 in MeOH. Conclusion: In conclusion, mild and efficient protocols for the deprotection of variety of silyl ethers using 20 mol % of Zn(OTf)2 at room temperature in MeOH have been established, in which both the acid and base sensitive groups are unaffected.

Background: Acylnitroso intermediates are considered as highly reactive and useful transient that have been used to synthesize a broad class of biological active compounds and synthetic drugs. Although there are some reported methods for the generation of these intermediates, but still challenge for mild and environmental benign protocol. Herein, we report the facile in situ synthesis of acylnitroso intermediates and their efficient hetero Diels-Alder (HDA) and ene reactions. Methods: Acylnitroso intermediates were readily obtained by hydrogen peroxide oxidation of hydroxamic acids catalyzed by Cu(I)-, Ir(I)- or Ru(II)-complexes and easily reacted with symmetric and asymmetric conjugated dienes beside their reaction with different alkenes which converted to biological active products. Results: The resulted acylnitroso intermediates were efficiently afforded the hetero Diels-Alder cycloadducts in the presence of cyclopentadiene, cyclohexadiene or α-terpinene in high yields along with good regioselectivity for the later. In case of N-dienyl lactams, the cycloadducts were formed in the yield up to 89% with complete regioselectivity. In the presence of optically active N-dienyl pyroglutamates, diastereoisomers were formed in high yields with up to 72 de. In addition, the transient acylnitroso species were trapped with alkene to form the ene product in yield up to 95 %. As an interesting transformation, the halocyclization of the ene products gave substituted oxazolidone in 77% yield which considered as one of the effective antimicrobial and antibiotic compounds. Conclusion: In a brief, we introduce a mild and effective route to deliver acylnitroso intermediates in situ by using environmentally benign, cost effective, and non-toxic hydrogen peroxide oxidant catalyzed by Cu(I)-, Ir(I)- or Ru(II)-complexes. Good to excellent yields, regio- and diastereoselectivity were obtained by trapping these intermediates in symmetric and asymmetric HDA and ene reactions. Interestingly, the ene products easily transformed to potent drugs.

Background#154;Several studies have shown excellent antitumor activity of erucin, but there are few studies on its analogues. The aim of the study involves the synthesis and the antitumor activities of novel erucin analogues. Ten novel erucin analogues were synthesized and evaluated for their efficacy as antitumor agents. Methods: Ten novel erucin analogues were synthesized by using 1, 4-dibromobutane and potassium phthalimide as starting materials, and the antitumor activities in vitro was screened against breast cancer cells (MCF-7), cervical cancer cells (HeLa-229) and lung cancer cells (A549). Results: The structures of these novel compounds were confirmed by 1H NMR, 13C NMR and elemental analysis. The preliminary bioassay results demonstrated that all of the tested compounds showed potent antitumor activities. Among these compounds, compound 6b showed the best inhibitory effect against MCF-7 with IC50 value of 0.46 μM and A549 with IC50 value of 0.44 μM. Compound 6f also displayed the best inhibitory effect against HeLa-229 with IC50 value of 0.32 μM. Conclusion: Synthesis and screening of antitumor activities were performed for a novel series of erucin analogues. All of the synthetic compounds showed potent antitumor activities against breast cancer cells (MCF-7), cervical cancer cells (HeLa-229) and lung cancer cells (A549). Compounds 6b and 6f were found to be the most active against most of the tested cancer cells.

Background: Chitosan is well-known as a metal chelating agent for removing metal ions in near-neutral conditions. Chemical modification of chitosan has attracted attention to improve its metalion adsorbent properties. Recently, dibenzo-24-crown-8 derivatives were synthesized and reported to chelate with metal ions such as cesium. However, to date, to the best of our knowledge, there is no report on the use of dibenzo-24-crown-8 to modify chitosan. In this paper, the modification of amino groups on chitosan by amide formation with dibenzo-24-crown-8 moieties in aqueous solution was investigated by three different methods: two dehydrative condensing reactions with dibenzo-24-crown-8 having a COOH group and the use of an activated ester derivative of dibenzo-24-crown-8. Methods: Three methods, i.e., the reactions of dibenzo-24-crown-8 having a COOH group with either EDC-1-hydroxybenzotriazole (HOBt) or EDC-N-hydroxysuccinimide (NHS) and the reaction using the succinimide-activated ester of dibenzo-24-crown-8, were compared on chitosan. The prepared chitosan- dibenzo-24-crown-8 conjugates were characterized by 1H NMR and IR spectroscopy. The degree of substitution (DS) by the dibenzo-24-crown-8 moieties at the amino groups on chitosan was calculated by 1H NMR analysis. Results: In both the EDC-HOBt and EDC-NHS methods, the maximum DS was only 4.1%. Conversely, a higher DS (15.2%) was afforded when the succinimide ester of dibenzo-24-crown-8 was reacted with chitosan under pH 6.0. The 1H NMR spectrum of the product showed signals from both chitosan and the crown ether. C=O bands attributable to the amide linkage between chitosan and the crown ether appeared at 1656 and 1552 cm−1 in the IR spectra. Conclusion: The use of the activated ester of dibenzo-24-crown-8 resulted in a higher DS at amino groups on chitosan when compared with the EDC-HOBt or EDC-NHS systems. This result implies that the use of activated ester derivatives is efficient for the modification of chitosan in aqueous solution.

Background: Euphorbia species are known for the diversity of terpenes, and the presence of toxic diterpenoids in Euphorbia species have raised occupational and eco-toxicological concerns. The present study reports the terpene profile of Euphorbia tortilis Rottler ex Ainslie, along with cytotoxicity assay. Method: Triterpenes were isolated from the hexane extract of E. tortilis through column chromatography and were characterized by various spectroscopic techniques. Phorbol esters were detected from the methanol extract of the latex through high performance liquid chromatography-electrospray ionizationquadrupole time of flight tandem mass spectrometry (HPLC-QTOF- MS/MS). Cytotoxicity of the extract was tested against human cervical cancer cell line HeLa and normal cardiac myoblasts cell line H9C2 using MTT assay. Results: The pentacyclic triterpenoids 3β-friedelinol, 3α-friedelinol, friedelin, epi-friedelinyl acetate and taraxerol were isolated and characterized from E. tortilis. Ten phorbol esters belonging to the tigliane family of diterpenoids were detected through HPLC-ESI-QTOF-MS/MS method. The major tumor promoting phorbol ester TPA (phorbol-12-myristate-13-acetate) reported from Euphorbiaceae family could not be detected in E. tortilis, whereas the potential anti HIV and cytotoxic phorbol ester prostratin has been detected. Latex extract was inactive on the normal cell line H9C2 within the concentration range of 10-100μg/ml, while the cell growth inhibition of the extract at 100μg/ml on Hela cell line was negligible (3.06%). Conclusion: Pentacyclic triterpenes were the major compounds isolated and characterized from E. tortilis. HPLC-ESI-QTOF-MS/MS method has been found as an ideal tool for the detection of minor phorbol esters. The terpenoid profile revealed the absence of toxic TPA. Furthermore, the latex extract was non toxic towards normal cell line H9C2. The findings are relevant in the context of toxicological concerns related to Euphorbia members.

Background: Pyrrole moiety is found in naturally occurring compounds such as chlorophyll, haem, and vitamin B12 and present in a number of drugs for example atorvastatin, ketorolac, elopiprazole, tolmetin and sunitinib. Various methods have been used for the synthesis of pyrrole derivatives; however, still there is a need for environmentally benign and economic protocol. Method: We have reported a simple, mild and speedy synthesis of N-substituted 2,5-dimethyl pyrrole derivatives in “GAAS” as medium and catalyst at room temperature and under ultrasound irradiation. Results: This protocol was employed for the synthesis of various 2,5-dimethyl-N-substituted pyrrolederivatives using both aliphatic as well as aromatic amines in short time (2 to 10 minutes)with excellent yield (84-95%) at room temperature and under ultrasonic irradiation. The catalytic system “GAAS” was regenerated and reused five times effectively without major loss of activity. Conclusion: In conclusion, we have developed an eco-friendly, simple, faster, reusable, mild, and efficient protocol for the synthesis of N-substituted pyrrole derivatives. This bio-based protocol is cost-effective and greener methodology for the synthesis of biologically active N-substituted pyrrole derivatives.

Hydroxymethylfurfural (HMF) is one of the important parameters to determine the quality and freshness of honey relating to thermal treatment and storage condition, respectively. Many studies have been extensively carried out to investigate the effect of heating temperature and duration on the formation of HMF. These data were collected from literature, and critically analyzed using statistical techniques including multivariate data analysis and neural network modelling. It was found that the formation of HMF follows zero order kinetics at low temperature (30-40°C), but first order kinetics at high temperature (90-100°C). No significant trend was found for the data between 50-80°C. A three dimensional bubble plot shows that the effect of heating duration is higher than temperature, especially at high temperature (90-100°C). An artificial neural network was also trained by the functions of log sigmoid and pure linear transfer using previously reported data on HMF content in relation with heating temperature and time as inputs in model development. The network was proven to show the goodness of the fit with high correlation coefficient, R2 0.9163 and low root mean square error, RMSE 0.0019 to the experimental data generated from the present study using Tualang honey heated at 90°C for 0-5 hours. The thermal treatment on Tualang honey have also shown to have moderate change on the chemical profile which was generated from liquid chromatography tandem mass spectrometry. The first two principal components have shown to have 33-38 % of the total variance in the chemical profile based on principal component analysis.