Letters in Organic Chemistry - Volume 14, Issue 3, 2017

Background: Pyrrolidine-based ring systems are ubiquitous in nature. (R)-Bgugaine is a 2-alkylated pyrrolidine alkaloid which has been isolated from the tubers of Arisarum vulgare, a toxic Araceae found along the Mediterranean coast. The construction of this heterocyclic ring system in an enantio-riched fashion has been the subject of attention in the recent years. This article covers the reports till 2016 on the isolation, biological activity studies and synthetic endeavours of bgugaine alkaloid. Method: The synthesis of (R)-Bgugaine was carried out. A structured search of Bgugaine was undertaken using bibliographic databases such as scifinder, scopus etc. The quality of the collected papers was evaluated using the impact factor (SCI) of journals in which the work was reported. The synthetic methodologies and chemical reactions from the screened papers were summarised wherein, the key reaction steps have been described in detail. Results: Thirty seven papers were summarized in the review to give snapshots of natural product i.e. bgugaine. The majority (20) articles focused on the introduction of the topic. These papers were published from different research groups working world-wide in the field of alkaloids chemistry. The general information about alkaloids, their medicinal uses, biological activity and structural elucidation comprises the highlights of this section. This demonstrates the importance of collaboration of experts working in multidisciplinary area to understand the topic in depth. Eight articles are corresponding to the synthetic protocol for construction of bgugaine via multistep synthesis. Remaining nine articles are citing the important reactions which are used as key steps for synthesis of bgugaine. Overall, this review has identified the scope and significance of collaboration between synthetic, medicinal, biochemists and natural product chemists to identify bioactive compounds showing drug-like properties. Conclusion: The findings and content of this review give explicit information regarding the importance of deceptively simple pyrrolidine alkaloid skeleton, their natural occurrence, biological activities as well as synthetic methodologies. The advancement of new methodologies towards the construction of bgugaine could be useful for rapid identification of new biological leads. It shall certainly be of help to make further progress and develop new strategies for bgugaine core and related heterocycles, based on this literature report.

Background: We previously reported the 1:1 condensation reaction between ophthalaldehyde and primary amine in the presence of 1,2,3-1H-benzotriazole and 2-mercaptoethanol as dual synthetic auxiliaries to provide phthalimidines (2,3-dihydroisoindol-1-ones) under mild reaction conditions in good isolated yields. However, this reaction was found to proceed via dissymmetrization of equi-oxidation stage functionalities (carbonyl groups herein), which would give rise to regioisomer(s) whenever the orientation of substituents in the target molecule phthalimidine was dissymmetrical. In order to overcome such defects, we focused on phthalide, which possessed identical electronic structure with that of target molecule phthalimidine. Thus, the condensation between a phthalide derivative and a primary amine would eliminate a water molecule, but does not accompany with any kind of redox paths. Therefore, dissymmetrical trends possessed by the phthalide derivative should transfer directly to the resulting phthalimidine, and as a result the formation of possible regioisomer(s) can completely be prevented. This strategy has existed as the oldest method of phthalimidine synthesis, however, Lewis acid catalysts utilized in the past were not appropriate to extend its scope. In this report, we demonstrate an improved method of phthalimidine synthesis along this line using InCl3 as a catalyst, which would allow the synthesis of this class to accommodate with the contemporary standard of organic syntheses. Method: In general, aniline (2.0 mmol, used at once as reagent and solvent) was added to the flask containing phthalide (1.0 mmol) and InCl3 (an appropriate amount) under Ar atmosphere over Ca. 3 min with stirring, and the whole mixture was heated at gentle reflux for an appropriate period. After usual work-up, crude products were purified by column chromatography on silica gel. Isolated components were ascertained by 1H NMR spectral comparison with the authentic samples prepared by our former methods. Results: Optimization of the reaction condition was explored using phthalide and aniline. Thus, decrement of yields occurred whenever amounts of InCl3 catalyst were reduced, however, longer reaction periods improved isolated yields every time. Even in the use of 1 mol% of InCl3 catalyst, reaction would complete within a few days. As a result, the direct condensation between phthalide and aniline with the use of a truly catalytic amount of Lewis acid catalyst was made possible for the first time in the history of phthalimidine syntheses. Extension of this strategy to some primary amines other than aniline was successful, too. Based on experimental results, our plausible mechanism was proposed, in which the reaction commenced by nucleophilic attack of an amino group towards 3-position of oxygen-chelated phthalide. Conclusion: We succeeded in the direct condensation reaction between phthalide and primary amine in the presence of a catalytic amount of Lewis acid catalyst, InCl3, for the first time. Although successful examples have thus far been limited to some combination that affords clear reaction mixtures (except for the catalyst) under high-temperature, solvent-free heating, we believe that we have attained a tacit basis to prepare a variety of phthalimidine derivatives possessing a variety of substituent patterns.

Background: Triazoline derivatives are important group of the heterocycle compounds possessing interesting medicinal and biological properties. Triazoline compounds can be applied in medicine because of their pharmaceutical properties as antiviral, antibacterial, anti-cancerous, antiasthmatic, analgesic and anti-inflammatory medicines. The essential oil of many plants contains Myrcene. The 1,3-cycloaddition reaction pathways of Myrcene with trimethylsilylazide were investigated to obtain the theoretical possibilities of the interesting varieties of its 1,2,3-triazoline derivatives. Methods: In this study, the 1,3-dipolar reactions of Myrcene (1) with trimethylsilylazide (TMS-N3; 2), the comparison of the three C=C of 1 in the kinetic and thermodynamic aspects, the structural studies of the 1,2,3-triazoline products and the transition states were investigated. The modeling of the reaction was performed by DFT-B3LYP/6-31G* method. This method was applied on the main configurations with less steric restraint effects. The experimental results of FT-IR were just carried out in this study to pursue the course of the reaction pathways. Results: The HOMO and LUMO orbital levels, ΔHOMO-LUMO gaps, dipole moments, the appropriate atoms Mulliken charges, thermodynamic and kinetic stabilities in vacuum were investigated for the components, transition states and the products (P1-P6) by the DFT method. The four important aspects about determination of the combining a dipolarophile (1) with a 1,3-dipole agents (TMS-N3(2)) to produce P1-P3 were determined. Conclusion: The kinetic and thermodynamic products of the 1,3-dipolar reactions were determined. The final result is that P4 is the kinetic and P6 is the thermodynamic product of the 1,3-dipolar cycloaddition reaction between Myrcene (1) and TMS-N3(2) during the two explained steps. The experimental results confirm the theoretical achievements.

Background: In spite of the fact that there are numerous reagents and methods to synthesize the dihydropyrimidinones via Biginelli reaction, but excellent yields, shorter reaction time and easy work-up are important factors which are not usually found together in a chemical reaction. This work aims to introduce a new reagent with above-mentioned capabilities in mild reaction conditions. Methods: With the benefit of NaHSO4 ionic liquid immobilized on silica as reusable heterogeneous catalyst, prepared via sol-gel method and characterized by SEM and XRD techniques, we could synthesize dihydropyrimidinones derivatives in mild conditions. Results: Data obtained from different identifying techniques, such as SEM and XRD for characterization of the structure of catalyst, and also IR, NMR and Mass spectroscopic techniques for characterization of products obviously confirm the efficacy and integrity of the method. Conclusion: In conclusion, the present procedure provides an efficient reagent for the synthesis of Biginelli compounds. Mild reaction conditions, ease in work-up, high yields, stability and recyclability of the reagent are features of this new procedure.

Background: α-Methylene cycloalkanones are considered of interest because of their biological activity. Herein, in this paper the synthesis of (±) HomoSarkomycine Esters was described and characterized. Methods: Using Bylis-Hillman adducts, triethlorthoacetate and propanoic acid, (±) HomoSarkomycine Esters could be synthesized by smoothly Johnson-Claisen rearrangement. Results: A small library of target compounds was prepared under optimized reaction conditions in moderate yields. The reaction mechanism and the DFT study have been investigated. Conclusion: This methodology provides ready access to 2-hydroxymethyl-2-cyclopentenone 1a which can be served as the raw materials of the synthesis of (±) HomoSarkomycine Ester.

Background: Thiazole derivatives are known as important sulfur containing heterocycles which are present in a wide range of biologically active natural products. Methods: A series of thiazolone derivatives were synthesized and evaluated for their soybean 15-LOX inhibitory activity. The title compounds were prepared by the reaction of 2-arylthiazol-4(5H)-ones and different aromatic aldehydes. All compounds were characterized and evaluated against soybean 15-LOX. Results: Among the synthesized thiazolone derivatives, 5-(4-methoxybenzylidene)-2-((2-methoxyphenyl) amino)thiazol-4(5H)-one (3l) was found to be the most active compound comparing with quercetin as the reference drug. Conclusion: It seems that prepared thiazolones having methoxy groups both on aryl and aminoaryl moieties can be considered for further drug discovery research.

Background: A novel route towards synthesis of N-glycosylated dihydropyrimidones (DHPMs) using epoxy sugar has been described. The DHPM derivatives were synthesised from aromatic aldehydes, urea/thiourea and ethyl acetoacetate in presence of CuCl and BF3.OEt2. The reported methodology of glycosylation of DHPMs is of synthetic importance and can overcome traditionally utilized multistep synthesis of N-glycosylated heterocycles. The proposed economical and convenient methodology can open new pathways to generate biologically important glycosylated molecules. The dihydropyrimidone derivatives and their corresponding glycosides were characterized using 1H, 13C NMR and elemental analytical methods. Methods: The compounds were purified via coloum chromatography using hexane/ethylacetate as solvent. Thin-layer chromatography (TLC) was performed on manually coated plates (Acme) with detection by UV light or iodine vapour. Column chromatography was performed using SiO2 (Acme 100-200 mesh). NMR spectra were recorded with Bruker Avance 300 (300 MHz) using tetramethyl silane as internal solvent. The solvent peak in 1H NMR and 13C NMR was adjusted to 7.5 and 77.23 ppm for CDCl3. Elemental analysis was carried out using Eager 300 C, H, N analyzer at IIT Bombay (Mumbai, India). Results: A series of structurally divergent dihydropyrimidones have been synthesised using aromatic aldehydes, urea/thiourea and ethyl acetoacetate in dry THF catalysed by Cu (I) and BF3.OEt2. Traditionally, N-glycosylation of heterocycles proceeds either via partial protection of saccharide moiety and (or) selective protection of active centres present in the heterocycle species using silyl protecting groups. Here we attempted to overcome the conventional methodology of selective protection of heterocycles by utilizing epoxy sugars derived from tri-O-acetyl glucal. Among the screened catalyst, sodium hydride was the potential catalyst and acetonitrile, acts as the prime solvent for N-glycosylation of DHPMs. The increased yield in the presence of acetonitrile and sodium hydride is due to its increased polarity leading to the greater ion-dipole interaction which thereby stabilizes the deprotonated DHPM and results in the expected product under favourable mild reaction conditions. Though both N1 and N3 of cyclic urea are susceptible for glycosylation; however, the steric and resonance stabilization leads to the favourable β-glycosylation at N1. Conclusion: The reported N-glycosylation methodology is an alternative pathway for N-glycosylation of heterocyclic moieties. Moreover, this novel methodology will open insights in understanding N-glycosylation reactions of structurally rigid and multifunctional heterocyclic molecules.

Background: Amino acids, short peptide sequences and benzimidazole derivatives play an increasingly important role as therapeutics in areas including antibacterial, antifungal, antiviral, antiinflammatory, antiparasitic, antibiofilm, antidiabetic, and anticancer. Methods: Some novel amino acids and glycine-glycine dipeptide benzimidazole conjugates were synthesized by facile acylation reactions through DCC mediated reactions and their structures were identified by 1H-NMR, 13C-NMR and FT-IR spectroscopic techniques and elemental analysis. In vitro antimicrobial activities of some compounds against Gram positive (Staphylococcus aureus and Enterobacter faceium NJ-1) and Gram negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and yeasts (Candida albicans and Candida tropicalis) were determined by MIC method. Their antioxidant activities were also detected by DPPH method. Results: Sixteen novel benzimidazole conjugates incorporating glycine, alanine, phenylalanine, cysteine and glycine-glycine dipeptide were synthesized and their structures were identified by spectroscopic techniques and elemental analysis. All of the compounds tested showed in vitro antimicrobial and antioxidant activities. Conclusion: Sixteen novel benzimidazole amino acid/dipeptide conjugates were synthesized using DCC mediated one step reaction in moderate yield and high purity, under mild reaction conditions, with full retention of the original chirality. Amino acid or dipeptide substitutions at position 1 of the benzimidazoles were synthesized first time in this work. The results have indicated that the newly synthesized compounds possess low to moderate antimicrobial and antioxidant activities.

Background: Metal organic frameworks square measure crystalline materials with fascinating chemical and physical attributes that include metal ions or clusters and multidentate organic particles. MOFs acquire the expected traits to be employed in classical applications similar to heterogeneous catalysis and storage and separation of gases and different Compounds. Post-synthetic modification (PSM) is an associate replacement method to prepare functionalized MOFs. Methods: The IRMOF-3-PI-RuCl3 was prepared by refluxing a combination of IRMOF-3-PI, [H(DMSO)2][RuCl4(DMSO)2] and ethanol. The amount of ruthenium metal in catalyst was found to be 2.35 w% based on ICP analysis. To perform the ring opening reaction, a solution of styrene oxide, indole, pyrole or alcohol nucleophile, in methanol, IRMOF-3-PI-RuCl3 was added. After completion of the reaction, the catalyst was precipitated. Results: A MOF-supported metal catalyst (IRMOF-3-PI-RuCl3) was designed and synthesized by postsynthetic method. The BET surface area of the final catalyst was slightly reduced as determined by N2 sorption experiments. The results showed that the provided catalyst has a high potential for the ring opening of epoxides with alcohols, indoles and pyrroles under gentle conditions. Conclusion: In summary, a simple, rapid, economical and an effective route for the alcoholysis of epoxides and therefore the Friedel-Crafts alkylation of indoles and pyrroles via an basically regioselective ring opening of epoxides with aliphatic and aromatic amines using IRMOF-3-PI-RuCl3 with cage type poriferous structure as heterogeneous catalysts, has been established. This methodology is very regioselective in numerous instances that give the products with high yield for e.g. in aromatic and aliphatic amines. Ease of separation and straightforward workup are among other advantages of this catalyst.

Background: Hepatitis C virus (HCV) Flaviviridae family comprises of positive sense singlestranded RNA ((+)ssRNA), which infects 3% of the world population that leads to the liver cirrhosis. There is no permanent cure available without side effects till date. Many drug discovery groups around the globe are heading to discover promising anti-HCV drug candidates for this deadly virus. Therefore, it is an urgent need to identify new anti viral agents that target HCV and ultimately give the permanent cure. The genome of HCV contains structural proteins (capsid protein C, membrane protein M, envelope protein E) and non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Protease/ helicase NS3 is one non-structural protein, a multifunctional enzyme with serine-protease and NTPase/ helicase activities implicated in the processing of viral polyprotein and to make copies of the HCV genome. Methods: A simple and efficient method has been developed for the synthesis of designed chiral piperazine ligands through the condensation of 1,2-diamino-cyclohexane or 1,2-diphenylethylenediamine with 3-hydroxynopinone derived from β-pinene in 4 steps with overall very good yields. Results: Four new piperazine based molecules have been designed, synthesized with limited DLP violations, good QPlogP, QPlogS values and excellent human % oral absorption values using Schrodinger suite. All the molecules showed better binding scores (G-Score & DG-Score) for drug like molecules. Conclusion: Molecular docking insights, interaction profiles and synthetic feasibilities of these molecules suggest that these could become good biologically active compounds against HIV and HCV. In future, we synthesized high enantiomeric excess biologically potent molecules with these diamine piperazine chiral auxiliaries.