Current Organic Synthesis - Volume 15, Issue 1, 2018

Background: The most frequently used chiral auxiliaries, oxazolidinones (Evans' oxazolidinones) have been employed in 1,4-congugate addition reactions to α,β-unsaturated carbonyl compounds. Supplementary to our previous reports in this mini-review, we attempted to underscore the applications of this strategy in a step (steps) in the total synthesis of some naturally occurring compounds exhibiting diverse biological activities. Objective: In this mini-review, we try to underscore the applications of oxazolidinones (Evans' oxazolidinones) in 1,4-congugate addition reactions to α,β-unsaturated carbonyl in the total synthesis of some naturally occurring compounds exhibiting diverse biological activities. Conclusion: In spite of well-known superiority of asymmetric catalyzed reactions, the use of auxiliarycontrolled reactions are still considered as commanding, vital and sometimes as only tools in the generation of stereogenic centers during the construction of complex molecules and total synthesis of naturally occurring compounds. The commercial availability, or readily accessibility of a wide variety of chiral amino alcohols as starting materials to synthesize a wide range of oxazolidinones is the merits of them. In addition, the ease of removal and subjection to various and diverse stereoselective reactions make oxazolidinones as the ideal and superior chiral auxiliaries. In this regard, they were successfully used in asymmetric 1,4-conjugate addition reactions with high stereoselectivities. The high degree of asymmetric induction can be attributed to the rigid chelation of N-acyloxazolidinones with metal ions, as well as the covering of one face of the system by the bulkiness of 4-substituent. In summary, in this report, the importance of the applications of chiral oxazolidinones as suitable chiral auxiliaries in the stereoselective, 1,4-conjugate addition reactions in asymmetric synthesis and in particular, the total synthesis of naturally occurring compounds and some complex molecules were underscored. Noticeably, in these total syntheses, this chiral auxiliary is controlling the stereochemistry of a newly created stereogenic center as well as preserving the configuration of other chiral centers, which already have been presented in the precursor. General methods have been established for the attachment of the chiral auxiliary as a moiety to the substrate molecule in high to excellent yields. At the end of these reactions, this auxiliary can be easily removed leaving various desired reactive motifs for the next step in multi-step synthesis.

Background: Coumarin is an important class of natural products with applications in different areas of knowledge. Due to its importance, several methodologies and strategies have been developed for the synthesis of different classes of compounds containing this nucleus. Objective: The aim of this review is to cover in the last five years the complex fused coumarin derivatives synthesized in one-pot three-component reactions. Conclusion: Considering that multicomponent reactions are a powerful tool to produce simple and complex compounds in one or few steps with high selectivity and yields while following the green chemistry principles.

Background: In modern chemistry, the asymmetric synthesis for the preparation of high purity chiral compounds to be used as pharmaceuticals or additives in foods have been of capital importance. Chiral auxiliary reagents are used to control the stereochemistry of the reaction in the generation of new chiral compounds, in this context, Ephedra compounds (ephedrines and pseudoephedrines) and some of their derivatives have been broadly used as chiral ligands in catalysis or chiral inductors in asymmetric synthesis. Objective: This review focuses on recent progress in the use of ephedra compounds and their N-substituted derivatives as chiral auxiliaries in the area of asymmetric synthesis, via the alkylation reaction of the enolates derived from their corresponding N-Acyl or O-Acyl derivatives, in the C-C bond formation. Conclusion: A vast amount of work has been done about the use of ephedra compounds in asymmetric synthesis area, in general, it was found that pseudoephedrines are much more effective than ephedrines and are preferred as chiral auxiliaries in the asymmetric alkylation of the corresponding N-acyl amides or O-Acyl esters. Alkylation with alkyl halides requires the use of more than 4 equivalents of LiCl to accelerate the alkylation rate and to complete the reaction without effecting the diastereoselectivity of the process. In contrast, the use of secondary alkyl halides was found to make the reaction very slow. Furthermore, a lot of work about the alkylation reaction in the opening of epoxides and aziridines, aldolic condensation, Manich reaction, addition of nucleophiles to α,β-unsaturated ephedrine amides and Michael additions have been demonstrated to be effective in the C-C bond formation. The aldol reaction of chiral enolates, proceeds with decreasing yields and enantioselectivities as the steric demand of the α-R of ephedrine amides and the size of carbonyl compound increase. In addition, the use of branched groups on N,N-disubstituted norephedrine esters is highly recommended in the aldol reactions of aromatic and aliphatic aldehydes.In the case of N-Acyl or O-Acyl ephedrines supported on polymers, the reaction proceed with good enantioselectivities but low yields, the enantioselectivities are goods but the yields are low. In general, the removal step of the auxiliary proceeds with low to high yields but without epimerization.

Background: The Hetero-Diels-Alder reaction (HDAR) is a method extensively used in organic chemistry as a tool in the synthesis of innumerous polycyclic compounds in particular nitrogen compounds, presents in many natural products, medicinally relevant substances and organic materials. The literature describes innumerable studies of HDAR using classic methods and modern developments such as reactions on the solid phase, the use of catalysts, transformations in aqueous solution and under microwaves. Objective: This review describes a variety of HDAR focused on obtaining nitrogen-containing compounds of considerable chemical and biological interest, and highlighting reported biological activity. Conclusion: This review has shown the importance of the HDA reaction as a tool of organic chemistry in the synthesis of nitrogen compounds. This type of reaction presents important properties including bond-forming economy, high regio- and stereoselectivities and thus provides highly efficient routes to access a wide range of polycyclic compounds. In addition to the variety of nitrogen compounds synthetized successfully by this method, they present relevant biological properties.

Aim and Objective: The objective of our work was to synthesize and fully characterize Pamamycin- 621D, one of the less abundant members of a large family of macrodiolides with antimycobacterial properties, which had never been synthesized before. Furthermore, we also wished to improve our general strategy by using a new unsaturated precursor. Material and Method: A new unsaturated ethylketone precursor was prepared using alkene cross metathesis, and a convergent and flexible strategy based on a key diastereoselective aldol addition was implemented to afford pamamycin-621D in 12 steps from that precursor. Results: Pamamycin-621D has been obtained and fully characterized for the first time. The structure of pamamycin-621D was confirmed by HRMS and comparison of 1H-NMR spectra with the natural pamamycin- 621D. Both optical rotation and 13C-NMR had not been published previously due to lack of material, and the latter are reported here for the first time. Given the scarce characterization available previously, our synthesis also gives additional support to the initial structural assignment of pamamycin-621D. A significant improvement of the key aldol addition via the use of a new unsaturated precursor is also reported. Conclusion: The work described above constitutes the first total synthesis of pamamycin-621D and has enabled us to fully characterize this scarcely available natural product. More importantly, this work highlights the fact that our synthetic approach provides ready access to various members of the pamamycin family, allowing possible studies on structure-activity relationships and mode of action of even the least abundant of these natural products. The synthesis of other pamamycin congeners and biological investigations will be published in due course.

Aim and Objective: To explore the use of naturally occurring biodegradable organic acids as a catalyst in organic synthesis. The development of a simple, inexpensive, highly efficient yet ecofriendly catalyst for the synthesis of bis(indolyl)methanes is explored. Materials and Method: A mixture of indole 1a (1.0 g, 8.53 mmol), benzaldehyde 2a (0.45 g. 4.26 mmol), and itaconic acid (0.12 g, 0.92 mmol, 20 mol%), in H2O (5.0 mL) was refluxed at 100°C for indicated time. After the completion of the reaction (TLC check), the reaction mixture was cooled to room temperature and extracted with ethyl acetate (3 5.0 mL), organic layer was dried over Na2SO4 and concentrated under vacuum. The crude residue was purified by column chromatography on silica gel using ethyl acetate:hexane as an eluent. Results: Initially optimal reaction conditions were developed for the synthesis of bis(indolyl)methanes by selecting model reaction between indole and benzaldehyde. It was found that optimal conditions for the synthesis of bis(indolyl)methanes are use of indole (1.0 mmol), aldehyde (0.5 mmol) and catalyst 20 mol% in water as a solvent, under air atmosphere and at 100°C. Moreover, it was found that aqueous solution of the catalyst can be reused with the same catalytic efficiency for ten times without any pre-treatment. This is an important achievement with regard to the efficiency and reusability of the catalyst in synthesis. Conclusion: We have shown that itaconic acid in water can be used as an excellent green catalyst with high reusability. It efficiently catalyzes electrophillic substitution reaction of indoles (ESRI) with various aldehydes to give the corresponding BIMs in an efficient manner. Therefore, itaconic acid in water as a catalyst can be a good alternative for the use of hazardous mineral acid and Lewis acid catalyst.

Aim and Objective: Lamotrigine antiepileptic drug, 3,5-diamino-6-(2',3'-dichlorophenyl)-1,2,4- triazine is used to treat epilepsy and bipolar disorder, lamotrigine is also effective in treating some diabetic neuropath. Recently, interest has focused on the synthesis of new lamotrigine analogues in view of their biocidal effects. This investigation focused on synthesis of novel fluorine substituted lamotrigine drug analogues using an efficient and environmental friendly process. Materials and Methods: Synthetic route to fluorinated lamotrigine analogues was furnished by aminolysis and ammionlysis of 6-(2'-amino-5'-fluorophenyl)-3-thioxo-1,2,4-triazin-5(2H,4H)one. The structures of the targets compounds have been deduced upon their elemental analysis and spectral data (UV, IR, 1HNMR, 13CNMR and Mass spectroscopy). The anti-inflammatory activities of the synthesized compounds are also evaluated. Results: The acute anti-inflammatory activity of the synthesis fluorine substituted lamotrigine analogues was evaluated and showed various anti-inflammatory effects at tested condition. Thus, compounds rich in fluorine showed higher activity in comparison with compounds lethal of fluorine atoms. In addition, compound with - COCF3 exhibited a higher activity over compounds with aromatic –CF. Furthermore, the higher number of fluorine atoms tend to a higher number of enzyme receptors involved in the inflammatory process. Conclusion: The present study described a simple and new route to synthesize some new fluorine substituted lamotrigine analogues starting from 3-thioxo-1,2,4-triazin-5-one through a simple nucleophilic displacement of SH and OH by amino groups. In addition, this study tends to search for new fluorinated lamotrigine analogues as anti-inflammatory agents. The obtained results revealed that compounds binding to -CF3 are more active in comparison with compound with aromatic –CF.

Aim and Objective: Enaminones belay to be extremely stable compounds and constitute a versatile group of salutary precursors for the synthesis of enormous classes of organic compounds. So, in this context, we synthesized a new enaminone, namely, (E)-3-(dimethylamino)-1-(8-phenyl-8H-[1,2,4]triazolo[4,3- a]perimidin-10-yl)prop-2-en-1-one (enaminone 2). Materials and Methods: The reaction of enaminone 2 with different types of hydrazonoyl chlorides or hydrazine hydrate afforded new substituted pyrazoles. Also, the reaction of enaminone with 6-amino-2- thioxopyrimidin-4-one in acetic acid under reflux produced 2-thioxopyridopyrimidinone derivative. The latter thione derivative reacts with hydrazonoyl chlorides to give pyridotriazolopyrimidines. 5-(8-Phenyl-8H- [1,2,4]triazolo[4,3-a]perimidin-10-yl)isoxazole was produced from the reaction of enaminone 2 with hydroxylamine. Results & Conclusion: The structure of all the novel perimidine derivatives was confirmed on the basis of spectral data and elemental analyses. The enaminone and the newly synthesized compounds were tested for their antimicrobial activity, and the results obtained revealed that some derivatives are more potent than the reference drugs used.

Aims and Objectives: When compared to five-membered N-heterocyclic carbene, recent reports have demonstrated that ring expanded NHCs showed rather different properties such as increased basicity (nucleophilicity) and greater steric demand. These unique features provide an opportunity to design new chiral ligands. This study was undertaken to design and synthesize a series of novel enantiopure pyrimidone salts, the precursors of N-heterocyclic carbenes, and their activity in asymmetric diethylzinc addition of arylaldehydes was demonstrated as well. Material and Method: Commercially available dimethylmalonic acid was treated with thionyl chloride to form dimethylmalony dichloride, followed by subsequent reaction with different chiral primary amine produced corresponding diamide. Next, conversion of diamide to monoamide was achieved by partial reduction with lithium aluminum hydride. Finally, cyclization of monoamide with triethyl orthoformate in the presence of ammonium salts provided pyrimidone salts in good yields. Results: Seven enantiopure pyrimidone salts, the precursors of N-heterocyclic carbenes, have been synthesized starting from dimethylmalonic acid. Their applicability in asymmetric diethylzinc addition of arylaldehydes has been demonstrated and the corresponding secondary alcohol was obtained with good yields and moderate enantioselectivities. Conclusion: Herein we developed an efficient route to prepare a series of novel N-heterocyclic carbene precursors, which were demonstrated as effective catalysts for asymmetric diethylzinc addition of arylaldehydes, and the corresponding secondary alcohol was obtained with good yields and moderate enantioselectivities.

Background: Azobenzol derivatives are important organic materials and show unique optical function. As a potential host, azobenzene has been broadly exploited in many areas because of its efficient inclusion ability and easy derivatization by functional groups. Objective: A series of twelve novel compounds have been synthesized and optimized based on azobenzol derivatives. Method: The binding properties were evaluated for biologically important anions (F-, Cl-, Br-, I-, AcO- and H2PO4-) by theoretical investigation, UV-vis, fluorescence experiments. Results: The compound containing three nitro groups displayed the strongest binding ability for AcO- ion among synthesized compounds. Theoretical investigation analysis revealed that the intramolecular hydrogen bond existed in the structure of the synthesized compounds. Conclusion: we have developed twelve compounds based on azobenzol derivatives. Compound 6 involving three nitro groups showed high sensitive and selective binding ability for acetate ion through multiple hydrogen bonds among anions tested including AcO-, F-, H2PO4-, Cl-, Br- and I- due to the conformational complementarity and higher basicity. Compound 6 also can be used as a colorimetric sensor for detecting acetate ion in environmental and pharmacy samples. The above results can provide a clue for the constructing of anion receptor based on azobenzol derivatives.