Current Organic Synthesis - Volume 14, Issue 6, 2017

Background: Polyhydroxyalkanoates (PHAs) are a natural origin biodegradable polyesters consisted of various 3- and 4-hydroxyacid derived repeating units produced by microorganisms as energy storage. PHAs have been intensively studied due to their biodegradability and biocompatibility enabling their use both in packaging and agriculture as well as in medicine and pharmacy. PHAs obtained via biotechnological routes can possess various functional groups in their side chains. However, the diversity in their functionality is limited due to issues of conservation of functional groups during the polymer formation. Objective: The review focuses on recent progress in the area of synthesis of PHAs functionalized with various reactive as well as bioactive end and side groups. Conclusion: A potent route to resolve the problem of functional group diversity in natural origin PHAs involves post-polymerization modification, where the desired side groups can be created. On the contrary, synthetically produced PHA analogs obtained directly via ring-opening polymerization of β-lactones offer various functionalities at different position throughout the polymer chain. The desired α- and ω-end groups can be introduced into the polymer chain using specific polymerization, initiation or termination strategies, respectively. The preferred side chain functionality is obtained by choosing the appropriate β-lactone monomers bearing respective functional groups. All functional groups may also be subjected to additional chemical modification. The degradation of PHA as a method for producing functional polymers as well as their possible further applications are also discussed.

Background: Currently, polymers can be created with specific properties that are tailored to a wide range of applications from medical to everyday products as packaging. There are different techniques to prepare novel polymer materials with various architectures and specific groups via a variety of reaction mechanisms of different complexity. End-group modification of polymers is a powerful tool for tailoring polymer properties. Objective: The review provides a brief description of the functional moieties and an outline of synthetic strategies used for tailoring the (bio)degradable polymer properties by end-group and in-chain functionalization. Conclusion: The contemporary synthetic strategies used in tailoring the (bio)degradable polymer properties by the end-group and in-chain functionalization demonstrate the importance of the relation between their subtle molecular structure, properties and function. When the development of (bio)degradable polymers is in its infancy the most crucial features are concentrated on the effect of macromolecular architecture, new monomer systems, polymerization mechanisms and different polymerization techniques on final (bio)degradable properties. Significant efforts have been directed towards the type of functional moieties and their influence on the degradation manner. Presented methods should help to design novel biodegradable polymeric materials and to avoid failures of the commercial products manufactured from them.

Background: Cross-linking structure of polyurethanes determines no degradability of these materials. However, introducing the hydrolysable substrates (of natural or synthetic origin) into the cross-linked polyurethanes structure makes them biodegradable. Moreover compounds (such as polycaprolactone triol, glycerin, lysine triisocyanate, etc.) that are used for polyurethane cross-linking are degraded in non-toxic products. All these kinds of compounds can be introduced into soft or hard segments via urethane bonds. Objective: The review focuses on kind of multifunctional polyols and isocyanates, and low molecular crosslinkers used for cross-linked polyurethanes obtaining. These compounds are natural substrates (in the native state or after modification) or are synthetic compounds with degradable linkages. They belong to polyesters, plant oils, proteins, saccharides, and others (e.g. lignocellulosic materials), and they are synthesized chemically or via biosynthesis by algae, plants, microorganisms, and by animals. Conclusion: Incorporation of degradable groups (such as ester moieties) into the polymer structure, and using of substrates with the structure known and metabolized by microorganisms for soft or hard segments building, facilitate degradation of cross-linked polyurethanes.

Background: Chitosan structure versatility toward a change in an external stimulus represents a “must have” for the pharmaceutical applications, especially for the pharmaceutical formulations. Chemical modification can open new ways to obtain materials with tailored properties. Despite the great interest for conventional graft modifications, controlled/living free radical polymerizations (i.e. RAFT, ATRP, etc.) and advanced chemistry techniques (i.e. click chemistry) seem more attractive nowadays and involve facile and fast procedure, high regioselectivity, quantitative yield, mild reaction conditions without generation of by-products. Objective: The present review provides a detailed state of art of the chemical modification of chitosan i.e. tailored side-chain functionalization using RAFT polymerization and click chemistry for specific applications within pharmaceutical formulations taking into account the applicative aspect regarding the need of pharmaceuticals. Conclusion: The review showed the routes of current approaches for side chain modification of chitosan including graft, block copolymers or other structural variations. The esterification of RAFT agents on chitosan by using carbonyl activating reagents enables producing chitosan graft and block copolymers with controlled architectures while the development of protection/ deprotection chemistry of chitosan made possible the regioselective modification of chitosan or other polysaccharides. Although these developments increased the potential of chitosan, still the chemical functionality and architectural diversity of the derivatives are limited. Application of modern techniques e.g. RAFT polymerization, “click” chemistry has opened new “doors” for the science of controlled and chemoselective synthesis of well- tailored derivatives with unique and superior properties.

Background: Functional groups have played a fundamental role in synthesis of polymers due to they decide about polymerization methods, and influence on their topologies, properties and applications. The functional polymers are used as a high-performance materials with well-adjusted properties by modification of functionalities that can be addressed selectively to a variety of applications, usually in biomedical field. Objective: In this minireview article hydroxy-functionalized polymers, mostly based on 2-hydroxyethyl methacrylate (HEMA) or 2-hydroxyethyl acrylate (HEA), are discussed as products of the controlled polymerizations and as substrates in the functionalization reactions. Conclusion: The hydroxyl group gives opportunity for prepolymerization reactions, including protection group and macromonomer preparation. Multifunctional (co)polymers of HEMA/HEA contain reactive hydroxyl groups, which are directly accessible or caring suitable protective groups that can be removed or/and modified by post-polymerization reactions. The variation of approaches let to obtain functional polymers with linear, star-shape and graft topologies as the well-defined structures for the advanced functional materials, including smart polymeric devices.

Background: Nanoreactors technology represents a promising tool for efficient and selective organic synthesis typically under “green” and sustainable reaction conditions. These structures with generating a confined reaction environment to accommodate that both reactants and catalysts can change the reaction pathways and induce new activities and selectivities. Objective: The paper reviews literature examples in which nanoreactors were employed in various types of organic and metal catalyzed reactions including multicomponent reactions, palladium-catalyzed coupling reactions, olefin metathesis, aza-Cope rearrangement, allylic alcohol isomerization, cyclization reactions, ring opening reactions, halogenation reactions, hydrolysis reactions, hydroformylation reactions, cascade reactions, addition reactions, oxidation reactions and reduction reactions. The reactions' survey is accompanied with the explanation of structure and performance of nanoreactors that are applied there. Conclusion: The availability of comprehensive information about the role of nanoreactors technology in green organic synthesis and investigation of different aspects of them such as their structures, mechanisms and synthetic utility can assist researchers in designing the greener approaches in organic synthesis.

Background: Pyrroles are organic cyclic compounds with an extensive and fascinating chemistry. These compounds have a wide structural variety and they are an important basis in technological development as they can be used as drugs, dyes, catalysts, pesticides, etc. Therefore, the production of these heterocyclic compounds by efficient clean methodologies is a great achievement in contemporary chemistry. In this paper, we show recent green procedures in the synthesis of pyrrole derivatives such as Hantzsch, Knorr and Paal- Knorr syntheses, as well as new eco-friendly synthetic procedures with high efficiency and low environmental impact. Objective: This work focusses on the recent advances in the pyrrole synthesis using clean techniques like ultrasound (US), microwaves (MW), high speed vibration milling (HSVM), catalysts use, solvent replace and other methodologies applied to common reactions to obtain the pyrrole core which follow the green chemistry principles. Conclusion: The main challenge of Green Chemistry is to gradually eliminate the generation of hazardous or harmful materials or replace them with less toxic and safer ones. However, this process must be driven by scientific developments. Its application in the synthesis of heterocyclic compounds such as pyrrole derivatives involves multiple economic and social benefits due to the biological importance of these compounds and their direct impact on the pharmaceutical industry. Although many processes are still under investigation using novel methodologies of green activation such as microwaves, ultrasound and HSVM, as well as synthetic processes in continuous flow and processes at room temperature, promising results such as cost and waste reduction and greater efficiency are achieved.

Background: Michaelis–Arbuzov reaction has played a key role for the synthesis of dialkyl or diaryl phosphonates by reacting various alkyl or aryl halides with trialkyl or triaryl phosphite. This reaction is very versatile in the formation of P-C bond from the reaction of aliphatic halides with phosphinites or phosphites to yield phosphonates, phosphinates, phosphine oxides. The Arbuzov reaction developed some methodologies, possible mechanistic pathways, selectivity, potential applications and biologically active various phosphonates. Objective: The synthesis of phosphonates via Michaelis–Arbuzov reaction with many new and fascinating methodologies were developed and disclosed in the literature, and these are explored in this review. Conclusion: This review has discussed past developments and vast potential applications of Arbuzov reaction in the synthesis of organophosphonates. As presented in this review, various synthetic methodologies were developed to prepare a large variety of phosphonates. Improvements in the reaction conditions of Lewis-acid mediated Arbuzov rearrangement as well as the development of MW-assisted Arbuzov rearrangement were discussed. Finally, to achieve high selectivities and yields, fine-tuning of reaction conditions including solvent type, temperature, and optimal reaction times to be considered.

Background: The synthesis of 3,4-dihydropyrano[3,2-c]chromenes via the one-pot three-component reactions of various aldehydes, malononitrile, and 4-hydroxycumarin at 60 °C in water as a solvent by the magnetic nanoparticles tag: piperidinium benzene-1,3-disulfonate ionic liquid as a green and efficient catalyst. Some benefits of the presented technique are significant cost impact, impressive catalysis and the ability to reuse of the catalyst. The current procedure offers high yield, short reaction times, neat reaction and simple reusable catalyst. Objective: A magnetic nanoparticles tag: piperidinium benzene-1,3-disulfonate ionic liquid as a green, efficient, reusable and heterogeneous catalyst was used for the synthesis of 3,4-dihydropyrano[3,2-c]chromenes. Method: We have described an efficient and green process for the synthesis of the one-pot three-component synthesis of 3,4-dihydropyrano[3,2-c]chromenes from the reaction between 4-hydroxy-coumarin with malononitrile and aldehydes in the presence of catalytic amount of magnetic nanoparticles tag: piperidinium benzene-1,3-disulfonate ionic liquid as a novel and powerful nano ionic liquid with good to excellent yields and in a short reaction time in water solvent at 60 °C. Result: The main advantage of this process is the simplicity of the work-up and the products can be isolated without chromatography. Conclusion: We suggest that the method has also various additional advantages such as low loading of catalyst, clean reaction, which makes it a suitable and noteworthy approach for the synthesis of 3,4- dihydropyrano[3,2-c]chromenes.

Aim and Objective: The brominated tyrosine alkaloids which have broad biological activity are commonly found in marine sponges of the Verongida order, However, with the discovery of itampolin A and B from the Madagascan sponge, Iotrochota purpurea, a plurality of brominated tyrosine derivatives have been found in the sponge Iotrochota purpurea. This study was undertaken to study antitumor activity of itampolin A and to explore the possible mechanism. Material and Method: The total synthesis of itampolin A was first performed to obtain purified brominated tyrosine alkaloid, then the cytotoxicities of itampolin A were evaluated by MTT method against H460 and A549 cells. To explore the possible mechanism, potential target identification by latest integrated pharmacophore matching platform of itampolin A was carried out using PharmMapper Server. Finally, expression of phospho p38α protein was studied using the western blot analysis. Results: Itampolin A and enantiomer of itampolin A were obtained, the latter is a novel compound named (-)- itampolin A, which exhibited significant anticancer activity in the biological tests. After potential target identification by latest integrated pharmacophore matching platform of itampolin A, p38α was screened out as the target protein. Then in the Western-blot analysis, it was proposed that (-)-itampolin A inhibited tumor cells by reducing the phospho-p38α expression. Conclusion: (+)-itampolin A was a brominated tyrosine derivative, isolated from the sponge Iotrochota purpurea. For the first time, the total synthesis of itampolin A was achieved. The enantiomer, (-)-itampolin A was found to show inhibitory activity on the cultured lung cancer A549 cells. The underlying anticancer mechanisms may be associated with its binding to p38α and then decrease in the phospho-p38 expression.

Background: Simple, efficient and enough versatile approaches to macrobicycles and macrotricycles, which are of great interest for the coordination of metal cations, were proposed in early 1990s using nucleophilic substitution reactions. Our research group was the first to begin a wide-range synthesis of N- and Ocontaining macrocycles using Pd-catalyzed amination reactions. Objective: The goal of the present research is to develop the catalytic synthesis of nitrogen- and oxygen containing macrobicycles organized around the central biphenyl moiety. Method: The method employed is the Pd(0)-catalyzed amination reactions which led to the formation of the first macrocycle comprising 3,3'-disubstituted biphenyl followed by the modification with two bromobenzyl moieties and the second Pd(0)-catalyzed macrocyclization which afforded target macrobicycles. Results: Macrocycles with the endocyclic 3,3'-disubstituted biphenyl moiety and diazadioxa, diazatrioxa, and tetraamine linkers were synthesized in 26-44% yields using Pd(0)-catalyzed amination reactions. They were modified with two 3-bromobenzyl substituents and introduced in the second Pd(0)-catalyzed macrocyclization to give macrobicycles in 8-27% yields. The result was shown to be dependent on the structure of the reacting compounds. The reaction with diazacrown ether provided a macrotricyclic derivative. Conclusion: An approach to a variety of N- and O-containing macrobicyclic compounds comprising a central biphenyl moiety and two oxadiamine (polyamine) chains via two consecutive Pd(0)-catalyzed amination reactions was elaborated.