Solid-phase Organic Synthesis Research Articles

Reflections on a Copenhagen-Minneapolis Axis in Bioorganic Chemistry.

The international peptide community rejoiced when one of its most distinguished members, Morten Meldal of Denmark, shared the 2022 Nobel Prize in Chemistry. In fact, the regiospecific solid-phase "copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides" (CuACC) reaction-that formed the specific basis for Meldal's recognition-was reported first at the 17th American Peptide Symposium held in San Diego in June 2001. The present perspective outlines intertwining conceptual and experimental threads pursued concurrently in Copenhagen and Minneapolis, sometimes by the same individuals, that provided context for Meldal's breakthrough discovery. Major topics covered include orthogonality in chemistry; the dithiasuccinoyl (Dts) protecting group for amino groups in α-amino acids, carbohydrates, and monomers for peptide nucleic acids (PNA); and poly(ethylene glycol) (PEG)-based solid supports such as PEG-PS, PEGA, and CLEAR [and variations inspired by them] for solid-phase peptide synthesis (SPPS), solid-phase organic synthesis (SPOS), and combinatorial chemistry that can support biological assays in aqueous media.

Antibacterial and anticancer activity of two NK-lysin-derived peptides from the Antarctic teleost Trematomus bernacchii

The NK-lysin antimicrobial peptide, first identified in mammals, possesses both antibacterial and cytotoxic activity against cancer cell lines. Homologue peptides isolated from different fish species have been examined for their functional characteristics in the last few years. In this study, a NK-lysin transcript was identified in silico from the head kidney transcriptome of the Antarctic teleost Trematomus bernacchii. The corresponding amino acid sequence, slightly longer than NK-lysins of other fish species, contains six cysteine residues that in mammalian counterparts form three disulphide bridges. Real time-PCR analysis indicated its predominant expression in T. bernacchii immune-related organs and tissues, with greatest mRNA abundance detected in gills and spleen. Instead of focusing on the full T. bernacchii derived NK-lysin mature molecule, we selected a 27 amino acid residue peptide (named NKL-WT), corresponding to the potent antibiotic NK-2 sequence found in human NK-lysin. Moreover, we designed a mutant peptide (named NKL-MUT) in which two alanine residues substitute the two cysteines found in the NKL-WT. The two peptides were obtained by solid phase organic synthesis to investigate their functional features. NKL-WT and NKL-MUT displayed antibacterial activity against the human pathogenic bacterium Enterococcus faecalis and the ESKAPE pathogen Acinetobacter baumannii, respectively. Moreover, at the determined Minimum Inhibitory Concentration and Minimum Bactericidal Concentration values against these pathogens, both peptides showed high selectivity as they did not exhibit any haemolytic activity on erythrocytes or cytotoxic activity against mammalian primary cell lines. Finally, the NKL-MUT selectively triggers the killing of the melanoma cell line B16F10 by means of a pro-apoptotic pathway at a concentration range in which no effects were found in normal mammalian cell lines. In conclusion, the two peptides could be considered as promising candidates in the fight against antibiotic resistance and tumour proliferative action, and also be used as innovative adjuvants, either to decrease chemotherapy side effects or to enhance anticancer drug activity.

Photocatalytic Cleavage of Trityl Protected Thiols and Alcohols

AbstractWe report the visible light photocatalytic cleavage of trityl thioethers or ethers under pH-neutral conditions. The method results in the formation of the respective symmetrical disulfides and alcohols in moderate to excellent yield. The protocol only requires the addition of a suitable photocatalyst and light rendering it orthogonal to several functionalities, including acid labile protective groups. The same conditions can be used to directly convert trityl-protected thiols into unsymmetrical disulfides or selenosulfides, and to cleave trityl resins in solid phase organic synthesis.

Methotrexate-loaded folic acid of solid-phase synthesis conjugated gold nanoparticles targeted treatment for rheumatoid arthritis

PurposeMethotrexate (MTX) is a first-line drug for rheumatoid arthritis (RA). Targeting of MTX to inflamed joints is essential to the prevention of potential toxicity and improving therapeutic effects. Gold nanoparticles (GNPs) are characterized by controllable particle sizes and good biocompatibilities, therefore, they are promising drug delivery systems. We aimed at developing a GNPs drug delivery system incorporating MTX and folic acid (FA) with strong efficacies against RA. MethodsMTX-Cys-FA was synthesized through solid-phase organic synthesis. Then, it was coupled with sulfhydryl groups in GNPs, thereby successfully preparing a GNPs/MTX-Cys-FA nanoconjugate with targeting properties. Physical and chemical techniques were used to characterize it. Moreover, we conducted its stability, release, pharmacokinetics, biodistribution and cell cytotoxicity, cell uptake, cell migration, as well as its therapeutic effect on CIA rats. The histopathology was conducted to investigate anti-RA effects of GNPs/MTX-Cys-FA nanoconjugates. ResultsThe GNPs/MTX-Cys-FA nanoconjugate exhibited a spherical appearance, had a particle size of 103.06 nm, a zeta potential of -33.68 mV, drug loading capacity of 11.04 %, and an encapsulation efficiency of 73.61%. Cytotoxicity experiments revealed that GNPs had good biocompatibilities while GNPs/MTX-Cys-FA exhibited excellent drug-delivery abilities. Cell uptake and migration experiment showed that nanoconjugates containing FA by LPS activated mouse mononuclear macrophages (RAW264.7) was significantly increased, and they exerted significant inhibitory effects on human fibroblast-like synoviocytes (HFLS) of RA (p<0.01). In addition, the nanoconjugate prolonged blood circulation time of MTX in collagen-induced arthritis (CIA) rats (p<0.01), enhanced MTX accumulation in inflamed joints (p<0.01), enhanced their therapeutic effects (p<0.01), and reduced toxicity to major organs (p<0.01). ConclusionGNPs/MTX-Cys-FA nanoconjugates provide effective approaches for RA targeted therapeutic strategies.

Multifunctional polyether grafted dendritic solid supports: Novel class of solvent like high loading hybrid supports for solid phase organic synthesis

Three novel multifunctional polyether grafted dendritic solid supports for organic synthesis were developed via single step, grafting from and hypergrafting strategies. In order to improve both the swelling capacity and loading capacity of conventional resins simultaneously, the hybrid supports were developed by grafting either multivalent linear polymers or dendritic architectures to the conventional resin. The ring opening polymerization of strained cyclic monomers was explored for the development of multivalent polymer grafts on the solid support. The physico-chemical properties of the dendritic solid supports were studied by various characterization techniques and analytical methods. Among the hybrid supports, Het-PG was found to be a novel solvent like high loading solid support. High functional group capacity of 7 mmol g−1 which was introduced via single step approach, increased accessibility of functional sites even at high loading etc. make Het-PG a versatile solid support for organic synthesis. The applicability of dendritic solid support (Het-PG) as a high loading hybrid support for multistep solid phase organic synthesis of small peptides was investigated. The high functional group capacity and increased accessibility of functional sites in Het-PG were exploited for addressing the poor industrial scalability issue of solid phase organic synthesis. A novel approach to solid phase peptide synthesis using solvent like high loading hybrid solid support is presented.

Neutral reducing agents supported on merrifield resin obtained by solid phase organic synthesis

An efficient methodology for the synthesis of neutral reducing agents supported on Merrifield resin has been developed. The process was carried out under mild conditions, varying the linker length, the bidentate chelating amine and the alkali metal tetrahydroborate. Fluorescence and infrared spectroscopies and thermogravimetric analysis were used for monitoring the chemical modifications. The developed methodology proved to be successful in obtaining a library of 40 neutral reducing agents supported on Merrifield resin in high yields (90–95%), with the potential to reduce carbonyl compounds and to be reusable. A chemically and thermally stable library of neutral reducing agents supported on Merrifield resin was readily obtained with high yields using an efficient methodology under mild conditions. The stability, high yields and easy preparation of the neutral supported reducing complexes make them attractive as reducing agents in heterogeneous organic synthesis.

Greening Solid-Phase Organic Synthesis: Environmentally Conscious Synthesis of Pharmaceutically Relevant Privileged Structures 5,6-Dihydropyridin-2(1H)-ones and Quinolin-2(1H)-ones.

Solid-phase organic synthesis (SPOS) is a very efficient methodology for the synthesis of diverse organic molecules, particularly exploited in drug discovery. Here, we present the transformation of the traditional SPOS to an eco-friendlier methodology on examples of pharmacologically relevant privileged structures 5,6-dihydropyridin-2(1H)-ones and quinolin-2(1H)-ones. The green approach is primarily based on the utilization of environmentally friendly solvent 2-MeTHF in all steps of the synthesis. Target heterocycles were synthesized by extending our previously published synthesis of five-membered tetramic acid analogues to six-membered cycles. The crucial step of the synthesis is cyclization via nonclassical Wittig olefination of resin-bound esters. Traditional and green protocols provided comparable results with respect to purity and yield of products, thus opening the way for greener access to a variety of diverse heterocycles.

Traceless Solid-Phase Organic Synthesis.

Traceless solid-phase synthesis represents an ultimate sophisticated synthetic strategy on insoluble supports. Compounds synthesized on solid supports can be released without a trace of the linker that was used to tether the intermediates during the synthesis. Thus, the target products are composed only of the components (atoms, functional groups) inherent to the target core structure. A wide variety of synthetic strategies have been developed to prepare products in a traceless manner, and this review is dedicated to all aspects of traceless solid-phase organic synthesis. Importantly, the synthesis does not need to be carried out on a linker designed for traceless synthesis; most of the synthetic approaches described herein were developed using standard, commercially available linkers (originally devised for solid-phase peptide synthesis). The type of structure prepared in a traceless fashion is not restricted. The individual synthetic approaches are divided into eight sections, each devoted to a different methodology for traceless synthesis. Each section consists of a brief outline of the synthetic strategy followed by a description of individual reported syntheses.

Polystyrene-supported 2-bromoallyl sulfone as an efficient reagent for synthesis of 3,5-disubstituted isoxazoles

A facile method has been developed for the solid-phase organic synthesis of 3,5-disubstituted isoxazoles from polystyrene-supported 2-bromoallyl sulfone. The advantages of this method include a straightforward and convenient procedure, high product yield, and good stability of this new polymeric reagent.

Stereoselective Reducing Complexes Supported in Solid Phase: Preparation and Reactivity Study

AbstractTwelve new chiral chelating resins have been prepared using solid phase organic synthesis with the Merrifield and Wang resins and the bidentate amine 1,2‐ethylenediamine, followed by the coupling of asymmetric ketones such as 1‐phenyletanone, 4‐methyl‐2‐pentanone 4‐nitroacetophenone and 4‐methoxyacetophenone to form prochiral imines. The enantioselective reduction with borane and (R)‐(+)‐2‐Methyl‐CBS‐oxazaborolidine leads to the chiral resins with yields greater than 86%. We used these chiral resins to prepare 24 reducing complexes with alkali tetrahydroborates in a very simple way giving yields greater than 87%. Finally, we achieved a preliminary enantioselective reduction of acetophenone employing the Merrifield's chiral chelating resins obtaining the corresponding S alcohol in a 70:30 ratio with the R analog alcohol.

Synthetic Routes for 1,4-disubstituted 1,2,3-triazoles: A Review

N-Heterocyclic compounds like 1,2,3-triazoles serve as a key scaffolds among organic compounds having diverse applications in the field of drug discovery, bioconjugation, material science, liquid crystals, pharmaceutical chemistry and solid phase organic synthesis. Various drugs containing 1,2,3-triazole ring which are commonly available in market includes Rufinamide, Cefatrizine, Tazobactam etc., Stability to acidic/basic hydrolysis along with significant dipole moment support triazole moiety for appreciable participation in hydrogen bonding and dipole-dipole interactions with biological targets. Huisgen 1,3-dipolar azide-alkyne cycloaddition culminate into a mixture of 1,4 and 1,5- disubstituted 1,2,3-triazoles. In 2001, Sharpless and Meldal came across with a copper(I) catalyzed regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles by cycloaddition between azides and terminal alkynes. This azide-alkyne cycloaddition has been labelled as a one of the important key click reaction. Click synthesis describes chemical reactions that are simple to perform, gives high selectivity, wide in scope, fast reaction rate and high yields. Click reactions are not single specific reaction, but serve as a pathway for construction of simple to complex molecules from a variety of starting materials. In the last few decades, 1,2,3-triazoles attracted attention of researchers all over the world because of their broad spectrum of biological activities. Keeping in view the biological importance of 1,2,3-triazole, in this review we focus on the various synthetic routes for the syntheisis of 1,4-disubstituted 1,2,3-triazoles. This review involves various synthetic protocols which involves copper and non-copper catalysts, different solvents as well as substrates. It will boost synthetic chemists to explore new pathway for the development of newer biologically active 1,2,3-triazoles.

Recent Advances in Solid Phase Organic Synthesis (SPOS)

Recent Advances in Solid Phase Organic Synthesis (SPOS)

Recent Application of Polystyrene-supported Triphenylphosphine in Solid-Phase Organic Synthesis

Recent years have witnessed a fast development of solid phase synthetic pathways, a variety of solid-supported reagent and its applications in diverse synthetic strategies and pharmaceutical applicability’s. Polymer-supported triphenylphosphine is getting a lot of applications owing to the speed and simplicity in the process. Furthermore, ease of recyclability and reuse of polymer-supported triphenylphosphine added its advantages. This review covers a wide range of useful organic transformations which are accomplished using cross-linked polystyrene-supported triphenylphosphine with the aim of giving renewed interest in the field of organic and medicinal-combinatorial chemistry.

Traceless Solid-Phase Synthesis of Ketones via Acid-Labile Enol Ethers: Application in the Synthesis of Natural Products and Derivatives.

In solid-phase organic synthesis, Wang resin is traditionally used for the immobilization of acids, alcohols, phenols, and amines. We report the use of Wang resin for the traceless synthesis of ketones via acid-labile enol ethers. We demonstrate the practicality of this synthetic strategy on the solid-phase synthesis of pyrrolidine-2,4-diones, which represent the core structure of several natural products, including tetramic acid. Base-triggered condensation of pyrrolidine-2,4-diones yielded 4-hydroxy-1,1′,2′,5-tetrahydro-2H,5′H-[3,3′-bipyrrole]-2,5′-diones.

Introduction of two polyvinyl alcohol resins for efficient solid support Cu‐catalyzed N‐arylation of α‐aminoacids with aryl halides in aqueous media

ABSTRACTIn this article, two polyvinyl alcohol (PVA)‐based resins were prepared by crosslinking of epoxidized PVA‐chains using of 4‐(4‐aminobenzyl)benzenamine as a crosslinker and polymerization of acrylated PVA chains in the another approach. The prepared PVA resins showed well hydrophilic and swelling properties in various organic solvents, which are used in solid‐phase organic synthesis (SPOS). Swelling properties of these resins were examined in dimethylformamide, tetrahydrofuran, water, ethanol, methanol, dichloromethane, and dioxane. Furthermore, the both resins were characterized by FTIR and 1H‐NMR and their properties such as epoxy equivalent weight (EEW) of epoxidized PVA and density of the resins were determined by analytical methods. Then, α‐amino acids such as L‐aspartic acid, L‐leucine, L‐alanine, L‐serine, L‐valine, L‐threonine, and L‐tyrosine were immobilized on both resins through esterification reaction between these α‐amino acids with the present hydroxyl groups on PVA resines, to carry out their solid‐phase N‐arylation reaction in the presence of CuI as a catalyst in milder and greener conditions than free resin protocols. Hydrolysis of the correponding N‐arylated α‐amino acids immobilized on the resins gave the N‐arylated α‐amino acids in high to excellent yields. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 136, 47597.

Parallel Solid-Phase Synthesis using a New Diethylsilylacetylenic Linker and Leading to Mestranol Derivatives with Potent Antiproliferative Activities on Multiple Cancer Cell Lines.

RM-133 belongs to a new family of aminosteroid derivatives demonstrating interesting anticancer properties, as confirmed in vivo in four mouse cancer xenograft models. However, the metabolic stability of RM-133 needs to be improved. After investigation, the replacement of its androstane scaffold by a more stable estrane scaffold led to the development of the mestranol derivative RM-581. Using solid-phase strategy involving five steps, we quickly synthesized a series of RM-581 analogs using the recently-developed diethylsilylacetylenic linker. To establish structure-activity relationships, we then investigated their antiproliferative potency on a panel of cancer cell lines from various cancers (breast, prostate, ovarian and pancreatic). Some of the mestranol derivatives have shown in vitro anticancer activities that are close to, or better than, those observed for RM-581. Compound 23, a mestranol derivative having a ((3,5-dimethylbenzoyl)- L-prolyl)piperazine side chain at position C2, was found to be active as an antiproliferative agent (IC50 = 0.38 ± 0.34 to 3.17 ± 0.10 µM) and to be twice as active as RM-581 on LNCaP, PC-3, MCF-7, PANC-1 and OVCAR-3 cancer cells (IC50 = 0.56 ± 0.30, 0.89 ± 0.63, 1.36 ± 0.31, 2.47 ± 0.91 and 3.17 ± 0.10 µM, respectively). Easily synthesized in good yields by both solid-phase organic synthesis and classic solution-phase chemistry, promising compound 23 could be used as an antiproliferative agent on a variety of cancers, notably pancreatic and ovarian cancers, both having very bad prognoses.

Green Transformation of Solid-Phase Peptide Synthesis

Peptides play key roles in medicinal chemistry, being found in therapeutics and diagnostic agents, among others. Furthermore, their synthetic protocols have also been optimized for other fields such as the solid-phase organic synthesis of other organic compounds. However, the classical protocols for peptide synthesis fall short of Green Chemistry parameters. The excess of reagents and solvents used in classical protocols is costly. Moreover, the widely used hazardous chemicals pose a threat to the environment and to human health. In this review, we examine peptide synthesis in the context of green chemistry and address its pros and cons. Furthermore, we discuss several attempts to make peptide synthesis greener. These attempts have followed two major pathways, namely reducing the amount of material used or replacing hazardous materials for friendlier ones. Although this work focuses mostly on the solid-phase peptide synthesis approach, a brief description of some reagents, solvents, methods or strategies ...

Current Parallel Solid-Phase Synthesis of Drug-like Oxadiazole and Thiadiazole Derivatives for Combinatorial Chemistry.

Solid-phase organic synthesis is a powerful tool in the synthesis of small organic molecules and building of libraries of compounds for drug discovery. Heterocyclic compounds are important components of the drug discovery field as well and serve as a core for hundreds of marketed drugs. In particular, oxadiazole and thiadiazole cores are compounds of great interest due to their comprehensive biological activities and structural features. Therefore, a plethora of oxadiazole and thiadiazole synthesis methodologies have been reported to date, including solution and solid-phase synthesis methodologies. In this review, we concentrate on and summarize solid-phase synthetic approaches of the oxadiazole and thiadiazole derivatives.

Greener solvents for solid-phase organic synthesis

Abstract Solid-phase organic synthesis is an essential method for the rapid synthesis of complex biological structures and libraries of small organic molecules. However, it is often associated with the use of large quantities of problematic solvents for the removal of excess reagents and reaction by-products. Given that solvent will often be the biggest contributor to waste generated in the average pharmaceutical/fine-chemical process, its exchange for a more desirable alternative often presents the biggest gains in terms of reducing environmental impact. This review aims to explore recent approaches to performing solid-phase organic synthesis, and associated solid-phase peptide synthesis, in neoteric solvents and reaction media that present greener alternatives.

Well-defined polymer microspheres formed by living dispersion polymerization: precisely functionalized crosslinked polymer microspheres from monomers possessing cumulated double bonds

The precise method for synthesizing well-defined polymer microspheres via π-allylnickel-catalyzed living coordination polymerization of allene derivatives under dispersion polymerization conditions is described. The π-allylnickel-catalyzed living coordination polymerization of allene derivatives such as phenoxyallene was carried out in protic solvents such as methanol in the presence of stabilizers such as polyvinylpyrrolidone to produce polymer microspheres with a narrowly dispersed diameter distribution (Dw/Dn) at a high yield. For example, polymer microspheres with a number-average diameter (Dn) of 1.10 μm and Dw/Dn of 1.01 were obtained at a yield of 97%; these microspheres are composed of a polymer with a controlled molecular weight (Mn=11 700) and narrow molecular weight distribution (Mw/Mn=1.06). The size of the resulting polymer microspheres proved to be affected by polymerization conditions such as the initial monomer concentrations, monomer structures, polymerization media and stabilizers. Unlike conventional dispersion polymerization systems, the use of a bifunctional monomer, 1,4-diallenoxybenzene, for this living dispersion polymerization successfully produced well-defined crosslinked living polymer microspheres that exhibited high solvent tolerance. The postpolymerization of functional allene monomers in the living dispersion polymerization was also successful, resulting in functionalized polymer microspheres that could be applied in solid-phase organic synthesis and solid-supported transition metal catalysis. A controllable process for producing uniform, robust microspheres can make mixed solid-liquid chemical reactions easier to perform. Tiny beads of polymers such as polystyrene are finding increasing use as supports for catalysts in organic synthesis. Now, Ikuyoshi Tomita from the Tokyo Institute of Technology and co-workers have used a ‘living’ coordination mechanism, which polymerizes molecules until directed to stop, to improve the size distribution and modification capabilities of microspheres. Nickel-based catalysts and unsaturated, bifunctional carbon reagents worked together to generate microspheres with cross-linked internal structures for additional strength and solvent tolerance. Furthermore, the microsphere surfaces contained living, growing ends that can attach to additional reagents. Synthetic trials revealed that decorating the microspheres with palladium produced a heterogeneous catalyst that could be recovered and reused multiple times with little loss of activity. The precision synthetic method of well-defined polymer microspheres by the π-allylnickel-catalyzed living coordination polymerization of allene derivatives under the dispersion polymerization conditions is described. Unlike the conventional dispersion polymerization systems, the use of a bifunctional monomer, 1,4-diallenoxybenzene, to this living dispersion polymerization successfully gave well-defined crosslinked living polymer microspheres that exhibit high solvent-tolerant properties. The postpolymerization of functional allene monomers in the living dispersion polymerization also proceeded smoothly to give functionalized polymer microspheres that enabled their applications to the solid-phase organic synthesis and the solid-supported transition metal catalysts.