Introduction Of Side Chains Research Articles

Total Synthesis of Putative 11-epi-Lyngbouilloside Aglycon.

We report here the total synthesis of 11-epi-lyngbouilloside aglycon. Our strategy features a Boeckman-type esterification followed by a RCM to form the 14-membered ring macrolactone and a late-stage side chain introduction via a Wittig olefination. Overall, the final product was obtained in 20 steps and 2% overall yield starting from commercially available 3-methyl-but-3-enol. Most importantly, the strategy employed is versatile enough to eventually allow us to complete the synthesis of the natural product and irrevocably confirm its structure.

ChemInform Abstract: Palladium‐Catalyzed Allylic Alkylation Reactions of Glycolates as a Tool for the Synthesis of Functionalized α‐Hydroxy Esters.

AbstractAn optimized protocol allows the introduction of side chains into the tert‐butyl glycolate (I) using allyl acetates.

Selective synthesis of propenyl‐branched diunsaturated fatty esters via catalytic codimerization of ethyl linoleate and propylene

A bimetallic catalyst system consisting of RhCl3 and Pd(MeCN)2Cl2 efficiently promotes the conversion of ethyl linoleate selectively to mono‐propenylated diunsaturated products. The reaction proceeds in high yields under mild conditions. The key advantage of the new process is that it is based on the readily available linoleate rather than a preformed conjuenic acid ester.Practical applications: The new protocol opens up a high yielding and environmentally friendly method for the introduction of side chains with a defined length into fatty acid derivatives. The products are of profound potential interest for industrial applications, e.g., in lubricants, cosmetics, plastics, and coatings, as branched fatty acids are known to have a lower solidifying point and viscosity and an increased solubility than their linear counterparts.Rh/Pd‐catalyzed selective conversion of ethyl linoleate to mono‐propenylated diunsaturated products under mild conditions.

Anion recognition by cyclic peptides.

Anion binding selectivity can often be controlled by judicious arrangement of recognition moieties around an anion of interest. Indeed, nature takes advantage of large peptides/proteins to provide highly efficient and selective anion receptors using a small number of amino acid building blocks placed in a precise arrangement. Cyclic peptides are ideal synthetic scaffolds to position binding residues in a similarly preorganised manner as their synthetic versatility and rigidified structure allows precise control over their size and shape. This review summarises the recent use of such cyclic peptide scaffolds as receptors for various anionic species.

Reactivity of Dipyrromethanes towards Azoalkenes: Synthesis of Functionalized Dipyrromethanes, Calix[4]pyrroles, and Bilanes

AbstractThe introduction of side chains at the 1‐ and 9‐positions of dipyrromethanes was explored by using the hetero‐Diels–Alder reaction of azoalkenes. New 5,5′‐diethyldipyrromethanes and 5‐phenyldipyrromethanes that were functionalized with open‐chain hydrazone moieties, including derivatives with tetrazolyl groups, were prepared. Furthermore, the synthesis of new calix[4]pyrroles and bilanes was achieved by employing the bis(hetero‐Diels–Alder) reaction of azoalkenes with 5,5′‐diethyldipyrromethane.

Self-directed orientation of molecular columns based on n-type hexaazatrinaphthylenes (HATNAs) for electron transport.

Self-organizing n-type hexaazatrinaphthylenes (HATNAs) with various bay-located side chains have been synthesized. The HATNA derivatives are able to form long-range molecular columns with self-directed growth directions. In particular, alkyl-substituted HATNAs showed in-plane molecular columns with axes parallel to substrates, whereas the columnar orientation of the HATNAs with alkylethynyl or alkylthio groups strongly depended on the length of the introduced side chains. Interestingly, the derivative with octylthio chains exhibited out-of-plane molecular columns, in which electron mobility of up to 10(-3) cm(2) V(-1) s(-1) was determined through the time-of-flight technique, highlighting the fact that such molecular columns based on bay-substituted HATNAs are promising n-type semiconductors for device applications.

Introduction to special issue in honor of Professor Povl Krogsgaard-Larsen.

May 15, 2012 Professor Povl Krogsgaard-Larsen celebrated his 70th birthday. As described in the following commentary by Dr. Klaus P. Bogeso, Povl KrogsgaardLarsen has been a giant in medicinal chemistry and in order to honor his achievements we decided to invite a number of his close colleagues and alumni to write contributions for the present special issue of Neurochemical Research. Professor Povl Krogsgaard-Larsen has dedicated his scientific career to development of novel selective pharmacological tool compounds for neurotransmitter receptors and transporters with particular focus on the neurotransmitters glutamate, c-amino butyric acid (GABA) and acetylcholine. His starting points for the ligand design have either been the endogenous signaling molecules or compounds isolated from natural products such as the mushroom fly ageric (Amanita muscaria), which he has made analogs of by e.g. bioisosteric replacement, cyclization including extensive use of heterocycles and introduction of side-chains. Professor Povl Krogsgaard-Larsen was early to adopt the concept of binding sites and receptor/ transporter models/structures and use these as models for rational ligand design of new analogs with improved properties. He was also early in realizing that close integration of chemistry and pharmacology was pivotal for success. He thus focused on interdisciplinary research and has been a main driver for expanding the original Department of Chemistry hosting his group four decades ago to the present day Department of Drug Design and Pharmacology, which includes medicinal chemistry, pharmacology, computational chemistry and X-ray crystallography. This interdisciplinary approach has led to development of Special Issue: In honor of Krogsgaard-Larsen.

Enhancing the Charge Transport in Solution‐Processed Perylene Di‐imide Transistors via Thermal Annealing of Metastable Disordered Films

The introduction of side chains in π‐conjugated molecules is a design strategy widely exploited to increase molecular solubility thus improving the processability, while directly influencing the self‐assembly and consequently the electrical properties of thin films. Here, a multiscale structural analysis performed by X‐ray diffraction, X‐ray reflectivity, and atomic force microscopy on thin films of dicyanoperylene molecules decorated with either linear or branched side chains is reported. The substitution with asymmetric branched alkyl chains allows obtaining, upon thermal annealing, field‐effect transistors with enhanced transport properties with respect to linear alkyl chains. Branched chains induce molecular disorder during the film growth from solution, effectively favouring 2D morphology. Post‐deposition thermal annealing leads to a structural transition towards the bulk‐phase for molecules with branched chains, still preserving the 2D morphology and allowing efficient charge transport between crystalline domains. Conversely, molecules with linear chains self‐assemble into 3D islands exhibiting the bulk‐phase structure. Upon thermal annealing, these 3D islands keep their size constant and no major changes are observed in the organic field effect transistor characteristics. These findings demonstrate that the disorder generated by the asymmetric branched chains when the molecule is physisorbed in thin film can be instrumental for enhancing charge transport via thermal annealing.

Direct and indirect single electron transfer (SET)-photochemical approaches for the preparation of novel phthalimide and naphthalimide-based lariat-type crown ethers.

In this review, we describe direct and indirect photochemical approaches that have been developed for the preparation of phthalimide- and naphthalimide-based, lariat-type crown ethers. The direct route utilizes a strategy in which nitrogen-linked side chains containing polyethoxy-tethered phthalimides and naphthalimides, possessing terminal α-trialkylsilyl groups, are synthesized utilizing concise routes and UV-irradiation to form macrocyclic ring systems. In contrast, the indirect route developed for the synthesis of lariat-type crown ethers employs sequences in which SET-promoted macrocyclization reactions of α-trialkylsilyl-terminated, polyethoxy-tethered phthalimides and naphthalimides are followed by a side chain introduction through substitution reactions at the amidol centers in the macrocyclic ethers. The combined observations made in these investigations demonstrate the unique features of SET-promoted photocyclization reactions that make them well-suited for the use in the synthesis of functionalized crown ethers. In addition, while some limitations exist for the general use of SET-photochemical reactions in large-scale organic synthesis, important characteristics of the photoinduced macrocyclization reactions make them applicable to unique situations in which high temporal and spatial control is required.

Design and synthesis of triazoloquinoxaline polymers with positioning alkyl or alkoxyl chains for organic photovoltaics cells

Four benzodithiophene-triazoloquinoxaline alternating polymers, PBDTT-BTzQx-EH-C1, PBDT-BTzQx-EH-C1, PBDT-BTzQx-EH-C12 and PBDT-BTzQx-C12, have been designed and synthesized to investigate the correlation of alkyl side chains with the opto-electronic properties of the resulting polymers. The introduction of side chains onto the thiophene spacer or quinoxaline unit lowers the highest occupied molecular orbital energy level of the polymers, while excessive chains prevent the polymer backbone from π–π stacking and result in a decreased short circuit current and fill factor in a photovoltaic application. The bulk heterojunction cells fabricated by blending PBDTT-BTzQx-EH-C1 with [6,6]-phenyl-C61-butyric acid methyl ester exhibit a best power conversion efficiency (PCE) of 1.40%, with a short-circuit current density of 4.12 mA cm−2, an open-circuit voltage of 0.62 V and a fill factor of 55%. The device was further optimized to 2.24% PCE by using PFN (5 nm)/Ca (5 nm) as a co-interfacial layer.

Solid-Phase Synthesis of Asymmetrically Branched Sequence-Defined Poly/Oligo(amidoamines)

We present for the first time the synthesis of asymmetrically branched sequence-defined poly/oligo(amidoamines) (PAAs) using solid-phase synthesis with the capability of introducing diversity at the side chains. We introduce two new versatile (diethylenetriamine) building blocks for solid-phase synthesis bearing Fmoc/Boc and Fmoc/Alloc protecting groups expanding recently used Fmoc/Boc protecting group strategy for linear PAAs to an Fmoc/Alloc/Boc strategy. This allows for orthogonal on-resin cleavage of Fmoc and Alloc protecting groups during solid-phase synthesis of PAAs with backbones differing in chain length and sequence. With these structures we then demonstrate the potential for generating asymmetrical branching by automated multiple on-resin cleavage of Alloc protecting groups as well as the introduction of side chains varying in length and number. Such systems have high potential as nonviral vectors for gene delivery and will allow for more detailed studies on the correlation between the degree of branching of PAAs and their resulting biological properties.

Mutational and Cysteine Scanning Analysis of the Glucagon Receptor N-terminal Domain

The glucagon receptor belongs to the B family of G-protein coupled receptors. Little structural information is available about this receptor and its association with glucagon. We used the substituted cysteine accessibility method and three-dimensional molecular modeling based on the gastrointestinal insulinotropic peptide and glucagon-like peptide 1 receptor structures to study the N-terminal domain of this receptor, a central element for ligand binding and specificity. Our results showed that Asp(63), Arg(116), and Lys(98) are essential for the receptor structure and/or ligand binding because mutations of these three residues completely disrupted or markedly impaired the receptor function. In agreement with these data, our models revealed that Asp(63) and Arg(116) form a salt bridge, whereas Lys(98) is engaged in cation-π interactions with the conserved tryptophans 68 and 106. The native receptor could not be labeled by hydrophilic cysteine biotinylation reagents, but treatment of intact cells with [2-(trimethylammonium)ethyl]methanethiosulfonate increased the glucagon binding site density. This result suggested that an unidentified protein with at least one free cysteine associated with the receptor prevented glucagon recognition and that [2-(trimethylammonium)ethyl]methanethiosulfonate treatment relieved this inhibition. The substituted cysteine accessibility method was also performed on 15 residues selected using the three-dimensional models. Several receptor mutants, despite a relatively high predicted cysteine accessibility, could not be labeled by specific reagents. The three-dimensional models show that these mutated residues are located on one face of the protein. This could be part of the interface between the receptor and the unidentified inhibitory protein, making these residues inaccessible to biotinylation compounds.

Influence of the grafted chain length on responsive behaviors of the grafted poly(DEA-co-DMAEMA) hydrogel

The poly(N,N-diethylacrylamide-co-(2-dimethylamino)ethyl methacrylate) (poly(DEA-co-DMAEMA)) macromonomers with three different chain lengths were prepared by telomerization of DEA and DMAEMA monomers with different ratios of the chain transfer agent, 2-mercaptoethanol. The number-average weight of three macromonomers determined by gel permeation chromatography of the terminal hydroxyl groups was 8355, 10,516 and 15,953, respectively. The comb-type grafted poly(DEA-co-DMAEMA) hydrogels having the different lengths of the grafted chains were synthesized in the presence of crosslinker. Equilibrium and dynamic swelling/deswelling properties of the prepared hydrogels responding to temperature and pH were investigated. Compared to normal-type hydrogel, the comb-type grafted hydrogels exhibited excellent variational values in response to an alternation of the temperature and pH. Moreover, the grafted hydrogels showed quite fast reswelling and deswelling behaviors in response to simultaneous dual temperature and pH stimuli. This is because that the introduction of side chains with freely mobile ends in the comb-type grafted hydrogels made the mobility of the networks increased. The responsive rates of the grafted hydrogels were also controlled by modifying the length of the grafted chains. The dual thermo- and pH-sensitive comb-type grafted poly(DEA-co-DMAEMA) hydrogels in this study may find various potential applications.

A Formal Synthesis of Porantheridine and an Epimer

A formal synthesis of porantheridine and a synthesis of its C6-epimer have been completed, employing silver-catalyzed allene cyclization to form a common cis-isoxazolidine intermediate and related N-acyl iminium ion intermediates for side-chain introduction. The stereochemistry of this step can be controlled by choice of the N-protection method.

Asymmetric Synthesis of Pyrido[1,2-c]pyrimidinones

“Asymmetric Electrophilic α-Amidoalkylation” reactions with a chiral alkylaminocarbonyl unit as chiral auxiliary are used for the stereoselective synthesis of 2-substituted piperidine derivatives. Intramolecular condensation of the nitrogen of the aminocarbonyl group with the keto function present in the newly introduced side chain of the amidoalkylation products results in the formation of hexahydropyrido[1,2-c]pyrimidinones. After reduction and removal of the N-alkyl moiety of the chiral auxiliary the target compounds, enantiopure octahydro-1H-pyrido[1,2-c]pyrimidin-1-ones, are obtained.

Stereoselective Syntheses of 2,6-disubstituted Piperidin-3-oles (alkaloid lipids)

Alkaloid lipids comprise a class of natural compounds with significant biological activities of medicinal interest. Their structural framework consists of a 2,6-disubstituted-3-piperidinol moiety (polar head group) and a lipid tail. Representative examples of alkaloid lipids are (+)-Cassine, (-)-Prosophylline, (-)-Prosopinine, (-)-Spectalline. Many synthetic strategies have been developed for the efficient stereoselective synthesis of various natural alkaloid lipids and their synthetic analogues. This mini-review focuses on the most successful approaches published during the new millennium. The synthetic strategies are grouped in two main sections, depending on whether the lipophilic side chain is introduced before (“early”) or after (“late”) piperidine ring formation. These sections are further organised based on the key ring forming reaction/strategy employed. For the strategies that opt to introduce the lipophilic side chain early on the synthetic sequence, the intramolecular reductive amination, either with or without isolation of the intermediate imine/enamine, constitutes one of the most popular methods for constructing the piperidine ring followed closely by approaches based on the intramolecular alkylation of suitable amine derivatives. Olefin ring closing metathesis and intramolecular hetero-Diels-Alder reactions have also been exploited to secure the azaheterocycle. The intramolecular alkylation of an amine or the, retrosynthetically related, intramolecular amine addition to an olefin have also been employed as key ring-forming reactions by syntheses that adopt the more convergent approach of introducing the side chain on a preformed heterocycle. In this regard the introduction of the side chain via alkylation of pyridinium salts, alkylation of a lactam (2-piperidone) or glutarimide derivatives have been investigated. Several groups have also exploited the oxidative cyclization of α-furylamines to prepare 2-dihydropyridones as a convenient scaffold for the late introduction of the lipid tail. In some cases, carbohydrates and aminoacids were used (either as starting materials or as chiral auxiliaries) for the enantioselective synthesis of alkaloid lipids. Enzymatic or chemical (Jacobsens epoxide hydrolysis protocol) resolutions of racemic starting materials and Sharpless asymmetric epoxidation, dihydroxylation or aminohydroxylation of olefins have also been utilized. Finally, it is noteworthy that in several cases, apart from the Witting reaction and the use of Grignard reagents, olefin cross-metathesis has also been successfully employed for the introduction of the lipid side chain.

Synthesis and Characterization of a Cationic Poly(β-hydroxyalkanoate)

Poly(beta-hydroxyalkanoates) (PHAs) are biodegradable polyesters produced by a wide range of bacteria. The structures of these polymers may be tuned by controlling the carbon source composition in the feed stock, but the range of functional groups accessible in this manner is limited to those that the organism is able to metabolize. Much effort has been made to chemically modify the side chains of these polymers to achieve new materials. Here, we report the synthesis of the first cationic PHA, poly(beta-hydroxy-octanoate)- co-(beta-hydroxy-11-(bis(2-hydroxyethyl)-amino)-10-hydroxyundecanoate) (PHON). Pseudomonas putida Gpo1 was used to produce poly(beta-hydroxy-octanoate)- co-(beta-hydroxy-10-undecenoate) (PHOU), whose vinyl-terminated side chains were first converted to terminal epoxides and then modified with diethanolamine. The modification of PHOU was examined using (1)H, COSY, and HSQC NMR and GPC and resulted in a loss of molecular weight due to aminolysis and also in the introduction of side chains terminated with tertiary amine groups, which are protonated at physiological pH. The polycationic PHA is soluble in polar solvents such as DMSO, DMF, and water. The new biodegradable cationic polymers are envisioned as nucleic acid delivery systems.

Concise Formal Synthesis of (±)-Shikonin Via a Highly α-Regioselective Prenylation of 1, 4, 5, 8-Tetramethoxynaphthalene-2-Carbaldehyde

A concise formal synthesis of (±)-shikonin via a highly α-regioselective prenylation is achieved. The novelty of the procedure lies in the introduction of side chain of shikonin in one step via prenylation of 1, 4, 5, 8- tetramethoxynaphthalene-2-carbaldehyde under mild conditions without producing any γ-isomer. Keywords: Shikonin, synthesis, regioselectivity, prenylation, oxonia-cope rearrangement

Structure and anti-proliferation function of 5,5-diphenyl-2-thiohydantoin (DPTH) derivatives in vascular endothelial cells

Previously, we identified DPTH, an analogue of antiepileptic drug phenytoin (5,5-diphenylhydantoin, DPT), capable of retarding the cell cycle in the human vascular endothelial cells. Our data suggest that DPTH inhibits human umbilical venous endothelial cells (HUVEC) proliferation by increasing the level of p21 protein, which in turn inhibits the activities of cyclin-dependent kinase (CDK)2 and CDK4, and finally interrupts the cell cycle. To search chemicals with more potency in anti-angiogenic activity, we designed and synthesized several chemical compounds based on the structure–activity relationship consideration. We evaluated the anti-angiogenic activity of these compounds by examining their effects on DNA synthesis, cell number, p21 induction and capillary-like tube formation. Our results showed that introduction of side chain containing an aromatic ring structure with right spatial arrangement at sulfur atom of DPTH enhanced the anti-angiogenic activity in HUVEC.

Effects on protease inhibition by modifying of helicase residues in hepatitis C virus nonstructural protein 3

This study of the full-length bifunctional nonstructural protein 3 from hepatitis C virus (HCV) has revealed that residues in the helicase domain affect the inhibition of the protease. Two residues (Q526 and H528), apparently located in the interface between the S2 and S4 binding pockets of the substrate binding site of the protease, were selected for modification, and three enzyme variants (Q526A, H528A and H528S) were expressed, purified and characterized. The substitutions resulted in indistinguishable K(m) values and slightly lower k(cat) values compared to the wild-type. The K(i) values for a series of structurally diverse protease inhibitors were affected by the substitutions, with increases or decreases up to 10-fold. The inhibition profiles for H528A and H528S were different, confirming that not only did the removal of the imidazole side chain have an effect, but also that minor differences in the nature of the introduced side chain influenced the characteristics of the enzyme. These results indicate that residues in the helicase domain of nonstructural protein 3 can influence the protease, supporting our hypothesis that full-length hepatitis C virus nonstructural protein 3 should be used for protease inhibitor optimization and characterization. Furthermore, the data suggest that inhibitors can be designed to interact with residues in the helicase domain, potentially leading to more potent and selective compounds.