Polymer-supported synthesis of regioregular head-to-tail-coupled Oligo(3-arylthiophene)s utilizing a traceless silyl linker

The solid-phase synthesis of regioregular head-to-tail-coupled oligo(3-arylthiophene)s has been achieved in high yield and purity by using a traceless silyl ether linkage. In the first step, the solution-phase synthesis of this class of conjugated oligomers was investigated. Benzyl alcohol was chosen to serve as a mimic for the anchoring group of the hydroxymethyl-substituted polystyrene matrix. The development of a novel regioselective iodination process for silyl-protected thiophenes faciliates the successful application of the solution-phase protocol to the solid phase. Satisfactory loading was obtained by reaction of chlorosilyl-functionalized 3-arylthiophene with hydroxymethyl polystyrene in the presence of imidazole. The suitability of the following iterative halogenation and Suzuki cross-coupling sequence is illustrated by the preparation of a quater(3-arylthiophene), the first regioregular head-to-tail-coupled oligothiophene that is synthesized on solid support. Removal of the conjugated oligomers from the solid support could be effectively achieved by treatment with tetrabutylammonium fluoride.     

Acetylenic scaffolding on solid support: poly(triacetylene)-derived oligomers by Sonogashira and Cadiot-Chodkiewicz-type cross-coupling reactions

We report the first synthesis of poly(triacetylene)-derived oligomers by Pd(0)-catalysed Sonogashira and Cadiot-Chodkiewicz-type cross-coupling reactions on solid support. Oligo(phenylene triacetylene)s, members of a new class of linearly pi-conjugated oligomers with all-carbon backbones, feature very high fluorescence intensities.     

Liquid‐Phase RNA Synthesis by Using Alkyl‐Chain‐Soluble Support

Recent progress in the RNA therapeutics has increased demand for the synthesis of large quantities of oligoribonucleotides. The assembly of RNA oligomers relies mainly on solid‐phase approaches. These allow rapid product purification and the ability to drive a target reaction to completion through the use of excess reagents. Despite the known advantages of solid‐phase synthesis, some issues in the process remain to be addressed, such as low and limited scale, reagent accessibility, and the use of a very large excess of reagents. Herein, we report a highly efficient and practical method of liquid‐phase synthesis of RNA oligomers by using alkyl‐chain‐soluble support. We demonstrate the utility of the liquid‐phase method through 21‐mer RNA synthesis on a gram scale.     

The iterative synthesis of discrete dimethylsiloxane oligomers: A practical guide

Discrete dimethylsiloxane oligomers are interesting building blocks for the synthesis of high χ–low N block co-oligomers (BCOs) forming highly organized nanostructures. Here, a practical guide to the synthesis of molecularly defined oligodimethylsiloxanes (oDMS) from 7-mer to 40-mer via a linear growth strategy is described. The iteration of a hydroxylation reaction and the condensation of mono- or bifunctional hydroxysiloxanes with chloro-octamethyltetrasiloxane results in asymmetric and symmetric siloxanes, respectively. The synthesis contains critical washing and purification steps to remove minor amounts of low and high-molecular weight byproducts, which are detected using Fourier transform infrared spectrometry, gas chromatography–mass spectrometry, and size-exclusion chromatography. The oligomers are obtained on a multigram scale in yields of 94–50% and in high purity with only one molar mass detected. The formation of the chloride, hydroxide or hydride functional groups is adequately analyzed using ²⁹Si NMR spectroscopy. The hydride terminated siloxane oligomers are used in Karstedt catalyzed hydrosilylation reactions with alkene-functional substrates to obtain oDMS-based oligomers and BCOs. Byproduct formation as a result of isomerization and reduction are followed by ¹H NMR spectroscopy and minimized using dry conditions and low-catalyst loadings.     

Some developments in the phosphitetriester method for synthesis of oligonucleotides

1,l-Dimethyl-2,2,2-trichloroethyl has merit as a protecting group for P-O in the phosphite-triester synthesis of oligonucleotides. Use of this group enables one to simplify procedures for preparing active nucleoside phosphorochloridite reagents, to remove oligonucleotide phosphotriester intermediates intact from a solid support, and to conduct block syntheses in solution or on a silica support viaphosphite chemistry. Deprotection can be achieved by warming the trihaloethyl phosphotriesters with tributylphosphine. The high efficiency of the coupling and deprotection reactions for oligomers bound to an insoluble support make this chemistry especially attractive.     

Snthesis of dna fragmenents linked to a solid support

Two simple procedures for the preparation of DNA fragments covalently and specifically linked to a solid support are presented. The first method consists of the preparation of a nucleoside primer which serves as the initiative site for conventional synthesis of oligomers in either 3' or 5' direction. The second procedure involves the direct attachment of independently synthesized and purified oligomers to a functionalized solid support. The accessibility of such supported oligodeoxynucleotides to enzymes is checked with restriction endonucleases.     

Synthesis and characterization of phenolic hydroxyl terminated phenylquinoxaline oligomers

The synthesis of phenylquinoxaline oligomers of predictable molecular weight and with phenolic hydroxyl functional end groups is reported. The synthetic procedure utilizes 4-hydroxybenzil as a substituted monofunctional monomer in a conventional PPQ synthesis to both control molecular weight and introduce the functional end groups. The molecular weights of the oligomers were determined by derivatization of the hydroxyl end groups with 3-(trimethylsilyl)propionyl chloride, followed by ¹H-NMR analysis. Comparison of the integration of the trimethylsilyl resonance to the aromatic resonances allowed calculation of the number average molecular weight. A plot of log(η) vs. log(M_n) correlated well with that reported for high molecular weight PPQ. The end groups influenced the solubility behavior of the oligomers in chlorinated solvents, possibly due to hydrogen bonding. The oligomers were chain-extendable to high molecular weight, confirming their suitability for utilization in copolymerizations to prepare phenylquinoxaline-based block copolymers.     

Selective Synthesis of Oligosaccharides by Mechanochemical Hydrolysis of Chitin over a Carbon-Based Catalyst

Oligosaccharides possess fascinating functions that are applicable in a variety of fields, such as agriculture. However, the selective synthesis of oligosaccharides, especially chitin-oligosaccharides, has remained a challenge. Chitin-oligosaccharides activate the plant immune system, enabling crops to withstand pathogens without harmful agrichemicals. Here, we demonstrate the conversion of chitin to chitin-oligosaccharides using a carbon catalyst with weak acid sites and mechanical milling. The catalyst produces chitin-oligosaccharides with up to 94 % selectivity in good yields. Monte-Carlo simulations indicate that our system preferentially hydrolyzes larger chitin molecules over oligomers, thus providing the desired high selectivity. This unique kinetics is in contrast to the fact that typical catalytic systems rapidly hydrolyze oligomers to monomers. Unlike other materials carbons more strongly adsorb large polysaccharides than small oligomers, which is suitable for the selective synthesis of small oligosaccharides.     

Chemical synthesis of linear ADP-ribose oligomers up to pentamer and their binding to the oncogenic helicase ALC1

ADP-ribosylation is a pivotal post-translational modification that mediates various important cellular processes producing negatively charged biopolymer, poly (ADP-ribose), the functions of which need further elucidation. Toward this end, the availability of well-defined ADP-ribose (ADPr) oligomers in sufficient quantities is a necessity. In this work, we demonstrate the chemical synthesis of linear ADPr oligomers of defined, increasing length using a modified solid phase synthesis method. An advanced phosphoramidite building block temporarily protected with the base sensitive Fm-group was designed and implemented in the repeating pyrophosphate formation via a P(v)–P(iii) coupling procedure on Tentagel solid support. Linear ADPr oligomers up to a pentamer were successfully synthesized and their affinity for the poly-(ADP-ribose)-binding macrodomain of the human oncogenic helicase and chromatin remodeling enzyme ALC1 was determined. Our data reveal a length-dependent binding manner of the nucleic acid, with larger ADPr oligomers exhibiting higher binding enthalpies for ALC1, illustrating how the activity of this molecular machine is gated by PAR.

We report the synthesis of linear ADPr oligomers of defined length up to a pentamer using an improved solid phase method. Binding study with human oncogenic helicase ALC1 shows that ADPr oligomers bind to ALC1 in a length-dependent manner.     

Synthesis of alpha-(2-->5)Neu5Gc oligomers

A facile synthesis of the sialic acid oligomers alpha-(2-->5)Neu5Gc (1) is presented. Monosaccharides 2-4 with suitable functionality were used as the building blocks. After selective removal of the paired carboxyl and amine protecting groups, the fully protected oligomers were assembled through consecutive coupling of the building blocks by well established peptide coupling techniques. By this approach, fully protected oligomers as large as an octasaccharide were synthesized. Deprotection of these fully protected oligomers was conducted in two steps (LiCl in refluxing pyridine and 0.1 n NaOH) to afford the desired products in high yield. Enzymatic degradation of the octamer with neuraminidase, monitored by capillary electrophoresis (CE), was also accomplished. The stepwise exo-cleavage adducts were all well separated and identified in the CE spectrum. The strategy described here for solution-phase synthesis also provides the basis for future solid-phase synthesis of poly-alpha-(2-->5)Neu5Gc.     

Preparation of High‐Loading Polymer Supports by Polymerization Reaction Useful for Oligonucleotide Synthesis

A simple protocol based on polymerization reactions has been developed for the preparation of high‐loading polymer supports, useful for large‐scale synthesis of oligonucleotides. Polymer supports of different pore sizes have been employed in the present investigation to improve the functional‐group density on them. A ten‐ to twelvefold increase in the loading of the functional groups, after the polymerization reaction, has been observed. The support was then used in the subsequent reaction to attach the leader nucleoside to obtain fully functionalized supports 6a – 6c by oligonucleotide synthesis in an automated DNA synthesizer. The aminoalkylated‐supports 5a – 5c were directly employed for the synthesis of oligonucleotide 3′‐phosphates. The oligonucleotides and oligonucleotide 3′‐phosphates synthesized on these supports were compared with the corresponding standard oligomers with respect to their retention time on HPLC. These were further characterized on MALDI‐TOF mass spectrometry.     

The synthesis of functionalized nanoscale molecular rods of defined length

We report a synthetic approach to spiro-ladder oligomers of defined length and structure that form water-soluble molecular rods. We describe the synthesis of a chiral molecular building block 1 and its assembly on solid support to form flexible chains that were then rigidified by the parallel formation of several diketopiperazine rings. Two molecular rods approximately 15 and 25 A in length were synthesized containing three and five monomers, respectively. The molecular rods were easily functionalized on both ends and were shown to have high water solubility, making them compatible with biological buffers. These molecules may find use as scaffolds for the display of ligands in chemical-biology applications and as spacers and construction materials for nanoscience applications.     

Synthesis of Functionalized Glutamine‐ and Asparagine‐Type Peptoids – Scope and Limitations

N‐Alkylated glycine oligomers (‘peptoids’) can serve as potent peptidomimetic systems. Installing different functional groups can often be a challenge, and minimizes yields and purities. Here, we describe the synthesis of different amide‐containing submonomers which were obtained as free bases, as well as their incorporation into peptoids. By using the free amines, the coupling results on solid support could be improved, and various functionalized peptoids were prepared. Additionally, an interesting dimerization side reaction leading to cross‐linked peptoids was observed during synthesis.     

A study on hydrogen bonding in controlled-structure benzoxazine model oligomers

The synthesis procedure for controlled-structure benzoxazine model oligomers is described. To understand the complex hydrogen bonding structure, a series of benzoxazine model oligomers is characterized by nuclear magnetic resonance spectroscopy (NMR), Fourier transform infrared spectroscopy (FT-IR). The NMR resonances for model oligomers are newly assigned. The FT-IR spectra for model benzoxazine oligomers are carefully investigated both in crystalline and solution states. The distribution of hydrogen bonding species in benzoxazine model oligomers is quantitatively analyzed using FT-IR spectra. The cyclic conformations for the oligomers are also proposed.     

Synthesis and characterization of cationic PNA bearing 5-ω-aminopropyl-uracil

5-ω-Aminopropyl-uracil bearing PNA monomers are synthesized for solid phase oligomer synthesis using FMOC protection. Several PNA oligomers with differing amounts of aminopropyluracil modification were prepared. These oligomers were found to associate with complementary DNA oligonucleotides.     

Synthesis and Photopatterning of Fluorene Based Reactive Mesogens

Summary: In this paper we report the synthesis, characterisation and photopatterning of polydisperse fluorene oligomers. The oligomers were synthesised using the Yamamoto coupling. The molecular weights of the oligomers and as a consequence the nematic-isotropic transition temperatures were tailored by an endcapping reaction. With the endcapping species we introduced reactive acrylate functionalities. Subsequent photocrosslinking through a test mask led to the formation of fluorescent microstructures with a resolution of 1 µm.     

Nucleotides,Part LXIX,Synthesis of Phosphoramidite Building Blocks of Isoxanthopterin N8‐(2′‐Deoxy‐β‐D‐ribonucleosides): New Fluorescence Markers for Oligonucleotide Synthesis

The chemical synthesis of isoxanthopterin and 6‐phenylisoxanthopterin N⁸‐(2′‐deoxy‐β‐D ‐ribofuranosyl nucleosides) is described as well as their conversion into suitably protected 3′‐phosphoramidite building blocks to be used as marker molecules for DNA synthesis. Applying the npe/npeoc (=2‐(4‐nitrophenyl)ethyl/[2‐(4‐nitrophenyl)ethoxy]carbonyl) strategy, we used the new building blocks in the preparation of oligonucleotides by an automated solid‐support approach. The hybridization properties of a series of labelled oligomers were studied by UV‐melting techniques. It was found that the newly synthesized markers only slightly interfered with the abilities of the labelled oligomers to form stable duplexes with complementary oligonucleotides.     

Synthesis, characterization, and application of cationic water-soluble oligofluorenes in DNA-hybridization detection

A simple and efficient approach was developed for the synthesis of a series of cationic water-soluble oligofluorenes up to a chain length of a heptamer. Bromoalkyl-substituted fluorenyl boronic esters as the key intermediates were synthesized by using a modified Miyaura reaction. With an increasing number of repeat units (trimer to hexamer), the size-specific oligomers have shown redshifts in both the absorption and emission maxima. The emission maximum reaches the limit for the hexamer in both water and buffer solution. The quantum yields of the oligomers decreased with increased oligomer size in water. Both fluorescence quenching of the oligomers by 9,10-anthraquinone-2,6-disulfonate and the fluorescence resonance energy transfer experiments with the oligomers as the donor and fluorescein (Fl)-labeled double-stranded DNA (dsDNA-Fl) as the acceptor revealed the chain-length-dependent behavior. The Stern-Volmer quenching constant increased with the molecular size, whereas the highest donor-sensitized Fl emission was observed for the hexamer. These size-specific oligomers also served as a model to study the structure-property relationships for cationic polyfluorenes.     

Ring-opening metathesis polymerization (ROMP) of isomerically pure functional monomers and acyclic diene metathesis depolymerization (retro-ADMET) of functionalized polyalkenamers

ROMP and retro-acyclic diene metathesis (ADMET) were used for the synthesis of new functional polymers and functional oligomers, respectively. Purely exo and enantiomerically pure norbornene and 7-oxanorbornene derivatives were prepared using stereospecific synthesis, effective fractionation and high yield condensation reactions. Successful ROMPs of those monomers were performed using either the new carbenic Schrock’s or Grubb’s catalysts or in some cases a classical bicomponent catalyst. New functional polymers such as optically active poly(norbornene-2-carboxylic acid), reactive poly(norbornene-2-azlactone), and side-chain liquid crystal polyoxanorbornenes were fully characterized. On the other hand, successful depolymerizations of 1,4-polyisoprene and of epoxidized 1,4-polybutadiene via cross-metathesis with 4-octene were performed using a stabilized bicomponent catalyst and the Grubb’s catalyst, respectively. Conditions for the controlled synthesis of epoxidized oligobutadienes and of epoxydienic monomers via retro-ADMET were clearly defined.