Silyl Linker Research Articles

Chemical synthesis and biochemical characterization of cyclic oligonucleotides containing acyl groups at both 5′- and 3′-terminal positions

Modified oligonucleotides, whose ON-OFF switch of hybridization can be controlled by an external stimulus, are important to understanding life phenomena and efficient treatment of diseases. The ON-OFF switch can be completely controlled by chemical modification of the oligonucleotide such as cyclization. However, their chemical modifications of the previous cyclic oligonucleotides remain after the addition of an external stimulus. To overcome this problem, we carried out the first synthesis of cyclic oligonucleotides containing acyl groups at both 5′- and 3′-terminal positions, which can be hydrolyzed by intracellular esterase. The cyclic oligonucleotides were successfully synthesized via disulfide bond formation and the phosphoramidite method without base protection on polymer supports containing a silyl linker. Subsequently, we were able to introduce a functional group into the cyclic oligonucleotide using the corresponding isothiocyanate reagent. Additionally, a cyclic oligonucleotide with acyl groups was found to have a much lower binding ability than the corresponding linear oligonucleotide. Moreover, we demonstrated its structural conversion to the corresponding linear oligonucleotide with two thiol groups under reducing conditions using dithiothreitol. It was also confirmed that the two terminal acyl groups of the linear oligonucleotide were hydrolyzed by pig liver esterase. These results indicate that hybridization of cyclic acylated nucleic acid drugs with high nuclease resistance is regulated by intracellular esterase under the reducing conditions in the cell cytoplasm.

Direct Installation of a Silyl Linker on Ready-Made NHC Ligands: Immobilized NHC-Pd Complex for Buchwald–Hartwig Amination

An immobilized N-heterocyclic carbene (NHC)-Pd complex was prepared via direct silyl linker installation onto the imidazole backbone of commercially available 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) ligand. The IPr backbone was lithiated and treated with Me2SiCl2 to afford ClMe2Si-IPr, which reacted with [Pd(π-allyl)Cl]2 to yield a ClMe2Si-IPr-Pd complex, and this was immobilized on Wang resin. The immobilized NHC-Pd complex facilitated quantitative Buchwald–Hartwig amination of aryl chlorides within 10 min, even at a low Pd loading of 0.2 mol %. The catalyst could be removed from the reaction mixture by simple filtration, and Pd leaching into the reaction medium was suppressed to below 1 ppm.

Silane: A new linker for chromophores in dye-sensitised solar cells

A series of ruthenium(II) polypyridyl complexes, with novel silane functionalisation, [Ru(bipy)2(bipy-sil)](PF6)2 (3), [Ru(bipy-sil)2Cl2] (6), and [Ru(bipy-sil)2(NCS)2] (7) have been synthesised and tested as chromophores (dyes) in TiO2 and WO3 based dye-sensitised solar cells (DSSCs). The performance of the respective DSSCs were compared to analogous dyes with ionic carboxylate ([Ru(bipy)2(dcbipy)](PF6)2 (1), [Ru(dcbipy)2Cl2] (4), [Ru(dcbipy)2(NCS)2] (5)) or phosphonate ([Ru(bipy)2(dpipy)](PF6)2 (2)) linking groups. The covalent silane–metal oxide linkage offers much needed improvement to the operating conditions, and lifetime of DSSCs, in terms of pH range and choice of solvent. UV–Vis spectroscopy of the deep-red solutions showed that the bis-bipy-sil complexes absorbed more visible light than the tris-bipy complex, as indicated by the presence of two absorption bands and higher ε values. The UV–Vis spectrum of (3) contained a single broad absorption at 400–600nm with: λmax=457nm; ε=10520±440Lmol−1cm−1, whereas two intense broad absorption bands were observed for novel bis-bipy-sil complexes (6): 340–370nm (λmax(1)=365nm, ε(1)=12716±180Lmol−1cm−1); and 440–540nm (λmax(2)=485nm, ε(2)=11070±150Lmol−1cm−1), and (7): 340–400nm (λmax=371nm, ε(1)=20690±485Lmol−1cm−1), and 460–530nm (λmax=500nm and ε(2)=20750±487Lmol−1cm−1). The bands in (7) being significantly more defined.A 10-fold improvement in the efficiency of the bipy-sil TiO2-based DSSCs was observed from (3) to (6) to (7). This performance was lower than that of the commercial N3 dye, [Ru(dcbipy)2(NCS)2] (5), but the current of (7) on WO3, was comparable to that of the carboxylate system (4). There is considerable potential for further improvement by modification of the silyl linker, reducing the long non-conjugated propyl chain between the amide group and the silatrane (bipy-sil), to a short, conjugated link. During an extensive synthetic study, the most promising strategy was identified as direct linkage, the formation of a direct Si–C bond, using butyllithium with 4,4′-dibromo-2,2′-bipyridine and either trimethylsilane or 1-ethoxysilatrane, provided that the product can be captured and stabilised prior to binding to a metal oxide coated DSSC substrate.

Optimized Fluoride Ions Treatment for Release of Base-Sensitive 2'-O-Modified Oligoribonucleotides from Various Solid Supports

To synthesize oligoribonucleotides containing base-sensitive 2'-O-modifications, we used the Q-linker or a silyl linker anchored to CPG or polystyrene resin. A fluoride ions treatment was optimized to release oligoribonucleotides from the solid-support and to remove TBDMS groups without affecting 2'-O-acyloxymethyl groups.

Efficient synthesis of functionalized oligodeoxyribonucleotides with base-labile groups using a new silyl linker

In this study, we developed new 3′-terminal deoxyribonucleoside-loading reagents 1 with a new silyl-type linker. These reagents could increase the efficiency of introduction of 3′-terminal deoxyribonucleoside components into polymer supports to a level of 17–29 μmol/g. The efficiency was higher than that of previous T-loading reagents because reagents 1 contain a 4-aminobutyryl residue as a spacer. Moreover, we could synthesize not only unmodified DNA oligomers but also a base-labile modified DNA oligomer using resins 9a– d in the activated phosphite method without base protection.

Facile Synthesis of 4-Arylsulfanylcoumarin Library through Reaction of 4-Tosyloxycoumarins with Thiols on Solid Phase

Abstract Diversified 4-arylsulfanylcoumarins were generated under extremely mild conditions on solid phase with a silyl linker based macro-beads by base-promoted reaction of 4-tosyloxycoumarins with thiols.

A simple access to ω-aminoalkyltrialkoxysilanes: Tunable linkers for self-organised organosilicas

A simple route to ω-aminoalkyltriethoxysilanes with variable alkylene chain lengths, (EtO) 3Si(CH 2) n NH 2 ( n = 5, 11) is described. These silyl linkers have been used to prepare urea-based compounds with H-bonding and hydrophobic interactions which enable the self-assembly of the molecules. These molecular precursors are suitable for the obtention of nano-structured hybrid silicas.

An Acid-Stabletert-Butyldiarylsilyl (TBDAS) Linker for Solid-Phase Organic Synthesis

[reaction: see text] A new, robust tert-butyldiarylsilyl (TBDAS) linker has been developed for solid-phase organic synthesis. This linker is stable to both protic and Lewis acidic reaction conditions, overcoming a significant limitation of previously reported silyl linkers. Solid-phase acetal deprotection, olefination, asymmetric allylation, and silyl protecting group deblocking reactions have been demonstrated with TBDAS-linked substrates.

Nanostructuring organo-silicas: combination of intermolecular interactions and molecular recognition properties to generate self-assembled hybrids with phenylene or adenine⋯thymine bridging units

Owing to hydrophobic interactions, silyl linkers containing long alkylene chains allowed the synthesis of self-organised hybrids. Lamellar organo-silicas with phenylene or a hydrogen-bonded adenine⋯thymine complex as the bridging units are reported.

Synthesis of functionalized cyclohexenephosphonates and their inhibitory activity towards bacterial sialidases

We have synthesized a series of cyclohexenephosphonates derived from d- and l-xylose, designed as core structures for the development of high affinity mimics of sialic acid and of the sialidase reaction transition state. Extension of our syntheses to both xylose enantiomers has given us access to two series of cyclohexenephosphonates with regioisomeric double bonds. We have demonstrated the selective functionalization of the hydroxyl groups towards introduction of a glycerol side chain mimic and immobilization via a silyl linker. The inhibitory activity of a selected set of compounds towards three bacterial sialidases has been tested and moderate activity was found.

Novel silyl linkers for solid-phase synthesis

The syntheses of two silyl chloride resins, 2 and 10 are described starting from Merrifield resin, 3-methyl-1,3-butanediol and diphenyldichlorosilane or dimethyldichlorosilane, respectively. The silyl chloride resin 2 was used for the attachment of 1° alcohols, 2° alcohols and phenols to the solid phase. A preliminary study of the stability of the diphenylsiloxane linker towards certain reaction conditions was also carried out. A more reactive silyl chloride resin 10 was found to be suitable for the attachment of 3° alcohols to the solid phase.

Toward the combinatorial synthesis of polyketide libraries: asymmetric aldol reactions with alpha-chiral aldehydes on solid support.

[reaction: see text] The viability of performing stereocontrolled aldol additions with alpha-chiral aldehydes attached by a silyl linker to a hydroxymethylpolystyrene resin is demonstrated for boron and titanium enolates. Subsequent ketone reduction and manipulation on the solid support leads to elaborate stereopentad sequences, as occur in 6-deoxyerythronolide B and discodermolide.

Silyl linker-based approach to the solid-phase synthesis of Fmoc glycopeptide thioesters.

An efficient solid-phase synthesis of Fmoc (glyco)peptide thioesters is described. Fmoc x Ser x OAll and Fmoc x Thr x OAll bound to resin with a silyl ether linker were deallylated by Pd(0) catalysis and condensed with thiophenol, benzyl mercaptane, and ethyl 3-mercaptopropionate by activation with DCC/HOBt. The thioesters were released from the resin either by treatment with CsF-AcOH or by acidic hydrolysis. The effectiveness of this silyl linker strategy is further demonstrated by the synthesis of more complex (glyco)peptide thioesters 25, 26 and 27 involving N-->C and C-->N peptide elongation.

A New Silyl Ether-Type Linker Useful for the Automated Synthesis of Oligonucleotides Having Base-Labile Protective Groups

Abstract A new silyl-type linker for the automated solid-phase synthesis of oligodeoxynucleotides was developed. A hydrosilane-type reagent for introduction of the silyl linker was synthesized in an overall yield of 50% from 1,4-dibromobenzene. By using this linker, an oligonucleotide having base-labile protecting groups could be isolated from the controlled pore glass under neutral conditions.

A new method for the synthesis of oligodeoxyribonucleotides containing 4-N-alkoxycarbonyldeoxycytidine derivatives and their hybridization properties.

Oligodeoxyribonucleotides incorporating 4-N-alkoxycarbonyldeoxycytidine derivatives were synthesized on polystyrene-type ArgoPore resins having a new benzyloxy(diisopropyl)silyl linker, by use of ZnBr(2) as the detritylating agent. The first 3'-terminal thymidine could be attached to the resin by successive in situ reactions of 5'-O-DMTr-thymidine with diisopropylsilanediyl ditriflate and an ArgoPore resin containing hydroxyl groups. The use of this new silanediyl-type linker allowed release of the DNA chain from the resin by treatment with TBAF under neutral conditions. The T(m) experiments apparently showed that incorporation of 4-N-alkoxycarbonyldeoxycytidines into DNA strands resulted in higher hybridization affinity with the complementary DNA strands than that of 4-N-acyldeoxycytidines. In addition, comparable T(m) studies using oligodeoxyribonucleotides incorporating acyl (RC(O)-) groups and alkoxyacyl (RO(CH(2))(n)C(O)-) groups having the same chain length show that the latter tend to exhibit higher T(m) values than the former. It turned out that 4-N-alkoxycarbonyldeoxycytidines can form base pairs not only with deoxyguanosine but also with deoxyadenosine. Based on the ab initio calculations of the hydrogen bond energies of the possible base pairs formed between 4-N-methoxycarbonyl-1-methylcytosine and 9-methyladenine and the NMR analysis of the base-pairs of (15)N-labeled 4-N-alkoxycarbonyldeoxycytidines with deoxyadenosine derivatives, we conclude that the base pair involves two unique hydrogen bonds between the cytosyl 4-NH group and the adenyl N(1) atom and between the O atom of the ester group and the adenyl 6-NH group.

A new silyl linker for reverse-direction solid-phase peptide synthesis

Treatment of a free amino acid ester with CO 2 followed by exposure to a chlorosilane-containing polystyrene results in its attachment to the solid support. The newly formed silyl carbamate can be employed to build polypeptides at the carboxyl terminus. Cleavage of the (poly)peptide using aqueous HF in CH 3CN leads to its free amine form which is isolated as a Boc derivative. The polymer support can be easily recycled.

Optimization study of Sonogashira cross-coupling reaction on high-loading macrobeads using a silyl linker

Two types of Sonogashira reactions were systematically evaluated on silyl linker based high-loading polystyrene macrobeads, this study paves the way for their future application in the combinatorial syntheses of some natural product-like molecules.

Preparation of novel 2-(trialkylsilyl)ethyl linkers and first synthesis of Tryprostatin B on solid phase

Two synthetic methods for novel polymer-supported 2-(trialkylsilyl)ethanol linkers 3 are described. The new silyl linker has been examined as a C-terminal linkage to provide several diketopiperazines. Using this synthetic method, the first solid phase synthesis of Tryprostatin B was accomplished. Several functionalized 2-(trialkylsilyl)ethyl linkers 12– 17 are synthesized from 2-(trialkylsilyl)ethanol linkers. During the course of preparations, the new silyl linkers proved resistant to various reaction conditions such as basic and moderately acidic media, oxidation, and elevated thermal conditions.

A Facile Silyl Linker Strategy for the Solid-Phase Synthesis of Protected Glycopeptide: Synthesis of an N-Terminal Fragment of IL-2 (1–10)

An N-terminal glycodecapeptide fragment of interleukin 2 ( 1) was synthesized by solid-phase method utilizing a new silyl linker. The O-silylated Fmoc–Thr–OAll was attached to the commercial HMP-resin and peptide chain elongation was performed by Fmoc protocol to produce a protected heptapeptide (3–10), which was cleaved from the resin by fluoridolysis and used as the amino component for further condensation on the solid support. On the other hand, 6-hydroxyl group of an Fmoc–Thr(GalNAc)–OAll derivative was silylated with the linker and attached to the resin. Deallylation, block condensation with the heptapeptide (3–10), and elongation at N-terminal with two amino acids were performed on the resin. Fluoride ion-mediated cleavage released the N- and C-protected glycopeptide from the solid support in good efficiency. Fully deprotected glycopeptide was also synthesized through on-resin deallylation and acidic cleavage of the silyl ether linkage.

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.