A new versatile linker for the solid-phase synthesis of secondary amines

A novel linker for the solid-phase synthesis of secondary amines based on an intramolecular cyclization was developed. The linker allows for a stepwise built-up of the secondary amines on the support. The feasibility was demonstrated in the parallel synthesis of a small set of different secondary amines.     

Synthesis of 2,3-disubstituted indole on solid phase by the Fischer indole synthesis

2,3-Disubstituted indoles were synthesized by solid-phase reaction using the Fischer indole synthesis. A "traceless" silicon linker was employed with the silicon-carbon bonding being cleaved with TFA. An oxygen atom was placed into the middle of the spacer/linker so as to enhance solid-phase synthesis by better solvation.     

Wang resin-type linker containing a nitro group for polymer support oligosaccharide synthesis: polymer-supported glycosyl donor

A nitro-introduced Wang resin-type linker for soluble and insoluble polymer support oligosaccharide synthesis is described. The linker was used for connecting glycosyl donors and polymer supports, and was completely stable under the glycosylation conditions tested. The cleavage of the linker was performed under reductive conditions without affecting the protecting groups to release disaccharides.     

Spatial photorelease of oligonucleotides, using a safety-catch photolabile linker

[reaction: see text] We report the development of a safety-catch photolabile linker that allows the light-directed synthesis and spatially selective photorelease of oligonucleotides from microarrays. The linker remains stable to light during DNA synthesis, and is activated for photorelease after acidic hydrolysis. We demonstrate that the photoreleased oligonucleotides can be amplified by PCR to produce double stranded DNA. The advantages offered by this linker could aid the development of an automated gene synthesis platform.     

Design and synthesis of a dual linker for solid phase synthesis of oleanolic acid derivatives

A hydrophilic amino-terminated poly(ethylene glycol)-type dual linker for solid phase synthesis of oleanolic acid derivatives using trityl chloride resin was designed and synthesized for the first time. Model reactions in both liquid and solid phase were performed to show the feasibility of its selective cleavage at two different sites. The biological assay results indicated that the long and flexible alkyl ether functionality in the linker is less likely to be critical for the binding event. Following the successful solid-phase synthesis of model compounds, the potential of this dual linker in reaction monitoring and target identification is deemed worthy of further study.     

Preparation of fluorinated linkers: use of 19F NMR spectroscopy to establish conditions for solid-phase synthesis of pilicide libraries

Three fluorinated linkers which are analogues of linkers commonly used in solid-phase peptide synthesis have been prepared. One of the linkers was used in combination with gel-phase 19F NMR spectroscopy to develop conditions for solid-phase synthesis of two libraries of pilicides, i.e. compounds designed to inhibit assembly of adhesive pili in uropathogenic Escherichia coli. Attachment to and cleavage from the linker could be monitored based on the chemical shift of the fluorine atom of the linker. In addition, use of the linker as internal standard allowed quantification and optimization of reactions occurring further away from the linker when fluorinated building blocks were employed. Importantly, high-quality 19F NMR spectra were obtained for compounds linked to a TentaGel resin in a standard NMR tube using an ordinary NMR instrument.     

The (2-phenyl-2-trimethylsilyl)ethyl-(PTMSEL)-linker in the synthesis of glycopeptide partial structures of complex cell surface glycoproteins

The (2-phenyl-2-trimethylsilyl)ethyl-(PTMSEL) linker represents a novel fluoride-sensitive anchor for the solid-phase synthesis of protected peptides and glycopeptides. Its cleavage is achieved under almost neutral conditions using tetrabutylammonium fluoride trihydrate in dichloromethane thus allowing the construction of complex molecules sensitive to basic and acidic media commonly required for the cleavage of standard linker systems. The advantages of the PTMSEL linker are demonstrated in the synthesis of glycopeptides from the liver intestine (LI)-cadherin and the mucin MUC1, bearing carbohydrate moieties such as N-linked chitobiose or O-linked sialyl-T(N)-residues. The synthesis of these types of glycopeptides is difficult because they are prone to secondary structure formation during the synthesis on the solid phase as well as in the completely deprotected form. Using the PTMSEL linker these molecules are accessible by automated synthesis according to the Fmoc strategy without frequently observed side reactions such as aspartimide or diketopiperazine formation.     

Dual linker with a reference cleavage site for information rich analysis of polymer-supported transformations

Two dual linker systems with specific reference cleavage sites were designed and synthesized to accelerate and simplify development and optimization of reaction conditions for solid-phase synthesis. The dual linker allows simple evaluation of cleavage rate of polymer-supported compounds from the linker and, at the same time, ensures that all resin-bound components are cleaved from the solid support. The dual linker 4 was assembled from two Wang linkers connected by a three carbon spacer. The linker 9 was synthesized using the PAL and HMPB linkers.     

Multistep solid-phase synthesis of an antibiotic and receptor tyrosine kinase inhibitors using the traceless phenylhydrazide linker

The hydrazide group is an oxidatively cleavable traceless linker for solid-phase chemistry. This linker technology was used to develop a multistep solid-phase synthesis of an antibiotic that is active against Mycobacterium tuberculosis. Furthermore, we describe an efficient method for the traceless synthesis of 2-aminothiazoles that display dual inhibitory activity against the receptor tyrosine kinases VEGFR-2 and Tie-2. The synthesis method proceeds through 9 steps on the solid phase and should give access to a much larger library of 2-aminothiazoles, from which a new class of anti-angiogenesis drugs may be developed.     

Evaluation of a new linker system cleaved using samarium(II) iodide. Application in the solid phase synthesis of carbonyl compounds

A new linker design for solid phase synthesis has been developed that is cleaved under mild, neutral conditions using samarium(II) iodide. The feasibility of the linker approach has been illustrated in the solid phase synthesis of ketones and amides using an oxygen linker. Insights into the mechanism of the samarium(II) iodide cleavage reaction are described and the potential of a sequential cleavage carbon-carbon bond forming process is assessed.     

A novel linker for solid-phase synthesis cleavable under neutral conditions

A novel linker cleavable under neutral conditions has been developed for the solid-phase synthesis of base-labile compounds. The linker is comprised of a 3-azidomethyl-4-hydroxybenzyl alcohol moiety, and the azidomethyl group in the linker is readily converted to an aminomethyl group by treatment with a phosphine reagent in the presence of water to result in an intramolecular cyclization to release the compounds. Using the linker, a base-labile dinucleoside methyl phosphate was synthesized on a highly cross-linked polystyrene (HCP) support and cleaved successfully from the resin without decomposition of the product.     

cis-Apa: a practical linker for the microwave-assisted preparation of cyclic pseudopeptides via RCM cyclative cleavage

A new linker cis-5-aminopent-3-enoic acid (cis-Apa) was prepared for the synthesis of cyclic pseudopeptides by cyclization-cleavage by using ring-closing methatesis (RCM). We developed a new synthetic pathway for the preparation of the cis-Apa linker that was tested in the cyclization-cleavage process of different RGD peptide sequences. Different macrocyclic peptidomimetics were prepared by using this integrated microwave-assisted method, showing that the readily available cis-Apa amino acid is well adapted as a linker in the cyclization-cleavage process.     

The use of a detectable,mass-spectrometry-cleavable linker for quality control on an addressable microelectrode array

The synthesis, site-selective placement, and TOF-SIMS cleavage properties of a new, fluorescent linker for attaching molecules to a microelectrode array are reported. The linker was developed to provide a handle for quality control assessment of the microelectrode arrays being used to probe the binding of molecular libraries with biological receptors.     

Library of biphenyl privileged substructures using a safety-catch linker approach

A biphenyl privileged structure library containing three attachment points were synthesized using a catechol-based safety-catch linker strategy. The method requires the attachment of a bromo-acid to the linker, followed by a Pd-catalyzed Suzuki cross-coupling reaction. Further derivatization, activation of the linker with strong acid and aminolysis afforded the respective products in high purity and good overall yield. To show the versatility of the synthesis, a 199-member library was generated. The library samples both conformational and chemical diversity about a well-known privileged substructure.     

A new photocleavable linker in solid-phase chemistry for ether cleavage

We have designed a new linker (1) for the solid-phase synthesis that cleaves ether bonds photolytically. The linker was prepared in nine steps and anchored to the support via an amide bond. Photocleavage is a two-step process in which the immobilized alcohols are released by photolytic generation of a radical that undergoes a spontaneous beta-bond scission. The pivaloyl linker (1) was found to cleave off alcohols in high yields and purities. Only traces of acid (pH approximately 5.5) are necessary for an efficient cleavage.     

Solid-phase synthesis of oligosaccharides and on-resin quantitative monitoring using gated decoupling (13)C NMR

A general strategy for solid-phase oligosaccharide synthesis capable of nondestructive quantitative monitoring has been developed. The synthesis was carried out on TentaGel using thioglycosides as glycosylating agents and dimethylthiomethylsulfonium triflate as the activator. An acylsulfonamide linker was introduced to cleave the oligosaccharide from the resin. The solid-phase reactions were monitored quantitatively by using the inverse gated decoupling technique of (13)C NMR, where two (13)C-enriched markers were used to monitor the reactions: one was (13)C-enriched glycine incorporated as a part of the linker and as an internal standard, and the other was a (13)C-enriched acetyl group used as a protecting group of the glycosylation reagent. A representative synthesis of sialyl Lewis X branched tetrasaccharide was demonstrated.     

Design, synthesis, and validation of a branched flexible linker for bioactive peptides

A branched flexible linker that incorporates a fluorescent dansyl moiety was synthesized and used to connect two high affinity NDP-alpha-MSH ligands or two low affinity MSH(4) ligands. The linker was incorporated into the conjugate by solid-phase synthesis. In vitro biological evaluations showed that potency of binding to the human melanocortin 4 receptor was not diminished for linker-ligand combinations relative to the corresponding ligand alone.     

Solid-phase synthesis of imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines

The synthesis of imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine derivatives by condensation between an α-bromoketone bound to solid support and various 2-aminopyridine or 2-aminopyrimidine derivatives was described. Either an acid labile linker or a base labile linker was used in this study.     

A novel solid-phase linker strategy for the side-chain anchoring of arginine: an expeditious route to arginine 7-amido-4-methylcoumarins

A novel linker strategy for the efficient side-chain anchoring of arginine is described. The utility of this approach was demonstrated by the facile synthesis of arginine-specific fluorogenic peptide substrates by standard Fmoc solid phase peptide synthesis methods.     

Solid-phase approach to tetrahydroquinolones using a sulfur linker cleaved by SmI2

[reaction: see text] A sulfur alpha-heteroatom-substituted carbonyl (HASC) linker has been utilized in a solid-phase approach to tetrahydroquinolones. The route illustrates the compatibility of the linker system with palladium-catalyzed transformations and its utility for library synthesis. The linker is cleaved by electron transfer from samarium(II) iodide.