New stable backbone linker resins for solid-phase peptide synthesis

[reaction: see text] Two new 4-methoxybenzaldehyde backbone linker resins were developed for the solid-phase synthesis of peptides. The linkers are very stable during the cleavage of common protecting groups for amines (Fmoc, Boc) and carboxylic acids (Me, All, tBu) in peptide synthesis. Cleavage from the resin with refluxing TFA is sufficiently mild for peptides containing polar and nonpolar amino acids.     

Facile, fmoc-compatible solid-phase synthesis of peptide C-terminal thioesters

A short route to peptide C-terminal thioesters was developed that does not require the use of special linkers or resins and is compatible with standard Fmoc chemistry. Following conventional solid-phase peptide synthesis, an excess of Me(2)AlCl and EtSH in dichloromethane cleaves peptides from Wang or Pam resins to give the corresponding thioesters directly in good yield and purity.     

A thermally-cleavable linker for solid-phase synthesis

Oxabicyclo[2.2.1]norbornenes constitute a convenient and readily cleaved linker for solid-phase organic synthesis. A simple and inexpensive furfuryl-substituted resin has been shown to capture and release maleimide dienophiles under conditions compatible with intermediate synthetic steps. The synthesis of β-amino, -thiophenoxy, and -hydrazino alcohols by epoxide ring opening, and maleimide-functionalized Leu-enkephalin by standard peptide coupling techniques, are described to illustrate the utility of the solid-phase synthesis methodology.     

A convenient semicarbazide resin for the solid-phase synthesis of peptide ketones and aldehydes

Use of a semicarbazide resin for the solid-phase preparation of peptide ketones and aldehyde led to optimal results in terms of both purity of the final product and overall yield. This resin was prepared without complication by activation of the commercial available aminomethyl polystyrene with CDI at room temperature, followed by treatment with tert-butyl carbazate. Furthermore, the TNBSA colorimetric assay has been adapted for checking the incorporation of the carbonyl moiety onto hydrazine-based resins.     

THAL, a sterically unhindered linker for the solid-phase synthesis of acid-sensitive protected peptide acids

The 5-(4-hydroxyphenyl)-3,4-ethylenedioxythienyl alcohol (THAL, Thiophene Acid Labile) is described as a new linker for the solid-phase synthesis of peptide carboxylic acids. It is based on the electron-rich 3,4-ethylenedioxythenyl (EDOTn) moiety and allows the obtention of free and tert-butyl-protected peptides by cleavage with 90% and 0.5% TFA, respectively. This very high acid lability makes it useful for the synthesis of sensitive peptides. Free and tert-butyl-protected Leu-enkephalins have been synthesized as models to demonstrate the utility of the linker.     

A nonacid degradable linker for solid-phase synthesis

Synthesis and applications of two new nonacid degradable linkers as an alternative to the Wang linker for solid-phase synthesis are described. Resin from linker 2 looks superior to linker 1 in terms of yields for both anchoring of the first building block and cleavage and in terms of higher purity of the final product. Use of linker 2 avoids side reactions associated with the use of Wang resin due to an undesired cleavage during final acid treatment.     

Development of the traceless phenylhydrazide linker for solid-phase synthesis

The hydrazide group is a new oxidatively cleavable traceless linker for solid-phase chemistry. It can be readily introduced by hydrazide formation between a carboxy-functionalized resin and different substituted hydrazines. In order to achieve high yields in this step, new carboxylic acid resins were developed that are not prone to undesired imide formation upon activation of the carboxylic acid. The polymer-bound acyl hydrazides were successfully employed in various transformations, namely Heck, Suzuki, Sonogashira, and Stille couplings, as well as Wittig and Grignard reactions. Traceless release of the coupling products from the solid support is achieved selectively under mild conditions and in high purity by oxidation of the aryl hydrazides to acyl diazenes with Cu(II) salts or N-bromosuccinimide (NBS) and subsequent nucleophilic attack of the acyl diazene intermediates. Traceless cleavage by oxidation with NBS can be carried out as a two-step process in which stable acyl diazenes are first generated by treatment with NBS in the absence of a nucleophile. After removal of the reagents by simple resin washing, the traceless release is effected by the addition of methanol, which leads to products of high purity without any additional separation steps.     

New selenyl linker for solid-phase synthesis of dehydropeptides

A novel linker possessing selenocyanate and masked carboxylic acid was developed for the solid-phase synthesis of dehydropeptides. This linker was used to demonstrate the synthesis of the model compound of RGD-conjugated dehydropeptide.     

A base-stable dithiomethyl linker for solid-phase synthesis of oligonucleotides

A novel linkage, useful for the synthesis of oligonucleotides is described. The linking function is compatible with all conditions used for oligonucleotide synthesis, orthogonal to all other protecting groups, but regenerates 3′-OH rapidly upon mild reduction under aqueous conditions. This method is employed in the removal of depurinated fragments during the synthesis of oligonucleotides.     

p-Nitromandelic acid as a highly acid-stable safety-catch linker for solid-phase synthesis of peptide and depsipeptide acids

[reaction: see text] p-Nitromandelic acid as a safety-catch linker for Boc/Bzl-SPPS of base-labile compounds like peptides and depsipeptides is described. This linker permits acidic removal of side-chain protection groups from the resin. For cleavage from the solid support, the p-nitro group was reduced with tin(II) chloride. After washing off the reducing agents, the (depsi)peptide acids with or without the side-chain protection schemes were obtained by microwave irradiation at 50 degrees C with 5% TFA in dioxane.     

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.     

A new phenoxyacetate-based linker system for the solid-phase synthesis of oligosaccharides

[structure: see text]. A novel linker system has been designed, and its first application to solid-phase oligosaccharide synthesis is described. The use of the highly reactive o-nitro-phenoxyacetate linker allows a fast and quantitative cleavage using mild basic conditions. This method combined with the trichloroacetimidate glycosylation exhibits highly promising results as demonstrated for the synthesis of tetrasaccharide 1 (n = 3) containing glucose beta(1 --> 4) and beta(1 --> 6) linkages.     

A 'triflate-like' tetrafluoroarylsulfonate linker for multifunctional solid-phase organic synthesis

An arylsulfonate solid-phase linker is suitable for 'traceless' synthesis and Pd(0) catalyzed cross-coupling reactions.     

A fluorinated selenide linker for solid-phase synthesis of n-pentenyl glycosides

[reaction: see text] A fluorine-labeled selenide linker for installing terminal isolated olefins has been synthesized in high overall yield. The resin-bound linker could be glycosylated both with glycosyl trichloroacetimidates and glycosyl fluorides. The linker did not decompose after oxidation with tBuOOH but underwent beta-elimination when it was subjected to heat. This allowed the released n-pentenyl glycoside 15 to be isolated in excellent yield and purity after filtration.     

Use of trichloroacetimidate linker in solid-phase Peptide synthesis

A solid-phase method for the preparation of C-terminal amino-alcohol-containing peptides using activated Wang resin is presented. A diverse set of (fluorenylmethoxy)carbonyl (Fmoc) protected amino alcohols was found to load rapidly and efficiently. The synthetic utility of this approach was demonstrated through the direct synthesis of the peptide drug octreotide with excellent yield and purity. These results suggest that the use of trichloroacetimidate activated resins offers an attractive alternative in the preparation of this class of peptides.     

Continuous-flow solid-phase peptide synthesis

We describe a simple manually operated synthesizer for solid-phase peptide synthesis (SPPS). The synthesis is performed on standard polystyrene-based resin in a flow reactor under low-pressure conditions. The usefulness of the present configuration of SPPS is exemplified on the synthesis of two octapeptide and one decapeptide amides.     

A new safety-catch protecting group and linker for solid-phase synthesis

The use of two derivatives of 2-methoxy-4-methylsulfinylbenzyl alcohol is demonstrated as a safety-catch protecting group and linker for solid-phase peptide synthesis. The protecting group and linker are stable to TFA and are readily removed under reductive acidolytic conditions.