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.     

An improved aldehyde linker for the solid phase synthesis of hindered amides

A novel aldehyde dual-linker system has been developed for the solid phase synthesis of sterically hindered amides. The linker [5-(4-formyl-3-hydroxyphenoxy)pentanoic acid] exploits an intramolecular oxygen-nitrogen acyl transfer mechanism to prepare compounds that are unattainable with current commercially available linkers. A dual linker system, exploiting the hyper-acid labile Sieber amide linker as part of the construct, enabled the initial reductive alkylation reactions of hindered amines and their subsequent acylation with a range of carboxylic acids with varying stereoelectronic properties to be monitored. Simple acylation conditions (HBTU/HOBt/NMM) sufficed to provide near quantitative reaction of test acids with support-bound hindered amines, reaction conditions which failed when commercial linkers were used.     

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.     

An oxidatively-activated safety catch linker for solid phase synthesis

A N-benzyl-4-amino-2,2-dimethylbutanoic acid-based system has been developed as a new oxidatively activated safety catch linker for reaction monitoring and optimisation on solid support. The CAN promoted oxidative debenzylation of the tertiary N-benzylamine moiety, followed by concomitant cyclisation and release of alcohols and amines has been demonstrated both in solution phase model studies and on the solid phase. The linker system has been applied to the solid phase synthesis of a collection of phenol derivatives, and to the demonstration of the attachment and release of a chiral auxiliary from a solid support.     

Solid phase synthesis of peptide aminoalkylamides development and application of new linking agents

A new method for the preparation of peptide aminoalkylamides by solid phase synthesis using a modified Fmoc strategy is described. Key step is the synthesis of compound6 as acid labile linker.     

3-(4-Hydroxymethylphenylsulfanyl)propanoic acid (HMPPA) as a new safety catch linker in solid phase peptide synthesis

A new safety catch linker, 3-(4-hydroxymethylphenylsulfanyl)propanoic acid (HMPPA), is described for use in solid phase peptide synthesis. The linker is readily synthesized from commercially available chemicals in a more cost efficient way compared to similar reported linkers. The HMPPA linker is easily attached to an amino derivatized solid support followed by on-resin oxidation of the thioether to sulfoxide, thereby making the linker very stable towards strong acid treatment. Final resin cleavage is performed by reductive acidolysis.     

A solid-supported,enantioselective synthesis suitable for the rapid preparation of large numbers of diverse structural analogues of (-)-saframycin A

A 10-step solid-supported, enantioselective synthesis suitable for the rapid preparation of large numbers of diverse structural analogues of saframycin A is described. The synthetic route, which bears analogy to solid-phase peptide synthesis, involves the directed condensation of N-protected alpha-amino aldehyde reactants. A novel dual linker was developed for attachment of intermediates to the solid support via a C-protective group, a substituted morpholino nitrile derivative. The route employs a novel diastereospecific cyclorelease mechanism, supports structural variation at multiple sites in the saframycin core, and obviates the need for chromatographic purification of the products or any intermediate. To demonstrate the feasibility of structural variation at multiple sites, a matrix of 16 saframycin A analogues was prepared by parallel synthesis with simultaneous variation of two sites. This work is notable not only as a preliminary step toward large-scale library construction but also as an example of the use of sequential stereoselective C-C bond-forming reactions on the solid phase for the preparation of natural product analogues.     

Reduction of alpha-aryloxy carbonyl compounds with samarium(II) iodide. A new traceless linker for the solid phase synthesis of carbonyl compounds

A new linker for the solid phase synthesis of functionalised carbonyl compounds which is cleaved under mild, neutral conditions using samarium(II) iodide has been developed; the manipulation of an immobilised gamma-butyrolactone has been carried out to illustrate the utility of the linker.     

Enzyme-cleavable linkers for peptide and glycopeptide synthesis

Hydroxymethylphenoxy linkers that are commonly used in solid phase peptide synthesis are surprisingly susceptible to efficient cleavage by the protease chymotrypsin with a broad range of amino acid residues being tolerated at the scissile bond; this enzyme-cleavable linker system has been applied to peptide and glycopeptide synthesis.     

Synthesis of a novel silicon bearing linker for solid phase synthesis

A novel linker for solid phase synthesis is described, which exhibits rapid cleavage under selective, orthogonal conditions, including stability under acidic conditions. The linker incorporates a pyridyl propionate system, with a pendant β-silyl group. Rapid cleavage of the product is effected by elimination of the silyl group on treatment with fluoride. Two systems of this type have been synthesised, and the stability of the linkers has been tested under acidic and basic conditions in solution.     

A solid phase linker strategy for the direct synthesis of EDANS-labelled peptide substrates

A novel linker strategy for the efficient synthesis of peptides C-terminally labelled with the EDANS fluorophore is described. Using this support, FRET peptide substrates bearing EDANS/Dabcyl fluorescent donor/acceptor groups can be readily prepared using standard Fmoc solid phase methods.     

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.     

Optimization of spiroimidazolidinone derivatives synthesis on solid phase using SynPhase™ Lanterns

We report the synthesis of 1,4,8-triazaspiro[4.5]decan-2-one derivatives from N-benzyl-4-piperidone and N-protected amino acid amides on solid support. We have translated the chemistry from solution to solid phase using a backbone amide linker (BAL) mimic. Using a parallel combinatorial approach, we performed the optimization of the synthesis on SynPhase™ Lanterns.     

Combination of solid phase and solution phase synthesis of oligosaccharides using sonication

An approach that combines solid phase and solution phase synthesis of oligosaccharides via the assistance of sonication has been developed. By employing the traceless linker, the designed oligosaccharides can be obtained in pure form and, more importantly, ready for incorporation to aglycons of interest via ‘Click’ chemistry or amide linkage. The overall strategy will facilitate the studies of roles of carbohydrates in bioactive compounds.     

Fmoc solid-phase synthesis of peptide thioesters using an intramolecularn,S-acyl shift

[reaction: see text] We describe the Fmoc solid-phase synthesis of peptide thioesters based on the alkylation of the safety-catch sulfonamide linker with a protected 2-mercaptoethanol derivative. The thioester is generated on the solid phase after the peptide chain assembly as a consequence of an intramolecular N,S-acyl shift. Depending on the stability of the spacer separating the sulfonamide linker from the resin toward TFA, treatment of the peptidyl resin with TFA led to a soluble or supported deprotected thioester.     

An efficient solid phase synthesis of 5'-phosphodiester and phosphoramidate monoester nucleoside analogues

An easy and efficient strategy to obtain libraries of 5'-phosphodiester and 5'-phosphoramidate monoester nucleoside analogues in a highly pure form has been developed, starting from a new nucleoside based solid support. The nucleoside scaffold has been anchored through a 5'-phosphodiester linkage to Tentagel HL resin, functionalized with a 3-chloro-4-hydroxyphenylacetic linker. The solid phase synthesis of small libraries of 5'-phosphodiester and 5'-phosphoramidate monoester thymidine analogues is also reported.     

Diastereofacial solid phase synthesis and self-promoted cleavage of a [2.2.1] bicyclic diversity scaffold

[reaction: see text]. We have previously described a diastereofacially selective 1,3-dipolar cycloaddition reaction of isomünchnones with vinyl ethers. While adapting this methodology for solid phase synthesis, we discovered a chemoselective and self-promoted linker aminolysis that provides liberated product in high purity, at a significantly enhanced rate. Herein we describe the implementation of a chiral auxiliary as a solid-phase linker, the detailed investigation of its unique aminolysis, and the utility of this cleavage within a chemical diversity format.     

Combinatorial chemistry of natural products: Solid phase synthesis of D- and L-cycloserine derivatives

An efficient methodology for a solid phase synthesis of D- and L-cycloserine derivatives is described. Fmoc-D-cycloserine 4 and its L-enantiomer 5 prepared by a selective amine acylation of bis-silylated parent compounds are immobilized on Sasrin or 2-chlorotrityl linker resins using Mitsunobu-type reaction or direct tritylation, respectively. The resulting Fmoc-cycloserine resins 7, 10, and 11 are deprotected with piperidine in DMF or DCM to generate immobilized cycloserine reagents with a primary amino group exposed for various synthetic transformations. An example of the parallel D-cycloserine library synthesis on a reaction plate is described.     

Towards a general solid phase approach for the iterative synthesis of conjugated oligomers using a germanium based linker--first solid phase synthesis of an oligo-(triarylamine)

The development of a germanium-based linker system for the solid phase synthesis (SPS) of 3-(n-hexyl)thiophene oligomers and the first SPS of triarylamine oligomers via iterative chain extension is described. The efficiency of the key steps in the oligomer syntheses and their compatibility with the germanium linker are demonstrated by the SPS of bi-[3-(n-hexyl)thiophene] 19 and ter-(triarylamine) 50. The use of a germanium-based linker in combination with appropriately selected silicon-based blocking/protecting groups allows double coupling to drive the key cross coupling steps to completion hence minimising deletion sequences and also allows for traceless and potentially functionalisative cleavage from the resin. The latter feature has yet to be fully explored but towards this end the first ipso-borodegermylation reaction of a 2-germyl-3-(n-hexyl)thiophene is presented.