Solid-phase synthesis of benzazoles,quinazolines, and quinazolinones using an alkoxyamine linker

An alkoxyamine linker was applied for the solid-phase synthesis of benzazoles, quinazolines, and quinazolinones. Aromatic aldehydes were anchored by aldoxime linkage. After some reactions on a solid support, the products were cleaved with paraformaldehyde under the acidic conditions to afford the corresponding aldehydes, which were subsequently subjected to oxidative coupling with 2-substituted anilines under air atmosphere to give the desired compounds.     

Solid-phase synthesis of benzothiazoles using an alkoxyamine linker

An alkoxyamine linker was applied for the solid-phase synthesis of benzothiazoles. The substrate was anchored by aldoxime linkage and products were cleaved from the solid-support by aldoxime-imine exchange coupled with air-oxidation under the weakly acidic conditions. The tether is highly robust under Mitsunobu reaction, nucleophilic substitution reaction, and Pd-catalyzed reaction conditions.     

The synthesis of acid- and base-labile lipopeptides on solid support

Lipidated peptides, including characteristic partial structures of human Ras proteins, were synthesized by means of a new solid-phase technique in 22-68 % yield. This technique gives access to farnesylated, palmitoylated, and doubly lipidated peptides as methyl esters or carboxylic acids carrying a fluorescent tag or a maleimide moiety for coupling to proteins. The peptide backbones were built up on the resin by using 9-fluorenylmethoxycarbonyl chemistry together with the oxidatively cleavable hydrazide linker. As a key step, the acid-labile farnesyl and basic-labile palmitoyl lipid groups were introduced onto the resin after the cleavage of appropriate acid- or reduction-sensitive protecting groups from the cysteine residues. Optional introduction of different fluorescent tags or a maleimide group into the peptide was followed by release of the resin-bound target peptide as the methyl ester or carboxylic acid by very mild copper(II)-mediated oxidation in slightly acidic or basic media. This new methodology should substantially facilitate the access to lipidated peptides for the study of important biological phenomena like biological signal transduction, localization, and vesicular transport.     

Solid-phase synthesis of neuroactive spider-wasp hybrid toxin analogues using a backbone amide linker

Polyamine toxins isolated from the venoms of spiders and wasps and their synthetic analogues are uncompetitive antagonists of ligand-gated ionotropic receptors in the central- and peripheral nervous systems, and have proved valuable as tools for the investigation of receptor structure and function. In the present letter we describe the efficient solid-phase synthesis (SPS) of novel hybrid toxins using a BAL resin. This strategy enables the bidirectional construction of toxin molecules and has a potential in SPS of chemically diverse libraries of toxin analogues for structure-activity relationship (SAR) studies.     

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.     

Solid-phase synthesis of phthalocyanine and tetraazaporphyrin triangular prisms

A solvent-free, solid-phase one-step reaction between tetra-tert-butylated oxotitanium(IV) phthalocyanine and tetraazaporphyrin with 2,3,6,7,10,11-hexahydroxytriphenylene yields novel azaporphyrin cyclic trimers with triangular prismatic orientations. The fluorescence arising from the phthalocyanine and tetraazaporphyrin chromophores is significantly quenched upon trimerization.     

Solid-phase synthesis of hydroxypiperazine derivatives using phenethylamine linker by oxidation-Cope elimination

A general method is reported for the parallel solid-phase synthesis of hydroxypiperazine derivatives based on the oxidation-Cope elimination of polymer-bound phenethylamine linker with m-CPBA. The key intermediate of phenethylamine N-oxide resins was separable on solid-phase for subsequent β-elimination, from which the desired hydroxypiperazine products could be obtained in high purities and yields without any significant contamination at 90 °C for 2 h. The utility of the methodology for solid-phase synthesis of general hydroxylamines was also investigated using the same linker. The progress of reactions could be monitored on polymer bound intermediates by ATR-FTIR spectroscopy on single bead. The desired products were obtained in good six-step overall yields upon cleavage from the resins and were characterized by LC/MS, ¹H NMR, and ¹³C NMR spectroscopy.     

Development of a new linker for the solid-phase synthesis of N-hydroxylated and N-methylated secondary amines

Merrifield resin was modified by the introduction of an ortho-nitrophenylethanal group that served as a linker moiety to attach amines to the resin by reductive amination. Resin-bound tertiary amines were shown to be readily transferred into the respective liberated N-hydroxylated or N-methylated derivatives by either an oxidation/Cope elimination or a permethylation/Hofmann elimination protocol. With these two divergent liberation/derivatization options, the new resin offers new flexibility in the solid phase synthesis of N-modified secondary amines, for instance in spider toxin synthesis.     

Solid-phase synthesis of isoquinolinones using Bischler-Napieralski cyclization

Isoquinolinone is a structural unit found in many natural products having various important biological activities. A traceless solid-phase synthetic approach has been developed to prepare isoquinolinone derivatives. This approach enables one to synthesize isoquinolinones having various moieties on benzene nuclei and also can produce derivatives with a proton on the amide nitrogen.     

General methodology for solid-phase synthesis of N-alkyl hydroxamic acids

Polymer-supported N-benzyloxy-2-nitrobenzenesulfonamides 1 were N-alkylated using three different routes: via Fukuyama reaction with alcohols, by N-alkylation with alkylbromides, and by Michael addition reaction with α,β-unsaturated carbonyl compounds. The N-alkylated products prepared on the linker 1b were obtained in excellent purity and yield. The 2-nitrobenzenesulfonyl (Nos) group was cleaved under mild conditions to yield polymer-supported N-alkylated benzyloxyamines. Acylation by carboxylic acids and cleavage with TFA yielded N-alkyl hydroxamic acids.     

Solid-phase carbohydrate synthesis via on-bead protecting group chemistry

Di- and tri-saccharides were synthesized on a solid phase. The procedure started with a non-protected sugar linked via either cysteine or glutamine to a polystyrene resin. Selective dimethoxytritylation chemistry and subsequent steps yielded a resin-bound acceptor that could be glycosylated to yield β1,6-linked disaccharides. Reiteration of the procedure produced the trisaccharide.     

Solid-phase synthesis of terminal oligonucleotide-phosphoramidate conjugates

A novel phosphoramidite, N,N-diisopropylamino-2-cyanoethyl-9-anthracenemethyl phosphoramidite 1, was prepared and coupled with the terminal 5′-hydroxyl of support-bound T₁₀ and the putative phosphite triester intermediate was subsequently reacted with iodine in the presence of either water or a series of primary and secondary amines. The reactivity of 1 compared to a previously reported benzyl phosphoramidite 2 was also investigated: oxidation of the product of coupling 2 with CPG-T₁₀-5′OH under aqueous conditions resulted in greater than 30% of the benzyl moiety being retained. In contrast, essentially complete loss of the 9-anthracenemethyl group was observed using 1 under the same conditions. Oligonucleotides modified with a terminal phosphate monoester, lipophilic, fluorescent or cationic groups were thus prepared.     

Solid-phase synthesis of lamellarins Q and O

An efficient solid phase synthesis of the pyrrole-based alkaloids lamellarins Q and O using Merrifield resin and N-protected methyl 3,4-dibromopyrrole-2-carboxylate as a scaffold is described.     

Solid-phase synthesis of metal-complex containing peptides

We report the synthesis of Fmoc protected single amino acid chelates (SAAC) and their metal complexes. The modified amino acids are suitable for solid-phase peptide synthesis. The use of 4-hydroxymethylbenzoic acid AM (HMBA-AM) resin allows the nucleophilic cleavage of the peptide-metal complexes from the resin without decomplexation.     

Solid-phase synthesis of an apoptosis-inducing tetrapeptide mimicking the Smac protein

An approach for the solid-phase synthesis of apoptosis-inducing Smac peptidomimetics is presented. Using a Rink linker strategy, tetrapeptides mimicking the N-4-terminal residue of the Smac protein [(N-Me)AVPF sequence] were synthesized on PEGA resin in excellent purities and yields. Following two synthetic routes, a known tetrapeptide, incorporating a substituted proline, previously shown to exhibit excellent biological activity in vitro as well as low toxicity, was synthesized effectively on a solid support.     

Solid-phase synthesis of head and tail bis-acridinylated peptides

Amino-acridine conjugates play an important role as biochemical probes and/or drugs. Solid-phase synthesis of such compounds suitable for library construction and biological screening is described.     

Solid-phase synthesis of amidines by the reduction of amidoximes

Amidines can be prepared on a solid support by reducing polymer-bound amidoximes with SnCl₂·2H₂O. The method has proved to be straightforward and highly efficient. Amidoximes attached to the solid support are readily available by treating resin-bound nitriles with hydroxylamine.