Solid-phase intermolecular radical reactions 2: synthesis of C-glycopeptide mimetics via a novel acrylate acceptor

[reaction: see text] A novel tetrafluorophenol-linked acrylate is reported as an activated acceptor for intermolecular radical reactions. Addition of alkyl radicals led to pure products in good yields. We include here the first syntheses of C1- and C6-linked glycosides using a solid-phase radical methodology.     

Solid-phase total synthesis of the pentacyclic system lamellarins U and L

[reaction: see text] A total solid-phase synthesis of lamellarins U and L has been achieved. The conversion of an aldehyde group into a formate by a Baeyer-Villiger reaction and a intramolecular [3 + 2] cycloaddition of a 3,4-dihydroisoquinolinium salt over a triple bond comprise the key steps of the process. Each transformation has been controlled with the proper spectroscopic and analytical methods.     

Solid-phase organometallic synthesis

A solid-phase synthesis approach for a class of molybdenum carbonyl complexes has been developed. The system can be used to perform metal-complexation, ligand substitution reactions and oxidative eliminations on the solid phase and to cleave the final complexes under mild and selective conditions. Comparison is made to corresponding soluble complexes and liquid-phase reactions.     

Solid-phase synthesis of beta-mannosides

The linkage of S-phenyl 2,3-di-O-benzyl-alpha-D-thiomannopyranoside to a cross-linked polystyrene support in the form of its 4,6-O-polystyrylborinate ester is described. The activation of this polymer-supported mannosyl donor is achieved at -60 degrees C in dichloromethane in the presence of 2,4,6-tri-tert-butylpyrimidine with the combination 1-benzenesulfinyl piperidine and trifluoromethanesulfonic anhydride. Addition of the donor alcohol at -60 degrees C followed by warming to room temperature and subsequent cleavage from the resin by gentle heating in aqueous acetone yields anomerically pure 2,3-di-O-benzyl-beta-D-mannopyranosides in excellent yield. Successful, diastereoselective coupling is demonstrated with a range of primary, secondary, and tertiary glycosyl acceptors, including typical carbohydrates and threonine derivatives.     

Solid-phase synthesis of isoxazolines

The polymer-supported synthesis of isoxazolines is described via nitrile oxide intermediates, starting from primary nitroalkanes in a one-pot process.     

Solid-phase synthesis of dibenzoxazepinones

Two novel solid-phase routes to the pharmaceutically relevant dibenzoxazepinone nucleus are described. In one, a key cyclisation step involves intramolecular phenolate displacement of an activated aryl fluoride. In the second, the tricyclic nucleus is prepared in solution prior to derivatisation on resin.     

Solid-phase synthesis of DOTA-peptides

A general synthetic route to two DOTA-linked N-Fmoc amino acids (DOTA-F and DOTA-K) is described that allows insertion of DOTA at any endo-position within a peptide sequence. Three model pentapeptides were prepared to test the general utility of these derivatives in solid-phase peptide synthesis. Both DOTA derivatives reacted smoothly by means of standard HBTU activation chemistry to the point of insertion of the DOTA amino acid, but extension of the peptide chain beyond the DOTA-amino acid insertion required the use of pre-activated C-pentafluorophenyl ester N-alpha-Fmoc amino acids. Three Gal-80 binding peptides (12-mers) were then prepared by using this methodology with DOTA positioned either at the N terminus or at one of two different internal positions;the binding of the resulting GdDOTA-12-mers to Gal-80 were compared. The methodology described here allows versatile, controlled introduction of DOTA into any location within a peptide sequence. This provides a potential method for the screening of libraries of DOTA-linked peptides for optimal targeting properties.     

Solid-phase synthesis of solanesol

An efficient and convergent solid-phase strategy for the total synthesis of All- E solanesol is described. This method features avoidance of iterative and difficult purifications comparing with solution-phase synthesis and is suitable for the preparation of other oligoprenols.     

Solid-phase synthesis of fullerene-peptides

The solid-phase synthesis of peptides (SPPS) containing [60]fullerene-functionalized amino acids is reported. A new amino acid, fulleropyrrolidino-glutamic acid (Fgu), is used for the SPPS of a series of analogues of different length based on the natural Leu(5)-Enkephalin and on cationic antimicrobial peptides. These fullero-peptides were prepared on different solid supports to analyze the influence of the resin on the synthesis. Optimized protocols for the coupling and deprotection procedures were determined allowing the synthesis of highly pure peptides in sufficient quantities for evaluation of biological activities. In particular, to avoid side reactions of the fullerene moiety with bases and nucleophiles, the removal of the protecting groups was performed under inert conditions (nitrogen or argon in the dark). We have encountered serious problems with the recovery of the crude compounds, especially when Fgu was inserted in the proximity of the resin core as fullero-peptides tend to remain embedded inside the resin. Eventually, all of the fullero-peptides were easily purified, and the cationic peptides were tested for their antimicrobial activities. They displayed a specific activity against the Gram-positive bacterium S. aureus and also lysed erythrocytes. The availability of a fullero-amino acid easily useable in the SPPS of fullero-peptides may thus open the way to the synthesis of new types of biologically active oligomers.     

Combinatorial solid-phase synthesis of hapalosin mimetics

The solid-phase synthesis of a small library of mimetics of the cyclic depsipeptide hapalosin is described. 3-Amino-4-hydroxy-5-nitrobenzoic acid was anchored through the anilino moiety to a backbone amide linker (BAL) handle support. Using chemoselective reactions and without the need for protecting group manipulations, the benzoic acid group was first amidated, then the aniline nitrogen was acylated, and finally the nitro group was reduced to an amine and acylated or reductively alkylated, to generate a 12-member library.     

Solid-phase synthesis and CD spectroscopic investigations of novel beta-peptides from L-aspartic acid and beta-amino-L-alanine

[structure: see text] A solid-phase synthesis method for the preparation of novel beta3- and beta2-peptides derived from l-aspartic acid and beta-amino-l-alanine, respectively, is described. The methodology allows independent buildup of the beta-peptide backbone and the introduction of sequential side chain substitutions. Representative peptides from the two classes, an amino-substituted beta3-hexapeptide and an acyl-substituted beta2-hexapeptide, have been prepared, and their solution conformation is studied by circular dichroism (CD) spectroscopy.     

Solid-phase synthesis of bicyclic dipeptide mimetics by intramolecular cyclization of alcohols, thiols, amines, and amides with N-acyliminium intermediates

A general strategy for the solid-phase synthesis of structurally diverse bicyclic dipeptide mimetics is presented. Depending on the amino acid side-chain (R(1)), peptide-derived N-acyliminium intermediates may undergo nucleophilic attack from either side-chain functional groups (-OH, -NH(2), -SH, and -CONH(2)) or the amide backbone (-CONH-) of the peptide, thus affording a range of aza-, thia-, and oxabicycloalkanes in excellent purity and diastereoselectivity. [reaction: see text]     

Solid-phase synthesis of nucleoside analogues

The synthesis of a 25 000 member library of nucleoside analogues as discrete compounds in milligram quantities is described. The use of the Nanokan technology developed by IRORI (Discovery Partners International) together with macroporous solid support allowed us to develop a highly reliable and practical synthetic route for the high-throughput derivatization of both the pyrimidine and purine nucleoside scaffold. A 2',3'-acetal linkage of the scaffolds to the solid support proved to be stable enough for the chemical transformations employed, yet labile enough for mild cleavage conditions to yield final products in high purity. The publication represents an example for combining synthetic organic chemistry on advanced scaffolds with the latest technologies of combinatorial chemistry in order to provide both industrial and academic institutions with compounds in high number and quality, thereby accelerating the search for novel biological targets and drug development.     

Solid-phase chemoenzymatic synthesis of C-sialosides

The chemoenzymatic regioselective acylation of Neu5Ac followed by SmI2-mediated C-glycosylation on a solid support is described for five C-glycosides. This method should facilitate the construction of combinatorial libraries of inhibitors of neuraminidase activity and hemagglutinin interaction as potential antiviral agents.     

Solid-phase synthesis of cyclic imides

A cyclative cleavage strategy for the synthesis of cyclic imides on a polystyrene resin is described. After optimization of the cleavage conditions, a small array of succinimides and phthalimides was synthesized. The methodology was then applied to a drug discovery project, in which it was used to synthesize a new class of delta-opioid receptor ligand by both automated and manual methods.     

Solid-phase synthesis of 1,2,4-oxadiazoles

The synthesis of 3,5-substituted 1,2,4-oxadiazoles on solid support is described. Benzoic acids bound to the Wang linker on a polystyrene resin are activated and allowed to react with N-hydroxyamidines. The resulting acylated N-hydroxyamidines are converted into 1,2,4-oxadiazoles at 125°C.     

Solid-phase synthesis of 5-aminotetrazoles

A solid-phase synthesis of 5-aminotetrazoles is described. Resin-bound thioureas were displaced by sodium azide in the presence of HgCl₂ and following nucleophilic cyclization produced the resin-bound products. The desired 5-aminotetrazoles were cleaved from the resin using 95% trifluoroacetic acid in dichloromethane in good yield and purity.     

Solid-phase synthesis of lipidated peptides

A new flexible and efficient methodology for the solid-phase synthesis of lipidated peptides has been developed. The approach is based on the use of previously synthesized building blocks and overcomes the limitations of previously reported methods, since long doubly lipidated peptides can be synthesized by using this route. Furthermore, it was thus possible to prepare a large number of N- and H-Ras peptides bearing a wide range of reporter and/or linking groups--efficient tools for the investigation of biological processes. In terms of efficiency and flexibility this solid-phase method is superior to the solution-phase synthesis. It gives pure peptides in multimilligram amounts within a much shorter time and with superior overall yield.     

Solid-phase synthesis of lipidated peptides

Characteristic partial structures of lipidated proteins embodying different lipid groups as well as additional fluorescent tags or a maleimide for coupling to proteins can be synthesized readily by means of a new solid-phase technique employing the oxidative cleavage of the hydrazide linker as well as on-resin farnesylation and palmitoylation after appropriate deprotection of cysteine thiol groups as the key steps.