Solid-phase synthesis of imidazoquinazolinone derivatives with three-point diversity

A novel imidazoquinazolinone-based tricyclic structure with three-point diversity has been synthesized using solid-phase methodology. The compounds were obtained by treating the amino group of polymer-linked amino acids with 2-nitrobenzaldehyde followed by reduction of the nitro group to an amine. Derivatization of amine with isothiocyanates and cyclization of the resulting thioureas with DIC followed by acidolytic cleavage yielded the desired imidazoquinazolinone based compounds in high purity and moderate to high yield.     

Solid-phase synthesis of indolizidine and quinolizidine derivatives

An efficient method for the construction of simple indolizidine and quinolizidine derivatives on solid support has been developed. An intramolecular tandem Michael reaction initiated by the nucleophilic attack of a suitably placed amino group on the tethered Wittig condensation products between 4- or 5-aminoaldehydes attached to a trityl chloride resin and 4-[(4-methylphenyl)sulfonyl]-1-(triphenylphosphoranylidene)-2-b utanon e is the key step.     

Solid-phase synthesis of monocyclic beta-lactam derivatives

Liquid-phase studies concerning the solid-phase synthesis of monocyclic beta-lactams via the ester-enolate imine condensation route have been conducted utilizing triazene esters 1 and 2 as model compounds. Esters were attached to benzylamine resin 6 by a triazene linker employing the respective diazonium salts. Immobilized ester-enolates 8 and 10 were reacted with various imines and imine precursors to give polymer-bound beta-lactams 14 and 17 in different substitution patterns. Traceless cleavage from the triazene linker yields the desired beta-lactams 16 and 19.     

Solid-phase synthesis of N-substituted 3,4-dihydroquinazolinone derivatives

An efficient solid-phase synthetic approach for the synthesis of N-substituted 3, 4-dihydroquinazolinone derivatives has been developed. Four different 2-nitrobenzoic acids and three different 2-phenylacetyl chlorides were employed in the synthesis of this library. After purification, all products were obtained in good yields.     

Solid-phase synthesis of a library of hydroxyproline derivatives

The synthesis of a library of N-alkylated O-arylated hydroxyproline derivatives has been achieved on solid phase. The choice of O-protection and the optimization of the Mitsunobu reaction involving a secondary alcohol were key to the success of this synthesis. First, acylation of resin-bound amines with N-Fmoc-O-THP-hydroxyproline was accomplished readily. Subsequent deprotection of the Fmoc and reductive amination with different aldehydes resulted in the tertiary amine intermediate. The deprotection of the THP group by p-toluenesulfonic acid was followed by a Mitsunobu reaction with a series of phenols. Finally, the products were cleaved from the resin using trifluoroacetic acid to produce a 10 200 member library.     

Solid-phase synthesis of 1,2-benzophenazine and some fused imidazole derivatives

The solid-phase synthesis of 1,2-benzophenazine and various N-methylbenzimidazoles using o-diaminoarenes is very promising and permits the synthesis of 1-methyl-4,5-[b]naphtho-1H-imidazole, which could not be obtained by the condensation of o-diaminoarenes with paraformaldehyde using the standard liquid-phase method.M. V. Lomonosov Moscow State University, 119899, Moscow, Institute for Synthetic Polymer Materials, 117461, Moscow, and Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 1424432, Moscow Oblast. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 672–674, May, 1996. Original article submitted April 3, 1996.     

Solid-phase combinatorial synthesis of aeruginosin derivatives and their biological evaluation

A 24-member combinatorial library based on the structure of aeruginosin 298-A (1a) was synthesized utilizing solid-phase, and their inhibitory activity against trypsin was evaluated. Among the library, we found that D-Hpla-D-Leu-L-Choi-Agma (1h) is 300 times more potent than the parent natural product 1a.     

Solid-phase synthesis of hydroxysteroid derivatives using the diethylsilyloxy linker

Four different types of hydroxysteroids (primary alcohol, secondary alcohols, and phenol), bearing either an oxirane or an azide as a precursor of molecular diversity, were linked in good yields to solid support using the butyldiethylsilane polystyrene (PS-DES) resin. These molecules were then used as scaffolds to generate hydroxysteroid derivatives containing two levels of diversity. The proposed libraries were tested by running steroidal alcohols through a model sequence of reactions (solid-phase coupling, aminolysis of oxirane or reduction of azide, amidation, and final cleavage). As a result, two linked secondary alcohols (17beta-hydroxy-spiro-3(R)-oxirane-5alpha-androstane and 3beta-hydroxy-spiro- 17(S)-oxirane-5alpha-androstane) and a primary alcohol (spiro-17(S)-oxirane-3-(hydroxymethyl)-1,3,5(10)-estratriene) afforded good overall yields (>45%) and high HPLC purities (>90%) of hydroxysteroids derivatized as alkylamides without purification. One limitation was noted for the fourth library: the phenolic steroid linked by the diethylsilyloxy linker gave a poor overall yield of 8% of the desired model compound. Finally, the diethylsilyloxy linker was used successfully for a rapid solid-phase synthesis of a model library of twenty C19-steroid derivatives (3beta-amido-3alpha-hydroxy-5alpha-androstane-17-ones), with an average yield of 53% and average HPLC purity of 97% without purification steps.     

Solid-phase synthesis of tetrahydro-1,4-benzodiazepine-2-one derivatives as a beta-turn peptidomimetic library

The beta-turn has been implicated as an important conformation for biological recognition of peptides or proteins. We adapted the concept of general Calpha atom positioning from the cluster analysis and recombination of each ideal beta-turn conformation pattern by Garland and Dean (J. Comput.-Aided Mol. Des. 1999, 13, 469) as one strategy of designing non-peptide beta-turn scaffolds. Herein, the Calpha positions of tetrahydro-1,4-benzodiazepin-2-one scaffold were analyzed after the calculation of the low-energy conformer using a semiempirical protocol. Three points of corresponding Calpha carbons for diverse substitutions in the scaffold were designated, and an efficient solid-phase synthesis of the peptidomimetic library was developed. The scaffold itself was synthesized in solution phase starting from 5-hydroxy-2-nitrobenzaldehyde and loaded to the 4-formyl-3,5-dimethoxyphenoxy (PL-FDMP) resin with high efficiency of reductive amination. Various building blocks for the derivatization of the 7-hydroxyl and N-1 amide nitrogen could be introduced via selective alkylation. Cleavage, parallel column chromatography, and NMR analysis of 62 final compounds confirmed the feasibility of this peptidomimetic library synthesis.     

Solid-phase synthesis of 1,5-disubstituted 2-aryliminoimidazolidines

The solid-phase synthesis of 1,5-disubstituted 2-aryliminoimidazolidines, starting from resin-bound N-acylated amino acid amides, is described. Exhaustive reduction of resin-bound acylated amino acid amides with borane-THF afforded the corresponding disecondary amines. Further reaction with arylisothiocyanates in the presence of mercuric chloride (HgCl(2)) yielded the corresponding resin-bound 1,5-disubstituted 2-aryliminoimidazolidines. Cleavage of the product from the resin using HF/anisole (95/5) for 1.5 h at 0 degrees C gave the desired products in good yield and purity. The preparation of a large combinatorial library of such compounds is also discussed.     

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.     

Solid-phase synthesis of new fused tetra, penta and hexacyclic β-carboline derivatives

The parallel synthesis of new fused tetra, penta and hexacyclic β-carbolines via the functionalization of resin-bound tetrahydro-β-carboline derivatives is described. Reduction of the amide bonds and/or nitro group is the key step in the formation of different described fused heterocycles.     

Solid-phase synthesis of naltrindole derivatives using Fischer indole synthesis based on one-pot release and cyclization methodology

[reaction: see text] We describe a new approach for the solid-phase synthesis of indoles 1 that involves a one-pot release and cyclization reaction of a solid-supported hydrazone through a Wang-type linker. Using this solid-phase methodology, we accomplished the synthesis of 40 naltrindole derivatives.     

Solid-phase synthesis and modification of Thiazole Orange and its derivatives and their spectral properties

A new solid-phase synthesis is shown to be effective in the preparation of cyanine dye Thiazole Orange (TO) and its derivatives, which can be obtained as a traceless cleavage of the Merrifield resin method. The influence of different solvents, substitutional groups, introduced to benzothiazole such as chlorine, methyl, and nitro was extensively studied. The changes of the special characteristic and fluorescence intensity of the TO derivatives were described. The phenomenon of the synergetic effect was also depicted after modifying the TO molecule with chitosan oligosaccharide (CTS) at the end of the alkyl, which can effectively improve the sensitivity of the fluorescent probe.     

Solid-phase synthesis of 1-substituted tetrahydroisoquinoline derivatives employing BOC-protected tetrahydroisoquinoline carboxylic acids

Compounds containing the tetrahydroisoquinoline ring system were prepared using solid-supported ester derivatives on a nucleophile-sensitive resin, starting from the corresponding BOC-protected amino acids. The key heterocyclic intermediates were obtained from the Pictet-Spengler reaction between ethyl glyoxylate or methyl 4-formylbenzoate and dopamine or 3-hydroxyphenethylamine. After the resulting amino esters were converted to the BOC derivatives, the phenolic hydroxyl groups were alkylated with a series of alkyl halides to afford the corresponding ethers. Ester hydrolysis afforded the BOC-protected tetrahydroisoquinoline carboxylic acid scaffolds, which were then attached to (4-hydroxyphenyl)sulfide resin (Marshall linker) as the corresponding ester. The BOC group was removed under acidic conditions, and the resulting support-bound amine hydrochlorides were converted to the corresponding amides using a set of carboxylic acids. The support-bound amides were liberated with amines to produce the desired tetrahydroisoquinoline carboxamides. Optimization of the resin loading conditions is described in addition to the identification of impurities observed during the development of the optimum conditions for solid-phase synthesis.     

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.