Microwave-assisted solid-phase synthesis of phthalimides

[reaction: see text] A traceless solid-phase synthesis of substituted phthalimides is proposed. The target compounds are obtained within minutes by a microwave-assisted cyclative cleavage in good yields and excellent purities.     

Ring-closing metathesis approaches for the solid-phase synthesis of cyclic peptoids

Cyclic peptoids were efficiently synthesized on a solid phase in high yields utilizing ring-closing metathesis (RCM). This method should be a valuable tool for easy access to cyclic peptoid libraries and various cyclic compounds.     

Design and facile solid-phase synthesis of conformationally constrained bicyclic peptoids

Triazine-bridged bicyclic peptoids as conformationally constrained peptidomimetics are described. Bicyclic peptoids composed of 6-12 peptoid residues (m, n = 3-6) were synthesized in excellent yields using a highly efficient solid-phase synthetic route.     

Microwave-assisted solid-phase synthesis of hydantoin derivatives

A microwave-assisted synthesis of 3,5- and 1,3,5-substituted hydantoins starting from various resins for solid-phase combinatorial chemistry has been developed. The hydantoins were synthesized from pre-loaded resins with amino acids via treatment with isocyanate or phenylisocyanate and subsequent intramolecular cyclization. Both reactions were performed under microwave irradiation. We studied the cyclative cleavage leading to hydantoin compounds dependent on the nature of the amino acid and the nucleofuge properties of the resin.     

Microwave-assisted solid-phase synthesis of 5-carboxamido-N-acetyltryptamine derivatives

[reaction: see text] The synthesis of the indole skeleton of new melatoninergic analogues was realized using solid-phase methodology in association with microwave irradiation. This combination speeds up the solid-phase drug discovery process in rigorously established conditions.     

Microwave-assisted solid-phase synthesis of pseudopeptides containing reduced amide bond

Procedures were developed for reducing the reaction time and improving the yield of reductive alkylation in solid phase pseudopeptide synthesis by utilizing microwave irradiation. We chose dipeptides containing the reduced amide bond ψ[CH₂NH] as a model system and optimized the microwave assisted reductive alkylation reaction in solid phase pseudopeptide synthesis using Fmoc chemistry. Under the optimized condition, the reductive alkylation reaction used for incorporating the reduced amide bond into the dipeptides was completed in only 8.5 min, whereas the normal reductive alkylation reaction required a total of 300 min. The purity and yield of the various dipeptides containing the reduced amide bond synthesized in this way are better than those achieved using the reductive alkylation method without microwave irradiation. We chose α helical peptides, which are known as a difficult sequence to synthesize, and incorporated the reduced amide bond by the microwave-assisted reductive alkylation reaction. We successfully synthesized pseudopeptides containing the reduced amide bond as a major product by using the novel microwave-assisted method, whereas the same products were obtained as a minor product when using the reductive alkylation method without microwave irradiation.     

Photolithographic synthesis of peptoids

We describe a novel photolithographic approach to the synthesis of peptoids (oligo-N-substituted glycines). This strategy enables the construction of a spatially addressable peptoid microarray, thus providing a potentially powerful tool for the discovery of protein ligands.     

Microwave-assisted, solid-phase synthesis of a chiral 1,2,3,4-tetrahydro-quinoline library

The synergy of a solution-phase preparation of scaffolds with a solid-phase combinatorial synthesis let to develop an efficient route to a small library of chiral, highly functionalized tetrahydroisoquinolines. Both loading on the Merrifield resin and the key acid-catalyzed Pictet-Spengler condensation were efficiently promoted by microwave irradiation. The library was designed such that up to five points of diversity would be potentially introduced, making the strategy in principle suitable for generation of a large number of compounds.     

Microwave-assisted solution- and solid-phase synthesis of 2-amino-4-arylpyrimidine derivatives

An efficient and rapid microwave-assisted solution-phase method for the synthesis of 2-amino-4-arylpyrimidine-5-carboxylic acid derivatives has been developed. The five-step linear protocol involves an initial Biginelli multicomponent reaction leading to dihydropyrimidine-2-thiones which are subsequently S-alkylated with methyl iodide. The resulting 2-methylthiodihydropyrimidines are sequentially oxidized first with manganese dioxide and then with Oxone to provide 2-methylsulfonyl-pyrimidines which serve as excellent precursors for the generation of a variety of 2-substituted pyrimidines via displacement of the reactive sulfonyl group with nitrogen, oxygen, sulfur, and carbon nucleophiles. A modified protocol using a solid-phase method has also been developed.     

Microwave-assisted solid-phase synthesis of 2,5-diketopiperazines: solvent and resin dependence

Solid-phase synthesis of diketopiperazines (DKPs) was preformed using various combinations of resins (polystyrene, TentaGel, ArgoGel, and PEGA) and solvents (toluene, tert-butyl alcohol, water, and toluene/2-butanol (1:4, v/v). The DKPs were synthesized from solid-phase bound dipeptides via intramolecular aminolysis. Both thermal and microwave-assisted solid-phase synthesis of DKPs gave high yields of products independently of resin and organic solvent used; however, only the PEGA resin resulted in high yields of DKPs in water independent of heating method. The short reaction times, high yields, and the possibility to run reactions in water when an appropriate resin is used makes the microwave-assisted solid-phase synthesis the method of choice. The method should be suitable for solid-phase synthesis of diketopiperazine-based libraries.     

Microwave-assisted solid-phase Dötz benzannulation reaction: a facile synthesis of 2,3-disubstituted-1,4-naphthoquinones

A microwave-assisted solid-supported Dötz benzannulation of chromium carbene complexes with various alkynes has been developed. The oxidative cleavage of the resulting resin-bound 1,4-naphthols affords 2,3-disubstituted-1,4-naphthoquinone derivatives in good to moderate yields with high purities.     

微波辅助合成邻羟基苯丁酮

利用微波辅助,以丁酸苯酯为原料,经Fries重排制备了邻羟基苯丁酮.通过单因素实验考察了反应时间、催化剂用量及反应温度对收率的影响,正交实验确定了最优工艺条件.结果表明,当n(催化剂):n(丁酸苯酯)=1.6,反应温度120℃,反应时间8 min时,丁酸苯酯完全转化,邻羟基苯丁酮收率45.0%.     

Microwave-assisted synthesis of corroles

The recently developed Gross's method for the synthesis of corroles has been modified and successfully applied to the preparation of new free base tris-aryl- and tris-pyrimidyl-corroles using solvent-free conditions and microwave irradiation. Compared to conventional heating, the microwave technique afforded an increase in corrole yields of ca. 30% and led to noticeably cleaner reaction mixtures. It is demonstrated that short reaction times and high temperatures are required to afford optimum yields.     

Microwave-assisted synthesis of metalloporphyrazines

The synthesis of metalloporphyrazines with enhanced yields directly from substituted maleonitriles is described. The one-step procedure involves tetramerization using hexamethyldisilazane, p-toluenesulfonic acid and DMF in a sealed tube under microwave irradiation. The reaction time has been drastically reduced from 24 h by classical oil-bath heating to just 15 min.     

Microwave-assisted synthesis of tetrahydroindoles

An efficient synthesis of tetrahydroindoles with different substituents in position 1 is described. Microwave-assisted aminolysis of 4-oxo-4,5,6,7-tetrahydrobenzofuran with different primary amines gives the corresponding tetrahydroindoles in few minutes. All attempts to use microwave dielectric heating to reduce the time required for preparation of 4-oxo-4,5,6,7-tetrahydrobenzofuran, starting from 1,3-cyclohexandione were on the other hand unsuccessful, demonstrating that in some cases, long time conventional heating may be superior to microwaves.     

Submonomer synthesis of peptoids containing trans-inducing N-imino- and N-alkylamino-glycines

The use of hydrazones as a new type of submonomer in peptoid synthesis is described, giving access to peptoid monomers that are structure-inducing. A wide range of hydrazones were found to readily react with α-bromoamides in routine solid phase peptoid submonomer synthesis. Conditions to promote a one-pot cleavage of the peptoid from the resin and reduction to the corresponding N-alkylamino side chains were also identified, and both the N-imino- and N-alkylamino glycine residues were found to favor the trans-amide bond geometry by NMR, X-ray crystallography, and computational analyses.

The use of hydrazones as a new type of submonomer in peptoid synthesis is described, giving access to peptoid monomers that are structure-inducing.     

Microwave-assisted solid-phase organic synthesis (MASPOS) as a key step for an indole library construction

[reaction: see text] Microwave-assisted solid-phase organic synthesis (MASPOS) has been demonstrated to significantly facilitate the Cu(II)- or Pd(II)-mediated ring closure of the resin-bound 2-alkynylanilides. Under microwave irradiation at 200 degrees C [for Cu(OAc)(2), NMP] or 160 degrees C [for Pd(MeCN)(2)Cl(2), THF] for 10 min, 1-acyl-2-alkyl-5-arenesulfamoylindoles were obtained, after cleavage from the resin, in 95-99% purities and in 65-82% overall yields via a 5-step synthetic sequence.     

Microwave-assisted coupling with DIC/HOBt for the synthesis of difficult peptoids and fluorescently labelled peptides—a gentle heat goes a long way

Mild thermal effects (Arrhenius based) achieved with microwave heating proved to be highly successful in enabling rapid and efficient secondary amine couplings and the labelling of peptides with a variety of fluorophores and quenchers in high yields and purities with just traditional, yet robust, HOBt/DIC chemistry.     

Cyclic peptoids

Foldamers are an intriguing family of biomimetic oligomers that exhibit a propensity to adopt stable secondary structures. N-Substituted glycine oligomers, or "peptoids", are a prototypical example of these foldamer systems and are known to form a helix resembling that of polyproline type I. Ongoing studies seek to improve the stability of peptoid folding and to discover new secondary structure motifs. Here, we report that peptoids undergo highly efficient head-to-tail macrocyclization reactions. A diverse array of peptoid sequences from pentamers to 20mers were converted to macrocyclic products within 5 min at room temperature. The introduction of the covalent constraint enhances conformational ordering, allowing for the crystallization of a cyclic peptoid hexamer and octamer. We present the first X-ray crystallographic structures of peptoid hetero-oligomers, revealing that peptoid macrocycles can form a reverse-turn conformation.