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.     

Microwave-assisted solid-phase synthesis of peptoids

Microwave irradiation reduces the reaction time for the solid-phase synthesis of peptoids. Under these conditions, coupling of each residue requires only 1 min. The purity and yields of peptoids synthesized in this way are as good as or better than those achieved using standard methods. [reaction: see text]     

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 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.     

Parallel solid-phase synthesis and structural characterization of a library of highly substituted chiral 1,3-oxazolidines

The rapid parallel synthesis and characterization of diverse chirally defined 1,3-oxazolidines is reported. Three diversity elements were incorporated in a 6 x 4 x 4 block approach to generate a 96-member 1,3-oxazolidine library. The synthetic route involved initial attachment of six nonracemic phenylglycidols, (2S,3S)1A-C and (2R,3R)-2A-C, to 2% cross-linked polystyrene resin via a chlorodiethylsilane linker (PS-DES), followed by regio- and stereoselective oxirane ring opening with four primary amines (3a-d). The key condensation reaction between the resulting polymer-bound beta-amino alcohols and four aldehydes (4a-d) was found to occur optimally in warm benzene (60 degrees C) in the presence of anhydrous magnesium sulfate. Cleavage of the oxazolidines from the resin support was achieved with TBAF to give the individual members (2R,4R,5R)-5Aaa-Cdd and (2S,4S,5S)-6Aaa-Cdd in good to excellent yields (51-99%) based on mass recovery. Purities of all these crude products was generally >85% (as measured by LCMS). 1H, 13C NMR, and 1D difference nOe of the library members confirmed the structural and stereochemical integrity of the substituents around the 1,3-oxazolidine core. The asymmetric induction at C-2 (cis or trans to the C-4 substituent) ratio ranged from 4 to I to 49 to 1 across the library. This report highlights the versatility of the 1,3-oxazolidine heterocycle as a scaffold for concise parallel library construction and opens the way for high-throughput screening of such compounds in the biological sphere.     

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 parallel synthesis of a 14-helical beta-peptide library

To facilitate the preparation of beta-peptide libraries in parallel, we have adapted reaction conditions for the solid-phase synthesis of 14-helical beta-peptides for use in a multimode microwave reactor. The low temperature/pressure requirements of microwave-assisted beta-peptide synthesis were found to be compatible with multiwell filter plates composed of polypropylene. Microwave heating of the 96-well plate was sufficiently homogeneous to allow the rapid preparation of a beta-peptide library in acceptable purity.     

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.     

Recent developments in oligosaccharide synthesis: tactics,solid-phase synthesis and library synthesis

Oligosaccharides, commonly found on the cell surfaces, are deeply involved in a variety of important biological functions, yet demanding difficulties synthesizing such structures limit the investigation of their functions. Technologies to chemically synthesize these oligosaccharides have dramatically advanced during the last two decades mainly due to the introduction of good anomeric leaving groups. In addition, tactical analyses have been addressed to enhance the overall efficiency of oligosaccharide synthesis. Based on the advancement of solution-phase chemistry, solid-phase technologies are being investigated in connection with the current trend of combinatorial chemistry and high throughput screening. This review summarizes the necessary solution-phase methodologies, the status of solid-phase synthesis of oligosaccharides, and combinatorial synthesis of oligosaccharide libraries.     

A chiral cyclohexanone linked to polystyrene for solid-phase synthesis of chiral alpha-carbonyls

Two chiral cyclohexanones were linked to polystyrene resin. The polymer-bound auxiliaries were subjected to a sequence of four reactions, the last of which cleaves the desired alpha-chiral carbonyl compound off the resin, concurrently regenerating the resin-bound auxiliary in its original form. The resin can then be reused.     

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 solvent-free synthesis of a quinoline-3,4-dicarboximide library on inorganic solid supports

Inorganic solid supports are useful media for the rapid and efficient synthesis of a library of quinoline-3,4-dicarboximides. In particular, wet clay K10 was shown to be the best medium for the condensation reaction between 2-methylquinoline-3,4-dicarboxylic anhydride and several primary amines. Microwave irradiation is essential for a rapid and complete conversion.     

Combinatorial solid-phase synthesis of 6-hydroxy-1,2,3,4-tetrahydro-beta-carbolines from l-5-hydroxytryptophan

A library of biologically relevant 6-hydroxy-tetrahydro-beta-carbolines (6-OH-THBCs) based on the L-5-OH-tryptophan scaffold was prepared. A solid-phase synthesis was developed, utilizing aminomethyl polystyrene resin and solid-phase-optimized reactions, such as Pictet-Spengler condensation. The library was designed such that three points of diversity would be readily introduced, making the strategy potentially suitable for generation of a large number of compounds.     

The solid-phase synthesis and use of N-monosubstituted piperazines in chemical library synthesis

An efficient solid-phase synthesis of mono-N-substituted piperazines is presented. The key transformation involves a selective borane amide bond reduction in the presence of a carbamate resin linkage. This synthetic route takes advantage of the large diverse pool of commercially available carboxylic acids, acid chlorides, and sulfonyl chlorides. The solid-phase approach facilitates parallel processing by eliminating the need for column chromatography after each synthetic step. The N-monosubstituted piperazines were shown to react with polymeric activated tetrafluorophenol (TFP) reagents to generate arrays of amides and sulfonamides in good purity for biological testing.     

Microwave-assisted parallel synthesis of a 4,6-diamino-2,2-dimethyl-1,2-dihydro-1-phenyl-s-triazine library

Microwave-assisted parallel synthesis of a library of 20 phenyl dihydrotriazines was successfully achieved and compared to an identical library generated by conventional parallel synthesis. Microwave synthesis dramatically decreased reaction times from an average of 22 h to 35 min, and compounds generated using microwave irradiation were purer. Isolated yields of all the compounds were comparable when the two methods were used.     

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.     

A solid-phase, library synthesis of natural-product-like derivatives from an enantiomerically pure tetrahydroquinoline scaffold

With the goal of developing a library synthesis of tetrahydroquinoline-derived natural-product-like small molecules, a practical synthesis of enantiomerically pure tetrahydroquinoline scaffold was achieved. An asymmetric aminohydroxylation reaction was the key step in this strategy. This scaffold was further immobilized onto the solid support for the library generation. The library was obtained from three diversity sites: (i) acylation of the hydroxyl group (R(1)), (ii) coupling of the Fmoc-protected amino acid to the amino group (R(2)), and (iii) amidation of the N-terminal amine group (R(3)).     

Parallel synthesis of a vitamin D(3) library in the solid-phase.

A highly efficient synthesis of the vitamin D(3) system on solid support is described. Two synthetic strategies for the solid-phase synthesis of vitamin D(3) were developed. One is for 11-hydroxy analogues, and the other is for most other synthetic analogues. In the latter strategy, the sulfonate-linked CD-ring 58 was initially immobilized on PS-DES resin to give solid-supported CD-ring 63 (Scheme 10). Similarly, solid-supported CD-ring 63 was prepared by attachment of the CD-ring 10 to the chlorosulfonate resin 64. The vitamin D(3) system was synthesized by Horner-Wadsworth-Emmons reaction of the A-ring phosphine oxide to a solid-supported CD-ring, followed by simultaneous introduction of the side chain and cleavage from resin with a Cu(I)-catalyzed Grignard reagent. Parallel synthesis of the vitamin D(3) analogues was accomplished by a split and pool methodology utilizing radio frequency encoded combinatorial chemistry, and a manual parallel synthesizer for side chain diversification and deprotection. Additionally, we demonstrated the synthesis of various A-rings in a similar protocol for efficient preparation of building blocks.     

Rapid solid-phase syntheses of a peptidic-aminoglycoside library

A library of mono- and di-amino acid peptidic-aminoglycosides (PAs), with kanamycin and neomycin as the model aminoglycosides, was systematically and rapidly synthesized via solid phase peptide synthesis. Aminoglycosides were first converted into N-Boc protected carboxylic acids and fifteen l-amino acids were then used in the diversification of the full library. The approach outlined describes a rapid synthetic procedure where >200?PA compounds can be synthesized in a few months with 85–95% purity. UV thermal denaturation assessed the binding stabilization by PAs to model human and bacterial A-site rRNA sequences. Significant differences were found in thermal melting profiles among PAs that were attributed to specific amino acid sequences. Neomycin PAs lead to a much larger variation in the stabilization of A-site rRNA sequences (ΔT_m?=?2.6–17.1?°C) as compared to kanamycin PAs (ΔTm?=?0.4–4.3?°C). Kanamycin PAs had little activity against Gram-negative and Gram-positive bacteria as compared with neomycin PAs that had significant antibacterial activity with MIC ranging from 2 to 16?μM.