Solution- and solid-phase syntheses of substituted guanidinocarboxylic acids

A library of guanidine-based compounds was produced to mimic the lead compound 1, which is a substance known to have intensely sweet-taste characteristics. Libraries of guanidinocarboxylic acids were therefore prepared via two synthetic methods. The solid-phase method involving trapping of solution-phase carbodiimides by supported amines was used to produce N,N'-dialkyl derivatives (Scheme 1). The second solid-phase method, featuring supported carbodiimides and solution-phase amines (Scheme 2), was devised to prepare N,N'-disubstituted and N,N',N'-trisubstituted guanidinocarboxylic acids. A small collection of guanadinoacetic acid dimers and trimers was also prepared, but this time via a solution-phase coupling of carbodiimides to a polyamine linker.     

Solution-phase combinatorial libraries: modulating cellular signaling by targeting protein-protein or protein-DNA interactions

The high-throughput synthesis and screening of compound libraries hold tremendous promise for drug discovery and powerful methods for both solid-phase and solution-phase library preparation have been introduced. The question of which approach (solution-phase versus solid-phase) is best for the preparation of chemical libraries has been replaced by which approach is most appropriate for a particular target or screen. Herein we highlight distinctions in the two approaches that might serve as useful considerations at the onset of new programs. This is followed by a more personal account of our own focus on solution-phase techniques for the preparation of libraries designed to modulate cellular signaling by targeting protein-protein or protein-DNA interactions. The screening of our libraries against a prototypical set of extracellular and intracellular targets, using a wide range of assay formats, provided the first small-molecule modulators of the protein-protein interactions studied, and a generalized approach for conducting such studies.     

Biological tuning of synthetic tactics in solid-phase synthesis: application to A beta(1-42)

The beta-amyloid(1-42) sequence has long been recognized as a challenging target for solid-phase peptide synthesis. We found that the known disaggregating role of Met-35 sulfoxide could be capitalized during stepwise solid-phase assembly of the A beta(1-42) peptide chain to mitigate on-resin peptide chain aggregation, a presumed major source of synthetic difficulties. Furthermore, we demonstrate a hitherto-unreported on-resin reduction of the sulfoxide "aggregation protecting group" to allow for standard cleavage protocols, obviating a separate solution-phase sulfoxide reduction step.     

Synthesis of novel substituted 3,8,11-triazaspiro[5,6]dodecan-7-ones

A synthesis of novel substituted 3,8,11-triazaspiro[5,6]dodecan-7-ones using a combination of solution-phase and solid-phase chemistries is described. A solution-phase approach was used to produce a key piperidine intermediate that was then incorporated into a solid-phase synthesis. The combined synthetic strategy was applied to provide a series of substituted 3,8,11-triazaspiro[5,6]dodecan-7-ones in good yield and high purity.     

Parallel synthesis of 3-amino-4H-quinolizin-4-ones, fused 3-amino-4H-pyrimidin-4-ones, and fused 3-amino-2H-pyran-2-ones

On the basis of the enaminone methodology, libraries of 3-amino-4H-quinolizin-4-ones, fused 3-amino-4H-pyrimidin-4-ones, and fused 3-amino-2H-pyran-2-ones were synthesized by the solid-phase and by the solution-phase parallel synthesis. The solution-phase approach turned out to be advantageous over the solid-phase approach. The solution-phase synthesis afforded, in most cases, analytically pure products in high yields, whereas the solid-phase approach gave products in poor yields and in low purity.     

The combined solid/solution-phase synthesis of nitrosamines: the evolution of the "libraries from libraries" concept

The generation of diverse chemical libraries using the "libraries from libraries" concept by combining solid-phase and solution-phase methods is described. The central features of the approaches presented are the use of solid-phase synthesis methods for the generation of a combinatorial polyamine library. Following cleavage from the resin with HF, the polyamine library was reacted with ethyl nitrite in the solution phase to yield the desired nitrosamine library in good yield and purity. The approaches described enable the efficient syntheses of individual nitrosamines as well as mixture-based nitrosamine libraries.     

Dansyl and dabsyl analytical constructs as tools for the accurate estimation of compounds in solid-phase synthesis

The presence of dansyl or dabsyl chromogenic moieties in a solid-phase analytical construct, an assembly of linkers/spacers/sensitizers for improving analytical characterization, allows the accurate estimation of products from solid-phase synthesis by UV detection during liquid chromatography-mass spectrometry analysis in the cleavage solution. The spectroscopic properties of dansylated molecules have been evaluated to verify the "compound-independent UV absorption" necessary for using the chromophore in the accurate estimation. First, measurements on commercial dansylated compounds were made, then a series of construct-like molecules were prepared by solution-phase synthetic procedures and their UV properties were determined. Compound calibration curves were determined, and UV absorption was shown to be both proportional to the compound concentration and compound-independent. An example of a dansyl construct derivative was then prepared on a polymeric matrix, and an accurate estimation using the calibration curves was carried out in the cleavage solution. Good agreement was found between the calculated amount of released compound using the UV calibration curves and the calculated amount using both (1)H NMR and LC/chemiluminescent nitrogen detection quantitative techniques. Preliminary studies using the dabsyl moiety as an improved chromophore with higher wavelength and extinction coefficient are also reported.     

Combined solution-phase and solid-phase synthesis of 2-amino-7,8-dihydropteridin-6(5H)-ones

An efficient and general synthesis of substituted 2-amino-7,8-dihydropteridin-6(5H)-ones using a combination of solution-phase and solid-phase chemistry is described. Solution-phase chemistry was used to produce two pyrimidine regioisomers that were separated by flash column chromatography. Utilizing the desired regioisomer, solid-phase chemistry was used to effect the rapid construction of the substituted 2-amino-7,8-dihydropteridin-6(5H)-one system in high overall yield and purity.     

固载化试剂和催化剂及其在液相组合合成中的应用

固载化试剂、催化剂及清洁树脂在液相合成中的应用, 极大地方便了液相合成的后处理, 提高了工作效率, 为液相平行组合合成提供了基础. 重点综述了近年来固载化试剂和催化剂在液相组合合成及多步液相合成中应用进展情况.     

Rapid synthesis of a glycosylphosphatidylinositol-based malaria vaccine using automated solid-phase oligosaccharide synthesis

Described is an automated synthesis of hexasaccharide malarial toxin 1, currently under development as a malaria vaccine candidate. Using a combination of automated solid-phase methods and solution-phase fragment coupling, the target glycosylphosphatidylinositol was assembled in a matter of days, compared with several weeks for a comparable solution-phase synthesis.     

Combinatorial Chemistry for Ligand Development in Catalysis: Synthesis and Catalysis Screening of Peptidosulfonamide Tweezers on the Solid Phase

On the basis of a pyrrolidine tweezer 1, a library of peptidosulfonamide tweezers (15a-e, 16a-e) was synthesized on the solid phase. This library was screened in a simultaneous substrate screening procedure for the ability to enantioselectively catalyze the Ti(O-i-Pr)(4)-mediated addition of diethylzinc to aldehydes. One of the best solid-phase tweezer catalyst (i.e., 16d, giving an ee of 32% in solid-phase catalysis) was resynthesized in solution (compounds 20 and 21). The now homogeneous solution-phase catalysis showed even better enantioselectivity (i.e., up to 66%).     

Desorption electrospray ionization and electrosonic spray ionization for solid- and solution-phase analysis of industrial polymers

Desorption electrospray ionization (DESI) and electrosonic spray ionization (ESSI), two new techniques, are used to measure average molecular weights and molecular weight distributions of solid-phase and solution-phase samples of the same polymers.     

Mannich型环肽的液相及固相合成比较

为了改善肽化合物的抗酶解能力，首次介绍了3肽Pro-Pro-Tyr分子的非天然环 化反应，其中分别采用液相及固相两种合成方式组装直链肽，再经过分子内 Mannich缩合，得到以Mannich碱为桥连结构的环肽5（产率5.38%)及10（产率72. 7%)。产物结构经氨基酸组分及质谱分析证明。结果表明，固相法环合可以避免分 子间反应，因此产物收率明显高于液相法。     

Preparation of tripeptide-bridged dicatechol ligands and their macrocyclic molybdenum(VI) complexes: fixation of the RGD sequence and the WKY sequence of urotensin ii in a cyclic conformation

Dicatechol ligands were prepared with caprylic acid (6-H(4)) or the naturally occurring RGD (23-H(4)) or WKY sequences (32-H(4)) as spacers. 6-H(4) was prepared by solution-phase amide coupling chemistry, while 16, the precursor of 23-H(4), was obtained by solution-phase and solid-phase preparation. In the latter case, a polystyrene resin with a hydrazine benzoate linker was used as the solid support. The last coupling step was performed simultaneously with cleavage of the peptide from the resin. The protecting groups of 16 were all removed in one step to yield the free ligand 23-H(4). The WKY-bridged derivative 32-H(4) was obtained by a similar solid-phase synthesis followed by deprotection. The reaction of all three ligands with dioxomolybdenum(VI) bis(acetylacetonate) afforded 19-membered metallamacrocycles in which the short peptides are conformationally fixed in a turn-type structure. Hereby, the side-chain functionalities of the peptides do not interfere in the metal complexation.     

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.     

Solution-phase synthesis of branched DNA hybrids based on dimer phosphoramidites and phenolic or nucleosidic cores

Branched oligonucleotides with "CG zippers" as DNA arms assemble into materials from micromolar solutions. Their synthesis has been complicated by low yields in solid-phase syntheses. Here we present a solution-phase synthesis based on phosphoramidites of dimers and phenolic cores that produces six-arm or four-arm hybrids in up to 61% yield. On the level of hybrids, only the final product has to be purified by precipitation or chromatography. A total of five different hybrids were prepared via the solution-phase route, including new hybrid (TCG)(4)TTPA with a tetrakis(triazolylphenyl)adamantane core and trimer DNA arms. The new method is more readily scaled up than solid-phase syntheses, uses no more than 4 equiv of phosphoramidite per phenolic alcohol, and provides routine access to novel materials that assemble via predictable base-pairing interactions.     

Tetrafluoroboric acid, a useful deprotecting reagent in peptide synthesis

We have found that tetrafluoroboric acid (HBF4) in trifluoroacetic acid (TFA) in the presence of thioanisole cleaves various protecting groups currently used in peptide synthesis. HBF4 in TFA cleaves an amino acid amide from 4-methylbenzhydrylamine resin more effectively than trifluoromethanesulfonic acid in TFA. Lamprey gonadotropin-releasing hormone (a 10-residue peptide amide) was synthesized using 1 M HBF4-thioanisole in TFA by both solution-phase and solid-phase methods.     

Synthesis and biological evaluation of a beauveriolide analogue library

Synthesis of beauveriolide III (1b), which is an inhibitor of lipid droplet accumulation in macrophages, was achieved by solid-phase assembly of linear depsipeptide using a 2-chlorotrityl linker followed by solution-phase cyclization. On the basis of this strategy, a combinatorial library of beauveriolide analogues was carried out by radio frequency-encoded combinatorial chemistry. After automated purification using preparative reversed-phase HPLC, the library was tested for inhibitory activity of CE synthesis in macrophages to determine structure-activity relationships of beauveriolides. Among them, we found that diphenyl derivative 7{9,1} is 10 times more potent than 1b.     

High-throughput synthesis of N3-acylated dihydropyrimidines combining microwave-assisted synthesis and scavenging techniques

[reaction: see text] The solution-phase synthesis of N3-acylated dihydropyrimidines was achieved utilizing microwave flash heating both in the synthesis (acylation) and purification (scavenging) steps. Quenching times for excess anhydrides using polystyrene or silica-supported diamine sequestration reagents were reduced from several hours to minutes utilizing microwave irradiation. The use of water as sequestration agent, coupled with an efficient solid-phase extraction workup technique allowed the rapid generation of a 20-member library of N3-acylated dihydropyrimidines.     

Synthesis of a family of cyclic peptide-based anion receptors

We report here the design and synthesis of a family of novel backbone modified cyclic peptides, bearing dipicolylamine side chains for metal complexation and subsequent anion binding studies. Two approaches to the cyclic peptides were investigated. Initially, a stepwise approach was employed, involving solid-phase assembly of oxazole-based building blocks, followed by solution-phase macrolactamisation of the resulting linear precursor. The alternative strategy involved the formation of linear bisoxazole fragments in solution-phase, followed by a cyclodimerisation reaction. The zinc(II) complexes of these receptors bind selectively to di- and tri-phosphate ions over hydrogenphosphate.