液相组合合成研究进展

综述了近年来液相组合合成的研究进展,主要包括液相组合合成法(LPCS),氟合成,树状载体组合合成及高分子辅助试剂在液相组合合成中的应用等。     

A convergent synthesis of new beta-turn mimics by click chemistry

Alkyne-azide cycloaddition ("click" chemistry) between two peptide strands derivatized with terminal azide and alkyne, respectively, provides an efficient convergent synthesis of triazole ring-based new beta-turn mimics.     

A solution-phase combinatorial synthesis of selective dopamine D4 ligands

Utilizing combinatorial synthesis and a preparative LC-MS automated chromatography system we have prepared and purified a library of 4-[2-(1,2,4-oxadiazolyl)]piperidines that were designed to be novel and selective dopamine D4 ligands. In one round of synthesis we identified N-4-chlorobenzyl-4-[2-(3-(2-thienyl)-1,2, 4-oxadiazolyl)]piperidine with a Kd of 5 nM for the human D4 receptor.     

Development of a solution-phase synthesis of minor groove binding bis-intercalators based on triostin A suitable for combinatorial synthesis

The development of a solution phase synthesis of azatriostin A (2) suitable for the preparation of combinatorial libraries enlisting only liquid-liquid acid/base extractions for the isolation and purification of all intermediates and the final product is disclosed.     

A photoactivated precipiton for reagent sequestration in solution-phase synthesis

Precipitons are molecular phase tags for chemical separations. They can be switched from a high-solubility to a low-solubility state to facilitate product, reagent, or catalyst isolation. This paper presents the first photoactivated precipiton and demonstrates that this precipiton is an efficient amine scavenging agent in solution-phase syntheses of amides, ureas, and imines. This approach to amine scavenging offers advantages over solid-phase scavenging methods. The amine is captured in a homogeneous medium, so the capture is much faster than seen with isocyanate resins, and only a small excess of the scavenger is required.     

Syntheses of second generation, 14-membered ring beta-turn mimics

Efficient solid phase syntheses of the constrained beta-turn peptidomimetics 1-3 were devised, and the conformational properties of three representative compounds in DMSO were determined.     

A two-step sulfurization for efficient solution-phase synthesis of phosphorothioate oligonucleotides

A solution-phase approach for the synthesis of phosphorothioate oligonucleotides that circumvents the use of chromatographic purifications of protected phosphorothioate intermediates was developed. Implementation of a two-step sulfurization protocol in the phosphoramidite method allows efficient isolation of the intermediate phosphorothioates by extractions. The viability of this approach is demonstrated by the synthesis of a hexameric phosphorothioate oligonucleotide fragment.     

Split-pool method for synthesis of solid-state material combinatorial libraries

The synthesis and analysis of inorganic material combinatorial libraries by the split-pool bead method were demonstrated at the proof-of-concept level. Millimeter-size spherical beads of porous gamma-alumina, a commonly used support material for heterogeneous catalysts, were modified with Al(13)O(4)(OH)(24)(H(2)O)(12)(7+) cations in order to promote irreversible adsorption of the anionic fluorescent dyes Cascade Blue, Lucifer Yellow, and Sulforhodamine 101. The compositions of individual beads were easily determined through three split-pool cycles using a conventional fluorescence plate reader. Small split-pool material libraries were made by adsorbing noble metal salts (H(2)PtCl(6), H(2)IrCl(6), and RhCl(3)) into the beads. Analysis of these beads by micro-X-ray fluorescence showed that quantitative adsorption of metal salts without cross-contamination of beads could be achieved at levels (0.3 wt % metal loading) relevant to heterogeneous catalysis. The method offers the potential for synthesis of rather large libraries of inorganic materials through relatively simple benchtop split-pool chemistry.     

An efficient method for solution-phase parallel synthesis of 2-quinoxalinol salen Schiff-base ligands

A solution-phase parallel method for the synthesis of 2-quinoxalinol salen ligands was designed and optimized. The synthesis begins with commercially available 1,5-difluoro-2, 4-dinitrobenzene (DFDNB) and employs a sequence of five straightforward and high-yielding reaction steps. Simple laboratory techniques with low sensitivity to water or air for solution-phase parallel reactions were coupled with convenient workup and purification procedures to give high-purity and yield a small ligand library of 20 compounds. The final step, a Schiff-base condensation of an aldehyde with the diaminoquinoxaline results in a new category of ligands for metal coordination or of potential bioactivity, based on the skeleton 2,2'-(1E,1'E)-(quinoxaline-6,7-diylbis(azan-1-yl-1-ylidene))bis(methan-1-yl-1-ylidene)diphenol. The approach described here is easily adaptable for parallel synthesis of a larger library.     

Synthesis of pipecolic acid-based spiro bicyclic lactam scaffolds as beta-turn mimics

A series of 6.5.5 spiro bicyclic lactam scaffolds were synthesized from pipecolic acid in a sequence of reactions that was initiated with the alpha-allylation of tert-butoxycarbonyl pipecolic acid. Oxidative cleavage of the olefin to give an aldehyde followed by condensation with D-cysteine methyl ester gave a mixture of pipecolyl thiazolidines. Cyclization of the pipecolyl thiazolidines with Mukaiyama's reagent yielded the spiro bicyclic lactams 4a-d. Epimerization of the 7'a bridgehead carbon under acidic conditions was observed for those spiro bicyclic lactam scaffolds with an S stereochemistry at this position. The 6.5.5 spiro bicyclic lactam scaffold with the 3'S,6'R,7'aR stereochemistry mimicked a type II beta-turn, while the scaffold with the 3'S,6'S,7'aR stereochemistry mimicked a right-handed poly-d-proline II helix.     

Fluorous electrophilic scavengers for solution-phase parallel synthesis

A fluorous isatoic anhydride and isocyanate are synthesized and used as scavengers for amines in solution-phase parallel synthesis of urea, thiourea, and β-hydroxyamine analogs. The resulting fluorous derivatives are readily separated from the reaction mixture by solid-phase extractions (SPE) over FluoroFlash™ cartridges to give products with good purity. The SPE cartridges can be reused.     

Directed-sorting method for synthesis of bead-based combinatorial libraries of heterogeneous catalysts

The synthesis and analysis of inorganic material combinatorial libraries by a directed-sorting, split-pool bead method was demonstrated. Directed-sorting, split-pool, metal-loaded libraries were synthesized by adsorbing metal salts (H2PtCl6, SnCl2, CuCl2, and NiCl2) and metal standards (Pt, Cu, Ni in HCl) onto 2-mg porous gamma-alumina beads in 96- or 384-well plates. A matrix algorithm for the synthesis of bead libraries treated each bead as a member of a row or column of a given matrix. Computer simulations and manual tracking of the sorting process were used to assess library diversity. The bead compositions were analyzed by energy-dispersive X-ray spectroscopy, X-ray fluorescence spectroscopy, electron probe microanalysis, inductively coupled plasma atomic emission spectroscopy, and inductively coupled plasma mass spectroscopy. The metal-loaded beads were analyzed by laser-activated membrane introduction mass spectroscopy (LAMIMS) for catalytic activity using methylcyclohexane dehydrogenation to toluene as a probe reaction. The catalytic activity of individual beads that showed minimal (approximately 20% of that of Pt on alumina) to high conversion could be determined semiquantitatively by LAMIMS. This method, therefore, provides an alternative to screening using microreactors for reactors that employ catalysts in the form of beads. The directed-sorting method offers the potential for synthesis of focused libraries of inorganic materials through relatively simple benchtop split-pool chemistry.     

Toward solution-phase automated iterative synthesis: fluorous-tag assisted solution-phase synthesis of linear and branched mannose oligomers

We report herein the first synthesis of linear and branched mannose oligosaccharides using fluorous-tag assistance with reagents and FSPE protocols that are amenable to automation. The particular fluorous linker proved to maintain solubility of the growing oligosaccharide chain such that identical reaction solvent conditions and purification protocols could be used between glycosylation and deprotection reactions, thereby rendering the procedures amenable to automation.     

Plate-to-plate fluorous solid-phase extraction for solution-phase parallel synthesis

A commercially available Argonaut VacMaster-96 plate-to-plate solid-phase extraction (SPE) station equipped with 24 FluoroFlash cartridges is employed for parallel purification of fluorous reaction mixtures. Each cartridge charged with 3 g of fluorous silica gel has the capability to produce up to 100 mg of purified small molecules. The 24-well receiving plate has a standard footprint that can be directly concentrated in a Genevac vacuum centrifuge. Important issues such as sample loading, product cross-contamination, cartridge reuse, and reproducibility are investigated. The SPE system has been demonstrated in the purification of three small libraries that were produced involving amine scavenging reactions with fluorous isatoic anhydride, amide coupling reactions with 2-chloro-4,6-bis[(perfluorohexyl)propyloxy]-1,3,5-triazine (fluorous CDMT), and amide coupling reactions with a newly developed fluorous Mukaiyama condensation reagent.     

Effect of sequence on peptide geometry in 5-tert-butylprolyl type VI beta-turn mimics

The influence of sequence on turn geometry was examined by incorporating (2S,5R)-5-tert-butylproline (5-(t)BuPro) into a series of dipeptides and tetrapeptides. (2S,5R)-5-tert-Butylproline and proline were respectively introduced at the C-terminal residue of N-acetyl dipeptide N'-methylamides 1 and 2. The conformational analysis of these analogues was performed using NMR and CD spectroscopy as well as X-ray diffraction to examine the factors that control the prolyl amide (in this text, the term "prolyl amide" refers to the tertiary amide composed of the pyrrolidine nitrogen of the prolyl residue and the carbonyl of the N-terminal residue) equilibrium and stabilize type VI beta-turn conformation. The high cis-isomer population with aromatic residues N-terminal to proline was shown to result from a stacking interaction between the partial positive charged prolyl amide nitrogen and the aromatic pi-system as seen in the crystal structure of 1c. The effect of sequence on the prolyl amide equilibrium of 5-(t)BuPro-tetrapeptides (Ac-Xaa-Yaa-5-(t)BuPro-Zaa-XMe, 13 and 14) was studied by varying the amino acids at the Xaa, Yaa, and Zaa positions. High (>80%) cis-isomer populations were obtained with alkyl groups at the Xaa position, an aromatic residue at the Yaa position, and either an alanine or a lysine residue at the Zaa position of the 5-(t)BuPro-tetrapeptide methyl esters in water. Tetrapeptides Ac-Ala-Phe-5-(t)BuPro-Zaa-OMe (Zaa = Ala, Lys), 14d and 14f, with high cis-isomer content adopted type VIa beta-turn conformations as shown by their NMR and CD spectra. Although a pattern of amide proton temperature coefficient values indicative of a hairpin geometry was observed in peptides 14d and 14f, the value magnitudes did not indicate strong hydrogen bonding in water.     

Solid-supported synthesis of a peptide beta-turn mimetic

[structure: see text]The solid-supported synthesis of a bicyclic diketopiperazine, a potential peptide beta-turn mimetic, is described. The Ugi reaction between the resin ester of alpha-N-Boc-diaminopropionic acid (an amine input), alpha-bromo acid, aldehyde, and isocyanide is the key step in the proposed protocol.     

Optimization of bivalent glutathione S-transferase inhibitors by combinatorial linker design

Dimeric glutathione S-transferases (GSTs) are pharmacological targets for several diseases, including cancer. Isoform specificity has been difficult to achieve due to their overlapping substrate selectivity. Here we demonstrate the utility of bivalent GST inhibitors and their optimization via combinatorial linker design. A combinatorial library with dipeptide linkers emanating symmetrically from a central scaffold (bis-3,5-aminomethyl benzoic acid, AMAB) to connect two ethacrynic acid moieties was prepared and decoded via iterative deconvolution, against the isoforms GSTA1-1 and GSTP1-1. The library yielded high affinity GSTA1-1 selective inhibitors (70-120-fold selectivity) and with stoichiometry of one inhibitor: one GSTA1-1 dimer. Saturation Transfer Difference (STD) NMR with one of these inhibitors, with linker structure (Asp-Gly-AMAB-Gly-Asp) and K(D) = 42 nM for GSTA1-1, demonstrates that the Asp-Gly linker interacts tightly with GSTA1-1, but not P1-1. H/D exchange mass spectrometry was used to map the protein binding site and indicates that peptides within the intersubunit cleft and in the substrate binding site are protected by inhibitor from solvent exchange. A model is proposed for the binding orientation of the inhibitor, which is consistent with electrostatic complementarity between the protein cleft and inhibitor linker as the source of isoform selectivity and high affinity. The results demonstrate the utility of combinatorial, or "irrational", linker design for optimizing bivalent inhibitors.     

Grafted macroporous polymer monolithic disks: a new format of scavengers for solution-phase combinatorial chemistry

Polyethylene encased porous poly(chloromethylstyrene-co-divinylbenzene) disks have been prepared by polymerization in a cylindrical glass mold and cut to a disk format. Following attachment of a free radical azo initiator 4,4'-azobis(4-cyanovaleric acid) to available functionalities at the surface of the pores, the polymerization of 2-vinyl-4,4-dimethylazlactone was initiated from the surface. To avoid an undesirable increase in flow resistance and to improve the yield of grafting, divinylbenzene was added to the polymerization mixture in order to form a layer of swellable reactive polymer gel within the pores. The use of these disks as scavenging filters to remove various amines from solutions in flow-through operations was demonstrated by effective removal of amines in a very short period of time from their solutions in a variety of solvents, even including alcohols and water.