This report describes a new four-component synthesis of substituted and spiro-conjugated 6-amino-2H,4H-pyrano[2,3-c]pyrazol-5-carbonitriles directly from aromatic aldehydes or heterocyclic ketones, malononitrile, beta-ke...This report describes a new four-component synthesis of substituted and spiro-conjugated 6-amino-2H,4H-pyrano[2,3-c]pyrazol-5-carbonitriles directly from aromatic aldehydes or heterocyclic ketones, malononitrile, beta-ketoesters, and hydrazine hydrate. The method provides a convenient one-pot route toward divers 2,4-dihydropyrano[2,3-c]pyrazoles, whereas a modified one-step sequential protocol gives access to spiro[indoline-3,4'-pyrano[2,3-c]pyrazol]-2-ones.
Cyanoacetic acid derivatives are the starting materials for a plethora of multicomponent reaction (MCR) scaffolds. However the diversity of these scaffolds is hampered by the low variability of the cyanoacetic acid deriv...Cyanoacetic acid derivatives are the starting materials for a plethora of multicomponent reaction (MCR) scaffolds. However the diversity of these scaffolds is hampered by the low variability of the cyanoacetic acid derivatives in the past. Here we describe valuable protocols for the parallel synthesis of arrays of cyanoacetamides on a multigram scale and involving very convenient work up by simple filtration and washing. Fifty-two products are described, and several applications are indicated. We foresee our protocol and the resulting derivatives to become very valuable to greatly expanding the large MCR scaffold space of cyanoacetic acid derivatives.
CuX(2)-mediated cyclization of 2-alkynylbenzaldehyde O-methyl oximes in N,N-dimethylacetamide (DMA) gave rise to 4-chloroisoquinolines in good yield, which underwent the palladium-catalyzed cross-coupling reactions of ar...CuX(2)-mediated cyclization of 2-alkynylbenzaldehyde O-methyl oximes in N,N-dimethylacetamide (DMA) gave rise to 4-chloroisoquinolines in good yield, which underwent the palladium-catalyzed cross-coupling reactions of arylboronic acids subsequently to afford the functionalized isoquinolines.
A series of new heterocyclic compounds, involving pyrimido[4,5-b][1,6]-, benzo[b][1,6]-, pyrazolo[3,4-b][1,6]naphthyridine, and aza-benzo[b]fluorene skeletons were successfully synthesized via the reaction of structurall...A series of new heterocyclic compounds, involving pyrimido[4,5-b][1,6]-, benzo[b][1,6]-, pyrazolo[3,4-b][1,6]naphthyridine, and aza-benzo[b]fluorene skeletons were successfully synthesized via the reaction of structurally diverse 3,5-dibenzylidenepiperidin-4-one with various enamine-likes (2,6-diaminopyrimidin-4(3H)-one, 3-amino-5,5-dimethylcyclohex-2-enone, 3-methyl-1-phenyl-1H-pyrazol-5-amine and 1H-benzo[d]imidazol-2-amine) in glycol under microwave irradiation. This method has the advantages of short synthetic route, operational simplicity, and increased safety for small-scale fast synthesis for biomedical screening.
An efficient reagent-controlled approach for the regiospecific synthesis of new 2,2'-bipyridine derivatives in high-temperature water via microwave-assisted multicomponent reactions of aldehydes, 3-aryl-3-oxopropanenitri...An efficient reagent-controlled approach for the regiospecific synthesis of new 2,2'-bipyridine derivatives in high-temperature water via microwave-assisted multicomponent reactions of aldehydes, 3-aryl-3-oxopropanenitrile, 2-acetylpyridine, and ammonium acetate is reported. Furthermore, aromatic aldehydes reacted with 1,2-diphenylethanone, resulting in structurally complex penta-arylpyridines. This chemistry provides an efficient and promising synthetic strategy to diversity-oriented construct poly arylpyridine skeleton.
A versatile combinatorial approach was developed for the rapid synthesis of 2-pyridones, 1,4-diazepines, and 1,4-oxazepines libraries. The synthetic strategy includes electrophilic addition, nucleophilic substitution, am...A versatile combinatorial approach was developed for the rapid synthesis of 2-pyridones, 1,4-diazepines, and 1,4-oxazepines libraries. The synthetic strategy includes electrophilic addition, nucleophilic substitution, amine-acid condensation, Dieckmann condensation, lactamization, ester hydrolysis, lactonization, and oxidation-elimination.
Combinatorial methods have been developed to study the phase behavior of biodegradable polyanhydrides for drug delivery applications. The polyanhydrides of interest are poly[1,6-bis(p-carboxyphenoxy) hexane] (CPH) and po...Combinatorial methods have been developed to study the phase behavior of biodegradable polyanhydrides for drug delivery applications. The polyanhydrides of interest are poly[1,6-bis(p-carboxyphenoxy) hexane] (CPH) and poly[sebacic anhydride] (SA). Both continuous and discrete polymer blend libraries were fabricated by using a combination of solution-based gradient deposition and rapid prototyping. Blend compositions were characterized via a high throughput transmission Fourier transform infrared (FTIR) sampling technique and compared against theoretical mass balance predictions. To obtain phase diagrams of CPH/SA, the effect of blend composition and annealing temperature on the miscibility of the blend was studied. This gradient library was observed with optical microscopy in order to determine cloud points. These results were compared with a theoretical phase diagram obtained from Flory-Huggins theory and with atomic force microscopy (AFM) experiments on blend libraries and the agreement between the methods was very good. The high throughput method demonstrates that the CPH/SA system exhibits upper critical solution temperature behavior. These libraries are amenable to other high throughput applications in biomaterials science including cell viability, cell activation, and protein/biomaterial interactions.
Polymer-supported alpha-acylamino ketones were transformed to seven types of structurally unrelated heterocyclic compounds. Syntheses involved variety of chemical routes and comprised diverse chemistries (C-C, C=C, C-N,...Polymer-supported alpha-acylamino ketones were transformed to seven types of structurally unrelated heterocyclic compounds. Syntheses involved variety of chemical routes and comprised diverse chemistries (C-C, C=C, C-N, C=N, and C-O bond formations). Different sizes of heterocycles (4-, 5-, 6-, and 7-membered rings) were prepared, including dihydro-pyrrol-2-ones, pyrazin-2-ones, dihydro-triazepin-6-ones, morpholin-3-ones, imidazoles, beta-lactams, and isoquinolin-1-ones. Further elaboration to fused ring systems was also documented.
Two different approaches were employed to study solid phase random glycosylations to obtain oligosaccharide libraries. In approach I, Wang resin esters were attached to the acceptors structures. Following their glycosyla...Two different approaches were employed to study solid phase random glycosylations to obtain oligosaccharide libraries. In approach I, Wang resin esters were attached to the acceptors structures. Following their glycosylation and resin cleavage, the peracetylated components of the oligosaccharide libraries were characterized. In approach II, polymer-linked donor components could be employed and processed correspondingly. Approach I proved to be superior regarding yield and versatility of products and also allowed the formation of higher oligomers.
C-5 arylated 2/9-substituted pyrimido[5,4-b]indolizines were synthesized via palladium-catalyzed direct arylation. A variety of substituents on both pyrimido[5,4-b]indolizines and aryl/heteroaryl bromides are tolerated,...C-5 arylated 2/9-substituted pyrimido[5,4-b]indolizines were synthesized via palladium-catalyzed direct arylation. A variety of substituents on both pyrimido[5,4-b]indolizines and aryl/heteroaryl bromides are tolerated, providing rapid access to substituted pyrimido[5,4-b]indolizines in good to excellent yields.
A series of new functionalized thiochromeno[2,3-b]pyridine derivatives have been synthesized via a sequence of Knoevenagel condensation, Michael addition, cyclization, and intramolecular nucleophilic substitution, which...A series of new functionalized thiochromeno[2,3-b]pyridine derivatives have been synthesized via a sequence of Knoevenagel condensation, Michael addition, cyclization, and intramolecular nucleophilic substitution, which is first catalyzed by KF/neutral Al(2)O(3) cooperated with PEG 6000 under microwave irradiation. Experimental results indicated that among the catalysts tested, KF/ neutral Al(2)O(3) with PEG 6000 exhibits the best catalytic activity, which leads to a substantial improvement in the overall yield and purity of the desired final products and significantly shorter reaction time.
A simple and straightforward methodology toward the synthesis of novel 4,5-biphenyl-2-pyrimidinylguanidine compounds has been developed by one-pot reaction of biguaninde or dimethyldiguanide with isoflavones. A series of...A simple and straightforward methodology toward the synthesis of novel 4,5-biphenyl-2-pyrimidinylguanidine compounds has been developed by one-pot reaction of biguaninde or dimethyldiguanide with isoflavones. A series of 20 new compounds was reported. All of them were characterized by FT-IR, NMR, and elemental analysis. A typical compound was determined by X-ray diffraction. A variety of substrates can participate in the process with good yields and high purities, making this methodology suitable for library synthesis in drug discovery.
Solid phase combinatorial chemistry provides fast and cost-effective access to large bead based libraries with compound numbers easily exceeding tens of thousands of compounds. Incubating one-bead one-compound library be...Solid phase combinatorial chemistry provides fast and cost-effective access to large bead based libraries with compound numbers easily exceeding tens of thousands of compounds. Incubating one-bead one-compound library beads with fluorescently labeled target proteins and identifying and isolating the beads which contain a bound target protein, potentially represents one of the most powerful generic primary high throughput screening formats. On-bead screening (OBS) based on this detection principle can be carried out with limited automation. Often hit bead detection, i.e. recognizing beads with a fluorescently labeled protein bound to the compound on the bead, relies on eye-inspection under a wide-field microscope. Using low resolution detection techniques, the identification of hit beads and their ranking is limited by a low fluorescence signal intensity and varying levels of the library beads' autofluorescence. To exploit the full potential of an OBS process, reliable methods for both automated quantitative detection of hit beads and their subsequent isolation are needed. In a joint collaborative effort with Evotec Technologies (now Perkin-Elmer Cellular Technologies Germany GmbH), we have built two confocal bead scanner and picker platforms PS02 and a high-speed variant PS04 dedicated to automated high resolution OBS. The PS0X instruments combine fully automated confocal large area scanning of a bead monolayer at the bottom of standard MTP plates with semiautomated isolation of individual hit beads via hydraulic-driven picker capillaries. The quantification of fluorescence intensities with high spatial resolution in the equatorial plane of each bead allows for a reliable discrimination between entirely bright autofluorescent beads and real hit beads which exhibit an increased fluorescence signal at the outer few micrometers of the bead. The achieved screening speed of up to 200,000 bead assayed in less than 7 h and the picking time of approximately 1 bead/min allow exploitation of one-bead one-compound libraries with high sensitivity, accuracy, and speed.
A sequential one-pot two-step tandem reaction for efficient synthesis of polysubstituted cyclopropanes has been developed. The three-component reaction of alpha-halogenated methylene compounds, aromatic aldehydes, and ac...A sequential one-pot two-step tandem reaction for efficient synthesis of polysubstituted cyclopropanes has been developed. The three-component reaction of alpha-halogenated methylene compounds, aromatic aldehydes, and acetonitrile derivatives produced first the intermediates pyridinium salts and electron-deficient olefins, followed by cyclopropanation of pyridinium ylide with electron-deficient olefins in situ to afford polysubstituted cyclopropanes. Target compounds were obtained in high yields and were diastereomerically pure after recrystallization.
Porous and rigid methacrylic Synbeads were optimized and applied efficiently to the solid phase peptide synthesis with the objective of improving significantly volumetric yields (0.33 mol/L calculated on the basis of max...Porous and rigid methacrylic Synbeads were optimized and applied efficiently to the solid phase peptide synthesis with the objective of improving significantly volumetric yields (0.33 mol/L calculated on the basis of maximum chemical accessibility, i.e. the maximum number of functional groups that can be acylated by FmocCl) as compared to swelling commercial polymers (from 0.06 to 0.12 mol/L). The effects of the density of functional groups and spacer length were investigated obtaining a chemical accessibility of the functional groups up to 1 mmol/g(dry). High resolution magic angle spinning (HR-MAS) was exploited to evidence the presence of "solution-like" flexible linkers anchored on the rigid methacrylic backbone of Synbeads and to study the degree of functionalization by the Wang linker. To demonstrate the efficiency of the optimized Synbeads, the peptides Somatostatin and Terlipressin were synthesized. In the case of Somatostatin, final synthetic yields of 45 and 60% were achieved by following the HCTU/DIPEA and DIC/HOBt routes respectively, with the HPLC purity always higher than 83%. In the case of Terlipressin, the synthesis was carried out in parallel on Synbeads and also on TentaGel, ChemMatrix, and PS-DVB for comparison (DIC/HOBt route). The profiles describing the synthetic efficiency demonstrated that Synbeads leads to synthetic efficiency (86%) comparable to PS-DVB (96%) or ChemMatrix (84%). In order to gain a more precise picture of chemical and morphological features of Synbeads, their matrix was also characterized by exploiting innovative approaches based on FTIR microspectroscopy with a conventional source and with synchrotron radiation. A uniform distribution of the functional groups was evidenced through a detailed chemical mapping.
A novel High-Throughput Continuous Hydrothermal (HiTCH) flow synthesis reactor was used to make directly and rapidly a 66-sample nanoparticle library (entire phase diagram) of nanocrystalline Ce(x)Zr(y)Y(z)O(2-delta) in...A novel High-Throughput Continuous Hydrothermal (HiTCH) flow synthesis reactor was used to make directly and rapidly a 66-sample nanoparticle library (entire phase diagram) of nanocrystalline Ce(x)Zr(y)Y(z)O(2-delta) in less than 12 h. High resolution PXRD data were obtained for the entire heat-treated library (at 1000 degrees C/1 h) in less than a day using the new robotic beamline I11, located at Diamond Light Source (DLS). This allowed Rietveld-quality powder X-ray diffraction (PXRD) data collection of the entire 66-sample library in <1 day. Consequently, the authors rapidly mapped out phase behavior and sintering behaviors for the entire library. Out of the entire 66-sample heat-treated library, the PXRD data suggests that 43 possess the fluorite structure, of which 30 (out of 36) are ternary compositions. The speed, quantity and quality of data obtained by our new approach, offers an exciting new development which will allow structure-property relationships to be accessed for nanoceramics in much shorter time periods.
As part of an oncology chemistry program directed toward discovery of orally bioavailable inhibitors of the 90 kDa heat shock protein (Hsp90), several solution-phase libraries were designed and prepared. A 2 x 89 library...As part of an oncology chemistry program directed toward discovery of orally bioavailable inhibitors of the 90 kDa heat shock protein (Hsp90), several solution-phase libraries were designed and prepared. A 2 x 89 library of racemic resorcinol amides was prepared affording 131 purified compounds. After evaluation in a binding assay, followed by an AKT-Luminex cellular assay, three potent analogs had functional activity between 0.1 and 0.3 microM. Resolution by preparative chiral SFC chromatography led to (+)-15, (+)-16, and (+)-17 having functional IC(50) = 27, 43, and 190 nM, respectively. (+)-15 exhibited high clearance in human hepatocytes driven primarily by glucuronidation as confirmed by metabolite identification. A second 8 x 14 exploratory library was designed to investigate heterocyclic replacements of the resorcinol ring. The second library highlights the use of the (-)-sparteine-mediated enantioselective Pd-catalyzed alpha-arylation of N-Boc-pyrrolidine to prepare chiral 2-arylpyrrolidines in parallel.