Generation of a library using parallel syntheses of multi-substituted benzo[b]thiophenes is described. The requisite 3-iodobenzo[b]thiophenes are readily prepared in excellent yields from various alkynes bearing electron...Generation of a library using parallel syntheses of multi-substituted benzo[b]thiophenes is described. The requisite 3-iodobenzo[b]thiophenes are readily prepared in excellent yields from various alkynes bearing electron-rich aromatic rings by electrophilic cyclization using I(2) in CH(2)Cl(2). The heteroaromatic carbon-iodine bonds allow further diversification by palladium-catalyzed Suzuki-Miyaura, Sonogashira, Heck, and carboalkoxylation chemistry to give multi-substituted benzo[b]thiophene derivatives.
Tetra- and pentasubstituted polyfunctional dihydropyrroles have been concisely synthesized in high yields by two different processes of the one-pot multicomponent reactions (MCRs) of but-2-ynedioates 1, amines 2, and ald...Tetra- and pentasubstituted polyfunctional dihydropyrroles have been concisely synthesized in high yields by two different processes of the one-pot multicomponent reactions (MCRs) of but-2-ynedioates 1, amines 2, and aldehydes 3 at room temperature or at 70 degrees C. The first one involves a domino hydroamination/nucleophilic addition/amidation-cyclization process and leads to the formation of tetrasubstituted polyfunctional dihydropyrroles 4. The second undergoes hydroamination/amidation/intramolecular cyclization/imine-enamine tautomerization sequence and results in pentasubstituted products 5. The structures of 4 and 5 were confirmed by single-crystal X-ray diffraction. These novel methodologies provide easy access to diversely multisubstituted polyfunctional dihydropyrrole libraries. The primary biological screening in vitro against HIV-1 has shown that 22 tested compounds have exhibited significant activity with IC(50) in micromolar range (38-58 microM).
The protein-protein interaction of p53 and mdm2 is an important anticancer target. The interface, however, is very hydrophobic and naturally results in very hydrophobic antagonists. We used the Orru three component react...The protein-protein interaction of p53 and mdm2 is an important anticancer target. The interface, however, is very hydrophobic and naturally results in very hydrophobic antagonists. We used the Orru three component reaction (O-3CR) along with a rapid and efficient, recently discovered amidation reaction to dramatically improve the water solubility of our recently discovered low molecular weight p53/mdm2 antagonists. Arrays of amides were synthesized with improved hydrophilicity and retainment and/or improvement of p53/mdm2 inhibitory activity.
A combinatorial approach was used to systematically investigate the photocatalytic activities of different kinds of ABO(3)-type oxides (A = Y, La, Nd, Sm, Eu, Gd, Dy, Yb; B = Al, In). Two novel photocatalysts, cubic YInO...A combinatorial approach was used to systematically investigate the photocatalytic activities of different kinds of ABO(3)-type oxides (A = Y, La, Nd, Sm, Eu, Gd, Dy, Yb; B = Al, In). Two novel photocatalysts, cubic YInO(3) and perovskite YAlO(3), were identified rapidly. Scale-up experiments confirmed that the two photocatalysts, especially the YInO(3), had excellent photocatalytic activity for toluene oxidation and water splitting under visible-light irradiation.
A highly diastereoselective domino reaction of 2,6-diaminopyrimidine-4-one with structurally diverse aryl aldehydes and various barbituric acids in water under microwave irradiation is described. The products are 6-spiro...A highly diastereoselective domino reaction of 2,6-diaminopyrimidine-4-one with structurally diverse aryl aldehydes and various barbituric acids in water under microwave irradiation is described. The products are 6-spiro-substituted pyrido[2,3-d]pyrimidines with high diastereoselectivities (up to 99: 1) in which the major diastereomer bears a cis relationship between substituents at the 5- and 7-positions. Furthermore, the mechanism for diastereoselectivity was confirmed by DFT (B3LYP) calculations.
We report herein a convenient method for the synthesis of libraries of 6,8-disubstituted-9-H-purines in two steps, including cyclization of 6-chloro-4,5-diaminopyrimidine with various arylcarboxylic acids or chlorides, f...We report herein a convenient method for the synthesis of libraries of 6,8-disubstituted-9-H-purines in two steps, including cyclization of 6-chloro-4,5-diaminopyrimidine with various arylcarboxylic acids or chlorides, followed by S(N)Ar with amines and alkoxides or Pd-catalyzed amidations at C-6. These reactions were highly efficient and allowed the synthesis of a 32-member library of 6,8-disubstituted purines.
Distamycin is a naturally occurring antibiotic that binds to AT-rich sequences in the minor groove of DNA in a noncovalent manner. It continues to be of interest as a "building block" for more-complex small-molecule liga...Distamycin is a naturally occurring antibiotic that binds to AT-rich sequences in the minor groove of DNA in a noncovalent manner. It continues to be of interest as a "building block" for more-complex small-molecule ligands capable of targeting specific DNA sequences for gene regulation purposes (i.e., transcription factor inhibitors). We report here a convenient and efficient synthesis of a library of 72 novel analogs (3a-f) of the parent distamycin on SynPhase Lanterns. To investigate structure-activity relationships including DNA-binding affinity and sequence-selectivity, two previously unexplored points of diversification have been introduced into the distamycin structure by replacing one of its pyrrole rings with novel biaryl motifs. The key aspects of the synthetic approach include the development of an efficient protocol for preparation of the heterocyclic polyamide chain, optimization of the Suzuki-Miyaura cross-coupling reaction and application of a split-and-mix technique based on radiofrequency encoding. In addition, a series of biaryl carboxamide derivatives (4a-f) has been synthesized utilizing the title library diversity reagents.
A sequential three-component synthesis of functionalized benzisothiazoline-3-acetic acid 1,1-dioxides utilizing a domino Heck-aza-Michael pathway is reported. This one-pot procedure rapidly assembles functionalized benzy...A sequential three-component synthesis of functionalized benzisothiazoline-3-acetic acid 1,1-dioxides utilizing a domino Heck-aza-Michael pathway is reported. This one-pot procedure rapidly assembles functionalized benzylsulfonamides, which undergo a palladium-catalyzed, domino, Heck-aza-Michael transformation in an experimentally straightforward manner. This attractive protocol has been utilized to synthesize three combinatorial sublibraries (I-III) comprising a total of 95 compounds in high purities (> or =95% for 75 compounds), yield and quantities.
In this manuscript, we describe the synthesis of a bicyclic beta-benzyloxy and beta-hydroxy amide library from cyanohydrin ethers. The benzyloxy amides were prepared through a one-pot sequence of hydrozirconation, acylat...In this manuscript, we describe the synthesis of a bicyclic beta-benzyloxy and beta-hydroxy amide library from cyanohydrin ethers. The benzyloxy amides were prepared through a one-pot sequence of hydrozirconation, acylation, and intramolecular Friedel-Crafts alkylation. Selected benzyl ethers were converted to alcohols by hydrogenolysis in a continuous flow reactor. Chemistry space BCUT metrics and 2D fingerprint similarity calculations showed that these compounds contribute chemical diversity value to existing chemical libraries.
We have developed an efficient iron-catalyzed method for the cascade synthesis of 1,2,4-benzothiadiazine 1,1-dioxide and quinazolinone derivatives. The protocol uses inexpensive and environmentally friendly FeCl(3) as th...We have developed an efficient iron-catalyzed method for the cascade synthesis of 1,2,4-benzothiadiazine 1,1-dioxide and quinazolinone derivatives. The protocol uses inexpensive and environmentally friendly FeCl(3) as the catalyst, and no ligand or additive was required. This is the first example of construction of nitrogen-containing heterocycles via iron-catalyzed N-arylation in the absence of ligand. Therefore, this method is of practical application for the synthesis of the two different nitrogen-containing heterocycles.
A structurally diverse library of potentially pharmacologically important compounds employing classical synthesis methods is described. These compounds are synthesized from beta-aryl pyrrolidines, providing products with...A structurally diverse library of potentially pharmacologically important compounds employing classical synthesis methods is described. These compounds are synthesized from beta-aryl pyrrolidines, providing products with the 2-arylethyl amine moiety, a structural feature often encountered in compounds active in the central nervous system. Tri- and tetracyclic scaffolds were obtained using the Pictet-Spengler reaction, resulting in hexahydropyrrolo[3,4-c]isoquinolines 1-3, an octahydropyrrolo[3',4':5,6]pyrido[3,4-b]indole 4, and a hexahydrofuro[2,3-d]pyrrolo[3,4-b]pyridine 5. These scaffolds were further derivatized in parallel fashion to make a 32-membered amide library with yields from 62 to 100% (90% average) and purities from 63 to 100% (93% average).
The synthesis of a 144-compound library of hydantoins and thiohydantoins spiro-fused to pyrrolidines is described. These compounds are synthesized from beta-aryl pyrrolidines, providing products with the 2-arylethyl amin...The synthesis of a 144-compound library of hydantoins and thiohydantoins spiro-fused to pyrrolidines is described. These compounds are synthesized from beta-aryl pyrrolidines, providing products with the 2-arylethyl amine moiety, a structural feature often encountered in compounds active in the central nervous system. All possible stereoisomers of the two-stereocenter products are synthesized. The 80-membered hydantoin sublibrary was obtained with yields ranging from 58 to 100% (87% average) and purities from 51 to 100% (87% average) and the 64-membered thiohydantoin sublibrary was obtained with yields ranging from 65 to 100% (89% average) and purities from 67 to 100% (93% average).
The one-step solution-phase parallel synthesis of two structurally diverse libraries of pharmacologically important compounds is described. The presented compounds combine three privileged structures: the 2-arylethyl ami...The one-step solution-phase parallel synthesis of two structurally diverse libraries of pharmacologically important compounds is described. The presented compounds combine three privileged structures: the 2-arylethyl amine moiety, a tetrahydro(hetero)areno[c]pyridine, and a (thio)hydantoin. These compounds are synthesized by annulation of a hydantoin or a 2-thiohydantoin ring to tri- or tetracyclic scaffolds, containing the 2-arylethyl amine moiety and a tetrahydroisoquinoline, a tetrahydro-beta-carboline, or a tetrahydrofuro[3,2-c]pyridine. The annulation leads to pharmacologically relevant structural motifs such as imidazopyrroloisoquinolines, dioxoloimidazopyrroloisoquinolines, furoimidazopyrrolopyridines, and imidazopyrrolopyridoindoles. Both libraries were obtained with quantitative yields. The 36-membered hydantoin library was obtained with purities from 57 to 100% (90% average) and the 32-membered thiohydantoin library with purities from 73 to 100% (94% average).
A practical and divergent solution-phase synthetic strategy has been optimized to prepare a highly diverse library of 2,4-diaryl- and 2,6-diarylpyrimidines. Structural elaboration of the starting heterocyclic scaffolds w...A practical and divergent solution-phase synthetic strategy has been optimized to prepare a highly diverse library of 2,4-diaryl- and 2,6-diarylpyrimidines. Structural elaboration of the starting heterocyclic scaffolds was accomplished by exploiting the potential for diversity offered by the Suzuki-Miyaura cross-coupling reaction. These studies enabled the identification of structurally simple, highly potent, and selective A(3) adenosine receptor antagonists.
This paper reports a versatile, good-yielding, solution-phase method that is a substituent diversity-directed synthesis of 1H-indoles (6-13, 17-20) and 1-hydroxyindoles (14, 15) starting from commercially available 1,5-d...This paper reports a versatile, good-yielding, solution-phase method that is a substituent diversity-directed synthesis of 1H-indoles (6-13, 17-20) and 1-hydroxyindoles (14, 15) starting from commercially available 1,5-difluoro-2,4-dinitrobenzene. The synthetic products possessed the maximum six diversity points.
An efficient three-component, two-step "catch and release" solid-phase synthesis of 3,4,5-trisubstituted pyrazoles and isoxazoles has been developed. The first step involves a base-promoted condensation of a 2-sulfonyl-...An efficient three-component, two-step "catch and release" solid-phase synthesis of 3,4,5-trisubstituted pyrazoles and isoxazoles has been developed. The first step involves a base-promoted condensation of a 2-sulfonyl- or a 2-carbonyl-acetonitrile derivative (1 or 7) with an isothiocyanate 2 and in situ immobilization of the resulting thiolate anion on Merrifield resin. Reaction of the resin-bound sulfonyl intermediate 4 with hydrazine or hydroxylamine, followed by release from the resin and intramolecular cyclization, affords 3,5-diamino-4-(arylsulfonyl)-1H-pyrazoles 5 or isoxazoles 6, respectively. Reaction of the resin-bound carbonyl intermediate 9 with hydrazine, on the other hand, leads to 3-(arylamino)-5-aryl-1H-pyrazole-4-carbonitriles 10.
A 23-member library of pyrrolobenzodiazepine derivatives with vasopressin agonist activity was purified on a 100-mg per injection scale using normal-phase (NP) automated mass-directed HPLC. Analytical NP APCI-LC/MS on an...A 23-member library of pyrrolobenzodiazepine derivatives with vasopressin agonist activity was purified on a 100-mg per injection scale using normal-phase (NP) automated mass-directed HPLC. Analytical NP APCI-LC/MS on an experimental monolith silica CN column utilizing gradients of methanol in ethoxynonafluorobutane (hexane-like solvent) was used to provide data on chromatographic purity and ionization of the solutes. The analytical data collected were used to program a preparative LC/MS instrument for "smart" fraction collection based on the protonated molecular ion of the component of interest. Preparative HPLC was carried out on a preparative cyano column with gradients of polar organic solvents in heptane containing n-propylamine as a basic additive. Flow rates twice as high as conventional ones were used for purification of library compounds. Small aliquots of the preparative flow were mixed with makeup solvent and introduced into an APCI source of a quadrupole mass spectrometer, which triggered collection of solutes. Two methods with fixed instrument parameters were used for purification. The system utilized commercially available instrumentation and software, which provided excellent recovery and purity of the library components and appeared to be useful as a fast and efficient alternative to traditional purification technologies based on reversed-phase LC/MS.
Copper(I)-catalyzed tandem reaction of 2-iodobenzenamine with isothiocyanate under mild conditions is described, which provides an efficient and practical route for the synthesis of 2-aminobenzothiazole.Copper(I)-catalyzed tandem reaction of 2-iodobenzenamine with isothiocyanate under mild conditions is described, which provides an efficient and practical route for the synthesis of 2-aminobenzothiazole.
An efficient and versatile method for the synthesis of imidazopyrazine ring using the modified Pictet-Spengler strategy has been reported. The two step strategy offers rapid assembly of druglike core templates pyridine o...An efficient and versatile method for the synthesis of imidazopyrazine ring using the modified Pictet-Spengler strategy has been reported. The two step strategy offers rapid assembly of druglike core templates pyridine or pyrimidine and imidazole into new annulated polycyclic skeletons: pyrido- and pyrimido-imidazopyrazines. The rate of endo cyclization of aryl/heteroaryl-amine substrates has been compared with traditionally used aliphatic amine substrates, and results have been discussed in the light of the pK(a) values of amines present in each substrate.