Copper-Catalyzed Synthesis of Substituted Primary Arylamines from Cyclohexenone Oxime Esters.

A novel protocol has been developed for the Cu-catalyzed synthesis of primary arylamines with meta-substituents using cyclohexenone oxime esters. Mechanistic insights suggest that the reaction proceeds via an intermolecular 1,5-H hydrogen atom transfer of an imine radical intermediate. This approach features high efficiency, a readily available catalyst system, and broad functional group tolerance.

Alkynyl Borrowing: Silver-Catalyzed Amination of Secondary Propargylic Alcohols via C(sp3)-C(sp) Bond Cleavage.

The silver-catalyzed alkynyl borrowing amination of secondary propargyl alcohols via C(sp3)-C(sp) bond cleavage has been developed. This new strategy was based on the ß-alkynyl elimination of propargyl alcohols and alkynyl as the borrowing subject. This alkynyl borrowing amination featured high atom economy, wide functional group tolerance, and high efficiency.

One-Pot Synthesis of 2,4-Diacyl Thiophenes from α-Oxo Ketene Dithioacetals and Propargylic Alcohols.

Although thiophenes having various functionalities are the basic structural units in numerous bioactive compounds and optoelectronic materials, synthetic routes to acylated thiophenes from aliphatic sulfur-containing starting materials are still rare. In particular, there have been no reports concerning the straightforward synthesis of 2,4-diacylthiophenes from alkynes. Herein, we describe a highly efficient and metal-free three-step one-pot synthetic approach to tetrasubstituted 2,4-diacylthiophenes from propargylic alcohols and α-oxo ketene dithioacetals. This research features a relay catalysis system that integrates Brønsted acid-catalyzed propargylation, molecular iodine-mediated electrophilic cyclization, and visible light-induced deiodinative oxygenation. The 2,4-diacylthiophenes serving as the key starting materials are readily synthesized, enabling facile construction of analogues of related biologically active compounds and the modular assembly of tetrasubstituted thienothiophenes.

Asymmetric Diels-Alder Reaction of 3-Vinylindoles and Nitroolefins Promoted by Multiple Hydrogen Bonds.

The first catalytic asymmetric Diels-Alder reaction of 3-vinylindole and nitroolefin is described. In the promotion of organocatalyst 3j, structurally diverse 1-nitro-hydrocarbazoles are produced in moderate-to-good yields and high-to-excellent enantioselectivities. All of these products are obtained as a single diastereoisomer. The 1-nitro-hydrocarbazole compounds can be converted into 1-amino-hydrocarbazole derivatives and structurally complex ring-fused indoles enantioseletively. Possible transition states were investigated by control experiments and DFT calculations.

Access to Multisubstituted Furan-3-carbothioates via Cascade Annulation of α-Oxo Ketene Dithioacetals with Isoindoline-1,3-dione-Derived Propargyl Alcohols.

A Brønsted acid-promoted, unprecedented formal (3 + 2) annulation strategy for the synthesis of multisubstituted furan-3-carbothioates is reported. This transformation represents the first regioselective annulation of α-oxo ketene dithio-acetals as 1,3-bis-nucleophiles in a cascade manner. The choice of isoindoline-1,3-dione-derived propargyl alcohols is crucial to the uncommon annulation mode between an alkyne-type bis-electrophile and a 1,3-bis-nucleophile under metal-free conditions. The scale-up of the synthesis and several interesting transformations of an as-synthesized product were further investigated. A Nazarov-like cyclization is proposed for the ring-closure process according to the experimental observations.

Iodine-Promoted Semmler-Wolff Reactions: Step-Economic Access to meta-Substituted Primary Anilines via Aromatization.

An atom- and step-economic access to an array of unprotected meta-substituted primary anilines was disclosed using the Semmler-Wolff reaction, promoted by molecular iodine. Therein, noble metal catalysts and inert atmosphere are unnecessary while the forcing reaction conditions and the lengthy synthesis can be avoided. The synthetic utility of this approach is evident in the de novo syntheses of three bioactive molecules with good total yields.

Metal-free phosphonation of heteroarene N-oxides with trialkyl phosphite at room temperature.

A new protocol is described for the conversion of heteroarene N-oxides to heteroarylphosphonates through in situ activation with bromotrichloromethane. The N-oxides of isoquinoline, quinoline, quinoxaline and 1,10-phenanthroline were fast transformed into the corresponding heteroarylphosphonates in up to 92% yield under mild conditions in the absence of solvent and metal catalysts. The good functional group tolerance, low cost, feasibility of scale up, and wide availability of reagents make this method a prominent complement to the Hirao coupling.

[2,6-Bis(5-eth-oxy-1,3-oxazol-2-yl)-4-meth-oxy-phenyl-κ(3) N,C (1),N']bromidopalladium(II).

In the title compound, [PdBr(C17H17N2O5)], the Pd(II) atom is coordinated by an N,C(1),N'-tridentate pincer ligand and a Br atom in a distorted square-planar geometry. In the crystal, mol-ecules are connected by C-H⋯Br and C-H⋯O hydrogen bonds, and π-π inter-actions between the oxazole and benzene rings [centroid-centroid distance = 3.7344 (19) Å], resulting in a three-dimensional supra-molecular structure.

Suzuki-Miyaura coupling of aryl iodides, bromides, and chlorides catalyzed by bis(thiazole) pincer palladium complexes.

Bis(thiazole) pincer palladium complexes showed efficient catalytic activity for the Suzuki-Miyaura coupling of aryl halides, allowing the synthesis of biaryls with very high turnover numbers and turnover frequencies. The complexes were successfully applied in the scalable and green synthesis of the key intermediates of bioactive LUF5771 and its analogues.

Novel bis(azole) pincer palladium complexes: synthesis, structures and applications in Mizoroki-Heck reactions.

Two novel NCN-pincer complex precursors bearing frameworks of 2,6-bis(oxazol-4-yl)benzene (A) and 2-(thiazol-4-yl)-6-(oxazol-4-yl)benzene (B) were synthesized. Palladations of A and B afforded two new bis(azole) pincer complexes, [(A-κ(3)NCN)PdBr] (1) and [(B-κ(3)NCN)PdBr] (2). Both complexes were fully characterized by NMR, MS, DSC-TGA and single-crystal X-ray diffraction analysis. Complex 1 crystallizes in a noncentrosymmetric orthorhombic space group Cmc2(1) (No. 36, Z=4). Complex 2 crystallizes in a centrosymmetric monoclinic space group P2(1)/n (No. 14, Z=4). Despite the similarity in their chemical formulas, the structures of the two complexes are subtly different: they are built up of two-dimensional supramolecular layers with identical topology, but stacked in different sequences, i.e., the layers in complex 1 are stacked in an AAAA-type fashion, while those in complex 2 are stacked in an alternating AA(-1)AA(-1) sequence (A denotes a layer; A(-1) stands for A's inversion symmetry equivalent). In addition, the complexes showed good catalytic activity toward Mizoroki-Heck reactions.

Inhibitors of type I MetAPs containing pyridine-2-carboxylic acid thiazol-2-ylamide. Part 1: SAR studies on the determination of the key scaffold.

Systematic SAR studies on the HTS hit pyridine-2-carboxylic acid thiazol-2-ylamide (PACT) analogues revealed that the scaffold of PCAT is indispensable for the inhibition of type I MetAP. For effective inhibition of the enzyme, the most suitable position to modify is the 3-position of the pyridine ring of PCAT, and the best substituents are those containing O or N atoms connected directly with the pyridine ring. These findings provide useful information for the design and discovery of more potent inhibitors of type I MetAPs.

Inhibitors of type I MetAPs containing pyridine-2-carboxylic acid thiazol-2-ylamide. Part 2: SAR studies on the pyridine ring 3-substituent.

Systematic SAR studies on the pyridine ring 3-substituent of PCAT, an inhibitor of EcMetAP1 and ScMetAP1, revealed that 3-substituents have different selectivity for EcMetAP1 and ScMetAP1. The selective inhibitors of type I MetAP are useful tools for investigating the detailed interactions between the enzymes and their inhibitors. In addition, these findings provide useful information for the design and discovery of more potent inhibitors of type I MetAPs.

Type I methionine aminopeptidase from Saccharomyces cerevisiae is a potential target for antifungal drug screening.

AIM: To screen antifungal drug candidates using in vitro and in vivo assays based on type I methionine aminopeptidase from Saccharomyces cerevisiae (ScMetAP1). METHODS: A colorimetric assay suitable for high throughput screening (HTS) using recombinant ScMetAP1 protein expressed in Escherichia coli was established for antifungal lead discovery. A series of pyridine-2-carboxylic acid derivatives were characterized and a chemical library of 12,800 pure organic compounds was screened with the in vitro ScMetAP1 assay. Active compounds from the in vitro assay were further evaluated by a growth inhibition assay on yeast strain with deletion of ScMetAP1 gene map1 in comparison with the wild-type yeast strain and the yeast strain with deletion of type II enzyme (ScMetAP2) gene map2. RESULTS: Active ScMetAP1 inhibitors were identified from HTS. Some of the pyridine-2-carboxylic acid derivatives (compound 2 and 3) had selective inhibition of the growth of map2 deletion yeast and weak inhibition on wild-type yeast growth, while no inhibition on map1 deletion yeast. CONCLUSION: ScMetAP1 is a novel potential target for developing antifungal drugs. The in vitro and in vivo ScMetAP1 assays can serve as tools in discovering antifungal drug candidates.

Characterization of full length and truncated type I human methionine aminopeptidases expressed from Escherichia coli.

Methionine aminopeptidase (MetAP) carries out an essential posttranslational modification of nascent proteins by removing the initiator methionine and is recognized as a potential target for developing antibacterial, antifungal, and anticancer agents. We have established an Escherichia coli expression system for human type I MetAP (HsMetAP1) and characterized the full length HsMetAP1 and its N-terminal-truncated mutants HsMetAP1(Delta1-66) and HsMetAP1(Delta1-135) for hydrolysis of several thiopeptolide and peptide substrates and inhibition by a series of nonpeptidic inhibitors. Although the N-terminal extension with zinc finger motifs in HsMetAP1 is not required for enzyme activity, it has a significant impact on the interaction of the enzyme with substrates and inhibitors. In hydrolysis of the thiopeptolide substrates, a relaxation of stringent specificity for the terminal methionine was observed in the truncated mutants. However, this relaxation of specificity was not detectable in hydrolysis of tripeptide or tetrapeptide substrates. Several nonpeptidic inhibitors showed potent inhibition of the mutant HsMetAP1(Delta1-66) but exhibited only weak or no inhibition of the full length enzyme. With the recombinant HsMetAP1 available, we have identified several MetAP inhibitors with submicromolar inhibitory potencies against E. coli MetAP (EcMetAP1) that do not affect HsMetAP1. These results have demonstrated the possibility of developing MetAP inhibitors as antibacterial agents with minimum human toxicity. In addition, micromolar inhibitors of HsMetAP1 identified in this study can serve as tools for investigating the functions of HsMetAP1 in physiological and pathological processes.

Specificity for inhibitors of metal-substituted methionine aminopeptidase.

Methionine aminopeptidases (MetAPs) have been studied in vitro as Co(II) enzymes, but their in vivo metal remains to be defined. While activation of Escherichia coli MetAP (EcMetAP1) by Co(II), Mn(II), and Zn(II) was detectable by a colorimetric Met-S-Gly-Phe assay, significant activation by Ni(II) was shown in a fluorescence Met-AMC assay, in addition to Co(II) and Mn(II) activation. When tested on the metal-substituted EcMetAP1s, a few inhibitors that we obtained recently from a random screening on Co-EcMetAP1 either became much weak or lost activity on Mn- or Zn-EcMetAP1, although they kept inhibitory activity on Ni-EcMetAP1. A couple of peptidic inhibitors and the methionine mimetic (3R)-amino-(2S)-hydroxyheptanoic acid (AHHpA, 6) maintained moderate activities on Co-, Mn-, Zn-, and Ni-EcMetAP1s. Our results clearly demonstrate that the metal-substitution has changed the enzyme specificity for substrates and inhibitors. Therapeutic applications call for inhibitors specific for MetAP with a physiologically relevant metal at its active site.

Discovery and structural modification of inhibitors of methionine aminopeptidases from Escherichia coli and Saccharomyces cerevisiae.

A series of pyridine-2-carboxylic acid derivatives were synthesized according to the leads from the screening, and potent inhibitors have been obtained by structural modification. They have shown submicromolar inhibition of the enzymes (for example, for 9n, IC(50) = 130 nM for EcMetAP1 and IC(50) = 380 nM for ScMetAP1). They represent small-molecule MetAP inhibitors with novel structures different from alkylating fumagillin derivatives and peptidic bestatin-based MetAP inhibitor.