Three-Component Coupling Reactions Involving Arynes, Phosphites, and Aldehydes toward 3-Mono-Substituted Benzoxaphosphole 1-Oxides.

A mild, efficient, and transition-metal-free three-component coupling reaction involving arynes, phosphites, and aldehydes was established to afford 3-mono-substituted benzoxaphosphole 1-oxides. A range of 3-mono-substituted benzoxaphosphole 1-oxides was obtained from both aryl- and aliphatic-substituted aldehydes in moderate to good yields. Moreover, the synthetic utility of the reaction was demonstrated by a Gram-scale reaction and the transformation of the products into various P-containing bicycles.

Discovery and Photoisomerization of New Pyrrolosesquiterpenoids Glaciapyrroles D and E, from Deep-Sea Sediment Streptomyces sp.

Two new pyrrolosesquiterpenes, glaciapyrroles D (1) and E (2) were discovered along with the previously reported glaciapyrrole A (3) from Streptomyces sp. GGS53 strain isolated from deep-sea sediment. This study elucidated the planar structures of 1 and 2 using nuclear magnetic resonance (NMR), mass spectrometry (MS), ultraviolet (UV), and infrared (IR) spectroscopic data. The absolute configurations of the glaciapyrroles were determined by Mosher's method, circular dichroism spectroscopy, and X-ray crystallography. Under 366 nm UV irradiation, the glaciapyrroles were systematically converted to the corresponding photoglaciapyrroles (4-6) via photoisomerization, resulting in the diversification of the glaciapyrrole family compounds. The transformation of the glaciapyrrole Z to E isomers occurred in a 1:1 ratio, based on virtual validation of the photoisomerization of these olefinic compounds by 1H-NMR spectroscopy and liquid chromatography/mass spectrometry (LC/MS) analysis. Finally, when encapsulated in poly(lactic-co-glycolic acid) nanoparticles, glaciapyrrole E and photoglaciapyrrole E displayed significant inhibitory activity against influenza A virus. This is the first report of antiviral effects from glaciapyrrole family compounds, whose biological functions have only been subjected to limited studies so far.

Tropolone-Bearing Sesquiterpenes from Juniperus chinensis: Structures, Photochemistry and Bioactivity.

The tropolone-bearing sesquiterpenes juniperone A (1) and norjuniperone A (2) were isolated from the folk medicinal plant Juniperus chinensis, and their structures were determined by a combination of spectroscopic and crystallographic methods. Photojuniperones A1 (3) and A2 (4), bearing bicyclo[3,2,0]heptadienones derived from tropolone, were photochemically produced and structurally identified by spectroscopic methods. Predicted by the machine learning-based assay, 1 significantly inhibited the action of tyrosinase. The new compounds also inhibited lipid accumulation and enhanced the extracellular glycerol excretion.

Modification of imidazothiazole derivatives gives promising activity in B-Raf kinase enzyme inhibition; synthesis, in vitro studies and molecular docking.

B-Raf mutation was identified as a key target in cancer treatment. Based on structural features of dabrafenib (potent FDA approved B-Raf inhibitor), the design of new NH2-based imidazothiazole derivatives was carried out affording new highly potent derivatives of imidazothiazole-based scaffold with amino substitution on the terminal phenyl ring as well as side chain with sulfonamide group and terminal substituted phenyl ring. In vitro enzyme assay was investigated against V600E B-Raf kinase. Compounds 10l, 10n and 10o showed higher inhibitory activities (IC50 = 1.20, 4.31 and 6.21 nM, respectively). In vitro cytotoxicity evaluation was assessed against NCI-60 cell lines. Most of tested derivatives showed cytotoxic activities against melanoma cell line. Compound 10k exhibited most potent activity (IC50 = 2.68 µM). Molecular docking study revealed that the new designed derivatives preserved the same binding mode of dabrafenib with V600E B-Raf active site. It was investigated that the new modification in the synthesized derivatives (substituted with NH2) had a significant inhibitory activity towards V600E B-Raf. This core scaffold is considered a key compound for further structural and molecular optimization.

Copper(I)-Catalyzed Synthesis of 1,4-Disubstituted 1,2,3-Triazoles from Azidoformates and Aryl Terminal Alkynes.

The copper(I)-catalyzed azide-alkyne cycloaddition reaction has been extensively studied and widely applied in organic synthesis. However, the formation of 1,2,3-triazoles with electron-deficient azide has been a challenging problem. In this report, we have demonstrated the formation of regioselective 1,4-disubstituted 1,2,3-triazoles from various types of aryl terminal alkynes and azidoformates, which are electron-deficient azides, using a commercialized [Cu(CH3CN)4]PF6 copper(I) catalyst under mild conditions.

Enantioselective Synthesis of Chiral α-Thio-Quaternary Stereogenic Centers via Phase-Transfer-Catalyzed α-Alkylation of α-Acylthiomalonates.

An efficient synthetic method for establishing chiral α-thio-α-quaternary stereogenic center was successfully developed. The enantioselective α-alkylation of α-acylthiomalonates under phase-transfer catalytic conditions [50% aq. KOH, toluene, -20 °C, and (S,S)-3,4,5-trifluorophenyl-NAS bromide] provided the corresponding α-acylthio-α-alkylmalonates in high chemical yields (up to 99%) and high optical yields (up to 98% ee).

Asymmetric Synthesis of (-)-6-Desmethyl-Fluvirucinine A1 via Conformationally-Controlled Diastereoselective Lactam-Ring Expansions.

The versatile synthesis of (-)-6-desmethyl-fluvirucinine A1 was accomplished at a 24% overall yield through a thirteen-step process from a known vinylpiperidine. The key part involved the elaboration of the distal stereocenters and a macrolactam skeleton via conformationally-induced diastereocontrol and the iterative aza-Claisen rearrangements of lactam precursors.

Construction of the Azacyclic Core of Tabernaemontanine-Related Alkaloids via Tandem Reformatsky-Aza-Claisen Rearrangement.

A divergent synthetic methodology for a tabernaemontanine-related alkaloid was developed. The synthetic route features practical improvements in the Pictet-Spengler cyclization for the tetrahydro-ß-carboline intermediate and an unprecedented tandem Reformatsky-aza-Claisen rearrangement to create the core carbon skeleton and stereochemistries of tabernaemontanine-related alkaloids.

Synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as mGluR5 (metabotropic glutamate receptor 5) antagonists.

We described here the synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as potential mGluR5 antagonists. We found that a series of thiazole derivatives 6 showed better inhibitory activity against mGluR5. Compounds 6bc and 6bj have been identified as potent antagonists (IC50=274 and 159nM) showing excellent in vitro stability profile. Molecular docking study using the crystal structure of mGluR5 revealed that our compounds 6bc and 6bj fit the allosteric binding site of mavoglurant well.

Synthesis, structure determination, and biological evaluation of phenylsulfonyl hydrazide derivatives as potential anti-inflammatory agents.

In our previous research, a novel series of phenylsulfonyl hydrazide derivatives were found to reduce LPS-induced PGE2 levels in RAW 264.7 macrophage cells via an inhibition of mPGES-1 enzyme. Recently, it was found that a regioisomeric mixture of phenylsulfonyl hydrazide was formed depending on the reaction conditions, which favor either of two regioisomers. One regioisomer corresponds to a kinetic product (7a-7c) and the other regioisomer corresponds to a thermodynamic product (8a-8c). Among them, the structure of kinetic product 7b was confirmed by measuring single X-ray crystallography. In vitro PGE2 assay studies showed that the kinetic product (7a and 7b; IC50=0.69 and 0.55µM against PGE2) is generally more potent than the thermodynamic product (8a and 8b; IC50=>10 and 0.79µM against PGE2). A molecular docking study also exhibited that the kinetic product (7a) has a higher MolDock Score (-147.4) than that of 8a (-142.4), which is consistent with the PGE2 assay results. A new potent phenylsulfonyl hydrazide (7d; IC50=0.06µM against PGE2) without affecting COX-1 and COX-2 enzyme activities was identified based on these overall results.

Construction of chiral α-amino quaternary stereogenic centers via phase-transfer catalyzed enantioselective α-alkylation of α-amidomalonates.

An efficient enantioselective synthetic method for α-amido-α-alkylmalonates via phase-transfer catalytic α-alkylation was successfully developed. The α-alkylation of α-amidomalonates under phase-transfer catalytic conditions (50% KOH, toluene, -40 °C) in the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide afforded the corresponding α-amido-α-alkylmalonates in high chemical yields (up to 99%) and optical yields (up to 97% ee), which could be readily converted to versatile chiral intermediates bearing α-amino quaternary stereogenic centers. The synthetic potential of this methodology was demonstrated via the synthesis of chiral azlactone, oxazoline, and unnatural α-amino acid.

Direct synthesis of 4-fluoroisoxazoles through gold-catalyzed cascade cyclization-fluorination of 2-alkynone O-methyl oximes.

A tandem protocol for the synthesis of fluorinated isoxazoles has been developed via catalytic intramolecular cyclizations of 2-alkynone O-methyl oximes and ensuing fluorination. The reactions proceed smoothly at room temperature in the presence of 5 mol % of (IPr)AuCl, 5 mol % of AgOTs, 2.5 equiv of Selectfluor, and 2 equiv of NaHCO3. This process features an efficient one-pot cascade route to fluoroisoxazoles with high yields and high selectivity under mild reaction conditions.

Facile diverted synthesis of pyrrolidinyl triazoles using organotrifluoroborate: discovery of potential mPTP blockers.

This article describes the rapid and diversified synthesis of pyrrolidinyl triazoles for the discovery of mitochondrial permeability transition pore (mPTP) blockers. The 1,3-dipolar cycloaddition of ethynyl trifluoroborate with azidopyrrolidine produced a key intermediate, triazolyl trifluoroborate 4, which subsequently underwent a Suzuki-Miyaura coupling reaction to afford a series of 1,4-disubstituted triazoles 2. Subsequent biological evaluation of these derivatives indicated 2ag and 2aj as the most potent mPTP blockers exhibiting excellent cytochrome P450 (CYP) stability when compared to the previously reported oxime analogue 1. The present work clearly demonstrates that a 1,2,3-triazole can be used as a stable oxime surrogate. Furthermore, it suggests that late-stage diversification through coupling reactions of organotrifluoroborates is suitable for the rapid discovery of biologically active molecules.

Efficient synthesis of mibefradil analogues: an insight into in vitro stability.

This article describes the synthesis and biological evaluation of a chemical library of mibefradil analogues to investigate the effect of structural modification on in vitro stability. The construction of the dihydrobenzopyran structure in mibefradil derivatives 2 was achieved through two efficient approaches based on a diastereoselective intermolecular Reformatsky reaction and an intramolecular carbonyl-ene cyclization. In particular, the second strategy through the intramolecular carbonyl-ene reaction led to the formation of a key intermediate 3 in a short and highly stereoselective way, which has allowed for practical and convenient preparation of analogues 2. Using this protocol, we could obtain 22 new mibefradil analogues 2, which were biologically tested for in vitro efficacies against T-type calcium channels and metabolic stabilities. Among the synthesized compounds, we found that analogue 2aa containing a dihydrobenzopyran ring and a secondary amine linker showed high % remaining activities of the tested CYP enzymes retaining the excellent T-type calcium channel blocking activity. These findings indicated that the structural modification of 1 was effective for improving in vitro stability, i.e., reducing CYP inhibition and metabolic degradation.

Synthesis and biological evaluation of 2-substituted quinoline 6-carboxamides as potential mGluR1 antagonists for the treatment of neuropathic pain.

A series of 2-amino and 2-methoxy quinoline-6-carboxamide derivatives have been synthesized and their metabotropic glutamate receptor type 1 (mGluR1) antagonistic activities were evaluated in a functional cell-based assay. The compound 13c showed the highest potency with IC50 value of 2.16 µM against mGluR1. Finally, in vivo evaluation of 13c in the rat spinal nerve ligation (SNL) model exhibited weak analgesic effects with regard to both mechanical allodynia and cold allodynia.

Crystal structure of (E)-N-[(E)-3-(4-meth-oxy-phen-yl)allyl-idene]naphthalen-1-amine.

In the title compound, C20H17NO, the dihedral angle between the mean planes of the 4-meth-oxy-phenyl ring and the naphthalene ring is 69.50 (7)°. The meth-oxy group is almost coplanar with the benzene ring to which it is connected [Cb-Cb-Om-Cm torsion angle of -7.9 (2)°; b = benzene and m = meth-oxy] and the imine group displays a C-C-N=C torsion angle is -57.2 (2)°. The imine (C=N) group has an E conformation. In the crystal, weak π-π inter-actions between the benzene rings [centroid-centroid distance = 3.7781 (10) Å] are observed.

Ca(II)-Catalyzed Cascade Reaction of Tryptamines with Propargylic Alcohols: Temperature-Driven Ring Opening and Closing via the Allene Migration Pathway for the Synthesis of Pyrrolo[1,2-a]indoles.

A temperature-dependent cascade of reactions between tryptamines and propargylic alcohols was developed to achieve selective formation of pyrroloindoline and pyrrolo[1,2-a]indole heterocycles by Ca(II) catalysis. The cascade consists of electrophilic addition of allene at the C3 carbon of indole followed by intramolecular cyclization at 60 °C to yield pyrroloindolines. Furthermore, simultaneous 1,2-allene migration and pyrrolidine ring opening were followed by intramolecular cyclization via C-N bond formation at reflux temperature to obtain pyrrolo[1,2-a]indole scaffolds. A wide range of substrates, a clean reaction profile, scalability, and good to excellent yields are the advantages of this protocol.

Synthesis and biological evaluation of 2-(arylethynyl)quinoline derivatives as mGluR5 antagonists for the treatment of neuropathic pain.

We described here the synthesis and biological evaluation of mGluR5 antagonists containing a quinoline ring structure. Using intracellular calcium mobilization assay (FDSS assay), we identified compound 5n, showing high inhibitory activity against mGluR5. In addition, it was found that compound 5n has excellent stability profile. Finally, this compound exhibited favorable analgesic effects in spinal nerve ligation model of neuropathic pain, which is comparable to gabapentin.

(E)-2,2'-[3-(4-Fluoro-phen-yl)prop-2-ene-1,1-di-yl]bis-(3-hy-droxy-5,5-dimethyl-cyclo-hex-2-en-1-one).

In the title compound, C25H29FO4, each cyclo-hexenone ring has an envelope conformation with the dimethyl-substituted atom as the flap. The hy-droxy and carbonyl groups form two intra-molecular O-H⋯O hydrogen bonds, as is typical for xanthene derivatives. In the crystal, very weak C-H⋯O hydrogen bonds link mol-ecules into dimers.

(E)-N-[(E)-3-(4-Nitro-phen-yl)allyl-idene]naphthalen-1-amine.

In the title compound, C19H14N2O2, the dihedral angle between the mean planes of the 4-nitro-phenyl ring and the naphthalene ring system is 12.79 (2)°. The imine group displays a C-C-N=C torsion angle of 41.0 (2)° and the C=N group has an E conformation. In the crystal, weak C-H⋯O hydrogen bonds link molecules into layers parallel to the b axis.