Synthesis of Diarylamines via Nitrosonium-Initiated C-N Bond Formation.

Electron-rich diarylamines, exemplified by anisole-derived amines, play pivotal roles in process chemistry, pharmaceuticals, and materials. In this study, homo-diarylamines were synthesized directly from the C-H activation of electron-rich arenes by sodium nitrate/trifluoroacetic acid and the successive treatment of iron powder. Mechanistic investigations reveal that nitrosoarene serves as the reaction intermediate, and the formation of the second C-N bond between the resulting nitrosoarene and electron-rich arene is catalyzed by the nitrosonium ion (NO+). Thus, hetero-diarylamines were synthesized using preformed nitrosoarenes and various electron-rich arenes. This reaction complements a range of cross-coupling reactions catalyzed by transition metal catalysts.

Enantioselective Synthesis of Nabscessin C.

Enantioselective synthesis of nabscessin C (1), an aminocyclitol amide with antimicrobial activity, is reported. Starting from myo-inositol, (+)-nabscessin C was synthesized in 12 isolation steps. Desymmetrization of 2-deoxygenated 4,6-dibenzylinositol was achieved using lipase from porcine pancreas (PPL), and the stereochemistry was established by X-ray crystallography. This method has the potential for synthesizing other cyclitol-derived compounds.

Synthesis of 2-Aryl Acetophenones via Hydrobromination and Oxy-isomerization of (o-Arylethynyl)benzyl Alcohols.

Hydrobromination and oxy-isomerization of (o-arylethynyl)benzyl alcohols to yield brominated aryl ketones were achieved with bromotrimethylsilane. The substrate scope suggested that vinyl carbocations, stabilized by the conjugated aryl groups, are the reaction intermediates. 1H-Isochromene was also detected by 1H NMR, and an isolated 1H-isochromene was converted to the product when retreated with TMSBr. The formation of 1H-isochromene is equivalent to a 6-endo-dig cyclization and contrasts with the corresponding reactions under basic conditions, in which the 5-exo-dig process dominated.

Addition of benzyl ethers to alkynes: a metal-free synthesis of 1H-isochromenes.

Bromotrimethylsilane (TMSBr)-promoted intramolecular cyclization of (o-arylethynyl)benzyl ethers to form 1H-isochromenes at room temperature is reported. Further studies indicated that vinyl carbocations are the reaction intermediates which are stabilized by the conjugated aryl groups. Thus, O-addition of benzyl ethers/tetrahydropyrans to alkynes was achieved under metal-free, acidic conditions. These reaction conditions were compatible with an alkynyl Prins reaction; therefore, 1H-isochromenes were produced directly from alkynyl benzaldehydes and alkynyl alcohols using a one-pot procedure.

Asymmetric Synthesis of Nabscessin A from Inositol and d-Camphor.

An enantiomer of nabscessin A (1), an aminocyclitol amide with antimicrobial activity, was synthesized from myo-inositol and dimethyl d-camphor acetal in 14 steps. Formal synthesis of natural nabscessin A was also achieved through the new approach to access both enantiomers of 4,5-di-O-benzyl-myo-inositol, derived from the same set of starting materials. This synthesis features utilizations of the existing framework of myo-inositol and a regioselective esterification.

Acid-base-sensitive allylic oxidation of 2-allylbenzoic acids to form phthalides.

Allylic oxidation of 2-allylbenzoic acids to phthalides, instead of Wacker-type isocoumarins, was achieved with 1,2-bis(phenylsulfinyl)ethane palladium(ii) acetate (White catalyst) and oxygen in DMSO. The selective formation of 3-ethylidenephthalides or 3-vinylphthalides was controlled by the addition of acids or bases, and the reaction conditions were applied to substituted 2-allylbenzoic acids to generate corresponding phthalides selectively. Mechanistic studies, including the corresponding reaction of (E)-2-(1-propenyl)benzoic acid to 3-methylisocoumarin, isomerization reaction of 3-vinylphthalide to 3-ethylidenephthalide, and the kinetic isotope effect using 2-(1,1-d2-allyl)benzoic acid, revealed the competition between Wacker-type oxidation and allylic C-H cleavage, which is the key step to generating phthalides. A natural product, 3-ethyl-6-hydroxyphthalide, was prepared by this method.

Mechanistic Study of Triazole Based Aminodiol Derivatives in Leukemic Cells-Crosstalk between Mitochondrial Stress-Involved Apoptosis and Autophagy.

Various derivatives that mimic ceramide structures by introducing a triazole to connect the aminodiol moiety and long alkyl chain have been synthesized and screened for their anti-leukemia activity. SPS8 stood out among the derivatives, showing cytotoxic selectivity between leukemic cell lines and human peripheral blood mononuclear cells (about ten times). DAPI nuclear staining and H&E staining revealed DNA fragmentation under the action of SPS8. SPS8 induced an increase in intracellular Ca2+ levels and mitochondrial stress in HL-60 cells identified by the loss of mitochondrial membrane potential, transmission electron microscopy (TEM) examination, and altered expressions of Bcl-2 family proteins. SPS8 also induced autophagy through the detection of Atg5, beclin-1, and LC3 II protein expression, as well as TEM examination. Chloroquine, an autophagy inhibitor, promoted SPS8-induced apoptosis, suggesting the cytoprotective role of autophagy in hindering SPS8 from apoptosis. Furthermore, SPS8 was shown to alter the expressions of a variety of genes using a microarray analysis and volcano plot filtering. A further cellular signaling pathways analysis suggested that SPS8 induced several cellular processes in HL-60, including the sterol biosynthesis process and cholesterol biosynthesis process, and inhibited some cellular pathways, in which STAT3 was the most critical nuclear factor. Further identification revealed that SPS8 inhibited the phosphorylation of STAT3, representing the loss of cytoprotective activity. In conclusion, the data suggest that SPS8 induces both apoptosis and autophagy in leukemic cells, in which autophagy plays a cytoprotective role in impeding apoptosis. Moreover, the inhibition of STAT3 phosphorylation may support SPS8-induced anti-leukemic activity.

Discovery of Novel Agents on Spindle Assembly Checkpoint to Sensitize Vinorelbine-Induced Mitotic Cell Death Against Human Non-Small Cell Lung Cancers.

Non-small cell lung cancer (NSCLC) accounts about 80% of all lung cancers. More than two-thirds of NSCLC patients have inoperable, locally advanced or metastatic tumors. Non-toxic agents that synergistically potentiate cancer-killing activities of chemotherapeutic drugs are in high demand. YL-9 was a novel and non-cytotoxic compound with the structure related to sildenafil but showing much less activity against phosphodiesterase type 5 (PDE5). NCI-H460, an NSCLC cell line with low PDE5 expression, was used as the cell model. YL-9 synergistically potentiated vinorelbine-induced anti-proliferative and apoptotic effects in NCI-H460 cells. Vinorelbine induced tubulin acetylation and Bub1-related kinase (BUBR1) phosphorylation, a necessary component in spindle assembly checkpoint. These effects, as well as BUBR1 cleavage, were substantially enhanced in co-treatment with YL-9. Several mitotic arrest signals were enhanced under combinatory treatment of vinorelbine and YL-9, including an increase of mitotic spindle abnormalities, increased cyclin B1 expression, B-cell lymphoma 2 (Bcl-2) phosphorylation and increased phosphoproteins. Moreover, YL-9 also displayed synergistic activity in combining with vinorelbine to induce apoptosis in A549 cells which express PDE5. In conclusion. the data suggest that YL-9 is a novel agent that synergistically amplifies vinorelbine-induced NSCLC apoptosis through activation of spindle assembly checkpoint and increased mitotic arrest of the cell cycle. YL-9 shows the potential for further development in combinatory treatment against NSCLC.

The (+)-Brevipolide H Displays Anticancer Activity against Human Castration-Resistant Prostate Cancer: The Role of Oxidative Stress and Akt/mTOR/p70S6K-Dependent Pathways in G1 Checkpoint Arrest and Apoptosis.

Because conventional chemotherapy is not sufficiently effective against prostate cancer, various examinations have been performed to identify anticancer activity of naturally occurring components and their mechanisms of action. The (+)-brevipolide H, an α-pyrone-based natural compound, induced potent and long-term anticancer effects in human castration-resistant prostate cancer (CRPC) PC-3 cells. Flow cytofluorometric analysis with propidium iodide staining showed (+)-brevipolide H-induced G1 arrest of cell cycle and subsequent apoptosis through induction of caspase cascades. Since Akt/mTOR pathway has been well substantiated in participating in cell cycle progression in G1 phase, its signaling and downstream regulators were examined. Consequently, (+)-brevipolide H inhibited the signaling pathway of Akt/mTOR/p70S6K. The c-Myc inhibition and downregulation of G1 phase cyclins were also attributed to (+)-brevipolide H action. Overexpression of myristoylated Akt significantly rescued mTOR/p70S6K and downstream signaling under (+)-brevipolide H treatment. ROS and Ca2+, two key mediators in regulating intracellular signaling, were determined, showing that (+)-brevipolide H interactively induced ROS production and an increase of intracellular Ca2+ levels. The (+)-Brevipolide H also induced the downregulation of anti-apoptotic Bcl-2 family proteins (Bcl-2 and Bcl-xL) and loss of mitochondrial membrane potential, indicating the contribution of mitochondrial dysfunction to apoptosis. In conclusion, the data suggest that (+)-brevipolide H displays anticancer activity through crosstalk between ROS production and intracellular Ca2+ mobilization. In addition, suppression of Akt/mTOR/p70S6K pathway associated with downregulation of G1 phase cyclins contributes to (+)-brevipolide H-mediated anticancer activity, which ultimately causes mitochondrial dysfunction and cell apoptosis. The data also support the biological significance and, possibly, clinically important development of natural product-based anticancer approaches.

Microwave-Assisted Direct Thioesterification of Carboxylic Acids.

A one-pot synthesis of thioesters directly from carboxylic acids, N,N'-diphenylthiourea, triethylamine, and primary alkyl halides is described. Microwave-assisted heating and a catalytic amount of 4-(dimethylamino)pyridine (DMAP) further improved the yields. Both aromatic and aliphatic carboxylic acids were converted to the corresponding thioesters, and many functional groups were compatible with this reaction. Several possible reaction intermediates were investigated, and the quaternary ammonium salts, derived from alkyl halides and tertiary amines, were the intermediates to yield thioesters. A new reaction mechanism for this thioesterification is proposed.

Synthesis of 2,3-dihydro-1H-pyrroles by intramolecular cyclization of N-(3-butynyl)-sulfonamides.

Hydroamination of 3-butynamine derivatives to give non-aromatic 2,3-dihydropyrroles was achieved by using PdCl2 or AuCl as the catalyst. With microwave-assisted heating, up to 92% isolated yield was obtained from this intramolecular 5-endo-dig cyclisation. The cyclopentane- and cyclohexane-fused 2,3-dihydropyrroles were transformed into the corresponding N-tosyl-pyrrolidine-2-carboxylic acids.

Enantioselective synthesis of (+)-brevipolide H.

The enantioselective synthesis of natural brevipolide H is reported for the first time. By way of Sharpless epoxidation of penta-1,4-dien-3-ol, both enantiomerically pure epoxides were converted to the corresponding olefins for cross metathesis. Subsequent transformations, including epoxide ring opening, esterifications, cyclopropanation, oxidation and ring-closing metathesis, provided the target molecule. This synthesis successfully addresses previous shortcomings in preparing brevipolides.

Formation of tetrahydrofurans via a 5-endo-tet cyclization of aziridines--synthesis of (-)-pachastrissamine.

The formation of tetrahydrofurans from 2-hydroxyalkyl-oxirane or aziridine is reported. The 5-endo-tet cyclization/ring opening of aziridine proceeded smoothly to give tetrahydrofurans (THFs) under mild conditions. In contrast, the corresponding process of oxirane was unsuccessful and a sequence of SN2 substitution/cyclization was required to form THFs. The application of the process to prepare ent-(-)-pachastrissamine is described.

Synthesis of the decalin core of codinaeopsin via an intramolecular Diels-Alder reaction.

We describe the synthesis of the decalin core of codinaeopsin (1), a tryptophan-polyketide hybrid natural product with promising antimalarial activity (IC50 4.7 µM, against Plasmodium falciparum), via an intramolecular Diels-Alder (IMDA) reaction. A convergent synthesis was developed to prepare the precursors for the IMDA reaction in 10 steps. The exo cycloadducts were derived from thermal, IMDA reactions of the substrates containing a Weinreb amide or ester conjugated dienophile, and the endo adducts were from Lewis acid promoted reactions of the substrates with a formyl group. Both exo and endo products of the IMDA were exclusively isolated and characterized by NMR spectroscopy. One endo cycloadduct was further confirmed with X-ray crystallography. Theoretical calculations reveal the influence of the substituents of the decalin core on the IMDA process.

Bortezomib congeners induce apoptosis of hepatocellular carcinoma via CIP2A inhibition.

CIP2A is an oncoprotein that upregulates p-Akt and promotes cancer cell proliferation and survival. The proteasome inhibitor bortezomib has been shown to reduce CIP2A and lead to cell apoptosis. Here; we modified the functional group of bortezomib to generate a series of novel compounds and conducted a structure-activity relationship (SAR) study. The results showed that compound 1 was able to repress CIP2A expression and cell apoptosis in the same manner as bortezomib, but with less potency in inhibition of proteasome activity. This finding provides a new direction for the design of CIP2A inhibitors.

Synthesis of Optically Active Organofluorides by Ring Opening of Oxazolidinone-Fused Aziridines.

A general method for synthesizing optically active, primary, secondary, and tertiary organofluorides was developed. This chiral pool synthesis utilized the skeleton of arabinose to generate diastereomerically pure 2-oxazolidinone-fused aziridines, which underwent ring opening with a fluoride anion. The adducts, polyoxygenated organofluorides, were useful precursors to various fluorinated compounds, such as fluorinated amino acids.

Characterization of the role of protein-cysteine residues in the binding with sodium arsenite.

To better characterize the interaction of protein-cysteines with sodium arsenite, arsenic-binding proteins were identified from the arsenic-resistant Chinese hamster ovary cell line SA7 using a p-aminophenylarsine oxide (PAO)-agarose matrix in combination with proteomic techniques. Twenty of the isolated arsenic-binding proteins were further peptide-mapped by MALDI-Q-TOF-MS. The binding capacity of PAO-agarose-retained proteins was then verified by re-applying Escherichia coli overexpressed recombinant proteins with various numbers of cysteine residues onto the PAO-agarose matrix. The results showed that recombinant heat shock protein 27 (HSP27, with one cysteine residue), reticulocalbin-3 (RCN3, with no cysteine residue), galectin-1 (GAL1, with six cysteine residues), but not peroxiredoxin 6 (Prdx6, with one cysteine residue but not retained by the PAO-agarose matrix), were bound to the PAO-agarose matrix. The six free cysteine residues in GAL1 were individually or double-mutated to alanine by means of site-directed mutagenesis and subjected to CD and ICP-MS analysis. The binding capacity of GAL1 for sodium arsenite was significantly attenuated in C16A, C88A and all double mutant clones. Taken together, our current data suggest that the cysteine residues in GAL1 may play a critical role in the binding of arsenic, but that in the case of RCN3 and Prdx6, this interaction may be mediated by other factors.

Direct Acetoxylation of Arenes.

Acetoxylation of arenes is an important reaction and an unmet need in chemistry. We report a metal-free, direct acetoxylation reaction using sodium nitrate under an anhydrous environment of trifluoroacetic acid, acetic acid, and acetic anhydride. Arenes (31 examples), with oxidation potentials (Eox, in V vs SCE) lower than benzene (2.48 V), were acetoxylated with good yields and regioselectivity. A stepwise, single electron-transfer mechanism is proposed.

Asymmetric synthesis of bis-tetrahydrofuran cores in annonaceous acetogenins.

The bis-THF cores of annonaceous acetogenins were synthesized using (3R,4R)-1,5-hexadiene-3,4-diol (1) as the sole source of carbon atoms. The methylene acetal function was applied as a new linker/tether to facilitate the ring-closing metathesis.

Synthesis of Methyl l-Kijanosides by Regio- and Stereoselective Ring Opening of 2-Oxazolidinone-Fused Aziridines.

Kijanose is one of the most highly functionalized deoxysugars found in nature and a challenging synthetic target. We found that the ring opening of trisubstituted, 2-oxazolidinone-fused aziridines is regio- and stereoselective, and the azide adduct has the same stereochemistry as that of kijanose after converting the azido to a nitro group. Therefore, both α- and ß-methyl l-kijanosides were prepared from ethyl l-lactate in 14% total yield.