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Functional organic dyes play a key role in many fields, namely in biotechnology and medical diagnosis. Herein, we report two novel 2,3- and 3,4-dihydroxyphenyl substituted rosamines ( 3 and 4 , respectively) that were successfully synthesized through a microwave-assisted protocol. The best reaction yields were obtained for rosamine 4 , which also showed the most interesting photophysical properties, specially toward biogenic amines (BAs). Several amines including n - and t -butylamine, cadaverine, and putrescine cause spectral changes of 4 , in UV-Vis and fluorescence spectra, which are indicative of their potential application as an effective tool to detect amines in acetonitrile solutions. In the gas phase, the probe response is more expressive for spermine and putrescine. Additionally, we found that methanolic solutions of rosamine 4 and n -butylamine undergo a pink to yellow color change over time, which has been attributed to the formation of a new compound. The latter was isolated and identified as 5 (9-aminopyronin), whose solutions exhibit a remarkable increase in fluorescence intensity together with a shift toward more energetic wavelengths. Other 9-aminopyronins 6a , 6b , 7a , and 7b were obtained from methanolic solutions of 4 with putrescine and cadaverine, demonstrating the potential of this new xanthene entity to react with primary amines.

A novel approach for synthesizing the key dolutegravir intermediate is described via MgBr 2 -promoted intramolecular cyclization. Condensation of commercially available methyl oxalyl chloride and ethyl 3-( N , N -dimethylamino)acrylate afforded the vinylogous amide in an excellent yield. Subsequent substitution by aminoacetaldehyde dimethyl acetal and methyl bromoacetate gave rise to the expected precursor for cyclization, which was promoted by MgBr 2 to highly selectively convert into pyridinone diester. The key dolutegravir intermediate was finally prepared by the selective hydrolysis of the corresponding diester via LiOH.

In the present work a series of heterocyclization reactions were adopted using cyclohexan-1,3-dione through its reaction with either furan-2-carbaldehyde or thiophene-2-carbaldehyde to give the corresponding ylidene derivatives 3a,b. The latter compounds underwent heterocyclization reactions to give thiophene and pyran derivatives 5a-d and 6a-d, respectively. Moreover, compounds 3a,b reacted with elemental sulfur and phenyl isothiocyanate to give the fused thiazole derivatives 8a,b. In addition, the reaction with either of hydrazine hydrate or phenylhydrazine has given the 4-hydrazono-4,5,6,7-tetrahydro-2H-indazole derivatives 10a-d, respectively. Similarly, the reaction of either 3a or 3b with hydroxylamine hydrochloride gave the 6,7-dihydrobenzo[c]isoxazol-4(5H)-one oxime derivatives 12a and 12b, respectively. Other fused heterocyclic compounds were produced and their structures were elucidated. Evaluation of the synthesized compounds against selected cancer cell lines was performed. The most active compounds were further evaluated against tyrosine kinases and Pim-1 kinase inhibitions.

Daldinins are a novel type of naturally occurring tricyclic heterocycles isolated from Daldinia concentrica. In this study, four daldinin A derivatives with different alkyl side chains were synthesized using the same synthetic protocol. Bioactivity tests first indicated that the daldinin A derivatives showed significant protection for endothelial cells against damage caused by high glucose. The derivative compound with three carbon atoms on the alkyl side exhibited the best effect.

The development of an improved short and efficient commercial synthesis of the JAK2 inhibitor, a complex pyrrolopyridine, BMS-911543, is described. During the discovery and development of this synthesis, a Pd-catalyzed C-H functionalization was invented which enabled the rapid union of the key pyrrole and imidazole fragments. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only six steps (longest linear sequence) from readily available materials.

The restricted number of antibiotics to treat infections caused by common multidrug resistant bacterial pathogens in the clinical setting demands a continuous search for new molecules with antibacterial properties. Bacterial iron deprivation represents a promising alternative, being iron chelators an attractive class for drug design in which particular compounds seem to have antibacterial effect. In this work, we report the synthesis and characterization of a new fluorescent 3-hydroxy-4-pyridinone (3,4-HPO) iron chelator functionalized with a carboxyrosamine fluorophore (MRB20). The antibacterial activity of MRB20 was assessed against representative strains from clinically relevant Gram-positive and Gram-negative bacterial species and further compared with the inhibitory effect of a set of structurally related iron chelators including Deferiprone (1,2-dimethyl-3-hydroxy-4-pyridinone). Compounds exhibiting a promising minimal inhibitory concentration (MIC < 10 mg/L) were further tested against a wider range of bacterial genera and species (Staphylococcus spp. Enterococcus spp. Listeria monocytogenes, Bacillus spp.), including multidrug resistant bacteria. With the exception of the novel compound (MRB20), all chelators inhibited the strains assayed at very high concentrations [minimum inhibitory concentrations (MIC) ranging from 70 mg/L to >180 mg/L]. MRB20 revealed a good antibacterial activity (6.7-13.2 mg/L) against Gram-positive strains from different genera and species, including clinically relevant species (Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecium, Enterococcus faecalis), which might be eventually compatible with a therapeutic application or as adjuvant., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A total synthesis of the diastereoisomeric pair of compounds, 4, assigned to the marine alkaloid discoipyrrole D is reported. A series of palladium-catalyzed cross-coupling and other reactions was employed to assemble the relevant 1,2,3,4-tetrasubstituted pyrrole (16) that was engaged in MoOPH-mediated oxidative cyclization, then conjugate addition, and redox processes to complete the synthesis. This work serves to confirm the structure (4) originally assigned to discoipyrrole D.

Xanthylium derivatives are yellow to orange pigments with a glyoxylic acid bridge formed by dimerization of flavanols, which are built by oxidative cleavage of tartaric acid. Although their structure and formation under wine-like conditions are well established, knowledge about their color properties and their occurrence and importance in wine is deficient. Xanthylium cations and their corresponding esters were synthesized in a model wine solution and isolated via high-performance countercurrent chromatography (HPCCC) and solid phase extraction (SPE). A Three-Alternative-Forced-Choice (3-AFC) test was applied to reveal the color perception threshold of the isolated compounds in white wine. Their presence and color impact was assessed in 70 different wines (58 white and 12 rosé wines) by UHPLC-DAD-ESI-MS n and the storage stability in wine was determined. The thresholds in young Riesling wine were 0.57 mg/L (cations), 1.04 mg/L (esters) and 0.67 mg/L (1:1 ( w / w ) mixture), respectively. The low thresholds suggest a possible impact on white wine color, but concentrations in wines were below the threshold. The stability study showed the degradation of the compounds during storage under several conditions. Despite the low perception threshold, xanthylium derivatives might have no direct impact on white wine color, but might play a role in color formation as intermediate products in polymerization and browning., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

First asymmetric synthesis of the marine natural product (-)-gracilioether F is described from a d-mannitol derived known compound. The key step involves intramolecular 1,4-conjugate addition of a hydroxymethyl radical generated from Ti (III) mediated ring opening of a terminal epoxy ring tethered to a butenolide to produce stereoselectively a five-membered ring fused bicyclic lactone, the core structure present in gracilioether F.

Efficient and concise approaches for the synthesis of three bioactive natural products, isohericerin, isohericenone, and erinacerin A, are described in this paper. The key reactions employed include a Mannich reaction with commercially available hydroxybenzoate and subsequent one-pot lactamization to afford the common precursor isoindolinone in 3 steps and a Suzuki-Miyaura coupling reaction to connect geranyl side chains to the isoindolinone core. In addition, the mild and efficient synthesis of the C5'-oxidized geranyl side unit of isohericenone is enabled by developing a highly regioselective and efficient method for the Cu-catalyzed methylboronation of functionalized terminal alkynes.

Background: Overexpression of Aurora A and B has been reported in a wide range of tumor types, including gastric cancer. Anti-angiogenesis has been considered as an important therapeutic modality in advanced gastric cancer. Here we identified a novel compound TY-011 with promising antitumor activity by targeting mitotic kinases (Aurora A and B) and angiogenic receptor tyrosine kinase (VEGFR2)., Methods: HTRF® KinEASE™ assay was used to detect the effect of TY-011 against Aurora A, Aurora B and VEGFR2 activities. Docking simulation study was performed to predict the binding mode of TY-011 with Aurora A and B kinases. CCK-8 assay was used to test cell growth. Cell cycle and cell apoptosis was analyzed by flow cytometry. Gastric cancer cell xenograft mouse models were used for in vivo study. TUNEL kit was used to determine the apoptosis of tumor tissues. Immunohistochemistry analysis and HUVEC tube formation assay were performed to determine the anti-angiogenesis ability. Immunofluorescence and western blot were used to test protein expression., Results: TY-011 was identified as a potential Aurora A and B inhibitor by HTRF® KinEASE™ assay. It effectively inhibited cellular Aurora A and B activities in a concentration-dependent manner. TY-011 occupied the ATP-binding site of both Aurora A and B kinases. TY-011 demonstrated prominent inhibitory effects on proliferation of gastric cancer cells. TY-011 treatment induced an obvious accumulation of cells at G2/M phase and a modest increase of cells with >4 N DNA content, which then underwent apoptosis. Meaningfully, orally administration of TY-011 demonstrated superior efficacy against the tumor growth in gastric cancer cell xenograft, with ~90% inhibition rate and 100% tumor regression at 9 mg/kg dose, and TY-011 did not affect the body weight of mice. Interestingly, we observed that TY-011 also antagonized tumor angiogenesis by targeting VEGFR2 kinase., Conclusions: These results indicate that TY-011 is a well-tolerated, orally active compound that targets mitosis and angiogenesis in tumor growth, and provides strong preclinical support for use as a therapeutic for human gastric cancers.

An efficient protocol for the direct transformation of chroman-4-ones to tricyclic fused pyridines with the skeleton of cassiarins, a family of alkaloids with antimalarial activity, was developed. Also, a general strategy for modular construction of polyheterocycles with diverse natural product-like skeletons was developed by using ketone-alkyne bifunctional substrates. These reactions involved a one-pot cascade oximation of ketones, rhodium-catalyzed C-H activation, and intermolecular/intramolecular alkyne annulations under mild conditions with high atom, step, and redox economy.

A series of halogeno derivatives of thiourea bearing a polycyclic imide core has been efficiently synthesized and evaluated for antimicrobial activity. The structures of the compounds were established by 1H and 13C NMR and MS methods. The molecular structure of 4Clc was determined by an X-ray crystallography. Compounds containing 3-chloro-4-fluorophenyl substituent (3Cl4Fb, 3Cl4Fd) were found to be the most promising against Gram-positive bacteria (MIC values ranged from 8 to 32 pg/mL for standard and 32 - 64 µg/mL for hospital strains). The in vitro cytotoxicity against MT-4 cells of all compounds was evaluated.

Herein, we report total syntheses of the tetramethyldihydroxanthene natural product rhodomyrtosone B and the related bis-furan β-triketone natural product rhodomyrtosone A. Nickel-(II)-catalyzed 1,4-conjugate addition of an α-alkylidene-β-dicarbonyl substrate was developed to access the congener rhodomyrtosone B, and oxygenation of the same monoalkylidene derivative followed by cyclization was employed to obtain the bis-furan natural product rhodomyrtosone A.

A formal synthesis of (-)-schulzeine B, a marine natural alkaloid possessing potent antidiabetic activity, has been achieved. A benzo[a]quinolizidin-4-one is a common skeleton of schulzeines (A-C). (-)-Schulzeine B possesses an (S)-stereogenic center at the C-3 carbon. The chiral (3S,11bS)-3-amino-9,11-dimethoxybenzo[a]quinolizidin-4-one has been prepared efficiently from (2-bromo-3,5-dihydroxyphenyl)acetonitrile in 17 steps including (i) a dehydrative intramolecular amination catalyzed by HClO4 and (ii) a proline or boric acid catalyzed transcycloamidation reaction for the construction of the δ-lactam ring.

BMS-911543 is a complex pyrrolopyridine investigated as a potential treatment for myeloproliferative disorders. The development of a short and efficient synthesis of this molecule is described. During the course of our studies, a Ni-mediated C-N bond formation was invented, which enabled the rapid construction of the highly substituted 2-aminopyridine core. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only eight steps starting from readily available materials.

High sensitivity and specificity are two desirable features in biomedical imaging. Raman imaging has surfaced as a promising optical modality that offers both. Here we report the design and synthesis of a group of near-infrared absorbing 2-thienyl-substituted chalcogenopyrylium dyes tailored to have high affinity for gold. When adsorbed onto gold nanoparticles, these dyes produce biocompatible SERRS nanoprobes with attomolar limits of detection amenable to ultrasensitive in vivo multiplexed tumour and disease marker detection.

An efficient synthesis of the tricyclic cyclopenta[1,2-b]pyrrolo[1,2-a]azepine nucleus of stemonamine alkaloids is reported. The key reaction utilizes a one-pot gold(I)-catalyzed cyclization and SnCl4-mediated Schmidt rearrangement. Notably, the phosphine ligand had a crucial effect on the gold(I)-catalyzed cyclization. As an application of this new methodology, the formal synthesis of (±)-stemonamine has been accomplished.

Direct one-pot base-promoted conjugate addition-elimination of 6,8-dibromo-4-chloroquinoline-3-carbaldehyde with methyl mercaptoacetate and subsequent cyclization afforded methyl [(6,8-dibromothieno[3,2-c]quinoline)]-2-carboxylate. The latter undergoes Suzuki-Miyaura cross-coupling with arylboronic acids to yield exclusively the corresponding alkyl [(6,8-diarylthieno[3,2-c]quinoline)]-2-carboxylates,. The cytotoxicity of the prepared compounds was evaluated against the human breast cancer cell line MCF-7 using the MTT assay. The effects of compounds 2, 3c and 4d on cell kinetics were further determined using the xCELLigence Real Time Cell Analysis (RTCA) system. In both the MTT assay and Real Time Cell Analysis, the compounds inhibited cancer cell growth in a dose- and time-dependent manner. Furthermore, on the basis of the calculated LC50 values, the compounds compared favourably with nocodazole, a well-established anticancer drug.

Concise and highly stereocontrolled total syntheses of racemic and enantiopure frog alkaloid 205B (1) were accomplished in 11 steps from 4-methoxypyridines 6 and 7 in overall yields of 8 and 8%, respectively. The assembly of the core of the natural product relies on a stereoselective Tsuji-Trost allylic amination reaction and a ring-closing metathesis. The synthesis features the use of an N-acylpyridinium salt reaction to introduce the first stereocenter and an unprecedented trifluoroacetic anhydride-mediated addition of an allylstannane to a vinylogous amide with complete facial selectivity. Deoxygenation of the C4 ketone proved difficult but was accomplished via a modified Barton-McCombie reaction in the presence of a catalytic amount of diphenyl diselenide.

Andrographolide (AGP) is the main bioactive constituent isolated from the traditional medicinal, Andrographis paniculata which contributes towards its various biological activities, including anticancer property. In this study, a series of new AGP derivatives were semi-synthesised and screened against the NCI in vitro 60 cell lines. From the screening results, we had identified SRS07 as the most potent AGP derivative, against breast and colon cancer cell lines. Subsequently, SRS07 was tested for its capability to induce cell cycle arrest and apoptosis in MCF-7 and HCT116 cancer cells. SRS07 effectively induced G1 cell cycle arrest in both cell lines and ultimately apoptosis by inducing DNA fragmentation in HCT116 cells. The apoptotic cell death induced by SRS07 was confirmed via FITC Annexin-V double staining. Western blot analysis of SRS07-treated HCT116 cells revealed that the compound induced apoptosis be activating caspase 8 which in turn cleaved Bid to t-Bid to initiate cell death cascade. Prediction of the possible mode of action of SRS07 by utilising NCI COMPARE analysis failed to reveal a distinct mechanism category. Hence, it is speculated that SRS07 possesses novel mechanism of action. In conclusion, SRS07 demonstrated superior in vitro anticancer profiles and emerged as a potential lead anticancer candidate., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Natural products continue to provide a rich source of inspiration for both chemists and biologists. The efficient synthesis of bioactive natural products or natural product-like molecules has offered tremendous opportunities for complex biological processes exploration and drug discovery. However, because natural products usually contain numerous stereogenic centres and polycyclic ring systems, significant synthetic challenges remain. Here we employ the build/couple/pair strategy that is frequently used in diversity-oriented synthesis to obtain skeletally diverse compounds with complexities comparable to natural products. Inspired by the functional group pairing patterns hidden in Lycopodium alkaloids, we efficiently and in parallel construct four natural products, (+)-Serratezomine A, (-)-Serratinine, (+)-8α-Hydroxyfawcettimine and (-)-Lycoposerramine-U, as well as six different unnatural scaffolds, following the advanced build/couple/pair algorithm. This newly developed strategy is expected to be applied to the efficient synthesis of other complex natural products possessing functional group pairing patterns as well as skeletally diverse natural product-like molecules.

Total syntheses of 5'- and 7'-oxidized geranyl resorcylates isolated from the fruiting bodies of Hericium erinaceum and the submerged cultures of a Stereum species were achieved. Our synthesis features derivatization of a suitably functionalized 5'-oxidized geranyl phthalide as a common intermediate, which was obtained by Stille coupling between the phthalide core and the side chain, into a series of natural products by divergent functional group manipulations. The crucial C5'-oxygen functionality was installed at the initial stage by alkylation by an α-cyano ethoxyethyl ether. From a common synthetic intermediate, eight total syntheses including hericenones A, B, and I, hericenols B-D, and erinacerins A and B were achieved (hericenol B and erinacerin B were synthesized as racemates). The structure of hericenone B established in the isolation paper was unambiguously revised as the carbonyl regioisomer at the lactam moiety.

A stereocontrolled general methodology to access all natural tetraponerines from (+)-T1 to (+)-T8 is detailed. Two consecutive indium-mediated aminoallylations with the appropriate enantiomer of chiral N-tert-butylsulfinamide and a thermodynamic control at the aminal stereocenter allow the formation of each natural tetraponerine with excellent stereoselectivity. The use of 4-bromobutanal in the first aminoallylation leads to the formation of 5-6-5 tetraponerines, while 5-bromopentanal is required to build the scaffold of 6-6-5 tetraponerines. A cross-metathesis reaction of the second aminoallylation product with cis-3-hexene is used to elongate the side chain up to 5 carbons so as to prepare the tetraponerines T5 to T8. The anticancer activity of these heavier tetraponerines against four different carcinoma human cell lines is examined, observing a promising cytotoxic activity of (+)-T7 against breast carcinoma cell line MCF-7.

A short and cost-effective synthesis of the important strigolactone analogue (+)-GR24 is described. Central to this new approach is the concise, enantioselective synthesis of the A-C ring system.

A recyclable asymmetric metal-based catalyst is a rare entity among the vast collection of asymmetric catalysts developed so far. Recently we found that the combination of a self-assembling metal-based asymmetric catalyst and multiwalled carbon nanotubes (MWNTs) produced a highly active and recyclable catalyst in which the catalytically active metal complex was dispersed in the MWNT network. Herein we describe an improved preparation procedure and full details of a Nd/Na heterobimetallic complex confined in MWNTs. Facilitated self-assembly of the catalyst with MWNTs avoided the sacrificial use of excess chiral ligand for the formation of the heterobimetallic complex, improving the loading ratio of the catalyst components. Eighty-five percent of the catalyst components were incorporated onto MWNTs to produce the confined catalyst, which was a highly efficient and recyclable catalyst for the anti-selective asymmetric nitroaldol reaction. The requisite precautions for the catalyst preparation to elicit reproducible catalytic performance are summarized. Superior catalytic profiles over the prototype catalyst without MWNTs were revealed in the synthesis of optically active 1,2-nitroalkanols, which are key intermediates for the synthesis of therapeutics.

The undecose nucleoside antibiotics herbicidin C and aureonuclemycin are biologically highly active and represent challenging targets for total synthesis. Herein, the gradual evolution of our synthetic strategy toward these natural products is described in detail. The initial route encompasses metalate addition chemistry but suffers from poor stereochemical control. In contrast, the ultimately successful strategy benefits from a variety of reagent-controlled stereoselective transformations, including a surprisingly facile and highly diastereoselective N-glycosylation process. The presented work also describes new building blocks that might find further application in carbohydrate chemistry.

Dengue viruses (DENV) infect 50 to 100 million people worldwide per year, of which 500,000 develop severe life-threatening disease. This mosquito-borne illness is endemic in most tropical and subtropical countries and has spread significantly over the last decade. While there are several promising vaccine candidates in clinical trials, there are currently no approved vaccines or therapeutics available for treatment of dengue infection. Here, we describe a novel small-molecule compound, ST-148, that is a potent inhibitor of all four serotypes of DENV in vitro. ST-148 significantly reduced viremia and viral load in vital organs and tended to lower cytokine levels in the plasma in a nonlethal model of DENV infection in AG129 mice. Compound resistance mapped to the DENV capsid (C) gene, and a direct interaction of ST-148 with C protein is suggested by alterations of the intrinsic fluorescence of the protein in the presence of compound. Thus, ST-148 appears to interact with the DENV C protein and inhibits a distinct step(s) of the viral replication cycle.

An efficient stereocontrolled preparation of tetraponerines T3 and T4 is detailed. The sequence takes advantage of two consecutive stereoselective aminoallylations of appropriate aldehydes with chiral tert-butanesulfinamide and in situ generated allyl indium species. The absolute configuration of the carbon stereogenic center at the aminal moiety is thermodynamically controlled. This was ascertained on the basis of an exhaustive DFT configurational study of tetraponerines, which fulfils the lack of detailed structural information for these systems. It was found that the trans-transoid-configuration of the AB rings is the most stable geometry for T3 and T4. However, the C ring prefers a cis-configuration in T3 (ttc-T3) and a trans-fusion in T4 (ttt-T4). Regarding their dynamic behavior, low activation barriers were found by DFT calculations for the inversion of the nitrogen at the indolizidine framework, allowing rapid equilibration between the major configurations (ttc and ttt) in T3 and T4.

The first enantioselective syntheses of cladoacetals A (1a, overall yield: 16%) and B (1b, overall yield: 34%) from crotonaldehyde in nine and seven steps, respectively, have been accomplished. Sharpless asymmetric dihydroxylation, Suzuki coupling, and acid-catalyzed intramolecular acetalization were the key steps in the syntheses. The absolute configuration of natural (+)-cladoacetal A was affirmed to be 1S,3S,4R, whereas that of (-)-cladoacetal B was affirmed to be 1R,3S,4S.

The total syntheses of the lycopodium alkaloids fawcettimine, fawcettidine, lycoflexine, and lycoposerramine B have been accomplished through an efficient, unified, and stereocontrolled strategy that relies on a Diels-Alder reaction to construct the cis-fused 6,5-carbocycles with one all-carbon quaternary center. Access to the enantioselective syntheses of both antipodes of those alkaloids can be achieved by kinetic resolution of the earliest intermediate via a Sharpless asymmetric dihydroxylation (Sharpless AD). Compared to existing approaches to these alkaloids, our synthetic route possesses superior stereocontrol over the C-4 and C-15 stereogenic centers as well as allowing for more functional variation on the 6-membered ring.

A method for the assembly of tricyclic structures containing the peroxide, monoperoxyacetal, and acetal moieties was developed based on the acid-catalyzed reaction of β,δ-triketones with H(2)O(2). Tricyclic compounds are formed selectively in yields from 39% to 90% by the reactions with the use of large amounts of strong acids, such as H(2)SO(4), HClO(4), or HBF(4), which act both as the catalyst and as the co-solvent. The reaction is unusual in that, despite the diversity of possible peroxidation pathways giving cyclic compounds and oligomers, the reaction proceeds with high selectivity and produces tricyclic peroxides via the monoperoxidation of the carbonyl groups in the β-positions and the transformation of the δ-carbonyl group into the acetal one. The syntheses are scaled up to tens of grams, and the resulting peroxides can be easily isolated from the reaction mixture.

A copper-catalyzed annulative amination approach to 3-aminobenzofurans and -indoles from o-alkynylphenols and -anilines has been developed. The Cu-based catalysis is based on an umpolung, electrophilic amination with O-benzoyl hydroxylamines and enables the mild and convergent synthesis of various 3-aminobenzoheteroles of biological and pharmaceutical interest. Some mechanistic investigations and an application of this protocol to construction of more complex tricyclic framework are also described.

A facile convergent synthesis of the tricyclic core 2 of roseophilin is described, which represents the shortest route so far for the formal synthesis of roseophilin. The key step was a tandem pyrrole acylation-Nazarov cyclization reaction to form the cyclopenta[b]pyrrole moiety 4.

Formal enantioselective total synthesis of schulzeines A-C was accomplished, featuring highly efficient Pd-catalyzed asymmetric allylic amination using novel diphosphonite ligands (BOPs) to provide 1-vinyltetrahydroisoquinoline key intermediates, as well as Ru-catalyzed ring-closing metathesis reaction to construct the key tricyclic cores in enantiopure form with correct absolute configurations.

The asymmetric synthesis of the core structure of leucosceptroids A-D has been achieved. The key steps of the synthesis includes the formation of the cis-2,5-disubstituted THF ring by TPAP catalytic oxidative cyclization followed by a highly diastereoselective intramolecular Diels-Alder reaction to fashion the fused tricyclic hydrindane ring system.

The first enantioselective total synthesis of (+)-(R)-concentricolide, the enantiomer of an anti-HIV-1 agent isolated from Daldinia concentrica, from 2-iodophenol in 7 steps reveals the (S)-configuration for the natural form of the furanophthalide. The key features include an anionic ortho-Fries rearrangement to furnish 3-iodosalicylamide, facile construction of the benzofuran system employing the tandem Sonogashira coupling annulation reaction, directed ortho metalation to introduce a propanoyl group, as well as CBS reduction, establishing the stereocenter enantioselectively.

A concise total synthesis of the G2/M DNA damage checkpoint inhibitor psilostachyin C is reported using a 1,4-addition-aldol condensation-ring-closing metathesis (RCM) strategy. Initial biological studies indicate that psilostachyin C could enhance the sensitivity of the HeLa cell toward camptothecin (CPT) treatment via the activation of the caspase-3 mediated apoptosis pathway., (© 2011 American Chemical Society)

We have developed an efficient strategy to a skeletally diverse chemical library, which entailed a sequence of enyne cycloisomerization, [4 + 2] cycloaddition, alkene dihydroxylation, and diol carbamylation. Using this approach, only 16 readily available building blocks were needed to produce a representative 191-member library, which displayed broad distribution of molecular shapes and excellent physicochemical properties. This library further enabled identification of a small molecule, which effectively suppressed glycolytic production of ATP and lactate in CHO-K1 cell line, representing a potential lead for the development of a new class of glycolytic inhibitors.

A facile total synthesis of marine natural product (±)-spiniferin-1 has been accomplished in eight steps with 28.9% overall yield, involving a rearrangement reaction initiated by polyfluoroalkanosulfonyl fluoride to construct the 1,6-methano[10]annulene core of the natural product as a key step.

A new tacrine based cholinesterase inhibitor, N-(bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine (1), was designed and synthesized to interact with specific regions of human acetylcholinesterase and human butyrylcholinesterase. Its inhibitory ability towards cholinesterases was determined and compared to tacrine (THA) and 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine (7-MEOTA). The assessment of IC50 values revealed 1 as a weak inhibitor of both tested enzymes.

Brefeldin A-mediated inhibition of ADP ribosylation factor (Arf) GTPases and their guanine nucleotide exchange factors, Arf-GEFs, has been a cornerstone of membrane trafficking research for many years. Brefeldin A (BFA) is relatively non-selective inhibiting at least three targets in human cells, Golgi brefeldin A resistance factor 1 (GBF1), brefeldin A inhibited guanine nucleotide exchange factor 1 (BIG1) and brefeldin A inhibited guanine nucleotide exchange factor 2 (BIG2). Here, we show that the previously described compound Exo2 acts through inhibition of Arf-GEF function, but causes other phenotypic changes that are not GBF1 related. We describe the engineering of Exo2 to produce LG186, a more selective, reversible inhibitor of Arf-GEF function. Using multiple-cell-based assays and GBF1 mutants, our data are most consistent with LG186 acting by selective inhibition of GBF1. Unlike other Arf-GEF and reported GBF1 inhibitors including BFA, Exo2 and Golgicide A, LG186 induces disassembly of the Golgi stack in both human and canine cells., (© 2010 John Wiley & Sons A/S.)

N,N',N''-trimethyltribenzo-1,4,7-triazacyclononatriene has been synthesized via sequential palladium-catalyzed Buchwald-Hartwig N-arylation reactions affording the 9-membered triaza o-cyclophane in 35% overall yield. An X-ray crystal structure shows the new cyclophane to have a C2-symmetric saddle conformation, as compared to the crown conformation exhibited by the related carbocyclic cyclotriveratrylene (CTV).

The total synthesis of (+)-fawcettimine was completed in a highly stereoselective manner starting from the oxatricyclo[7.3.0.0(1,5)]dodecanedione derivative. The crucial step in this total synthesis involves the efficient construction of the azonane framework by the intramolecular Mitsunobu reaction. Furthermore, the first total synthesis of (+)-lycoposerramine-B was also accomplished via the common synthetic intermediate.

A practical asymmetric synthesis of a novel aminopiperidine-fused imidazopyridine dipeptidyl peptidase IV (DPP-4) inhibitor 1 has been developed. Application of a unique three-component cascade coupling with chiral nitro diester 7, which is easily accessed via a highly enantioselective Michael addition of dimethyl malonate to a nitrostyrene, allows for the assembly of the functionalized piperidinone skeleton in one pot. Through a base-catalyzed, dynamic crystallization-driven process, the cis-piperidionone 16a is epimerized to the desired trans isomer 16b, which is directly crystallized from the crude reaction stream in high yield and purity. Isomerization of the allylamide 16b in the presence of RhCl(3) is achieved without any epimerization of the acid/base labile stereogenic center adjacent to the nitro group on the piperidinone ring, while the undesired enamine intermediate is consumed to <0.5% by utilizing a trace amount of HCl generated from RhCl(3). The amino lactam 4, obtained through hydrogenation and hydrolysis, is isolated as its crystalline pTSA salt from the reaction solution directly, as such intramolecular transamidation has been dramatically suppressed via kinetic control. Finally, a Cu(I) catalyzed coupling-cyclization allows for the formation of the tricyclic structure of the potent DPP-4 inhibitor 1. The synthesis, which is suitable for large scale preparation, is accomplished in 23% overall yield.

A simple and practical synthetic method of pyrimido[1,2-c][1,3]benzothiazin-6-imines and related tricyclic heterocycles has been developed. Treatment of 2-(2-haloaryl)tetrahydropyrimidines with NaH and a heterocumulene such as carbon disulfide, isothiocyanates, and isocyanates in DMF provides the desired cyclization products through a regioselective S(N)Ar-type reaction. This method provides direct access to PD 404182 and related compounds.

A series of twenty arylpiperazine derivatives of 1,7,8,9-tetrachloro-10,10-dimethoxy-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione have been prepared. These derivatives were tested in vitro with the aim of identifying novel lead compounds active against emergent and re-emergent human and cattle infectious diseases (AIDS, hepatitis B and C, tuberculosis, bovine viral diarrhea). In particular, these compounds were evaluated in vitro against representatives of different virus classes, such as a HIV-1 (Retrovirus), a HBV (Hepadnavirus) and the single-stranded RNA(+) viruses Yellow fever virus (YFV) and Bovine viral diarrhea virus (BVDV), both belonging to the Flaviridae. Compounds 2c, 2g and 3d showed a modest activity against CVB-2. The molecular structures of the starting imide 1 and one of propyl-piperazine derivatives, 3b, have been determined by an X-ray crystallography study.

A Yamaguchi-type cyclization of 5 and subsequent photochemical oxidation of the furanic ring are the key steps in the first synthesis of the marine metabolite (+)-luffalactone 4 and its epimer at C-16, 16-epi-luffalactone, 27. With this work, we have successfully established the absolute configuration of the natural product. The key intermediate 5 was obtained from the easily accessible diacetate 6a/6b.

A practical large-scale chromatography-free synthesis of EP4 antagonist MF-310, a potential new treatment for chronic inflammation, is presented. The synthetic route provided MF-310 as its sodium salt in 10 steps and 17% overall yield from commercially available pyridine dicarboxylate 7. The key features of this sequence include a unique regioselective reduction of succinimide 2 controlled by the electronic properties of a remote pyridine ring, preparation of cyclopropane carboxylic acid 3 via a Corey-Chaykovsky cyclopropanation, and a short synthesis of sulfonamide 5.

Readily available 4-formyloxyazetidinone was enantioselectively transformed into 3,4-benzo-2-hydroxy-5-oxacephams and 4-phenyloxyazetidinones upon treatment with 0.1 equiv of the cinchona alkaloid in toluene via intermolecular nucleophilic trapping of N-acyliminium intermediate by the hydroxyl moiety of phenols or o-hydroxybenzaldehydes. Additionally, the absolute configuration of title compounds was established by CD spectroscopy.