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Copper-promoted dehydrosulfurative C–N cross-coupling of 3,4-dihydropyrimidin-1H-2-thione with amine accompanied by concomitant aromatization to generate 2-aryl(alkyl)aminopyrimidine derivatives is described.

A Pd-catalyzed/Cu-mediated oxidative dehydrosulfurative carbon-oxygen cross-coupling reaction of 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) with aryl alcohols is described. Due to the ready availability of diverse DHPMs and aryl alcohols, the reaction method offers facile access to biologically and pharmacologically valuable 2-aryloxypyrimidine derivatives with rapid diversification.

An aerobic Cu-promoted oxidative dehydrosulfurative carbon–oxygen cross-coupling of 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) with both aliphatic and aromatic alcohols is described. Together with the ready availability of DHPMs and both alcohols, the method furnishes facile access to biologically valuable 2-alkoxypyrimidines with rapid diversification.

A reaction method is described for the one-step synthesis of 2-alkynylpyrimidines from 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) via dehydrosulfurative Sonogashira cross-coupling with concomitant o...

An aerobic Cu-promoted oxidative dehydrosulfurative carbon-oxygen cross-coupling of 3,4-dihydropyrimidin-1

A reaction method is described for selective reductive cleavage of 2-(phenylthio)pyrimidines using Pd(OAc)2 and Et3SiH to produce 2-(H)pyrimidines. The reaction proceeds efficiently with a wide range of 2-(phenylthio)pyrimidines. Considering the ready availability of 2-(arylthio)pyrimidines derived from oxidative C S cross coupling of 3,4-dihydropyrimidin-1H-2-thiones (DHPMs), this method unambiguously provides a shortcut to the preparation of 2-(H)pyrimidines with unprecedented diversity.

Alloy structures with high catalytic surface areas and tunable surface energies can lead to high catalytic selectivity and activities. Herein, the synthesis of sponge-like Pd

Decarboxylative C C cross-couplings of 2-aminopyrimidine-5-carboxylic acids under a Pd/Ag-based catalytic system opens a new platform for the introduction of diverse C5 substituents. The reaction methods proceeded efficiently with a wide range of the acids and the coupling partners of aryl iodides, alkenes, bromoalkynes, and azoles. Considering ready availability of 2-aminopyrimidine-5-carboxylic acid from the oxidative dehydrosulfurative C N cross-coupling of the 3,4-dihydropyrimidin-1H-2-thiones, this reaction method unambiguously pave a shortcut to densely substituted 2-aminopyrimidine derivatives with unprecedented diversity.

This report describes a cascade reaction method for the synthesis of 2-arylpyrimidine derivatives via dehydrosulfurative carbon-carbon cross-coupling and concomitant oxidative dehydrogenation under a Pd/Cu catalytic system. It provides rapid and general access to a diverse range of 2-arylpyrimidines in a single step from a wide range of 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) and arylboronic acids.

It is well-known that Ru-based Grubbs catalysts undergo a highly selective α-addition to alkynes to promote exo-cyclization during ring-closing enyne metathesis (RCEYM) or to produce conjugated polyenes containing five-membered rings during the cyclopolymerization (CP) of 1,6-heptadiynes. There are a few reports of β-selective addition to alkynes using Schrock catalysts based on Mo but none for readily accessible and easy-to-use Ru-based catalysts. We report the first example of β-selective addition to alkynes using Grubbs Z-selective catalyst, which produces only endo products during the RCEYM reaction of terminal enynes and promotes the CP of 1,6-heptadiyne derivatives to give conjugated polyenes containing a six-membered ring as a major repeat unit. This unique preference for β-selectivity originated from the side-bound approach of alkynes to the catalyst, where the steric hindrance between the chelating N-heterocyclic carbene ligand of the catalyst and the alkynes disfavored α-addition. To enhance the β-selectivity for CP further, one could increase the size of the substrates on the monomers and lower the reaction temperature to obtain conjugated polyenes containing up to 95% six-membered rings. Moreover, the physical properties of the resulting polymer were analyzed in detail and compared with those of the conjugated polyenes containing only five-membered rings prepared from the same monomer but with a conventional Grubbs catalyst.

A copper-mediated oxidative dehydrosulfurative carbon–oxygen cross-coupling reaction with boric ester and six-membered cyclic thiourea for single-step production of densely substituted 2-alkoxypyrimidines incorporated in a privileged scaffold is described. This is the first demonstration of boric ester acting as an alkoxy donor in a metal-catalyzed coupling reaction to produce ether. The reaction method offers a shortcut for producing 2-alkoxypyrimidine derivatives with rapid diversification and expands the utility of boric ester and the scope of Liebeskind–Srogl-type reactions.

Described is a copper-catalyzed cascade reaction method for the conversion of 3,4-dihydropyrimidine-2(1 H )-thiones to arylthiopyrimidines, likely proceeded via C–S cross-coupling and oxidative dehydrogenation under aerobic conditions. The reaction method proceeded efficiently with a wide range of the dihydropyrimidinethione substrates and aryl iodides as coupling partners.

Simultaneously growing multiple nanocrystallites in a crowded space can cause a shortage of precursors, and this can lead to a vertical growth of nanocrystallites on a given substrate. The presence of surfactant-surfactant interactions among adjacent nanocrystals can also place a unique structural constraint on the growing nanocrystallites, resulting in novel nanocrystal facet control. Herein, we report the growth of Rh on Au@Pt nanowires with multiple twinning boundaries, which are found along the entire nanowire length. The Au@Pt nanowires exhibit numerous bead-like structures, resulting from the preferred Pt deposition on the twinning boundaries, which can serve as nucleation sites for Rh. The heteroepitaxial growth of Rh on the Au@Pt nanowires results in unusual crystal growth behaviours. First, novel morphologies of Rh nanorods, nanoplates, and tangled manes are obtained temperature-dependently, which are not obtained in the absence of the Au@Pt nanowire substrate. Secondly, the thickness of vertically grown nanorods and nanoplates is tightly controlled. We also report the structure-catalytic activity relationship on the catalytic hydrogenation of phthalimides by the new Rh nanostructures.

A simple and efficient aerobic oxidative dehydrogenation reaction method for the conversion of 2-(alkylthio)-1,4-dihydropyrimidines to 2-(alkylthio)pyrimidines using copper catalyst with no additives, such as an oxidant, acid, or base, has been developed. The reaction was successful with a wide range of 2-(alkylthio)-1,4-dihydropyrimidine substrates.

Surface-energy fine-tuned five-fold twinned nanostructures with a core-shell Pt3Ni@Rh structural motif, namely, a core-shell Pt3Ni@Rh pentagon, a core-shell Pt3Ni@Rh starfish, and a paddlewheel with a Pt3Ni crankshaft and two Rh five-fold starfish wheels, are prepared by rationally designed stepwise heteroepitaxial growth. Unusual selective hydrogenation of the phenyl ring in phthalimide is accomplished with moderately active core-shell Pt3Ni@Rh pentagons and starfish-like nanoparticles. The most active paddlewheel structure proceeds to further reduce one carbonyl group, indicating the sequential nature of phthalimide reduction by Rh nanoparticle catalysis.

Functionality preferences of metathesis Ru carbenes to various alkenes and alkynes with electronic and steric diversity were determined by using time-dependent fluorescence quenching. The functionality preferences depend not only on the properties of multiple bonds but also on the ligands on Ru. There was a good correlation between functionality preference and the metathesis reaction outcome. The correlation between functionality preference and exo/endo product ratio offers a solution to resolve the mechanistic issue related with alkene- vs alkyne-initiated pathway in ring-closing enyne metathesis. The correlation indicates the preference is likely to dictate the reaction pathway and eventually the outcome of the reaction. The Ru catalyst favoring alkyne over alkene provides more endo product, indicating that the reaction mainly initiates at the alkyne. By changing the substitution pattern, the preference can be reversed to give an exclusive exo product.

A method for the synthesis of 2-aryl(alkyl)aminopyrimidines from readily available 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) via dehydrosulfurative C–N cross-coupling and concomitant oxidative dehydrogenation under a Pd/Cu catalytic system is described. This reaction protocol provides unprecedented diversity of fully substituted 2-aryl(alkyl)aminopyrimidines in a single step from a wide range of DHPMs and amine coupling partners.

As a guide for selective reactions toward either Z- or E-alkene in a metathesis reaction, the relative preference of metathesis Ru catalysts for each stereoisomer was determined by a method using time-dependent fluorescence quenching. We found that Ru-1 prefers the Z-isomer over the E-isomer, whereas Ru-2 prefers the E-isomer over the Z-isomer. The Z/E-alkene preference of the catalysts precisely predicted the Z/E isomeric selectivity in the metathesis reactions of diene substrates possessing combinations of Z/E-alkenes. For the diene substrates, the rate order of the reactions using Ru-1 was Z,Z-1,6-diene > Z,E-1,6-diene > E,E-1,6-diene, while the completely opposite order of E,E-1,6-diene > Z,E-1,6-diene > Z,Z-1,6-diene was exhibited in the case of Ru-2.

E-mail: sohnjh@cnu.ac.krReceived October 31, 2011, Accepted November 1, 2011Key Words : Arteminolide, Santonin, Farnesyltransferase, Photochemical rearrangementArteminolides A-D (1-4), isolated from the leaves ofArtemisia sylvatica Maxim, are triterpene lactones (Figure1) and have been reported to be strong inhibitors offarnesyltransferase (FTase).

Herein we present the long-sought quantitative catalyst−substrate association relationships based on experimentally measured quantitative association preferences of diverse metathesis Mo and Ru catalysts (Mo-1, Schrock Mo; Mo-2, Schrock−Hoveyda Mo; Ru-1, Grubbs first generation Ru; Ru-2, Grubbs second generation Ru; Ru-3:, Grubbs−Hoveyda first generation Ru; and Ru-4, Grubbs−Hoveyda second generation Ru) to their substrates (alkenes, alkynes and allenes), determined directly by a general method based on FRET principle. The determined substrate preferences are proved to be dependent on the molecular identity of the catalyst, exhibiting the preference order of alkyne > alkene > allene for Mo-1 and Mo-2, allene > alkene > alkyne for Ru-1 and Ru-3, and alkyne > allene > alkene for Ru-2 and Ru-4. The results enable us to probe metathesis mechanisms by answering issues in metathesis reactions including the controversial reaction initiation in enyne or allenyne metathesis.

We describe a rapid and efficient method for selective deprotection of methoxymethyl (MOM) ethers using ZnBr2 and n-PrSH, which completely removed MOM from diverse MOM ethers of primary, secondary, and tertiary alcohols or phenol derivatives. The deprotection takes less than ten minutes with both high yield and selectivity in the presence of other protecting groups. In addition, the rapid deprotection of MOM ethers of tertiary hydroxyls in high yield with no epimerization allows MOM to be a suitable protecting group for tertiary alcohols.

Described are the studies on the mechanism of the asymmetric Biginelli reaction using proline ester salt catalyst to explain the enantioselectivity of the 3,4-dihydropyrimidin-2(1H)-one (DHPM) formation. Of the three possible activation methods by the catalyst that could provide asymmetric induction we revealed that the steric environment of the chiral enamine formed by the condensation of β-keto ester with the catalyst is most responsible for the enantioselectivity. This assumption is supported by experiments with the N-methylated catalyst, and the combination sets of L- or D-proline ester catalyst with racemic or chiral BINOL-derived phosphoric acid as counter acid. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Described is a copper-catalyzed cascade reaction method for the conversion of 3,4-dihydropyrimidine-2(1 H )-thiones to arylthiopyrimidines, likely proceeded via C–S cross-coupling and oxidative dehydrogenation under aerobic conditions. The reaction method proceeded efficiently with a wide range of the dihydropyrimidinethione substrates and aryl iodides as coupling partners.

For the presented approach no further additives like oxidants, acids, or bases are required.

Facet-controlled dendritic nanostructures are expected to exhibit excellent catalytic properties because both aggregation-free nature and controlled facet-originated activity and selectivity can be accomplished. However, such examples are extremely rare due to the incompatibility of the dendrite formation process with the usage of surface-stabilizing moieties, which are typically used to control facets. Herein, we demonstrate that regiospecific growth on a facet-controlled core nanoparticle can induce the facet-control of the branch nanoparticles. Specifically, facet-controlled dendritic nanostructures of {100}Rh–Pt and {100}Pt–Pt can be conveniently prepared by transferring the crystallographic behaviour of the {100}Pt dendritic core nanocube to the {100}Rh or {100}Pt branch nanocubes.

Impurity doping has yielded a number of useful optical and catalytic alloy nanoparticles, by providing synthetic routes to unprecedented nanostructures. However, Zn is difficult to use as a dopant in alloy nanoparticles due to the difficulty in reduction, and therefore little has been reported on Zn-doped alloy nanoparticles and their potential applications. Herein we report an unusual role of the dopant Zn as a crystal growth modifying agent to cause the formation of novel concave Rh nanostructures, namely nanotents. We could further prepare unprecedented hierarchically stacked Rh nanoframes and dendritic nanostructures derived from them by understanding the role of various surface-stabilizing moieties. We also report the usage of new Rh nanostructures in selective hydrogenation of phthalimides.

Described are general protocols for the rapid construction of various C-15-substituted analogues of vindoline using palladium-catalyzed cross-coupling reactions. The required bromo- and iodovindolines were prepared in high yield by the reaction of vindoline with N-bromosuccinimide or N-iodosuccinimide, respectively. The study not only led to the preparation of a number of structurally novel vindoline analogues but also opens the door to new strategies for the synthesis of vinblastine, vincristine, and related anticancer agents. Also described is the conversion of ent-tabersonine to ent-vindoline.

The first example of tripeptide inhibitors of farnesyltransferase with sub-micromolar inhibition activity was developed based on the fact that CVFM is not a substrate for farnesyltransferase.

Common intermediates to biogenic precursors of arteminolides are synthesized via a key silicon-tethered intramolecular [5 + 2]oxidopyrylium cycloaddition reaction.

The oxidopyrylium cycloaddition reaction of allenes was investigated. Contrary to other cycloaddition reactions, electron deficient allenes were not reactive at all and electron rich allenes were slightly more reactive than neutral allenes. The intermolecular cycloaddition reaction occurred at the terminal position regardless of substitution patterns. For the intramolecular reaction only the perhydroazulene structure was obtained over other possible products.

Functionality preferences of metathesis Ru carbenes to various alkenes and alkynes with electronic and steric diversity were determined by using time-dependent fluorescence quenching. The functionality preferences depend not only on the properties of multiple bonds but also on the ligands on Ru. There was a good correlation between functionality preference and the metathesis reaction outcome. The correlation between functionality preference and exo/endo product ratio offers a solution to resolve the mechanistic issue related with alkene- vs alkyne-initiated pathway in ring-closing enyne metathesis. The correlation indicates the preference is likely to dictate the reaction pathway and eventually the outcome of the reaction. The Ru catalyst favoring alkyne over alkene provides more endo product, indicating that the reaction mainly initiates at the alkyne. By changing the substitution pattern, the preference can be reversed to give an exclusive exo product.

involving metathesis reactions for the preparation of diene fragments (III) and (V) as the key steps

A novel nonpeptidic reverse-turn scaffold containing urea fragments that are connected by a conformationally constrained d-prolyl-cis-1,2-diaminocyclohexane (d-Pro-DACH) linker is reported. The scaffold adopts a well-defined reverse-turn conformation that is stabilized by dual intramolecular hydrogen bonding in both solution and solid states.

Compound (III), which has the common ring skeleton of the B- and B′-rings of arteminolides, is synthesized in eight steps starting from 1,3-propanediol via an unprecedented intramolecular [5 + 2] oxidopyrylium cycloaddition reaction with vinylsilyl ether tether as key step.

We describe a rapid and efficient method for selective deprotection of methoxymethyl (MOM) ethers using ZnBr2 and n-PrSH, which completely removed MOM from diverse MOM ethers of primary, secondary, and tertiary alcohols or phenol derivatives. The deprotection takes less than ten minutes with both high yield and selectivity in the presence of other protecting groups. In addition, the rapid deprotection of MOM ethers of tertiary hydroxyls in high yield with no epimerization allows MOM to be a suitable protecting group for tertiary alcohols.

The oxidopyrylium cycloaddition reaction of allenes was investigated. Contrary to other cycloaddition reactions, electron deficient allenes were not reactive at all and electron rich allenes were slightly more reactive than neutral allenes. The intermolecular cycloaddition reaction occurred at the terminal position regardless of substitution patterns. For the intramolecular reaction only the perhydroazulene structure was obtained over other possible products.

The first example of tripeptide inhibitors of farnesyltransferase with sub-micromolar inhibition activity was developed based on the fact that CVFM is not a substrate for farnesyltransferase.

Drugs currently available for leishmaniasis treatment often show parasite resistance, highly toxic side effects and prohibitive costs commonly incompatible with patients from the tropical endemic countries. In this sense, there is an urgent need for new drugs as a treatment solution for this neglected disease. Here we show the development and implementation of an automated high-throughput viability screening assay for the discovery of new drugs against Leishmania. Assay validation was done with Leishmania promastigote forms, including the screening of 4,000 compounds with known pharmacological properties. In an attempt to find new compounds with leishmanicidal properties, 26,500 structurally diverse chemical compounds were screened. A cut-off of 70% growth inhibition in the primary screening led to the identification of 567 active compounds. Cellular toxicity and selectivity were responsible for the exclusion of 78% of the pre-selected compounds. The activity of the remaining 124 compounds was confirmed against the intramacrophagic amastigote form of the parasite. In vitro microsomal stability and cytochrome P450 (CYP) inhibition of the two most active compounds from this screening effort were assessed to obtain preliminary information on their metabolism in the host. The HTS approach employed here resulted in the discovery of two new antileishmanial compounds, bringing promising candidates to the leishmaniasis drug discovery pipeline., Author Summary Every year, more than 2 million people worldwide suffer from leishmaniasis, a neglected tropical disease present in 88 countries. The disease is caused by the single-celled protozoan parasite species of the genus Leishmania, which is transmitted to humans by the bite of the sandfly. The disease manifests itself in a broad range of symptoms, and its most virulent form, named visceral leishmaniasis, is lethal if not treated. Most of the few available treatments for leishmaniasis were developed decades ago and are often toxic, sometimes even leading to the patient's death. Furthermore, the parasite is developing resistance to available drugs, making the discovery and development of new antileishmanials an urgent need. To tackle this problem, the authors of this study employed the use of high-throughput technologies to screen a large library of small, synthetic molecules for their ability to interfere with the viability of Leishmania parasites. This study resulted in the discovery of two novel compounds with leishmanicidal properties and promising drug-like properties, bringing new candidates to the leishmaniasis drug discovery pipeline.