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Novel substituted chromenopyrrolidinones were synthesized from natural amino acid derivatives through an unprecedented route involving a Knoevenagel/transesterification sequence and an allylative palladium-catalyzed cyclization reaction. The products were nature-inspired heterocycles derived from natural amino acids. The targets were synthesized with varying degrees of stereoselectivity: racemization is a known issue with amino acids, and this provided a formidable challenge to our method development. In total, six derivatives were synthesized in moderate to good yields.

Calyculins are a class of highly cytotoxic metabolites originally isolated from the marine sponge Discodermia calyx. To date, a total of twelve different calyculins (A–J) and calyculinamides (A, B and F) have been described, the most abundant (in D. calyx) being calyculins A and C. Herein, we demonstrate a concise route to access the C1–C12 tetraene fragment of calyculin C using transition-metal-catalyzed coupling reactions (Suzuki–Miyaura, Stille, Negishi and Heck) for the key connections. The synthesis starts from propionaldehyde and proceeds in 10 steps with 7.5% overall yield. We also describe an efficient route for the preparation of (Z)-3-iodobut-2-enenitrile in four steps and 68% yield.

A highly efficient synthetic route towards dibrominated, substituted carbazoles via an environmentally benign, regioselective bromination as the key step has been developed. Electron-rich and electron-deficient aromatic as well as aliphatic groups are well tolerated enabling access to these versatile ligand precursors in high overall yields. On larger scale the whole sequence can be performed under chromatography-free conditions.

Tetrahydro-β-carbolines, a privileged structural feature in natural products and pharmaceutically active compounds, has been the cause for considerable research interest, spanning many decades. Herein is reported the synthesis of the structurally closely related compounds denoted as (indol-2-yl)methanamines, in 99 % ee using amino acid starting materials, coupled with a 9-phenyl-9-fluorenyl (Pf) protecting group strategy. Furthermore a conformational study of Pf-protected α-amino carbonyl compounds were undertaken by means of DFT refined molecular mechanics calculation, X-ray crystallography measurements and NMR experiments in order to elucidate the stereochemical protecting properties induced by the Pf group.

A direct palladium-catalyzed C–H arylation method to synthesize biaryls from dicyanobenzenes has been developed. The reaction is selective towards C2-arylation of 1,3-dicyanobenzene and provides biaryls from both electron-rich and electron-poor aryl bromides containing para and meta substituents. A variety of functional groups are tolerated, and yields up to 83 % can be obtained. The methodology can be extended to C–H activation of other electron-deficient benzonitriles.

The Rho family of Ras superfamily small GTPases regulates a broad range of biological processes such as migration, differentiation, cell growth and cell survival. Therefore, the availability of small molecule modulators as tool compounds could greatly enhance research on these proteins and their biological function. To this end, we designed a biochemical, high throughput screening assay with complementary follow-up assays to identify small molecule compounds inhibiting MgcRacGAP, a Rho family GTPase activating protein involved in cytokinesis and transcriptionally upregulated in many cancers. We first performed an in-house screen of 20,480 compounds, and later we tested the assay against 342,046 compounds from the NIH Molecular Libraries Small Molecule Repository. Primary screening hit rates were about 1% with the majority of those affecting the primary readout, an enzyme-coupled GDP detection assay. After orthogonal and counter screens, we identified two hits with high selectivity towards MgcRacGAP, compared with other RhoGAPs, and potencies in the low micromolar range. The most promising hit, termed MINC1, was then examined with cell-based testing where it was observed to induce an increased rate of cytokinetic failure and multinucleation in addition to other cell division defects, suggesting that it may act as an MgcRacGAP inhibitor also in cells.

Fast pyrolysis bio-oil has unfavorable properties that restrict its use in many applications. Among the main issues are high acidity, instability, and water and oxygen content, which give rise to corrosiveness, polymerization during storage, and a low heating value. Esterification and azeotropic water removal can improve all of these properties. In this work, low acidity biooils were produced from fast pyrolysis bio-oil via esterification with methanol or n-butanol. Esterification conversion was enhanced by azeotropic water removal prior to and/or during esterification. An additional hydrocarbon entrainer (n-heptane or petroleum ether) was required for efficient water removal. The product oils had total acid numbers ranging from 5 to 10 mg KOH/g and pH values from 4.0 to 5.6. The best results were obtained with 1:0.9:0.1 wt ratio of bio-oil, n-butanol, and n-heptane and p-toluenesulfonic acid (p-TSA) as catalyst. Removal of homogeneous catalyst (2 wt % p-toluenesulfonic acid (p-TSA)) was attempted by precipitation, centrifugation, and water washing, but only 41−82 wt % of the catalyst could be recovered from the product oil based on sulfur content. Solid acid catalysts were more efficient with methanol than n-butanol in dry conditions. An organic base (triethylamine) was tested for neutralizing the methanol esterified bio-oil’s residual acidity. Nitrogen content increased by 0.1−0.4 wt % when pH values of 6−8 were obtained.

An alternative route to the tetrahydro-β-carboline scaffold is presented, where the amino acid l -alanine was transformed to (S)-eleagnine in a straightforward and scalable manner yielding the target compound in enantiopure form on gram scale.

Harmicine, a chiral tetrahydro-β-carboline with a rare tetracyclic pyrrolidine framework, was isolated from the plant Kopsia griffithii in 1998. Before that, harmicine had already appeared frequently in the chemical literature as a starting material for natural product synthesis and it had been used as a model substrate in various methodology studies. Herein we review the relevant information available on this heterocyclic natural product before and after its isolation and classification as a natural product.

(S)- and (R)-Harmicine were synthesized from L- and D-proline, respectively. This chiral pool synthesis constitutes a new approach towards C1 substituted tetrahydro-β-carbolines. The developed route makes use of the 9-phenyl-9-fluorenyl protecting group strategy of amino acids to prevent racemization of the vulnerable α-amino carbonyl stereocenter. Enantiopure harmicine (> 99 % ee) was obtained in nine steps from commercially available starting material. The synthesis was performed without the use of any silica gel flash chromatography.

In 1976 Mukaiyama published a paper that was to make a major impact on the development of the aldol reaction in the future. Mild enolate formation by treatment of a ketone with dibutylboron triflate in the presence of a tertiary amine generates a relatively stable boron enolate, which can subsequently react with an aldehyde to give the cross-aldol product in good yields. This reaction has become a reliable tool for the practicing synthetic chemist. Nearly 10000 polyketides are known, and of these about 600 contain the tripropionate unit with a stereotetrad, four contiguous stereocenters with alternating methyl and hydroxyl substituents in the main chain. The versatility of the boron enolate aldol reaction is showcased with selected applications in the synthesis of these structural motifs.

we reasoned that suitableactivation of the enone moiety could facilitate this ringclosure mode. We then realized that an allyl carbamate(Alloc) group would be ideal for this purpose. The maskednitrogen nucleophile can be liberated under neutral condi-tions, a very important factor considering the sensitive natureof the enone. A related 6-exo heterocyclization has beendemonstrated previously by Martin and co-workers, and a 5-exo cyclization by Tsuji et al.

Aldehydes may be dimerized to symmetric esters via the Tishchenko reaction. This process is traditionally catalyzed by aluminum alkoxides, but a wide variety of different metal catalysts has been explored and implemented, ranging from simple alkali metal compounds to actinoid complexes. The mechanistic key step is a hydride transfer from a hemiacetal intermediate to an aldehyde, both participants being coordinated to the metal catalyst in the transition state. Recent research on the Tishchenko reaction has especially focused on the controlled synthesis of unsymmetrical esters. In the aldol-Tishchenko variant, an aldol reaction takes place first between two aldehydes, or a ketone and an aldehyde. In the subsequent Tishchenko step, another aldehyde molecule coordinates to the aldol product, forming a hemiacetal intermediate. An intramolecular hydrogen transfer from the hemiacetal to the carbonyl group takes place, giving a 1,3-diol monoester product. With -hydroxy ketone substrates, the reaction is highly diastereoselective towards 1,3-anti-diols due to a highly organized six-membered transition state promoted by coordination of a metal catalyst to both the hemiacetal and carbonyl groups. Thus, recent research has strongly focused on the development of direct catalytic asymmetric aldol-Tishchenko reactions. The Evans-Tishchenko reaction is a further variant of the aldol-Tishchenko reaction, being used to reduce preformed -hydroxy ketones to anti-1,3-diols under relatively mild conditions. This method is applied to various total syntheses of natural products. Samarium iodide is commonly used as the catalyst, and nearly any aldehyde is suitable as the reducing agent. The reaction has also been exploited in a reverse fashion to oxidize complex aldehydes to carboxylic acids using a simple sacrificial -hydroxy ketone as the oxidant. This review covers the literature from the discovery of the Tishchenko reaction in 1887 up to early 2014. Different catalyst systems for both Tishchenko and aldol-Tishchenko reactions are discussed and compared in the “Scope and Limitations” section, and the state of the art in substrate complexity for the reaction is presented in the “Tabular Survey”.

An efficient demethylation reaction for aromatic methyl ethers has been developed. Deprotection reactions give high yields with butylpyridinium bromide under microwave irradiation. Basic and acidic functional groups are tolerated if the reaction is performed under acidic conditions.

Asymmetric synthesis of the title compound was accomplished starting from L-serine. Stannoxane-mediated lactamization provided the key intermediate in good yield.

The asymmetric Michael addition of Meldrum’s acid to nitroalkenes was studied using a novel type of Cinchona alkaloid-based bifunctional thiourea organocatalyst. The functionality of the thiourea catalysts was also probed by preparing and testing thiourea-N-methylated analogues of the well-known bis-(3,5-trifluoromethyl)phenyl-substituted catalyst.

Carbamates are a well-established class of fatty acid amide hydrolase (FAAH) inhibitors. Here we describe the synthesis of meta-substituted phenolic N-alkyl/aryl carbamates and their in vitro FAAH inhibitory activities. The most potent compound, 3-(oxazol-2yl)phenyl cyclohexylcarbamate (2 a), inhibited FAAH with a sub-nanomolar IC(50) value (IC(50)=0.74 nM). Additionally, we developed and validated three-dimensional quantitative structure-activity relationships (QSAR) models of FAAH inhibition combining the newly disclosed carbamates with our previously published inhibitors to give a total set of 99 compounds. Prior to 3D-QSAR modeling, the degree of correlation between FAAH inhibition and in silico reactivity was also established. Both 3D-QSAR methods used, CoMSIA and GRID/GOLPE, produced statistically significant models with coefficient of correlation for external prediction (R(2) (PRED)) values of 0.732 and 0.760, respectively. These models could be of high value in further FAAH inhibitor design.

The influence of catalyst components in the copper–TEMPO (2,2,6,6-tetramethylpiperidine N-oxide) catalysed aerobic oxidation of alcohols was investigated. The type and amount of base greatly influences reactivity. The bipyridyl ligand concentration had no major influence on catalysis, but excessive amounts led to a decrease in activity for longer reaction times. The kinetic dependency for TEMPO was found to be 1.15, and for copper 2.25, which is an indication of a binuclear catalytic system. Optimised conditions with various allylic and aliphatic alcohols give good to excellent rapid oxidations.

A series of quinolinyl and isoquinolinyl phenyl ketones was synthesized and their CB(2) receptor-dependent G-protein activities were determined using the [(35)S]GTPgammaS binding assay. Both quinoline and isoquinoline derivatives exhibited similar CB(2) receptor agonist activity, the most potent ligands being the 2-(Me(2)N)-phenyl substituted derivatives, which were also full agonists at the CB(2)-receptor.

This paper describes a new procedure for the enantioselective synthesis of the important anticonvulsant drug Pregabalin, which shows biological properties as the (S) enantiomer only. The key step of the synthetic sequence is the Michael addition reaction of Meldrum's acid to a nitroalkene mediated by a quinidine derived thiourea. A variety of novel catalysts bearing different groups at the thiourea moiety were synthesized and tested. The most successful catalyst that incorporates a trityl substituent provided up to 75 % ee of (S)-4. The conjugate addition reaction was carried out on a multigram scale with low loadings of catalyst (10 mol-%). Moreover, the catalyst can be recycled showing the same capability in chemical yield and asymmetric induction. Then, hydrogenation of nitroalkane 4 followed by decarboxylation of diacid 5 provides Pregabalin hydrochloride in 59 % overall yield. Enantioenrichment by crystallization of the free amino acid 1 improves the (S)/(R) enantiomeric ratio to 9:1.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

A short total synthesis of the cytotoxic natural product pachastrissamine is described. The synthesis includes eight steps starting from Garner’s aldehyde and proceeds in 20% overall yield. Pd(0)-mediated intramolecular cyclisation and Ru-mediated cross-metathesis are the key reactions in this sequence.

C2-dissymmetric PyOX-ligands have been applied to the asymmetric Henry reaction. This widely applicable reaction is easy to perform, requires no inert atmospheres or dry solvents, and gives good selectivities. By adjusting ligand side-chains, a significant impact on selectivities was observed.

Improved ways to cleave peptide chains at engineered sites easily and specifically would form useful tools for biochemical research. Uses of such methods include the activation or inactivation of enzymes or the removal of tags for enhancement of recombinant protein expression or tags used for purification of recombinant proteins. In this work we show by gel electrophoresis and mass spectroscopy that salts of Co(II) and Cu(II) can be used to cleave fusion proteins specifically at sites where sequences of His residues have been introduced by protein engineering. The His residues could be either consecutive or spaced with other amino acids in between. The cleavage reaction required the presence of low concentrations of ascorbate and in the case of Cu(II) also hydrogen peroxide. The amount of metal ions required for cleavage was very low; in the case of Cu(II) only one to two molar equivalents of Cu(II) to protein was required. In the case of Co(II), 10 molar equivalents gave optimal cleavage. The reaction occurred within minutes, at a wide pH range, and efficiently at temperatures ranging from 0 degrees C to 70 degrees C. The work described here can also have implications for understanding protein stability in vitro and in vivo.

The condensation reaction of 2-amino-3-hydroxypyridine with different carboxylic acids by microwave-assisted heating is a fast method for producing libraries based on fused 2-substituted oxazolo[4,5-b]pyridines in moderate to good yields.

Whereas starting compound (III) is already known, an efficient approach to the analogous amino acid derivatives (I) and (V) is investigated to prepare them in a reasonable yield.

Harmicine, a chiral tetrahydro-β-carboline with a rare tetracyclic pyrrolidine framework, was isolated from the plant Kopsia griffithii in 1998. Before that, harmicine had already appeared frequently in the chemical literature as a starting material for natural product synthesis and it had been used as a model substrate in various methodology studies. Herein we review the relevant information available on this heterocyclic natural product before and after its isolation and classification as a natural product.

Aldehydes may be dimerized to symmetric esters via the Tishchenko reaction. This process is traditionally catalyzed by aluminum alkoxides, but a wide variety of different metal catalysts has been explored and implemented, ranging from simple alkali metal compounds to actinoid complexes. The mechanistic key step is a hydride transfer from a hemiacetal intermediate to an aldehyde, both participants being coordinated to the metal catalyst in the transition state. Recent research on the Tishchenko reaction has especially focused on the controlled synthesis of unsymmetrical esters. In the aldol-Tishchenko variant, an aldol reaction takes place first between two aldehydes, or a ketone and an aldehyde. In the subsequent Tishchenko step, another aldehyde molecule coordinates to the aldol product, forming a hemiacetal intermediate. An intramolecular hydrogen transfer from the hemiacetal to the carbonyl group takes place, giving a 1,3-diol monoester product. With -hydroxy ketone substrates, the reaction is highly diastereoselective towards 1,3-anti-diols due to a highly organized six-membered transition state promoted by coordination of a metal catalyst to both the hemiacetal and carbonyl groups. Thus, recent research has strongly focused on the development of direct catalytic asymmetric aldol-Tishchenko reactions. The Evans-Tishchenko reaction is a further variant of the aldol-Tishchenko reaction, being used to reduce preformed -hydroxy ketones to anti-1,3-diols under relatively mild conditions. This method is applied to various total syntheses of natural products. Samarium iodide is commonly used as the catalyst, and nearly any aldehyde is suitable as the reducing agent. The reaction has also been exploited in a reverse fashion to oxidize complex aldehydes to carboxylic acids using a simple sacrificial -hydroxy ketone as the oxidant. This review covers the literature from the discovery of the Tishchenko reaction in 1887 up to early 2014. Different catalyst systems for both Tishchenko and aldol-Tishchenko reactions are discussed and compared in the “Scope and Limitations” section, and the state of the art in substrate complexity for the reaction is presented in the “Tabular Survey”.

Preparation of novel chiral gold nanoparticles (AuNP) is described. The major advantage of nanoparticles is to combine the easy handling of solid-supported ligands and the efficiency of soluble ligands, as the molecular size of the support approaches the minimum. This is even of industrial interest, because this kind of technology offers a way of avoiding leaching of the catalyst metal in the reaction and separation of the entire catalyst using simple filtration. In this paper, we describe the attachment of a chiral soluble PyOX-ligand on a nano support via simple ligand exchange. As a result, we achieved a core smaller than ever before in experimental chemistry (1.2 ± 0.2 nm) and promising enantioselectivity in a preliminary test reaction.

The synthesis of novel metal chelation driven molecular pincers based on crown ether and salen ligand substructures are described. Their functionality was monitored by fluorescence spectroscopy using pyrene groups as fluorescence probes. The pincer was shown to function reversibly with respect to metal chelation with Zn2+ and also to chelate ditopically with 100 mol % of Zn2+ and 100 mol % Li+ or 200 mol % of Li+ ion.

A synthetic route for a new, phenolic Dpa-based aza ligand is presented and its chelation with zinc ions and imidazole were studied using UV/vis and mass spectrometry. A bathochromic shift of 30 nm was observed for the 2∗Zn complex of the ligand in UV/vis zinc titration experiments. The mass spectrum indicated formation of an imidazole anion zinc chelate complex.

A novel supported amino alcohol linker was synthesized and utilized for attachment of picolinic acid derivatives onto different supports. When the resin bound molecule was further activated, the PyOX-moiety could be constructed reliably in enantiopure form. Furthermore, an efficient Pd-catalyzed modification of a picolinic acid derivative is presented.

The mechanism of the double intramolecular hetero-Michael addition, a key reaction in the planned synthesis of the natural product calyculin C, has been studied by NMR. The cyclization follows Baldwin’s rules and proceeds first through a six-membered ring closure (6-endo-dig), followed by a five-membered ring cyclization (5-exo-trig). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

The bicyclo[4.3.0]nonane substructure is an abundant structure found in several natural compounds. A novel enantioselective organocatalytic cycloaddition was used to prepare the bicyclo[4.3.0]nonane skeleton. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

The metathesis reaction of Cp*(CO)3MoBr and NaW(CO)3Cp produced Cp*(CO)3Mo–W(CO)3Cp (1), featuring an unsupported Mo–W bond. Exposure of solutions of 1 to light leads to the quantitative formation of the corresponding homometallic dimers. In the solid state, the title complex exhibits an anti-arrangement of the η5-cyclopentadienyl and the η5-pentamethyl-cyclopentadienyl ligands and six terminal carbonyls. Comparison to corresponding complexes of molybdenum and tungsten reveals that the Mo–W distance is dictated by the presence of a Cp and a Cp* ligand. This is the first time that an unsupported Mo–W single bond distance is reported.

Highly diastereoselective aldol additions of (2 R ,4 S )-3- tert -butyl 4-methyl 2- tert -butyloxazolidine-3,4-dicarboxylate ( 1 ) are reported. The utility of the highly substituted oxazolidines of type 1 for diastereoselective α-addition of the fully protected amino acid l -serine with achiral and chiral carbonyl compounds is demonstrated and the relative and absolute configuration of the aldol products are discussed on the basis of NOESY data and solid state structures of selected examples. The aldol products represent highly useful intermediates in the syntheses of sphingosine-related metabolites.

A new short strategy to prepare the spiroketal fragment of calyculins is presented. A novel Seyferth–Gilbert type homologation of hindered lactols to the corresponding alkynes has been achieved for the first time. The spirocyclization was achieved efficiently via a DIHMA (double intramolecular hetero-Michael addition) process of this hindered ynone. The spirocyclization rate is not dependent on the stereochemistry of the alkoxy substituent in the oxolane ring.

A highly diastereoselective synthesis of the title fragment of calyculin C has been developed based on an internal asymmetric induction between a chiral aldehyde and Z-crotyl trifluorosilane.