Thirty years of pyrimidine chemistry in the laboratory of organic chemistry at the Wageningen Agricultural University,The Netherlands (review)

In this review attention is paid to two topics, which were of great interest to us during 30 years of studies in pyrimidine chemistry in our laboratory: first, the development of our concepts of the AIYRORC processes, which occur in ring transformation reactions; second, the intra- and intermolecular inverse Diels-Alder reactions in which the pyrimidine ring acts as the electron poor diazadiene system. Their use in synthetic chemistry is illustrated and evidence is presented, based on experiments and molecular mechanics calculations, that in intermolecular Diels-Alder reactions the geometry of the side-chain plays a vital role.     

The influence of hydrophobic amino acid side groups on the acidity of the aromatic imidazole ring of histidine: A theoretical study

In this study we have calculated the acidity constant (pKa) of imidazole ring in Histidine‐Hydrophobic amino acid dipeptides using the quantum chemistry and continuum solvation methods. Density functional theory calculations with the large basis sets are used to determine the Gibbs free energy of deprotonate in the gas and liquid phases. Based on our results ΔG_S values are located between ?69.38 and ?18.82 kcal mol^?1 which are related to His⁺–Gly and His forms, respectively. pKa of the dipeptides in the aqueous phase was obtained from the calculated gas‐phase and solvation free energies through a thermodynamic cycle and the solvation model chemistry of Martin Karplus et al. Solvation effects are treated using a self‐consistent reaction field formalism involving polarized continuum models. According to our calculations pKa values are between 5.50 and 8.19 that are belong to His⁺–ILe and His⁺–Ala forms, respectively. Natural bond orbital analysis of dipeptides reveals that the electron delocalization in imidazole ring is the most effective factor in determination of acidity order for these compounds. Structural analysis confirmed that the orientation of carbonyl group with respect to imidazole ring is an effective factor in imidazole ring stability. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Synthetic organic chemistry based on small ring compounds

Small ring systems are important topics in both organic and inorganic chemistry, and draw considerable attention from both theoretical and preparative perspectives. This review intends to summarize the studies, focusing on the preparative aspects, that have been carried out in our laboratory. Namely, synthesis of (+)- and (-)-alpha-cuparenone, (+)-ipomeamarone, (+)-epiipomeamarone, (-)-ngaione, (-)-alpha-bisabolol, (-)-aplysin, (-)-debromoaplysin, (-)-mesembrine, (-)-filiformin, (-)-debromofiliformin, and (-)-4-deoxyverrucarol via successive asymmetric epoxidation and enantiospecific ring expansion of cyclopropylidenes, (+)-equilenin via successive ring expansion-insertion reaction, estrone, estradiol, chenodeoxycholic acid, 19-norspironolactone, 19-nordeoxycorticosterone, cortisone, adrenosterone, 11-oxoprogesterone, and 1alpha,25-dihydroxyvitamin D3 via intramolecular cycloaddition reaction of o-quinodimethanes. Medicinal chemistry aiming at developing a new type of anti-influenza agent, novel reaction mode of electrocyclic reaction, and substituent effect on that reaction are also discussed.     

Renaissance of Ring‐Opening Chemistry of Benzotriazoles: New Wine in an Old Bottle

1,2,3‐Benzotriazoles could undergo ring cleavage to form ortho‐amino arenediazonium or α‐diazo‐imine species via a Dimroth‐type equilibrium. Historically, the synthetic potential of this unique reactivity had remained underdeveloped. Recently, some new strategies have been developed to effect the ring‐opening chemistry of benzotriazoles in more practical manners. A wide range of conceptually novel and synthetically useful reactions have been developed, which enable the access to diverse valuable heterocycles and ortho‐amino arene derivatives. As one of the players in this field, our group has also contributed a series of intriguing transition‐metal‐catalyzed denitrogenative functionalizations of benzotriazoles. In this account, we aim to provide an overview of the ring‐opening chemistry of benzotriazoles, with a focus on relevant works published in the past decade. In order to show a whole picture of the research field, some pioneering works in its developing history will also be discussed briefly.     

The Evolution of the Total Synthesis of Rocaglamide

The complex flavagline, (?)‐rocaglamide, possesses a synthetically intriguing tricyclic scaffold with five contiguous stereocenters and also exhibits potent anticancer, anti‐inflammatory and insecticidal activity. This full account details distinct approaches to (±)‐ and (?)‐rocaglamide utilizing Brønsted acid catalyzed and asymmetric Pd⁰‐catalyzed Nazarov chemistry developed in our laboratory, respectively. The successful asymmetric synthesis revealed unforeseen mechanistic complexity that required adjusting our strategy to overcome an unanticipated racemization process, an unusual reversible ring‐cleavage step and a very facile trialkylsilyl group migration.     

A Unified Mechanism on the Formation of Acenes,Helicenes, and Phenacenes in the Gas Phase

A unified low-temperature reaction mechanism on the formation of acenes, phenacenes, and helicenes—polycyclic aromatic hydrocarbons (PAHs) that are distinct via the linear, zigzag, and ortho-condensed arrangements of fused benzene rings—is revealed. This mechanism is mediated through a barrierless, vinylacetylene mediated gas-phase chemistry utilizing tetracene, [4]phenacene, and [4]helicene as benchmarks contesting established ideas that molecular mass growth processes to PAHs transpire at elevated temperatures. This mechanism opens up an isomer-selective route to aromatic structures involving submerged reaction barriers, resonantly stabilized free-radical intermediates, and systematic ring annulation potentially yielding molecular wires along with racemic mixtures of helicenes in deep space. Connecting helicene templates to the Origins of Life ultimately changes our hypothesis on interstellar carbon chemistry.     

硅杂四元环化合物的合成和反应

硅杂四元环化合物在有机硅化学中是一类非常重要的小分子环系化合物, 广泛应用于有机化学、金属有机化学以及材料化学. 环上只含有一个硅原子的硅杂环丁烷可以通过γ-卤代丙基硅烷的Grignard反应、Si＝C键与烯烃的 [2＋2]环加成反应以及硅杂环丙烷的扩环反应合成, 环上只含有一个硅原子的硅杂环丁烯可以通过格氏试剂或锂试剂参与的Si—C键的关环反应、硅杂环丁烷的转化反应、硅卡宾对C—H键的插入反应、Si＝C键与炔烃的[2＋2]环加成反应以及二炔基硅烷的分子内成环反应等途径合成. 硅杂环丁烷和硅杂环丁烯由于存在环张力和具有一定的Lewis酸性, 能够通过扩环反应生成五元和六元含硅杂环化合物, 也能够通过开环反应生成不同结构的有机硅分子和聚合物, 抑或实现有机反应在温和条件下的转化.     

The fast and the curious: High‐throughput experimentation in synthetic polymer chemistry

The application of automated synthetic parallel methods in polymer chemistry is described. A brief overview of all different polymerization techniques that have been used is provided. Furthermore, the equipment and methodologies that were used in our approach for automated parallel polymerization reactions are discussed followed by detailed insight into recent developments on automated cationic ring‐opening polymerization, atom transfer radical polymerization, and emulsion polymerizations. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 2425–2434, 2003     

A Unified Mechanism on the Formation of Acenes,Helicenes, and Phenacenes in the Gas Phase

A unified low‐temperature reaction mechanism on the formation of acenes, phenacenes, and helicenes—polycyclic aromatic hydrocarbons (PAHs) that are distinct via the linear, zigzag, and ortho‐condensed arrangements of fused benzene rings—is revealed. This mechanism is mediated through a barrierless, vinylacetylene mediated gas‐phase chemistry utilizing tetracene, [4]phenacene, and [4]helicene as benchmarks contesting established ideas that molecular mass growth processes to PAHs transpire at elevated temperatures. This mechanism opens up an isomer‐selective route to aromatic structures involving submerged reaction barriers, resonantly stabilized free‐radical intermediates, and systematic ring annulation potentially yielding molecular wires along with racemic mixtures of helicenes in deep space. Connecting helicene templates to the Origins of Life ultimately changes our hypothesis on interstellar carbon chemistry.     

Synthesis of Methylene Tetrahydrofurane-Fused Carbohydrates

A reliable method is disclosed to introduce a fused methylene tetrahydrofuran ring into carbohydrates. The resulting bicyclic saccharides can be used as scaffolds in medicinal chemistry and drug design. In addition, the enol ether functionality serves as a handle that enables modification in biological systems via photoclick chemistry. The approach is based on the regioselective oxidation of the C-3 hydroxy group in gluco-configured pyranosides, followed by stereoselective indium-mediated allylation. The ring formation is induced by an iodocyclization reaction with a neighboring hydroxy group. Subsequent dehydrohalogenation affords the desired methylene-tetrahydrofuran-containing carbohydrates.     

Photogeneration and chemistry of biphenyl quinone methides from hydroxybiphenyl methanols

The photosolvolysis of several biphenyl methanols (Ph-PhCH[Ph]OH) substituted with hydroxy or methoxy groups on the benzene ring not containing the -CH(Ph)OH moiety has been studied in aqueous solution. This work is a continuation of our studies of photosolvolysis of hydroxy-substituted arylmethanols that generate quinone methide intermediates, some of which are known to be relevant intermediates in toxicology and in biological and organic chemistry in general. In this study, we further probe the ability of the biphenyl ring system to transmit charge from the ring substituted with a potential electron-donating group (hydroxy and methoxy) to the adjacent benzene ring that contains a labile benzyl alcohol moiety. We show that in systems with a hydroxy substituent, biphenyl quinone methides (BQM) are the first formed intermediates that are detectable by nanosecond laser flash photolysis, and are responsible for the observed overall photosolvolysis reaction of these compounds. The highly conjugated BQM are found to absorb at long wavelengths (lambda(max) 580 and approximately 750 nm for the p,p' and o,p'-isomers, respectively) with relatively long lifetimes in neutral aqueous solution (500 and 30 micros, respectively). The BQM from the o,p'-isomer was found to undergo a competing intramolecular Friedel-Crafts alkylation, to give a fluorene derivative.     

Reagent‐Based DOS: Developing a Diastereoselective Methodology to Access Spirocyclic‐ and Fused Heterocyclic Ring Systems

Herein, we report a diversity‐oriented‐synthesis (DOS) approach for the synthesis of biologically relevant molecular scaffolds. Our methodology enables the facile synthesis of fused N‐heterocycles, spirooxoindolones, tetrahydroquinolines, and fused N‐heterocycles. The two‐step sequence starts with a chiral‐bicyclic‐lactam‐directed enolate‐addition/substitution step. This step is followed by a ring‐closure onto the built‐in scaffold electrophile, thereby leading to stereoselective carbocycle‐ and spirocycle‐formation. We used in silico tools to calibrate our compounds with respect to chemical diversity and selected drug‐like properties. We evaluated the biological significance of our scaffolds by screening them in two cancer cell‐lines. In summary, our DOS methodology affords new, diverse scaffolds, thereby resulting in compounds that may have significance in medicinal chemistry.     

Molecular building kit of fused-proline-derived peptide mimetics allowing specific adjustment of the dihedral Psi angle

Proline-derived peptide mimetics have become an area of paramount importance in peptide and protein chemistry. Since protein crystal structures frequently display Psi angles of 140-170 degrees for prolyl moieties, our intention was to design a completely novel series of 2,3-fused-proline-derived lactams covering this particular conformational space. Extending our recently described toolset of spirocyclic reverse-turn mimetics, we synthesized pyrrolidinyl-fused seven-, eight-, and nine-membered unsaturated lactam model peptides taking advantage of Grubbs' ring-closing metathesis. Investigating the seven-membered lactam 3a by means of IR and NMR spectroscopy and semiempirical molecular dynamics simulations, we could not observe a U-turn conformation; however, increasing the ring size to give eight- and nine-membered congeners revealed moderate and high type IotaIota beta-turn inducing properties. Interestingly, the conformational properties of our model systems depend on both the ring size of the fused dehydro-Freidinger lactam and the position of the endocyclic double bond. Superior reverse-turn inducing properties could be observed for the fused azacyclononenone 3e. According to diagnostic transanular NOEs, a discrete folding principle of the lactam ring strongly deviating from the regioisomeric lactams 3c,f explains the conformational behavior. Hence, we were able to establish a molecular building kit that allows adjustments of a wide range of naturally occurring proline Psi angles and thus can be exploited to probe molecular recognition and functional properties of biological systems.     

Negative ion MALDI‐TOF MS,ISD and PSD of neutral underivatized oligosaccharides without anionic dopant strategies,using 2,5‐DHAP as a matrix

Oligosaccharides represent complex class of analytes for mass spectrometric analysis due to the high variety of structural isomers concerning glycosidic linkages and possible branching. A systematic study of the negative ion mode matrix‐assisted laser desorption/ionization (MALDI) mass spectrometry of various neutral oligosaccharides under selection of an appropriate matrix, like 2,5‐dihydroxyacetophenone (2,5‐DHAP) is reported here, without commonly used anion dopant strategies. Nevertheless, we were able to generate relevant in‐source decay (ISD) cross‐ring fragment ions, typically obtained in the negative ion mode. Data observed indicate that the intrinsic property of the terminal non‐reduced aldose is crucial for this behavior. A systematic study of the post source decay (PSD) of molecular, pseudomolecular and ISD cross‐ring cleavage precursor ions is reported here. A direct comparison of the positive and negative ion mode MALDI MS1 and PSD behavior of neutral oligosaccharides could also be performed under the use of the same matrix preparation, because 2,5‐DHAP is fully compatible with positive ion mode acquisition. We found that PSD spectra of deprotonated neutral oligosaccharides obtained in the negative ion mode are richer, because they contained both glycosidic and cross‐ring fragment ions. However, we also found that cross‐ring fragment ions are readily produced in the positive ion mode when potassiated precursor ions were selected. In addition, we show evidence that non‐anionic dopants and specific instrumental parameters can also significantly influence the ISD fragmentation. Taken together, our results should increase our understanding of oligosaccharide behavior in the negative ion mode as well as increase our knowledge regarding many aspects of in‐source MALDI chemistry. Copyright © 2016 John Wiley & Sons, Ltd.     

Some past vignettes of and future prospects for Main Group chemistry

The present article traces, from the author's perspective, some of the important developments in the chemistry of the Group 13 and 15 elements that have taken place over the past three decades. Included in the review are compounds that feature multiple bonding between heavier Main Group elements, the coordination chemistry of Group 13 and 15 carbene analogues, and novel ring systems involving these elements. Some materials science and medicinal aspects of this area of chemistry are also presented.     

Synthesis and NMR studies of novel chromone‐2‐carboxamide derivatives

Chromones are heterocyclic compounds of natural or synthetic origin that possess relevant pharmacological activities. Versatile functionalization of the chromone nucleus allows attaining of a chemical diversity suitable to perform structure–activity relationships in drug discovery and development programs. Accordingly, the synthesis and identification of novel chromone carboxamide derivatives with electron‐donating and electron‐withdrawing substituents in different positions of the exocyclic ring are reported in this work. Their complete structural characterization was performed using one‐dimensional and two‐dimensional resonance techniques. The data acquired are useful for a prompt analysis of related compounds that encompass our integrated medicinal chemistry sketch. Copyright © 2013 John Wiley & Sons, Ltd.     

Design and synthesis of cyclo[-Arg-Gly-Asp-Ψ(triazole)-Gly-Xaa-] peptide analogues by click chemistry

A simple and mild synthesis of a new family of cyclopeptide analogues cyclo[-Arg-Gly-Asp-Ψ(triazole)-Gly-Xaa-] that is obtained by cyclization with click chemistry was investigated. In addition, the method was also successfully expanded to the synthesis of their analogues of different ring sizes. The result supports the potential utility of click chemistry in the preparation of novel integrin domain-binding antagonists and other cyclopeptide analogues.     

Synthesis of fused indolines by interrupted Fischer indolization in a microfluidic reactor

This study describes our development of a microfluidic reaction scheme for the synthesis of fused indoline ring systems found in several bioactive compounds. We have utilized a continuous-flow microfluidic reactor for the reaction of hydrazines with latent aldehydes through the interrupted Fischer indolization reaction to form fused indoline and azaindoline products. We have identified optimal conditions and evaluated the scope of this microfluidic reaction using various hydrazine and latent aldehyde surrogates. This green chemistry approach can be of general utility to rapidly produce indoline scaffolds and intermediates in a continuous manner.     

Chain and Ring Phosphorus Compounds—Analogies between Phosphorus and Carbon Chemistry

Up to about 15 years ago compounds with a skeleton of phosphorus chains or rings were regarded as “exotic” in the field of nonmetal chemistry. Aside from a number of examples of molecules with two P atoms directly bonded to each other and a few sporadically discovered monocyclic ring compounds, only solids of undefined composition and structure were known. Since then the state of our knowledge in this sector has made considerable progress: between PH₃ and its derivatives on the one hand, and the high-molecular modifications of elementary phosphorus on the other, an unexpected variety of well defined compounds have been discovered, showing many similarities to the analogous compounds of carbon. However, surprises can still occur even with “small” phosphorus-containing molecules, as shown by the likewise recently discovered field of phosphorus three-membered ring compounds.     

Bonding Properties of Cyclopropane and Their Chemical Consequences

Among the cyclic compounds of carbon, cyclopropane and its derivatives are outstanding by virtue of their unusual structural, spectroscopic, and chemical properties. The cyclopropane ring more closely resembles the C?C double bond than the cyclobutane ring: it is a small ring with “double bond character”. Cyclopropyl and vinyl groups interact with neighbouring π-electron systems and p-electron centers; both cyclopropane derivatives and olefins form metal complexes, and add strong acids, halogens, and ozone; they both undergo catalytic hydrogenation and cycloadditions. While distinct differences in reactivity do exist–the double bond usually being more reactive than the three-membered ring–there are no fundamental differences in behavior.–Although cyclopropane derivatives have been known for more than 90 years, intensive studies have been limited to the past 25 years. The development of carbene chemistry has rendered cyclopropane derivatives far more readily accessible. In recent years, the synthetic potential of the small-ring function has been increasingly exploited. A considerable number of newly developed methods utilizing this approach clearly demonstrates that the reactivity of the cyclopropene ring, like that of the C?C double bond, qualify it as a “functional carbon group”. This development is in full swing; we may therefore justifiably devote considerable effort to the study of cyclopropane chemistry.