Mini-Reviews in Organic Chemistry - Volume 8, Issue 3, 2011

The major aim of molecular modelling is to predict structures and other properties of molecules and molecular assemblies. In principle, conformation and dynamics of any molecule can be studied by equilibrium simulation in an appropriate environment. However, for example de novo prediction of protein structures by simulating the folding process is still a dream rather than a routine method and it has been successfully applied only on several examples of fast-folding mini-proteins. Contrary to proteins, carbohydrate molecular modelling is an equivalent partner to experimental techniques, mostly due to properties of carbohydrates that are favourable for molecular modelling and unfavourable for experimental studies. Also many studies on carbohydrates belong to the classics of computational chemistry. This performance was achieved during the boom of glycochemistry and glycobiology, when carbohydrates have been intensively studied in different contexts ranging from drug design to biofuel production. This special issue presents reviews on selected carbohydrate-specific topics of molecular modelling and bioinformatics. The contribution of Laercio Pol-Fachin and Hugo Verli presents approaches in modelling and molecular dynamics simulation of glycoproteins. Renato R. Andrade and Clarissa O. da Silva review the issue of potential energy modelling of monosacharides supported by a case study of xylopyranose. Solvent effects and solvation modelling in glycochemistry are reviewed by myself and Alfred D. Fench. Free energy modelling methods and their application on carbohydrates are presented in the article of Michelle M. Kuttel. Petety V. Balaji presents a review of carbohydrate-aromatic interactions and their role in carbohydrate recognition. The article (number six) by Igor Tvaroska presents the state of art in QM/MM modelling of carbohydrate biosynthesis by glycosyl transferases. And finally, structural bioinformatics of carbohydrate processing enzymes is presented by the review of Natallia Kulik and Kristyna Slamova. I would like to thank all authors for their excellent contributions and reviewers for their responsible work. Finally, my thanks goes to editors of Mini Reviews in Organic Chemistry and especially Miss Qurrat-ul-Ain Khan for giving me the chance to organize this special issue and for nice cooperation.

X-ray crystallographic studies have shown that C-H groups of saccharides interact with aromatic amino acid residues in binding sites in proteins. Such C-H…pi interactions have been shown to be dominated by London's dispersion interactions. The strength of interaction depends on a number of factors: (i) the nature of aromatic residue and saccharide, (ii) the form (acyclic, pyranose or furanose) and conformation of the saccharide, (iii) the functional groups present in modified saccharides (e.g., N-acetyl group), and (iv) the mutual position-orientation of the interacting moieties; this, in turn, determines the number of interacting C-H groups and the geometry of interaction. The strength of interaction also depends on the surrounding medium and on the microenvironment in a protein's binding sites. A variety of experimental techniques such as isothermal titration calorimetry, turbidity measurements, NMR spectroscopy, infrared ion depletion spectroscopy and fluorescence spectroscopy have been used to investigate C-H…pi interactions. Quantum chemical calculations of saccharide - aromatic systems have shown that their interaction is stabilizing. The interaction energy ranges between 1 and 12 kcal/mol and is thus comparable in strength to a conventional hydrogen bond. However, experiments that mimic double mutant cycles are needed to be designed, and performed, to determine the contribution of C-H…pi interactions to the affinity of glycans to proteins and the glycan specificity of proteins.

Glycoproteins are synthesized in most of the living organisms, being major components of the outer surface of mammalian cells and most of the secreted proteins in eukaryotes. Accordingly, a better comprehension of the biological processes in which they are involved requires the characterization of their structure and conformation. As such rationale faces several difficulties from both experimental and theoretical approaches, this review summarizes the current state of the art and methods employed to model and represent glycoproteins, including their carbohydrate moieties, through computer simulations.

Many theoretical studies on carbohydrates have been published in the last century. Building on these developments, a procedure is presented to select stable conformations of monosaccharides in aqueous solution from samplings on potential energy surfaces (PES) obtained from quantum mechanics. Considerations regarding the property chosen to validate conformational samplings are also presented. The conformations found for D-xylopyranose present an optical rotation value of +20.35°, which coincides with the experimental value (+18.8°).

Carbohydrates are polar molecules and their conformational and anomeric equilibrium can be strongly influenced by solvents. This review provides examples of studies addressing different issues of glycochemistry, such as anomeric equilibrium, conformational changes in rings, modelling of inter-residue linkages or complex carbohydrates and formation of carbohydrate-protein complexes. All these phenomena provide benchmark systems for testing of different solvent models.

Although free energy calculations have been extensively employed to explore the conformational space of proteins, to date carbohydrates have received considerably less attention. This review provides a survey of recent computational free energy studies of the preferred conformations and characteristic dynamics of carbohydrate molecules in solution. The article comprises a motivation for employing expensive free energy calculations for carbohydrates, an outline of the principal computational methods and techniques employed for free energy determinations, together with a summary of the development of the field in recent years and the principal findings to date. Finally, possible future directions in free energy investigations of this type are discussed.

Glycosyltransferases comprise a group of enzymes that catalyze the transfer of glycosyl residues from donors containing nucleoside phosphates to other molecules. The molecular details of the catalytic mechanism involving these enzymes are not well understood. Hybrid QM/MM methods have become important in providing new insights into the atomic details of enzymatic reactions. The QM/MM calculations of GnT-I and β4GalT-1 show that inverting glycosyltransferases utilize an SN2 type mechanism, with one amino acid functioning as a base catalyst. In addition, the computed transition state structures provide a rational basis for the design of transition state analog inhibitors.

Besides their implication in human physiology and disease, β-N-acetylhexosaminidases (EC 3.2.1.52, CAZy GH 20) have recently gained a lot of attention thanks to their great potential in the enzymatic synthesis of carbohydrates and glycomimetics. Extracellular β-N-acetylhexosaminidases from filamentous fungi proved to be a powerful synthetic tool for the preparation of both natural and modified glycosides under mild conditions with good yields. A homology model of β-N-acetylhexosaminidase from the filamentous fungus Aspergillus oryzae has recently been reported, and its quality was corroborated by vibrational spectroscopy and biochemical studies. Computational modelling and analysis helped to identify active site amino acids and other basic structural features of this enzyme important in the catalytic process; moreover, the surface interactions of the subunits of the glycosylated enzyme were identified. The model of β-N-acetylhexosaminidase from Aspergillus oryzae prepared the ground for further in silico studies of enzyme-substrate complexes including prediction and explanation of its substrate specificity.

Traditional chemistry has typically involved thermal energy to drive chemical reactions. In the 20th century, photochemical, catalytic, sonic, and high pressure techniques have been exploited to drive chemical reactions, thereby providing the tools to expand the breadth of organic chemistry. The early organic syntheses performed in the mid-1980s that used microwave radiation as the principal heating source were carried out in a domestic microwave oven. The number of publications in microwave-assisted chemistry focused particularly on organic syntheses has witnessed considerable growth recently. However, features of the microwave radiation have, in many instances, not been discussed, described, or otherwise demonstrated in several literature reports. This special issue is focused on the individuality and characteristics of microwaves in organic syntheses. It is organized in terms of various contents of the fundamentals and applications of microwave organic chemistry. The various contributions that used microwave technology are introduced so as to cover a wide range of interests with due regard to some feature elements of the principles of microwave heating, microwave specific effects, heterogeneous catalytic reactions, the photochemistry taking place with a microwave discharge lamp, background of organometallic synthesis, and the scale-up in polymer synthesis. The apparatuses used to effect microwaveassisted organic syntheses are also introduced for use under several synthesis conditions. Recent years have witnessed extensive use of microwaves in organic syntheses reported in several excellent reviews and technical books. It is our wish that researchers, in general, and organic chemistry researchers, in particular, will enjoy reading the challenging contributions in this special number. I am grateful to all the authors for having taken time out from their busy schedules to write these review articles and to the editors of Mini-Reviews in Organic Chemistry for the opportunity to organize this special issue on an otherwise very exciting topic, and for doing the bulk of the work in arranging this special issue.

This review article is the second of the comprehensive series on survey of the microwave photochemical and photocatalytic processes, and is focused specially on the microwave-assisted photochemical applications of the electrodeless discharge lamps (EDLs) in organic synthesis. The concept of microwave organic photochemistry is an important issue in synthetic chemistry and material science, and is presented in several schemes. Likewise, the various microwave photochemical reactor types (batch with external or internal light source, flow-through with external light source, annular flow-through with internal EDL, cylindrical flow-through surrounded with EDL, and mixed flow-through with internal EDL) with different arrangement of the lamps are described.

A broad range of research on chemical reactions by microwave heating has been conducted, because unlike reactions by conventional heating, reactions by microwave heating underwent a reaction acceleration phenomenon. The microwave effect on chemical reactions has been previously discussed as a thermal or non-thermal effect without universal knowledge. Measuring temperature accurately is essential for discussing reaction kinetics such as reaction acceleration, however, it is difficult to measure temperature distribution accurately in a microwave reaction vessel. This mini- review introduces recent researches on the measurements of temperature distributions in microwave reaction vessels using multiple fluorescent fiber optic thermometers, and also proposes precautions on how to measure temperatures for microwave-assisted chemical reactions. Furthermore, this mini- review presents a new thermometer for measuring local heating by microwave irradiation.

This brief article reviews the behavior of microwaves in organic syntheses from the viewpoint of the frequency effect, which has been examined on various common solvents with a newly fabricated 5.80-GHz microwave organic synthesis apparatus, whose features are compared with a similar 2.45-GHz microwave apparatus. Results from usage of the 5.80-GHz microwaves are also compared to the more frequently used MW frequency of 2.45 GHz. The frequency effect was examined for various organic reactions such as the Diels-Alder reaction, the synthesis of benzimidazole-based room-temperature ionic liquids, and the Suzuki-Miyaura coupling reaction. Non-polar solvents can prove particularly useful in organic reactions with the higher frequency microwaves. In this regard, further experiments on microwave-assisted organic syntheses will extend our understanding of the microwave frequency effect(s).

Microwave-assisted polymerizations such as radical polymerization, polycondensation, and cation polymerization have been numerously reported. Recently, researches on condensed polymers by microwave heating have been energetically conducted about not only basic synthesis research but also scale-up for a commercial process. This mini review focuses on microwave-assisted polyester and polyamide syntheses and describes our works to develop a 30 kg scale microwave reactor in anticipation of a commercial process.

Microwave heating has received considerable attention as a powerful synthetic tool for metal complexes in many fields of inorganic chemistry and material science. Since the 1990s, numerous metal complexes have been synthesized using the microwave technique. However, only a few studies have discussed such synthesis. In this review, we focus on microwave-assisted synthesis of metal complexes. We discuss the background to microwave chemistry in metal complex synthesis, the use of domestic microwave ovens for both closed- and open-system reactions, and some useful microwave heating techniques. In addition, we present a summary of reaction schemes from selected publications published in the past two decades.

Several reviews have been published on the application of microwaves to various aspects of chemistry, such as heterogeneous catalysis and eco-friendly green chemistry. In particular, the investigation of metal-catalyzed reactions, such as Suzuki-Miyaura and Heck reactions, has attracted the attention of organic chemists. The aim of this review is to show how microwave effects have been used in metal-catalyzed reactions.

Electrophilic amination constitutes a unique strategy for the synthesis of C-N bonds. One often-overlooked example of this type of process involves the reaction of organometallic nucleophiles with electrophilic nitrogen sources to yield aryl and alkyl amine derivatives. Such transformations are mechanistically intriguing and have the potential to drastically alter the logic by which nitrogencontaining compounds are synthesized.