Combinatorial Chemistry & High Throughput Screening - Volume 10, Issue 9, 2007

Microwave irradiation has become a widely accepted unconventional energy source for performing organic reactions. Microwave heating is very attractive for chemical applications as it produces a rapid and volumetric heating of samples that depends strongly on the properties of the material. In contrast, conventional heating is slow, superficial and less dependent on the properties of the material. In the period following the pioneering work of Gedye and Giguere, numerous reactions were carried out in domestic microwave ovens due to the spectacular accelerations observed in many cases. Reactions were performed under uncontrolled conditions and this led to conditions that were not easily reproduced and, in certain cases, false effects involving microwave irradiation were described. Microwave chemistry and its related instrumentation were developed as a result of the efforts of many pioneers, who believed that this technology would represent the bunsen burner of the 21st century and provide an alternative to conventional heating to obtain results that are not achieveble under other conditions. In particular, the work of Loupy in France, Strauss in Australia and Varma in the United States are worth highlighting. The increasing number of related publications in recent years - particularly since 2003 - could be related to this work and the general availability of new and reliable microwave instrumentation in which almost all of the reaction parameters can be controlled. At this moment, any chemical transformation known can be performed under microwave irradiation, at temperatures ranging from -80 to 300 °C or more, and this methodology can be combined with other techniques such as, for example, photochemistry, electrochemistry and ultrasound, or employed in conjuntion with sustainable solvents like water and ionic liquids. A large number of reactions and conditions have been described in organic synthesis: cycloaddition reactions, synthesis of radioisotopes, Fullerene chemistry, Polymers, Heterocyclic chemistry, carbohydrates and natural products, Medicinal Chemistry, Combinatorial Chemistry and High Throughput Chemistry, solvent-free reactions, homogeneous and heterogeneous catalysis, Green Chemistry and, more recently, this approach has been extended to proteomics and biological chemistry. Microwave-Assisted Organic Synthesis is characterised by the rapid heating induced by the radiation, which cannot be reproduced by classical heating. Higher yields, milder reaction conditions and shorter reaction times can be obtained and many processes can be improved. Indeed, even reactions that do not occur by conventional heating can be performed using microwaves, especially when the reaction requires the use of harsh conditions or involves sensitive reagents and/or products. The effect of microwave exposure results from material/wave interactions. These effects are highly dependent on the properties of the material and produce thermal effects (which may be easily estimated by temperature measurements) and probably specific (i.e., not purely thermal) effects. This selective mode of heating sometimes produces interesting modifications in the selectivity. Microwave reactions are characterised by short reaction times and by clean reactions, a factor that often simplifies the work-up procedure. In addition, microwave systems can be easily automated both in terms of sample preparation and analysis. These characteristics make it the technology of choice when High Throughput Chemistry is required. Further developments in microwave reactors and appropriate instrumentation for Combinatorial and High Throughput Chemistry will in future improve the utility of microwave chemistry. The aim of this special issue, included in two parts (Vol. 10, No. 9 and Vol. 10, No. 10), is to show some of the most recent advances in the field of Microwave Assisted High Throughput Chemistry. Eleven contributions from highly prestigious research groups have been selected to cover a wide range of applications of microwave chemistry in this field; including Heterocycles, Fullerenes and nanotubes, Medicinal Chemistry, Proteomics, Parallel reactions, Solid-Phase reactions and Flow conditions.

Microwave-assisted organic synthesis is an enabling technology that has been exploited for a variety of applications including medicinal chemistry/drug discovery projects where speed is often a critical factor. In this review, applications of microwave-assisted organic synthesis employing a parallel processing regime are summarized. Examples include parallel synthesis in domestic microwave ovens, the use of specialized multivessel rotors and microtiter plates in dedicated multimode microwave reactors, and applications of SPOT synthesis on cellulose matrices.

Biotechnology has recently celebrated 30 years both as a science and as a multi-billion dollar industry. One application of biotechnology is to use human genetic information to discover, develop, manufacture, and commercialize biotherapeutics. Recombinant proteins can be produced in large quantities at high purity. High-throughput proteomic analysis is at the heart of the biotechnology research and development process, and the industry is constantly striving to streamline and automate the analytical processes involved. Microwave-assisted proteomics has recently emerged as a tool for increasing the bio-catalysis of several processes including tryptic digestions [1-3] lipase selectivities [4], identification of metal-catalyzed oxidation sites on proteins [5], identification of protein N- and C-termini [6, 7] and enzyme catalyzed Nlinked deglycosylation [8]. Here, we explore the above mentioned methods, and describe our experiences evaluating microwave- technology for other common proteomic protocols including: removal of N-terminal pyroglutamyl for antibody characterization, beta elimination and Michael addition for identification of phosphorylation sites on recombinant proteins and enzyme mediated O-linked deglycosylation.

Microwave irradiation is an important tool in the functionalization of fullerenes and carbon nanotubes. These are compounds with excellent properties that make them useful for the development of optoelectronic organic devices. The applications of microwaves in the chemistry of these materials are reviewed.

A microwave-enhanced, palladium-catalyzed protocol for the α-arylation of a protected glycine in neat water is described. This reaction proceeds rapidly, under non-inert conditions, to afford a range of phenylglycine derivatives in moderate to good yields. Based on this α-arylation, a number of aryl L-methionine-SR-sulfoximine (MSO) analogues were prepared and evaluated for their Mycobacterium tuberculosis glutamine synthetase (TB-GS) inhibitory activity.

Microwave-assisted Suzuki-Miyaura and Stille cross-coupling reactions for the synthesis of highly electronrich and diversely functionalized biaryl intermediates are presented. Microwave-irradiation has been demonstrated to be a very powerful tool for performing difficult transition metal-catalyzed cross-coupling reactions with unfavorably substituted coupling partners. The key biaryl intermediates were used for the microwave-enhanced construction of the 5,6,7,8- tetrahydrobenzo[c,e]azocine skeleton of the Apogalanthamine analogs. The success of the strategy is demonstrated by synthesizing a number of hitherto unknown, diversely functionalized, natural product analogs.