Abstract
Laboratory Automation and High-Throughput Chemistry
Comprehensive Survey of Combinatorial Library Synthesis: 2003
Roland E. Dolle (Adolor Corporation, Exton, PA) published the seventh comprehensive survey in an ongoing annual review series about combinatorial chemistry. Libraries demonstrating biological activity are described as well as libraries belonging to certain structural classes. Polymer-supported reagents and scavengers, polymer-supported linkers, and polymer-supported chiral ligands are also listed with more than 400 references. Publications of large libraries (greater than 1000 members), which were prevalent in the late 1990s for broad screening purposes and structure-activity relationship (SAR) development, have given way to small, focused, compound arrays for lead optimization. Of the 120 biologically active libraries with a defined number of members, 79 percent have fewer than 500 members, 6 percent contained 500 to 1000 members, and 15 percent contained more than 1000 members. Researchers are increasingly utilizing both solid- and solution-phase techniques to analogue multiple regions of a lead molecule to establish SAR (J. Comb. Chem.
Gel Permeation Chromatography as a Combinatorial Screening Method: Identification of Highly Active Heteroligated Phenoxyimine Polymerization Catalysts
Combinatorial and high-throughput screening techniques were originally developed by the pharmaceutical industry to rapidly identify biologically active compounds, but they have become increasingly common in other areas of research. In homogeneous catalysis, automated parallel devices are now used to screen potential catalysts and to optimize reaction conditions. As more reactions are run simultaneously, the need for faster screening methods will increase. Although new techniques have been developed for the rapid screening of small-molecule catalysts, efforts to screen polymerization catalysts have focused on improving existing technologies, particularly gel permeation chromatography (GPC). GPC analysis of polymers formed by a set of pooled catalyst libraries is used by Andrew F. Mason and Geoffrey W. Coates (Cornell University, Ithaca, NY) to identify a class of syndiospecific heteroligated phenoxyimine catalysts that are unusually active for propylene polymerization. A combinatorial approach is used to drastically reduce the number of reactions needed to identify these compounds. GPC can be an effective tool for identifying high molecular weight polymers formed by either fast catalysts or catalysts with limited chain transfer, although there is a limit to the number of catalysts that can be analyzed per GPC run (J. Am. Chem. Soc. 2004, 126, 10798).
Accelerated Luminophore Discovery through Combinatorial Synthesis
Stefan Bernhard et al. (Princeton University, Princeton, NJ) published a method for accelerating the discovery of ionic luminophors using combinatorial techniques. The photophysical properties of the resulting transition-metal-based chromophores are compared against a series of analogous, traditionally prepared species. The strong overlap between these two sets confirms the identity of the parallel synthesis products and supports the truthfulness of the combinatorial results. Further support for the combinatorial method comes from the adherence of these complexes to the energy gap law. The relationship between the structure of a complex and its photophysical properties is also considered, and static DFT calculations are used to assess whether it is feasible to predict the luminescent behavior of novel materials (J. Am. Chem. Soc.
Simultaneous In-Situ Monitoring of Parallel Polymerization Reactions Using Light Scattering; a New Tool for High-Throughput Screening
A recently introduced technique, simultaneous multiple sample light scattering (SMSLS), is used by Wayne F. Reed et al. (Tulane University, New Orleans, LA) to monitor parallel polymerization reactions in situ. SMSLS is designed for real-time, high-throughput screening and provides a time-dependent light scattering signature for each reaction, which contains both qualitative and semiquantitative information. Qualitatively, the signature immediately indicates whether the reaction occurs or not, whether there is an initial lag period, and how long the reaction takes until it stops. The signature also provides estimates of the reaction rate and weight average molecular mass Mw, and its shape can help identify mechanistic aspects (e.g., controlled versus free radical polymerization and presence of impurities). The method is inherently adapted to small sample volumes and requires no special sample preparation or postpolymerization characterization. The demonstration involves the free radical polymerization of acrylamide under varying conditions and should be readily applicable to a wide variety of other reactions. Results are cross-checked with multidetector gel permeation chromatography (J. Comb. Chem.
Combinatorial Synthesis of Insoluble Oxide Library from Ultrafine/Nano Particle Suspension Using a Drop-on-Demand Inkjet Delivery System
Although the combinatorial approach has been widely adapted in the search for novel functional materials, parallel synthesis and high-throughput characterization are still the major obstacles hampering the application to a diversity of materials. In solution-based parallel synthesis, droplets of precursor solutions are laid into predefined microreactors from microdispensers. Then, the precursors are mixed and reacted to form a materials library. Through this method, materials libraries including phosphors, catalysts, etc., are fabricated from solution precursors. Inkjet delivery shows many advantages over other microdispense devices, such as nanoliter dispensing capability with high accuracy. Chen Gao et al. (University of Science & Technology of China, Hefei, China) reports the synthesis of combinatorial material libraries from suspensions prepared from insoluble oxides using a drop-on-demand inkjet delivery system. A method to prepare inkjet-compatible insoluble oxide suspension with an ultrafine/nano particle size, high surface tension, low viscosity, and high concentration was also developed (J. Comb. Chem.
Synthesis and Evaluation of the Antitumor Agent TMC-69–6H and a Focused Library of Analogs
A concise, efficient and flexible total synthesis of the potent antitumor agent TMC-69–6H is described by Alois Fürstner et al. (Tetrahedron
Microfluidic Chip Technology and Micro Reactor Technology
Design of a Capillary-Microreactor for Efficient Suzuki Coupling Reactions
A Pyrex glass capillary (0.4 mm internal diameter) microreactor was developed and used for Suzuki coupling reactions by Hian Kee Lee, Suresh Valiyaveettil, and colleagues (National University of Singapore, Singapore). Capillary-microreactors are more attractive than photolithographic microfluidic devices in terms of simplicity, low cost, and ease of handling. Compared with the conventional synthesis procedure, their approach of using a capillary-microreactor offers a convenient and highly efficient means for optimizing reaction conditions and the performance of catalysts. The procedure exhibits good precision, reproducibility, and high reaction yield for a range of reactants investigated. The capillary microreactor produced high yields (82–95 percent in comparison with 11–23 percent for the conventional method) (Tetrahedron Lett.
An Investigation into the Use of Silica-supported Bases within EOF-based Flow Reactors
Using a series of silica-supported bases, Charlotte Wiles, Paul Watts, and Stephen J. Haswell (University of Hull, Hull, United Kingdom) demonstrate the synthesis of eight condensation products within an electroosmotic flow (=EOF) based flow reactor. In all cases, high yields (>99%) and product purity are obtained. The reactions were carried out using a single capillary device with capillary dimensions of 500 μm i.d. x 3.0 cm. To hold the supported reagent in place, microporous silica frits were placed at either end of the capillary (Tetrahedron
The Preparation of D-glucitol in a Multi-tube Airlift Loop Reactor with Low H/D Ratio
W. Jianping et al. describe the preparation of D-glucitol in a multi-tube airlift loop reactor with low H/D ratio (Chem. Biochem. Eng. Q.
Microwave Heating of Heterogeneously Catalysed Suzuki Reactions in a Micro Reactor
Ping He et al. report the development of a microwave-based technique capable of delivering heat locally to a heterogeneous Pd-supported catalyst located within a micro reactor device (LabChip, 2004, 4, 38). The ability to spatially control localized concentrations of reactant, intermediates, and products within the micro-channel networks of micro reactors enables a level of reaction control that is not achievable in bulk reactors. In addition to the control of local concentrations, the ability to deliver localized heating and the more effective use of in situ supported reagents such as catalysts add a further dimension of reaction control, and hence, extend the range of potential applications of micro reactors. The authors describe a microwave (MW) based localized heating technique used in conjunction with an immobilized palladium catalyst to perform a number of exemplary Suzuki-based reactions. The reactions are conducted in a glass micro reactor with a 10–15 nm gold film patch, located on the outside surface of the base of a glass micro reactor. It is found to efficiently assist in the heating of the catalyst when irradiated with 5–7 W of microwave power at 2.45 GHz. Using a hydrodynamically pumped system, reactant-catalyst contact times of less than 60s are found to give conversions for different substrates that are in the range 50–99 percent. Also investigated are two methods for loading catalysts that required either 1.5 or 6 mg of material into the micro reactor. To more fully exploit the use of micro reactor technology in chemical and biochemical synthesis, methods for the controlled localized heating and the utilization of highly intensive surface properties need to be established. While micro reactor-based heating may be achieved using, for example, localized electrical resistance, in this work a contactless technique based upon MW induced heating is used. In this way the controlled heating of a reaction can be achieved using selective MW absorption into both a catalyst and an externally applied gold film. In addition, a simple and practical technique is described for the loading and removal of an alumina and polymer supported metal catalyst from a micro reactor device. The results clearly point the way to developing a wider range of chemical methods and process applications of micro reactor technology.
High-Throughput Analytics
One-Minute Full-Gradient HPLC/UV/ELSD/MS Analysis to Support High-Throughput Parallel Synthesis
High-throughput parallel synthesis of library compounds for early drug discovery requires high-throughput analytical methods to confirm synthesis, identify reaction products, and determine purity. An ultrafast 1.0 min HPLC/UV/ELSD/MS method was developed by James N. Kyranos and colleagues (ArQule Inc., Woburn, MA) and compared to their standard 2.5 and 5.0 min methods to determine if the faster method is appropriate for the evaluation of compound synthesis and to determine purity. In addition to using standard test mixtures, a 400-member library produced by high-throughput parallel synthesis is used for comparing the various methods. Mass spectrometric detection was used for compound identification, while UV and ELSD data offer purity assessments. Compared to longer separations, chromatographic separation achieved using the 1.0 min method is sufficient for compound evaluation and purity assessment. This ultrafast 1.0 min HPLC/UV/ELSD/MS method is expected to increase analytical throughput tremendously, provide important information faster, and reduce the overall cycle time from synthesis to screening (J. Comb. Chem.
Atmospheric Pressure MALDI-Fourier Transform Mass Spectrometry
The first developments of laser desorption-FTMS began some twenty years ago, and because of increasing interest in high-resolution analysis of polar, non-volatile, and thermally labile compounds, new improvements are of topical interest. D. Fabris and coworkers describe a new coupling of atmospheric pressure matrix-assisted laser desorption/ionisation with Fourier transform mass spectrometry on the basis of high-resolution analysis of complex peptide mixtures (Anal. Chem.
An Automated High Performance Capillary Liquid Chromatography-Fourier Transform Ion Cyclotron Resonance Mass Spectrometer for High-Throughput Proteomics
Mikhail E. Belov and coworkers describe a fully automated high-performance LC-FTICR mass spectrometer and depict the possibility for high-throughput and unattended operation for proteomics research (J. Am. Soc. Mass Spectrom. 2003, 15, 212). In addition to a short overview of the pros and cons of existing techniques, the authors give detailed insight into the instrumentation, experimentation, preparation, and system software of the automated capillary LC-9.4 tesla FTICR instrument. One topic is the new calibration methodology based on a dual-channel electrodynamic ion funnel, which allows the real time introduction of calibrant to the sample and leads to a decreased dispersion of mass measurement errors for the identification of peptides. Another quality worth mentioning is the reliability and robustness of a system whose particular characteristics for proteomic analyses are more likely sensitivity, accuracy, high-resolution, and a high dynamic range.