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Miniaturized and Automated Synthesis of Biomolecules— PROGRESS REPORT Chemical-Synthesis Miniaturization www.advmat.de Miniaturized and Automated Synthesis of Biomolecules— Overview and Perspectives Daniela S. Mattes, Nicole Jung,* Laura K. Weber, Stefan Bräse, and Frank Breitling* to select suitable mechanisms and proce- Chemical synthesis is performed by reacting different chemical building blocks dures, followed by a trial-and-error phase. with defined stoichiometry, while meeting additional conditions, such as tem- This was also true some 100 years ago [1] perature and reaction time. Such a procedure is especially suited for automation when Haber asked his technicians at the and miniaturization. Life sciences lead the way to synthesizing millions of dif- Technical University in Karlsruhe to manu- ally mix and process thousands of different ferent oligonucleotides in extremely miniaturized reaction sites, e.g., pinpointing mixtures of nanoparticles to eventually find active genes in whole genomes, while chemistry advances different types of the catalyst that transforms nitrogen and automation. Recent progress in matrix-assisted laser desorption/ionization hydrogen into ammonia—to manufacture mass spectrometry (MALDI-MS) imaging could match miniaturized chemical the fertilizer that a fast growing population synthesis with a powerful analytical tool to validate the outcome of many dif- needed so desperately. Some 80 years later, the Heidelberg University spin-off company ferent synthesis pathways beyond applications in the life sciences. Thereby, due high-throughput experimentation (HTE),[2] to the radical miniaturization of chemical synthesis, thousands of molecules now a subsidiary of BASF with some can be synthesized. This in turn should allow ambitious research, e.g., finding 300 employees) automated Fritz Haber’s novel synthesis routes or directly screening for photocatalysts. Herein, different screening procedure by employing pipet- technologies are discussed that might be involved in this endeavor. A special ting robots and by adding a professional emphasis is given to the obstacles that need to be tackled when depositing tiny analytical pipeline made of liquid chroma- tography (LC)-coupled and gas chromatog- amounts of materials to many different extremely miniaturized reaction sites. raphy (GC)-coupled mass spectrometers to screen for all kinds of catalysts.[2b] Although impressive, this type of min- 1. Introduction iaturization only moderately increases the number of different chemicals that can be screened, e.g., for the novel types of fuel cell Miniaturized structures in computer chips have reached the needed nowadays. In organic chemistry, one obstacle to more rad- lower nanoscale and have thereby revolutionized our world. ical miniaturization has been the absence of an analytical method Chemical synthesis is another field that is suited for automation that: i) can handle very small amounts of synthesized molecules, and radical miniaturization. Synthesis is done by mixing different and, in addition, ii) would do so for tens of thousands, maybe chemical building blocks in a solvent and in exactly defined stoi- millions of reaction sites in a few minutes. There are certainly addi- chiometry, while meeting additional conditions, e.g., temperature tional points on the wish list: iii) synthesized molecules should be and reaction time. Synthesis usually starts with a planning phase analyzed quantitatively, iv) a method to follow the reaction kinetics would be helpful, and v) above all, synthesis sites should be Dr. D. S. Mattes, Dr. L. K. Weber, Prof. F. Breitling reliably supplied with extremely miniaturized amounts of mate- Institute of Microstructure Technology (IMT) rials that are needed for chemical synthesis (chemical building Karlsruhe Institute of Technology (KIT) Hermann-von-Helmholtz-Platz 1 blocks, catalysts, scavengers, acids, or bases). 76344 Eggenstein-Leopoldshafen, Germany Herein, we summarize recent examples that promise to min- E-mail: [email protected] iaturize and automate organic synthesis, with an emphasis on Dr. N. Jung, Prof. S. Bräse the challenges of handling tiny amounts of chemicals in defined Institute of Organic Chemistry (IOC) stoichiometry. In addition, recent progress in matrix-assisted Karlsruhe Institute of Technology (KIT) [3] Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany laser desorption/ionization mass spectrometry (MALDI-MS) E-mail: [email protected] imaging, which could indeed match miniaturized chemical syn- thesis with at least one important analytical tool to validate the The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adma.201806656. outcome of a very large number of different synthesis routes, is briefly discussed. If combined, automation, miniaturization, and © 2019 Karlsruhe Institute of Technology, IMT. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. This is an open analytical methods that can handle many different reaction sites access article under the terms of the Creative Commons Attribution- promise to drastically reduce the efforts that are needed to find NonCommercial-NoDerivs License, which permits use and distribution novel chemical synthesis pathways or even novel reaction mecha- in any medium, provided the original work is properly cited, the use is nisms. When mated to the material sciences, and similar to Fritz non-commercial and no modifications or adaptations are made. Haber’s screening for novel catalysts, strong economic, scientific, DOI: 10.1002/adma.201806656 and societal interests will presumably advance these efforts. Adv. Mater. 2019, 1806656 1806656 (1 of 23) © 2019 Karlsruhe Institute of Technology, IMT. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de 2. Automated, Autonomous Synthesis for Organic Chemistry Daniela S. Mattes studied chemistry at Karlsruhe The (fully) automated, autonomous synthesis of organic Institute of Technology. In molecules is a challenge that many research groups in aca- her Ph.D. thesis, she gener- demia and industry have tried to address for many decades. In ated peptide and peptoid comparison to the fully automated solutions in engineering, arrays and developed a new experimental molecule chemistry, in particular for research trifunctional linker for 3D purposes or synthesis on a small scale, has never reached assembled peptide structure this progress in automation. In essence, there are in general arrays. She received her two synergistic approaches to reach this aim: some projects Ph.D. working with Frank intend to automate parts of a chemical synthesis to enhance Breitling and Stefan Bräse the throughput of a chemistry lab; other projects aim for the at KIT. Since 2017, she has machine-driven handling of all traditionally human-based pro- worked as a postdoctoral researcher in the group of Frank cedures with the focus on autonomous synthesis, which does Breitling. She works with a laser-based method to generate not necessarily have to lead to a high-throughput procedure. molecule arrays and to carry out nanoscale-structuring for material sciences. 2.1. Automated Combinatorial and High-Throughput Synthesis Nicole Jung studied chemistry (of Submilligram Entities) at the University Frankfurt am Main and did her Ph.D. Automated combinatorial synthesis arose as a well-known thesis with Stefan Bräse at procedure for half-automated synthesis of small organic com- the Karlsruhe Institute of pounds in the 1990s. In particular, the chemical industry Technology. She works on searching for large libraries of different compounds for bio- the development of novel logical screening campaigns, operated departments that were methods for organic syn- able to synthesize, analyze, and purify dozens of thousands of theses on solid phases and compounds in a few months. Combinatorial chemistry is sup- heterocycle syntheses applied ported and enhanced using automated systems like pipetting in biological systems and for robots (liquid handlers), automated synthesis stations, auto- materials sciences. Besides mated tracking systems, automated purification stations, and synthetic chemistry, she is involved in software develop- the generation of possible libraries via virtual design. Many of ment for research data management and cheminformatics. those approaches use solid-phase organic synthesis (invented She works in the group of Stefan Bräse and coordinates by Merrifield in the 1960s)[4] as a methodology to be able to deal the work of the Compound Platform (ComPlat). with the large number of different compounds in combination Frank Breitling studied with an easy handling of batches in special resin-containing biochemistry at the [5] vessels. As an example, systems like the IRORI technique, in University of Heidelberg. combination with the use of reaction mini blocks, have been He developed the tech- shown to be efficient for the upscaling of compound numbers. nology of recombinant As a result, the amount of isolated reaction product per reac- antibodies at the German tion had to be decreased to allow a reduction of reagent costs Cancer Research Centre and to ensure the fast purification of the obtained compounds (DKFZ), before he switched via high-performance liquid chromatography (HPLC). to solid-material-based, While combinatorial synthesis was very successful in terms high-density peptide arrays. of synthesis of small molecules in a high-throughput manner, Since September 2009, he the procedure was criticized due to the low impact of the has headed the department
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