Miniaturized and Automated Synthesis of Biomolecules—Overview and Perspectives

Abstract

Chemical synthesis is performed by reacting different chemical building blocks with defined stoichiometry, while meeting additional conditions, such as temperature and reaction time. Such a procedure is especially suited for automation and miniaturization. Life sciences lead the way to synthesizing millions of different oligonucleotides in extremely miniaturized reaction sites, e.g., pinpointing active genes in whole genomes, while chemistry advances different types of automation. Recent progress in matrix‐assisted laser desorption/ionization mass spectrometry (MALDI‐MS) imaging could match miniaturized chemical synthesis with a powerful analytical tool to validate the outcome of many different synthesis pathways beyond applications in the life sciences. Thereby, due to the radical miniaturization of chemical synthesis, thousands of molecules can be synthesized. This in turn should allow ambitious research, e.g., finding novel synthesis routes or directly screening for photocatalysts. Herein, different technologies are discussed that might be involved in this endeavor. A special emphasis is given to the obstacles that need to be tackled when depositing tiny amounts of materials to many different extremely miniaturized reaction sites.

Modern machine learning for tackling inverse problems in chemistry: molecular design to realization

“…The latter objective would help in producing systems with the ability to synthesize molecules based on the provided retrosynthetic steps without necessarily leading to a high-throughput procedure. 118 A recent analysis of small drug like molecules found a lot of redundancy in the fragments present in them in terms of heterocyclic motifs. 119 In other words, the estimated number of drug like molecules is practically infinite, but the number of different fragments that form these molecules is less.…”

Automated, Accelerated Nanoscale Synthesis of Iminopyrrolidines

“…Synthesis and exploration of chemical space is usually a sequential, expensive, and slow process. However, acceleration and miniaturization of synthetic chemistry is becoming more and more important for the timely discovery of novel drugs and materials in an age of big data and artificial intelligence . For example, nanoscale optimization procedures to explore the scope and limitations of Pd‐catalyzed cross‐coupling reactions were recently described .…”

Production of high-complexity frameshift neoantigen peptide microarrays

“…This requires the use of 300 photolithographic masks, a noted challenge of photolithographic peptide array production systems. 3 We show that we can synthesize a library of this complexity at a scale compatible with the development of a diagnostic assay. We demonstrate that this system can be used to produce large numbers of peptide microarrays.…”