Fully Automated Chemical Synthesis: Toward the Universal Synthesizer

Abstract

Automated peptide and oligonucleotide synthesizers enabled a revolution in molecular biology and helped pave the way to modern synthetic biology. Similarly, fully automated synthetic chemistry could herald a new wave of innovation in biology and materials sciences by greatly facilitating access to known and novel molecules. Here, we report on an automated multistep chemical synthesizer, AutoSyn, that makes milligram-to-gram-scale amounts of virtually any drug-like small molecule in a matter of hours and demonstrate its versatility with the synthesis of ten known drugs. Of the FDA-approved small-molecule drugs for which we were able to compute a synthetic route, 87% are predicted to be synthesizable on AutoSyn. Moreover, AutoSyn enables digital synthesis protocols that ensure the reproducibility and transferability of synthesis protocols from one lab to another.

Digitising chemical synthesis in automated and robotic flow

“…With all these advances in mind, an automated synthesis platform, "AutoSyn CityScape", which emulates a miniaturised chemical plant, has been designed to produce milligram-togram quantities of small organic molecules. 18 The conguration, shown in Fig. 10, resembles a city's high-rise landscape, with a subway map of ow components that can be operated with minimal intervention by a single-user.…”

“…The exibility of AutoSyn was chosen as the predominant attribute (rather than yield or full optimisation), demonstrating a step closer towards a "universal synthesiser". 18 Further optimisations of the synthesis procedures will in the future help increase yields and efficiency. For example, levels 1 and 2 are similar to the processes of Chematica and Cronin, respectively; 10,52,53,63 however, benet would be revealed by introducing machine learning techniques incorporating the huge number of reactions stored in databases as in the works of Segler et al 28 and Coley and Jenson et al 22,55,58 Moreover, AutoSyn is designed to produce products in usable quantities (mg to g) which is a necessity for large, complicated (but wellknown) multistep syntheses, i.e.…”

“…These are preferably avoided in automated ow, and reaction conditions compatible with all steps are carefully chosen. 18 On the other hand, most continuous ow setups focus on core motifs rather than on a specic compound. Extending their capabilities to automatic and recongurable systems will require multistep syntheses of complex molecules, involving several unit operations that do not occur in the same order.…”

Addressing Environmental Challenges of Porphyrin Mixtures Obtained from Statistical Syntheses

“…[27][28][29] Nevertheless, in the last few years great steps towards automation in synthetic chemistry were made and reported by several groups, [30,31] including the so-called "Chemputer", developed by Cronin and co-workers, [32] or the "Auto-Syn" system, developed by the group around Collins and coworkers. [33] Hereby, especially the synthesis of small organic molecules, which are of industrial relevance will experience a tremendous boost. [34] However, such techniques and technological advances often do not reach academic laboratories, because the research funding is limited, and often the isolation of the target molecule is prioritized over a sustainable pathway.…”

“…To date, automation is mainly known in the field of peptides and nucleotides [27–29] . Nevertheless, in the last few years great steps towards automation in synthetic chemistry were made and reported by several groups, [30,31] including the so‐called “Chemputer”, developed by Cronin and co‐workers, [32] or the “AutoSyn” system, developed by the group around Collins and co‐workers [33] . Hereby, especially the synthesis of small organic molecules, which are of industrial relevance will experience a tremendous boost [34] .…”