Organic synthesis in a modular robotic system driven by a chemical programming language

Abstract

One Sentence Summary: A modular platform for synthesis is demonstrated that makes purified organic compounds autonomously without physical reconfiguration and is driven using a chemical programming language.Abstract: The synthesis of complex organic compounds is largely a manual process that is often incompletely documented. To address these shortcomings, we developed an abstraction that maps commonly reported methodological instructions into discrete steps amenable to automation. These unit operations were implemented in a modular robotic platform using a chemical programming language which formalizes and controls the assembly of the molecules.We validated the concept by directing the automated system to synthesize three pharmaceutical compounds, Nytol, Rufinamide, and Sildenafil, without any human intervention. Yields and purities of products and intermediates were comparable to or better than those achieved manually. The syntheses are captured as digital code that can be published, versioned, and transferred flexibly between platforms with no modification, thereby greatly enhancing reproducibility and reliable access to complex molecules.The automation of chemical synthesis is currently expanding, and this is driven by the availability of digital labware. The field currently encompasses areas as diverse as the design of new reactions (1), chemistry in reactionware (2), reaction monitoring and optimization (3,4), flow chemistry (5) for reaction optimization and scale up, to full automation of the synthesis

Autonomous Discovery in the Chemical Sciences Part II: Outlook

“…As the community begins to undertake this challenge, it's imperative that we pay attention to affordability, lest we discourage/inhibit adoption. Homegrown systems can be made inexpensively through integration of common hardware components and open-source languages for control [185,201]. Miniaturization reduces material consumption costs, but can complicate system fabrication and maintenance.…”

Universal Chemical Synthesis and Discovery with ‘The Chemputer’

“…Methodologies for the automation of chemical synthesis, optimization, and discovery have not generally been designed for the realities of laboratory-based research, tending instead to focus on engineering solutions to practical problems. We argue that the potential of rapidly developing technologies (e.g., machine learning and robotics) are more fully realized by operating seamlessly with the way that synthetic chemists currently work ( Figure 1) [1]. This is because the organic chemist often works by thinking backwards as much as they do forwards when planning a synthetic procedure.…”

“…In the following paragraphs, we show how chemometrics can be synergistically combined with automation. As we will demonstrate through several examples, the process of automation allows 1 WestCHEM, School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK *Correspondence: Lee.Cronin@glasgow.ac.uk Recent advances in chemical programming enable adoption and universal automation of chemical discovery and synthesis, combined with artificial intelligence, to efficiently perform laboratory tasks, including the closed-loop data exploration for new reactivity.…”

“…We recently showed a modular platform for automating batch organic synthesis, which embodies our abstraction in 'the Chemputer' (Figure 4) [1]. Our abstraction of organic synthesis ( Figure 4A) contains the key four stages of synthetic protocols: reaction, workup, isolation, and purification, that can be linked to the physical operations of an automated robotic platform.…”

I2 Robot

“…In a recent article in Science, the team reports that these syntheses without any human intervention achieved results comparable to or better than the equivalent manual procedures. 1 The total cost of the setup used was less than £23,000, including the stirrers, evaporator etc.…”