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

Clear directions for a robotic platform The chemistry literature contains more than a century's worth of instructions for making molecules, all written by and for humans. Steiner et al. developed an autonomous compiler and robotic laboratory platform to synthesize organic compounds on the basis of standardized methods descriptions (see the Perspective by Milo). The platform comprises conventional equipment such as round-bottom flasks, separatory funnels, and a rotary evaporator to maximize its compatibility with extant literature. The authors showcase the system with short syntheses of three common pharmaceuticals that proceeded comparably to manual synthesis. Science, this issue p. eaav2211; see also p. 122 A compiler directs a robotic platform to conduct short organic syntheses using standard protocols and laboratory equipment. INTRODUCTION Outside of a few well-defined areas such as polypeptide and oligonucleotide chemistry, the automation of chemical synthesis has been limited to large-scale bespoke industrial processes, with laboratory-scale and discovery-scale synthesis remaining predominantly a manual process. These areas are generally defined by the ability to synthesize complex molecules by the successive iteration of similar sets of reactions, allowing the synthesis of products by the automation of a relatively small palette of standardized reactions. Recent advances in areas such as flow chemistry, oligosaccharide synthesis, and iterative cross-coupling are expanding the number of compounds synthesized by automated methods. However, there is no universal and interoperable standard that allows the automation of chemical synthesis more generally. RATIONALE We developed a standard approach that mirrors how the bench chemist works and how the bulk of the open literature is reported, with the round-bottomed flask as the primary reactor. We assembled a relatively small array of equipment to accomplish a wide variety of different syntheses, and our abstraction of chemical synthesis encompasses the four key stages of synthetic protocols: reaction, workup, isolation, and purification. Further, taking note of the incomplete way chemical procedures are reported, we hypothesized that a standardized format for reporting a chemical synthesis procedure, coupled with an abstraction and formalism linking the synthesis to physical operations of an automated robotic platform, would yield a universal approach to a chemical programming language. We call this architecture and abstraction the Chemputer. RESULTS For the Chemputer system to accomplish the automated synthesis of target molecules, we developed a program, the Chempiler, to produce specific, low-level instructions for modular hardware of our laboratory-scale synthesis robot. The Chempiler takes information about the physical connectivity and composition of the automated platform, in the form of a graph using the open-source GraphML format, and combines it with a hardware-independent scripting language [chemical assembly (ChASM) language], which provides instructions for the machine operations of the automated platform. The Chempiler software allows the ChASM code for a protocol to be run without editing on any unique hardware platform that has the correct modules for the synthesis. Formalization of a written synthetic scheme by using a chemical descriptive language (XDL) eliminates the ambiguous interpretation of the synthesis procedures. This XDL scheme is then translated into the ChASM file for a particular protocol. An automated robotic platform was developed, consisting of a fluidic backbone connected to a series of modules capable of performing the operations necessary to complete a synthetic sequence. The backbone allows the efficient transfer of the required chemicals into and out of any module of the platform, as well as the flushing and washing of the entire system during multistep procedures in which the modules are reused multiple times. The modules developed for the system consist of a reaction flask, a jacketed filtration setup capable of being heated or cooled, an automated liquid-liquid separation module, and a solvent evaporation module. With these four modules, it was possible to automate the synthesis of the pharmaceutical compounds diphenhydramine hydrochloride, rufinamide, and sildenafil without human interaction, in yields comparable to those achieved in traditional manual syntheses. CONCLUSION The Chemputer allows for an abstraction of chemical synthesis, when coupled with a high-level chemical programming language, to be compiled by our Chempiler into a low-level code that can run on a modular standard robotic platform for organic synthesis. The software and modular hardware standards permit synthetic protocols to be captured as digital code. This code can be published, versioned, and transferred flexibly between physical platforms with no modification. We validated this concept by the automated synthesis of three pharmaceutical compounds. This represents a step toward the automation of bench-scale chemistry more generally and establishes a standard aiming at increasing reproducibility, safety, and collaboration. Abstraction of organic synthesis to the Chemputer software and hardware standards. The Chemputer system can perform multistep organic synthesis protocols on the bench by using a modular system with hardware and software standards. 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 by using a chemical programming language that formalizes and controls the assembly of the molecules. We validated the concept by directing the automated system to synthesize three pharmaceutical compounds, diphenhydramine hydrochloride, 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.