Flow Chemistry Guided by Computer-Aided Synthesis Planning
Synthetic organic chemistry provides access to valuable materials and molecules that enable advancements across scientific disciplines. New advancements in synthetic technology continue to push the boundaries of how rapidly and efficiently complex matter can be produced. Despite this, it is often di...
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Massachusetts Institute of Technology
2022
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| Online Access: | https://hdl.handle.net/1721.1/144099 https://orcid.org/0000-0002-1762-5977 |
| Summary: | Synthetic organic chemistry provides access to valuable materials and molecules that enable advancements across scientific disciplines. New advancements in synthetic technology continue to push the boundaries of how rapidly and efficiently complex matter can be produced. Despite this, it is often difficult for practitioners outside the core field of organic synthesis to fully leverage these advances, in part due to lack of experience in planning and executing synthetic sequences as well as often times incomplete communication of procedural information known only to expert practitioners.
New tactics for planning and executing syntheses that disrupt conventional approaches to process development must be established in order for the utility of synthetic chemistry to become more broadly accessible. Computer-aided synthesis planning tools that utilize machine learning techniques is one such tactic wherein a computer program suggests synthetic routes to user defined small molecule targets. While there has been much attention paid to the development and refinement of computer-aided synthesis planning tools, reports that detail validation of synthetic routes proposed in silico remain rare. Continuous flow chemistry, wherein reagents are pumped through volumes in a time-dependant fashion rather than in fixed reactor volume batches, has been established as successful strategy for pushing the limits of synthetic chemistry through process intensification. In this thesis, the marriage of computer-aided synthesis planning, flow chemistry, and often times automation technology, is showcased through the preparation of active pharmaceutical ingredients according to synthetic strategies and tactics proposed by a computer-aided synthesis program.
In the 1st chapter, the concepts of continuous flow chemistry, computer-aided synthesis planning, automated experimentation, and the interplay of these concepts are introduced. The general approach and maturity of laboratory scale continuous flow chemistry for is first established. This is followed by a discussion of how automated continuous flow systems can use decision-making algorithms to enable closed-loop feedback in optimization experiments. Applications of this paradigm in the areas of reaction parameter measurements, materials synthesis, nano-materials synthesis, modern synthetic organic methods, and all-purpose synthesis machines is then discussed. The chapter concludes by outlining current challenges in the field and by proposing avenues of future work.
The 2nd chapter describes a strategy for the continuous synthesis of angiotensin converting enzyme inhibitors, including quinapril and enalapril. This strategy was informed by ASKCOS, a computer-aided synthesis program, and developed manually using bench-top flow reactors as well as batch chemistry techniques. An optimization effort guided by in situ Fourier-transform infrared spectroscopy analysis resulted in a general amide coupling approach facilitated by N‐carboxyanhydride activation that was further characterized by reaction kinetics analysis in batch. The three‐step continuous process was demonstrated by synthesizing 8 different ACE inhibitors in up to 88% yield with throughput values in the range of 0.5 g h-1, all while avoiding both isolation of reactive intermediates and process intensive reaction conditions. The process was further developed by preparing enalapril, a World Health Organization essential medicine, in an industrially relevant flow platform that scaled throughput to 1 g h-1. The results of this effort motivated translation of the process to an automated reaction execution platform described in the next chapter.
The 3rd chapter outlines a step toward a paradigm of chemical synthesis that relieves chemists from routine tasks, combining artificial intelligence-driven synthesis planning and a robotically controlled experimental platform. Synthetic routes are proposed through generalization of millions of published chemical reactions and validated in silico to maximize their likelihood of success. Additional implementation details are determined by expert chemists and recorded in reusable recipe files, which are executed by a modular continuous-flow platform that is automatically reconfigured by a robotic arm to set up the required unit operations and carry out the reaction. This strategy for computer-augmented chemical synthesis is demonstrated for 15 drug or drug-like substances, five of which were translated from the process detailed in chapter 1.
In the 4th and final chapter, the telescoped flow synthesis of sonidegib, an important chemotherapeutic agent, according to the computer-aided synthesis program, ASKCOS, is described. The program proposed three potential pathways that were evaluated as telescoped flow sequences. It was found that a three step synthesis of the target could be performed as a fully telescoped flow process in 86.6 \% overall yield. One of the other options, involving an amide coupling and Pd-catalyzed C-N coupling sequence, could be performed as a batch process but could not be translated to continuous flow. The other two step sequence, amide coupling followed by an SNAr did not proceed under the CASP program reaction conditions. This work establishes a general approach for using CASP suggestions to guide development of telescoped flow chemistry. During this project, all work was performed by C.P.B. under T.F.J.'s guidance.
Portions of this thesis have been reprinted, adapted, or both, with permission from their respective publishers.
Breen, C.P.; Nambiar, A.M.K.; Jamison, T.F.; Jensen, K.F. Ready, Set, Flow! Automated Continuous Synthesis and Optimization Trends Chem. 2021 3, 373-386. Copyright 2021 Elsevier Incorporated. C.P.B. and A.M.K.N. contributed equally to preparing the manuscript. T.F.J. and K.F.J. provided guidance and helped edit the manuscript.
Christopher P. Breen and Timothy F. Jamison. Continuous Flow Synthesis of ACE Inhibitors From N-Substituted L-Alanine Derivatives. Chem. Eur. J. 2019 25, 14527-14531. Copyright 2019 John Wiley & Sons. All work was performed by C.P.B. under T.F.J.'s guidance.
Coley, C.W.; Thomas, D.A. III; Lummiss, J.A.M.; Jaworski, J.N.; Breen, C.P.; Schultz, V.; Hart, T.; Fishman, J.S.; Rogers, L.; Gao, H.; Hicklin, R.W.; Plehiers, P.P.; Byington, J.; Piotti, J.S.; Green, W.H.; Hart, A.J.; Jamison, T.F.; Jensen, K.F. A Robotic Platform for Flow Synthesis of Organic Compounds Informed by AI Planning. Science 2019, 365, eaax1566. Copyright 2019 American Association for the Advancement of Science. Reprinted with Permission from AAAS. C.W.C. designed, developed, and implemented the synthesis-planning software; D.A.T. designed, developed, and supervised construction of the robotic platform; J.A.M.L., J.N.J., C.P.B., V.S., and L.R. developed chemistry, performed experiments with the robotic platform, and interpreted results; T.H., J.S.F., J.B., and J.S.P. assisted in the development, maintenance, and assembly of the robotic platform; H.G. and P.P.P. assisted in the development of synthesis-planning code; R.W.H., W.H.G., and K.F.J. advised on the development of the synthesis-planning software; A.J.H. and K.F.J. advised on the development of the robotic platform; T.F.J. supervised chemistry development; C.W.C., D.A.T., and J.A.M.L. prepared the manuscript; T.F.J., K.F.J., and A.J.H. edited the manuscript; and K.F.J. supervised the project and secured funding. |
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