Bayesian Optimization of Computer-Proposed Multistep Synthetic Routes on an Automated Robotic Flow Platform

24 February 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Computer-aided synthesis planning (CASP) tools can propose retrosynthetic pathways and forward reaction conditions for the synthesis of organic compounds, but the limited availability of context-specific data currently necessitates experimental development to fully specify process details. We plan and optimize a CASP-proposed and human-refined multistep synthesis route towards an exemplary small molecule, sonidegib, on a modular, robotic flow synthesis platform with integrated process analytical technology (PAT) for data-rich experimentation. Human insights address catalyst deactivation and improve yield by strategic choices of order of addition. Multi-objective Bayesian optimization identifies optimal values for categorical and continuous process variables in the multistep route involving 3 reactions (including heterogeneous hydrogenation) and 1 separation. The platform’s modularity, robotic reconfigurability, and flexibility for convergent synthesis are shown to be essential for allowing variation of downstream residence time in multistep flow processes and controlling the order of addition to minimize undesired reactivity. Overall, the work demonstrates how automation, machine learning, and robotics enhance manual experimentation through assistance with idea generation, experimental design, execution, and optimization.


multistep flow chemistry
Bayesian optimization
process analytical technology
computer-aided synthesis planning
data-rich experimentation

Supplementary materials

Supporting Information
Additional details on automated synthesis platform, computer-aided synthesis planning recommendations, optimization algorithm, materials and methods, and experimental results
Supplementary Movie
Movie summarizing results, including videos of robotic synthesis platform in operation during optimization campaigns

Supplementary weblinks


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