Coley CW,
Thomas III DA,
Lummiss JA. M,
Jaworski JN,
Breen CP,
Schultz V,
Hart T,
Fishman JS,
Rogers L,
Gao H,
Hicklin RW,
Plehiers PP,
Byington J,
Piotti JS,
Green WH,
Hart AJ,
Jamison TF.
*
Jensen KF.
* Massachusetts Institute of Technology, Cambridge, USA
A Robotic Platform for Flow Synthesis of Organic Compounds Informed by AI Planning.
Science 2019;
365
DOI:
10.1126/science.aax1566
Key words
artificial intelligence - reaction design - flow synthesis - automated synthesis -
robot synthesizer
Significance
This paper details a remarkable achievement in the synthesis of complex drug molecules
by using artificial intelligence (AI) and robotics. In this process, synthetic route
selection is performed by using AI-aided synthesis planning and, after revision by
experienced organic chemists, is carried out on a robotic platform in which flow systems
are assembled, processes are run, and the reactors are disassembled and stored. This
paper demonstrates this process for 15 small drug molecules (e.g., lidocaine, as shown
above). Some interesting components of the planning process include the ability of
the software to predict side reactions and to flag potentially complicated reaction
mixtures due to incompatibility or chemoselectivity issues, as well as the ability
to choose a reagent from various options on the basis of the predicted confidence
that the reagent will provide the best outcome.
Comment
One challenge acknowledged by the authors is the direct translation of batch processes
from patent and literature reports into continuous processing, which requires the
external influence of a chemist to evaluate the process for performance in flow (stoichiometry,
solubility, impurities). As new processes are enabled by flow technologies, a richer
database for reactions that are compatible for this technology will become available,
and this might remove the need for human intervention during route optimization and
definition of the chemical recipe files, permitting rapid transfer of synthetic routes
to the automated robotic platform.
