Developing Methods for Reaction Informatics and Automation

Abstract

As the field of organic synthesis enters the digital age, an unprecedented number of tools are opened up for analyzing, planning and executing chemical reactions. This thesis will describe the development of two methods for analyzing reactions between organic molecules, and one for the automation of setting up high-throughput experiments. First, an extensive exploration of amine–carboxylic acid reaction space was conducted through computational enumeration of all theoretically possible matrix-encoded transformations between a simple amine–acid pair, delving into an under-explored axis of chemical space exploration. The extent of physicochemical property modulation enabled by this technique is analyzed using both small and large building blocks. The performance of reaction enumeration method in generating virtual libraries from one single building block pair was evaluated against the conventional approach of coupling many building blocks through one robust reaction. Next, the matrix encoding technique was applied to analysis of reactions throughout a total synthesis route. A new method of synthetic route visualization was developed by charting the graph edit distance between each intermediate and the target, producing a graph from which valuable high-impact steps can be quickly identified and analyzed. By merging this technique with computer-aided synthesis planning software, two enantioselective syntheses of the alkaloid stemoamide were conducted. At the length of six and three steps respectively, they mark the shortest synthesis of this molecule to date. Lastly, a platform for automated setup of high-throughput experiments in 24- and 96-wellplates was developed, combining the online electronic notebook phactor™ with the Opentrons OT-2 autopipettor. Benchmarking test against the existing manual workflow reveal that the robotic setup performs adequately in most conditions, with the main exception being poorly soluble solid reagents. An alternative manual dosing of such solids was developed using custom spatula designs. The automated platform enables many novel experimental designs, such as remote collaboration over teleconferencing software, and small-scale library synthesis of nearly 100 products in a single wellplate.