Reconfigurable Flow Platform for Automated Reagent Screening and Autonomous Optimization for Bioinspired Lignans Synthesis

Naturally occurring benzoxanthenones, which belong to the vast family of lignans, are promising biologically relevant targets. They are biosynthetically produced by the oxidative dimerization of 2-propenyl phenols. In this manuscript, we disclose a powerful automated flow-based strategy for identifying and optimizing a cobalt-catalyzed oxidizing system for the bioinspired dimerization of 2-propenyl phenols. We designed a reconfigurable flow reactor associating online monitoring and process control instrumentation. Our machine was first configured as an automated screening platform to evaluate a matrix of 4 catalysts (plus the blank) and 5 oxidants (plus the blank) at two different temperatures, resulting in an array of 50 reactions. The automated screening was conducted on micromole scale at a rate of one fully characterized reaction every 26 min. After having identified the most promising cobalt-catalyzed oxidizing system, the automated screening platform was straightforwardly reconfigured to an autonomous self-optimizing flow reactor by implementation of an optimization algorithm in the closed-loop system. The optimization campaign allowed the determination of very effective experimental conditions in a limited number of experiments, which allowed us to prepare the natural products carpanone and polemannone B as well as synthetic analogues.