Frugal Sampling Strategies for Navigating Complex Reaction Spaces

As the complexity of the chemical space continues to
grow, innovative
strategies are required to enhance screening efficiency. With the
main goal of identifying overarching trends, we introduce novel high-throughput
experimentation (HTE) sampling strategies that explore broader chemical
spaces and only require 25% of the experiments compared to full factorial
designs. Our carefully designed quasi-random sampling methods maximize
plate layout diversity while preserving practicality for 96-well microtiter
plates. The frugal samplings were successfully applied to four challenging
metal-catalyzed cross-coupling reactions. The resulting screens retained
sufficient information to understand the main tendencies and enable
informed decision-making for subsequent optimization activities. In
one case study, the method was coupled with a Bayesian optimization
workflow to enable cost-effective transformations within the explored
chemical space by introducing a cost-penalized yield as an optimization
objective.