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.