Higher-Level Strategies for Computer-Aided Retrosynthesis

Abstract Retrosynthesis is a core technique in organic chemistry that simplifies target molecules into more readily available components. Computer-aided synthesis planning (CASP) automates this process by recursively proposing immediate precursors to identify multistep synthetic pathways. However, CASP typically struggles for complex molecules that require longer synthetic pathways and present a greater number of possible disconnections. Here, we introduce a new higher-level framework for computer-aided retrosynthesis. Our approach abstracts detailed substructures in pathway intermediates not appearing in the target product, allowing the algorithm to emphasize higher-level strategies while postponing the consideration of specific functional group choices, thus reducing the effective width and depth of the search space. This framework achieves higher top-k accuracy in single-step retrosynthesis and identifies multistep routes for more targets than the original approach. Through case studies on complex drugs and natural products, we demonstrate how routes proposed by our framework provide a powerful basis for developing full synthesis plans, particularly in challenging cases where the original approach fails, while enabling chemists to leverage their expertise to refine the synthesis design. Ultimately, focusing on higher-level strategies enables an effective and intuitive approach for challenging targets in computer-aided retrosynthesis.