Higher-level Strategies for Computer-Aided Retrosynthesis

Retrosynthesis is a core technique in organic chemistry that involves simplifying target molecules into more readily available components. Computer-aided synthesis planning (CASP) tools automate this process by recursively proposing immediate precursors of molecules to identify multistep synthetic pathways. However, the application of CASP tools becomes particularly challenging for complex molecules due to the increased length of synthetic pathways and the increased number of possible disconnections. We introduce a new framework for computer-aided retrosynthesis, \emph{higher-level} retrosynthesis, that focuses on the broader retrosynthetic strategy. We abstract the detailed substructures in the intermediates of a synthetic pathway that do not appear in the target product, allowing our algorithm to emphasize the general, higher-level strategies and postpone the consideration of chemically-equivalent functional groups to a later stage. This approach leads to shorter and narrower search trees, letting the search algorithm allocate its computational resources more efficiently and discover retrosynthetic strategies that the original approach does not generate. We demonstrate the empirical effectiveness of our approach with higher success rates in single- and multi-step retrosynthetic planning. We further underscore the value of our framework through case studies involving complex drugs and natural products. We illustrate how the strategies identified through our framework provide chemists with a powerful basis to develop full synthesis plans, particularly in challenging cases where the original approach to computer-aided retrosynthesis trained on the same dataset yields no viable solutions, while also enabling them to leverage their expertise and intuition to refine the synthesis design process. Ultimately, focusing on higher-level strategies in computer-aided retrosynthesis enhances its effectiveness and enables a more intuitive approach to addressing challenging retrosynthesis problems.