RetrOrchestrator: A Multi-Step Retrosynthesis Agent Dynamically Orchestrating Single-Step Transition Models

Abstract (source: OpenReview · © authors)

Multi-step retrosynthesis planning is a fundamental challenge in organic chemistry, defined by its enormous search space. Existing methods typically formulate it as a Markov Decision Process (MDP) with a fixed choice of transition model (i.e., a single-step retrosynthesis model), and focus on improving *how to search* through better policies and value functions. However, *how the transition space itself is navigated* remains largely unexplored. This limitation is particularly urgent given our observation of pronounced *skill disparity* among single-step prediction models: different models exhibit substantially different performance across molecule states. Motivated by this observation, we introduce RetrOrchestrator, an LLM-powered agent that explicitly accounts for model skill disparity by reframing retrosynthesis planning as a Partially Observable Markov Decision Process (POMDP). By regarding each single-step prediction model as a tool, we further propose a scaffold-aware reinforcement learning algorithm to optimize navigation policy within the transition space. As a result, RetrOrchestrator jointly searches which molecule to expand and which single-step model to apply for the molecule at the current step. Empirically, RetrOrchestrator significantly outperforms static baselines on the Retro*-190 benchmark, achieving a state-of-the-art 94.21% success rate (vs. 9.47% off-the-shelf LLM and 82.63\% non-LLM state-dependent router), with 92.49% of solved routes invoking two or more SSRs—evidence that the policy is not collapsing to a single specialist or a static router. The same gain persists on a larger out-of-distribution set (PDB-600), with RetrOrchestrator Pareto-optimal in both wall-clock time and model-query count. Code: https://github.com/ScottLiao920/verl-retro-agent.

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