用AI设计复杂天然产物合成路线,效果媲美人类专家。
Strategy-first synthesis planning for complex natural products

- 基于大模型构建自主规划框架,先定策略再执行步骤。
- 生成路线收敛性更好,覆盖传统工具无法触及的反应空间。
- 专家盲评认可其关键步骤质量,适合前沿合成研究者使用。
复杂分子的全合成是化学领域最具挑战性的智力与实验任务之一:化学家需前瞻多步,设计构建块拼装路径,制定备选方案并预判操作难点,同时极具创造性。过去半个世纪,自动化逆合成设计主要依赖已收录反应库,现有工具在基准测试中表现接近完美,但这些工具适应的是已有化学数据,难以应对自然产物等前沿分子——其高度官能团化、多环结构对创新化学提出更高要求。机器能否像专家一样合理设计此类合成仍不清楚。本文展示,基于大语言模型的智能体框架SynthEx可规划出超越传统算法能力的复杂天然产物合成路径。SynthEx能提出多种竞争性策略,将常规与关键步骤整合为连贯路线,并自我批判优化;其偏好更收敛的合成路径,覆盖传统工具无法触及的反应区域。最显著的是,在盲评中,专家认为其关键步骤与已发表的人类合成相当,且视为真实可行的合成计划,这是算法路线预测首次达成此效果。我们公开发布超过一千种天然产物的合成路线,形成开源交互数据库SynthAtlas,期望成为无文献路线的复杂目标分子共享资源。
原文摘要 · Abstract (English)
The total synthesis of a complex molecule is among the most demanding intellectual and experimental feats in chemistry: a chemist must plan many steps ahead for how to assemble simple building blocks into an intricate target, devise backup strategies, and anticipate procedural challenges. It is also a profoundly creative activity. For half a century, efforts to automate the retrosynthetic design of natural products and other complex molecules have drawn on catalogued reactions, and the resulting tools now report near-complete success on benchmarks built from that same source. But these tools were shaped to fit benchmarked chemistry, and they falter on many natural products, the frontier of the field, whose densely functionalized, polycyclic architectures demand precisely the inventive chemistry the record contains least. Whether a machine could reasonably design such syntheses like an expert chemist does has remained unclear. Here, we show that SynthEx, an agentic framework built on large language models, plans routes to complex natural products that lie beyond the reach of conventional design algorithms. SynthEx proposes competing strategies, assembles a sequence of routine and key steps into a cohesive route, and critiques and improves its own design; the chemistry it favours is more convergent than existing tools produce, and spans a region of reaction space that catalogue-based tools cannot match. Most notably, in blinded assessments, expert chemists judged its key steps comparable to those of published human syntheses and engaged with them as genuine synthesis plans, a response algorithmic route prediction has not previously accomplished. We release routes to more than a thousand natural products as SynthAtlas, an open, interactive database, and anticipate it will become a shared resource for a collection of complex target molecules that lack existing literature routes.
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