Strategy-first synthesis planning for complex natural products

Imagine you're a chemist tasked with synthesizing a complex natural product. You need to plan multiple steps ahead, anticipate challenges, and devise creative strategies to assemble simple building blocks into a sophisticated target. Traditional tools for retrosynthetic design often rely on catalogued reactions, which work well on benchmarked chemistry but struggle with the intricate architectures of many natural products. This limitation is known as the 'benchmark bias,' where tools excel in familiar scenarios but falter in real-world applications that require more inventive approaches. To address this gap, a new framework called SynthEx has been developed, which utilizes large language models to generate synthesis routes for complex molecules. SynthEx not only proposes various strategies but also critiques and refines its own designs, leading to more convergent and innovative solutions than conventional methods. In blind assessments, expert chemists found SynthEx's proposed key steps comparable to those of human syntheses, indicating that it can produce genuine synthesis plans that were previously unattainable by algorithmic predictions. This advancement opens up new possibilities for chemists, as SynthEx provides access to a database of over a thousand natural products, offering a valuable resource for tackling complex synthesis challenges.

SynthEx introduces a novel approach to retrosynthetic design using large language models.

The assessments by expert chemists provide a solid validation of SynthEx's outputs.