Autonomous chemical research with large language models.

Transformer-based large language models are making significant strides in various fields, such as natural language processing1-5, biology6,7, chemistry8-10 and computer programming11,12. Here, we show the development and capabilities of Coscientist, an artificial intelligence system driven by GPT-4 that autonomously designs, plans and performs complex experiments by incorporating large language models empowered by tools such as internet and documentation search, code execution and experimental automation. Coscientist showcases its potential for accelerating research across six diverse tasks, including the successful reaction optimization of palladium-catalysed cross-couplings, while exhibiting advanced capabilities for (semi-)autonomous experimental design and execution. Our findings demonstrate the versatility, efficacy and explainability of artificial intelligence systems like Coscientist in advancing research.

Guided discovery of chemical reaction pathways with imposed activation.

Computational power and quantum chemical methods have improved immensely since computers were first applied to the study of reactivity, but the de novo prediction of chemical reactions has remained challenging. We show that complex reaction pathways can be efficiently predicted in a guided manner using chemical activation imposed by geometrical constraints of specific reactive modes, which we term imposed activation (IACTA). Our approach is demonstrated on realistic and challenging chemistry, such as a triple cyclization cascade involved in the total synthesis of a natural product, a water-mediated Michael addition, and several oxidative addition reactions of complex drug-like molecules. Notably and in contrast with traditional hand-guided computational chemistry calculations, our method requires minimal human involvement and no prior knowledge of the products or the associated mechanisms. We believe that IACTA will be a transformational tool to screen for chemical reactivity and to study both by-product formation and decomposition pathways in a guided way.

A Stereoselective Photoinduced Cycloisomerization Inspired by Ophiobolin A.

A stereoselective synthetic entry point to the 5-8-5 carbocyclic core of the ophiobolins was developed. This strategy exploits the chiral tertiary alcohol of ophiobolin A to guide assmebly of the 5-8-5 scaffold in a single step via a photoinitiated cycloisomerization. Mechanistic insights into the origin of stereocontrol in this reaction are described, as are efforts to elaborate the resultant fused 5-8-5 ring system to the pharmacophore of ophiobolin A.