Correlated first-principles methods for applications in exploration-supported synthesis planning

在这项提议中，将利用第一原理量子化学计算来探索所提议的化学反应级联的可行性。具体地说，当合成新化合物时，通常需要对通向化合物的多条路径进行评估。路径通常从最终目标开始生成，然后分解成较小的所谓合成子，这一过程称为逆向合成。这些逆向合成建议将在合成化合物的实验工作开始之前进行计算评估。允许这种验证的灵活算法的关键要求是一个自动基准系统，它允许创建的程序在内部验证其计算。对于通常未知的反应路径，必须有一个健壮的电子结构方法，允许准确计算在探索反应空间时遇到的任何系统。在这里，我们建议开发一种计算上可行的多组态方法来进行精确的内部基准测试。我们计划将用密度泛函理论(DFT)描述短程电子-电子相互作用和用密度矩阵重整化群(DMRG)算法优化的完全活性空间波函数来描述长程电子-电子相互作用相结合。特别是，我们提出了一种开壳电子结构的无自旋污染方法，如果用不受限制的Kohn-Sham理论处理，这些结构将受到自旋污染的困扰。最终的实现将被集成到允许自动探索反应空间的软件中，以验证反合成建议。为此，将扩展现有的探索软件，以推动其沿着预定的路线进行探索，并评估可能的副反应。最后，该实施将在已知药物化合物的合成上进行测试，以便在未来应用于未知化合物的合成。

In this proposal, first-principles quantum chemical calculations shall be exploited to probe the viability of proposed chemical reaction cascades. Specifically when new chemical compounds are synthesized, there is usually an evaluation of multiple paths leading to the compound.The paths are often generated starting from the final target, then breaking into smaller so-called synthons, this process is called retrosynthesis.These retrosynthetic suggestions will be evaluated computationally before experimental efforts to synthesize the compund are started.The key requirement for a flexible algorithm that allows for such a validation is an automated benchmarking system that allows the created program to validate its calculations internally.For a generally unknown reaction path it is imperative to have a robust electronic structure method that allows for the accurate calculation of any system encountered during the exploration of the reaction space.Here, we propose to develop a computationally feasible multi-configuration approach for accurate internal benchmarking.We plan to combine the description of short-range electron-electron interactions by density functional theory (DFT), and the description of long-range electron-electron interactions by a complete-active-space wave function optimized by the density matrix renormalization group (DMRG) algorithm.In particular, we propose a spin-contamination-free approach for open-shell electronic structures, which are known to be plagued by spin contamination if treated by unrestricted Kohn-Sham theory. The resulting implementation will be integrated into software that allows for the automated exploration of reaction space in order to validate retrosynthetic suggestions.To this end, the existing exploration software will be extended to drive its exploration along a predetermined path and evaluate possible side reactions.Finally the implementation will be tested on the syntheses of known pharmaceutical compounds, in order to be applied to the syntheses of unkown compunds in the future.