Chen Miao, Dong Guangbin
Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States.
ACS Cent Sci. 2025 May 29;11(6):843-854. doi: 10.1021/acscentsci.5c00526. eCollection 2025 Jun 25.
Fully automated preparation of diverse small organic molecules remains a formidable challenge due to the inherent constraints of conventional synthetic philosophies. The existing automation approaches require access to either almost unlimited kinds of chemical reagents or custom-made building blocks (BBs). Herein we propose atom-by-atom iterative synthesis (AIS) as a new synthetic logic to tackle this challenge. By viewing complex organic molecules as assemblies of single-carbon- or heteroatom-based units, AIS aims to construct molecular skeletons through iterative coupling of simple atomic-scale BBs by a unified type of reactionboron homologations. Compared with conventional approaches, the AIS strategy uses only a few types of chemical reactions and a small set of BBs, making it more suitable for automation and artificial intelligence-assisted synthetic route design. To date, enormous progresses have been made on the synthetic chemistry that serves for the purpose of AIS, such as introducing heteroatoms and sp-carbons, forming ring structures, developing thermostable carbenoid reagents, and achieving stereochemical controls. On the other hand, substantial challenges and limitations remain to be overcome for realizing fully automated construction of diverse molecules. This Outlook article describes the AIS concept, recent progress, current limitations, and future opportunities in this field.
由于传统合成理念的固有局限性，实现各种小分子有机化合物的全自动化制备仍然是一项艰巨的挑战。现有的自动化方法要么需要使用几乎无限种类的化学试剂，要么需要定制的构件（BBs）。在此，我们提出逐原子迭代合成（AIS）作为一种新的合成逻辑来应对这一挑战。通过将复杂有机分子视为基于单碳或杂原子单元的组装体，AIS旨在通过一种统一类型的反应——硼同系化反应，对简单原子尺度的BBs进行迭代偶联，从而构建分子骨架。与传统方法相比，AIS策略仅使用几种类型的化学反应和一小套BBs，使其更适合自动化和人工智能辅助的合成路线设计。迄今为止，在服务于AIS目的的合成化学方面已经取得了巨大进展，例如引入杂原子和sp-碳、形成环状结构、开发热稳定的类卡宾试剂以及实现立体化学控制。另一方面，要实现各种分子的全自动化构建，仍有诸多挑战和限制有待克服。这篇展望文章描述了该领域的AIS概念、近期进展、当前局限性以及未来机遇。
