Department of Chemistry, Scripps Research, La Jolla, California 92037, United States.
Graduate School of Chemical and Biological Sciences, Scripps Research, La Jolla, California 92037, United States.
Acc Chem Res. 2023 Nov 7;56(21):3089-3098. doi: 10.1021/acs.accounts.3c00543. Epub 2023 Oct 27.
Natural product research originates from a desire to explore, understand, and perturb biological function with atomic precision. To reach these goals at all, let alone efficiently, requires thoughtful and creative problem solving. Often this means bold disconnections that would simplify access to complex structures, if only the methods existed to bridge these theoretical gaps. Whereas biological interrogations provide long-term intellectual value and impetus, methods come as attractive fringe benefits of natural product synthesis. This Account describes strategic, methodological solutions to the syntheses of natural products [(-)-eugenial C, alkaloids GB18, GB22, GB13, and himgaline] featuring new, convergent disconnections as important problem-solving steps, which themselves were inspired by recent methods that arose from our group. Each target required the invention of first-row transition metal-catalyzed cross-coupling procedures to satisfy the biological goals of the project. In these cases, synthetic strategy identified the methodological gap (the absence of stereo- and chemoselective couplings of appropriate fragments), but the tactical advantage conferred by first-row metals met the challenge. These methods were competent to handle the dense, sterically encumbered motifs common to natural products due to, in many cases, elementary steps that did not require bond formation between the hindered substrate and the metal center. Instead, these sterically lenient reactions appeared to involve metal-ligand-substrate reactions (i.e., outer-sphere steps), in contrast to the metal-substrate, coordinative reactions of precious metals (i.e., inner-sphere steps). Key observations from our previous studies, combined with the observations in seminal publications from other laboratories (Mattay, Weix, and MacMillan), led to the optimization of ligand-controlled, stereoselective reactions and the introduction of complementary catalytic cycles that revealed new modes of reactivity and generated novel structural motifs. Optimized access to bioactive natural product space accelerated our timeline of biological characterization, fulfilling a common premise of natural products research. The integration of methodology, complex natural product synthesis, diversification, and bioassay into a single Ph.D. dissertation would have been unmanageable in a prior era. The unique ability of first-row transition metals to effect Csp-Csp cross-coupling with high chemo- and stereoselectivity has significantly lowered the barrier to reach the avowed goal of natural product synthesis and reduced the burden (real or perceived) of integrating natural products into functional campaigns.
天然产物研究源于以原子精度探索、理解和干扰生物功能的愿望。要实现这些目标，更不用说高效地实现这些目标，需要有深思熟虑和创造性的问题解决能力。通常情况下，这意味着需要大胆地切断连接，以便更容易地获得复杂结构，只要存在弥合这些理论差距的方法。虽然生物研究提供了长期的智力价值和动力，但方法只是天然产物合成的吸引人的附带好处。本账户描述了天然产物[（-）- Eugenial C、生物碱 GB18、GB22、GB13 和 Himgaline]合成中的战略、方法学解决方案，这些解决方案以新的、会聚的断开连接为重要的问题解决步骤，这些断开连接本身是受我们小组最近出现的方法的启发而产生的。每个目标都需要发明第一行过渡金属催化交叉偶联程序，以满足项目的生物学目标。在这些情况下，合成策略确定了方法上的差距（缺乏合适片段的立体和化学选择性偶联），但第一行金属赋予的战术优势满足了挑战。由于许多情况下不需要受阻底物与金属中心之间形成键，这些方法能够处理天然产物中常见的密集、空间位阻较大的基序。这些反应似乎涉及金属配体底物反应（即外球步骤），而不是贵金属的金属底物配位反应（即内球步骤）。我们之前研究中的关键观察结果，结合其他实验室（Mattay、Weix 和 MacMillan）的开创性出版物中的观察结果，导致了配体控制的立体选择性反应的优化，并引入了互补的催化循环，这些循环揭示了新的反应模式并生成了新的结构基序。优化对生物活性天然产物空间的访问加速了我们的生物学特征描述时间表，实现了天然产物研究的共同前提。在以前的时代，将方法学、复杂的天然产物合成、多样化和生物测定整合到一篇博士论文中是无法管理的。第一行过渡金属能够以高化学和立体选择性实现 Csp-Csp 交叉偶联的独特能力，显著降低了实现天然产物合成既定目标的障碍，并降低了将天然产物纳入功能研究的负担（真实或感知）。
