Skeletal Editing Strategies Driven by Total Synthesis.

IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Accounts of Chemical Research Pub Date : 2025-06-03 Epub Date: 2025-05-15 DOI:10.1021/acs.accounts.5c00174
Sojung F Kim, Charis Amber, G Logan Bartholomew, Richmond Sarpong
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引用次数: 0

Abstract

ConspectusSingle-atom skeletal editing strategies that precisely modify the core frameworks of molecules have the potential to streamline and accelerate organic synthesis by enabling conceptually simple, but otherwise synthetically challenging, retrosynthetic disconnections. In contrast to broader skeletal remodeling and rearrangement strategies, these methodologies more specifically target single-atom changes with high selectivity, even within complex molecules such as natural products or pharmaceuticals. For the past several years, our laboratory has developed several skeletal editing methodologies, including single-atom ring contractions, expansions, and transpositions of both saturated and unsaturated heterocycles, as well as other carbon scaffolds. This Account details the evolution of "skeletal editing logic" within the context of our extensive work on natural product total synthesis.Early work in the Sarpong group leveraged metal-mediated C-C bond cleavage of in situ-generated strained intermediates to accomplish total syntheses of natural products, such as the icetexane diterpenoids and cyathane diterpenes. Continuing our focus on leveraging C-C bond cleavage through "break-it-to-make-it" strategies, we then developed carvone remodeling strategies to access a variety of terpenoids (including longiborneol sesquiterpenoids, phomactins, and xishacorenes) from hydroxylated pinene derivatives. In applying this skeletal remodeling and C-C cleavage framework to alkaloid natural products, such as the preparaherquimides and lycodine-type alkaloids, we recognized that single-atom changes to the saturated nitrogen-containing rings within these natural products would enable the direct conversion between distinct but structurally related natural product families. Thus, we began developing methods that selectively modify the core frameworks of N-heterocycles; this focus led to our work on the deconstructive fluorination and diversification of piperidines and ultimately to our recent body of work on direct, single-atom core framework modifications (single-atom skeletal editing). In the context of saturated heterocycles, we developed photomediated enantioselective ring contractions of α-acylated motifs and reductive ring contractions of cyclic hydroxylamines. For unsaturated heterocycles, we have developed ring contractions of azines (e.g., pyrimidine to pyrazole), 15N isotopic labeling of azines, and phototranspositions of indazoles to benzimidazoles. To direct our focus on reaction development, a cheminformatic analysis of heteroaromatic skeletal edits served to quantitatively inform which transformations would most significantly expand the accessible chemical space. Apart from heterocycles, we also reported single-nitrogen insertion through the reductive amination of carbonyl C-C bonds. Ultimately, the goal of this research is to develop mild and selective skeletal editing methodologies that can be applied to total synthesis and organic synthesis more generally. While recent total syntheses from our group have targeted simplified retrosyntheses through single-atom skeletal editing logic (e.g., daphenylline and harringtonolide), multiple steps were still required to achieve the formal desired "edit". As such, the continued development of truly single-step, mild, and selective reactions that can edit the cores of highly complex molecules remains highly desirable.

全合成驱动的骨架编辑策略。
精确修改分子核心框架的单原子骨架编辑策略有可能通过实现概念上简单但合成上具有挑战性的反合成断开来简化和加速有机合成。与更广泛的骨骼重塑和重排策略相比,这些方法更有针对性地以高选择性靶向单原子变化,即使是在复杂的分子中,如天然产物或药物。在过去的几年中,我们的实验室开发了几种骨架编辑方法,包括单原子环收缩、膨胀和饱和和不饱和杂环的转位,以及其他碳支架。本帐户详细介绍了“骨骼编辑逻辑”的演变在我们广泛的工作范围内的自然产物全合成。Sarpong小组的早期工作利用金属介导的C-C键裂解原位生成的应变中间体来完成天然产物的全合成,如冰己烷二萜和氰烷二萜。我们继续专注于通过“断成键”策略利用C-C键裂解,然后我们开发了香芹酮重塑策略,以从羟基化蒎烯衍生物中获得各种萜类(包括长冰片倍半萜类、药效素和西沙草烯)。在将这种骨骼重塑和C-C裂解框架应用于生物碱天然产物,如制备herquimide和lycodine型生物碱时,我们认识到这些天然产物中饱和含氮环的单原子变化将使不同但结构相关的天然产物家族之间的直接转化成为可能。因此,我们开始开发选择性修饰n -杂环核心框架的方法;这种关注导致了我们对解构氟化和哌啶多样化的研究,并最终导致了我们最近对直接的单原子核心框架修改(单原子骨架编辑)的研究。在饱和杂环的背景下,我们开发了α-酰化基序的光电介导的对映选择性环收缩和环羟胺的还原性环收缩。对于不饱和杂环,我们已经开发了嘧啶的环收缩(例如,嘧啶到吡唑),嘧啶的15N同位素标记,以及茚唑到苯并咪唑的光转位。为了指导我们对反应发展的关注,对杂芳香骨架编辑进行了化学信息学分析,以定量地告知哪些转化将最显著地扩展可访问的化学空间。除了杂环外,我们还报道了通过羰基C-C键的还原胺化进行单氮插入。最终,本研究的目标是开发温和的和选择性的骨骼编辑方法,可以更普遍地应用于全合成和有机合成。虽然我们小组最近的全合成针对的是通过单原子骨架编辑逻辑(例如,苯胺和哈林酮内酯)简化的反合成,但仍然需要多个步骤来实现正式所需的“编辑”。因此,能够编辑高度复杂分子核心的真正的单步、温和和选择性反应的持续发展仍然是非常可取的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
期刊介绍: Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.
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