gem-Difluorobicyclo[2.1.1]hexanes via Photochemical [2π + 2σ] Cycloaddition Initiated by Oxidative Activation of gem-Difluorodienes

IF 4.9 1区化学 Q1 CHEMISTRY, ORGANIC

Organic Letters Pub Date : 2024-11-15 DOI:10.1021/acs.orglett.4c03798

Zhenda Fu, Jianzheng Cheng, Xiao-Xi Li, Xingwei Li, Songjie Yu

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Abstract

The incorporation of fluorine atoms into three-dimensional sp³-rich scaffolds represents an attractive tactic during bioisosteric evolution campaigns by endowing bioisosteric candidates with improved pharmacokinetic properties. Photo- or Lewis acid-mediated bicyclo[1.1.0]butane cycloaddition has offered an efficient approach for the construction of numerous regular bicyclo[n.1.1] scaffolds (n = 1–5) but remains a significant challenge to the synthesis of related 3D fluorinated scaffolds. Herein, we unveiled a photochemical single-electron oxidative strategy for gem-difluorodiene activation and subsequent [2π + 2σ] cycloaddition with bicyclo[1.1.0]butanes to provide a broad range of gem-difluorobicyclo[2.1.1]hexane scaffolds containing several post-transformable handles. A combination of experimental and computational mechanistic studies suggested that the conjugated π system of gem-difluorodiene plays important dual roles in promoting its preferential single-electron oxidation and stabilizing various radical-involved intermediates during the cyclization.

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通过氧化活化gem-Difluorodienes引发的光化学[2π + 2σ]环加成，制备gem-Difluorobicyclo[2.1.1]己烷

在三维富含 sp3 的支架中加入氟原子是生物异构进化过程中的一种极具吸引力的策略，可使生物异构候选物具有更好的药代动力学特性。光或路易斯酸介导的双环[1.1.0]丁烷环化反应为构建大量规则的双环[n.1.1]支架（n = 1-5）提供了一种有效的方法，但对于合成相关的三维含氟支架仍是一项重大挑战。在此，我们揭示了一种光化学单电子氧化策略，用于宝石-二氟二烯活化以及随后与双环[1.1.0]丁烷的[2π + 2σ]环加成，从而提供含有多种后可转化柄的多种宝石-二氟双环[2.1.1]己烷支架。结合实验和计算机理研究表明，gem-二氟二烯的共轭 π 系统在促进其优先单电子氧化和稳定环化过程中各种自由基参与的中间产物方面发挥着重要的双重作用。

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来源期刊

Organic Letters 化学-有机化学

CiteScore

9.30

自引率

11.50%

发文量

1607

审稿时长

1.5 months

期刊介绍： Organic Letters invites original reports of fundamental research in all branches of the theory and practice of organic, physical organic, organometallic,medicinal, and bioorganic chemistry. Organic Letters provides rapid disclosure of the key elements of significant studies that are of interest to a large portion of the organic community. In selecting manuscripts for publication, the Editors place emphasis on the originality, quality and wide interest of the work. Authors should provide enough background information to place the new disclosure in context and to justify the rapid publication format. Back-to-back Letters will be considered. Full details should be reserved for an Article, which should appear in due course.