3-Oxabicyclo[3.1.1]heptanes as Isosteres of meta-Substituted Benzene Rings

IF 5 1区化学 Q1 CHEMISTRY, ORGANIC Organic Letters Pub Date : 2025-03-20 DOI:10.1021/acs.orglett.5c00646

Jennifer Morvan, Evelien Renders, Peter J. J. A. Buijnsters, Pavel Ryabchuk

引用次数: 0

Abstract

Replacement of the aromatic rings in drug candidates with isosteric rigid sp³-rich scaffolds can improve physicochemical properties, increase the chance of progressing the molecule in development, and open new chemical space. Isosteres of meta-substituted benzenes remain challenging due to the difficulty of mimicking the exit vector angles and bond distances. Herein, we report the synthesis of 1,5-disubstituted 3-oxabicyclo[3.1.1]heptanes (oxa-BCHeps), which can serve as saturated isosteres of meta-substituted phenyl rings with a similar geometric arrangement. This structural motif can be obtained under mild reaction conditions via acid-mediated isomerization of (2-oxaspiro[3.3]heptan-6-yl)methanols using catalytic quantities of pyridinium chloride (PyrHCl). We demonstrate the utility of this methodology by preparing various building blocks for use in medicinal chemistry and incorporating 3-oxa-BCHep into the anticancer drug sonidegib, improving its physicochemical properties, such as permeability, metabolic stability, and solubility.

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3-氧沙环[3.1.1]庚烷作为间取代苯环的同位异构体

用富含 sp3 的异构刚性支架取代候选药物中的芳香环可以改善理化性质，增加分子在研发中取得进展的机会，并打开新的化学空间。由于难以模仿出口矢量角和键距，元取代苯的异构化仍然具有挑战性。在此，我们报告了 1,5-二取代 3-氧杂双环[3.1.1]庚烷（oxa-BCHeps）的合成，它可以作为具有类似几何排列的元取代苯环的饱和异构体。在温和的反应条件下，通过使用催化量的氯化吡啶（PyrHCl）对（2-氧杂螺[3.3]庚烷-6-基）甲醇进行酸介导的异构化反应，可以获得这种结构基团。我们通过制备用于药物化学的各种构筑基块，并将 3-oxa-BCHep 加入到抗癌药物 sonidegib 中，改善了其物理化学特性，如渗透性、代谢稳定性和溶解性，证明了这种方法的实用性。

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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.

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