6,6-Difluorobicyclo[3.1.0]hexane as a Rigidified 4,4-Difluorocyclohexane Mimetic: Multigram Synthesis, Physicochemical Characterization, and Incorporation into Maraviroc Analogs

IF 1.7 4区化学 Q3 CHEMISTRY, INORGANIC & NUCLEAR

Journal of Fluorine Chemistry Pub Date : 2023-11-03 DOI:10.1016/j.jfluchem.2023.110215

Bohdan Moroz , Kostiantyn P. Melnykov , Serhii Holovach , Andrey A. Filatov , Oleksii Raievskyi , Maksym Platonov , Oleksandr Liashuk , Dmytro M. Volochnyuk , Oleksandr O. Grygorenko

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Abstract

Multigram synthesis of diastereomerically pure cis- and trans-6,6-difluorobicyclo[3.1.0]hexane building blocks starting from commercially available compounds is described. The diastereomeric mixture obtained by reaction of TMSCF₃ – NaI system with non-activated cyclopentene fragment using the slow addition protocol was effectively separated by flash column chromatography. Further simple chemical transformations produced diastereopure amines and carboxylic acids – promising building blocks for drug discovery. Physicochemical properties (i.e., pK_a and LogP) were measured for the title scaffold derivatives and compared with those with monocyclic and non-fluorinated counterparts. Two rigidified analogues of marketed anti-HIV drug Maraviroc were synthesized and evaluated by docking and molecular dynamics studies.

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6,6-二氟双环[3.1.0]己烷作为刚性4,4-二氟环己烷的模拟物:多重图合成、物理化学表征和纳入马拉维洛克类似物

描述了从市售化合物开始的非对映纯顺式和反式6,6-二氟双环[3.1.0]己烷构建块的多重图合成。TMSCF3 - NaI体系与非活化环戊烯片段用慢加成法反应得到的非对映体混合物采用闪蒸柱色谱法有效分离。进一步的简单化学转化产生了非对纯胺和羧酸，这是药物发现的有希望的基石。测量了标题支架衍生物的物理化学性质(即pKa和LogP)，并与单环和非氟化衍生物进行了比较。合成了两种已上市抗hiv药物马拉韦洛克的刚性类似物，并通过对接和分子动力学研究对其进行了评价。

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来源期刊

Journal of Fluorine Chemistry 化学-无机化学与核化学

CiteScore

3.80

自引率

10.50%

发文量

审稿时长

33 days

期刊介绍： The Journal of Fluorine Chemistry contains reviews, original papers and short communications. The journal covers all aspects of pure and applied research on the chemistry as well as on the applications of fluorine, and of compounds or materials where fluorine exercises significant effects. This can include all chemistry research areas (inorganic, organic, organometallic, macromolecular and physical chemistry) but also includes papers on biological/biochemical related aspects of Fluorine chemistry as well as medicinal, agrochemical and pharmacological research. The Journal of Fluorine Chemistry also publishes environmental and industrial papers dealing with aspects of Fluorine chemistry on energy and material sciences. Preparative and physico-chemical investigations as well as theoretical, structural and mechanistic aspects are covered. The Journal, however, does not accept work of purely routine nature. For reviews and special issues on particular topics of fluorine chemistry or from selected symposia, please contact the Regional Editors for further details.