Donnelly Kian, Singh Amritpal, Tuttle Tell, Baumann Marcus
School of Chemistry, University College Dublin, Belfield, D04 N2E2, Ireland.
Pure & Applied Chemistry, University of Strathclyde, Glasgow, G1 1XL, UK.
Chemistry. 2023 Sep 26;29(54):e202301861. doi: 10.1002/chem.202301861. Epub 2023 Aug 18.
The introduction of fluorinated moieties into drugs as well as the increase of their overall three-dimensionality have become key strategies amongst medicinal chemists to generate sets of compounds with favorable drug-like properties. However, the introduction of fluorinated cyclopropane ring systems which combines both strategies is not widely exploited to date. This paper reports synthetic strategies exploiting the reactivity of gem-difluorocyclopropenes in dipolar cycloaddition reactions with azomethine ylides to afford sets of new fluorine-containing 3-azabicyclo[3.1.0]hexanes. In addition, the unexpected formation of complex trifluorinated scaffolds arising from proline esters and gem-difluorocyclopropenes is highlighted along with computational studies to elucidate the underlying mechanism. This study presents new avenues towards pharmaceutically relevant fluorinated 3-azabicyclo[3.1.0]hexanes that are accessible via robust and short synthetic sequences.
在药物中引入氟化基团以及增加其整体三维结构已成为药物化学家生成具有良好类药性质的化合物集的关键策略。然而，结合这两种策略的氟化环丙烷环系统的引入迄今为止尚未得到广泛应用。本文报道了利用偕二氟环丙烯与甲亚胺叶立德在偶极环加成反应中的反应性来合成一系列新型含氟3-氮杂双环[3.1.0]己烷的合成策略。此外，还强调了由脯氨酸酯和偕二氟环丙烯意外形成复杂的三氟支架，并通过计算研究来阐明其潜在机制。这项研究为通过稳健且简短的合成序列可获得的与药学相关的氟化3-氮杂双环[3.1.0]己烷开辟了新途径。
