Mechanistic Studies and Radiofluorination of Structurally Diverse Pharmaceuticals with Spirocyclic Iodonium(III) Ylides.
Mechanistic Studies and Radiofluorination of Structurally Diverse Pharmaceuticals with Spirocyclic Iodonium(III) Ylides.
复制标题
DOI：
10.1039/c6sc00197a
复制
发表时间：
2016-07-01
期刊：
影响因子：
8.4
通讯作者：
Liang SH
中科院分区：
文献类型：
--
作者：
Rotstein BH;Wang L;Liu RY;Patteson J;Kwan EE;Vasdev N;Liang SH
理论研究提供了深入了解非活化的富电子和空间位阻的18F-芳烃使用一类新的金刚烷基螺环碘鎓（III）叶立德前体的放射性。由于现有的放射性同位素方法的局限性，非活化的富电子和空间位阻的18 F-芳烃的合成仍然是一个主要的挑战。在这里，我们报告我们的机制调查螺环碘鎓（iii）叶立德前体芳烃radiofluorescence，包括它们的反应性，选择性和稳定性与无载体添加[18 F]氟化物。在G2[ECP]水平的基准计算表明，在碘（iii）的伪旋转和还原消除可以通过适当选择的色散校正的密度泛函方法建模。反应途径的模拟表明，氟化物-碘鎓（iii）加合物中间体被强烈活化，并且对于所需[18 F]氟代芳烃的还原消除具有高度区域选择性（势垒差异，ΔΔG> 25 kcal mol-1）。螺环助剂的优势进一步支持NMR光谱研究，支持的证据，可以克服的放射性碘（III）前体的潜在的分解过程。使用一种新的金刚烷基助剂，空间位阻碘鎓叶立德已被开发，以实现高效率的富电子芳烃，包括药学上相关的含氮杂环和叔胺的片段的放射性同位素。此外，该方法已用于合成放射性药物6-[18 F]氟-间-酪氨酸（[18 F]FMT，11 ± 1%分离放射化学产率，非衰变校正（RCY，n. d.c.），n = 3）和Meta-[18 F]氟苄基胍（[18 F]mFBG，14 ± 1%分离的RCY，n. d.c.，n = 3），其不能使用常规亲核芳族取代与[18F]氟化物直接放射性标记。
Theoretical studies provide insight into radiofluorination of non-activated electron-rich and sterically hindered 18F-arenes using a new class of adamantyl-based spirocyclic iodonium(iii) ylide precursors. Synthesis of non-activated electron-rich and sterically hindered 18F-arenes remains a major challenge due to limitations of existing radiofluorination methodologies. Herein, we report on our mechanistic investigations of spirocyclic iodonium(iii) ylide precursors for arene radiofluorination, including their reactivity, selectivity, and stability with no-carrier-added [18F]fluoride. Benchmark calculations at the G2[ECP] level indicate that pseudorotation and reductive elimination at iodine(iii) can be modeled well by appropriately selected dispersion-corrected density functional methods. Modeling of the reaction pathways show that fluoride–iodonium(iii) adduct intermediates are strongly activated and highly regioselective for reductive elimination of the desired [18F]fluoroarenes (difference in barriers, ΔΔG‡ > 25 kcal mol–1). The advantage of spirocyclic auxiliaries is further supported by NMR spectroscopy studies, which bolster evidence for underlying decomposition processes which can be overcome for radiofluorination of iodonium(iii) precursors. Using a novel adamantyl auxiliary, sterically hindered iodonium ylides have been developed to enable highly efficient radiofluorination of electron-rich arenes, including fragments of pharmaceutically relevant nitrogen-containing heterocycles and tertiary amines. Furthermore, this methodology has been applied for the syntheses of the radiopharmaceuticals 6-[18F]fluoro-meta-tyrosine ([18F]FMT, 11 ± 1% isolated radiochemical yield, non-decay-corrected (RCY, n.d.c.), n = 3), and meta-[18F]fluorobenzylguanidine ([18F]mFBG, 14 ± 1% isolated RCY, n.d.c., n = 3) which cannot be directly radiolabeled using conventional nucleophilic aromatic substitution with [18F]fluoride.