Cascade Synthesis of Fluorinated Spiroheterocyclic Scaffolding for Peptidic Macrobicycles
Cascade Synthesis of Fluorinated Spiroheterocyclic Scaffolding for Peptidic Macrobicycles
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肽大二环氟化螺杂环支架的级联合成
DOI：
10.1021/jacs.3c03071
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发表时间：
2023
影响因子：
15
通讯作者：
Harran, Patrick G.
中科院分区：
文献类型：
--
作者：
Mendoza, Angel;Bernardino, Salvador J.;Dweck, Morris J.;Valencia, Isabel;Evans, Declan;Tian, Haowen;Lee, William;Li, Yu;Houk, Kendall N.;Harran, Patrick G.
八氟环戊烯 (OFCP) 与线性、未受保护的肽参与多取代级联，产生复杂的氟化多环。该反应在 0–25 °C 的温度下在单个烧瓶中进行，不需要催化剂或重金属。 OFCP 可以使用天然功能直接多环化线性序列，或者可以用外源亲核试剂拦截氟螺杂环中间体。后一种策略产生由肽、糖、脂质和杂环成分组成的分子杂化物。该平台可以产生单环和双环大环的立体异构体。计算表明后者可以模拟不同的蛋白质表面环。分子的子集具有低能量构象，通过分子内氢键保护极性表面区域。在平行的人工膜渗透性测定中，测试的 OFCP 衍生大环化合物的很大一部分显示出中等至高的被动渗透性。
Octafluorocyclopentene (OFCP) engages linear, unprotected peptides in polysubstitution cascades that generate complex fluorinated polycycles. The reactions occur in a single flask at 0–25 °C and require no catalysts or heavy metals. OFCP can directly polycyclize linear sequences using native functionality, or fluorospiroheterocyclic intermediates can be intercepted with exogenous nucleophiles. The latter tactic generates molecular hybrids composed of peptides, sugars, lipids, and heterocyclic components. The platform can create stereoisomers of both single- and double-looped macrocycles. Calculations indicate that the latter can mimic diverse protein surface loops. Subsets of the molecules have low energy conformers that shield the polar surface area through intramolecular hydrogen bonding. A significant fraction of OFCP-derived macrocycles tested show moderate to high passive permeability in parallel artificial membrane permeability assays.