Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095, United States.
Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Alcalá de Henares 28805, Spain.
J Am Chem Soc. 2023 Jul 26;145(29):15888-15895. doi: 10.1021/jacs.3c03071. Epub 2023 Jul 13.
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.
八氟环戊烯（OFCP）使线性、无保护的肽参与多取代级联反应，生成复杂的氟化多环化合物。反应在 0-25°C 的单烧瓶中进行，不需要催化剂或重金属。OFCP 可以使用天然官能团直接多环化线性序列，或者可以用外源亲核试剂拦截氟代螺杂环中间体。后一种策略生成由肽、糖、脂质和杂环组成的分子杂种。该平台可以构建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，通过分子内氢键屏蔽极性表面积。经平行人工膜渗透率测定，OFCP 衍生的大环中相当一部分具有中等至高的被动渗透率。
