环肽在药物中是越来越重要的结构,但是它们的发展可能受到与其合成相关的困难的阻碍。这里,我们引入了3-氨基氮杂环丁烷(3-AAz)亚基作为一种新的诱导元件,用于有效合成小的头尾环肽。大大改善了四元的环化,在标准反应条件下的五肽和六肽(28个实施例)通过在线性肽前体中引入该元素来实现。用强酸实现氨基酸侧链的环化后脱保护,而不会降解四元氮杂环丁烷。该化学的特殊特征是可以通过3-AAz单元实现所得大环肽的进一步后期修饰。这是通过以下方式完成的:(i)在氮杂环丁烷氮上的化学选择性去保护和取代,或通过(ii)在氮杂环丁烷氮上使用2-丙炔基氨基甲酸酯的基于点击的方法。这样,很容易产生一系列染料和生物素标记的大环化合物。通过XRD分析环状四肽获得的结构见解表明,氮杂环丁烷环鼓励进入不太稳定的全反式构象。此外,与同源大环相比,将3-AAz引入代表性的环己肽中可提高对蛋白酶的稳定性。
Cyclic peptides are increasingly important structures in drugs but their development can be impeded by difficulties associated with their synthesis. Here, we introduce the 3-aminoazetidine (3-AAz) subunit as a new turn-inducing element for the efficient synthesis of small head-to-tail cyclic peptides. Greatly improved cyclizations of tetra-, penta- and hexapeptides (28 examples) under standard reaction conditions are achieved by introduction of this element within the linear peptide precursor. Post-cyclization deprotection of the amino acid side chains with strong acid is realized without degradation of the strained four-membered
azetidine. A special feature of this chemistry is that further late-stage modification of the resultant macrocyclic peptides can be achieved via the 3-AAz unit. This is done by: (i) chemoselective deprotection and substitution at the
azetidine nitrogen, or by (ii) a click-based approach employing a 2-propynyl carbamate on the
azetidine nitrogen. In this way, a range of dye and biotin tagged macrocycles are readily produced. Structural insights gained by XRD analysis of a cyclic tetrapeptide indicate that the
azetidine ring encourages access to the less stable, all-trans conformation. Moreover, introduction of a 3-AAz into a representative cyclohexapeptide improves stability towards proteases compared to the homodetic macrocycle.