Tetrahydroisoquinoline-Based Spirocyclic Lactam as a Type II′ β-Turn Inducing Peptide Mimetic

We present here spirocyclic lactam derivatives, embodying d-Phe and l-Ala amino acids as the central core and acting as tetrapeptide and hexapeptide mimetics. An efficient route for their synthesis is demonstrated by using the strategic combination of Seebach’s self-reproduction of chirality chemistry and the Pictet−Spengler condensation as key steps. The conformational behavior of peptide mimetics was investigated by molecular modeling, X-ray crystallography, NMR (solvent and temperature dependence), IR spectroscopy, and circular dichroism. All data suggest very stable and highly predictable type II′ β-turn conformations.

本研究报道了一类以D-苯丙氨酸（d-Phe）与L-丙氨酸（l-Ala）为核心骨架的螺环内酰胺衍生物，可作为四肽与六肽的肽模拟物。本研究开发了一条高效合成路线，以西贝克（Seebach）手性自复制化学策略与匹克特−斯彭格勒（Pictet−Spengler）缩合反应作为关键步骤。本研究通过分子建模、X射线晶体学、核磁共振波谱（NMR，考察溶剂与温度依赖性）、红外光谱（IR）以及圆二色谱（circular dichroism）对该类肽模拟物的构象行为进行了系统表征。所有实验数据均表明，该类衍生物具有稳定性极强且构象高度可预测的II'型β转角构象。