Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
Department of Chemistry, University of South Florida, Tampa, Florida 33620, United States.
J Org Chem. 2020 Mar 20;85(6):4207-4219. doi: 10.1021/acs.joc.9b03384. Epub 2020 Mar 9.
Peptides featuring backbone N-amino substituents exhibit unique conformational properties owing to additional electrostatic, hydrogen-bonding, and steric interactions. Here, we describe the synthesis and conformational analysis of three δ-azaproline derivatives as potential proline surrogates. Our studies demonstrate stereoelectronic tuning of heterocyclic ring pucker, / amide propensity, and amide isomerization barriers within a series of oxidation state variants. A combination of NMR, X-ray diffraction, and density functional theory calculations shows that electron density and hybridization at the δ position play a dominant role in the conformational preferences of each analogue. Both δ-azaproline and γ,δ-dehydro-δ-azaproline exhibit strong amide rotamer propensities irrespective of ring conformation, while a novel residue, γ-oxo-δ-azaproline, features rapid amide isomerization kinetics and isoenergetic amide bond geometries influenced by torsional strain and H-bonding interactions. The introduction of the δ heteroatom in each residue allows the decoupling of structural effects that are typically linked in proline and its pyrrolidine-substituted analogues. δ-Azaproline derivatives thus represent useful probes of prolyl amide isomerism with potential applications in peptidomimetic drug design and protein folding.
具有主链 N-氨基取代基的肽由于额外的静电、氢键和空间相互作用，表现出独特的构象性质。在这里，我们描述了三种 δ-氮杂脯氨酸衍生物的合成和构象分析，它们是潜在的脯氨酸类似物。我们的研究表明，在一系列氧化态变体中，杂环环张力、酰胺倾向和酰胺异构化势垒可以进行立体电子调谐。NMR、X 射线衍射和密度泛函理论计算的组合表明，δ 位的电子密度和杂化在每个类似物的构象偏好中起主导作用。δ-氮杂脯氨酸和 γ,δ-脱氢-δ-氮杂脯氨酸都表现出强烈的酰胺构象倾向，而不管环构象如何，而一种新型的残基 γ-氧代-δ-氮杂脯氨酸则具有快速的酰胺异构化动力学和等能量的酰胺键几何形状，受扭转应变和氢键相互作用的影响。每个残基中 δ 杂原子的引入允许将通常在脯氨酸及其吡咯烷取代类似物中相关的结构效应解耦。因此，δ-氮杂脯氨酸衍生物是脯氨酸酰胺异构化的有用探针，在肽模拟药物设计和蛋白质折叠中有潜在的应用。
