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首页> 外文期刊>Chemistry: A European journal >A highly practical RCM approach towards a molecular building kit of spirocyclic reverse turn mimics
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A highly practical RCM approach towards a molecular building kit of spirocyclic reverse turn mimics

机译：一种高度实用的RCM方法，用于螺环逆向模拟的分子构建试剂盒

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The development of privileged molecular scaffolds efficiently mimicking reverse turn motifs and thus increasing both binding and selectivity and enabling the elucidation of the bioactive conformation of a natural peptide has attracted remarkable interest. The frequent occurrence of proline in various turn patterns initiated the design of proline-based reverse turn mimetics. As a structural hybridization of a highly potent type VI beta-turn inducer I with saturated spirocyclic lactams 3 efficiently mimicking type 11 beta turns, we developed a versatile synthetic route towards unsaturated spirocyclic lactams of type 2, when Seebach's self-reproduction of chirality methodology was combined with a peptide coupling reaction and Grubbs' ring-closing metathesis. By this means, a variety of model peptides with six- up to nine-memembered lactam rings were accessible following a uniform pathway. Introduction of suitably protected templates into solid-phase peptide synthesis gave rise to unsaturated spirocyclic analogues of the naturally occurring neuropeptide neurotensin. Spectroscopic investigations as well as DFT calculations on a high level of theory revealed a remarkable dependence of the reverse-turn inducing potency on the ring size. While the secondary structure of the unsaturated spirocyclic epsilon-lactam 12 closely agrees with the reference gamma-lactam 3a, the unsaturated delta-lactam 11 serves as an extraordinarily potent beta-turn inducer which is even superior to beta-lactams of type 3b. The eight-membered unsaturated spirocyclic lactam 13 adopts a conformation almost ideally matching the prerequisites for a canonical type 11 beta turn with the highest stability of the whole series. In contrast, the nine-membered spirolactam 14 represents a scaffold with a high conformational flexibility.
机译：特权分子支架的开发有效地模仿了反向转位基序，从而增加了结合和选择性，并使得能够阐明天然肽的生物活性构象引起了人们的极大兴趣。脯氨酸在各种转向模式中的频繁出现引发了基于脯氨酸的反向转向模拟物的设计。作为高效模拟VI型11β转角的高效VI型β转角诱导物I与饱和螺环内酰胺3的结构杂交，当Seebach的手性方法的自我重现性得到提高时，我们开发了一条通向2型不饱和螺环内酰胺的通用合成路线。与肽偶联反应和Grubbs的闭环复分解反应相结合。通过这种方法，可以通过一条统一的途径获得具有6至9个成员的内酰胺环的各种模型肽。将适当保护的模板引入固相肽合成中会产生天然存在的神经肽神经降压素的不饱和螺环类似物。在高水平的理论上进行的光谱研究和DFT计算表明，反向旋转诱导能力对环尺寸的显着依赖性。尽管不饱和螺环ε-内酰胺12的二级结构与参考γ-内酰胺3a非常吻合，但不饱和δ-内酰胺11用作非常有效的β-转角诱导剂，其甚至优于3b型β-内酰胺。八元不饱和螺环内酰胺13所采用的构型几乎理想地匹配了规范11型β转体的先决条件，并且具有整个系列的最高稳定性。相反，九元螺内酰胺14代表具有高构象柔韧性的支架。

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