Intramolecular Hydrogen Bonding Enables a Zwitterionic Mechanism for Macrocyclic Peptide Formation: Computational Mechanistic Studies of CyClick Chemistry.
Intramolecular Hydrogen Bonding Enables a Zwitterionic Mechanism for Macrocyclic Peptide Formation: Computational Mechanistic Studies of CyClick Chemistry.
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分子内氢键使大环肽形成的两性离子机制成为可能：CyClick 化学的计算机制研究。
DOI：
10.1002/anie.202307210
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Houk,KendallN
中科院分区：
文献类型：
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作者：
Shao,Huiling;Adebomi,Victor;Bruce,Angele;Raj,Monika;Houk,KendallN
大环肽在制药工业中越来越重要。我们对最近开发的“CyClick”化学反应机理进行了详细的计算研究，该化学反应可以在不使用催化剂或导向基团的情况下，从线性肽醛选择性地形成咪唑烷酮环肽。化学。Int。Ed.2019, 58岁,19073 - 19080)。通过计算机制研究了分子内氢键（IMHBs）在促进五肽醛AFGPA“CyClick”的两性离子机制中的作用。我们的DFT计算强调了IMHB在静息状态的预组织、两性中间体的稳定和产物立体选择性控制中的重要性。此外，我们还发现低环应变能促进六肽醛AAGPFA的“CyClick”形成热力学上更稳定的15+5咪唑烷酮环肽产物。相反，大的环应变能抑制四肽醛AFPA形成9+5咪唑烷酮环肽产物的“CyClick”反应活性。
Macrocyclic peptides have become increasingly important in the pharmaceutical industry. We present a detailed computational investigation of the reaction mechanism of the recently developed “CyClick” chemistry to selectively form imidazolidinone cyclic peptides from linear peptide aldehydes, without using catalysts or directing groups (Angew. Chem. Int. Ed.2019,58, 19073–19080). We conducted computational mechanistic to investigate the effects of intramolecular hydrogen bonds (IMHBs) in promoting a kinetically facile zwitterionic mechanism in “CyClick” of pentapeptide aldehyde AFGPA. Our DFT calculations highlighted the importance of IMHB in pre‐organization of the resting state, stabilization of the zwitterion intermediate, and the control of the product stereoselectivity. Furthermore, we have also identified that the low ring strain energy promotes the “CyClick” of hexapeptide aldehyde AAGPFA to form a thermodynamically more stable 15+5 imidazolidinone cyclic peptide product. In contrast, large ring strain energy suppresses “CyClick” reactivity of tetra peptide aldehyde AFPA from forming the 9+5 imidazolidinone cyclic peptide product.