Asymmetric Hydrogen Bonding Catalysis for the Synthesis of Dihydroquinazoline-Containing Antiviral, Letermovir,Journal of the American Chemical Society

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Asymmetric Hydrogen Bonding Catalysis for the Synthesis of Dihydroquinazoline-Containing Antiviral, Letermovir
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2017-07-25 00:00:00 , DOI: 10.1021/jacs.7b05806
Cheol K. Chung ₁ , Zhijian Liu ₁ , Katrina W. Lexa ₁ , Teresa Andreani ₁ , Yingju Xu ₁ , Yining Ji ₁ , Daniel A. DiRocco ₁ , Guy R. Humphrey ₁ , Rebecca T. Ruck ₁

Affiliation

A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C₂-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,β-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4-dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues.

中文翻译：

不对称氢键催化合成含二氢喹唑啉类抗病毒药物，来特莫韦

已经开发出弱的布朗斯台德酸催化的不对称胍氮杂-共轭加成反应。C ₂对称的双氢键供体双三氟化物被证明在激活α，β-不饱和酯朝着侧基胍基亲核分子的分子内加成方面非常有效。初步的机械研究，包括密度泛函理论计算和动力学研究，都认为共轭加成途径比替代性电环化途径在能量上更有利。该方法已成功应用于含3,4-二氢喹唑啉的抗病毒药物，来特莫韦和一系列类似物的合成。

更新日期：2017-07-26

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