Journal of the American Chemical Society
Journal of the American Chemical Society
5 years ago

Asymmetric Hydrogen Bonding Catalysis for the Synthesis of Dihydroquinazoline-Containing Antiviral, Letermovir

Asymmetric Hydrogen Bonding Catalysis for the Synthesis of Dihydroquinazoline-Containing Antiviral, Letermovir
Katrina W. Lexa, Teresa Andreani, Zhijian Liu, Cheol K. Chung, Yingju Xu, Guy R. Humphrey, Rebecca T. Ruck, Yining Ji, Daniel A. DiRocco
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.

Publisher URL: http://dx.doi.org/10.1021/jacs.7b05806

DOI: 10.1021/jacs.7b05806

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