Access to Chiral Hydropyrimidines through Palladium‐Catalyzed Asymmetric Allylic C−H Amination

• Published in: Angewandte Chemie International Edition Vol. 56; no. 50; pp. 16032 - 16036
• Main Authors: Wang, Pu‐Sheng, Shen, Meng‐Lan, Wang, Tian‐Ci, Lin, Hua‐Chen, Gong, Liu‐Zhu
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 11-12-2017
• Edition: International ed. in English
• Subjects: allylic amination; Amides; Amination; Asymmetric synthesis; Asymmetry; C−H activation; Diels–Alder reaction; Palladium; palladium catalysis; Sodium; Stereoselectivity; palladium catalysis; asymmetric synthesis; C−H activation; Diels-Alder reaction; allylic amination
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201709681

A palladium‐catalyzed asymmetric intramolecular allylic C−H amination controlled by a chiral phosphoramidite ligand was established for the preparation of various substituted chiral hydropyrimidinones, the precursors of hydropyrimidines, in high yields with high enantioselectivities. In particular, dienyl sodium N‐sulfonyl amides bearing an arylethene‐1‐sulfonyl group underwent a sequential allylic C−H amination and intramolecular Diels–Alder (IMDA) reaction to produce chiral fused tricyclic tetrahydropyrimidinone frameworks in high yields and with high levels of stereoselectivity. Significantly, this method was used as the key step in an asymmetric synthesis of letermovir.
Getting to the core of it: An asymmetric palladium‐catalyzed intramolecular allylic C−H amination controlled by a chiral phosphoramidite ligand was used to provide efficient access various substituted chiral hydropyrimidines. This methodology was successfully applied to the asymmetric synthesis of letermovir (see scheme; IMDA=intramolecular Diels–Alder reaction).