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

Abstract

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.

Recent Advances in Enantioselective Pd-Catalyzed Allylic Substitution: From Design to Applications

“…In 2017, Gong and co-workers reported the first example of a direct enantioselective allylic C–H amination. 691 They used chiral phosphoramidite ligand ( R,R )- L151 together with 2,5-dimethyl-benzoquinone (2,5-DMBQ) for the enantioselective cyclization of N -((2-allylphenyl)carbamoyl)sulfonamides to hydropyrimidinones in high yields and good enantioselectivity (82–91% ee ; Scheme 273 ). This research group had previously demonstrated that the related phosphoramidite ligand ( S )- L148 was beneficial in enantioselective allylic C–H oxidation (see Scheme 270 above).…”

Catalytic Enantioselective Methylene C(sp3)−H Amidation of 8‐Alkylquinolines Using a Cp*RhIII/Chiral Carboxylic Acid System

“…Herein, we report directed enantioselective methylene C(sp 3 )−H functionalization reactions using a Cp*Rh III /chiral carboxylic acid (CCA) hybrid catalytic system (Scheme c), in which a binaphthyl‐based CCA assists the enantioselective cleavage of methylene C(sp 3 )−H bonds to construct a C−N bond at the stereocenter. Although such directing‐group‐assisted catalytic C−H activation with the differentiation of methylene C(sp 3 )−H bonds has been intensively studied using palladium and other metal catalysts in recent years, most studies have focused on C−C or C−B bond formation reactions, leaving enantioselective C−N bond formation reactions barely explored …”

A bifunctional iminophosphorane squaramide catalyzed enantioselective synthesis of hydroquinazolinesviaintramolecular aza-Michael reaction to α,β-unsaturated esters

“…6 A palladium-catalyzed enantioselective allylic C-H amination to generate the chiral hydroquinazoline core in good yield and high enantioselectivity was later described by Gong and coworkers. 7 Specifically, for dihydroquinazolines bearing a trifluoromethyl group attached to a newly generated quaternary carbon center, an extensive range of metal and metal-free catalyzed enantioselective addition reactions to reactive cyclic ketimines using alkyne, 8 ketone, 9 nitroalkane, 10 β-keto acid, 11 nitrile, 12 alcohol 13 and isocyanoacetate 14 nucleophiles, have been developed. 15 Enantioselective aza-Michael reactions enabled by metal-free catalysts is another powerful and promising approach to access such pharmaceutically relevant N-heterocycles.…”

“… 6 A palladium-catalyzed enantioselective allylic C–H amination to generate the chiral hydroquinazoline core in good yield and high enantioselectivity was later described by Gong and coworkers. 7 …”