Enantioselective synthesis of 3-arylquinazolin-4(3H)-ones via peptide-catalyzed atroposelective bromination.
We report the development of a tertiary amine-containing β-turn peptide that catalyzes the atroposelective bromination of pharmaceutically relevant 3-arylquinazolin-4(3H)-ones (quinazolinones) with high levels of enantioinduction over a broad substrate scope. The structure of the free catalyst and the peptide-substrate complex were explored using X-ray crystallography and 2D-NOESY experiments. Quinazolinone rotational barriers about the chiral anilide axis were also studied using density functional theory calculations and are discussed in light of the high enantioselectivities observed. Mechanistic studies also suggest that the initial bromination event is stereodetermining, and the major monobromide intermediate is an atropisomerically stable, mono-ortho-substituted isomer. The observation of stereoisomerically stable monobromides stimulated the conversion of the tribromide products to other atropisomerically defined products of interest. For example, (1) a dehalogenation Suzuki-Miyaura cross-coupling sequence delivers ortho-arylated derivatives, and (2) a regioselective Buchwald-Hartwig amination procedure installs para-amine functionality. Stereochemical information was retained during these subsequent transformations.
Department of Chemistry, Yale University , New Haven, Connecticut 06520-8107, United States.
Matthew E
ME
Diener
Department of Chemistry, Yale University , New Haven, Connecticut 06520-8107, United States.
Anthony J
AJ
Metrano
Department of Chemistry, Yale University , New Haven, Connecticut 06520-8107, United States.
Shuhei
S
Kusano
Department of Chemistry, Yale University , New Haven, Connecticut 06520-8107, United States.
Scott J
SJ
Miller
D000588:Amines / Q000737:chemistry; D002384:Catalysis; D054879:Halogenation; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D000588:Amines; D010455:Peptides; D052999:Quinazolinones