Chiral phosphoric acids have received a lot of recent attention due to their excellent performance in asymmetric catalysis. Here, the origin of enantioselectivity in a catalytic asymmetric synthesis of 2,3-dihydroquinazolinones by Huang and co-workers is explored (ACS Catal. 2013, 3, 2244). In their study, 2,3-dihydroquinazolinones (DHQZ’s) were synthesized with high enantioselectivity using SPINOL-derived chiral phosphoric acid catalysts. The wide use of DHQZs in pharmacological activities make them a highly sought after synthetic target. However, preventing racemization of DHQZ’s has remained an ongoing challenge. Using density functional theory calculations, we show that the enantioselectivity of this reaction is determined during the rate-limiting transition state of the cascade sequence involving stereoselective intramolecular amine addition which affords the final cyclic product. Aspects of stereoselectivity involving non-covalent interactions of particular substituent configurations are explored. The high enantioselectivity of aryl R-groups and ortho substituents on the R-groups is caused by the presence of strong non-covalent interactions between the catalyst and the substrate.

Unraveling the origin of enantioselectivity in SPINOL-phosphoric acid catalyzed syntheses of 2,3-dihydroquinazolinones

251st National Meeting (2016)

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