General Model of Enantioselectivity for Phase Transfer-Catalyzed Conjugate Cyclization of Ureas

Enantioselective phase-transfer catalysis (PTC, also called ion pairing catalysis) is a major asset for asymmetric organic synthesis. Within this field, the reactions of anionic organic nucleophiles with chiral ammonium salts as catalysts (most often derived from Cinchona alkaloids) have found the most extensive applications in medicinal and industrial chemistry. However, despite their importance, the rules that govern the selectivity imparted by the catalysts in these reactions are still poorly understood. Using density functional theory calculations (M06-2X/Def2TZVPP/SMD//B3LYP-D3(BJ)/6–31G(d)/SMD), we have studied the quininium-catalyzed conjugate cyclization of ureas reported by Merck scientists for the synthesis of letermovir. Important conformations of the stereodetermining transition structures (TSs) were sampled with a multi-tiered computational procedure involving successive scans, constrained optimizations, and full TS searches. Analysis of the lowest-energy structures shows that the preferred (S)-leading TSs contain more noncovalent interactions between the substrate and acidic C─H and O─H bonds of the catalyst and that π–π stacking interactions do not govern the selectivity in this reaction. Using those insights, we have developed a general model of selectivity showcasing the binding pockets available within Cinchona-derived ammonium catalysts and how the chirality inherent to these pockets guides the enantioselectivity in PTC reactions of enolate nucleophiles and α,β-unsaturated carbonyl electrophiles.