Understanding the mechanism of procedure-controlled enantioselectivity switch in cinchona alkaloid thiourea catalyzed [3 + 2] cycloaddition: H-bonds controlled enantioselectivity.

Density functional theory has been applied to the novel procedure-controlled enantioselectivity switch in the synthesis of chiral 2-oxazolidinone ( 3 ) through [3 + 2] cycloaddition between γ-hydroxy-α,β-unsaturated carbonyl compound ( 1 ) and isocyanate ( 2 ) catalyzed by a cinchona-alkaloid based aminothiourea catalyst. The study shows that three stages are involved in the whole process. In stage one, for Procedure A, 1 reacts with 2 to give carbamate intermediate. Then catalyst 4 is added. For Procedure B, catalyst 4 first activates 2 via quinuclidine N attacking isocyanate C. Then 1 is involved. In stage two, hydrogen is transferred from carbamate N to Ts O atom which is different from the quinuclidine N protonation mechanism. The last step is ring closure in which carbamate N attacks C atom of C C bond. From free energy profiles, the enantioselectivities of the reaction are determined by stage two. Further analysis shows that H-bond is the key in the procedure-controlled enantioselectivity switch. Different H-bonds (N A H A ⋯O A C and N B H B ⋯O A C in Procedure A vs N A H A ⋯O A C and N B H B ⋯O B S in Procedure B) lead to different relationships between thiourea and carbamate planes (vertical or parallel). In Procedure A, C C listing above carbamate plane is the favorable pathway to give R-3 . However, in Procedure B, C C listing behind carbamate plane is more favorable to generate S-3 . [ABSTRACT FROM AUTHOR]