Abstract
We investigate the effects of water addition on a highly stereocontrolled fluorination of dienamine generated by α-branched enals and 6′-hydroxy-9-amino-9-deoxy-epi-quinidine with N-fluorobenzenesulfonimide (NFSI) in the presence of Brønsted acid both experimentally and theoretically. It is experimentally found that water addition to organic solvent significantly shortens the reaction time whereas excessive water addition decreases the enantiomeric excess. The results calculated with three-dimensional reference interaction site model self-consistent field (3D-RISM-SCF) method are in good agreement with the experimental ones. It is revealed that the shortness of reaction time is caused by the reactant destabilization and that the decrease in enantiomeric excess is due to the difference of hydration free energy between two transition states.
Highlights
IntroductionWater addition into organic solvents often enhances the reactivity and the selectivity [1,2,3,4,5,6]
In organic synthesis, water addition into organic solvents often enhances the reactivity and the selectivity [1,2,3,4,5,6]
We liked to run the reaction in DMF instead of NMP to obtain a comparable data of the later density functional theory (DFT) calculation
Summary
Water addition into organic solvents often enhances the reactivity and the selectivity [1,2,3,4,5,6]. Maruoka et al found that water addition for asymmetric aldol reactions with a chiral organocatalyst greatly increases the enantiomeric excess up to ~90% ee [4]. Such effects of water addition on the reactivity and selectivity are widely known, the understanding of detailed mechanisms is still limited. We developed the asymmetric fluorination of dienamines generated by α-branched enals and 60 -hydroxy-9-amino-9-deoxy-epi-quinidine in the presence of NFSI and Brønsted acid [7,8], and the reaction gave the excellent α-regioselectivity and enantioselectivity regardless of substituents on R1 and R2 ; both electron-withdrawing and electron-donating groups on the aromatic ring of. In the previous density functional theory (DFT) investigation, Molecules 2019, 24, 3428; doi:10.3390/molecules24193428 www.mdpi.com/journal/molecules
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