Cinchona-Based Primary Amine Catalyzed a Proximal Functionalization of Dienamines: Asymmetric α-Fluorination of α-Branched Enals

Abstract

Fluorination of dienamines generated by α-branched enals and 6′-hydroxy-9-amino-9-deoxy-epi-quinidine (30 mol %) with NSFI show excellent α-regioselectivity to construct allylic fluorides containing a highly stereocontrolled quaternary fluorinated carbon (E/Z ≥ 20/1 and up to 93% enantiometric excess (ee)). By DFT calculation, the quinuclidine moiety of the catalyst was shown to function as a coordinating group to promote a reaction at the proximal α-position, and the nonclassical CH hydrogen bond plays an important role in the high enantioselectivity.

Effects of Water Addition on a Catalytic Fluorination of Dienamine

“…In contrast, the activation free energy of TS- R is higher than that of TS- S . This result indicates that the TS- R configuration is more stabilized with the counterion, which is consistent with our previous result [9]. It is noted that the counterion strongly interacts with the TS substrate in pure DMF solution.…”

“…Next, we investigated the effects of water addition with the 3D-RISM-SCF method. Our previous study showed that two catalysts, quinuclidine and counterion of Brønsted acid, control the regio- and stereoselectivity at the transition state (TS) in a concerted manner (Figure 2) [9]. The fluorination proceeds at the α position because of the quinuclidine located close to the α position whereas the counterion preferentially stabilizes the TS- R configuration connecting to the major product due to the nonclassical CH hydrogen bonds.…”

“…The density functional theory with M06-2X functional and 6-31G(d,p) basis set was employed for the electronic structure calculation of solutes. The solute geometries were taken from our previous study [9], in which the geometries were optimized at the SMD(DMF)-M06-2X/6-31G(d,p) level. The thermal corrections to the free energy were also added at the SMD(DMF)-M06-2X/6-31G (d,p) level.…”

“…Calculated transition state (TS) geometries Breaking and forming bonds (purple, in Å) and important hydrogen bonds (black) are shown with dotted lines. Adapted with permission from [9]. Copyright 2017 American Chemical Society.…”

“…Recently, we developed the asymmetric fluorination of dienamines generated by α-branched enals and 6′-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 R 1 and R 2 ; thus, both electron-withdrawing and electron-donating groups on the aromatic ring of R 1 have no significant influence, and all maintain excellent enantioselectivity over 90% ee. On the other hand, in the cases of benzyl group on R 1 or ethyl on R 2 , the reactions gave slightly lower enantioselectivities, 81% and 77%, respectively (Scheme 1) [9]. During the optimization of the reaction condition, the addition of 40 equiv.…”