Rhodium‐Catalyzed Asymmetric Synthesis of 1,2‐Disubstituted Allylic Fluorides

• Published in: Angewandte Chemie International Edition 2023-11, Vol.62 (48), p.e202314843-n/a
• Main Authors: Usman, Fuad O., Gogoi, Achyut R., Mixdorf, Jason C., Gutierrez, Osvaldo, Nguyen, Hien M.
• Format: Article
• Language: English
• Subjects: 1,2-Disubstituted Allylic Fluorides; Asymmetric Fluorination; Asymmetric synthesis; Asymmetry; Catalysts; Chemical synthesis; Conformation; DFT; Enantiomers; Fluorides; Intermediates; Ionization; Isomerization; Rhodium; Rhodium Catalysis; Substrates
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202314843

Although there are many methods for the asymmetric synthesis of monosubstituted allylic fluorides, construction of enantioenriched 1,2‐disubstituted allylic fluorides has not been reported. To address this gap, we report an enantioselective synthesis of 1,2‐disubstituted allylic fluorides using chiral diene‐ligated rhodium catalyst, Et3N ⋅ 3HF as a source of fluoride, and Morita Baylis Hillman (MBH) trichloroacetimidates. Kinetic studies show that one enantiomer of racemic MBH substrate reacts faster than the other. Computational studies reveal that both syn and anti π‐allyl complexes are formed upon ionization of allylic substrate, and the syn complexes are slightly energetically favorable. This is in contrast to our previous observation for formation of monosubstituted π‐allyl intermediates, in which the syn π‐allyl conformation is strongly preferred. In addition, the presence of an electron‐withdrawing group at C2 position of racemic MBH substrate renders 1,2‐disubstituted π‐allyl intermediate formation endergonic and reversible. To compare, formation of monosubstituted π‐allyl intermediates was exergonic and irreversible. DFT calculations and kinetic studies support a dynamic kinetic asymmetric transformation process wherein the rate of isomerization of the 1,2‐disubstituted π‐allylrhodium complexes is faster than that of fluoride addition onto the more reactive intermediate. The 1,2‐disubstituted allylic fluorides were obtained in good yields, enantioselectivity, and branched selectivity. Access to enantioenriched 1,2‐disubstituted allylic fluorides in good to high levels of enantiomeric excess was achieved using a chiral diene‐ligated rhodium catalyst. Experimental results together with DFT calculations support a dynamic kinetic asymmetric transformation process, whose efficiency is impacted by developing steric interactions in the syn and anti π‐allyl intermediate complexes.