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

Author:

Usman Fuad O.1,Gogoi Achyut R.2,Mixdorf Jason C.3,Gutierrez Osvaldo2,Nguyen Hien M.1ORCID

Affiliation:

1. Department of Chemistry Wayne State University Detroit MI 48202 USA

2. Department of Chemistry Texas A&M University College Station TX 77843 USA

3. Department of Medical Physics University of Wisconsin School of Medicine and Public Health Madison WI 53705 USA

Abstract

AbstractAlthough 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.

Funder

National Institute of General Medical Sciences

Welch Foundation

Publisher

Wiley

Subject

General Medicine

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