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ACS Omega. 2019 May 22;4(5):8862-8873. doi: 10.1021/acsomega.9b00465. eCollection 2019 May 31.

Organocatalytic Asymmetric Addition of Aldehyde to Nitroolefin by H-d-Pro-Pro-Glu-NH2: A Mechanistic Study.

Author information

1
Institut des Biomolécules Max Mousseron, UMR CNRS-UM-ENSCM 5247, UFR des Sciences Pharmaceutiques et Biologiques, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France.
2
Department of Nursing, Cheju Halla University, Cheju 63092, Republic of Korea.
3
Department of Chemistry, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea.

Abstract

The mechanism of the asymmetric addition of aldehyde (butanal) to nitroolefin (β-nitrostyrene) catalyzed by H-d-Pro-Pro-Glu-NH2 (dPPE-NH2; 1) was explored using density functional theory methods in chloroform. By conformational search, it was confirmed that catalyst 1 and its enamine intermediate adopted a dominant conformation with a βI structure stabilized by a C10 H-bond between the C=O of d-Pro1 and C-terminal NH2 proton and by an additional H-bond between the side chain and the backbone of Glu3. This βI turn structure was conserved all along the catalytic cycle. Consistently with the kinetic studies, the C-C bond formation between the enamine and electrophile was also confirmed as the rate-determining step. The stereoselectivity results from a rere prochiral approach of enamine and β-nitrostyrene with a gauche- orientation of the double bonds. Although it was suggested as the possible formation of dihydrooxazine oxide species, this process was confirmed to be kinetically less accessible than the formation of acyclic nitronate. In particular, our calculated results supported that the carboxylic acid group of Glu3 in 1 played a central role by acting as general acid/base all along the catalytic cycle and orienting the asymmetric C-C bond formation.

Conflict of interest statement

The authors declare no competing financial interest.

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