Catalytic, Asymmetric Mannich-type Reactions of N-Acylimino Esters: Reactivity, Diastereo- and Enantioselectivity, and Application to Synthesis of N-Acylated Amino Acid Derivatives
Shu Kobayashi,* Ryosuke Matsubara, Yoshitaka Nakamura, Hidetoshi Kitagawa and Masaharu Sugiura
*Contribution from the Graduate School of Pharmaceutical Sciences, The
University of Tokyo, Hongo, Bunkyou-ku, Tokyo, 113-0033, Japan, Email: skobayas
mol.f.u-tokyo.ac.jp
S. Kobayashi, R. Matsubara, Y. Nakamura, H. Kitagawa, M. Sugiura, J. Am. Chem. Soc., 2003, 125, 2507-2515.
DOI: 10.1021/ja0281840
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Abstract
In the presence of a catalytic amount of Cu(OTf)2 and a chiral diamine ligand, various N-acylimino esters reacted smoothly with silyl enol ethers and alkyl vinyl ethers to afford the corresponding Mannich-type adducts in high yields with high diastereo- and enantioselectivities. The reaction mechanism is discussed.
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Details
The document discusses the development of catalytic, asymmetric Mannich-type reactions of N-acylimino esters with silyl enol ethers and alkyl vinyl ethers using Cu(OTf)2-chiral diamine complexes. These reactions yield Mannich-type adducts with high enantioselectivity and diastereoselectivity. The study explores various catalysts, reaction conditions, and substrates, revealing that the combination of Cu(OTf)2 and chiral diamine 3e is particularly effective. The reaction mechanism and catalyst structure were investigated using X-ray crystallography, PM3 calculations, and FT-IR analyses. The research also highlights the synthesis of (1R,3R)-N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12), a new inhibitor of ceramide trafficking, using the developed Mannich-type reaction as a key step. The synthesis of HPA-12 was achieved in three steps with an 82.9% total yield. The study provides a detailed account of the reactivity, selectivity, and application of these reactions in synthesizing biologically important compounds. The work was supported by various scientific grants and acknowledges contributions from several researchers. The findings were published with corrections made to the initial online version.
Key Words
β-amino ketones, α-amino acids
ID: J48-Y2003-1340
