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Download fileCatalytic, Asymmetric Mannich-type Reactions of N-Acylimino Esters: Reactivity, Diastereo- and Enantioselectivity, and Application to Synthesis of N-Acylated Amino Acid Derivatives
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posted on 2003-02-06, 00:00 authored by Shū Kobayashi, Ryosuke Matsubara, Yoshitaka Nakamura, Hidetoshi Kitagawa, Masaharu SugiuraIn the presence of a catalytic amount of Cu(OTf)2-chiral diamine 3e complex, N-acylimino esters
reacted with silyl enol ethers to afford the corresponding Mannich-type adducts in high yields with high
enantioselectivities. A wide variety of silyl enol ethers derived from ketones, as well as esters and thioesters,
reacted smoothly. In the reactions of α-substituted silyl enol ethers (α-methyl or benzyloxy), the desired
syn-adducts were obtained in high yields with high diastereo- and enantioselectivities. Several intermediates
for the synthesis of biologically important compounds were prepared using this novel catalytic asymmetric
Mannich-type reaction, and at the same time, absolute and relative stereochemical assignments were made.
In addition, it has been revealed that alkyl vinyl ethers reacted with N-acylimino esters in the presence of
a catalytic amount of the Cu(II) catalyst to give the corresponding Mannich-type adducts in high yields with
high enantioselectivities. This is the first example of catalytic asymmetric Mannich-type reactions with alkyl
vinyl ethers. The reaction mechanism, structure of chiral catalyst-electrophile complexes, and transition
states of these catalytic asymmetric reactions were assumed based on X-ray crystallographic analysis of
the Cu(II)-chiral amine complex, PM3 calculations, and FT-IR analyses, etc. Finally, (1R,3R)-N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12, 1), a new inhibitor of ceramide trafficking from
endoplasmic reticulum to the site of sphingomyerin (SM) synthesis, has been synthesized efficiently using
the present Mannich-type reaction as a key step. The synthesis involved three steps (two-pot), and total
yield was 82.9%.