title: Catalytic, asymmetric Mannich-type reactions of N-acylimino esters: reactivity, diastereo- and enantioselectivity, and application to synthesis of N-acylated amino acid derivatives.
abstract: In 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 alpha-substituted silyl enol ethers (alpha-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%.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyou-ku, Tokyo 113-0033, Japan. skobayas@mol.f.u-tokyo.ac.jp
authors.forename: Shū
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Matsubara
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Masaharu
authors.initials: M
authors.lastname: Sugiura
mesh_terms: D000215:Acylation; D000577:Amides / Q000138:chemical synthesis*; D000596:Amino Acids / Q000138:chemical synthesis*; D002384:Catalysis; D018360:Crystallography, X-Ray; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: D000577:Amides; D000596:Amino Acids; C441643:N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide