Stereo-controlled synthesis of functionalized tetrahydropyridines based on the cyanomethylation of 1,6-dihydropyridines and generation of anti-hepatitis C virus agents.
Densely functionalized tetrahydropyridines were stereoselectively synthesized from 1,6-dihydropyridines. Exploiting a carbonyl group installed at the C3 position of the 1,6-dihydropyridine system, we devised a strategy for cyanomethylation at C2/C6 and subsequent divergent installation of an allyl group at C3/C5 in a highly regio- and stereo-controlled manner. This versatile protocol for programmable functionalization of the 1,6-dihydropyridine system allows the divergent and streamlined synthesis of multiply-substituted tetrahydropyridines as an important class of biologically and medicinally relevant scaffolds. Two of the N-heterocyclic compounds bearing an alkyl nitrile group showed anti-hepatitis C virus (HCV) activity.
Division of Chemistry, Graduate School of Science, Hokkaido University, North 10 West 8, Sapporo 060-0810, Japan.
Ryo
R
Watanabe
Division of Chemistry, Graduate School of Science, Hokkaido University, North 10 West 8, Sapporo 060-0810, Japan.
Haruki
H
Mizoguchi
Division of Chemistry, Graduate School of Science, Hokkaido University, North 10 West 8, Sapporo 060-0810, Japan.
Hideaki
H
Oikawa
Department of Virology II, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Applied Biological Sciences, Tokyo University of Science, Graduate School of Science and Technology, Noda, Chiba 278-8510, Japan.
Hirofumi
H
Ohashi
Department of Virology II, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Applied Biological Sciences, Tokyo University of Science, Graduate School of Science and Technology, Noda, Chiba 278-8510, Japan; JST, CREST, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
Koichi
K
Watashi
Division of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei, Tokyo 184-8588, Japan; JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan. Electronic address: h_oguri@cc.tuat.ac.jp.
Hiroki
H
Oguri
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016174:Hepacivirus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D011725:Pyridines
Allylation; Anti-hepatitis C virus activity; Cyanomethylation; Dihydropyridine; Tetrahydropyridine