Stereo-controlled synthesis of functionalized tetrahydropyridines based on the cyanomethylation of 1,6-dihydropyridines and generation of anti-hepatitis C virus agents

Ryo Watanabe; Haruki Mizoguchi; Hideaki Oikawa; Hirofumi Ohashi; Koichi Watashi; Hiroki Oguri

doi:10.1016/j.bmc.2017.03.011

Stereo-controlled synthesis of functionalized tetrahydropyridines based on the cyanomethylation of 1,6-dihydropyridines and generation of anti-hepatitis C virus agents

Bioorg Med Chem. 2017 Jun 1;25(11):2851-2855. doi: 10.1016/j.bmc.2017.03.011. Epub 2017 Mar 7.

Authors

Ryo Watanabe¹, Haruki Mizoguchi¹, Hideaki Oikawa¹, Hirofumi Ohashi², Koichi Watashi³, Hiroki Oguri⁴

Affiliations

¹ Division of Chemistry, Graduate School of Science, Hokkaido University, North 10 West 8, Sapporo 060-0810, Japan.
² 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.
³ 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.
⁴ 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.

PMID: 28314509
DOI: 10.1016/j.bmc.2017.03.011

Abstract

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.

Keywords: Allylation; Anti-hepatitis C virus activity; Cyanomethylation; Dihydropyridine; Tetrahydropyridine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Dose-Response Relationship, Drug
Hepacivirus / drug effects*
Microbial Sensitivity Tests
Molecular Structure
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Stereoisomerism
Structure-Activity Relationship

Substances

Antiviral Agents
Pyridines