Diastereoselective preparation of 2,4,6-trisubstituted-2'-cyanopiperidines: application to the construction of the carbon framework of perhydrohistrionicotoxin.
The anodic cyanation of methanolic solutions of the 2-alkyl-N-phenylpiperidines 6b-d was performed in a flow cell equipped with a graphite felt anode. The reaction led to the formation of the 2-cyano-6-alkyl-N-phenylpiperidines 2b-d and proceeded with a high degree of regioselectivity. The 1H NMR spectra of the aminonitriles 2b-d showed an epimeric mixture at C-6. The major isomer has a trans configuration in which the cyano group is axial and the alkyl substituent is equatorial. Conversely, electrochemical oxidation of the 4-methyl-6-pentyl-N-phenylpiperidine 6e afforded the trisubstituted aminonitrile 2e as a single diastereomer (> 98% de). The 4-cyanobutyl side chain was incorporated in a two-step procedure to yield dinitrile 4e. This latter compound was directly converted into spiropiperidine 5e by using the Thorpe-Ziegler annulation procedure. The overall sequence (4 steps, 43%) allows the construction of the basic carbon framework of perhydrohistrionicotoxin.
Malassene
Richard
R
Laboratoire d'Electrochimie, UMR 6509, Institut de Chimie, Université de Rennes I, Campus de Beaulieu, F-35042 Rennes, France.
Vanquelef
Enguerran
E
Toupet
Loic
L
Hurvois
Jean-Pierre
JP
Moinet
Claude
C
D000664:Amphibian Venoms / Q000138:chemical synthesis / Q000737:chemistry*; D003486:Cyanides / Q000737:chemistry*; D008958:Models, Molecular; D009498:Neurotoxins; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D013141:Spiro Compounds / Q000737:chemistry; D013237:Stereoisomerism
D000664:Amphibian Venoms; D003486:Cyanides; D009498:Neurotoxins; D010880:Piperidines; D013141:Spiro Compounds; C004792:perhydrohistrionicotoxin