Aza-cope rearrangement-mannich cyclizations for the formation of complex tricyclic amines: stereocontrolled total synthesis of (+/-)-gelsemine.
A detailed examination of the use of aza-Cope rearrangement-Mannich cyclization sequences for assembling the azatricyclo[4.4.0.0(2,8)]decane core of gelsemine is described. Iminium ions and N-acyloxyiminium ions derived from endo-oriented 1-methoxy- or 1-hydroxybicyclo[2.2.2]oct-5-enylamines do not undergo the first step of this sequence, cationic aza-Cope rearrangement, to form cis-hydroisoquinolinium ions. However, the analogous base-promoted oxy-aza-Cope rearrangement does take place to form cis-hydroisoquinolones containing functionality that allows iminium ions or N-acyloxyiminium ions to be generated regioselectively in a subsequent step. Mannich cyclization of cis-hydroisoquinolones prepared in this way efficiently assembles the azatricyclo[4.4.0.0(2,8)]decane unit of gelsemine. Using a sequential base-promoted oxy-aza-Cope rearrangement/Mannich cyclization sequence, gram quantities of azatricyclo[4.4.0.0(2,8)]decanone 18, a central intermediate in our total of (+/-)-gelsemine, were prepared from 3-methylanisole in 12 steps and 16% overall yield.
Earley
William G
WG
Department of Chemistry, University of California, Irvine, 516 Rowland Hall, Irvine, California 92697-2025, USA.
Jacobsen
Jon E
JE
Madin
Andrew
A
Meier
G Patrick
GP
O'Donnell
Christopher J
CJ
Oh
Taeboem
T
Old
David W
DW
Overman
Larry E
LE
Sharp
Matthew J
MJ
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D000473:Alkanes / Q000138:chemical synthesis / Q000737:chemistry; D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry; D001372:Aza Compounds / Q000737:chemistry*; D003500:Cyclization; D013237:Stereoisomerism
D000470:Alkaloids; D000473:Alkanes; D000588:Amines; D001372:Aza Compounds; C063230:gelsemine; C012867:decane