Double Reductive Cyclisations

The asymmetric syntheses of pyrrolizidine, indolizidine and quinolizidine alkaloids have been achieved using the diastereoselective conjugate addition of enantiopure lithium amides to α-alkenyl-α,β-unsaturated esters followed by diastereoselective protonation of the resultant enolates as the key stereodefining steps. The azabicyclic scaffolds were then efficiently constructed upon sequential oxidative cleavage of the olefinic units within the resultant β-amino esters and hydrogenolytic N-debenzylation of the corresponding dialdehydes, which occurs with concomitant double reductive cyclisation. Subsequent reduction of the ester moieties with LiAlH4 gave (+)-trachelanthamidine, (+)-tashiromine and (+)-epilupinine in only six steps from commercially available starting materials.
 


 

This double reductive cyclisation strategy has also been used in the synthesis of a range of highly substituted pyrrolizidines, including the three 1-hydroxymethyl-7-hydroxy substituted pyrrolizidines (–)-hastanecine, (–­)-turneforcidine and (–)-platynecine, the 1-hydroxymethyl-2-hydroxy substituted pyrrolizidines (–)-macronecine, (–)-petasinecine, (–)-1-epi-macronecine and (+)-1-epi-petasinecine, and the 1-hydroxymethyl-2,7-dihydroxy substituted pyrrolizidine (+)-2-epi-rosmarinecine.
 

Key Publications: 

  1. Pyrrolizidines, indolizidines and quinolizidines via a double reductive cyclisation protocol: concise asymmetric syntheses of (+)-trachelanthamidine, (+)-tashiromine and (+)-epilupinine
    Brambilla, M.; Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E.; Zimmer, D. 
    Tetrahedron 201672, 7417 [View Journal Page]
  2. Asymmetric syntheses of the 1-hydroxymethyl-2-hydroxy substituted pyrrolizidines (–)-macronecine, (–)-petasinecine, (–)-1-epi-macronecine, (+)-1-epi-petasinecine and (+)-2-epi-rosmarinecine
    Brambilla, M.; Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Tetrahedron2016
    72, 7449 [View Journal Page]
  3. Asymmetric syntheses of (–)-hastanecine, (–)-turneforcidine and (–)-platynecine
    Brambilla, M.; Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Tetrahedron 2016
    72, 4523 [View Journal Page]
  4. Asymmetric syntheses of (–)-isoretronecanol and (–)-trachelantamidine
    Brambilla, M.; Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Tetrahedron 2014
    70, 204 [View Journal Page]

 

 

 

 


Site Map | Printable View | © 2008 - 2017 Department of Chemistry - University of Oxford

Powered by mojoPortal | HTML 5 | CSS | Design by styleshout