Asymmetric synthesis of (−)-(1R,7aS)-absouline

The most efficient and concise asymmetric synthesis of (−)-(1R,7aS)-absouline to date, which was accomplished in eight steps and 20% overall yield from commercially available starting materials, is described. The doubly diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)-amide to an enantiopure α,β-unsaturated ester derived from l-proline was employed as the key step. Subsequent hydrogenolytic N-debenzylation and acid-promoted cyclisation of the resultant β-amino ester produced the 1-aminopyrrolizidin-3-one scaffold, then reduction with DIBAL-H was followed by DCC-mediated coupling with (E)-p-methoxycinnamic acid to complete the synthesis of (−)-(1R,7aS)-absouline.

Graphical abstractDownload full-size imageThe asymmetric synthesis of (−)-(1R,7aS)-absouline was accomplished in eight steps and 20% overall yield from commercially available starting materials by employing the doubly diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to an enantiopure α,β-unsaturated ester derived from l-proline as the key step.