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Keywords:

  • allylic compounds;
  • chirality;
  • morphine;
  • sigmatropic rearrangement;
  • total synthesis

Abstract

A detailed exploration of the synthesis of (−)-morphine based on sequential [3,3]-sigmatropic rearrangements is described. The sequential Claisen/Claisen rearrangements of an allylic vicinal diol resulted in the stereoselective formation of the two contiguous carbon centers, including a sterically encumbered quaternary carbon, in a single operation. The two ethyl esters generated in this reaction were successfully differentiated during a subsequent Friedel–Crafts-type cyclization. The (−)-morphine double bond was introduced at a late stage in our first-generation synthesis, but was formed at an earlier stage in the second-generation synthesis, resulting in a more efficient route to the end product.