Synthesis of (-)-Morphine: Application of Sequential Claisen/Claisen Rearrangement of an Allylic Vicinal Diol

摘要

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.