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

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. Pain‐free synthesis! The sequential sigmatropic rearrangements of allylic vicinal diols offer a practical process for the synthesis of structurally complex chiral compounds. The synthesis of (−)‐morphine was achieved by employing a sequential Claisen/Claisen rearrangement as a key step (see scheme). The reaction of an allylic vicinal diol was employed to introduce a vicinal tertiary and quaternary carbon centers, and the resulting bis‐ester was differentiated in a subsequent Friedel–Crafts‐type cyclization.