Six-step total syntheses of (−)-galanthamine and (−)-

Abstract

The Amaryllidaceae alkaloid (−)-galanthamine (1) is a reversible, competitive acetylcholinesterase inhibitor deployed clinically to treat the dementia associated with Alzheimer’s disease. Here, we describe a six-step synthesis of this natural product from simple, readily accessible starting materials. Enantioselective 1,2-reduction, Mitsunobu coupling, Heck cyclization and diastereoselective allylic oxidation reactions are used in our approach, which provides the shortest synthetic route to compound 1 reported to date. A simple modification to the closing stages of the sequence allows equally facile access to (−)-N-norgalanthamine (2), a compound with a range of distinctive biological properties. The concise and operationally simple synthetic protocols reported here could obviate the need to manipulate naturally sourced galanthamine in the pursuit of analogues required for pharmacological studies.