Devising New Syntheses of the Alkaloid Galanthamine, a Potent and Clinically Deployed Inhibitor of Acetylcholine Esterase

The alkaloid (-)-galanthamine (1), a potent inhibitor of acetylcholinesterase (AChE), is used clinically for the symptomatic treatment of mild to moderate forms of Alzheimer's disease. The clinical demand for (-)-galanthamine together with the erosion of habitat of at least some of the source plants has created supply issues that have prompted numerous synthetic studies. Four distinct approaches for the assembly of the tetracyclic framework of compound 1 developed in the authors' laboratories are described here. Two of these exploit an enantiomerically pure metabolite produced through the whole-cell dihydroxylation of bromobenzene as a precursor to the A-ring of natural product 1. The second of these rapidly provides enantiomerically pure compounds that molecular docking studies suggest should be strong inhibitors of AChE. A third synthesis of (-)-galanthamine involving the de novo assembly of the aromatic C-ring is also described, as is a failed radical cyclization-based approach.