Total synthesis of (±)-galanthamine via a C3-selective Stille coupling and IMDA cycloaddition cascade of 3,5-dibromo-2-pyrone

Abstract

Galanthamine (1; Figure 1) is the parent member of the galanthamine-type amaryllidaceae alkaloids, isolated from several plants including daffodil bulbs. It is a selective, competitive and reversible inhibitor of acetylcholinesterase (Ache), as well as an allosteric modulator of the neural nicotinic receptor for acetylcholine, and currently marketed as Reminyl for the symptomatic treatment of senile dementia of the Alzheimer`s disease (AD) patients. Its limited availability from natural sources and intriguing biological activities has stimulated many synthetic efforts, leading to the invention of various elegant synthetic strategies. In search for more potent inhibitors with less adverse effects, a series of galanthamine derivatives have been synthesized and evaluated. As a part of our current study exploring the synthetic utility of the Diels-Alder cycloadducts of 3,5-dibromo-2-pyrone, we envisaged the tricyclic core of galanthamine with all required functional groups including the characteristic quaternary benzylic carbon could be readily forged from 5-endo, the IMDA cycloaddition product of 6, attainable from the C3-selective Stille coupling reaction of 2-pyrone 7 with aryl stannane 8. One carbon homologation of the lactone ring opening product 4 would permit the assembly of the benzazepine unit. Inversion of the stereochemistry of the secondary hydroxyl group and the removal of the vinyl bromide would conclude the synthesis. It is noteworthy that the vinyl bromide group could be used as a handle for further synthetic elaborations. We found that the Stille coupling reaction of aryl stannane 8 with 3,5-dibromo-2-pyrone 7, proceeded not only the expected regioselective coupling reaction at C3, but also IMDA cycloaddition reaction in a tandem fashion, directly providing the bicyclolactone 5-endo in 55% yield. Subsequent chemical transformations toward galanthamine will be presented. We wish to acknowledge the financial support of Center for Bioactive Molecular Hybrids (CBMH), Seoul Fellowship and BK21.