Organic chemistry

摘要

Galanthamine (1) is effective in the treatment of Alzheimer's disease and large quantities are needed in phase III clinical trials in Europe and the US. A very short enantiomerically controlled large-scale synthesis has now been reported, though a crucial detail is left deliberately vague. The start is a conventional phenolic coupling, with a bromine substituent placed to ensure regiocontrol. The end is also conventional, with an interconversion of narwedine (3) into galanthamine. The key stages, and the novelty and elegance of the route, lie in between. Protection of the enone, removal of the bromine with LiAlH_4, and deprotection provide racemic narwedine, which is enhanced to optical purity by a second-order asymmetric transformation. The enantiomers of narwedine need to interconvert in this process, and this is achieved by using triethylamine to open the central ring and provide a symmetrical structure.