Stereoselective synthesis of (-)-galanthamine and lupin-type alkaloids

Abstract

A new asymmetric synthetic route to (-)-galanthamine (1.01), a potent Amaryllidaceae alkaloid used in the symptomatic treatment of early on-set Alzheimer's Disease (AD), was successfully developed with complete stereocontrol. Key to achieving high chemo- and stereo-selectivity in this approach was the use of transition metal (TM) mediated reactions, in the form of: an enyne RCM; a Heck coupling and a titanium based asymmetric allylation. Additionally, application of an asymmetric imino-aldol reaction resulted in the short total synthesis of two Lupin-type alkaloids, tashiromine (3.01) and epilupinine (3.02). These syntheses were undertaken to confirm the diastereomeric outcome of our modified imino-aldol reaction. Extensive modification to literature reaction conditions in a model system 3.42 was required to successfully reinstate the same sense of diastereoselectivity after, curiously, we obtained a different diastereomeric product to the one reported. Subsequently, to expand this area of interest, we applied our findings towards the synthesis of (+)-leontine (3.03), a more complex, naturally occurring, tetracyclic alkaloid. Significant progress was made up to a quinolizidinone intermediate (-)-6.12 which incorporated the desired relative stereochemistry at C5 and C6 and most of the carbon framework for transformation to the natural product.

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