A concise total synthesis of Lycopodium alkaloids

The present project deals with the chemical preparation of alkaloids (-)-Magellanine, (+)- Magellaninone and (+)-Paniculatine, compounds which were isolated from Lycopodium, a club moss. Some members of the lycopodium alkaloid family act as bioactive components, amongst other things as acetylcholinesterase inhibitors for the treatment of Alzheimers disease. Like many other compounds of natural origin these alkaloids have a highly complex chemical structure and three- dimensional shape. To make such molecules entirely by chemical means ("total synthesis") from simple starting material is a formidable challenge for organic chemistry. In the past, several groups have successfully completed total syntheses of these natural products in 14 to 45 chemical steps, depending on the synthetic strategy used. The most challenging part often was the correct assembly of the carbon skeleton. The chemical methods used for this purpose forced chemists in the past to prepare complex precursors or to make major changes in the molecules structure after assembly of its four rings. This led to long and relatively circuitous reaction sequences. With only 8-9 steps the herein proposed route will assemble Magellanine and related compounds with an unprecedented level of efficiency. The proposed synthetic sequence was developed based on a number of guidelines: We focus on reactions which will generate functional groups exactly in the way they are required in the final product rather than preparing precursors for these functionalities. Secondly, we have selected reactions which allow us to make big steps toward the target compounds, e.g. multi-component- reactions. Furthermore, mild and selective reaction conditions were chosen to ensure transformations to occur at the intended position only, avoiding potential side-reactions. Under these conditions, sensitive functional groups do not need special protection. Furthermore, through the use of catalytic processes, costs and chemicals can be saved, enabling a gramm-scale synthesis. It is the main objective to showcase the feasibility of a synthesis guided by the principles mentioned above and to demonstrate the overall increase in effectivity of this approach.