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Bräuchle, Laura (2005): Totalsynthese invers prenylierter Bromindole aus dem Moostierchen Flustra foliacea. Dissertation, LMU München: Fakultät für Chemie und Pharmazie



The marine bryozoan Flustra foliacea is known as source of unique brominated indole alkaloids. Flustra alkaloids are structurally related to the highly toxic acetylcholinesterase inhibitor physostigmine which is clinically tested as a possible remedy for Alzheimer's disease. The concentration of those natural products can vary strongly, depending on location and season. Thus, exploration of the total synthesis of the Flustra alkaloids is required for any detailed analysis of their biological activity. As a recent member of the family, we isolated deformyl-flustrabromine (dFBr) which shows promising activity at the nicotinic acetylcholine receptor (nAChR). Deformylflustrabromine may be a biosynthetic precursor of other Flustra alkaloids such as flustraminol A. An efficient first total synthesis of dFBr and three of its congeners has been developed. Key step of the synthesis is the inverse prenylation at the indole 2-position. When treated with tert-BuOCl and prenyl[9-BBN], Nb-Formyl-Nb-methyl-tryptamine cleanly reacts affording the inversely 2-prenylated compound in a yield of 75 %. However, inverse prenylation of the indole 2-position was not suitable for the 6-brominated analog, synthesized via the Batcho-Leimgruber route. The influence of 6-bromination on the reactivity of several indoles was investigated confirming that deactivating effect. For the synthesis of dFBr we had to turn back to non-brominated indoles. Surprisingly good regioselectivity for the indole 6-position was observed on monobromination of the corresponding, 2-inversely prenylated indole precursor with one equivalent of NBS in HOAc/HCO2H (3:1). The product flustrabromine crystallizes as the E-rotamer. Alkaline hydrolysis afforded deformylflustrabromine which was synthesized within four steps and an overall yield of 53 % starting from Nb-methyl-tryptamine. Now, gram quantities of material are accessible for further biological studies. During this study, interesting formation of traces of inversely prenylated THF was observed. This phenomenon has been further studied by performing the actual reaction in the absence of indole derivatives. It was possible to convert unsubstituted tetrahydrofuran to the 2-inversely prenylated compound simply by treatment with NCS and prenyl[9-BBN] at room temperature, in a yield of 88 %. This is a new reaction.