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Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06 Podcast
Totalsynthese invers prenylierter Bromindole aus dem Moostierchen Flustra foliacea

Totalsynthese invers prenylierter Bromindole aus dem Moostierchen Flustra foliacea

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06 vor 21 Jahren

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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.