of the aforementioned families of sponges against predatory
reef fish6,7b (Figure 1).
sis of (Z)-hymenialdisine 1, the most pharmaceutically
intriguing compound in the triad, was accomplished by
Annoura’s17a and Horne’s17b groups in the 1990s. Well-pre-
cedented disconnection showed aldisine 8a17,18a,19 and 2-bro-
moaldisine 8b17a as promising intermediates for achieving
our goals (Figure 3).
Biogenesis elucidation of these marine alkaloids still re-
mains a partially unresolved task. However, recent publica-
tions7 help to cast some light on this subject, especially in
identifying amino acids proline 5, ornithine 6, and histidine
7 as their potential precursors (Figure 2).
Figure 2.
Figure 3.
(Z)-Hymenialdisine 1 was found to be a nanomolar
inhibitor of mitogen-activated protein kinase 1 (MEK-1),8
glycogen synthase kinase-3â (GSK-3â),9 casein kinase 1
(CK1),9 and different cyclin-dependent kinases (crystals of
the complex with CDK2 have been obtained).9a Furthermore,
(Z)-2-debromohymenialdisine 2 was found to possess nano-
molar inhibitory activity of the G2 DNA damage checkpoint
and protein kinases Chk1 and Chk2.10 A number of patents
claiming pharmacological activities of these compounds for
the prevention and treatment of neurodegenerative disorders,8
diabetes,11 inflammatory pathologies,11 cancer,8,12 osteoar-
thritis,13 and ocular disorders14 have recently appeared. These
data prompted us to devise a common short synthetic
pathway to the most biologically relevant alkaloids, namely,
1 and 2. Large-scale preparation of (Z)-2-debromohy-
menialdisine 215,16 and (Z)-3-bromohymenialdisine 315 has
been recently described. On the other hand, total synthe-
Thus, reacting the commercially available 2-trichloro-
acetylpyrrole 9 with ethyl 3-aminopropionic acid hydrochlo-
ride led to amide 10, which underwent alkaline hydrolysis
to give acid 11. After intramolecular cyclization, we obtained
the required aldisine 8a in an improved 78% overall yield
without resorting to a time-consuming continuous extraction18b
(Scheme 1).
Scheme 1
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2-bromoaldisine 8b. The previously reported preparation17a
suffered from the observed bromine atom scrambling during
the PPA/P2O5-mediated cyclization step. Furthermore, regio-
selective bromination of the pyrrole amide 10 proved to be
much more difficult than expected.
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Contrary to the previously reported results17a on the
corresponding methyl ester, bromination in THF using NBS
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(16) Portevin, B.; Golsteyn, R. M.; Pierre´, A.; De Nanteuil, G.
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5642
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