MSc dissertation
School of Chemistry
Faculty of Science
0004984F / Many azapolycyclic aromatic ring systems, whether they are naturally
occurring or synthetically made, display important biological activities. One
important class of naturally occurring azapolycyclic aromatic ring systems are
the dibenzopyrrocoline alkaloids, which contain an indole ring fused to an
isoquinoline moiety, where they share a common nitrogen. The basic skeleton
of these alkaloids is the indolo[2,1-a]isoquinoline nucleus. Both the
dibenzopyrrocoline alkaloids and the indolo[2,1-a]isoquinolines have been
found to inhibit tubulin polymerization and thus possess antitumour and
antileukemic activities.
In our laboratories, a variety of indolo[2,1-a]isoquinolines, for example 5,12-
dimethyl-6-phenylindolo[2,1-a]isoquinoline, have been synthesized using the
Suzuki-Miyaura cross coupling reaction and reaction conditions for the
formation of aromatic rings (KOBut in DMF and a light source – developed in
our laboratories) as key steps. In this dissertation we discuss the synthesis of
(±)-5,6-dihydro-6-phenylindolo[2,1-a]isoquinolin-5-ol and ethyl indolo[2,1-
a]isoquinoline-6-carboxylate using these reaction conditions as our key steps.
The syntheses commenced with the N-protection of isatin with a benzyl and
an ethyl acetate group to afford 1-benzylindoline-2,3-dione and ethyl 2-(2,3-
dioxoindolin-1-yl)acetate respectively. The next step was the synthesis of the
brominated compounds 1-benzyl-2-bromo-1H-indole and ethyl 2-(2-bromo-
1H-indol-1-yl)acetate by means of a functional group interconversion of the
oxygen in the 3-position to two chlorine atoms, followed by
hydrodehalogenation, using zinc in AcOH, and then bromination, using POBr3
in CH2Cl2. Having obtained the brominated compounds we went on and
coupled them with 2-formylphenylboronic acid using the Suzuki-Miyaura cross
coupling reaction to obtain the coupled products 2-(1-benzyl-1H-indol-2-
yl)benzaldehyde and ethyl 2-(2-(2-formylphenyl)-1H-indol-1-yl)acetate in 92
and 77% yield, respectively. Aromatisation of ethyl 2-(2-(2-formylphenyl)-1Hindol-
1-yl)acetate to ethyl indolo[2,1-a]isoquinoline-6-carboxylate occurred smoothly in 2 minutes using 10 mol % KOBut in DMF at room temperature.
Using the same reaction conditions on 2-(1-benzyl-1H-indol-2-
yl)benzaldehyde to form 6-phenylindolo-[2,1-a]isoquino-line resulted in (±)-
5,6-dihydro-6-phenylindolo[2,1-a]iso-quinolin-5-ol being obtained in 75% yield
(7:3 ratio of anti:syn). An attempt to dehydrate this compound using p-TSA in
CH2Cl2 in the presence of molecular sieves was not successful. Time
constraints prevented any further attempts at dehydrating (±)-5,6-dihydro-6-
phenylindolo[2,1-a]iso-quinolin-5-ol.
In conclusion, we managed to synthesize (±)-5,6-dihydro-6-phenylindolo[2,1-
a]isoquinolin-5-ol and ethyl indolo[2,1-a]isoquinoline-6-carboxylate using the
Suzuki-Miyaura cross coupling reaction and specific reaction conditions, using
the base KOtBu, for the formation of aromatic rings, both as key steps.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/1504 |
| Date | 31 October 2006 |
| Creators | Lotter, Angelique Natalia Cassandra |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 2037239 bytes, application/pdf, application/pdf |
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