Many naturally occurring and synthetically made azapolycyclic aromatic ring
systems display important biological activities. One class of naturally occurring
azapolycyclic aromatic ring systems is the dibenzopyrrocoline alkaloids, made
from an indole nucleus fused to an isoquinoline system sharing the same
nitrogen, i.e. the indolo[2,1-a]isoquinoline nucleus. The indolo[2,1-a]isoquinoline
and its analogues have been reported to possess antileukemic, tubulin
polymerization inhibitory and antitumor activity.
A variety of indolo[2,1-a]isoquinolines have been synthesized in our labs. This
includes, the 5,12-dimethyl-6-phenylindolo[2,1-a]isoquinoline, using the Suzuki-
Miyaura cross-coupling reaction and reaction conditions for the formation of
aromatic rings (KOBut in DMF) developed in our laboratories. In this dissertation,
we outline the syntheses of (±)-5,6-dihydro-6-phenylindolo[2,1-a]isoquinolin-5-ol
and 2-(1-benzyl-1H-benzo[d]imidazol-2-yl)benzaldehyde. We also discuss the
synthesis and the modelling studies, (docked in silico) of the 3-substituted
oxindoles in the X-ray crystal structure of the PfPK5 cyclin dependent kinase
(CDK).
The synthesis of indolo[2,1-a]isoquinolines started with N-protection of isatin and
benzimidazole with a benzyl group to afford 1-benzylindoline-2,3-dione and 1-
benzyl-1H-benzo[d]imidazole, respectively. The next step was the synthesis of
the brominated compound, 1-benzyl-2-bromo-1H-indole, and the iodated
compound, 1-benzyl-2-iodo-1H-benzo[d]imidazole. 1-Benzyl-2-bromo-1H-indole
was synthesized by means of a functional group interconversion of the oxygen in
the 3-position of isatin to two chlorine atoms initially, followed by removal of those
chlorine atoms with activated zinc, followed by the conversion of the carbonyl of
the oxindole to give a 2-bromoindole using POBr3. 1-Benzyl-2-iodo-1Hbenzo[
d]imidazole was synthesized in two ways. Firstly, 1-benzyl-1Hbenzo[
d]imidazole was exposed to LDA followed by iodinating the 2-position by
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exposure of the intermediate to diiodoethane. The second method uses a
halogenating method developed in our labs. 1-Benzyl-1H-benzo[d]imidazole was
exposed to isopropylmagnesium chloride lithium chloride followed by I2. Having
obtained the halogenated products, both sets of halogenated precursors were
coupled with 2-formylphenylboronic acid using the Suzuki-Miyaura crosscoupling
reaction to obtain the products, 2-(1-benzyl-1H-indol-2-yl)benzaldehyde
and 2-(1-benzyl-1H-benzo[d]imidazol-2-yl)benzaldehyde in 98 and 67% yield,
respectively. Aromatization of 2-(1-benzyl-1H-indol-2-yl)benzaldehyde occurred
easily using tBuOK in DMF at room temperature to afford (±)-5,6-dihydro-6-
phenylindolo[2,1-a]isoquinolin-5-ol in 75% yield (7:3 ratio of anti-: syn-) but
exposing 2-(1-benzyl-1H-benzo[d]imidazol-2-yl)benzaldehyde to the same
reaction conditions did not afford the desired product. Dehydrating (±)-5,6-
dihydro-6-phenylindolo[2,1-a]isoquinolin-5-ol using methanesulfonyl chloride in
CH2Cl2 was unsuccessful. Further attempts at dehydrating (±)-5,6-dihydro-6-
phenylindolo[2,1-a]isoquinolin-5-ol were prevented due to time constraints.
In the last part of the project, a library of 3-substituted oxindoles (13 molecules)
was synthesized successfully and the compounds were docked in silico in the
active site of an X-ray crystal structure of PfPK5, a cyclin dependent kinase of
the Plasmodium falciparum, the agent causing the most severe form of human
malaria. Eleven of the thirteen compounds were synthesized by condensation of
oxindole and a suitable aldehyde in the presence of piperidine. The other two, 3-
(propan-2-ylidene)indolin-2-one and 5,6-dimethoxy-3-(methylthio)indolin-2-one,
were synthesized differently. 3-(Propan-2-ylidene)indolin-2-one was synthesized
by reacting the oxindole with acetone in the presence of HCl and 5,6-dimethoxy-
3-(methylthio)indolin-2-one was synthesized following Gassman’s methodology.
Two molecules scored well in the molecular modelling studies using the X-ray
crystal structure of PfPK5, namely, (E/Z)-3-(3,4-dimethoxybenzylidene)indolin-2-
one and (Z)-3-(4-hydroxybenzylidene)indolin-2-one.
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In conclusion, we managed to synthesize (±)-5,6-dihydro-6-phenylindolo[2,1-
a]isoquinolin-5-ol using the Suzuki Miyaura cross-coupling reaction and reaction
conditions that lead to aromatization (tBuOK in DMF at room temperature) as key
steps and 2-(1-benzyl-1H-benzo[d]imidazol-2-yl)benzaldehyde using the Suzuki-
Miyaura cross-coupling reaction. A library of 3-substituted oxindoles was made
and using molecular modelling were docked in silico into the crystal structure of
the active site of PfPK5 with 2 compounds showing promise, for further studies.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/5598 |
| Date | 08 September 2008 |
| Creators | Sello, Thato Saoeni |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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