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A novel method for the synthesis of Indolo[2,1-a]isoquinolines and modelling studies of 3-substituted oxindoles against PfPK5Sello, Thato Saoeni 08 September 2008 (has links)
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.
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Total synthesis of indole alkaloids: pt. 1. Asymmetric synthesis of (-)-ibogamine. pt. 2. An approach toward the synthesis of koumineChoi, Younggi 04 February 2003 (has links)
PART I. The preparation of (-)-ibogamine (1) in fourteen steps from
benzoquinone and in 10% overall yield is a powerful illustration of the value of
the asymmetric Diels-Alder reaction as a starting point in a multistep synthesis.
All four cycloadducts, 70, 77, 84 and 96, obtained with the (S)-BINOL-TiCl���
complex were found to have the same absolute configuration. Furthermore, they
are in the same enantiomeric series that Mikami observed with 1,4-naphthoquinone using the same catalyst, lending confidence to future stereochemical predictions that may be made with this system.
PART II. Three different routes for the synthesis of the
hexahydroisoquinoline 98 met obstacles which defeated our approach to
koumine. The Diels-Alder reaction of cyclic 1-azadienes 102 and 108 was
abandoned due to the lack of reactivity of the dienes. An anionic oxy-Cope
rearrangement of the azabicyclo[2.2.2]octane system caused mainly
decomposition of the starting materials. Finally, an intramolecular [2+2]
photocycloaddition generated "crossed", "straight" and hydroisoquinoline
products in varying ratios, depending on the substituent pattern of the substrate,
but this approach was not synthetically useful. The results from this last study
may be valuable for predicting the regiochemical outcome of certain
intramolecular photocycloadditions. / Graduation date: 2003
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Structures of indole alkaloids from Strychnos angustiflora.Au, Tak-yan, Francis. January 1973 (has links)
Thesis (M. Sc.)--University of Hong Kong, 1973.
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Structures of indole alkaloids from Strychnos angustifloraAu, Tak-yan, Francis, 區德仁 January 1973 (has links)
(Uncorrected OCR)
�Abstract of thesis entitled "Structures of Indole
Alkaloids from Strychnos angustiflora" submitted by ~
AU Tak-yan, Francis for the degree of Master of Science at the University of Hong Kong in March 1973.
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ABSTRACT
From the leaves of Strychnos angustiflora Benth,three orange-coloured alkaloids angustoline, angus tine and angustidine have been isolated in low yield.
/
Molecular formulae and electronic spectra
indicate that all three alkaloids have the same highly
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conjugated polycyclic skeleton.
Structure~ shown below
\
are proposed�
H
Alkaloid Formula Rl R2
Angustoline C2'OH1702N3 CH(OH)CH3 H
Angustine C20'H1SON3 CH=CH2 !
Angustidine Cl9H1SON3 H CH3 The major alkaloid, angustoline, is monoacidic and the hydrochloride-and the picr~te sa~ts have been prepared.
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The presence of a l-hydroxyethyl side chain shown by n.m.r. has been confir.med by acetylation to g~ve an
/
acetate.
Chemical correlation between angustoline and angustine has been achieved in two ways. Firstly, the
former was converted to the latter 'by acidic catalysed dehydration � Secondly, an~ustoline or its acetate on heating with collidine yielded dihydroangustine, also obtained from angustine by hydrogenation.
Arguments are presented for the structures of the three alkaloids, based substantially on n.m.r. data
(including long-range coupling and N.O.E. data) and biogenetic considerations.
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The three alkaloids are postulated to be derived biogenetically from vincoside, the fused pyridine ring being formed via opening of the iridoid glycoside ring by ammonia (or equivalent). / abstract / toc / Chemistry / Master / Master of Science
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Synthetic study of seco-yuehchukene and inverto-yuehchukene李輝途, Lee, Victor. January 1987 (has links)
published_or_final_version / Chemistry / Master / Master of Philosophy
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A general synthetic route to Yuehchukene analogues via 7alpha-methoxycarbonyl-9-methyl-6-oxo-5,6,6abeta,7betaB,8,10aB-hexahydroindeno [2,1-b] indole, and related studies on 1-methoxyindole黃子達, Wong, Tze-tat, Edward. January 1992 (has links)
published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy
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Synthetical experiments related to the indole alkaloids / by David Roland Liljegren.Liljegren, David Roland January 1962 (has links)
Typewritten / 153 leaves / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Organic Chemistry, 1962
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Isolation of a piperitol epimer, and Studies on the Fischer indole synthesis /Barnes, Charles Stalley. January 1950 (has links) (PDF)
Thesis (M.S) -- University of Adelaide, 1950. / Typewritten copy.
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Rearrangements in the indolo[2,3-b]quinoline system : a novel approach to the synthesis of perophoramidine and the communesins /Voûte, Nicholas. January 2008 (has links)
Thesis (Ph.D.) - University of St Andrews, January 2008. / Restricted until 15th January 2009.
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Structures of indole alkaloids from Strychnos angustifloraAu, Tak-yan, Francis. January 1973 (has links)
Thesis (M.Sc.)--University of Hong Kong, 1973. / Also available in print.
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