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 5 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. 6 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.

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

Thesis (M. Sc.)--University of Hong Kong, 1973.

(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. - i - 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 I 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. - ii - 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. I i 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

published_or_final_version / Chemistry / Master / Master of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

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

Thesis (M.S) -- University of Adelaide, 1950. / Typewritten copy.

Thesis (Ph.D.) - University of St Andrews, January 2008. / Restricted until 15th January 2009.

Thesis (M.Sc.)--University of Hong Kong, 1973. / Also available in print.