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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.

This thesis describes the host-guest chemistry between cucurbit[7]uril (CB[7]) and various guests that contain isoquinoline groups, including tacrine, papaverine, N-methyl papaverinium, N-methyl laudanosinium, 6,7-dimethoxy-1,2,3,4,-tetrahydroisoquinoline, N, N-dimethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinium, α,α'-bis(isoquinolinium)-p-xylene and a series of 1,n-bis(isoquinolinium) alkane dications (Isq(CH2)nIsq2+, where n = 2, 4-6, 8-10 and 12). The stoichiometries and strengths of the host-guest interactions were studied using UV-visible and 1H NMR spectroscopy and high-resolution electrospray ionization mass spectrometry. A focus of this thesis is an investigation of the effects of varying the chemical structure within a series of isoquinoline-based guest on the strength of the binding affinity . The 1H NMR spectra indicates that CB[7] prefers the saturated ring of tacrine as opposed to the aromatic ring, resulting in a binding constant of (2.7 ± 0.25) x 104 M-1. The N-methylations of papaverine and 6,7-dimethoxy-1,2,3,4,-tetrahydroisoquinoline increased their respective binding constants from those of the protonated forms and changed the nature of the interaction of the guest with CB[7]. . With the series of 1,n-bis(isoquinolinium)-alkane dications, the mode of binding to CB[7] depends on the number of carbons in the polymethylene chain that bridges the two isoquinolinium groups. When the bridge is less than six carbons, CB[7] binds sequentially on the isoquinolinium groups to form 1:1 and 2:1 host-guest complexes. If the polymethylene chain length is between six and ten carbons, or is replaced with a p-xylyl group, the first CB[7] will bind over the central bridge, resulting in both of the polar portals forming ion-dipole interactions with both positively charged nitrogens. A second CB[7] binds to a terminal isoquinolinium group, which forces the original bound CB[7] to relocate to the other isoquinolinium group. When the polymethylene bridges contains twelve carbons, two CB[7] binds sequentially to the isoquinolinium groups, as observed with the shortest polymethylene bridges. With this series of guest, the binding constant is the largest when the bridge is two carbons long. This is due to the two isoquinolinium groups being in close proximity to each other, allowing CB[7] to interact with both nitrogens while still binding around the isoquinoline group. / Thesis (Master, Chemistry) -- Queen's University, 2011-09-30 10:02:47.285

iii, 192 leaves : ill., tables ; 30 cm. / 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, 1979

Thesis (Ph.D.) -- University of Adelaide, Dept. of Organic Chemistry, 1979.

The objectives of this project were to investigate the application of new methodologies for the preparation of benzyltetrahydroisoquinoline monomers and secondly, to synthesise the bisbenzyltetrahydroisoquinoline neferine and its analogues. Neferine was isolated from the roots of Nelumbo nucifera. This compound has been reported to exhibit important biological activities, which include anti-arrhymia, anti-platelet aggregation, anti-thrombosis, anti-cancer as well as anti-HIV activities. Moreover, neferine showed lower cytotoxicity compared to other isoquinolines. However, the total synthesis of this compound has not been reported. Two methodolologies based on the intramolecular hydroamination of aminostilbenes and aminoalkynes were investigated for the preparation of benzyltetrahydroisoquinolines with different oxygenation patterns. In these strategies, the aminostilbene and aminoalkyne precursors were successfully synthesised by the Heck and Sonogashira coupling reactions, respectively. The attempts to cyclise the aminostilbenes into the corresponding tetrahydroisoquinolines under base-catalysed, metal-catalysed and acid-catalysed conditions were unsuccessful. On the other hand, cyclisation of aminoalkynes into dihydroisoquinolines was achieved with the aid of titanium catalysts. Different titanium catalysts were tested for this hydroaminationation reaction. Optimum results were obtained with bis-(cyclopentadienyl)dimethyl titanium(IV) catalyst, albeit the yields were inconsistent when the reaction was performed on a larger scale. Induction of the desired stereochemistry on the dihydroisoquinolines prepared by the hydroamination of aminoalkynes was attempted with the chiral BINOL phosphoric acid catalyst without success. The catalyst was prepared in good yields and high enantiomeric excess from cheap and readily-available starting materials. Had this reaction been successful, this would have been a breakthrough in the stereoselective reduction of dihydroisoquinolines as most chiral catalysts, which are currently employed are expensive, difficult to prepare and some are air and moisture-sensitive. Although the first objectives of this project are not fully met, the results obtained in the synthesis of benzyltetrahydroisoquinolines by the hydroamination of aminostilbenes and aminoalkynes contribute greatly to the prevailing literature on the synthesis of benzyltetrahydroisoquinolines by these reactions. Presently, there is limited literature on the synthesis of benzyltetrahydroisoquinolines by these methods. Moreover, there is a need for the development of new synthetic strategies that would render benzyltetrahydroisoquinolines in minimum steps and good yields. It was planned that, upon successful synthesis of benzyltetrahydroisoquinolines from aminostilbene and aminoalkyne precursors, these modern methodologies would be applied in the synthesis of the two benzyltetrahydroisoquinoline scaffolds of neferine. However, these routes could not be pursued due to failure to ringclose the aminostilbenes and irreproducibility of results in the preparation of dihydroisoquinolines from aminoalkynes. Therefore, classical procedures were employed for the preparation of benzylisoquinoline nuclei of neferine. Three different synthetic routes were followed for the synthesis of neferine and its analogues. The first two methods were based on the Ullmann coupling reaction for the formation of the diaryl ether bond. The first method entailed an early construction of the ether link and late construction of the two isoquinoline rings on the ether bridge. The second method involved synthesis of the two isoquinoline nuclei, and coupling of the two units by the Ullmann reaction in the late stages of the synthesis. In the last synthetic strategy, the diaryl ether bridge was constructed by the nucleophilic aromatic substitution reaction. In all the three methods, the two isoquinoline rings were formed by the Bischler-Napieralski cyclisation reaction. In the first route, we succeeded in preparing the two major building blocks, which were N-(3,4-dimethoxyphenylethyl)-4-benzyloxy-3-iodophenylacetamide and [2- (4’-hydroxy-3’-methoxyphenyl)ethyl]carbamic acid tert-butyl ester. The Ullmann coupling of the two compounds afforded the diphenyl ether N-(3,4- dimethoxyphenylethyl)-4-benzyloxy-3-(4-(3-methoxyphenoxy)ethyl-tertbutylcarbamate) phenylacetamide, albeit in low yields. Although N-(3,4- dimethoxyphenylethyl)-4-benzyloxy-3-(4-(3-methoxyphenoxy)ethyl-tertbutylcarbamate) phenylacetamide was obtained in low yields, the successful formation of the diaryl ether bond from electron-rich haloacetamide and hydroxyphenethylamine is a great advancement in the synthesis of bisbenzyltetrahydroisoquinolines. In the second approach, the two benzyltetrahydroisoquinoline precursors for the Ullmann coupling reaction were successfully synthesised. These were the 7-hydroxybenzyltetrahydroisoquinoline and the 3’-iodobenzyltetrahydroisoquinoline. The Ullmann coupling reaction of the two isoquinolines did not give any fruitful results. In the last synthetic strategy, the formation of the diaryl ether bridge was based on the nucleophilic aromatic substitution reaction. In this route, we managed to synthesise the two coupling partners for the nucleophilic aromatic substitution reaction leading to Omethylneferine. One of the building blocks was the natural benzyltetrahydroisoquinoline, hydroxylaudanidine, and its coupling partner was N- [2-(4-fluoro-3-nitrophenyl)ethyl]-2-(4-methoxyphenyl)-N-methylacetamide. The major challenges in this route were encountered in the preparation the fluoroacetamide, which involved several low-yielding synthetic steps and tedious chromatographic purifications. The nucleophilic aromatic substitution reaction of the two precursors was attempted in vain. Even though the total synthesis of neferine could not be accomplished, it is strongly believed that the developed synthetic routes will enable us to complete the synthesis of the targeted compound and other naturally-occurring bisbenzyltetrahydroisoquinolines. The results obtained herein represent a significant advance considering the importance of the bisbenzyltetrahydroisoquinolines as biologically active compounds. / Thesis (Ph.D.)-University of KwaZulu-Natal, Pietermaritzburg, 2011.

Part¢¹¡GStudies of Electroorganic Reactions toward the Syntheses of Isoquinoline Alkaloids, and its possible mechanism. Part ¢º: Application of Radical Cyclization Reactions toward the Syntheses of Alkaloids, and other derivatives.

This thesis describes the first total synthesis of ancistrotanzanine A, a member of the naphthylisoquinoline class of natural products. In Chapter 1 the synthetic challenges presented by the naphthylisoquinoline alkaloids are discussed and strategies that have been adopted in previous syntheses of naphthylisoquinoline alkaloids overviewed. Chapter 2 describes the preparation of the key 5,3'-biaryl linkage via the Pinhey-Barton reaction. Studies into forming the linkage atropselectively were investigated using chiral hydrobenzoin acetal auxiliaries. This was found to have limited success with an atropisomeric ratio of 65:35 obtained. Changing the base from the achiral pyridine to the chiral brucine was also investigated and found to give no enhancement in the diastereoselectivity. From the results presented in Chapter 2, it was concluded that hydrobenzoin acetal auxiliaries were not appropriate for the diastereoselective synthesis of the key biaryl linkage of ancistrotanzanine A. As the chiral acetal strategy outlined in Chapter 2 failed to yield an atropselective process, efforts were re-focused on a new approach to the naphthylisoquinolines. In Chapter 3, an overview of all the methods available for the synthesis of chiral 3,4-dihydroisoquinolines is provided. From this, it was decided to apply the alkylation of o-tolylnitriles with chiral sulfinimines, as originally developed by Davis, to the synthesis of naphthylisoquinolines. Synthesis of the o-tolylnitrile lead reagent was readily achieved, but it was found that the amount of lead tetraacetate had to be carefully controlled to avoid side-reactions in the Pinhey-Barton reaction. After careful optimisation, the key 5,3'-biaryl linkage was prepared in high yield. Application of the Davis methodology to the MOM protected biaryl failed, with no reaction resulting. After much experimentation, it was established that the reaction was very sensitive to steric hindrance. A successful reaction was finally achieved by changing the base to lithium diethylamide. However, it was found the diastereoselection of the alkylation was quite low when p-tolyl sulfinimine was used. The use of the t-butane sulfinimine meant that the diastereoselection was significantly improved, with a ratio of 85:15 being obtained. After 3 more steps, the total synthesis was completed and ancistrotanzanine A was obtained, as a 1:1 mixture of atropisomers. Efforts to separate the atropisomers formed failed and even the use of chiral HPLC failed to resolve the material. To complete the Chapter, two analogues of ancistrotanzanine A were prepared – the tetrahydroisoquinoline and the methoxy ether. Chapter 4 summarises the above results and discusses the future potential of this research. / Thesis (Ph.D.) -- University of Adelaide, School of Chemistry and Physics, 2010

Isoquinoline alkaloids and analogs play an important role in today's pharmaceutical industry. The need to synthesize single stereoisomers of these alkaloids is important. Many times only a single stereoisomer exhibits the desired activity, while other stereoisomers of the alkaloid exhibit undesired side effects. The stereoselective synthesis of 1, 1-disubstituted 1,2,3,4- tetrahydroisoquinolines using Reissert compound chemistry containing chiral acyl auxiliaries was studied with the ultimate goal of synthesizing spirobenzylisoquinoline alkaloids. / Ph. D.

Isoquinoline alkaloids have long been known for their biological activity. Many of the isoquinoline alkaloids have been made as racemic mixtures. The present investigation was aimed at developing methodology for the asymmetric synthesis of some isoquinoline alkaloids through Reissert compound chemistry. The stereochemistry of lepidine and isoquinoline Reissert compounds has not been reported. To better understand the stereochemistry of these compounds, selected Reissert compounds were synthesized and subsequently studied by proton NMR. The two types of isomerism studied were amide isomerism and aryl / carbonyl rotation. In at least some cases, both amide isomers and restricted aryl / carbonyl rotamers were observed. For other cases only the restricted aryl / carbonyl rotamers were observed. The presence of ortho substituents on the aroyl moiety was found to greatly increase the chance amide isomerism on the NMR time scale. (-)-Menthy] chloroformate, (+)-menthy] chloroformate, and (-)-menthoxyacety] chloride have been utilized as chiral acyl auxiliaries to induce the stereochemistry at C,, resulting in diastereomeric isoquinoline Reissert compounds. By reaction of a mixture of the diastereomeric Reissert anions of 2-(1)-(mentho1 ,x2-ydichyadrroisboqouinnayldolni)tr-il e (110) with pivaldehyde we were able to form the resulting diastereomeric carbonates of 1-isoquinolyl-t-butyl carbinyl menthyl carbonate (120) in a 77:23 ratio by NMR [82 : 18 ratio by HPLC). After obtaining the major diastereomer of the carbonate in pure form, hydrolysis yielded the enantiomerically pure (S)-(-)-1-isoquinoy] t-buty] carbinol (121). The proton NMR spectra of the diastereomeric Reissert compounds led to elucidation of the stereochemistry. The diastereomeric ratios were determined for both 110 and 2-(1)-methoxyacetyl- 1 ,2-dihydroisoquinaldonitrile (125). Amide isomerism was observable in the case of 110 but not in the case of 125. Aromatic solvent induced shift (ASIS) studies of the compound 125 showed the s-trans amide to be predominant. The reaction of the diastereomeric Reissert anion of 110 with CS, and partial conversion with pivaldehyde allowed us to determine that the Reissert anion equilibrates. Reaction of the anion of 125 with pivaldehyde gave 1-isoquinolyl t-butyl carbinyl menthyl acetate (127) in quantitative yield and 0 % de. However, the diastereomers are easily separated using simple silica gel column chromatography. / Master of Science