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

Department of Chemistry / PhD (Chemistry) / This thesis is concerned with the computational study of naphthylisoquinoline alkaloids having antimalarial properties. The study was considered interesting because of the importance of gathering information on antimalarial molecules and because these molecules had not yet been studied computationally. The alkaloids considered in this study had been isolated from tropical lianas belonging to the Dioncophyllaceae and Ancistrodaceae families. They comprise alkaloids with both monomeric and dimeric structures. The monomeric structures consist of one unit and the dimeric ones of two units, with each unit containing a naphthalene moiety and an isoquinoline moiety. 33 monomeric molecules were studied, which represent a large portion of all the monomeric naphthylisoquinoline alkaloids isolated so far. Two dimeric molecules with antimalarial activity were investigated, namely, jozimine A2 and mbandakamine A. A third dimeric molecule, with a structure close to that of jozimine A2 but different activity (michellamine A, anti-HIV) was also calculated for comparison purposes. This work utilised electronic structures methods and involved the conformational study of all the molecules selected to identify the stabilising factors in vacuo and in solution. Two levels of theory (HF/ 6-31G (d,p) and DFT/B3LYP/ 6-31+G(d,p)) were utilised to compare their performance for compounds of this type, also in view of a future study extending to other compounds of the same class. The molecules were firstly studied in vacuo and secondly in three different solvents – chloroform, acetonitrile and water – characterized by different polarities and different H-bonding abilities. Quantum chemical calculations in solution were carried out using the Polarisable Continuum Model (PCM). The main stabilizing factors are the presence and types of intramolecular hydrogen bonds (IHBs), which are the dominant factors, and also the mutual orientation of the moieties. The possible IHBs comprise OH⋯O (or OH⋯N and NH⋯O for mbandakamine A) and other H-bond types interactions such as OH⋯ and CH⋯O (or CH⋯O and CH⋯N for mbandakamine A). The moieties prefer to be perpendicular one to another, which is a common tendency of aromatic vii systems. In monomeric structures, there may be only one OH⋯O and possibly also one of each of the other two types of IHBs interactions. In dimeric structures, there may be up to four (five in mbandakamine A) OH⋯O IHBs simultaneously and also other H-bond type interactions. The results provide a comprehensive picture of the molecular properties of these compounds, such as conformational preferences, dipole moments, HOMO-LUMO energy gaps, harmonic vibrational frequencies, solvent effect and influence of the solvent on molecular properties which respond to polarisation by the solvent. Altogether, these results may contribute to a better understanding of their biological activity and to the design of molecular structures with enhanced biological activity. This is the reason of focusing the efforts on the investigation of chemical and physical properties of these alkaloids molecules. / NRF