published_or_final_version / Chemistry / Master / Master of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

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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

Ph.D. / The objective of the research described in this thesis was to develop a synthetic method that can be applied to the synthesis of the natural bisbenzyltetrahydroisoquinoline alkaloids cissacapine, insularine, insularoline, cycleanine and analogues thereof. In this study two different strategies that allow easy entry to the precursors of these alkaloids were developed, and these set the scene for future total synthesis of these alkaloids. The key features of the first approach comprise the linkage of the two appropriate rings to form the diaryl ether moiety as well as the preparation of the 11H-dibenzo[b,e][1,4]dioxepine tricyclic system. Previous approaches to the diaryl ether formation are not suitable for large-scale reactions. We have herein described the preparation of the diaryl ether precursors in high yields and our approach is suitable for large-scale preparations. A search of the literature method revealed only two published methods for the preparation of the 11H-dibenzo[b,e][1,4]dioxepine system. Both these two methods produce compounds containing this moiety in low yields. In our studies this aspect was addressed satisfactorily. Unfortunately, our attempts to complete the synthesis of these alkaloids through Bischler-Napieralski reaction was met with no success, the problem been ascribed to the unoptimised Bischler-Napieralski conditions used. Our second approach involves the preparation of benzylisoquinoline units that are precursors of cycleanine. The published method to the derivatives of the cycleanine precursors is non-stereopecific and produces racemic benzylisoquinolines. Our synthetic route is a chiral auxiliary-based asymmetric version that produces the optically-pure benzylisoquinoline monomers. The key features of this route involve incorporation of the chiral auxiliary on the nitrogen atom, Bischler-Napieralski cyclisation of the resultant chiral amides and finally stereoselective reduction of the 3,4-dihydroisoquinolinium ion possessing the chiral auxiliary. This route employs both optically-pure (S)- and (R)-1-phenethylamine as the chiral source. Optically pure diastereomers were obtained. Our approach is a vast improvement compared to the previously described non-stereospecific method since it allows easy and good stereoselective access to both diastereomers in good yield. Unfortunately, one of the concluding steps leading to the formation of the dimeric stereoisomers of cycleanine through diaryl ether formation using the recently published methods was not successful. This is ascribed to the electron-rich nature of the isoquinoline ring.

The occurrence and syntheses of the pyrrolizidine alkaloids from 1976 to March 1988 is reviewed, and a stereoselective total synthesis of swazinecic acid dilactone was attempted. One approach involved an asymmetric synthesis of the allylic α-hydroxy acid 2-hydroxy-2,3-dimethyl-3-butenoic acid employing oxazolines as chiral auxilaries. The oxazoline, (4S,5S)-2-(1-bromoethyl)-4-methoxymethyl-5-phenyl-2-oxazoline, was obtained by direct halogenation of the 2-ethyl oxazoline analogue. This was condensed with acetone in a Darzens type reaction and the resultant epoxy oxazoline rearranged to an allylic α-hydroxy oxazoline which was then hydrolysed to the chiral hydroxy acid in low enantiomeric excess. The hydroxy acid, as the O-silylated ethyl ester, was elaborated by allylic diethyl malonate to bromination and condensation with diethyl 5-carboethoxy-2-methyl-3- methylene-2-0-tert-butyldimethylsilylhexanedioate. Removal of the silyl protecting group and epoxidation provided an epoxy triester, which on hydrolysis provided a mixture of acids of uncertain structures.

Graduation date: 2003

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Master / Master of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy