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The usefulness of imines and iminium salts in the convergent synthesis of alkaloids and their synthetic analogues is described. Thus the anion derived from [3,4-c]pyridin-3[1H]-one, by treatment with LDA (lithium diisopropylamide) or LHS, (lithium bis-trimethylsilylamide) reacts with 2-methyl-3, 4-dihydro- isoquinolinium salts yielding aza analogues of phthalideisoquinoline alkaloids. The condensation of the same anion with 3,4-dihydroisoquinolines has provided, in a single step, azaprotoberberines containing the benzo[a)pyrido[3,4-g]quinolizine structure found in a number of Alangium alkaloids. The reaction of methyllithium with oxoberberine as a means of introducing a methyl group C-8 is described. The resulting iminium salt was reduced to a mixture of racemic a- and B-8-methylcanadines. This reaction has been applied to the synthesis of the Alangium alkaloid (+/-)-alamaridine. Condensation of lithium salts of 3-cyano-4-methylpyridine and 3-cyano-4-methyl-5-vinylpyridine with a complex of 3 ,4-dihydroisoquinolines and trimethylsilyl trifluoromethanesulphonate has been studied. The amidines formed as condensation products were transformed by hydrolysis into 5,6,13,14-tetrahydro-8H-isoquino[2,1-b][2,7]-naphthyridin-8-ones, a ring system found in several alkaloids of Alangtum lamarckii. These reactions have been employed in the synthesis of the Alangium alkaloids, (±)-alangimaridine and alangimarine. The usefulness of this reaction has been further demonstrated in the synthesis of N-benzyl derivatives of 3,14-dihydronauclefine and 3,14-dihydroangustine containing 8,13,13b,14-tetrahydroindolo[2•,3•:3,4]pyrido[1,2-b][2,7]-naphthyridin- 5[7H]-one. / Thesis / Doctor of Philosophy (PhD)

Student Number : 0011001D - PhD thesis - School of Chemistry - Faculty of Science / The subject of this thesis is the development of a potentially simple, general and economical synthetic protocol for the potent antimalarial alkaloid febrifugine (1) and its analogues. In Chapter 1, the interesting history of 1, which includes a description of several reported total syntheses of 1, is discussed. Natural products derived from 1, as well as promising synthetic derivatives that display good antimalarial activity, are also discussed. The structure-activity relationships determined to date for 1 and its derivatives are presented in order to substantiate the need for the development of new synthetic strategies towards derivatives of 1 and its 3″-unsubstituted analogue, (±)- deoxyfebrifugine (14). A brief overview of the general strategies used in the Organic Chemistry Group at the University of the Witwatersrand for the synthesis of alkaloids is given in Chapter 2. The Eschenmoser sulfide contraction reaction between a thiolactam and an α- bromocarbonyl compound results in the formation of a vinylogous amide (or “enaminone”) product, which can be further manipulated to produce commonly encountered alkaloidal molecular skeletons. The chosen approach to 1 is based on reaction between the pivotal bromide 3-(3-bromo-2-oxopropyl)quinazolin-4(3H)-one (105) and suitable 3-substituted piperidine-2-thiones. A series of model studies, described in Chapter 3, was performed in order to test the feasibility of the synthetic strategy. These studies resulted in a new preparation of the key bromide 105 and a new and efficient synthesis of (±)-deoxyfebrifugine (14). Enaminone analogues derived from five-, seven-, eight-, nine- and thirteen-membered thiolactams were also prepared for comparison. An interesting difference in the sensitivity of the five- and six-membered model cyclic vinylogous amides towards reducing agents was observed. Whereas three piperidine analogues of 14 could be prepared in high yields by the chemoselective hydrogenation of six-membered cyclic vinylogous amide precursors, the five-membered analogues either reacted nonselectively under various standard hydrogenation conditions, or resisted reduction entirely. An extension of the approach towards the synthesis of a 3″-amino analogue of febrifugine (1) from L-ornithine is discussed in Chapter 4. Several 3-aminated piperidin-2-ones and thiones were prepared, but the subsequent enaminones were stable and characterizable only when the piperidinylidene ring nitrogen was alkylated. However, chemoselective reduction of the enaminone C=C bond in 3-{(E)-3-[(3S)-3- (tert-butoxycarbonylamino)-1-(4-methoxybenzyl)piperidin-2-ylidene]-2-oxopropyl}- quinazolin-4(3H)-one (221), an interesting 3-acylamino dehydro analogue of 1, did not give the desired azafebrifugine, but instead yielded a 5,6,7,8-tetrahydro-1Hpyrido[ 3,2-c][1,2]oxazine derivative. Several approaches to febrifugine (1) itself based on the successful model studies are discussed in Chapter 5. Initially, stereoselective α-bromination and subsequent substitution by oxygen of piperidin-2-ones derived from the chiral auxiliary (S)- phenylglycinol was explored. Unexpected racemization occurred at the α-position of the lactam during this route. A second approach to 3-hydroxypiperidin-2-one from Larginine was also problematic. Finally, the utility of α-hydroxylation methodology (including Davis methodology) on N-substituted piperidin-2-ones was explored. This route yielded a range of 3-oxygenated lactams and thiolactams, many of which displayed optical activity. The crystal structures of several 3-substituted thiolactams were determined and compared. However, attempts to apply the sulfide contraction procedure to these precursors were unsuccessful. Some investigations designed to explore the structural differences between vinylogous amides derived from the quinazoline-containing bromide 105 and thiolactams of different ring sizes are discussed in Chapter 6. Single crystal X-ray diffraction and NMR spectral data are compared for this series of compounds, the results revealing that the enaminone group in the five-membered ring derivative 3- [(3Z)-2-oxo-3-(pyrrolidin-2-ylidene)propyl]quinazolin-4(3H)-one 155 possesses a significantly different electronic distribution to the other analogues in the series.

A variety of heterocyclic alcohols were coupled with silyl ketene acetals and other [pi]-nucleophiles in the presence of trimethylsilyl trifluoromethanesulfonate to provide an array of substituted [beta]-heteroaryl propionates, including those with contiguous quaternary centers. This reaction also proceeds with high diastereoselectivity when the [pi]-nucleophile bears a chiral auxiliary. The formal synthesis of N-methylwelwitindolinone C isothiocyanate, a densely functionalized alkaloid with the ability to reverse multiple drug resistance, was completed featuring several key transformations. The first key transformation consisted of coupling a heterocyclic alcohol with a silyl ketene acetal to give a highly functionalized intermediate. Next, a palladium catalyzed enolate arylation followed by an intramolecular allylic alkylation successfully constructed the bicyclo(4.3.1)decane backbone of the N-methylwelwitindolinone C isothiocyanate. / text