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.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/1743 |
| Date | 15 November 2006 |
| Creators | Pienaar, Daniel Petzer |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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