Systhesis and characterizationof analogues of the antimalaria alkaloid febrifugine

[摘要] The subject of this thesis is the development of a potentially simple, general andeconomical synthetic protocol for the potent antimalarial alkaloid febrifugine (1) andits analogues. In Chapter 1, the interesting history of 1, which includes a descriptionof several reported total syntheses of 1, is discussed. Natural products derived from 1,as well as promising synthetic derivatives that display good antimalarial activity, arealso discussed. The structure-activity relationships determined to date for 1 and itsderivatives are presented in order to substantiate the need for the development of newsynthetic 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 theUniversity 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 commonlyencountered alkaloidal molecular skeletons. The chosen approach to 1 is based onreaction 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 thefeasibility of the synthetic strategy. These studies resulted in a new preparation of thekey bromide 105 and a new and efficient synthesis of (±)-deoxyfebrifugine (14).Enaminone analogues derived from five-, seven-, eight-, nine- and thirteen-memberedthiolactams were also prepared for comparison. An interesting difference in thesensitivity of the five- and six-membered model cyclic vinylogous amides towardsreducing agents was observed. Whereas three piperidine analogues of 14 could beprepared in high yields by the chemoselective hydrogenation of six-membered cyclicvinylogous amide precursors, the five-membered analogues either reacted nonselectivelyunder various standard hydrogenation conditions, or resisted reductionentirely.An extension of the approach towards the synthesis of a 3″-amino analogue offebrifugine (1) from L-ornithine is discussed in Chapter 4. Several 3-aminatedpiperidin-2-ones and thiones were prepared, but the subsequent enaminones werestable 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, didnot 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 arediscussed in Chapter 5. Initially, stereoselective α-bromination and subsequentsubstitution by oxygen of piperidin-2-ones derived from the chiral auxiliary (S)-phenylglycinol was explored. Unexpected racemization occurred at the α-position ofthe lactam during this route. A second approach to 3-hydroxypiperidin-2-one from Largininewas also problematic. Finally, the utility of α-hydroxylation methodology(including Davis methodology) on N-substituted piperidin-2-ones was explored. Thisroute yielded a range of 3-oxygenated lactams and thiolactams, many of whichdisplayed optical activity. The crystal structures of several 3-substituted thiolactamswere determined and compared. However, attempts to apply the sulfide contractionprocedure to these precursors were unsuccessful.Some investigations designed to explore the structural differences betweenvinylogous amides derived from the quinazoline-containing bromide 105 andthiolactams of different ring sizes are discussed in Chapter 6. Single crystal X-raydiffraction and NMR spectral data are compared for this series of compounds, theresults 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 asignificantly different electronic distribution to the other analogues in the series.

[发布机构] University of the Witwatersrand