Abstract:
(+)-Febrifugine is a potential antimalarial quinazolinone alkaloid isolated from the roots and leaves of Dichroa febrifuga and Hydrangea umbellata. A synthetic strategy to febrifugine has been designed that utilizes a chiral-pool derived 3-benzyloxy-3,4,5,6- tetrahydropyridine A-oxide 181a as a key intermediate.
3-Hydroxy-3,4,5,6-tetrahydropyridine A-oxides are synthesized from L-glutamic acid in seven steps. Diazotisation of L-glutamic acid 161 with sodium nitrite in aqueous hydrochloric acid gave lactone 176, which underwent acid catalyzed esterification to give hydroxydiester 160. The hydroxy group of the hydroxydiester 160 was protected using benzyl bromide to provide the benzyl ether 177. Reduction of compound 177 by lithium aluminium hydride afforded diol 178, which was subjected to standard tosylation conditions to give 1,5-ditosylate 179. Cyclization of 179 proceeded, in the presence of hydroxylamine hydrochloride in a basic medium, to provide A-hydroxy-3-benzyloxypiperidine 180, which was oxidized using manganese dioxide to give a mixture of readily separable regioisomeric nitrones 181a and 181b in a 6:1 ratio, respectively.
The chemistry of intermediate 181a was probed by investigation of reactions with dipolarophiles and nucleophiles. Cycloaddition of nitrone 181a and styrene provided a 3a,4- trans and -cis isoxazolidine, 213a and 213b respectively, in a ratio of 2:1 in favour of the trans-isomer in an excellent overall yield. The addition proceeded with a complete exoselectivity and perfect regioselectivity. The major 3a,4-trans isoxazolidine 213a resulted from an exo/anti approach of the reactants. No trace of products arising from an endo
approach of reactants was detected. Cycloaddition of nitrone 181a and 2-(trimethylsilyloxy) propene provided two 3a,4-trans and a -cis isoxazolidine 220a, 220c and 220b, respectively, in a moderate overall yield. The addition proceeded with exo/endo- and antz/syn-selectivity in a ratio of 3.6:1 and 2.4:1, respectively, and 100% regioselectivity. In a similar fashion to isoxazolidine 213a, the major 3a,4-tra«s isoxazolidine 220a resulted from an exo/anti approach of the reactants. Nucleophilic addition of allylmagnesium bromide to nitrone 181a proceeded with a complete fra«s-selectivity, to generate adduct 229. In a similar fashion, addition of ethylmagnesium bromide to nitrone 181a provided adduct 230 as the sole product of the reaction. However, both additions proceeded in low yield.
The final part of this thesis discusses a convergent approach to (+)-febrifugine that centres on the ring-opening of isoxazolidine 235a, formed by stereo- and regioselective 1,3- dipolar cycloaddition of yV-allylquinazolone 157 to chiral optically active 3-benzyloxy- 3,4,5,6-tetrahydropyridine tV-oxide 181a. N-0 Bond cleavage of isoxazolidine 235a provided alcohol 239, which was protected by di-tert-butyl dicarbonate to give a Bocprotected 3-hydroxyamine 241. Oxidation of alcohol 241 gave TV-Boc, O-benzyl protected febrifugine 242, which underwent deprotection under acidic conditions to provide (+)- febrifugine 20 as the final product in 67% yield.