2013WilliamsRLphd.pdf (8.52 MB)
Synthesis and Applications of Structurally Modified Cinchona Alkaloid Derivatives
thesisposted on 2013-09-13, 10:48 authored by Rebecca Louise Williams
Quinidinone was formed diastereoselectively from quinine and reacted with a variety of nucleophiles to produce a series of 9-substituted quinidine analogues. The configuration at the C9 position was determined to be (S) by X-ray crystallography, which supports the proposed chelation control mechanism of nucleophilic addition to quinidinone. Hydrogenation of the C10-C11 double bonds of the new compounds also allowed access to a series of 9-substituted-10,11-dihydroquinidine derivatives. 8-Fluoroquinidinone and 8-fluoroquininone were prepared from quinidinone, and both were reacted independently with nucleophiles to produce a series of 9-(R)-substituted-8-(S)-fluoro-epi-quinidines and 9-(S)-substituted-8-(R)-fluoro-epi-quinines, the configurations of which were confirmed by X-ray crystallography, supporting a Felkin-Ahn type mechanism for nucleophilic addition to 8-fluoroquinidinone and 8-fluoroquininone. A small series of 9-(R)-substituted-8-(S)-fluoro-10,11-dihydro-epiquinidines were also synthesised by hydrogenation of the C10-C11 double bonds in the corresponding 9-(R)-substituted-8-(S)-fluoro-epi-quinidine derivatives. All of the novel Cinchona alkaloid derivatives were screened as enantioselective electrophilic fluorinating reagents in the asymmetric fluorination of ethyl-1-indanone-2-carboxylate. Moderate enantioselectivities were achieved; the best, 64% enantiomeric excess, was obtained with 9-phenyl-8-fluoro-10,11-dihydro-epi-quinidine and was a significant improvement on the 30% enantiomeric excess obtained using quinidine. Excellent enantioselectivities were obtained when the novel Cinchona derivatives were screened as chiral aminoalcohol ligands in the enantioselective addition of diethylzinc to benzaldehyde. The best enantiomeric excess achieved was 92%, using 9-(3,5-bis-trifluoromethylphenyl)-10,11-dihydroquinidine. Preliminary screening of antimalarial activity has revealed that five of the novel Cinchona alkaloid derivatives possess antimalarial activity against the Plasmodium falciparum parasite. The active Cinchona alkaloid derivatives all contained either a fluorine atom at the C8 position or a trifluoromethyl group on the aromatic ring of the 9-aryl quinidine or 9-aryl-10,11-dihydroquinidine derivatives.
Date of award2013-07-31
Awarding institutionUniversity of Leicester