Structural modification of cinchona alkaloids for the synthesis of novel chiral fluorinating agents

The diastereoisomers 8-fluoroquininone and 8-fluoroquinidinone were synthesised, separated and their structures were determined by HOESY spectroscopy and X-ray crystallography. The addition of a methyl group to the carbonyl of 8-fluoroquinidinone led to a single diastereoisomer of 8-fluoro-9-methyl quinidine and NOESY spectroscopy confirmed the 8-(S), 9-(S) configuration. Although the introduction of fluorine at the C8 position prevented the mutarotation of the ketones in solution, the strong electron-withdrawing effect of the fluorine also reduced the nucleophilicity of the quinuclidine nitrogen.;A small library of new derivatised cinchona alkaloids containing a quaternary carbon at the C9 position were synthesised in three steps. After oxidising quinine to quinidinone, the diastereoselective addition of a Grignard reagent to the ketone was developed and the hydroxyl function was protected in the third step. The stereochemistry at the C8 and C9 positions of 9-methylquinidine and the novel 9-phenylquinidine were determined by NOESY spectroscopy and the 8-(R) and 9-(S) configurations were assigned. Finally, the quinuclidine nitrogen of the new quinidine analogues was fluorinated using Selectfluor and NFSI for the synthesis of novel asymmetric fluorinating agents.;The novel modified cinchona alkaloids were screened in the asymmetric fluorinations of the beta-ketoesters, ethyl 1-indanone-2-carboxylate and tert-butyl 1-indanone-2-carboxylate, and the acyclic ester, alpha-cyano- p-tolylacetic acid. High isolated yields were obtained in most cases and both 9-methylquinidine and 9-phenylquinidine gave comparable, if slightly better, enantioselectivities compared to quinidine.;The ease at which the derivatised quinidines could be quaternised was also investigated leading to the synthesis of two novel quaternary ammonium salts, N-benzyl-9-methylquinidinium bromide and N-benzyl-O-acetyl-9-methylquinidinium bromide. This new class of chiral quaternary ammonium salts could potentially be used in asymmetric phase transfer catalysis.