University of Leicester
U521709.pdf (11.3 MB)

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

Download (11.3 MB)
posted on 2014-12-15, 10:35 authored by Carla M Jones
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.


Date of award


Author affiliation


Awarding institution

University of Leicester

Qualification level

  • Doctoral

Qualification name

  • PhD



Usage metrics

    University of Leicester Theses


    No categories selected



    Ref. manager