Kinetic resolution by lithiation of substituted 1,2-dihydroquinolines and dihydrobenzoxazines

The dihydroquinoline (DHQ) moiety is found in many compounds which have biological activity. This thesis discusses the lithiation-substitution reactions of 2-aryl DHQs with a variety of electrophiles, which react at the 4-position. The DHQ compounds synthesised in this thesis were fully deprotonated within a few minutes and the lithiated intermediates were configurationally stable at low temperature. Kinetic resolutions were attempted using n-BuLi/sparteine chiral base and the starting materials were recovered in good yield and excellent enantiomer ratios (ers). Lithiation-substitution of enantioenriched recovered starting material occurred with retention of configuration.
Lithiation-substitution of enantioenriched 4-methyl-2-phenyl-1,2-DHQ obtained by kinetic resolution gave enantioenriched 2,4,4-trisubstituted products. Both enantiomers of highly enantioenriched 2,4,4-trisubstituted-1,4-DHQs can be obtained from the same enantiomer of sparteine.
Hydrogenation by reduction of the 1,4-DHQ gave 2,4-disubstituted tetrahydroquinoline as cis- product. The Boc protecting group was removed under acidic conditions and by oxidation 2,4-disubstituted quinoline was prepared. This was applied to a short synthesis of the anti-malarial drug M5717.
Lithiation-electrophilic quench reactions and kinetic resolution of N-Boc-2-alkyl-DHQs were also attempted. However, poor results were obtained and was not studied further.
Enantioenriched 7,8-difluoro-3-phenyl-benzoxazine obtained by kinetic resolution was used to synthesise an analogue of antibiotic levofloxacin which was screened for its activity.