Synthesis of Substituted Tetrahydroquinolines Using Chiral Organolithium Chemistry

The tetrahydroquinoline (THQ) moiety is found in many natural products and compounds which have biological activity. This thesis describes the development of methodologies to carry out lithiation–substitution reactions of N-Boc-2-aryltetrahydroquinolines. Most of the THQ compounds fully deprotonated within a few minutes and the lithiated intermediates were configurationally stable at low temperature. A variety of novel α-substituted products were obtained in good to excellent yields. Kinetic resolutions were attempted using the n-BuLi / (+)-sparteine ‘chiral base’ and a number of the starting materials were recovered in good yields and excellent enantiomer ratios (ers). The enantioenriched recovered starting materials were then used in lithiation-substitution reactions in order to give the α-substituted products in good to excellent yields and ers. When cyanoformates were used as the electrophiles in the lithiation–substitution sequence, the ortho-substituted products were formed as opposed to the α-substituted products obtained when chloroformates were used as the electrophiles. This change in regioselectivity when different electrophiles were used was unprecedented in the area of organolithium chemistry. When triethylborane was added to the lithiated intermediate, an N–C Boc migration was promoted. The secondary amine product was obtained in good yield and in high er when enantioenriched N-Boc-2-phenyl-THQ was used in the reaction. Kinetic resolutions using the n-BuLi / (+)-sparteine ‘chiral base’ have also been attempted on a number of N-Boc-3-aryl-1,2,3,4-tetrahydro-1,4-benzoxazines. While no α-substituted products could be obtained due to β-elimination, the starting materials were recovered from these reactions in good to excellent yields and ers