UVM Theses and Dissertations
Format:
Print
Author:
Potter, Rachel Aranha
Dept./Program:
Chemistry
Year:
2009
Degree:
Ph. D.
Abstract:
This dissertation describes the development of the novel 1,3-diaza Claisen rearrangement with a focus on investigating the electronic and structural factors that influence the transformation.
This work builds upon our previous work on the 1,3-diaza Claisen reactions of azanorbomene derived compounds with isocyanates/ isothiocyanates to yield bicyclic ureas and thioureas. It was found that the reaction in the case of the azanorbomene derivatives were relatively facile which is presumably due to the destabilization of the reactants due to strain. Interestingly, attempts to effect this transformation with simpler tertiary allylic amines (N, N-dimethylallylamine and triallylamine) did not afford rearrangement product, instead evaluation of more forcing conditions resulted in isocyanate decomposition. NMR experiments performed revealed that the reaamagement involves a fast and reversible addition step followed by a slow rearrangement step. Thus, experiments were designed to lower the energy of activation for the rearrangement step.
These efforts included, increasing the electrophilicity of the heterocumulene, carrying out the reaction at a higher temperature and using tertiary allylic amines bearing an electron-withdrawing group on the alkene. The latter experiments demonstrated that tertiary allylic amines bearing an electron withdrawing substitutent result in an accelerated rearrangement. Competition experiments performed to investigate the influence of the alkene electron-withdrawing substitutent on the rate of the rearrangement suggest that the electronic effect may be offset by the steric effect.
During the course of this work, it was observed that the isourea/isothiourea product could undergo a complete isomerization to the corresponding urea/thiourea product in the presnce of' excess heterocumulene and heat. We propose an ionic mechanism for the observed isomerization. The isomerization process was further simplified by the use of a catalytic amount of Lewis acid. Additionally, to examine the limitations and probe the scope of the reaction, experiments aimed at correlating the ring strain and reactivity in azanorbomene and azabicyclooctene derived substrates were undertaken. The experimental results combined with theoretical evaluations confirm that less strained substrates like the aza-bicyclo[2.2.2]octene are less reactive toward the 1,3-diaza Claisen rearrangement. Even more impressively the experimental results suggest that the concentration of the reactive conformer is an important factor in controlling the reactivity and selectivity of the substrates in the rearrangement process.
Using the lead peptide sequence LRKKKKKH, a potent and selective inhibitor of cyclic GMP-dependent protein kinase PKG we have been successful in the synthesis of a few peptide -peptoid hybrids in which the lysine residues have been replaced by the peptoid lysine analogue. Herein, we describe a preliminary investigation into the effects of altering the peptidic backbone on PKG inhibition and its role in platelet activation.
This work builds upon our previous work on the 1,3-diaza Claisen reactions of azanorbomene derived compounds with isocyanates/ isothiocyanates to yield bicyclic ureas and thioureas. It was found that the reaction in the case of the azanorbomene derivatives were relatively facile which is presumably due to the destabilization of the reactants due to strain. Interestingly, attempts to effect this transformation with simpler tertiary allylic amines (N, N-dimethylallylamine and triallylamine) did not afford rearrangement product, instead evaluation of more forcing conditions resulted in isocyanate decomposition. NMR experiments performed revealed that the reaamagement involves a fast and reversible addition step followed by a slow rearrangement step. Thus, experiments were designed to lower the energy of activation for the rearrangement step.
These efforts included, increasing the electrophilicity of the heterocumulene, carrying out the reaction at a higher temperature and using tertiary allylic amines bearing an electron-withdrawing group on the alkene. The latter experiments demonstrated that tertiary allylic amines bearing an electron withdrawing substitutent result in an accelerated rearrangement. Competition experiments performed to investigate the influence of the alkene electron-withdrawing substitutent on the rate of the rearrangement suggest that the electronic effect may be offset by the steric effect.
During the course of this work, it was observed that the isourea/isothiourea product could undergo a complete isomerization to the corresponding urea/thiourea product in the presnce of' excess heterocumulene and heat. We propose an ionic mechanism for the observed isomerization. The isomerization process was further simplified by the use of a catalytic amount of Lewis acid. Additionally, to examine the limitations and probe the scope of the reaction, experiments aimed at correlating the ring strain and reactivity in azanorbomene and azabicyclooctene derived substrates were undertaken. The experimental results combined with theoretical evaluations confirm that less strained substrates like the aza-bicyclo[2.2.2]octene are less reactive toward the 1,3-diaza Claisen rearrangement. Even more impressively the experimental results suggest that the concentration of the reactive conformer is an important factor in controlling the reactivity and selectivity of the substrates in the rearrangement process.
Using the lead peptide sequence LRKKKKKH, a potent and selective inhibitor of cyclic GMP-dependent protein kinase PKG we have been successful in the synthesis of a few peptide -peptoid hybrids in which the lysine residues have been replaced by the peptoid lysine analogue. Herein, we describe a preliminary investigation into the effects of altering the peptidic backbone on PKG inhibition and its role in platelet activation.