Type of Document Thesis Author Lee, Joshua William Author's Email Address email@example.com URN etd-05022008-144859 Title Studies Toward the Diastereoselective Semisynthesis of Taxol Degree Master of Science Department Chemistry and Biochemistry, Department of Advisory Committee
Advisor Name Title Robert Holton Committee Chair Gregory Dudley Committee Member Kenneth Goldsby Committee Member Marie Krafft Committee Member Keywords
- Lanthanide Alkoxides
Date of Defense 2008-04-24 Availability unrestricted AbstractABSTRACT
Substantial attention has been given to the synthesis of Taxol due to its cytotoxic activity towards certain cancers. Because of Taxol’s structural complexity, total synthesis of the molecule cannot provide a commercial supply. Its semisynthesis from the more abundant 10-DAB solved the supply problem and allowed the drug to be produced in mass quantities. The key step in the semisynthesis is the attachment of a chiral side chain at C-13 by acylation through the use of a β-lactam.
The coupling reaction with a racemic N-benzoyl β-lactam proved to be diastereoselective giving a 3:1 ratio in favor of Taxol, which means it is possible to attach the chiral side chain by kinetic resolution of the racemic material. However, the separation of Taxol from its epimer proved to be difficult and time consuming
We envisaged that the selectivity could be improved to favor Taxol exclusively. An investigation has been launched to test the potential of this selectivity towards Taxol through the use of aromatic, ethereal and non-aromatic solvents, counter ions and coordination ligands.
This study has revealed that the selectivity can be improved by the use of fluorinated aromatic solvents. Secondly, the counter ion on the C-13 alkoxide has a significant effect on the selectivity. Also, the use of alkoxyamines as coordination ligands increases this selectivity in-favor of Taxol.
Finally, this work has resulted in the improvement in the selectivity to 8:1 in favor of Taxol by the use of fluorinated aromatic solvents, cerium alkoxides, and alkoxyamines as coordination ligands.
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