Titanocene as a Bifunctional Catalyst for the Rapid Assembly of All-Carbon Tertiary Centers
Developing solutions for the construction of biologically active compounds lies at the heart of the field of synthetic organic chemistry. In particular, methods that allow for the efficient assembly of multiple C–C bonds in a single process greatly increase synthetic efficiency. The calyxins, a family of curcumin-derived, diarylheptanoid natural products containing all-carbon tertiary centers have not been examined as anti-cancer agents due to their limited bioavailability. A method that allows for the efficacious synthesis of curcumin and calyxin analogs will permit their evaluation as potential chemotherapeutics.
This dissertation describes the development of a multicomponent coupling that uses catalytic titanocene to generate all-carbon tertiary centers from readily accessible aromatic aldehyde starting materials. Iodoalkynes and silyl enol ethers are harnessed as nucleophiles to construct symmetrical 1,4-diynes, unsymmetrical 1,4-diynes, and b-alkynyl carbonyls in a single operation. This seminal work has laid the foundation for further work in our group by Gianino and Lepore to construct diarylethynyl methanes and 1,5-enynes, respectively. Intriguing, strain-driven ring openings and expansions are observed with cyclopropane and cyclobutane carboxaldehyde starting materials. In these cases, iodide incorporation leads to the formation of 1,3-iodoenynes instead of the expected three component coupling products.
Our titanocene-catalyzed multicomponent coupling protocol has been applied as a key step in work towards the synthesis of the trimethoxy analog of calyxin L. Modification of each coupling partner also allows for the strategic design and examination of a diverse array of curcumin-derived arylheptanoid analogs. C1 and C3 aryl-substituted analogs of curcumin have been constructed with two of the C3-arylated analogs showing mM activity against a series of glioblastoma and neuroblastoma cell lines. In vitro toxicity to hematopoietic cells was not observed, providing a foundation for the synthesis of diarylheptanoid analogs that are cytotoxic to brain and peripheral nervous system cancers.
History
Date Created
2016-05-04Date Modified
2019-02-19Defense Date
2016-01-04Research Director(s)
Brandon L. AshfeldCommittee Members
Kenneth W. Henderson Paul Helquist Xavier CrearyDegree
- Doctor of Philosophy
Degree Level
- Doctoral Dissertation
Language
- English
Program Name
- Chemistry and Biochemistry