UVM Theses and Dissertations
Format:
Print
Author:
Ganorkar, Rakesh R.
Dept./Program:
Chemistry
Year:
2006
Degree:
PhD
Abstract:
The two main projects for this thesis were: the synthesis of proline templated lysine and the studies towards the total synthesis of the naturally occurring iboga alkaloids, viz., 3-hydroxy-3,4-secocoronaridine and catharanthine. The poly-L-proline type I1 (PPII) secondary structure is a critical recognition element in mediating protein-protein interactions and thereby regulating cellular signaling. Therefore the design of PPII mimics is highly desirable, as they can potentially be used as chemotherapeutic agents. These PPII mimics can be obtained from peptides constructed of proline templated amino acids. In our ongoing efforts towards the design and synthesis of such PPII mimics, we have synthesized the 4-substituted proline templated lysine in 8 easy steps starting from commercially available materials, with an overall yield of more than 25%. The key feature of our strategy included a one pot stereoselective reduction of a double bond, accompanying the reduction of a nitrile group to the corresponding amine with simultaneous protection of the newly generated primary amine. Proper selection of protecting groups and the sequence of the reactions were instrumental towards the synthesis. This unnatural amino acid was then incorporated into a peptide chain and PKG binding studies were conducted.
The second project of this thesis involved studies toward the synthesis of naturally occurring iboga alkaloids. This study mainly involved investigating the scope of a novel Diels-Alder reaction towards the synthesis of various iboga alkaloids, especially, catharanthine and 3-hydroxy-3, 4-secocoronaridine. It had been shown that some of the congeners of catharanthine displayed some anti-addiction activities; hence we wanted to screen various other iboga alkaloids. In order to do so we required a general synthetic methodology which could be utilized in the synthesis of these alkaloids. A novel intramolecular Diels-Alder reaction proved to be the method of choice. Employing this Diels-Alder reaction on substrates of various kinds, one can generate the tetracyclic core common to the structure of most of the iboga alkaloids. This key reaction involved a onepot pyrolysis of indoloazepine, followed by its coupling with an iodide or aldehyde to generate an intermediate (which has both the functionalities of a diene and a dienophile), which undergoes the intramolecular Diels-Alder reaction. This reaction sets three stereocenters of the teracycle. Herein we investigated the novel reaction for various substrates including iodoester, aldehyde-ester and thio-ketal aldehyde. Multigram quantities of these substrates were prepared. Apart from these, a few other interesting routes to achieve the total synthesis of catharanthine using similar Diels-Alder reaction were explored.
The second project of this thesis involved studies toward the synthesis of naturally occurring iboga alkaloids. This study mainly involved investigating the scope of a novel Diels-Alder reaction towards the synthesis of various iboga alkaloids, especially, catharanthine and 3-hydroxy-3, 4-secocoronaridine. It had been shown that some of the congeners of catharanthine displayed some anti-addiction activities; hence we wanted to screen various other iboga alkaloids. In order to do so we required a general synthetic methodology which could be utilized in the synthesis of these alkaloids. A novel intramolecular Diels-Alder reaction proved to be the method of choice. Employing this Diels-Alder reaction on substrates of various kinds, one can generate the tetracyclic core common to the structure of most of the iboga alkaloids. This key reaction involved a onepot pyrolysis of indoloazepine, followed by its coupling with an iodide or aldehyde to generate an intermediate (which has both the functionalities of a diene and a dienophile), which undergoes the intramolecular Diels-Alder reaction. This reaction sets three stereocenters of the teracycle. Herein we investigated the novel reaction for various substrates including iodoester, aldehyde-ester and thio-ketal aldehyde. Multigram quantities of these substrates were prepared. Apart from these, a few other interesting routes to achieve the total synthesis of catharanthine using similar Diels-Alder reaction were explored.