Unsaturated carbazole frameworks are found in several important naturally occurring and synthetic biologically active compounds. We envisaged synthesising compounds of this type using an intermolecular Diels-Alder reaction between 3-vinyl-1H-indole and a dienophile, followed by an intermolecular ene reaction between the resultant Diels-Alder adduct (6) and an enophile. This route was tested using tosyl protected 3-vinyl-1H-indole (4) and N-methylmaleimide (5) in a Diels- Alder reaction, followed by ene reactions with a range of enophiles to give unsaturated carbazoles (7) in yields of 50-60% over the two steps. Through utilisation of Soos’s organo-catalyst3, we have been able to control the Diels-Alder reaction between 3-vinyl-1H-indole (8) and N-methylmaleimide (5), to form the Diels-Alder adduct (9) with high enantiomeric excess. The subsequent stereospecific ene reaction then gives unsaturated carbazoles (10) in >96% ee. We then developed a sequential “one-pot” Diels-Alder / ene methodology with an Nprotected 3-vinyl-1H-indole (11), a dienophile and an enophile to make unsaturated carbazoles and pyridazino[3,4-b]indoles (13). This methodological approach gave increased overall yields and reduced purification steps. When Cbz N-protected 3-vinyl-1H-indoles were used the Diels-Alder / ene products (14) could then be deprotected through a PtO2 catalysed hydrogenation reaction to give molecules (15). Several of the synthesised compounds (15) showed moderate biological activity against Escherichia coli, Staphylococcus aureus and Schizosaccharomyces pombe. Compounds (15) are also moderate (μM) inhibitors of several important kinases, including Chk2, Aurora B, Src and JAK2, which are potential targets for cancer treatment.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:658339 |
| Date | January 2014 |
| Creators | Cowell, Joseph |
| Publisher | University of Newcastle upon Tyne |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10443/2719 |
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