Diels-Alder/ene reactions of 3-vinyl-1H-indoles : rapid synthesis of unsaturated carbazoles and pyradazino[3,4-b]indoles
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...
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ndltd-bl.uk-oai-ethos.bl.uk-6583392017-04-20T03:21:17ZDiels-Alder/ene reactions of 3-vinyl-1H-indoles : rapid synthesis of unsaturated carbazoles and pyradazino[3,4-b]indolesCowell, Joseph2014Unsaturated 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.615.7University of Newcastle upon Tynehttp://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.658339http://hdl.handle.net/10443/2719Electronic Thesis or Dissertation |
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615.7 Cowell, Joseph Diels-Alder/ene reactions of 3-vinyl-1H-indoles : rapid synthesis of unsaturated carbazoles and pyradazino[3,4-b]indoles |
description |
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. |
author |
Cowell, Joseph |
author_facet |
Cowell, Joseph |
author_sort |
Cowell, Joseph |
title |
Diels-Alder/ene reactions of 3-vinyl-1H-indoles : rapid synthesis of unsaturated carbazoles and pyradazino[3,4-b]indoles |
title_short |
Diels-Alder/ene reactions of 3-vinyl-1H-indoles : rapid synthesis of unsaturated carbazoles and pyradazino[3,4-b]indoles |
title_full |
Diels-Alder/ene reactions of 3-vinyl-1H-indoles : rapid synthesis of unsaturated carbazoles and pyradazino[3,4-b]indoles |
title_fullStr |
Diels-Alder/ene reactions of 3-vinyl-1H-indoles : rapid synthesis of unsaturated carbazoles and pyradazino[3,4-b]indoles |
title_full_unstemmed |
Diels-Alder/ene reactions of 3-vinyl-1H-indoles : rapid synthesis of unsaturated carbazoles and pyradazino[3,4-b]indoles |
title_sort |
diels-alder/ene reactions of 3-vinyl-1h-indoles : rapid synthesis of unsaturated carbazoles and pyradazino[3,4-b]indoles |
publisher |
University of Newcastle upon Tyne |
publishDate |
2014 |
url |
http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.658339 |
work_keys_str_mv |
AT cowelljoseph dielsalderenereactionsof3vinyl1hindolesrapidsynthesisofunsaturatedcarbazolesandpyradazino34bindoles |
_version_ |
1718440198015025152 |