dc.contributor.advisor |
Sperry, Jonathan |
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dc.contributor.author |
Nabi, Ardalan Ali |
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dc.date.accessioned |
2021-05-27T02:02:16Z |
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dc.date.available |
2021-05-27T02:02:16Z |
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dc.date.issued |
2020 |
en |
dc.identifier.uri |
https://hdl.handle.net/2292/55169 |
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dc.description.abstract |
This thesis describes synthetic efforts towards inducamide C (125) and breitfussin B (107), two alkaloids containing a rare 4-oxy-6-haloindole (highlighted in red)…. Our studies were focused on developing a new route to this unusual indole substitution pattern that could be incorporated into a synthesis of both natural products. Beginning with synthetic studies towards inducamide C (125), 6-chloroindole (290) was subjected to an iridium-catalysed triborylation-diprotodeboronation sequence to give 4-borylindole 292. Oxidative-hydrolysis and O-alkylation gave 4-isopropoxy-6-chloroindole (308), which subsequently converted to the key tryptophan 352 using β-C(sp3)-H arylation methodology in good enantiomeric excess. Coupling of 352 with the chlorosalicylic acid 372 provided 377 that upon Lewis acid-mediated dealkylation followed by ester hydrolysis gave the lactonisation precursor 379. Interestingly, EDC-mediated lactonization gave the oxepinoindole 380, resulting from C4-OH (red arrow) participating in the cyclisation, instead of the desired benzoxazepine 125 resulting from C15-OH (blue arrow) engaging. The NMR spectroscopic data for 380 did not align well with that of inducamide C (125). Subsequent efforts focused on masking the C4-OH to prevent the undesired lactonization pathway. The alternative lactonisation precursor 382 was readily accessed from 377 by selective demethylation followed by ester hydrolysis. EDC-mediated lactonisation gave O-isopropyl inducamide C (383) bearing the desired benzoxazepine. However, deisopropylation gave the previously observed oxepinoindole 380, as resulted in dealkylation followed by rearrangement. Attempts to suppress this rearrangement were unsuccessful. Due to the stability issues associated with the benzoxazepine ring, it was concluded that the natural product might have been misassigned, and focus turned to reassign the chlorosalicylic acid component (highlighted in red). We proposed that the alternative chlorosalicylic acid 387 could possibly arise biosynthetically from an ortho-chlorination (with respect to phenol) of the naturally occurring 6-methylsalicylic acid (131) as opposed to the para-chlorination proposed in the isolation paper. This led us to postulate that the regioisomer 388 could be the true structure of inducamide C. The tryptophanamide 392 was assembled by analogy to chemistry developed previously. Lewis acid-mediated dealkylation followed by ester hydrolysis delivered the lactonisation precursor 393. However, upon subjecting 393 to EDC-mediated cyclisation, only the undesired oxepinoindole 400 was observed, the same outcome as observed in our work towards the initially proposed structure. To date, the correct structure of inducamide C (125) remains unsolved. The net C4-alkoxylation of indole methodology that developed during synthetic studies towards inducamide C (125) was incorporated into a formal synthesis of breitfussin B (107). The iridium-catalysed C-H triborylation of 6-bromoindole (417) gave 2,4,7- triboryl-6-bromoindole (418) that upon bismuth-catalysed diprotodeboronation followed by Chan-Evan-Lam coupling with methanol gave 4-methoxy-6-bromoindole (108). The indole 108 was readily converted to amide 120, thus completing a formal synthesis of breitfussin B. |
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dc.publisher |
ResearchSpace@Auckland |
en |
dc.relation.ispartof |
PhD Thesis - University of Auckland |
en |
dc.relation.isreferencedby |
UoA |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. |
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dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.rights.uri |
http://creativecommons.org/licenses/by-nc-sa/3.0/nz/ |
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dc.title |
Synthetic Studies Towards Inducamide C and Breitfussin B |
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dc.type |
Thesis |
en |
thesis.degree.discipline |
Chemical Sciences |
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thesis.degree.grantor |
The University of Auckland |
en |
thesis.degree.level |
Doctoral |
en |
thesis.degree.name |
PhD |
en |
dc.date.updated |
2021-05-21T01:25:43Z |
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dc.rights.holder |
Copyright: The author |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |
dc.identifier.wikidata |
Q112953190 |
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