Synthesis of 4-Acylbenzoxazoles from Indoles and Synthetic Studies Towards the Marine Alkaloid Violatinctamine

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dc.contributor.advisor Sperry, Jonathan
dc.contributor.advisor Leung, Ivanhoe
dc.contributor.author Anderson, Kirsty
dc.date.accessioned 2021-01-18T02:12:35Z
dc.date.available 2021-01-18T02:12:35Z
dc.date.issued 2021 en
dc.identifier.uri https://hdl.handle.net/2292/54293
dc.description.abstract This thesis describes the development of a novel indole to benzoxazole rearrangement enabled by C-H borylation (Chapter 1) and synthetic studies towards the alkaloid violatinctamine (503) (Chapter 2). In Chapter 1, a new route to C4-acylbenzoxazoles has been developed from readily available indoles 202. Iridium-catalysed C-H borylation affords 7-borylindoles 203 that undergoes a one-pot oxidative-hydrolysis of the aryl boronate and oxidative cleavage of the indole 2,3-bond using either m-CPBA or ozone. The resulting o-amidophenols 204 undergo cyclisation to give 4-acylbenzoxazoles 205. A variety of substituents tolerate this process, and the final cyclisation in TFA is compatible with aldehydes, ketones, halogens and the nitro group. The newly developed procedure was also modified to include skatole derivatives, where a diborylation-protodeborylation sequence provides 7-borylindole 392. Subjecting 392 to ozone followed by acidic workup gave o-aminophenol 393. Treatment of 393 with orthoformates gives facile access to benzoxazoles 394 with different substituents at C2. Violatinctamine (503) was isolated from the marine tunicate Cystodytes cf. violatinctus and is composed of a unique benzothiazole-dihydroisoquinoline heteroaromatic core. In Chapter 2, synthetic efforts towards this structurally unprecedented natural product are described. In a model study, the benzothiazole-2-carbaldehyde (605) successfully underwent reaction with m-tyramine (506) to give the heteroaromatic core (616) resulting from a novel biomimetic Pictet-Spengler autoxidation process. With the success of the model study, attention turned to the natural product itself. A first-generation approach to violatinctamine (503) focused on performing the Pictet-Spengler reaction as the last step. In pursuit of the required benzothiazole (514), a biomimetic synthesis of benzothiazole-ester 522 was achieved from N-acetyldopamine (516) and cysteine (520). However, we were unable to convert this compound to the desired aldehyde 514. Our second-generation approach to violatinctamine (503) involved assembling the dihydroisoquinoline using the Pictet-Spengler reaction followed by construction of the dimethylamino side chain. The deacetylation-double reductive amination sequence gave access to synthetic product 503, which we tentatively assigned as the proposed structure of violatinctamine (503). Spectroscopic comparison of the (limited) NMR data for synthetic 503 to the data reported for violatinctamine (503) was inconclusive. However, we discovered that 1H NMR for violatinctamine (503) is virtually identical to that reported for tintamine (498, isolated from the same source and same molecular formula as 503). NMR spectroscopic comparison between synthetic 503 with tintamine (498) showed better agreement.
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.isreferencedby UoA99265331299802091 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.
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.title Synthesis of 4-Acylbenzoxazoles from Indoles and Synthetic Studies Towards the Marine Alkaloid Violatinctamine
dc.type Thesis en
thesis.degree.discipline Chemical Sciences
thesis.degree.grantor The University of Auckland en
thesis.degree.level Doctoral en
thesis.degree.name PhD en
dc.date.updated 2021-01-12T03:27:04Z
dc.rights.holder Copyright: The author en
dc.rights.accessrights http://purl.org/eprint/accessRights/OpenAccess en


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