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Studies towards the synthesis of the caulamidine core
Thesis (PhD)--Stellenbosch University, 2021.
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2022
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| _version_ | 1867613740253315072 |
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| access_status_str | Open Access |
| author | Jurisch, Christopher David |
| author2 | Arnott, Gareth E. |
| author_browse | Arnott, Gareth E. Jurisch, Christopher David |
| author_facet | Arnott, Gareth E. Jurisch, Christopher David |
| author_sort | Jurisch, Christopher David |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2021. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/125162 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:40:56.936Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2022 |
| publishDateRange | 2022 |
| publishDateSort | 2022 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/125162 Studies towards the synthesis of the caulamidine core Jurisch, Christopher David Arnott, Gareth E. Van Otterlo, Willem A. L. Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. Medicinal plants -- Biotechnology Natural products Drug development Molecular pharmacology UCTD Thesis (PhD)--Stellenbosch University, 2021. ENGLISH ABSTRACT: Caulamidines A and B are trihalogenated marine alkaloids isolated from the bryozoan Caulibugula intermis that have an unprecedented structural scaffold. These compounds were shown to be nontoxic to human cells and displayed low micromolar antiplasmodial activities against both wild-type and drug-resistant strains of P. falciparum. Researchers have recently fully elucidated the complex carbon and nitrogen framework of these compounds. Although they have been isolated and fully characterised, the synthesis of caulamidines A and B has not yet been reported in the chemical literature. This provided an excellent opportunity to lay a foundation for the synthesis of these novel marine alkaloids and their analogues. Plans were therefore put into place to develop methods for the synthesis of the dimeric, hexacyclic amidine core structure of caulamidines A and B. The primary aim of this study was to synthesise a novel naphthyridine-1,5-dione that was envisaged to be a key precursor to the caulamidine core. The successful synthesis of this compound could provide access to a core scaffold that has the potential to serve as a synthetic building block for further functionalisation. Two synthetic strategies with slightly different disconnections were devised and investigated for the synthesis of the naphthyridine-1,5-dione precursor. The conjugate addition of a cyanomethyl nucleophile to the alkyne moiety of dimethylacetylene dicarboxylate, a key step of the primary synthetic strategy, was unfortunately unsuccessful despite extensive efforts. Focus was therefore shifted to the secondary synthetic strategy, which involved a Diels-Alder cycloaddition approach. Important findings were made along this route, and two novel dialdehyde dibisulfite adducts were synthesised. However, the secondary synthetic strategy was also ultimately unsuccessful. The secondary aim of the project was to investigate bond formation strategies for the synthesis of the caulamidine quaternary carbon centers, structural elements that were envisaged to be key for the synthesis of these compounds. A novel hexacyclic target compound that resembled the caulamidine core structure was identified and disconnected retrosynthetically to an enedione that mimicked the original naphthyridine-1,5-dione precursor. The enedione served as a model for quaternary carbon center formation and was successfully synthesised according to literature procedures. The primary strategy for the synthesis of the first quaternary carbon center via conjugate addition was thoroughly investigated but was unsuccessful. The first four rings of the target hexacyclic model compound were subsequently installed via an alternative indole-based strategy, which marked the successful synthesis of the first quaternary carbon center and a new hexahydrobenzo[d]carbazole derivative that was fully characterised as a new compound. Oxidation of this compound afforded a target hexahydrobenzo[d]carbazolone that has only been reported once before and was therefore fully characterised for the first time using modern analytical techniques. The subsequent synthesis of a key thermodynamic silyl enol ether was unsuccessful, which meant that the current synthetic strategy could not be investigated further. Focus was therefore shifted, and important foundations were laid for the synthesis of the dihydroquinoline fragment. AFRIKAANSE OPSONNING: Caulamidiene A en B is trihalogeneerde mariene alkaloïede geïsoleer vanaf die bryozoan Caulibugula intermis wat 'n ongekende strukturele steierwerk het. Hierdie verbindings is getoon om nie-toksi es vir menslike selle te wees en het lae mikromolar antiplasmodiale aktiwiteite teen beide wilde-tipe en dwelmbestande stamme van P. falciparum vertoon. Navorsers het onlangs die komplekse koolstof- en stikstofraamwerk van hierdie verbindings ten volle ontwyk. Alhoewel hulle geïsoleer en ten volle gekenmerk is, is die sintese van caulamidiene A en B nog nie in die chemiese literatuur aangemeld nie. Dit het 'n uitstekende geleentheid gebied om 'n grondslag te lê vir die sintese van hierdie nuwe mariene alkaloïede en hul analoë. Planne is dus in plek gestel om metodes te ontwikkel vir die sintese van die dimeriese, heksasiklies amidien kernstruktuur van caulamidiene A en B. Die primêre doel van hierdie studie was om 'n nuwe naphthyridien-1,5-dioon te sintetiseer wat beoog is om 'n belangrike voorloper van die caulamidien kern te wees. Die suksesvolle sintese van hierdie verbinding kan toegang bied tot 'n kernsteierwerk wat die potensiaal het om as 'n sintetiese boublok vir verdere funksionalisering te dien. Twee sintetiese strategieë met effens verskillende ontkoppelings is ontwerp en ondersoek vir die sintese van die naphthyridien-1,5-dioon voorloper. Die samevoeging van 'n ianometiel nukleofiel tot die alkyngroep van dimetielasetileen dikarboksilaat, 'n belangrike stap van die primêre sintetiese strategie, was ongelukkig onsuksesvol ten spyte van uitgebreide pogings. Fokus is dus verskuif na die sekondêre sintetiese strategie wat 'n Diels-Alder-siklisasie behels het. Belangrike bevindings is tydens hierdie roete gemaak, en twee nuwe dialdehied dibisulfiet addukte is gesintetiseer. Die sekondêre sintetiese strategie was egter ook uiteindelik onsuksesvol. Die sekondêre doel van die projek was om verbandvormingstrategieë te ondersoek vir die sintese van die caulamidien kwaternêre koolstofsentrums, strukturele elemente wat beoog is om die sleutel vir die sintese van hierdie verbindings te wees. 'n Nuwe heksasikliese teikenverbinding wat lyk soos die caulamidien kernstruktuur is geïdentifiseer en retrosinteties ontkoppel aan 'n eendioon wat die oorspronklike naphthyridien-1,5-dioon voorloper. Die eendioon het gedien as 'n model vir kwaternêre koolstofsentrumvorming en is suksesvol gesintetiseer volgens literatuurprosedures. Die primêre strategie vir die sintese van die eerste kwaternêre koolstofsentrum via gekonjugeerde toevoeging is deeglik ondersoek, maar was onsuksesvol. Die eerste vier ringe van die teiken heksasikliese modelverbinding is daarna geïnstalleer via 'n alternatiewe indool-gebaseerde strategie, wat die suksesvolle sintese van die eerste kwaternêre koolstofsentrum en 'n nuwe heksahidrobenzo[d]karbasool afgeleide wat ten volle gekenmerk is as 'n nuwe verbinding gemerk. Oksidasie van hierdie verbinding het 'n teiken hexahidrobenzo[d]karbazoloon opgegee wat net een keer tevore aangemeld is en is dus ten volle gekenmerk vir die eerste keer met behulp van moderne analitiese tegnieke. Die daaropvolgende sintese van 'n sleutel termodinamiese silyl enol eter was onsuksesvol, wat beteken het dat die huidige sintetiese strategie nie verder ondersoek kon word nie. Fokus is dus verskuif, en belangrike fondamente is gelê vir die sintese van die dihidrokinolien fragment. Doctoral 2022-01-17T09:42:10Z 2022-04-29T12:56:45Z 2023-01-04T03:00:07Z 2021-09 Thesis http://hdl.handle.net/10019.1/125162 en_ZA Stellenbosch University 187 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Medicinal plants -- Biotechnology Natural products Drug development Molecular pharmacology UCTD Jurisch, Christopher David Studies towards the synthesis of the caulamidine core |
| title | Studies towards the synthesis of the caulamidine core |
| title_full | Studies towards the synthesis of the caulamidine core |
| title_fullStr | Studies towards the synthesis of the caulamidine core |
| title_full_unstemmed | Studies towards the synthesis of the caulamidine core |
| title_short | Studies towards the synthesis of the caulamidine core |
| title_sort | studies towards the synthesis of the caulamidine core |
| topic | Medicinal plants -- Biotechnology Natural products Drug development Molecular pharmacology UCTD |
| url | http://hdl.handle.net/10019.1/125162 |
| work_keys_str_mv | AT jurischchristopherdavid studiestowardsthesynthesisofthecaulamidinecore |