Total Synthesis of Lasionectrin and Synthetic Studies Towards Pestaloxazine A

This thesis describes our efforts towards the synthesis of two natural products which exhibit promising biological activity and is therefore divided in two parts. Part one describes the first enantioselective synthesis and structural confirmation of naphthopyrone lasionectrin (13), which was extracted from the fungus Lasionectra sp. and exhibited antimalarial activity (IC50 = 11 μM). Lasionectrin (13) is a naphthalene derivative which contains a fused pyrone-tetrahydrofuran ring system. Several synthetic strategies were explored to prepare the carbon skeleton of lasionectrin (13). Our initial approach which hinged on formation of the fused bicycle in a single step using chiral hypervalent iodine was ultimately unsuccessful. Our revised synthetic route to lasionectrin (13) involved late-stage installation of the fused pyrone-tetrahydrofuran ring system via tandem dihydroxylation-tosylate displacement beginning from alkene 199, followed by a carboxylation-cyclisation sequence. Key alkene 199 was efficiently assembled with high stereoselectivity from aldehyde 129 and sulfone 119 using a Julia-Kocienski olefination. Part two details our synthetic efforts towards the synthesis of pestaloxazine A (208). Natural product 208 was extracted from a marine-derived fungus belonging to the Pestalotiopis genus, and exhibited antiviral activity against EV71 (IC50 = 16.1 μM). Pestaloxazine A (208) is a racemic alkaloid dimer which contains a unique spiro[1,2-oxazinane-diketopiperazine] moiety. We sought to access the 1,2-oxazinane ring system by the application of oxidative radical cyclisation conditions to a N-hydroxylamine precursor. Our initial synthetic strategy hinged on the preparation of the diketopiperazine ring system prior to installation of the 1,2-oxazine moiety, which was ultimately unsuccessful. Our revised approach involved Mitsunobu reaction of known alcohol 291 and hydroxamate 311 to give hydroxamic acid 309. However, attempts to effect 1,6-hydrogen abstraction with hydroxamic acid 309 to provide the 1,2-oxazine ring system were unsuccessful.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Chemical Sciences

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2016

Author dc:creator

• Poral, Vincent

Advisors dc:contributor.advisor

• Brimble, MA
• Furkert, DP

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.

Licence dc:rights.uri

• https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm

Handle dc:identifier.uri

https://hdl.handle.net/2292/32338

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/32338