Synthetic Studies towards Opaliferin, a Tetracyclic Polyketide Metabolite

Opaliferin (12) was originally isolated and characterised from an entomopathogenic fungus of Cordyceps sp. NBRC 106954 by the Grudniewska group in 2014. The fungus Cordyceps sp. is a single ascospore isolated from a fruiting body found on the larvae of Meimuna opalifera also known as Walker’s cicada. Opaliferin (12) possesses interesting structural features, which are a 5,5-spiroketal centre, and a functionalised THF ring connected by an external alkene to the cyclopentanone ring. To date, it has only been reported elsewhere in oudenone (31) that has similar exo-alkene THF structural motif. Our initial retrosynthetic strategy was devised around the acid-catalysed spirocyclisation of advanced intermediate 201, which was anticipated to be assembled via modular synthetic strategy. With this strategy, compounds 204 and 274 were identified as key precursors. Dihydrofuran 204 was able to be accessed efficiently based on a recent established literature method, but allylation of dihydrofuran 204 proved unsuccessful. Our focus then shifted to access compound 274. Despite successfully synthesising compound 272 from alkene 176, bromination of compound 272 afforded only complex mixture. Another strategy to synthesise compound 274 via Julia-Kocienski reaction was investigated. Both coupling partner aldehyde 282 and sulfone 295 were able to be synthesised efficiently, but the Julia-Kocienski reaction proved unproductive. Given these problems, an alternative strategy was proposed based on Au(I)-catalysed cyclisation of dihydroxyalkyne substrate to access opaliferin (12). Accordingly, the key diols 357a,b were successfully assembled stereoselectively, from alkyne 340 and aldehydes 185a,b over several steps. Disappointingly, the attempted spirocyclisation of diols 357a,b proved to be challenging, despite screening of reaction conditions, as furan byproduct 360 was consistently observed as the major product with spiroketals 358a,b only detected in trace amount. A revised synthetic strategy was finally devised, to employ hemiacetalisation/oxa-Michael cyclisation to build a spiroketal precursor for opaliferin (12). Successful preparation of advanced silyl enol ethers 406a,b from ketones 404a,b has laid a solid foundation for the research group to go on to complete the total synthesis of opaliferin (12) in the near future, based on the findings of this project.

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

2022

Author dc:creator

• Yudhipratama, Indra

Advisors dc:contributor.advisor

• Brimble, Dame Margaret
• Furkert, Dan

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Licence dc:rights.uri

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

Handle dc:identifier.uri

https://hdl.handle.net/2292/64483

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/64483