Synthetic Studies Towards the Gombaspiroketals and a Cobalt-Catalysed Epoxide Olefination

The gombaspiroketals (14-16) are 6,6-spiroketal-containing natural products, which were isolated from a South Korean marine sponge (Clathria gombawuiensis) in 2014. The gombaspiroketals belong to a family of sesterterpenoids derived from the alotane skeleton, some of which exhibit potent and varied bioactivities. Recent total syntheses of alotane natural products has demonstrated the importance of total synthesis efforts in furthering the field of organic chemistry, and for investigating structure-activity relationships and biological properties. Therefore the gombaspiroketals were chosen as a target for synthetic studies. Epoxide 171 was identified as a possible intermediate towards the gombaspiroketals, which was envisioned to be accessed by Hosomi-Sakurai allylation of allylsilane 45 and cyclic acetal 172 followed by epoxidation. This work describes efforts in the syntheses of allylsilane 45 and cyclic acetal 172. Towards allylsilane 45, the literature cuprate conjugate addition of bromide 54 with acrylate 55 was irreproducible, affording ester 56 in varying yields of 0-66%. Alternative transformations were investigated for access to ester 56, including addition of organometallic nucleophiles and transition metal catalysis. Although no method was found to provide reliable access to 56 in consistently good yield, the cobalt- and nickel-catalysed conjugate additions emerged as potential alternatives worthy of further investigation. Subsequent elaboration to allylsilane 45 via intramolecular Horner-Wadsworth-Emmons reaction of 58 proceeded smoothly. Synthesis of aldehyde 303 en route to acetal 172 was investigated. The literature sequence reported from 2-methylcyclohexanone (299) was ineffective, due to presence of inseparable impurities in the final products. 303 was obtained in excellent purity by intramolecular Horner-Wadsworth-Emmons reaction of phosphonate 345 which was reliably accessed on large scale. Aldehyde 303 was unified with phosphonium 358 (derived from lactone 359) by phosphoniosilylation alkylation. Subsequent conjugate addition of a methyl group to 357 was unsuccessful, due to the preference for isomerisation to 1,3-dienes. Model cyclic acetals 415 and 416 were prepared from 357 instead, for use in model allylations with alyllsilane 45. Alongside synthetic studies towards the gombaspiroketals, a cobalt-catalysed epoxide olefination to homoallylic alcohols was investigated. This thesis describes the discovery, synthetic utility, and mechanistic considerations of this novel methodology.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Chemistry

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2019

Author dc:creator

• Quach, ML

Advisors dc:contributor.advisor

• Brimble, M
• Furkert, D

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/2292/47516

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/47516