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Studies on the Synthesis of Marine Natural Product (-)-Zampanolide and its Analogues

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posted on 15.11.2021, 15:02 authored by Wang, Jingjing

(-)-Zampanolide is a microtubule-stabilising marine natural product, with promise as a cancer drug candidate. The potential therapeutic application of zampanolide has fuelled worldwide interest in its total synthesis, but few analogue studies have been reported. Analogues afford the possibility of examining the structure-activity relationships with a view to optimising for potency and medicinal viability. This project seeks to devise a new route to zampanolide and generate a series of analogues for bioactivity evaluation.   The initial approach to zampanolide and a number of designed analogues was through disconnections at C20 by an N-aldol reaction, at C1 by Yamaguchi esterification, at C8-C9 by metathesis and at C15-C16 by alkynylation. During the development of fragment syntheses, problems were encountered with protection of the secondary hydroxyl group at C19 and establishment of an aldehyde at C15. Useful natural and analogue fragments were generated during this exploratory phase.  The order of connections was revised, and effort has been put towards the improvement of the synthetic efficiency. A three-component reaction involving (triphenylphosphoranylidene)-ketene, also known as Bestmann ylide, as a linchpin was envisaged to provide the dienoate of zampanolide. This is an expanded application of Bestmann ylide and therefore the scope of this linchpin reaction was investigated using simple alcohols and aldehydes. Success in the scoping study fortified this approach, and the coupling of the C3-C8 and C16-C20 fragments of zampanolide proceeded with good yields and stereoselectivity of the E,Z-geometry.  The planned late stage connections were tested on model substrates. The side arm attachment by a chiral boron reagent-promoted aza-aldol reaction failed to produce desired product on a simple model. However, model substrates that better account for the functionality of the zampanolide macrocycle are proposed for subsequent studies. In case these also do not succeed, reliable alternative methods described in the literature would be used. Several methods were scanned for the asymmetric alkynylation required for the C15-C16 bond connection. That involving ProPhenol and diethylzinc produced an excellent yield with a model alkyne. Although the stereoselectivity of the alkynylation is yet to be optimized, it was also tested on the full zampanolide fragment generated from the Bestmann ylide reaction. A small amount of the desired product was isolated, establishing 16 out of the 18 carbons of the macrocycle. Formation of a macrocycle is close at hand.

History

Copyright Date

01/01/2016

Date of Award

01/01/2016

Publisher

Te Herenga Waka—Victoria University of Wellington

Rights License

Author Retains Copyright

Degree Discipline

Chemistry

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level

Doctoral

Degree Name

Doctor of Philosophy

Victoria University of Wellington Unit

Centre for Biodiscovery

ANZSRC Type Of Activity code

1 PURE BASIC RESEARCH

Victoria University of Wellington Item Type

Awarded Doctoral Thesis

Language

en_NZ

Victoria University of Wellington School

School of Chemical and Physical Sciences

Advisors

Harvey, Joanne; Teesdale-Spittle, Paul