thesis_access.pdf (6.45 MB)
Download file

Toward the Synthesis of (–)-TAN-2483B Lactam Analogues

Download (6.45 MB)
thesis
posted on 22.11.2021, 15:43 authored by Stirrat, Hedley

Natural products continue to be an abundant source of lead compounds for drug discovery and development. (–)-TAN-2483A and (–)-TAN-2483B, isolated from the culture of a filamentous fungus, incorporate an unusual furo[3,4-b]pyran-5-one scaffold. TAN-2483A was initially reported to inhibit the c-Src tyrosine kinase enzyme, a potential anticancer target, and parathyroid hormone-induced bone resorption. TAN-2483B, on the other hand, was not isolated in sufficient quantities for biological testing. The synthesis of TAN-2483B is therefore desirable from a drug discovery perspective. Several analogues of TAN-2483B that are functionalised at the propenyl sidechain have previously been synthesised in the Harvey group and have shown promising biological activity. For example, the (Z)-ethyl ester analogue showed micromolar inhibition of HL-60 cells and Bruton’s tyrosine kinase, a protein involved in B-cell maturation that is implicated in certain cancers. The lactone moiety of TAN-2483B and its sidechain analogues, however, appears to be unstable to nucleophilic attack.  The aim of this thesis was to investigate the viability of a synthetic route toward lactam analogues of TAN-2483B. It was proposed that substituting the lactone for a lactam would increase the stability of the compound in nucleophilic media. Moreover, the lactam nitrogen may provide a site for further functionalisation of the compound for future structure-activity relationship studies. Because installation of the (Z)-ethyl ester sidechain via Wittig conditions has previously been found to be more facile than installation of the (E)-propenyl sidechain found in the natural product, investigations into forming the lactam ring system were carried out on the ethyl ester advanced intermediates. Reductive amination of a ketone intermediate was envisaged to install the amine prior to a palladium-catalysed carbonylation/lactam formation step. The promising bioactivity of the (Z)-ethyl ester analogue was anticipated to be retained in the target lactam analogues.  It was found that the substrates of the proposed reductive amination, the advanced ketone intermediates, were incompatible with the tested conditions, presumably due to base sensitivity. Three by-products from the reductive amination experiments were isolated and tentatively characterised by NMR spectroscopy and HRMS. An alternative route toward lactam analogues of TAN-2483B, via intermediate amines accessed by the substitution of an activated alcohol, was briefly investigated with encouraging results.  Further optimisation of the synthetic route toward analogues of TAN-2483B was also achieved. Removal of a purification step enabled the more expedient two-step synthesis of a diol intermediate. The two-step transformation to (Z)- and (E)-ethyl ester intermediates, via sodium periodate-mediated diol cleavage and Wittig olefination, proceeded in the highest yield obtained to date. Investigations into the desilylation of a trimethylsilyl-protected acetylene were also conducted.  Although lactam analogues of TAN-2483B were not obtained in this study, progress was made toward their synthesis. The alternative route toward amines that was briefly explored here appears promising, and work is ongoing in the Harvey group to access lactam (and other) analogues of TAN-2483B, in addition to the natural product itself.

History

Copyright Date

01/01/2017

Date of Award

01/01/2017

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

Masters

Degree Name

Master of Science

Victoria University of Wellington Unit

Centre for Biodiscovery

ANZSRC Type Of Activity code

4 EXPERIMENTAL DEVELOPMENT

Victoria University of Wellington Item Type

Awarded Research Masters Thesis

Language

en_NZ

Victoria University of Wellington School

School of Chemical and Physical Sciences

Advisors

Harvey, Joanne