Studies towards the total synthesis of the pyrronazols
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In 2014, the pyrronazols, a family of closely related natural products were isolated from a soil dwelling myxobacteria, Nannocystis pusilla strain Ari7. The family represent a novel structural class of secondary metabolites, containing a conjugated chlorinated pyrrole-oxazole unit. The total synthesis of pyrronazols A and A2, 20 and 21, has still to be accomplished and is of specific interest, not only for its unusual and interesting structure, but also to expand on the very limited biological profile. This could be probed further through the synthesis of structural analogues, thus requiring a synthetic strategy that tolerates rapid modifications to probe SAR. A synthetic strategy for the pyrronazol family must be flexible to allow for the synthesis of both isomers from a single privileged intermediate. Through our attempts towards the synthesis of the pyrronazol family this work details a highly syn-selective, substrate controlled vinylogous Mukaiyama aldol reaction (vMAR) which has been developed and optimised to install the required stereocentres on the pyranone ring. The (4S,5S) C₁-C₇ pyranone fragment has been utilised in the synthesis of two advanced intermediates, both a single reduction step away from pyrronazol A2, that have proved resistant to reduction. The alkene geometry, directing the synthesis towards pyrronazol A2, was set by an unprecedently selective Knoevenagel condensation between 5-chloro-2-formylpyrrole and amidoester partners. Our C₁-C₇ fragment has also been used in a convergent, modular synthesis of pyrronazol B, which afforded the natural product alongside an isomeric product.
Thesis, PhD Doctor of Philosophy
Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/
Embargo Date: 2024-02-19
Embargo Reason: Thesis restricted in accordance with University regulations. Electronic copy restricted until 19th February 2024. (Print copy restricted until 19th February 2023)
Description of related resourcesData underpinning Ross Sinclair McLennan's PhD thesis (Thesis data) McLennan, R.S., University of St Andrews, DOI: https://doi.org/10.17630/75e2eed6-8cbd-4861-b618-f00b72472f54
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