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Title: Total synthesis and semi-synthesis of secondary metabolites isolated from the fermentation of Amycolatopsis DEM30355
Author: Morton, Stephanie
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2016
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The novel antibacterial DEM30355/A 1 was isolated from the fermentation broth of Amycolatopsis DEM30355. We aimed to synthesise DEM30355/A 1 to determine the absolute stereochemistry and access DEM30355/A analogues. Using a Baylis-Hillman reaction between tricarbonyl 2 and ketone 3, we constructed the oxygenated quaternary centre at C4a of DEM30355/A 1 in adducts 4 and 5 (Figure 1). Figure 1: Left - structure of DEM30355/A 1. Right - Baylis-Hillman reactions to synthesise adducts 4 and 5 In an alternate route, a Diels-Alder reaction between diene 6 and dienophile 7 was used to generate cycloadducts 8 - 11, containing the A, B, C ring core of DEM30355/A 1 (Figure 2). Figure 2: Synthesis of cycloadducts 8 - 11 via a Diels-Alder reaction from isobenzofuran 6 Alongside this Diels-Alder route, we aimed to synthesise dienophile 12 from shikimic acid 13, to generate DEM30355/A 1 as a single enantiomer (Figure 3). Figure 3: Planned route to DEM30355/A 1 as a single enantiomer from shikimic acid 13 Following the synthesis of alkene 14, a key sterically directed dihydroxylation reaction gave diol 15, which was oxidised to ketone 16. Base-catalysed conversion of ketone 16 to dienophile 12 was attempted, however the product of this reaction is compound 17 (Figure 4). Abstract III Figure 4: Two-step synthesis of ketone 16 from alkene 14 and the subsequent reaction with base generating aromatic compound 17 Part 2 Antibacterial DEM30355/B2 18 was identified in the fermentation broth of A. DEM30355 (Figure 5). We targeted new drug leads via semi-synthetic modification of DEM30355/B2 18. Figure 5: Structure of DEM30355/B2 18 Following isolation of DEM30355/B2 18 via a key acid-base extraction, we successfully generated semi-synthetic DEM30355/B2 derivatives 19 and 20 (Figure 6). These compounds are undergoing investigation to assess their inhibition activity against drug-resistant bacterial dependent RNA polymerase.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available