Total Syntheses of 1,2,4-Thiadiazole Natural Products

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dc.contributor.advisor Sperry, J en Davison, Emma en 2018-11-26T03:29:31Z en 2018 en
dc.identifier.uri en
dc.description.abstract Only five distinct natural products have been assigned as containing a 1,2,4-thiadiazole motif, of which, dendrodoine (5) and penicilliumthiamine B (19) have been previously synthesised.This thesis describes the total syntheses of all remaining 1,2,4-thiadiazole-containing natural products; polycarpathiamines A and B (12 and 13) derived from the ascidian Polycarpa aurata, along with the Isatis indigotica derived insatindigothiadiazoles A-D (33a-d) and the unnamed alkaloids 24a and 24b.Thioacylguanidine 126 underwent a novel one-pot, copper(II)-catalysted benzylic oxidationoxidative heterocyclisation sequence to form the 3-amino-5-acyl-1,2,4-thiadiazole core of the polycarpathiamines 132. Simple deprotection steps then completed the synthesis of polycarpathiamines A and B (12 and 13). Initial synthetic efforts towards the Istais indigotica derived alkaloids 24a and 24b focused on a late-stage intermolecular Heck coupling of 5-chloro-1,2,4-thiadiazole 217 with spiro-5',6'-dihydrothiopyran (±)-280 to forge the heterocyclic framework of the natural products (±)-289. Ultimately, this strategy was unsuccessful since the desired 5',6'-dihydrothiopyran (±)-280 was formed as a minor product alongside the 3',6'-dihydrothiopyran (±)-281, and attempts to suppress isomerisation in the intramolecular Heck cyclisation were ineffective. A successful approach to 24a and 24b was inspired by the proposed biosynthesis of the natural product. Insatindigothiadiazoles A-D (33a-d) were first prepared through the oxidative dimerisation of thioamide (±)-388. A selective dehydration of insatindigothiadiazoles A-D (33a-d) furnished diene (±)-31 which underwent regioselective thio-Diels-Alder reaction with 3-thioisatin 32 to form natural products 24a and 24b, along with diastereomer 144a/b. The result of the biomimetic thio-Diels-Alder reaction was supported by DFT analysis and corroborated the postulate made in the original report that the C-2' alcohol of (±)-31 is too distant from the forming spirocentre to exert any diastereocontrol in the cycloaddition. As such, diastereomer 144 was also thought to be present in Isatis indigotica. Recent communication with the isolation author, Professor Jiangong Shi, verified this postulate by confirming the recent isolation of both 144a and 144b from I. indigotica. en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.isreferencedby UoA99265115613602091 en
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. en
dc.rights.uri en
dc.title Total Syntheses of 1,2,4-Thiadiazole Natural Products en
dc.type Thesis en Chemistry en The University of Auckland en Doctoral en PhD en
dc.rights.holder Copyright: The author en
dc.rights.accessrights en
pubs.elements-id 756865 en Science en Chemistry en
pubs.record-created-at-source-date 2018-11-26 en
dc.identifier.wikidata Q111963874

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