Diels-Alder Approaches Towards T-2 Toxin and Related Trichothecenes

Brown, Beverley Anne (1986) Diels-Alder Approaches Towards T-2 Toxin and Related Trichothecenes. PhD thesis, University of Glasgow.

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Abstract

The trichothecenes are a group of some 80 structurally complex sesquiterpenoids of considerable environmental importance. It is difficult to obtain many of these compounds in significant amounts from natural sources, and much effort has been directed towards devising efficient, practicable syntheses of these molecules and their analogues. In the course of this research, a study of intermolecular Diels-Alder routes towards potential trichothecene precursors was carried out. Particular attention was paid to devising a general route towards T2 toxin (185), a highly oxygenated trichothecene which has yet to yield to total synthesis. To this end the cycloaddition reaction between a suitably functionalised 1,3-butadiene and an alkyl coumalate was investigated. Two major areas of study were undertaken: the Diels-Alder reaction between isoprene and a coumalic acid derivative and the cycloaddition reaction between a 2-silyloxy-substituted buta-1,3-diene and methyl coumalate. The Diels-Alder reaction between isoprene and methyl coumalate suffered from poor regioselectivity and afforded low yields of the desired adduct (157a). Significant improvements in both the regioselectivity and yield of desired adduct were obtained when coumalyl chloride (191) was employed as dienophile. Seleno- and iodolactonisation of carboxylic acid (186a) derived from adduct (157a) afforded the unexpected bicyclo [2.2.2] octane systems (192) and (195) respectively, neither of which could be converted into useful trichothecene precursors. Alternatively, bromination of the conjugate addition product (158), followed by a sequence of acetolysis and hydrolysis, furnished a 1:1 mixture of alpha-allylic alcohol (200a) and beta-allylic alcohol (200b). alpha-Allylic alcohol (200a) possesses ideal functionality for further elaboration to T2 toxin, and was accordingly converted into the corresponding gamma-lactone (203), thereby establishing the desired a-configuration of the 8-hydroxyl group. Catalytic osmylation of the conjugate addition product (158) afforded cis diol (205a) as the major product, which after a sequence of silylation, dehydration and finally fluoride-induced desilylation was transformed into the same alpha-allylic alcohol (200a)'. Cycloaddition between 2-silyloxy-substituted buta-1,3-dienes and methyl coumalate was observed to be a highly regiospecific process, affording the expected silyl enol ethers in respectable yields. In an attempt to prepare alpha-bromoketone (228) it was observed that the product obtained from bromination of the t-butyldimethylsilyl enol ether (218a) depended upon the reaction conditions employed. In the absence of pyridine the expected alpha-bromoketone was obtained. Interestingly, however, in the presence of pyridine the alpha-bromo silyl enol ether (231) was formed regioselectively.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Organic chemistry
Date of Award: 1986
Depositing User: Enlighten Team
Unique ID: glathesis:1986-77422
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jan 2020 11:53
Last Modified: 14 Jan 2020 11:53
URI: http://theses.gla.ac.uk/id/eprint/77422

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