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Title: The biomimetic synthesis of polyether antibiotic fragments
Author: Mason, Ian
ISNI:       0000 0001 3620 7132
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1987
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The asymmetric synthesis of the C13-C27 moiety 44 of the polyether antibiotic etheromycin is described. The final step in the synthesis was the formation of the tricyclic fragment 44 by a biomimetic triepoxide cyclisation cascade. The cyclisation cascade, 144 to 44, is stereospecific and entirely dependent upon the epoxides stereochemistry. The absolute stereochemistry of each of the three epoxides was independently controlled by the Sharpless asymmetric epoxidation methodology. The carbon skeleton of 44 was constructed from geraniol, (R)-methyl 3-hydroxy-2-methylpropionate 117, and two units of t-butyl acetate. Apart from C26, the chiral centres were all controlled by the Sharpless asymmetric epoxidation. The synthetic strategy was designed to effect the stepwise enantioselective introduction of the three epoxides while building the C13-C27 carbon skeleton, and directing a subsequent cascade reaction by an internal nucleophile. Two trisubstituted epoxides were introduced stepwise with >20:1 stereoselectivity by asymmetric epoxidation of a geraniol derived segment. The fragment was manipulated between epoxidations to allow stepwise introduction of the epoxides, and to ensure terminal differentiation of the groups. Both hydroxyl groups used to control epoxidation were subsequently and separately utilised, after conversion to the iodide, in alkyation reactions with the lithium enolate of t-butyl acetate to extend the carbon chain. No other conditions investigated to selectively react α to epoxides were satisfactory. Of the two t-butyl ester groups introduced, one (C_24) was reduced to the aldehyde and coupled in a Julia reaction with a sulphone derived from 117. The resulting trans olefin was converted into a trans homoallylic alcohol, which was epoxidised by Sharpless methodology with 3 : 1 stereoselectivity. The second of the t-butyl esters (C_13) was used as an internal nucleophile to induce the cascade reaction. The natural ring stereochemistry of 44 was assumed from the high predictability and stereocontrol of the epoxidation reactions and confirmed by ^1H NMR nOe difference experiments. The synthesis of the sulphone 161, in which the three contiguous chiral centres and methyl ketone represents a common polyether terminus, was also demonstrated using a stereocontrolled aldol reaction.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Organic chemistry