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Title: Synthesis of 1,2-dioxolanes related to marine sponge metabolites
Author: Maidwell, Nicola
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1997
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The plakinic and epiplakinic acids A, C and D, and a related series of natural products were isolated from marine sponges. They are reported to exhibit general anti-microbial activity and bear several common structural features. They each contain a 1,2-dioxolane ring with 3,5- dimethyl substitution, a 3-carboxymethyl substituent and a large hydrophobic moiety attached to C5 which we refer to as R1. This work describes the synthesis of a series of naturally occurring and other structural analogues of the plakinic acids which contain the quaternary substituted 1,2-dioxolane. Our approach to the synthesis of the functionalised target 1,2-dioxolane was to use peroxymercuriation/ demercuriation of an appropriately substituted diene carboxylate. In the first instance, as a model system, we describe the synthesis and characterisation of ethyl 3,5- dimethylhexa-2,4-dienoate and its isomeric esters. These dienes were then treated with two mole equivalents of mercury acetate and 30% H2O2 followed by sodium borohydride demercuriation to produce the first unnatural analogue of the natural products. We then describe the development of a general method of synthesis of further analogues, by variation of R1, which in its most refined form comprises only 3 steps. LDA-induced condensation of alkan-2-ones with ethyl 3-methylbut-2-eneoate generated (2Z)-3,5-dimethyl- 2.4-dienoic acids which after structural modification served as the diene substrate. Peroxymercuriation/ demercuriation of the ethyl ester analogue of the 2Z-diene acid gave the 3.5-dimethyl-1,2-dioxolane esters, which upon saponification furnished the 1,2-dioxolane acids. The first example of a naturally occurring analogue was synthesised using this route. Alternatively conversion of the 2Z-diene to the 2E-isomer followed by peroxymercuriation/ demercuriation gave the functionalised 1,2-dioxolane acid directly. In all cases the 1,2-dioxolanes were produced as a pair of diastereoisomers. The relative stereochemistry of each isomer was determined by comparison of the 1H NMR of the analogue where R1=C7H15 with the data reported for the natural products, and from nOe experiments. To probe structure activity relationships a series of spiro 1,2-dioxolanes were synthesised, and modifications to the carboxylate were made with the peroxide ring in place. Finally as a model for the total synthesis of the plakinic and epiplakinic acids we describe the synthesis of an analogue where R1 contains unsaturation which was achieved by employing Wittig methodology in the presence of the 1,2-dioxolane.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available