Maidwell, Nicola; (1997) Synthesis of 1,2-dioxolanes related to marine sponge metabolites. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

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.

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