Ellwood, A.R.; (2011) A synthetic approach to the sarain core and development of new thioamide-based methodologies. Doctoral thesis , UCL (University College London).

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Abstract

Sarain A is a marine alkaloid that was isolated from the Mediterranean sponge Reniera sarai; the alkaloid possesses antibacterial, insecticidal and antitumour properties. As a result of the intriguing structure of this alkaloid, it has quickly become a popular target for organic chemists. Arguably the most challenging part of its synthesis is the tricyclic core, which is surrounded by two macrocyclic rings. This thesis describes two separate approaches towards the core, both utilising a thia-Claisen rearrangement as a key step. The first approach involved the ring expansion of a 5,5-bicyclic aminal to form an iminium ion intermediate which could be transformed into the core. However, the inherent lack of nucleophilicity of an N-tosyl sulfonamide nitrogen atom in the bicyclic aminal made it difficult to perform the ring expansion. The second method involved a modification of an acid catalysed rearrangement previously attempted within the Porter group; in the previous approach, a differentially protected bicyclic aminal opened with cleavage of a C-NTs rather than a C-NBn bond, leading to an undesired tricyclic product. In the newly devised route, the protecting groups on the two nitrogen atoms of the bicycle were reversed in order to encourage ring opening in the desired fashion; however, the only attempt at this step did not result in the formation of the sarain core. In a different project that is related to the aforementioned research, a diastereoselective thia-Claisen rearrangement was developed which allows the formation of a key intermediate en route to the sarain core, in enantiomerically pure form. To achieve this, thia-Claisen rearrangements were carried out on several S-allyl N,S-ketene acetals bearing a stereogenic centre on the allyl portion of the molecule to give diastereomeric ratios of 2:1 to 30:1. Interestingly, introduction of a bromine atom onto the double bond of the allylic portion of the precursor increased and reversed the diastereoselectivity. Finally, following a discovery that was made whilst working towards the sarain core, a novel reaction for the high-yielding conversion of a wide range of alcohols into iodides using a thioiminium salt has been investigated and optimised. The reaction conditions are essentially neutral, no aqueous workup is required, many functional groups can be tolerated and reaction times are generally short. Furthermore, the thioiminium salt can be stored for long periods without degradation. This type of chemistry has since been further examined, and it can now be used to allow the conversion of alcohols directly into sulfide products that are precursors in Julia-Kocienski reactions.

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