Pang, P.S.; (2008) Studies towards the synthesis of the core of Sarains A, B, & C. Doctoral thesis , UCL (University College London).

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Abstract

Sarains A-C are alkaloids isolated from the Mediterranean sponge Reniera sarai, which possess moderate antibacterial, insecticidal and antitumour properties. These alkaloids are popular targets for total synthesis, thanks to their rather unusual and challenging structure, which consists of a central diazatricyclic cage attached to two peripheral macrocycles. Arguably the most challenging aspect of their synthesis is that of the tricyclic core, and our approach involves a novel rearrangement of a simpler bicyclic aminal system. This thesis describes various attempts to synthesise cis-fused octahydropyrrolo[2,3-b]pyrrole ring systems that bear an endo acetaldehyde-derived substituent in the 3-position. The research into the synthesis of this ring system began with enantioselective approaches, utilising asymmetric Diels-Alder reactions to establish the stereochemistry required for subsequent transformations into the bicyclic aminal. Progress from these reactions was troublesome. In racemic approaches, the use of a Michael reaction was unsuccessful, but successful installation of the required stereochemistry was achieved by use of a thio-Claisen rearrangement. Using this method, the aforementioned functionalised acetaldehyde was produced in good yield in ten steps from simple starting materials. This provided a branching point for the exploration of four different, but related routes to the sarain core involving the generation of diazoketones, a bromoketone and hydroxy-aldehydes. Substrates to test our proposed rearrangement reaction were synthesised, but transformations into the sarain core proved unfruitful. However, a different tricyclic compound has been produced from a hydroxy-aldehyde approach. In a separate investigation instigated by a result from previous research into synthesis of the sarain core, it was found that treatment of tertiary formamides with a silylated diazoester in the presence of rhodium acetate leads to formation of 3-amino-2- silyloxyacrylates in good yields. The scope and limitations of this novel reaction were investigated.

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