Nandra, Gurdeep Singh; (2004) Studies towards the synthesis of the core structure of sarains A, B, and C. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Sarains A-C are marine alkaloids produced by the sponge Reniera sarai, which exhibit antitumor, antibacterial, and insecticidal activities. Sarains A-C have a complex structure, which comprises of a 1,5-diazatetracyclo[6.2.1.1³,⁹.0⁴,¹¹]dodecane tricyclic core surrounded by two macrocycles. To date four groups have communicated the construction of the tricyclic core, however the total synthesis of sarains A-C has yet to be reported. This thesis describes the work undertaken towards the synthesis of a tricycle that contains the core structure of sarains A-C, by the use of a novel carbene mediated ylide rearrangement reaction. The initial objective was to construct the precursor for this rearrangement, a cis-fused octahydropyrrolo[2,3-b]pyrrole ring system bearing an endo acetic acid substituent in the three position. A number of strategies towards the construction of the desired octahydropyrrolo[2,3-b)]pyrrole ring system were investigated, these included: The electrophilic azidation of a cis-fused hexahydro-isoindole. The cyclisation of α-amino-(β-iodopyrrolidines). The formation of cyclic amidines. The Diels-Alder reaction between 2-(tert-butyldimethylsilyloxy)buta-1,3-diene and an N-protected-pyrrolin-2-one dienophile. However, these approaches were unsuccessful. Following this, two closely related strategies were pursued, which gave promising results. A non-stereoselective strategy to the bicyclic system by the ring opening of butadiene monoxide with a lactam enolate was investigated. A cis-fused octahydropyrrolo[2,3-b]pyrrole ring system was formed using a model system based on an azido-lactam synthesised in this strategy. Finally, the use of a [3,3]-sigmatropic rearrangement provided a stereoselective method for construction of the required octahydropyrrolo[2,3-b]pyrrole ring system.

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