Chavda, JK; (2013) Studies towards the synthesis of Nakadomarin A. Doctoral thesis , UCL (University College London).

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Abstract

Nakadomarin is a manzamine related alkaloid isolated from the marine sponge Amphimedon off the coast of the Kerama islands, Okinawa. This alkaloid possesses numerous biological activities including anti-tumour, anti-fungal and anti-bacterial. This along with its intricate structure, consisting of a fused tetracyclic ring system flanked by two macrocycles, has prompted numerous investigations into its synthesis. This thesis describes various attempts at the construction of the tetracyclic ring system. Key steps in the synthetic plan include a thio-Claisen rearrangement to establish two of the four stereocentres in the molecule, and an iminium ion/furan cyclisation to form the B ring. The first strategy involved the successful development of a thio N-acyliminium ion/furan ring cyclisation; the iminium ion was formed through the reaction of an unprotected thiolactam and a bromo ester. Application of this methodology to the synthesis of the core was unsuccessful. Another approach investigated the synthesis of a Z allylic bromide for use in the thio-Claisen rearrangement; the resultant product would contain precursor groups which would be used to synthesise the A ring. Attempts at synthesising a suitable allylic bromide led to isomeric mixtures. The final approach led to the development of a one pot thio-Claisen/acylation protocol. Attempts at acylating a tertiary thiolactam had proved unsuccessful, thus an alternative strategy was considered that involved conversion of the thioamide to an N,S-ketene acetal following S-allylation. The resultant ketene could behave as a nucleophile and undergo reaction with an acylating agent. This hypothesis was tested through allylation with E cinnamyl bromide followed by acylation with numerous acylating agents. Unfortunately, the N,S-ketene acetal underwent thio-Claisen rearrangement before acylation could take place. However, allylation with Z cinnamyl bromide allowed for an acylation of the resultant ketene with phenyl isocyanate, which then underwent spontaneous thio-Claisen rearrangement to give the desired thiolactam adduct with excellent diastereoselectivity.

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