Horsfall, L.R.; (2011) Stereoselective synthesis of pyrrolidinones via nitro-Mannich reaction: towards the synthesis of popolohuanone E. Doctoral thesis , UCL (University College London).

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Abstract

Part 1: The first section of this thesis details the stereoselective synthesis of pyrrolidinones via the nitro-Mannich reaction. Expanding on previous work within the Anderson group, conjugate addition of a diorganozinc species to nitroacrylate 141 was carried out successfully. Subsequent in situ nitro-Mannich reaction was then followed by spontaneous lactamisation to afford the desired five-membered ring pyrrolidinone structure. The reaction was performed in one pot, generating three contiguous stereocentres in a highly diastereoselective manner. The scope of the reaction was investigated by varying substituents on the imine partner. This led to the synthesis of a broad range of analogues incorporating alkyl, aryl and heteroaryl functional groups, each isolated as a single diastereoisomer in 48-84% yield. Studies to develop an asymmetric variant of the reaction were performed, with Feringa’s phosphoramidite ligand 299 enabling formation of the pyrrolidinone with a moderate 52% e.e. Analysis of the reaction mechanism and the origin of the observed diastereoselectivity have been investigated, followed by further functionalisation of the pyrrolidinone structure to yield a wide range of synthetically useful building blocks. Anderson, J. C.; Stepney, G. J.; Mills, M. R.; Horsfall, L. R.; Blake, A. J.; Lewis, W. J. Org. Chem. 2011, 76, 1961 (featured article). Part 2: This section describes work towards the total synthesis of popolohuanone E (1), a marine natural product isolated from the Dysidea sp. sponge in 1990. The molecule contains a unique trihydroxylated dibenzofuran-1,4-dione core and two identical sesquiterpene units. The complex molecular structure and interesting biological activity of popolohuanone E (1) has made this compound a particularly interesting target. Synthesis of model system 132 was successfully achieved, which allowed investigations into the key oxidative dimerisation reaction. Extensive studies led to isolation of the desired bis-quinone 133 in 40% yield, followed by acid catalysed cyclisation to form the dibenzofuran core present in popolohuanone E (1), in 26% yield. Focus then turned to the synthesis of the proposed precursor to popolohuanone E (1), 6’-hydroxyarenarol (7), based on the route developed within the Anderson group. Studies began with the enantioselective synthesis of intermediate iodide 83 utilising Myers’ pseudo-ephedrine auxillary. The remaining stereocentres were subsequently installed via an intramolecular Hosomi-Sakurai reaction in high yield and diastereoselectivity. With the cis-decalin framework in hand, construction of the phenolic portion was achieved by addition of lithiated 1,2,4-trimethoxybenzene to neo-pentyl aldehyde 74, followed by deoxygenation using Barton-McCombie conditions. Installation of the exo-cyclic alkene, followed by removal of the three methyl ether protecting groups, then afforded the required precursor 6’- hydroxyarenarol (7). Finally, dimerisation was attempted as developed previously on model system 132, however none of the desired bis-quinone (18) was observed.

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