Stereoselective synthesis of pyrrolidinones via nitro-Mannichreaction: towards the synthesis of popolohuanone E

Field: Chemistry (Physical Sciences)

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.