Coleophomones, metabolites reported first in a Japanese patent in 1998 and then by
Merck in 2000 from a Coleophoma fungus, have antifungal and antibacterial
properties and inhibit bacterial cell-wall transglycosylase and human heart chymase.
Their unique molecular architecture contains a cyclic tricarbonyl moiety embedded in
an ll-membered macrocycle. In our synthetic strategy the reactive ~,~-tricarbonyl
structure is masked as an isoxazole to allow elaboration elsewhere in the molecule.
We have investigated two isoxazole based approaches to these targets: 1) via an
isoxazole ring with ketone or ester substituents; and 2) via a reduced benzisoxazole.
The formation of isoxazole building blocks for the two approaches was by nitrile
oxide l,3-dipolar cycloaddition. Several substituted phenylisoxazole diesters were
made from approach 1 successfully, however, the attempt for 6-membered ring
closure failed. For approach 2, a number of benzisoxazoles with different substituted
phenyl groups were made in moderate to good yield. The side chain additions towards
these building blocks have also been elaborated, and the formation of II-membered
macrocycles have been attempted by ring closing metathesis (RCM) with Grubbs II
Precursors for total synthesis of coleophomone A, B, C and D have been made.
Irradiation reactions have been used to prepare oxime precursors for coleophomone D
and use of co-solvent (HMAP and DMPU) was applied in the synthesis to alkylate the
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.