Synthetic Studies Towards Aromatic Polyketide Derived Natural Products

Abstract

The first part of this thesis describes the successful synthesis of a series of 6,6- bisbenzannulated spiroketal analogues of the rubromycin family. The synthesis of spiroketals 183a-183e and spiroaminal 237 were successfully executed using a novel microwave-assisted DIHMA approach. Coupling of an aryl acetylene and an aryl aldehyde via acetylide anion addition resulted in the formation of an alkynol which was followed by oxidation to the desired ynone. Spirocyclisation using the DIHMA protocol afforded the desired bisbenzannulated spiroketals 183a-183e and spiroaminal 237 in good yields. Hydroxy-substituted 6,6- bisbenzannulated spiroketal 182 was successfully furnished by the reduction of ketosubstituted 6,6-bisbenzannulated spiroketal 183a with sodium borohydride. The second part of this research presents synthetic attempts to access the chiral 3-substituted phthalide containing natural products; aigialospirol (256) and herbaric acid (255). The synthesis of chiral vinylphthalide 406 proved challenging and was overcome by the use of a microwave-assisted chemoenzymatic resolution to install the C3 stereocenter of phthalide 406. Despite various attempts to functionalise vinylphthalide 406 towards the synthesis of aigialospirol, results were unsuccessful. With chiral vinylphthalide 406 in hand, the first synthesis and the structural assignment of (--)-herbaric acid (255) was accomplished. This was achieved via heteroatom-directed Wacker oxidation on vinylphthalide 406 to form aldehyde 460. Aldehyde 460 underwent smooth oxidation with Oxone® affording acid 488 which underwent facile methyl ester formation to facilitate purification, thus delivering enantioenriched lactone ester 489. Smooth demethylation with concomitant ester hydrolysis was effected by boron tribromide to give (--)-herbaric acid (255). The realisation of this entirely regioselective anti-Markovnikov addition of water during the Wacker oxidation provides a mild alternative to hydroboration/oxidation protocols that are traditionally used for terminal alkenes.