Chemoenzymatic Routes to Biologically Active Natural Products and Related Compounds

Abstract

Various genetically modified microorganisms that over-express dioxygenase-type enzymes can be used for the large scale production of compounds such as A (and known as cis-1,2-dihydrocatechols) from the corresponding aromatic precursor. These metabolites, which are almost invariably obtained in near enantiomerically pure form, have served, over many decades, as valuable starting materials in chemical synthesis. The papers presented in this thesis by publication reinforce this proposition.In order to appropriately contextualize the work undertaken by the author, an extended survey of the use of compounds such as A in total syntheses undertaken by the Banwell Group (and within which the author worked) is provided. Copies of the author’s four publications (and, where relevant, the associated Supporting Information documents) are then presented. The first publication (Publication 1) associated with this body of work represents an invited review article and also serves to contextualise, albeit from a somewhat broader perspective than given in the above-mentioned survey, the work reported in the next parts of the thesis by describing various of the contemporary ways in which homochiral and microbially-derived cis-1,2-dihydrocatechols such as A have been exploited as starting materials in the stereochemically-controlled synthesis of a range of natural products and their analogues.Publication 2 details syntheses of a series of twenty-eight analogues of the phytotoxic geranylcyclohexentriol (–)-phomentrioloxin A (B). These have been prepared through cross-couplings of various enantiomerically pure iodoconduritols or certain deoxygenated derivatives with either terminal alkynes or borylated alkenes. Some of these analogues display modest herbicidal activities and physiological profiling studies suggest that one, C, inhibits photosystem II in isolated thylakoids. Publication 3 is concerned with the development of so-called chemoenzymatic total syntheses of the natural product (+)-asperpentyn and the enantiomer of the structure assigned to aspergillusol A. These syntheses start from the enantiomerically pure cis-dihydrocatechol D, itself obtained through the whole-cell biotransformation of iodobenzene.Specifically, then, Publication 3 details the establishment of a concise (five step) synthesis of (+)-asperpentyn (E) and an eight-step reaction sequence leading to compound F, the enantiomer of the structure, G, assigned to the natural product aspergillusol A. Both routes employ the enantiomerically pure cis-1,2-dihdrocatechol D as starting material and use Sonogashira cross-coupling chemistry to install the required enyne side-chain.On the other hand, Publication 4 describes syntheses of certain di- and mono-oxygenated derivatives (e.g. H and I, respectively) as well as analogues such as K-M of both the (–)- and (+)-enantiomeric forms of the alkaloid galanthamine (J). All have been assessed for their capacities to inhibit acetylcholinesterase but, in contrast to the predictions from docking studies, none binds strongly to this enzyme.