This thesis describes the work perfonned towards the enantioselective synthesis of the marine alkaloid, ptilomycalin A and also the development of a methodology for the preparation of structural analogues of the natural product.
An attempted stereospecific synthesis of the tert-butyl ester derivative of the
pentacyclic core of ptilomycalin A is reported. A convergent synthesis is employed in the preparation of the chiral precursors; an unsaturated aldehyde prepared starting from (S)-( + )-2-aminobutyric acid and a chiral P-keto ester synthesised from ethyl (R)-3-hydroxybutyrate. The preparation of a bis-a,P-unsaturated ketone double Michael acceptor via a somewhat problematical Knoevenagel condensation reaction between these precursors, and the attempted guanidine addition-cyclisation reaction are also described.
The Knoevenagel condensation reaction was also investigated in a further effort to optimise the reaction conditions using a related unsaturated aldehyde and a selection of P-keto esters. In addition, an alternative approach towards the ester-substituted pentacyclic core of ptilomycalin A utilising the Wadsworth-Emmons reaction is also discussed. Initial attempts being directed towards the preparation of a functionalised guanidine tricycle.
The synthesis of a chiral pentacycle is reported, having an identical stereochemistry to the pentacyclic core of ptilomycalin A The key steps involve a Wittig reaction leading to a bis-a,P-unsaturated ketone, followed by the addition of guanidine to generate the pentacyclic core. The stereochemistry of the pentacycle is confirmed by means of TOCSY and NOESY experiments and by comparison with the spectroscopic data quoted for the pentacyclic cores of ptilomycalin A and 13,14,15-isocrarnbescidin 800.
A synthetic methodology enabling the preparation of advanced, hexacyclic
analogues of ptilomycalin A is described. The analogue consists of a hexacyclic core, linked to a spennidine residue via a 16-carbon aliphatic chain. Two tetrahydropyranyl spiro N,O-acetal units are incorporated within the hexacyclic unit which possesses an identical stereochemistry to the pentacyclic nucleus of ptilomycalin A.