The Total Synthesis of Aigialomycin D and Analogues

Abstract

<p>In 2002 a new family of 14-membered resorcylic macrolides, the aigialomycins, were isolated from the mangrove fungus Aigialus parvus BCC 5311. Subsequent biological testing of these new natural products found aigialomycin D (Am D) to be the most biologically active member of the family, exhibiting moderate activity against malaria (Plasmodium falciparum K1, IC50 19.7 Mu) and modest cytotoxicity towards certain cancer cells (KB cells: IC50 9.0 Mu and BC-1 cells: 53.8 Mu). More recently, Am D has been shown to inhibit the kinases CDK1/5 and GSK at low Mu concentrations. At the onset of this research project, with only one total synthesis of Am D reported in the literature, there remained a need for an efficient synthesis of Am D that would be amenable to the synthesis of a range of analogues. This thesis reports two synthetic approaches to Am D that differ primarily in the chemistry utilised to install the (E)-olefins at C1'-C2' and C7'-C8': a Horner-Wadsworth-Emmons (HWE) strategy and a Ramberg-Backlund (RB) strategy. The Ramberg-Backlund strategy ultimately proved to be successful, providing Am D in 16 steps with 9% overall yield. A retrosynthetic analysis of Am D disconnects the molecule into three major fragments: an aromatic fragment, a C2'-C7' carbohydrate-derived fragment and a C8'-C11' alcohol fragment. The synthesis of the three fragments for each strategy is described and the attempts made to couple the fragments together, first with HWE methodology and then successfully with ring-closing metathesis (RCM) and RB reactions, are discussed. The synthesis of several Am D analogues and their preliminary biological testing is also described.</p>