Total Synthesis of Virgatolide B

Abstract

This thesis describes the first, enantioselective synthesis of the natural product virgatolide B (2). Virgatolides A-C (1-3) are a family of polyketide metabolites isolated from the endophytic fungus Pestalotiopsis virgatula, cultured from the leaves of Dracontomelon duperreanum. The compounds were discovered during a biological screening programme aimed at identifying fungal metabolites with cytotoxicity against HeLa (cervical epithelium) cells. Isolation of compounds 1-3 (IC50 19.0, 22.5, and 20.6 μM respectively) from an active extract enabled structural elucidation, revealing that the compounds share a common tetracyclic core, differing from one another only at C-4 and C-13. A convergent and flexible strategy was developed to provide access to the 6,6-benzannulated spiroketal in an efficient manner. Three key fragments: trifluoroboratoamide 158, bromide 261 and aldehyde 245, were synthesised using readily available starting materials. In particular, trifluoroboratoamide 158 was obtained from the chiral pool reagent (R,R)-pseudoephedrine, thus enabling the synthesis to be conducted in an enantioselective manner. Trifluoroboratoamide 158 and bromide 261 were successfully united using an sp3-sp2 Suzuki cross-coupling reaction, providing the challenging α-chiral β-arylated carbonyl motif. A 1,3-anti selective Mukaiyama aldol reaction between methyl ketone 300 and aldehyde 245 afforded spiroketalisation precursor 299. Initial attempts to construct the spiroketal core employed an EOM-protected cyclisation precursor. However, the acidic conditions required for deprotection resulted in elimination of the β -hydroxyl group. A revised protecting group strategy was therefore devised in order to employ pH-neutral deprotection conditions. Exchange of the EOM protecting groups for BOM and incorporation of the alkene side chain prior to the Suzuki coupling increased the convergence of the synthesis, enabling the synthesis of spiroketal precursor 299. Global deprotection under hydrogenolysis, concomitant spiroketalisation and a mild equilibration procedure furnished virgatolide B (2). The regioselectivity of the spirocyclisation was governed by intramolecular hydrogen-bonding. In addition to the total synthesis of virgatolide B (2) this thesis also describes investigations towards the synthesis of virgatolide A (1). Four synthetic strategies for the synthesis of virgatolide A (1) via intermediates readily accessible from the synthesis of virgatolide B (2) were evaluated on model systems: carbene insertion, cross-metathesis, hydroalkoxylation and a ketone-ketone aldol reaction. Although unsuccessful, these investigations provide important synthetic insights relevant to future attempts towards virgatolide A (1).