Abstract:
This thesis describes the enantioselective synthesis of the natural product (-)-peniphenone A (1). Peniphenones A-D (1-4) are a family of natural products consisting of a pair of 6,6-benzannulated spiroketal enantiomers (1) and three biosynthetically related compounds (2-4). Compounds 2-4 were isolated and characterised in 2013 by She et al.1 These compounds were discovered during an investigation into bioactive metabolites from the mangrove fungus Penicilium dipodomycola strain HN4-3A, which was cultured from the stem of the mangrove plant Acanthus ilicifolius, found in the South China sea. A convergent strategy was developed to provide access to the 6,6-benzannulated spiroketal in an efficient and enantioselective manner. Three key fragments: bromide 163, aldehyde 75 and trifluoroboratoamide 70, were synthesised using readily available starting materials. Unfortunately, coupling of bromide 163 and trifluoroboratoamide 70 was unsuccessful. However, the challenging α-chiral β-arylated carbonyl motif was accessed via an sp3-sp2 Negishi cross-coupling of bromide 163 and iodide 194. A diastereoselective aldol reaction between ethyl ketone 188 and aldehyde 75 afforded spiroketal precursors 229a and 229b, which in turn furnished (-)-peniphenone A (1). This thesis also describes investigations towards (-)-peniphenone A (1) following a more ambitious pathway which hinges both on the development of new synthetic methods and the application of recently reported methodologies. Key fragments, vinyl silane 245 and monoprotected diol 244 were prepared from available starting materials. Ruthenium-catalysed hydrohydroxyalkylation of vinyl silane 245 and chiral alcohol 244 then provided access to stereotriad 243 in a highly-efficient and enantioselective manner. Finally, attempts to access alcohol 242 via an sp2 Brook-type rearrangement - epoxide ring opening sequence were conducted. Preparation of oxetane 241 was also attempted via alkylation of the lithiate derived from vinyl bromides 315 and 320 by (S)-propylene oxide (299), or via diastereoselective aldol reaction of ketone 335 and formaldehyde (327).