Abstract:
This thesis describes the synthetic studies towards the total synthesis of apoptosis inducing natural products, jahanyne (18) and opaliferin (251). The first section of this thesis describes the first total synthesis of the novel highly N-methylated alkynyl fatty acid-containing lipopeptide, jahanyne (18), which was isolated from the methanol extract of the marine cyanobacterium Lyngbya sp., and exhibited inhibitory activity against the growth of HeLa cells (IC50 1.8 uM) and HL60 cells (IC50 0.63 uM), and was also shown to induce apoptosis in HeLa cells. Jahanyne (18) includes two rare partial structures; a 2-(1-oxo-ethyl)-pyrrolidine (Oep) (blue) unit and a 2,4-dimethyldec-9-ynoic fatty acid moiety (red). A concise and flexible strategy was developed to afford the fatty acid moiety in an efficient manner. The fatty acid was obtained from the key intermediate 151, which was in turn synthesised from iodide 153 utilising iterative chiral auxiliary-mediated alkylation. Fatty acid 84 was then coupled to the N-terminus of the N-methylated peptide 171, which was synthesised using a modified Fmoc solid-phase synthesis strategy to effectively couple multiple sterically hindered N-methylated amino acids while suppressing epimerisation. Finally, a late-stage solution-phase coupling was employed to introduce the C-terminus ketone pyrrolidine moiety. The second section of this thesis describes the investigations towards the synthesis of opaliferin (251), an apoptosis inducing polyketide with a novel C19 skeleton, obtained from cultures of a rare entomopathogenic fungus (Cordyceps sp. NBRC 106954), isolated from a fruiting body on a larva of cicada (Meimuna opalifera Walker) in Japan. The key intermediate 846 towards the fused-[5,5]-spiroketal moiety of opaliferin (251) was synthesised utilising cross-metathes is and a tert-butyldimethylsilyl group-mediated Rh(II)-catalysed CH-insertion, and converted to the spirocyclisation precursor 848. Although our attempts to synthesise spiroacetal 849 from 848 utilising a Pd(II)-catalysed Wacker-type oxidative spiroketalisation reaction were unsuccessful, these investigations provide important and relevant insights for future attempts towards the total synthesis of opaliferin (251).