Abstract:
The integrastatins, epicoccolide A (5) and epicocconigrone A (6) belong to a novel family of natural products, defined by an unprecedented [6.6.6.6]-tetracyclic core structure. These compounds exhibit an array of biological activities, revealing the significance of the tetracyclic architecture as a novel clinically relevant scaffold. This thesis describes synthetic endeavours towards the tetracyclic core 33 of the integrastatins, with the view that the methodology established would provide general access to these natural products. Three synthetic approaches were explored in this work to construct the tetracyclic core 33 of the integrastatins.The initial strategy hinged on the styryllithium addition approach using styryllithium 84 and acetophenone 85. Despite devoting considerable efforts to prepare 84, failure to access 84 prohibited our effort to pursue this synthetic approach. A model study conducted in the revised umpolung alkylation approach employed umpolung anion 164 and aldehyde 173, which enabled efficient synthesis of the tetracyclic core 34 of epicoccolide A (5) and epicocconigrone A (6). This model work allowed further investigation into total syntheses of these natural products via umpolung alkylation approach. Unfortunately, application of this approach for the synthesis of the tetracyclic core 33 of the integrastatins using acetophenone 85 proved to be challenging due to the presence of the extra methyl substituents. A practical synthesis of tetracyclic core 33 was accomplished via addition of aryllithium 119 to aldehyde 226, which also enabled investigation of the applicability of this synthetic methodology for the total synthesis of integrastatin B (4).The successful syntheses of tetracyclic core structures present in the integrastatins, epicoccolide A (5) and epicocconigrone A (6) provided a sound platform for future endeavours to achieve total syntheses of these natural products and analogues, which will be useful for the future development of effective drugs.
