Synthetic studies towards portimine A | The direct synthesis of 1,4-diketones in complex natural products

Abstract

TThe synthesis of 1,4-diketones and derivatives in complex natural products poses a significant synthetic challenge. This thesis describes synthetic endeavours towards the key 1,4-diketone intermediate of the marine natural product portimine A (7) and expands into the development of efficient methods for the direct synthesis 1,4-diketones applicable to the general synthesis of complex aliphatic 1,4-diketones. A survey of literature methods at the outset of this study found the NHC-catalysed Stetter reaction to provide one of the most promising methods for the direct synthesis of 1,4-diketones, such as key intermediate 268 of portimine A (7). Portimine A (7) displays an interesting and varied biological profile, including (but not limited to) promising anti-leukaemia and anti-HIV activity. Model studies for direct formation of the 1,4-diketone intermediate 268 via an intermolecular Stetter reaction found the yields of this reaction decreased significantly with increased steric bulk on the aldehyde coupling partner (332). As sterically non-trivial aliphatic aldehydes represented a limitation in the scope of the intermolecular Stetter reaction, attention turned to tuning the NHC catalyst to improve the reactivity of these substrates. Investigation of novel and literature thiazolium NHC pre-catalysts found that novel catalyst NHC7 successfully catalysed the intermolecular Stetter reaction of sterically non-trivial aliphatic aldehydes with enones to form 1,4-diketones, with significantly improved yields and decreased reaction times compared to literature catalysts. Steric analysis of novel and literature NHC catalyst found that NHC7 displayed unique steric features arising from the orientation of the N-mesityl substituent. The steric and electronic quantification of novel and literature NHCs has provided new insight into the underlying properties of NHC organocatalysts responsible for specific reactivity profiles and this will inform the design of future NHC organocatalysts for the intermolecular Stetter reaction and related applications.