Total synthesis of salinosporamide a

Salinosporamide A is a natural product isolated from actinomycete bacteria which live in tropical and subtropical ocean sediments. It's structure contains a four-membered lactone fused to a five-membered lactam, a ring structure which is also seen in the related compound omuralide. Omuralide has been of interest as a highly specific inhibitor of the 20S proteosome, an abundant complex that is responsible for the fragmentation and removal of unwanted proteins from within cells. As a result, omuralide and it's precursor lactacystin have been used as tools for the study of protein biochemistry. Salinosporamide A is approximately 35 times more effective at proteosome inhibition, and also displays highly potent cytotoxicity against a range of tumour cell lines.The proposed research seeks to develop an efficient total synthesis of salinosporamide A. The synthesis will demonstrate the utility of recently developed catalytic enantioselective methodology for the assembly of the densely functionalised core structure. The brevity and modular nature of the synthesis should allow the production of significant quanities of the natural product, as well as ready access to a range of analogues which will be tested for their biological activity.

1. We have developed a range of reductive aldol cyclisation methodologies that result in beta-hydroxylactones and lactams. These include cobalt, nickel, and copper-catalysed processes that employ either diethylzinc or siloxanes as stoichiometric reducing agents. We originally hoped these methods could be applied to the synthesis of the natural product salinosporamide A.
2. In particular, we have discovered that a nickel-catalysed reductive aldol cyclisation-lactonisation cascade proved to be particularly suitable for application to our target molecule, which ultimately resulted in our completion of a formal total synthesis of salinsporamide A.