A concise and straightforward total synthesis of (+/-)-salinosporamide A, based on a biosynthesis model |
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Authors: | Mulholland Nicholas P Pattenden Gerald Walters Iain A S |
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Institution: | School of Chemistry, University of Nottingham, Nottingham, UK. |
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Abstract: | A 14-step total synthesis of (+/-)-salinosporamide A (1), a potent inhibitor of the 20S proteasome isolated from the marine bacterium Salinospora tropica, is described. The synthesis is based on a diastereoselective intramolecular aldolisation of a substituted beta-keto amide intermediate, i.e. 13, derived from a beta-keto acid, viz. 21, and an alpha-amino malonate, leading to the pyrrolidinone ring 24 in the natural product. This synthetic approach closely mimics the origin of the pyrrolidinone ring in salinosporamide A in vivo. Another key feature of the total synthesis is a regioselective reduction of the malonate derivative 31 to the key aldehyde intermediate 32, using Super-hydride. |
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