P-64 Salinosporamide Aの全合成(ポスター発表の部)

概要

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Salinosporamide A (1), a potent 20S proteasome inhibitor, was first isolated from marine actinomycete Salinospora tropicana by Fenical and colleagues in 2003. The β-lactone-γ-lactam bicycle structure is very similar to that of omuralide (2), a well-known potent 20S proteasome inhibitor derived from lactacystin (3) and first discovered by us in 1991 as a result of microbial screening for nerve growth factor-like activity. The proteasome inhibitory activity of 1 is approximately 35 times greater than 2; thus indicating that it is a strong candidate for development of new anticancer drugs. Indeed, related compounds are currently in clinical trials for the treatment of cancer. This biological profile and its structural complexity have prompted substantial efforts for the total synthesis of salinosporamide A (1). Herein, we report the total synthesis of salinosporamide A (1). The outstanding feature of our synthetic route is the stereoselective construction of the cyclohexene ring by controlling the C5 and C6 stereogenic centers through a chelation-controlled aldol reaction as a crucial reaction in an early stage of the total synthesis. This strategy differs from total syntheses previously reported. Other important features of our total synthesis include enzymatic desymmetrization, intramolecular aldol reaction, and intermolecular Reformatsky-type reaction followed by 1,4-reduction.
天然有機化合物討論会の論文
2008-09-01