P-46 プロテアソーム阻害活性天然物Salinosporamide Aの合成研究(ポスター発表の部)
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Salinosporamide A (1, NPI-0052) was isolated from a marine bacterium of the new genus Salinospora (strain CNB-392) by W. Fenical et al. in 2003. This compound displays remarkable in vitro cytotoxicity towards many tumour cell lines (IC_<50> of approximately 10nM), and its activity appears to be directed to the inhibition of the 20S proteasome. Owing to the potent biological activity and the fascinating inhibitory mechanism, as well as this complex chemical structure, 1 has been an attractive target for the synthetic chemist, and several total synthesis of the metabolite have now been published. Encouraged by the recent SAR studies showing that the chloroethyl moiety of 1 is responsible to the enhanced biological activities compared with omuralide (2), we have continued our studies to develop a convergent route to 1, featuring the intermolecular aldolization to connect the C2-C3 juncture. In the beginning, we started the model studies on the synthesis of 7,8-dihydrosalinosporamide A. The oxazoline 14 was synthesized from commercially available aldehyde 9 via azide 11, on treatment under various aldolization conditions, 14 brought about retro-Dieckmann decomposition. To avoid this pitfall, we converted keto ester 14' to ketone 17, which was subjected to Reformatsky reaction developed by Honda et al. to give 18a and 18b as a 1:1 stereoisomeric mixture. DBU-induced epimerization at C2 position afforded 18b from 18a in excellent yield After leading 18b to 21 in 5 steps, the treatment of diol 21 with 1-MeAZADO/PhI(OAc)_2 system provided β-lactone in one step, thereby confirming the feasibility of our strategy. Chiral azide 28 was synthesized from (S)-methyl lactate via 13 steps sequence (total 16 steps) involving Ireland-Claisen reaction, RCM using the 1st Grubbs catalyst We also developed more efficient route: oxazoline 35 was elaborated from (R)-Garner aldehyde via 10 steps. The details of the synthesis and progress toward the total synthesis of salinosporamide A will be discussed.
- 天然有機化合物討論会の論文
- 2008-09-01
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