89(P-26) ペプチド性チオストレプトン系抗生物質の合成研究(ポスター発表の部)

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In 1955, thiostrepton was isolated from the culture broth of Streptomyces azureus by Squibb group. Other structurally related antibiotics, the siomycins and the thiopeptins, were also isolated. The characteristic structure of this thiostrepton family of peptide antibiotics is the bicyclic structure containing a tetrasubstituted dehydropiperidine and/or piperidine moiety, a tetrasubstituted dihydroquinoline moiety, four thiazole moieties, a thiazoline moiety, dehydroamino acid moieties, and a dihydroxyisoleucine moiety. These antibiotics show strong activities against Gram-positive bacteria and mycobacteria. Herein, we report the syntheses of the tetrasubstituted dehydropiperidine moiety (segment A), the tetrasubstituted dihydroquinoline moiety (segment C), and a dehydroamino acid moiety (segment D) toward the total synthesis of siomycins. The one-pot, three components coupling of (R)-(-)-p-toluenesulfinamide 18, the aldehyde derivative 17, and the dehydropyrrolidine derivative 12 afforded the desired coupling product 20. After removal of the sulfinyl group of 20, the stereoselective reduction of the resulting mixture of 21, 22 and 23 afforded the desired piperidine derivative 24 as the sole product. Condensation of 24 with an L-alanine derivative, followed by regioselective dehydrogenation of the piperidine ring, afforded the desired tetrasubstituted dehydropiperidine moiety 26 (segment A). Dihydroquinoline derivative 31 was prepared from 5,6,7,8-tetrahydroquinoline 27 by the modified Reissert-Henze reaction, the aromatic radical substitution reaction, and the Boekelheide rearrangement as the key steps. This dihydroquinoline 31 was converted to the chiral epoxide 33 by the asymmetric epoxidation, followed by regioselective bromination and oxidation. Dehydrobromination and the protective group manipulation gave the tetrasubstituted dihydroquinoline moiety 36 of siomycin D_1 (segment C). Furthermore, the diastereoselective methylation of 33, followed by dehydrobromination, afforded the tetrasubstituted dihydroquinoline moiety 38 of thiostrepton and siomycins. The regioselective opening of the epoxide of 39 with an L-valine derivative, as the model coupling between segment C and segment D, afforded the tetrasubstituted dihydroquinoline moiety 40 of siomycin D_1. Consecutive condensation of β-phenylselenoamino acids, 42 and 43, and an L-valine derivative 41 afforded the precusor 44 of the dehydroamino acid moiety.
天然有機化合物討論会の論文
2002-09-01

89(P-26) ペプチド性チオストレプトン系抗生物質の合成研究(ポスター発表の部)

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