118(P-52) ロゼオフィリンの全合成研究(ポスター発表の部)

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Roseophilin (1) isolated from Streptomyces griseoviridis by Seto et al. in 1992, exhibits potent cytotoxicity against human cancer cell lines. The structure of 1 was revealed by extensive spectroscopic studies to have a unique ansa-bridged cyclopenta[b]pyrrole skeleton incorporated with a characteristic conjugated heterocyclic ring system containing furan and pyrrole moieties. Its remarkable biological properties as well as its novel structural features make 1 an exceptionally intriguing and timely target for total synthesis. In 1998, Furstner et al. reported the first total synthesis of 1. Subsequently to this report, the formal total synthesis of 1 was disclosed by several research groups. Herein we wish to present our own results with respect to the formal total synthesis of 1. Roseophilin (1) can be disconnected retrosynthetically to provide the heterobiaryl part 2 and the macrotricyclic part 3. At first, we pursued the synthesis of 2 starting from the known 3-chloro-2-formylpyrrole (5) prepared from commercially available 4-nitropyridine N-oxide (12). Conversion of 5 to the diketone 15 was conducted by a five-step sequence of reactions. The diketone 15 was treated with a catalytic amount of camphorsulfonic acid in methanol to give the desired 2-furylpyrrole 17 (76%) in one-pot reaction by sequential deprotection of the THP group, ring closure, and O-methylation. Further deprotection of the tosyl group in 17 furnished the heterobiaryl part 2. Next, we investigated the synthesis of the macrotricyclic part 3, the coupling partner of 2, staring from the known 3-formylpyrrole (11). Thus, 3-formylpyrrole (11) was transformed to the iodide 23, the substrate for the first key macrocyclization, in 34% over all yield through an eight-step sequence. The crucial macrocyclization was found to be effected by treating 23 with cesium carbonate in DMF at 90℃ under a diluted condition (5.0mM), providing the macrocyclic olefin 24 in 38% yield. After hydrogenation of the double bond in 24, the resulting product 25 was further converted to the bromopyrrole 27, the second key cyclization precursor, in 63% overall yield via three step operations. Lithiation of 27 with n-BuLi at ?78℃ underwent the cyclization, affording the desired pyrrole-fused cyclopentanone system 28 in 39% yield. Finally, 28 was subjected to demethoxycarbonylation to give the requisite macrotricyclic part 3. The total synthesis of roseophilin (1) by the coupling reaction of 2 and 3 has been established by Furstner et al., therefore, our synthesis of 2 and 3 constitutes the formal total synthesis of 1. In summary, we have succeeded in developing a novel synthetic pathway to the heterobiaryl part 2 and the macrotricyclic part 3 of roseophilin (1). The sequence for the synthesis of 2 involves the furan ring formation from the diketone 15 as the key step. Furthermore, the method for the synthesis of 3 features the macrocyclization of the iodide 23 to elaborate the desired thirteen-membered carbocycle 24 (23→24) and the base-induced annulation of the bromopyrrole 27 to construct the requisite pyrrole-fused cyclopentanone ring system 28 (27→28) as the key steps. Our successful synthesis of 2 and 3 signifies the formal total synthesis of 1.
天然有機化合物討論会の論文
2000-10-01

118(P-52) ロゼオフィリンの全合成研究(ポスター発表の部)

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