PD 125375三環結構的合成研究
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2017
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1987年由C. Rithner團隊在Streptomyces achromogenes中所分離出三種化合物，兩種為具有pyrrolobenzodiazepine (PBD)結構的生物鹼，且具有抗菌活性的已知化合物Tomaymycin和Oxotomaymycin，第三種為本篇主要化合物PD 125375。PD 125375具有5-6-5三環結構且含有兩個連續的手性中心，在pyrrolidine上具有一個E form的3- ethylidine取代，而結構是與Tomaymycin類似，雖然PD 125375與Tomaymycin皆有3-ethylidinepyrrolidine的結構，但PD 125375的生物合成途徑及全合成是尚未被研究的，而我們則致力於利用化學合成途徑去合成出PD 125375，我們開發了一個使用簡單的方法，讓氮上具有保護的prolinal與N-Ts-pyrrole利用LDA的鹼性條件下進行反應，進而得到具有高立體選擇性的單一產物，經由一些官能基的轉換，再由分子內提供羰基和進行分子內合環反應而得到5-6-5三環結構之化合物。
PD 125375 and the well-known antibiotic Tomaymycin, a pyrrolobenzodiazepine (PBD) alkaloid, were isolated from the Streptomyces achromogenes and characterized by C. Rithner. It has a 5-6-5 tricyclic core with two contiguous chiral carbons, as well as the E form of 3-ethylidene on the pyrrolidine ring, which was structurally related to Tomaymycin. Although the novel structure of PD 125375 includes the 3-ethylidenepyrrolidine moiety also present in Tomaymycin, the biosynthetic pathway leading to PD 125375 is not developed. We were particularly interested in the synthesis of PD 125375. We have developed a simple method to synthesize the coupled product from N-protected prolinal and lithiated N-Ts-pyrrole by LDA with high stereoselectivity. After functional group manipulations, the removal of both N-protecting groups, and the introduction of the bridged carbonyl group between two nitrogens, the 5-6-5 tricyclic core could be obtained as a single stereoisomer in 11 synthetic steps.
PD 125375 and the well-known antibiotic Tomaymycin, a pyrrolobenzodiazepine (PBD) alkaloid, were isolated from the Streptomyces achromogenes and characterized by C. Rithner. It has a 5-6-5 tricyclic core with two contiguous chiral carbons, as well as the E form of 3-ethylidene on the pyrrolidine ring, which was structurally related to Tomaymycin. Although the novel structure of PD 125375 includes the 3-ethylidenepyrrolidine moiety also present in Tomaymycin, the biosynthetic pathway leading to PD 125375 is not developed. We were particularly interested in the synthesis of PD 125375. We have developed a simple method to synthesize the coupled product from N-protected prolinal and lithiated N-Ts-pyrrole by LDA with high stereoselectivity. After functional group manipulations, the removal of both N-protecting groups, and the introduction of the bridged carbonyl group between two nitrogens, the 5-6-5 tricyclic core could be obtained as a single stereoisomer in 11 synthetic steps.
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脯胺酸, 吡咯, 全合成, proline, pyrrole, PD 125375