PD 125375 的結構及合成研究

Abstract

在1987年，Rithner團隊從Streptomyces sp.中分離出已知生物鹼tomaymycin以及oxotomaymycin。也意外發現未知的第三個生物鹼PD 125375。其中tomaymycin和oxotomaymycin曾經廣泛地被研究過，已被發現具有抗腫瘤以及抗菌活性。第三個生物鹼PD 125375具有吡咯-吡咯烷的特殊骨架結構，雖然PD 125375缺乏抗腫瘤和抗菌活性，但由於其結構的特色，引起本實驗室的關注。 PD 125375具有5-6-5三環核心骨架，並且具有兩個連續的掌性中心，以及在吡咯烷的2號位上上有一個E組態的環外亞乙基取代。在文獻上尚未有人研究PD 125375的生物合成以及全合成。在本論文中，我們使用了一個簡單的方法來合成PD 125375。在EDCI的條件下，將4-亞乙基-L-脯胺醇與吡咯2-羧酸進行耦合反應，得到脯胺醇-吡咯耦合產物。並使用戴斯－馬丁氧化劑完成將一級醇氧化成醛，氧化後產物在弱酸性條件下進行分子內加成反應，得到合環產物。In 1987, Rithner’s group isolated tomaymycin, oxotomaymycin known to have antibacterial activity, from Streptomyces sp. and, simultaneously, also unexpectedly isolated the unknown third metabolite, PD 125375. Tomaymycin and oxotomaymycin are both well-known alkaloids exhibited antibacterial activities. The third metabolite, PD125375, was isolated and characterized as a pyrrole-pyrrolidine containing alkaloid. Although this compound is devoid of antitumor and antimicrobial activity, its marvelous structure has received our attention. PD 125375 possesses a 5-6-5 tricyclic core with two contiguous chiral carbons, as well as an E form of excocyclic 2-ethylidene on the pyrrolidine ring. The biosynthesis and total synthesis of PD 125375 have not been studied. We herein developed a simple method to synthesize PD 125375. We used a concise strategy to synthesize the proline-pyrrole coupled adduct from 4-ethylidene-L-prolinol and pyrrole carboxylic acid under EDCI condition. The oxidation of primary alcohol to aldehyde was accomplished with Dess-Martin periodinane, and the resulting aldehyde precursor immediately underwent intramolecular addition reaction under weak acidic condition to afford ring-closure product.