Identification of the quinol metabolite "sorbicillinol", a key intermediate postulated in bisorbicillinoid biosynthesis
Identification of the quinol metabolite "sorbicillinol", a key intermediate postulated in bisorbicillinoid biosynthesis
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DOI：
10.1021/ja003013l
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发表时间：
2000-12-20
影响因子：
15
通讯作者：
Hirota, A
中科院分区：
文献类型：
--
作者：
Abe, N;Sugimoto, O;Hirota, A
Nicolaou等人最近定义了“双环菌素”1。为了指定一组与山梨素2相关的二聚体天然产物，其中不同的结构3和有趣的生物活性4被几个组报道。已知一些真菌属(木霉、黄萎病和青霉菌)会产生双孢霉素类化合物，其生物合成引起了许多研究者的兴趣。德雷丁等人。在1981、3a、1983、3c和1986年假设了从山梨素(2)到双维菌素(3b)和/或双维菌素(4)的假想生物合成方案。三曲曲宁(6b)和双龙吉喹内酯(6a)的三维生物发生是由Satake等人报道的。3h和Crews等人，分别为3k。我们还在1998年提出了一条不同的生物合成路线来合成双长链喹内酯(双环丁烯内酯6a)和双环菌素内酯(7)。3j所有这些由独立研究人员假设的生物合成途径都提出了一个共同的关键中间体--苯二酚1(方案1)，该中间体可以互变异构体的形式存在。Corey等人。以对苯二酚中间体(S)-1为原料合成了三氯二聚醇(5)。5另一方面，Nicolaou和他的同事在我们提出的生物合成路线的基础上，在双球菌素(3a)、双长喹内酯(biorbibutenolide，6a)和5的仿生全合成中生成了喹酚中间体(()-1)。3J，6在这些合成研究中，苯二酚中间体1在反应条件下自发发生二聚反应，没有得到假定中间体的证据。因此，对苯二酚中间体1似乎具有很高的活性，很难分离。我们分离了10个与山梨素有关的化合物，它们可以清除自由基团1，1-二苯基-2-苦基肼(DPPH)。3I，J，m，L木霉产生的双孢菌素类化合物的高效液相色谱连续分析。USF-2690表明，发酵早期积累了一种不稳定的代谢物。该化合物对浓度和溶剂萃取高度敏感，并迅速转化为其他化合物。我们认为未知化合物很可能是对苯二酚中间体1，因此我们试图确定它的结构。该菌株在30℃的倒置摇床上培养；7通过高效液相分析对产物进行监测，8在4.3分钟时检测到一种未知的代谢物(代谢物X，图1A)。随着双环菌素类化合物的产生，峰面积逐渐减小。溶剂提取使X峰迅速消失，而在16.8min处出现一峰，与双球菌素(3a)的保留时间一致。此外，浓度至干燥，包括冷冻干燥，增加了22.7分钟的三氯二聚醇(5)的峰值，伴随着X峰的降低。这些结果强烈地表明代谢产物X是生物合成的共同前体。
The “Bisorbicillinoids” 1 were recently defined by Nicolaou et al. to designate a group of dimeric sorbicillin2-related natural products, the diverse structures3 and interesting biological activities4 of which were reported by several groups. It is known that a few fungal genera (Trichoderma, Verticillium, and Penicillium) produce bisorbicillinoids, and their biosynthesis is of interest to many investigators. Dreiding et al. postulated a hypothetical biosynthetic scheme from sorbicillin (2) to bisvertinoquinol (3b) and/or to bisvertinol (4) in 1981, 3a 1983, 3c and 1986. 3d Biogenesis of trichotetronine (6b) and bislongiquinolide (6a) were reported by Satake et al. 3h and Crews et al., 3k respectively. We also proposed a different biosynthetic route to bislongiquinolide (bisorbibutenolide 6a) and bisorbicillinolide (7) in 1998. 3j All of these biosynthetic pathways, postulated by independent investigators, proposed a common key intermediate, quinol 1 (Scheme 1), which can exist in tautomeric forms. Corey et al. synthesized trichodimerol (5) by way of the quinol intermediate (S)-1. 5 On the other hand, Nicolaou and co-workers generated quinol intermediate (()-1 in biomimetic total synthesis of bisorbicillinol (3a), bislongiquinolide (bisorbibutenolide, 6a), and 5, on the basis of our proposed biosynthetic route. 3j, 6 In these synthetic studies, dimerization of quinol intermediate 1 occurred spontaneously under the reactive conditions and no evidence for the postulated intermediate was obtained. Therefore, quinol intermediate 1 seemed to be highly reactive and difficult to isolate. We have isolated 10 sorbicillin-related compounds, which can scavenge a free radical species, 1, 1-diphenyl-2-picrylhydrazyl (DPPH). 3i, j, m, l A continuous, careful HPLC analysis of bisorbicillinoids produced by Trichoderma sp. USF-2690 indicated that an unstable metabolite accumulated in the early stages of the fermentation. The compound was highly sensitive to concentration and solvent extraction, and quickly changed into other compounds. We thought that the unknown was likely to be the quinol intermediate 1, hence we tried to determine its structure. The strain was cultivated on a reciprocal shaker at 30 C; 7 the products were monitored by HPLC analysis, 8 and an unidentified metabolite at 4.3 min was detected (Metabolite X, Figure 1A). The area of the peak gradually reduced with production of bisorbicillinoids. Solvent extraction caused rapid disappearance of the peak of X, while a peak at 16.8 min, which was consistent with the retention time of bisorbicillinol (3a), appeared in the HPLC analysis. In addition, concentration to dryness, including lyophilization, increased the peak at 22.7 min for trichodimerol (5), with concomitant decrease of peak X. These results strongly suggested Metabolite X was the biosynthetic common precursor