Total synthesis of chlorofusin, its seven chromophore diastereomers, and key partial structures.
Total synthesis of chlorofusin, its seven chromophore diastereomers, and key partial structures.
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DOI：
10.1021/ja8012819
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发表时间：
2008-09-17
影响因子：
15
通讯作者：
Boger, Dale L.
中科院分区：
文献类型：
--
作者：
Clark, Ryan C.;Lee, Sang Yeul;Boger, Dale L.
Chlorofusin是最近分离到的一种天然存在的p53 - MDM2复合物形成抑制剂，其结构由密集功能化的氮唑啉衍生的发色团组成，通过鸟氨酸的末端胺连接到9个残基环肽。本文报道了氯藻素全合成的全部细节，从而导致了复合发色团的绝对立体化学的分配和相对立体化学的重新分配。将氮杂酚酮发色团前体的每个对映体与受保护的鸟氨酸苏氨酸二肽的n -胺缩合，然后对反应性最强的烯烃进行一步氧化/螺旋环化反应，得到了完整合成的发色团-二肽共轭物的所有八个非对映体。将这8种化合物的光谱性质与天然产物的简单模型的光谱性质进行比较，可以完全分配氯藻素发色团的（4R,8S,9R）立体化学。二肽偶联物的天然非对映异构体在聚类全合成中被纳入，证实了其立体化学重配，并建立了其绝对立体化学。同样地，在整个合成的后期聚合点上，剩余的7个发色团-二肽偶联物被单独地结合到氯藻素的9个残基环肽中（每个步骤4），提供了天然产物的所有剩余的7个可能的发色团非对映体。
Chlorofusin is a recently isolated, naturally occurring inhibitor of p53−MDM2 complex formation whose structure is composed of a densely functionalized azaphilone-derived chromophore linked through the terminal amine of ornithine to a nine residue cyclic peptide. Herein we report the full details of the total synthesis of chlorofusin, resulting in the assignment of the absolute stereochemistry and reassignment of the relative stereochemistry of the complex chromophore. Condensation of each enantiomer of an azaphilone chromophore precursor with the Nδ-amine of a protected ornithinethreonine dipeptide, followed by a one-step oxidation/spirocyclization of the most reactive olefin provided all eight diastereomers of the fully elaborated chromophore−dipeptide conjugate. Comparison of the spectroscopic properties for these eight compounds and those of simpler models with that reported for the natural product allowed the full assignment of the (4R,8S,9R)-stereochemistry of the chlorofusin chromophore. The natural, but stereochemically reassigned, diastereomer of the dipeptide conjugate was incorporated in a convergent total synthesis of chlorofusin confirming the stereochemical reassignment and establishing its absolute stereochemistry. Similarly and enlisting the late stage convergent point in the total synthesis, the remaining seven diastereomers of the chromophore−dipeptide conjugates were individually incorporated into the 9-residue cyclic peptide of chlorofusin (4 steps each) providing all seven remaining possible chromophore diastereomers of the natural product.
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影响因子：
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