Total synthesis of dehydrodidemnin B. Use of uronium and phosphonium salt coupling reagents in peptide synthesis in solution
Total synthesis of dehydrodidemnin B. Use of uronium and phosphonium salt coupling reagents in peptide synthesis in solution
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DOI：
10.1021/jo961932h
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发表时间：
1997-01-24
影响因子：
3.6
通讯作者：
Giralt, E
中科院分区：
文献类型：
--
作者：
Jou, G;Gonzalez, I;Giralt, E
本文报道了didemnin A和dehydrodidemnin B的新的全合成方法。后者didemnin具有最高的抗增殖活性的大环缩酚肽家族的所有成员。它是通过将侧链Pyr-Pro-OH偶联到didemnin A上产生的，didemnin A本身是通过两种新路线合成的。其中之一是基于线性七缩酚酸肽的加工，其掺入地德明侧链的第一个氨基酸（R）-N（Me）-Leu。将该线性前体的氨基和羧基末端脱保护，然后进行大环化，得到受保护的didemnin A衍生物。第二条路线涉及从缺少（R）-N（Me）-Leu的线性六缩酚酸肽合成Boc-保护的didemnin大环。从大环上除去Soc基团，然后将其与Boc-（R）-N（Me）-Leu-OH偶联，得到Boc-didemnin A。总收率远高于第二种策略（27%，而第一种合成为4%），但两者都允许制备与天然样品相同的合成didemnin A。广泛使用磷鎓和脲鎓盐基偶联试剂，如BOP、PyBrOP、PyAOP、HBTU和HATU，用于形成这些复杂缩肽中存在的仲酰胺键和叔酰胺键。
New total syntheses of didemnin A and of dehydrodidemnin B are described. The latter didemnin has the highest antiproliferative activity of all members of this family of macrocyclic depsipeptides. It was produced on coupling the side chain Pyr-Pro-OH to didemnin A, which was itself synthesized by two novel routes. One of these was based on the elaboration of a linear heptadepsipeptide incorporating the first amino acid of the didemnin side chain, (R)-N(Me)-Leu. Deprotection of the amino and carboxyl terminii of this Linear precursor followed by macrocyclization gave a protected derivative of didemnin A. The second route involved synthesis of the Boc-protected didemnin macrocycle from a linear hexadepsipeptide lacking (R)-N(Me)-Leu. Removal of the Soc group from the macrocycle followed by its coupling with Boc-(R)-N(Me)-Leu-OH then gave Boc-didemnin A. The overall yield was much higher far the second strategy (27% compared to 4% for the first synthesis), but both allowed synthetic didemnin A, identical with a natural sample, to be prepared. Extensive use was made of phosphonium and uronium salt-based coupling reagents, such as BOP, PyBrOP, PyAOP, HBTU, and HATU for the formation of both the secondary and tertiary amide bonds present in these complex depsipeptides.