Total synthesis of the antimitotic bicyclic peptide celogentin C.
Total synthesis of the antimitotic bicyclic peptide celogentin C.
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抗魔法双环肽Celogentin C的总合成。
DOI：
10.1021/ja909870g
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发表时间：
2010-01-27
影响因子：
15
通讯作者：
Castle SL
中科院分区：
文献类型：
--
作者：
Ma B;Banerjee B;Litvinov DN;He L;Castle SL
报道了celogentin C的全合成方法。从右向左合成这种双环八肽的方法是不成功的，因为无法详细说明右手环的衍生物。在这些努力的过程中，发现McFadyen-Stevens反应的温和Braslau修饰提供了将柠檬酸酯还原为醛的有用方法。然后检查从左到右的合成策略。不寻常的Leu-Trp侧链的交联存在于左手的大环是通过一个由分子间Knoevenagel缩合，自由基共轭加成，和SmI 2介导的硝基还原三步序列形成的。随后的大环内酰胺化提供了所需的环系统。左手环合成的高产率和简洁性抵消了自由基共轭加成的适度非对映选择性。然后通过吲哚-咪唑氧化偶联完成右侧环的Trp-His侧链连接特征的形成。值得注意的是，在该反应中需要Pro-OBn作为添加剂。详细的机理研究表明，Pro-OBn缓和了反应混合物中NCS的浓度，从而使不希望的二氯化副产物的产生最小化。经大环内酰胺化和脱保护后得到天然产物。咪唑氢原子的化学位移表现出显着的温度，浓度和pH值的依赖性。抗肿瘤筛选表明，celogentin C抑制某些癌细胞系的生长。
An account of the total synthesis of celogentin C is presented. A right-to-left synthetic approach to this bicyclic octapeptide was unsuccessful due to an inability to elaborate derivatives of the right-hand ring. In the course of these efforts, it was discovered that the mild Braslau modification of the McFadyen–Stevens reaction offers a useful method of reducing recalcitrant esters to aldehydes. A left-to-right synthetic strategy was then examined. The unusual Leu–Trp side-chain cross-link present in the left-hand macrocycle was fashioned via a three-step sequence comprised of an intermolecular Knoevenagel condensation, a radical conjugate addition, and a SmI2-mediated nitro reduction. A subsequent macrolactamization provided the desired ring system. The high yield and concise nature of the left-hand ring synthesis offset the modest diastereoselectivity of the radical conjugate addition. Formation of the Trp–His side chain linkage characteristic of the right-hand ring was then accomplished by means of an indole–imidazole oxidative coupling. Notably, Pro-OBn was required as an additive in this reaction. Detailed mechanistic investigations indicated that Pro-OBn moderates the concentration of NCS in the reaction mixture, thereby minimizing the production of an undesired dichlorinated byproduct. The natural product was obtained after macrolactamization and deprotection. The chemical shifts of the imidazole hydrogen atoms exhibited significant dependence on temperature, concentration, and pH. Antitumor screening indicated that celogentin C inhibits the growth of some cancer cell lines.
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影响因子：
3.6
作者：
BOGER, DL;PATEL, M
通讯作者：
PATEL, M
DOI：
10.1002/cber.19610940337
发表时间：
1961-01-01
期刊：
CHEMISCHE BERICHTE-RECUEIL
影响因子：
--
作者：
BIRKOFER, L;BIERWIRTH, E;RITTER, A
通讯作者：
RITTER, A
影响因子：
2.6
作者：
Abaee, M. Saeed;Mojtahedi, Mohammad M.;Khavasi, Hamidreza
通讯作者：
Khavasi, Hamidreza
影响因子：
3.6
作者：
Casimir, JR;Guichard, G;Briand, JP
通讯作者：
Briand, JP
影响因子：
2.1
作者：
Engqvist, R;Bergman, J
通讯作者：
Bergman, J