Total syntheses of thiocoraline and BE-22179: Establishment of relative and absolute stereochemistry
Total syntheses of thiocoraline and BE-22179: Establishment of relative and absolute stereochemistry
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DOI：
10.1021/ja0001660
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发表时间：
2000-03-29
影响因子：
15
通讯作者：
Ichikawa, S
中科院分区：
文献类型：
--
作者：
Boger, DL;Ichikawa, S
噻可拉林（1，图1）是一种从小单孢菌L-13-ACM 2 -092中分离的强效抗肿瘤药物1。它构成了2重对称双环八缩酚肽的最新成员，包括BE-221792（2），triostin A3（3）和echinomycin 4（4），它们通过二插层与DNA结合。5，6与BE-22179不同，噻可拉林不抑制DNA拓扑异构酶I或II，但在抑制细胞周期进展和克隆形成的浓度下，它确实抑制DNA聚合酶R。7发现它解旋双链DNA，7因此它可以双插层DNA，类似于曲骨菌素、棘霉素和较大的环状十肽的成员，包括桑德拉霉素、8、9卢佐肽、9、10和喹恶肽。11对噻可拉林和BE-22179的研究已经确定了它们的二维结构，但没有确定它们的相对和绝对立体化学。1，2 Triostin和棘霉素在与喹喔啉发色团（D-Ser）的酰胺键的R-位置处具有D-立体化学，并且在剩余的立体中心处具有L-立体化学。我们已经证明，sandramycin和quinoxapeptins的类似中心，11和luzopeptins一样，10也包含D-Ser。因此，我们预期1和2可能具有类似的立体化学，并包含一个不寻常的带有D-Cys的发色团。本文报道了噻可拉林和BE-22179的首次全合成，测定了它们的相对和绝对立体化学，并制备了足够的材料进行进一步的研究。该方法的关键要素包括后期引入的发色团，对称的四肽耦合，macrocyclization的26元octadepsipeptide进行在单一的仲酰胺位点后，二硫化物形成，和收敛的组装的tetradepsipeptide与不稳定的硫酯键在最后的耦合反应在近外消旋自由的条件下。由于发色团的后期引入，尽管由于大环硫醇酯的潜在裂解而在合成中施加了挑战，但该方法提供了一系列发色团类似物的现成途径。由三肽15和N-Cbz-D-Cys-OTce（12）沿着的四缩肽16的组装以及在1中发现的三个适当官能化的Cys残基的制备总结在方案1中。用乙酰氨基甲基（Acm）基团（1.5当量的N-羟甲基乙酰胺、H2SO 4、H2O，25 ℃，12小时）和BOC基团（1.2当量的BOC 2 O、NaOH、THF-H2O，25 ℃，12小时，62%）对N-Me-Cys-OH（5）12进行顺序的S-和N-保护，得到6，桥接二硫化物Cys残基的前体。N-Me-Cys-OH的选择性S-甲基化（5，12，1.0当量的MeI，2.0当量的NaHCO 3，THF-H2O，25 ℃，3小时），接着BOC保护（1.2当量的BOC 2 O，NaOH，THF-H2O，25 ℃，12小时，73%），得到7。酯化7（1.0当量的TMSCHN 2，89%），然后对8（3 M HCl-AcOEt，91%）进行BOC脱保护，得到9，第二个L-Cys残基的前体。（1）（a）罗密欧，F.; Espliego，F.; Baz，JP; de克萨达，TG; Gravalos，D.; de la Calle，F.; Fernando-Puentes，JL J. Antibiot. 1997，50，734。(b)Perez Baz，J.; Canedo，LM; Fernando-Puentes，JL J. Antibiot. 1997，50，738。(c)Perez Baz，J.; Millan，FR; De克萨达，TG; Gravalos，DG PCT国际应用，W0952773，1995; Chem.Abst.1995，124，115561。(2)Okada，H.;铃木，H.; Yoshinari，T.; Arakawa，H.; Okura，A.;苏达，
Thiocoraline (1, Figure 1) is a potent antitumor antibiotic1 isolated from Micromonospora sp. L-13-ACM2-092. It constitutes the newest member of the 2-fold symmetric bicyclic octadepsipeptides which include BE-221792 (2), triostin A3 (3), and echinomycin4 (4), which bind to DNA with bisintercalation. 5, 6 Unlike BE-22179, thiocoraline does not inhibit DNA topoisomerase I or II, but it does inhibit DNA polymerase R at concentrations that inhibit cell cycle progression and clonogenicity. 7 It was found to unwind double-stranded DNA, 7 and thus it may bisintercalate DNA analogous to triostin, echinomycin, and members of the larger cyclic decadepsipeptides including sandramycin, 8, 9 luzopeptins, 9, 10 and quinoxapeptins. 11 Studies on thiocoraline as well as BE-22179 have established their twodimensional structures but not their relative and absolute stereochemistry. 1, 2 Triostin and echinomycin possess a D-stereochemistry at the R-position of the amide linkage to the quinoxaline chromophore (D-Ser) and L-stereochemistry at the remaining stereogenic centers. We have shown that the analogous centers of sandramycin8 and the quinoxapeptins, 11 like the luzopeptins, 10 also incorporate D-Ser. Thus, we anticipated that 1, as well as 2, might possess a similar stereochemistry with incorporation of an unusual chromophore bearing D-Cys. Herein, we report the first total syntheses of thiocoraline and BE-22179, the determination of their relative and absolute stereochemistry, and the preparation of sufficient material with which further studies may be conducted. Key elements of the approach include the late stage introduction of the chromophore, symmetrical tetrapeptide coupling, macrocyclization of the 26-membered octadepsipeptide conducted at the single secondary amide site following disulfide formation, and a convergent assemblage of the tetradepsipeptide with introduction of the labile thiol ester linkage in the final coupling reaction under near racemization free conditions. By virtue of the late stage introduction of the chromophore and despite the challenges this imposes in the synthesis because of a potential cleavage of the macrocyclic thiol ester, this approach provides ready access of a range of chromophore analogues. The assemblage of tetradepsipeptide 16 from tripeptide 15 and N-Cbz-D-Cys-OTce (12) along with the preparation of the three suitably functionalized Cys residues found in 1 are summarized in Scheme 1. Sequential S-and N-protection of N-Me-Cys-OH (5) 12 with an acetamidomethyl (Acm) group (1.5 equiv of N-hydroxymethylacetamide, H2SO4, H2O, 25 C, 12 h) and BOC group (1.2 equiv of BOC2O, NaOH, THF-H2O, 25 C, 12 h, 62%) gave 6, the precursor to the bridging disulfide Cys residue. Selective S-methylation of N-Me-Cys-OH (5, 12 1.0 equiv of MeI, 2.0 equiv of NaHCO3, THF-H2O, 25 C, 3 h) followed by BOC protection (1.2 equiv of BOC2O, NaOH, THF-H2O, 25 C, 12 h, 73%) provided 7. Esterification of 7 (1.0 equiv of TMSCHN2, 89%) followed by BOC deprotection of 8 (3 M HCl-AcOEt, 91%) provided 9, the precursor to the second L-Cys residue.(1)(a) Romeo, F.; Espliego, F.; Baz, JP; de Quesada, TG; Gravalos, D.; de la Calle, F.; Fernandez-Puentes, JL J. Antibiot. 1997, 50, 734.(b) Perez Baz, J.; Canedo, LM; Fernandez-Puentes, JL J. Antibiot. 1997, 50, 738.(c) Perez Baz, J.; Millan, FR; De Quesada, TG; Gravalos, DG PCT Int. Appl., WO952773, 1995; Chem. Abstr. 1995, 124, 115561.(2) Okada, H.; Suzuki, H.; Yoshinari, T.; Arakawa, H.; Okura, A.; Suda,