Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Aoba, Sendai 980-8578, Japan.
Chem Asian J. 2011 Jan 3;6(1):180-8. doi: 10.1002/asia.201000549.
Two approaches for the solid-phase total synthesis of apratoxin A and its derivatives were accomplished. In synthetic route A, the peptide was prepared by the sequential coupling of the corresponding amino acids on trityl chloride SynPhase Lanterns. After cleavage from the polymer-support, macrolactamization of 10, followed by thiazoline formation, provided apratoxin A. This approach, however, resulted in low yield because the chemoselectivity was not sufficient for the formation of the thiazoline ring though its analogue 33 was obtained. However, in synthetic route B, a cyclization precursor was prepared by solid-phase peptide synthesis by using amino acids 13-15 and 18. The final macrolactamization was performed in solution to provide apratoxin A in high overall yield. This method was then successfully applied to the synthesis of apratoxin analogues. The cytotoxic activity of the synthetic derivatives was then evaluated. The epimer 34 was as potent as apratoxin A, and O-methyl tyrosine can be replaced by 7-azidoheptyl tyrosine without loss of activity. The 1,3-dipolar cycloaddition of 38 with phenylacetylene was performed in the presence of a copper catalyst without affecting the thiazoline ring.
两种固相全合成 apratoxin A 及其衍生物的方法已完成。在合成路线 A 中，通过在 trityl chloride SynPhase Lanterns 上依次偶联相应的氨基酸来制备肽。从聚合物载体上裂解后，进行 10 的大环内酯化，然后形成噻唑啉，得到 apratoxin A。然而，由于化学选择性不足以形成噻唑啉环，该方法的产率较低，尽管得到了其类似物 33。然而，在合成路线 B 中，通过使用氨基酸 13-15 和 18 在固相肽合成中制备了环化前体。最后在溶液中进行大环内酯化，以高总产率提供 apratoxin A。然后该方法成功应用于 apratoxin 类似物的合成。然后评估了合成衍生物的细胞毒性活性。外消旋体 34 与 apratoxin A 一样有效，并且可以用 7-叠氮庚基酪氨酸代替 O-甲基酪氨酸而不损失活性。在铜催化剂的存在下，进行了 38 与苯乙炔的 1,3-偶极环加成反应，而不影响噻唑啉环。
