Convergent synthesis and SAR of dolastatin 15 by solid phase coupling

Dolastatin 15是Pettit et. al.于1989年从海洋软体动物Dolabella auricularia中分离到的一种细胞抑制沉积肽。在dolastatin中，从印度洋海中分离出了一系列前所未有的线性和环状抗肿瘤和/或细胞抑制肽，其中dolastatin 15和dolastatin 10因其强大的选择性活性而成为最重要的两个成员。为了完成dolastatin 15的合成，采用CIP/HOAt法在肽片段和非肽片段之间进行单步缩合，因为在Pro残基上活化是抵抗异构化的。N， N-二甲胺酸被纳入肽片段2，因为cip介导的激活预计对溶液中的受阻偶联足够有效。采用Pro、2-羟基异戊酸（Hiva）和苯丙氨酸（Phe）制备非肽片段。吡咯烷酮环是通过cip介导的苯丙氨酸和麦尔德拉姆酯作为C2单元偶联而成。对于肽片段的制备，选择cip介导的n -甲胺酸在固体载体上偶联的激活作为促进dolastatin 15实际合成的较好方案。因此，在根据该方案合成dolastatin 15之前，我们评估了cip介导的激活在固体载体上制备含有n -甲胺酸的肽序列的效率。综上所述，以CIP-HOAt为高效偶联剂，实现了片段与吡咯烷酮片段单步缩合的聚合合成。cip介导的反应也成功地应用于n -甲胺酸在固体载体上的偶联，证明了固相法在天然产物合成中的首次实际应用

Dolastatin 15 is a cytostatic depsipeptide isolated from the marine mollusk Dolabella auricularia by Pettit et. al. in 1989. Among the dolastatins, an unprecedented series of linear and cyclic antineoplastic and/or cytostatic peptide isolated from the Indian Ocean sea hare, dolastatin 15 as well as dolastatin 10 represent the two most important members because of the strong and selective activities.For completing the synthesis of dolastatin 15, single step segment condensation between peptide fragment and nonpeptide fragment by the CIP/HOAt method was used, since activation at the Pro residue is resistance to isomerization. N, N-dimethylamino acid was incorporated in peptide fragment 2 since CIP-mediated activation is expected to be efficient enough for hindered couplings in solution. Pro, 2-hydroxyisovaleric acid (Hiva), and Phe was employed for the preparation of nonpeptide fragment. The Pyrrolidone ring of was constructed by the CIP-mediated coupling of Phe and Meldrum's ester employed as C2 unit. For the preparation of peptide fragment, CIP-mediated activation for the coupling of N-methylamino acid on solid support was selected as a preferable scheme to facilitate the practical synthesis of dolastatin 15. Thus, prior to the synthesis of dolastatin 15 according to the scheme, we evaluated CIP-mediated activation for its efficiency in preparing peptide sequence containing N-methylamino acids on solid support.In conclusion, a convergent synthesis utilizing single step condensation of fragment and pyrrolidone fragment using CIP-HOAt as an efficient coupling reagent was achieved. The CIP-mediated reaction was also successfully applied for coupling of N-methylamino acid on solid support, demonstrating the first practical application of the solid-phase procedure for natural product synthesis