Convergent synthesis and SAR of dolastatin 15 by solid phase coupling

固相偶联聚合合成多拉司他汀15及比吸收率

• 批准号: 10672011
• 负责人: AKAJI Kenichi
• 金额: $ 2.3万
• 依托单位: Osaka University (1999)Kyoto Pharmaceutical University (1998)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10672011/
• 关键词: solid pahse synthesis; coupling reaction; dolastatin 15; CIP reagent; 固相上縮合; 縮合剤; Nメチルアミノ酸; デブシペプチド

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

Dolastatin 15是Pettit et.在1989年。海兔素是从印度洋海兔中分离得到的一系列新颖的线性和环状多肽，其中海兔素15和海兔素10具有很强的活性和选择性，是海兔素中最重要的两个成员。因为在Pro残基处的活化是对异构化的抗性。将N，N-二甲基氨基酸掺入肽片段2中，因为CIP介导的活化预期对于溶液中的受阻偶联足够有效。用Pro、2-羟基异戊酸（Hiva）和Phe制备非肽片段。通过CIP介导的Phe和用作C2单元的Meldrum酯的偶联构建吡咯烷酮环。为了制备多肽片段，选择CIP介导的活化用于在固体支持物上偶联N-甲基氨基酸作为优选方案，以促进多拉司他汀15的实际合成。因此，在根据该方案合成多拉司他汀15之前，我们评估了CIP介导的活化在固体载体上制备含有N-甲基氨基酸的肽序列的效率。总之，使用CIP-HOAt作为有效偶联试剂，实现了利用片段和吡咯烷酮片段的单步缩合的会聚合成。CIP介导的反应也成功地应用于N-甲基氨基酸在固体载体上的偶联，证明了固相过程在天然产物合成中的首次实际应用

项目成果

Kenichi Akaji: "Convergent Synthesis of Dolastatin 15 by Solid Phase Coupling of an N-Methylamino Acid"J. Org. Chem.. 64(2). 405-411 (1999)

Kenichi Akaji：“通过 N-甲基氨基酸固相偶联合成多拉司他汀 15”J。

Kenichi Akaji: "Efficient Synthesis of Peptaibol Using a Chloro Imidazolidium Coupling Reagent,CIP" Tetrahedron. 53. 567-584 (1997)

Kenichi Akaji：“使用氯咪唑啉偶联试剂，CIP 有效合成 Peptaibol”四面体。

Kenichi Akaji: "Convergent Synthesis of Dolastatin 15 by Solid Phase Coupling of N-Methylamino Acid"Peptide Chemistry,1998. 9-12 (1999)

Kenichi Akaji：“通过 N-甲基氨基酸固相偶联合成多拉司他汀 15”肽化学，1998 年。

Kenichi Akaji: "Convergent Synthesis of Dolastatin 15 by Solid Phase Coupling of N-Methylamino Acid"Peptide Chemistry, 1998. 9-12 (1999)

Kenichi Akaji：“通过 N-甲基氨基酸固相偶联合成多拉司他汀 15”肽化学，1998. 9-12 (1999)