总合成的拉莫普拉宁A2和拉莫普拉诺酸甘的总合成
Wanlong Jiang1, Jutta Wanner, Richard J Lee
1Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Journal of the American Chemical Society
|February 13, 2003
概括
这项研究详细介绍了拉莫普拉宁A2及其亚格利康的融合合成. 关键步骤包括准备三个子单元,将它们合起来,并循环形成depsipeptide核心,从而使未来的抗微生物模拟开发成为可能.
科学领域:
- 有机化学 有机化学
- 药用化学 医学化学
- 合成生物学 合成生物学
背景情况:
- 拉莫普拉宁A2是一种复杂的糖抗生素,具有显著的抗菌活性.
- 由于其复杂的结构,拉莫普拉宁A2及其亚格利康的总合成具有相当大的挑战.
- 了解合成对于开发新型抗菌剂至关重要.
研究的目的:
- 为了披露拉莫普拉宁A2及其亚格利康的融合总合成的全部细节.
- 建立一种可用于制备具有潜在抗菌应用的类似物的合成途径.
- 为了研究宏循环化策略,以有效地形成depsipeptide核心.
主要方法:
- 融合合成涉及三个关键子单元:七,五和五.
- 对于pentadepsipeptide骨干雌激素的l-threo-beta-hydroxyasparagine的不对称合成.
- 优化化条件 (EDCI,DMAP,0°C) 以尽量减少种族化和化阻碍的酒精.
- 战略性合地点的选择,以最大限度地实现融合,并防止晚期种族化.
- 针对49个成员环闭的两个宏环化位点 (Phe{9) -d-Orn{10) 和Gly{14) -Leu{15) 的研究.
- 后期结合了depsipeptide子单元和Asn(1) 侧链.
主要成果:
- 三个关键子单元的成功准备和顺序合.
- 有效地形成了49个成员的aglycon.peptide核心的有效形成.
- 高产量 (89%) 宏循环在Phe{9}-d-Orn{10}位点,可能有助于β-sheet预组织.
- 可接受的产量 (40-50%) 在Gly(14) -Leu(15) 位点进行宏环化,适用于模拟合成.
- 已证明用于模拟开发的后期修改的可行性.
结论:
- 已经实现了拉莫普拉宁A2亚格利康的强大且融合的总合成.
- 开发的合成策略允许高效地构建复杂的宏环脱核.
- 该方法提供了一个平台,通过后期修改来访问新型,强效的抗微生物类似物.
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