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Intramolecularcyclization by solid-phase olefination and its application to combinatorial synthesis

固相烯化分子内环化及其在组合合成中的应用

基本信息

批准号：
10557210
负责人：
AKAJI Kenichi
金额：
$ 3.65万
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 (B)
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

项目摘要

We selected intramolecular macrocyclization as a suitable reaction that could be carried out efficiently on solid support rather than in solution because of the "pseudo-dilution" effect. For macrocyclization, we used Heck reaction, a palladium-mediated vinylation of organic halide, as a suitable carbon-carbon bond forming reaction. Based on the above approach, we synthesized a cyclic tetrapeptide derivative using the Heck coupling of acrylic acid amide to a 3-iodobenzyl amine moiety on solid support. The cyclic derivative contains a new 3-substituted cinnamic acid template to construct the rigid cyclic structure and Arg-Gly-Asp (RGD), a tripeptide sequence known to bind to the glycoprotein IIb/IIIa (GP IIb/IIIa). GPIIb/IIIa is a membrane protein expressed on the surface of activated platelets which binds to fibrinogen to cause platelet aggregation.Palladium(0)-mediated macrocyclization employing Pd(OAc)ィイD22ィエD2 with PhィイD23ィエD2PandBuィイD24ィエD2NCI in a DMF/HィイD22ィエD2O/EtィイD23ィエD2N solvent system was carried out at 37℃ for 4h. The homogeneous product was obtained form the resin in 30% overall yield (calculated form the starting resin). We then investigate cyclization efficiency on solid support in comparison with that in solution phase. The intramolecular cyclization in solution proceeded in proportion to the reaction time, but was relatively slow. In contrast, most of the precursor was converted to the product within 2h. The results clearly showed that Pd(0)-mediated intramolecular macrocyclization is a unique reaction especially suitable for solid phase organic synthesis.In conclusion, we have demonstrated that Heck reaction can be used to prepare macrocyclic derivatives on solid support. The mild reaction conditions and high efficiency allow the application of this procedure to combinatorial library synthesis for designing high affinity ligands of GPIIb/IIIa.

我们选择分子内大环化作为一种合适的反应，由于“伪稀释”效应，它可以在固体载体上有效地进行，而不是在溶液中进行。对于大环化，我们使用Heck反应，钯介导的有机卤化物乙烯化反应，作为一个合适的碳-碳键形成反应。基于上述方法，我们在固体载体上利用丙烯酸酰胺与3-碘苄基胺的Heck偶联合成了一个环四肽衍生物。该环衍生物包含一个新的3-取代肉桂酸模板来构建刚性环结构和Arg-Gly-Asp (RGD)，这是一个已知与糖蛋白IIb/IIIa （GP IIb/IIIa）结合的三肽序列。GPIIb/IIIa是一种表达在活化血小板表面的膜蛋白，它与纤维蛋白原结合导致血小板聚集。钯(0)介导的大环化反应以Pd(OAc) φ φ D22 φ φ D2和Ph φ φ D23 φ φ D2PandBu φ φ D24 φ D2NCI为原料，在DMF/H φ φ D22 φ D2O/Et φ D23 φ D2N溶剂体系中进行，温度37℃，反应时间4h。以30%的总收率（从起始树脂计算）得到均匀的产物。然后，我们比较了固相和固相的循环效率。溶液中的分子内环化与反应时间成正比，但相对缓慢。相比之下，大部分前体在2h内转化为产物。结果清楚地表明，Pd(0)介导的分子内大环化反应是一种特别适合于固相有机合成的独特反应。总之，我们已经证明了Heck反应可以用于制备固体载体上的大环衍生物。该方法反应条件温和，效率高，可用于设计GPIIb/IIIa高亲和配体的组合文库合成。