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

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。对于大环化，我们曾经使用过赫克反应，一种钯介导的有机卤化物乙烯基化，是一种适合的碳-碳键形成反应。根据上面的方法，我们合成了一种循环四肽衍生物，使用Heck对丙烯酸酰胺到固体支持的3-碘联苯胺动力学。环衍生物含有一个新的3改性的肉桂酸模板，用于构建刚性环结构和Arg-Gly-Asp（RGD），一个已知的三肽序列与糖蛋白IIb/IIIa （GP IIb/IIIa）结合在一起。GPIIb/IIIa是一个membrane protein expressed on the surface of activated platelets which binds to fibrinogen to cause platelet aggregation。Palladium（0）-mediated macrocyclization employing Pd（OAc）-D22-D2 with Ph-D23-D2PandBu-D24-D2NCI in a DMF/H-D22-D2O/Et-D23-D2N solvent system was carried out at 37-for 4 h。同源产品在总产量为30%的土地上形成了树脂（计算形成了初始树脂）。然后，我们将在与解决方案阶段的固体支持进行比较时进行研究。在解决方案中发生的内分子循环化在反应时间的增加中，但相对缓慢。在对比度下，大多数的预制剂在2小时内转换成了产品。结果清楚地显示了Pd（0）介导的内聚大环化是固体相位有机合成的一种独特反应，特别适合于固体支持的一种独特反应，在凝聚中，我们已经证明了Heck反应可以用来准备固体支持上的大环衍生物。微反应条件和高效率允许将此程序应用到组合库合成器中，用于设计GPIIb/IIIa的高亲和力标志。

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.