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

我们所选择的intramolecular macrocyclization as a suitable reaction that could be carried outefficiently on solid support rather than in solution because of the pseudo-dilution effect. Formacrocyclization, we used Heck reaction, a palladium-mediated vinylation of organic halideas a suitable carbon-carbon bond forming reaction. Based on the above approach Based on the above approach我们将cyclic tetrapeptide derivative using the Heck coupling of acrylic acid amide to aiodobenzyl amine moiety on solid support. The cyclic derivative contains a new 3-substitutedcinnamic acid template to construct the rigid cyclic structure and Arg-Gly-Asp （RGD）tripeptide sequence known to bind to the glycoprotein IIb/IIIa (GP IIb/IIIa). GPIIb/IIIa is amembrane protein expressed on the surface of activated platelets which to fibrinogen to causeplatelet aggregation.Palladium(0)-mediated macrocyclization employing Pd(OAc) - D22 - D2 withD2PandBu D2NCI in a DMF/H D22 D2O/Et D23 D2N solvent system was carried out at37℃for 4h. The homogeneous product was obtained form The resin in 30% overall yield (calculatedform the starting resin . We then投资cyclization efficiency on solid support in comparisonwith in solution phase. The intramolecular cyclization in solution proceeded in proportion tothe reaction time，但relatively slow. In contrast，大多数前cursor was converted to the product within 2h. the results clearly showed thatPd(0)-mediated intramolecular macrocyclization is a unique reaction especially suitable for solidphase organic synthesis.In conclusion，我们已经demonstrated that Heck reaction can be used to prepare macrocyclic derivatives on solidsupport. The mild reaction conditions and high efficiency allow The application of this procedure tocombinatorial library synthesis for designing high affinity ligands of GPIIb/IIIa。

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.