1999 Fiscal Year Final Research Report Summary
Intramolecularcyclization by solid-phase olefination and its application to combinatorial synthesis
| Project/Area Number |
10557210
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Osaka University (1999)
Kyoto Pharmaceutical University (1998) |
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Principal Investigator |
AKAJI Kenichi Institute for Protein Research, Osaka University, Associate Professor, 蛋白質研究所, 助教授 (60142296)
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| Co-Investigator(Kenkyū-buntansha) |
赤路 健一 大阪大学, 蛋白質研究所, 助教授 (60142296)
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| Project Period (FY) |
1998 – 1999
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| Keywords | solid pahse synthesis / intramolecular cyclization / Heck reaction / RGD structure / fibrinogen binding |
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| Research Abstract |
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.
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