40 天然物の母骨格を有する化合物ライブラリーの構築 : マクロスフェライド誘導体のコンビナトリアル合成(口頭発表の部)

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Macrosphelide A and B, isolated from the culture medium of macrospaeropsis sp. FO-5050 by the Omura group, have been shown to strongly inhibit the adhesion of human leukemia HL-60 cells to human-umbilical-vein endothelial cells (HUVEC) in a dose-dependent fashion. Consequently, macrosphelides have received much attention as a lead compound for the development of new anti-cancer drugs and hence, a synthetic method for producing those molecules and their analogues is urgently required. We wish to report a highly convergent synthesis of a library of macrosphelide analogues on a solid-support utilizing a palladium-catalyzed chemoselective carbonylation of vinyl halides. In considering an efficient strategy for the combinatorial synthesis of macrosphelide analogues, we chose a solid-phase synthesis utilizing the three synthetic building blocks A, B, and C as illustrated in Scheme 1. The process involves: (i) attachment of the secondary alcohol in building block A to solid-support, (ii) esterification with building block B, (iii) chemoselective carbonylation of the vinyl iodide in unit A with alcohol C (iv) carbonylative macrolactonization utilizing the rather less reactive vinyl bromide on solid-support, (v) cleavage from the polymer-support. The synthesis of a macrosphelide library was accomplished by split & pool method by means of radiofrequency encoded combinatorial chemistry. The 128 IRORI MicroKans, each containing ca. 30mg of PS-DHP resin were split into individual vessels, according to radiofrequency signals. After attachment of building block A with PPTS, MicroKans were pooled together for deprotection of the TBS group. These microreactors were decoded and split, followed by esterification with building block B to afford the polymer-bound ester. Further sorting, followed by carbonylative esterification of vinyl iodides with building block C to provide the polymer-bound diester. The microreactors were again pooled for the deprotection of the MPM group with DDQ and the carbonylative macrolactonization utilizing Pd_2(dba)_3/dppf as a catalyst to provide 16-membered lactone on solid-support. Finally, the microreactors were divided and treated with 4N-HCl in parallel for removal of the MEM group and cleavage for the polymer-support. Purification by automated preparative HPLC provided 122-member macrosphelide analogues among 128 trials.
天然有機化合物討論会の論文
2003-09-01

40 天然物の母骨格を有する化合物ライブラリーの構築 : マクロスフェライド誘導体のコンビナトリアル合成(口頭発表の部)

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