Synthetic Studies on Substituted Citrate Natural Products based on the Cinchona Alkaloid-Catalyzed Asymmetric Baylis-Hillman reaction

基于金鸡纳生物碱催化不对称Baylis-Hillman反应的取代柠檬酸盐天然产物的合成研究

• 批准号: 13672221
• 负责人: IWABUCHI Yoshiharu
• 金额: $ 2.37万
• 依托单位: Tohoku University (2002)Nagasaki University (2001)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672221/
• 关键词: Baylis-Hillman reaction; asymmetric synthesis; asymmetric catalvsis; substituted citrate; tertiary amines; nucleophilic catalysis; cinchona alkaloids; Baylis-Hillman反応

We have previously developed a highly enantioselective asymmetric BaylisHillman reaction which allows us to construct a wide variety of (α-methylene-β-hydroxy)esters with highly optical purity (>90% ee). The reaction relies upon the combinatorial use of two important reagents, 1,1,1,3,3,3-hexafluoroisopropyl acrylate as an activated alkene and (3R, 8K,,9S)-10,11-dihydro-3,9-epoxy-6'-hydroxy-cinchonane as a chiral, nucleophilic amine catalyst. In this research program, we have established the synthetic utility of the reaction system in a practical sense, by demonstrating its applicability to the crucial step in total syntheses of biologically active natural products, including a potent immunosuppressant amino acid, (-)-mycestericin E, and a novel proteasome inhibitor epopromycin B. The reaction was found to be applicable to α-keto ester-type substrates to furnish the corresponding α-methylene-β-alkoxycatbonyl-β-hydroxy)esters in good chemical yield with modest enantioselectivity. These reaction products should serve as useful synthons for the preparation of a series of substituted citratetype compounds.

我们已经开发了一种高对映选择性的不对称Baylis-Hillman反应，该反应使我们能够构建多种具有高光学纯度（> 90%ee）的（α-亚甲基-β-羟基）酯。该反应依赖于两种重要试剂的组合使用，作为活化烯烃的丙烯酸1，1，1，3，3，3-六氟异丙酯和作为手性亲核胺催化剂的（3R，8 K，9 S）-10，11-二氢-3，9-环氧-6 ′-羟基-辛可南。在这项研究计划中，我们已经建立了一个实际意义上的反应系统的合成效用，通过证明其适用性的生物活性天然产物，包括一个强大的免疫抑制剂氨基酸，（-）-mycestericin E，和一个新的蛋白酶体抑制剂epopromycin B的总合成的关键步骤。发现该反应适用于α-酮酯型底物，以良好的化学产率和适度的对映选择性提供相应的α-亚甲基-β-烷氧基羰基-β-羟基）酯。这些反应产物可作为制备一系列取代柠檬酸酯类化合物的有用试剂。

项目成果

Y.Iwabuchi, T.Sugihara, T.Esumi, S.Hatakeyama: "An enantio-and stereocontrolled route to epopromycin B via cinchona alkaloid catalyzed Baylis-Hillman reaction"Tetrahedron Letters. 42・44. 7867-7871 (2001)

Y.Iwabuchi、T.Sugihara、T.Esumi、S.Hatakeyama：“通过金鸡纳生物碱催化的 Baylis-Hillman 反应生成依普霉素 B 的对映体和立体控制途径”Tetrahedron Letters 42・44。

Y.Iwabuchi, T.Sugihara, T.Esumi, S.Hatakeyama: "An enantio-and stereocontrolled route to epopromycin B via cinchoha alkaloid catalyzed Baylis-Hillman reaction"Tetrahedron Letters. 42・44. 7867-7871 (2001)

Y.Iwabuchi、T.Sugihara、T.Esumi、S.Hatakeyama：“通过金鸟生物碱催化的 Baylis-Hillman 反应生成依普霉素 B 的对映体和立体控制途径”Tetrahedron Letters 42・44。

Y.Iwabochi, T.Sngihara, T.Esumi, S.Hatakeyama: "An enantio- and stereocontrolled route to epopromycin B via cinchoha alkaloid catalyzed Baylis-Hillman reaction"Tetrahedron Letters. 42. 7867-7871 (2001)

Y.Iwabochi、T.Sngihara、T.Esumi、S.Hatakeyama：“通过金鸟生物碱催化的 Baylis-Hillman 反应生成依普霉素 B 的对映体和立体控制途径”四面体快报。

Y.Iwabuchi, M.Furukawa, T.Esumi, S.Hatakeyama: "An enantio-and stereocontrolled synthesis of (-)-mycestericin E via cinchona alkaloid-catalyzed asymmetric Baylis-Hiliman reaction"ChemicalCommunications. 19. 2030-2031 (2001)

Y.Iwabuchi、M.Furukawa、T.Esumi、S.Hatakeyama：“通过金鸡纳生物碱催化的不对称 Baylis-Hiliman 反应对映体和立体控制合成 (-)-mycestericin E”ChemicalCommunications。

Y.Iwabuchi, M.Furukawa, T.Esumi, S.Hatakeyama: "An enantio-and stereocontrolled synthesis of (-)-mycestericin E via cinchona alkaloid-catalyzed asymmetric Baylis-Hillman reaction"Chemical Communications. 2030-2031 (2001)

Y.Iwabuchi、M.Furukawa、T.Esumi、S.Hatakeyama：“通过金鸡纳生物碱催化的不对称 Baylis-Hillman 反应对映体和立体控制合成 (-)-mycestericin E”《化学通讯》。