New Method for Construction of Contiguous Chiral Centers with Hetero-atom Substituent

构建杂原子取代基连续手性中心的新方法

• 批准号: 03671022
• 负责人: NAITO Takeaki
• 金额: $ 1.34万
• 依托单位: Kobe Women's College of Pharmacy
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-03671022/
• 关键词: Nucleophilic Addition; Thiophenol; Benzyl Mercaptan; Unsaturated Acid; Diltiazem; Isositsirikine; gamma-Lactone; Stereoselectivity; チオフェノ-ル; γーラクトン

Considering that contiguous stereogenic centers with hetero-atom substituent are shown in the structures of not only many medicinals but also the biologically active compounds, we investigated to explore a new method for the construction of contiguous stereogenic centers via the route involving the stereospecific nucleophilic addition reaction of hetero-atom centered nucleophiles to electron-withdrawing olefins. Among the nucleophilic addition reactions investigated, the addition of thiols to alpha, beta- unsaturated esters proceeded stereospecifically in the presence of small amount of lithium thiophenoxide to give the erythro- and threoadducts from E- and Z-olefins, respectively.Adducts prepared by the addition reaction were found to be potential synthons by demonstrating the synthesis of natural alkaloids with ethylidene group and asymmetric synthesis of a famous drug (+)-diltiazem. Combination of the newly developed stereospecific nucleophilic addition of thiols and syn-elimination of the corresponding sulfoxide of the resulting adducts completed the total synthesis of the whole alkaloids of isositsirikine group.Addition reactions of thiols to the unsaturated acid derivatives having chiral auxiliary proceeded smoothly to give the chiral adducts diastereoselectively which was effectively converted into (+)-diltiazem, a cardiac drug. The other chiral ad-duct was also effectively converted to (+)-trans-whisky and cognac lactones via stereoselective nucleophilic substitution of the corresponding sulfonium group.Thus, we have now developed a new strategy for construction of the contiguous stereogenic centers with hetero-atom substituent via stereospecific nucleophilic addition reaction of thiols.

考虑到具有杂原子取代基的连续立体中心不仅存在于许多药物的结构中，而且存在于生物活性化合物的结构中，我们研究了通过杂原子中心的亲核试剂与吸电子烯烃的立体特异性亲核加成反应来构建连续立体中心的新方法。在研究的亲核加成反应中，巯基与α、β -不饱和酯的加成反应在少量噻吩氧化锂的存在下进行了立体特异性反应，分别从E-烯烃和z -烯烃中得到红加和三加。加成反应制备的加合物是潜在的合成物，通过对天然生物碱与乙基的合成和著名药物(+)-地尔硫卓的不对称合成进行了论证。结合新建立的立体特异性亲核巯基加成和相应的亚砜的共消，完成了异西sirikine族整个生物碱的全合成。巯基与具有手性助剂的不饱和酸衍生物的加成反应顺利进行，使手性加合物具有非对映选择性，有效地转化为(+)-地尔硫卓，一种心脏药物。另一种手性加合管也通过相应的磺酸基的立体选择性亲核取代有效地转化为(+)-反式威士忌和干邑内酯。因此，我们现在开发了一种新的策略，通过立体定向的亲核加成反应来构建具有杂原子取代基的连续立体中心。

项目成果

内藤 猛章: "Stereoselective Isomerization of Ethylidene Lactam for the Synthesis of (+)-Z-Isositsirikines" Tetrahedron Lett.,. 30. 2941-2944 (1989)

Takeaki Naito：“亚乙基内酰胺的立体选择性异构化用于合成 (+)-Z-Isositsirikines”Tetrahedron Lett., 30. 2941-2944 (1989)

宮田 興子: "A New Stereoselective Route to γ-Butyrolactones:Asymmetric Synthesis of (+)-trans-Whisky and (+)-trans-Cognac Lactones" Chem.Pharm.Bull.40. 2579-2581 (1992)

Kiko Miyata：“γ-丁内酯的新立体选择性路线：(+)-反式威士忌和(+)-反式干邑内酯的不对称合成”Chem.Pharm.Bull.40 2579-2581 (1992)。

二宮 一彌: "Synthesis of Corynanthe Alkaloids Corynantheine,Hirsuteine,and the Isositsirikines" Heterocycles,. 30. 1031-1077 (1990)

Kazuya Ninomiya：“Corynanthe 生物碱 Corynantheine、Hirsuteine 和 Isositsirikines 的合成”Heterocycles，30。1031-1077 (1990)

宮田 興子: "A Facile Conversion of (Z)-2-Alkenoic Esters into the (E)-Isomers with Diphenyl Disulfide" Synthesis. 1123-1126 (1990)

Koko Miyata：“用二苯基二硫醚将 (Z)-2-烯酸酯轻松转化为 (E)-异构体”合成 1123-1126 (1990)。

宮田 興子: "A Facile Conversion of (Z)-2-Alkenoic Esters into the (E)-Isomers with Diphenyl Disulfide" Synthesis,. 1123-1126 (1990)

Koko Miyata：“用二苯基二硫醚将 (Z)-2-烯酸酯轻松转化为 (E)-异构体”合成，1123-1126 (1990)。