Environmentally benign reactions for large-scale syntheses of bioactive natural products and their application to drug discovery

大规模合成生物活性天然产物的环境友好反应及其在药物发现中的应用

• 批准号: 13853010
• 负责人: KITA Yasuyuki
• 金额: $ 76.13万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (S)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13853010/
• 关键词: environmentally benign reactions; recyclable reagent; reactions in water; dynamic kinetic optical resolution; domino reaction; hypervalent iodine reagent; enzymatic reaction; bioactive natural product synthesis; リサイクル型点反応剤; ディスコルハブディンアルカロイド; スキホ

1) Study using hypervalent iodine reagents : Efficient synthetic method of spiro dienone skeletons from phenyl ethers has been developed. The method was applied to the total synthesis of galanthamine and its analogues, in which the compound as a candidate drug for Alzheimer disease was found. Anti-tumor marine natural products, discorhabdins A, E, F, O and prianosin B, were synthesized. Among the synthesized analogues, a stable oxa analogue having almost the same biological activity as unstable discorhabdin A was found. Various transformation reactions activated by KBr in water have been developed. New recyclable and environmentally benign hypervalent iodine reagents have been developed.2) Study using radical reactions : Radical cyclization and efficient synthetic method of thioesters or amides from aldehydes in water have been achieved by the combination of water-soluble radical initiator and surfactant. New radical reaction without toxic Sn compound has been developed.3) Study using … More lipase catalyst : Versatile synthetic methods for chiral quaternary carbons using a new acylating agent, ethoxyvinyl 2-furoate, and lipase. Anti-cancer antibiotics, fredericmycin A, was synthesized in optically active form by this method as a key reaction. This asymmetric synthetic method of chiral quaternary carbons was also applied to concise asymmetric syntheses of the key intermediates for the syntheses of biologically active indole alkaloids. Unprecedented and efficient domino reactions, first optical resolution of alcohol with our acyl reagent and successive intramolecular Diels-Alder reaction, have been developed. These domino reactions were expanded to dynamic kinetic optical resolutions by using originally developed ruthenium catalyst, which does not inhibit the activity of lipase.4) Study using cation species : Efficient and versatile syntheses of various 2,3-disubstituted indole alkaloids have been developed by aromatic Pummerer-type reaction. Aromatic Pummerer-type reaction was also effective for regioselective introduction of carbon nucleophiles to thiophens and furans. Stereoselective rearrangement of 2,3-epoxy-1-alcohol derivatives has been developed to give chiral spiro centers and chiral quaternary carbon centers. The reaction was applied to the asymmetric syntheses of (-)-herbertenediol and (-)-α-herbertenol. Concise asymmetric synthesis of scyphostatin, which is recognized as a lead compound for the treatment such as inflammation and autoimmune disease, has been achieved by the intramolecular haloetherification and deprotection of acetals with TESOTf-base combination developed by us as key reactions. Less

1)高价碘试剂的研究：开发了以苯基醚为原料合成螺二烯酮骨架的高效方法。将该方法应用于加兰他敏及其类似物的全合成，发现该化合物可作为阿尔茨海默病的候选药物。合成了抗肿瘤的海洋天然产物二叉菜素A、E、F、O和prianosin B。在合成的类似物中，发现了一种稳定的oxa类似物，其生物活性与不稳定的discorhabdin a几乎相同。研究了KBr在水中活化的各种转化反应。开发了可回收、环保的新型高价碘试剂。2)自由基反应的研究：通过水溶性自由基引发剂与表面活性剂的结合，实现了醛类化合物在水中的自由基环化和高效合成硫酯或酰胺的方法。开发了一种新的不含有毒锡化合物的自由基反应。3)使用更多脂肪酶催化剂的研究：使用一种新的酰化剂、乙氧基2-糠酸酯和脂肪酶合成手性季碳的多种方法。以该方法为关键反应合成了具有旋光性的抗癌抗生素弗雷德里克霉素A。这种手性季碳的不对称合成方法也被应用于合成具有生物活性的吲哚类生物碱的关键中间体的简明不对称合成。前所未有的高效多米诺反应，首次用我们的酰基试剂光学分解醇和连续的分子内Diels-Alder反应，已经被开发出来。这些多米诺骨牌反应扩展到动态动力学光学分辨率使用最初开发的钌催化剂，它不抑制脂肪酶的活性。4)正离子研究：利用芳香族pummer型反应，高效、通用地合成了多种2,3-二取代吲哚类生物碱。芳香族pummerer型反应对碳亲核试剂在噻吩和呋喃上的区域选择性引入也很有效。2,3-环氧-1-醇衍生物的立体选择性重排得到了手性螺旋中心和手性季碳中心。将该反应应用于(-)-草烯二醇和(-)-α-草烯醇的不对称合成。以我们开发的以tesotf为基础的缩醛分子内卤化醚化和脱保护为关键反应，实现了硫磷抑素的简洁不对称合成，被认为是治疗炎症和自身免疫性疾病的先导化合物。少

项目成果

Asymmetric Total Synthesis of Fredericamycin A via Intramolecular Cycloaddition Pathway

分子内环加成途径不对称全合成 Fredericamycin A

• 发表时间: 2005
• 期刊: Chemistry A-European Journal 11
• 作者: AKAI;Shuji;KITA;Yasuyuki et al.
• 通讯作者: Yasuyuki et al.

Chapter 8 : Synthetic Applications (Total Synthesis and Natural Product Synthesis) ; 'Hypervalent Iodine Compounds', Top.Current Chem.(T.Wirth, Ed.)

第8章：合成应用（全合成和天然产物合成）；

• 发表时间: 2003
• 作者: TOHMA;Hirofumi
• 通讯作者: Hirofumi

MATSUGI, Masato: "^1H HMR Determination of Absolute Configuration of 1-or 2-Aryl-Substituted Alcohols and Amines by Means of Their Diastereomers : Novel Separation Technique of Diastereomeric Derivatives of Pyridyl Alcohols by Extraction"Chem. European J.

MATSUGI, Masato：“^1H HMR 通过非对映异构体测定 1-或 2-芳基取代的醇和胺的绝对构型：通过萃取提取吡啶醇非对映异构衍生物的新颖分离技术”Chem.

FUJIOKA, Hiromichi: "Kinetically Controlled Optical Resolution of Racemic Norbomene Aldehyde Derivatives"Chirality. 15. 60-67 (2003)

藤冈弘道：“外消旋降冰片烯醛衍生物的动力学控制光学拆分”手性。

KITA, Yasuyuki: "A Novel and Efficient Methodology for the C-C Bond Forming Radical Cyclization of Hydrophobic Substartes in Water"Organic Letters. 3. 1157-1160 (2001)

KITA，Yasuyuki：“一种新颖有效的 C-C 键形成水中疏水基团自由基环化的方法”有机快报。