Catalytic Asymmetric Synthesis of Bioactive Molecules

生物活性分子的催化不对称合成

• 批准号: 07557139
• 负责人: TOMIOKA Kiyoshi
• 金额: $ 7.87万
• 依托单位: KYOTO UNIVERSITY (1996-1997)Osaka University (1995)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07557139/
• 关键词: chiral ligand; lithiumthiolate; conjugate addition; lithium enolate; catalytic reaction; asymmetric reaction; 2-trimethylsilythiphenol; 炭素-イオウ結合; 三成分錯体; リチウムアミド; β-ラクタム; 有機銅; 付加反応; 立体選択性; 反応面; 求核付加反応; イミン; 不斉補助剤

As our continuing studies toward enantioselective reactions of organolithiums based on an external chiral ligand, we have developed the catalytic asymmetric addition of thiophenol to enoates using lithium thiophenolate as a catalytic nucleophile which has higher reactivity than thiophenol activated by amine. The 2-substituent of thiophenol exerts profound effects on reactivity and enantioselectivity in the asymmetric addition reaction with enoates catalyzed by lithium thiophenolate and a chiral ligand. The bulky substituent gave the higher reactivity and enantioselectivity. The asymmetric reaction of 2-trimethylsilylthiophenol with methyl enoates was catalyzed by the combination of 0.08 eq of lithium 2-trimethylsilylthiophenolate and 0.1 eq of the chiral ligand, (1R,2R)-1-dimethylamino-2-(2-methoxyphenoxy)-1,2-diphenylethane, in toluene-hexane (1 : 1) to afford the corresponding methyl 3-(2-trimethylsilylphenylthio) carboxylates in excellently high ees. The chiral ligand was recovered quantitatively for reuse without racemization. The 2-trimethylsilyl group was protodesilylated by treatment with triflic acid to give the corresponding 3-phenylthiocarboxylates in excellently high yield without racemization. The kinetic control is operative in the asymmetric addition reaction.

作为我们对有机锂化合物基于外手性配体的不对称加成反应的继续研究，我们开发了苯硫酚与烯酸酯的催化不对称加成反应，其中苯硫酚锂作为催化亲核试剂，比苯硫酚被胺活化具有更高的反应活性。在硫酚锂与手性配体催化的烯酸酯不对称加成反应中，硫酚的2-位取代基对反应活性和对映选择性有重要影响。取代基的体积越大，反应活性和对映选择性越高。在甲苯-己烷（1：1）中，0.08eq的2-三甲基硅基硫酚锂和0.1eq的手性配体（1 R，2 R）-1-二甲氨基-2-（2-甲氧基苯氧基）-1，2-二苯基乙烷催化2-三甲基硅基硫酚与烯酸甲酯的不对称反应，得到了3-（2-三甲基硅基苯硫基）羧酸甲酯。手性配体被定量回收，无需外消旋即可重复使用。用三氟甲磺酸处理2-三甲基硅烷基，得到相应的3-苯硫代羧酸酯，产率很高，没有外消旋。动力学控制在不对称加成反应中起作用。

项目成果

N.Nishimura: "Steric Tuning of Reactivity and Enantioselectivity in Addition of Thiophenol to α.β-Unsaturated Esters Mediated by a Chiral Ligand" J.Am.Chem.Soc.119・52. 12974-12975 (1997)

N. Nishimura：“手性配体介导的苯硫酚与 α.β-不饱和酯的反应性和对映选择性的空间调节”J.Am.Chem.Soc.119·52 (1997)。

K.Tomioka: "Enantioselective Addition of Thiazolylliithium to Aldimines with the Aid of Chiral Ligand" Heterocycles. 47. 77-78 (1998)

K.Tomioka：“在手性配体的帮助下，噻唑基锂对醛亚胺的对映选择性加成”杂环。

Y.Nagaoka: "Structural Requirements of External,Chiral Amidophospine Ligand for Asymmetric Reaction of Organocopper Reagent." Tetradroon Letters. 37・43. 7805-7808 (1996)

Y. Nagaoka：“有机铜试剂不对称反应的外部手性氨基膦配体的结构要求”37・43 (1996)。

Masashi Mizuno, Kunihiko Fujii, and Kiyoshi Tomioka: "The Asymmetric Horner-Wadsworth-Emmons Reaction Mediated by An External Chiral Ligand." Angew.Chem.Int.Ed.Engl. 37(4). 515-517 (1998)

Masashi Mizuno、Kunihiko Fujii 和 Kiyoshi Tomioka：“外部手性配体介导的不对称霍纳-沃兹沃斯-埃蒙斯反应”。

Katsumi Nishimura, Takashi Ono, Yasuo Nagaoka, and Kiyoshi Tomioka: "Steric Tuning of Reactivity and Enantioselectivity in Addition of Thiophenol to alpha, beta-Unsaturated Esters Mediated by a Chiral Ligand." J.Am.Chem.Soc.119(52). 12974-12975 (1997)

Katsumi Nishimura、Takashi Ono、Yasuo Nagaoka 和 Kiyoshi Tomioka：“在手性配体介导的 α、β-不饱和酯中添加苯硫酚，对反应性和对映选择性进行空间调节。”