Development of reactions based on addition of electrophiles to methylenebisphosphonates

基于向亚甲基二膦酸酯添加亲电子试剂的反应的发展

• 批准号: 12672053
• 负责人: NAGAOKA Yasuo
• 金额: $ 1.86万
• 依托单位: Kansai University (2001-2002)Kyoto University (2000)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672053/
• 关键词: alkenylphosphonate; allene; chiral phosphine ligand; conjugate addition; conjugate reduction; vinyl anion; Michael reaction; ヒストン脱アセチル化酵素; HDAC; ホスホナート; 環化反応

Allenes are recent focus of versatile class of intermediates in a variety of organic synthetic processes. We developed a novel method to synthesize allenes by successive Horner-Wadsworth-Emmons olefination starting from methylene-bisphosphonate and two carbonyl compounds. The key to success is KH or KH-18-crown-6 as a base for second HWE olefination of hydroxyalkenylphosphonates. Asymmetric allene synthesis based on this method is now in progress.As our continuing studies of efficient synthetic application of lithium phosphonates, we have developed cyclization reaction of bis-alkenylphosphonate 1. Although the reaction of 1 with organolithium reagents afforded both tandem Michael cyclization products and α-deprotonation-cyclization products, the latter was selectively formed in high yield by simply treating 1 with LDA. Application of chiral bis-alkenylphosphonate 2 opens a simple synthetic way to chiral phosphine ligand 5. Treatment of 2 with LDA followed by electrophilic trapping of intermediate cyclic lithium phosphonate 3 with benzaldehyde afforded aldol-type adduct 4 in 54%. The alcohol 4 was transformed to 5 by 6 steps in 16% yield.

烯类化合物是近年来广泛应用于各种有机合成工艺的多用途中间体。以二膦酸亚甲酯和两个羰基化合物为起始原料，采用Horner-Wadsworth-Emmons连续烯烃法合成了烯类化合物。成功的关键是KH或KH-18冠-6作为羟基烯基膦酸盐二次HWE烯烃的碱。基于这种方法的不对称烯的合成正在进行中。随着我们对磷酸锂高效合成应用的不断研究，我们开发了磷酸二烯基1的环化反应。虽然1与有机锂试剂的反应可以产生串联Michael环化产物和α-去质子环化产物，但α-去质子环化产物是通过对1进行简单的LDA处理而选择性形成的，产率较高。手性膦酸二烯基2的应用为手性膦配体5的合成开辟了一条简单的途径。用LDA处理2，然后用苯甲醛对中间环磷酸锂3进行亲电捕获，得到了54%的醛型加合物4。乙醇4经6步转化为5，收率为16%。

项目成果

Hideki Inoue, Yasuo Nagaoka, Kiyoshi Tomioka: "A New Methodology for Synthesis of A Chiral Phosphinocarboxylic Acid Through Micael Cyclization-Aldol Tandem Reaction of Chiral α,β,χ,ψ-Unsaturated Bisphosphine Oxide and Application in Palladium-Catalyzed As

Hideki Inoue、Yasuo Nagaoka、Kiyoshi Tomioka：“通过手性 α,β,χ,ψ-不饱和双膦氧化物的 Micael 环化-羟醛串联反应合成手性膦羧酸的新方法及其在钯催化 As 中的应用

Masashi Ono, Katsumi Nishimura, Hiroshi Tsubouchi, Yasuo Nagaoka, Kiyoshi Tomioka: "Total Synthesis of (-)-Neplanocin A by Using Lithium Thiolate-Initiated Michael-Aldol Tandem Cyclization Reaction"J.Org.Chem.. 66(24). 8199-8203 (2001)

Masashi Ono、Katsumi Nishimura、Hiroshi Tsubouchi、Yasuo Nagaoka、Kiyoshi Tomioka：“利用硫醇锂引发的 Michael-Aldol 串联环化反应全合成 (-)-Neplanocin A”J.Org.Chem.. 66(24)。

Hideki Inoue, Hiroshi Tsubouchi, Yasuo Nagaoka, Kiyoshi Tomioka: "Synthesis of Allenes by Double Horner-Wadsworth-Emmons Reaction"Tetrahedron. 58(1). 83-90 (2002)

Hideki Inoue、Hiroshi Tsubouchi、Yasuo Nagaoka、Kiyoshi Tomioka：“通过双霍纳-沃兹沃斯-埃蒙斯反应合成艾伦烯”四面体。

Shinichi Uesato, Manabu Kitagawa, Yasuo Nagaoka, Taishi Maeda, Hiroshi Kuwajima, Takao Yamori: "Novel Histone Deacetylase Inhibitors : N-Hydroxy-carboxamids Possessing a Terminal Bicyclic Aryl Group"Bioorg.Med.Chem.Lett.. 12(10). 1347-1349 (2002)

Shinichi Uesato、Manabu Kitakawa、Yasuo Nagaoka、Taishi Maeda、Hiroshi Kuwajima、Takao Yamori：“新型组蛋白脱乙酰酶抑制剂：具有末端双环芳基的 N-羟基-羧酰胺”Bioorg.Med.Chem.Lett.. 12(10)。

Kiyoshi Tomioka, Yoshio Shioya, Yasuo Nagaoka, Ken-ichi Yamada: "Electronic and Steric Control in Regioselective Addition Reaction of Organolithium Reagents with Enaldimines"J. Org. Chem.. 66 (21). 7051-7054 (2001)

Kiyoshi Tomioka、Yoshio Shioya、Yasuo Nagaoka、Ken-ichi Yamada：“有机锂试剂与烯醛亚胺的区域选择性加成反应中的电子和空间控制”J。