EFFICIENT ENANTIOMER SYNTHESIS BY USE OF TOLERANT LEWIS ACID CATALYSTS : ASYMMETRIC CONJUGATE ADDITION REACTIONS

使用耐受性路易斯酸催化剂进行高效对映体合成：不对称共轭加成反应

• 批准号: 11450350
• 负责人: KANEMASA Shuji
• 金额: $ 9.34万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11450350/
• 关键词: tolerant chiral Lewis acid catalyst; strongly coordinating nucleophile; R,R-DBFOX; Ph; enantioselective conjugate addition reaction; enantioselective conjugate addition; O-benzylhydroxylamine; Michael addition of marononitrile; cyclobutanone forma

One of the unsolved problems in the field of Lewis acid-catalyzed stereoselective reactions is the development of chiral Lewis acid catalysts which are tolerant to strongly coordinating nucleophiles and applications to organic synthesis. From this standpoint, we have developped a variety of transition metal complexes of 4, 6-dibenzofurandiyl-2, 2'-bis(4-phenyloxazoline)(R, R-DBFOX/Ph) and the copper(II) complex of isopropylidene-2, 2'-bis[4-(o-hydroxybenzyl)oxazoline] (R,R-BOX/o-HOBn) and utilized to the catalyzed asymmetric conjugate additions of O-benzylhydroxylamine, malononitrile, and cyclic 1, 3-diketones. The floowing results have been obtained.1. Enantioselective Conjugate Additions of a Hydroxylamine : The copper(II) complex of R, R-BOX/o-HOBn was found to act as an efficient chiral Lewis acid catalyst in conjugate addition reactions of O-benzylhydroxylamine. 1-Crotonoyl-3-isopropyl-2-imidazolidinone was the best acceptor which provided the maximum enantioselectivity up to 97% … More ee when the reaction was performed in a dilute condition (0.03 M) at -40℃. Acceptor molecules having a variety of substituents at β-position can be successfully employed showing that this reaction proves to be useful and convenient access to enantiomers of β-amino acid delivertives.2. Enantioselective Conjugate Additions of Malononitrile : In the reactions of malononitrile activated by a catalytic amount of 2, 2, 6, 6-tetramethylpiperidine (TMP) with 3-crotonoyl-2-oxazolidinone activated by the nickel(II) aqua complex of R, R-DBFOX/Ph, the corresponding Michael adduct was produced in enantioselectivities up to 94% ee. This reaction provides the first successful example for the double activation type catalyzed asymmetric reactions in which both of acceptor and donor molecules have been activated separately by Lewis acid and base catalysts.3. Enantioselective Cyclobutanone Formation Reactions : It has been found that, when 1, 3-cyclohexanedione activated by a catalytic amount of 2, 2, 6, 6-tetramethylpiperidine (TMP) was reacted with 1-crotonoyl-3, 5-dimethylpyrozole activated by the nickel(II) aqua complex of R, R-DBFOX/Ph, the corresponding spiro cyclobutanone is produced in enantioselectivities up to 96% ee. Both acid and base catalysts are essential and the pyrrazole acceptors are especially efficient for the formation of cyclobutanones. Less

刘易斯酸催化的立体选择性反应领域中尚未解决的问题之一是开发耐受强配位亲核试剂的手性刘易斯酸催化剂及其在有机合成中的应用。从这个角度出发，我们开发了一系列过渡金属配合物4，6-二苯并呋喃二基-2，2 '-双（4-苯基恶唑啉）（R，R-DBFOX/Ph）和铜（II）配合物异亚丙基-2，2'-双[4-（邻羟基苄基）恶唑啉]（R，R-BOX/o-HOBn），并用于催化邻苄基羟胺、丙二腈和环状1，3-二酮的不对称共轭加成反应。取得了如下结果.羟胺的对映选择性共轭加成反应：研究发现R，R-BOX/o-HOBn的铜（II）配合物在O-苄基羟胺的共轭加成反应中作为一种有效的手性刘易斯酸催化剂。1-巴豆酰基-3-异丙基-2-咪唑啉酮是最好的受体，其对映选择性高达97% ...更多信息 ee当反应在稀释条件（0.03 M）下于-40℃下进行时。在β-位上具有多种取代基的受体分子可以被成功地使用，表明该反应被证明是有用的和方便的获得β-氨基酸的对映体递送物.丙二腈的对映选择性共轭加成：在由催化量的2，2，6，6-四甲基哌啶（TMP）活化的丙二腈与由R，R-DBFOX/Ph的镍（II）水络合物活化的3-巴豆酰基-2-恶唑烷酮的反应中，相应的迈克尔加合物的对映选择性高达94% ee.该反应为双活化型催化的不对称反应提供了第一个成功的例子，其中受体和供体分子都分别被刘易斯酸和碱催化剂活化.对映选择性环丁酮形成反应：发现当用催化量的2，2，6，6-四甲基哌啶（TMP）活化的1，3-环己二酮与用镍（II）的R，R-DBFOX/Ph水络合物活化的1-巴豆酰基-3，5-二甲基吡唑反应时，相应的螺环丁酮以高达96%ee的对映选择性制备。酸和碱催化剂都是必需的，并且吡唑受体对于环丁酮的形成特别有效。少

项目成果

E.Wada, G.Kumaran, S.Kanemasa: "A Novel Tandem Transetherification-Intramolecular Hetero Diels-Alder Reactions for Construction of Fused Heterocycles"Tetrahedron Lett.. 41 (1). 73-76 (2000)

E.Wada、G.Kumaran、S.Kanemasa：“用于构建稠合杂环的新型串联醚交换-分子内杂狄尔斯-阿尔德反应”Tetrahedron Lett.. 41 (1)。

S.Fukuda, A.Kamimura, S.Kanemasa, K.Hori: "An ab initio Molecular Orbital Study on the Magnesium Controlled 1,3-Cycloaddition of Nitrile Oxides and Allylic Alcohols with Regio- and Stereoselectivity"Tetrahedron. 56 (12). 1637-1647 (2000)

S.Fukuda、A.Kamimura、S.Kanemasa、K.Hori：“对具有区域和立体选择性的氧化氮和烯丙醇的镁控制 1,3-环加成的从头开始分子轨道研究”四面体。

S.Kanemasa,T.Kanai,E.Wada: "Lewis Acid Catalyzed Reactions of Ethyl Diazoacetate with Akdehydes.Synthesis of α-Formyl Esters by a Sequence of Aldol Reaction and 1,2-Nuckeophilic Rearrangement"Tetrahedron Lett.. 40. 5055-5058 (1999)

S.Kanemasa、T.Kanai、E.Wada：“路易斯酸催化重氮乙酸乙酯与 Akdehydes 的反应。通过一系列羟醛反应和 1,2-亲核重排合成 α-甲酰酯”Tetrahedron Lett.. 40. 5055 -5058 (1999)

S.Fukuda,A.Kamimura,S.Kanemasa,K.Hori: "An ab initio Molecular Orbital Study on the Magnesium Controlled 1,3-Cycloaddition of Nitrile Oxides and Allylic Alcohols with Regio-and Stereoselectivity"Tetrahedron. 56. 1637-1647 (2000)

S.Fukuda、A.Kamimura、S.Kanemasa、K.Hori：“具有区域和立体选择性的氧化腈和烯丙醇的镁控制 1,3-环加成反应的从头开始分子轨道研究”四面体。

S.Kanemasa.Y.Odaraotoshi,E.Wada: "Asymmetric Conjugate Addition of Thiols to a 3-(2-Alkenoyl)-2-oxazolidinone Catalzed by DBFOX/ph Aqya Complex of Nichel(II)Perchlorate"J.Am.Chem.Soc.. 121. 8675-8676 (1999)

S.Kanemasa.Y.Odaraotoshi，E.Wada：“由 Nichel(II) 高氯酸盐的 DBFOX/ph Aqya 复合物催化，硫醇与 3-(2-烯酰基)-2-恶唑烷酮的不对称共轭加成”J.Am.Chem