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

在Lewis酸催化的立体选择性反应领域中，一个悬而未决的问题是手性Lewis酸催化剂的开发及其在有机合成中的应用。从这个角度出发，我们合成了多种过渡金属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)的异亚丙基-2，2’-双[4-(邻羟基苯基)恶唑啉](R，R-box/o-HOBN)配合物，并用于催化O-苄基羟胺、丙二腈和环1，3-二酮的不对称共轭加成反应。目前已取得了漂浮效果。羟胺的不对称共轭加成反应：R，R-box/o-HOBN的铜(II)络合物在O-苄基羟胺的共轭加成反应中是一种有效的手性Lewis酸催化剂。1-巴豆酰-3-异丙基-2-咪唑烷酮是最好的受体，其对映体选择性最高可达97%…当反应在-40℃的稀释条件下(0.03M)进行时，Ee更大。在β-位具有多种取代基的受体分子可以被成功地利用，这表明该反应被证明是有用的和方便地获得β-氨基酸递送的对映体。丙二腈的对映选择性加成反应：在催化剂量2，2，6，6-四甲基哌啶(TMP)活化的丙二腈与R，R-DBFOX/Ph的镍(II)水溶液络合物活化的3-巴豆酰基-2-恶唑烷酮的反应中，生成相应的Michael加合物，对映选择性高达94%ee。该反应为双活化型催化不对称反应提供了第一个成功的例子，在该反应中，受体分子和给体分子分别被Lewis酸和碱催化剂活化。环丁酮的不对称生成反应：研究发现，当催化剂量2，2，6，6-四甲基哌啶(TMP)活化的1，3-环己二酮与R，R-DBFOX/Ph的镍(II)水溶液活化的1-巴豆酰基-3，5-二甲基吡唑反应时，生成相应的螺环丁酮，对映选择性高达96%ee。酸和碱催化剂都是必不可少的，而吡唑受体对环丁酮的形成特别有效。较少

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.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 (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.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