CN114456052B - 一种不饱和羰基或不饱和亚胺化合物的不对称1,4-加成方法 - Google Patents

一种不饱和羰基或不饱和亚胺化合物的不对称1,4-加成方法 Download PDF

Info

Publication number
CN114456052B
CN114456052B CN202210085186.XA CN202210085186A CN114456052B CN 114456052 B CN114456052 B CN 114456052B CN 202210085186 A CN202210085186 A CN 202210085186A CN 114456052 B CN114456052 B CN 114456052B
Authority
CN
China
Prior art keywords
unsaturated
asymmetric
addition
unsaturated carbonyl
beta
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202210085186.XA
Other languages
English (en)
Other versions
CN114456052A (zh
Inventor
游恒志
王君雯
卿晶
李国威
陈凯
贾雪雷
陈芬儿
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Zhonghe Headway Bio Sci & Tech Co ltd
Shenzhen Graduate School Harbin Institute of Technology
Original Assignee
Shenzhen Zhonghe Headway Bio Sci & Tech Co ltd
Shenzhen Graduate School Harbin Institute of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Zhonghe Headway Bio Sci & Tech Co ltd, Shenzhen Graduate School Harbin Institute of Technology filed Critical Shenzhen Zhonghe Headway Bio Sci & Tech Co ltd
Priority to CN202210085186.XA priority Critical patent/CN114456052B/zh
Publication of CN114456052A publication Critical patent/CN114456052A/zh
Application granted granted Critical
Publication of CN114456052B publication Critical patent/CN114456052B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/69—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/12—[b,e]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明提供一种不饱和羰基或不饱和亚胺化合物的不对称1,4‑加成方法，是将不饱和羰基化合物或亚胺化合物与有机锌试剂在高分子有机铜试剂催化下发生不对称1,4‑加成反应；所述高分子有机铜试剂的分子结构式为：

Description

一种不饱和羰基或不饱和亚胺化合物的不对称1,4-加成方法
技术领域
本发明涉及不对称加成反应技术，具体涉及一种不饱和羰基或不饱和亚胺化合物的不对称1,4-加成方法。
背景技术
不对称共轭加成反应，是手性碳-碳键构建策略中一种高效合成目标产物的方法。它以原子经济性、优良的不对称选择性、广泛的官能团耐受性以及产物的高可拓展性等多种优点，成为手性不对称催化领域的研究前沿和热点。在目前的报道中，均存在着昂贵的催化剂不可回收，金属残留，分离困难及其造成的产率下降等等局限。
发明内容
针对现有技术存在的问题，本发明提供一种不饱和羰基或不饱和亚胺化合物的不对称1,4-加成方法。本发明的技术方案为：
一种不饱和羰基或不饱和亚胺化合物的不对称1,4-加成方法，是将不饱和羰基化合物或亚胺化合物与有机锌试剂在高分子有机铜试剂催化下发生不对称1,4-加成反应；所述高分子有机铜试剂的分子结构式为：
进一步地，所述不对称1,4-加成方法具体包括：
步骤1，惰性气体保护下，将不饱和羰基化合物或亚胺化合物和高分子有机铜试剂在溶剂中混合均匀，于-30～-42℃加入有机锌试剂，加毕保温反应4～5h；
步骤2，采用饱和氯化铵溶液淬灭反应，然后萃取并洗涤有机相，干燥后浓缩得到加成产物。
进一步地，所述不饱和羰基化合物包括直链α,β-不饱和酮、环状α,β-不饱和酮，所述不饱和亚胺化合物包括环状α,β-不饱和亚胺。
进一步地，所述直链α,β-不饱和酮的不对称1,4-加成方法所涉及的反应方程式如下：
其中R1为苯基或甲基；R2为芳基；R为乙基。
进一步地，所述直链α,β-不饱和酮为以下6a～6u中的一种，所述6a～6u的分子结构式如下：
进一步地，所述环状α,β-不饱和酮或所述环状α,β-不饱和亚胺的不对称1,4-加成方法所涉及的反应方程式如下：
其中，X为O或N；R′为甲基或乙基。
进一步地，所述环状α,β-不饱和酮或环状α,β-不饱和亚胺为以下5h～5p中的一种，所述5h～5p的分子结构式如下：
进一步地，所述高分子有机铜试剂摩尔用量为不饱和羰基或不饱和亚胺化合物摩尔量的0.15～0.18倍。
进一步的，所述有机锌试剂摩尔用量为不饱和羰基或不饱和亚胺化合物摩尔量的2～2.5倍。
进一步地，所述溶剂包括甲苯、二氯甲烷、乙醚、四氢呋喃、对二甲苯中的一种或多种混合。
优选地，所述溶剂为甲苯。
可选地，所述不对称1,4-加成方法采用连续流装置，具体包括：
步骤1，将高分子有机铜试剂填入固载床，将固载床接入连续流装置，并用氮气吹扫连续流装置的管路；
步骤2，将不饱和羰基或不饱和亚胺化合物以及有机锌试剂分别溶于溶剂中，将两种溶液使用注射泵以恒定流速注入连续流装置进行反应，反应结束后收集流出液，稀释后提取有机相并干燥，减压浓缩后采用柱色谱层析，即得。
与现有技术相比，本发明具有以下突出优点和积极效果：
本发明利用新型高分子负载手性催化剂对不饱和羰基化合物或亚胺化合物进行不对称1,4-加成，不但有着优秀的反应活性以及对映选择性。而且还具有催化剂可回收循环使用，无金属浸出，分离简便等等优势。
具体实施方式
本发明实施例采用的高分子有机铜试剂的合成方法参照专利CN202210081358.6。
在本发明的描述中，需要说明的是，实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
下面结合具体实施方式对本发明作进一步详细的说明，以帮助本领域的技术人员对本发明的发明构思、技术方案有更完整、准确和深入的理解，本发明的保护范围包括但不限于以下实施例，在不偏离本申请的精神和范围的前提下任何对本发明的技术方案的细节和形式所做出的修改均落入本发明的保护范围内。
本发明具体实施例一共制备了12种直链α,β-不饱和酮的加成产物7a～7u和9种环状α,β-不饱和酮及环状α,β-不饱和亚胺的加成产物，反应方程式及产物的分子结构式如下：(注：以下方程式中的3a表示高分子有机铜试剂)
实施例1
化合物7a的合成
向装有搅拌棒的干燥schlenk管中加入直链α,β-不饱和酮6a(0.3mmol)、高分子有机铜试剂(34mg，5mmol％)，并用真空泵置换3次Ar。在Ar下加入甲苯(2.0mL)并将混合物冷却至-40℃10分钟。用注射泵在8分钟内加入ZnEt2(0.6毫升，1M甲苯溶液)。将反应在-40℃搅拌4小时，然后用2.0mL饱和NH4Cl水溶液淬灭。混合物用10mL EtOAc稀释，用H2O和盐水洗涤，用MgSO4干燥。然后用无水MgSO4干燥有机相，过滤并减压浓缩。通过硅胶柱色谱纯化得到预期产物，收率为95％，ee值为92％。
化合物7a的分析测试如下：
1)Rf(n-pentane:ethyl acetate 10:1)＝0.59.
2)1H NMR(400MHz,Chloroform-d)δ7.32(t,J＝7.5Hz,2H),7.22(dd,J＝7.8,6.6Hz,3H),3.13–3.00(m,1H),2.76(d,J＝7.2Hz,2H),2.04(s,3H),1.79–1.67(m,1H),1.67–1.53(m,1H),0.82(t,J＝7.4Hz,3H).
3)13C NMR(101MHz,Chloroform-d)δ208.10,144.32,128.47,127.58,126.37,50.56,43.01,30.65,29.40,12.03.
4)IR:v 3413.95,3028.62,2963.48,1716.72,1617.51,1494.29,1453.31,1405.21,1356.69,1162.61,757.31,700.92.
5)HRMS(ESI)calcd for C12H17O+[(M+H)+]177.1274,found 177.1271.
6)通过HPLC分析测定对映体过量情况，采用Daicel Chiralpak ID柱，等度洗脱：正己烷/异丙醇99.5:0.5、流速1.0mL/min、保留时间9.103min(次要对映体)、10.503min(主要对映体)：92％ee。
7)[α]D(25.0℃，CHCl3中的C＝1.0)＝-20.8°。
实施例2
化合物7b的合成
采用直链α,β-不饱和酮6b，具体过程同实施例1，收率为86％，ee值为93％。
化合物7a的分析测试如下：
1)Rf(n-pentane:ethyl acetate 10:1)＝0.54.
2)1H NMR(400MHz,Chloroform-d)δ7.13–7.03(m,2H),6.84(dd,J＝8.5,1.8Hz,2H),3.78(t,J＝2.4Hz,3H),3.07–2.88(m,1H),2.71(d,J＝7.3Hz,2H),2.02(s,3H),1.77–1.60(m,1H),1.60–1.47(m,1H),0.79(t,J＝7.3Hz,3H).
3)13C NMR(101MHz,Chloroform-d)δ208.33,158.03,136.26,128.42,113.82,55.17,50.77,42.28,30.65,29.54,12.00.
4)IR:v 3380.18,2975.25,1708.48,1613.06,1514.12,1402.84,1251.79,1179.22,1086.14,1048.95,880.55,643.44,574.74,555.07,402.61.
5)HRMS(ESI)calcd for C13H19O2 +[(M+H)+]207.1380,found 207.1380.
6)通过HPLC分析测定对映体过量情况，采用Daicel Chiralpak AD-H柱，等度洗脱：正己烷/异丙醇90:10、流速1.0mL/min、保留时间4.843min(次要对映体)、5.147min(主要对映体)：93％ee。
7)[α]D(25.0℃，c＝1.0in CHCl3)＝-37.6°.
实施例3
化合物7c的合成
采用直链α,β-不饱和酮6c，具体过程同实施例1，收率为95％，ee值为96％。
化合物7c的分析测试如下：
1)Rf(n-pentane:ethyl acetate 10:1)＝0.49.Mp:70.5-73.2℃.
2)1H NMR(400MHz,Chloroform-d)δ7.67(d,J＝7.3Hz,2H),7.61(d,J＝8.0Hz,2H),7.49(t,J＝7.6Hz,2H),7.39(t,J＝7.3Hz,1H),7.32(d,J＝8.0Hz,2H),3.23–3.11(m,1H),2.82(dd,J＝7.3,1.4Hz,2H),2.10(s,3H),1.84–1.73(m,1H),1.73–1.60(m,1H),0.90(t,J＝7.3Hz,3H).
3)13C NMR(101MHz,Chloroform-d)δ208.05,143.62,141.02,139.26,128.88,128.12,127.24,127.08,50.54,42.65,30.73,29.48,12.18.
4)IR:v 3413.54,2957.90,1713.00,1487.81,1411.85,1167.87,838.52,761.70,726.84,690.81,561.05,519.99,404.72.
5)HRMS(ESI)calcd for C18H21O+[(M+H)+]253.1587,found 253.1583.
6)通过HPLC分析测定对映体过量情况，采用Daicel Chiralpak AD-H柱，等度洗脱：正己烷/异丙醇90:10、流速1.0mL/min、保留时间5.007min(次要对映体)、5.370min(主要对映体)：96％ee。
7)[α]D(25.0℃，c＝1.5in CHCl3)＝-19.7°.
实施例4
化合物7d的合成
采用直链α,β-不饱和酮6d，具体过程同实施例1，收率为90％，ee值为96％。
化合物7d的分析测试如下：
1)Rf(n-pentane:ethyl acetate 10:1)＝0.60.
2)1H NMR(400MHz,Chloroform-d)δ7.29–7.22(m,2H),7.12(dd,J＝8.4,2.0Hz,2H),3.13–2.92(m,1H),2.71(d,J＝6.4Hz,2H),2.03(s,3H),1.68(dddd,J＝13.1,7.4,5.6,1.9Hz,1H),1.54(dq,J＝14.0,7.3Hz,1H),0.77(t,J＝7.4Hz,3H).
3)13C NMR(101MHz,Chloroform-d)δ207.58,142.92,131.93,128.99,128.59,42.25,30.67,29.31,11.95.
4)IR:v 3412.74,2963.56,1717.39,1493.11,1410.67,1359.24,1162.26,1090.90,1013.76,831.79,542.75.
5)HRMS(ESI)calcd for C12H16ClO+[(M+H)+]211.0884,found 211.0883.
6)通过HPLC分析测定对映体过量情况，采用Daicel Chiralpak AD-H柱，等度洗脱：正己烷/异丙醇99:1、流速1.0mL/min、保留时间6.650min(次要对映体)、8.293min(主要对映体)：96％ee。
7)[α]D(25.0℃，c＝1.5in CHCl3)＝-23.6°.
实施例5
化合物7e的合成
采用直链α,β-不饱和酮6e，具体过程同实施例1，收率为95％，ee值为94％。
化合物7e的分析测试如下：
1)Rf(n-pentane:ethyl acetate 5:1)＝0.44.
2)1H NMR(400MHz,Chloroform-d)δ7.98(d,J＝7.0Hz,2H),7.27(d,J＝7.0Hz,2H),3.92(s,3H),3.18–3.08(m,1H),2.77(d,J＝7.1Hz,2H),2.05(s,3H),1.78–1.66(m,1H),1.65–1.52(m,1H),0.79(d,J＝8.5Hz,3H).
3)13C NMR(101MHz,Chloroform-d)δ207.45,167.09,149.99,129.86,128.38,127.69,52.06,50.13,42.81,30.69,29.19,11.94.
4)IR:v 2961.01,1720.05,1610.32,1436.11,1282.23,1181.53,1112.21,1018.63,856.28,769.58,708.39,547.00.
5)HRMS(ESI)calcd for C14H19O3 +[(M+H)+]235.1329,found 235.1325.
6)通过HPLC分析测定对映体过量情况，采用Daicel Chiralpak AD-H柱，等度洗脱：正己烷/异丙醇95:5、流速1.0mL/min、保留时间8.483min(次要对映体)、9.257min(主要对映体)：94％ee。
7)[α]D(25.0℃，c＝1.5in CHCl3)＝-40.5°
实施例6
化合物7f的合成
采用直链α,β-不饱和酮6f，具体过程同实施例1，收率为97％，ee值为90％。
化合物7f的分析测试如下：
1)Rf(n-pentane:ethyl acetate 5:1)＝0.77.Mp:67.9-70.1℃.
2)1H NMR(400MHz,Chloroform-d)δ8.05–7.89(m,2H),7.63–7.54(m,1H),7.48(t,J＝7.5Hz,2H),7.41–7.30(m,4H),7.30–7.20(m,1H),3.41–3.28(m,3H),1.88(dtd,J＝14.8,7.4,4.5Hz,1H),1.82–1.66(m,1H),0.91(t,J＝7.3Hz,3H).
3)13C NMR(101MHz,Chloroform-d)δ199.28,144.81,137.37,133.05,128.67,128.56,128.19,127.80,126.42,45.71,43.12,29.37,12.27.
4)IR:v 2954.94,1680.37,1448.13,1407.97,1274.51,1214.46,977.91,761.53,748.15,700.25,684.08,565.11.
5)HRMS(ESI)calcd for C17H19O+[(M+H)+]239.1430,found 239.1435.
6)通过HPLC分析测定对映体过量情况，采用Daicel Chiralpak AD-H柱，等度洗脱：正己烷/异丙醇95:5、流速1.0mL/min、保留时间5.900min(次要对映体)、6.873min(主要对映体)：90％ee。
7)[α]D(25.0℃，c＝1.5in CHCl3)＝-7.8°.
实施例7
化合物7g的合成
采用直链α,β-不饱和酮6g，具体过程同实施例1，收率为44％，ee值为92％。
化合物7g的分析测试如下：
1)Rf(n-pentane:ethyl acetate 10:1)＝0.55.
2)1H NMR(400MHz,Chloroform-d)δ7.14(d,J＝3.9Hz,1H),6.91(dd,J＝5.1,3.4Hz,1H),6.82(d,J＝3.5Hz,1H),3.41(dt,J＝14.2,7.1Hz,1H),2.86–2.69(m,2H),2.08(s,3H),1.80–1.68(m,1H),1.60(ddd,J＝13.5,9.0,7.3Hz,1H),0.87(t,J＝7.3Hz,3H).
3)13C NMR(101MHz,Chloroform-d)δ207.47,148.33,126.60,124.10,123.05,51.23,38.21,30.67,30.44,11.89.
4)IR:v 3412.85,2966.29,2929.51,1716.53,1618.25,1405.31,1359.27,1251.23,1232.90,1162.36,1082.93,1050.05,699.73.
5)HRMS(ESI)calcd for C10H15SO+[(M+H)+]183.0838,found 183.0839.
6)通过HPLC分析测定对映体过量情况，采用Daicel Chiralpak OD-H柱，等度洗脱：正己烷/异丙醇95:5、流速1.0mL/min、保留时间5.543min(次要对映体)、6.100min(主要对映体)：92％ee。
7)[α]D(25.0℃，c＝1.0in CHCl3)＝-30.5°.
实施例8
化合物7q的合成
采用直链α,β-不饱和酮6q，具体过程同实施例1，收率为94％，d.r.为99：1。
化合物7q的分析测试如下：
1)Rf(n-pentane:ethyl acetate 10:1)＝0.43.
2)1H NMR(400MHz,Chloroform-d)δ7.99(d,J＝8.2Hz,2H),7.27(d,J＝8.3Hz,2H),4.93(td,J＝10.9,4.4Hz,1H),3.19–3.07(m,1H),2.77(d,J＝7.1Hz,2H),2.13(d,J＝12.2Hz,1H),2.06(s,3H),1.99(pd,J＝7.0,2.7Hz,1H),1.80–1.66(m,3H),1.65–1.51(m,3H),1.21–1.05(m,2H),0.94(dd,J＝6.8,2.3Hz,7H),0.84–0.75(m,6H).
3)13C NMR(101MHz,Chloroform-d)δ207.45,166.06,149.74,129.84,129.09,127.62,74.68,50.15,47.31,42.81,41.04,34.37,31.48,30.68,29.23,26.46,23.62,22.10,20.85,16.52,11.96.
4)IR:v 2956.92,1712.68,1610.11,1418.14,1274.39,1179.27,1112.13,1018.51,963.16,855.53,768.28,706.95.
5)HRMS(ESI)calcd for C23H34NaO3 +[(M+Na)+]384.2400,found 384.2400.
6)[α]D(25.0℃，c＝1.4in CHCl3)＝-3.5°.
实施例9
化合物7r的合成
采用直链α,β-不饱和酮6q，具体过程同实施例1，收率为96％，d.r.为99：1。
化合物7r的分析测试如下：
1)Rf(n-pentane:ethyl acetate 3:1)＝0.26.
2)1H NMR(400MHz,Chloroform-d)δ7.98(d,J＝6.7Hz,2H),7.25(d,J＝6.9Hz,2H),5.57(d,J＝4.4Hz,1H),4.66(d,J＝7.9Hz,1H),4.51(dd,J＝10.0,5.0Hz,1H),4.42(dd,J＝11.4,7.4Hz,1H),4.38–4.30(m,2H),4.25–4.15(m,1H),3.12(dq,J＝12.8,6.4Hz,1H),2.75(d,J＝7.2Hz,2H),2.04(s,3H),1.70(dt,J＝14.1,7.2Hz,1H),1.65–1.55(m,1H),1.53(s,3H),1.48(s,3H),1.35(d,J＝8.2Hz,6H),0.77(t,J＝7.3Hz,3H).
3)13C NMR(101MHz,Chloroform-d)δ207.40,166.36,150.07,129.99,128.27,127.68,109.70,108.84,96.36,71.16,70.75,70.57,66.16,63.79,50.11,42.82,30.67,29.18,26.04,25.02,24.53,11.93.
4)IR:v 2930.67,1735.68,1606.84,1491.85,1403.38,1265.79,1149.38,1068.89,1014.32,765.99,702.71,422.14.
5)HRMS(ESI)calcd for C25H35O8 +[(M+H)+]463.2326,found 463.2326.
6)[α]D(25.0℃，c＝0.8in CHCl3)＝-3.1°.
实施例10
化合物7s的合成
采用直链α,β-不饱和酮6s，具体过程同实施例1，收率为69％，d.r.为99：1。
化合物7s的分析测试如下：
1)Rf(n-pentane:ethyl acetate 3:1)＝0.22.
2)1H NMR(400MHz,Chloroform-d)δ8.15(d,J＝8.3Hz,2H),7.36(dd,J＝7.9,5.6Hz,3H),7.04–6.94(m,2H),3.25–3.13(m,1H),3.00–2.93(m,2H),2.81(d,J＝7.1Hz,2H),2.54(dd,J＝18.8,8.6Hz,1H),2.49–2.42(m,1H),2.35(td,J＝10.6,4.0Hz,1H),2.25–2.15(m,1H),2.15–1.98(m,5H),1.76(ddd,J＝13.1,7.5,5.6Hz,2H),1.71–1.57(m,4H),1.57–1.43(m,3H),0.95(s,3H),0.83(t,J＝7.3Hz,3H).
3)13C NMR(101MHz,Chloroform-d)δ220.94,207.36,165.40,150.79,148.92,138.12,137.44,127.90,126.52,121.79,118.95,50.50,48.03,44.24,42.88,38.08,35.93,31.62,30.71,29.49,29.23,26.42,25.84,21.66,13.90,11.98.
4)IR:v 2989.94,1717.28,1610.44,1384.26,1277.95,1069.30,1005.86,898.75,768.57,708.18,515.01,409.37.
5)HRMS(ESI)calcd for C31H37O4 +[(M+H)+]473.2686,found 473.2684.
6)[α]D(25.0℃，c＝1.1in CHCl3)＝42.7°.
实施例11
化合物7t的合成
采用直链α,β-不饱和酮6t，具体过程同实施例1，收率为67％，ee值为92％。
化合物7t的分析测试如下：
1)Rf(n-pentane:ethyl acetate 3:1)＝0.67.
2)1H NMR(400MHz,Chloroform-d)δ8.24(d,J＝2.4Hz,1H),7.91(dd,J＝7.7,1.4Hz,1H),7.55(qd,J＝8.5,8.0,1.9Hz,2H),7.47(td,J＝7.6,1.3Hz,1H),7.37(dd,J＝7.4,1.3Hz,1H),7.21–7.14(m,2H),7.08(d,J＝8.5Hz,1H),7.06–7.01(m,2H),5.19(s,2H),3.89(s,2H),3.11–3.00(m,1H),2.71(d,J＝7.1Hz,2H),2.03(s,3H),1.73–1.61(m,1H),1.54(ddq,J＝14.3,9.3,7.3Hz,1H),0.78(t,J＝7.3Hz,3H).
3)13C NMR(101MHz,Chloroform-d)δ207.94,190.87,170.01,160.69,149.10,142.07,140.45,136.41,135.60,132.92,132.64,129.54,129.35,127.95,127.35,125.27,121.35,115.43,73.67,50.50,42.28,40.32,30.72,29.35,12.02.
4)IR:v 2961.92,1754.93,1712.63,1647.81,1491.19,1300.76,1202.83,1120.12,1015.95,761.67,641.66.
5)HRMS(ESI)calcd for C28H27O5 +[(M+H)+]443.1853,found 443.1851.
6)通过HPLC分析测定对映体过量情况，采用Daicel Chiralpak AD-H柱，等度洗脱：正己烷/异丙醇80:20、流速1.0mL/min、保留时间22.163min(次要对映体)、25.180min(主要对映体)：92％ee。
7)[α]D(25.0℃，c＝1.0in CHCl3)＝-10.0°.
实施例12
化合物7u的合成
采用直链α,β-不饱和酮6u，具体过程同实施例1，收率为35％，d.r.为99：1。
化合物7u的分析测试如下：
1)Rf(n-pentane:ethyl acetate 10:1)＝0.46.
2)1H NMR(400MHz,Chloroform-d)δ7.99(d,J＝6.8Hz,1H),7.27(d,J＝7.2Hz,1H),4.96(tt,J＝10.8,4.8Hz,1H),3.13(dt,J＝13.0,6.6Hz,1H),2.77(d,J＝7.1Hz,2H),2.06(s,1H),1.98(dd,J＝17.3,13.5Hz,1H),1.83(td,J＝14.0,4.3Hz,1H),1.77–1.66(m,2H),1.65–1.50(m,2H),1.43–1.23(m,3H),1.21–0.99(m,4H),0.90(dt,J＝4.6,1.9Hz,7H),0.80(t,J＝7.3Hz,3H),0.69(s,3H).
3)13C NMR(101MHz,Chloroform-d)δ207.53,166.13,149.67,129.83,129.21,127.58,74.30,56.49,56.33,54.30,50.20,44.77,42.86,42.66,40.05,39.58,36.86,36.23,35.87,35.57,34.20,32.07,30.71,29.23,28.71,28.31,28.07,27.66,24.28,23.90,22.89,22.63,21.28,18.73,12.36,12.14,11.95.
4)IR:v 3416.10,3130.40,2932.77,1708.78,1609.99,1466.88,1400.80,1279.24,1181.32,1115.01,1019.60.
5)HRMS(ESI)calcd for C40H63O3 +[(M+H)+]591.4772,found 591.4770.
6)[α]D(25.0℃，c＝1.0in CHCl3)＝16.6°.
实施例13
化合物7h的合成
向装有搅拌棒的干燥schlenk管中加入环状α,β-不饱和酮5h(0.3mmol)、高分子有机铜试剂(34mg，5mmol％)，并用真空泵置换3次Ar。在Ar下加入甲苯(2.0mL)并将混合物冷却至-40℃10分钟。用注射泵在8分钟内加入ZnEt2(0.6毫升，1M甲苯溶液)。将反应在-40℃搅拌4小时，然后用2.0mL饱和NH4Cl水溶液淬灭。混合物用10mL EtOAc稀释，用H2O和盐水洗涤，用MgSO4干燥。然后用无水MgSO4干燥有机相，过滤并减压浓缩。通过硅胶柱色谱纯化得到预期产物(24mg)，无色油状物，收率为63％，ee值为97％。
化合物7h的分析测试如下：
1)Rf(n-pentane:ethyl acetate 10:1)＝0.66.
2)1H NMR(400MHz,Chloroform-d)δ2.49–2.41(m,1H),2.41–2.33(m,1H),2.28(td,J＝13.7,13.1,6.1Hz,1H),2.12–1.98(m,2H),1.98–1.89(m,1H),1.81–1.54(m,2H),1.47–1.24(m,3H),0.93(t,J＝7.4Hz,3H).
3)13C NMR(101MHz,Chloroform-d)δ212.33,47.93,41.58,40.84,30.96,29.37,25.36,11.24.
4)IR:v 3395.91,3181.61,2960.80,2921.59,2849.53,2849.53,2361.95,1645.66,1468.76,1401.01,1262.13,1188.53,1083.11,404.54.
5)HRMS(ESI)calcd for C8H15O+[(M+H)+]127.1117,found 127.1118.
6)通过GC分析测定对映体过量情况，采用Supelcoγ-DEX 225柱，70℃恒温测定；保留时间72.391min(主要对映体)，76.676min(次要对映体)：97％ee。
7)[α]D(25.0℃，c＝1.0in CHCl3)＝-16.1°.
实施例14
化合物7i的合成
采用环状α,β-不饱和酮5i，具体过程同实施例13，收率为73％，ee值为93％。
化合物7i的分析测试如下：
1)Rf(n-pentane:ethyl acetate 10:1)＝0.63.
2)1H NMR(400MHz,Chloroform-d)δ2.48–2.33(m,2H),2.25(dddd,J＝14.8,5.9,3.7,2.1Hz,1H),2.07–1.95(m,1H),1.74–1.51(m,3H),1.44–1.32(m,1H),1.01(s,3H),0.97(s,3H),0.86(t,J＝7.4Hz,3H).
3)13C NMR(101MHz,Chloroform-d)δ212.41,48.87,42.29,40.53,38.35,32.95,28.75,23.32,19.53,12.24.
4)IR:v 3414.94,3140.26,2963.85,2875.32,1716.48,1617.77,1468.31,1400.33,1368.17,1296.51,1245.41,1146.99.
5)HRMS(ESI)calcd for C10H19O+[(M+H)+]155.1430,found 155.1425.
6)通过GC分析测定对映体过量情况，采用Hydrodexβ-6TBDM柱，60℃保温10min，再以1℃/min的升温速度升至120℃，然后以20℃/min的升温速度升至200℃；保留时间104.314min(主要对映体)，104.599min(次要对映体)：93％ee。
7)[α]D(25.0℃，c＝1.3in CHCl3)＝-16.9°.
实施例15
化合物7j的合成
采用环状α,β-不饱和酮5j，具体过程同实施例13，收率为81％，ee值为99％。
化合物7j的分析测试如下：
1)Rf(n-pentane:ethyl acetate 10:1)＝0.67.
2)1H NMR(400MHz,Chloroform-d)δ2.42–2.35(m,3H),2.35–2.25(m,1H),1.81(td,J＝12.2,4.5Hz,3H),1.52(ddd,J＝14.4,8.3,5.7Hz,2H),1.41–1.13(m,4H),0.82(t,J＝7.4Hz,3H).
3)13C NMR(101MHz,Chloroform-d)δ214.47,49.52,43.84,37.64,36.44,30.00,28.51,24.38,11.35.
4)IR:v 3130.94,2927.37,2858.08,1701.50,1458.27,1402.75,1348.80,1321.38,1253.66,1165.55,1075.42.
5)HRMS(ESI)calcd for C9H17O+[(M+H)+]144.1274,found 141.1276.
6)通过GC分析测定对映体过量情况，采用Supelcoγ-DEX 225柱，70℃恒温测定；保留时间123.169min(次要对映体)，123.264min(主要对映体)：99％ee。
7)[α]D(25.0℃，c＝1.1in CHCl3)＝-37.5°.
实施例16
化合物7k的合成
采用环状α,β-不饱和酮5k，有机锌试剂的R′为Me，具体过程同实施例13，收率为57％，ee值为97％。
化合物7k的分析测试如下：
1)Rf(n-pentane:ethyl acetate 10:1)＝0.47.
2)1H NMR(400MHz,Chloroform-d)δ2.34–2.22(m,2H),2.16(dddd,J＝14.0,12.2,6.1,1.3Hz,1H),2.01–1.90(m,2H),1.88–1.74(m,2H),1.65–1.52(m,1H),1.37–1.16(m,1H),0.95(d,J＝6.3Hz,3H).
3)13C NMR(101MHz,Chloroform-d)δ211.80,49.92,41.06,34.16,33.23,25.27,22.02.
4)IR:v 3413.35,3139.25,2955.17,1716.41,1617.56,1456.17,1400.79,1317.12,1275.46,1224.64,1111.69,1056.89.
5)HRMS(ESI)calcd for C7H13O+[(M+H)+]113.0961,found 113.0964.
6)通过GC分析测定对映体过量情况，采用Supelcoγ-DEX 225柱，70℃恒温测定；保留时间34.277min(次要对映体)，34.857min(主要对映体)：97％ee。
7)[α]D(25.0℃，c＝1.0in CHCl3)＝-10.4°.
实施例17
化合物7l的合成
采用环状α,β-不饱和酮5l，有机锌试剂的R′为Me，具体过程同实施例13，收率为70％，ee值为92％。
化合物7l的分析测试如下：
1)Rf(n-pentane:ethyl acetate 10:1)＝0.53.
2)1H NMR(400MHz,Chloroform-d)δ2.44(dd,J＝7.9,3.6Hz,2H),2.39(d,J＝7.1Hz,2H),1.82(tdd,J＝13.3,9.2,4.0Hz,4H),1.67–1.51(m,1H),1.45–1.31(m,1H),1.31–1.18(m,1H),0.96(d,J＝6.7Hz,3H).
3)13C NMR(101MHz,Chloroform-d)δ214.46,51.78,44.06,39.21,31.28,28.58,24.22,23.55.
4)IR:v 3476.67,3415.28,2955.51,2925.96,2870.81,1701.19,1637.43,1617.61,1457.44,1401.76.
5)HRMS(ESI)calcd for C8H15O+[(M+H)+]127.1117,found 127.1112.
6)通过GC分析测定对映体过量情况，采用Hydrodexβ-6TBDM柱，70℃恒温测定；保留时间77.403min(主要对映体)，85.666min(次要对映体)：92％ee。
7)[α]D(25.0℃，c＝1.0in CHCl3)＝-8.9°.
实施例18
化合物7m的合成
向装有搅拌棒的干燥schlenk管中加入环状α,β-不饱和亚胺5m(0.3mmol)、高分子有机铜试剂(34mg,5mmol％)，并用真空泵置换3次Ar。在Ar下加入甲苯(2.0mL)。并将混合物冷却至-30℃搅拌10分钟。用注射泵在8分钟内加入ZnEt2(0.6毫升，1M甲苯溶液)。将反应在-30℃搅拌1小时，然后用0.5mL饱和NH4Cl水溶液淬灭。混合物用无水MgSO4干燥。然后用无水MgSO4干燥有机相，过滤并减压浓缩得加成粗产物。共轭加成的粗产物溶解在乙腈(3mL)溶液中，并加入外消旋催化剂RuCl(pcymene)[Ts-DPEN](9.5mg，15.0mol)和甲酸和三乙胺的混合物(5:2)(188uL,0.45mmol)，将反应混合物在室温下搅拌16小时，然后将溶液倒入半饱和盐水(10mL)中，并用EtOAc(3×10mL)萃取。合并的有机相用盐水洗涤，用MgSO4干燥，过滤，减压浓缩，并通过硅胶快速柱色谱纯化，得到白色固体，收率为84％，ee值为92％，dr＞99：1。
化合物7m的分析测试如下：
1)Mp:72.3-74.2℃.
2)Rf(n-pentane:ethyl acetate 10:1)＝0.25.
3)1H NMR(400MHz,Chloroform-d)δ7.81(d,J＝8.1Hz,2H),7.32(d,J＝8.0Hz,2H),5.10(d,J＝7.2Hz,1H),3.53(s,1H),2.44(s,3H),1.68–1.55(m,2H),1.54–1.47(m,1H),1.43(d,J＝9.0Hz,2H),1.32(d,J＝31.8Hz,2H),1.14(dh,J＝13.6,6.6Hz,3H),0.98–0.84(m,1H),0.76(t,J＝7.4Hz,3H).
4)13C NMR(101MHz,Chloroform-d)δ143.15,138.23,129.66,127.07,49.43,37.33,33.56,31.64,31.25,28.66,21.57,20.34,11.31.
5)IR:v 3278.96,2930.96,1599.50,1422.88,1325.24,1165.82,1093.52,1042.58,819.67,677.03,553.36,402.70.
6)HRMS(ESI)calcd for C15H24SNO2 +[(M+H)+]282.1522,found 282.1517.
7)通过HPLC分析测定对映体过量情况，采用Daicel Chiralpak IA柱，等度洗脱：正己烷/异丙醇98:2、流速1.0mL/min、保留时间35.057min(主要对映体)、44.210min(次要对映体)：92％ee。
8)[α]D(25.0℃，c＝1.1in CHCl3)＝+16.6°.
实施例19
化合物7n的合成
采用环状α,β-不饱和亚胺5n，具体过程同实施例18，收率为81％，ee值为97％，dr＞99：1。
化合物7n的分析测试如下：
1)Mp:85.3-87.2℃.
2)Rf(n-pentane:ethyl acetate 10:1)＝0.35.
3)1H NMR(400MHz,Chloroform-d)δ7.79(d,J＝8.2Hz,2H),7.33(d,J＝8.1Hz,2H),4.76(d,J＝6.1Hz,1H),3.54(dt,J＝6.6,3.8Hz,1H),2.45(s,3H),1.66(d,J＝13.7Hz,1H),1.44(s,3H),1.29(d,J＝4.2Hz,2H),1.22–1.09(m,2H),1.02(s,3H),0.99–0.93(m,1H),0.86(s,3H),0.79(t,J＝7.4Hz,3H).
4)13C NMR(101MHz,Chloroform-d)δ143.24,137.72,129.67,127.22,49.79,45.18,43.19,37.02,33.66,30.73,30.24,29.39,28.39,21.58,11.37.
5)IR:v 3416.06,2953.44,1617.53,1401.22,1323.97,1158.47,1094.51,811.43,689.29,657.38,553.18,475.03,421.01,408.51.
6)HRMS(ESI)calcd for C17H28SNO2 +[(M+H)+]310.1835,found 310.1832.
7)通过HPLC分析测定对映体过量情况，采用Daicel Chiralpak IC柱，等度洗脱：正己烷/异丙醇98:2、流速1.0mL/min、保留时间61.203min(主要对映体)、68.647min(次要对映体)：97％ee。
8)[α]D(25.0℃，c＝1.0in CHCl3)＝-6.3°.
实施例20
化合物7o的合成
采用环状α,β-不饱和亚胺5o，具体过程同实施例18，收率为87％，ee值为95％，dr＞99：1。
化合物7o的分析测试如下：
1)Mp:97.3-99.6℃.
2)Rf(n-pentane:ethyl acetate 5:1)＝0.41.
3)1H NMR(400MHz,Chloroform-d)δ7.82(d,J＝8.0Hz,2H),7.31(d,J＝8.0Hz,2H),5.29(d,J＝7.0Hz,1H),3.48(s,1H),2.44(s,3H),1.62–1.49(m,3H),1.49–1.40(m,1H),1.40–1.29(m,1H),1.23–1.13(m,2H),1.08(t,J＝10.5Hz,1H),0.89(s,3H),0.79(dq,J＝13.9,5.6,4.0Hz,1H),0.71(d,J＝9.0Hz,6H).
4)13C NMR(101MHz,Chloroform-d)δ143.13,138.25,129.69,127.08,49.33,42.60,35.15,32.76,31.42,29.69,27.59,22.02,21.56,12.44.
5)IR:v 3265.23,1598.57,1401.19,1327.28,1166.29,677.98,550.39,503.56,481.22,428.84,416.86.
6)HRMS(ESI)calcd for C17H28SNO2 +[(M+H)+]310.1835,found 310.1836.
7)通过HPLC分析测定对映体过量情况，采用Daicel Chiralpak IA柱，等度洗脱：正己烷/异丙醇98:2、流速1.0mL/min、保留时间32.727min(次要对映体)、39.650min(主要对映体)：95％ee。
8)[α]D(25.0℃，c＝1.0in CHCl3)＝-25.6°.
实施例21
化合物7p的合成
采用环状α,β-不饱和亚胺5p，有机锌试剂的R′为Me，具体过程同实施例18，收率为84％，ee值为98％。
化合物7p的分析测试如下：
1)Mp:111.5-113.0℃.
2)Rf(n-pentane:ethyl acetate 10:1)＝0.37.
3)1H NMR(400MHz,Chloroform-d)δ7.80(d,J＝8.1Hz,2H),7.33(d,J＝8.1Hz,2H),4.81(d,J＝7.1Hz,1H),3.53(s,1H),2.46(s,3H),1.65–1.57(m,2H),1.56–1.47(m,2H),1.41(d,J＝6.7Hz,2H),1.30(d,J＝12.6Hz,1H),1.13(s,1H),0.93(q,J＝10.4,9.7Hz,1H),0.83(d,J＝6.3Hz,3H).
4)13C NMR(101MHz,Chloroform-d)δ143.21,138.11,129.68,127.07,49.44,39.58,33.58,26.93,21.62,20.33.
5)IR:v 3265.23,1598.57,1401.19,1327.28,1166.29,677.98,550.39,503.56,481.22,428.84,416.86.
6)HRMS(ESI)calcd for C14H22SNO2 +[(M+H)+]268.1366,found 268.1366.
7)通过HPLC分析测定对映体过量情况，采用Daicel Chiralpak IA柱，等度洗脱：正己烷/异丙醇98:2、流速1.0mL/min、保留时间35.633min(主要对映体)、40.923min(次要对映体)：98％ee。
8)[α]D(25.0℃，c＝1.0in CHCl3)＝-2.3°.
实施例22
高分子有机铜试剂回收套用实验
向装有搅拌棒的干燥schlenk管中加入直链α,β-不饱和酮6a(0.3mmol)、高分子有机铜试剂(34mg，5mmol％)，并用真空泵置换3次Ar。在Ar下加入甲苯(2.0mL)并将混合物冷却至-40℃10分钟。用注射泵在8分钟内加入ZnEt2(0.6毫升，1M甲苯溶液)。将反应在-40℃搅拌4小时，然后用2.0mL饱和NH4Cl水溶液淬灭。混合物过滤，滤液用10mL EtOAc稀释，用H2O和盐水洗涤，用MgSO4干燥。然后用无水MgSO4干燥有机相，过滤并减压浓缩。通过硅胶柱色谱纯化得到预期产物，收率为92％，ee值为97％。滤饼用依次用水，乙醇，丙酮，石油醚洗涤，40℃真空干燥1小时得回收高分子有机铜试剂。将回收的高分子有机铜试剂装入带有搅拌棒的干燥schlenk管，再加入直链α,β-不饱和酮6a(0.3mmol)，并用真空泵置换3次Ar。在Ar下加入甲苯(2.0mL)并将混合物冷却至-40℃10分钟。用注射泵在8分钟内加入ZnEt2(0.6毫升，1M甲苯溶液)。将反应在-40℃搅拌4小时，然后用2.0mL饱和NH4Cl水溶液淬灭。混合物过滤，并重复以上操作得目标产物以及回收的高分子有机铜试剂。能稳定维持反应活性以及选择性4个循环，结果如表1所示。
表1 4个循环的收率及ee值
循环一 循环二 循环三 循环四
收率 92 90 80 73
ee值 97 92 90 87
实施例23
化合物7a的合成
本实施例提供了7a的另一种制备方法，是采用现有的连续流装置，具体过程如下：先将150mg高分子有机铜试剂填入固载床，将固载床接入连续流装置，并用氮气吹扫连续流装置管路，再使用无水甲苯(乙醚，四氢呋喃，乙二醇二甲醚，二氯甲烷等也可)溶剂排出连续流装置管道中的气体。配制直链α,β-不饱和酮6a(24mmol)的甲苯溶液(0.6M)40mL，二乙基锌(48mmol)的甲苯溶液(1.2M)40mL，将两种溶液使用注射泵以0.05ml/min的流速打入连续流系统，待溶液全部进完后。使用无水甲苯5以相同的流速，将管路清洗一遍。收集流出液，滤液用10mL EtOAc稀释，用H2O和盐水洗涤，用MgSO4干燥。然后用无水MgSO4干燥有机相，过滤并减压浓缩。通过硅胶柱色谱层析。得产物3.92g,收率93％，ee值92％。连续流装置在本领域属于常规反应装置，应用于很多化合物的制备，但在本发明不饱和羰基或不饱和亚胺化合物的不对称1，4-加成中尚属首例，其它化合物的制备过程同实施例23，这里不一一列举。
综上所述，本发明利用新型高分子负载手性催化剂对不饱和羰基化合物或亚胺化合物进行不对称1,4-加成，不但有着优秀的反应活性以及对映选择性。而且还具有催化剂可回收循环使用，无金属浸出，分离简便等等优势。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (5)

1.一种不饱和羰基化合物的不对称1,4-加成方法，其特征在于：是将不饱和羰基化合物与有机锌试剂在高分子有机铜试剂催化下发生不对称1,4-加成反应；所述高分子有机铜试剂的分子结构式为：
所述不饱和羰基化合物为直链α,β-不饱和酮、环状α,β-不饱和酮；
在所述直链α,β-不饱和酮所涉及的不对称1,4-加成反应中，所述有机锌试剂的结构式为ZnR2，R为乙基，所述直链α,β-不饱和酮为以下6f，所述6f的分子结构式如下：
在所述环状α,β-不饱和酮涉及的不对称1,4-加成反应中，所述有机锌试剂的结构式为Zn R′2，R′为甲基或乙基，所述环状α,β-不饱和酮为以下5j、5k、5i中的一种，所述5j、5k、5i的分子结构式如下：
2.根据权利要求1所述的一种不饱和羰基化合物的不对称1,4-加成方法，其特征在于：所述不对称1,4-加成方法具体包括：
步骤1，惰性气体保护下，将不饱和羰基化合物和高分子有机铜试剂在溶剂中混合均匀，于-30～-42℃加入有机锌试剂，加毕保温反应4～5h；
步骤2，采用饱和氯化铵溶液淬灭反应，然后萃取并洗涤有机相，干燥后浓缩得到加成产物。
3.根据权利要求1所述的一种不饱和羰基化合物的不对称1,4-加成方法，其特征在于：所述高分子有机铜试剂摩尔用量为不饱和羰基化合物摩尔量的0.15～0.18倍。
4.根据权利要求1所述的一种不饱和羰基化合物的不对称1,4-加成方法，其特征在于：所述有机锌试剂摩尔用量为不饱和羰基化合物摩尔量的2～2.5倍。
5.根据权利要求2所述的一种不饱和羰基化合物的不对称1,4-加成方法，其特征在于：所述溶剂包括甲苯、二氯甲烷、乙醚、四氢呋喃、对二甲苯中的一种或多种混合。
CN202210085186.XA 2022-01-25 2022-01-25 一种不饱和羰基或不饱和亚胺化合物的不对称1,4-加成方法 Active CN114456052B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210085186.XA CN114456052B (zh) 2022-01-25 2022-01-25 一种不饱和羰基或不饱和亚胺化合物的不对称1,4-加成方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210085186.XA CN114456052B (zh) 2022-01-25 2022-01-25 一种不饱和羰基或不饱和亚胺化合物的不对称1,4-加成方法

Publications (2)

Publication Number Publication Date
CN114456052A CN114456052A (zh) 2022-05-10
CN114456052B true CN114456052B (zh) 2023-08-25

Family

ID=81411438

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210085186.XA Active CN114456052B (zh) 2022-01-25 2022-01-25 一种不饱和羰基或不饱和亚胺化合物的不对称1,4-加成方法

Country Status (1)

Country Link
CN (1) CN114456052B (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2734365A1 (de) * 1976-07-29 1978-02-09 Ici Ltd Heterocyclische verbindungen, verfahren zu ihrer herstellung und diese verbindungen enthaltende fungizide zusammensetzungen
CN106939059A (zh) * 2017-03-08 2017-07-11 浙江大学 基于1,1′‑联‑2‑萘酚的纯手性分子构建多孔聚合物的方法
CN110041174A (zh) * 2019-04-28 2019-07-23 南方科技大学 一种ebinol轴手性化合物及其合成方法和应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2766324A1 (en) * 2011-10-14 2014-08-20 Isis Innovation Limited Asymmetric synthesis of organic compounds
US20230331673A1 (en) * 2020-06-27 2023-10-19 Crescenta Biosciences Composition of compounds that modulate cell metabolism and methods of use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2734365A1 (de) * 1976-07-29 1978-02-09 Ici Ltd Heterocyclische verbindungen, verfahren zu ihrer herstellung und diese verbindungen enthaltende fungizide zusammensetzungen
CN106939059A (zh) * 2017-03-08 2017-07-11 浙江大学 基于1,1′‑联‑2‑萘酚的纯手性分子构建多孔聚合物的方法
CN110041174A (zh) * 2019-04-28 2019-07-23 南方科技大学 一种ebinol轴手性化合物及其合成方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Porous Polymerized Organocatalysts Rationally Synthesized from the Corresponding Vinyl-Functionalized Monomers as Efficient Heterogeneous Catalysts;Ying Huangfu et al.;《ACS Catalysis》;第5卷(第3期);1556-1559 *

Also Published As

Publication number Publication date
CN114456052A (zh) 2022-05-10

Similar Documents

Publication Publication Date Title
Sprinz et al. Phosphinoaryl-and phosphinoalkyloxazolines as new chiral ligands for enantioselective catalysis: Very high enantioselectivity in palladium catalyzed allylic substitutions
Müller et al. C2‐Symmetric 4, 4′, 5, 5′‐Tetrahydrobi (oxazoles) and 4, 4′, 5, 5′‐Tetrahydro‐2, 2′‐methylenebis [oxazoles] as Chiral Ligands for Enantioselective Catalysis Preliminary Communication
CN110548546A (zh) 一种铱/线型膦-亚磷酰胺体系催化亚胺不对称氢化方法
Peron et al. Functional ruthenium (II) allenylidene and diynyl (arene) derivatives formed by activation of a diyne via a Ru: C: C: C: C: CR2 intermediate
US6369243B1 (en) Chemical transformation of substrates using nonmetallic, organic catalyst compositions
CN114456052B (zh) 一种不饱和羰基或不饱和亚胺化合物的不对称1,4-加成方法
CN114436949B (zh) 一种四齿配体及金属络合物及其制备方法和应用
JP3802585B2 (ja) ハロゲン化ビフェニル−２，２′−ジイルビスジフェニルホスフィンおよびそれらの製法
CN111848675B (zh) 四氢喹啉骨架手性膦-氮配体及其制备方法和应用
AU2001234505A1 (en) Chemical transformation of substrates using nonmetallic, organic catalyst compositions
Baysdon et al. Synthesis and reaction studies of phthaloylcobalt cations. Application to naphthoquinone synthesis
Godajdar et al. Polyethylene glycol functionalized magnetic dicationic ionic liquids as a novel catalyst and their application in ring opening of epoxides in water
Quintard et al. Synthesis of new calix [4] arene based chiral ligands bearing β-amino alcohol groups and their application in asymmetric transfer hydrogenation
CN112920173A (zh) 一种手性苯并二氢吡喃化合物及其合成方法
CN111229312B (zh) 一种无溶剂催化剂及其制备方法和应用
McCaw et al. Delivering enhanced efficiency in the synthesis of α-diazosulfoxides by exploiting the process control enabled in Flow
CN115108937A (zh) 含三级立体中心的α-叠氮酮的合成方法
JPH024819A (ja) ３，４―ビス（ジアリールホスフィノ）ピロリジンの光学活性ロジウム複合体および不斉水素添加によるホスフィノトリシンの製造に当該複合体を使用する方法
CN113980053A (zh) 手性硫醚-膦化合物及其制备方法
CN109053800B (zh) 季鏻盐支载手性氨基-硫脲及其制备方法和用途
CN109320447B (zh) 一种手性3,3-二取代吲哚-2-酮衍生物的合成方法
EP1862446A2 (de) Verfahren zur Herstellung von enantiomerenangereicherten Hydroxylaminderivaten
CN114933516B (zh) 一种在离子液体介质中合成氘代化合物的方法
CN111499520B (zh) 一种含氮四齿配体和中间体及其制备方法
Sayyahi Preparation and application of 1, 1’-bis-methyl-3, 3’-methylene-bisimidazolium dicyanide as a task-specific ionic liquid: an efficient catalyst in benzoin condensations

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant