CN115322151A - 铜催化合成手性多立体中心吡唑烷类化合物的方法 - Google Patents
铜催化合成手性多立体中心吡唑烷类化合物的方法 Download PDFInfo
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- 150000003218 pyrazolidines Chemical class 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 19
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 17
- 229910052802 copper Inorganic materials 0.000 title claims abstract description 8
- 239000010949 copper Substances 0.000 title claims abstract description 8
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 title abstract description 5
- 238000006555 catalytic reaction Methods 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- 150000002576 ketones Chemical class 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 7
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229940126214 compound 3 Drugs 0.000 claims abstract description 4
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 239000003446 ligand Substances 0.000 claims description 11
- -1 copper salt Chemical class 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
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- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
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- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- ORWKVZNEPHTCQE-UHFFFAOYSA-N acetic formic anhydride Chemical compound CC(=O)OC=O ORWKVZNEPHTCQE-UHFFFAOYSA-N 0.000 description 1
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- OWIUPIRUAQMTTK-UHFFFAOYSA-M n-aminocarbamate Chemical compound NNC([O-])=O OWIUPIRUAQMTTK-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/04—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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
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Abstract
本发明公开了铜催化合成手性多立体中心吡唑烷类化合物的方法，属于有机化学中技术领域。以N‑酯酰基腙1和β‑三氟甲基‑α,β‑不饱和酮2为原料，在CuOAc/Ph‑Phosferrox存在下，碱性条件下有机溶剂中反应，得到手性多立体中心吡唑烷类化合物3。本合成方法采用廉价金属，反应原料易得，催化剂结构简单，催化效率高，反应条件温和，后处理简单，得到高光学活性的具有三个立体选择中心的手性吡唑烷衍生物。
Description
技术领域
本发明具体涉及铜催化合成手性多立体中心吡唑烷类化合物的方法，属于有机化学中的不对称合成技术领域。
背景技术
含有氮氮键杂环是许多天然产物和生物活性化合物中常见的结构亚基。其中，吡唑烷和吡唑啉衍生物是重要的有机杂环，具有广泛的转化价值和生物活性。无环偶氮甲碱亚胺通常由腙在金属或强酸存在下形成，并作为1,3-偶极子有效组装手性吡唑烷衍生物。
在过去几十年中，已经开发了以几种良好对映选择性策略以腙为起始原料，通过手性路易斯酸催化剂构建手性各种吡唑烷衍生物。然而，由于N-酯酰基腙分子中RN-CO-OR结构单元可以形成p-π-p共轭，因此电子云密度和键长趋于平均，导致反应性降低。
因此，寻找一种简便合成高对映选择性N-酯酰基腙对吡唑烷的方法，仍然存在很大的挑战。
发明内容
为了克服上述技术缺陷，本发明公开了铜催化合成手性多立体中心吡唑烷类化合物的方法。以N-酯酰基腙1和β-三氟甲基-α,β-不饱和酮2为原料，在铜盐/Phosferrox类配体存在下，碱性条件下有机溶剂中反应，得到手性多立体中心吡唑烷类化合物3。本合成方法采用廉价金属，反应原料易得，催化剂结构简单，催化效率高，反应条件温和，后处理简单，得到高光学活性的具有三个立体选择中心的手性吡唑烷衍生物。
本发明所述一种合成手性多立体中心吡唑烷类化合物的方法，反应方程式表示为：
其中：R1选自C1-C4烷基、苄基；R2选自苄基、取代苄基、苯基、取代苯基、噻吩基、呋喃基、喹啉基；R3选自苯基、取代苯基、苯乙基、苯乙烯基、噻吩基、呋喃基；前述取代均为卤素、C1-C4烷基、C1-C4烷氧基、腈基或硝基。
一种合成手性多立体中心吡唑烷类化合物的方法，包括如下步骤：以N-酯酰基腙1与β-三氟甲基-α,β-不饱和酮2为原料，在铜盐/Phosferrox类配体存在下，有机溶剂中反应，得到手性多立体中心吡唑烷类化合物3。
进一步地，在上述技术方案中，所述有机溶剂选自甲苯、二氯甲烷、四氢呋喃、均三甲苯、氯苯、三氟甲基苯、溴苯、五氟苯、间二甲苯、邻二甲苯、乙醚或乙腈。
进一步地，在上述技术方案中，所述铜盐选自醋酸亚铜、溴化亚铜或碘化亚铜。
进一步地，在上述技术方案中，所述配体选自(S,Sp)-iPr-Phosferrox、(S,Sp)-Bn-Phosferrox或(S,Sp)-Ph-Phosferrox；对应结构为：
进一步地，在上述技术方案中，所述N-酯酰基腙1、β-三氟甲基-α,β-不饱和酮2、铜盐与配体摩尔比为1：1-1.2：0.02-0.05：0.05-0.12。
进一步地，在上述技术方案中，反应体系中加入碱性添加剂。所述碱性添加剂选自碳酸钾、碳酸铯、三乙胺、DBU、二乙胺、叔丁基胺和乙二胺。
进一步地，在上述技术方案中，反应温度为-25℃至0℃；时间为1-5小时。
进一步地，在上述技术方案中，反应在惰性气体氛围下进行。
发明有益效果：
本发明反应原料易得，反应条件温和，后处理简单，使用较为廉价金属及配体，产物收率高，具有良好的对映选择性。
具体实施方式
实施例1:反应条件筛选
a反应条件：1a(0.1mmol)、2a(0.12mmol)、CuOAc(0.005mmol)、配体(0.012mmol)、有机溶剂(2.0mL)、添加剂(0.1mmol)；b分离收率；cee值通过手性柱HPLC手性分析得到；ddr值通过NMR核磁数据分析得到。
在反应条件的筛选过程中，首先考察了不同配体对反应影响(标号1-11)，最终确定了配体L4为最佳，然后考察了溶剂对反应影响(标号12-22)，最终确定了甲苯为最佳溶剂。随后，考察了添加剂对反应的影响(标号23-29)，最终确定了三乙胺为最佳添加剂。同时考察了加入最佳添加剂条件下溶剂对反应影响(标号30-33)，最终确定了甲苯为最佳溶剂。
反应条件的考察(以标号29为例)：
氮气保护下，采用1.0mL甲苯溶解CuOAc(0.61mg,5mol％)和L4(6.18mg,12mol％)，室温搅拌1h，接着降温至-25℃，依次加入N-酯酰基腙1a(0.1mmol,1.0eq)、Et3N(0.1mmol,1.0eq)和β-三氟甲基-αβ-不饱和酮2a(0.12mmol,1.2eq)。原料消耗后(TLC监测)，去除有机溶剂，用柱层析法纯化残渣得到产物，然后用高效液相色谱法直接测定对映体过量。减压除去溶剂后直接快速硅胶柱层析分离纯化得到白色固体产物3aa，收率92％；95％ee；>20:1dr；m.p.:164.7-165.6℃；HPLC CHIRALPAK OD-H,正己烷/异丙醇＝95/5,流速0.5mL/min,λ＝254nm,tR(1)＝17.597min(major),tR(2)＝11.930min(minor)；
(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ8.08-7.95(m,2H),7.66(t,J＝7.4Hz,1H),7.54(t,J＝7.6Hz,2H),7.21-7.12(m,3H),7.11-7.05(m,2H),5.72-5.46(m,1H),4.44(t,J＝6.9Hz,1H),4.15-3.86(m,1H),2.39(dd,J＝14.2,10.6Hz,1H),2.15(dd,J＝14.2,3.2Hz,1H),1.57(s,9H)；13C{1H}NMR(100MHz,CDCl3)δ193.2,155.9,138.0,136.1,134.4,129.6,129.3,128.5,128.3,126.7,125.8(q,J＝279.5Hz),82.3,64.6,61.4(q,J＝31.1Hz),55.9,34.9,28.3；19F{1H}NMR(376MHz,CDCl3)δ-74.87；HRMS(ESI)calcd.for C23H25F3N2 O3Na([M+Na]+):457.1709,found:450.1702.
实施例2:
氮气保护下，采用1.0mL甲苯溶解CuOAc(0.61mg,5mol％)和L4(6.18mg,12mol％)，室温搅拌1h，接着降温至-25℃，依次加入(E)-2-(2-苯亚乙基)肼甲酸叔丁酯1a(0.1mmol,1.0eq)、Et3N(0.1mmol,1.0eq)和4,4,4-三氟-1-(4-氟苯基)-丁-2-烯-1-酮2c(0.12mmol,1.2eq)。原料消耗后(TLC监测)，去除有机溶剂，用柱层析法纯化残渣得到产物，然后用高效液相色谱法直接测定对映体过量。减压除去溶剂后直接快速硅胶柱层析分离纯化得到白色固体产物3ac，收率87％；94％ee；>20:1dr；m.p.:130.8-131.7℃；HPLC CHIRALPAK IG,正己烷/异丙醇＝90/10,流速1.0mL/min,λ＝254nm,tR(1)＝6.810min(major),tR(2)＝13.238min(minor)；
(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ8.07-7.96(m,2H),7.22-7.10(m,5H),7.10-7.05(m,2H),5.64-5.40(m,1H),4.39(t,J＝6.9Hz,1H),4.15-3.90(m,2H),2.44(dd,J＝14.2,10.2Hz,1H),2.14(dd,J＝14.2,3.9Hz,1H),1.57(s,9H)；13C{1H}NMR(100MHz,CDCl3)δ191.7,166.5(d,J＝250Hz),155.8,137.7,132.5(d,J＝3.0Hz),131.2(d,J＝9.5Hz),129.5,128.3,126.8,125.7(q,J＝279.4Hz),116.5(d,J＝22.1Hz),82.5,64.4,61.5(q,J＝31.1Hz),55.6,34.9,28.3；19F{1H}NMR(376MHz,CDCl3)δ-74.84,-102.68；HRMS(ESI)calcd.for C24H27F3N2O3Na([M+Na]+):475.1615,found:475.1612.
实施例3:
氮气保护下，采用1.0mL甲苯溶解CuOAc(0.61mg,5mol％)和L4(6.18mg,12mol％)，室温搅拌1h，接着降温至-25℃，依次加入(E)-2-(2-苯亚乙基)肼甲酸叔丁酯1a(0.1mmol,1.0eq)、Et3N(0.1mmol,1.0eq)和4,4,4-三氟-1-(3-氟苯基)-丁-2-烯-1-酮2j(0.12mmol,1.2eq)。原料消耗后(TLC监测)，去除有机溶剂，用柱层析法纯化残渣得到产物，然后用高效液相色谱法直接测定对映体过量。减压除去溶剂后直接快速硅胶柱层析分离纯化得到白色固体产物3aj，收率88％；94％ee；>20:1dr；m.p.:140.4-141.0℃；HPLC CHIRALPAK IA,正己烷/异丙醇＝90/10,流速1.0mL/min,λ＝254nm,tR(1)＝5.337min(major),tR(2)＝13.690min(minor)；
(c 1.0,CHCl3)；1H NMR(600MHz,CDCl3)δ7.92-7.89(m,1H),7.83(d,J＝7.8Hz,1H),7.64-7.59(m,1H),7.46(t,J＝7.9Hz,1H),7.18-7.10(m,3H),7.09-7.04(m,2H),5.60-5.48(m,1H),4.37(t,J＝7.0Hz,1H),4.10-3.98(m,1H),2.44(dd,J＝14.3,10.1Hz,1H),2.13(dd,J＝14.3,4.1Hz,1H),1.56(s,9H)；13C{1H}NMR(150MHz,CDCl3)δ192.1,155.9,137.5(two peaks),135.7,134.3,130.5,129.6,128.5,128.3,126.8,126.4,125.6(q,J＝279.1Hz),82.4,64.4,61.5(q,J＝31.1Hz),55.9,35.0,28.3；19F{1H}NMR(565MHz,CDCl3)δ-74.86；HRMS(ESI)calcd.for C23H24ClF3N2O3Na([M+Na]+):491.1320,found:491.1310.
实施例4:
氮气保护下，采用1.0mL甲苯溶解CuOAc(0.61mg,5mol％)和L4(6.18mg,12mol％)，室温搅拌1h，接着降温至-25℃，依次加入(E)-2-(2-苯亚乙基)肼甲酸叔丁酯1a(0.1mmol,1.0eq)、Et3N(0.1mmol,1.0eq)和4,4,4-三氟-1-(2-甲氧基苯基)-丁-2-烯-1-酮2q(0.12mmol,1.2eq)。原料消耗后(TLC监测)，去除有机溶剂，用柱层析法纯化残渣得到产物，然后用高效液相色谱法直接测定对映体过量。减压除去溶剂后直接快速硅胶柱层析分离纯化得到白色固体产物3aq，收率91％；93％ee；>20:1dr；m.p.:140.4-141.0℃；HPLCCHIRALPAK OD-H,正己烷/异丙醇＝90/10,流速1.0mL/min,λ＝254nm,tR(1)＝9.080min(major),tR(2)＝5.680min(minor)；
(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ7.88-7.73(m,1H),7.61-7.46(m,1H),7.24-7.11(m,5H),7.11-6.99(m,2H),5.58-5.26(m,1H),4.65(t,J＝6.6Hz,1H),4.02-3.95(m,1H),3.93(s,3H),2.45(dd,J＝14.2,10.7Hz,1H),2.27(dd,J＝14.2,3.4Hz,1H),1.57(s,9H)；13C{1H}NMR(100MHz,CDCl3)δ195.4,158.9,155.9,138.8,135.0,131.4,129.6,128.2,127.1,126.5,125.8(q,J＝279.1Hz),121.4,112.0,82.1,64.2,62.1(q,J＝30.9Hz),59.6,55.8,35.5,28.3；19F{1H}NMR(376MHz,CDCl3)δ-74.85；HRMS(ESI)calcd.for C24H27F3N2O4Na([M+Na]+):487.1815,found:487.1810.
实施例5:
氮气保护下，采用1.0mL甲苯溶解CuOAc(0.61mg,5mol％)和L4(6.18mg,12mol％)，室温搅拌1h，接着降温至-25℃，依次加入(E)-2-(2-(4-氟苯基)亚乙基)肼甲酸叔丁酯1b(0.1mmol,1.0eq)、Et3N(0.1mmol,1.0eq)和β-三氟甲基-αβ-不饱和酮2a(0.12mmol,1.2eq)。原料消耗后(TLC监测)，去除有机溶剂，用柱层析法纯化残渣得到产物，然后用高效液相色谱法直接测定对映体过量。减压除去溶剂后直接快速硅胶柱层析分离纯化得到白色固体产物3ba，收率为92％；92％ee；>20:1dr；m.p.:153.6-154.1℃；HPLC CHIRALPAK OD-H,正己烷/异丙醇＝90/10,流速1.0mL/min,λ＝254nm,tR(1)＝15.745min(major),tR(2)＝19.530min(minor)；
(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ8.05-7.92(m,2H),7.74-7.60(m,1H),7.59-7.49(m,2H),7.09-6.96(m,2H),6.94-6.78(m,2H),5.68-5.43(m,1H),4.53-4.35(m,1H),4.04-3.90(m,1H),3.61(s,1H),2.35(dd,J＝14.2,10.6Hz,1H),2.11(dd,J＝14.2,3.0Hz,1H),1.56(s,9H)；13C{1H}NMR(100MHz,CDCl3)δ193.0,161.8(d,J＝243.1Hz),155.8,135.9,134.5,133.6(d,J＝3.1Hz),131.1(d,J＝7.9Hz),129.4,128.4,125.7(q,J＝279.5Hz),115.0(d,J＝21.1Hz),82.5,64.6,61.4(q,J＝32.1Hz),55.9,34.1,28.3；19F{1H}NMR(376MHz,CDCl3)δ-74.91,-116.55；HRMS(ESI)calcd.for C23H24F4N2O3Na([M+Na]+):475.1615,found:475.1606.
实施例6:
氮气保护下，采用1.0mL甲苯溶解CuOAc(0.61mg,5mol％)和L4(6.18mg,12mol％)，室温搅拌1h，接着降温至-25℃，依次加入(E)-2-(2-(3-氟苯基)亚乙基)肼甲酸叔丁酯1e(0.1mmol,1.0eq)、Et3N(0.1mmol,1.0eq)和β-三氟甲基-αβ-不饱和酮2a(0.12mmol,1.2eq)。原料消耗后(TLC监测)，去除有机溶剂，用柱层析法纯化残渣得到产物，然后用高效液相色谱法直接测定对映体过量。减压除去溶剂后直接快速硅胶柱层析分离纯化得到白色固体产物3ea，收率94％；92％ee；>20:1dr；m.p.:172.3-172.8℃；HPLC CHIRALPAK IF,正己烷/异丙醇＝90/10,流速1.0mL/min,λ＝254nm,tR(1)＝5.587min(major),tR(2)＝7.888min(minor)；
(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ8.01(dd,J＝8.2,2.6Hz,2H),7.72-7.63(m,1H),7.55(t,J＝7.8Hz,2H),7.18-7.06(m,1H),6.94-6.76(m,3H),5.63-5.50(m,1H),4.56(s,1H),4.46(t,J＝7.0Hz,1H),4.06-3.91(m,1H),2.36(dd,J＝14.2,11.0Hz,1H),2.12(dd,J＝14.2,3.2Hz,1H),1.57(s,9H)；13C{1H}NMR(100MHz,CDCl3)δ193.0,162.8(d,J＝250.0Hz),155.9,140.5(d,J＝7.8Hz),136.0,134.5,129.7(d,J＝8.4Hz),129.4,128.4,125.7(q,J＝279.0Hz),125.2(d,J＝2.9Hz),116.6(d,J＝21.5Hz),113.6(d,J＝21.0Hz),82.5,64.3,61.4(q,J＝31.0Hz),56.0,34.6,28.3；19F{1H}NMR(376MHz,CDCl3)δ-74.92,-113.63；HRMS(ESI)calcd.for C23H24F4N2O3Na([M+Na]+):475.1615,found:475.1609.
实施例7:
氮气保护下，采用1.0mL甲苯溶解CuOAc(0.61mg,5mol％)和L4(6.18mg,12mol％)，室温搅拌1h，接着降温至-25℃，依次加入(E)-2-(2-(2-氟苯基)亚乙基)肼甲酸叔丁酯1h(0.1mmol,1.0eq)、Et3N(0.1mmol,1.0eq)和β-三氟甲基-αβ-不饱和酮2a(0.12mmol,1.2eq)。原料消耗后(TLC监测)，去除有机溶剂，用柱层析法纯化残渣得到产物，然后用高效液相色谱法直接测定对映体过量。减压除去溶剂后直接快速硅胶柱层析分离纯化得到白色固体产物3ha。收率90％；93％ee；>20:1dr；m.p.:183.9-184.5℃；HPLC CHIRALPAK IA,正己烷/异丙醇＝90/10,流速1.0mL/min,λ＝254nm,tR(1)＝6.413min(major),tR(2)＝27.283min(minor)；
(c 1.0,CHCl3)。1H NMR(600MHz,CDCl3)δ8.10-7.96(m,2H),7.66(t,J＝7.3Hz,1H),7.54(t,J＝7.7Hz,2H),7.33(t,J＝7.8Hz,1H),7.15-7.08(m,1H),7.01(t,J＝7.5Hz,2H),6.86-6.78(m,1H),5.77-5.52(m,1H),4.47(t,J＝7.0Hz,1H),4.28-4.05(m,1H),2.40(dd,J＝14.2,3.2Hz,1H),2.18(dd,J＝14.2,11.1Hz,1H),1.58(s,9H)；13C{1H}NMR(100MHz,CDCl3)δ193.1,161.1(d,J＝250.0Hz),155.7,135.9,134.4,132.9(d,J＝3.7Hz),129.2,128.6(d,J＝8.2Hz),128.5,125.8(q,J＝279.3Hz),124.9(d,J＝14.6Hz),124.0(d,J＝3.2Hz),114.9(d,J＝21.3Hz),82.3,62.8,61.4(q,J＝30.9Hz),56.1,28.9,28.3；19F{1H}NMR(376MHz,CDCl3)δ-74.93,-118.77；HRMS(ESI)calcd.for C23H24F4N2O3Na([M+Na]+):475.1615,found:475.1609.
实施例8:
根据上述实施例2-7中合成手性吡唑烷衍生物类化合物的方法，仅仅更换反应底物(E)-2-(2-(2-氟苯基)亚乙基)肼甲酸叔丁酯1或β-三氟甲基-αβ-不饱和酮2，反应结果如下：
实施例9:
将化合物3aa(86.8mg,0.2mmol)溶解在四氢呋喃(1.0mL)中，加入LiAlH4(8.3mg,0.22mmol)。将混合物在0□搅拌0.5小时。乙酸乙酯萃取，合并有机层饱和食盐水洗涤，无水硫酸钠干燥，过滤减压浓缩。柱色谱法(PE/EA＝10/1)纯化残余物，得到无色油状物4aa，收率57％，94％ee；>20:1dr；HPLC CHI RALPAK IF,正己烷/异丙醇＝90/10,流速1.0mL/min,λ＝220nm,tR(1)＝6.110min(major),tR(2)＝8.650min(minor)；
(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ7.46-7.30(m,7H),7.27-7.17(m,3H),5.03-4.88(m,1H),4.73-4.45(m,1H),4.21(s,1H),3.71-3.52(m,1H),3.23-3.11(m,1H),3.06-2.93(m,1H),2.44-2.27(m,2H),1.53(s,9H)；13C{1H}NMR(100MHz,CDCl3)δ156.6,142.2,140.2,129.8,129.0,128.7,128.2,126.4,126.3,125.6(q,J＝280.0Hz),82.0,72.8,64.1,60.8(q,J＝30.7Hz),54.3,34.1,28.4；19F{1H}NMR(376MHz,CDCl3)δ-74.52；HRMS(ESI)calcd.for C23H27F3 N2O2Na([M+Na]+):443.1917,found:443.1913.
实施例10:
将化合物3aa(86.8mg,0.2mmol)溶解在7mL二氯甲烷，加入Et3N(277μL,2.0mmol)，然后加入I2(25 3mg,1.0mmol)，反应混合物在室温下搅拌18小时。然后依次采用1.0MNa2S2O3、1.0M盐酸水溶液和饱和食盐水洗。无水硫酸钠干燥，过滤并浓缩。硅胶快速色谱法纯化(PE/EA＝10/1)，得到白色固体5aa，收率67％，98％ee；>20:1dr；m.p.:152.6-153.0℃；HPLC CHIRALPA K OJ–H,正己烷/异丙醇＝90/10,流速1.0mL/min,λ＝254nm,tR(1)＝6.053min(major),tR(2)＝8.917min(minor)；
(c 1.0,CHCl3)；1H NMR(600MHz,CDCl3)δ7.77-7.68(m,2H),7.67-7.62(m,1H),7.45(t,J＝7.8Hz,2H),7.29-7.16(m,3H),7.07-6.94(m,2H),5.29-5.11(m,1H),4.75(d,J＝3.6Hz,1H),3.97(d,J＝15.6Hz,1H),3.26(d,J＝15.6Hz,1H),1.58(s,9H)；13C{1H}NMR(100MHz,CDCl3)δ192.8,153.3,151.6,135.0,134.8,134.7,129.2,129.1,129.0,127.5,124.3(q,J＝280.6Hz),83.2,62.16(q,J＝32.3Hz),55.3,35.5,28.3；19F{1H}NMR(565MHz,CDCl3)δ-75.68；HRMS(ESI)calcd.forC23H23F3N2O3Na([M+Na]+):455.1553,found:455.1548.
实施例11:
向甲酸(94μL,1.0mmol)中逐滴加入乙酸酐(37μL,1.0mmol)，并将所得混合物在40℃下搅拌15分钟得到混合甲酸-乙酸酐。将化合物3aa(86.8mg,0.2mmol)/1.0mL二氯甲烷冷却至0℃，通过注射器滴加上述混合酸酐，并将反应混合物室温下搅拌24小时。滴加饱和NaHCO3水溶液(20mL)淬灭，水层用二氯甲烷(3×20mL)萃取，无水硫酸钠干燥，过滤并减压浓缩，得到白色固体6aa，收率81％，96％ee；>20:1dr；m.p.:88.9-89.5℃；HPLC CHI RALPAKIE,正己烷/异丙醇＝90/10,流速1.0mL/min,λ＝254nm,tR(1)＝11.657min(major),tR(2)＝6.183min(minor)；
(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ8.28(s,1H),8.05-7.94(m,2H),7.71-7.62(m,1H),7.58-7.49(m,2H),7.22-7.02(m,5H),5.76-5.59(m,1H),5.45-5.29(m,1H),4.50-4.37(m,1H),2.47(dd,J＝15.0,11.0Hz,1H),2.36(dd,J＝14.9,4.2Hz,1H),1.50(s,9H)；13C{1H}NMR(100MHz,CDCl3)δ191.7,165.8,156.0,135.9,135.4,134.8,129.5,128.9,128.6,128.5,127.1,125.0(q,J＝278.43Hz),84.6,60.8(q,J＝29.9Hz),58.1,53.1,34.3,28.0；19F{1H}NMR(376MHz,CDCl3)δ-75.46；HRMS(ESI)calcd.forC24H25F3N2O4Na([M+Na]+):485.1658,found:485.1653.
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。
Claims (9)
1.一种合成手性多立体中心吡唑烷类化合物的方法，其特征在于，包括如下步骤：以N-酯酰基腙1与β-三氟甲基-α,β-不饱和酮2为原料，在铜盐/Phosferrox类配体存在下，有机溶剂中反应，得到手性多立体中心吡唑烷类化合物3；反应方程式表示为：
其中：R1选自C1-C4烷基、苄基；R2选自苄基、取代苄基、苯基、取代苯基、噻吩基、呋喃基、喹啉基；R3选自苯基、取代苯基、苯乙基、苯乙烯基、噻吩基、呋喃基；前述取代均为卤素、C1-C4烷基、C1-C4烷氧基、腈基或硝基。
2.根据权利要求1所述合成手性吡唑烷衍生物类化合物的方法，其特征在于：所述有机溶剂选自甲苯、二氯甲烷、四氢呋喃、均三甲苯、氯苯、三氟甲基苯、溴苯、五氟苯、间二甲苯、邻二甲苯、乙醚或乙腈。
3.根据权利要求1所述合成手性吡唑烷衍生物类化合物的方法，其特征在于：所述铜盐选自醋酸亚铜、溴化亚铜或碘化亚铜。
4.根据权利要求1所述合成手性吡唑烷衍生物类化合物的方法，其特征在于：所述配体选自(S,Sp)-iPr-Phosferrox、(S,Sp)-Bn-Phosferrox或(S,Sp)-Ph-Phosferrox。
5.根据权利要求1所述合成手性吡唑烷衍生物类化合物的方法，其特征在于：所述N-酯酰基腙1、β-三氟甲基-α,β-不饱和酮2、铜盐与配体摩尔比为1：1-1.2：0.02-0.05：0.05-0.12。
6.根据权利要求1所述合成手性吡唑烷衍生物类化合物的方法，其特征在于：反应体系中加入碱性添加剂。
7.根据权利要求6所述合成手性吡唑烷衍生物类化合物的方法，其特征在于：所述碱性添加剂选自碳酸钾、碳酸铯、三乙胺、DBU、二乙胺、叔丁基胺和乙二胺。
8.根据权利要求1-7任意一项所述合成手性吡唑烷衍生物类化合物的方法，其特征在于：反应温度为-25℃至0℃；反应时间为1-5小时。
9.根据权利要求1-7任意一项所述合成手性吡唑烷衍生物类化合物的方法，其特征在于：反应在惰性气体氛围下进行。
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