WO2016019630A1 - 一种高光学活性1，3-二取代联烯的合成方法 - Google Patents

一种高光学活性1，3-二取代联烯的合成方法 Download PDF

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WO2016019630A1
WO2016019630A1 PCT/CN2014/088308 CN2014088308W WO2016019630A1 WO 2016019630 A1 WO2016019630 A1 WO 2016019630A1 CN 2014088308 W CN2014088308 W CN 2014088308W WO 2016019630 A1 WO2016019630 A1 WO 2016019630A1
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麻生明
黄鑫
傅春玲
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Zhejiang University ZJU
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    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a chemical synthesis method, and more particularly to a method for synthesizing a highly optically active 1,3-disubstituted olefin.
  • the invention overcomes all the above-mentioned shortcomings in the prior art, and provides a divalent copper salt as a catalyst, and uses a terminal alkyne and a chiral ⁇ , ⁇ -diphenylprolinol to prepare a high optical activity in a simple and efficient manner. , a method of 3-disubstituted olefin.
  • the object of the present invention is to provide a simple and highly efficient synthesis method of a highly optically active 1,3-disubstituted olefin, namely by functional grouping of a terminal alkyne, an aldehyde and a chiral ⁇ , ⁇ -diphenylnonanol, in two A method for preparing a highly optically active 1,3-disubstituted olefin in one step under the catalysis of a valence copper salt.
  • the invention discloses a method for efficiently synthesizing an optically active 1,3-disubstituted olefin. Under the catalysis of a divalent copper salt, a functionalized terminal alkyne, an aldehyde and a chiral secondary amine are heated and reacted in an organic solvent. A variety of functionalized chiral 1,3-disubstituted olefins are produced with the following reaction formula:
  • R 1 may comprise a plurality of functional groups such as a glycoside unit, a primary alcohol, a secondary alcohol, a tertiary alcohol, an amide, a dimethyl malonate, an alkyl group or an aryl group, and R 2 is an alkyl group or an aryl group.
  • step 2) After the reaction of step 1) is completed, the reaction tube is taken from the oil bath, naturally returned to room temperature, diluted with an organic solvent, transferred to a separatory funnel, washed with dilute hydrochloric acid, and the organic phase is separated, and the same organic solvent is used for the aqueous phase. The organic phase is extracted, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography.
  • the present invention uses a divalent copper salt as a catalyst, and the catalyst is copper bromide, copper chloride, copper acetate, copper sulfate or copper triflate.
  • the chiral secondary amine of the present invention is (S)-3a or its enantiomer, and the structural variant (S)-3b-c or its enantiomer with (S)-3a as a template :
  • reaction solvent of the present invention is 1,4-dioxane, toluene, benzene, chlorobenzene, p-xylene, o-xylene, m-xylene or mesitylene.
  • the invention overcomes the disadvantages of the conventional method and has the following advantages: (1) greatly reducing the amount of the metal salt catalyst; (2) having a wide universality of the substrate, good functional group compatibility, and no protection; (3) the reaction is very Excellent diastereoselectivity or enantioselectivity; (4) The product is easy to separate and purify.
  • the innovation of the invention lies in the development of a simple and efficient synthesis method of high optically active 1,3-disubstituted olefin. It is first discovered that the divalent copper salt can directly catalyze the three-component reaction of terminal alkyne, aldehyde and chiral secondary amine. The reaction selectivity is good, and the de or ee values are all greater than 90%.
  • equiv represents the equivalent
  • mol represents the mole
  • 1,4-dioxane represents 1,4-dioxane
  • de represents the diastereomeric excess
  • ee represents the enantiomeric excess
  • Embodiment 1 The operation is referred to in Embodiment 1.
  • CuBr 2 (89.3 mg, 0.4 mmol), propargyl glucoside 1a (772.5 mg, 2.0 mmol), ⁇ , ⁇ -diphenylnonanol (R)-3a (607.6 mg, 2.4 mmol), freshly steamed Octanal 2a (360.6 mg, 2.8 mmol) and 1,4-dioxane (6.0 mL).
  • Embodiment 1 The operation is referred to in Embodiment 1.
  • CuBr 2 (44.9 mg, 0.2 mmol), propargyl glucoside 1a (388.1 mg, 1.0 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (303.3 mg, 1.2 mmol), freshly distilled benzene Acetaldehyde 2b (168.8 mg, 1.4 mmol) and 1,4-dioxane (3.0 mL).
  • Embodiment 1 The operation is referred to in Embodiment 1.
  • CuBr 2 (45.0 mg, 0.2 mmol), propargyl glucoside 1a (385.2 mg, 1.0 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (305.0 mg, 1.2 mmol), freshly distilled benzene Propionaldehyde 2c (187.7 mg, 1.4 mmol) and 1,4-dioxane (3.0 mL).
  • Embodiment 1 The operation is referred to in Embodiment 1.
  • CuBr 2 (45.0 mg, 0.2 mmol), propargyl glucoside 1a (385.4 mg, 1.0 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (304.1 mg, 1.2 mmol), new steaming Valeraldehyde 2d (121.2 mg, 1.4 mmol) and 1,4-dioxane (3.0 mL).
  • Embodiment 1 The operation is referred to in Embodiment 1.
  • CuBr 2 (45.0 mg, 0.2 mmol), propargyl glucoside 1a (388.5 mg, 1.0 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (305.5 mg, 1.2 mmol), fresh steam ring Hexylformaldehyde 2e (157.5 mg, 1.4 mmol) and 1,4-dioxane (3.0 mL).
  • Embodiment 1 The operation is referred to in Embodiment 1.
  • CuBr 2 (44.7 mg, 0.2 mmol), propargyl glucoside 1a (384.2 mg, 1.0 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (305.5 mg, 1.2 mmol), new steaming Butyraldehyde 2f (101.4 mg, 1.4 mmol) and 1,4-dioxane (3.0 mL).
  • Embodiment 1 The operation is referred to in Embodiment 1.
  • CuBr 2 (89.7 mg, 0.4 mmol), propargyl glucoside 1a (386.8 mg, 1.0 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (304.6 mg, 1.2 mmol), p-chlorobenzene Formaldehyde 2g (196.8 mg, 1.4 mmol) and 1,4-dioxane (3.0 mL).
  • Embodiment 1 The operation is referred to in Embodiment 1.
  • CuBr 2 (45.0 mg, 0.2 mmol), propargyl glucoside 1b (498.9 mg, 1.0 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (304.1 mg, 1.2 mmol), fresh steam ring Hexylformaldehyde 2e (156.9 mg, 1.4 mmol) and 1,4-dioxane (3.0 mL).
  • Embodiment 1 The operation is referred to in Embodiment 1.
  • CuBr 2 (44.9 mg, 0.2 mmol), propargyl glucoside 1c (472.5 mg, 1.0 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (303.2 mg, 1.2 mmol), fresh steam ring Hexylformaldehyde 2e (158.1 mg, 1.4 mmol) and 1,4-dioxane (3.0 mL).
  • Embodiment 1 The operation is referred to in Embodiment 1.
  • CuBr 2 (67.0 mg, 0.3 mmol), propargyl glucoside 1d (457.3 mg, 1.0 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (304.0 mg, 1.2 mmol), fresh steam ring Hexylformaldehyde 2e (157.3 mg, 1.4 mmol) and 1,4-dioxane (3.0 mL).
  • Embodiment 1 The operation is referred to in Embodiment 1.
  • CuBr 2 (67.3 mg, 0.3 mmol), propargylgalactoside 1e (388.0 mg, 1.0 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (303.7 mg, 1.2 mmol), freshly steamed Cyclohexylcarbaldehyde 2e (158.0 mg, 1.4 mmol) and 1,4-dioxane (3.0 mL).
  • Embodiment 1 The operation is referred to in Embodiment 1.
  • CuBr 2 (44.9 mg, 0.2 mmol), propargyl glucosinolate 1f (400.8 mg, 1.0 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (304.6 mg, 1.2 mmol), freshly steamed Cyclohexylcarbaldehyde 2e (157.2 mg, 1.4 mmol) and 1,4-dioxane (3.0 mL).
  • Embodiment 1 The operation is referred to in Embodiment 1.
  • CuBr 2 (44.7 mg, 0.2 mmol), high propargyl glucoside 1 g (402.0 mg, 1.0 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (306.1 mg, 1.2 mmol), freshly steamed Cyclohexylcarbaldehyde 2e (157.2 mg, 1.4 mmol) and 1,4-dioxane (3.0 mL).
  • Embodiment 1 The operation is referred to in Embodiment 1.
  • CuBr 2 (44.9 mg, 0.2 mmol), propargyl diglucoside 1 h (862.1 mg, 1.0 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (304.4 mg, 1.2 mmol), fresh steamed ring Hexylformaldehyde 2e (157.5 mg, 1.4 mmol) and 1,4-dioxane (3.0 mL).
  • Embodiment 1 The operation is referred to in Embodiment 1.
  • CuBr 2 (45.0 mg, 0.2 mmol), propargyl diglucoside 1i (861.1 mg, 1.0 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (304.2 mg, 1.2 mmol), fresh steamed ring Hexylformaldehyde 2e (157.2 mg, 1.4 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (44.9 mg, 0.2 mmol), propargyl alcohol 1j (84.6 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (252.6 mg, 1.0 mmol), freshly distilled n-hexanal 2 h (150.2 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (45.0 mg, 0.2 mmol), propargyl alcohol 1j (84.2 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (253.1 mg, 1.0 mmol), freshly distilled phenylpropanal 2c (201.4 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (44.6 mg, 0.2 mmol), propargyl alcohol 1j (84.5 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (253.6 mg, 1.0 mmol), freshly distilled isovaleraldehyde 2d (129.5 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (44.7 mg, 0.2 mmol), propargyl alcohol 1j (84.8 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (252.2 mg, 1.0 mmol), freshly distilled cyclohexylformaldehyde 2e (168.2 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (44.7 mg, 0.2 mmol), propargyl alcohol 1k (126.8 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (253.2 mg, 1.0 mmol), freshly distilled cyclohexylformaldehyde 2e (168.6 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (44.9 mg, 0.2 mmol), propargyl alcohol 1 l (186.8 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (252.7 mg, 1.0 mmol), freshly distilled cyclohexylformaldehyde 2e (168.2 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (44.7 mg, 0.2 mmol), chiral propargyl alcohol (S)-1 m (197.6 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (252.7 mg, 1.0 mmol) , freshly distilled cyclohexylcarbaldehyde 2e (168.3 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (45.0 mg, 0.2 mmol), chiral propargyl alcohol (R)-1 m (198.5 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (253.7 mg, 1.0 mmol) , freshly distilled cyclohexylcarbaldehyde 2e (168.1 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (45.0 mg, 0.2 mmol), chiral propargyl alcohol (S)-1 m (198.2 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (R)-3a (253.8 mg, 1.0 mmol) , freshly distilled cyclohexylcarbaldehyde 2e (167.9 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (45.0 mg, 0.2 mmol), chiral propargyl alcohol (R)-1 m (197.6 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (R)-3a (254.0 mg, 1.0 mmol) , freshly distilled cyclohexylcarbaldehyde 2e (169.2 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (45.0 mg, 0.2 mmol), high propargyl alcohol 1 n (106.0 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (252.6 mg, 1.0 mmol), freshly distilled cyclohexyl Formaldehyde 2e (168.4 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (45.0 mg, 0.2 mmol), propargylamine 1o (313.4 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (253.9 mg, 1.0 mmol), freshly distilled cyclohexyl Formaldehyde 2e (167.8 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (44.9 mg, 0.2 mmol), propargylamine 1p (238.4 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (254.3 mg, 1.0 mmol), freshly distilled isoprene Aldehyde 2d (129.9 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (44.9 mg, 0.2 mmol), propargylamine 1q (232.8 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (253.2 mg, 1.0 mmol), freshly steamed 2- Ethylbutyraldehyde 2i (150.6 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (45.0 mg, 0.2 mmol), terminal alkyne 1r (255.7 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (252.5 mg, 1.0 mmol), freshly distilled isovaleraldehyde 2d (129.6 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (44.8 mg, 0.2 mmol), terminal alkyne 1r (255.7 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (252.8 mg, 1.0 mmol), freshly distilled cyclohexylformaldehyde 2e (168.2 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (44.9 mg, 0.2 mmol), n-alkyne 1s (207.8 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (253.4 mg, 1.0 mmol), freshly distilled phenylpropanal 2c (201.5 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).
  • Example 17 The operation is referred to in Example 17.
  • CuBr 2 (44.8 mg, 0.2 mmol), phenylacetylene 1t (153.2 mg, 1.5 mmol), ⁇ , ⁇ -diphenylnonanol (S)-3a (253.1 mg, 1.0 mmol), freshly distilled cyclohexylcarbaldehyde 2e (168.4 mg, 1.5 mmol) and 1,4-dioxane (3.0 mL).

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Abstract

公开了一种合成光学活性1，3-二取代联烯的方法，即通过官能团化末端炔烃、醛和手性α，α-二苯基脯氨醇，在二价铜盐催化下，一步制备光学活性的l，3-二取代联烯的方法。本方法操作简单，原料和试剂易得，底物普适性广，可以兼容多种官能团，如多种糖苷单元、伯醇、仲醇、叔醇、酸胺类、丙二酸二甲酯类等，且无需进一步保护，所得轴手性联烯收率中等到良好、非对映选择性或对映选择性优秀。

Description

一种高光学活性1,3-二取代联烯的合成方法 技术领域
本发明涉及一种化学合成方法，具体地说，是一种高光学活性1,3-二取代联烯的合成方法。
背景技术
由于联烯化合物独特的结构、活泼的反应性能及其在有机合成中发挥的越来越重要的作用，联烯化学受到越来越多的关注(S.Yu,S.Ma,Angew.Chem.,Int.Ed.2012,51,3074；M.A.Tius,Chem.Soc.Rev.2014,43,2979；J.L.Bras,J.Muzart,Chem.Soc.Rev.2014,43,3003；S.Kitagaki,F.Inagaki,C.Mukai,Chem.Soc.Rev.2014,43,2956；M.P.
Figure PCTCN2014088308-appb-000001
Chem.Soc.Rev.2014,43,3164；C.S.Adams,C.D.Weatherly,E.G.Burke,J.M.Schomaker Chem.Soc.Rev.2014,43,3136；R.Zimmer,H.U.Reissig,Chem.Soc.Rev.,2014,43,2888；m)W.Yang,A.S.K.Hashmi,Chem.Soc.Rev.,2014,43,2941；B.Alcaide,P.Almendros,C.Aragoncillo,Chem.Soc.Rev.2014,43,3106；T.
Figure PCTCN2014088308-appb-000002
F.M.Truscott,R.Rodriguez,G.Maestri,M.Malacria,Chem.Soc.Rev.2014,43,2916；F.López,J.L.
Figure PCTCN2014088308-appb-000003
Chem.Soc.Rev.2014,43,2904；Z.Wang,X.Xu,O.Kwon,Chem.Soc.Rev.2014,43,2927)。因此如何简单高效地合成各种联烯化合物、特别是具有光学活性的1,3-二取代联烯，目前已经成为化学家们日益关注的问题之一(L.K.Sydnes,Chem.Rev.2003,103,1133；N.Krause,A.Hoffmann-
Figure PCTCN2014088308-appb-000004
Tetrahedron 2004,60,11671；K.M.Brummond,J.E.Deforrest,Synthesis 2007,795；M.Ogasawara,Tetrahedron:Asymmetry 2009,20,259；g)S.Yu,S.Ma,Chem.Commun.,2011,47,5384)。较早关于光学活性1,3-二取代联烯的合成方法，需要使用危险的化学品如正丁基锂或乙基溴化镁以及氢化铝锂，操作不方便，不利于大规模合成(L.-I.Olsson,A.Claesson,Acta Chem.Scand.1977,B31,614；A.Claesson,L.-I.Olsson,J.Am.Chem.Soc.1979,101,7302；R.A.Smith,R.L.White,A.Krantz,J.Med.Chem.1988,31, 1558；J.Stichler-Bonaparte,H.Kruth,R.Lunkwitz,C.Tschierske,Liebigs Ann.1996,1375)。最近我们课题组发展了一系列利用末端炔烃、醛和手性胺在锌盐或者锌盐与一价铜盐共同促进的条件下合成光学活性1,3-二取代联烯的方法，虽然相对传统方法已经取得了很大的进步，但是仍然具有底物范围窄、需要使用大量的金属盐、以及对某些特定官能团需要经过保护、脱保护的多步操作等缺点(J.Ye,S.Li,B.Chen,W.Fan,J.Kuang,J.Liu,Y.Liu,B.Miao,B.Wan,Y.Wang,X.Xie,Q.Yu,W.Yuan,S.Ma,Org.Lett.2012,14,1346；J.Ye,W.Fan,S.Ma,Chem.Eur.J.2013,19,716；J.Ye,R.Lü,W.Fan,S.Ma,Tetrahedron 2013,69,8959；R.Lü,J.Ye,T.Cao,B.Chen,W.Fan,W.Lin,J.Liu,H.Luo,B.Miao,S.Ni,X.Tang,N.Wang,Y.Wang,X.Xie,Q.Yu,W.Yuan,W.Zhang,C.Zhu,S.Ma,Org.Lett.2013,15,2254)。
本发明克服了现有技术中上述的所有缺点，提供了一种二价铜盐为催化剂，利用末端炔烃、和手性α,α-二苯基脯氨醇一步简单高效制备高光学活性1,3-二取代联烯的方法。
发明内容
本发明的目的是提供一种高光学活性1,3-二取代联烯的简单高效合成方法，即通过官能团化末端炔烃、醛和手性α,α-二苯基脯氨醇，在二价铜盐催化下，一步制备高光学活性的1,3-二取代联烯的方法。
本发明是采用以下具体技术方案来实现的：
本发明公开了一种高效合成光学活性1,3-二取代联烯的方法，在二价铜盐催化作用下，官能团化末端炔烃，醛和手性仲胺，在有机溶剂中加热反应，生成多种官能团化的轴手性1,3-二取代联烯，其反应式如下：
Figure PCTCN2014088308-appb-000005
其中R1可包含多种官能团如糖苷单元、伯醇、仲醇、叔醇、酰胺类、丙二酸二甲酯类、烷基或者芳基，R2为烷基或者芳基。
作为进一步地改进，本发明所述的具体操作步骤如下：
1)、在氮气气氛中向经过无水无氧处理的反应管中依次加入二价铜盐，手性仲胺，末端炔烃，醛和有机溶剂，加热反应12～24小时；
2)、待步骤1)反应完全后，将反应管从油浴中提出，自然回复室温，有机溶剂稀释，转至分液漏斗中，稀盐酸洗，分出有机相，水相用相同有机溶剂萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，柱层析得产物轴手性联烯。
作为进一步地改进，本发明使用二价铜盐作为催化剂，催化剂是溴化铜、氯化铜、醋酸铜、硫酸铜或三氟甲磺酸铜。
作为进一步地改进，本发明所述的手性仲胺为(S)-3a或其对映体，及以(S)-3a为模板的结构变种(S)-3b～c或其对映体：
Figure PCTCN2014088308-appb-000006
作为进一步地改进，本发明所述反应溶剂为1,4-二氧六环，甲苯，苯，氯苯，对二甲苯，邻二甲苯，间二甲苯或均三甲苯。
本发明克服了传统方法的弊端，具有以下优点：(1)大大降低了金属盐催化剂的用量；(2)底物普适性广，官能团兼容性好，且无需保护；(3)反应具有非常优秀的非对映选择性或者对映选择性；(4)产物易分离纯化。
本发明的创新点在于发展了高光学活性1,3-二取代联烯的简单高效合成方法，首次发现二价铜盐可以直接催化末端炔烃、醛、手性仲胺的三组分反应，反应选择性好，de或ee值均大于90％。
具体实施方式
下面通过具体实施例对本发明的具体技术方案作进一步地详细说明：
实施例1
Figure PCTCN2014088308-appb-000007
其中，equiv表示当量，mol表示摩尔，1,4-dioxane表示1,4-二氧六环，de表示非对映体过量，ee表示对映体过量。
氮气保护下，向干燥的Schlenk反应管中依次加入CuBr2(44.9mg,0.2mmol),炔丙基葡萄糖苷1a(387.0mg,1.0mmol),α,α-二苯基脯氨醇(S)-3a(304.5mg,1.2mmol)和新蒸正辛醛2a(180.1mg,1.4mmol)和干燥的1,4-二氧六环(3.0mL)，加完后在反应管中插入冷凝管，关闭反应管活塞，将反应管放置于事先已加热到130℃的油浴中搅拌16小时，薄层层析(TLC)跟踪显示反应结束。停止加热和搅拌，将反应管从油浴中提出，冷至室温。加入30mL乙酸乙酯稀释，所得混合液转至分液漏斗中，用稀盐酸(v/v＝10％)洗，分出有机相，水相用20mL乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥。过滤，旋干，柱层析(淋洗剂：石油醚/乙酸乙酯＝3/1)得液体轴手性联烯葡萄糖苷(R)-4aa(246.5mg,49％):98％de(HPLC测定条件:Chiralcel AS-H柱,正己烷/异丙醇＝95/5,0.3mL/min,λ＝214nm,tR(大峰)＝24.9min,tR(小峰)＝26.8min)；[α]D 20＝-32.2(c＝1.07,CHCl3)；1H NMR(300MHz,CDCl3)δ5.28-4.95(m,5H),4.64(d,J＝7.8Hz,1H),4.35-4.24(m,2H),4.19-4.07(m,2H),3.74-3.63(m,1H),2.09(s,3H,Me),2.05(s,3H,Me),2.03(s,3H,Me),2.01(s,3H,Me),2.12-1.94(m,2H,CH2),1.48-1.17(m,10H,CH2×5),0.89(t,J＝6.9Hz,3H,Me)；13C NMR(75Hz,CDCl3)δ205.4,170.5,170.2,169.3,169.2,98.8,92.1,87.2,72.8,71.6,71.0,68.2,67.8,61.7,31.7,28.98,28.95,28.9,28.3,22.5,20.6,20.52,20.45,20.4,13.9；IR(neat)ν(cm-1)2928,2856,1963,1757,1435,1370,1226,1165,1041；MS(ESI,m/z)521(M+Na+),516(M+NH4 +)；Anal.Calcd.for C25H38O10(％):C 60.23,H 7.68；Found:C 60.21,H 7.37.
实施例2
Figure PCTCN2014088308-appb-000008
操作参考实施例1。CuBr2(89.3mg,0.4mmol),炔丙基葡萄糖苷1a(772.5mg,2.0mmol),α,α-二苯基脯氨醇(R)-3a(607.6mg,2.4mmol),新蒸正辛醛2a(360.6mg,2.8mmol)和1,4-二氧六环(6.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝3/1)得液体轴手性联烯葡萄糖苷(Sa)-4aa(508.2mg,51％):98％de(HPLC测定条件:Chiralcel AS-H柱,正己烷/异丙醇＝＝95/5,0.4mL/min,λ＝214nm,tR(小峰)＝35.5min,tR(大峰)＝36.5min)；[α]D 20＝+36.8(c＝0.975,CHCl3)；1H NMR(300MHz,CDCl3)δ5.28-4.95(m,5H),4.64(d,J＝7.8Hz,1H),4.34-4.25(m,2H),4.18-4.07(m,2H),3.75-3.66(m,1H),2.08(s,3H,Me),2.04(s,3H,Me),2.03(s,3H,Me),2.00(s,3H,Me),2.12-1.95(m,2H,CH2),1.48-1.18(m,10H,CH2×5),0.88(t,J＝6.6Hz,3H,Me)；13C NMR(75Hz,CDCl3)δ205.1,170.3,169.9,169.1,169.0,98.7,92.0,87.1,72.6,71.5,70.9,68.1,67.5,61.6,31.5,28.8,28.7,28.1,22.3,20.39,20.35,20.3,13.8；IR(neat)ν(cm-1)2929,2857,1962,1759,1435,1367,1227,1166,1040；MS(ESI,m/z)516(M+NH4 +)；Anal.Calcd.for C25H38O10(％):C 60.23,H 7.68；Found:C 60.61,H 7.71.
实施例3
Figure PCTCN2014088308-appb-000009
操作参考实施例1。CuBr2(44.9mg,0.2mmol),炔丙基葡萄糖苷1a(388.1mg,1.0mmol),α,α-二苯基脯氨醇(S)-3a(303.3mg,1.2mmol)，新蒸苯乙醛2b(168.8mg,1.4mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝2.5/1)得液体轴手性联烯葡萄糖苷(Ra)-4ab(273.0mg,55％):97％de(HPLC测定条件:Chiralcel IA-H柱,正己烷/异丙醇＝95/5,1.0mL/min,λ＝214nm,tR(大峰)＝16.4min,tR(小峰)＝23.0min)；[α]D 20＝-30.4(c＝1.405, CHCl3)；1H NMR(300MHz,CDCl3)δ7.39-7.19(m,5H,ArH),5.50-5.37(m,1H),5.22-5.11(m,2H),5.06(t,J＝9.6Hz,1H),4.95(t,J＝8.9Hz,1H),4.35(d,J＝7.8Hz,1H),4.32-4.19(m,2H),4.13-4.02(m,2H),3.55-3.29(m,3H),2.07(s,3H,Me),2.029(s,3H,Me),2.026(s,3H,Me),2.00(s,3H,Me)；13C NMR(75Hz,CDCl3)δ205.7,170.4,170.0,169.15,169.06,139.2,128.34,128.28,126.3,98.2,91.5,88.0,72.5,71.3,70.8,68.0,67.0,61.5,34.7,20.5,20.42,20.35；IR(neat)ν(cm-1)3063,3028,2945,2884,1964,1756,1602,1495,1450,1433,1370,1226,1165,1041；MS(ESI,m/z)529(M+K+),513(M+Na+),508(M+NH4 +)；Anal.Calcd.for C25H30O10(％):C 61.22,H6.16；Found:C 61.32,H 6.03.
实施例4
Figure PCTCN2014088308-appb-000010
操作参考实施例1。CuBr2(45.0mg,0.2mmol),炔丙基葡萄糖苷1a(385.2mg,1.0mmol),α,α-二苯基脯氨醇(S)-3a(305.0mg,1.2mmol),新蒸苯丙醛2c(187.7mg,1.4mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝2.5/1)得液体轴手性联烯葡萄糖苷(Ra)-4ac(321.0mg,64％):>99％de(HPLC测定条件:Chiralcel OD-H柱,正己烷/异丙醇＝90/10,1.0mL/min,λ＝214nm,tR(大峰)＝17.8min)；[α]D 20＝-37.9(c＝0.80,CHCl3)；1H NMR(300MHz,CDCl3)δ7.33-7.10(m,5H),5.31-4.93(m,5H,ArH),4.57(d,J＝7.8Hz,1H),4.32-4.18(m,2H),4.18-3.97(m,2H),3.72-3.58(m,1H),2.73(t,J＝7.7Hz,2H),2.40-2.27(m,2H),2.06(s,3H,Me),2.02(s,6H,Me×2),2.00(s,3H,Me)；13C NMR(75Hz,CDCl3)δ205.2,170.3,169.9,169.1,169.0,141.1,128.2,128.1,125.7,99.0,91.3,87.8,72.6,71.4,70.9,68.0,67.5,61.6,34.9,29.8,20.42,20.38,20.3；IR(neat)ν(cm-1)3063,3024,2942,2861,1964,1757,1603,1496,1453,1432,1369,1225,1165,1041；MS(ESI,m/z)527(M+Na+),522(M+NH4 +)；Anal. Calcd.for C26H32O10(％):C 61.90,H 6.39；Found:C 61.41,H 6.25.HRMS calcd.for C26H36NO10(M+NH4 +):522.2334；Found:522.2322.
实施例5
Figure PCTCN2014088308-appb-000011
操作参考实施例1。CuBr2(45.0mg,0.2mmol),炔丙基葡萄糖苷1a(385.4mg,1.0mmol),α,α-二苯基脯氨醇(S)-3a(304.1mg,1.2mmol),新蒸异戊醛2d(121.2mg,1.4mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝3/1)得固体轴手性联烯葡萄糖苷(Ra)-4ad(245.2mg,54％):97％de(HPLC测定条件:Chiralcel AD-H柱,正己烷/异丙醇＝95/5,1.0mL/min,λ＝214nm,tR(小峰)＝17.6min,tR(大峰)＝18.9min)；[α]D 20＝-26.7(c＝1.00,CHCl3)；熔点68-69℃(二氯甲烷/正己烷)；1H NMR(300MHz,CDCl3)δ5.28-4.95(m,5H),4.63(d,J＝8.1Hz,1H),4.36-4.21(m,2H),4.20-4.04(m,2H),3.73-3.61(m,1H),2.09(s,3H,Me),2.06(s,3H,Me),2.04(s,3H,Me),2.02(s,3H,Me),2.17-1.87(m,2H,CH2),1.76-1.59(m,1H,CH),0.94(d,J＝6.6Hz,6H,Me×2)；13C NMR(75Hz,CDCl3)δ205.9,170.5,170.2,169.23,169.16,98.8,90.5,86.5,72.7,71.6,71.0,68.1,67.8,61.7,37.8,28.1,22.0,21.9,20.54,20.51,20.44,20.42；IR(KBr)ν(cm-1)2957,2871,1964,1757,1434,1369,1226,1165,1041；MS(ESI,m/z)479(M+Na+),474(M+NH4 +)；Anal.Calcd.for C22H32O10(％):C 57.88,H 7.07；Found:C 57.89,H 7.08.
实施例6
Figure PCTCN2014088308-appb-000012
操作参考实施例1。CuBr2(45.0mg,0.2mmol),炔丙基葡萄糖苷1a(388.5mg,1.0mmol), α,α-二苯基脯氨醇(S)-3a(305.5mg,1.2mmol),新蒸环己基甲醛2e(157.5mg,1.4mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝3/1)得固体轴手性联烯葡萄糖苷(Ra)-4ae(275.1mg,57％):99％de(HPLC测定条件:Chiralcel AD-H柱,正己烷/异丙醇＝95/5,1.0mL/min,λ＝214nm,tR(小峰)＝16.4min,tR(大峰)＝19.1min)；[α]D 20＝-37.5(c＝0.92,CHCl3)；熔点102-103℃(二氯甲烷/正己烷)；1H NMR(300MHz,CDCl3)δ5.27-4.96(m,5H),4.66(d,J＝8.1Hz,1H),4.36-4.22(m,2H),4.19-4.05(m,2H),3.72-3.63(m,1H),2.09(s,3H,Me),2.05(s,3H,Me),2.03(s,3H,Me),2.01(s,3H,Me),2.22-1.89(m,1H,CH),1.81-1.60(m,5H,CH2×2and one proton of CH2),1.40-1.00(m,5H,CH2×2and one proton of CH2)；13C NMR(75Hz,CDCl3)δ204.3,170.4,170.0,169.2,169.1,98.7,98.0,88.1,72.7,71.5,71.0,68.1,67.8,61.6,36.6,32.8,32.6,25.8,25.6,20.5,20.42,20.36；IR(KBr)ν(cm-1)2925,2851,1965,1741,1447,1412,1380,1287,1260,1227,1171,1115,1094,1058,1036；MS(ESI,m/z)505(M+Na+),500(M+NH4 +)；Anal.Calcd.for C24H34O10(％):C 59.74,H 7.10；Found:C 59.80,H7.04.
实施例7
Figure PCTCN2014088308-appb-000013
操作参考实施例1。CuBr2(44.7mg,0.2mmol),炔丙基葡萄糖苷1a(384.2mg,1.0mmol),α,α-二苯基脯氨醇(S)-3a(305.5mg,1.2mmol),新蒸异丁醛2f(101.4mg,1.4mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝2.5/1)得液体轴手性联烯葡萄糖苷(Ra)-4af(233.9mg,53％):99％de(HPLC测定条件:Chiralcel IA-H柱,正己烷/异丙醇＝95/5,1.0mL/min,λ＝214nm,tR(小峰)＝15.1min,tR(大峰)＝16.1min)；[α]D 20＝-23.1(c＝1.08,CHCl3)；1H NMR(300MHz,CDCl3)δ5.30-5.14(m,3H),5.10(t,J＝9.6Hz,1H),5.01(dd,J1＝9.6Hz,J2 ＝8.1Hz,1H),4.66(d,J＝7.8Hz,1H),4.36-4.24(m,2H),4.17-4.07(m,2H),3.72-3.64(m,1H),2.40-2.24(m,1H,CH),2.09(s,3H,Me),2.05(s,3H,Me),2.03(s,3H,Me),2.01(s,3H,Me),1.03(d,J＝6.6Hz,6H,Me×2)；13C NMR(75Hz,CDCl3)δ204.0,170.5,170.2,169.3,169.2,99.5,98.7,88.5,72.8,71.6,71.1,68.2,67.9,61.8,27.5,22.3,22.2,20.6,20.51,20.45,20.4；IR(neat)ν(cm-1)2962,2871,1961,1755,1434,1367,1227,1165,1040；MS(ESI,m/z)460(M+NH4 +)；Anal.Calcd.for C21H30O10(％):C 57.01,H 6.83；Found:C 57.05,H 6.72.
实施例8
Figure PCTCN2014088308-appb-000014
操作参考实施例1。CuBr2(89.7mg,0.4mmol),炔丙基葡萄糖苷1a(386.8mg,1.0mmol),α,α-二苯基脯氨醇(S)-3a(304.6mg,1.2mmol),对氯苯甲醛2g(196.8mg,1.4mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝2/1)得液体轴手性联烯葡萄糖苷(Ra)-4ag(277.3mg,54％):99％de(HPLC测定条件:Chiralcel AD-H柱,正己烷/异丙醇＝95/5,0.6mL/min,λ＝214nm,tR(大峰)＝57.1min,tR(小峰)＝62.3min)；[α]D 20＝-111.8(c＝1.04,CHCl3)；1H NMR(300MHz,CDCl3)δ7.34-7.27(m,2H,ArH),7.25-7.19(m,2H,ArH),6.23(dt,J1＝6.2Hz,J2＝2.3Hz,1H,one proton of CH＝C＝CH),5.65(dd,J1＝13.8Hz,J2＝6.3Hz,1H,one proton of CH＝C＝CH),5.22(t,J＝9.5Hz,1H),5.14-4.97(m,2H),4.65(d,J＝7.8Hz,1H),4.47-4.37(m,1H),4.29-4.18(m,2H),4.10(dd,J1＝12.3Hz,J2＝2.4Hz,1H),3.66-3.58(m,1H),2.03(s,3H,Me),2.02(s,3H,Me),2.00(s,3H,Me),1.99(s,3H,Me)；13C NMR(75Hz,CDCl3)δ206.4,170.3,169.9,169.1,169.0,132.8,132.0,128.7,127.9,99.2,94.9,91.8,72.7,71.7,71.1,68.2,66.6,61.7,20.4,20.3；IR(neat)ν(cm-1)2956,2925,2869,2849,1953,1755,1492,1456,1429,1376,1224,1039；MS(ESI,m/z)535(M(37Cl)+Na+),533(M(35Cl)+Na+),530 (M(37Cl)+NH4 +),528(M(35Cl)+NH4 +)；HRMS calcd.for C24H31 35ClNO10(M(35Cl)+NH4 +):528.1631；Found:528.1614.
实施例9
Figure PCTCN2014088308-appb-000015
操作参考实施例1。CuBr2(45.0mg,0.2mmol),炔丙基葡萄糖苷1b(498.9mg,1.0mmol),α,α-二苯基脯氨醇(S)-3a(304.1mg,1.2mmol),新蒸环己基甲醛2e(156.9mg,1.4mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝2.5/1)得固体轴手性联烯葡萄糖苷(R)-4be(297.4mg,50％):99％de(HPLC测定条件:Chiralcel IA-H柱,正己烷/异丙醇＝80/20,1.0mL/min,λ＝214nm,tR(小峰)＝9.5min,tR(大峰)＝10.9min)；[α]D 20＝-21.6(c＝0.97,CHCl3)；熔点117-118℃(乙酸乙酯/正己烷)；1H NMR(300MHz,CDCl3)δ7.78(d,J＝8.4Hz,2H,ArH),7.35(d,J＝8.1Hz,2H,ArH),5.27-5.08(m,3H),4.97-4.86(m,2H),4.58(d,J＝8.1Hz,1H),4.27-4.17(m,1H),4.16-3.97(m,3H),3.77-3.68(m,1H),2.45(s,3H),2.03(s,3H,Me),2.00(s,3H,Me),1.99(s,3H,Me),2.10-1.95(m,1H,CH),1.82-1.59(m,5H,CH2×2and one proton of CH2),1.40-0.98(m,5H,CH2×2and one proton of CH2)；13C NMR(75Hz,CDCl3)δ204.2,170.1,169.3,169.1,145.0,132.2,129.8,127.9,98.7,98.2,88.2,72.4,71.3,70.8,68.4,67.9,67.5,36.6,32.8,32.7,25.9,25.7,21.5,20.47,20.42,20.39；IR(KBr)ν(cm-1)2926,2852,1962,1758,1598,1449,1369,1245,1218,1178,1040；MS(ESI,m/z)612(M+NH4 +)；Anal.Calcd.for C29H38O11S(％):C 58.57,H 6.44；Found:C 58.81,H 6.38.
实施例10
Figure PCTCN2014088308-appb-000016
操作参考实施例1。CuBr2(44.9mg,0.2mmol),炔丙基葡萄糖苷1c(472.5mg,1.0mmol),α,α-二苯基脯氨醇(S)-3a(303.2mg,1.2mmol),新蒸环己基甲醛2e(158.1mg,1.4mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝1.5/1)得液体轴手性联烯葡萄糖苷(Ra)-4ce(256.2mg,45％):99％de(HPLC测定条件:Chiralcel AD-H柱,正己烷/异丙醇＝95/5,1.0mL/min,λ＝214nm,tR(小峰)＝27.3min,tR(大峰)＝29.6min)；[α]D 20＝-38.9(c＝1.35,CHCl3)；1H NMR(300MHz,CDCl3)δ5.89(t,J＝5.4Hz,1H),5.27-5.13(m,3H),5.02-4.85(m,2H),4.62(d,J＝8.1Hz,1H),4.34-4.24(m,1H),4.18-4.07(m,1H),3.61-3.40(m,3H),2.23-2.11(m,2H),2.06(s,3H,Me),2.05(s,3H,Me),2.00(s,3H,Me),2.10-1.95(m,1H,CH),1.82-1.54(m,7H,CH2×3and one proton of CH2),1.39-1.00(m,13H,CH2×6and one proton of CH2),0.88(t,J＝6.6Hz,3H,Me)；13C NMR(75Hz,CDCl3)δ204.3,173.1,170.1,169.5,169.2,99.2,98.3,88.3,72.7,72.4,71.1,68.7,68.4,38.8,36.7,36.5,32.9,32.7,31.5,29.1,28.9,25.9,25.7,25.4,22.5,20.52,20.47,13.9；IR(neat)ν(cm-1)3312,2926,2853,1961,1760,1651,1538,1447,1373,1248,1220,1165,1050；MS(ESI,m/z)604(M+K+),588(M+Na+),566(M+H+)；Anal.Calcd.for C30H47NO9(％):C 63.70,H 8.37,N 2.48；Found:C 63.60,H 8.39,N 2.29.
实施例11
Figure PCTCN2014088308-appb-000017
操作参考实施例1。CuBr2(67.0mg,0.3mmol),炔丙基葡萄糖苷1d(457.3mg,1.0mmol),α,α-二苯基脯氨醇(S)-3a(304.0mg,1.2mmol),新蒸环己基甲醛2e(157.3mg,1.4mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝2.5/1)得液体轴手性联烯葡萄糖苷(Ra)-4de(255.0mg,46％):98％de(HPLC测定条件:Chiralcel AD-H柱,正己烷/异丙醇＝80/20,0.5mL/min,λ＝214nm,tR(小峰)＝12.2min,tR(大峰)＝14.3min)；[α]D 20＝-30.0(c＝ 1.375,CHCl3)；1H NMR(300MHz,CDCl3)δ5.26-5.12(m,3H),4.96(dd,J1＝9.8Hz,J2＝8.0Hz,1H),4.88(t,J＝9.5Hz,1H),4.52(d,J＝8.1Hz,1H),4.25(ddd,J1＝11.4Hz,J2＝6.3Hz,J3＝2.7Hz,1H),4.06(ddd,J1＝11.7Hz,J2＝7.5Hz,J3＝2.4Hz,1H),3.76(s,3H,Me),3.74(s,3H,Me),3.67(dd,J1＝9.6Hz,J2＝5.1Hz,1H),3.52(td,J1＝9.6Hz,J2＝2.9Hz,1H,CH),2.30-2.19(m,1H),2.13-1.94(m,11H),1.81-1.60(m,5H,CH2×2and one proton of CH2),1.40-1.00(m,5H,CH2×2and one proton of CH2)；13C NMR(75Hz,CDCl3)δ204.1,170.1,169.5,169.2,169.1,169.0,99.2,98.1,88.3,72.6,71.6,71.1,71.0,68.1,52.6,52.5,47.4,36.6,32.8,32.7,30.2,25.9,25.7,20.52,20.49,20.4；IR(neat)ν(cm-1)2927,2852,1961,1755,1436,1367,1245,1218,1159,1046；MS(ESI,m/z)577(M+Na+),572(M+NH4 +)；Anal.Calcd.for C27H38O12(％):C 58.47,H6.91；Found:C 58.04,H 6.68.HRMS calcd.for C27H42NO12(M+NH4 +):572.2702；Found:572.2688.
实施例12
Figure PCTCN2014088308-appb-000018
操作参考实施例1。CuBr2(67.3mg,0.3mmol),炔丙基半乳糖苷1e(388.0mg,1.0mmol),α,α-二苯基脯氨醇(S)-3a(303.7mg,1.2mmol),新蒸环己基甲醛2e(158.0mg,1.4mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝3/1)得液体轴手性联烯半乳糖苷(Ra)-4ee(240.3mg,50％):96％de(HPLC测定条件:Chiralcel AD-H柱,正己烷/异丙醇＝95/5,1.0mL/min,λ＝214nm,tR(大峰)＝20.0min,tR(小峰)＝23.5min)；[α]D 20＝-26.7(c＝1.24,CHCl3)；1H NMR(300MHz,CDCl3)δ5.40(d,J＝3.0Hz,1H),5.27-5.13(m,3H),5.02(dd,J1＝10.4Hz,J2＝3.2Hz,1H),4.62(d,J＝8.1Hz,1H),4.37-4.27(m,1H),4.23-4.07(m,3H),3.89(t,J＝6.6Hz,1H),2.16(s,3H,Me),2.09(s,3H,Me),2.06(s,3H,Me),1.99(s,3H,Me), 2.20-1.93(m,1H,CH),1.83-1.60(m,5H,CH2×2and one proton of CH2),1.40-0.99(m,5H,CH2×2and one proton of CH2)；13C NMR(75Hz,CDCl3)δ204.3,170.12,170.09,170.0,169.2,99.2,98.0,88.2,70.8,70.4,68.6,67.8,66.8,61.1,36.6,32.8,32.6,25.8,25.7,20.5,20.43,20.36；IR(neat)ν(cm-1)2926,2852,1961,1754,1449,1370,1223,1170,1132,1075,1057；MS(ESI,m/z)505(M+Na+),500(M+NH4 +)；Anal.Calcd.for C24H34O10(％):C 59.74H 7.10；Found:C59.77,H 6.97.
实施例13
Figure PCTCN2014088308-appb-000019
操作参考实施例1。CuBr2(44.9mg,0.2mmol),炔丙基葡萄硫苷1f(400.8mg,1.0mmol),α,α-二苯基脯氨醇(S)-3a(304.6mg,1.2mmol),新蒸环己基甲醛2e(157.2mg,1.4mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝3/1)得固体轴手性联烯葡萄硫苷(Ra)-4fe(230.3mg,46％):96％de(HPLC测定条件:Chiralcel AS-H柱,正己烷/异丙醇＝95/5,0.5mL/min,λ＝214nm,tR(小峰)＝23.0min,tR(大峰)＝24.5min)；[α]D 20＝-47.9(c＝1.24,CHCl3)；熔点103-104℃(乙酸乙酯/正己烷)；1H NMR(300MHz,CDCl3)δ5.27-5.14(m,3H),5.14-5.01(m,2H),4.58(d,J＝9.9Hz,1H),4.25(dd,J1＝12.5Hz,J2＝5.0Hz,1H),4.13(dd,J1＝12.2Hz,J2＝2.0Hz,1H),3.71-3.62(m,1H),3.35(ddd,J1＝13.8Hz,J2＝7.5Hz,J3＝2.3Hz,1H),3.24(ddd,J1＝13.8Hz,J2＝6.5Hz,J3＝3.0Hz,1H),2.08(s,3H,Me),2.07(s,3H,Me),2.03(s,3H,Me),2.02(s,3H,Me),2.12-1.94(m,1H,CH),1.82-1.60(m,5H,CH2×2and one proton of CH2),1.40-1.00(m,5H,CH2×2and one proton of CH2)；13C NMR(75Hz,CDCl3)δ203.7,170.5,170.0,169.2,98.5,88.8,82.7,75.7,73.8,69.7,68.1,61.9,37.2,33.0,32.9,30.1,25.9,25.7,20.6,20.5,20.4；IR(KBr)ν(cm-1)2926,2852,1953,1756,1448,1371,1225,1040；MS(ESI, m/z)516(M+NH4 +)；Anal.Calcd.for C24H34O9S(％):C 57.81,H 6.87；Found:C 58.03,H 6.82.
实施例14
Figure PCTCN2014088308-appb-000020
操作参考实施例1。CuBr2(44.7mg,0.2mmol),高炔丙基葡萄糖苷1g(402.0mg,1.0mmol),α,α-二苯基脯氨醇(S)-3a(306.1mg,1.2mmol),新蒸环己基甲醛2e(157.2mg,1.4mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝2.5/1)得固体轴手性3,4-联烯基葡萄糖苷(Ra)-4ge(183.2mg,37％):98％de(HPLC测定条件:Chiralcel IC柱,正己烷/异丙醇＝96/4,0.4mL/min,λ＝214nm,tR(小峰)＝76.6min,tR(大峰)＝78.3min)；[α]D 20＝-47.8(c＝1.38,CHCl3)；熔点86-87℃(二氯甲烷/正己烷)；1H NMR(300MHz,CDCl3)δ5.21(t,J＝9.5Hz,1H),5.14-4.94(m,4H),4.53(d,J＝8.1Hz,1H),4.28(dd,J1＝12.3Hz,J2＝4.8Hz,1H),4.13(dd,J1＝12.3Hz,J2＝2.4Hz,1H),3.92(dt,J1＝9.6Hz,J2＝6.9Hz,1H),3.71(ddd,J1＝10.1Hz,J2＝4.8Hz,J1＝2.4Hz,1H),3.55(dt,J1＝9.6Hz,J2＝7.2Hz,1H),2.32-2.20(m,2H,CH2),2.09(s,3H,Me),2.05(s,3H,Me),2.03(s,3H,Me),2.01(s,3H,Me),2.13-1.88(m,1H,CH),1.80-1.58(m,5H,CH2×2and one proton of CH2),1.37-0.97(m,5H,CH2×2and one proton of CH2)；13C NMR(75Hz,CDCl3)δ203.2,170.6,170.2,169.3,169.2,100.7,97.4,87.4,72.7,71.6,71.1,69.7,68.2,61.8,36.9,32.9,32.8,29.3,26.0,25.8,20.6,20.5,20.4；IR(KBr)ν(cm-1)2926,2852,1959,1757,1448,1369,1225,1170,1040；MS(ESI,m/z)514(M+NH4 +)；Anal.Calcd.for C25H36O10(％):C 60.47,H 7.31；Found:C 60.54,H 7.25.
实施例15
Figure PCTCN2014088308-appb-000021
操作参考实施例1。CuBr2(44.9mg,0.2mmol),炔丙基二糖苷1h(862.1mg,1.0mmol),α,α-二苯基脯氨醇(S)-3a(304.4mg,1.2mmol),新蒸环己基甲醛2e(157.5mg,1.4mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝1.5/1)得液体轴手性联烯基二糖苷(R)-4he(456.7mg,48％):98％de(HPLC测定条件:(超临界流体色谱)Chiralcel IA柱,正己烷/异丙醇＝80/20,1.5mL/min,λ＝214nm,tR(小峰)＝8.3min,tR(大峰)＝14.2min)；[α]D 20＝-13.8(c＝1.21,CHCl3)；1H NMR(300MHz,CDCl3)δ7.98-7.88(m,4H,ArH),7.84-7.78(m,2H,ArH),7.55-7.45(m,2H,ArH),7.43-7.32(m,5H,ArH),7.28-7.20(m,2H,ArH),5.88(t,J＝9.6Hz,1H),5.51(dd,J1＝9.6Hz,J2＝8.1Hz,1H),5.41(t,J＝9.8Hz,1H),5.26-5.12(m,3H),5.11-4.98(m,2H),4.94(d,J＝7.8Hz,1H),4.65(d,J＝7.8Hz,1H),4.43-4.33(m,1H),4.29-4.12(m,2H),4.10-3.97(m,3H),3.78(dd,J＝18.8Hz,J＝11.3Hz,1H),3.74-3.65(m,1H),2.09(s,3H,Me),2.01(s,3H,Me),2.00(s,3H,Me),1.99(s,3H,Me),2.12-1.85(m,1H,CH),1.79-1.57(m,5H,CH2×2and one proton of CH2),1.34-0.95(m,5H,CH2×2and one proton of CH2)；13C NMR(75Hz,CDCl3)δ204.1,170.3,170.0,169.2,169.1,165.5,165.1,164.8,133.4.133.02,132.99,129.6,129.54,129.47,129.1,128.5,128.4,128.3,128.11,128.05,100.6,99.2,98.2,88.2,73.5,72.8,72.6,71.6,71.5,70.9,69.5,68.2,68.0,67.7,61.6,36.5,32.8,32.5,25.8,25.7,25.6,20.5,20.4,20.3；IR(neat)ν(cm-1)3063,2927,2852,1959,1754,1739,1602,1452,1369,1284,1251,1224,1176,1094,1069,1037；MS(MALDI,m/z)995(M+K+)979(M+Na+)；Anal.Calcd.for C51H56O18(％):C 64.01,H 5.90；Found:C 64.00,H 5.80.
实施例16
Figure PCTCN2014088308-appb-000022
操作参考实施例1。CuBr2(45.0mg,0.2mmol),炔丙基二糖苷1i(861.1mg,1.0mmol),α,α-二苯基脯氨醇(S)-3a(304.2mg,1.2mmol),新蒸环己基甲醛2e(157.2mg,1.4mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝1.5/1)得液体轴手性联烯基二糖苷(Ra)-4ie(492.2mg,51％):98％de(HPLC测定条件:(超临界流体色谱)Chiralcel IA柱,正己烷/异丙醇＝70/30,1.5mL/min,λ＝214nm,tR(小峰)＝4.5min,tR(大峰)＝6.1min)；[α]D 20＝-13.5(c＝1.12,CHCl3)；1H NMR(300MHz,CDCl3)δ7.80-7.88(m,4H,ArH),7.85-7.78(m,2H,ArH),7.55-7.20(m,9H,ArH),5.88(t,J＝9.8Hz,1H),5.51(dd,J1＝9.8Hz,J2＝8.0Hz,1H),5.46-5.36(m,2H),5.26(dd,J1＝10.4Hz,J2＝8.0Hz,1H),5.20-5.12(m,2H),5.03(dd,J1＝10.4Hz,J2＝3.5Hz,1H),4.95(d,J＝7.8Hz,1H),4.62(d,J＝7.8Hz,1H),4.44-4.34(m,1H),4.25-3.97(m,5H),3.92(t,J＝6.5Hz,1H),3.79(dd,J1＝10.8Hz,J2＝7.5Hz,1H),2.110(s,3H,Me),2.107(s,3H,Me),2.01(s,3H,Me),1.98(s,3H,Me),2.18-1.85(m,1H,CH),1.79-1.57(m,5H,CH2×2and one proton of CH2),1.34-0.95(m,5H,CH2×2and one proton of CH2)；13C NMR(75Hz,CDCl3)δ204.1,170.1,170.0,169.9,169.2,165.5,165.1,164.8,133.4,133.02,132.98,129.5,129.4,129.0,128.5,128.4,128.3,128.1,128.0,101.0,99.2,98.2,88.2,73.5,72.8,71.5,70.7,70.4,69.5,68.4,68.2,67.7,66.8,61.0,36.4,32.8,32.5,25.8,25.7,25.6,20.6,20.4,20.33,20.28；IR(neat)ν(cm-1)3066,2927,2852,1959,1740,1602,1451,1370,1281,1255,1218,1177,1090,1069；MS(MALDI,m/z)979(M+Na+)；Anal.Calcd.for C51H56O18(％):C 64.01,H5.90；Found:C 64.04,H 5.88.
实施例17
Figure PCTCN2014088308-appb-000023
氮气保护下，向干燥的带四氟乙烯塞的反应管中依次加入CuBr2(44.7mg,0.2mmol),α,α-二苯基脯氨醇(S)-3a(253.1mg,1.0mmol),炔丙醇1j(84.3mg,1.5mmol),干燥的1,4-二氧六环(1.5mL),新蒸正辛醛2a(192.4mg,1.5mmol)和干燥的1,4-二氧六环(1.5mL)，加完后旋紧四氟乙烯塞，关闭反应管活塞，将反应管放置于事先已加热到130℃的油浴中搅拌12小时，薄层层析(TLC)跟踪显示反应结束。停止加热和搅拌，将反应管从油浴中提出，冷至室温。加入30mL乙醚稀释，所得混合液转至分液漏斗中，用稀盐酸(3M,20mL)洗，分出有机相，水相用20mL乙醚萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥。过滤，旋干，柱层析(淋洗剂：石油醚/乙酸乙酯＝8/1)得液体轴手性联烯醇(Ra)-4ja(86.8mg,52％):95％ee(HPLC测定条件:Chiralcel AS-H柱,正己烷/异丙醇＝98/2,0.6mL/min,λ＝214nm,tR(大峰)＝10.9min,tR(小峰)＝11.8min)；[α]D 20＝-68.9(c＝1.005,CHCl3)(文献值:97％ee；[α]D 20＝-66.1(c＝1.03,CHCl3))；1H NMR(300MHz,CDCl3)δ5.37-5.24(m,2H,CH＝C＝CH),4.17-4.07(m,2H,OCH2),2.08-1.96(m,2H,CH2),1.57(t,J＝4.8Hz,1H,OH),1.48-1.20(m,10H,CH2×5),0.88(t,J＝6.8Hz,3H,Me)；13C NMR(75MHz,CDCl3)δ202.9,94.0,91.7,60.8,31.8,29.08,29.07,29.0,28.6,22.6,14.1；IR(neat)ν(cm-1)3336,2956,2926,2855,1963,1465,1376,1013；MS(EI):m/z(％)168(M+,0.04),55(100).(参考文献：J.Ye,W.Fan,S.Ma,Chem.Eur.J.2013,19,716)。
实施例18
Figure PCTCN2014088308-appb-000024
操作参考实施例17。CuBr2(44.9mg,0.2mmol),炔丙醇1j(84.6mg,1.5mmol),α,α-二苯基脯氨醇(S)-3a(252.6mg,1.0mmol),新蒸正己醛2h(150.2mg,1.5mmol)和1,4-二氧六环(3.0 mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝8/1)得液体轴手性联烯醇(Ra)-4jh(75.2mg,54％):94％ee(HPLC测定条件:Chiralcel AS-H柱,正己烷/异丙醇＝100/1,0.5mL/min,λ＝214nm,tR(大峰)＝18.9min,tR(小峰)＝20.0min)；[α]D 20＝-78.5(c＝1.11,CHCl3)(文献值:98％ee；[α]D 21＝-78.4(c＝1.03,CHCl3))；1H NMR(300MHz,CDCl3)δ5.36-5.23(m,2H,CH＝C＝CH),4.11(dd,J1＝5.6Hz,J2＝3.2Hz,2H,OCH2),2.08-1.96(m,2H,CH2),1.80(s,1H,OH),1.49-1.21(m,6H,CH2×3),0.89(t,J＝7.1Hz,3H,Me)；13C NMR(75MHz,CDCl3)δ203.0,93.9,91.6,60.7,31.2,28.7,28.6,22.4,14.0；IR(neat)ν(cm-1)3337,2957,2927,2857,1963,1466；MS(EI):m/z(％)122((M-H2O)+,0.68),55(100).(参考文献：J.Ye,W.Fan,S.Ma,Chem.Eur.J.2013,19,716)。
实施例19
Figure PCTCN2014088308-appb-000025
操作参考实施例17。CuBr2(45.0mg,0.2mmol),炔丙醇1j(84.2mg,1.5mmol),α,α-二苯基脯氨醇(S)-3a(253.1mg,1.0mmol),新蒸苯丙醛2c(201.4mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝8/1)得液体轴手性联烯醇(Ra)-4jc(106.1mg,61％):95％ee(HPLC测定条件:Chiralcel AS-H柱,正己烷/异丙醇＝100/1,1.0mL/min,λ＝214nm,tR(大峰)＝22.4min,tR(小峰)＝24.4min)；[α]D 20＝-38.0(c＝0.89,CHCl3)(文献值:96％ee；[α]D 20＝-38.7(c＝1.05,CHCl3))；1H NMR(300MHz,CDCl3)δ7.36-7.13(m,5H,ArH),5.35-5.21(m,2H,CH＝C＝CH),4.04-3.90(m,2H,OCH2),2.83-2.64(m,2H,CH2),2.46-2.24(m,2H,CH2),1.62(s,1H,OH)；13C NMR(75MHz,CDCl3)δ203.2,141.4,128.4,128.2,125.9,92.9,92.1,60.4,35.0,29.9；IR(neat)ν(cm-1)3366,3084,3062,3026,2923,2856,1962,1603,1496,1453,1062,1011；MS(EI)m/z(％):174(M+,0.03),156((M-H2O)+,41.67),91(100).(参考文献：J.Ye,W.Fan,S.Ma,Chem.Eur.J.2013,19,716)。
实施例20
Figure PCTCN2014088308-appb-000026
操作参考实施例17。CuBr2(44.6mg,0.2mmol),炔丙醇1j(84.5mg,1.5mmol),α,α-二苯基脯氨醇(S)-3a(253.6mg,1.0mmol),新蒸异戊醛2d(129.5mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝8/1)得液体轴手性联烯醇(Ra)-4jd(57.3mg,45％):96％ee(HPLC测定条件:Chiralcel AD-H柱,正己烷/异丙醇＝200/1,1.0mL/min,λ＝214nm,tR(大峰)＝18.7min,tR(小峰)＝22.0min)；[α]D 20＝-79.9(c＝0.955,CHCl3)(文献值:98％ee；[α]D 22＝-80.3(c＝1.01,CHCl3))；1H NMR(300MHz,CDCl3)δ5.35-5.19(m,2H,CH＝C＝CH),4.11(dd,J1＝5.9Hz,J2＝2.9Hz,2H,OCH2),1.97-1.89(m,2H,CH2),1.76-1.57(m,2H,CH and OH),0.93(d,J＝6.6Hz,6H,Me×2)；13C NMR(75MHz,CDCl3)δ203.6,92.3,91.0,60.8,38.1,28.4,22.12,22.10；IR(neat)ν(cm-1)3338,2956,2926,2893,2870,1962,1466,1384,1367,1056,1014；MS(EI)m/z(％):126(M+,0.10),108((M-H2O)+,31.12),55(100).(参考文献：J.Ye,W.Fan,S.Ma,Chem.Eur.J.2013,19,716)。
实施例21
Figure PCTCN2014088308-appb-000027
操作参考实施例17。CuBr2(44.7mg,0.2mmol),炔丙醇1j(84.8mg,1.5mmol),α,α-二苯基脯氨醇(S)-3a(252.2mg,1.0mmol),新蒸环己基甲醛2e(168.2mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝8/1)得液体轴手性联烯醇(Ra)-4je(94.2mg,62％):94％ee(HPLC测定条件:Chiralcel AS-H柱,正己烷/异丙醇＝98/2,0.6mL/min,λ＝214nm,tR(大峰)＝15.7min,tR(小峰)＝18.6min)；[α]D 20＝-98.1(c＝1.045,CHCl3)(文献值:99％ee；[α]D 22＝-100.3(c＝1.00,CHCl3))；1H NMR(300MHz,CDCl3)δ5.41-5.25(m,2H,CH＝C＝CH),4.10(dd,J1＝5.7Hz,J2＝3.0Hz,2H,OCH2),2.08-1.93(m,1H,CH from Cy), 1.88-1.58(m,6H,OH and five protons from Cy),1.37-1.00(m,5H,five protons from Cy)；13C NMR(75MHz,CDCl3)δ201.8,99.9,92.6,60.8,37.0,33.0,32.9,26.0,25.9；IR(neat)ν(cm-1)3331,2924,2851,1961,1448,1412,1011；MS(EI)m/z(％):152(M+,0.38),134((M-H2O)+,6.78),55(100).(参考文献：J.Ye,W.Fan,S.Ma,Chem.Eur.J.2013,19,716)。
实施例22
Figure PCTCN2014088308-appb-000028
操作参考实施例17。CuBr2(44.7mg,0.2mmol),炔丙醇1k(126.8mg,1.5mmol),α,α-二苯基脯氨醇(S)-3a(253.2mg,1.0mmol),新蒸环己基甲醛2e(168.6mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝12/1)得液体轴手性联烯醇(Ra)-4ke(89.3mg,50％):97％ee(HPLC测定条件:Chiralcel AD-H柱,正己烷/异丙醇＝95/5,0.6mL/min,λ＝214nm,tR(大峰)＝8.9min,tR(小峰)＝10.2min)；[α]D 20＝-99.2(c＝0.97,CHCl3)(文献值:97％ee；[α]D 20＝-99.5(c＝1.15,CHCl3))；1H NMR(300MHz,CDCl3)δ5.38-5.26(m,2H,CH＝C＝CH),2.07-1.92(m,1H,CH from Cy),1.84-1.59(m,6H,OH and five protons from Cy),1.34(s,6H,Me×2),1.37-0.98(m,5H,five protons from Cy)；13C NMR(75MHz,CDCl3)δ199.1,102.1,101.0,69.5,37.2,33.02,32.99,30.0,29.9,26.03,26.00；IR(neat)ν(cm-1)3358,2974,2925,2851,1960,1448,1373,1361,1228,1149；MS(EI)m/z(％):180(M+,0.29),165(M-Me)+,3.81),59(100).(参考文献：J.Ye,S.Li,B.Chen,W.Fan,J.Kuang,J.Liu,Y.Liu,B.Miao,B.Wan,Y.Wang,X.Xie,Q.Yu,W.Yuan,S.Ma,Org.Lett.2012,14,1346)。
实施例23
Figure PCTCN2014088308-appb-000029
操作参考实施例17。CuBr2(44.9mg,0.2mmol),炔丙醇1l(186.8mg,1.5mmol),α,α-二苯基脯氨醇(S)-3a(252.7mg,1.0mmol),新蒸环己基甲醛2e(168.2mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝20/1)得液体轴手性联烯醇(Ra)-4le(115.6mg,53％):98％ee(HPLC测定条件:Chiralcel AD-H柱,正己烷/异丙醇＝100/1,0.5mL/min,λ＝214nm,tR(大峰)＝23.5min,tR(小峰)＝26.2min)；[α]D 20＝-106.6(c＝1.21,CHCl3)(文献值:96％ee；[α]D 20＝-108.6(c＝0.98,CHCl3))；1H NMR(300MHz,CDCl3)δ5.31(d,J＝4.2Hz,2H,CH＝C＝CH),2.08-1.90(m,1H,CH from Cy),1.87-1.40(m,15H),1.40-1.00(m,6H)；13C NMR(75MHz,CDCl3)δ199.9,101.3,100.8,70.4,38.4,38.2,37.2,33.1,33.0,26.00,25.97,25.5,22.4；IR(neat)ν(cm-1)3373,2926,2851,1960,1448,1347,1262,1242,1146,1056,1034；MS(EI)m/z(％):220(M+,0.69),99(100).(参考文献：J.Ye,S.Li,B.Chen,W.Fan,J.Kuang,J.Liu,Y.Liu,B.Miao,B.Wan,Y.Wang,X.Xie,Q.Yu,W.Yuan,S.Ma,Org.Lett.2012,14,1346)。
实施例24
Figure PCTCN2014088308-appb-000030
操作参考实施例17。CuBr2(44.7mg,0.2mmol),手性炔丙醇(S)-1m(197.6mg,1.5mmol),α,α-二苯基脯氨醇(S)-3a(252.7mg,1.0mmol),新蒸环己基甲醛2e(168.3mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝12/1)得液体轴手性联烯醇(S,Ra)-4me(152.0mg,67％):>99％de,>99％ee(主要异构体)(HPLC测定条件:Chiralcel OD-H柱,正己烷/异丙醇＝98/2,1.0mL/min,λ＝214nm,tR(大峰)＝19.4min；[α]D 20＝-69.7(c＝1.24, CHCl3)(文献值:92％de,>99％ee；[α]D 20＝-60.7(c＝1.02,CHCl3))；1H NMR(300MHz,CDCl3)δ7.42-7.21(m,5H,ArH),5.47-5.38(m,1H,one proton from HC＝C＝CH),5.38-5.30(m,1H,one proton from HC＝C＝CH),5.21(d,J＝5.4Hz,1H,PhCH),2.33(s,1H,OH),2.07-1.91(m,1H,CH from Cy),1.80-1.56(m,5H,five protons from Cy),1.35-0.96(m,5H,five protons from Cy)；13C NMR(75MHz,CDCl3)δ201.2,143.2,128.3,127.5,126.0,100.9,96.9,72.3,37.1,32.9,26.0,25.9；IR(neat)ν(cm-1)3365,3063,3029,2924,2850,1960,1599,1489,1449,1015；MS(EI)m/z(％):228(M+,2.53),107(100).(参考文献：J.Ye,S.Li,B.Chen,W.Fan,J.Kuang,J.Liu,Y.Liu,B.Miao,B.Wan,Y.Wang,X.Xie,Q.Yu,W.Yuan,S.Ma,Org.Lett.2012,14,1346)。
实施例25
Figure PCTCN2014088308-appb-000031
操作参考实施例17。CuBr2(45.0mg,0.2mmol),手性炔丙醇(R)-1m(198.5mg,1.5mmol),α,α-二苯基脯氨醇(S)-3a(253.7mg,1.0mmol),新蒸环己基甲醛2e(168.1mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝12/1)得液体轴手性联烯醇(R,Ra)-4me(133.3mg,58％):98％de,>99％ee(主要异构体)(HPLC测定条件:Chiralcel OD-H柱,正己烷/异丙醇＝98/2,1.0mL/min,λ＝214nm,tR(大峰)＝11.1min；[α]D 20＝-52.6(c＝0.98,CHCl3)(reported value:94％de,97％ee；[α]D 20＝-56.8(c＝0.98,CHCl3))；1H NMR(300MHz,CDCl3)δ7.40-7.29(m,4H,ArH),7.29-7.21(m,1H,ArH),5.47-5.38(m,1H,one proton from HC＝C＝CH),5.37-5.30(m,1H,one proton from HC＝C＝CH),5.18(dd,J1＝5.9Hz,J2＝2.6Hz,1H,PhCH),2.30(s,1H,OH),2.07-1.93(m,1H,CH from Cy),1.80-1.56(m,5H,five protons from Cy),1.36-0.98(m,5H,five protons from Cy)；13C NMR(75MHz,CDCl3)δ200.9,143.1,128.3,127.5,126.1,101.2,97.0,72.1,37.1,32.9,26.0,25.9；IR(neat)ν(cm-1)3373,3063,3029,2924, 2850,1961,1599,1493,1449,1014；MS(EI)m/z(％):228(M+,2.17),107(100).(参考文献：J.Ye,S.Li,B.Chen,W.Fan,J.Kuang,J.Liu,Y.Liu,B.Miao,B.Wan,Y.Wang,X.Xie,Q.Yu,W.Yuan,S.Ma,Org.Lett.2012,14,1346)。
实施例26
Figure PCTCN2014088308-appb-000032
操作参考实施例17。CuBr2(45.0mg,0.2mmol),手性炔丙醇(S)-1m(198.2mg,1.5mmol),α,α-二苯基脯氨醇(R)-3a(253.8mg,1.0mmol),新蒸环己基甲醛2e(167.9mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝12/1)得液体轴手性联烯醇(S,Sa)-4me(131.5mg,57％):97％de,99％ee(主要异构体)(HPLC conditions:Chiralcel OD-H柱,正己烷/异丙醇＝98/2,1.0mL/min,λ＝214nm,tR(小峰)＝11.7min,tR(大峰)＝16.1min；[α]D 20＝+56.6(c＝1.34,CHCl3)(文献值:89％de,>99％ee；[α]D 20＝+54.7(c＝1.17,CHCl3))；1H NMR(300MHz,CDCl3)δ7.41-7.21(m,5H,ArH),5.47-5.38(m,1H,one proton from HC＝C＝CH),5.37-5.30(m,1H,one proton from HC＝C＝CH),5.18(dd,J1＝5.7Hz,J2＝2.4Hz,1H,PhCH),2.33(s,1H,OH),2.08-1.93(m,1H,CH from Cy),1.80-1.56(m,5H,five protons from Cy),1.36-0.98(m,5H,five protons from Cy)；13C NMR(75MHz,CDCl3)δ200.9,143.1,128.3,127.5,126.1,101.2,97.0,72.1,37.0,32.9,26.0,25.9；IR(neat)ν(cm-1)3365,3062,3029,2924,2850,1961,1602,1492,1449,1014；MS(EI)m/z(％):228(M+,1.93),107(100).(参考文献：J.Ye,S.Li,B.Chen,W.Fan,J.Kuang,J.Liu,Y.Liu,B.Miao,B.Wan,Y.Wang,X.Xie,Q.Yu,W.Yuan,S.Ma,Org.Lett.2012,14,1346)。
实施例27
Figure PCTCN2014088308-appb-000033
操作参考实施例17。CuBr2(45.0mg,0.2mmol),手性炔丙醇(R)-1m(197.6mg,1.5mmol),α,α-二苯基脯氨醇(R)-3a(254.0mg,1.0mmol),新蒸环己基甲醛2e(169.2mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝12/1)得液体轴手性联烯醇(R,Sa)-4me(153.4mg,67％):98％de,>99％ee(主要异构体)(HPLC测定条件:Chiralcel OD-H柱,正己烷/异丙醇＝98/2,1.0mL/min,λ＝214nm,tR(major)＝13.4min；[α]D 20＝+73.0(c＝1.165,CHCl3)(文献值:93％de,>99％ee；[α]D 20＝+60.8(c＝0.62,CHCl3))；1H NMR(300MHz,CDCl3)δ7.41-7.21(m,5H,ArH),5.47-5.38(m,1H,one proton from HC＝C＝CH),5.37-5.30(m,1H,one proton from HC＝C＝CH),5.19(d,J＝5.7Hz,1H,PhCH),2.40(s,1H,OH),2.07-1.91(m,1H,CH from Cy),1.80-1.56(m,5H,five protons from Cy),1.35-0.97(m,5H,five protons from Cy)；13C NMR(75MHz,CDCl3)δ201.2,143.2,128.3,127.5,126.0,100.8,96.9,72.3,37.1,32.87,32.85,26.0,25.9；IR(neat)ν(cm-1)3358,3062,3029,2924,2850,1961,1602,1493,1449,1015；MS(EI)m/z(％):228(M+,2.23),107(100).(参考文献：J.Ye,S.Li,B.Chen,W.Fan,J.Kuang,J.Liu,Y.Liu,B.Miao,B.Wan,Y.Wang,X.Xie,Q.Yu,W.Yuan,S.Ma,Org.Lett.2012,14,1346)。
实施例28
Figure PCTCN2014088308-appb-000034
操作参考实施例17。CuBr2(45.0mg,0.2mmol),高炔丙醇1n(106.0mg,1.5mmol),α,α-二苯基脯氨醇(S)-3a(252.6mg,1.0mmol),新蒸环己基甲醛2e(168.4mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝6/1)得液体轴手性联烯醇(Ra)-4ne(83.5 mg,50％):96％ee(HPLC测定条件:Chiralcel IC柱,正己烷/异丙醇＝100/1,0.6mL/min,λ＝214nm,tR(小峰)＝20.5min,tR(大峰)＝22.0min)；[α]D 20＝-84.5(c＝1.095,CHCl3)；1H NMR(300MHz,CDCl3)δ5.18-5.07(m,2H,CH＝C＝CH),3.70(t,J＝6.3Hz,2H,OCH2),2.30-2.19(m,2H,CH2),2.05-1.89(m,1H,CH from Cy),1.89-1.57(m,6H,OH and five protons from Cy),1.37-0.98(m,5H,five protons from Cy)；13C NMR(75MHz,CDCl3)δ203.4,97.7,88.0,62.0,37.1,33.04,33.02,32.4,26.1,26.0；IR(neat)ν(cm-1)3340,2924,2851,1961,1448,1049；MS(EI)m/z(％):166(M+,6.05),67(100)；HRMS calcd for C11H18O[M+]:166.1358,found:166.1365.
实施例29
Figure PCTCN2014088308-appb-000035
操作参考实施例17。CuBr2(45.0mg,0.2mmol),炔丙基胺1o(313.4mg,1.5mmol),α,α-二苯基脯氨醇(S)-3a(253.9mg,1.0mmol),新蒸环己基甲醛2e(167.8mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝5/1)得液体轴手性联烯(Ra)-4oe(180.0mg,59％):98％ee(HPLC测定条件:Chiralcel AD-H柱,正己烷/异丙醇＝95/5,0.5mL/min,λ＝214nm,tR(大峰)＝34.1min,tR(小峰)＝35.6min)；[α]D 20＝-102.0(c＝1.05,CHCl3)(文献值:99％ee；[α]D 20＝-105.5(c＝1.07,CHCl3))；1H NMR(300MHz,CDCl3)δ7.80-7.72(m,2H,ArH),7.30(d,J＝7.8Hz,2H,ArH),5.21-5.12(m,1H,one proton of CH＝C＝CH),5.11-5.01(m,1H,one proton of CH＝C＝CH),4.85(t,J＝5.9Hz,1H,NH),3.60-3.50(m,2H,NCH2),2.42(s,3H,CH3),1.98-1.82(m,1H,CH from Cy),1.73-1.53(m,5H,five protons from Cy),1.32-0.89(m,5H,five protons from Cy)；13C NMR(75MHz,CDCl3)δ202.3,143.3,137.0,129.6,127.0,100.4,88.4,42.0,36.7,32.8,32.7,25.9,25.8,21.4；IR(neat)ν(cm-1)3284,2924,2850,1962,1598,1495,1418,1329,1161,1094；MS(EI)m/z(％):305(M+,1.14),91(100).(参考文献：J.Ye,W.Fan,S.Ma,Chem.Eur.J.2013,19,716)。
实施例30
Figure PCTCN2014088308-appb-000036
操作参考实施例17。CuBr2(44.9mg,0.2mmol),炔丙基胺1p(238.4mg,1.5mmol),α,α-二苯基脯氨醇(S)-3a(254.3mg,1.0mmol),新蒸异戊醛2d(129.9mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝5/1)得液体轴手性联烯(Ra)-4pd(136.8mg,59％):93％ee(HPLC测定条件:Chiralcel AY-H柱,正己烷/异丙醇＝90/10,1.0mL/min,λ＝214nm,tR(大峰)＝9.8min,tR(小峰)＝11.2min)；[α]D 20＝-92.5(c＝0.78,CHCl3)；1H NMR(300MHz,CDCl3)δ7.82-7.73(m,2H,ArH),7.51-7.35(m,3H,ArH),6.52(bs,1H,NH),5.30-5.19(m,2H,CH＝C＝CH),4.05-3.95(m,2H,NCH2),1.96-1.86(m,2H,CH2),1.73-1.55(m,1H,CH),0.894(d,J＝6.6Hz,3H,Me),0.891(d,J＝6.6Hz,3H,Me)；13C NMR(75MHz,CDCl3)δ203.8,167.3,134.5,131.3,128.4,126.8,92.9,87.8,38.5,38.0,28.3,22.1,22.0；IR(neat)ν(cm-1)3320,3064,2955,2927,2869,1964,1727,1644,1603,1578,1538,1489,1465,1308,1076；MS(EI)m/z(％):229(M+,7.05),105(100)；HRMS calcd for C15H19NO[M+]:229.1467,found:229.1469.
实施例31
Figure PCTCN2014088308-appb-000037
操作参考实施例17。CuBr2(44.9mg,0.2mmol),炔丙基胺1q(232.8mg,1.5mmol),α,α-二苯基脯氨醇(S)-3a(253.2mg,1.0mmol),新蒸2-乙基丁醛2i(150.6mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝50/1～20/1)得液体轴手性联烯(Ra)-4qi(160.3mg,67％):96％ee(HPLC测定条件:Chiralcel OD-H柱,正己烷/异丙醇＝100/0,1.0mL/min,λ＝214nm,tR(小峰)＝19.7min,tR(大峰)＝20.4min)；[α]D 20＝-63.5(c＝1.055,CHCl3)； 1H NMR(300MHz,CDCl3)δ5.22-5.12(m,1H,one proton of CH＝C＝CH),5.11-5.03(m,1H,one proton of CH＝C＝CH),4.71(bs,1H,NH),3.77-3.63(m,2H,NCH2),1.93-1.78(m,1H,CH),1.53-1.21(m,13H,Me×2and CH2×2),0.90(t,J＝7.4Hz,3H,Me),0.89(t,J＝7.4Hz,3H,Me)；13C NMR(75MHz,CDCl3)δ203.0,155.6,97.7,89.0,79.1,42.7,39.3,28.3,27.5,27.2,11.6,11.4；IR(neat)ν(cm-1)3351,2965,2931,2875,1963,1698,1505,1456,1392,1366,1250,1172,1053；MS(EI)m/z(％):239(M+,0.01),183((M-tBu+H)+,45.91),57(100)；HRMS calcd for C14H25NO2[M+]:239.1885,found:239.1878.
实施例32
Figure PCTCN2014088308-appb-000038
操作参考实施例17。CuBr2(45.0mg,0.2mmol),末端炔烃1r(255.7mg,1.5mmol),α,α-二苯基脯氨醇(S)-3a(252.5mg,1.0mmol),新蒸异戊醛2d(129.6mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝20/1)得液体轴手性联烯(Ra)-4rd(121.9mg,51％):94％ee(HPLC测定条件:Chiralcel OD-H柱,正己烷/异丙醇＝100/1,0.7mL/min,λ＝214nm,tR(小峰)＝10.9min,tR(大峰)＝11.7min)；[α]D 20＝-64.4(c＝0.87,CHCl3)；1H NMR(300MHz,CDCl3)δ5.15-5.04(m,2H,CH＝C＝CH),3.74(s,6H,Me×2),3.51(t,J＝7.5Hz,1H,CH),2.62-2.54(m,2H,CH2),1.90-1.82(m,2H,CH2),1.72-1.56(m,1H,CH),0.910(d,J＝6.6Hz,3H,Me),0.906(d,J＝6.6Hz,3H,Me)；13C NMR(75MHz,CDCl3)δ204.6,169.3,169.2,91.3,86.6,52.4,51.3,38.2,28.3,28.0,22.09,22.06；IR(neat)ν(cm-1)2956,2927,2869,1964,1754,1739,1436,1342,1271,1232,1154,1044；MS(EI)m/z(％):240(M+,27.06),97(100)；HRMS calcd for C13H20O4[M+]:240.1362,found:240.1362.
实施例33
Figure PCTCN2014088308-appb-000039
操作参考实施例17。CuBr2(44.8mg,0.2mmol),末端炔烃1r(255.7mg,1.5mmol),α,α-二苯基脯氨醇(S)-3a(252.8mg,1.0mmol),新蒸环己基甲醛2e(168.2mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚/乙酸乙酯＝15/1)得液体轴手性联烯(Ra)-4re(135.7mg,51％):95％ee(HPLC测定条件:Chiralcel OD-H柱,正己烷/异丙醇＝100/1,1.0mL/min,λ＝214nm,tR(小峰)＝9.0min,tR(大峰)＝9.6min)；[α]D 20＝-84.0(c＝1.045,CHCl3)(文献值:99％ee；[α]D 20＝-85.4(c＝1.05,CHCl3))；1H NMR(300MHz,CDCl3)δ5.20-5.08(m,2H,CH＝C＝CH),3.740(s,3H,Me),3.737(s,3H,Me),3.51(t,J＝7.5Hz,1H,CH),2.63-2.54(m,2H,CH2),2.00-1.85(m,1H,CH from Cy),1.78-1.57(m,5H,five protons from Cy),1.35-0.95(m,5H,five protons from Cy)；13C NMR(75MHz,CDCl3)δ202.7,169.33,169.29,98.9,88.2,52.4,51.2,37.1,32.82,32.78,28.0,26.0,25.9；IR(neat)ν(cm-1)2926,2851,1959,1757,1738,1617,1436,1343,1233,1155,1035；MS(EI)m/z(％):266(M+,6.72),91(100).(参考文献：J.Ye,W.Fan,S.Ma,Chem.Eur.J.2013,19,716)。
实施例34
Figure PCTCN2014088308-appb-000040
操作参考实施例17。CuBr2(44.9mg,0.2mmol),正葵炔1s(207.8mg,1.5mmol),α,α-二苯基脯氨醇(S)-3a(253.4mg,1.0mmol),新蒸苯丙醛2c(201.5mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚)得液体轴手性联烯(Ra)-4sc(119.3mg,47％):90％ee(HPLC测定条件:Chiralcel OD-H柱,正己烷/异丙醇＝100/0,0.3mL/min,λ＝214nm,tR(小峰)＝17.9min,tR(大峰)＝19.7min)；[α]D 20＝-50.0(c＝0.84,CHCl3)；1H NMR(300MHz,CDCl3)δ 7.30-7.21(m,2H,ArH),7.21-7.12(m,3H,ArH),5.16-5.02(m,2H,CH＝C＝CH),2.72(t,J＝7.8Hz,2H,CH2),2.35-2.20(m,2H,CH2),1.99-1.87(m,2H,CH2),1.42-1.18(m,12H,CH2×6),0.88(t,J＝6.8Hz,3H,Me)；13C NMR(75MHz,CDCl3)δ204.0,141.9,128.5,128.2,125.8,91.5,90.2,35.5,31.9,30.7,29.4,29.3,29.2,29.1,28.9,22.7,14.1；IR(neat)ν(cm-1)3086,3063,3027,2924,2854,1962,1721,1604,1496,1455,1373,1331,1284,1075,1028；MS(EI)m/z(％):256(M+,12.85),91(100)；HRMS calcd for C19H28[M+]:256.2191,found:256.2194.
实施例35
Figure PCTCN2014088308-appb-000041
操作参考实施例17。CuBr2(44.8mg,0.2mmol),苯乙炔1t(153.2mg,1.5mmol),α,α-二苯基脯氨醇(S)-3a(253.1mg,1.0mmol),新蒸环己基甲醛2e(168.4mg,1.5mmol)和1,4-二氧六环(3.0mL)。柱层析(淋洗剂：石油醚)得液体轴手性联烯(Ra)-4te(90.1mg,46％):96％ee(HPLC测定条件:Chiralcel OD-H柱,正己烷/异丙醇＝100/0,0.3mL/min,λ＝214nm,tR(大峰)＝20.1min,tR(小峰)＝22.1min)；[α]D 20＝-355.3(c＝1.01,CHCl3)(文献值:99％ee；[α]D 19＝-330.3(c＝0.94,CHCl3))(我们重复文献反应所得结果:99％ee；[α]D 20＝-379.0(c＝1.125,CHCl3))；1H NMR(300MHz,CDCl3)δ7.32-7.23(m,4H,ArH),7.21-7.11(m,1H,ArH),6.15(dd,J1＝6.6Hz,J2＝3.0Hz,1H,one proton from CH＝C＝CH),5.56(t,J＝6.3Hz,1H,one proton from CH＝C＝CH),2.20-2.04(m,1H,CH),1.90-1.57(m,5H,five protons from Cy),1.38-1.09(m,5H,five protons from Cy)；13C NMR(75MHz,CDCl3)δ204.1,135.2,128.5,126.6,126.4,101.0,95.4,37.6,33.2,33.1,26.1,26.0；IR(neat)ν(cm-1)3082,3062,3030,2924,2851,1946,1597,1496,1458,1257,1071,1028；MS(EI)m/z(％):198(M+,30.22),130(100).(参考文献：R.Lü,J.Ye,T.Cao,B.Chen,W.Fan,W.Lin,J.Liu,H.Luo,B.Miao,S.Ni,X.Tang,N.Wang,Y.Wang,X.Xie,Q.Yu,W.Yuan,W.Zhang,C.Zhu,S.Ma,Org.Lett.2013,15,2254)。
最后，还需要注意的是，以上列举的仅是本发明的具体实施例子。显然，本发明不限于以上实施例子，还可以有许多变形。本领域的普通技术人员能从本发明公开的内容直接导出或联想到的所有变形，均应认为是本发明的保护范围。

Claims (5)

  1. 一种高效合成光学活性1,3-二取代联烯的方法，其特征在于，在二价铜盐催化作用下，官能团化末端炔烃，醛和手性仲胺，在有机溶剂中加热反应，生成多种官能团化的轴手性1,3-二取代联烯，其反应式如下：
    Figure PCTCN2014088308-appb-100001
    其中R1可包含多种官能团如糖苷单元、伯醇、仲醇、叔醇、酰胺类、丙二酸二甲酯类、烷基或者芳基，R2为烷基或者芳基。
  2. 根据权利要求1所述的高效合成光学活性1,3-二取代联烯的方法，其特征在于，具体操作步骤如下：
    1)、在氮气气氛中向经过无水无氧处理的反应管中依次加入二价铜盐，手性仲胺，末端炔烃，醛和有机溶剂，加热反应12～24小时；
    2)、待步骤1)反应完全后，将反应管从油浴中提出，自然回复室温，有机溶剂稀释，转至分液漏斗中，稀盐酸洗，分出有机相，水相用相同有机溶剂萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，柱层析得产物轴手性联烯。
  3. 如权利要求1或2所述的高效合成光学活性1,3-二取代联烯的方法，其特征在于，使用二价铜盐作为催化剂，所述的催化剂是溴化铜、氯化铜、醋酸铜、硫酸铜或三氟甲磺酸铜。
  4. 如权利要求1所述的高效合成光学活性1,3-二取代联烯的方法，其特征在于，所述的手性仲胺为(S)-3a或其对映体，及以(S)-3a为模板的结构变种(S)-3b～c或其对映体：
    Figure PCTCN2014088308-appb-100002
  5. 如权利要求1或2或4所述的高效合成光学活性1,3-二取代联烯的方法，其特征是所述反应溶剂为1,4-二氧六环，甲苯，苯，氯苯，对二甲苯，邻二甲苯，间二甲苯或均三甲苯。
PCT/CN2014/088308 2014-08-06 2014-10-10 一种高光学活性1，3-二取代联烯的合成方法 Ceased WO2016019630A1 (zh)

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