WO2020119549A1 - 一种直接构建高光学活性四取代联烯酸类化合物的方法 - Google Patents

一种直接构建高光学活性四取代联烯酸类化合物的方法 Download PDF

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WO2020119549A1
WO2020119549A1 PCT/CN2019/123005 CN2019123005W WO2020119549A1 WO 2020119549 A1 WO2020119549 A1 WO 2020119549A1 CN 2019123005 W CN2019123005 W CN 2019123005W WO 2020119549 A1 WO2020119549 A1 WO 2020119549A1
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hydrocarbon group
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麻生明
郑伟锋
钱辉
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复旦大学
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Priority to EP19897072.5A priority patent/EP3896053A4/en
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    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/36—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by hydroxy groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/10—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction with carbon monoxide
    • C07C51/12—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction with carbon monoxide on an oxygen-containing group in organic compounds, e.g. alcohols
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    • C07—ORGANIC CHEMISTRY
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    • C07B53/00—Asymmetric syntheses
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/10—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction with carbon monoxide
    • C07C51/14—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction with carbon monoxide on a carbon-to-carbon unsaturated bond in organic compounds
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/58—One oxygen atom, e.g. butenolide
    • 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
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the invention belongs to the technical field of chemical synthesis, and in particular relates to a method for directly constructing highly optically active tetra-substituted allenoic acid compounds.
  • Axial chiral allene compounds are widely present in natural products and drug molecules, and are a very important class of compounds (Ref: (a) Hoffmann- A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43, 1196. (b) Rivera-Fuentes, P.; Diederich, F. Angew. Chem., Int. Ed. 2012, 51,2818 .). How to construct a four-substituted chiral quaternary carbon center has been extensively studied in the past ten years and has achieved fruitful results.
  • Chiral senoic compounds are mainly resolved by racemic senoic acid compounds or senonitrile compounds (Ref: (a) Ma, S.; Wu, S. Chem. Commun. 2001,0, 441. (b) Ao, Y.-F.; Wang, D.-X.; Zhao, L.; Wang, M.-XJOrg. Chem. 2014, 79, 3103.) and chiral allenoate were prepared by hydrolysis (Ref: (a) Marshall, JA; Bartley, GS; Wallace, EMJ Org. Chem. 1996, 61, 5729. (b) Yu, J.; Chen, W.-J.; Gong, L.-Z. Org. Lett.
  • the object of the present invention is to provide a method for directly constructing a highly optically active tetra-substituted allenoic acid compound with axial chirality, that is, through a third-order propargyl alcohol, carbon monoxide and water, in a palladium catalyst, a chiral bisphosphine ligand , Under the action of monophosphine ligand and organic phosphoric acid, react in an organic solvent to directly construct an axially chiral, highly optically active tetra-substituted allenoic acid compound in one step.
  • the method for directly constructing a highly optically active tetra-substituted alloic acid compound with axial chirality includes: under the action of a palladium catalyst, a chiral bisphosphine ligand, a monophosphine ligand and an organic phosphoric acid, with Tertiary propargyl alcohol with different substituents, carbon monoxide and water, catalyzed by transition metal in an organic solvent to produce asymmetrical alkylene reaction, one-step generation of highly optically active tetra-substituted alloic acid compounds with axial chirality, the reaction process
  • the following reaction formula (I) is shown:
  • R 1 is a hydrocarbon group, a hydrocarbon group with a functional group, phenyl, aryl or heterocyclic group
  • R 2 is a hydrocarbon group, a hydrocarbon group with a functional group, phenyl, aryl or heterocyclic group
  • R 3 is a hydrocarbon group, with Hydrocarbyl group with functional group, phenyl group, aryl group or heterocyclic group
  • the aryl group is a phenyl group with electron donating or electron-withdrawing substituents at the ortho, m, and para positions
  • the heterocyclic group is thienyl, furyl, Naphthyl or pyridyl, or thiophene, furan, naphthalene or pyridine with electron-donating or electron-withdrawing substituents.
  • R 1 is a C1-C20 hydrocarbon group with a C1-C20 hydrocarbon group at the end, a phenyl group, an aryl group or a heterocyclic group
  • R 2 is a C1-C10 hydrocarbon group with a functional group at the end C1-C10 hydrocarbon group, phenyl group, aryl group or heterocyclic group
  • R 3 is C1-C10 hydrocarbon group, C1-C10 hydrocarbon group with functional group at the end, phenyl, aryl or heterocyclic group; wherein, the terminal In a C1-C20 hydrocarbon group with a functional group or a C1-C10 hydrocarbon group with a functional group at the end, the functional group is selected from a carbon-carbon double bond, a carbon-carbon triple bond, an ester group, a hydroxyl group, an acyl group, an acyloxy group, and an amide group , Halogen, carboxyl, cyano; the ary
  • R 1 is a C1-C10 hydrocarbon group with a C1-C10 hydrocarbon group having a functional group at the end, a phenyl group, an aryl group or a heterocyclic group
  • R 2 is a C1-C10 hydrocarbon group with a terminal C1-C10 hydrocarbon group of functional group, phenyl group, aryl group or heterocyclic group
  • R 3 is C1-C5 hydrocarbon group, C1-C5 hydrocarbon group with functional group at the end, phenyl group, aryl group or heterocyclic group.
  • the C1-C10 hydrocarbon group is alkyl, alkenyl, phenyl, aryl or heterocyclic group;
  • the C1-C5 hydrocarbon group is methyl, ethyl, n-propyl (and its isomer Body), n-butyl (and its isomers) and n-pentyl (and its isomers);
  • the heterocyclic group is thienyl, furanyl, naphthyl or pyridyl, or thiophene, furan, naphthalene or pyr
  • R 1 is selected from a C1-C10 linear alkyl group, a C1-C10 cycloalkyl group, a C1-C10 alkyl group having a functional group at the end, a phenyl group, an aryl group or a heterocyclic group ;
  • R 2 is selected from C1-C10 linear alkyl, C1-C10 cycloalkyl, C1-C10 alkyl with a functional group at the end, phenyl, aryl or heterocyclic group;
  • R 3 is selected from C1-C5 linear Alkyl, C1-C5 cycloalkyl, C1-C5 alkyl with functional group at the end, phenyl, aryl or heterocyclic group; wherein, C1-C10 alkyl with functional group at the end or terminal In the C1-C5 alkyl group of the functional group, the functional group is selected from a carbon-carbon double bond, a carbon-carbon triple
  • the electron-withdrawing substituent includes halogen, nitro, ester, carboxyl, Acyl, amide, and cyano.
  • the electron-donating substituents include alkyl, alkenyl, phenyl, hydrocarbyloxy, hydroxyl, and amino.
  • R 1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and styrene Group, 4-chlorobutyl, 3-methylbutyl, 3-cyanopropyl, allyl;
  • R 2 is selected from n-propyl, tert-butyl, phenyl, o-methylphenyl, m-methyl Phenyl, p-methylphenyl, m-methoxyphenyl, p-chlorophenyl, p-bromophenyl, p-esterylphenyl, 2-naphthyl, 3-thienyl;
  • R 3 is selected from methyl, ethyl base.
  • the amount of the organic solvent is 1.0-10.0 mL/mmol; preferably, 5.0 mL/mmol. Based on the amount of functionalized tertiary propargyl alcohol ( ⁇ 1) represented by formula (I).
  • step (2) After the reaction in step (1) is completed, the reaction tube is taken out of the low temperature bath, after returning to room temperature, a certain volume of ethyl acetate is added to the reaction tube, the resulting mixture is filtered through a silica gel short column, and a certain amount of ethyl acetate is used After the ester was washed, it was concentrated and flash column chromatography gave a highly optically active alkenic acid compound with axial chirality.
  • the certain volume of ethyl acetate refers to the amount of the functionalized tertiary propargyl alcohol ( ⁇ 1) shown in formula (I), and the amount of the ethyl acetate is 1.0-100 mL/mmol; Preferably, it is 5.0 mL/mmol.
  • the palladium catalyst described in the present invention is bis(allyl palladium chloride), tetrakis(triphenylphosphine) palladium, tris(dibenzylideneacetone) dipalladium, bis(cinnamyl palladium chloride) ), any one or more of bis(dibenzylideneacetone)-palladium, palladium chloride, palladium acetate, bis(triphenylphosphine)palladium chloride, bis(acetonitrile)palladium chloride, etc.; preferably , For palladium chloride.
  • the chiral bisphosphine ligands of the present invention are selected from (R)-L1 to (R)-L4 and their enantiomers (S)-L1 to (S)-L4
  • the chiral bisphosphine ligand is (R)-L4 and/or its enantiomer (S)-L4.
  • Ar is phenyl, aryl or heterocyclic group
  • the aryl group is a phenyl group substituted with a hydrocarbon group or a hydrocarbon oxy group at the ortho, m, or para position
  • the hydrocarbon group includes a methyl group, an ethyl group, or a propyl group , Isopropyl, butyl, isobutyl, tert-butyl
  • the hydrocarbyloxy group includes ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy
  • the heterocyclic group is thienyl, furyl or pyridyl; preferably, the Ar is phenyl, 3,5-di-tert-butyl-4-methoxyphenyl.
  • the chiral bisphosphine ligand of the present invention is selected from (R)-L4a, (R)-L4b, (R)-L4c and its enantiomer (S)-L4a, (S )-L4b, one or more of (S)-L4c; wherein, the structure of (R)-L4a, (R)-L4b, (R)-L4c is as follows:
  • the monophosphine ligand of the present invention is selected from tributylphosphine, tricyclohexylphosphine, triphenylphosphine, tri(o-methylphenyl)phosphine, tri(m-methylphenyl)phosphine , Tri(p-methylphenyl)phosphine, tri(p-methoxyphenyl)phosphine, tri(3,5-ditrifluoromethylphenyl)phosphine, trifuranylphosphine, etc. Species; preferably, triphenylphosphine.
  • the organic phosphoric acid of the present invention is selected from any one or more of organic phosphoric acid 1, organic phosphoric acid 2, organic phosphoric acid 3, etc.; wherein, R 1 is hydrogen, a C1-C6 hydrocarbon group, a phenyl group or An aryl group, the aryl group is a phenyl group substituted with a C1-C6 hydrocarbon group in the ortho, m, and para positions; R 2 is a C1 to C6 hydrocarbon group, a phenyl group, or an aryl group, and the aryl group is an ortho, m, or para position A phenyl group substituted with a C1-C6 hydrocarbon group; preferably, R 1 and R 2 are phenyl groups.
  • the organic solvent of the present invention is selected from N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, chlorobenzene, toluene, trifluorotoluene, difluorotoluene Any one or more of methyl chloride, 1,1-dichloroethane, 1,2-dichloroethane, chloroform, acetic acid, etc.; preferably, it is toluene.
  • reaction temperature of the present invention is -20-60°C; preferably, -20-0°C; further preferably, -5-0°C.
  • reaction time of the present invention is 4-36 hours; preferably, it is 18 hours.
  • the molar ratio of tertiary propargyl alcohol ( ⁇ 1) with different substituents ( ⁇ 1), water, palladium catalyst, chiral bisphosphine ligand, monophosphine ligand and organic phosphoric acid according to the present invention
  • the ratio is 1.0: (1.0-30.0): (0.005-0.1): (0.005-0.1): (0.01-0.3): (0.01-0.3); preferably, it is 1.0: 20.0: 0.02: 0.048: 0.2: 0.2.
  • the invention also provides a highly optically active senoic compound with axial chirality, the structure of which is shown in (R)-2, (S)-2:
  • R 1 is a hydrocarbon group, a hydrocarbon group with a functional group, phenyl, aryl or heterocyclic group
  • R 2 is a hydrocarbon group, a hydrocarbon group with a functional group, phenyl, aryl or heterocyclic group
  • R 3 is a hydrocarbon group, with Hydrocarbyl group with functional group, phenyl group, aryl group or heterocyclic group
  • the aryl group is a phenyl group with electron donating or electron-withdrawing substituents at the ortho, m, and para positions
  • the heterocyclic group is thienyl, furyl, Naphthyl or pyridyl, or thiophene, furan, naphthalene or pyridine with electron-donating or electron-withdrawing substituents.
  • R 1 is a C1-C20 hydrocarbon group with a C1-C20 hydrocarbon group at the end, a phenyl group, an aryl group or a heterocyclic group
  • R 2 is a C1-C10 hydrocarbon group with a functional group at the end C1-C10 hydrocarbon group, phenyl group, aryl group or heterocyclic group
  • R 3 is C1-C10 hydrocarbon group, C1-C10 hydrocarbon group with functional group at the end, phenyl, aryl or heterocyclic group; wherein, the terminal In a C1-C20 hydrocarbon group with a functional group or a C1-C10 hydrocarbon group with a functional group at the end, the functional group is selected from a carbon-carbon double bond, a carbon-carbon triple bond, an ester group, a hydroxyl group, an acyl group, an acyloxy group, and an amide group , Halogen, carboxyl, cyano; the ary
  • R 1 is a C1-C10 hydrocarbon group with a C1-C10 hydrocarbon group having a functional group at the end, a phenyl group, an aryl group or a heterocyclic group
  • R 2 is a C1-C10 hydrocarbon group with a terminal C1-C10 hydrocarbon group of functional group, phenyl group, aryl group or heterocyclic group
  • R 3 is C1-C5 hydrocarbon group, C1-C5 hydrocarbon group with functional group at the end, phenyl group, aryl group or heterocyclic group.
  • the C1-C10 hydrocarbon group is alkyl, alkenyl, phenyl, aryl or heterocyclic group;
  • the C1-C5 hydrocarbon group is methyl, ethyl, n-propyl (and its isomer Body), n-butyl (and its isomers) and n-pentyl (and its isomers);
  • the heterocyclic group is thienyl, furanyl, naphthyl or pyridyl, or thiophene, furan, naphthalene or pyr
  • R 1 is selected from a C1-C10 linear alkyl group, a C1-C10 cycloalkyl group, a C1-C10 alkyl group having a functional group at the end, a phenyl group, an aryl group or a heterocyclic group ;
  • R 2 is selected from C1-C10 linear alkyl, C1-C10 cycloalkyl, C1-C10 alkyl with a functional group at the end, phenyl, aryl or heterocyclic group;
  • R 3 is selected from C1-C5 linear Alkyl, C1-C5 cycloalkyl, C1-C5 alkyl with functional group at the end, phenyl, aryl or heterocyclic group; wherein, C1-C10 alkyl with functional group at the end or terminal In the C1-C5 alkyl group of the functional group, the functional group is selected from a carbon-carbon double bond, a carbon-carbon triple
  • the electron-withdrawing substituent includes halogen, nitro, ester, carboxyl, Acyl, amide, and cyano.
  • the electron-donating substituents include alkyl, alkenyl, phenyl, hydrocarbyloxy, hydroxyl, and amino.
  • R 1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and styrene Group, 4-chlorobutyl, 3-methylbutyl, 3-cyanopropyl, allyl;
  • R 2 is selected from n-propyl, tert-butyl, phenyl, o-methylphenyl, m-methyl Phenyl, p-methylphenyl, m-methoxyphenyl, p-chlorophenyl, p-bromophenyl, p-esterylphenyl, 2-naphthyl, 3-thienyl;
  • R 3 is selected from methyl, ethyl base.
  • the present invention also provides a highly optically active alkenoic acid compound with axial chirality represented by formula (R)-2 in the preparation of ⁇ -butyrolactone compounds containing tetra-substituted chiral quaternary carbon centers, tetra-substituted allenes Application in alcohol and other compounds.
  • the present invention proposes the following possible mechanism for the reaction: organophosphoric acid (HB) activates tertiary propargyl alcohol to form intermediate I, and then palladium species (PdL*) oxidizes and adds it to remove the water to form the alkenyl palladium intermediate II. Subsequently, intermediate II reacts with carbon monoxide and water to form intermediate III or intermediate IV, followed by reduction and elimination to obtain optically active tetra-substituted allenoic acid, and regenerated palladium species (PdL*).
  • organophosphoric acid HB
  • PdL* palladium species
  • intermediate II reacts with carbon monoxide and water to form intermediate III or intermediate IV, followed by reduction and elimination to obtain optically active tetra-substituted allenoic acid, and regenerated palladium species (PdL*).
  • the specific mechanism is shown in the following formula.
  • the innovation of the present invention is that the present invention uses a simple and easily available functionalized tertiary propargyl alcohol as a starting material under the action of a palladium catalyst, a chiral bisphosphine ligand, a monophosphine ligand and an organic phosphoric acid.
  • a palladium catalyst a chiral bisphosphine ligand
  • a monophosphine ligand an organic phosphoric acid.
  • One-step synthesis of tetra-substituted allenoic acid compounds with high optical activity with axial chirality is achieved.
  • the chiral allenoic acid compounds obtained by the present invention can be used as important synthetic intermediates for the construction of ⁇ -butyrolactone compounds containing tetra-substituted chiral quaternary carbon centers.
  • the beneficial effects of the present invention also include: the raw materials and reagents are simple and easy to obtain, the preparation is convenient; the reaction conditions are mild, the operation is simple; the substrate has a wide universality; the functional group compatibility is good; Alkenic acid compounds; the product has high enantioselectivity (90%ee ⁇ >99%ee); the product is easy to separate and purify.
  • mol means mole
  • toluene means toluene
  • CO balloon means carbon monoxide balloon
  • ee means enantiomeric excess percentage
  • PdCl 2 (0.0036g, 0.02mmol), chiral bisphosphine ligand (R)-L4c (0.057g, 0.048mmol), monophosphine ligand PPh 3 (0.0527g, 0.2) were added to a dry Schlenk reaction tube mmol), and (PhO) 2 PO 2 H (0.0501 g, 0.2 mmol).

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Abstract

一种直接构建光学活性四取代联烯酸类化合物的方法，通过三级炔丙醇与一氧化碳和水，在钯催化剂、手性双膦配体、单膦配体和有机磷酸的作用下，在有机溶剂中反应，一步直接构建轴手性的光学活性联烯酸类化合物。光学活性联烯酸类化合物可以作为中间体用于构筑含有四取代手性季碳中心的γ-丁内酯类化合物、四取代联烯醇类化合物。

Description

一种直接构建高光学活性四取代联烯酸类化合物的方法 技术领域
本发明属于化学合成技术领域，具体涉及一种直接构建高光学活性四取代联烯酸类化合物的方法。
技术背景
含轴手性的联烯化合物广泛存在于天然产物及药物分子中，是一类非常重要的化合物(Ref:(a)Hoffmann-
Figure PCTCN2019123005-appb-000001
A.；Krause,N.Angew.Chem.,Int.Ed.2004,43,1196.(b)Rivera-Fuentes,P.；Diederich,F.Angew.Chem.,Int.Ed.2012,51,2818.)。如何构建四取代的手性季碳中心，在过去十几年里得到广泛的研究，并取得了丰硕的成果，然而相对于构建含有四取代的手性季碳中心的化合物，四取代的轴手性联烯化合物的合成依然存在较大的挑战，报道的方法仍十分有限，主要原因在于联烯分子中含有一个在空间上互相垂直的累积碳碳双键，联烯基1,3-位的取代基处在距离较远的互相垂直的空间上，相比于中心手性的形成它需要更大的手性屏蔽环境去诱导其轴手性的生成(Ref:(a)Hayashi,T.；Tokunaga,N.；Inoue,K.Org.Lett.2004,6,305.(b)Qian,D.；Wu,L.；Lin,Z.；Sun,J.Nat.Commun.2017,8,567.(c)Hashimoto,T.；Sakata,K.；Tamakuni,F.；Dutton,M.J.；Maruoka,K.Nat.Chem.2013,5,240.(d)Mbofana,C.T.；Miller,S.J.J.Am.Chem.Soc.2014,136,3285.(e)Wang,G.；Liu,X.；Chen,Y.；Yang,J.；Li,J.；Lin,L.；Feng,X.ACS Catal.2016,6,2482.(f)Tang,Y.；Xu,J.；Yang,J.；Lin,L.；Feng,X.；Liu,X.Chem.2018,4,1658.(g)Tap,A.；Blond,A.；Wakchaure,V.N.；List,B.Angew.Chem.,Int.Ed.2016,55,8962)。
手性联烯酸类化合物主要通过消旋联烯酸化合物或联烯腈化合物的拆分方式(Ref:(a)Ma,S.；Wu,S.Chem.Commun.2001,0,441.(b)Ao,Y.-F.；Wang,D.-X.；Zhao,L.；Wang,M.-X.J.Org.Chem.2014,79,3103.)和手性联烯酸酯的水解方式制备得到(Ref:(a)Marshall,J.A.；Bartley,G.S.；Wallace,E.M.J.Org.Chem.1996,61,5729.(b)Yu,J.；Chen,W.-J.；Gong,L.-Z.Org.Lett.2010,12,4050)，并且上述方法对四取代联烯酸类化合物的制备的例子非常有限。通常，这些方法有较大的局限性，比如反应产率低，底物范围窄，官能团容忍性不好，原子经济学差等。因此发展一种从简单易得的原料出发，高效率、高对映选择性的合成四取代轴手性 联烯酸类化合物的方法将是对现有合成方法的重要突破。
发明内容
本发明的目的是提供一种直接构建具有轴手性的高光学活性四取代联烯酸类化合物的方法，即通过三级炔丙醇与一氧化碳和水，在钯催化剂、手性双膦配体、单膦配体和有机磷酸的作用下，在有机溶剂中反应，一步直接构建轴手性的高光学活性四取代联烯酸类化合物。
本发明是采用以下具体技术方案来实现的：
本发明提供的直接构建具有轴手性的高光学活性四取代联烯酸类化合物的方法，包括：在钯催化剂、手性双膦配体、单膦配体和有机磷酸的作用下，带有不同取代基的三级炔丙醇与一氧化碳和水，在有机溶剂中通过过渡金属催化发生不对称联烯化反应，一步生成具有轴手性的高光学活性四取代联烯酸类化合物，反应过程如下反应式(I)所示：
Figure PCTCN2019123005-appb-000002
反应式(I)
其中，R 1为烃基，带有官能团的烃基，苯基，芳基或杂环基；R 2为烃基，带有官能团的烃基，苯基，芳基或者杂环基；R 3为烃基，带有官能团的烃基，苯基，芳基或杂环基；所述芳基是邻、间、对位有给电子或吸电子取代基的苯基，所述杂环基是噻吩基、呋喃基、萘基或吡啶基、或者有给电子或吸电子取代基的噻吩、呋喃、萘或吡啶。
优选地，反应式(I)中，R 1为C1-C20烃基，末端带有官能团的C1-C20烃基，苯基，芳基或者杂环基；R 2为C1-C10烃基，末端带有官能团的C1-C10烃基，苯基，芳基或者杂环基；R 3为C1-C10烃基，末端带有官能团的C1-C10烃基，苯基、芳基或者杂环基；其中，所述的末端带有官能团的C1-C20烃基或末端带有官能团的C1-C10烃基中，所述官能团选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、酰胺基、卤素、羧基、氰基；所述芳基是邻、间、对位带有吸电子或给电子取代的苯基；所述杂环基是噻吩基、呋喃基、萘基或吡啶基、 或者有吸电子或给电子取代基的噻吩、呋喃、萘或吡啶，所述吸电子取代基包括卤素、硝基、酯基、羧基、酰基、酰胺基、氰基，所述给电子取代基包括烷基、烯基、苯基、烃氧基、羟基、氨基。
进一步优选地，反应式(I)中，R 1为C1-C10烃基，末端带有官能团的C1-C10烃基，苯基，芳基或者杂环基；R 2为C1-C10烃基，末端带有官能团的C1-C10烃基，苯基，芳基或者杂环基；R 3为C1-C5烃基，末端带有官能团的C1-C5烃基，苯基、芳基或者杂环基。其中，所述的C1-C10的烃基是烷基，烯基，苯基，芳基或者杂环基；所述的C1-C5的烃基是甲基、乙基、正丙基(及其异构体)、正丁基(及其异构体)和正戊基(及其异构体)；所述的末端带有官能团的C1-C10烃基或末端带有官能团的C1-C5烃基中，所述官能团选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、酰胺基、卤素、羧基、氰基；所述芳基是邻、间、对位带有吸电子或给电子取代的苯基；所述杂环基是噻吩基、呋喃基、萘基或吡啶基、或者有吸电子或给电子取代基的噻吩、呋喃、萘或吡啶，所述吸电子取代基包括卤素、硝基、酯基、羧基、酰基、酰胺基、氰基，所述给电子取代基包括烷基、烯基、苯基、烃氧基、羟基、氨基。
进一步优选地，反应式(I)中，R 1选自C1-C10直链烷基，C1-C10环烷基，末端带有官能团的C1-C10烷基，苯基，芳基或者杂环基；R 2选自C1-C10直链烷基，C1-C10环烷基，末端带有官能团的C1-C10烷基，苯基，芳基或者杂环基；R 3选自C1-C5直链烷基，C1-C5环烷基，末端带有官能团的C1-C5烷基，苯基，芳基或者杂环基；其中，所述的末端带有官能团的C1-C10烷基或末端带有官能团的C1-C5烷基中，所述官能团选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、酰胺基、卤素、羧基、氰基；所述杂环基是噻吩基、呋喃基、萘基或吡啶基、或者有吸电子或给电子取代基的噻吩、呋喃、萘或吡啶，所述吸电子取代基包括卤素、硝基、酯基、羧基、酰基、酰胺基、氰基，所述给电子取代基包括烷基、烯基、苯基、烃氧基、羟基、氨基。
进一步优选地，反应式(I)中，R 1选自甲基，乙基，正丙基，异丙基，正丁基，正戊基，正己基，正庚基，正辛基，苯乙基，4-氯丁基，3-甲基丁基，3-氰基丙基，烯丙基；R 2选自正丙基，叔丁基，苯基，邻甲基苯基，间甲基苯基，对甲基苯基，间甲氧基苯基，对氯苯基，对溴苯基，对酯基苯基，2-萘基，3-噻 吩基；R 3选自甲基，乙基。
作为进一步地改进，本发明的具体操作步骤如下：
(1)向干燥的反应管中依次投入钯催化剂、手性双膦配体、单膦配体和有机磷酸，将反应管用橡皮塞塞好后，连接真空泵，在氩气氛围下置换氩气，加入官能化三级炔丙醇、水，加入一定体积的有机溶剂；将反应管置于液氮浴中冷冻，插上一氧化碳气球后，在一氧化碳氛围下置换一氧化碳进入反应体系，冻抽完后待反应体系恢复室温融化后，将反应管置于预先设定的低温浴或油浴中，搅拌。
其中，所述有机溶剂的用量为1.0-10.0mL/mmol；优选地，为5.0mL/mmol。以式(I)所示的官能化三级炔丙醇(±1)的用量为基准。
(2)待步骤(1)反应完全后，将反应管提出低温浴，恢复室温后，向反应管中加入一定体积的乙酸乙酯，所得混合液用硅胶短柱过滤，并用一定量的乙酸乙酯洗涤后，浓缩，快速柱层析得具有轴手性的高光学活性联烯酸类化合物。
其中，所述一定体积的乙酸乙酯是指以式(I)所示的官能化三级炔丙醇(±1)的用量为基准，所述乙酸乙酯的用量为1.0-100mL/mmol；优选地，为5.0mL/mmol。
作为进一步地改进，本发明所述的钯催化剂为二(烯丙基氯化钯)，四(三苯基膦)钯，三(二亚苄基丙酮)二钯，二(肉桂基氯化钯)，二(二亚苄基丙酮)一钯，氯化钯，醋酸钯，二(三苯基膦)氯化钯，二(乙腈)氯化钯等中的任意一种或多种；优选地，为氯化钯。
作为进一步地改进，本发明所述的手性双膦配体选自以下结构的(R)-L1～(R)-L4及其对映异构体(S)-L1～(S)-L4的一种或多种；优选地，所述的手性双膦配体为(R)-L4和/或其对映异构体(S)-L4。
其中，Ar为苯基、芳基或者杂环基，所述芳基是邻、间、对位有烃基或烃氧基取代的苯基，其中，所述烃基包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基，所述烃氧基包括乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基；所述杂环基是噻吩基、呋喃基或吡啶基；优选地，所述Ar为苯基、3,5-二叔丁基-4-甲氧基苯基。
Figure PCTCN2019123005-appb-000003
作为进一步地改进，本发明所述的手性双膦配体选自(R)-L4a，(R)-L4b，(R)-L4c及其对映异构体(S)-L4a，(S)-L4b，(S)-L4c中的一种或几种；其中，所述(R)-L4a，(R)-L4b，(R)-L4c的结构如下所示：
Figure PCTCN2019123005-appb-000004
作为进一步地改进，本发明所述的单膦配体选自三丁基膦，三环己基膦，三苯基膦，三(邻甲基苯基)膦，三(间甲基苯基)膦，三(对甲基苯基)膦，三(对甲氧基苯基)膦，三(3,5-二三氟甲基苯基)膦，三呋喃基膦等中的任意一种或多种；优选地，为三苯基膦。
作为进一步地改进，本发明所述有机磷酸选自有机磷酸1，有机磷酸2，有机磷酸3等中的任意一种或多种；其中，R 1为氢、C1～C6的烃基、苯基或芳基，所述芳基是邻、间、对位有C1～C6烃基取代的苯基；R 2为C1～C6的烃基、苯基或芳基，所述芳基是邻、间、对位有C1～C6烃基取代的苯基；优选地，R 1、R 2为苯基。
Figure PCTCN2019123005-appb-000005
作为进一步地改进，本发明所述的有机溶剂选自N-甲基吡咯烷酮，1,4-二氧六环，四氢呋喃，乙腈，甲基叔丁基醚、氯苯、甲苯、三氟甲苯、二氯甲烷、1,1-二氯乙烷、1,2-二氯乙烷、氯仿、乙酸等中的任意一种或多种；优选地，为甲苯。
作为进一步地改进，本发明所述的反应温度为-20-60℃；优选地，为-20-0℃；进一步优选地，为-5-0℃。
作为进一步地改进，本发明所述的反应时间为4-36小时；优选地，为18小时。
作为进一步地改进，本发明所述式(I)带有不同取代基的三级炔丙醇(±1)、水、钯催化剂、手性双膦配体、单膦配体和有机磷酸的摩尔比为1.0：(1.0-30.0)：(0.005-0.1)：(0.005-0.1)：(0.01-0.3)：(0.01-0.3)；优选地，为1.0：20.0：0.02：0.048：0.2：0.2。
本发明还提供了具有轴手性的高光学活性联烯酸类化合物，其结构如(R)-2，(S)-2所示：
Figure PCTCN2019123005-appb-000006
其中，R 1为烃基，带有官能团的烃基，苯基，芳基或杂环基；R 2为烃基，带有官能团的烃基，苯基，芳基或者杂环基；R 3为烃基，带有官能团的烃基，苯基，芳基或杂环基；所述芳基是邻、间、对位有给电子或吸电子取代基的苯基，所述杂环基是噻吩基、呋喃基、萘基或吡啶基、或者有给电子或吸电子取代基的噻吩、呋喃、萘或吡啶。
优选地，反应式(I)中，R 1为C1-C20烃基，末端带有官能团的C1-C20烃基，苯基，芳基或者杂环基；R 2为C1-C10烃基，末端带有官能团的C1-C10烃基，苯基，芳基或者杂环基；R 3为C1-C10烃基，末端带有官能团的C1-C10烃基，苯基、芳基或者杂环基；其中，所述的末端带有官能团的C1-C20烃基或末端带有官能团的C1-C10烃基中，所述官能团选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、酰胺基、卤素、羧基、氰基；所述芳基是邻、间、对位带有吸电子或给电子取代的苯基；所述杂环基是噻吩基、呋喃基、萘基或吡啶基、或者有吸电子或给电子取代基的噻吩、呋喃、萘或吡啶，所述吸电子取代基包括 卤素、硝基、酯基、羧基、酰基、酰胺基、氰基，所述给电子取代基包括烷基、烯基、苯基、烃氧基、羟基、氨基。
进一步优选地，反应式(I)中，R 1为C1-C10烃基，末端带有官能团的C1-C10烃基，苯基，芳基或者杂环基；R 2为C1-C10烃基，末端带有官能团的C1-C10烃基，苯基，芳基或者杂环基；R 3为C1-C5烃基，末端带有官能团的C1-C5烃基，苯基、芳基或者杂环基。其中，所述的C1-C10的烃基是烷基，烯基，苯基，芳基或者杂环基；所述的C1-C5的烃基是甲基、乙基、正丙基(及其异构体)、正丁基(及其异构体)和正戊基(及其异构体)；所述的末端带有官能团的C1-C10烃基或末端带有官能团的C1-C5烃基中，所述官能团选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、酰胺基、卤素、羧基、氰基；所述芳基是邻、间、对位带有吸电子或给电子取代的苯基；所述杂环基是噻吩基、呋喃基、萘基或吡啶基、或者有吸电子或给电子取代基的噻吩、呋喃、萘或吡啶，所述吸电子取代基包括卤素、硝基、酯基、羧基、酰基、酰胺基、氰基，所述给电子取代基包括烷基、烯基、苯基、烃氧基、羟基、氨基。
进一步优选地，反应式(I)中，R 1选自C1-C10直链烷基，C1-C10环烷基，末端带有官能团的C1-C10烷基，苯基，芳基或者杂环基；R 2选自C1-C10直链烷基，C1-C10环烷基，末端带有官能团的C1-C10烷基，苯基，芳基或者杂环基；R 3选自C1-C5直链烷基，C1-C5环烷基，末端带有官能团的C1-C5烷基，苯基，芳基或者杂环基；其中，所述的末端带有官能团的C1-C10烷基或末端带有官能团的C1-C5烷基中，所述官能团选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、酰胺基、卤素、羧基、氰基；所述杂环基是噻吩基、呋喃基、萘基或吡啶基、或者有吸电子或给电子取代基的噻吩、呋喃、萘或吡啶，所述吸电子取代基包括卤素、硝基、酯基、羧基、酰基、酰胺基、氰基，所述给电子取代基包括烷基、烯基、苯基、烃氧基、羟基、氨基。
进一步优选地，反应式(I)中，R 1选自甲基，乙基，正丙基，异丙基，正丁基，正戊基，正己基，正庚基，正辛基，苯乙基，4-氯丁基，3-甲基丁基，3-氰基丙基，烯丙基；R 2选自正丙基，叔丁基，苯基，邻甲基苯基，间甲基苯基，对甲基苯基，间甲氧基苯基，对氯苯基，对溴苯基，对酯基苯基，2-萘基，3-噻吩基；R 3选自甲基，乙基。
本发明还提供了式(R)-2所示的具有轴手性的高光学活性联烯酸类化合物在制备含有四取代手性季碳中心的γ-丁内酯类化合物、四取代联烯醇等化合物中的应用。
本发明对反应提出了以下可能的机理：有机磷酸(HB)活化三级炔丙醇形成中间体I，然后钯物种(PdL*)对其进行氧化加成脱除水生成联烯基钯中间体II。随后中间体II与一氧化碳和水反应，生成中间体III或者中间体IV，紧接着发生还原消除得到光学活性四取代联烯酸，以及再生钯物种(PdL*)，具体机理如下式所示。
Figure PCTCN2019123005-appb-000007
本发明的创新点在于，本发明通过以简单易得的官能化三级炔丙醇为起始原料，在钯催化剂，手性双膦配体，单膦配体和有机磷酸的作用下，首次实现了一步合成具有轴手性的高光学活性的四取代联烯酸类化合物。本发明得到的手性联烯酸类化合物可以作为重要的合成中间体，用于构建含有四取代手性季碳中心的γ-丁内酯类化合物。
本发明的有益效果还包括：原料和试剂简单易得，制备方便；反应条件温和，操作简单；底物普适性广；官能团兼容性好；可一步构建含有轴手性的光学纯四取代联烯酸类化合物；产物具有高对映选择性(90％ee～>99％ee)；产物易分离纯化等。
具体实施方式
结合以下具体实施例，对本发明作进一步的详细说明。实施本发明的过程、条件、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。所有实施例中所涉及的手性双膦配体的具体结构式和对应编号如下所示：
Figure PCTCN2019123005-appb-000008
实施例1
Figure PCTCN2019123005-appb-000009
其中，mol表示摩尔，toluene表示甲苯，CO balloon表示一氧化碳气球，ee表示对映异构体过量百分数。
往一个干燥的Schlenk反应管中依次加入PdCl 2(0.0036g,0.02mmol)，手性双膦配体(R)-L4c(0.057g,0.048mmol)，单膦配体PPh 3(0.0527g,0.2mmol)，和(PhO) 2PO 2H(0.0501g,0.2mmol)。将反应管用橡皮塞塞好后，连接真空泵，在氩气氛围下置换氩气三次，在氩气保护氛围下，加入三级炔丙醇(±)-1a(0.2016g,1mmol)，甲苯(3mL)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(2mL)。关闭氩气后将反应管置于液氮浴中冷冻3分钟，插上一氧化碳气球(约1升)， 在一氧化碳氛围下置换一氧化碳三次，然后撤去液氮浴，待反应体系恢复室温融化为液体后，将反应管置于预先设定的-5℃低温浴中，搅拌18小时。将反应提出低温浴，恢复室温后，加入H 2O 2(40μL,d＝1.13g/mL,30wt.％in H 2O,0.0135g,0.4mmol)，室温搅拌30分钟后，加入乙酸乙酯(5mL)稀释反应液，所得混合液用硅胶短柱(3cm)过滤，并用乙酸乙酯(20mL)洗涤后，浓缩，快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2a(0.1033g,45％):固体；93％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝7.9min,t R(minor)＝10.0min)；[α] D 26＝+21.2(c＝1.10,CHCl 3)。熔点：88.4-90.1℃(溶剂挥发干后直接测定)。 1H NMR(400MHz,d 6-DMSO):δ＝12.41(s,1H,COOH),7.44-7.32(m,4H,Ar-H),7.32-7.22(m,1H,Ar-H),2.24(t,J＝7.4Hz,2H,CH 2),2.12(s,3H,CH 3),1.46-1.22(m,4H,2x CH 2),0.84(t,J＝7.0Hz,3H,CH 3)； 13C NMR(100MHz,d 6-DMSO):δ＝210.4,167.9,135.2,128.7,127.5,125.8,103.6,101.9,29.9,28.2,21.8,16.3,13.8；IR(neat):ν＝3210-2410(br),1935,1678,1416,1279,1061cm -1；MS(70eV,EI)m/z(％):230(M +,3.01),143(100)；Anal.Calcd.for C 15H 18O 2:C 78.23,H 7.88；found:C 78.03,H 7.94.
实施例2
Figure PCTCN2019123005-appb-000010
操作同实施例1。PdCl 2(0.0036g,0.02mmol)，(R)-L4c(0.0564g,0.048mmol)，PPh 3(0.0523g,0.2mmol)，(PhO) 2PO 2H(0.05g,0.2mmol)，(±)-1b(0.2157g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2b(0.1029g,42％): 油状物；96％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.5min,t R(minor)＝9.3min)；[α] D 26＝+106.7(c＝1.50,CHCl 3)； 1H NMR(400MHz,CDCl 3):δ＝7.29-7.22(m,1H,Ar-H),7.22-7.12(m,3H,Ar-H),2.40(s,3H,CH 3),2.35-2.05(m,5H,CH 2 and CH 3),1.55-1.40(m,2H,CH 2),1.40-1.27(m,2H,CH 2),0.90(t,J＝7.2Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝210.2,173.8,136.2,136.0,130.6,127.9,127.6,125.9,104.5,98.9,30.1,28.1,22.2,20.4,19.9,13.8；IR(neat):v＝3200-2410(br),1947,1674,1415,1274,1041cm -1；MS(70eV,EI)m/z(％):245(M ++1,2.27),244(M +,11.75),143(100)；HRMS calcd for C 16H 20O 2[M +]:244.1463,found:244.1467.
实施例3
Figure PCTCN2019123005-appb-000011
操作同实施例1。PdCl 2(0.0036g,0.02mmol)，(R)-L4c(0.0571g,0.048mmol),PPh 3(0.0526g,0.2mmol)，(PhO) 2PO 2H(0.0499g,0.2mmol)，(±)-1c(0.2165g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在-5℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2c(0.0687g,28％):固体；94％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.5min,t R(minor)＝7.8min)；[α] D 26＝+16.5(c＝1.00,CHCl 3)。熔点：96.8-98.5℃(溶剂挥发干后直接测定)。 1H NMR(400MHz,CDCl 3):
δ＝7.27-7.20(m,1H,Ar-H),7.20-7.15(m,2H,Ar-H),7.07(d,J＝7.2Hz,1H,Ar-H),2.40-2.28(m,5H,CH 2 and CH 3),2.18(s,3H,CH 3),1.51-1.41(m,2H,CH 2),1.41-1.28(m,2H,CH 2),0.88(t,J＝7.4Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3): δ＝212.6,172.8,138.1,134.9,128.42,128.37,126.7,123.2,105.2,101.6,30.2,28.3,22.3,21.5,16.4,13.8；IR(neat):v＝3250-2400(br),1932,1674,1418,1276,1063cm -1；MS(70eV,EI)m/z(％):245(M ++1,3.90),244(M +,9.06),157(100)；Anal.Calcd.for C 16H 20O 2:C 78.65,H 8.25；found C 78.57,H 8.21.
实施例4
Figure PCTCN2019123005-appb-000012
操作同实施例1。PdCl 2(0.0037g,0.02mmol)，(R)-L4c(0.0569g,0.048mmol)，PPh 3(0.0525g,0.2mmol)，(PhO) 2PO 2H(0.05g,0.2mmol)，(±)-1d(0.2175g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在-5℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2d(0.0909g,37％):固体；90％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝7.9min,t R(minor)＝8.5min)；[α] D 26＝+15.8(c＝1.00,CHCl 3)。熔点：109.3-111.1℃(溶剂挥发干后直接测定)。 1HNMR(400MHz,CDCl 3):δ＝7.26(d,J＝8.0Hz,2H,Ar-H),7.14(d,J＝7.6Hz,2H,Ar-H),2.40-2.25(m,5H,CH 2 and CH 3),2.17(s,3H,CH 3),1.54-1.40(m,2H,CH 2),1.40-1.27(m,2H,CH 2),0.87(t,J＝7.2Hz,3H,CH 3)； 13CNMR(100MHz,CDCl 3):δ＝212.5,173.1,137.4,132.0,129.2,126.0,105.0,101.7,30.2,28.3,22.2,21.1,16.3,13.8；IR(neat):v＝3210-2400(br),1936,1673,1417,1278,1066cm -1；MS(70eV,EI)m/z(％):245(M ++1,10.17),244(M +,6.23),157(100)；Anal.Calcd.for C 16H 20O 2:C78.65,H 8.25；found C 78.65,H 8.22.
实施例5
Figure PCTCN2019123005-appb-000013
操作同实施例1。PdCl 2(0.0036g,0.02mmol)，(R)-L4c(0.0566g,0.048mmol)，PPh 3(0.0524g,0.2mmol)，(PhO) 2PO 2H(0.0504g,0.2mmol)，(±)-1e(0.2324g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)在-5℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝20/1/1)得到手性联烯酸产物(S)-2e(0.0963g,37％):固体；91％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝95/5,1.3mL/min,λ＝214nm,t R(major)＝4.7min,t R(minor)＝5.8min)；[α] D 27＝+16.8(c＝1.11,CHCl 3)。熔点：58.5-60.0℃(石油醚/二氯甲烷重结晶)。 1H NMR(400MHz,CDCl 3):δ＝7.26(t,J＝8.0Hz,1H,Ar-H),7.03-6.88(m,2H,Ar-H),6.80(dd,J 1＝8.0Hz,J 2＝2.0Hz,1H,Ar-H),3.80(s,3H,OCH 3),2.32(t,J＝7.4Hz,2H,CH 2),2.18(s,3H,CH 3),1.55-1.27(m,4H,2x CH 2),0.88(t,J＝7.4Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝212.6,172.8,159.7,136.5,129.5,118.6,112.8,112.0,105.1,101.8,55.2,30.2,28.3,22.2,16.3,13.2；IR(neat):v＝3200-2410(br),1936,1679,1465,1417,1374,1320,1283,1204,1175,1122,1084,1047,1032,1010cm -1；MS(70eV,EI)m/z(％):261(M ++1,2.06),260(M +,11.47),173(100)；HRMS:Calcd for C 16H 20O 3(M +):260.1407；Found:260.1402.
实施例6
Figure PCTCN2019123005-appb-000014
操作同实施例1。PdCl 2(0.0036g,0.02mmol)，(R)-L4c(0.0564g,0.048mmol)，PPh 3(0.053g,0.2mmol)，(PhO) 2PO 2H(0.0505g,0.2mmol)，(±)-1f(0.2356g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在-5℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2f(0.1086g,41％):固体；94％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝8.4min,t R(minor)＝10.4min)；[α] D 26＝+37.8(c＝1.20,CHCl 3)。熔点：110.4-111.7℃(溶剂挥发干后直接测定)。 1H NMR(400MHz,CDCl 3):δ＝7.30(s,4H,Ar-H),2.32(t,J＝7.4Hz,2H,CH 2),2.16(s,3H,CH 3),1.50-1.40(m,2H,CH 2),1.40-1.28(m,2H,CH 2),0.88(t,J＝7.4Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝212.5,172.9,133.6,133.4,128.7,127.3,104.4,102.2,30.2,28.2,22.2,16.3,13.8；IR(neat):v＝3200-2410(br),1936,1672,1416,1281,1089cm -1；MS(70eV,EI)m/z(％):266(M +( 37Cl),2.09),264(M +( 35Cl),4.20),177(100)；Anal.Calcd.for C 15H 17ClO 2:C 68.05,H 6.47；found C 67.95,H 6.43.
实施例7
Figure PCTCN2019123005-appb-000015
操作同实施例1。PdCl 2(0.0036g,0.02mmol)，(R)-L4c(0.0578g,0.048mmol)，PPh 3(0.0525g,0.2mmol)，(PhO) 2PO 2H(0.05g,0.2mmol)，(±)-1g(0.2813g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在-5℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝5/1)得到手性联烯酸产物(S)-2g(0.0928g,30％):固体；92％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝95/5,0.9mL/min,λ＝214nm,t R(major)＝6.2min,t R(minor)＝7.7min)；[α] D 26＝+25.0(c＝1.01,CHCl 3)。熔点：125.1-126.0℃(石油醚/二氯甲烷重结晶)。 1H NMR(400MHz,CDCl 3):δ＝7.46(d,J＝8.4Hz,2H,Ar-H),7.23(d,J＝8.4Hz,2H,Ar-H),2.32(d,J＝7.4Hz,2H,CH 2),2.17(s,3H,CH 3),1.52-1.29(m,4H,2x CH 2),0.88(t,J＝7.2Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝212.4,172.2,134.1,131.7,127.6,121.6,104.5,102.2,30.2,28.3,22.2,16.2,13.8；IR(neat):v＝3200-2400(br),1940,1685,1416,1280,1075cm -1；MS(70eV,EI)m/z(％):310(M +( 81Br),1.97),308(M +( 79Br),1.84),142(100)；HRMS calcd for C 15H 17O 2 81Br[M +]:310.0387,found:310.0370.
实施例8
Figure PCTCN2019123005-appb-000016
操作同实施例1。PdCl 2(0.0037g,0.02mmol)，(R)-L4c(0.0571g,0.048mmol)，PPh 3(0.0527g,0.2mmol)，(PhO) 2PO 2H(0.05g,0.2mmol)，(±)-1h(0.2607g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝20/1/1， 石油醚(60～90℃)/乙酸乙酯＝7/1)得到手性联烯酸产物(S)-2h(0.1013g,35％):固体；97％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝90/10,1.0mL/min,λ＝214nm,t R(minor)＝6.2min,t R(major)＝7.7min)；[α] D 26＝+22.1(c＝1.00,CHCl 3)。熔点：125.3-127.5℃(溶剂挥发干后直接测定)。 1H NMR(400MHz,CDCl 3):δ＝8.00(d,J＝8.4Hz,2H,Ar-H),7.44(d,J＝8.4Hz,2H,Ar-H),3.92(s,3H,OCH 3),2.34(t,J＝7.4Hz,2H,CH 2),2.21(s,3H,CH 3),1.52-1.40(m,2H,CH 2),1.40-1.28(m,2H,CH 2),0.88(t,J＝7.4Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝213.1,172.4,166.8,139.9,129.8,129.0,125.9,104.7,102.3,52.1,30.1,28.2,22.2,16.2,13.8；IR(neat):v＝3250-2400(br),1938,1680,1423,1270,1107cm -1；MS(70eV,EI)m/z(％):289(M ++1,2.11),288(M +,10.34),143(100)；Anal.Calcd.for C 17H 20O 4:C 70.81,H 6.99；found C 70.67,H 7.13.
实施例9
Figure PCTCN2019123005-appb-000017
操作同实施例1。PdCl 2(0.0035g,0.02mmol)，(R)-L4c(0.0578g,0.048mmol)，PPh 3(0.0524g,0.2mmol)，(PhO) 2PO 2H(0.05g,0.2mmol)，(±)-1i(0.2523g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1到10/1/1)得到手性联烯酸产物(S)-2i(0.1037g,37％):固体；92％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝95/5,1.3mL/min,λ＝214nm,t R(major)＝4.5min,t R(minor)＝5.6min)；[α] D 27＝-9.2(c＝1.02,CHCl 3)。熔点：137.5-138.4℃(石油醚/乙酸乙酯)。 1H NMR(400MHz,CDCl 3):δ＝7.94-7.61(m,4H,Ar-H),7.62-7.30(m,3H,Ar-H),2.60-2.08(m,5H,CH 3 and CH 3),1.64-1.29(m,4H, 2x CH 2),0.88(t,J＝7.0Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝213.2,172.6,133.5,132.8,132.4,128.10,128.06,127.6,126.3,126.1,124.8,124.2,105.5,102.1,30.2,28.4,22.3,16.3,13.8；IR(neat):v＝3200-2410(br),1936,1680,1412,1277,1247cm -1；MS(70eV,EI)m/z(％):281(M ++1,4.05),280(M +,15.75),193(100)；Anal.Calcd.for C 19H 20O 2:C 81.40,H 7.19；found C 81.45,H 7.20.
实施例10
Figure PCTCN2019123005-appb-000018
操作同实施例1。PdCl 2(0.0036g,0.02mmol)，(R)-L4c(0.0571g,0.048mmol)，PPh 3(0.0524g,0.2mmol)，(PhO) 2PO 2H(0.05g,0.2mmol)，(±)-1j(0.2086g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在-5℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2j(0.1037g,37％):固体；92％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝10.5min,t R(minor)＝13.2min)；[α] D 27＝+11.5(c＝1.00,CHCl 3)。熔点：82.6-83.8℃(溶剂挥发干后直接测定)。 1H NMR(400MHz,CDCl 3):δ＝7.28(d,J＝4.8Hz,1H,one proton fromthieny),7.16(d,J＝2.8Hz,1H,one proton fromthieny),7.04(d,J＝4.8Hz,1H,one proton fromthieny),2.31(t,J＝7.6Hz,2H,CH 2),2.17(s,3H,CH 3),1.52-1.41(m,2H,CH 2),1.40-1.29(m,2H,CH 2),0.88(t,J＝7.2Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝212.8,172.3,136.5,126.3,125.9,120.6,101.4,101.3,30.2,28.4,22.3,16.7,13.8；IR(neat):v＝3200-2410(br),1936,1673,1417,1279,1079cm -1；MS(70eV,EI)m/z(％):237 (M ++1,1.29),236(M +,7.96),149(100)；Anal.Calcd.for C 13H 16O 2S:C 66.07,H 6.82；found C 65.93,H 6.70.
实施例11
Figure PCTCN2019123005-appb-000019
操作同实施例1。PdCl 2(0.0036g,0.02mmol)，(R)-L4c(0.057g,0.048mmol)，PPh 3(0.0524g,0.2mmol)，(PhO) 2PO 2H(0.0501g,0.2mmol)，(±)-1k(0.1831g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2k(0.076g,36％):油状物；99％ee(HPLC conditions:AD-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(minor)＝6.9min,t R(major)＝7.4min)；[α] D 27＝+38.5(c＝1.36,CHCl 3)； 1H NMR(400MHz,CDCl 3):δ＝2.25-2.13(m,2H,CH 2),1.77(s,3H,CH 3),1.45-1.29(m,4H,2x CH 2),1.10(s,9H,3x CH 3),0.90(t,J＝7.2Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝208.0,173.9,113.0,99.4,34.2,30.3,28.8,28.0,22.3,14.0,13.9；IR(neat):v＝3210-2400(br),1946,1669,1412,1274,1240,1114cm -1；MS(ESI)m/z:211(M+H +)；HRMS calcd for C 13H 23O 2[M+H +]:211.1693,found:211.1692.
实施例12
Figure PCTCN2019123005-appb-000020
操作同实施例1。PdCl 2(0.0036g,0.02mmol)，(R)-L4c(0.0569g,0.048mmol)，PPh 3(0.0526g,0.2mmol)，(PhO) 2PO 2H(0.0495g,0.2mmol)，(±)-1l(0.2175g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2l(0.0984g,40％):固体；93％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝7.4min,t R(minor)＝11.5min)；[α] D 27＝+11.2(c＝1.00,CHCl 3)。熔点：93.2-93.6℃(溶剂挥发干后直接测定)。 1H NMR(400MHz,CDCl 3):δ＝7.45-7.29(m,4H,Ar-H),7.29-7.20(m,1H,Ar-H),2.32(t,J＝7.6Hz,2H,CH 2),2.19(s,3H,CH 3),1.58-1.38(m,2H,CH 2),1.36-1.16(m,4H,2x CH 2),0.84(t,J＝6.6Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝212.6,173.1,135.0,128.5,127.5,126.0,105.1,101.8,31.3,28.5,27.7,22.4,16.3,14.0；IR(neat):v＝3200-2410(br),1937,1675,1413,1275,1064,1023cm -1；MS(70eV,EI)m/z(％):244(M +,3.21),143(100)；Anal.Calcd.for C 16H 20O 2:C 78.65,H 8.25；found C 78.68,H 8.38.
实施例13
Figure PCTCN2019123005-appb-000021
操作同实施例1。PdCl 2(0.0037g,0.02mmol)，(R)-L4c(0.057g,0.048mmol)，PPh 3(0.0524g,0.2mmol)，(PhO) 2PO 2H(0.0501g,0.2mmol)，(±)-1m(0.2298g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2m(0.1081g,42％):固体；90％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.6min,t R(minor)＝9.4min)；[α] D 26＝+7.4(c＝1.20,CHCl 3)。熔点：76.9-78.1℃(溶剂挥发干后直接测定)。 1H NMR(400MHz,CDCl 3):δ＝7.46-7.30(m,4H,Ar-H),7.30-7.21(m,1H,Ar-H),2.32(t,J＝7.4Hz,2H,CH 2),2.19(s,3H,CH 3),1.53-1.41(m,2H,CH 2),1.38-1.11(m,6H,3x CH 2),0.84(t,J＝6.4Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝212.6,173.0,135.0,128.5,127.5,126.1,105.2,101.8,31.6,28.8,28.6,28.0,22.6,16.3,14.0；IR(neat):v＝3250-2410(br),1936,1679,1417,1272,1026cm -1；MS(70eV,EI)m/z(％):258(M +,3.96),143(100)；Anal.Calcd.for C 17H 22O 2:C 79.03,H 8.58；found C 78.86,H 8.62.
实施例14
Figure PCTCN2019123005-appb-000022
操作同实施例1。PdCl 2(0.0037g,0.02mmol),(R)-L4c(0.0567g,0.048mmol),PPh 3(0.0526g,0.2mmol),(PhO) 2PO 2H(0.0501g,0.2mmol),(±)-1n(0.2578g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2n(0.1144g,40％):油状物；98％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min, λ＝214nm,t R(major)＝6.0min,t R(minor)＝9.0min)；[α] D 27＝+69.4(c＝1.34,CHCl 3)； 1H NMR(400MHz,CDCl 3):δ＝7.29-7.22(m,1H,Ar-H),7.20-7.12(m,3H,Ar-H),2.40(s,3H,CH 3),2.35-2.15(m,2H,CH 2),2.13(s,3H,CH 3),1.54-1.41(m,2H,CH 2),1.35-1.15(m,8H,4x CH 2),0.87(t,J＝6.8Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝210.2,173.8,136.2,136.0,130.6,127.9,127.5,125.9,104.5,98.9,31.8,29.11,29.05,28.3,28.0,22.6,20.4,19.9,14.1；IR(neat):v＝3220-2410(br),1948,1675,1414,1274,1043cm -1；MS(70eV,EI)m/z(％):287(M ++1,2.48),286(M +,11.23),143(100)；HRMS calcd for C 19H 26O 2[M +]:286.1933,found:286.1930.
实施例15
Figure PCTCN2019123005-appb-000023
操作同实施例1。PdCl 2(0.0037g,0.02mmol),(R)-L4c(0.0569g,0.048mmol),PPh 3(0.0525g,0.2mmol),(PhO) 2PO 2H(0.05g,0.2mmol),(±)-1o(0.2922g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2o(0.1315g,41％):固体；94％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.0min,t R(minor)＝7.8min)；[α] D 27＝+30.1(c＝1.27,CHCl 3)。熔点：89.2-90.6℃(溶剂挥发干后直接测定)。 1H NMR(400MHz,CDCl 3):δ＝7.30(s,4H,Ar-H),2.31(t,J＝7.6Hz,2H,CH 2),2.17(s,3H,CH 3),1.49-1.40(m,2H,CH 2),1.34-1.15(m,10H,5x CH 2),0.86(t,J＝7.0Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝212.5,173.0,133.6,133.4,128.6,127.3,104.4,102.2,31.8,29.3,29.2,29.1,28.5,28.0,22.6,16.2,14.0；IR(neat):v＝3200-2410(br),1938,1675,1415,1274,1091cm -1；MS(70eV,EI)m/z(％):322(M +( 37Cl),1.34),320(M +( 35Cl), 3.62),177(100)；Anal.Calcd.for C 19H 25ClO 2:C 71.12,H 7.85；found C 71.18,H7.87.
实施例16
Figure PCTCN2019123005-appb-000024
操作同实施例1。PdCl 2(0.0037g,0.02mmol),(R)-L4c(0.0566g,0.048mmol),PPh 3(0.0527g,0.2mmol),(PhO) 2PO 2H(0.0501g,0.2mmol),(±)-1p(0.2504g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝10/1)得到手性联烯酸产物(S)-2p(0.0834g,30％):固体；94％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝13.7min,t R(minor)＝24.1min)；[α] D 25＝-23.3(c＝1.00,CHCl 3)。熔点：87.4-89.1℃(溶剂挥发干后直接测定)。 1H NMR(400MHz,CDCl 3):δ＝7.33-7.20(m,7H,Ar-H),7.19-7.12(m,3H,Ar-H),2.83(t,J＝7.6Hz,2H,CH 3),2.76-2.57(m,2H,CH 2),2.02(s,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝212.9,172.6,141.1,134.7,128.5,128.3,127.6,126.1,125.9,105.5,100.7,34.1,30.3,16.1；IR(neat):v＝3200-2410(br),1934,1676,1417,1279,1253,1065cm -1；MS(70eV,EI)m/z(％):279(M ++1,1.97),278(M +,9.71),91(100)；Anal.Calcd.for C 19H 18O 2:C81.99,H 6.52；found C 82.12,H 6.39.
实施例17
Figure PCTCN2019123005-appb-000025
操作同实施例1。PdCl 2(0.0037g,0.02mmol),(R)-L4c(0.0571g,0.048mmol),PPh 3(0.0525g,0.2mmol),(PhO) 2PO 2H(0.0375g,0.15mmol),(±)-1q(0.2356g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝10/1)得到手性联烯酸产物(S)-2q(0.0871g,33％):固体；91％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝95/5,1.3mL/min,λ＝214nm,t R(major)＝5.8min,t R(minor)＝7.4min)；[α] D 27＝-4.1(c＝1.00,CHCl 3)。熔点：70.7-72.7℃(溶剂挥发干后直接测定)。 1H NMR(400MHz,CDCl 3):δ＝7.45-7.30(m,4H,Ar-H),7.30-7.22(m,1H,Ar-H),3.50(t,J＝6.6Hz,2H,CH 2),2.36(t,J＝7.6Hz,2H,CH 2),2.20(s,3H,CH 3),1.87-1.73(m,2H,CH 2),1.72-1.55(m,2H,CH 2)； 13C NMR(100MHz,CDCl 3):δ＝212.6,172.8,134.7,128.6,127.7,126.1,105.7,101.1,44.6,32.0,27.8,25.3,16.3；IR(neat):v＝3300-2300(br),1933,1672,1418,1272,1101,1059,1015cm -1；MS(70eV,EI)m/z(％):266(M +( 37Cl),2.35),264(M +( 35Cl),7.78),143(100)；Anal.Calcd.for C 15H 17ClO 2:C 68.05,H 6.47；found C 67.77,H 6.59.
实施例18
Figure PCTCN2019123005-appb-000026
操作同实施例1。PdCl 2(0.0037g,0.02mmol),(R)-L4c(0.057g,0.048mmol),PPh 3(0.0526g,0.2mmol),(PhO) 2PO 2H(0.0501g,0.2mmol),(±)-1r(0.2166g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在-5℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝10/1)得到手性联烯酸产物(S)-2r(0.0808g,33％):固体；93％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝7.1min,t R(minor)＝9.0min)；[α] D 27＝+5.5(c＝1.10, CHCl 3)。熔点：75.2-76.7℃(溶剂挥发干后直接测定)。 1H NMR(400MHz,CDCl 3):δ＝7.47-7.28(m,4H,Ar-H),7.28-7.18(m,1H,Ar-H),2.33(t,J＝7.8Hz,2H,CH 3),2.18(s,3H,CH 3),1.65-1.51(m,1H,CH),1.43-1.29(m,2H,CH 2),0.87(t,J＝6.2Hz,6H,2x CH 3)； 13C NMR(100MHz,CDCl 3):δ＝212.5,173.1,135.0,128.5,127.6,126.0,105.2,102.0,37.1,27.6,26.6,22.44,22.40,16.3；IR(neat):v＝3250-2410(br),1936,1674,1467,1418,1279,1256,1066cm -1；MS(70eV,EI)m/z(％):244(M +,2.72),143(100)；Anal.Calcd.for C 16H 20O 2:C 78.65,H 8.25；found C 78.54,H 8.32.
实施例19
Figure PCTCN2019123005-appb-000027
操作同实施例1。PdCl 2(0.0036g,0.02mmol),(R)-L4c(0.0569g,0.048mmol),PPh 3(0.0525g,0.2mmol),(PhO) 2PO 2H(0.075g,0.3mmol),(±)-1s(0.2133g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙酸乙酯＝10/1后5/1)得到手性联烯酸产物(S)-2s(0.0702g,29％):固体；93％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝90/10,1.3mL/min,λ＝214nm,t R(major)＝9.9min,t R(minor)＝12.3min)；[α] D 25＝+23.7(c＝1.10,CHCl 3)。熔点：64.4-65.6℃(石油醚/乙醚重结晶)。 1H NMR(400MHz,CDCl 3):δ＝7.39-7.33(m,4H,Ar-H),7.33-7.27(m,1H,Ar-H),2.52-2.44(m,2H,CH),2.35(t,J＝7.2Hz,2H,CH 2),2.22(s,3H,CH 3),1.89(quint,J＝7.4Hz,2H,CH 2)； 13C NMR(100MHz,CDCl 3):δ＝212.4,171.9,134.3,128.7,128.0,126.1,119.2,106.3,99.7,27.7,23.9,16.5,16.3；IR(neat):v＝3400-2650(br),2262,1939,1697,1450,1394,1216,1030cm -1；MS(70eV, EI)m/z(％):242(M ++1,3.44),241(M +,19.06),143(100)；Anal.Calcd.for C 15H 15NO 2:C 74.67,H 6.27；found C 74.43,H 6.33.
实施例20
Figure PCTCN2019123005-appb-000028
操作同实施例1。PdCl 2(0.0036g,0.02mmol),(R)-L4c(0.0571g,0.048mmol),PPh 3(0.0526g,0.2mmol),(PhO) 2PO 2H(0.0502g,0.2mmol),(±)-1t(0.1867g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2t(0.0668g,31％):固体；90％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝10.4min,t R(minor)＝12.6min)；[α] D 26＝-2.2(c＝1.00,CHCl 3)。熔点：94.6-96.1℃(溶剂挥发干后直接测定)。 1H NMR(400MHz,CDCl 3):δ＝7.41-7.30(m,4H,Ar-H),7.29-7.22(m,1H,Ar-H),5.97-5.74(m,1H,＝CH),5.13(d,J＝16.8Hz,1H,one proton of＝CH 2),5.03(d,J＝10.0Hz,1H,one proton of＝CH 2),3.08(d,J＝6.8Hz,2H,CH 2),2.19(s,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝212.9,172.1,134.8,134.7,128.6,127.7,126.1,116.5,105.8,100.2,33.1,16.3；IR(neat):v＝3200-2410(br),1933,1677,1414,1263,1065cm -1；MS(70eV,EI)m/z(％):215(M ++1,5.09),214(M +,16.32),171(100)；HRMS calcd for C 14H 14O 2[M +]:214.0994,found:214.0995.
实施例21
Figure PCTCN2019123005-appb-000029
操作同实施例1。PdCl 2(0.0036g,0.02mmol),(R)-L4c(0.057g,0.048mmol),PPh 3(0.0524g,0.2mmol),(PhO) 2PO 2H(0.0501g,0.2mmol),(±)-1u(0.2672g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2u(0.0947g,32％):固体；>99％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,0.8mL/min,λ＝214nm,t R(major)＝13.6min)；[α] D 26＝+84.6(c＝1.32,CHCl 3)。熔点：119.2-120.9℃(石油醚/二氯甲烷)。 1H NMR(400MHz,CDCl 3):δ＝7.46(d,J＝8.8Hz,2H,Ar-H),7.25(d,J＝8.4Hz,2H,Ar-H),2.80(heptet,J＝6.8Hz,1H,CH),2.18(s,3H,CH 3),1.09(d,J＝6.8Hz,6H,2x CH 3)； 13C NMR(100MHz,CDCl 3):δ＝211.3,172.4,134.0,131.7,127.4,121.5,109.0,105.8,28.2,22.1,22.1,16.2；IR(neat):v＝3200-2410(br),1938,1673,1484,1412,1271,1074cm -1；MS(70eV,EI)m/z(％):296(M +( 81Br),63.64),294(M +( 79Br),63.57),155(100)；HRMS calcd for C 14H 15 79BrO 2[M +]:294.0255,found:294.0256.
实施例22
Figure PCTCN2019123005-appb-000030
操作同实施例1。PdCl 2(0.0036g,0.02mmol),(R)-L4c(0.057g,0.048mmol),PPh 3(0.0526g,0.2mmol),(PhO) 2PO 2H(0.05g,0.2mmol),(±)-1v(0.2165g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2v(0.1004g,41％):油状物；94％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.3min,t R(minor)＝8.8min)；[α] D 28＝+103.4(c＝1.10,CHCl 3)； 1H NMR(400MHz,CDCl 3):δ＝7.29-7.08(m,4H,Ar-H),2.50-2.32(m,5H,CH 2 and CH 3),2.32-2.12(m,2H,CH 2),1.60-1.42(m,2H,CH 2),1.11(t,J＝7.4Hz,3H,CH 3),0.93(t,J＝7.4Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝209.2,174.1,136.02,135.97,130.4,128.4,127.5,125.8,111.2,100.6,30.5,27.1,21.4,20.0,13.8,12.2；IR(neat):v＝3200-2410(br),1948,1674,1414,1270,1130cm -1；MS(70eV,EI)m/z(％):245(M ++1,12.45),244(M +,69.97),229(100)；HRMS calcd for C 16H 20O 2[M +]:244.1458,found:244.1455.
实施例23
Figure PCTCN2019123005-appb-000031
操作同实施例1。PdCl 2(0.0037g,0.02mmol),(R)-L4c(0.0571g,0.048mmol), PPh 3(0.0525g,0.2mmol),(PhO) 2PO 2H(0.05g,0.2mmol),(±)-1w(0.229g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2w(0.0723g,28％):油状物；92％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝5.6min,t R(minor)＝7.7min)；[α] D 27＝+86.2(c＝1.10,CHCl 3)； 1H NMR(400MHz,CDCl 3):δ＝7.26-7.20(m,1H,Ar-H),7.20-7.11(m,3H,Ar-H),2.50-2.15(m,7H,2x CH 2 and CH 3),1.54-1.40(m,2H,CH 2),1.40-1.28(m,2H,CH 2),1.12(t,J＝7.4Hz,3H,CH 3),0.90(t,J＝7.2Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝209.1,174.1,136.01,135.96,130.4,128.4,127.5,125.8,111.2,100.7,30.3,28.0,27.1,22.3,20.0,13.8,12.2；IR(neat):v＝3200-2400(br),1949,1675,1414,1275,1086cm -1；MS(70eV,EI)m/z(％):259(M ++1,6.05),258(M +,32.38),129(100)；HRMS calcd for C 17H 22O 2[M +]:258.1620,found:258.1623.
实施例24
Figure PCTCN2019123005-appb-000032
操作同实施例1。PdCl 2(0.0036g,0.02mmol),(R)-L4c(0.057g,0.048mmol),PPh 3(0.0527g,0.2mmol),(PhO) 2PO 2H(0.0501g,0.2mmol),(±)-1x(0.2287g,1mmol)，水(360μL,d＝1.0g/mL,0.36g,20mmol)，甲苯(5mL)，在-5℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2x(0.0928g,36％):固体；90％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝9.2min,t R(minor)＝11.2min)。熔点：107.7-108.6℃(溶剂 挥发干后直接测定)。 1H NMR(400MHz,CDCl 3):δ＝7.39-7.29(m,1H,Ar-H),7.17-7.05(m,3H,Ar-H),2.82(t,J＝6.2Hz,2H,CH 2),2.72-2.56(m,2H,CH 2),2.33(t,J＝7.4Hz,2H,CH 2),2.20-1.83(m,2H,CH 2),1.52-1.41(m,2H,CH 2),1.41-1.28(m,2H,CH 2),0.88(t,J＝7.4Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝210.5,173.0,136.8,129.4,129.3,127.5,127.3,126.2,106.2,102.8,30.2,29.8,28.4,28.0,22.7,22.3,13.8；IR(neat):v＝3200-2400,1931,1670,1418,1279cm -1；MS(70eV,EI)m/z(％):257(M ++1,1.91),256(M +,8.77),169(100)；Anal.Calcd.for C 17H 20O 2:C 79.65,H 7.86；found C 79.16,H 7.83.
实施例25
Figure PCTCN2019123005-appb-000033
往一个干燥的Schlenk反应瓶中依次加入PdCl 2(0.0356g,0.2mmol)，手性双膦配体(R)-L4c(0.5776g,0.48mmol)，单膦配体PPh 3(0.5242g,2mmol)，和(PhO) 2PO 2H(0.5006g,2mmol)。将反应管用橡皮塞塞好后，连接真空泵，在氩气氛围下置换氩气三次，在氩气保护氛围下，加入三级炔丙醇(±)-1a(2.0240g，10mmol)，甲苯(30mL)，水(3.6041g,200mmol)，甲苯(20mL)。关闭氩气后将反应管置于液氮浴中冷冻15分钟，插上一氧化碳气球(约2升)，在一氧化碳氛围下置换一氧化碳三次，然后撤去液氮浴，待反应体系恢复室温融化为液体后，将反应管置于预先设定的0℃低温浴中，搅拌18小时。将反应提出低温浴，恢复室温后，加入H 2O 2(400μL,d＝1.13g/mL,30wt.％in H 2O,0.135g,4mmol)，室温搅拌30分钟后，加入乙酸乙酯(50mL)稀释反应液，所得混合液用硅胶短柱(3cm)过滤，并用乙酸乙酯(100mL)洗涤后，浓缩，快速柱层析(淋洗 剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2a(0.8259g,37％)和(S)-1a(1.0516g,52％)。
(S)-2a:93％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝8.5min,t R(minor)＝10.7min). 1H NMR(400MHz,CDCl 3):δ＝7.45-7.29(m,4H,Ar-H),7.29-7.17(m,1H,Ar-H),2.32(t,J＝7.4Hz,2H,CH 2),2.19(s,3H,CH 3),1.54-1.40(m,2H,CH 2),1.40-1.27(m,2H,CH 2),0.88(t,J＝7.4Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝212.5,172.8,135.0,128.5,127.5,126.1,105.2,101.8,30.2,28.3,22.3,16.3,13.8.
(S)-1a:63％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(minor)＝7.2min,t R(major)＝11.9min). 1H NMR(400MHz,CDCl 3):δ＝7.64(d,J＝7.2Hz,2H,Ar-H),7.32(t,J＝7.6Hz,2H,Ar-H),7.28-7.20(m,1H,Ar-H),2.64(s,1H,OH),2.25(t,J＝7.0Hz,2H,CH 2),1.72(s,3H,CH 3),1.58-1.48(m,2H,CH 2),1.48-1.34(m,2H,CH 2),0.91(t,J＝7.2Hz,3H,CH 3).
操作同实施例25。PdCl 2(0.0177g,0.1mmol),(S)-L4c(0.2896g,0.24mmol),PPh 3(0.2624g,1mmol),(PhO) 2PO 2H(0.2501g,1mmol),(S)-1a(1.0109g,5mmol)，水(1.8052g,100mmol)，甲苯(25mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(R)-2a(0.8172g,71％):固体；98％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(minor)＝8.1min,t R(major)＝9.8min)；[α] D 28＝-26.2(c＝0.90,CHCl 3)。熔点：92.2-93.3℃(溶剂挥发干后直接测定)。 1H NMR(400MHz,CDCl 3):δ＝7.44-7.29(m,4H,Ar-H),7.29-7.20(m,1H,Ar-H),2.32(t,J＝7.6Hz,2H,CH 2),2.19(s,3H,CH 3),1.54-1.41(m,2H,CH 2),1.41-1.26(m,2H,CH 2),0.88(t,J＝7.4Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝212.5,172.8,135.0,128.5,127.6,126.1,105.2,101.8,30.2,28.3,22.3,16.3,13.8；IR(neat):v＝3200-2410(br),1936,1678,1446,1280,1066cm -1；MS(70eV,EI)m/z(％):230(M +,2.74),143(100)；HRMS calcd for C 15H 18O 2[M +]:230.1301,found:230.1295.
实施例26
Figure PCTCN2019123005-appb-000034
操作同实施例25。PdCl 2(0.0358g,0.2mmol),(R)-L4c(0.5779g,0.48mmol),PPh 3(0.5253g,2mmol),(PhO) 2PO 2H(0.5005g,2mmol),(±)-1f(2.3685g,10mmol)，水(3.6031g,200mmol)，甲苯(50mL)，在0℃中，反应24小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝5/1)得到手性联烯酸产物(S)-2f(1.0946g,41％)和(S)-1f(1.2385g,52％)。
(S)-2f:95％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝8.6min,t R(minor)＝9.6min). 1H NMR(400MHz,CDCl 3):δ＝7.29(s,4H,Ar-H),2.32(t,J＝7.6Hz,2H,CH 2),2.16(s,3H,CH 3),1.50-1.40(m,2H,CH 2),1.40-1.28(m,2H,CH 2),0.87(t,J＝7.2Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝212.5,172.9,133.6,133.4,128.7,127.3,104.4,102.2,30.2,28.2,22.2,16.3,13.8.
(S)-1f:75％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(minor)＝7.3min,t R(major)＝10.1min). 1H NMR(400MHz,CDCl 3):δ＝7.58(d,J＝8.4Hz,2H,Ar-H),7.31(d,J＝8.4Hz,2H,Ar-H),2.33-2.20(m,3H,CH 2 and OH),1.71(s,3H,CH 3),1.57-1.48(m,2H,CH 2),1.48-1.36(m,2H,CH 2),0.93(t,J＝7.4Hz,3H,CH 3).
操作同实施例25。PdCl 2(0.0185g,0.1046mmol),(S)-L4c(0.3025g,0.251mmol),PPh 3(0.2748g,1.046mmol),(PhO) 2PO 2H(0.2621g,1.046mmol),(S)-1f(1.2385g,5.23mmol)，水(1.8883g,104.6mmol)，甲苯(25mL)，在0℃中， 反应24小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝5/1)得到手性联烯酸产物(R)-2f(0.9115g,66％):固体；98％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(minor)＝8.9min,t R(major)＝9.8min)；[α] D 26＝-39.7(c＝1.00,CHCl 3)。熔点：108.6-110.0℃(溶剂挥发干后直接测定)。 1H NMR(400MHz,CDCl 3):δ＝7.31(s,4H,Ar-H),2.33(t,J＝7.6Hz,2H,CH 2),2.17(s,3H,CH 3),1.50-1.40(m,2H,CH 2),1.40-1.29(m,2H,CH 2),0.88(t,J＝7.2Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝212.5,172.9,133.6,133.4,128.7,127.3,104.4,102.2,30.1,28.2,22.2,16.2,13.8；IR(neat):v＝3200-2410(br),1940,1680,1416,1280,1090cm -1；MS(70eV,EI)m/z(％):266(M +( 37Cl),1.42),264(M +( 35Cl),3.93),177(100)；HRMS calcd for C 15H 17 35ClO 2[M +]:264.0912,found:264.0913.
实施例27
Figure PCTCN2019123005-appb-000035
操作同实施例25。PdCl 2(0.0357g,0.2mmol),(R)-L4c(0.5774g,0.48mmol),PPh 3(0.524g,2mmol),(PhO) 2PO 2H(0.7505g,3mmol),(±)-1k(1.8235g,10
mmol)，水(3.6009g,200mmol)，甲苯(50mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2k(0.9668g,46％)和(S)-1k(0.7841g,43％)。
(S)-2k:熔点:42.0-44.3℃(石油醚/二氯甲烷重结晶)；>99％ee(HPLC conditions:AD-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major) ＝7.4min). 1H NMR(400MHz,CDCl 3):δ＝2.27-2.10(m,2H,CH 2),1.77(s,3H,CH 3),1.47-1.28(m,4H,2x CH 2),1.10(s,9H,3x CH 3),0.90(t,J＝7.0Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝208.2,174.5,112.8,99.4,34.2,30.3,28.8,28.0,22.3,14.0,13.9.
(S)-1k:>99％ee(HPLC conditions:IC column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝4.7min). 1H NMR(400MHz,CDCl 3):δ＝2.20(t,J＝6.8Hz,2H,CH 2),1.78(s,1H,OH),1.55-1.34(m,7H,2x CH 2 and CH 3),1.03(s,9H,3x CH 3),0.91(t,J＝7.2Hz,3H,CH 3).
操作同实施例25。PdCl 2(0.0152g,0.086mmol),(S)-L4c(0.2489g,0.2064mmol),PPh 3(0.2253g,0.86mmol),(PhO) 2PO 2H(0.3226g,1.29mmol),(S)-1k(0.7841g,4.3mmol)，水(1.5471g,86mmol)，甲苯(21mL)，在0℃中，反应24小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(R)-2k(0.7248g,80％):固体；>99％ee(HPLC conditions:AD-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.7min)；[α] D 27＝-37.4(c＝1.00,CHCl 3)。熔点：42.5-44.2℃(石油醚/二氯甲烷重结晶)。 1H NMR(400MHz,CDCl 3):δ＝2.26-2.10(m,2H,CH 2),1.77(s,3H,CH 3),1.48-1.28(m,4H,2x CH 2),1.10(s,9H,3x CH 3),0.91(t,J＝7.0Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝208.1,174.5,112.8,99.4,34.2,30.3,28.8,28.0,22.3,14.0,13.9；IR(neat):v＝3210-2410(br),1947,1669,1413,1276,1241,1113cm -1；MS(ESI)m/z:211(M+H +)；HRMS calcd for C 13H 23O 2[M+H +]:211.1693,found:211.1697.
实施例28
Figure PCTCN2019123005-appb-000036
操作同实施例25。PdCl 2(0.03576g,0.2mmol),(R)-L4c(0.5779g,0.48mmol),PPh 3(0.5247g,2mmol),(PhO) 2PO 2H(0.5006g,2mmol),(±)-1v(2.1625g,10mmol),水(3.6017g,200mmol)，甲苯(50mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2v(0.9553g,39％)和(S)-1v(1.1165g,52％)。
(S)-2v:93％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.6min,t R(minor)＝9.2min). 1H NMR(400MHz,CDCl 3):δ＝7.27-7.20(m,1H,Ar-H),7.20-7.11(m,3H,Ar-H),2.47-2.32(m,5H,CH 2 and CH 3),2.32-2.12(m,2H,CH 2),1.58-1.44(m,2H,CH 2),1.11(t,J＝7.4Hz,3H,CH 3),0.93(t,J＝7.4Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝209.2,174.1,136.02,135.97,130.4,128.4,127.5,125.8,111.2,100.6,30.5,27.1,21.4,20.0,13.8,12.2.
(S)-1v(1.1165g,52％):63％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(minor)＝5.6min,t R(major)＝7.1min). 1H NMR(400MHz,CDCl 3):δ＝7.77-7.68(m,1H,Ar-H),7.23-7.10(m,3H,Ar-H),2.58(s,3H,CH 3),2.25(t,J＝7.0Hz,2H,CH 2),2.21(s,1H,OH),2.09-1.90(m,2H,CH 2),1.60-1.51(m,2H,CH 2),1.08-0.91(m,6H,2x CH 3).
操作同实施例25。PdCl 2(0.0181g,0.1032mmol),(S)-L4c(0.2981g,0.248mmol),PPh 3(0.2704g,1.032mmol),(PhO) 2PO 2H(0.2581g,1.032mmol),(S)-1v (1.1165g,5.16mmol)，水(1.8582g,103.2mmol)，甲苯(25.8mL)，在0℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(R)-2v(0.8785g,70％):油状物；99％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(minor)＝5.6min,t R(major)＝6.7min)；[α] D 28＝-107.5(c＝1.00,CHCl 3)； 1H NMR(400MHz,CDCl 3):δ＝7.30-7.08(m,4H,Ar-H),2.48-2.32(m,5H,CH 2 and CH 3),2.32-2.10(m,2H,CH 2),1.61-1.49(m,2H,CH 2),1.11(t,J＝7.2Hz,3H,CH 3),0.93(t,J＝7.4Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝209.1,174.1,136.01,135.97,130.4,128.4,127.5,125.8,111.2,100.6,30.5,27.1,21.4,20.0,13.8,12.2；IR(neat):v＝3200-2410(br),1949,1675,1414,1268,1121cm -1；MS(70eV,EI)m/z(％):245(M ++1,9.12),244(M +,45.59),129(100)；HRMS calcd for C 16H 20O 2[M +]:244.1458,found:244.1454.
实施例29
Figure PCTCN2019123005-appb-000037
操作同实施例25。PdCl 2(0.1779g,1.0mmol),(R)-L4c(2.8891g,2.4mmol),PPh 3(2.6243g,10mmol),(PhO) 2PO 2H(2.5036g,10mmol),(±)-1a(10.1061g,50mmol)，水(18.0050g,1000mmol)，甲苯(250mL)，在0℃中，反应24小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝5/1)得到手性联烯酸产物(S)-2a(5.1316g,45％)和(S)-1a(5.1163g,51％)。
(S)-2a:93％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0 mL/min,λ＝214nm,t R(major)＝7.9min,t R(minor)＝9.7min). 1H NMR(400MHz,CDCl 3):δ＝7.45-7.28(m,4H,Ar-H),7.27-7.18(m,1H,Ar-H),2.33(t,J＝7.4Hz,2H,CH 2),2.18(s,3H,CH 3),1.55-1.40(m,2H,CH 2),1.40-1.27(m,2H,CH 2),0.87(t,J＝7.2Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝212.6,173.1,135.0,128.5,127.5,126.1,105.2,101.8,30.2,28.3,22.2,16.3,13.8.
(S)-1a:69％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(minor)＝7.1min,t R(major)＝11.2min). 1H NMR(400MHz,CDCl 3):δ＝7.65(d,J＝7.2Hz,2H,Ar-H),7.35(t,J＝7.4Hz,2H,Ar-H),7.31-7.23(m,1H,Ar-H),2.36(s,1H,OH),2.28(t,J＝7.0Hz,2H,CH 2),1.74(s,3H,CH 3),1.58-1.49(m,2H,CH 2),1.49-1.35(m,2H,CH 2),0.93(t,J＝7.2Hz,3H,CH 3).
操作同实施例25。PdCl 2(0.09g,0.5063mmol),(S)-L4c(1.4634g,1.2151mmol),PPh 3(1.3287g,5.0631mmol),(PhO) 2PO 2H(1.268g,5.0631mmol),(S)-1a(5.1163g,25.31mmol)，水(9.1162g,506.31mmol)，甲苯(127mL)，在0℃中，反应20小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(R)-2a(4.3055g,74％):固体；96％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(minor)＝8.4min,t R(major)＝10.4min)； 1H NMR(400MHz,CDCl 3):δ＝7.43-7.29(m,4H,Ar-H),7.29-7.21(m,1H,Ar-H),2.33(t,J＝7.6Hz,2H,CH 2),2.19(s,3H,CH 3),1.54-1.41(m,2H,CH 2),1.41-1.28(m,2H,CH 2),0.88(t,J＝7.2Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝212.6,173.1,135.0,128.5,127.5,126.0,105.2,101.8,30.2,28.3,22.2,16.3,13.8.
实施例30
Figure PCTCN2019123005-appb-000038
往一个干燥的Schlenk反应管中加入(R)-2a(0.1153g,0.5mmol,98％ee)后， 将反应管带入手套箱称取CuCl(0.0023g,0.02mmol)，带出手套箱后在氩气保护下加入甲醇(5mL)，并将反应管置于预先加热至60℃的油浴中，搅拌，10小时后薄层层析(TLC)监测反应完成。将甲醇旋干后，加入乙酸乙酯(5mL)将产物溶解，快速过滤硅胶短柱(3cm)，乙酸乙酯洗脱(15mL)，浓缩，快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝50/1/1)得到手性环状产物(S)-3(0.1097g,95％):油状物；98％ee(HPLC conditions:AD-H column,hexane/i-PrOH＝100/1,0.9mL/min,λ＝214nm,t R(minor)＝26.8min,t R(major)＝29.9min)；[α] D 27＝-167.8(c＝1.15,CHCl 3)； 1H NMR(400MHz,CDCl 3):δ＝7.44-7.26(m,5H,Ar-H),7.23(s,1H,＝CH),2.35-2.19(m,2H,CH 2),1.78(s,3H,CH 3),1.60-1.47(m,2H,CH 2),1.43-1.27(m,2H,CH 2),0.92(t,J＝7.4Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝173.1,152.2,140.1,132.2,128.6,127.9,124.6,86.5,29.3,26.7,24.6,22.1,13.6；IR(neat):v＝2957,2929,2865,1751,1448,1258,1039cm -1；MS(70eV,EI)m/z(％):231(M ++1,1.77),230(M +,11.21),187(100)；HRMS calcd for C 15H 18O 2[M +]:230.1307,found:230.1304.
实施例31
Figure PCTCN2019123005-appb-000039
往一个干燥的Schlenk反应管中依次加入(R)-2a(0.1151g,0.5mmol,98％ee)，NBS(0.1075g,0.6mmol)，氯仿(5mL)，并将反应管置于室温中，搅拌，2小时后薄层层析(TLC)监测反应完成。将氯仿旋干后，快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝50/1/1)得到手性环状产物(R)-4(0.1484g,96％):固体；98％ee(HPLC conditions:AD-H column,hexane/i-PrOH＝100/1,0.7mL/min,λ＝214nm,t R(minor)＝11.6min,t R(major)＝12.9min)；[α] D 27＝-149.4(c＝1.30,CHCl 3)。熔点：49.4-49.9℃(石油醚/二氯甲烷)。 1H NMR(400MHz,CDCl 3):δ＝7.44-7.29(m,5H,Ar-H),2.36(t,J＝7.6Hz,2H,CH 2),1.91(s,3H,CH 3),1.65-1.50(m,2H,CH 2),1.44-1.26(m,2H,CH 2),0.93(t,J＝7.4Hz,3H,CH 3)； 13C  NMR(100MHz,CDCl 3):δ＝170.4,150.4,137.2,131.2,128.8,128.6,125.5,88.1,29.0,24.8,23.8,22.3,13.7；IR(neat):v＝2957,2930,2862,1757,1650,1448,1247,1042cm -1；MS(ESI)m/z(％):311(M( 81Br)+H +),309(M( 79Br)+H +)；Anal.Calcd.for C 15H 17BrO 2:C 58.27,H 5.54；found:C 58.18,H 5.56.
实施例32
Figure PCTCN2019123005-appb-000040
往一个干燥的Schlenk反应管中依次加入(R)-2a(0.1152g,0.5mmol,98％ee)，PdCl 2(0.0044g,0.025mmol)，烯丙基溴(260uL,d＝1.398g/mL,0.3635g,3.0mmol)，在氩气保护下加入DMA(N,N-二甲基乙酰胺)(5mL)，并将反应管置于预先加热至50℃的油浴中，搅拌，20小时后薄层层析(TLC)监测反应完成。加入水(5mL)淬灭反应，水相用乙醚萃取(5mL x 3)，合并有机相，分出后无水硫酸钠干燥。过滤，浓缩，快速硅胶柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝50/1/1)得到手性环状产物(R)-5(0.1127g,83％):油状物；97％ee(HPLC conditions:IF column,hexane/i-PrOH＝95/5,1.0mL/min,λ＝214nm,t R(major)＝14.0min,t R(minor)＝15.7min)；[α] D 27＝-193.6(c＝1.27,CHCl 3)； 1H NMR(400MHz,CDCl 3):δ＝7.45-7.23(m,5H,Ar-H),5.58-5.38(m,1H,＝CH),5.02(d,J＝4.4Hz,1H,one proton of＝CH 2),4.98(s,1H,one proton of＝CH 2),2.99(dd,J 1＝15.6Hz,J 2＝6.0Hz,1H,one proton of CH 2),2.86(dd,J 1＝15.6Hz,J 2＝7.2Hz,1H,one proton of CH 2),2.30(t,J＝7.8Hz,2H,CH 2),1.84(s,3H,CH 3),1.60-1.48(m,2H,CH 2),1.43-1.28(m,2H,CH 2),0.93(t,J＝7.2Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝173.8,164.2,138.3,132.3,128.5,128.3,127.5,125.4,117.5,87.8,30.6,30.0,23.4,23.2,22.6,13.7；IR(neat):v＝2954,2930,2865,1748,1448,1257,1207,1038cm -1；MS(70eV,EI)m/z(％):271(M ++1,3.32),270(M +,16.82),229(100)；HRMS calcd for C 18H 22O 2[M +]:270.1620,found:270.1622.
实施例33
Figure PCTCN2019123005-appb-000041
往一个干燥的Schlenk反应管中加入(R)-2a(0.1152g,0.5mmol,98％ee)和PdCl 2(0.0045g,0.025mmol)，置换三次氩气后，加入联烯醇(0.0875g,1.25mmol)，TFA(三氟乙酸)(30uL,d＝1.535g/mL,0.0456g,0.4mmol)和DMA(N,N-二甲基乙酰胺)(5mL)，并将反应管置于预先加热至30℃的油浴中，搅拌，8小时后薄层层析(TLC)监测反应完成。加入水(5mL)淬灭反应，水相用乙醚萃取(5mL x3)，合并有机相，饱和食盐水洗一次(5mL)，分出后无水硫酸钠干燥。过滤，浓缩，快速硅胶柱层析(淋洗剂：石油醚(60～90℃)/乙酸乙酯＝50/1)得到手性环状产物(R)-6(0.1113g,79％):油状物；97％ee(HPLC conditions:AD-H column,hexane/i-PrOH＝95/5,1.0mL/min,λ＝214nm,t R(minor)＝6.8min,t R(major)＝7.4min)；[α] D 28＝-176.7(c＝1.0,CHCl 3)； 1H NMR(400MHz,CDCl 3):δ＝7.40-7.17(m,5H,Ar-H),6.28(dd,J 1＝17.4Hz,J 2＝10.6Hz,1H,＝CH),5.27(s,1H,one proton of＝CH 2),5.00(d,J＝10.4Hz,1H,＝CH 2),4.74(d,J＝17.6Hz,1H,＝CH 2),4.47(s,1H,one proton of＝CH 2),2.26-2.07(m,2H,CH 2),1.84(s,3H,CH 3),1.58-1.42(m,2H,CH 2),1.35-1.21(m,2H,CH 2),0.87(t,J＝7.2Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝173.3,163.3,138.7,138.3,135.8,128.6,128.3,128.1,125.4,120.1,117.2,88.0,29.7,24.3,24.0,22.5,13.7；IR(neat):v＝2955,2865,1753,1450,1221,1040cm -1；MS(70eV,EI)m/z(％):283(M ++1,1.95),282(M +,9.60),91(100)；HRMS calcd for C 19H 22O 2[M +]:282.1614,found:282.1614.
实施例34
Figure PCTCN2019123005-appb-000042
往一个干燥的Schlenk反应管中依次加入(R)-2a(0.1151g,0.5mmol,98％ee)，K 2CO 3(0.1034g,0.75mmol)，DMF(N,N-二甲基甲酰胺)(2.5mL)，将反应管置于 -5℃冷浴后加入CH 3I(碘甲烷)(47μL,d＝2.28g/mL,0.1061g,0.75mmol)，反应在-5℃冷浴中搅拌，1.5小时后薄层层析(TLC)监测反应完成。加入水(10mL)淬灭反应，水相用乙醚萃取(10mL x 3)，合并有机相，饱和氯化铵水溶液洗一次(10mL)，饱和食盐水洗一次(10mL)，分出后无水硫酸钠干燥。过滤，浓缩，快速硅胶柱层析(淋洗剂：石油醚(60～90℃)/乙酸乙酯＝20/1)得到油状手性联烯酸酯S1，S1直接用于下一步反应。往一个干燥的Schlenk反应管中加入上一步所得的全部S1和甲苯(5mL)，将反应管置于-78℃冷浴后逐滴滴入DIBAL-H(二异丁基氢化铝)(1.05mL,1.0M in Hexane,1.05mmol)，反应在-78℃冷浴中搅拌，4小时后薄层层析(TLC)监测反应完成。在-78℃下加入甲醇(5mL)淬灭反应，将反应管提出冷浴，恢复室温后，加入水(10mL)和1mol/L盐酸水溶液(10mL)，水相用乙醚萃取(10mL x 3)，合并有机相，饱和食盐水洗一次(10mL)，分出后无水硫酸钠干燥。过滤，浓缩，快速硅胶柱层析(淋洗剂：石油醚(60～90℃)/乙酸乙酯＝20/1)得到手性联烯醇(R)-7(0.0834g,77％):油状物；97％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(minor)＝8.5min,t R(major)＝11.2min)；[α] D 23＝+62.0(c＝1.01,CHCl 3)； 1H NMR(400MHz,CDCl 3):δ＝7.40(d,J＝7.6Hz,2H,Ar-H),7.31(t,J＝7.6Hz,2H,Ar-H),7.20(t,J＝7.2Hz,1H,Ar-H),4.27-3.99(m,2H),2.22-2.02(m,5H,CH 2 and CH 3),1.59(s,1H,OH),1.53-1.42(m,2H,CH 2),1.42-1.28(m,2H,CH 2),0.89(t,J＝7.2Hz,3H,CH 3)； 13C NMR(100MHz,CDCl 3):δ＝199.0,137.5,128.3,126.7,125.6,108.0,104.8,63.2,29.9,29.4,22.5,17.4,13.9；IR(neat):v＝3315,2954,2925,2858,1948,1597,1462,1067,1024cm -1；MS(70eV,EI)m/z(％):216(M +,1.40),143(100)；HRMS calcd for C 15H 20O[M +]:216.1509,found:216.1512.
实施例35
Figure PCTCN2019123005-appb-000043
操作同实施例1。[PdCl(π-allyl)] 2(0.0015g,0.004mmol)，(R)-L4c(0.0148g,0.012mmol)，PPh 3(0.0105g,0.04mmol)，(PhO) 2PO 2H(0.001g,0.004mmol)，(±)-1a(0.0432g,1mmol)，水(72μL,d＝1.0g/mL,0.072g,4mmol)，甲苯(1mL)，在25℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2a(0.0167g,44％):油状物；85％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.4min,t R(minor)＝9.4min)。
实施例36
Figure PCTCN2019123005-appb-000044
操作同实施例1。Pd(PPh 3) 4(0.0045g,0.004mmol)，(R)-L4c(0.0143g,0.012mmol)，(PhO) 2PO 2H(0.0011g,0.004mmol)，(±)-1a(0.0406g,0.2mmol)，水(72μL,d＝1.0g/mL,0.072g,4mmol)，甲苯(1mL)，在25℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2a(0.0203g,44％):油状物；63％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.4min,t R(minor)＝9.3min)。
实施例37
Figure PCTCN2019123005-appb-000045
操作同实施例1。Pd 2(dba) 3·CHCl 3(0.0045g,0.004mmol)，(R)-L4c(0.0143g,0.012mmol)，PPh 3(0.0108g,0.04mmol)，(PhO) 2PO 2H(0.0012g,0.004mmol)，(±)-1a(0.0412g,0.2mmol)，水(72μL,d＝1.0g/mL,0.072g,4mmol)，甲苯(1mL)，在25℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2a(0.0188g,40％):油状物；86％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.6min,t R(minor)＝9.4min)。
实施例38
Figure PCTCN2019123005-appb-000046
操作同实施例1。PdCl 2(0.0015g,0.004mmol)，(R)-L4c(0.0146g,0.012mmol)，P(2-furyl) 3(0.0096g,0.04mmol)，(PhO) 2PO 2H(0.001g,0.004mmol)，(±)-1a(0.0409g,1mmol)，水(72μL,d＝1.0g/mL,0.072g,4mmol)，甲苯(1mL)，在25℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2a(0.0256g,55％):油状物；65％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.5min,t R(minor)＝9.7min)。
实施例39
Figure PCTCN2019123005-appb-000047
操作同实施例1。PdCl 2(0.0016g,0.004mmol)，(R)-L4c(0.0143g,0.012mmol)，P(2-MeC 6H 4) 3(0.0122g,0.04mmol)，(PhO) 2PO 2H(0.0011g,0.004mmol)，(±)-1a(0.0411g,1mmol)，水(72μL,d＝1.0g/mL,0.072g,4mmol)，甲苯(1mL)，在25℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2a(0.0286g,61％):油状物；40％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.5min,t R(minor)＝9.7min)。
实施例40
Figure PCTCN2019123005-appb-000048
操作同实施例1。PdCl 2(0.0015g,0.004mmol)，(R)-L4c(0.0148g,0.012mmol)，P(3-MeC 6H 4) 3(0.0129g,0.04mmol)，(PhO) 2PO 2H(0.0011g,0.004mmol)，(±)-1a(0.0422g,1mmol)，水(72μL,d＝1.0g/mL,0.072g,4mmol)，甲苯(1mL)，在25℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2a(0.0226g,47％):油状物；66％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.4min,t R(minor)＝9.5min)。
实施例41
Figure PCTCN2019123005-appb-000049
操作同实施例1。PdCl 2(0.0015g,0.004mmol)，(R)-L4c(0.0145g,0.012mmol)，P(4-MeC 6H 4) 3(0.0129g,0.04mmol)，(PhO) 2PO 2H(0.0011g,0.004mmol)，(±)-1a(0.0425g,1mmol)，水(72μL,d＝1.0g/mL,0.072g,4mmol)，甲苯(1mL)，在25℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2a(0.0218g,45％):油状物；80％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.5min,t R(minor)＝9.5min)。
实施例42
Figure PCTCN2019123005-appb-000050
操作同实施例1。PdCl 2(0.0016g,0.004mmol)，(R)-L4c(0.0144g,0.012mmol)，P(4-MeOC 6H 4) 3(0.0149g,0.04mmol)，(PhO) 2PO 2H(0.0011g,0.004mmol)，(±)-1a(0.0416g,1mmol)，水(72μL,d＝1.0g/mL,0.072g,4mmol)，甲苯(1mL)，在25℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2a (0.0128g,27％):油状；68％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.6min,t R(minor)＝9.4min)。
实施例43
Figure PCTCN2019123005-appb-000051
操作同实施例1。PdCl 2(0.0016g,0.004mmol)，(R)-L4c(0.0145g,0.012mmol)，P(3,5-CF 3C 6H 3) 3(0.0271g,0.04mmol)，(PhO) 2PO 2H(0.0012g,0.004mmol)，(±)-1a(0.0413g,1mmol)，水(72μL,d＝1.0g/mL,0.072g,4mmol)，甲苯(1mL)，在25℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2a(0.0071g,15％):油状；92％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.7min,t R(minor)＝9.6min)。
实施例44
Figure PCTCN2019123005-appb-000052
操作同实施例1。PdCl 2(0.0016g,0.004mmol)，(R)-L4c(0.0145g,0.012mmol)，PPh 3(0.0105g,0.04mmol)，有机磷酸(S)-1A(0.0017g,0.004mmol)，(±)-1a(0.0397g,1mmol)，水(72μL,d＝1.0g/mL,0.072g,4mmol)，甲苯(1mL)，在25℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2a(0.0226g,50％):油状物；70％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.6min,t R(minor)＝9.6min)。
实施例45
Figure PCTCN2019123005-appb-000053
操作同实施例1。PdCl 2(0.0015g,0.004mmol)，(R)-L4c(0.0143g,0.012mmol)，PPh 3(0.0106g,0.04mmol)，有机磷酸(R)-1A(0.0014g,0.004mmol)，(±)-1a(0.041g,1mmol)，水(72μL,d＝1.0g/mL,0.072g,4mmol)，甲苯(1mL)，在25℃中，反应18小时。快速柱层析(淋洗剂：石油醚(60～90℃)/乙醚/二氯甲烷＝30/1/1，石油醚(60～90℃)/乙酸乙酯＝8/1)得到手性联烯酸产物(S)-2a(0.0229g,49％):油状物；61％ee(HPLC conditions:AS-H column,hexane/i-PrOH＝98/2,1.0mL/min,λ＝214nm,t R(major)＝6.5min,t R(minor)＝9.4min)。
本领域的普通技术人员都会理解，在本发明的保护范围内，对于上述实施例进行修改、添加和替换都是可行的，其都没有超出本发明的保护范围。

Claims (12)

  1. 一种直接构建含有轴手性高光学活性联烯酸类化合物的方法，其特征在于，在钯催化剂、手性双膦配体、单膦配体和有机磷酸的作用下，带有不同取代基的三级炔丙醇与一氧化碳和水，在有机溶剂中通过过渡金属催化发生不对称联烯化反应，一步生成具有轴手性的高光学活性联烯酸类化合物，反应过程如下反应式(I)所示：
    Figure PCTCN2019123005-appb-100001
    其中，R 1为烃基，带有官能团的烃基，苯基，芳基或杂环基；R 2为烃基，带有官能团的烃基，苯基，芳基或者杂环基；R 3为烃基，带有官能团的烃基，苯基，芳基或杂环基；所述芳基是邻、间、对位有给电子或吸电子取代基的苯基，所述杂环基是噻吩基、呋喃基、萘基或吡啶基、或者有给电子或吸电子取代基的噻吩、呋喃、萘或吡啶。
  2. 根据权利要求1所述的直接构建具有轴手性的高光学活性联烯酸类化合物的方法，其特征在于，R 1为C1-C20烃基，末端带有官能团的C1-C20烃基，苯基，芳基或者杂环基；R 2为C1-C10烃基，末端带有官能团的C1-C10烃基，苯基，芳基或者杂环基；R 3为C1-C10烃基，末端带有官能团的C1-C10烃基，苯基、芳基或者杂环基；其中，所述的末端带有官能团的C1-C20烃基或末端带有官能团的C1-C10烃基中，所述官能团选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、酰胺基、卤素、羧基、氰基；所述芳基是邻、间、对位带有吸电子或给电子取代的苯基，所述杂环基是噻吩基、呋喃基、萘基或吡啶基、或者有吸电子或给电子取代基的噻吩、呋喃、萘或吡啶，所述吸电子取代基包括卤素、硝基、酯基、羧基、酰基、酰胺基、氰基，所述给电子取代基包括烷基、烯基、苯基、烃氧基、羟基、氨基。
  3. 根据权利要求1所述的直接构建具有轴手性的高光学活性联烯酸类化合物的方法，其特征在于，所述方法包括以下步骤：
    1)向干燥的反应管中依次投入钯催化剂、手性双膦配体、单膦配体和有机磷酸，将反应管用橡皮塞塞好后，连接真空泵，在氩气氛围下置换氩气，加入官能化三 级炔丙醇、水，加入一定体积的有机溶剂；将反应管置于液氮浴中冷冻，插上一氧化碳气球后，在一氧化碳氛围下置换一氧化碳进入反应体系，冻抽完后待反应体系恢复室温融化后，将反应管置于预先设定到-20-60℃的低温浴或油浴中，搅拌4-36小时；其中，所述一定体积的有机溶剂是指以式(1)所示的官能化三级炔丙醇的用量为基准，所述有机溶剂的用量为1.0-10.0mL/mmol；
    2)待步骤1)反应完全后，将反应管提出低温浴，恢复室温后，向反应管中加入一定体积的乙酸乙酯，所得混合液用硅胶短柱过滤，并用一定量的乙酸乙酯洗涤后，浓缩，快速柱层析得具有轴手性的高光学活性联烯酸类化合物；其中，所述一定体积的乙酸乙酯是指以式(1)所示的官能化三级炔丙醇的用量为基准，所述乙酸乙酯的用量为1.0-100mL/mmol。
  4. 根据权利要求1-3之任一项所述的直接构建具有轴手性的高光学活性联烯酸类化合物的方法，其特征在于，所述的钯催化剂为二(烯丙基氯化钯)，四(三苯基膦)钯，三(二亚苄基丙酮)二钯，二(肉桂基氯化钯)，二(二亚苄基丙酮)一钯，氯化钯，醋酸钯，二(三苯基膦)氯化钯，二(乙腈)氯化钯中的任意一种或多种。
  5. 根据权利要求1-3之任一项所述的直接构建具有轴手性的高光学活性联烯酸类化合物的方法，其特征在于，所述的手性双膦配体选自以下结构的(R)-L1～(R)-L4及其对映异构体(S)-L1～(S)-L4中的一种或多种；其中，Ar为苯基、芳基或者杂环基，所述芳基是邻、间、对位有烃基或烃氧基取代的苯基；所述杂环基是噻吩、呋喃或吡啶及其有烃基或烃氧基取代的噻吩、烃基或烃氧基取代的呋喃或烃基或烃氧基取代的吡啶；
    Figure PCTCN2019123005-appb-100002
  6. 根据权利要求5所述的直接构建具有轴手性的高光学活性联烯酸类化合物的方法，其特征在于，所述的手性双膦配体选自(R)-L4及其对映异构体(S)-L4，所述(R)-L4的结构如下所示：其中，Ar为3,5-二烷基-4-烷氧基苯基、3,5-二烷基苯 基或苯基；
    Figure PCTCN2019123005-appb-100003
  7. 根据权利要求1-3之任一项所述的直接构建具有轴手性的高光学活性联烯酸类化合物的方法，其特征在于，所述的单膦配体选自三丁基膦，三环己基膦，三苯基膦，三(邻甲基苯基)膦，三(间甲基苯基)膦，三(对甲基苯基)膦，三(对甲氧基苯基)膦，三(3,5-二三氟甲基苯基)膦，三呋喃基膦中的任意一种或多种；和/或，所述的有机溶剂选自N-甲基吡咯烷酮，1,4-二氧六环，四氢呋喃，乙腈，甲基叔丁基醚、氯苯、甲苯、三氟甲苯、二氯甲烷、1,1-二氯乙烷、1,2-二氯乙烷、氯仿、乙酸中的任意一种或多种。
  8. 根据权利要求1-3之任一项所述的直接构建具有轴手性的高光学活性联烯酸类化合物的方法，其特征在于，所述的有机磷酸选自有机磷酸1，有机磷酸2，有机磷酸3中的任意一种或多种，其结构如下所示；其中，R 1为氢、C1～C6的烃基、苯基或芳基，所述芳基是邻、间、对位有C1～C6烃基取代的苯基；R 2为C1～C6的烃基、苯基或芳基，所述芳基是邻、间、对位有C1～C6烃基取代的苯基，
    Figure PCTCN2019123005-appb-100004
  9. 根据权利要求1所述的直接构建具有轴手性的高光学活性联烯酸类化合物的方法，其特征在于，所述式(I)带有不同取代基的三级炔丙醇(±1)、水、钯催化剂、手性双膦配体、单膦配体和有机磷酸的摩尔比为1.0：(1.0-30.0)：(0.005-0.1)：(0.005-0.1)：(0.01-0.3)：(0.01-0.3)；和/或，所述的反应温度为-20-60℃；和/或，所述的有机溶剂的用量为1.0-10.0mL/mmol，以式(I)所示的 官能化三级炔丙醇(±1)的用量为基准。
  10. 一类具有轴手性的高光学活性联烯酸类化合物，其特征在于，其结构如下(R)-2，(S)-2所示：
    Figure PCTCN2019123005-appb-100005
    其中，R 1为烃基，带有官能团的烃基，苯基，芳基或杂环基；R 2为烃基，带有官能团的烃基，苯基，芳基或者杂环基；R 3为烃基，带有官能团的烃基，苯基，芳基或杂环基；所述芳基是邻、间、对位有给电子或吸电子取代基的苯基，所述杂环基是噻吩基、呋喃基、萘基或吡啶基、或者有给电子或吸电子取代基的噻吩、呋喃、萘或吡啶。
  11. 根据权利要求10所述的具有轴手性的高光学活性联烯酸类化合物，其特征在于，R 1为C1-C20烃基，末端带有官能团的C1-C20烃基，苯基，芳基或者杂环基；R 2为C1-C10烃基，末端带有官能团的C1-C10烃基，苯基，芳基或者杂环基；R 3为C1-C10烃基，末端带有官能团的C1-C10烃基，苯基、芳基或者杂环基；其中，所述的末端带有官能团的C1-C20烃基或末端带有官能团的C1-C10烃基中，所述官能团选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、酰胺基、卤素、羧基、氰基；所述芳基是邻、间、对位带有吸电子或给电子取代的苯基，所述杂环基是噻吩基、呋喃基、萘基或吡啶基、或者有吸电子或给电子取代基的噻吩、呋喃、萘或吡啶，所述吸电子取代基包括卤素、硝基、酯基、羧基、酰基、酰胺基、氰基，所述给电子取代基包括烷基、烯基、苯基、烃氧基、羟基、氨基。
  12. 根据权利要求10或11所述的具有轴手性的高光学活性联烯酸类化合物在制备含有四取代手性季碳中心的γ-丁内酯类化合物、四取代联烯醇化合物中的应用。
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