CN106866443A - Chiral beta-diaryl-alpha-amino acid derivatives and application thereof - Google Patents

Chiral beta-diaryl-alpha-amino acid derivatives and application thereof Download PDF

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CN106866443A
CN106866443A CN201510909172.5A CN201510909172A CN106866443A CN 106866443 A CN106866443 A CN 106866443A CN 201510909172 A CN201510909172 A CN 201510909172A CN 106866443 A CN106866443 A CN 106866443A
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diaryl
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CN106866443B (en
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邓卫平
何福生
金京海
杨忠涛
李丛杉
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East China University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D307/38—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—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
    • 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

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Abstract

The present invention relates to a kind of chiral beta-diaryl-alpha-amino acid derivatives and application thereof.Described beta-diaryl-alpha-amino acid derivatives are compound shown in formula I (concrete structure is referring to specification).Compound shown in the formula I can be used for compound shown in a of formula I (concrete structure is referring to specification).The present invention can conveniently and efficiently obtain a series of key intermediates (compound shown in formula I) for preparing chiral beta-diaryl-alpha-amino acid derivatives (compound shown in a of formula I) with glycinate schiff bases simple and easy to get and to methylene benzoquinones as initiation material.The present invention is easy to get with raw material, and preparation condition is gentle, the advantages of the yield and purity high of product.

Description

Chiral beta-diaryl-alpha-amino acid derivatives and application thereof
Technical field
The present invention relates to a kind of non-natural alpha-amino acid and application thereof, specifically, it is related to a kind of chiral beta-diaryl-a-amino acid Derivative and its application in the β chiral beta-diaryl-alpha-amino acid derivatives for different aryl as substitution base are prepared.
Background technology
Non-natural alpha-amino acid is the important composition unit of polypeptide, protein, natural products and many bioactive molecules, while They are also widely used in chiral catalyst design and fully synthetic field.Therefore, the pure non-natural alpha-amino acid of synthesizing optical Cause the broad interest of chemists.[document 1：a)Unnatural Amino Acids:Methods and Protocols(Eds.:L. Pollegioni,S.Servi),Springer,New York,2012；b)C.Nájera,J.M.Sansano,Chem.Rev.2007,107, 4584；c)H.Vogt,S.Org.Biomol.Chem.2007,5,406；d)A.F.M.Noisier,M.A.Brimble, Chem.Rev.2014,114,8775；e)A.E.Metz,M.C.Kozlowski,J.Org.Chem.2015,80,1.]
β, beta-diaryl alanine class compound is the significant construction unit in medicine and natural product chemistry of a class. [document 2：a)D.E.Patterson,J.D.Powers,M.LeBlanc,T.Sharkey,E.Boehler,E.Irdam,M.H. Osterhout,Org.Process Rev.Dev.2009,13,900；b)M.Nilsson,M.M.Ivarsson,J. Gottfries,Y.Xue,S.Hansson,R.Isaksson,T.Fex,J.Med.Chem.2009,52,2708；c)J.A. McCauley,S.Crane,C.Beaulieu,D.J.Bennett,C.J.Bungard,R.K.Chang,T.J.Greshock,L.Hao, K.Holloway,J.J.Manikowski,D.Mckay,C.Molinaro,O.M.Moradei,P.G.Nantermet,C. Nadeau,S.Tummanapalli,W.Shipe,S.K.Singh,V.L.Truong,V.Sivalenka,P.D.Williams,C.M. Wiscount,WO 2014043019 A1,2014.].At present, on β, the big portion of synthetic method of beta-diaryl alanine class compound It is divided to and concentrates on product at β containing two reports of identical aryl substituent, and realizes the beta-diaryl containing β-Stereocenter The efficient asymmetric syntheses of-a-amino acid remains huge challenge.
In recent years, methods of some synthesis beta-diaryl-a-amino acids have been disclosed successively, including phenylalanine derivative is non- Enantioselectivity SN1 reaction, aziridine open loop, the alkylated reaction of chiral auxiliary induction, the alanine of part control spread out Biological β-C-H arylations and asymmetric hydrogenation etc..[document 3：a)B.V.S.Reddy,L.R.Reddy,E.J.Corey,Org. Lett.2006,8,3391；b)Y.Sui,L.Liu,J.-L.Zhao,D.Wang,Y.-J.Chen,Tetrahedron 2007,63,5173； c)J.Wang,S.Zhou,D.Lin,X.Ding,H.Jiang,H.Liu,Chem.Commun.2011,47,8355；d)D. Wilcke,E.Herdtweck,T.Bach,Chem.Asian.J.2012,7,1372；e)L.D.Tran,O.Daugulis,Angew. Chem.Int.Ed.2012,51,5188；f)J.He,S.Li,Y.Deng,H.Fu,B.N.Laforteza,J.E.Spangler,A. Homs,J.-Q.Yu,Science 2014,343,1216；g)G.Chen,T.Shigenari,P.Jain,Z.Zhang,Z.Jin,J.He, S.Li,C.Mapeli,M.M.Miller,M.A.Poss,P.M.Scola,K.-S.Y,J.-Q.Yu,J.Am.Chem.Soc.2015, 137,3338；h)C.Molinaro,J.P.Scott,M.Shevlin,C.Wise,A.Ménard,A.Gibb,E.M.Junker,D. Lieberman,J.Am.Chem.Soc.2015,137,999.]。
But exist needs extra blocking group, homing device or part, palladium catalyst consumption be big, substrate in the prior art Expand that scope is limited or the defect such as operation complexity.Therefore this area in the urgent need to it is a kind of easy, efficiently, high atom economy, The method for preparing non-natural chirality beta-diaryl-alpha-amino acid derivatives of cis-selectivity high, enantioselectivity high.
The content of the invention
It is an object of the present invention to disclose a kind of novel beta-diaryl-alpha-amino acid derivatives of structure.
Beta-diaryl-alpha-amino acid derivatives of the present invention, it is compound shown in formula I：
In formula I, R1And R2It is respectively and independently selected from：C1~C4It is a kind of in straight or branched alkyl；R3For 5~6 yuan of aromatic ring yls or The aromatic heterocyclic of oxygen-containing (O) or sulphur (S), 5~6 yuan of substituted aromatic ring yls or the aromatic heterocyclic containing O or S, or naphthyl； And β upper two substitution base is different；
Wherein, the substitution base of 5~6 yuan of substituted aromatic ring yls or aromatic heterocyclic is selected from：Halogen (F, Cl, Br or I), C1~ C3Straight or branched alkyl, C1~C3In straight or branched alkoxyl or phenyl one or two or more kinds (containing two kinds).
Another object of the present invention is to disclose a kind of purposes of compound shown in formula I, i.e., compound is preparing β shown in formula I (compound is preparation i.e. shown in formula I for application in chiral beta-diaryl-alpha-amino acid derivatives for different aryl as substitution base β is key intermediate of the different aryl as the chiral beta-diaryl-alpha-amino acid derivatives of substitution base).
Wherein described β is that different aryl are chemical combination shown in a of formula I as the chiral beta-diaryl-alpha-amino acid derivatives of substitution base Thing：
In a of formula I, R1And R3Text as defined above is described identical, R4It is hydrogen (H) or C1~C3Straight or branched alkyl, and β upper two substitution base is different.
The method of compound, comprises the following steps shown in a of formula I that the present invention is provided：
(1) under the compound, ferrocene class part and alkali existence condition for having inert gas, cupric or silver, by shownization of formula II Compound and compound shown in formula III react in organic solvent, the step of obtain compound (intermediate) shown in formula I；With
(2) under lewis acid (such as alchlor) and alkali existence condition, compound and iodomethane reaction as shown in formula I, The step of obtaining object (compound shown in a of formula I)；
Wherein, the compound of the cupric or silver is silver acetate, copper acetate, the acetonitrile copper of tetrafluoro boric acid four, the acetonitrile copper of perchloric acid four Or the acetonitrile copper of hexafluorophosphoric acid four, the ferrocene class part is compound shown in formula IV (being abbreviated as " Foxap ")：
R is C1~C4Straight or branched alkyl, phenyl or benzyl (Bn),
The alkali is organic base or inorganic base, R1~R3Text as defined above is described identical, shown in compound shown in formula II and formula III The synthesis of compound is please respectively referring to document：A.Pintér,G.Haberhauer,Eur.J.Org.Chem.2008,2375-2387； W.-D.Chu,L.-F.Zhang,X.Bao,X.-H.Zhao,C.Zeng,J.-Y.Du,G.-B.Zhang,F.-X.Wang,X.-Y. Ma,C.-A.Fan,Angew.Chem.Int.Ed.2013,52,9229；And Richter, D.；Hampel,N.；Singer,T.；Ofial, R.A.；Mayr,H.Eur.J.Org.Chem.2009,3203.
There is above-mentioned technical proposal to understand, the present invention with glycinate schiff bases simple and easy to get and to methylene benzoquinones as initiation material, A series of chiral beta-diaryls with cis-selectivity high and enantioselectivity-a-amino acid can be conveniently and efficiently obtained to derive Thing.
Specific embodiment
In an optimal technical scheme of the invention, R1And R2It is respectively and independently selected from：C1~C4It is a kind of in straight or branched alkyl, R3It is the phenyl or 5 yuan of heteroaryl ring groups containing O or S of 5 yuan of heteroaryl ring groups containing O or S, phenyl, naphthyl, or substitution；
Wherein, the substitution base of the substituted phenyl or 5 yuan of heteroaryl ring groups containing O or S is selected from：Halogen (F, Cl, Br or I), C1~C3Straight or branched alkyl, C1~C3In straight or branched alkoxyl or phenyl one or two or more kinds (containing two kinds)；
Further preferred technical scheme is：R1And R2It is respectively and independently selected from：It is a kind of in methyl, ethyl or the tert-butyl group, R3It is furan Mutter base, thienyl, phenyl, naphthyl, or substitution phenyl or thienyl；
Wherein, the substitution base of substituted phenyl or the thienyl is selected from：F, Br, C1~C3Straight or branched alkoxyl or phenyl In one or two or more kinds (contain two kinds)；
Technical scheme still further preferably is：R1And R2It is respectively and independently selected from：It is a kind of in methyl, ethyl or the tert-butyl group, R3 It is 2- furylsPhenyl, naphthyl, substituted phenyl or thienyl；
Wherein, the substitution base of substituted phenyl or the thienyl is selected from：One kind or two in F, Br, methyl, methoxyl group or phenyl (contain two kinds) more than kind.
In presently preferred technical scheme, compound shown in formula II is 1 with the mol ratio of compound shown in formula III: (1~ 3)。
In another optimal technical scheme of the invention, compound shown in formula II is 1 with the mol ratio of cupric or the compound of silver: (0.005~0.2), compound shown in formula II is 1 with the mol ratio of ferrocene class part: (0.005~0.2).
In another optimal technical scheme of the invention, compound shown in formula II is 1 with the mol ratio of the compound of alkali: (0.01~ 4)。
In another optimal technical scheme of the invention, compound shown in formula II is 1 with the mol ratio of iodomethane: (1~5), more Preferred mol ratio is 1: (2~4).
In another optimal technical scheme of the invention, compound shown in formula II is 1 with the mol ratio of aluminium chloride: (1~20), more Preferred mol ratio is 1: (10~20).
To sum up, the method for compound shown in a of formula of the present invention I, specifically includes following steps：
(1) compound of cupric or silver, ferrocene class part and organic solvent are placed in the reactor with agitating device, Room temperature state is stirred at least 1 hour, and in the reactor, ratio adds compound and alkali shown in formula II as previously described, continues to stir Mix 10 minutes, then in the reactor, ratio adds compound shown in formula III as previously described, is stirred under the conditions of 0 DEG C, adopts Reaction to raw material point being tracked with TLC to disappear, stopping reaction, add diatomite filtering, decompression removal solvent is dissolved the residue in In organic solvent, acid stirring 1-5 hours (hydrolysis) is added, adds saturated sodium bicarbonate solution neutralization reaction liquid, stand a point liquid, Water is mutually extracted with ethyl acetate 3-5 times, after merging organic phase, anhydrous sodium sulfate drying, filtering, decompression removal solvent, silica gel Column chromatography, obtains compound shown in formula I；
(2) compound and organic solvent shown in formula I are placed in the reactor with agitating device, are pressed above in the reactor The ratio adds iodomethane, stirs, and then to the system, ratio adds alchlor as previously described, rises high-temperature to 60 DEG C Continue to stir, TLC tracking reaction to raw material point disappears, and adds the appropriate remaining alchlor of water consumption, stratification, water Mutually it is extracted with ethyl acetate 3-5 times, after merging organic phase, anhydrous sodium sulfate drying, filtering, decompression removal solvent, silicagel column Chromatography, obtains object (compound shown in a of formula I).
Wherein, organic solvent used can be：Tetrahydrofuran, dichloromethane, chloroform, ether, ethyl acetate, the chloroethenes of 1,2- bis- Alkane, Isosorbide-5-Nitrae-dioxane, toluene, acetonitrile or methyl tertiary butyl ether(MTBE), alkali used can be：Triethylamine, diisopropylamine, 1,8- bis- Carbon -7- alkene (DBU) of azabicyclic [5.4.0] 11 or 1,4- diazabicylos [2.2.2] octane (DABCO)；
The carbonate (such as potassium carbonate, sodium carbonate or carbonic acid) of alkali preferred as alkali used, acetate (such as sodium acetate or acetic acid Potassium etc.) or C1~C4Aliphatic alkoxide (such as potassium tert-butoxide).
The method of preparation chirality beta-diaryl-alpha-amino acid derivatives (compound shown in a of formula I) that the present invention is provided, with original Material is easy to get, and preparation condition is gentle, the advantages of product yield high and product purity high.
The present invention is further elaborated below by embodiment, its purpose is only that and is best understood from present disclosure.Therefore, The cited case is not limited the scope of the invention.
Embodiment 1
The preparation of compound shown in the a-1 of formula I：
(1) under nitrogen protection, 0.011 mM of part Ph-Foxap (compounds Ⅳ -1), 0.01 mmoles are added in reaction bulb Your acetonitrile copper of tetrafluoro boric acid four and 5 milliliters of dry toluene, stirs 1 hour at room temperature, adds 0.1 mM of institute of formula II -1 Show compound and 0.2 mM of potassium carbonate, be cooled to 0 DEG C, stir 5 minutes, add 0.11 mM of shownization of formula III -1 Compound, TLC tracking reaction to raw material point is disappeared, and reaction solution is filtered through diatomite, decompression removal solvent, residue tetrahydrochysene Furans dissolves, and adds 1 milliliter of aqueous hydrochloric acid solution of 1M, then adds saturated sodium bicarbonate solution, adjusts pH value of solution>8, Ethyl acetate is extracted, and merges organic phase, and anhydrous sodium sulfate drying, filtering is depressurized and removes solvent, silica gel column chromatography (petroleum ether: Ethyl acetate=4: 1 (v/v)), obtain yellow solid (compound shown in formula I -1)；
(2) compound and tetrahydrofuran shown in formula I -1 are placed in reactor, sequentially add 0.15 mM of potassium tert-butoxide and 0.12 mM of iodomethane, TLC tracking reaction to raw material point disappears.Then 2 mMs of aluminium chloride are added to the system, is raised Temperature continues to stir to reaction and terminates (TLC tracking and monitorings) to 60 DEG C, adds the appropriate remaining aluminium chloride of water consumption, stands Liquid, water is divided mutually to be extracted with ethyl acetate 3-5 times, after merging organic phase, anhydrous sodium sulfate drying, filtering, decompression removal solvent, Silica gel column chromatography (dichloromethane: methyl alcohol=95: 5 (v/v)), obtains object (compound shown in the a-1 of formula I).White solid, m.p.:113 DEG C, its separation yield is 77%.
1H NMR(400MHz,CDCl3)δ1.49(bs,2H),3.52(s,3H),3.75(s,3H),3.76(s,3H),3.77(s, 3H), 4.17 (d, J=9.1Hz, 1H), 4.59 (d, J=9.1Hz, 1H), 6.43 (d, J=2.4Hz, 1H), 6.47 (dd, J=8.4 Hz, 2.4Hz, 1H), 6.78 (d, J=8.5Hz, 2H), 7.16 (d, J=8.4Hz, 1H), 7.22 (d, J=8.7Hz, 2H)；
13C NMR(100MHz,CDCl3)δ47.8,51.7,55.1,55.3,55.4,58.3,98.8,104.3,113.5,121.5, 129.1,129.2,133.9,158.0,158.4,159.5,175.4；
HRMS(ESI,m/z):Theoretical value (Calcd for):C19H24NO5[M+H]+:346.1649, experiment value (found): 346.1655。
Embodiment 2
The preparation of compound shown in the a-2 of formula I：
Divided by chemical combination beyond the region of objective existence, other conditions and step and embodiment shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -2 1 is similar, obtains compound (yellow oil) shown in Formulas I a-2, yield 90%.
1H NMR(400MHz,CDCl3) δ 1.59 (bs, 2H), 2.41 (d, J=0.9Hz, 3H), 3.54 (s, 3H), 3.77 (s, 3 ), H 4.00 (d, J=7.7Hz, 1H), 4.41 (d, J=7.7Hz, 1H), 6.57-6.58 (m, 1H), 6.71 (d, J=3.4Hz, 1H), 6.81–6.85(m,2H),7.26–7.30ppm(m,2H)；
13C NMR(100MHz,CDCl3)δ15.3,51.3,51.9,55.2,60.2,113.8,124.7,125.7,129.1,133.1, 139.2,141.2,158.5,174.3；
HRMS(ESI,m/z):Theoretical value (Calcd for):C16H20NO3S[M+H]+:306.1158, experiment value (found): 306.1154。
Embodiment 3
The preparation of compound shown in the a-3 of formula I：
Divided by chemical combination beyond the region of objective existence, other conditions and step and embodiment shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -3 1 is similar, obtains compound (white solid), m.p. shown in Formulas I a-3:120 DEG C, yield 98%.
Wherein, the ee of compound shown in Formulas I -3>99%, [α]D 25=+10.4 (c 0.85, CHCl3)；
1H NMR(400MHz,CDCl3) δ 7.39 (d, J=8.3Hz, 2H), 7.23 (d, J=8.3Hz, 2H), 7.01 (s, 2H), 5.12(s,1H),4.11(s,2H),3.55(s,3H),1.49(s,2H),1.40(s,18H)；
13C NMR(100MHz,CDCl3)δ174.9,153.0,141.2,136.3,131.5,130.1,130.0,125.1,120.6, 59.2,56.0,52.0,34.5,30.4；
HRMS(ESI,m/z):Theoretical value (Calcd for)：C24H33BrNO3[M+H]+:462.1644, experiment value (found)： 462.1639；
HPLC (Chiralpak AD-H, n-hexane/i-propanol=100/5,0.8mL/min, 220nm) tR=10.26min, 16.18min。
Compound shown in Formulas I a-3：
1H NMR(400MHz,CDCl3) δ 7.39 (d, J=8.3Hz, 2H), 7.22 (d, J=8.3Hz, 2H), 7.18 (d, J= 8.3Hz, 2H), 6.85 (d, J=8.3Hz, 2H), 4.00 (d, J=9.2Hz, 1H), 3.96 (d, J=9.2Hz, 1H), 3.81 (s, 3H),1.58(s,2H),1.40(s,18H)；
13C NMR(100MHz,CDCl3)δ171.5,158.1,139.5.6,132.8,132.1,130.4,120.6,114.8,81.4, 64.5,55.8,51.9,43.8；
HRMS(ESI,m/z):Theoretical value (Calcd for):C17H18BrNO3[M+H]+:364.2113, experiment value (found): 364.2107。
Embodiment 4
The preparation of compound shown in the a-4 of formula I：
Divided by chemical combination beyond the region of objective existence, other conditions and step and embodiment shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -4 1 is similar, obtains compound (white solid), m.p. shown in the a-4 of formula I:108-109 DEG C, yield 85%.
Wherein, compound shown in formula I -4：ee>99%, [α]D 25=+26.4 (c 0.84, CHCl3)；
1H NMR(400MHz,CDCl3) δ 7.33 (d, J=7.5Hz, 2H), 7.26 (dd, J=8.9,6.2Hz, 2H), 7.17 (t, J =7.2Hz, 1H), 7.07 (s, 2H), 5.10 (s, 1H), 4.16 (d, J=8.9Hz, 1H), 4.11 (d, J=8.9Hz, 1H), 3.50 (s, 3H),1.49(s,2H),1.41(s,18H)；
13C NMR(100MHz,CDCl3)δ175.1,152.9,142.0,136.1,130.7,128.5,128.2,126.7,125.2, 59.5,57.0,51.9,34.5,30.4；
HRMS(ESI,m/z):Calcd for C24H34NO3[M+H]+:384.2539,found:384.2539；
HPLC (Chiralpak AD-H, n-hexane/i-propanol=100/1,0.8mL/min, 220nm) tR=22.44min, 24.45min。
Compound shown in the a-4 of formula I：
1H NMR(400MHz,CDCl3) δ 7.29-7.22 (m, 4H), 7.19 (s, 1H), 7.16 (d, J=7.5Hz, 2H), 7.01 - 6.96 (m, 2H), 4.64 (d, J=8.9Hz, 1H), 3.92 (d, J=8.9Hz, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 2.16 (s, 2H)；
13C NMR(100MHz,CDCl3)δ172.6,157.1,142.1,134.6,130.4,130.4,129.4,129.4,129.0, 129.0,127.5,114.3,114.3,58.1,56.0,54.3,52.2；
HRMS(ESI,m/z):Theoretical value (Calcd for):C17H19NO3[M+H]+:286.2539, experiment value (found): 286.2539。
Embodiment 5
The preparation of compound shown in the a-5 of formula I：
Divided by chemical combination beyond the region of objective existence, other conditions and step and embodiment shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -5 1 is similar, obtains compound (yellow solid), m.p. shown in the a-5 of formula I:98-99 DEG C, yield 94%.
Wherein, wherein, compound shown in formula I -5：ee>99%, [α]D 25=+25.0 (c 0.86, CHCl3)；
1H NMR(400MHz,CDCl3) δ 7.63 (d, J=7.8Hz, 1H), 7.51 (d, J=8.0Hz, 1H), 7.28 (d, J= 7.5Hz, 1H), 7.13 (s, 2H), 7.03 (t, J=7.6Hz, 1H), 5.10 (s, 1H), 4.72 (d, J=8.8Hz, 1H), 4.19 (d, J =8.8Hz, 1H), 3.57 (s, 3H), 1.51 (s, 2H), 1.40 (s, 18H)；
13C NMR(100MHz,CDCl3)δ174.5,152.9,141.5,136.1,133.2,129.7,129.0,128.1,127.5, 125.4,125.1,58.9,54.2,52.1,34.5,30.4；
HRMS(ESI,m/z):Calcd for C24H33BrNO3[M+H]+:462.1644,found:462.1649；
HPLC (Chiralpak AD-H, n-hexane/i-propanol=100/5,0.8mL/min, 220nm) tR=9.31min, 10.42min。
Compound shown in the a-5 of formula I：
1H NMR(400MHz,CDCl3) δ 7.41 (d, J=7.8Hz, 1H), 7.33-7.26 (m, 2H), 7.20 (d, J=8.0 Hz, 1H), 7.02 (dd, J=12.3,6.8Hz, 4H), 4.64 (d, J=8.8Hz, 1H), 3.92 (d, J=8.8Hz, 1H), 3.82 (s, 3H),3.78(s,3H),1.50(s,2H)；
13C NMR(100MHz,CDCl3)δ172.6,157.4,140.3,134.9,134.5,131.3,130.3,130.3,128.1, 127.8,122.0,114.2,114.2,59.0,56.0,54.0,52.2；
HRMS(ESI,m/z):Theoretical value (Calcd for):C17H18BrNO3[M+H]+:364.1644, experiment value (found): 364.1649。
Embodiment 6
The preparation of compound shown in the a-6 of formula I：
Divided by chemical combination beyond the region of objective existence, other conditions and step and embodiment shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -6 1 is similar, obtains compound (yellow oil), yield 86% shown in the a-6 of formula I.
Wherein, compound shown in formula I -6：ee>99%, [α]D 25=+22.3 (c 1.06, CHCl3)；
1H NMR(400MHz,CDCl3) δ 7.50 (s, 1H), 7.31 (t, J=6.8Hz, 2H), 7.15 (t, J=7.8Hz, 1H), 7.02(s,2H),5.14(s,1H),4.11(s,2H),3.56(s,3H),1.48(s,2H),1.41(s,18H)；
13C NMR(100MHz,CDCl3)δ174.9,153.1,144.5,136.3,131.5,130.0,129.8,129.8,126.8, 125.3,122.5,59.2,56.2,52.0,34.5,30.4；
HRMS(ESI,m/z):Calcd for C24H33BrNO3[M+H]+:462.1644,found:462.1635；
HPLC (Chiralpak AD-H, n-hexane/i-propanol=100/5,0.6mL/min, 220nm) tR=14.08min, 14.88min。
Compound shown in the a-6 of formula I：
1H NMR(400MHz,CDCl3) δ 7.38 (d, J=15.7Hz, 2H), 7.31 (s, 2H), 7.15 (s, 1H), 7.08 (s, 1H), 7.03(s,2H),4.64(s,1H),3.92(s,1H),3.83(s,3H),3.73(s,3H),1.41(s,2H)；
13C NMR(100MHz,CDCl3)δ172.6,157.1,147.5,134.6,130.6,130.4,130.4,130.0,129.9, 129.5,124.4,114.3,114.3,58.1,56.0,53.7,52.2；
HRMS(ESI,m/z):Theoretical value (Calcd for):C17H18BrNO3[M+H]+:364.1644, experiment value (found): 364.1635。
Embodiment 7
The preparation of compound shown in the a-7 of formula I：
Divided by chemical combination beyond the region of objective existence, other conditions and step and embodiment shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -7 1 is similar, obtains compound (white solid), m.p. shown in the a-7 of formula I:114 DEG C, yield 87%.
Wherein, compound shown in formula I -7：ee>99%, [α]D 25=+24.4 (c 0.99, CHCl3)；
1H NMR(400MHz,CDCl3) δ 7.21 (d, J=7.9Hz, 2H), 7.07 (d, J=4.0Hz, 4H), 5.08 (s, 1H), 4.14 (d, J=8.8Hz, 1H), 4.07 (d, J=8.9Hz, 1H), 3.52 (s, 3H), 2.28 (s, 3H), 1.50 (s, 2H), 1.40 (s, 18H)；
13C NMR(100MHz,CDCl3)δ175.1,152.8,139.0,136.2,136.1,131.0,129.2,128.0,125.2, 59.6,56.7,51.9,34.5,30.4,21.1；
HRMS(ESI,m/z):Calcd for C25H36NO3[M+H]+:398.2695,found:398.2693；
HPLC (Chiralpak AD-H, n-hexane/i-propanol=100/5,0.5mL/min, 220nm) tR=15.41min, 17.76min。
Compound shown in the a-7 of formula I：
1H NMR(400MHz,CDCl3) δ 7.24 (d, J=7.9Hz, 2H), 7.06 (d, J=4.0Hz, 4H), 7.01-6.96 (m, 2H), 4.64 (d, J=8.8Hz, 1H), 3.92 (d, J=8.9Hz, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 2.35-2.29 (s, 3H),2.21(s,2H)；
13C NMR(100MHz,CDCl3)δ172.6,157.1,139.3,137.3,134.6,130.4,130.4,130.3,130.2 129.5,129.5,114.3,114.3,58.1,56.0,54.3,52.2,21.3；
HRMS(ESI,m/z):Theoretical value (Calcd for):C18H21NO3[M+H]+:300.2695, experiment value (found): 300.2693。
Embodiment 8
The preparation of compound shown in the a-8 of formula I：
Divided by chemical combination beyond the region of objective existence, other conditions and step and embodiment shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -8 1 is similar, obtains compound (yellow oil), yield 91% shown in formula I -9.
Wherein, compound shown in formula I -8：ee>99%, [α]D 25=+5.1 (c 0.71, CHCl3)；
1H NMR(400MHz,CDCl3) δ 7.35 (s, 1H), 7.08 (s, 2H), 6.29 (s, 1H), 6.16 (d, J=3.0Hz, 1H), 5.15 (s, 1H), 4.26 (d, J=7.3Hz, 1H), 4.09 (d, J=7.3Hz, 1H), 3.65 (s, 3H), 1.53 (s, 2H), 1.41 (s, 18H)；
13C NMR(100MHz,CDCl3)δ174.5,155.0,153.3,141.7,136.1,127.9,125.5,110.2,107.0, 58.8,52.1,50.3,34.5,30.4；
HRMS(ESI,m/z):Calcd for C22H32NO4[M+H]+:374.2331,found:374.2330；
HPLC (Chiralpak AD-H, n-hexane/i-propanol=100/1,0.6mL/min, 220nm) tR=49.20min, 54.53min。
Compound shown in the a-8 of formula I：
1H NMR(400MHz,CDCl3)δ7.36(s,1H),7.21(s,2H),6.93–6.86(m,2H),6.23(s,1H), 6.15 (d, J=3.0Hz, 1H), 5.10 (d, J=7.3Hz, 1H), 3.92 (d, J=7.3Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H),1.29(s,2H)；
13C NMR(100MHz,CDCl3)δ171.9,158.4,152.7,140.4,130.3,130.3,127.5,114.6,114.6, 111.2,105.4,56.8,56.04,52.2,52.1.
HRMS(ESI,m/z):Theoretical value (Calcd for):C15H17NO4[M+H]+:276.2331, experiment value (found): 276.2330。
Embodiment 9
The preparation of compound shown in the a-9 of formula I：
Divided by chemical combination beyond the region of objective existence, other conditions and step and embodiment shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -9 1 is similar, obtains compound (white solid), m.p. shown in the a-9 of formula I：70-72 DEG C, yield 86%.
Wherein, compound shown in formula I -9：ee>99%, [α]D 25=+11.9 (c 0.91, CHCl3)；
1H NMR(400MHz,CDCl3) δ 8.17 (d, J=8.3Hz, 1H), 7.84-7.78 (m, 2H), 7.72 (d, J=8.2 Hz, 1H), 7.46 (dd, J=11.8,8.2Hz, 3H), 7.13 (s, 2H), 5.08 (s, 1H), 5.05 (d, J=7.9Hz, 1H), 4.31 (d, J=7.9Hz, 1H), 3.47 (s, 3H), 1.67 (s, 2H), 1.37 (s, 18H)；
13C NMR(100MHz,CDCl3)δ175.2,152.8,138.3,136.0,134.1,131.7,130.5,128.9,127.4, 126.1,125.5,125.4,125.4,124.9,123.8,59.4,52.1,50.4,34.5,30.4；
HRMS(ESI,m/z):Calcd for C28H36NO3[M+H]+:434.2695,found:434.2695；
HPLC (Chiralpak AD-H, n-hexane/i-propanol=100/5,0.8mL/min, 220nm) tR=11.97min, 14.00min。
Compound shown in the a-9 of formula I：
1H NMR(400MHz,CDCl3) δ 7.91 (s, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 7.46 (d, J=11.9Hz, 2H), 7.36 (s, 1H), 7.31 (s, 1H), 7.21-7.11 (m, 2H), 6.96-6.91 (m, 2H), 4.64 (d, J=7.9Hz, 1H), 3.92 (d, J=7.9Hz, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 1.57 (s, 2H)；
13C NMR(100MHz,CDCl3)δ172.8,157.1,135.6,135.9,134.5,132.7,130.8,130.8,128.7, 127.5,127.2,126.6,126.3,126.0,125.7,114.2,114.2,57.2,56.0,52.1,50.2；
HRMS(ESI,m/z):Theoretical value (Calcd for):C21H21NO3[M+H]+:336.2695, experiment value (found): 336.2695。
Embodiment 10
The preparation of compound shown in the a-10 of formula I：
Divided by chemical combination beyond the region of objective existence, other conditions and step and embodiment shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -10 1 is similar, obtains compound (white solid), m.p. shown in the a-10 of formula I:155-156 DEG C, yield 94%.
Wherein, compound shown in formula I -10：ee>99%, [α]D 25=+49.3 (c 1.0, CHCl3)；
1H NMR(400MHz,CDCl3) δ 7.32-7.22 (m, 4H), 7.17 (t, J=6.9Hz, 1H), 6.89 (s, 2H), 4.16 (d, J=9.1Hz, 1H), 4.07 (d, J=9.1Hz, 1H), 3.49 (s, 3H), 2.20 (s, 6H)；
13C NMR(100MHz,CDCl3)δ175.2,151.6,141.8,131.7,128.7,128.5,128.0,126.7,123.8, 59.0,56.2,51.9,16.3；
HRMS(ESI,m/z):Calcd for C18H22NO3[M+H]+:300.1600,found:300.1602；
HPLC (Chiralpak AD-H, n-hexane/i-propanol=90/10,0.8mL/min, 220nm) tR=23.75min, 26.55min。
Compound shown in the a-10 of formula I：
1H NMR(400MHz,CDCl3) δ 7.32-7.22 (m, 4H), 7.17 (t, J=6.9Hz, 1H), 6.89 (s, 2H), 4.16 (d, J=9.1Hz, 1H), 4.07 (d, J=9.1Hz, 1H), 3.78 (s, 3H), 3.49 (s, 3H), 2.20 (s, 6H)；
13C NMR(100MHz,CDCl3)δ175.2,151.6,141.8,131.7,128.7,128.5,128.0,126.7,123.8, 60.7,59.0,56.2,51.9,16.3；
HRMS(ESI,m/z):Theoretical value (Calcd for):C19H23NO3[M+H]+:314.1600, experiment value (found): 314.1602。

Claims (10)

1. a kind of beta-diaryl-alpha-amino acid derivatives, it is compound shown in formula I：
In formula I, R1And R2It is respectively and independently selected from：C1~C4It is a kind of in straight or branched alkyl；R3For 5~6 yuan of aromatic ring yls or Oxygen-containing or sulphur aromatic heterocyclic, substituted 5~6 yuan of aromatic ring yls or oxygen-containing or sulphur aromatic heterocyclic, or naphthyl；
Wherein, the substitution base of 5~6 yuan of substituted aromatic ring yls or aromatic heterocyclic is selected from：Halogen, C1~C3Straight or branched alkane Base, C1~C3In straight or branched alkoxyl or phenyl one or two or more kinds.
2. beta-diaryl-alpha-amino acid derivatives as claimed in claim 1, it is characterised in that wherein, R3It is sulfur-bearing or oxygen 5 yuan of heteroaryl ring groups, phenyl, naphthyl, substitution phenyl or oxygen-containing or sulphur 5 yuan of heteroaryl ring groups；
Wherein, the substitution base of the substituted phenyl or 5 yuan of heteroaryl ring groups containing O or S is selected from：Halogen, C1~C3Straight chain or Branched alkyl, C1~C3In straight or branched alkoxyl or phenyl one or two or more kinds.
3. beta-diaryl-alpha-amino acid derivatives as claimed in claim 2, it is characterised in that wherein, R3It is furyl, The phenyl or thienyl of thienyl, phenyl, naphthyl, or substitution；
Wherein, the substitution base of substituted phenyl or the thienyl is selected from：F, Br, C1~C3Straight or branched alkoxyl or phenyl In one or two or more kinds.
4. beta-diaryl-the alpha-amino acid derivatives as described in any one in claims 1 to 3 are in chemical combination shown in a of formula I Application in thing：
In a of formula I, R1And R3Definition it is identical with the definition described in any one in claims 1 to 3, R4It is hydrogen or C1~ C3Straight or branched alkyl, and β upper two substitution base is different.
5. application as claimed in claim 4, it is characterised in that the method for compound shown in the wherein described a of formula I, bag Include following steps：
(1) under the compound, ferrocene class part and alkali existence condition for having inert gas, cupric or silver, by shownization of formula II Compound and compound shown in formula III react in organic solvent, the step of obtain compound shown in formula I；With
(2) under Louis's acid and alkali existence condition, compound and iodomethane reaction as shown in formula I, the step of obtain object；
Wherein, the compound of the cupric or silver is silver acetate, copper acetate, the acetonitrile copper of tetrafluoro boric acid four, the acetonitrile copper of perchloric acid four Or the acetonitrile copper of hexafluorophosphoric acid four, the ferrocene class part is compound shown in formula IV：
R is C1~C4Straight or branched alkyl, phenyl or benzyl, the alkali are organic base or inorganic base, R1~R3Definition with Definition in claims 1 to 3 described in any one is identical.
6. application as claimed in claim 5, it is characterised in that wherein, compound shown in formula II and compound shown in formula III Mol ratio is 1: (1~3).
7. application as claimed in claim 5, it is characterised in that wherein, compound shown in formula II and cupric or the compound of silver Mol ratio be 1: (0.005~0.2), the mol ratio of compound shown in formula II and ferrocene class part is 1: (0.005~0.2).
8. application as claimed in claim 5, it is characterised in that wherein, compound shown in formula II and the compound of alkali mole Than being 1: (0.01~4).
9. application as claimed in claim 5, it is characterised in that wherein, compound shown in formula II is with the mol ratio of iodomethane It is 1: (2~4)；Compound shown in formula II is 1 with lewis acidic mol ratio: (10~20).
10. application as claimed in claim 5, it is characterised in that wherein described alkali is the carbonate of alkali metal, acetate Or C1~C4Aliphatic alkoxide.
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CN115490653A (en) * 2021-06-18 2022-12-20 唐山师范学院 Synthesis and application of 4-furylmethylene-2,6-di-tert-butyl-2,5-cyclohexadiene-1-one compound
CN115490666A (en) * 2021-06-18 2022-12-20 唐山师范学院 Synthesis and application of 4-thiophenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one compound

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WEN-DAO CHU ET AL: "Asymmetric Catalytic 1,6-Conjugate Addition/Aromatization of para-Quinone Methides: Enantioselective Introduction of Functionalized Diarylmethine Stereogenic Centers", 《ANGEW. CHEM.》 *

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Publication number Priority date Publication date Assignee Title
CN115490653A (en) * 2021-06-18 2022-12-20 唐山师范学院 Synthesis and application of 4-furylmethylene-2,6-di-tert-butyl-2,5-cyclohexadiene-1-one compound
CN115490666A (en) * 2021-06-18 2022-12-20 唐山师范学院 Synthesis and application of 4-thiophenylmethylene-2, 6-di-tert-butyl-2, 5-cyclohexadiene-1-one compound

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