CN106866443B - 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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CN106866443B
CN106866443B CN201510909172.5A CN201510909172A CN106866443B CN 106866443 B CN106866443 B CN 106866443B CN 201510909172 A CN201510909172 A CN 201510909172A CN 106866443 B CN106866443 B CN 106866443B
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yuan
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CN106866443A (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.Beta-diaryl-the alpha-amino acid derivatives are compound shown in formula I (specific structure is referring to specification).Compound shown in the formula I can be used for compound shown in I a of preparation formula (specific structure is referring to specification).The present invention, as starting material, can conveniently and efficiently obtain a series of key intermediates (compound shown in formula I) for being used to prepare chiral beta-diaryl-alpha-amino acid derivatives (compound shown in I a of formula) using glycinate schiff bases simple and easy to get and to methylene benzoquinones.The advantages that present invention is easy to get with raw material, and preparation condition is mild, the yield and purity is 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 acids and application thereof, specifically, being related to a kind of chiral beta-diaryl-α- Amino acid derivativges and its β are being prepared as in chiral beta-diaryl-alpha-amino acid derivatives of the different aryl as substituent group Application.
Background technique
Non-natural alpha-amino acid is the important composition unit of polypeptide, protein, natural products and many bioactive molecules, They are also widely used in chiral catalyst design and fully synthetic field simultaneously.Therefore, the pure non-natural α-of synthesizing optical Amino acid causes 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 are a kind of knots being of great significance in drug and natural product chemistry Structure unit.[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.].Currently, the synthetic method of beta-diaryl alanine class compound is largely focused on product and contains two at β about β The report of a identical aryl substituent, and to realize containing the efficient asymmetry of β-Stereocenter beta-diaryl-a-amino acid Synthesis remains huge challenge.
In recent years, some synthesis beta-diaryl-a-amino acid methods have been disclosed successively, including phenylalanine derives The cis-selectivity S of objectNThe third of alkylated reaction, ligand control that 1 reaction, aziridine open loop, chiral auxiliary induce β-C-H the arylation of threonine derivative 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.]。
However exist in the prior art need additional blocking group, homing device or ligand, palladium catalyst dosage it is big, Substrate expands the defects of range is limited or operation is complicated.Therefore there is an urgent need in the art to a kind of easy, efficient, high atoms to pass through Ji property, high cis-selectivity, high enantioselectivity prepare non-natural chirality beta-diaryl-alpha-amino acid derivatives side Method.
Summary of the invention
It is an object of the present invention to disclose a kind of beta-diaryl-alpha-amino acid derivatives of structure novel.
Beta-diaryl-alpha-amino acid derivatives of the present invention are compound shown in formula I:
In formula I, R1And R2It is respectively and independently selected from: C1~C4It is a kind of in linear or branched alkyl group；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 aromatic heterocyclic or naphthalene containing O or S；And on the position β Two substituent group differences；
Wherein, the substituent group of substituted 5~6 yuan of aromatic ring yls or aromatic heterocyclic is selected from: halogen (F, Cl, Br or I), C1 ~C3Linear or branched alkyl group, C1~C3(containing two kinds) one or two or more kinds of in straight or branched alkoxyl or phenyl.
Another object of the present invention is, discloses a kind of purposes of compound shown in formula I, i.e., compound shown in formula I is in preparation β Position is different aryl as the application in chiral beta-diaryl-alpha-amino acid derivatives of substituent group, and (i.e. compound shown in formula I is β are prepared as key intermediate of the different aryl as chiral beta-diaryl-alpha-amino acid derivatives of substituent group).
Wherein described β is I a institute of formula as chiral beta-diaryl-alpha-amino acid derivatives of substituent group for different aryl Show compound:
In I a of formula, R1And R3Text as defined above is described identical, R4For hydrogen (H) or C1~C3Linear or branched alkyl group, and β Upper two substituent group differences.
The method of compound shown in I a of preparation formula provided by the invention, includes the following steps:
(1) under the compound, ferrocene class ligand and alkali existence condition for having inert gas, cupric or silver, by II institute of formula The step of showing that compound reacts in organic solvent with compound shown in formula III, obtaining compound shown in formula I (intermediate)；With
(2) under lewis acid (such as alchlor) and alkali existence condition, the compound as shown in formula I and iodomethane are anti- The step of answering, obtaining object (compound shown in I a of formula)；
Wherein, the compound of the cupric or silver is silver acetate, copper acetate, four acetonitrile copper of tetrafluoro boric acid, perchloric acid tetrem Four acetonitrile copper of nitrile copper or hexafluorophosphoric acid, the ferrocene class ligand are compound (being abbreviated as " Foxap ") shown in formula IV:
R is C1~C4Linear or branched alkyl group, phenyl or benzyl (Bn),
The alkali is organic base or inorganic base, R1~R3Text as defined above is described identical, compound shown in formula II and formula III The synthesis of shown compound is please respectively referring to document: A.Pint é r, 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 it is found that the present invention is with glycinate schiff bases simple and easy to get and to methylene benzoquinones Beginning raw material can conveniently and efficiently obtain a series of chiral beta-diaryl-α-with high cis-selectivity and enantioselectivity Amino acid derivativges.
Specific embodiment
In an optimal technical scheme of the invention, R1And R2It is respectively and independently selected from: C1~C4One in linear or branched alkyl group Kind, R3For 5 yuan of heteroaryl ring groups containing O or S, phenyl, naphthalene, or the phenyl replaced or 5 yuan of heteroaryl ring groups containing O or S；
Wherein, the substituted phenyl or the substituent group of 5 yuan of heteroaryl ring groups containing O or S are selected from: halogen (F, Cl, Br or I), C1~C3Linear or branched alkyl group, C1~C3(containing two kinds) one or two or more kinds of in straight or branched alkoxyl or phenyl；
Further preferred technical solution is: R1And R2It is respectively and independently selected from: a kind of in methyl, ethyl or tert-butyl, R3For Furyl, thienyl, phenyl, naphthalene, or the phenyl or thienyl that replace；
Wherein, the substituent group of the substituted phenyl or thienyl is selected from: F, Br, C1~C3Straight or branched alkoxyl or (containing two kinds) one or two or more kinds of in phenyl；
Technical solution still further preferably is: R1And R2It is respectively and independently selected from: a kind of in methyl, ethyl or tert-butyl, R3 For 2- furylPhenyl, naphthalene, substituted phenyl or thienyl；
Wherein, the substituent group of the substituted phenyl or thienyl is selected from: a kind of in F, Br, methyl, methoxyl group or phenyl Or two kinds or more (containing two kinds).
In presently preferred technical solution, the molar ratio of compound shown in formula II and compound shown in formula III is 1: (1~3).
In another optimal technical scheme of the invention, the molar ratio of compound shown in formula II and cupric or silver-colored compound Be 1: the molar ratio of (0.005~0.2), compound shown in formula II and ferrocene class ligand is 1: (0.005~0.2).
In another optimal technical scheme of the invention, the molar ratio of the compound of compound shown in formula II and alkali is 1: (0.01~4).
In another optimal technical scheme of the invention, the molar ratio of compound shown in formula II and iodomethane is 1: (1~ 5), preferred molar ratio is 1: (2~4).
In another optimal technical scheme of the invention, the molar ratio of compound shown in formula II and aluminium chloride is 1: (1~ 20), preferred molar ratio is 1: (10~20).
To sum up, the method for compound shown in I a of preparation formula of the present invention, specifically comprises the following steps:
(1) compound, ferrocene class ligand and the organic solvent of cupric or silver are placed in the reactor with agitating device In, it is stirred at least 1 hour in room temperature state, into the reactor, compound and alkali shown in formula II is added in ratio as previously described, Continue stirring 10 minutes, then compound shown in formula III is added in ratio as previously described into the reactor, stirs under the conditions of 0 DEG C It mixes, is disappeared using TLC tracking reaction to raw material point, stop reaction, diatomite filtering, decompression removal solvent, by residue is added It is dissolved in organic solvent, acid stirring 1-5 hours (hydrolysis) is added, saturated sodium bicarbonate solution neutralization reaction liquid, standing point is added Liquid, water phase are extracted with ethyl acetate 3-5 times, and after merging organic phase, anhydrous sodium sulfate is dried, filtered, decompression removal solvent, silica gel Column chromatography, obtains compound shown in formula I；
(2) compound shown in formula I and organic solvent are placed in the reactor with agitating device, are pressed into the reactor Iodomethane is added in ratio described previously, and stirring, then to the system, alchlor is added in ratio as previously described, increases temperature extremely 60 DEG C are continued to stir, and TLC tracking reaction to raw material point disappears, and are added the remaining alchlor of suitable water consumption, stratification, Water phase is extracted with ethyl acetate 3-5 times, and after merging organic phase, anhydrous sodium sulfate is dried, filtered, decompression removal solvent, silicagel column Chromatography, obtains object (compound shown in I a of formula).
Wherein, organic solvent used may is that tetrahydrofuran, methylene chloride, chloroform, ether, ethyl acetate, 1,2- dichloro Ethane, Isosorbide-5-Nitrae-dioxane, toluene, acetonitrile or methyl tertiary butyl ether(MTBE), alkali used may is that triethylamine, diisopropylamine, 1,8- bis- 11 carbon -7- alkene (DBU) of azabicyclic [5.4.0] or 1,4- diazabicylo [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 Potassium acetate etc.) or C1~C4Aliphatic alkoxide (such as potassium tert-butoxide).
The method provided by the invention for preparing chiral beta-diaryl-alpha-amino acid derivatives (compound shown in I a of formula), tool There is raw material to be easy to get, the advantages that preparation condition is mild, product yield high and high product purity.
The present invention is further elaborated below by embodiment, purpose, which is only that, is best understood from the contents of the present invention. Therefore, the cited case does not limit the scope of the invention.
Embodiment 1
The preparation of compound shown in I a-1 of formula:
(1) under nitrogen protection, 0.011 mM of ligand Ph-Foxap (compounds Ⅳ -1) of addition in reaction flask, 0.01 MM four acetonitrile copper of tetrafluoro boric acid and 5 milliliters of dry toluene, at room temperature stir 1 hour, 0.1 mM of formula II -1 is added Shown compound and 0.2 mM of potassium carbonate are cooled to 0 DEG C, stir 5 minutes, add 0.11 mM of formula, III -1 shownization Object is closed, TLC tracking reaction to raw material point disappears, reaction solution is filtered through diatomite, decompression removal solvent, residue tetrahydro furan It mutters dissolution, the aqueous hydrochloric acid solution of 1 milliliter of 1M is added, then add saturated sodium bicarbonate solution, adjust pH value of solution > 8, acetic acid second Ester extraction, merges organic phase, and anhydrous sodium sulfate dries, filters, decompression removal solvent, silica gel column chromatography (petroleum ether: ethyl acetate =4: 1 (v/v)), obtain yellow solid (compound shown in formula I -1)；
(2) compound shown in formula I -1 and tetrahydrofuran are placed in reactor, sequentially add 0.15 mM of potassium tert-butoxide With 0.12 mM of iodomethane, TLC tracking reaction to raw material point disappears.Then 2 mMs of aluminium chloride are added to the system, increase Temperature, which continues stirring to 60 DEG C, terminates (TLC tracking and monitoring) to reaction, and the remaining aluminium chloride of suitable water consumption is added, and stands and divides Liquid, water phase are extracted with ethyl acetate 3-5 times, and after merging organic phase, anhydrous sodium sulfate is dried, filtered, decompression removal solvent, silica gel Column chromatographs (methylene chloride: methanol=95: 5 (v/v)), obtains object (compound shown in I a-1 of formula).White solid, m.p.: 113 DEG C, separation yield 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 =8.4Hz, 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 I a-2 of formula:
Outside divided by compound shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -2, other conditions and step with Embodiment 1 is similar, obtains compound shown in Formulas I a-2 (yellow oil), 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, 3H), 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 I a-3 of formula:
Outside divided by compound shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -3, other conditions and step with Embodiment 1 is similar, obtains compound shown in Formulas I a-3 (white solid), m.p.:120 DEG C, yield 98%.
Wherein, ee > 99% of compound shown in Formulas I -3, [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 I a-4 of formula:
Outside divided by compound shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -4, other conditions and step with Embodiment 1 is similar, obtains compound (white solid) shown in I a-4 of formula, and m.p.: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 I a-4 of formula:
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 I a-5 of formula:
Outside divided by compound shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -5, other conditions and step with Embodiment 1 is similar, obtains compound (yellow solid) shown in I a-5 of formula, and m.p.: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 I a-5 of formula:
1H NMR(400MHz,CDCl3) δ 7.41 (d, J=7.8Hz, 1H), 7.33-7.26 (m, 2H), 7.20 (d, J= 8.0Hz, 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 I a-6 of formula:
Outside divided by compound shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -6, other conditions and step with Embodiment 1 is similar, obtains compound (yellow oil), yield 86% shown in I a-6 of formula.
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 I a-6 of formula:
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 I a-7 of formula:
Outside divided by compound shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -7, other conditions and step with Embodiment 1 is similar, obtains compound (white solid) shown in I a-7 of formula, and m.p.: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 I a-7 of formula:
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, 130.2129.5,129.5,114.3,114.3,58.1,56.0,54.3,52.2,21.3；
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 I a-8 of formula:
Outside divided by compound shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -8, other conditions and step with Embodiment 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 I a-8 of formula:
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 I a-9 of formula:
Outside divided by compound shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -9, other conditions and step with Embodiment 1 is similar, obtains compound (white solid) shown in I a-9 of formula, and m.p.: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= 8.2Hz, 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 I a-9 of formula:
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 I a-10 of formula:
Outside divided by compound shown in the Chinese style III -1 of compound alternative embodiment 1 shown in formula III -10, other conditions and step with Embodiment 1 is similar, obtains compound (white solid) shown in I a-10 of formula, and m.p.: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 I a-10 of formula:
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 (8)

1. a kind of method of compound shown in preparation formula Ia comprising following steps:
(1) under the compound, ferrocene class ligand and alkali existence condition for having inert gas, cupric or silver, change as shown in Formula II Close the step of object reacts in organic solvent with compound shown in formula III, obtains compound shown in Formulas I；With
(2) under Louis's acid and alkali existence condition, compound and iodomethane reaction as shown in Formulas I, the step of obtaining object；
The compound of the cupric or silver is silver acetate, copper acetate, four acetonitrile copper of tetrafluoro boric acid, four acetonitrile copper of perchloric acid or hexafluoro Four acetonitrile copper of phosphoric acid, the alkali are organic base or inorganic base, and the ferrocene class ligand is compound shown in formula IV:
R1And R2It is respectively and independently selected from: C1~C4It is a kind of in linear or branched alkyl group；R3For 5~6 yuan of aromatic ring yls or oxygen-containing or sulphur Aromatic heterocyclic, 5~6 yuan of substituted aromatic ring yls or oxygen-containing or sulphur aromatic heterocyclic or naphthalene；R4For hydrogen or C1~C3Straight chain or branch Alkyl group, and β upper two substituent group differences；R is C1~C4Linear or branched alkyl group, phenyl or benzyl；
Wherein, the substituent group of substituted 5~6 yuan of aromatic ring yls or aromatic heterocyclic is selected from: halogen, C1~C3Linear chain or branched chain alkane Base, C1~C3It is one or two or more kinds of in straight or branched alkoxyl or phenyl.
2. the method as described in claim 1, which is characterized in that wherein, R3For 5 yuan of heteroaryl ring groups of sulfur-bearing or oxygen, phenyl, naphthalene Base, or the phenyl replaced or oxygen-containing or sulphur 5 yuan of heteroaryl ring groups；
The substituted phenyl or the substituent group of oxygen-containing or sulphur 5 yuan of heteroaryl ring groups are selected from: halogen, C1~C3Linear chain or branched chain alkane Base, C1~C3It is one or two or more kinds of in straight or branched alkoxyl or phenyl.
3. method according to claim 2, which is characterized in that wherein, R3For furyl, thienyl, phenyl, naphthalene, or substitution Phenyl or thienyl；
The substituent group of the substituted phenyl or thienyl is selected from: F, Br, C1~C3It is a kind of in straight or branched alkoxyl or phenyl Or two kinds or more.
4. the method as described in any one of claims 1 to 3, which is characterized in that wherein, compound and formula shown in Formula II The molar ratio of compound shown in III is 1: (1~3).
5. the method as described in any one of claims 1 to 3, which is characterized in that wherein, compound and cupric shown in Formula II Or the molar ratio of the compound of silver is 1: the molar ratio of (0.005~0.2), compound shown in Formula II and ferrocene class ligand is 1: (0.005~0.2).
6. the method as described in any one of claims 1 to 3, which is characterized in that wherein, compound and alkali shown in Formula II The molar ratio of compound is 1: (0.01~4).
7. the method as described in any one of claims 1 to 3, which is characterized in that wherein, compound shown in Formula II and iodine first The molar ratio of alkane is 1: (2~4)；Compound shown in Formula II and lewis acidic molar ratio are 1: (10~20).
8. the method as described in any one of claims 1 to 3, which is characterized in that wherein the alkali is the carbon of alkali metal Hydrochlorate, acetate or C1~C4Aliphatic alkoxide.
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Asymmetric Catalytic 1,6-Conjugate Addition/Aromatization of para-Quinone Methides: Enantioselective Introduction of Functionalized Diarylmethine Stereogenic Centers;Wen-Dao Chu et al;《Angew. Chem.》;20130716;第125卷;第9399-9403页
Catalytic, Asymmetric, and Stereodivergent Synthesis of Non-Symmetric β,β-Diaryl-α-Amino Acids;Carmela Molinaro et al;《J. Am. Chem. Soc.》;20141218;第137卷;第999-1006页

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