CN108341757A - Chiral amino acid esters compound and preparation method and purposes - Google Patents

Chiral amino acid esters compound and preparation method and purposes Download PDF

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CN108341757A
CN108341757A CN201710060822.2A CN201710060822A CN108341757A CN 108341757 A CN108341757 A CN 108341757A CN 201710060822 A CN201710060822 A CN 201710060822A CN 108341757 A CN108341757 A CN 108341757A
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CN108341757B (en
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徐明华
陈建萍
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Shanghai Institute of Materia Medica of CAS
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
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    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/12—Formation of amino and carboxyl groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
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    • C07D311/12—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 3 and unsubstituted in position 7
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    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/34—Other additions, e.g. Monsanto-type carbonylations, addition to 1,2-C=X or 1,2-C-X triplebonds, additions to 1,4-C=C-C=X or 1,4-C=-C-X triple bonds with X, e.g. O, S, NH/N
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Abstract

The present invention relates to a kind of chiral amino acid esters compound and preparation methods and purposes.Specifically, the present invention carries out 1 using the complex-catalyzed organoboron reagent that monovalence rhodium metal and chiral diene ligand are formed to α aminomethyls acrylate, α aminoethyls acrylate or α aminopropyl esters of acrylic acid substrates and its derivative, 4 additions/asymmetry protonation reaction, using water as proton source, respective optical activity non-natural β is obtained2Amino-acid ester, γ2Amino-acid ester and δ2Amino acid esters compound.The present invention realizes high-optical-purity non-natural β2Or γ2Or δ2The catalysis asymmetric syntheses of amino-acid ester, method are simple, efficient.

Description

Chiral amino acid esters compound and preparation method and purposes
Technical field
The invention belongs to chemical fields, and in particular, to a kind of chiral beta2Or γ2Or δ2Amino acid esters compound and Its synthetic method and purposes.
Background technology
Amino acid is the basic component of life entity, is all scientist in biology, chemistry and medicinal chemistry art Fall over each other further investigation project.In recent years, non-with the needs that the extensive use of combinatorial chemistry technique and peptide medicament are researched and developed The synthesis of natural amino acid causes the great interest of organic chemist.It is chiral as important one kind in non-natural amino acid β2Or γ2Or δ2Amino acid because its in terms of structure and pharmacodynamics reflected important function, by chemist and The extensive concern of Pharmaceutical Chemists, therefore realize chiral beta2Or γ2Or δ2The efficient asymmetric syntheses of amino acid is to pushing The development of pharmaceutical chemistry and life science has great importance.
Domestic and international synthesizing chiral beta2Or γ2Or δ2The strategy of amino acid mainly has：The asymmetry of biocatalyst catalysis Reduction reaction (Swiderska, M.A.；Stewart, J.D.Org.Lett.2006,26,613), organocatalysis not (Morita, Y. are reacted in symmetrical aminomethylation；Yamamoto,T.；Nagai,H.；Shimizu,Y.；Kanai,M.； J.Am.Chem.Soc.2015,137,7075), asymmetric hydrogenation (Guo, the Y.J. of metal catalytic；Shao,G.；Li, L.N.；Wu,W.H.；Li,R.H.；Li,J.J.；Song,J.；Qiu,L.Q.；Prashad,M.；Kwongc, F.Y.Adv.Synth.Catal.2010,352,1539), conjugate addition reaction (Wiesner, the M. of organocatalysis； Revell,J.D.；Tonazzi,S.；Wennemers, H.J.Am.Chem.Soc.2008,130,5610) and chiral resolution etc. (Andersson,I.E.；Batsalova,T.；Haag,S.；Dzhambazov,B.；Holmdahl,R.；Kihlberg,J.； Linusson,A.J.Am.Chem.Soc.2011,133,14368).In addition, transition metal-catalyzed organoboron reagent is to α-ammonia 1,4- additions/asymmetry protonation reaction of alkyl-substituted-α, β-unsaturation acrylate is also a kind of than relatively straightforward structure The method for building this amino acid, but due to the difficult problem of reaction stereoselectivity control, chiral beta is used for by this method2- Or γ2Or δ2The example of Amino acid synthesis is seldom.Up to the present, single report is Sibi groups with rhodium and chiral diphosphine α-aminomethyl acrylic acid uncle that the compound that ligand is formed protects N- phthalyls as catalyst, catalysis aryl boric acid Isosorbide-5-Nitrae-addition/asymmetry protonation reaction of butyl ester, prepares chiral alpha-arylmethyl-β2Amino-acid ester (Sibi, M.P.； Tatamidani,H.；Patil,K.Org.Lett.2005,7,2571.).But under the catalyst system and catalyzing, reaction must be with equivalent Phthalic amide as proton source, the substrate universality of reaction is poor and the optical purity of product it is also not ideal enough (63~ 91%ee).
Currently, developing simple, efficient method realizes high-optical-purity β2Or γ2Or δ2The catalysis of amino-acid ester is not right Claim the project that synthesis is still urgently to be resolved hurrily.
Invention content
The object of the present invention is to provide a kind of high enantioselectivities to prepare β2Or γ2Or δ2Amino acid esters compound Method.
The first aspect of the present invention provides β shown in a kind of preparation structure formula 3/ or ent-32Or γ2Or δ2Amino The method of acid esters compound, the method includes the steps：
Catalyst monovalence rhodium metal and chiral diene ligand it is complex-catalyzed under, 1 compound of formula (α-aminomethyl propylene Acid esters, α-aminoethyl acrylate or α-aminopropyl acrylate) and the progress 1,4- of organoboron reagent 2 additions/asymmetry proton Change reaction, obtains chiral beta shown in structural formula 3/ or ent-32Or γ2Or δ2Amino acid esters compound：
In formula, n=1,2 or 3；
R1、R2It is each independently hydrogen, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C6-30Aryl, substitution Or unsubstituted C6-30Arylmethyl, substituted or unsubstituted C6-30Aryl sulfonyl, substituted or unsubstituted C6-30Aroyl, R '- O-C (O)-, or combinations thereof；Or R1、R2Substituted or unsubstituted C is formed with the N being connected6-30Aromatic amide；
R3For the C of linear chain or branched chain1-6Alkyl, C6-30Aryl, C6-30Arylmethyl；
[B] is selected from the group：B(OR)2Or (BO)3, wherein R is H or C1-6Linear chain or branched chain alkyl；
R4It is selected from the group：Substituted or unsubstituted C6-30Aryl,
R ' is selected from the group：C1-6Alkyl, C1-6Halogenated alkyl, substituted or unsubstituted C6-30It is aryl, substituted or unsubstituted C6-30Arylmethyl；
Wherein, the substitution refers to that the hydrogen atom on group is mono-substituted or polysubstituted；The substituent group is respectively only It is vertical to be selected from the group：Halogen, nitro, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, benzyloxy, C6-10 Aryl；
In another preferred example, the chiral diene ligand has the following structure formula (preferably, the Formulas I and formula Ent-I chiral diene ligands enantiomter, Formula II and formula ent-II chiral diene ligands enantiomter each other each other)：
Or
In formula,
Ar is selected from the group：Substituted or unsubstituted C6-30Aryl, substituted or unsubstituted C4-12Heteroaryl, wherein two Ar Group can be the same or different, and the substitution refers to that the hydrogen atom on group is replaced by one or more (such as 1-5) Base replaces, and the hetero atom that the heteroaryl contains is oxygen or sulphur；
The substituent group is selected from the group：Halogen, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Haloalkoxy Base, benzyloxy, C6-10Aryl, or combinations thereof；The halogen is F, Cl, Br or I.
In another preferred example, by the gauge of using of α-acrylate class substrate 1, monovalence rhodium metal catalysis Agent dosage is 1~30mol%；The chiral diene ligand dosage is 1~30mol%.
In another preferred example, R1、R2Phthalyl aminoethyl, phthalyl aminopropyl are formed with the N being connected.
In another preferred example, the chiral diene ligand is selected from the group：
In another preferred example, the monovalence rhodium metal compound is selected from the group：[Rh(C2H4)2Cl]2、[Rh(C2H4)2OH]2、[Rh(COE)2Cl]2、[Rh(COE)2OH]2, or combinations thereof.
In another preferred example, in the reaction equation in organoboron reagent 2, [B] is B (OR)2Or (BO)3, wherein R is H or C1-6Linear chain or branched chain alkyl.The dosage of organoboron reagent 2 is 100mol%~500mol%.
In another preferred example, the method also has one or more features selected from the group below：
(1) reaction carried out in the presence of additive aqueous solution, the additive aqueous solution be a concentration of 0.5mol/L~ The aqueous solution of the compound selected from the group below of 5mol/L：KF、KOH、K2CO3、Na2CO3、K3PO4、K2HPO4；
(2) reaction carries out in the presence of additive aqueous solution, and the dosage of the additive is 10mol%~500mol%；
(3) reaction carries out in organic solvent, and organic solvent used is selected from the group：Dichloromethane (CH2Cl2), ether (Et2O), toluene (Toluene), Isosorbide-5-Nitrae-dioxane (Dioxane), tetrahydrofuran (THF), or combinations thereof；
(4) temperature reacted is 0~100 DEG C；
(5) reaction time is 1~24 hour.
The second aspect of the present invention, providing a kind of structural formula 3/ or ent-3 compounds represented, the compound has Following structural formula：
In formula, n, R1、R2、R3、R4As the first aspect of the present invention defines.
In another preferred example, the structural formula 3/ or ee value >=85% of ent-3 compounds, more preferably >=95%.
In another preferred example, the R1、R2、R3、R4Equal groups are respectively that institute is right in each particular compound in embodiment The group answered.
In another preferred example, the compound is compound prepared in embodiment.
In another preferred example, each substituent group respectively stands alone as in embodiment corresponding base in each particular compound in various Group.
In another preferred example, the compound is selected from the group：
The third aspect of the present invention provides and changes shown in structural formula 3/ or ent-3 as described in respect of the second aspect of the invention The purposes of object is closed, a kind of representative purposes is as follows, is used for：
I) to structural formula 3/ or ent-3 compounds represented, the removing of corresponding substituent group and the tertiary fourth of amino on amido are carried out Oxygen carbonyl protection prepares chiral beta2Or γ2Or δ2Amino-acid ester 4 or ent-4；
Ii) to structural formula 4/ or ent-4 compounds represented, the corresponding removing of substituent group and the water of ester group on amido are carried out Solution, prepares chiral beta2Or γ2Or δ2Amino acid 5 or ent-5；
Iii structural formula 3/ or ent-3 compounds represented are reacted by function dough), a variety of chiral benzos can be prepared Heterocyclic compound.
In another preferred example, (iii-a) works as R to structural formula 3/ or ent-3 compounds represented7For methoxy substitution When remove methoxyl group, carry out cyclization and prepare chiral chromane-2-one 6 or ent-6；
(iii-b) to structural formula 3/ or ent-3 compounds represented, work as R7Bromo, amino contracting are carried out when replacing for methyl It closes reaction and prepares chiral benzo-aza heptatomic ring class compound 7 or ent-7；
(iii-c) to structural formula 3/ or ent-3 compounds represented, work as R7Catalyzing by metal palladium is carried out when replacing for chlorine atom Lower coupling reaction prepares chiral tetrahydroquinoline class compound 8 or ent-8；
In above formula,
N, R1, R2, R3It is defined as above；
R5And R6Coupled carbon atom connects to form substituted or unsubstituted phenyl, wherein the substitution refers to base Hydrogen atom in group is replaced by one or more (such as 1-5) substituent groups, and the substituent group is selected from the group：Halogen, C1-6Alkane Base, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, benzyloxy, C6-10Aryl, or combinations thereof；The halogen be F, Cl, Br or I.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.
Specific implementation mode
The present invention realizes under the conditions of monovalent metal rhodium/chiral diene complex is proton source as catalyst, water, has Machine borane reagent is to α-aminomethyl acrylate, α-aminoethyl acrylate or α-aminopropyl esters of acrylic acid substrate and its derivative Isosorbide-5-Nitrae-addition/asymmetry protonation reaction, efficiently build chiral beta2Or γ2Or δ2Amino acid esters compound.In this base On plinth, inventor completes the present invention.
Term
As used herein, term " alkyl " refers to linear or branched alkyl group, preferably C1-6Alkyl, in the present invention, alkyl It further include the group that one or more H on alkyl are replaced by substituent group selected from the group below：Halogen, substituted or unsubstituted benzene Base, the unsubstituted or C that is replaced by one or more halogens1-6Alkyl.It should be understood that the term further includes C3-10Substitution does not take The naphthenic base in generation.
As used herein, term " alkoxy " refers to C1-6Linear chain or branched chain alkoxy, in the present invention, alkoxy is also The group replaced by substituent group selected from the group below including one or more H on alkyl：Halogen, substituted or unsubstituted benzene Base, the unsubstituted or C that is replaced by one or more halogens1-6Alkyl.
As used herein, term " aryl " or " Ar " refer to C6-30Aryl, representative example be phenyl, naphthalene, anthryl, Phenanthryl.In the present invention, aryl further includes the group that one or more H on aryl are replaced by substituent group selected from the group below： Halogen, phenyl, the unsubstituted or C that is replaced by one or more halogens1-6It is alkyl, unsubstituted or by one or more halogens Substituted C1-6Alkoxy.
As used herein, term " one or more " is often referred to 1-6, preferably 1-5, more preferably 1-3.
As used herein, term " Ph " indicates that phenyl, term " Ts " indicate that 4- Methyl benzenesulfonyl bases, term " Ns " indicate 4- Nitrobenzenesulfonyl, term " Boc " expression tertbutyloxycarbonyl, term "nPr " indicates that n-propyl, term " Bn " indicate benzyl, art Language "tBu " indicates tertiary butyl.
As used herein, term " RT " indicates room temperature, such as 10~40 DEG C.
Preparation method
The synthetic method of the present invention can be indicated by following typical reaction formulas:
Reaction substrate 1 is α-aminomethyl, α-aminoethyl or α-aminopropyl esters of acrylic acid substrate, wherein n=1,2 or 3； R1、R2It is each independently hydrogen, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C6-30Aryl, substitution or unsubstituted C6-30Arylmethyl, substituted or unsubstituted C6-30Aryl sulfonyl, substituted or unsubstituted C6-30Aroyl, R '-O-C (O)-, Or combinations thereof；Or R1、R2Substituted or unsubstituted C is formed with the N being connected6-30Aromatic amide；R3For the C of linear chain or branched chain1-6 Alkyl, C6-30Aryl, C6-30Arylmethyl；
Reaction substrate 2 is organoboron reagent, wherein R4For substituted or unsubstituted C6-30Aryl, wherein the substitution is Referring to, there are one or more (such as 1-5) substituent groups, the substituent group to be selected from the group：Halogen, C1-6Alkyl, C1-6Alkyl halide Base, C1-6Alkoxy, C1-6Halogenated alkoxy, benzyloxy, unsubstituted or substituted C6-10Aryl, or combinations thereof；The halogen is F, Cl, Br or I；[B] is B (OR)2Or (BO)3, wherein R is H or C1-6Linear chain or branched chain alkyl；
[Rh (I)] refers to monovalence rhodium metal catalyst, and representative example includes (but being not limited to):[Rh(C2H4)2Cl]2、 [Rh(C2H4)2OH]2、[Rh(COE)2Cl]2、[Rh(COE)2OH]2, or combinations thereof.
In the present invention, representative chiral diene ligand has the following structure formula：
Or
In formula,
Ar is selected from the group：Substituted or unsubstituted C6-30Aryl, substituted or unsubstituted C4-12Heteroaryl, wherein two Ar Group can be the same or different, and the substitution refers to that the hydrogen atom on group is replaced by one or more (such as 1-5) Base replaces, and the hetero atom that the heteroaryl contains is oxygen or sulphur；
The substituent group is selected from the group：Halogen, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Haloalkoxy Base, benzyloxy, C6-10Aryl, or combinations thereof；The halogen is F, Cl, Br or I.
In the present invention, the structural formula of the typical compound of representative chiral diene ligand includes (but being not limited to)：
In the present invention, the additive can be KF, KOH, K of a concentration of 0.5mol/L~5mol/L2CO3、 Na2CO3、K3PO4、K2HPO4Aqueous solution etc..
In the present invention, the dosage of used reaction additives can be 10mol%~500mol%.
In the present invention, used organic solvent can be dichloromethane (CH2Cl2), ether (Et2O), toluene (Toluene), Isosorbide-5-Nitrae-dioxane (Dioxane), tetrahydrofuran (THF), or combinations thereof.
In the present invention, the temperature of reaction can be 0~100 DEG C, wherein preferably with 10~70 DEG C, most with 25~55 DEG C It is good.
In the present invention, the reaction time is not particularly limited, and can be 1~24 hour.
In the preference of the present invention, representative synthetic method can be described as follows：
Under oxygen free condition, by monovalence rhodium catalyst, chiral diene ligand, organoboron reagent, α-aminomethyl, α-aminoethyl or The acrylate of α-aminopropyl substitution is dissolved in organic solvent, is placed in complexation reaction at room temperature 30 minutes, then, additive is added And the reaction was continued 1-24 hours differs, and can obtain chiral beta of the present invention2Or γ2Or δ2Amino acid esters compound. In the reaction, additive can be KF, KOH, K of a concentration of 0.5mol/L~5mol/L2CO3、Na2CO3、K3PO4、K2HPO4Deng Aqueous solution, preferably 1.0mol/L KOH aqueous solutions；The dosage of additive can be 10mol%~500mol%, preferably 50mol%；Organic solvent can be dichloromethane (CH2Cl2), ether (Et2O), toluene (Toluene), 1,4- dioxane (Dioxane), tetrahydrofuran (THF) etc., preferably toluene (Toluene)；Monovalence rhodium metal catalyst can be [Rh (C2H4)2Cl]2、[Rh(C2H4)2OH]2、[Rh(COE)2Cl]2、[Rh(COE)2OH]2Or combinations thereof, preferably [Rh (COE)2Cl]2；Monovalence rhodium Amount of metal catalyst is 1~30mol%, preferably 2.5mol%；Chiral diene ligand dosage is 1~30mol%, preferably 5.5mol%；Organoboron reagent 2 can be boric acid, borate, boric anhydride, potassium fluoborate, four aryl boron sodium etc., preferred boric acid；Have The molar ratio of machine borane reagent 2 and α-acrylate 1 is (1~5)：1, preferably 3：1；Reaction temperature is 25~60 DEG C, excellent Select 25 DEG C.
High-optical-purity β2Or γ2Or δ2Amino acid esters compound
Method through the invention can efficiently prepare the β of high-optical-purity2Or γ2Or δ2Amino acid esters compound.
In the present invention, some representative β2Or γ2Or δ2Amino acid esters compound is listed in table 1, table 2 and table 3 In.
Using toluene as solvent, the KOH aqueous solutions of a concentration of 1.0mol/L of 0.5 equivalent (50mol%) are as addition Agent, monovalence rhodium [Rh (COE)2Cl]2For the compound formed with chiral diene ligand is as catalyst, catalysis organic boronic 2 is right Required reaction production can be efficiently made in Isosorbide-5-Nitrae-addition/asymmetry protonation reaction of α-acrylate class substrate 1a-i Object, well, enantioselectivity (ee) is outstanding for yield (yield), and highest can reach 98% ee values.
The organic boronic 2 of 1. rhodium of table (I) catalysis protonates 1,4- additions/asymmetry of α-aminomethyl acrylate 1a-f Reaction
The method can be also used for the expansion of following substrate.Preferably, in the method, using toluene as molten Agent, the KOH aqueous solutions of a concentration of 1.0mol/L of 0.5 equivalent (50mol%) are as additive, monovalence rhodium [Rh (COE)2Cl]2 For the compound formed with chiral diene ligand is as catalyst, be catalyzed organic boronic 2 to α-aminoethyl acrylate 1g or Required reaction production can be efficiently made in Isosorbide-5-Nitrae-addition/asymmetry protonation reaction of α-aminopropyl esters of acrylic acid substrate 1h-1i Object, well, enantioselectivity (ee) is outstanding for yield (yield), and highest can reach 98% ee values.
The organic boronic 2 of 2. rhodium of table (I) catalysis protonates 1,4- additions/asymmetry of α-aminoethyl acrylate 1g anti- It answers
1,4- addition/asymmetry proton of the organic boronic 2 of 3. rhodium of table (I) catalysis to α-aminopropyl acrylate 1h, 1i Change reaction
Chiral beta2Or γ2Or δ2The application of amino acid esters compound
The present invention also provides the β in the present invention2Or γ2Or δ2The application of amino acid esters compound, a kind of representative The purposes of property is as follows：
I) to structural formula 3/ or ent-3 compounds represented, the removing of corresponding substituent group and the tertiary fourth of amino on amido are carried out Oxygen carbonyl protection prepares chiral beta2Or γ2Or δ2Amino-acid ester 4 or ent-4；
In another preference of the present invention, representative purposes can be described as follows：
(i-a) by organoboron reagent to 1,4- additions/asymmetry protonation reaction product of α-aminomethyl acrylate 1a 3ai is to tertbutyloxycarbonyl on amido under triethylamine effect, and then ultrasonic reaction removes in methanol under magnesium, ammonium chloride effect P-toluenesulfonyl obtains α-(2- menaphthyls)-β of optical purity holding2Amino tert-butyl acrylate 4ai.
In another preference of the present invention, representative purposes can be described as follows：
(i-b) by organoboron reagent to 1,4- additions/asymmetry protonation reaction product of α-aminoethyl acrylate 1g 3ga removes phthalyl under hydrazine hydrate effect, then by under triethylamine alkaline condition to tertbutyloxycarbonyl system on amino Standby chiral alpha-(4- methyoxy-benzyls)-γ2Amino tert-butyl acrylate 4ga.
Another representative purposes is as follows：
Ii) to structural formula 4/ or ent-4 compounds represented, the corresponding removing of substituent group and the water of ester group on amido are carried out Solution, prepares chiral beta2Or γ2Or δ2Amino acid 5 or ent-5；
In another preference of the present invention, representative purposes can be described as follows：
α-tertbutyloxycarbonyl aminopropyl acrylate 3hi is removed into tertbutyloxycarbonyl and the hydrolysis tert-butyl ester under the conditions of hydrochloric acid Base can stereoselectivity retentively prepare corresponding amino acid 5hi.
Another representative purposes is as follows：
Iii structural formula 3/ or ent-3 compounds represented are reacted by function dough), a variety of chiral benzos can be prepared Heterocyclic compound, specifically：
(iii-a) to structural formula 3/ or ent-3 compounds represented, work as R7To remove methoxyl group when methoxy substitution, into Row cyclization prepares chiral chromane-2-one 6 or ent-6；
(iii-b) to structural formula 3/ or ent-3 compounds represented, work as R7Bromo, amino contracting are carried out when replacing for methyl It closes reaction and prepares chiral benzazepine class compound 7 or ent-7；
(iii-c) to structural formula 3/ or ent-3 compounds represented, work as R7Catalyzing by metal palladium is carried out when replacing for chlorine atom Lower coupling reaction prepares chiral tetrahydroquinoline class compound 8 or ent-8；
In another preference of the present invention, representative purposes can be described as follows：
(iii-a) organoboron reagent produces 1,4- additions/asymmetry protonation reaction of α-aminomethyl acrylate 1a Object 3ak removes tertiary butyl under the conditions of trifluoroacetic acid, then carries out being cyclized again in -78 degrees Celsius of lower Boron tribromide removing methyl anti- It should can prepare chiral chromane-2-one 6ak.
In another preference of the present invention, representative purposes can be described as follows：
(iii-b) organoboron reagent produces 1,4- additions/asymmetry protonation reaction of α-aminomethyl acrylate 1a Object 3al benzyl methyl bromide generation, the then chiral benzo-aza heptatomic ring class compound of progress amino condensation reaction preparation under NBS effects 7al。
In another preference of the present invention, representative purposes can be described as follows：
(iii-c) organoboron reagent produces 1,4- additions/asymmetry protonation reaction of α-aminomethyl acrylate 1a Object 3am, coupling reaction prepares chiral tetrahydroquinoline class compound 8am under catalyzing by metal palladium.
In above formula,
N, R1, R2, R3It is defined as above；
R5And R6Coupled carbon atom connects to form substituted or unsubstituted phenyl, wherein the substitution refers to base Hydrogen atom in group is replaced by one or more (such as 1-5) substituent groups, and the substituent group is selected from the group：Halogen, C1-6Alkane Base, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, benzyloxy, C6-10Aryl, or combinations thereof；The halogen be F, Cl, Br or I.
Main advantages of the present invention include：
(1) for the present invention using the complex that monovalence rhodium metal/diene ligand is formed as catalyst, water is real as proton source Efficient 1,4- addition/asymmetry matter of the cheap organoboron reagent to α-acrylate class substrate and its derivative is showed Sonization is reacted；
(2) method reaction condition of the invention is mild, easy to operate；
(3) method substrate universality of the invention is good, for various types of organoboron reagent and α-aminoalkyl third Olefin(e) acid esters substrate and its derivative can obtain preferable result；
(4) method of the invention reaction stereoselectivity is high, can effectively prepare the chiral beta of various high-optical-purities2Or γ2Or δ2Amino acid esters compound, product can prepare chiral beta through further conversion2Or γ2Or δ2Amino acid and a variety of Chiral Benzoheterocyclic compounds have good application prospect；
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Embodiment 1
The synthesis of compound 3aa：
Under argon gas protection, by 2- (4- tosyls aminomethyl) tert-butyl acrylate substrate 1a (0.1mmol), 4- methoxyl groups Phenyl boric acid 2a (0.3mmol), [Rh (COE)2Cl]2(rhodium of 2.5mol%, 0.005mmol), chiral diene ligand (1R, 5R)-Ia (0.0055mmol, 5.5mol%) is put into reaction bulb, and toluene (1mL) is added, past after being stirred to react 30min at room temperature The KOH aqueous solutions (0.05mL) of 1.0M are added in system, the reaction was continued.TLC monitorings are spin-dried for reaction solution, silicon after the reaction was complete The isolated product 3aa of plastic column chromatography (98% yield, 96%ee).
1H NMR(300MHz,CDCl3):δ 7.68 (d, J=9.0Hz, 2H), 7.28 (d, J=9.0Hz, 2H), 7.03 (d, J =9.0Hz, 2H), 6.79 (d, J=9.0Hz, 2H), 5.09-5.05 (m, 1H), 3.79 (s, 3H), 3.03-2.99 (m, 2H), 2.86-2.81(m,1H),2.73-2.65(m,2H),2.42(s,3H),1.36(s,9H)；13C NMR(125MHz,CDCl3):δ 173.4,158.4,143.5,137.0,130.1,130.1,129.8,127.2,114.0,81.7,55.4,47.5,43.5, 34.9,28.1,21.6；[α]D 20-7.3(c 1.8,CHCl3)；ESI-MS (m/z, %) 442 [M+Na]+.
Embodiment 2
The synthesis of compound 3aa '：
Chiral ligand (1R, 5R)-Ia used in embodiment 1 is changed to (1S, 5S)-Ia, remaining experimental implementation is the same as implementation Example 1 obtains the opposite product 3aa ' of configuration (96% yield, 96%ee).
1H NMR(300MHz,CDCl3):δ 7.70 (d, J=9.0Hz, 2H), 7.23 (d, J=9.0Hz, 2H), 7.06 (d, J =9.0Hz, 2H), 6.75 (d, J=9.0Hz, 2H), 5.12-5.07 (m, 1H), 3.81 (s, 3H), 3.05-2.97 (m, 2H), 2.88-2.84(m,1H),2.77-2.62(m,2H),2.47(s,3H),1.35(s,9H)；13C NMR(125MHz,CDCl3):δ 173.2,158.1,143.5,137.3,130.3,129.9,129.8,127.5,114.1,81.8,55.2,47.6,43.8, 35.1,27.9,21.5；[α]D 20+6.9(c 1.1,CHCl3)；ESI-MS (m/z, %) 442 [M+Na]+.
Embodiment 3
The synthesis of compound 3ab：
4- methoxyphenylboronic acids 2a used in embodiment 1 is changed to 4- methylphenylboronic acid 2b, remaining experimental implementation is the same as real Apply example 1.Obtain product 3ab (99% yield, 91%ee).
1H NMR(300MHz,CDCl3):δ 7.67 (d, J=9.0Hz, 2H), 7.27 (d, J=9.0Hz, 2H), 7.03 (dd, J=22.5,7.5Hz, 4H), 5.09-5.04 (m, 1H), 3.03-3.01 (m, 2H), 2.92-2.83 (m, 1H), 2.74-2.72 (d, J=7.5Hz, 2H), 2.42 (s, 3H), 2.31 (s, 3H), 1.36 (s, 9H)；13C NMR(125MHz,CDCl3):δ173.3, 143.5,137.0,136.2,134.9,129.8,129.2,129.0,127.2,81.7,47.4,43.51,35.3,28.1, 21.6,21.1；ESI-MS (m/z, %) 426 [M+Na]+.
Embodiment 4
The synthesis of compound 3ac：
4- methoxyphenylboronic acids 2a used in embodiment 1 is changed to 4- tert-butylbenzeneboronic acid 2c, remaining experimental implementation is same Embodiment 1.Obtain product 3ac (99% yield, 92%ee).
1H NMR(300MHz,CDCl3):δ 7.68 (d, J=6.0Hz, 2H), 7.28 (d, J=9.0Hz, 4H), 7.04 (d, J =9.0Hz, 2H), 5.04 (t, J=6.0Hz, 1H), 3.04-3.01 (m, 2H), 2.88-2.82 (m, 1H), 2.76-2.70 (m, 2H),2.42(s,3H),1.33(s,9H),1.30(s,9H)；13C NMR(125MHz,CDCl3):δ173.4,149.6,143.5, 137.0,135.0,129.8,128.78,127.2,125.5,81.7,47.3,43.7,35.3,34.5,31.5,28.0,21.6； ESI-MS (m/z, %) 468 [M+Na]+.
Embodiment 5
The synthesis of compound 3ad：
4- methoxyphenylboronic acids 2a used in embodiment 1 is changed to 4- chlorophenylboronic acid 2d, remaining experimental implementation is the same as implementation Example 1.Obtain product 3ad (99% yield, 93%ee).
1H NMR(300MHz,CDCl3):δ 7.68 (d, J=6.0Hz, 2H), 7.29 (d, J=9.0Hz, 2H), 7.23 (d, J =6.0Hz, 2H), 7.06 (d, J=6.0Hz, 2H), 5.10 (t, J=6.0Hz, 1H), 3.04-2.97 (m, 2H), 2.91-2.85 (m,1H),2.79-2.67(m,2H),2.42(s,3H),1.35(s,9H)；13C NMR(125MHz,CDCl3):δ173.0, 143.6,136.8,136.7,132.6,130.5,129.9,128.7,127.2,82.0,47.2,43.4,35.0,28.1, 21.6；ESI-MS (m/z, %) 446 [M+Na]+.
Embodiment 6
The synthesis of compound 3ae：
4- methoxyphenylboronic acids 2a used in embodiment 1 is changed to 4- fluorobenzoic boric acid 2e, remaining experimental implementation is the same as implementation Example 1.Obtain product 3ae (99% yield, 94%ee).
1H NMR(300MHz,CDCl3) δ 7.68 (d, J=9.0Hz, 2H), 7.28 (d, J=9.0Hz, 2H), 7.10-* 7.06 (m, 2H), 6.94 (t, J=9.0Hz, 2H), 5.11 (t, J=6.0Hz, 1H), 3.07-3.00 (m, 2H), 2.90-2.84 (m,1H),2.76-2.63(m,2H),2.42(s,3H),1.34(s,9H)；13C NMR(125MHz,CDCl3)δ173.1, 161.0,143.6,136.9,133.8,130.6(d,JCF=7.5Hz), 129.8,127.2,115.4 (d, JCF=21.3Hz), 81.9,47.4,43.5,34.9,28.1,21.6；ESI-MS (m/z, %) 430 [M+Na]+.
Embodiment 7
The synthesis of compound 3af：
4- methoxyphenylboronic acids 2a used in embodiment 1 is changed to 4- trifluoromethylbenzene boronic acid 2f, remaining experimental implementation With embodiment 1.Obtain product 3af (83% yield, 95%ee).
1H NMR(300MHz,CDCl3):δ 7.69 (d, J=9.0Hz, 2H), 7.52 (d, J=6.0Hz, 2H), 7.27 (t, J =9.0Hz, 4H), 5.15 (t, J=6.0Hz, 1H), 3.05-2.74 (m, 5H), 2.42 (s, 3H), 1.34 (s, 9H)；13C NMR (125MHz,CDCl3):δ172.8,143.7,142.4,136.8,129.9,129.5,129.1(d,JCF=32.5Hz), 127.2,125.49,125.47,123.2,82.2,47.1,43.5,35.4,28.0,21.6；480 [M+ of ESI-MS (m/z, %) Na]+.
Embodiment 8
The synthesis of compound 3ag：
4- methoxyphenylboronic acids 2a used in embodiment 1 is changed to 3- methoxyphenylboronic acid 2g, remaining experimental implementation is same Embodiment 1.Obtain product 3ag (90% yield, 94%ee).
1H NMR(300MHz,CDCl3):δ 7.67 (d, J=6.0Hz, 2H), 7.28 (d, J=9.0Hz, 2H), 7.18 (t, J =7.5Hz, 1H), 7.77-7.69 (m, 3H), 5.06 (t, J=6.0Hz, 1H), 3.79 (s, 3H), 3.02-3.00 (m, 2H), 2.91-2.85(m,1H),2.77-2.71(m,2H),2.41(s,3H),1.36(s,9H)；13C NMR(125MHz,CDCl3)δ 173.3,159.8,143.5,139.7,136.9,129.8,129.6,127.2,121.4,114.7,112.3,81.8,55.3, 47.2,43.5,35.8,28.1,21.6；ESI-MS (m/z, %) 442 [M+Na]+.
Embodiment 9
The synthesis of compound 3ah：
4- methoxyphenylboronic acids 2a used in embodiment 1 is changed to 3- fluorobenzoic boric acid 2h, remaining experimental implementation is the same as implementation Example 1.Obtain product 3ah (86% yield, 90%ee).
1H NMR(300MHz,CDCl3) δ 7.68 (d, J=9.0Hz, 2H), 7.29 (d, J=9.0Hz, 2H), 7.24-7.19 (m, 1H), 6.97-6.85 (m, 2H), 6.81 (d, J=9.0Hz, 1H), 5.01 (t, J=6.0Hz, 1H), 3.04-3.00 (m, 2H),2.90(dd,J1=12.0Hz, J2=6.0Hz, 1H), 2.79-2.68 (m, 2H), 2.43 (s, 3H), 1.35 (s, 9H)；13C NMR(125MHz,CDCl3)δ173.0,162.9(d,JCF=245.0Hz), 143.7,140.7,140.7,136.9,130.1 (d, JCF=7.5Hz), 129.9,127.2,124.9,116.0 (d, JCF=21.3Hz), 113.7 (d, JCF=21.3Hz), 82.1, 47.1,43.6,35.5,28.1,21.7；ESI-MS (m/z, %) 430 [M+Na]+.
Embodiment 10
The synthesis of compound 3ai：
4- methoxyphenylboronic acids 2a used in embodiment 1 is changed to 2- naphthalene boronic acids 2i, the same embodiment of remaining experimental implementation 1.Obtain product 3ai (99% yield, 93%ee).
1H NMR(300MHz,CDCl3):δ 7.88-7.70 (m, 3H), 7.64 (d, J=9.0Hz, 2H), 7.57 (s, 1H), 7.47-7.44 (m, 2H), 7.27-7.24 (m, 2H), 7.20 (d, J=9.0Hz, 2H), 5.13 (t, J=6.0Hz, 1H), 3.11- 2.81(m,5H),2.38(s,3H),1.34(s,9H)；13C NMR(125MHz,CDCl3):δ173.3,143.5,136.8, 135.6,133.5,132.4,129.8,128.3,127.7,127.6,127.3,127.1,126.2,125.7,81.9,47.3, 43.6,35.9,28.1,21.6；ESI-MS (m/z, %) 462 [M+Na]+.
Embodiment 11
The synthesis of compound 3aj：
4- methoxyphenylboronic acids 2a used in embodiment 1 is changed to 1- naphthalene boronic acids 2j, the same embodiment of remaining experimental implementation 1.Obtain product 3aj (87% yield, 95%ee).
1H NMR(300MHz,CDCl3)δ7.96(dd,J1=6.0Hz, J2=3.0Hz, 1H), 7.89-7.853 (m, 1H), 7.76 (d, J=9.0Hz, 1H), 7.60 (d, J=9.0Hz, 2H), 7.51-7.48 (m, 2H), 7.40-7.35 (m, 1H), 7.28 (t, J=6.0Hz, 1H), 7.18 (d, J=9.0Hz, 2H), 5.15 (t, J=6.0Hz, 1H), 3.47 (dd, J1=9.0Hz, J2= 6.0Hz, 1H), 3.16-3.01 (m, 3H), 2.86-2.77 (m, 1H), 2.38 (s, 3H), 1.36 (d, J=1.5Hz, 9H)；13C NMR(125MHz,CDCl3)δ173.5,143.4,136.9,134.2,134.1,131.7,129.8,129.1,127.7, 127.7,127.1,126.3,125.7,125.5,123.5,81.9,46.2,43.6,32.9,28.1,21.6；ESI-MS(m/ Z, %) 462 [M+Na]+.
Embodiment 12
The synthesis of compound 3ak：
4- methoxyphenylboronic acids 2a used in embodiment 1 is changed to 2- methoxyphenylboronic acid 2k, remaining experimental implementation is same Embodiment 1.Obtain product 3ak (86% yield, 98%ee).
1H NMR(300MHz,CDCl3):δ 7.67 (d, J=9.0Hz, 2H), 7.28 (d, J=9.0Hz, 2H), 7.18 (t, J =7.5Hz, 1H), 6.77-6.69 (m, 3H), 5.09-5.05 (m, 1H), 3.79 (s, 3H), 3.08-3.01 (m, 2H), 2.91- 2.85(m,1H),2.77-2.67(m,2H),2.42(s,3H),1.36(s,9H)；13C NMR(125MHz,CDCl3):δ173.3, 159.8,143.5,139.7,136.9,129.8,129.6,127.2,121.4,114.7,112.3,81.8,55.3,47.2, 43.5,35.8,28.1,21.6；ESI-MS (m/z, %) 442 [M+Na]+.
Embodiment 13
The synthesis of compound 3al：
4- methoxyphenylboronic acids 2a used in embodiment 1 is changed to 2- methylphenylboronic acid 2l, remaining experimental implementation is the same as real Apply example 1.Obtain product 3al (88% yield, 94%ee).
1H NMR(300MHz,CDCl3):δ 7.66 (d, J=9.0Hz, 2H), 7.28 (d, J=9.0Hz, 2H), 7.14- 7.04(m,4H),5.05-5.00(m,1H),3.11-3.02(m,2H),2.99-2.89(m,1H),2.74-2.65(m,2H), 2.42(s,3H),2.26(s,3H),1.34(s,9H)；13C NMR(125MHz,CDCl3):δ173.5,143.5,137.0, 136.5,136.4,130.6,130.0,129.9,127.2,127.0,126.1,81.8,45.9,43.7,33.2,28.1, 21.7,19.4；ESI-MS (m/z, %) 426 [M+Na]+.
Embodiment 14
The synthesis of compound 3am：
4- methoxyphenylboronic acids 2a used in embodiment 1 is changed to 2- chlorophenylboronic acid 2m, remaining experimental implementation is the same as implementation Example 1.Obtain product 3am (81% yield, 94%ee).
1H NMR(300MHz,CDCl3) δ 7.69 (d, J=9.0Hz, 2H), 7.36-7.31 (m, 1H), 7.28 (d, J= 9.0Hz, 2H), 7.18-7.15 (m, 3H), 5.12 (t, J=6.0Hz, 1H), 3.10-2.99 (m, 3H), 2.89-2.82 (m, 2H),2.41(s,3H),1.33(s,9H)；13C NMR(125MHz,CDCl3)δ173.1,143.5,136.9,136.0,134.2, 131.7,129.9,129.7,128.3,127.2,126.9,81.9,45.2,43.7,33.5,28.0,21.6；ESI-MS(m/ Z, %) 446 [M+Na]+.
Embodiment 15
The synthesis of compound 3an：
4- methoxyphenylboronic acids 2a used in embodiment 1 is changed to 2- fluorobenzoic boric acid 2n, remaining experimental implementation is the same as implementation Example 1.Obtain product 3an (75% yield, 90%ee).
1H NMR(300MHz,CDCl3) δ 7.69 (d, J=9.0Hz, 2H), 7.28 (d, J=9.0Hz, 2H), 7.23-7.12 (m, 2H), 7.06-6.96 (m, 2H), 5.08 (t, J=6.0Hz, 1H), 3.05 (t, J=6.0Hz, 2H), 2.95-2.89 (m, 1H),2.83-2.76(m,2H),2.42(s,3H),1.32(s,9H)；13C NMR(125MHz,CDCl3)δ173.0,161.3(d, JCF=243.8Hz), 143.5,137.0,131.6 (d, JCF=3.8Hz), 129.9,128.7 (d, JCF=7.5Hz), 127.2, 125.2(d,JCF=15Hz), 124.2 (d, JCF=3.8Hz), 115.4 (d, JCF=22.5Hz), 81.9,45.9,43.8, 29.3,28.0,21.6；ESI-MS (m/z, %) 430 [M+Na]+.
Embodiment 16
The synthesis of compound 3ao：
4- methoxyphenylboronic acids 2a used in embodiment 1 is changed to phenyl boric acid 2o, remaining experimental implementation is the same as embodiment 1. Obtain product 3ao (99% yield, 94%ee).
1H NMR(300MHz,CDCl3):δ 7.68 (d, J=9.0Hz, 2H), 7.29-7.20 (m, 5H), 7.11 (d, J= 6.0Hz, 2H), 5.06 (t, J=6.0Hz, 1H), 3.01 (m, 2H), 2.95-2.81 (m, 1H), 2.81-2.62 (m, 2H), 2.42 (s,3H),1.34(s,9H)；13C NMR(125MHz,CDCl3):δ173.3,143.5,138.1,137.0,129.8,129.1, 128.6,127.2,126.7,81.8,47.3,43.6,35.8,28.1,21.6；ESI-MS (m/z, %) 412 [M+Na]+.
Embodiment 17
The synthesis of compound 3ap：
4- methoxyphenylboronic acids 2a used in embodiment 1 is changed to 4- bromobenzeneboronic acid 2p, remaining experimental implementation is the same as implementation Example 1.Obtain product 3ap (99% yield, 95%ee).
1H NMR(300MHz,CDCl3) δ 7.68 (d, J=9.0Hz, 2H), 7.38 (d, J=6.0Hz, 2H), 7.29 (d, J =6.0Hz, 2H), 7.01 (d, J=9.0Hz, 2H), 514-5.07 (m, 1H), 3.02-2.97 (m, 2H), 2.90-2.82 (m, 1H),2.77-2.65(m,2H),2.43(s,3H),1.35(s,9H)；13C NMR(125MHz,CDCl3)δ173.0,143.6, 137.2,136.8,131.6,130.9,129.9,127.2,120.6,82.1,47.2,43.4,35.0,28.1,21.7；ESI- MS (m/z, %) 490 [M+Na]+.
Embodiment 18
The synthesis of compound 3ba：
Para toluene sulfonamide Tert-butyl Methacrylate substrate 1a used in embodiment 1 is changed to tert-butyl acrylate bottom Object 1b, remaining experimental implementation is the same as embodiment 1.Obtain product 3ba (98% yield, 92%ee).
1H NMR(300MHz,CDCl3) δ 7.59 (d, J=7.9Hz, 2H), 7.25 (d, J=7.7Hz, 2H), 7.07 (d, J =8.2Hz, 2H), 6.80 (d, J=8.2Hz, 2H), 3.78 (s, 3H), 3.23 (qd, J=14.3,7.0Hz, 2H), 2.97 (dt, J=22.6,7.0Hz, 3H), 2.73 (d, J=7.5Hz, 2H), 2.40 (s, 3H), 1.59-1.36 (m, 2H), 1.30 (s, 9H), 0.80 (t, J=7.3Hz, 3H)；ESI-MS (m/z, %) 484 [M+Na]+.
Embodiment 19
The synthesis of compound 3ca：
Para toluene sulfonamide Tert-butyl Methacrylate substrate 1a used in embodiment 1 is changed to tert-butyl acrylate bottom Object 1c, remaining experimental implementation is the same as embodiment 1.Obtain product 3ca (98% yield, 92%ee).
1H NMR(300MHz,CDCl3) δ 7.38 (d, J=8.2Hz, 2H), 7.32-7.24 (m, 3H), 7.20 (d, J= 8.0Hz, 2H), 6.99 (d, J=8.5Hz, 4H), 6.76 (d, J=8.5Hz, 2H), 3.89-3.66 (m, 4H), 3.57 (dd, J= 13.4,6.2Hz, 1H), 2.79 (d, J=7.3Hz, 2H), 2.68 (dd, J=14.2,6.6Hz, 1H), 2.40 (s, 3H), 1.28 (s,9H)；ESI-MS (m/z, %) 518 [M+Na]+.
Embodiment 20
The synthesis of compound 3da：
Para toluene sulfonamide Tert-butyl Methacrylate substrate 1a used in embodiment 1 is changed to tert-butyl acrylate bottom Object 1d, remaining experimental implementation is the same as embodiment 1.Obtain product 3da (96% yield, 91%ee).
1H NMR(300MHz,CDCl3) δ 7.67 (d, J=7.9Hz, 2H), 7.29 (d, J=5.8Hz, 7H), 6.84 (d, J =8.3Hz, 2H), 6.73 (d, J=8.3Hz, 2H), 4.49-4.17 (m, 2H), 3.76 (s, 3H), 3.43-3.15 (m, 2H), 2.66 (dd, J=13.2,6.3Hz, 1H), 2.64-2.48 (m, 2H), 2.42 (s, 3H), 1.24 (s, 9H)；ESI-MS(m/ Z, %) 532 [M+Na]+.
Embodiment 21
The synthesis of compound 3ea：
Para toluene sulfonamide Tert-butyl Methacrylate substrate 1a used in embodiment 1 is changed to tert-butyl acrylate bottom Object 1e, remaining experimental implementation is the same as embodiment 1.Obtain product 3ea (96% yield, 99%ee).
1H NMR(300MHz,CDCl3) δ 7.79 (d, J=6.7Hz, 2H), 7.24 (d, J=7.8Hz, 2H), 7.13 (d, J =7.0Hz, 2H), 6.79 (d, J=6.6Hz, 2H), 3.77 (s, 3H), 3.59 (q, J=14.8Hz, 2H), 3.23 (s, 1H), 2.90 (d, J=10.2Hz, 1H), 2.79-2.59 (m, 1H), 2.40 (s, 3H), 1.27 (s, 9H), 1.23 (s, 9H)；ESI-MS (m/z, %) 498 [M+Na]+.
Embodiment 22
The synthesis of compound 3fa：
Para toluene sulfonamide Tert-butyl Methacrylate substrate 1a used in embodiment 1 is changed to tert-butyl acrylate bottom Object 1f, remaining experimental implementation is the same as embodiment 1.Obtain product 3fa (96% yield, 96%ee).
1H NMR(300MHz,CDCl3):δ 7.64 (d, J=9.0Hz, 2H), 7.32 (m, 2H), 7.15 (d, J=9.0Hz, 2H), 6.68 (d, J=9.0Hz, 2H), 5.13-5.02 (m, 1H), 3.83 (s, 3H), 3.13-3.09 (m, 2H), 2.86-2.81 (m,1H),2.72-2.65(m,2H),1.39(s,9H)；ESI-MS (m/z, %) 473 [M+Na]+.
Embodiment 23
The synthesis of compound 3ga：
Under argon gas protection, by 3- (phthalyl aminoethyl) tert-butyl acrylate substrate 1g (0.1mmol), 4- methoxyl groups Phenyl boric acid 2a (0.3mmol), [Rh (COE)2Cl]2(rhodium of 2.5mol%, 0.005mmol), chiral diene ligand (1R, 5R)-Ia (0.0055mmol, 5.5mol%) is put into reaction bulb, and toluene (1mL) is added, past after being stirred to react 30min at room temperature The KOH aqueous solutions (0.05mL) of 1.0M are added in system, the reaction was continued.TLC monitorings are spin-dried for reaction solution, silicon after the reaction was complete The isolated product 3ga of plastic column chromatography (95% yield, 96%ee).
1H NMR(300MHz,CDCl3) δ 7.84 (dd, J=6.2,2.2Hz, 2H), 7.71 (dd, J=5.4,2.9Hz, 2H), 7.09 (d, J=8.2Hz, 2H), 6.79 (d, J=8.4Hz, 2H), 3.77 (s, 3H), 3.72 (t, J=7.5Hz, 2H), 2.87 (dd, J=13.6,8.3Hz, 1H), 2.75 (dd, J=13.7,6.4Hz, 1H), 2.65-2.44 (m, 1H), 2.09-1.90 (m, 1H), 1.83 (td, J=13.7,7.5Hz, 1H), 1.38 (s, 9H)13C NMR(125MHz,CDCl3)δ174.0,168.4, 158.3,134.0,132.3,131.1,130.2,123.3,113.8,80.9,55.4,46.3,37.6,36.3,30.5,28.1； [α]D 20-5.4(c 1.2,CHCl3)；ESI-MS (m/z, %) 432 [M+Na]+.
Embodiment 24
The synthesis of compound 3ga '：
Chiral ligand (1R, 5R)-Ia used in embodiment 23 is changed to (1S, 5S)-Ia, remaining experimental implementation is the same as implementation Example 23 obtains the opposite product 3ga ' of configuration (95% yield, 96%ee).
1H NMR(300MHz,CDCl3) δ 7.83 (dd, J=6.2,2.3Hz, 2H), 7.73 (dd, J=5.5,2.9Hz, 2H), 7.11 (d, J=8.2Hz, 2H), 6.80 (d, J=8.4Hz, 2H), 3.78 (s, 3H), 3.72 (t, J=7.5Hz, 2H), 2.87 (dd, J=13.6,8.3Hz, 1H), 2.76 (dd, J=13.7,6.4Hz, 1H), 2.67-2.42 (m, 1H), 2.11-1.79 (m, 1H), 1.81 (td, J=13.7,7.5Hz, 1H), 1.36 (s, 9H)13C NMR(125MHz,CDCl3)δ174.2,168.3, 158.4,134.5,132.1,131.2,130.4,123.1,113.6,80.9,55.3,46.1,37.7,36.5,30.1,28.2； [α]D 20+5.8(c 1.5,CHCl3)；ESI-MS (m/z, %) 432 [M+Na]+.
Embodiment 25
The synthesis of compound 3gb：
4- methoxyphenylboronic acids 2a used in embodiment 23 is changed to 4- methylphenylboronic acid 2b, remaining experimental implementation is the same as real Apply example 23.Obtain product 3gb (98% yield, 95%ee).
1H NMR(300MHz,CDCl3)δ7.93-7.78(m,2H),7.77-7.56(m,2H),7.05(s,4H),3.72 (t, J=9.0Hz, 2H), 2.90 (dd, J=12.0,6.0Hz, 1H), 2.76 (dd, J=12.0,6.0Hz, 1H), 2.68-2.46 (m,1H),2.29(s,3H),2.12-1.89(m,1H),1.90-1.73(m,1H),1.38(s,9H).13CNMR(125MHz, CDCl3)δ173.9,168.3,135.9,135.8,134.0,132.3,129.1,129.1,123.3,80.8,46.1,38.0, 36.3,30.4,28.1,28.1,21.2；ESI-MS (m/z, %) 416 [M+Na]+.
Embodiment 26
The synthesis of compound 3gd：
4- methoxyphenylboronic acids 2a used in embodiment 23 is changed to 4- chlorophenylboronic acid 2d, remaining experimental implementation is the same as implementation Example 23.Obtain product 3gd (85% yield, 93%ee).
1H NMR(300MHz,CDCl3) δ 7.84 (dd, J=4.6,2.2Hz, 2H), 7.71 (dd, J=5.8,2.6Hz, 2H), 7.21 (d, J=7.5Hz, 2H), 7.11 (d, J=7.5Hz, 2H), 3.73 (t, J=6.0Hz, 2H), 3.00-2.65 (m, 2H),2.65-2.42(m,1H),2.09-1.91(m,1H),1.91-1.69(m,1H),1.37(s,9H).13C NMR(125MHz, CDCl3)δ173.6,168.3,137.5,134.1,132.3,132.2,130.6,128.5,123.4,81.1,45.9,37.6, 36.1,30.6,28.1；ESI-MS (m/z, %) 436 [M+Na]+.
Embodiment 27
The synthesis of compound 3gf：
4- methoxyphenylboronic acids 2a used in embodiment 23 is changed to 4- trifluoromethylbenzene boronic acid 2f, remaining experimental implementation With embodiment 23.Obtain product 3gf (95% yield, 98%ee).
1H NMR(300MHz,CDCl3) δ 7.84-7.79 (m, 2H), 7.72-7.70 (m, 2H), 7.50 (d, J=9.0Hz, 2H), 7.30 (d, J=9.0Hz, 2H), 3.74 (t, J=7.5Hz, 2H), 3.03-2.77 (m, 2H), 2.69-2.47 (m, 1H), 2.13-1.94(m,1H),1.90-1.80(m,1H),1.35(s,9H).13C NMR(125MHz,CDCl3)δ173.4,168.3, 143.2,134.1,132.2,129.6,125.4,125.3,123.4,81.3,45.7,38.0,36.0,30.7,28.0；ESI- MS (m/z, %) 470 [M+Na]+.
Embodiment 28
The synthesis of compound 3gi：
4- methoxyphenylboronic acids 2a used in embodiment 23 is changed to 2- naphthalene boronic acids 2i, the same embodiment of remaining experimental implementation 23.Obtain product 3gi (82% yield, 94%ee).
1H NMR(300MHz,CDCl3)δ7.86-7.66(m,7H),7.63(s,1H),7.48-7.37(m,2H),7.33 (d, J=8.3Hz, 1H), 3.76 (t, J=7.2Hz, 2H), 3.11 (dd, J=13.6,8.3Hz, 1H), 2.98 (dd, J= 13.5,6.5Hz 1H), 2.82-2.59 (m, 1H), 2.12-1.96 (m, 1H), 1.89 (ddd, J=13.5,9.8,3.4Hz, 1H),1.35(s,9H).13C NMR(125MHz,CDCl3)δ173.9,168.4,136.6,134.0,133.6,132.3, 132.3,128.1,127.7,127.7,127.7,127.6,126.0,125.5,123.3,81.0,46.0,38.6,36.3, 30.6,28.1；ESI-MS (m/z, %) 452 [M+Na]+.
Embodiment 29
The synthesis of compound 3gj：
4- methoxyphenylboronic acids 2a used in embodiment 23 is changed to 1- naphthalene boronic acids 2j, the same embodiment of remaining experimental implementation 23.Obtain product 3gj (52% yield, 96%ee).
1H NMR(300MHz,CDCl3) δ 8.02 (d, J=9.0Hz, 1H), 7.85-7.74 (m, 3H), 7.71-7.68 (m, 3H), 7.57-7.30 (m, 4H), 3.71 (t, J=7.5Hz, 2H), 3.47 (dd, J=12.0,7.5Hz, 1H), 3.16 (dd, J= 15,7.5Hz,1H),2.90-2.70(m,1H),2.25-2.01(m,1H),2.02-1.80(m,1H),1.36(s,9H).13C NMR(125MHz,CDCl3)δ174.0,168.3,135.0,134.0,133.9,132.2,131.9,128.9,127.5, 127.4,126.1,125.6,125.4,123.8,123.3,81.0,45.2,36.3,35.8,30.7,28.0；ESI-MS(m/ Z, %) 452 [M+Na]+.
Embodiment 30
The synthesis of compound 3gk：
4- methoxyphenylboronic acids 2a used in embodiment 23 is changed to 2- methoxyphenylboronic acid 2k, remaining experimental implementation is same Embodiment 23.Obtain product 3gk (93% yield, 97%ee).
1H NMR(300MHz,CDCl3)δ7.85-7.82(m,2H),7.77-7.63(m,2H),7.22-7.01(m,2H), (6.82 dd, J=12.9,7.6Hz, 2H), 3.78 (s, 3H), 3.72 (t, J=7.5Hz, 2H), 2.86 (d, J=9.0Hz, 2H), 2.81-2.63(m,1H),2.11-1.92(m,1H),1.91-1.74(m,1H),1.36(s,9H).13C NMR(125MHz, CDCl3)δ174.0,168.4,158.3,134.0,132.3,131.1,130.2,123.3,113.9,80.9,55.4,46.3, 37.6,36.3,30.5,28.1；ESI-MS (m/z, %) 432 [M+Na]+.
Embodiment 31
The synthesis of compound 3gl：
4- methoxyphenylboronic acids 2a used in embodiment 23 is changed to 2- methylphenylboronic acid 2l, remaining experimental implementation is the same as real Apply example 23.Obtain product 3gl (98% yield, 93%ee).
1H NMR(300MHz,CDCl3)δ7.84-7.81(m,2H),7.76-7.61(m,2H),7.19-6.84(m,4H), 3.71 (t, J=7.5Hz, 2H), 2.95 (dd, J=13.5,7.5Hz, 1H), 2.87-2.68 (m, 1H), 2.69-2.53 (m, 1H), 2.31 (s, 3H), 2.14-1.93 (m, 1H), 1.86 (td, J=12.8,7.0Hz, 1H), 1.35 (s, 9H)13C NMR (125MHz,CDCl3)δ174.0,168.2,137.2,136.3,134.0,132.2,130.4,129.8,126.6,125.9, 123.3,80.8,44.7,36.3,35.9,30.7,28.0,19.6；ESI-MS (m/z, %) 416 [M+Na]+.
Embodiment 32
The synthesis of compound 3gm：
4- methoxyphenylboronic acids 2a used in embodiment 23 is changed to 2- chlorophenylboronic acid 2m, remaining experimental implementation is the same as implementation Example 23.Obtain product 3gm (81% yield, 90%ee).
1H NMR(300MHz,CDCl3)δ7.85-7.82(m,2H),7.72-7.69(m,2H),7.35-7.29(m,1H), 7.24-7.21 (m, 1H), 7.18-7.07 (m, 2H), 3.74 (t, J=7.5Hz, 2H), 3.07-2.90 (m, 2H), 2.86-2.69 (m,1H),2.12-1.99(m,1H),1.95-1.79(m,1H),1.37(s,9H).13C NMR(125MHz,CDCl3)δ174.0, 168.4,158.3,134.0,132.3,131.1,130.2,123.3,113.8,80.9,55.4,46.3,37.6,36.3, 30.5,28.1；ESI-MS (m/z, %) 436 [M+Na]+.
Embodiment 33
The synthesis of compound 3gg：
4- methoxyphenylboronic acids 2a used in embodiment 23 is changed to 3- methoxyphenylboronic acid 2g, remaining experimental implementation is same Embodiment 23.Obtain product 3gg (78% yield, 92%ee).
1H NMR(300MHz,CDCl3) δ 7.80-7.74 (m, 2H), 7.68-7.61 (m, 2H), 7.12 (t, J=8.0Hz, 1H), 6.74-6.67 (m, 3H), 3.74 (s, 3H), 3.69 (t, J=6.0Hz, 2H), 3.01-2.81 (m, 1H), 2.75 (dd, J =13.3,6.6Hz, 1H), 2.65-2.41 (m, 1H), 2.04-1.91 (m, 1H), 1.88-1.67 (m, 1H), 1.35 (s, 9H) .13C NMR(126MHz,CDCl3)δ173.8,168.3,159.6,140.5,134.0,132.2,129.3,123.3,121.5, 114.7,112.0,80.9,55.2,45.9,38.4,36.2,30.5,28.0；ESI-MS (m/z, %) 432 [M+Na]+.
Embodiment 34
The synthesis of compound 3gq：
4- methoxyphenylboronic acids 2a used in embodiment 23 is changed to 3- chlorophenylboronic acid 2q, remaining experimental implementation is the same as implementation Example 23.Obtain product 3gq (85% yield, 97%ee).
1H NMR(300MHz,CDCl3) δ 7.84 (dd, J=7.6,4.4Hz, 2H), 7.72 (dd, J=8.8,3.7Hz, 2H), 7.24-7.11 (m, 3H), 7.10-7.05 (m, 1H), 3.73 (t, J=7.5Hz, 2H), 2.99-2.70 (m, 2H), 2.71- 2.45(m,1H),2.20-1.92(m,1H),1.88-1.81(m,1H),1.37(s,9H).13C NMR(125MHz,CDCl3)δ 173.5,168.4,141.1,134.2,134.1,132.2,129.7,129.3,127.4,126.7,123.4,81.2,45.8, 38.0,36.1,30.7,28.0；ESI-MS (m/z, %) 436 [M+Na]+.
Embodiment 35
The synthesis of compound 3go：
4- methoxyphenylboronic acids 2a used in embodiment 23 is changed to phenyl boric acid 2o, the same embodiment of remaining experimental implementation 23.Obtain product 3go (93% yield, 93%ee).
1H NMR(300MHz,CDCl3) δ 7.84 (dd, J=6.0,3.0Hz, 2H), 7.71 (dd, J=6.0,3.0Hz, 2H), 7.33-7.21 (m, 3H), 7.18 (d, J=6.0Hz, 2H), 3.73 (t, J=7.5Hz, 2H), 2.87 (ddd, J=21, 12,7.5Hz,2H),2.70-2.44(m,1H),2.13-1.91(m,1H),1.92-1.73(m,1H),1.36(s,9H).13C NMR(125MHz,CDCl3)δ173.9,168.4,139.0,134.0,132.3,129.2,128.4,126.5,123.4,80.9, 46.0,38.4,36.2,30.6,28.0；ESI-MS (m/z, %) 402 [M+Na]+.
Embodiment 36
The synthesis of compound 3hi：
Under argon gas protection, by 4- (tertbutyloxycarbonyl aminopropyl) tert-butyl acrylate substrate 1h (0.1mmol), 2- naphthalene boronic acids 2i (0.3mmol), [Rh (COE)2Cl]2(rhodium of 2.5mol%, 0.005mmol), chiral diene ligand (1R, 5R)-Ia (0.0055mmol, 5.5mol%) is put into reaction bulb, and toluene (1mL) is added, past after being stirred to react 30min at room temperature The KOH aqueous solutions (0.05mL) of 1.0M are added in system, the reaction was continued.TLC monitorings are spin-dried for reaction solution, silicon after the reaction was complete The isolated product 3hi of plastic column chromatography (63% yield, 89%ee).
1H NMR(300MHz,CDCl3)δ7.83-7.63(m,3H),7.59(s,1H),7.47-7.34(m,2H),7.29 (d, J=7.9Hz, 1H), 4.51 (s, 1H), 3.17-2.97 (m, 3H), 2.84 (dd, J=13.4,6.2Hz, 1H), 2.63 (dd, J=17.8,8.5Hz, 1H), 1.63 (d, J=11.3Hz, 2H), 1.53-1.44 (m, 2H), 1.41 (s, 9H), 1.29 (s, 9H) .13C NMR(125MHz,CDCl3)δ174.8,156.0,137.0,133.6,132.3,128.0,127.7,127.6,127.5, 126.1,125.4,80.6,79.2,48.0,40.5,39.0,29.6,28.5,28.1,28.0；436 [M+ of ESI-MS (m/z, %) Na]+.
Embodiment 37
The synthesis of compound 3ia：
(tertbutyloxycarbonyl aminopropyl) the tert-butyl acrylate substrates of 4- used in embodiment 36 1h is changed to 4- (adjacent benzene two Formyl aminopropyl) tert-butyl acrylate 1i, 2- naphthalene boronic acids 2i is changed to 4- methoxyphenylboronic acid 2a, the same embodiment of remaining experimental implementation 36.Obtain product 3ia (78% yield, 89%ee).
1H NMR(300MHz,CDCl3) δ 7.84 (t, J=7.5Hz, 2H), 7.75-7.64 (m, 2H), 7.06 (d, J= 7.5Hz, 2H), 6.77 (d, J=7.5Hz, 2H), 3.76 (s, 3H), 3.67 (t, J=6.3Hz, 2H), 2.89-2.68 (m, 1H), 2.67-2.56(m,1H),2.54(s,1H),1.79-1.53(m,3H),1.53-1.44(m,1H),1.33(s,9H).13C NMR (125MHz,CDCl3)δ174.6,168.5,158.1,134.0,132.2,131.5,130.1,123.3,113.7,80.5, 55.3,48.1,37.8,37.8,29.4,28.1,26.4；[α]D 20+2.2(c 1.7,CHCl3)；446 [M of ESI-MS (m/z, %) +Na]+.
Embodiment 38
The synthesis of compound 3ia '：
Chiral ligand (1R, 5R)-Ia used in embodiment 37 is changed to (1S, 5S)-Ia, remaining experimental implementation is the same as implementation Example 37 obtains the opposite product 3ia ' of configuration (75% yield, 89%ee).
1H NMR(300MHz,CDCl3) δ 7.82 (t, J=7.5Hz, 2H), 7.76-7.62 (m, 2H), 7.08 (d, J= 7.5Hz, 2H), 6.75 (d, J=7.5Hz, 2H), 3.77 (s, 3H), 3.65 (t, J=6.3Hz, 2H), 2.91-2.65 (m, 1H), 2.68-2.52(m,1H),2.52(s,1H),1.81-1.52(m,3H),1.51-1.45(m,1H),1.32(s,9H).13C NMR (125MHz,CDCl3)δ174.3,168.4,158.0,134.2,132.4,131.6,130.2,123.4,113.8,80.6, 55.1,48.3,37.8,37.7,29.2,28.3,26.2；[α]D 20-1.9(c 0.9,CHCl3)；446 [M of ESI-MS (m/z, %) +Na]+.
Embodiment 39
The synthesis of compound 3if：
(tertbutyloxycarbonyl aminopropyl) the tert-butyl acrylate substrates of 4- used in embodiment 36 1h is changed to 4- (adjacent benzene two Formyl aminopropyl) tert-butyl acrylate 1i, 2- naphthalene boronic acids 2i is changed to 4- trifluoromethylbenzene boronic acid 2f, and remaining experimental implementation is the same as implementing Example 36.Obtain product 3if (48% yield, 93%ee).
1H NMR(300MHz,CDCl3) δ 7.88-7.77 (m, 2H), 7.73-7.71 (m, 2H), 7.49 (d, J=6.0Hz, 2H), 7.27 (d, J=6.0Hz, 2H), 3.69 (t, J=6.0Hz, 2H), 3.02-2.83 (m, 1H), 2.81-2.68 (m, 1H), 2.70-2.58(m,1H),1.87-1.61(m,3H),1.58-1.45(m,1H),1.32(s,9H).13C NMR(125MHz, CDCl3)δ174.1,168.5,143.6,134.1,132.2,129.5,125.3,125.3,123.4,80.9,47.5,38.4, 37.7,29.6,28.1,27.9,26.2；ESI-MS (m/z, %) 484 [M+Na]+.
Embodiment 40
The synthesis of compound 3io：
(tertbutyloxycarbonyl aminopropyl) the tert-butyl acrylate substrates of 4- used in embodiment 36 1h is changed to 4- (adjacent benzene two Formyl aminopropyl) tert-butyl acrylate 1i, 2- naphthalene boronic acids 2i is changed to phenyl boric acid 2o, and remaining experimental implementation is the same as embodiment 36.It obtains Product 3io (66% yield, 90%ee).
1H NMR(300MHz,CDCl3) δ 7.87-7.75 (m, 2H), 7.71 (d, J=3.0Hz, 2H), 7.26-7.20 (m, 2H), 7.17-7.14 (m, 3H), 3.67 (t, J=6.0Hz, 2H), 2.86 (dd, J=15.0,9.0Hz, 1H), 2.72-2.54 (m,2H),1.76-1.57(m,3H),1.55-1.46(m,1H),1.32(s,9H).13C NMR(125MHz,CDCl3)δ174.5, 168.4,139.3,134.0,132.2,129.1,128.3,126.3,123.3,80.5,77.4,77.2,76.9,47.8, 38.7,37.8,29.5,28.0,26.3；ESI-MS (m/z, %) 416 [M+Na]+.
Embodiment 41
The synthesis of compound 4ai：
Compound 3ai (0.1mmol) is dissolved in tetrahydrofuran (1mL) in round-bottomed flask, then to being added three in system Ethamine (0.2mmol), di-tert-butyl dicarbonate (0.2mmol), 4-dimethylaminopyridine (5mol%), reaction are stirred at room temperature After 8 hours, TLC detection reactions, which finish, is added 5mL methanol, magnesium powder (5mmol), ultrasonic reaction after ammonium chloride (2.5mmol) solid Obtain within two hours product 4ai (74% yield, 93%ee).
1H NMR(300MHz,CDCl3) δ 7.74 (q, J=9.3Hz, 3H), 7.60 (s, 1H), 7.41 (p, J=7.3Hz, 2H), 7.30 (d, J=9.0Hz, 1H), 4.85 (s, 1H), 3.42-3.16 (m, 2H), 3.05 (dd, J=15.4,10.5Hz, 1H),2.96-2.81(m,2H),1.41(s,9H),1.31(s,9H).13C NMR(125MHz,CDCl3)δ173.7,156.0, 136.2,133.6,132.4,128.2,127.7,127.6,127.6,127.5,126.1,125.5,81.2,79.4,48.1, 42.1,36.3,28.5,28.1；ESI-MS (m/z, %) 408 [M+Na]+.
Embodiment 42
The synthesis of compound 4ga：
Compound 3ga (0.1mmol) is dissolved in tetrahydrofuran (1mL) in round-bottomed flask, then to water is added in system Hydrazine (0.5mmol) is closed, reaction is filtered after stirring 8 hours at room temperature, ethyl acetate extraction, by organic phase after anhydrous sodium chloride washing It is spin-dried for, tetrahydrofuran (1mL), triethylamine (0.2mmol), di-tert-butyl dicarbonate (0.2mmol), 4- diformazan ammonia is added thereto Yl pyridines (5mmol), after reaction is stirred 2 hours at room temperature, TLC detection reactions finish to obtain product 4ga (71% yield, 94%ee).
1H NMR(300MHz,CDCl3) δ 7.08 (d, J=8.4Hz, 2H), 6.81 (d, J=8.4Hz, 2H), 4.60 (s, 1H),3.78(s,3H),3.23-2.99(m,2H),2.90-2.74(m,1H),2.74-2.60(m,1H),2.61-2.47(m, 1H),1.84-1.55(m,2H),1.43(s,9H),1.35(s,9H).13C NMR(125MHz,CDCl3)δ178.6,137.9, 135.0,133.7,129.0,128.6,128.5,128.4,128.4,127.0,126.5,40.6,39.6,29.7,26.5； ESI-MS (m/z, %) 402 [M+Na]+.
Embodiment 43
The synthesis of compound 5hi：
Compound 3hi (0.1mmol) is dissolved in the saturation hydrochloric acid solution of ethyl acetate in round-bottomed flask, reacts on room temperature It is lower stirring 2 hours after, TLC detection reaction finishes and has white solid precipitation, filter filter cake be product 5hi (85% yield, 88%ee).
1H NMR(300MHz,CD3OD)δ7.91-7.72(m,3H),7.67(s,1H),7.57-7.16(m,3H),3.13 (dd, J=12.3,8.5Hz, 1H), 2.89 (ddd, J=34.5,14.9,7.1Hz, 4H), 1.65 (dd, J=38.1,7.9Hz, 4H).13C NMR(125MHz,MeOD)δ178.6,137.9,135.0,133.7,129.0,128.6,128.5,128.4, 128.4,127.0,126.5,40.6,39.6,29.7,26.5；ESI-MS (m/z, %) 258 [M+H]+
Embodiment 44
The synthesis of compound 6ak：
Compound 3ak (0.1mmol) is dissolved in after being stirred 1 hour in dichloromethane/trifluoroacetic acid (v 5/3), is added full Reaction is quenched with sodium carbonate liquor, ethyl acetate extraction is spin-dried for organic phase decompression to obtain crude product.It will slightly be produced under argon gas protection Object is dissolved under -78 degree in dichloromethane, is added Boron tribromide (0.25mmol) low-temp reaction 5h, and TLC monitorings are after the reaction was complete Aqueous ammonium chloride solution is added, reaction is quenched, you can prepares chirality chromane-2-one 6ak (75% yield, 93%ee).
1H NMR(300MHz,CDCl3) δ 7.76 (d, J=6.0Hz, 2H), 7.33 (d, J=9.0Hz, 2H), 7.26 (t, J =6.0Hz, 1H), 7.19 (d, J=6.0Hz, 1H), 7.1 (t, J=6.0Hz, 1H), 7.03 (d, J=6.0Hz, 1H), 5.32 (t, J=4.5Hz, 1H), 3.41-3.34 (m, 1H), 3.32-3.20 (m, 2H), 3.10-2.91 (m, 2H), 2.43 (s, 3H)；13C NMR(125MHz,CDCl3)δ170.5,151.2,143.9,137.0,130.0,128.7,128.3,127.1,125.0, 122.3,116.8,43.1,40.1,27.4,21.7；ESI-MS (m/z, %) 332 [M+H]+.
Embodiment 45
The synthesis of compound 7al：
After compound 3al (0.1mmol) is dissolved in carbon tetrachloride (5mL) return stirring 5 hours, saturated potassium carbonate is added Solution is stirred to react 1 hour, and ethyl acetate is obtained by extraction organic phase decompression and is spin-dried for, you can obtaining compound 7al, (two steps 45% are received Rate, 94%ee).
1H NMR(300MHz,CDCl3) δ 7.52 (d, J=8.1Hz, 2H), 7.26-7.22 (m, 1H), 7.20-7.17 (m, 4H), 7.13-7.08 (m, 1H), 4.73 (d, J=15.0Hz, 1H), 4.17-4.07 (m, 2H), 3.28 (dd, J1=12Hz, J2 =9Hz, 1H), 3.09-2.97 (m, 2H), 2.45-2.42 (m, 1H), 2.38 (s, 3H), 1.43 (s, 9H)；13C NMR (125MHz,CDCl3)δ172.0,143.3,138.8,136.9,136.8,130.1,129.7,129.2,128.3,127.3, 127.1,81.5,53.3,52.5,43.9,36.9,28.1,21.6；ESI-MS (m/z, %) 424 [M+Na]+.
Embodiment 46
The synthesis of compound 8am：
By compound 3am (0.1mmol), palladium (5mol%), 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyls (5.5mol%), for potassium carbonate (0.1mmol) in reaction tube, reaction is added 10 under nitrogen protection:1 1,4- dioxane and The mixed solvent of water.React under 80 degree react 4 hours can prepare chiral benzo tetrahydroquinoline 8am (98% yield, 94% ee)。
1H NMR(300MHz,CDCl3) δ 7.77 (d, J=9.0Hz, 1H), 7.51 (d, J=9.0Hz, 2H), 7.22-7.17 (m,3H),7.11-7.02(m,2H),4.36(dd,J1=15Hz, J2=6.0Hz, 1H), 3.47 (dd, J1=15Hz, J2= 12Hz, 1H), 2.63 (d, J=9.0Hz, 2H), 2.48-2.41 (m, 1H), 2.39 (s, 3H), 1.43 (s, 9H)
Embodiment 47
Compound 3aa uses the synthesis of other chiral diene ligands：
Chiral ligand (1R, 5R)-Ia used in embodiment 1 is changed to the chiral diene ligand listed by following table, point It is not reacted, remaining experimental implementation obtains product 3aa results such as following table with embodiment 1：
entry L Yield (%) Ee (%)
1 (1R,5R)-Ib 76 96
2 (1R,5R)-If 76 95
3 (1R,5R)-Ig 80 96
4 (1R,5R)-Ih 87 96
5 (1R,5R)-Ii 96 93
6 (1R,4R)-IIa 79 -96
7 (1R,4R)-IIf 83 -95
8 (1R,4R)-IIi 78 -96
Embodiment 48
Compound 3ga uses the synthesis of other chiral diene ligands：
Chiral ligand (1R, 5R)-Ia used in embodiment 23 is changed to the chiral diene ligand listed by following table, point It is not reacted, remaining experimental implementation obtains product 3ga with embodiment 23.
entry L Yield (%) Ee (%)
1 (1R,5R)-If 89 93
2 (1R,5R)-Ig 90 96
3 (1R,5R)-Ih 91 94
4 (1R,4R)-IIa 89 -94
5 (1R,4R)-IIf 91 -95
6 (1R,4R)-IIi 93 -95
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To be made various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (10)

1. chiral beta shown in a kind of formula 3/ or ent-32Or γ2Or δ2The preparation method of amino acid esters compound, feature It is, the method includes the steps：
Catalyst monovalence rhodium metal and chiral diene ligand it is complex-catalyzed under, 1 compound of formula and organoboron reagent 2 carry out Isosorbide-5-Nitrae-addition/asymmetry protonation reaction, obtains chiral beta shown in formula 3/ or ent-32Or γ2Or δ2Amino acid esters Close object：
In formula, n=1,2 or 3；
R1、R2It is each independently hydrogen, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C6-30Aryl, substitution or not Substituted C6-30Arylmethyl, substituted or unsubstituted C6-30Aryl sulfonyl, substituted or unsubstituted C6-30Aroyl, R '-O-C (O)-, or combinations thereof；Or R1、R2Substituted or unsubstituted C is formed with the N being connected6-30Aromatic amide；
R3For the C of linear chain or branched chain1-6Alkyl, C6-30Aryl, C6-30Arylmethyl；
[B] is selected from the group：B(OR)2Or (BO)3, wherein R is H or C1-6Linear chain or branched chain alkyl；
R4It is selected from the group：Substituted or unsubstituted C6-30Aryl,
R ' is selected from the group：C1-6Alkyl, C1-6Halogenated alkyl, substituted or unsubstituted C6-30Aryl, substituted or unsubstituted C6-30Virtue Methyl；
Wherein, the substitution refers to that the hydrogen atom on group is mono-substituted or polysubstituted, and the substituent group respectively independently selects From the following group：Halogen, nitro, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, benzyloxy, C6-10Aryl；
The chiral diene ligand has the following structure formula：
Or
In formula,
Ar is selected from the group：Substituted or unsubstituted C6-30Aryl, substituted or unsubstituted C4-12Heteroaryl, wherein two Ar groups It can be the same or different, the substitution refers to that the hydrogen atom on group is mono-substituted or polysubstituted, described heteroaryl The hetero atom contained is oxygen or sulphur；The substituent group is selected from the group：Halogen, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, benzyloxy, C6-10Aryl, or combinations thereof；The halogen is F, Cl, Br or I.
2. the method as described in claim 1, which is characterized in that use gauge, the monovalence rhodium metal to urge by 1 compound of formula Agent dosage is 1~30mol%；The chiral diene ligand dosage is 1~30mol%.
3. the method as described in claim 1, which is characterized in that Formulas I and formula ent-I chiral diene ligands enantiomerism each other Body；Formula II and formula ent-II chiral diene ligands enantiomter each other.
4. the method as described in claim 1, which is characterized in that the chiral diene ligand is selected from the group：
5. the method as described in claim 1, which is characterized in that the monovalence rhodium metal compound is selected from the group：[Rh (C2H4)2Cl]2、[Rh(C2H4)2OH]2、[Rh(COE)2Cl]2、[Rh(COE)2OH]2, or combinations thereof.
6. the method as described in claim 1, which is characterized in that in the reaction equation in organoboron reagent 2, [B] is B (OR)2 Or (BO)3, wherein R is H or C1-6Linear chain or branched chain alkyl, the dosage of organoboron reagent 2 be 100mol%~ 500mol%.
7. the method as described in claim 1, which is characterized in that the method also has selected from the group below one or more special Sign：
(1) reaction carries out in the presence of additive aqueous solution, and the additive aqueous solution is a concentration of 0.5mol/L~5mol/L Compound selected from the group below aqueous solution：KF、KOH、K2CO3、Na2CO3、K3PO4、K2HPO4Or combination thereof；
(2) reaction carries out in the presence of additive aqueous solution, and the dosage of the additive is 10mol%~500mol%；
(3) reaction carries out in organic solvent, and organic solvent used is selected from the group：Dichloromethane (CH2Cl2), ether (Et2O), toluene (Toluene), Isosorbide-5-Nitrae-dioxane (Dioxane), tetrahydrofuran (THF), or combinations thereof；
(4) temperature reacted is 0~100 DEG C；
(5) reaction time is 1~24 hour.
8. a kind of structural formula 3/ or ent-3 compounds represented, it is characterised in that：
In formula, n, R1、R2、R3、R4As defined in claim 1.
9. compound as claimed in claim 8, which is characterized in that the compound is selected from the group：
10. the purposes of structural formula 3/ as claimed in claim 8 or ent-3 compounds represented, which is characterized in that be used for：
I) chiral beta is prepared2Or γ2Or δ2Amino-acid ester 4 or ent-4；
Ii chiral beta) is prepared2Or γ2Or δ2Amino acid 5 or ent-5；
Iii chiral Benzoheterocyclic compounds) are prepared, the chirality Benzoheterocyclic compounds are：
N, R1, R2, R3, R4As defined in claim 1；
R5And R6Coupled carbon atom connects to form substituted or unsubstituted phenyl, wherein the substitution refers on group Hydrogen atom be substituted by one or more substituents, the substituent group is selected from the group：Halogen, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, benzyloxy, C6-10Aryl, or combinations thereof.
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