CN103570600B - A kind of chiral alpha methylene beta-lactam class compound and its preparation method and application - Google Patents

A kind of chiral alpha methylene beta-lactam class compound and its preparation method and application Download PDF

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CN103570600B
CN103570600B CN201210253862.6A CN201210253862A CN103570600B CN 103570600 B CN103570600 B CN 103570600B CN 201210253862 A CN201210253862 A CN 201210253862A CN 103570600 B CN103570600 B CN 103570600B
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CN103570600A (en
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丁奎岭
王晓明
孟繁烨
王正
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Shanghai Institute of Organic Chemistry of CAS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/10—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
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    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
    • C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
    • 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

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Abstract

The invention discloses a kind of chiral alpha methylene beta-lactam class compound and its preparation method and application.The complex compound formed using chiral phosphine ligand and Metal Palladium is the asymmetric pi-allyl aminating reaction of catalyst one kind Morita Baylis Hillman adducts as committed step, can high activity and selectivity the carboxylic acid derivates for preparing key intermediate chiral beta amido α methylene, by a step cyclisation can prepare chirality α methylene beta-lactam class compounds.Such compound has antitumor activity.

Description

A kind of chiral alpha-methylene beta-lactam compound and its preparation method and application
Technical field
The present invention relates to medicinal chemistry arts, relate in particular to a kind of chiral alpha-methylene beta-lactam compound and Its preparation method and application.
Background technology
Chiral beta-lactam is a kind of construction unit being widely present in natural products and medicine.As beta-lactam resists Raw element, it is a kind of material using beta-lactam four-membered ring as precursor structure, because it has strong bacteriostasis so as in anti-sense It is extremely important in dye clinical practice.In recent years, occurs substantial amounts of antibacterial due to widely using for antibiotic Material, therefore synthesis for antibiotic and its transformation of structure, with regard to extremely urgent, what especially exploitation was new has antibacterial activity New construction 'beta '-lactam compounds just have great importance.
The carboxylic acid derivates of chiral β-aryl amine alpha-methylene are the important centres of a kind of medicine and natural products synthesis Body (Chem.Rev.2003,103,811-891;Chem.Eur.J.2011,17,13676.).Because the asymmetric MBH of azepine is anti- It should require to be connected with electron withdraw group on the nitrogen-atoms of imines, this causes this method in the structure of substrate type and product allyl amine On be all limited by very large.Other transition metal or the MBH of small molecule catalysis add anti-with the Asymmetric allylic alkylation of thing Should be the important method of the carboxylic acid derivates for the beta-amido alpha-methylene for preparing chirality, but regrettably, up to now, there has been no As nucleopilic reagent, the carboxylic acid that high region and mapping selectively synthesize β-aryl amine alpha-methylene derives the aromatic amine of weakly nucleophilic The report of thing.
The content of the invention
It is an object of the invention to provide a kind of chiral alpha-methylene beta-lactam compound.
The present invention also provides the synthetic method of above-mentioned chiral alpha-methylene beta-lactam compound, including among its key The synthetic method of the carboxylic acid derivates of body chirality beta-amido alpha-methylene.
The first aspect of the present invention, there is provided a kind of beta-lactam compound, structure is shown in formula I：
In formula：R1、R2It is respectively and independently selected from substituted or unsubstituted following group：C1-6Alkyl, C3-10Cycloalkyl, C6-20 Aryl；It is described to substitute the substituent for referring to be selected from the group to substitute：Halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl halide Base ,-OR11Or-NR12, wherein R11、R12It is each independently selected from hydrogen, acetyl group, propiono, tert-butoxycarbonyl, benzyl, benzyl Oxygen carbonyl, trityl, trimethyl silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or diphenyl methyl silicon substrate；
* stereogenic centres are represented, compound of formula I is R configurations or is S configurations；
Or * represents that compound of formula I is raceme.
In another preference, the compound is：
In another preference, the compound be the compound of Formulas I -1 and the compound group of Formulas I -2 into raceme.
In various：R1、R2, * it is defined as described above.
The second aspect of the present invention, there is provided the preparation method of the compound described in first aspect, including step：
(a) in organic solvent, in the presence of alkali, network is formed using chiral phosphine ligand and transition-metal catalyst precursor Compound is as catalyst R2-NH2Asymmetric pi-allyl aminating reaction occurs with the compound of formula 1, prepares key intermediate formula 2 Compound；
(b) in organic solvent, the compound of formula 2 cyclization in the presence of alkali, obtains the compound described in first aspect.
In various：R1、R2, * it is defined as described above；
R3For methyl, ethyl, isopropyl, normal-butyl, the tert-butyl group, benzyl or adamantyl；
LG is acetyl group (Ac), tert-butoxycarbonyl (Boc), methoxycarbonyl (- CO2) or two (ethyoxyl) phosphine oxygen Me Base (POEt2)。
In another preference, described catalyst is by described chiral phosphine ligand with transition-metal catalyst precursor lazy Under property atmosphere, in organic solvent, react 0.1~1.0 hour and obtain under -78 °C~100 °C.Preferably 0~25 °C Lower reaction 0.5~1.0 hour.
In another preference, the mol ratio of described chiral phosphine ligand and transition-metal catalyst precursor is (1~10)： 1.Preferably 1~2：1.
In another preference, the transition-metal catalyst precursor is palladium catalyst precursor, is Pd (OAc)2、PdCl2、 Pd2(dba)3、Pd2(dba)3·CHCl3、Pd(dba)2、[Pd(C3H5)Cl]2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(CH3CN) Cl2One or both of more than.
In another preference, described chiral phosphine ligand has following structure：
R4、R5、R6、R7、R8、R9It is respectively and independently selected from hydrogen, halogen, substituted or unsubstituted following group：C1~C10Alkane Base, C1~C4Alkoxy, C3~C30Cycloalkyl or aryl；
R10、R11It is respectively and independently selected from substituted or unsubstituted following group：C3~C10Cycloalkyl, C1~C10Alkyl, 2- furyls or aryl；X is selected from CH2, NH, NCH3, O or S；N=0~4；
Wherein described substitution is substituted by following substituent：Halogen, C1-6Alkyl, C1-6Haloalkyl or C1-6Alkoxy.
In another preference, the chiral phosphine ligand is
In another preference, in the step (a), described alkali, R2-NH2With the mol ratio of the compound of formula 1 for 1~ 10：1~10：1；And/or the mol ratio of described catalyst and the compound of formula 1 is 0.00001~0.1：1.
In another preference, described alkali be potassium carbonate, potassium phosphate, cesium carbonate, triethylamine, diisopropyl ethyl amine, Double (trimethylsilyl) acetamides (BSA) of N, O-, one kind in the fluoro triphenyl silicate (TBAT) of tetra-n-butyl ammonium two or It is two or more.
In another preference, in the step (b), the mol ratio of described alkali and the compound of formula 2 is 1~10：1.
In another preference, in the step (b), described alkali and the mol ratio of the compound of formula 2 are 1~2：1.
In another preference, the reaction temperature of the step (b) is -80 °C~150 °C, is preferably -20 °C~110 ° C.Reaction time is 0.5~48 hour, preferably 6~12 hours.
In another preference, in the step (b), described alkali is two (the silicon substrate amido of hexamethyl two) tin (Sn [N (TMS)2]2), LHMDS (LHMDS), lithium diisopropylamine (LDA), tert-butyl group magnesium chloride, tert-butyl bromide Change more than one or both of magnesium, isopropylmagnesium chloride, isopropyl magnesium bromide.
In another preference, described organic solvent be benzene,toluene,xylene, dichloromethane, chloroform, carbon tetrachloride, At least one in 1,2- dichloroethanes, ether, tetrahydrofuran, methanol, ethanol, DMF or dimethyl sulfoxide (DMSO) Kind.
The third aspect of the present invention, there is provided the application of the compound described in first aspect, for preparing prevention and/or treatment The medicine of tumour.
In another preference, the prevention, treatment are realized by suppressing the growth of tumour cell.
The fourth aspect of the present invention, there is provided a kind of compound of formula 2,
In formula：* stereogenic centres are represented, are R configurations or S configurations；
R1、R2It is respectively and independently selected from substituted or unsubstituted following group：C1-6Alkyl, C3-10Cycloalkyl, C6-20Virtue Base；It is described to substitute the substituent for referring to be selected from the group to substitute：Halogen, C1-6Alkyl, C1-6Alkoxy or C1-6Haloalkyl ,- OR11、-NR12, wherein R11、R12Be each independently selected from hydrogen, acetyl group, propiono, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl group, Trityl, trimethyl silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or diphenyl methyl silicon substrate；
R3For methyl, ethyl, isopropyl, normal-butyl, the tert-butyl group, benzyl or adamantyl.
The fifth aspect of the present invention, there is provided the preparation method of the compound of formula 2, including step：
In organic solvent, in the presence of alkali, formed and be complexed using chiral phosphine ligand and transition-metal catalyst precursor Thing is as catalyst R2-NH2Asymmetric pi-allyl aminating reaction occurs with the compound of formula 1, the compound of formula 2 is prepared；
In various：R1、R2、R3, * it is defined as described above.
Organic solvent, alkali, chiral phosphine ligand, transition-metal catalyst precursor and the selection of reaction condition and of the invention second Step (a) is identical in aspect.
The present invention is catalyst using the biphosphine ligand of chiral fragrant Spiroketals skeleton and the complex compound of Metal Palladium, real first The MBH adducts of high region and high enantioselectivity are showed（The compound of formula 1）Pi-allyl aminating reaction, single step reaction synthesizes The carboxylic acid derivates of chiral beta-amido alpha-methylene.And again through a step conversion can synthesis of chiral the β with bioactivity- Lactam analog compound.
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, so as to form new or preferable technical scheme.As space is limited, exist This no longer tires out one by one states.
Brief description of the drawings
Fig. 1 is compound (S) -3d of the gained of embodiment 16 mono-crystalline structures figure.
Fig. 2 is compound (R, R, R) -5a of the gained of embodiment 36 mono-crystalline structures figure.
Specific implementation method
Present inventor in depth studies by extensive, prepares a kind of new chiral phosphine ligand, and with this Phosphine ligands realize the pi-allyl aminating reaction of the MBH adducts of high region and high enantioselectivity as catalyst, and a step is anti- The carboxylic acid derivates of the beta-amido alpha-methylene of chirality should have been synthesized.And again through a step conversion can synthesis of chiral have biology The beta-lactam compound of activity, have the function that to suppress tumour growth.On this basis, the present invention is completed.
Term
Term " alkyl " represents the linear or branched chain hydrocarbon moiety of saturation, such as-CH3Or-CH (CH3)2.Term " alkoxy " table Show and refer to the generation group after alkyl links with oxygen atom, such as-OCH3,-OCH2CH3.Term " cycloalkyl " represents the cyclic hydrocarbon of saturation Base section, such as cyclohexyl.Term " aryl " represents the hydrocarbyl portion for including one or more aromatic rings, including but not limited to benzene Base, benzyl, phenylene, naphthyl, naphthylene, pyrenyl, anthryl, phenanthryl.
Unless otherwise indicated, alkyl as described herein, alkoxy, cycloalkyl and aryl simultaneously including substitution and do not take The part in generation.Possible substituent includes, but are not limited on alkyl, alkoxy, cycloalkyl and aryl：C1-C6Alkyl, C1-C6 Haloalkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C10Cycloalkyl, C3-C10Cycloalkenyl group, C1-C6Alkoxy, aryl, hydroxyl, halogen Element, amino.
Phosphine ligands
The Phosphine ligands that the present invention uses have following structure：
In formula, R4、R5、R6、R7、R8、R9It is respectively and independently selected from hydrogen, halogen, substituted or unsubstituted following group：C1~C10 Alkyl, C1~C4Alkoxy, C3~C30Cycloalkyl or aryl；
R10、R11It is respectively and independently selected from substituted or unsubstituted following group：C3~C10Cycloalkyl, C1~C10Alkyl, 2- furyls or aryl；X is selected from CH2, NH, NCH3, O or S；N=0~4；
Wherein described substitution is substituted by following substituent：Halogen, C1-6Alkyl, C1-6Haloalkyl or C1-6Alkoxy.
In another preference, it is described substitution be by following substituent it is monosubstituted, two substitution or three substitution：Halogen, C1-6Alkane Base, C1-6Haloalkyl or C1-6Alkoxy.
In another preference, R4、R5、R6、R7、R8、R9It is respectively and independently selected from hydrogen, C1~C6Alkyl, C1~C4Alcoxyl Base, C3~C30Cycloalkyl, halogen or phenyl；
R10、R11Independently selected from C3~C10Cycloalkyl, C1~C10Alkyl, 2- furyls or phenyl, the cycloalkanes Base, alkyl, phenyl are optionally substituted by following substituent：Halogen, C1-6Alkyl, C1-6Haloalkyl or C1-6Alkoxy.
In another preference, R4、R5、R6、R7、R8、R9It is respectively and independently selected from hydrogen, C1~C6Alkyl, C1~C4Alcoxyl Base, C3~C10Cycloalkyl, phenyl or halogen；
R11、R10It is respectively and independently selected from phenyl, the phenyl of substitution, C3~C6Cycloalkyl or C2~C6Alkyl, the substitution For by following substituent it is monosubstituted, two substitution or three substitution：Halogen, C1-6Alkyl, C1-6Haloalkyl or C1-6Alkoxy；
X is selected from CH2、O、NCH3, or S.
In another preference, R4With R9For identical group；R5With R8For identical group；R6With R7For identical base Group.
In another preference, R10With R11For identical group.
In another preference, described Phosphine ligands are
Various middle R4、R5、R6、R7、R8、R9、R10、R11It is defined as described above.
The compound of formula 2
The compound of formula 2 of the present invention, has following structure：
In formula：* stereogenic centres are represented, are R configurations or S configurations；
R1、R2It is respectively and independently selected from substituted or unsubstituted following group：C1-6Alkyl, C3-10Cycloalkyl, C6-20Virtue Base；It is described to substitute the substituent for referring to be selected from the group to substitute：Halogen, C1-6Alkyl, C1-6Alkoxy or C1-6Haloalkyl ,- OR11、-NR12, wherein R11、R12Be each independently selected from hydrogen, acetyl group, propiono, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl group, Trityl, trimethyl silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or diphenyl methyl silicon substrate；
R3For methyl, ethyl, isopropyl, normal-butyl, the tert-butyl group, benzyl or adamantyl.
In another preference, R3For benzyl or adamantyl.
In another preference, * represents stereogenic centres, and the compound of formula 2 is R configurations.
In another preference, R1、R2It is respectively and independently selected from substituted or unsubstituted following group：C1-6Alkyl, C3-10's Cycloalkyl；It is described to substitute the substituent for referring to be selected from the group to substitute：Halogen, C1-6Alkyl, C1-6Alkoxy or C1-6Alkyl halide Base ,-OR11、-NR12, wherein R11、R12It is each independently selected from hydrogen, acetyl group, propiono, tert-butoxycarbonyl, benzyl, benzyloxy Carbonyl, trityl, trimethyl silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or diphenyl methyl silicon substrate.
The preparation method of the compound of formula 2 of the present invention, including step：
In organic solvent, in the presence of alkali, formed and be complexed using chiral phosphine ligand and transition-metal catalyst precursor Thing is as catalyst R2-NH2Asymmetric pi-allyl aminating reaction occurs with the compound of formula 1, the compound of formula 2 is prepared；
In various：R1、R2、R3, * it is defined as described above；
LG is acetyl group (Ac), tert-butoxycarbonyl (Boc), methoxycarbonyl (- CO2) or two (ethyoxyl) phosphine oxygen Me Base (POEt2)。
The compound of formula 1 is Morita-Baylis-Hillman adducts.
Described organic solvent is benzene,toluene,xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes, second At least one of ether, tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide or dimethyl sulfoxide (DMSO).
Described alkali be potassium carbonate, potassium phosphate, cesium carbonate, triethylamine, diisopropyl ethyl amine, N, the double (trimethyl silicanes of O- Alkyl) acetamide (BSA), it is more than one or both of the fluoro triphenyl silicate (TBAT) of tetra-n-butyl ammonium two.It can adopt With the aqueous solution of alkali, such as wet chemical, concentration is 0.1~8.0 mole every liter, preferable 0.5~5 mole every liter.
In another preference, the alkali is wet chemical (1~2 mole every liter) or triethylamine.
Described catalyst by described chiral phosphine ligand and transition-metal catalyst precursor under atmosphere of inert gases, In organic solvent, react 0.1~1.0 hour and obtain under -78 °C~100 °C.Reaction 0.5~1.0 is small under preferably 0~25 °C When.
The mol ratio of described chiral phosphine ligand and transition-metal catalyst precursor is (1~10)：1.Preferably 1~2：1.
Described Phosphine ligands areR4、R5、R6、R7、 R8、R9、R10、R11It is defined as described above.
The transition-metal catalyst precursor is palladium catalyst precursor, is Pd (OAc)2、PdCl2、Pd2(dba)3、Pd2 (dba)3·CHCl3、Pd(dba)2、[Pd(C3H5)Cl]2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(CH3CN)Cl2In one kind It is or two or more.
In another preference, the palladium catalyst precursor is [Pd (C3H5)Cl]2。
Described alkali, R2-NH2Mol ratio with the compound of formula 1 is 1~10：1~10：1；And/or
The mol ratio of described catalyst and the compound of formula 1 is 0.00001~0.1：1.
It is preferred that described alkali, R2-NH2Mol ratio with the compound of formula 1 is 1~3：1~3：1；And/or
The mol ratio of described catalyst and the compound of formula 1 is 0.01~0.05：1.
In another preference, withComplex compound is formed with transition-metal catalyst precursor to make For catalyst R2-NH2Reacted with the compound of formula 1, prepare key intermediate formula 2-1 compounds.
In another preference, withComplex compound conduct is formed with transition-metal catalyst precursor Catalyst R2-NH2Reacted with the compound of formula 1, prepare the enantiomer of key intermediate formula 2-1 compounds.
Compound of formula I
The compound of formula I of the present invention, is a kind of alpha-methylene beta-lactam compound, has following structure：
In formula：R1、R2It is respectively and independently selected from substituted or unsubstituted following group：C1-6Alkyl, C3-10Cycloalkyl, C6-20 Aryl；It is described to substitute the substituent for referring to be selected from the group to substitute：Halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl halide Base ,-OR11Or-NR12, wherein R11、R12It is each independently selected from hydrogen, acetyl group, propiono, tert-butoxycarbonyl, benzyl, benzyl Oxygen carbonyl, trityl, trimethyl silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or diphenyl methyl silicon substrate；
* stereogenic centres are represented, compound of formula I is R configurations or is S configurations；
Or * represents that compound of formula I is raceme.
In another preference, * represents stereogenic centres, and compound of formula I is R configurations.
In another preference, the R1、R2It is respectively and independently selected from substituted or unsubstituted following group：C1-6Alkyl, C3-10Cycloalkyl；It is described to substitute the substituent for referring to be selected from the group to substitute：Halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogen Substituted alkyl ,-OR11Or-NR12, wherein R11、R12It is each independently selected from hydrogen, acetyl group, propiono, tert-butoxycarbonyl, benzyl Base, benzyloxycarbonyl group, trityl, trimethyl silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or diphenyl methyl Silicon substrate；* stereogenic centres are represented, compound of formula I is S configurations.
In another preference, the R1、R2It is respectively and independently selected from substituted C6-20Aryl；The substitution refers to be chosen Substitute from the substituent of the following group：Halogen, C1-6Alkyl, C1-6Haloalkyl ,-OR11Or-NR12, wherein R11、R12Independently of one another Selected from hydrogen, acetyl group, propiono, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl group, trityl, trimethyl silicon substrate, the tert-butyl group two Methylsilyl, tert-butyl diphenyl silicon substrate or diphenyl methyl silicon substrate；* stereogenic centres are represented, compound of formula I is R configurations.
In another preference, R1Selected from phenyl, optionally substituted by following substituent：Halogen, C1-6Alkyl, C1-6Alkyl halide Base, C1-6Alkoxy ,-OR11Or-NR12；
R2Selected from C1-6Alkyl, C3-10Cycloalkyl, benzyl or substituted phenyl, optionally substituted by following substituent：Halogen, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxy ,-OR11Or-NR12；
R11、R12It is defined as described above.
In another preference, * represents stereogenic centres, and compound of formula I is S configurations, and R1、R2It is not phenyl or C1-6 The phenyl of alkoxy substitution.
In another preference, * represents that compound of formula I is raceme, and R1、R2It is not phenyl or C1-6Alkoxy substitution Phenyl.
It is described substitution be it is monosubstituted, two substitution, three substitution, four substitution or five substitution, it is preferred that for it is monosubstituted, two substitution, Or three substitution.It is able to can also be differed with identical when for two substitutions, three substitutions, four substitutions or five substitutions, substituent, such as-OR11Take The phenyl in generation, can be by 1,2,3 or 4-OR on phenyl11Substitution, each R11It independently is hydrogen, acetyl group, propiono, tertiary fourth oxygen Base carbonyl, benzyl, benzyloxycarbonyl group, trityl, trimethyl silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or Diphenyl methyl silicon substrate
In another preference, the compound is：
In various, R1、R2It is defined as described above.
The preparation method of compound of formula I
The preparation method of the compound of formula I of the present invention, methods described include step：
(a) in organic solvent, in the presence of alkali, complex compound is formed using Phosphine ligands and transition-metal catalyst precursor As catalyst R2-NH2Asymmetric pi-allyl aminating reaction occurs with the compound of formula 1, prepares the chemical combination of key intermediate formula 2 Thing；
(b) in organic solvent, the compound of formula 2 cyclization in the presence of alkali, obtains compound of formula I.
In various：R1、R2, * it is defined as described above；
R3For methyl, ethyl, isopropyl, normal-butyl, the tert-butyl group, benzyl or adamantyl；
LG is acetyl group (Ac), tert-butoxycarbonyl (Boc), methoxycarbonyl (- CO2) or two (ethyoxyl) phosphine oxygen Me Base (POEt2)。
Described organic solvent is benzene,toluene,xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes, second At least one of ether, tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide or dimethyl sulfoxide (DMSO).
The experiment condition of the step (a) is as previously described.
In the step (b), described alkali is two (the silicon substrate amido of hexamethyl two) tin (Sn [N (TMS)2]2), hexamethyl two Silicon substrate amido lithium (LHMDS), lithium diisopropylamine (LDA), tert-butyl group magnesium chloride, tert-butyl group magnesium bromide, isopropylmagnesium chloride, It is more than one or both of isopropyl magnesium bromide.
In another preference, in the step (b), the alkali is two (the silicon substrate amido of hexamethyl two) tin (Sn [N (TMS)2]2) or LHMDS (LHMDS).
In the step (b), the mol ratio of described alkali and the compound of formula 2 is 1~10：1.
In another preference, in the step (b), described alkali and the mol ratio of the compound of formula 2 are 1~2：1.
In another preference, the reaction temperature of the step (b) is -80 °C~150 °C, is preferably -20 °C~110 ° C.Reaction time is 0.5~48 hour, preferably 6~12 hours.
In another preference, the cyclization in the presence of alkali of formula 2-1 compounds, the compound of Formulas I -1 is obtained.
In another preference, enantiomer cyclization in the presence of alkali of formula 2-1 compounds, the compound of Formulas I -2 is obtained.With On the way
The compound of formula I of the present invention, In Leukemic Cells In Vitro cell HL60, lung cell A549, HepG-2 cell, breast The tumour cells such as adenocarcinoma cell MDA-MB-231, stomach cancer MKN-45 have obvious inhibiting effect.Therefore, prevention can be prepared, controlled Treat tumour medicine.It is preferred that for preparing preventing/treating leukaemia, lung cancer or the medicine of liver cancer.
The medicine can be as active component and pharmacologically acceptable excipient or carrier system by compound of formula I Standby pharmaceutical composition.
" pharmaceutically acceptable excipient or carrier " can be one or more biocompatible solids or liquid filler or Gelatinous mass, they are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representational method of application includes (but being not limited to)：Orally, in knurl, rectum, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
The present invention compound of formula I can be administered alone, or with other pharmaceutically acceptable compounds（As other are anti- Tumour medicine）Administering drug combinations.Representational antineoplastic（Such as chemotherapeutics）Including（But it is not limited to）：Cis-platinum, carboplatin, happiness Set alkali, adriamycin, bleomycin, fluorouracil.
Due to alpha-methylene construction unit, can carry out converting as intermediate the more novel chiral beta of preparation structure- Lactam analog compound.
The present invention is advantageous in that：
(1) a kind of new alpha-methylene beta-lactam compound is provided, available for preparing anti-tumor drug.
(2) a kind of preparation method of new alpha-methylene beta-lactam compound is provided.
(3) method of the invention, using amine as nucleopilic reagent, using new chiral fragrant Spiroketals skeleton Phosphine ligands and The complex compound that Metal Palladium is formed is the aminating reaction of catalyst Morita-Baylis-Hillman adducts, can high activity With high region and the carboxylic acid derivates for preparing key intermediate chirality beta-amido alpha-methylene of enantioselectivity, by a step Cyclisation can prepare the alpha-methylene beta-lactam compound of chirality, and method is simple and easy.
The present invention is specifically described below by embodiment, it is necessary to it is pointed out here that be：Following examples are only It is used to further illustrate the present invention, it is impossible to be interpreted as limiting the scope of the invention, those skilled in the art Protection scope of the present invention is belonged to according to some nonessential modifications and adaptations that the above of the present invention is made.
Embodiment 1
The present embodiment is using aniline as nucleopilic reagent, N, and double (trimethylsilyl) acetamides (BSA) of O- are alkali, biphosphine ligand (R, R, R)-La and metal salt Pd2(dba)3Catalyst is prepared in situ, under different solvents, catalysis substrate 1a asymmetric allyl Base aminating reaction.Reaction equation is as follows：
Reaction is as follows：Under argon atmosphere, Pd2(dba)3(4.5mg, 0.005mmol) and (R, R, R)-La (8.2mg, 0.0125mmol) it is separately added into a schlenk pipes, adds solvent (5mL) in table 1, after stirring 10 minutes at room temperature, successively adds Enter substrate 1a (117.1mg, 0.5mmol), double (trimethylsilyl) the acetamide BSA (305mg, 1.5mmol) of N, O- and aniline (140mg,1.5mmol).After stirring three hours at room temperature, (3 × 10mL), anhydrous sodium sulfate drying, mistake are extracted with dichloromethane After filter concentration, column chromatography purifies, and obtains the product of asymmetric amination.
Table 1：Influence of the solvent to asymmetric amination results
[α] D20=+ 79.8 ° (c1.0, CHCl3), 78%ee [are determined, chiral AD-H posts by high performance liquid chromatography;n-Hex/i-PrOH=95: 5,1.0mL/min,254nm;tR(major)=7.51min;tR(minor)=8.21min].1H NMR(300MHz,CDCl3)δ= 7.37-7.27(m,5H),7.14(t,J=8.1Hz,2H),6.71(t,J=7.2Hz,1H),6.56(d,J=7.8Hz,2H),6.38 (s,1H),5.96(s,1H),5.40(s,1H),4.15(s,1H),3.69(s,3H)ppm.
Embodiment 2
For the present embodiment using aniline as nucleopilic reagent, dichloromethane is solvent, biphosphine ligand (R, R, R)-La and metal salt Pd2 (dba)3Catalyst is prepared in situ, in the presence of different alkali, catalysis substrate 1a asymmetric pi-allyl aminating reaction.Reaction equation It is as follows：
Reaction is as follows：Under argon atmosphere, Pd2(dba)3(4.5mg, 0.005mmol) and (R, R, R)-La (8.2mg, 0.0125mmol) it is separately added into a schlenk pipes, adds anhydrous methylene chloride (5mL), after stirring 10 minutes at room temperature, first Substrate 1a (117.1mg, 0.5mmol), alkali (1.5mmol) described in table 2 and aniline (140mg, 1.5mmol) are added afterwards.Room temperature After lower stirring three hours, extracted (3 × 10mL) with dichloromethane, anhydrous sodium sulfate drying, after filtering and concentrating, column chromatography purifying, Obtain the product of asymmetric amination.
Table 2：Influence of the alkali to asymmetric amination results
Embodiment 3
For the present embodiment using aniline as nucleopilic reagent, dichloromethane is solvent, biphosphine ligand (R, R, R)-La and different gold Catalyst is prepared in situ in category palladium salt, and 1 mole of every liter of wet chemical is alkali, and catalysis substrate 1a asymmetric pi-allyl amination is anti- Should.Reaction equation is as follows：
Reaction is as follows：Under argon atmosphere, metal palladium salt precursor (0.01mmol, for palladium atom) and (R, R, R)-La (8.2mg, 0.0125mmol) is separately added into a schlenk pipes, adds anhydrous methylene chloride (5mL), stirs 10 points at room temperature Zhong Hou, successively add substrate 1a (117.1mg, 0.5mmol), wet chemical (1M, 1.5mL, 1.5mmol) and aniline (140mg,1.5mmol).After stirring three hours at room temperature, (3 × 10mL), anhydrous sodium sulfate drying, mistake are extracted with dichloromethane After filter concentration, column chromatography purifies, and obtains the product of asymmetric amination.
Table 3：Influence of the metal palladium salt precursor to asymmetric amination results
Embodiment 4
For the present embodiment using aniline as nucleopilic reagent, dichloromethane is solvent, biphosphine ligand (R, R, R)-La and [Pd (C3H5) Cl]2Catalyst is prepared in situ, 1 mole of every liter of wet chemical is alkali, is catalyzed the asymmetric pi-allyl of the substrate of different ester groups Aminating reaction.Reaction equation is as follows：
Reaction is as follows：Under argon atmosphere, [Pd (C3H5)Cl]2(1.8mg, 0.005mmol) and (R, R, R)-La (0.0125mmol) is separately added into a schlenk pipes, adds anhydrous CH2Cl2(5mL), after stirring 10 minutes at room temperature, successively Add substrate (0.5mmol), K2CO3(the 1.0M aqueous solution, 1.5mL, 1.5mmol) and aniline (140mg, 1.5mmol).At room temperature After stirring three hours, extracted (3 × 10mL) with dichloromethane, anhydrous sodium sulfate drying, after filtering and concentrating, column chromatography purifying, obtained The product of asymmetric amination.
Table 4：Influence of the ester group to asymmetric amination results in substrate
Embodiment 5
The present embodiment is using aniline as nucleopilic reagent, different biphosphine ligands (R, R, R)-L and metal salt [Pd (η-C3H5) Cl]2Catalyst is prepared in situ, is catalyzed substrate 1b asymmetric pi-allyl aminating reaction, reaction equation is as follows：
Reaction is as follows：Under argon atmosphere, [Pd (C3H5)Cl]2(1.8mg, 0.005mmol) and (R, R, R)-L (0.0125mmol) is separately added into a Schlenk pipes, adds anhydrous CH2Cl2(5mL), after stirring 10 minutes at room temperature, successively Add substrate 1b (124.1mg, 0.5mmol), K2CO3(the 1.0M aqueous solution, 1.5mL, 1.5mmol) and aniline (140mg, 1.5mmol).After stirring three hours at room temperature, (3 × 10mL), anhydrous sodium sulfate drying, filtering and concentrating are extracted with dichloromethane Afterwards, column chromatography purifies, and obtains aminate.
Table 5：It is asymmetry of the catalyst to substrate 1b with different biphosphine ligand (R, R, R)-L and Metal Palladium complex compound Amination results
2a,[α]D 20=+120.0(c1.00,CHCl3), 96%ee [is determined, chiral AD-H posts by high performance liquid chromatography；Just oneself Alkane/isopropanol=95:5,1.0mL/min,254nm;tR(major)=7.07min;tR(minor)=7.81min].1H NMR (400MHz,CDCl3)δ=7.38-7.27(m,5H),7.16(t,J=8.4Hz,2H),6.72(t,J=7.2Hz,1H),6.57(d, J=8.8Hz,2H),6.38(s,1H),5.94(s,1H),5.40(d,J=4.8Hz,1H),4.19-4.09(m,3H),1.20(t,J =7.2Hz,3H)ppm;13C NMR(100MHz,CDCl3)δ=166.1,146.6,140.6,140.2,129.1,128.7, 127.7,127.5,125.9,117.8,113.3,60.7,59.0,14.0ppm.
Embodiment 6
The present embodiment is using different amine as nucleopilic reagent, biphosphine ligand (R, R, R)-Lc and metal salt [Pd (η-C3H5)Cl]2 Catalyst, catalysis substrate 1b asymmetric pi-allyl aminating reaction is prepared in situ (reaction equation is as follows)：
Reaction is as follows：Under argon atmosphere, [Pd (C3H5)Cl]2(1.8mg, 0.005mmol) and (R, R, R)-Lc (9.6mg, 0.0125mmol) it is separately added into a schlenk pipes, adds anhydrous CH2Cl2(5mL), after stirring 10 minutes at room temperature, successively add Enter substrate 1b (124.1mg, 0.5mmol), K2CO3(the 1.0M aqueous solution, 1.5mL, 1.5mmol) and aromatic amine (1.5mmol).Room After the lower stirring of temperature three hours, (3 × 10mL) is extracted with dichloromethane, anhydrous sodium sulfate drying, after filtering and concentrating, column chromatography is pure Change, obtain chiral aminate 9.Experimental result is as follows：
2b, colorless oil, 88% yield, [α]D 20=+98.4(c1.00,CHCl3), 95%ee [is surveyed by high performance liquid chromatography It is fixed, chiral AD-H posts；N-hexane/isopropanol=95:5,1.0mL/min,254nm;tR(major)=11.08min;tR(minor)= 12.12min].1H NMR(400MHz,CDCl3)δ=7.38-7.25(m,5H),6.75(d,J=8.8Hz,2H),6.54(d,J= 9.2Hz,2H),6.37(s,1H),5.93(s,1H),5.32(s,1H),4.18-4.09(m,2H),3.94(s,1H),3.72(s, 3H),1.20(t,J=7.2Hz,3H)ppm;13C NMR(100MHz,CDCl3)δ=166.2,152.2,141.0,140.9, 140.5,128.6,127.6,127.4,125.8,114.7,114.6,60.7,59.7,55.7,14.0ppm.
2c, colorless oil, 89% yield, [α]D 20=+78.9(c1.00,CHCl3), 95%ee [is surveyed by high performance liquid chromatography It is fixed, chiral AD-H posts；N-hexane/isopropanol=99:1,1.0mL/min,254nm;tR(major)=18.31min;tR(minor)= 22.32min].1H NMR(400MHz,CDCl3)δ=7.37-7.25(m,5H),6.86(t,J=8.8Hz,2H),6.51-6.48 (m, 2H), 6.37 (s, 1H), 5.89 (s, 1H), 5.33 (s, 1H), 4.16-4.13 (m, 2H), 4.08 (s, br, 1H), 1.21 (t, J=7.2Hz,3H)ppm;13C NMR(100MHz,CDCl3)δ=166.1,155.9(d,J(F,C)=234.0Hz),143.0(d, J(F,C)=1.8Hz),140.4(d,J(F,C)=23.4Hz),128.7(s),127.7(s),127.4(s),125.9(s),115.6 (s),115.4(s),114.2(d,J(F,C)=7.4Hz),60.8,59.5,14.0ppm;19F-NMR(376MHz,CDCl3)δ- 127.4ppm.
2d, white solid, 83% .Mp78-80 DEG C of yield, [α]D 20=+115.0(c1.00,CHCl3), 95%ee is [by efficient Liquid chromatogram measuring, chiral AD-H posts；N-hexane/isopropanol=98:2,1.0mL/min,254nm;tR(major)= 16.31min;tR(minor)=18.01min].1H NMR(400MHz,CDCl3)δ=7.33-7.19(m,7H),6.42(d,J= 8.8Hz,2H),6.36(s,1H),5.85(s,1H),5.35(s,1H),4.16-4.05(m,3H),1.18(t,J=7.2Hz,3H) ppm;13C NMR(100MHz,CDCl3)δ=165.9,145.5,140.0,139.8,131.7,128.6,127.7,127.3, 125.9,114.9,109.3,60.7,58.8,13.9ppm.
2e, colorless oil, 67% yield, [α]D 20=+53.3(c1.00,CHCl3), 96%ee [is surveyed by high performance liquid chromatography It is fixed, chiral AD-H posts；N-hexane/isopropanol=99:1,1.0mL/min,254nm;tR(major)=7.96min;tR(minor)= 8.76min].1H NMR(400MHz,CDCl3)δ=7.43-7.25(m,6H),7.11(t,J=10.8Hz,1H),6.59-6.54 (m,2H),6.38(s,1H),5.85(s,1H),5.49(d,J=8.0Hz,1H),4.87(d,J=7.6Hz,1H),4.21-4.10 (m,2H),1.20(t,J=9.2Hz,3H)ppm;13C NMR(100MHz,CDCl3)δ=165.9,143.4,140.0,139.9, 132.2,128.7,128.3,127.8,127.3,125.9,118.2,112.4,109.8,60.8,58.5,13.9ppm.
2f, colorless oil, 91% yield, [α]D 20=+95.2(c1.00,CHCl3), 95%ee [is surveyed by high performance liquid chromatography It is fixed, chiral AD-H posts；N-hexane/isopropanol=98:2,1.0mL/min,254nm;tR(major)=11.66min;tR(minor)= 12.88min].1H NMR(400MHz,CDCl3)δ=7.37-7.22(m,5H),6.96(d,J=8.0Hz,2H),6.50(d,J= 8.4Hz,2H),6.37(s,1H),5.93(s,1H),5.37(s,1H),4.18-4.03(m,3H),2.22(s,3H),1.19(t, J=7.2Hz,3H)ppm;13C NMR(100MHz,CDCl3)δ=166.2,144.4,140.8,140.4,129.6,128.6, 127.6,127.4,127.0,125.8,113.5,60.7,59.2,20.3,14.0ppm.
2g, colorless oil, 86% yield, [α]D 20=+102.8(c1.00,CHCl3), 96%ee is [by high performance liquid chromatography Measure, chiral AD-H posts；N-hexane/isopropanol=99:1,1.0mL/min,254nm;tR(major)=15.11min;tR (minor)=16.75min].1H NMR(400MHz,CDCl3)δ=7.37-7.23(m,5H),7.04(t,J=7.6Hz,1H), 6.54(d,J=7.2Hz,1H),6.40-6.38(m,3H),5.93(s,1H),5.39(s,1H),4.18-4.09(m,3H),2.25 (s,3H),1.20(t,J=7.2Hz,3H)ppm;13C NMR(100MHz,CDCl3)δ=166.2,146.7,140.8,140.3, 138.9,129.0,128.6,127.6,127.4,125.8,118.7,114.1,110.4,60.7,58.9,21.5,14.0ppm.
2h, colorless oil, 85% yield, [α]D 20=+86.6(c1.00,CHCl3), 96%ee [is surveyed by high performance liquid chromatography It is fixed, chiral AD-H posts；N-hexane/isopropanol=85:15,1.0mL/min,254nm;tR(major)=10.38min;tR(minor) =12.36min].1H NMR(400MHz,CDCl3)δ=7.38-7.24(m,5H),6.39(s,1H),5.95(s,1H),5.82(s, 2H),5.40(s,1H),4.19-4.10(m,3H),3.73(s,9H),1.20(t,J=7.2Hz,3H)ppm;13C NMR (100MHz,CDCl3)δ=166.0,153.5,143.3,140.4,130.0,128.5,127.5,127.2,125.7,90.8, 60.7,60.6,59.0,55.6,13.8ppm.
Embodiment 7
The present embodiment is using aniline as nucleopilic reagent, biphosphine ligand (R, R, R)-Lc and metal salt [Pd (η-C3H5)Cl]2Scene Prepare catalyst, be catalyzed the asymmetric pi-allyl aminating reaction of substrate 1 (reaction equation is as follows)：
Reaction is as follows：Under argon atmosphere, [Pd (C3H5)Cl]2(1.8mg, 0.005mmol) and (R, R, R)-Lc (9.6mg, 0.0125mmol) it is separately added into a schlenk pipes, adds anhydrous CH2Cl2(5mL), after stirring 10 minutes at room temperature, successively add Enter substrate 1 (0.5mmol), K2CO3(the 1.0M aqueous solution, 1.5mL, 1.5mmol) and aniline (139.6mg, 1.5mmol).At room temperature After stirring three hours, extracted (3 × 10mL) with dichloromethane, anhydrous sodium sulfate drying, after filtering and concentrating, column chromatography purifying, obtained Chiral aminate.Experimental result is as follows：
2i, white solid, 64% .Mp93-94 DEG C of yield, [α]D 20=+146.5(c1.00,CHCl3), 91%ee is [by efficient Liquid chromatogram measuring, chiral AD-H posts；N-hexane/isopropanol=98:2,1.0mL/min,254nm;tR(major)=6.91min; tR(minor)=8.44min].1H NMR(400MHz,CDCl3)δ=7.24-7.13(m,6H),6.71(t,J=7.2Hz,1H), 6.55(d,J=8.0Hz,2H),6.43(s,1H),5.89(s,1H),5.60(s,1H),4.20-4.07(m,2H),3.85(s, Br, 1H), 2.40 (s, 3H), 1.18 (t, J=7.2Hz, 3H) ppm;13C NMR(100MHz,CDCl3)δ=166.4,146.8, 140.0,138.7,136.7,130.7,129.1,127.7,126.3,126.2,126.0,117.6,112.8,60.7,54.7, 19.1,14.0ppm.
2j, white solid, 89% .Mp56-57 DEG C of yield, [α]D 20=+131.8(c1.00,CHCl3), 97%ee is [by efficient Liquid chromatogram measuring, chiral AD-H posts；N-hexane/isopropanol=98:2,1.0mL/min,254nm;tR(major)=9.52min; tR(minor)=11.05min].1H NMR(400MHz,CDCl3)δ=7.21-7.07(m,6H),6.70(t,J=7.6Hz,1H), 6.56(d,J=8.4Hz,2H),6.37(s,1H),5.93(s,1H),5.36(s,1H),4.19-4.08(m,3H),2.33(s, 3H),1.20(t,J=7.2Hz,3H)ppm;13C NMR(100MHz,CDCl3)δ=166.2,146.7,140.6,140.2, 138.3,129.1,128.5,128.4,128.2,125.7,124.5,117.7,113.3,60.7,58.9,21.4,14.0ppm.
2k, colorless oil, 90% yield, [α]D 20=+129.6(c1.00,CHCl3), 95%ee is [by high performance liquid chromatography Measure, chiral AD-H posts；N-hexane/isopropanol=98:2,1.0mL/min,254nm;tR(major)=12.55min;tR (minor)=14.98min].1H NMR(400MHz,CDCl3)δ=7.26-7.22(m,2H),7.16-7.12(m,4H),6.70 (t,J=8.4Hz,1H),6.56(d,J=8.4Hz,2H),6.36(s,1H),5.92(s,1H),5.36(s,1H),4.18-4.09 (m,3H),2.32(s,3H),1.21(t,J=7.6Hz,3H)ppm;13C NMR(100MHz,CDCl3)δ=166.2,146.7, 140.3,137.7,137.4,129.3,129.1,127.4,125.5,117.7,113.3,60.7,58.6,21.0,14.0ppm.
2l, colorless oil, 96% yield, [α]D 20=+132.6(c1.00,CHCl3), 95%ee is [by high performance liquid chromatography Measure, chiral AD-H posts；N-hexane/isopropanol=98:2,1.0mL/min,254nm;tR(major)=20.63min;tR (minor)=23.04min].1H NMR(400MHz,CDCl3)δ=7.28(d,J=8.4Hz,2H),7.15(t,J=7.6Hz,2H), 6.86(d,J=8.4Hz,2H),6.71(t,J=7.2Hz,1H),6.56(d,J=8.0Hz,2H),6.35(s,1H),5.92(s, 1H),5.35(s,1H),4.19-4.09(m,3H),3.78(s,3H),1.21(t,J=7.2Hz,3H)ppm;13C NMR (100MHz,CDCl3)δ=166.2,159.0,146.7,140.3,132.7,129.0,128.6,125.3,117.7,114.0, 113.3,60.7,58.3,55.2,14.0ppm.
2m, colorless oil, 96% yield, [α]D 20=+89.9(c1.00,CHCl3), 97%ee [is surveyed by high performance liquid chromatography It is fixed, chiral AD-H posts；N-hexane/isopropanol=98:2,1.0mL/min,254nm;tR(major)=12.72min;tR(minor)= 13.89min].1H NMR(400MHz,CDCl3)δ=7.35-7.32(m,2H),7.16(t,J=8.0Hz,2H),7.01(t,J= 8.8Hz,2H),6.73(t,J=7.2Hz,1H),6.57(d,J=8.0Hz,2H),6.38(s,1H),5.92(s,1H),5.38(s, 1H), 4.18-4.13 (m, 3H), 1.21 (t, J=6.8Hz, 3H) ppm;13C NMR(100MHz,CDCl3)δ=166.0,162.2 (d,J(F,C)=244.0Hz),146.5(s),140.1(s),136.4(d,J(F,C)=2.9Hz),129.1(d,J(F,C)=7.8Hz), 126.0 (s), 118.0 (s), 115.6 (s), 115.4 (s), 113.4 (s), 60.8,58.3,14.0ppm;19F-NMR(376MHz, CDCl3)δ-114.6ppm
2n, white solid, 85% .Mp80-81 DEG C of yield, [α]D 20=+94.8(c1.00,CHCl3), 97%ee is [by efficient liquid Phase chromatographic determination, chiral AD-H posts；N-hexane/isopropanol=98:2,1.0mL/min,254nm;tR(major)=15.55min;tR (minor)=17.82min].1H NMR(400MHz,CDCl3)δ=7.43-7.41(m,2H),7.24-7.22(m,2H),7.15- 7.11(m,2H),6.70(t,J=7.2Hz,1H),6.55-6.53(m,2H),6.37(s,1H),5.88(s,1H),5.36(s, 1H),4.18-4.09(m,3H),1.19(t,J=7.6Hz,3H)ppm;13C NMR(100MHz,CDCl3)δ=165.8,146.3, 139.8,139.6,131.6,129.1,129.0,126.2,121.5,117.9,113.3,60.8,58.3,13.9ppm.
2o, white solid, 90% .Mp74-75 DEG C of yield, [α]D 20=+97.0(c1.00,CHCl3), 96%ee is [by efficient liquid Phase chromatographic determination, chiral AD-H posts；N-hexane/isopropanol=98:2,1.0mL/min,254nm;tR(major)=14.26min;tR (minor)=15.88min].1H NMR(400MHz,CDCl3)δ=7.30-7.25(m,4H),7.12(t,J=7.6Hz,2H), 6.70(t,J=7.2Hz,1H),6.54(d,J=8.4Hz,2H),6.36(s,1H),5.88(s,1H),5.37(s,1H),4.17- 4.07(m,3H),1.18(t,J=7.6Hz,3H)ppm;13C NMR(100MHz,CDCl3)δ=165.8,146.3,139.9, 139.1,133.3,129.0,128.7,128.6,126.2,117.9,113.3,60.7,58.2,13.9ppm.
2p, colorless oil, 83% yield, [α]D 20=+94.6(c1.00,CHCl3), 98%ee [is surveyed by high performance liquid chromatography It is fixed, chiral OD-H posts；N-hexane/isopropanol=90:10,1.0mL/min,254nm;tR(minor)=5.92min;tR(major)= 6.38min].1H NMR(400MHz,CDCl3)δ=7.36(s,1H),7.24-7.21(m,3H),7.13(t,J=7.6Hz,2H), 6.70(t,J=7.2Hz,1H),6.54(d,J=8.0Hz,2H),6.38(s,1H),5.88(s,1H),5.37(d,J=5.2Hz, 1H),4.20-4.07(m,3H),1.19(t,J=7.2Hz,3H)ppm;13C NMR(100MHz,CDCl3)δ=165.7,146.3, 142.7,139.6,134.3,129.8,129.0,127.7,127.4,126.5,125.6,117.9,113.3,60.8,58.3, 13.8ppm.
Embodiment 8
The present embodiment is using P-nethoxyaniline as nucleopilic reagent, biphosphine ligand (R, R, R)-Lc and metal [Pd (C3H5)Cl]2 Complex compound is prepared in situ as catalyst, catalysis substrate 1c asymmetric pi-allyl aminating reaction (reaction equation is as described below)：
Reaction is as follows：Under argon atmosphere, [Pd (C3H5)Cl]2(1.8mg, 0.005mmol) and (R, R, R)-Lc (9.6mg, 0.0125mmol) it is separately added into a schlenk pipes, adds anhydrous CH2Cl2(5mL), after stirring 10 minutes at room temperature, successively add Enter substrate 1c (139.1mg, 0.5mmol), K2CO3(the 1.0M aqueous solution, 1.5mL, 1.5mmol) and P-nethoxyaniline (185mg, 1.5mmol).After stirring three hours at room temperature, (3 × 10mL), anhydrous sodium sulfate drying, filtering and concentrating are extracted with dichloromethane Afterwards, column chromatography purifies, and obtains chiral aminate.Experimental result is as follows：
2q, yellow solid, 91% .Mp88-89 DEG C of yield, [α]D 20=+67.5(c1.00,CHCl3), 96%ee is [by efficient liquid Phase chromatographic determination, chiral AD-H posts；N-hexane/isopropanol=95:5,1.0mL/min,254nm;tR(major)=21.10min;tR (minor)=22.50min].1H NMR(400MHz,CDCl3)δ=7.28(d,J=8.0Hz,2H),6.85(d,J=8.0Hz,2H), 6.74(d,J=8.4Hz,2H),6.52(d,J=8.0Hz,2H),6.34(s,1H),5.91(s,1H),5.27(s,1H),4.18- 4.07 (m, 2H), 3.90 (s, br, 1H), 3.77 (s, 3H), 3.72 (s, 3H), 1.21 (t, J=6.8Hz, 3H) ppm;13C NMR (100MHz,CDCl3)δ=166.3,159.0,152.1,141.0,140.6,132.9,128.6,125.3,114.6,114.5, 113.9,60.6,59.1,55.6,55.1,14.0ppm.
Embodiment 9
The present embodiment with 3,4,5- trimethoxy-anilines for nucleopilic reagent, biphosphine ligand (R, R, R)-Lc and metal [Pd (C3H5)Cl]2Complex compound is prepared in situ as catalyst, (reaction equation is as follows for catalysis substrate 1c asymmetric pi-allyl aminating reaction It is described)：
Reaction is as follows：Under argon atmosphere, [Pd (C3H5)Cl]2(1.8mg, 0.005mmol) and (R, R, R)-Lc (9.6mg, 0.0125mmol) it is separately added into a schlenk pipes, adds anhydrous CH2Cl2(5mL), after stirring 10 minutes at room temperature, successively add Enter substrate 1c (139.1mg, 0.5mmol), K2CO3(the 1.0M aqueous solution, 1.5mL, 1.5mmol) and 3,4,5- trimethoxy-anilines (274.8mg,1.5mmol).After stirring three hours at room temperature, extracted (3 × 10mL) with dichloromethane, anhydrous sodium sulfate drying, After filtering and concentrating, column chromatography purifying, chiral aminate is obtained.Experimental result is as follows：
2r, colorless oil, 90% yield, [α]D 20=+101.7(c1.00,CHCl3), 96%ee is [by high performance liquid chromatography Measure, chiral AD-H posts；N-hexane/isopropanol=90:10,1.0mL/min,254nm;tR(major)=25.19min;tR (minor)=27.66min].1H NMR(400MHz,CDCl3)δ=7.28(d,J=8.8Hz,2H),6.84(d,J=8.8Hz,2H), 6.35 (s, 1H), 5.94 (s, 1H), 5.82 (s, 2H), 5.35 (s, 1H), 4.23 (s, br, 1H), 4.18-4.09 (m, 2H), 3.74-3.72(m,12H),1.21(t,J=7.2Hz,3H)ppm;13C NMR(100MHz,CDCl3)δ=165.9,158.7, 153.3,143.3,140.5,132.3,129.7,128.2,125.0,113.6,90.6,60.5,60.4,58.2,55.4, 54.8,13.7ppm.
Embodiment 10
The present embodiment with 3,4,5- trimethoxy-anilines for nucleopilic reagent, biphosphine ligand (R, R, R)-Lc and metal [Pd (C3H5)Cl]2Complex compound is prepared in situ as catalyst, (reaction equation is as follows for catalysis substrate 1d asymmetric pi-allyl aminating reaction It is described)：
Reaction is as follows：Under argon atmosphere, [Pd (C3H5)Cl]2(1.8mg, 0.005mmol) and (R, R, R)-Lc (9.6mg, 0.0125mmol) it is separately added into a schlenk pipes, adds anhydrous CH2Cl2(5mL), after stirring 10 minutes at room temperature, successively add Enter substrate 1d (169.1mg, 0.5mmol), K2CO3(the 1.0M aqueous solution, 1.5mL, 1.5mmol) and 3,4,5- trimethoxy-anilines (274.8mg,1.5mmol).After stirring three hours at room temperature, extracted (3 × 10mL) with dichloromethane, anhydrous sodium sulfate drying, After filtering and concentrating, column chromatography purifying, chiral aminate is obtained.Experimental result is as follows：
2s, colorless oil, 92% yield, [α]D 20=+102.5(c1.00,CHCl3), 98%ee is [by high performance liquid chromatography Measure, chiral AD-H posts；N-hexane/isopropanol=80:20,1.0mL/min,254nm;tR(minor)=14.57min;tR (major)=19.44min].1H NMR(400MHz,CDCl3)δ=6.62(s,2H),6.40(s,1H),5.98(s,1H),5.86 (s, 2H), 5.34 (s, 1H), 4.29 (s, br, 1H), 4.20 (m, 2H), 3.82-3.74 (m, 18H), 1.25 (t, J=7.2Hz, 3H)ppm;13C NMR(100MHz,CDCl3)δ=165.9,153.3,152.9,143.2,140.1,136.9,135.9,129.8, 125.4,104.0,90.6,60.5,60.4,60.3,59.1,55.6,55.4,13.7ppm.
Embodiment 11
The present embodiment with 3,4,5- trimethoxy-anilines for nucleopilic reagent, biphosphine ligand (R, R, R)-Lc and metal [Pd (C3H5)Cl]2Complex compound is prepared in situ as catalyst, (reaction equation is as follows for catalysis substrate 1e asymmetric pi-allyl aminating reaction It is described)：
Reaction is as follows：Under argon atmosphere, [Pd (C3H5)Cl]2(1.8mg, 0.005mmol) and (R, R, R)-Lc (9.6mg, 0.0125mmol) it is separately added into a schlenk pipes, adds anhydrous CH2Cl2(5mL), after stirring 10 minutes at room temperature, successively add Enter substrate 1e (204.2mg, 0.5mmol), K2CO3(the 1.0M aqueous solution, 1.5mL, 1.5mmol) and 3,4,5- trimethoxy-anilines (274.8mg,1.5mmol).After stirring three hours at room temperature, extracted (3 × 10mL) with dichloromethane, anhydrous sodium sulfate drying, After filtering and concentrating, column chromatography purifying, chiral aminate is obtained.Experimental result is as follows：
2t, white solid, 84% .Mp133-135 DEG C of yield, [α]D 20=+86.1(c1.00,CHCl3), 93%ee is [by efficient Liquid chromatogram measuring, chiral AS-3 posts；N-hexane/isopropanol=95:5,1.0mL/min,254nm;tR(major)=8.34min; tR(minor)=10.65min].1H NMR(400MHz,CDCl3)δ=6.91-6.78(m,3H),6.33(s,1H),5.87(s, 1H),5.80(s,2H),5.27(d,J=4.4Hz,1H),4.17-4.08(m,3H),3.77-3.73(m,12H),1.21(t,J= 6.8Hz,3H),0.96(s,9H),0.11(s,6H)ppm;13C NMR(100MHz,CDCl3)δ=166.2,153.6,150.3, 144.8,143.5,140.7,132.9,129.9,125.3,120.5,120.0,111.8,90.8,60.9,60.6,58.4, 55.6,55.3,25.5,18.3,13.9,-4.7ppm.
Embodiment 12
The present embodiment is using para-fluoroaniline as nucleopilic reagent, biphosphine ligand (R, R, R)-Lc and metal [Pd (C3H5)Cl]2Scene Complex compound is prepared as catalyst, catalysis substrate 1f asymmetric pi-allyl aminating reaction (reaction equation is as described below)：
Reaction is as follows：Under argon atmosphere, [Pd (C3H5)Cl]2(1.8mg, 0.005mmol) and (R, R, R)-Lc (9.6mg, 0.0125mmol) it is separately added into a schlenk pipes, adds anhydrous CH2Cl2(5mL), after stirring 10 minutes at room temperature, successively add Enter substrate 1f (133.1mg, 0.5mmol), K2CO3(the 1.0M aqueous solution, 1.5mL, 1.5mmol) and 3,4,5- trimethoxy-anilines (274.8mg,1.5mmol).After stirring three hours at room temperature, extracted (3 × 10mL) with dichloromethane, anhydrous sodium sulfate drying, After filtering and concentrating, column chromatography purifying, chiral aminate is obtained.Experimental result is as follows：
2u, colorless oil, 82% yield, [α]D 20=+67.2(c1.00,CHCl3), 94%ee [is surveyed by high performance liquid chromatography It is fixed, chiral AD-H posts；N-hexane/isopropanol=95:5,1.0mL/min,254nm;tR(major)=32.84min;tR(minor)= 35.96min].1H NMR(400MHz,CDCl3)δ=7.37-7.33(m,2H),7.00(t,J=8.8Hz,2H),6.39(s,1H), 5.94(s,1H),5.83(s,2H),5.38(s,1H),4.22-4.12(m,3H),3.74-3.73(m,9H),1.22(t,J= 7.2Hz,3H)ppm;13CNMR(100MHz,CDCl3)δ=165.7,161.8(d,J(F,C)=244.6Hz),153.4(s),143.1 (s),140.3(s),136.2(d,J(F, C)=3.0Hz),130.0(s),128.7(d,J(F,C)=8.2Hz),125.7(s),115.1 (d,J(F,C)=21.2Hz),90.8,60.6,60.5,59.9,58.2,55.4ppm;19F NMR(376MHz,CDCl3)δ- 114.6ppm.
Embodiment 13
The present embodiment is cyclized under alkali LHMDS (LHMDS) effect and prepared using compound 2a as substrate Beta-lactam.Reaction equation is as described below：
Reaction is as follows：Substrate 2a (112.5mg, 0.4mmol) is added in a schlenk pipes, adds anhydrous tetrahydro furan (3mL), is cooled to -20 °C, LHMDS (1.0mol/L in hexanes, 0.6mL, 0.6mmol) is slowly added dropwise, under -20 °C After stirring 2 hours, add 0.1mL water quenchings and go out reaction, dichloromethane extracts (10mL × 3), anhydrous sodium sulfate drying, filtering and concentrating Afterwards, column chromatography purifies.3a, white solid, 85% .Mp149-150 DEG C of yield, [α]D 20=+98.9(c1.00,CHCl3),96%ee [determined by high performance liquid chromatography, chiral OD-H posts；N-hexane/isopropanol=95:5,1.0mL/min,254nm;tR(minor)= 8.22min;tR(major)=10.43min].1H NMR(400MHz,CDCl3)δ=7.38-7.31(m,7H),7.23(t,J= 8.0Hz,2H),7.03(t,J=7.6Hz,1H),5.81(s,1H),5.38(s,1H),5.12(s,1H)ppm;13C NMR (100MHz,CDCl3)δ=160.8,149.7,137.4,136.3,129.0,128.9,128.6,126.4,124.0,117.0, 110.7,63.3ppm.
Embodiment 14
The present embodiment is using compound 2b as substrate, in two (the silicon substrate amido of hexamethyl two) tin (Sn [N (TMS)2]2) under effect Cyclisation prepares beta-lactam 3b.Reaction equation is as described below：
Reaction is as follows：Substrate 2b (311.3mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 4 hours, after being cooled to room temperature, concentrated, column chromatography purifying.
3b, white solid, 94% .Mp134-135 DEG C of yield [lit.8127-129℃],[α]D 20=+111.0(c1.64, CHCl3), 95%ee [is determined, chiral OD-H posts by high performance liquid chromatography；N-hexane/isopropanol=90:10,1.0mL/min, 254nm;tR(minor)=9.98min;tR(major)=10.99min].1H NMR(400MHz,CDCl3)δ=7.35-7.26(m, 7H),6.77(d,J=8.8Hz,2H),5.76(s,1H),5.33(s,1H),5.08(s,1H),3.69(s,3H)ppm;13C NMR (100MHz,CDCl3)δ=160.2,156.0,149.7,136.3,130.9,128.8,128.5,126.4,118.2,114.2, 109.9,63.3,55.2ppm.
Embodiment 15
With reference to the method for embodiment 14, beta-lactam 3c is prepared.
Reaction is as follows：Substrate 2c (299.3mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3c, white solid, 79% .Mp125-126 DEG C of yield, [α]D 20=+95.5(c1.48,CHCl3), 95%ee is [by efficient Liquid chromatogram measuring, chiral OD-H posts；N-hexane/isopropanol=90:10,1.0mL/min,254nm;tR(minor)= 6.86min;tR(major)=7.57min].1H NMR(400MHz,CDCl3)δ=7.37-7.28(m,7H),6.91(t,J= 8.8Hz,2H),5.80(t,J=1.6Hz,1H),5.37(s,1H),5.13(s,1H)ppm;13C NMR(100MHz,CDCl3)δ= 160.4,158.9(d,J(F, C)=242Hz),149.6,135.9,133.6(d,J(F,C)=2.6Hz),129.0(s),128.7(s), 126.4(s),118.3(d,J(F,C)=7.8Hz),115.7(d,J(F,C)=22.7Hz),110.8(s),63.4ppm;19F NMR (376MHz,CDCl3)δ-109.0ppm.
Embodiment 16
With reference to the method for embodiment 14, beta-lactam 3d is prepared.
Reaction is as follows：Substrate 2d (360.2mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3d, white solid, 73% .Mp135-136 DEG C of yield, [α]D 20=+115.4(c1.00,CHCl3), 95%ee is [by height Effect liquid phase chromatogram determines, chiral OD-H posts；N-hexane/isopropanol=90:10,1.0mL/min,254nm;tR(minor)= 7.20min;tR(major)=7.99min].1H NMR(400MHz,CDCl3)δ=7.36-7.32(m,7H),7.22-7.19(m, 2H),5.83(t,J=1.6Hz,1H),5.37(s,1H),5.16(s,1H)ppm;13C NMR(100MHz,CDCl3)δ=160.6, 149.5,136.3,135.8,132.0,129.1,128.8,126.4,118.5,116.7,111.3,63.4ppm.
Fig. 1 is the X ray crystallogram of the compound 3d obtained by the present embodiment, and resulting change can be confirmed by Fig. 1 Compound 3d absolute configuration is (S).Embodiment 13-15, compound 3a-3c, 3e-3u prepared by 17-33 absolute configuration pass through Comparison with (S) -3d Cotton effects determines that absolute configuration is (S).
Embodiment 17
With reference to the method for embodiment 14, beta-lactam 3e is prepared.
Reaction is as follows：Substrate 2e (360.2mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3e, white solid, 72% .Mp107-108 DEG C of yield, [α]D 20=+47.5(c0.60,CHCl3), 95%ee is [by efficient Liquid chromatogram measuring, chiral OD-H posts；N-hexane/isopropanol=95:5,1.0mL/min,254nm;tR(minor)=9.38min; tR(major)=11.18min].1H NMR(400MHz,CDCl3)δ=7.60(d,J=1.2Hz,1H),7.58(d,J=1.2Hz, 1H),7.46-7.21(m,6H),7.00-6.96(m,1H),6.02(s,1H),5.89(t,J=1.6Hz,1H),5.20(t,J= 1.2Hz,1H)ppm;13C NMR(100MHz,CDCl3)δ=161.9,150.0,136.3,134.3,133.7,128.7,128.6, 127.9,127.7,127.1,126.3,116.1,111.3,66.3ppm.
Embodiment 18
With reference to the method for embodiment 14, beta-lactam 3f is prepared.
Reaction is as follows：Substrate 2f (295.3mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3f, white solid, 81% .Mp127-128 DEG C of yield, [α]D 20=+127.0(c1.66,CHCl3), 97%ee is [by height Effect liquid phase chromatogram determines, chiral OD-H posts；N-hexane/isopropanol=95:5,1.0mL/min,254nm;tR(minor)= 7.86min;tR(major)=9.27min].1H NMR(400MHz,CDCl3)δ=7.35-7.30(m,5H),7.23(d,J= 8.4Hz,2H),7.03(d,J=8.4Hz,2H),5.78(t,J=2.0Hz,1H),5.34(s,1H),5.10(t,J=2.0Hz, 1H),2.24(s,3H)ppm;13C NMR(100MHz,CDCl3)δ=160.5,149.8,136.4,134.9,133.6,129.5, 128.9,128.5,126.4,116.9,110.3,63.2,20.7ppm.
Embodiment 19
With reference to the method for embodiment 14, beta-lactam 3g is prepared.
Reaction is as follows：Substrate 2g (295.3mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3g, white solid, 74% .Mp97-98 DEG C of yield, [α]D 20=+117.9(c1.46,CHCl3), 97%ee is [by efficient Liquid chromatogram measuring, chiral OD-H posts；N-hexane/isopropanol=95:5,1.0mL/min,254nm;tR(minor)=7.48min; tR(major)=9.28min].1H NMR(400MHz,CDCl3)δ=7.38-7.30(m,6H),7.10(t,J=8.0Hz,1H), 7.00(d,J=8.8Hz,1H),6.84(d,J=7.6Hz,1H),5.80(t,J=1.6Hz,1H),5.36(t,J=1.2Hz,1H), 5.12 (t, J=1.6Hz, 1H), 2.26 (s, 3H) ppm;13C NMR(100MHz,CDCl3)δ=160.8,149.7,139.0, 137.3,136.4,128.9,128.7,128.6,126.4,124.9,117.8,113.9,110.5,63.3,21.3ppm.
Embodiment 20
With reference to the method for embodiment 14, beta-lactam 3h is prepared.
Reaction is as follows：Substrate 2h (371.4mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3h, white solid, 74% .Mp149-150 DEG C of yield, [α]D 20=+53.7(c1.28,CHCl3), 96%ee is [by efficient Liquid chromatogram measuring, chiral AD-H posts；N-hexane/isopropanol=85:15,1.0mL/min,254nm;tR(minor)= 10.00min;tR(major)=11.54min].1H NMR(400MHz,CDCl3)δ=7.41-7.33(m,5H),6.60(s,2H), 5.82(s,1H),5.37(s,1H),5.15(s,1H),3.76(s,3H),3.70(s,6H)ppm;13C NMR(100MHz, CDCl3)δ=160.4,153.2,149.3,136.2,134.3,133.4,128.8,128.6,126.5,110.5,94.4, 63.6,60.6,55.6ppm.
Embodiment 21
With reference to the method for embodiment 14, beta-lactam 3i is prepared.
Reaction is as follows：Substrate 2i (295.1mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3i, white solid, 83% .Mp133-134 DEG C of yield, [α]D 20=+195.7(c1.00,CHCl3), 91%ee is [by height Effect liquid phase chromatogram determines, chiral OD-H posts；N-hexane/isopropanol=90:10,1.0mL/min,254nm;tR(minor)= 6.64min;tR(major)=7.60min].1H NMR(400MHz,CDCl3)δ=7.31-7.18(m,7H),7.15-7.11(m, 1H),7.06-7.01(m,1H),5.79(t,J=2.0Hz,1H),5.68(s,1H),5.18-5.17(m,1H),2.51(s,3H) ppm;13C NMR(100MHz,CDCl3)δ=160.8,149.2,137.4,135.2,133.8,131.0,129.0,128.2, 126.6,125.8,124.0,117.0,110.3,60.8,19.4ppm.
Embodiment 22
With reference to the method for embodiment 14, beta-lactam 3j is prepared.
Reaction is as follows：Substrate 2j (295.1mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3j, white solid, 90% .Mp119-120 DEG C of yield, [α]D 20=+115.2(c1.00,CHCl3), 97%ee is [by height Effect liquid phase chromatogram determines, chiral OD-H posts；N-hexane/isopropanol=95:5,1.0mL/min,254nm;tR(minor)= 6.99min;tR(major)=8.75min].1H NMR(400MHz,CDCl3)δ=7.35-7.33(m,2H),7.25-7.11(m, 6H),7.04-7.00(m,1H),5.80(t,J=2.0Hz,1H),5.33(s,1H),5.12(t,J=1.6Hz,1H),2.31(s, 3H)ppm;13C NMR(100MHz,CDCl3)δ=160.8,149.7,138.7,137.5,136.2,129.4,128.9,128.8, 126.9,123.9,123.6,116.9,110.6,63.3,21.2ppm.
Embodiment 23
With reference to the method for embodiment 14, beta-lactam 3k is prepared.
Reaction is as follows：Substrate 2k (295.1mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3k, white solid, 92% .Mp107-108 DEG C of yield, [α]D 20=+107.6(c1.20,CHCl3), 95%ee is [by height Effect liquid phase chromatogram determines, chiral OD-H posts；N-hexane/isopropanol=95:5,1.0mL/min,254nm;tR(minor)= 7.03min;tR(major)=8.89min].1H NMR(400MHz,CDCl3)δ=7.35-7.32(m,2H),7.27-7.20(m, 4H),7.16-7.14(m,2H),7.03-6.99(m,1H),5.79(t,J=1.6Hz,1H),5.34(s,1H),5.11(t,J= 1.6Hz,1H),2.31(s,3H)ppm;13C NMR(100MHz,CDCl3)δ=160.9,149.9,138.5,137.4,133.3, 129.6,128.9,126.4,123.9,117.0,110.5,63.2,21.0ppm.
Embodiment 24
With reference to the method for embodiment 14, beta-lactam 3l is prepared.
Reaction is as follows：Substrate 2l (311.1mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3l, white solid, 74% .Mp94-95 DEG C of yield, [lit.795℃][α]D 20=+67.5(c1.00,CHCl3),94% Ee [is determined, chiral OD-H posts by high performance liquid chromatography；N-hexane/isopropanol=90:10,1.0mL/min,254nm;tR (minor)=8.27min;tR(major)=10.07min].1H NMR(400MHz,CDCl3)δ=7.34-7.28(m,4H),7.21 (t, J=7.6Hz, 2H), 7.00 (t, J=7.6Hz, 1H), 6.87 (d, J=8.8Hz, 2H), 5.79 (s, 1H), 5.33 (s, 1H), 5.11(s,1H),3.74(s,3H)ppm;13C NMR(100MHz,CDCl3)δ=160.8,159.7,150.0,137.4,128.9, 128.1,127.8,123.8,116.9,114.2,110.4,62.9,55.0ppm.
Embodiment 25
With reference to the method for embodiment 14, beta-lactam 3m is prepared.
Reaction is as follows：Substrate 2m (299.1mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3m, white solid, 73% .Mp102-103 DEG C of yield, [α]D 20=+81.0(c1.16,CHCl3), 96%ee is [by efficient Liquid chromatogram measuring, chiral OD-H posts；N-hexane/isopropanol=90:10,1.0mL/min,254nm;tR(minor)= 6.88min;tR(major)=8.78min].1H NMR(400MHz,CDCl3)δ=7.38-7.31(m,4H),7.24(t,J= 7.6Hz,2H),7.06-7.01(m,3H),5.82(t,J=2.0Hz,1H),5.38(s,1H),5.14(t,J=1.2Hz,1H) ppm;13C NMR(100MHz,CDCl3)δ=162.7(d,J(F,C)=246.5Hz),160.6(s),149.6(d,J(F,C)= 1.1Hz),137.2(s),132.1(d,J(F,C)=3.4Hz),129.0(s),128.2(d,J(F,C)=8.6Hz),124.1(s), 116.9(s),115.9(d,J(F,C)=21.6Hz),110.9(s),62.5ppm;19F NMR(376MHz,CDCl3)δ- 112.5ppm.
Embodiment 26
With reference to the method for embodiment 14, beta-lactam 3n is prepared.
Reaction is as follows：Substrate 2n (359.0mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3n, white solid, 80% .Mp115-116 DEG C of yield, [α]D 20=+83.7(c1.00,CHCl3), 97%ee is [by efficient Liquid chromatogram measuring, chiral OD-H posts；N-hexane/isopropanol=90:10,1.0mL/min,254nm;tR(minor)= 7.12min;tR(major)=9.51min].1H NMR(400MHz,CDCl3)δ=7.48(d,J=8.4Hz,2H),7.31-7.22 (m,6H),7.04(t,J=7.2Hz,1H),5.82(t,J=2.0Hz,1H),5.35(s,1H),5.14(t,J=1.2Hz,1H) ppm;13C NMR(100MHz,CDCl3)δ=160.4,149.2,137.1,135.3,132.1,129.0,128.1,124.1, 122.6,116.8,111.0,62.5ppm.
Embodiment 27
With reference to the method for embodiment 14, beta-lactam 3o is prepared.
Reaction is as follows：Substrate 2o (315.7mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3o, white solid, 93% .Mp133-134 DEG C of yield, [α]D 20=+93.0(c1.00,CHCl3), 94%ee is [by efficient Liquid chromatogram measuring, chiral OD-H posts；N-hexane/isopropanol=90:10,1.0mL/min,254nm;tR(minor)= 6.87min;tR(major)=9.05min].1H NMR(400MHz,CDCl3)δ=7.34-7.29(m,6H),7.25-7.21(m, 2H),7.03(t,J=7.2Hz,1H),5.81(t,J=2.0Hz,1H),5.36(s,1H),5.13(s,1H)ppm;13C NMR (100MHz,CDCl3)δ=160.4,149.3,137.1,134.8,134.4,129.1,129.0,127.8,124.1,116.8, 111.0,62.5ppm.
Embodiment 28
With reference to the method for embodiment 14, beta-lactam 3p is prepared.
Reaction is as follows：Substrate 2p (315.7mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3p, white solid, 82% .Mp110-111 DEG C of yield, [α]D 20=+96.7(c0.9,CHCl3), 96%ee is [by efficient Liquid chromatogram measuring, chiral OD-H posts；N-hexane/isopropanol=90:10,1.0mL/min,254nm;tR(minor)= 7.11min;tR(major)=8.99min].1H NMR(400MHz,CDCl3)δ=7.38(s,1H),7.32-7.23(m,7H), 7.05(t,J=7.6Hz,1H),5.83(s,1H),5.34(s,1H),5.16(s,1H)ppm;13C NMR(100MHz,CDCl3)δ= 160.4,149.1,138.5,137.1,134.9,130.3,129.1,128.9,126.5,124.5,124.2,116.8, 111.2,62.5ppm.
Embodiment 29
With reference to the method for embodiment 14, beta-lactam 3q is prepared.
Reaction is as follows：Substrate 2q (341.1mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3q, white solid, 76% .Mp76-77 DEG C of yield, [α]D 20=+77.8(c1.30,CHCl3), 95%ee is [by efficient liquid Phase chromatographic determination, chiral OD-H posts；N-hexane/isopropanol=90:10,1.0mL/min,254nm;tR(minor)=13.05min; tR(major)=14.26min].1H NMR(400MHz,CDCl3)δ=7.30-7.26(m,4H),6.88(d,J=8.8Hz,2H), 6.77(d,J=8.8Hz,2H),5.76(t,J=1.6Hz,1H),5.30(s,1H),5.09(t,J=1.6Hz,1H),3.76(s, 3H),3.70(s,3H)ppm;13C NMR(100MHz,CDCl3)δ=160.4,159.7,156.0,150.1,130.9,128.2, 127.9,118.2,114.2,114.1,109.8,63.0,55.2,55.0ppm.
Embodiment 30
With reference to the method for embodiment 14, beta-lactam 3r is prepared.
Reaction is as follows：Substrate 2r (401.4mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3r, colorless oil, 74% yield [α]D 20=+41.5(c1.00,CHCl3), 96%ee [is surveyed by high performance liquid chromatography It is fixed, chiral AD-H posts；N-hexane/isopropanol=90:10,1.0mL/min,254nm;tR(minor)=18.05min;tR(major) =25.54min].1H NMR(400MHz,CDCl3)δ=7.34(d,J=8.8Hz,2H),6.91(d,J=8.8Hz,2H),6.61(s, 2H),5.82(t,J=1.6Hz,1H),5.34(s,1H),5.15(t,J=1.6Hz,1H),3.78(s,3H),3.76(s,3H), 3.72(s,6H)ppm;13C NMR(100MHz,CDCl3)δ=160.6,159.8,153.2,149.7,134.2,133.5, 128.0,127.9,114.2,110.3,94.4,63.3,60.6,55.7,55.0ppm.
Embodiment 31
With reference to the method for embodiment 14, beta-lactam 3s is prepared.
Reaction is as follows：Substrate 2s (461.2mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3s, white solid, 80% .Mp160-161 DEG C of yield, [α]D 20=+28.7(c1.00,CHCl3), 98%ee is [by efficient Liquid chromatogram measuring, chiral AD-H posts；N-hexane/isopropanol=80:20,1.0mL/min,254nm;tR(minor)= 11.81min;tR(major)=13.90min].1H NMR(400MHz,CDCl3)δ=6.63-6.62(m,4H),5.85(t,J= 2.0Hz,1H),5.30(s,1H),5.22(t,J=1.6Hz,1H),3.85-3.84(m,9H),3.78(s,3H),3.75(s,6H) ppm;13C NMR(100MHz,CDCl3)δ=160.5,153.5,153.2,149.1,138.0,134.3,133.5,131.8, 110.6,103.3,94.4,63.9,60.6,60.5,55.9,55.6ppm.
Embodiment 32
With reference to the method for embodiment 14, beta-lactam 3t is prepared.
Reaction is as follows：Substrate 2t (531.2mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3t, colorless oil, 92% yield [α]D 20=+37.3(c1.00,CHCl3), 95%ee [is surveyed by high performance liquid chromatography It is fixed, chiral OD-H posts；N-hexane/isopropanol=95:5,1.0mL/min,254nm;tR(minor)=5.80min;tR(major)= 6.74min].1H NMR(400MHz,CDCl3)δ=6.91-6.88(m,1H),6.78-6.76(m,2H),6.52(s,2H),5.72 (s,1H),5.20(s,1H),5.06(s,1H),3.71(s,3H),3.68(s,3H),3.64(s,6H),0.86(t,J=2.8Hz, 9H),0.01(d,J=4.8Hz,6H)ppm;13C NMR(100MHz,CDCl3)δ=160.5,153.1,151.1,149.6, 145.2,134.2,133.4,128.4,120.1,118.9,111.8,110.1,94.5,63.2,60.5,55.6,55.1, 25.3,18.1,-5.01ppm.
Embodiment 33
With reference to the method for embodiment 14, beta-lactam 3u is prepared.
Reaction is as follows：Substrate 2u (389.1mg, 1.0mmol) and Sn [N (TMS)2]2(659.2mg, 1.5mmol) adds one In Schlenk pipes, dry toluene (5mL) is added, is heated to reflux 3-12 hours, after being cooled to room temperature, concentration, column chromatography purifying.
3u, white solid, 82% .Mp134-135 DEG C of yield, [α]D 20=+43.5(c1.50,CHCl3), 94%ee is [by efficient Liquid chromatogram measuring, chiral AD-H posts；N-hexane/isopropanol=85:15,1.0mL/min,254nm;tR(minor)= 10.03min;tR(major)=12.07min].1H NMR(400MHz,CDCl3)δ=7.42-7.38(m,2H),7.09(t,J= 8.8Hz,2H),6.57(s,2H),5.84(t,J=2.0Hz,1H),5.38(s,1H),5.17(t,J=1.2Hz,1H),3.77(s, 3H),3.73(s,6H)ppm;13C NMR(100MHz,CDCl3)δ=162.7(d,J(F,C)=246.9Hz),160.4(s),153.3 (s),149.4(d,J(F,C)=1.2Hz),134.5(s),133.3(s),132.1(d,J(F,C)=3.4Hz),128.3(d,J(F,C)= 8.1Hz),115.9(d,J(F, C)=21.9Hz),110.8(s),94.5,62.9,60.7,55.8ppm;19F NMR(376MHz, CDCl3)δ-112.3ppm.
The cell in vitro of embodiment 34 suppresses experiment
Logarithmic phase HL-60 cells cell is collected, adjusts concentration of cell suspension, it is 2.5 × 10 to make cell concentration4/ Ml, per hole（96 orifice plates）The μ l of cell suspension 90 are added, add the μ l/ holes of formula 3a ~ 3u compounds 10 of various concentrations gradient, Mei Genong Degree 4 holes of inoculation are as repeating to test, to improve the accuracy of experimental data.(only add in addition, separately setting a zeroing hole on every block of plate Nutrient solution, without cell and medicine).Continue culture in incubator by the 3rd day, using tetrazolium (Methyl-Thiazol- Tetrozolium, MTT) reducing process detect formula 3a ~ 3u compounds to the inhibitory action of HL-60 cells cell, measuring Compound 3a-3u is to HL-60 cells half-inhibition concentration (IC50)。
As a result show, compound 3a-3u is to HL-60 cells half-inhibition concentration (IC50) it is less than 80 μ g/mL, wherein Compound 3b, 3c, 3t, 3l, 3s, 3u etc. are to HL-60 cells half-inhibition concentration (IC50) it is about 20-30 μ g/mL；Chemical combination Thing 3g, 3h, 3j, 3k, 3m, 3r etc. are to HL-60 cells half-inhibition concentration (IC50) it is about 0.1-10 μ g/mL；3g、3h、 3k, 3m, 3r etc. are to HL-60 cells half-inhibition concentration (IC50)≤1μg/mL。
Logarithmic phase lung cell A549 is collected, adjusts concentration of cell suspension, it is 2 × 10 to make cell concentration4/ ml, per hole（96 Orifice plate）The μ l of cell suspension 100 are added, it is 4000 to make the cell number in every hole.In incubator after culture 24h cell attachments, inhale Going out each 100 μ l of formula 3a ~ 3u compounds that nutrient solution adds various concentrations gradient, each concentration is inoculated with 4 holes and tested as repetition, with Improve the accuracy of experimental data.And set corresponding Vehicle controls and acellular zeroing hole.Continue to cultivate 72h in incubator, adopt Formula 3a ~ 3u compounds are determined to lung cell A549 with Sulforhodamine B (sulforhodamine B, SRB) protein staining method Inhibitory action, incline nutrient solution, add ice precooling 10% solution of trichloroacetic acid fix cell, 4 DEG C place 1h after with distillation Water washing 5 times, is spontaneously dried in air.Then 4mg/ml SRB is added（Sigma, St Louis, MO, USA）Solution, room temperature Middle dyeing 15min, removes dyeing liquor, is washed 5 times, is air-dried with 1% glacial acetic acid.Tris solution (pH10.5) is eventually adding, it is adjustable Wavelength type microwell plate ELIASA (VERSAmaxTM, Molecular Device Corporation, Sunnyvale, CA, USA) OD values, IC are determined under 515nm wavelength50Value is calculated using Logit methods.
As a result show, compound 3a-3u is to lung cell A549 half-inhibition concentration (IC50) it is less than 85 μ g/mL, wherein changing Compound 3c, 3e, 3f, 3q etc. are to lung cell A549 half-inhibition concentration (IC50) it is about 20-50 μ gmL；Compound 3i, 3j, 3l, 3m, 3t, 3u, 3g etc. are to lung cell A549 half-inhibition concentration (IC50) it is about 0.1-20 μ gmL；Wherein 3i, 3j, 3l, 3m etc. To lung cell A549 half-inhibition concentration (IC50)≤10μg/mL。
The preparation of the formula 30a compounds of embodiment 35
The addition 3- bromosalicylaldehydes (10.25g, 51.0mmol) into 50mL single port bottles, cyclohexanone (2.5mL, 25.0mmol), Ethanol (20.0mL), sodium hydrate aqueous solution (20wt%, 15mL), it is stirred at room temperature 24 hours；100mL is added into reaction system Distilled water, the aqueous hydrochloric acid solution for being 6mol/L with concentration are neutralized to pH=5, filtering, and solid is dried after using distillation water washing；With third Ketone-petroleum ether recrystallization, obtains 4.6g yellow solid formula 30a compounds, yield 60%.
30a, mp174-175 DEG C；1H NMR(400MHz,DMSO-d6) δ 9.62 (s, br, 2H), 7.75 (s, 2H), 7.54 (d,J=8.0Hz,2H),7.29(d,J=7.6Hz,2H),6.86(t,J=8.0Hz,2H),2.76(t,J=5.6Hz,4H),1.68- 1.62(m,2H)ppm；13C NMR(100MHz,DMSO-d6)δ188.9,152.5,137.1,133.3,131.5,129.5, 125.8,120.9,111.8,28.0,22.8ppm.
The preparation method of reference implementation example 35, formula 30b, 30c, 30d, 30h, 30i, 30j compound is prepared for respectively.
30b,mp194-195℃.1H NMR(400MHz,DMSO-d6) δ 9.32 (s, br, 2H), 7.72 (s, 2H), 7.35 (s,2H),7.07(s,2H),2.75(t,J=5.2Hz,4H),2.22(s,6H),1.66-1.63(m,2H)ppm;13C NMR (100MHz,DMSO-d6)δ188.8,150.2,136.9,133.4,131.6,129.9,129.7,125.5,111.7,28.0, 22.8,19.7ppm.
30c, mp123-125 DEG C；1H NMR(400MHz,DMSO-d6) δ 9.94 (s, br, 2H), 7.65-7.63 (m, 4H), 7.28(d,J=2.4Hz,2H),2.73(t,J=4.8Hz,4H),1.67-1.64(m,2H)ppm；13C NMR(100MHz,DMSO- d6)δ188.5,151.7,138.0,132.1,130.5,128.6,126.8,123.6,112.5,27.8,22.5ppm.
30d, mp110-111 DEG C；1H NMR(300MHz,acetone-d6)δ9.05(s,2H),7.84(s,2H),7.45 (d,J=2.4Hz,2H),7.34(dd,J=9.0Hz,2.4Hz,2H),2.88(t,J=5.1Hz,4H),3.36(s,6H),1.82- 1.74(m,2H)ppm；13C NMR(75MHz,acetone-d6)δ189.2,156.5,138.0,133.3,133.1,131.1, 126.2,118.4,111.5,29.1,23.9,20.1ppm.
30h, mp184-185 DEG C；1HNMR(400MHz,DMSOd6) δ 9.91 (s, 2H), 7.72 (s, 2H), 7.53 (d, J= 4.4Hz, 2H), 7.34 (d, J=4.4Hz, 2H), 6.88 (t, J=7.6Hz, 2H), 2.69 (t, J=5.2Hz, 4H), 1.71-1.61 (m,2H)ppm；13CNMR (100MHHz, DMSO-d6) δ 189.5,151.4,136.1,131.1,129.7,128.6,126.1, 123.6,122.8,26.5ppm.
30i, mp171-173 DEG C；1H NMR(400MHz,DMSO-d6)δ10.03(s,2H),7.81(s,2H),7.63(d,J =4.4Hz,2H),7.45(d,J=4.6Hz,2H),6.90(t,J=7.8Hz,2H),4.82(s,4H)ppm；13C NMR(100MHz, DMSO-d6)δ184.1,156.8,133.1,131.8,130.8,129.5,121.0,119.6,115.4,67.6ppm.
30j, mp145-146 DEG C；1H NMR(400MHz,acetone-d6)δ8.99(s,2H),7.63(s,2H),7.41 (d,J=7.8Hz,2H),7.21-7.17(m,2H),6.90(t,J=7.2Hz,2H),2.77-2.67(m,4H),1.98-1.84 (m,4H)ppm；13C NMR(100MHz,acetone-d6)δ198.1,155.1,142.5,131.8,129.7,129.3, 122.5,118.6,114.9,28.9,26.5ppm.
The preparation of following compound is illustrated by embodiment 36.
Embodiment 36
Using compound 30a prepared by embodiment 35 as hydrogenation substrate, using compound 7a as catalyst (catalyst 7a), prepare Chiral fragrant spiroketalization compound (R, R, R) -5a.Reaction is as follows：30a (46.4mg, 0.1mmol), catalyst 7a (1.6mg, 0.001mmol), 2mL anhydrous methylene chlorides are added in hydrogenation bottle, and autoclave is transferred in glove box.Replacing hydrogen After three times, hydrogen is filled with to 50 atmospheric pressure, is reacted at room temperature 24 hours.After being vented hydrogen, opening reactor, removal of solvent under reduced pressure, The suitable inverse ratio for determining product is slightly composed by nuclear-magnetism, residue is through column chromatography for separation.The yield for obtaining (R, R, R) -5a is 93%, ee values For>99%.
Fig. 2 is the X ray crystallogram of the compound obtained by the present embodiment, and resulting chemical combination can be confirmed by Fig. 2 Trans-the 5a of thing absolute configuration is (R, R, R), the chiral fragrant spiroketalization compound 5b-5j's prepared in following embodiment Absolute configuration is determined by the comparison of the Cotton effects with (R, R, R) -5a.
(R, R, R) -5a, white solid, mp97-98 DEG C；[α]D 20=-85.2(c0.80,CHCl3),>99%ee is [by efficient Liquid chromatogram measuring chirality AD-H posts;Normal hexane/isobutanol=99:1,0.5mL/min,230nm;tR(major)=11.74min; tR(minor)=13.10min].1H NMR(300MHz,CDCl3)δ7.36(dd,J=8.1,0.9Hz,2H),7.03(dd,J= 7.5,0.6Hz,2H),6.77(t,J=7.5Hz,2H),3.05(dd,J=16.8,6.3Hz,2H),2.70(dd,J=16.8Hz, 7.2Hz,2H),2.40-2.36(m,2H),1.85-1.80(m,2H),1.62-1.50(m,4H)ppm;13C NMR(75MHz, CDCl3)δ148.5,131.0,128.3,122.6,121.7,110.8,101.9,33.3,27.8,27.3,19.1ppm;IR (neat)ν3058,2924,2853,1566,1447,1358,1329,1223,1178,1149,1117,960,879,774, 717,647,624cm-1;HRMS-EI m/z)M+calcd.for C20H18O2Br2447.9674found447.9678。
It is prepared by catalyst 7a reference literatures Angew.Chem.Int.Ed.2009,48,5345 method.
Using compound 30b prepared by embodiment 35 as hydrogenation substrate, using compound 7a as catalyst, chiral fragrant spiral shell is prepared Ketal compound (R, R, R) -5b.Reaction is as follows：30b (49.2mg, 0.1mmol), catalyst 7a (4.8mg, 0.003mmol), 2mL anhydrous methylene chlorides are added in hydrogenation bottle, and autoclave is transferred in glove box.Replacing hydrogen three times after, be filled with Hydrogen reacts at room temperature 24 hours to 50 atmospheric pressure.After being vented hydrogen, reactor is opened, removal of solvent under reduced pressure, is slightly composed by nuclear-magnetism really The suitable inverse ratio of fixed output quota thing, residue is through column chromatography for separation.The yield for obtaining (R, R, R) -5b is that 85%, ee values are>99%.
(R, R, R) -5b, white solid, mp237-238 DEG C, [α]D 20=-98.8(c1.26,CHCl3),>99%ee is [by height Effect liquid phase chromatogram determines chiral AD-H posts;Normal hexane/isobutanol=99:1,1.0mL/min,230nm;tR(major)= 4.95min;tR(minor)=7.17min].1H NMR(400MHz,CDCl3)δ7.17(s,2H),6.82(s,2H),2.99(dd, J=16.4,6.0Hz,2H),2.63(dd,J=16.4,7.2Hz,2H),2.35-2.32(m,2H),2.24(s,6H),1.83- 1.79(m,2H),1.59-1.46(m,4H)ppm;13C NMR(75MHz,CDCl3)δ146.2,131.3,131.2,128.8, 122.1,110.3,101.8,33.2,27.7,27.2,20.2,19.0ppm.
Using compound 30c prepared by embodiment 35 as hydrogenation substrate, using compound 7a as catalyst, chiral fragrant spiral shell is prepared Ketal compound (R, R, R) -5c.Reaction is as follows：30c (53.3mg, 0.1mmol), catalyst 7a (4.8mg, 0.003mmol), 2mL anhydrous methylene chlorides are added in hydrogenation bottle, and autoclave is transferred in glove box.Replacing hydrogen three times after, be filled with Hydrogen reacts at room temperature 24 hours to 50 atmospheric pressure.After being vented hydrogen, reactor is opened, removal of solvent under reduced pressure, is slightly composed by nuclear-magnetism really The suitable inverse ratio of fixed output quota thing, residue is through column chromatography for separation.The yield for obtaining (R, R, R) -5c is 86%, ee values>99%.
(R, R, R) -5c, white solid, mp200-202 DEG C；[α]D 20=-75.8(c0.90,CHCl3),>99%ee is [by height Effect liquid phase chromatogram determines chiral AD-H posts;Normal hexane/isobutanol=98:2,1.0mL/min,230nm;tR(major)= 5.37min;tR(minor)=5.97min].1H NMR(400MHz,CDCl3)δ7.36(d,J=2.8Hz,2H),7.03(d,J= 2.4Hz,2H),3.00(dd,J=16.8Hz,6.0Hz,2H),2.67(dd,J=16.8Hz,7.2Hz,2H),2.36-2.32(m, 2H),1.85-1.80(m,2H),1.61-1.47(m,4H)ppm;13C NMR(100MHz,CDCl3)δ147.2,130.5, 128.0,126.0,123.6,111.2,102.2,33.1,27.6,27.2,18.9ppm.
Using compound 30d prepared by embodiment 35 as hydrogenation substrate, using compound 7a as catalyst, chiral fragrant spiral shell is prepared Ketal compound (R, R, R) -5d.Reaction is as follows：30d (49.2mg, 0.1mmol), catalyst 7a (3.2mg, 0.002mmol), 2mL anhydrous methylene chlorides are added in hydrogenation bottle, and autoclave is transferred in glove box.Replacing hydrogen three times after, be filled with Hydrogen reacts at room temperature 24 hours to 50 atmospheric pressure.After being vented hydrogen, reactor is opened, removal of solvent under reduced pressure, is slightly composed by nuclear-magnetism really The suitable inverse ratio of fixed output quota thing, residue is through column chromatography for separation.The yield for obtaining (R, R, R) -5d is 88%, ee values>99%.
(R, R, R) -5d, white solid, mp160-161 DEG C；[α]D 20=-33.1(c1.00,CHCl3),>99%ee is [by height Effect liquid phase chromatogram determines chiral AD-H posts;Normal hexane/isobutanol=90:10,1.0mL/min,230nm;tR(minor)= 4.99min;tR(major)=7.57min].1H NMR(300MHz,CDCl3)δ7.20-7.18(m,2H),6.82-6.78(m, 2H),2.90(dd,J=16.5,6.0Hz,2H),2.65(dd,J=17.1,7.5Hz,2H),2.32(s,6H),2.29-2.26(m, 2H),1.83-1.77(m,2H),1.61-1.47(m,4H)ppm;13C NMR(75MHz,CDCl3)δ150.9,131.8,130.2, 123.0,118.5,113.0,100.8,33.1,27.9,26.8,20.1,19.1ppm.
Using compound 30h prepared by embodiment 35 as hydrogenation substrate, using compound 7a as catalyst, optical activity is prepared Chiral fragrant spiroketalization compound (R, R, R) -5h.Reaction is as follows：30h (45.0mg, 0.1mmol), catalyst 7a (4.8mg, 0.003mmol), 2mL anhydrous methylene chlorides are added in hydrogenation bottle, and autoclave is transferred in glove box.Replacing hydrogen After three times, hydrogen is filled with to 50 atmospheric pressure, is reacted at room temperature 24 hours.After being vented hydrogen, opening reactor, removal of solvent under reduced pressure, Residue is through column chromatography for separation.Obtain (R, R, R) -5h, yield 60%.Ee values 95%.It is reachable after step recrystallization>99% ee.
(R, R, R) -5h, white solid, mp111-112 DEG C；[α]D 20=+98.4(c1.00,CHCl3),>99%ee is [by height Effect liquid phase chromatogram determines, chiral AD-H posts;Normal hexane/isobutanol=95:5,1.0mL/min,254nm;tR(major)= 11.08min;tR(minor)=12.12min]..1H NMR(400MHz,CDCl3)δ7.12-7.08(m,4H),6.96-6.88 (m,2H),2.79(dd,J=14.2,4.6Hz,2H),2.32-2.29(m,2H),1.21-1.95(m,2H),1.78-1.71(m, 2H),1.56-1.47(m,2H)ppm.
Using compound 30i prepared by embodiment 35 as hydrogenation substrate, using compound 7a as catalyst, optical activity is prepared Chiral fragrant spiroketalization compound (S, SR) -5i.Reaction is as follows：30i (46.6mg, 0.1mmol), catalyst 7a (4.8mg, 0.003mmol), 2mL anhydrous methylene chlorides are added in hydrogenation bottle, and autoclave is transferred in glove box.Replacing hydrogen After three times, hydrogen is filled with to 50 atmospheric pressure, is reacted at room temperature 24 hours.After being vented hydrogen, opening reactor, removal of solvent under reduced pressure, The suitable inverse ratio for determining product is slightly composed by nuclear-magnetism, residue is through column chromatography for separation.(S, SR) -5i, yield 70% are obtained, ee values are 96%.After step recrystallization>99%ee.
(S, S, R) -5i, white solid, mp147-149 DEG C；[α]D 20=-23.9(c0.90,CHCl3),>99%ee is [by height Effect liquid phase chromatogram determines, chiral AD-H posts;Normal hexane/isobutanol=98:2,1.0mL/min,254nm;tR(major)= 16.31min;tR(minor)=18.01min].1H NMR(400MHz,CDCl3)δ7.14-7.09(m,2H),6.97-6.87(m, 4H),3.99(dd,J=16.2,4.8Hz,2H),3.61(dd,J=15.6,5.9Hz,2H),3.05(dd,J=16.8,6.4Hz, 2H),2.83-2.79(m,2H),2.41-2.37(m,2H)ppm.
Using compound 30j prepared by embodiment 35 as hydrogenation substrate, using compound 7a as catalyst, optical activity is prepared Chiral fragrant spiroketalization compound (R, R, R) -5j.Reaction is as follows：30j (47.8mg, 0.1mmol), catalyst 7a (4.8mg, 0.003mmol), 2mL anhydrous methylene chlorides are added in hydrogenation bottle, and autoclave is transferred in glove box.Replacing hydrogen After three times, hydrogen is filled with to 50 atmospheric pressure, is reacted at room temperature 24 hours.After being vented hydrogen, opening reactor, removal of solvent under reduced pressure, The suitable inverse ratio for determining product is slightly composed by nuclear-magnetism, residue is through column chromatography for separation.Obtain (R, R, R) -5j, yield 60%, ee values> 99%。
(R, R, R) -5j, white solid, mp124-125 DEG C；[α]D 20=-45.1(c1.10,CHCl3),>99%ee is [by height Effect liquid phase chromatogram determines chiral AD-H posts;Normal hexane/isobutanol=95:5,1.0mL/min,230nm;tR(minor)= 4.86min;tR(major)=7.09min].1H NMR(400MHz,CDCl3)δ7.09(d,J=12.8Hz,2H),6.99(t,J= 7.2Hz,2H),6.89-6.83(m,2H),2.68(dd,J=16.8,4.8Hz,2H),2.31-2.23(m,2H),1.99-1.98 (m,2H),1.79-1.71(m,4H),1.62-1.47(m,4H)ppm.
(R, R, R)-La~(R, R, R)-Lo preparation method is described by following examples.
Embodiment 37
(R, R, R)-La preparation, reaction scheme are as follows.
After the processing of 10mL schlenk pipes anhydrous and oxygen-free, substrate (R, R, R) -5a (175mg, 0.389mmol) is added, it is anhydrous Tetrahydrofuran (4mL), is cooled at -78 DEG C, be slowly added dropwise n-BuLi (0.39mL, 2.5M in hexane, 0.972mmol), after reactant mixture stirs half an hour at -78 DEG C, be slowly added dropwise diphenyl phosphine chloride (0.18mL, 0.972mmol), it is warmed to room temperature, is stirred at room temperature 10 hours naturally after adding.After reaction is quenched in addition 10mL distilled water, use Dichloromethane extracts (3 × 10mL), after organic phase anhydrous sodium sulfate drying, filtering and concentrating, the purifying of residue column chromatography, obtains mesh Mark product (R, R, R)-La (187mg, 73% yield) (R, R, R)-La, Mp101-103 DEG C of white solid, [α]D 20=+113.4 (c1.00, CHCl3).1HNMR (400MHz, CDCl3) δ 7.30-726 (m, 20H), 6.89 (d, J=7.2Hz, 2H), 6.74 (t, J= 7.2Hz, 2H) 6.53-6.50 (m, 2H), 2.34-2.30 (m, 4H), 1.95-1.92 (m, 2H), 1.30-129 (m, 2H), 1.17- 1.15 (m, 4H) ppm；13CNMR (100MHz, CDCl3) δ 153.1 (d, J(P,C)=14.2Hz), 137.1 (d, J(P,C)=11.8Hz), 136.7 (d, J(P,C)=10.9Hz), 134.2 (d, J(P,C)=21.9HZ), 133.9 (d, J(P,C)=20.2Hz), 130.9 (d, J(P,C)= 3.2Hz), 129.9 (S), 128.5 (S), 1282-128.1 (m), 124.9 (d, J(P,C)=14.1Hz), 120.4-120.3 (m), 101.3,33.5,27.6,26.7,19.4ppm；31P (162MHz, CDCl3)δ-15.8(s)ppm.
Using above-mentioned identical test method, diphenyl phosphine chloride is replaced by two (o-methyl-phenyl) phosphonium chlorides, is prepared into To chiral fragrant Spiroketals skeleton biphosphine ligand (R, R, R)-Lb.
(R, R, R)-Lb, white solid, 40% .Mp125-127 DEG C of yield, [α]D 20=+143.5(c1.00,CHCl3).1H NMR(400MHz,CDCl3)δ=7.24-7.12(m,8H),7.05(t,J=7.2Hz,4H),6.88-6.85(m,4H),6.79- 6.72(m,4H),6.53-6.50(m,2H),2.39(s,6H),2.34-2.23(m,2H),2.18(s,6H),1.99-1.95(m, 2H),1.34-1.15(m,8H)ppm;13C NMR(75MHz,CDCl3)δ153.5(d,J(P,C)=15.2Hz),143.2(d,J(P,C) =28.3Hz),142.7(d,J(P,C)=25.9Hz),135.3(d,J(P,C)=11.4Hz),134.9(d,J(P,C)=13.8Hz), 133.5(d,J(P,C)=40.1Hz),131.0(d,J(P,C)=2.9Hz),130.0-129.6(m),128.3(d,J(P,C)= 15.8Hz),125.8(d,J(P,C)=24.0Hz),123.3(d,J(P,C)=12.7Hz),120.6-120.5(m),101.4,33.3, 27.7,26.6,21.2(d,J(P,C)=21.1Hz),21.0(d,J(P,C)=23.7Hz),19.3ppm;31P(121MHz,CDCl3)δ- 33.4ppm.
Using above-mentioned identical test method, difference is to replace hexichol by two (3,5- 3,5-dimethylphenyl) phosphonium chlorides Base phosphonium chloride, chiral fragrant Spiroketals skeleton biphosphine ligand (R, R, R)-Lc is prepared
(R, R, R)-Lc, white solid, 70% .Mp102-103 DEG C of yield, [α]D 20=+166.5(c1.00,CHCl3).1H NMR(300MHz,CDCl3)δ=6.93-6.84(m,14H),6.73(t,J=6.9Hz,2H),6.47(t,J=4.8Hz,2H), 2.45-2.38(m,4H),2.24(s,12H),2.21(s,12H),2.04-1.97(m,2H),1.30-1.26(m,2H),1.12- 1.07(m,4H)ppm;13CNMR(75MHz,CDCl3)δ=153.1(d,J(P,C)=14.7Hz),137.3(d,J(P, C)=7.4Hz), 137.2(d,J(P, C)=7.8Hz),136.9(d,J(P,C)=10.2Hz),136.5(d,J(P,C)=10.9Hz),132.1(s),131.8 (s),131.5(s),130.8(d,J(P,C)=1.5Hz),130.2(s),129.8(d,J(P,C)=41.7Hz),125.5(d,J(P,C)= 14.2Hz),120.1(s),120.1(d,J(P,C)=1.7Hz),101.1,33.4,27.3,26.7,21.3,21.2,19.5ppm ;31P(121MHz,CDCl3)δ-15.2ppm.
Using above-mentioned identical test method, difference is to replace two by two (3,5- di-tert-butyl-phenyl) phosphonium chlorides Tetraphenylphosphonium chloride phosphine, chiral fragrant Spiroketals skeleton biphosphine ligand (R, R, R)-Ld is prepared.
(R, R, R)-Ld, white solid, 45% .Mp100-101 DEG C of yield, [α]D 20=+140.5(c1.00,CHCl3).1H NMR(400MHz,CDCl3)δ=6.91-6.82(m,14H),6.69(t,J=6.6Hz,2H),6.37(t,J=5.0Hz,2H), 2.41-2.32(m,4H),2.28(s,36H),2.15(s,36H),2.10-1.97(m,2H),1.30-1.28(m,2H),1.11- 1.09(m,4H)ppm;13CNMR(100MHz,CDCl3)δ=155.1(d,J(P,C)=15.0Hz),139.5(d,J(P,C)=8.4Hz), 137.7(d,J(P,C)=8.0Hz),136.1(d,J(P,C)=10.8Hz),135.4(d,J(P,C)=11.2Hz),133.4(s),131.8 (s),130.9(s),130.8(d,J(P,C)=12.0Hz),130.4(s),129.6(d,J(P,C)=42.2Hz),126.5(d,J(P,C) =16.2Hz),120.9(s),120.4(d,J(P,C)=2.2Hz),99.1,33.4,29.8,27.3,26.7,25.6,21.3, 21.2,19.5ppm;31P(121MHz,CDCl3)δ-17.8ppm.
Using above-mentioned identical test method, difference is to replace diphenyl chlorine by two (p-methylphenyl) phosphonium chlorides Change phosphine, chiral fragrant Spiroketals skeleton biphosphine ligand (R, R, R)-Le is prepared.
(R, R, R)-Le, white solid, 67% .Mp90-92 DEG C of yield, [α]D 20=+118.5(c1.00,CHCl3).1H NMR (400MHz,CDCl3)δ=7.21-7.14(m,8H),7.10-7.07(m,8H),6.87(d,J=7.2Hz,2H),6.73(t,J= 7.6Hz,2H),6.54(t,J=5.6Hz,2H),2.36-2.25(m,16H),1.96-1.92(m,2H),1.32-1.26(m, 2H),1.19-1.15(m,4H)ppm;13C NMR(100MHz,CDCl3)δ=153.1(d,J(P,C)=14.5Hz),138.2(s), 137.8(s),134.3-133.8(m),133.4(d,J(P,C)=10.4Hz),130.8(d,J(P, C)=2.6Hz),129.7(s), 129.0-128.9(m),125.5(d,J(P,C)=14.0Hz),120.3-120.2(m),101.2,33.4,27.6,26.7,21.3, 19.4ppm;31P NMR(162MHz,CDCl3)δ-17.9ppm.
Using above-mentioned identical test method, difference is to replace diphenyl chlorination by two (p-fluorophenyl) phosphonium chlorides Phosphine, chiral fragrant Spiroketals skeleton biphosphine ligand (R, R, R)-Lf is prepared.
(R, R, R)-Lf, white solid, 80% .Mp76-77 DEG C of yield, [α]D 20=+88.0(c1.00,CHCl3).1H NMR (400MHz,CDCl3)δ=7.27-7.20(m,8H),6.99-6.93(m,10H),6.76(t,J=7.6Hz,2H),6.49-6.46 (m,2H),2.50-2.39(m,4H),2.01-1.94(m,2H),1.33-1.32(m,2H),1.20-1.11(m,4H)ppm;31P NMR(162MHz,CDCl3)δ-17.8ppm;19F NMR(376MHz,CDCl3)δ-112.3,-112.5ppm.
Using above-mentioned identical test method, difference is to replace diphenyl by two (p-methoxyphenyl) phosphonium chlorides Phosphonium chloride, chiral fragrant Spiroketals skeleton biphosphine ligand (R, R, R)-Lg is prepared.
(R, R, R)-Lg, white solid, 65% .Mp91-92 DEG C of yield, [α]D 20=+122.5(c1.00,CHCl3).1HNMR (400MHz,CDCl3)δ=7.26-7.19(m,8H),6.88-6.87(m,2H),6.84-6.81(m,8H),6.73(t,J= 7.2Hz,2H),6.51(t,J=5.2Hz,2H),3.75(s,6H),3.71(s,6H),2.35-2.31(m,4H),1.94-1.91 (m,2H),1.31-1.26(m,3H),1.20-1.16(m,3H)ppm;13C NMR(100MHz,CDCl3)δ=159.8(d,J(P, C)= 38.8Hz),152.8(d,J(P, C)=13.9Hz),135.5-135.0(m),130.4(s),129.5(s),128.3(d,J(P,C)= 8.1Hz),127.6(d,J(P, C)=9.0Hz),125.8(d,J(P, C)=13.3Hz),120.1(d,J(P, C)=1.6Hz),113.8- 113.7(m),101.0,55.0,54.9,33.4,27.6,26.6,19.3ppm;31PNMR(162MHz,CDCl3)δ-18.8ppm.
Using above-mentioned identical test method, difference is to replace diphenyl phosphine chloride by dicyclohexyl phosphonium chloride, Chiral fragrant Spiroketals skeleton biphosphine ligand (R, R, R)-Lh is prepared.
(R, R, R)-Lh, white solid, 55% .Mp95-96 DEG C of yield, [α]D 20=+88.5(c1.00,CHCl3).1H NMR (400MHz,CDCl3)δ=7.21-7.15(m,4H),6.89-6.85(m,2H),2.39-2.30(m,8H),1.98-1.87(m, 6H),1.30-1.25(m,18H),1.23-1.14(m,20H)ppm;31P NMR(162MHz,CDCl3)δ-21.6ppm.
Using above-mentioned identical test method, difference is to replace diphenyl phosphine chloride by di-t-butylchlorophosphine, Chiral fragrant Spiroketals skeleton biphosphine ligand (R, R, R)-Li is prepared.
(R, R, R)-Li, white solid, 81% yield [α]D 20=+78.1(c1.00,CHCl3).1H NMR(400MHz, CDCl3)δ=7.28-7.21(m,2H),6.99-6.81(m,4H),2.38-2.21(m,4H),1.98-1.88(m,6H),1.66- 1.45(m,14H),1.30-1.29(m,8H),1.17-1.15(m,16H)ppm;31PNMR(162MHz,CDCl3)δ-22.8ppm.
Using above-mentioned identical test method, difference is with (R, R, R) -5b for raw material, prepares chiral fragrant spiral shell Ketal skeleton biphosphine ligand (R, R, R)-Lj.
(R, R, R)-Lj, white solid, 70% .Mp98-100 DEG C of yield, [α]D 20=+109.3(c1.00,CHCl3).1H NMR(400MHz,CDCl3)δ7.31-7.24(m,20H),6.69(s,2H),6.35(d,J=5.6Hz,2H),2.31-2.26(m, 4H),2.11(s,6H),1.92-1.86(m,2H),1.28-1.25(m,2H),1.16-1.13(m,4H)ppm;13C NMR (100MHz,CDCl3)δ151.2,151.1,137.3,137.2,137.0,136.9,134.3,134.1,133.9,133.7, 131.5,131.4,130.6,129.2,128.9,128.4,128.1,128.0,125.2,124.4,124.3,120.1, 101.2,33.4,27.7,26.7,20.6,19.4ppm;31P(162MHz,CDCl3)δ-15.3ppm.
Using above-mentioned identical test method, difference is with (R, R, R) -5c for raw material, prepares chiral fragrant spiral shell Ketal skeleton biphosphine ligand (R, R, R)-Lk.
(R, R, R)-Lk, white solid, 65% .Mp98-100 DEG C of yield, [α]D 20=+101.1(c1.00,CHCl3).1H NMR(400MHz,CDCl3)δ7.33-7.24(m,20H),6.85(s,2H),6.46-6.44(m,2H),2.34-2.19(m, 4H),1.91-1.85(m,2H),1.28-1.26(m,2H),1.14-1.11(m,4H)ppm;13C NMR(100MHz,CDCl3)δ 151.4,151.3,136.2,136.1,135.6,135.5,134.2,134.05,134.02,133.8,130.2,130.1, 129.4,128.9,128.6,128.46,128.42,128.38,128.34,127.7,127.5,125.5,122.02, 122.01,101.6,33.2,27.5,26.6,19.2ppm;31P(162MHz,CDCl3)δ-15.5ppm.
Using above-mentioned identical test method, difference is with (R, R, R) -5d for raw material, prepares chiral fragrant spiral shell Ketal skeleton biphosphine ligand (R, R, R)-Ll.
(R, R, R)-Ll, white solid, 47% .Mp110-112 DEG C of yield, [α]D 20=+100.3(c0.90,CHCl3).1H NMR(400MHz,CDCl3)δ7.31-7.24(m,20H),6.88-6.79(m,2H),6.56-6.37(m,2H),2.36-2.29 (m,4H),2.18(s,6H),1.94-1.83(m,2H),1.29-1.21(m,2H),1.17-1.12(m,4H)ppm;31P (162MHz,CDCl3) δ -14.6ppm. use above-mentioned identical test method, difference is with (R, R, R) -5h for original Material, prepare chiral fragrant Spiroketals skeleton biphosphine ligand (R, R, R)-Lm.
(R, R, R)-Lm, white solid, 75% .Mp109-111 DEG C of yield, [α]D 20=+83.1(c1.00,CHCl3).1H NMR(400MHz,CDCl3)δ7.42-7.17(m,20H),6.95(d,J=7.2Hz,2H),6.76(t,J=7.6Hz,2H),6.58 (t,J=7.2Hz,2H),2.45(dd,J=16.0Hz,6.4Hz,2H),2.28(dd,J=16.0Hz,6.8Hz,2H),1.98- 1.95(m,2H),1.47-1.43(m,2H),1.12-1.08(m,2H)ppm;31P(162MHz,CDCl3)δ-15.5ppm.
Using above-mentioned identical test method, difference is with (S, S, R) -5i for raw material, prepares chiral fragrant spiral shell Ketal skeleton biphosphine ligand (S, S, R)-Ln.
(S, S, R)-Ln, white solid, 79% .Mp111-112 DEG C of yield, [α]D 20=+75.2 (c1.10, CHCl3).1H NMR(400MHz,CDCl3)δ7.45-7.16(m,20H),6.99-6.81(m,4H),6.63-6.58(m,2H),3.34-3.31 (m, 4H), 2.48-2.44 (m, 2H), 2.32-2.29 (m, 2H), 1.48-1.41 (m, 2H) ppm;31P(162MHz,CDCl3)δ- 17.3ppm.
Using above-mentioned identical test method, difference is with (R, R, R) -5j for raw material, prepares chiral fragrant spiral shell Ketal skeleton biphosphine ligand (R, R, R)-Lo.
(R, R, R)-Lo, white solid, 81% .Mp89-92 DEG C of yield, [α]D 20=+112.2(c1.30,CHCl3).1H NMR (400MHz,CDCl3)δ7.35-7.14(m,20H),6.91-6.85(m,2H),6.76-6.58(m,4H),2.46-2.41(m, 2H), 2.34-2.31 (m, 2H), 1.48-1.41 (m, 6H), 1.22-1.09 (m, 4H) ppm;31P(162MHz,CDCl3)δ- 13.4ppm.
(S, S, the S) -5a of embodiment 37 and (S, S, S)-La preparation
Using compound 30a prepared by embodiment 35 as hydrogenation substrate, using compound 7b as catalyst, chiral fragrant spiral shell is prepared Ketal compound (S, S, S) -5a.Reaction is as follows：30a (46.4mg, 0.1mmol), catalyst 7b (1.6mg, 0.001mmol), 2mL anhydrous methylene chlorides are added in hydrogenation bottle, and autoclave is transferred in glove box.Replacing hydrogen three times after, be filled with Hydrogen reacts at room temperature 24 hours to 50 atmospheric pressure.After being vented hydrogen, reactor is opened, removal of solvent under reduced pressure, is slightly composed by nuclear-magnetism really The suitable inverse ratio of fixed output quota thing, residue is through column chromatography for separation.The yield for obtaining (S, S, S) -5a is that 91%, ee values are>99%.
It is prepared by catalyst 7b reference literatures Angew.Chem.Int.Ed.2009,48,5345 method.
After the processing of 50mL schlenk pipes anhydrous and oxygen-free, substrate (S, S, S) -5a (350mg, 0.77mmol) is added, it is anhydrous Tetrahydrofuran (6mL), is cooled at -78 DEG C, and n-BuLi (0.8mL, 2.5M hexane, 1.9mmol), reaction mixing is slowly added dropwise After thing stirs half an hour at -78 DEG C, diphenyl phosphine chloride (0.36mL, 1.9mmol) is slowly added dropwise, room is risen to naturally after adding Temperature, it is stirred at room temperature 10 hours.After reaction is quenched in addition 15mL distilled water, (3 × 20mL), organic phase are extracted with dichloromethane After anhydrous sodium sulfate drying, filtering and concentrating, the purifying of residue column chromatography, target product (S, S, S)-La (375mg, 72% production are obtained Rate).
Embodiment 38
The method of reference implementation example 6, using para-fluoroaniline as nucleopilic reagent, biphosphine ligand (S, S, S)-La and metal salt [Pd (C3H5)Cl]2Complex compound is prepared in situ as catalyst, catalysis substrate 1b asymmetric pi-allyl aminating reaction, obtain formula (R)- 2c compounds.
(R) -2c, colorless oil, 86% yield, [α]D 20=-78.6(c1.00,CHCl3), 95%ee is [by high-efficient liquid phase color Spectrum measure, chiral AD-H posts；N-hexane/isopropanol=99:1,1.0mL/min,254nm;tR(minor)=18.31min;tR (major)=22.32min].1H NMR(400MHz,CDCl3)δ=7.37-7.25(m,5H),6.86(t,J=8.8Hz,2H), 6.51-6.48 (m, 2H), 6.37 (s, 1H), 5.89 (s, 1H), 5.33 (s, 1H), 4.16-4.13 (m, 2H), 4.08 (s, br, 1H),1.21(t,J=7.2Hz,3H)ppm;13C NMR(100MHz,CDCl3)δ=166.1,155.9(d,J(F,C)=234.0Hz), 143.0(d,J(F,C)=1.8Hz),140.4(d,J(F,C)=23.4Hz),128.7(s),127.7(s),127.4(s),125.9 (s),115.6(s),115.4(s),114.2(d,J(F,C)=7.4Hz),60.8,59.5,14.0ppm;19F-NMR(376MHz, CDCl3)δ-127.4ppm.
The method of reference implementation example 14, using formula (R) -2c compounds as substrate, prepare beta-lactam formula (R) -3c compounds.
(R) -3c, white solid, 84% .Mp125-126 DEG C of yield, [α]D 20=-95.5(c1.40,CHCl3), 95%ee [by High performance liquid chromatography determines, chiral OD-H posts；N-hexane/isopropanol=90:10,1.0mL/min,254nm;tR(major)= 6.80min;tR(minor)=7.56min].1H NMR(400MHz,CDCl3)δ=7.37-7.28(m,7H),6.91(t,J= 8.8Hz,2H),5.80(t,J=1.6Hz,1H),5.37(s,1H),5.13(s,1H)ppm;13C NMR(100MHz,CDCl3)δ= 160.4,158.9(d,J(F,C)=242Hz),149.6,135.9,133.6(d,J(F,C)=2.6Hz),129.0(s),128.7(s), 126.4(s),118.3(d,J(F,C)=7.8Hz),115.7(d,J(F,C)=22.7Hz),110.8(s),63.4ppm;19F NMR (376MHz,CDCl3)δ-109.0ppm.
Embodiment 39
The method of reference implementation example 6, respectively using cyclohexylamine, n-butylamine and benzylamine as nucleopilic reagent, biphosphine ligand (S, S, S)-La and metal salt [Pd (C3H5)Cl]2Complex compound is prepared in situ as catalyst, catalysis substrate 1b asymmetric allyl amine Change reaction, respectively obtain formula (R) -2v, (R) -2w, (R) -2x compounds.
(R) -2v, colorless oil, 74% yield, [α]D 20=-74.3(c1.30,CHCl3), 94%ee is [by high-efficient liquid phase color Spectrum measure, chiral AD-H posts；N-hexane/isopropanol=99:1,1.0mL/min,230nm;tR(minor)=6.46min;tR (major)=7.29min].1H NMR(400MHz,CDCl3)δ=7.34-7.22(m,5H),6.32(s,1H),5.88(s,1H), 4.85(s,1H),4.14-4.10(m,2H),2.39-2.31(m,1H),1.19-1.82(m,2H),1.74-1.67(m,2H), 1.25-1.11(m,9H)ppm.
(R) -2w, colorless oil, 73% yield, [α]D 20=-83.1(c1.00,CHCl3), 91%ee is [by high-efficient liquid phase color Spectrum measure, chiral AD-H posts；N-hexane/isopropanol=99:1,1.0mL/min,230nm;tR(minor)=6.51min;tR (major)=7.18min].1H NMR(400MHz,CDCl3)δ=7.36-7.22(m,5H),6.33(s,1H),5.91(s,1H), 4.65(s,1H),4.14-4.10(m,2H),2.57-2.48(m,2H),1.49-1.43(m,2H),1.36-1.30(m,2H), 1.25-1.19(m,3H),0.88(t,J=7.6Hz,3H)ppm.
(R) -2x, colorless oil, 71% yield, [α]D 20=-74.3(c1.30,CHCl3), 91%ee is [by high-efficient liquid phase color Spectrum measure, chiral OD-H posts；N-hexane/isopropanol=95:5,1.0mL/min,230nm;tR(minor)=4.38min;tR (major)=5.37min].1H NMR(400MHz,CDCl3)δ=7.39-7.18(m,10H),6.34(s,1H),5.95(s,1H), 4.70(s,1H),4.11-4.04(m,2H),3.69(dd,J=22.4Hz,13.2Hz,2H),1.16(t,J=6.8Hz,3H)ppm.
Embodiment 40
The method of reference implementation example 14, respectively using formula (R) -2v, (R) -2w, (R) -2x compounds as substrate, preparation β-interior Acid amides formula (R) -3v, (R) -3w, (R) -3x compounds.
(R) -3v, 73% yield.EI-MS(70eV)(m/z)341(M+).(R) -3w, 79% yield.EI-MS(70eV)(m/ z)215(M+).(R) -3x, 60% yield.1H NMR(400MHz,CDCl3)δ=7.34-7.14(m,10H),5.73(s,1H), 5.02(s,1H),4.90(d,J=14.8Hz,1H),4.81(s,2H),4.88(d,J=15.2Hz,1H)ppm。
Embodiment 41
The method of reference implementation example 6, using to benzyloxy-aniline as nucleopilic reagent, biphosphine ligand (S, S, S)-La and metal [Pd(C3H5)Cl]2Complex compound is prepared in situ as catalyst, catalysis substrate 1g asymmetric pi-allyl aminating reaction, obtains formula (R) -2y compounds.
(R) -2y, colorless oil, 87% yield, [α]D 20=-78.9(c1.20,CHCl3), 94%ee is [by high-efficient liquid phase color Spectrum measure, chiral OD-H posts；N-hexane/isopropanol=90:10,1.0mL/min,254nm;tR(minor)=9.81min;tR (major)=12.21min].EI-MS(70eV)(m/z)502(M+)。
Embodiment 42
The method of reference implementation example 6, using m- tert-butoxycarbonyl amido aniline as nucleopilic reagent, biphosphine ligand (S, S, S)-La and metal salt [Pd (C3H5)Cl]2Complex compound is prepared in situ as catalyst, catalysis substrate 1h asymmetric allyl amine Change reaction, obtain formula (R) -2z compounds.
(R) -2z, colorless oil, 89% yield, [α]D 20=-98.2(c1.15,CHCl3), 93%ee is [by high-efficient liquid phase color Spectrum measure, chiral AD-H posts；N-hexane/isopropanol=95:5,1.0mL/min,254nm;tR(minor)=13.83min;tR (major)=15.34min].EI-MS(70eV)(m/z)454(M+)。
Embodiment 43
The method of reference implementation example 14, respectively using formula (R) -2y, (R) -2z compounds as substrate, prepare beta-lactam formula (R) -3y, (R) -3z compounds.
(R) -3y, 73% yield.EI-MS(70eV)(m/z)456(M+).(R) -3z, 79% yield.EI-MS(70eV)(m/ z)408(M+)。
Embodiment 44
The suppression tumour cell effect of the compound prepared using the method for embodiment 34 to embodiment 40 and 43 is surveyed Examination.
As a result show that compound prepared by embodiment 40 and 43 shows IC to the inhibitory action of HL-60 cells50Value Less than 60 μ g/mL, and (R) -3y and two kinds of compounds of (R) -3z show IC50Value scope is even below 10 μ g/mL；Embodiment 40 IC is shown to the inhibitory action of lung cell A549 with 43 compounds prepared50Value is less than 55 μ g/mL, and (R) -3v, (R) - 3w compounds show IC50Value scope is even below 15 μ gmL, has preferably to the inhibitory action of tumour cell.
All it is incorporated as referring in this application in all documents that the present invention refers to, it is independent just as each document It is incorporated as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can To be made various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited Enclose.

Claims (11)

1. a kind of preparation method of compound of formula I, it is characterised in that methods described includes step：
(a) in organic solvent, in the presence of alkali, complex compound is formed using chiral phosphine ligand and transition-metal catalyst precursor As catalyst R2-NH2Asymmetric pi-allyl aminating reaction occurs with the compound of formula 1, prepares the chemical combination of key intermediate formula 2 Thing；
(b) in organic solvent, the compound of formula 2 cyclization in the presence of alkali, obtains compound of formula I,
In various：R1、R2It is respectively and independently selected from substituted or unsubstituted following group：C1-6Alkyl, C3-10Cycloalkyl, C6-20's Aryl；It is described to substitute the substituent for referring to be selected from the group to substitute：Halogen, C1-6Alkyl ,-OR11Or-NR12, wherein R11、R12Respectively From independently selected from hydrogen, acetyl group, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl group or t-Butyldimethylsilyl；
* stereogenic centres are represented, compound of formula I is R configurations or is S configurations；Or * represents that compound of formula I is raceme；
R3For methyl, ethyl, isopropyl, normal-butyl, the tert-butyl group, benzyl or adamantyl；
LG is acetyl group, tert-butoxycarbonyl, methoxycarbonyl or two (ethyoxyl) phosphine epoxides；
Wherein, described chiral phosphine ligand has following structure：
In formula, R4、R5、R6、R7、R8、R9It is respectively and independently selected from hydrogen, halogen, substituted or unsubstituted following group：C1~C10Alkane Base, C1~C4Alkoxy, C3~C30Cycloalkyl or aryl；R10、R11aIt is respectively and independently selected from substituted or unsubstituted following base Group：C3~C10Cycloalkyl, C1~C10Alkyl, 2- furyls or aryl；X is selected from CH2, NH, NCH3, O or S；N=0~4； Wherein described substitution is substituted by following substituent：Halogen, C1-6Alkyl, C1-6Haloalkyl or C1-6Alkoxy；Each aryl is only It is on the spot：Phenyl, benzyl, naphthyl, pyrenyl, anthryl, phenanthryl；
In the step (a), described alkali, R2-NH2Mol ratio with the compound of formula 1 is 1~10：1~10：1；Described catalysis The mol ratio of agent and the compound of formula 1 is 0.00001~0.1：1；Described chiral phosphine ligand and transition-metal catalyst precursor Mol ratio is (1~10)：1；Described alkali is potassium carbonate, potassium phosphate, cesium carbonate, triethylamine, diisopropyl ethyl amine, N, O- double It is more than one or both of (trimethylsilyl) acetamide, the fluoro triphenyl silicate of tetra-n-butyl ammonium two；
The transition-metal catalyst precursor is palladium catalyst precursor, is Pd (OAc)2、PdCl2、Pd2(dba)3、Pd2(dba)3· CHCl3、Pd(dba)2、[Pd(C3H5)Cl]2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(CH3CN)Cl2One or both of with On；
In the step (b), the mol ratio of described alkali and the compound of formula 2 is 1~10：1；
In the step (b), described alkali is two (the silicon substrate amido of hexamethyl two) tin, LHMDS, diisopropyl One or both of base lithium amide, tert-butyl group magnesium chloride, tert-butyl group magnesium bromide, isopropylmagnesium chloride, isopropyl magnesium bromide with On.
2. preparation method as claimed in claim 1, it is characterised in that described catalyst is by described chiral phosphine ligand and mistake Metal catalysts precursors are crossed under atmosphere of inert gases, in organic solvent, it is small that 0.1~1.0 are reacted at -78 DEG C~100 DEG C When and obtain.
3. preparation method as claimed in claim 1, it is characterised in that before described chiral phosphine ligand and transition-metal catalyst The mol ratio of body is 1~2：1.
4. preparation method as claimed in claim 1, it is characterised in that the palladium catalyst precursor is [Pd (C3H5)Cl]2。
5. preparation method as claimed in claim 1, it is characterised in that in described chiral phosphine ligand, R4、R5、R6、R7、R8、R9 It is respectively and independently selected from hydrogen, C1~C6Alkyl, C1~C4Alkoxy, C3~C30Cycloalkyl, halogen or phenyl；
R10、R11aIndependently selected from C3~C10Cycloalkyl, C1~C10Alkyl, 2- furyls or phenyl, the cycloalkyl, alkane Base, phenyl are optionally substituted by following substituent：Halogen, C1-6Alkyl, C1-6Haloalkyl or C1-6Alkoxy.
6. preparation method as claimed in claim 1, the chiral phosphine ligand areOr
7. preparation method as claimed in claim 1, it is characterised in that in the step (a), described alkali, R2-NH2With formula 1 The mol ratio of compound is 1~3：1~3：1；The mol ratio of described catalyst and the compound of formula 1 is 0.01~0.05：1.
8. preparation method as claimed in claim 1, it is characterised in that in the step (b), described alkali and the compound of formula 2 Mol ratio be 1~2：1.
9. preparation method as claimed in claim 1, it is characterised in that withUrged with transition metal Agent precursor forms complex compound as catalyst R2-NH2Reacted with the compound of formula 1, prepare key intermediate formula 2-1 Compound,
10. preparation method as claimed in claim 1, it is characterised in that described organic solvent is benzene,toluene,xylene, two Chloromethanes, chloroform, carbon tetrachloride, 1,2- dichloroethanes, ether, tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide or At least one of dimethyl sulfoxide (DMSO).
11. a kind of preparation method of the compound of formula 2, it is characterised in that methods described includes step：
In organic solvent, in the presence of alkali, form complex compound using chiral phosphine ligand and transition-metal catalyst precursor and make For catalyst R2-NH2Asymmetric pi-allyl aminating reaction occurs with the compound of formula 1, the compound of formula 2 is prepared；
In various：* stereogenic centres are represented, are R configurations or S configurations；
R1、R2It is respectively and independently selected from substituted or unsubstituted following group：C1-6Alkyl, C3-10Cycloalkyl, C6-20Aryl；Institute The substituent that substitution refers to be selected from the group is stated to substitute：Halogen, C1-6Alkyl ,-OR11、-NR12, wherein R11、R12Independently of one another Selected from hydrogen, acetyl group, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl group or t-Butyldimethylsilyl；
R3For methyl, ethyl, isopropyl, normal-butyl, the tert-butyl group, benzyl or adamantyl；
Wherein, LG is acetyl group, tert-butoxycarbonyl, methoxycarbonyl or two (ethyoxyl) phosphine epoxides；
Wherein, described chiral phosphine ligand has following structure：
In formula, R4、R5、R6、R7、R8、R9It is respectively and independently selected from hydrogen, halogen, substituted or unsubstituted following group：C1~C10Alkane Base, C1~C4Alkoxy, C3~C30Cycloalkyl or aryl；R10、R11aIt is respectively and independently selected from substituted or unsubstituted following base Group：C3~C10Cycloalkyl, C1~C10Alkyl, 2- furyls or aryl；X is selected from CH2, NH, NCH3, O or S；N=0~4； Wherein described substitution is substituted by following substituent：Halogen, C1-6Alkyl, C1-6Haloalkyl or C1-6Alkoxy；Each aryl is only It is on the spot：Phenyl, benzyl, naphthyl, pyrenyl, anthryl, phenanthryl；
Described alkali, R2-NH2Mol ratio with the compound of formula 1 is 1~10：1~10：1；Described catalyst and the compound of formula 1 Mol ratio be 0.00001~0.1：1；The mol ratio of described chiral phosphine ligand and transition-metal catalyst precursor for (1~ 10)：1；Described alkali is potassium carbonate, potassium phosphate, cesium carbonate, triethylamine, diisopropyl ethyl amine, the double (trimethyl silanes of N, O- Base) it is more than one or both of acetamide BSA, the fluoro triphenyl silicate TBAT of tetra-n-butyl ammonium two；
The transition-metal catalyst precursor is palladium catalyst precursor, is Pd (OAc)2、PdCl2、Pd2(dba)3、Pd2(dba)3· CHCl3、Pd(dba)2、[Pd(C3H5)Cl]2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(CH3CN)Cl2One or both of with On；
Described alkali is potassium carbonate, potassium phosphate, cesium carbonate, triethylamine, diisopropyl ethyl amine, N, O- pairs (trimethylsilyl) It is more than one or both of acetamide, the fluoro triphenyl silicate of tetra-n-butyl ammonium two.
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