WO2014012495A1

WO2014012495A1 - Chiral α-methylene-β-lactam compound and preparation method and application thereof

Info

Publication number: WO2014012495A1
Application number: PCT/CN2013/079543
Authority: WO
Inventors: 丁奎岭; 王晓明; 孟繁烨; 王正
Original assignee: 中国科学院上海有机化学研究所
Priority date: 2012-07-20
Filing date: 2013-07-17
Publication date: 2014-01-23
Also published as: CN103570600A; CN103570600B

Abstract

Disclosed are a chiral α-methylene-β-lactam compound and a preparation method and an application thereof. An asymmetric allyl amination reaction of catalyzing a class of Morita-Baylis-Hillman adducts by using a complex formed by a chiral phosphine ligand and metal palladium as a catalyst is a key step, and a key midbody chiral α-methylene-β-substituted amino carboxylic acid derivative can be prepared with high activity and high selectivity, and a chiral α-methylene-β-lactam compound can be prepared through a cyclization step. This class of compounds has antitumor activity.

Description

Chiral α-methylene lactam compound and preparation method and application thereof

Technical field

The present invention relates to the field of medical chemistry, and in particular to a chiral α-methylene-β-lactam compound and a preparation method and application thereof. Background technique

Chiral β-lactams are a class of structural units that are widely found in natural products and drugs. For example, β-lactam antibiotics are a kind of drugs with β-lactam quaternary ring as the parent structure, which has extremely important significance in anti-infective clinical application because of its strong antibacterial action. In recent years, due to the increasing abuse of antibiotics and drug resistance, the synthesis of new antibiotics and their structural transformation are imminent. Therefore, the development of a highly efficient synthesis method for a novel β-lactam compound having pharmacological activity has important academic significance and potential application value.

Chiral (X-methylene-β-arylaminocarboxylic acid derivatives are important intermediates in the synthesis of a class of pharmaceuticals and natural products (C1⁄2m. Rev. 2003, 103, 811-891; Chem. Eur. J. 2011) , 17, 13676.) ° Due to the asymmetry of the aza, the Morita-Baylis-Hillman (MBH) reaction requires an electron withdrawing group attached to the nitrogen atom of the imine, which makes the method in the substrate type and the product allylamine The structure is greatly limited. In addition, the asymmetric allyl substitution reaction of the transition metal or small molecule catalyzed MBH adduct is prepared by chiral (X-methylene-β-aminocarboxylic acid derivative). An important method of the substance, but unfortunately, there has not been a weakly nucleophilic aromatic amine as a nucleophilic reagent, high region and enantioselective synthesis (X-methylene-β-arylaminocarboxylic acid derivative) Report. Summary

It is an object of the present invention to provide a class of chiral ex-methylene-β-lactam compounds.

The present invention also provides the above chiral (X-methylene-β-lactam compound synthesis method, including its key intermediate chirality (Synthesis method of X-methylene-β-aminocarboxylic acid derivative. In a first aspect of the invention, a β-lactam structure is provided as shown in Formula I:

Wherein R ¹ and R ² are each independently selected from the group consisting of substituted or unsubstituted: d- ₆ fluorenyl, C^. Cyclodecyl, C ₆ _ ₂ . The aryl group; the substitution means substitution with a substituent selected from the group consisting of halogen, _Cr6 alkyl, d- ₆ methoxy, d- ₆ halogenated fluorenyl, -OR ¹¹ , or -NR ¹² , Wherein R ^u and R ¹² are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl Base, tert-butyldiphenylsilyl or diphenylmethylsilyl;

* indicates a stereogenic center, the compound of formula I is in a configuration or an S configuration; or * indicates that the compound of formula I is a racemate. In another preferred embodiment, the compound is:

In another preferred embodiment, the compound is a racemate composed of a compound of the formula 1-1 and a compound of the formula 1-2.

In the formulas: R, R ² , * are as defined above.

In another preferred embodiment, the compound is of formula II

Wherein Ar is selected from substituted or unsubstituted C ₅ _ ₂ . The aryl group; the substitution means substitution with a substituent selected from the group consisting of halogen, C^alkyl, CM alkoxy, C haloalkyl, -OR ¹¹ or -NR ¹² wherein R ^U and R ¹² are each Independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxy, benzyl, oxy-oxyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl or diphenylmethylsilyl;

* indicates a stereogenic center, the hydrazine compound is in a configuration or an S configuration; or * indicates that the compound of formula II is a racemate. In another preferred embodiment, R and R ^{2 are} not simultaneously a phenyl group.

In another preferred embodiment, when one of R and R ² is a phenyl group, the other is not a p-methoxyphenyl group. According to a second aspect of the invention, there is provided a process for the preparation of the compound of the first aspect, comprising the steps of:

(a) Asymmetric allyl amination of R ² -NH ₂ with a compound of formula 1 using a chiral phosphine ligand and a transition metal catalyst precursor as a catalyst in an organic solvent under the action of a base Reaction, preparation of key intermediates of formula 2;

(b) The compound of the formula 2 is subjected to a ring under an action of a base in an organic solvent to obtain the compound I according to the first aspect.

In the formulas: R, R ² , * are as defined above;

R ³ is methyl, ethyl, isopropyl, n-butyl, tert-butyl, benzyl or adamantyl;

LG is acetyl (Ac), tert-butoxycarbonyl (Boc), methoxycarbonyl (-C0 ₂ Me), or bis(ethoxy)phosphinooxy (POEt ₂ ). In another preferred embodiment, the catalyst is reacted with the chiral phosphine ligand and the transition metal catalyst precursor in an inert gas atmosphere at -78 ° C to 100 ° C in an organic solvent. 1.0 hours. Preferably, the reaction is 0.5 to 0 at 25 ° C.

1.0 hour.

In another preferred embodiment, the molar ratio of the chiral phosphine ligand to the transition metal catalyst precursor is (1 to 10): 1. Preferably, it is (1 to 2): 1.

In another preferred embodiment, the transition metal catalyst precursor is a palladium catalyst precursor, which is Pd(OAc) ₂ , PdCl ₂ , Pd ₂ (dba) ₃ Pd ₂ (dba) ₃ 'CHCl ₃ , Pd (dba) ₂ , one or more of [Pd(C ₃ H ₅ )Cl] ₂ , Pd(PPh ₃ ) ₄ , Pd(PPh ₃ ) ₂ Cl ₂ , Pd(CH ₃ CN)Cl ₂ .

In another preferred embodiment, the chiral phosphine ligand has the following structure:

R ⁴ , R ⁵ , R ⁶ , and RRR ⁹ are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted, alkyl, decyloxy, C ₃ ～ C ₃ o fluorenyl or aryl base;

R ^1Q and R ¹¹ are each independently selected from the group substituted or unsubstituted: 3⁄4~. Cyclodecyl, C^CK) fluorenyl, 2-furanyl, or aryl; X is selected from CH ₂ , NH, NCH ₃ , 0 or S; n = 0 to 4;

base.

In another preferred embodiment, in the step (a), the molar ratio of the base, R ² —NH ₂ to the compound of the formula 1 is from 1 to 10:1 to 10:1; and/or the catalyst The molar ratio to the compound of formula 1 is 0.00001 to 0.1:1.

In another preferred embodiment, the base is potassium carbonate, potassium phosphate, cesium carbonate, triethylamine, diisopropylethylamine, hydrazine, hydrazine-bis(trimethylsilyl)acetamide (BSA). One or more of tetra-n-butylammonium difluorotriphenylsilicate (TBAT).

In another preferred embodiment, in the step (b), the molar ratio of the base to the compound of the formula 2 is from 1 to 10:1.

In another preferred embodiment, in the step (b), the molar ratio of the base to the compound of the formula 2 is from 1 to 2:1.

In another preferred embodiment, the reaction temperature of the step (b) is -80 ° C to 150 ° C, preferably -20 ° C to 110 ° C. The reaction time is from 0.5 to 48 hours, preferably from 6 to 12 hours.

In another preferred embodiment, in the step (b), the base is bis(hexamethyldisilazide)tin (Sn[N(TMS) ₂ ] ₂ ), hexamethyldisilazide One or more of lithium (LHMDS), lithium diisopropylamide (LDA), t-butylmagnesium chloride, t-butylmagnesium bromide, isopropyl magnesium chloride, and isopropyl magnesium bromide.

In another preferred embodiment, the organic solvent is benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, methanol, ethanol, N, At least one of N-dimethylformamide or dimethyl sulfoxide. In a third aspect of the invention, the use of the compound of the first aspect for the preparation of a medicament for the prevention and/or treatment of a tumor is provided.

In another preferred embodiment, the prevention or treatment is achieved by inhibiting the growth of tumor cells. According to a fourth aspect of the invention, there is provided a compound of formula 2,

2 Where: * represents a stereogenic center, in a configuration or an S configuration;

RR ^{2 is} independently selected from the group consisting of substituted or unsubstituted groups: d- ₆ fluorenyl, C. Cyclodecyl, C ₆ _ ₂ . Aryl; refers to a substituent selected from the group of substituents: halogen, d- ₆ alkyl, d- ₆ alkoxy or - ₆ haloalkyl, -OR ^U,

-N ¹² , wherein R ^U and R ¹² are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyl Dimethylsilyl, tert-butyldiphenylsilyl or diphenylmethylsilyl;

R ³ is methyl, ethyl, isopropyl, n-butyl, tert-butyl, benzyl or adamantyl. In a fifth aspect of the invention, there is provided a method for preparing a compound of formula 2, comprising the steps of:

1 2

In an organic solvent, a complex of a chiral phosphine ligand and a transition metal catalyst precursor is used as a catalyst to catalyze the asymmetric allyl amination reaction of R ² —NH ₂ with the compound of formula 1 under the action of a base. Obtaining a compound of formula 2;

In the formulas, R, R ² , R ³ , and * are as defined above.

The selection of the organic solvent, base, chiral phosphine ligand, transition metal catalyst precursor and reaction conditions is the same as step (a) in the second aspect of the invention. According to a sixth aspect of the invention, there is provided a compound of formula II,

* indicates a stereogenic center, and the hydrazine compound is in a configuration or an S configuration; or * indicates that the compound of the formula II is a racemate.

Wherein R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are each independently selected from the group consisting of substituted or unsubstituted: CM fluorenyl, Cw. Cyclodecyl, C ₅ _ ₂ . The aryl group; the substitution means substitution with a substituent selected from the group consisting of halogen, d- ₆ alkyl, CM alkoxy, C haloalkyl, -OR ¹¹ , or -NR ¹² , wherein R ^U , R ¹² are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl or diphenylmethylsilyl; X is derived from a nitrogen, oxygen or sulfur atom;

* indicates a stereogenic center, and the compound of the formula III, IV, V is a configuration or an S configuration; or * indicates that the compound of the formula III, IV, V is a racemate. In an eighth aspect of the invention, a formula VI is provided, the structure is as shown in the formula:

Wherein Ar is selected from substituted or unsubstituted C ₅ _ ₂ . Aryl; refers to a substituent selected from the group of substituents: halogen, d- ₆ alkyl, CM alkoxy, CM haloalkyl, -OR ^11, or -NR ^12, wherein R ^U, R ¹² are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl or diphenylmethylsilyl;

* indicates a stereogenic center, and the compound of formula VI is in the R configuration or the S configuration; or * indicates that the compound of formula VI is a racemate. In the present invention, the preparation method of the compound of the formula II, III, IV, V, VI, VII is similar to the preparation method of the compound of the formula I. According to a ninth aspect of the invention, there is provided a compound of VII,

Wherein: = 0 or 1; Ar is selected from substituted or unsubstituted C ₅ _ ₂ . The aryl group; the substitution means substitution with a substituent selected from the group consisting of halogen, d- ₆ alkyl, CM alkoxy, CM haloalkyl, -OR ¹¹ or -NR ¹² , wherein R ^u , R ¹² Each is independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenyl a silyl group or a diphenylmethylsilyl group; R ²² , R ²³ , R ²⁴ , and R ²⁵ are each independently selected from the group consisting of a substituted or unsubstituted group: CM fluorenyl group, Cw. Cyclodecyl, C ₅ _ ₂ . Aryl, hydroxy or amino; said substitution means selected Substituted from the following group of substituents: halogen, d- ₆ alkyl, CM alkoxy, CM haloalkyl, -OR ¹¹ or -NR ¹² , wherein R ^U ,

R ^{12 is} each independently selected from the group consisting of hydrogen, acetyl, propionyl, t-butoxymethyl, benzyl, benzyloxy, trityl, trimethylsilyl, tert-butyldimethylsilyl, uncle Butyl diphenylsilyl or diphenylmethylsilyl;

* indicates a stereoisomer center, the compound of formula VII is a configuration or an S configuration; or * indicates that the compound of formula VII is a racemate. According to a tenth aspect of the invention, there is provided a compound of formula VIII,

VIII

Where: * indicates a stereogenic center, either a configuration or an S configuration; or a racemate.

Wherein Ar is selected from substituted or unsubstituted C ₅ _ ₂ . The aryl group; the substitution means substitution with a substituent selected from the group consisting of halogen, d- ₆ alkyl, CM alkoxy, CM haloalkyl, -OR ^U , or -NR ¹² , wherein R ^U , R ¹² are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl or diphenylmethylsilyl;

R ³ is methyl, ethyl, isopropyl, n-butyl, tert-butyl, benzyl or adamantyl.

In the present invention, the preparation method of the compound of the formula VIII is similar to the preparation method of the compound of the formula 2. In an eleventh aspect of the invention, the use of the compound of the sixth, seventh, eighth, or ninth aspect for the preparation of a medicament for preventing and/or treating a tumor is provided.

In another preferred embodiment, the prevention or treatment is achieved by inhibiting the growth of tumor cells. The present invention uses a complex of a bisphosphine ligand of a chiral aromatic snail ketal skeleton and a metal palladium as a catalyst to realize a high region for the first time.

An allyl amination reaction of ± or a highly enantioselective MBH adduct (compound of formula 1), a chiral (X-methylene-β-aminocarboxylic acid derivative) is synthesized in one step. The chiral biologically active β-lactam compound can be synthesized by one-step conversion. It should be understood that within the scope of the present invention, the above various technical features of the present invention and the techniques specifically described below (as in the examples) The features can be combined with each other to form a new or preferred technical solution. Due to space limitations, the description will not be repeated here.

Fig. 1 is a view showing the single crystal structure of the compound -3d obtained in Example 16.

2 is a single crystal structure diagram of the compound obtained in Example 36 (W^^-Sa). The inventors of the present application have extensively and intensively studied to prepare a novel chiral phosphine ligand, and use the phosphine ligand as a catalyst to realize a high region and a high enantioselectivity of the MBH adduct of the olefin. A propylation reaction, a chiral β-amino group (X-methylene carboxylic acid derivative) is synthesized in one step, and a chiral biologically active β-lactam compound can be synthesized by one-step conversion. , has the effect of inhibiting tumor growth. On this basis, the present invention has been completed.

The term "alkyl" means a saturated linear or branched hydrocarbon moiety, such as -CH ₃ or -CH (CH ₃₎ _2. The term "alkoxy" refers to a group formed by linking an alkyl group to an oxygen atom, such as -OCH ₃ , -OCH ₂ CH ₃ . The term "cycloalkyl" denotes a saturated cyclic hydrocarbyl moiety, such as cyclohexyl. The term "aryl" refers to a hydrocarbyl moiety containing one or more aromatic rings including, but not limited to, phenyl, benzyl, phenylene, naphthyl, naphthylene, anthracenyl, fluorenyl, phenanthryl.

Unless otherwise stated, the alkyl, alkoxy, cycloalkyl, and aryl groups described herein include both substituted and unsubstituted moieties. Possible substituents on the alkyl, alkoxy, cycloalkyl, and aryl groups include, but are not limited to: dC ₆ alkyl, dC ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ block , C ₃ -C _{1 ()} cyclodecyl, C ₃ -C _{1 ()} cycloalkenyl, C _r C ₆ decyloxy, aryl, hydroxy, halogen, amino. Phosphine ligand

The phosphine ligand used in the present invention has the following

Wherein R ⁴ , R ⁵ , R ⁶ , RR\ R ⁹ are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted: a C ₁₀ alkyl group, a Ci~C ₄ alkoxy group, C a cycloalkyl or aryl group of _{3 to} C ₃ o;

R ^1Q and R ¹¹ are each independently selected from the group consisting of a substituted or unsubstituted group: a C ₃ -C _1Q cyclodecyl group, a ~ 浣 fluorenyl group, a 2-furyl group, or an aryl group; X is selected from CH ₂ , NH , NCH ₃ , O or S; n=0~4;

Wherein the substituted group is substituted with the following substituents: halogen, C _r6 Huan group, halogenated d- ₆ Huan group, or d- ₆ Huan group. In another preferred embodiment, the substituent group is substituted by mono-, di- or tri-substituted by: halo, C _r6 Huan group, C _r6 haloalkyl, or. ^ alkoxy.

In another preferred ^{^{embodiment, R 4, R 5, R}} 6, R 7, R 8, R 9 are each independently selected from hydrogen, Huan group of ~ ^ ~ _[4 alkoxy, C ₃ ~C _3Q of Cycloalkyl, halogen or phenyl;

R ^1Q and R ^{11 are} independently selected from a C ₃ -C _{1 (} cycloalkyl ₎ group, a C do alkyl group, a 2-furyl group, or a phenyl group, and the cycloalkyl group, the hospital group, and the phenyl group are optionally Substituted by the following substituents: halogen, d- ₆ alkyl, d- ₆ haloalkyl, or. ^ alkoxy.

In another preferred embodiment, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are each independently selected from the group consisting of hydrogen, hydrazino group, 〜 alkoxy group, and C ₃ ～C _{1 ()} . Cyclodecyl, phenyl or halogen;

R ^u and R ^1Q are each independently selected from a phenyl group, a substituted phenyl group, a C ₃ ～C ₆ cycloalkyl group or a C ₂ ～C ₆ alkyl group, and the substitution is monosubstituted, disubstituted or Trisubstituted: halogen, d- ₆ fluorenyl, d- ₆ halodecyl, or - ₆ alkoxy;

X is selected from CH ₂ , 0, NCH ₃ , or 8.

In another preferred embodiment, R ⁴ and R ⁹ are the same group; R ⁵ and R ⁸ are the same group; and R ⁶ and R ⁷ are the same group. In another preferred embodiment, R ^1Q and R ¹¹ are the same group. In another preferred embodiment, the phosphine ligand is

In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^1Q , R ¹¹ are as defined above for the compound of formula 2

The compound of the formula 2 of the present invention has the following structure:

Where: * indicates a stereogenic center, in a configuration, or an S configuration;

RR ^{2 is} independently selected from the group consisting of substituted or unsubstituted groups: d- ₆ fluorenyl, C^. Cyclodecyl, C ₆ _ ₂ . Aryl; refers to a substituent selected from the group of substituents: halogen, d- ₆ alkyl, d- ₆ alkoxy or - ₆ haloalkyl, -OR ^u, -N ^12, wherein R ^u And R ¹² are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, uncle Butyl diphenylsilyl or diphenylmethylsilyl;

R ³ is methyl, ethyl, isopropyl, n-butyl, tert-butyl, benzyl or adamantyl.

In another preferred embodiment, R ³ is benzyl or adamantyl.

In another preferred embodiment, * represents a stereoisomer center, and the compound of formula 2 is in a configuration.

In another preferred embodiment, R and R ² are each independently selected from the group consisting of substituted or unsubstituted: d- ₆ fluorenyl, C ₃ _-1Q cyclodecyl; said substitution means selected from the group consisting of Substituent substitution: halogen, d- ₆ alkyl, d- ₆ alkoxy or d- ₆ haloalkyl, -OR ^U ,

-N ¹² , wherein R ^u and R ¹² are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyl Dimethylsilyl, tert-butyldiphenylsilyl or diphenylmethylsilyl.

A method for preparing a compound of the formula 2 of the present invention,

In the formula: R, R ² , R ³ , * are as defined above;

LG is acetyl (Ac), tert-butoxycarbonyl (Boc), methoxycarbonyl (-C0 ₂ Me), or bis(ethoxy)phosphinooxy (POEt ₂ ). The compound of formula 1 is a Morita-Baylis-Hillman adduct.

The organic solvent is benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide Or at least one of dimethyl sulfoxide.

The base is potassium carbonate, potassium phosphate, cesium carbonate, triethylamine, diisopropylethylamine, N,0-bis(trimethylsilyl) One or more of acetamide (BSA:) and tetra-n-butylammonium difluorotriphenylsilicate (TBAT). An aqueous alkali solution such as an aqueous potassium carbonate solution may be used in a concentration of 0.1 to 8.0 moles per liter, preferably 0.5 to 5 moles per liter.

In another preferred embodiment, the base is an aqueous solution of potassium carbonate (1 to 2 moles per liter) or triethylamine.

The catalyst is obtained by reacting the chiral phosphine ligand and the transition metal catalyst precursor in an inert gas atmosphere in an organic solvent at -78 ° C to 100 ° C for 0.1 to 1.0 hours. Preferably, the reaction is carried out at 0 to 25 ° C for 0.5 to 1.0 hour.

1.

The definitions of R', RR ⁹ , R ^1Q , and R ¹¹ are as described above.

The transition metal catalyst precursor is a palladium catalyst precursor, which is Pd(OAc) ₂ , PdCl ₂ , Pd ₂ (dba) ₃ , Pd ₂ (dba) ₃ -CHC13, Pd(dba) ₂ , [Pd(C ₃ One or more of H ₅ )Cl] ₂ , Pd(PPh ₃ ) ₄ , Pd(PPh ₃ ) ₂ Cl ₂ , and Pd(CH ₃ CN)Cl ₂ .

In another preferred embodiment, the palladium catalyst precursor is [Pd(C ₃ H ₅ )Cl] ₂ .

The molar ratio of the base, R ² -NH ₂ to the compound of formula 1 is 1 to 10: 1 to 10: 1;

The molar ratio of the catalyst to the compound of formula 1 is 0.00001 to 0.1:1.

Preferably, the molar ratio of the base, R ² -NH ₂ to the compound of formula 1 is 1 to 3: 1 to 3: 1; and/or

The molar ratio of the catalyst to the compound is 0.01 to 0.05:1.

In another preferred example,

Forming a complex with a transition metal catalyst precursor as a catalyst catalyzes the reaction of R ² -NH ₂ with the compound of formula 1 to prepare a key intermediate compound of formula 2-1.

In another preferred example,

The complex with the transition metal catalyst precursor is used as a catalyst to catalyze the reaction of R ² -NH ₂ with the compound of formula 1 to prepare the enantiomer of the key intermediate compound of formula 2-1.

Compound of formula I

The compound of the formula I of the present invention is a type of α-methylene β-lactam compound having the following structure:

I

Wherein R ¹ and R ² are each independently selected from the group consisting of substituted or unsubstituted: d- ₆ fluorenyl, C^. Cyclodecyl, C ₆ _ ₂ . The aryl group; the substitution means substitution with a substituent selected from the group consisting of halogen, _Cr6 alkyl, d- ₆ methoxy, d- ₆ halogenated fluorenyl, -OR ¹¹ , or -NR ¹² , Wherein R ^u and R ¹² are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl a tert-isobutyldiphenylsilyl or diphenylmethylsilyl; * represents a stereogenic center, and the compound of formula I is in a configuration or in an S configuration;

Or * indicates that the compound of formula I is a racemate.

In another preferred embodiment, * represents a stereogenic center, and the compound of formula I is in a configuration.

In another preferred embodiment, the RR ² each independently unsubstituted or substituted with a group selected from the following group: d- ₆ Huan group, C ₃ - ₁₀ cycloalkyl; refers to the substituent selected from the group Substituent substitution: halogen, d- ₆ alkyl, d- ₆ alkoxy, d- ₆ haloalkyl,

-OR ¹¹ , or -NR ¹² , wherein R ^u and R ¹² are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl Base, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or diphenylmethylsilyl; * represents a stereogenic center, and the compound of formula I is in the S configuration.

In another preferred embodiment, the RR ^{2 is} independently selected from the group consisting of substituted C ₆ _ ₂ . The aryl group; the substitution means substitution with a substituent selected from the group consisting of halogen, d- ₆ alkyl, d- ₆ haloalkyl, -OR ¹¹ , or -NR ¹² , wherein R ^u and R ¹² are each independently Selected from hydrogen, acetyl, propionyl, tert-butoxy, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenyl a silyl group or a diphenylmethylsilyl group; * represents a stereogenic center, and the compound of formula I is in a configuration.

In another preferred embodiment, R ^{1 is} selected from phenyl, optionally substituted by the following substituents: halogen, d- ₆ alkyl, d- ₆ haloalkyl, d- ₆ alkoxy, -OR ^u , or -N ¹² ;

R ^{2 is} selected from d- ₆ alkyl, C ₃ _-1( ) cycloalkyl, benzyl or substituted phenyl, optionally substituted by the following substituents: halogen, d- ₆ alkyl, d- ₆ haloalkyl , d- ₆ alkoxy, -OR ^u , or -N ¹² ;

The definitions of R ^u and R ¹² are as described above.

In another preferred embodiment, * represents a stereoisomer center, the compound of formula I is in the S configuration, and R, R ^{2 are} not phenyl or d- ₆ alkoxy substituted phenyl.

In another preferred embodiment, * indicates that the compound of formula I is a racemate, and R, R ^{2 are} not phenyl or d- ₆ alkoxy substituted phenyl. The substitution is a monosubstituted, disubstituted, trisubstituted, tetrasubstituted or pentasubstituted, preferably a monosubstituted, disubstituted, or trisubstituted. When disubstituted, trisubstituted, tetrasubstituted or pentasubstituted, the substituents may be the same or different, such as a -OR ¹¹ substituted phenyl group, which may be substituted by 1, 2, 3 or 4 -OR ¹¹ , Each R ^{11 is} independently hydrogen, acetyl, propionyl, tert-butoxy, base, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl or diphenylmethylsilyl

In another preferred embodiment, the compound is:

(1-2); In each formula, R and R ² are as defined above. Method for preparing compound of formula I

A method of preparing a compound of formula I of the invention, the method comprising the steps of:

(a) in an organic solvent, using a phosphine ligand to form a complex with a transition metal catalyst precursor as a catalyst to catalyze the asymmetric allylation of R ² -NH ₂ with the compound of formula 1 under the action of a base, Preparation of key intermediates of formula 2;

(b, the compound of formula 2 is ring-closed under the action of a base to give a compound of formula I.

In the formulas: R, R ² , * are as defined above;

R ³ is methyl, ethyl, isopropyl, n-butyl, tert-butyl, benzyl or adamantyl;

LG is acetyl (Ac), tert-butoxycarbonyl (Boc), methoxycarbonyl (-C0 ₂ Me), or bis(ethoxy)phosphinooxy (POEt ₂ ). The organic solvent is benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide Or at least one of dimethyl sulfoxide.

The experimental conditions of the step (a) are as described above. In the step (b), the base is bis(hexamethyldisilazide)tin (S _n [N(TMS) ₂ ] ₂ ), hexamethyldisilazide lithium (LHMDS) One or more of lithium diisopropylamide (LDA:), tert-butylmagnesium chloride, t-butylmagnesium bromide, isopropylmagnesium chloride, and isopropyl magnesium bromide.

In another preferred embodiment, in the step (b), the base is bis(hexamethyldisilazide)tin (Sn[N(TMS) ₂ ] ₂ ) or hexamethyldisilazide Lithium base (LHMDS).

In the step (b), the molar ratio of the base to the compound of the formula 2 is from 1 to 10:1.

In another preferred embodiment, the compound of the formula 2-1 is ring-closed under the action of a base to give a compound of the formula 1-1.

In another preferred embodiment, the enantiomer of the compound of formula 2-1 is cleaved under the action of a base to give a compound of formula 1-2.

Use

The compound of the formula I, II, III, IV, V, VI, VII of the invention, the leukemia cell HL60, the lung cancer cell A549, the hepatoma cell HepG-2, the breast cancer cell MDA-MB-231, the gastric cancer MKN-45 and the like The cells have a significant inhibitory effect. Therefore, it is possible to prepare a medicament for preventing and treating cancer. Preferably, it is used for the preparation of a medicament for preventing/treating leukemia, lung cancer or liver cancer. The medicament may be a pharmaceutical composition prepared from a compound of formula I, Π, III, IV, V, VI, VII as an active ingredient together with a pharmaceutically acceptable excipient or carrier.

A "pharmaceutically acceptable excipient or carrier" may be one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.

The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .

The compounds of formula I, Π, III, IV, V, VI, VII of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds such as other antitumor drugs. Representative anti-tumor drugs (such as chemotherapeutic drugs) include (but are not limited to): cisplatin, carboplatin, camptothecin, doxorubicin, bleomycin, fluorouracil.

Since it has (X-methylene structural unit, it can be converted as an intermediate to prepare a chiral β-lactam compound having a more novel structure. The present invention is advantageous in that:

(1) A novel class of β-lactam compounds are provided for the preparation of antitumor drugs.

(2) A novel method for producing an X-methylene β-lactam compound is provided.

(3) The method of the present invention, using an amine as a nucleophilic reagent, a complex of a phosphine ligand of a chiral aromatic spiroketal skeleton and a metal palladium as a catalyst for catalyzing an amine of a Morita-Baylis-Hillman adduct The reaction, high activity and high area and enantioselective preparation of key intermediate chiral β-amino group (X-methylene carboxylic acid derivative, can be prepared by one-step cyclization (X) - Methylene β-lactam compounds, the method is simple and easy. The present invention will be specifically described by way of examples, and it is necessary to point out that the following examples are only used to further illustrate the present invention, and are not understood as For the limitation of the scope of the present invention, some non-essential improvements and adjustments made by those skilled in the art based on the above-mentioned contents of the present invention are all within the scope of the present invention.

In this embodiment, aniline is used as a nucleophilic reagent, N,O-bis(trimethylsilyl)acetamide (BSA) is used as a base, and a bisphosphine ligand (foot-size?)-La and a metal salt Pd ₂ (dba) _{3 are used.} The catalyst was prepared in situ to catalyze the asymmetric allyl amination of substrate la under different solvents. Reaction formula

The reaction was as follows: Pd ₂ (dba) ₃ (4.5 mg, 0.005 mmol) and (scale)?-La (8.2 mg, 0.0125 mmol) were added to a schlenk tube under argon atmosphere, and the solvent in Table 1 was added (5). After stirring for 10 minutes at room temperature, the substrate la (117.1 mg, 0.5 mmol), N,0-bis(trimethylsilyl)acetamide BSA (305 mg, 1.5 mmol) and aniline (140 mg) were added. , 1.5 mmol). After stirring at room temperature for three hours, it was extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography

Table 1: Effect of Solvents on Asymmetric Amination Results

Solvent B yield (%) B/L B

1 CH ₃ CN 20 24/76 30

2 THF 80 83/17 60

3 toluene toluene 85 90/10 14

4 CH ₂ C1 ₂ 87 89/11 78

5 Dimethylformamide DMF 50 58/42 78

6 Dimethyl ether DME 38 41/59 32

7 CHC1 ₃ 94 97/3 56

8 MeOH - 8/92 -

[a] _D ²⁰ = +79.8. (c 1.0, CHC1 ₃ ), 78% ee [determined by high performance liquid chromatography, chiral AD-H column; n-Hex I z-PrOH = 95 : 5, 1.0 mL/min, 254 nm; 3⁄4 (major) = 7.51 min; 3⁄4 (minor) = 8.21 min]. 1H NMR (300 MHz, CDCI3) δ = 7.37-7.27 (m, 5H), 7.14 (t, J = 8.1 Hz, 2H), 6.71 (t, J = 7.2 Hz, 1H), 6.56 (d, J = 7.8 Hz, 2H), 6.38 (s, 1H), 5.96 (s, 1H), 5.40 (s, 1H), 4.15 (s, 1H), 3.69 (s, 3H) ppm.

Example 2

In this embodiment, aniline is used as a nucleophilic reagent, dichloromethane is used as a solvent, and a bisphosphine ligand (scale)?-La and a metal salt Pd ₂ (dba) _{3 are used to} prepare a catalyst in the presence of a different base. Asymmetric allyl amination of la. The reaction formula is as follows:

The reaction was as follows: Pd ₂ (dba) ₃ (4.5 mg, 0.005 mmol) and (scale)?-La (8.2 mg, 0.0125 mmol) were added to a schlenk tube under argon atmosphere, and anhydrous dichloromethane C5 was added. After stirring for 10 minutes at room temperature, the substrate la (117.1 mg, 0.5 mmol), the base (1.5 mmol) and aniline (140 mg, 1.5 mmol) in Table 2 were added. After stirring at room temperature for three hours, it was extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography

Table 2: Effect of alkali on the results of asymmetric amination

Base β equivalent) B yield (%) B/LB _ei %)

1 ― 0 0/100 -

2 K ₃ P0 ₄ 74 80/20 75

3 Cs ₂ C0 ₃ 28 91/9 77 4 ₂ C0 ₃ 86 93/7 79

5 K ₂ C0 ₃ (aq) 85 90/10 82

6 NEt ₃ 79 82/18 78

7 ^; Pr ₂ NEt 71 76/34 73

8 BSA 83 89/11 78

9 TBAT 85 86/14 76 Example 3

In this embodiment, aniline is used as a nucleophilic reagent, dichloromethane is used as a solvent, a bisphosphine ligand (foot-size?)-La and a different metal palladium salt are used to prepare a catalyst in situ. One mole per liter of potassium carbonate aqueous solution is used as a base, and the catalytic substrate is used. Asymmetric allyl amination of la. The reaction formula is as follows:

The reaction was as follows: Under an argon atmosphere, a metal palladium salt precursor (0.01 mmol for palladium atoms) and (foot gauge? La (8.2 mg, 0.0125 mmol) were added to a schlenk tube, respectively, and anhydrous dichloromethane was added. (5 mL), after stirring at room temperature for 10 minutes, add the substrate la (117.1 mg, 0.5 mmol), aqueous potassium carbonate (1M, 1.5 mL, 1.5 mmol) and aniline (140 mg, 1.5 mmol). After three hours, it was extracted with dichloromethane (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give the product.

Table 3: Effect of metal palladium salt precursors on the results of asymmetric amination

[M] Yield of B (B/L B

1 Pd ₂ (dba) ₃ 85 90/10 82

2 Pd(OAc) ₂ 81 89/11 81

3 Pd(PPh ₃ ) ₂ Cl ₂ 87 93/7 67

4 Pd(CH ₃ CN) ₂ Cl ₂ 89 94/6 82

5 [Pd(T -C ₃ H ₅ )Cl] ₂ 92 96/4 84 Example 4

In this embodiment, aniline is used as a nucleophilic reagent, dichloromethane is used as a solvent, and a bisphosphine ligand (strip-La and [Pd(C ₃ H ₅ )Cl] _{2 is} prepared in situ, and 1 mol per liter of potassium carbonate solution is used. A base, an asymmetric allyl amination reaction that catalyzes the substrate of different ester groups. The reaction formula is as follows:

B (Branched) (Linear) The reaction was as follows: [Pd(C ₃ H ₅ )Cl] ₂ (1.8 mg, 0.005 mmol) and (scale)?-La (0.0125 mmol) were separately added to a schlenk tube under argon atmosphere, and anhydrous CH _{2 was} added. C1 ₂ (5 mL), stirred for 10 minutes at room temperature, has addition of substrate (0.5 mmol), the K ₂ C0 ₃ (1.0 M aq, 1.5 mL, 1.5 mmol) and aniline (140 mg, 1.5 mmol) o rt After stirring for three hours, it was extracted with methylene chloride (3×10 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give the product.

Table 4: Effect of ester groups in the substrate on the results of asymmetric amination

Yield of R B (%) B/L B

1 Me 92% 96/4 84

2 Et 90% 94/6 93

3, Bu 83% 90/10 90 Example 5

In this embodiment, aniline is used as a nucleophile, and different bisphosphine ligands (scales L and metal salts [Pd(T!-C ₃ H ₅ )Cl] _{2 are} prepared in situ to catalyze the asymmetric olefin of the substrate lb. The propyl amination reaction has the following reaction formula:

The reaction was as follows: [Pd(C ₃ H ₅ )Cl] ₂ (1.8 mg, 0.005 mmol) and (foot-size?)-L (0.0125 mmol) were separately added to a Schlenk tube under argon atmosphere, and anhydrous CH _{2 was} added. C1 ₂ (5 mL), after stirring at room temperature for 10 min, lb (124.1 mg, 0.5 mmol), K ₂ C0 ₃ (1.0 M aqueous solution, 1.5 mL, 1.5 mmol) and aniline (140 mg, 1.5 mmol) ). After stirring at room temperature for three hours, it was extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate.

Table 5: Asymmetric amination of substrate lb with different bisphosphine ligands (the complex of scale-L with metal palladium as a catalyst) Ligand yield of B C%) B/L ee (%)

1 (RJlJl)-La 90 94/6 (+)-94

2 (R,R,R)-U 71 90/10 (+)-59

3 89 92/8 (+)-96

4 (i?,i?,i?)-Ld 89 91/9 (+)-95

5 (R,R,R)-^ 90 92/8 (+)-93

6 (RJIJI)- 87 92/8 (+)-89

7 88 90/10 (+)-90

8 ( ?„)-Lh 85 91/9 (+)-89

9 (R,R,R)-U 80 85/15 (+)-87

10 82 89/11 (+)-93 11 ( ?„)-Lk 87 92/8 (+)-93

12 (R,R,K)-U 81 90/10 (+)-88

13 (i?J?J?)-Lm 79 88/12 (+)-87

14 C)-Ln 80 86/14 (+)-92

15 (RJlJl)-Lo 85 91/9 (+)-93

2a, [a] _D ²⁰ = +120.0 (c 1.00, CHC1 ₃ ), 96% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/isopropanol = 95:5, 1.0 mL/ Min, 254 nm; t _R (major) = 7.07 min; t _R (minor) = 7.81 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.38-7.27 (m, 5H), 7.16 (t, J= 8.4 Hz, 2H), 6.72 (t, J= 7.2 Hz, 1H), 6.57 (d, J= 8.8 Hz, 2H), 6.38 (s, 1H), 5.94 (s, 1H), 5.40 (d, J= 4.8 Hz, 1H), 4.19-4.09 (m, 3H), 1.20 (t, J = 7.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 14.0 ppm.

Example ό

In this example, a different amine is used as a nucleophile, a bisphosphine ligand (foot-size?)-Lc and a metal salt [Pd(T!-C ₃ H ₅ )Cl] _{2 are} prepared in situ to catalyze the substrate lb. Symmetrical allyl amination reaction (reaction formula is as follows):

The reaction was as follows: [Pd(C ₃ H ₅ )Cl] ₂ (1.8 mg, 0.005 mmol) and (foot-size?)-Lc (9.6 mg, 0.0125 mmol) were added to a schlenk tube under argon atmosphere, respectively. Water CH ₂ C1 ₂ (5 mL), after stirring at room temperature for 10 min, then lb (124.1 mg, 0.5 mmol), K ₂ C0 ₃ (1.0 M aqueous solution, 1.5 mL, 1.5 mmol) and aromatic amine (1.5) Mm). After stirring at room temperature for three hours, it was extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate. The experimental results are as follows:

2b, colorless oil, 88% yield, [a] _D ²⁰ = +98.4 (c 1.00, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/different Propanol = 95:5, 1.0 mL/min, 254 nm; t _R (major) = 11.08 min; t _R (minor) = 12.12 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.38-7.25 (m , 5H), 6.75 (d, J= 8.8 Hz, 2H), 6.54 (d, J= 9.2 Hz, 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 = 7.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 14.0 m.

2c, colorless oil, 89% yield, [a] _D ²⁰ = +78.9 (c 1.00, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/different Propanol = 99:1, 1.0 mL/min, 254 nm; t _R (major) = 18.31 min; t _R (minor) = 22.32 NMR NMR (400 MHz, CDC1 ₃ ) δ = 7.37-7.25 (m, 5H), 6.86 (t, J = 8.8 Hz, 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 = 7.2 Hz, 3H) ppm; ¹³ C NMR ( 100 MHz, CDC1 ₃ ) δ = 166.1, 155.9 (d, J _(F , _C) = 234.0 Hz), 143.0 (d, J _(F , _C) = 1.8 Hz), 140.4 (d, J _(F , C) = 23.4 Hz), 128.7 (s), 127.7 (s), 127.4 (s), 125.9 (s), 115.6 (s), 115.4 (s), 114.2 (d, J _(F , _C) = 7.4 Hz), 60.8, 59.5, 14.0 ppm; ¹⁹ F-NMR (376 MHz, CDC1 ₃ ) δ -127.4 ppm.

2d, white solid, 83% yield. Mp 78-. C, [a] _D ²⁰ = +115.0 (c 1.00, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexanol/isopropanol = 98:2, 1.0 mL/ Min, 254 nm; t _R (major) = 16.31 min; t _R (minor) = 18.01 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.33-7.19 (m, 7H), 6.42 (d, J= 8.8 Hz, 2H), 6.36 (s, 1H) _: 5.85 (s, 1H), 5.35 (s, 1H), 4.16-4.05 (m, 3 H), 1.18 (t, J = 7.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 5 = 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, 13.9

2e, colorless oil, 67% yield, [a] _D ²⁰ = +53.3 (c 1.00, CHC1 ₃ ), 96% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/iso Propanol = 99:1, 1.0 mL/min, 254 nm; t _R (major) = 7.96 min; t _R (minor) = 8.76 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.43-7.25 (m , 6H), 7.11 (t, J= 10.8 Hz, 1H), 6.59-6.54 (m, 2H), 6.38 (s, 1H), 5.85 (s, 1H), 5.49 (d, J= 8.0 Hz, 1 H ), 4.87 (d, J = 7.6 Hz, 1H), 4.21-4.10 (m, 2H), 1.20 (t, J = 9.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 13.9 ppm.

2f, colorless oil, 91% yield, [a] _D ²⁰ = +95.2 (c 1.00, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/different Propyl alcohol = 98:2, 1.0 mL/min, 254 nm; t _R (major) = 11.66 min; t _R (minor) = 12.88 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.37-7.22 (m , 5H), 6.96 (d, J= 8.0 Hz, 2H), 6.50 (d, J= 8.4 Hz, 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 = 7.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 14.0 ppm.

2g, colorless oil, 86% yield, [a] _D ²⁰ = +102.8 (c 1.00, CHC1 ₃ ), 96% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/iso Propanol = 99:1, 1.0 mL/min, 254 nm; t _R (major) = 15.11 min; t _R (minor) = 16.75 NMR NMR (400 MHz, CDC1 ₃ ) δ = 7.37-7.23 (m, 5H), 7.04 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 7.2 Hz, 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 = 7.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 14.0 ppm.

2h, colorless oil, 85% yield, [a] _D ²⁰ = +86.6 (c 1.00, CHC1 ₃ ), 96% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/iso Propanol = 85:15, 1.0 mL/min, 254 nm; t _R (major) = 10.38 min; t _R (minor) = 12.36 min]. 1H NMR (400 MHz, CDC1 ₃ ) 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 = 7.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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 , 13.8 ppm. Example 7

In this example, an aniline is used as a nucleophilic reagent, a bisphosphine ligand (scale)?-Lc and a metal salt [Pd(T!-C ₃ H ₅ )Cl] _{2 are} prepared in situ to catalyze the asymmetric olefin of the substrate 1. Propyl amination reaction (reaction formula is as follows):

The reaction was as follows: [Pd(C ₃ H ₅ )Cl] ₂ (1.8 mg, 0.005 mmol) and (foot-size?)-Lc (9.6 mg, 0.0125 mmol) were added to a schlenk tube under argon atmosphere, respectively. Water CH ₂ C1 ₂ (5 mL), after stirring at room temperature for 10 min, then added 1 (0.5 mmol), K ₂ C0 ₃ (1.0 M aqueous solution, 1.5 mL, 1.5 mmol) and aniline (139.6 mg, 1.5 mmol) ). After stirring at room temperature for three hours, it was extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography The experimental results are as follows:

2i, white solid, 64% yield. Mp 93-94. C, [a] _D ²⁰ = +146.5 (c 1.00, CHC1 ₃ ), 91% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexanol/isopropanol = 98:2, 1.0 mL/ Min, 254 nm; t _R (major) = 6.91 min; t _R (minor) = 8.44 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.24-7.13 (m, 6H), 6.71 (t, J= 7.2 Hz, 1H), 6.55 (d, J= 8.0 Hz, 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 = 7.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 14.0 ppm.

2j, white solid, 89% yield. Mp 56-57. C,

CHC1 ₃ ), 97% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexyl/isopropanol = 98:2, 1.0 mL/min, 254 nm; t _R (major) = 9.52 min; t _R (minor) = 11.05 min]. NMR NMR (400 MHz, CDC1 ₃ ) δ = 7.21-7.07 (m, 6H), 6.70 (t, J = 7.6 Hz, 1H), 6.56 (d, J = 8.4 Hz, 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 = 7.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 14.0 ppm.

2k, colorless oil, 90% yield, [a] _D ²⁰ = +129.6 (c 1.00, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/iso Propanol = 98:2, 1.0 mL/min, 254 nm; t _R (major) = 12.55 min; t _R (minor) = 14.98 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.26-7.22 (m , 2H), 7.16-7.12 (m, 4H), 6.70 (t, J= 8.4 Hz, 1H), 6.56 (d, J= 8.4 Hz, 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 = 7.6 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 14.0 ppm.

21, colorless oil, 96% yield, [a] _D ²⁰ = +132.6 (c 1.00, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/different Propyl alcohol = 98:2, 1.0 mL/min, 254 nm; t _R (major) = 20.63 min; t _R (minor) = 23.04 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.28 (d, J = 8.4 Hz, 2H), 7.15 (t, J= 7.6 Hz, 2H), 6.86 (d, J= 8.4 Hz, 2H), 6.71 (t, J = 7.2 Hz, 1H), 6.56 (d, J = 8.0 Hz, 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= 7.2 Hz , 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 14.0 ppm.

2m, colorless oil, 96% yield, [a] _D ^2Q = +89.9 (c 1.00, CHC1 ₃ ), 97% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/different Propanol = 98:2, 1.0 mL/min, 254 nm; t _R (major) = 12.72 min; t _R (minor) = 13.89 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.35-7.32 (m , 2H), 7.16 (t, J= 8.0 Hz, 2H), 7.01 (t, J= 8.8 Hz, 2H), 6.73 (t, J= 7.2 Hz, 1H), 6.57 (d, J= 8.0 Hz, 2H ), 6.38 (s, 1H), 5.92 (s, 1H), 5.38 (s, 1H), 4.18-4.13 (m, 3H), 1.21 (t, J = 6.8 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 166.0, 162.2 (d, J _(F , _C) = 244.0 Hz), 146.5 (s), 140.1 (s), 136.4 (d, J _(F , _C) = 2.9 Hz), 129.1 (d, J _(F , _C) = 7.8 Hz), 126.0 (s), 118.0 (s), 115.6 (s) _: 115.4 (s), 113.4 (s), 60.8, 58.3, 14.0 ppm; ¹⁹ F-NMR (376 MHz, CDC1 ₃ ) δ -114.6 ppm.

2n, white solid, 85% yield. Mp 80-81. C, [a] _D ²⁰ = +94.8 (c 1.00, CHC1 ₃ ), 97% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexanol/isopropanol = 98:2, 1.0 mL/ Min, 254 nm; t _R (major) = 15.55 min; t _R (minor) = 17.82 min]. NMR (400 MHz, CDC1 ₃ ) δ = 7.43-7.41 (m, 2H), 7.24-7.22 (m, 2H), 7.15-7.11 (m, 2H) _: 6.70 (t, J = 7.2 Hz , 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= 7.6 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 13.9 m.

2o, white solid, 90% yield. Mp 74-75. C, [a] _D ² ° = +97.0 (c 1.00, CHC1 ₃ ), 96% ee [determined by high performance liquid chromatography, chiral AD-H column; hexamethylene / isopropanol = 98:2, 1.0 mL /min, 254 nm; t _R (major) = 14.26 min; t _R (minor) = 15.88 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.30-7.25 (m, 4H), 7.12 (t, J = 7.6 Hz, 2H), 6.70 (t, J = 7.2 Hz, 1H), 6.54 (d, J = 8.4 Hz, 2H), 6.36 (s, 1H), 5.88 (s, 1H), 5.37 (s, 1H ), 4.17-4.07 (m, 3H), 1.18 (t, J = 7.6 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 13.9 ppm.

2p, colorless oil, 83% yield, [a] _D ²⁰ = +94.6 (c 1.00, CHC1 ₃ ), 98% ee [determined by high performance liquid chromatography, chiral OD-H column; Propanol = 90:10, 1.0 mL/min, 254 nm; t _R (minor) = 5.92 min; t _R (major) = 6.38 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.36 (s, 1H ), 7.24-7.21 (m, 3H), 7.13 (t, J = 7.6 Hz, 2H), 6.70 (t, J = 7.2 Hz, 1H), 6.54 (d, J = 8.0 Hz, 2H), 6.38 (s , 1H), 5.88 (s, 1H), 5.37 (d, J = 5.2 Hz, 1H), 4.20-4.07 (m, 3H), 1.19 (t, J = 7.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 13.8 ppm.

Example 8

In this embodiment, p-methoxyaniline is used as a nucleophilic reagent, and a bisphosphine ligand (scale)?-Lc and a metal [Pd(C ₃ H ₅ )Cl] ₂ are used as catalysts in the field to catalyze a substrate. Asymmetric allyl amination of lc (reaction formula is as follows):

The reaction was as follows: [Pd(C ₃ H ₅ )Cl] ₂ (1.8 mg, 0.005 mmol) and (foot-size?)-Lc (9.6 mg, 0.0125 mmol) were added to a schlenk tube under argon atmosphere, respectively. Water CH ₂ C1 ₂ C5 mL), after stirring at room temperature for 10 min, then substrate 1 (^139.1 mg, 0.5 mmol), K ₂ C0 ₃ (1.0 M aqueous solution, 1.5 mL, 1.5 mmol) and p-methoxy Aniline (185 mg, 1.5 mmol). After stirring at room temperature for three hours, it was extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography The experimental results are as follows:

2q, yellow solid, 91% yield. Mp 88-89 ° C, [a] _D ²⁰ = +67.5 (c 1.00, CHC1 ₃ ), 96% ee [determined by high performance liquid chromatography, chiral AD-H column ; = / / isopropanol = 95:5, 1.0 mL / min, 254 nm; t _R (major) = 21.10 min; t _R (minor) = 22.50 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.28 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 6.74 (d, J = 8.4 Hz, 2H), 6.52 (d, J = 8.0 Hz, 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 = 6.8 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDCI3) 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, 14.0 ppm.

Example 9

In this embodiment, 3,4,5-trimethoxyaniline is used as a nucleophilic reagent, and a bisphosphine ligand (foot-size?)-Lc is combined with a metal [Pd(C ₃ H ₅ )C in situ to prepare a complex as a catalyst. Catalytic substrate lc (reaction formula is as follows):

The reaction was as follows: [Pd(C ₃ H ₅ )Cl] ₂ (1.8 mg, 0.005 mmol) and (foot-size?)-Lc (9.6 mg, 0.0125 mmol) were added to a schlenk tube under argon atmosphere, respectively. Water CH ₂ C1 ₂ C5 mL), after stirring at room temperature for 10 minutes, add substrate 1 (^139.1 mg, 0.5 mmol), K ₂ C0 ₃ (1.0 M aqueous solution, 1.5 mL, 1.5 mmol) and 3, 4, 5-Trimethoxyaniline (274.8 mg, 1.5 mmol) o After stirring at room temperature for three hours, it is extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography. Amine product. The experimental results are as follows:

2r, colorless oil, 90% yield, [a] _D ²⁰ = +101.7 (c 1.00, CHC1 ₃ ), 96% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/iso Propanol = 90:10, 1.0 mL/min, 254 nm; t _R (major) = 25.19 min; t _R (minor) = 27.66 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.28 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 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 = 7.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 13.7 ppm.

Example 10

In this embodiment, 3,4,5-trimethoxyaniline is used as a nucleophilic reagent, and a bisphosphine ligand (foot-size?)-Lc is combined with a metal [Pd(C ₃ H ₅ )C in situ to prepare a complex as a catalyst. Asymmetric allyl amination reaction of the substrate Id (reaction formula is as follows):

The reaction was as follows: [Pd(C ₃ H ₅ )Cl] ₂ (1.8 mg, 0.005 mmol) and (foot-size?)-Lc (9.6 mg, 0.0125 mmol) under argon atmosphere Add a schlenk tube, add anhydrous CH ₂ C1 ₂ C5 mL), and stir for 10 minutes at room temperature, then add substrate Id (169.1 mg, 0.5 mmol), K ₂ C0 ₃ (1.0 M aqueous solution, 1.5 mL, 1.5 mmol) and 3,4,5-trimethoxyaniline (274.8 mg, 1.5 mmol) o After stirring at room temperature for three hours, extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate After purification by column chromatography, a chiral amination product is obtained. Experimental result

20 .

2s, colorless oil, 92% _{^{yield, [a] D 2lJ = +102.5}} (c 1.00, CHC1 3), 98% ee [ determined by high performance liquid chromatography, chiral AD-H column; n-hexane / iso Propanol = 80:20, 1.0 mL/min, 254 nm; t _R (minor) = 14.57 min; t _R (major) = 19.44 min]. 1H NMR (400 MHz, CDC1 ₃ ) 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 = 7.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDCI3) 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, 13.7 ppm.

Example 11

In this example, 3,4,5-trimethoxyaniline is used as a nucleophilic reagent, and a bisphosphine ligand (foot-size?)-Lc is prepared in situ with a metal [Pd(C ₃ H ₅ )Cl] ₂ complex.

The reaction was as follows: [Pd(C ₃ H ₅ )Cl] ₂ (1.8 mg, 0.005 mmol) and (foot-size?)-Lc (9.6 mg, 0.0125 mmol) were added to a schlenk tube under argon atmosphere, respectively. Water CH ₂ C1 ₂ (5 mL:), after stirring at room temperature for 10 min, then the substrate le (204.2 mg, 0.5 mmol), K ₂ C0 ₃ (1.0 M aqueous solution, 1.5 mL, 1.5 mmol) and 3,4 ,5-trimethoxyaniline (274.8 mg, 1.5 mmol) o After stirring at room temperature for three hours, it was extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate Achiral amination product. The experimental results are as follows:

2t, white solid, 84% yield. Mp 133-135. C, [a] _D ²⁰ = +86.1 (c 1.00, CHC1 ₃ ), 93% ee [determined by high performance liquid chromatography, chiral AS-3 column; n-hexanol / isopropanol = 95:5, 1.0 mL/ Min, 254 nm; t _R (major) = 8.34 min; t _R (minor) = 10.65 min]. 1H NMR (400 MHz, CDCI3) δ = 6.91-6.78 (m, 3H), 6.33 (s, 1H), 5.87 (s, 1H), 5.80 (s, 2H), 5.27 (d, J = 4.4 Hz, 1H), 4.17-4.08 (m, 3H), 3.77-3.73 (m, 12H), 1.21 (t, J = 6.8 Hz, 3H), 0.96 (s, 9H), 0.11 (s, 6H) ppm; ¹³ C NMR (100 MHz, CDCI3) 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, -4.7 ppm.

Example 12 In this embodiment, p-fluoroaniline is used as a nucleophile, a bisphosphine ligand (scale)?-Lc and a metal [Pd(C ₃ H ₅ )Cl] ₂ 3⁄4 field are used as a catalyst to catalyze a substrate.

The reaction was as follows: [Pd(C ₃ H ₅ )Cl] ₂ (1.8 mg, 0.005 mmol) and (foot-size?)-Lc (9.6 mg, 0.0125 mmol) were added to a schlenk tube under argon atmosphere, respectively. Water CH ₂ C1 ₂ C5 mL), after stirring at room temperature for 10 minutes, the substrate If (133.1 mg, 0.5 mmol), K ₂ C0 ₃ (1.0 M aqueous solution, 1.5 mL, 1.5 mmol) and 3,4,5 -Trimethoxyaniline (274.8 mg, 1.5 mmol) o After stirring at room temperature for three hours, it is extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography. Amination product. The experimental results are as follows:

2u, colorless oil, 82% yield, [a] _D ²⁰ = +67.2 (c 1.00, CHC1 ₃ ), 94% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/iso Propanol = 95:5, 1.0 mL/min, 254 nm; t _R (major) = 32.84 min; t _R (minor) = 35.96 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.37-7.33 (m , 2H), 7.00 (t, J= 8.8 Hz, 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 = 7.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 165.7, 161.8 (d, J _(F , _C) = 244.6 Hz), 153.4 (s), 143.1 (s), 140.3 (s), 136.2 (d, J _(F , C) = 3.0 Hz), 130.0 (s), 128.7 (d, J _(F , _C) = 8.2 Hz), 125.7 (s), 115.1 (d, J _(F , _C) = 21.2 Hz), 90.8, 60.6, 60.5, 59.9, 58.2, 55.4 ppm; ¹⁹ FNMR (376 MHz, CDC1 ₃ ) δ -114.6 ppm .

Example 13

In this example, compound 2a was used as a substrate, and a β-lactam was prepared by cyclization of alkali hexamethyldisilazide lithium (LHMDSM®). The reaction formula is as follows:

The reaction was as follows: Substrate 2a (1 12.5 mg, 0.4 mmol) was added to a schlenk tube, anhydrous tetrahydrofuran (3 mL) was added, cooled to -20 ° C, and LHMDS (1.0 mol/L in hexanes, 0.6 mL) was slowly added dropwise. After stirring at -20 ° C for 2 hours, the reaction was quenched with EtOAc (EtOAc)EtOAc.

3a, white solid, 85% yield. Mp 149-150. C, [a] _D ²⁰ = +98.9 (c 1.00, CHC1 ₃ ), 96% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexanol / isopropanol = 95:5, 1.0 mL/ Min, 254 nm; t _R (minor) = 8.22 min; t _R (major) = 10.43 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.38-7.31 (m, 7H), 7.23 (t, J = 8.0 Hz, 2H), 7.03 (t, J = 7.6 Hz, 1H), 5.81 (s, 1H), 5.38 (s, 1H), 5.12 (s, 1 H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ δ = 160.8, 149.7, 137.4, 136.3, 129.0, 128.9, 128.6, 126.4, 124.0, 117.0, 110.7, 63.3 ppm. Example 14

In this example, compound 2b was used as a substrate to cyclize to produce β-lactam 3b under the action of bis(hexamethyldisilazide)tin (Sn[N(TMS) ₂ ]2). The reaction formula is as follows

The reaction was carried out as follows: Substrate 2b (311.3 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, and anhydrous toluene (5 mL) was added and heated to reflux for 4 hours. Concentrated and purified by column chromatography.

3b, white solid, 94% yield. Mp 134-135. C [lit. ⁸ 127-129. C], [a] _D ²⁰ = +111.0 (c 1.64, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexanol / isopropanol = 90:10, 1.0 mL /min, 254 nm; t _R (minor) = 9.98 min; t _R (major) = 10.99 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.35-7.26 (m, 7H), 6.77 (d, J = 8.8 Hz, 2H), 5.76 (s, 1H), 5.33 (s, 1H), 5.08 (s, 1H), 3.69 (s, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 55.2 ppm.

Example 15

In this embodiment, on the one hand, the compound 2c is used as a substrate, and the β-lactam 3c is cyclized by the action of bis(hexamethyldisilazide)tin (Sn[N(TMS) ₂ ]2). Reaction formula

The reaction was as follows: Substrate 2c (299.3 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After cooling to room temperature, concentrating and purification by column chromatography afforded compound 3c, white solid.

In another aspect of the present invention, β-lactam is prepared by cyclization of compound 2c as a substrate under the action of lithium hexamethyldisilazide (LHMDS). The reaction formula is as follows:

The reaction was as follows: Substrate 2cCl 19 mg, 0.4 mmol) was added to a schlenk tube, anhydrous tetrahydrofuran (3 mL) was added, and cooled. To -20 ° C, slowly add LHMDS (1.0 mol / L in hexanes, 0.6 mL, 0.6 mmol), stir at -20 ° C for 2 hours, then add 0.1 mL of water to quench the reaction, extract with dichloromethane (10 mL) 3), dried over anhydrous sodium sulfate, concentrated by filtration and purified by column chromatography to afford compound 3c, white solid, 80% yield.

Mp 125-126. C, [a] _D ² ° = +95.5 (c 1.48, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexanol/isopropanol = 90:10, 1.0 mL _{/ min, 254 nm; t R} (minor) = 6.86 min; t R (major) = 7.57 min ^ H NMR (400 MHz, CDCI3) δ = 7.37-7.28 (m, 7H), 6.91 (t, J = 8.8 Hz, 2H), 5.80 (t, J = 1.6 Hz, 1H), 5.37 (s, 1H), 5.13 (s, lH) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 160.4, 158.9 (d, J _(F , _C) = 242 Hz), 149.6, 135.9, 133.6 (d, J _(F , c) = 2.6 Hz), 129.0 (s), 128.7 (s), 126.4 (s), 118.3 (d, J _(F , _C) = 7.8 Hz), 115.7 (d, J _(F , _C) = 22.7 Hz), 110.8 (s), 63.4 ppm; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -109.0 ppm.

Example 16

The β-lactam 3d was prepared by the method of Example 14.

The reaction was as follows: substrate 2d (360.2 mg, 1.0 mmol of BSn [N(TMS) ₂ ] 2 (659.2 mg, 1.5 mmol) was added to a Schlenk tube, anhydrous toluene (5 mL) was added and the mixture was heated to reflux for 3-12 hours. After cooling to room temperature, it was concentrated and purified by column chromatography.

3d, white solid, 73% yield. Mp 135-136. C,

(c 1.00, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexyl / isopropanol = 90:10, 1.0 mL/min, 254 nm; t _R (minor) = 7.20 min; t _R (major) = 7.99 min]. 1H NMR (400 MHz, CDCI3) δ = 7.36-7.32 (m, 7H), 7.22-7.19 (m, 2H), 5.83 (t, J = 1.6 Hz , 1H), 5.37 (s, 1H), 5.16 (s, 1H) ppm; ¹³ C NMR (100 MHz, CDCI3) δ = 160.6, 149.5, 136.3, 135.8, 132.0, 129.1, 128.8, 126.4, 118.5, 116.7, 111.3, 63.4 ppm.

Fig. 1 is an X-ray crystal diffraction pattern of the compound 3d obtained in the present Example. From Fig. 1, it was confirmed that the obtained compound 3d had an absolute configuration of (5). The absolute configuration of the compounds 3a-3c, 3e-3u prepared in Examples 13-15, 17-33 was determined by comparison with the Cotton effect of (5)-3d, and the absolute configuration was (5).

The reaction was as follows: substrate 2e (360.2 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After cooling to room temperature, concentrate and purify by column chromatography.

3e, white solid, 72% yield. Mp 107-108. C, [a] _D ²⁰ = +47.5 (c 0.60, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexanol / isopropanol = 95:5, 1.0 mL/ _{min, 254 nm; t R (} minor) = 9.38 min;. t R (major) = 11.18 min] 1H NMR (400 MHz, CDCI3) δ = 7.60 (d, J = 1.2 Hz, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.46-7.21 (m, 6H), 7.00-6.96 (m, 1H), 6.02 (s, 1H), 5.89 (t, J = 1.6 Hz, 1H), 5.20 (t, J = 1.2 Hz, 1H) ppm; ¹³ C NMR (100 MHz, CDCI3) 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, 66.3 ppm.

Example 18

The β-lactam 3f was prepared by the method of Example 14.

The reaction was as follows: Substrate 2f (295.3 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After that, it was concentrated and purified by column chromatography.

3f, white solid, 81% yield. Mp 127-128 °C,

1.66, CHC1 ₃ ), 97% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexyl / isopropanol = 95:5, 1.0 mL/min, 254 nm; t _R (minor) = 7.86 t; _R (major) = 9.27 min]. 1H NMR (400 MHz, CDCI3) δ = 7.35-7.30 (m, 5H), 7.23 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 5.78 (t, J = 2.0 Hz, 1H), 5.34 (s, 1H), 5.10 (t, J = 2.0 Hz, 1H), 2.24 (s, 3H) ppm; ¹³ C NMR (100 MHz , CDCI3) 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, 20.7 ppm.

Example 19

With reference to the method of Example 14, 3 g of β-lactam was prepared.

The reaction was as follows: Substrate 2g (295.3 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After that, it was concentrated and purified by column chromatography.

3g, white solid, 74% yield. Mp 97-98

(c 1.46, CHC1 ₃ ), 97% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexyl / isopropanol = 95:5, 1.0 mL/min, 254 nm; t _R (minor) = 7.48 min; t _R (major) = 9.28 min]. 1H NMR (400 MHz, CDCI3) δ = 7.38-7.30 (m, 6H), 7.10 (t, J = 8.0 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.80 (t, J = 1.6 Hz, 1H), 5.36 (t, J = 1.2 Hz, lH), 5.12 (t = 1.6 Hz, 1H), 2.26 (s, 3H) ppm; ¹³ C NMR (100 MHz, CDCI3) 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, 21.3 ppm.

The reaction was as follows: substrate 2 h (371.4 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After cooling to room temperature, concentrate and purify by column chromatography.

3h, white solid, 74% yield. Mp 149-150. C, [a] _D ² ° = +53.7 (c 1.28, CHCI3), 96% ee [by high performance liquid phase Chromatographic determination, chiral AD-H column; n-hexanol / isopropanol = 85:15, 1.0 mL/min, 254 nm; t _R (minor) = 10.00 min; t _R (major) = 11.54 min]. 1H NMR (400 MHz, CDC1 ₃ ) 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; ¹³ C NMR (100 MHz, CDCI3) 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, 55.6 ppm .

Example 21

The β-lactam 3ί was prepared by the method of Example 14.

The reaction was as follows: substrate 2i (295.1 mg, 1.0 mmol) and Sn[N(TMS) ₂ ]2 (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After hours, after concentration, purification by column chromatography.

3i, white solid, 83% yield. Mp 133-134. C, [a] _D ^: +195.7 (c 1.00, CHCI3), 91% ee [determined by high performance liquid chromatography, chiral OD-H column; hexanol / isopropanol = 90: 10, 1.0 mL/min, 254 nm; t _R (minor) = 6.64 min; t _R (major) = 7.60 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.31-7.18 (m, 7H), 7.15-7.11 (m, 1H) , 7.06-7.01 (m, 1H), 5.79 (t, J = 2.0 Hz, 1H), 5.68 (s, 1H), 5.18-5.17 (m, 1H), 2.51 (s, 3H) ppm; ¹³ C NMR ( 100 MHz, CDCI3) 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, 19.4 ppm.

Example 22

The β-lactam 3j was prepared by the method of Example 14.

The reaction was as follows: substrate 2j (295.1 mg, 1.0 mmol) and Sn[N(TMS) ₂ ]2 (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After cooling to room temperature, concentrate and purify by column chromatography.

3j, white solid, 90% yield. Mp 119-120. C, [a] _D ²⁰ = +115.2 (c 1.00, CHC1 ₃ ), 97% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexanol / isopropanol = 95:5, 1.0 mL/ Min, 254 nm; t _R (minor) = 6.99 min; t _R (major) = 8.75 min]. 1H NMR (400 MHz, CDCI3) δ = 7.35-7.33 (m, 2H), 7.25-7.11 (m, 6H ), 7.04-7.00 (m, 1H), 5.80 (t, J = 2.0 Hz, 1H), 5.33 (s, 1H), 5.12 (t, J = 1.6 Hz, 1H), 2.31 (s, 3H) ppm; ¹³ C NMR (100 MHz, CDCI3) 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, 21.2 ppm.

Example 23

The β-lactam 3k was prepared by the method of Example 14.

The reaction was as follows: substrate 2k (295.1 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added, and heated to reflux for 3-12 hours. After cooling to room temperature, concentration and purification by column chromatography.

3k, white solid, 92% yield. Mp 107-108. C, [a] _D ²⁰ = +107.6 (c 1.20, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexanol / isopropanol = 95:5, 1.0 mL/ Min, 254 nm; t _R (minor) = 7.03 min; t _R (major) = 8.89 min]. 1H NMR (400 MHz, CDC1 ₃ ) 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= 1.6 Hz, 1H), 5.34 (s, 1H), 5.11 (t, J= 1.6 Hz, 1H ), 2.31 (s, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 21.0 ppm.

Example 24

The β-lactam 31 was prepared by the method of Example 14.

The reaction was as follows: Substrate 21 (311.1 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After cooling to room temperature, concentrate and purify by column chromatography.

31, white solid, 74% yield. Mp 94-95. C, [lit. ⁷ 95. C] [a] _D ²⁰ = +67.5 (c 1.00, CHC1 ₃ ), 94% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexanol / isopropanol = 90:10, 1.0 mL/ Min, 254 nm; t _R (minor) = 8.27 min; t _R (major) = 10.07 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.34-7.28 (m, 4H), 7.21 (t, J= 7.6 Hz, 2H), 7.00 (tj= 7.6 Hz, 1H), 6.87 (d, J= 8.8 Hz, 2H), 5.79 (s, 1H), 5.33 (s, 1H), 5.11 (s, 1H), 3.74 (s, 3H) ppm; ¹³ C NMR (100 MHz, CDCI3) 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, 55.0 ppm.

The reaction was as follows: Substrate 2m (299.1 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-1 After warming, concentrate and purify by column chromatography.

3 m, white solid, 73% yield. Mp 102-103. C,

1.16, CHC1 ₃ ), 96% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexanol / isopropanol = 90:10, 1.0 mL/min, 254 nm; t _R (minor) = 6.88 t; _R (major) = 8.78 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.38-7.31 (m, 4H), 7.24 (t, J = 7.6 Hz, 2H), 7.06-7.01 (m, 3H), 5.82 (t, J = 2.0 Hz, 1H), 5.38 (s, 1H), 5.14 (t, J = 1.2 Hz, 1H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 162.7 (d , J _(F , c) = 246.5 Hz), 160.6 (s), 149.6 (d, J _(F , _C) = 1.1 Hz), 137.2 (s), 132.1 (d, J _(F , _C) = 3.4 Hz ), 129.0 (s), 128.2 (d, J _(F , _C) = 8.6 Hz), 124.1 (s), 116.9 (s), 115.9 (d, J _(F , _C) = 21.6 Hz), 110.9 (s ), 62.5 ppm; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -112.5 ppm. Example 26

The β-lactam 3n was prepared by the method of Example 14.

The reaction was as follows: substrate 2n (359.0 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3 After -12, concentrate and purify by column chromatography.

3n, white solid, 80% yield. Mp 115-116 °C,

1.00, CHC1 ₃ ), 97% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexyl / isopropanol = 90: 10, 1.0 mL/min, 254 m; t _R (minor) = 7.12 _{min;. t R (major)} = 9.51 min] 1H NMR (400 MHz, CDC1 3) δ = 7.48 (d, J = 8.4 Hz, 2H), 7.31-7.22 (m, 6H), 7.04 (t, J = 7.2 Hz, 1H), 5.82 (t, J = 2.0 Hz, 1H), 5.35 (s, 1H), 5.14 (t, J = 1.2 Hz, 1H) ppm; ¹³ C NMR (100 MHz, CDCI3) δ = 160.4 , 149.2, 137.1, 135.3, 132.1, 129.0, 128.1, 124.1, 122.6, 116.8, 111.0, 62.5 ppm.

Example 27

The β-lactam 3o was prepared by the method of Example 14.

The reaction was as follows: Substrate 2ο (315.7 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 , concentrated, purified by column chromatography.

3o, white solid, 93% yield. Mp 133-134

(c 1.00, CHC1 ₃ ), 94% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexanol/isopropanol = 90: 10, 1.0 mL/min, 254 nm; t _R (minor) = 6.87 min; t _R (major) = 9.05 min]. 1H NMR (400 MHz, CDCI3) δ = 7.34-7.29 (m, 6H), 7.25-7.21 (m, 2H), 7.03 (t, J = 7.2 Hz) , 1H), 5.81 (t, J = 2.0 Hz, 1H), 5.36 (s, 1H), 5.13 (s, 1H) ppm; ¹³ C NMR (100 MHz, CDCI3) δ = 160.4, 149.3, 137.1, 134.8, 134.4, 129.1, 129.0, 127.8, 124.1, 116.8, 111.0, 62.5 ppm.

Example 28

The β-lactam 3p was prepared by the method of Example 14.

The reaction was as follows: substrate 2p (315.7 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 , concentrated, purified by column chromatography.

3p, white solid, 82% yield. Mp 110-111

(c 0.9, CHC1 ₃ ), 96% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexanol/isopropanol = 90: 10, 1.0 mL/min, 254 nm; t _R (minor) = 7.11 min; t _R (major) = 8.99 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.38 (s, 1H), 7.32-7.23 (m, 7H), 7.05 (t, J = 7.6 Hz, 1H), 5.83 (s, 1H), 5.34 (s, 1H), 5.16 (s, 1H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 62.5 ppm. The β-lactam 3q was prepared by the method of Example 14.

The reaction was as follows: substrate 2q (341.1 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After cooling to room temperature, concentrate and purify by column chromatography.

3q, white solid, 76% yield. Mp 76-77. C, [a] _D ²⁰ = +77.8 (c 1.30, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexanol / isopropanol = 90:10, 1.0 mL/ Min, 254 nm; t _R (minor) = 13.05 min; t _R (major) = 14.26 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.30-7.26 (m, 4H), 6.88 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 5.76 (t, J = 1.6 Hz, 1H), 5.30 (s, 1H), 5.09 (t, J = 1.6 Hz, 1H), 3.76 (s, 3H), 3.70 (s, 3H) ppm; ¹³ C NMR (100 MHz, CDCI3) 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 , 55.0 ppm.

Example 30

The β-lactam 3r was prepared by the method of Example 14.

The reaction was as follows: substrate 2r (401.4 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After cooling to room temperature, concentrate and purify by column chromatography.

3r, colorless oil, 74% yield. [a] _D ²⁰ = +41.5 (c 1.00, CHC1 ₃ ), 96% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/different Propanol = 90:10, 1.0 mL/min, 254 nm; t _R (minor) = 18.05 min; t _R (major) = 25.54 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.34 (d, J = 8.8 Hz, 2H), 6.91 (d, J= 8.8 Hz, 2H), 6.61 (s, 2H), 5.82 (t, J = 1.6 Hz, 1H), 5.34 (s, 1H), 5.15 (t, J = 1.6 Hz, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.72 (s, 6H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, 55.0 ppm.

Example 31

The β-lactam 3s was prepared by the method of Example 14.

The reaction was as follows: Substrate 2s (461.2 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After cooling to room temperature, concentrate and purify by column chromatography.

3s, white solid, 80% yield. Mp 160-161. C, [a] _D ²⁰ = +28.7 (c 1.00, CHC1 ₃ ), 98% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexanol / isopropanol = 80:20, 1.0 mL/ Min, 254 nm; t _R (minor) = 11.81 min; t _R (major) = 13.90 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 6.63-6.62 (m, 4H), 5.85 (t, J= 2.0 Hz, 1H), 5.30 (s, 1H), 5.22 (t, J= 1.6 Hz, 1H), 3.85-3.84 (m, 9H), 3.78 (s, 3H), 3.75 (s, 6H) ppm; ¹³ C NMR (100 MHz, CDCI3) 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, 55.6 ppm.

Example 32

The β-lactam 3t was prepared by the method of Example 14.

The reaction was as follows: Substrate 2t (531.2 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After cooling to room temperature, concentrate and purify by column chromatography.

3t, colorless oil, 92% yield. [a] _D ²⁰ = +37.3 (c 1.00, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexane/iso Propanol = 95:5, 1.0 mL/min, 254 nm; t _R (minor) = 5.80 min; t _R (major) = 6.74 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 6.91-6.88 (m , (1,1H) s, 3H), 3.64 (s, 6H), 0.86 (t, J = 2.8 Hz, 9H), 0.01 (d, J = 4.8 Hz, 6H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) 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, -5.01 ppm.

Example 33

The β-lactam 3u was prepared by the method of Example 14.

The reaction was as follows: substrate 2u (389.1 mg, 1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added and heated to reflux 3-12 After cooling to room temperature, concentrate and purify by column chromatography.

3u, white solid, 82% yield. Mp 134-135 ° C, [a] _D ²⁰ = +43.5 (c 1.50, CHC1 ₃ ), 94% ee [determined by high performance liquid chromatography, chiral AD-H column ; = / / isopropanol = 85:15, 1.0 mL / min, 254 nm; t _R (minor) = 10.03 min; t _R (major) = 12.07 min]. 1H NMR (400 MHz, CDCI3) δ = 7.42 -7.38 (m, 2H), 7.09 (t, J= 8.8 Hz, 2H), 6.57 (s, 2H), 5.84 (t, J= 2.0 Hz, 1H), 5.38 (s, 1H), 5.17 (t, J = 1.2 Hz, 1H), 3.77 (s, 3H), 3.73 (s, 6H) ppm; ¹³ C NMR (100 MHz, CDCI3) δ = 162.7 (d, J _(F , _C) = 246.9 Hz), 160.4 (s), 153.3 (s), 149.4 (d, J _(F , _C) = 1.2 Hz), 134.5 (s), 133.3 (s), 132.1 (d, J _(F , _C) = 3.4 Hz), 128.3 (d, J _(F , _C) = 8.1 Hz), 115.9 (d, J _(F , _C) = 21.9 Hz), 110.8 (s), 94.5, 62.9, 60.7, 55.8 ppm; ¹⁹ F NMR (376 MHz, CDCI3) δ -112.3 ppm.

Example 34 In vitro cytostatic assay

Collect log phase leukemia cell HL60 cells, adjust the cell suspension concentration to a cell concentration of 2.5 X 10 ⁴ /ml, per well (96 The wells were added to the cell suspension 90 μl, and the compounds of the formula 3a to 3u ΙΟμΙ/well of different concentration gradients were added, and 4 wells were inoculated at each concentration as repeated experiments to improve the accuracy of the experimental data. In addition, there is a separate zero hole on each plate (only culture medium, no cells and drugs). The culture was continued in the incubator until the third day, and the inhibitory effect of the compound of the formula 3a~3u on the leukemia cell line HL60 was detected by the Methyl-Thiazol-Tetrozolium (MTT) reduction method, and the compound 3a-3u was detected on the leukemia cell. HL60 half-inhibitory concentration (IC ₅ o).

The results showed that the half-inhibitory concentration (IC ₅ o) of compound 3a-3u on leukemia cell HL60 was lower than 8 (^g mL, in which compound 3b, 3c, 3t, 31, 3s, 3u, etc., half-inhibitory concentration of leukemia cell HL60 (IC) ₅₀ ) is about 20-3 (^g/mL _; compound 3g, 3h, 3j, 3k, 3m, 3r, etc. The half-inhibitory concentration (IC ₅ Q) of leukemia cells HL60 is about 0.1-10μ3⁄4 ηΛ; 3g, 3h, 3k , 3m, 3r and other HL60 half-inhibitory concentration (IC ₅ o) of leukemia cells 1 g / mL.

The logarithmic lung cancer cells A549 were collected, and the cell suspension concentration was adjusted so that the cell concentration was 2 X 10 ⁴ /ml, and 100 μl of the cell suspension was added to each well (96-well plate) to make the number of cells in each well 4000. After the cells were cultured for 24 hours in the incubator, the culture solution was aspirated and 100 μl of each of the compounds of the formula 3a to 3u with different concentration gradients were added, and 4 wells were inoculated as repeated experiments to improve the accuracy of the experimental data. And set the corresponding vehicle control and cell-free zeroing. The culture was continued for 72 hours. The inhibitory effect of the compound of formula 3a~3u on lung cancer cell A549 was determined by sulforhodamine B (SRB) protein staining method. The culture solution was decanted and added with ice precooled 10% of three. The cells were fixed in chloroacetic acid solution, left at 4 ° C for 1 h, washed 5 times with distilled water, and naturally dried in the air. Then a 4 mg/ml SRB (Sigma, St Louis, MO, USA) solution was added, stained for 15 min at room temperature, de-stained, washed 5 times with 1% glacial acetic acid, and air dried. Finally, the Tris solution (pH 10.5) was added, and the OD value was measured at a wavelength of 515 nm using a tunable wavelength microplate reader (VERSAmaxTM, Molecular Device Corporation, Sunnyvale, CA, USA), and the IC ₅₀ value was calculated by the Logit method.

The results showed that the compound inhibitory concentration (IC ₅ o) of compound 3a-3u on lung cancer cells was lower than 85 g/mL, of which compound 3c,

The half-inhibitory concentration (IC ₅ ) of 3e, 3f, 3q, etc. on lung cancer cells A549 is about 20-5 (^g/mL; compound 3i, 3j, 31, 3m, 3t, 3u, 3g, etc. Concentration CIC _5Q ) is about 0.1-2 (^g mL _; among them, 3i, 3j, 31, 3m, etc., half-inhibitory concentration of lung cancer cells A549 (IC ₅ Q) l (^g mL.

Add 3-bromo salicylaldehyde (10.25 g, 51.0 mmol), cyclohexanone (2.5 mL, 25.0 mmol), ethanol (20.0 mL), sodium hydroxide aqueous solution C20 wt%, 15 mL) to a 50 mL vial, stir at room temperature 24 hours; 100 mL of distilled water was added to the reaction system, neutralized to pH = 5 with a 6 mol/L aqueous hydrochloric acid solution, filtered, and the solid was washed with distilled water and dried; and recrystallized from acetone- petroleum ether to obtain 4.6 g of a yellow solid. Compound 30a, yield 60%.

30a, mp 174-175 ° C; 1H NMR (400 MHz, DMSO- 6) δ 9.62 (s, br, 2H), 7.75 (s, 2H), 7.54 (d, J =

8.0 Hz, 2H), 7.29 (d, J= 7.6 Hz, 2H), 6.86 (t, J= 8.0 Hz, 2H), 2.76 (t, J= 5.6 Hz, 4H), 1.68-1.62 (m, 2H) P, ¹³ C NMR (100 MHz, DMSO- ₆ ) δ 188.9, 152.5, 137.1, 133.3, 131.5, 129.5, 125.8, 120.9, 111.8, 28.0, 22.8 ppm.

Referring to the preparation method of Example 35, the compounds of the formulae 30b, 30c, 30d, 30h, 30, 30j were respectively prepared.

30i 30j

30b, mp 194-195°C. 1H NMR (400 MHz, DMSO- ₆ ) δ 9.32 (s, br, 2H), 7.72 (s, 2H), 7.35 (s, 2H), 7.07 (s, 2H), 2.75 (t, J = 5.2 Hz, 4H), 2.22 (s, 6H), 1.66-1.63 (m, 2H) ppm; ¹³ C NMR (100 MHz, DMSO- ₆ ) δ 188.8, 150.2, 136.9, 133.4, 131.6 , 129.9, 129.7, 125.5, 111.7, 28.0, 22.8, 19.7 ppm.

30c, mp 123-125 ° C; 1H NMR (400 MHz, DMSO- 6) δ 9.94 (s, br, 2H), 7.65-7.63 (m, 4H), 7.28 (d, J = 2.4 Hz, 2H), 2.73 (t, J = 4.8 Hz, 4H), 1.67-1.64 (m, 2H) ppm; ¹³ C NMR (100 MHz, DMSO- ₆ ) δ 188.5, 151.7, 138.0, 132.1, 130.5, 128.6, 126.8, 123.6, 112.5, 27.8, 22.5 ppm.

30d, mp 110-l irC ; 1H NMR (300 MHz, acetone-e) δ 9.05 (s, 2H), 7.84 (s, 2H), 7.45 (d, J = 2.4 Hz, 2H), 7.34 (dd, J = 9.0 Hz, 2.4 Hz, 2H), 2.88 (t, J = 5.1 Hz, 4H), 3.36 (s, 6H), 1.82-1.74 (m, 2H) ppm; ¹³ C NMR (75 MHz, acetone- ₆ ) δ 189.2, 156.5, 138.0, 133.3, 133.1, 131.1, 126.2, 118.4, 111.5, 29.1, 23.9, 20.1 ppm.

30h, mp 184-185°C; ^! ΗΝΜΚ ( 00 MHz, DMSC ) δ 9.91 (s, 2H), 7.72 (s, 2H), 7.53 (d, J = 4.4 Hz, 2H), 7.34 (d, J= 4.4 Hz, 2H), 6.88 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 5.2 Hz, 4H), 1.71-1.61 (m, 2H) ppm _; ¹³ CNMR (imMHz, DMSCk3⁄4) 6 189.5, 151.4, 136.1, 131.1, 129.7, 128.6, 126.1, 123.6, 122.8, 26.5 ppm.

30i, mp 171-173 ° C; 1HNMR (400 MHz, DMSO- 6) δ 10.03 (s, 2H), 7.81 (s, 2H), 7.63 (d, J = 4.4 Hz, 2H), 7.45 (d, J = 4.6 Hz, 2H), 6.90 (t, J = 7.8 Hz, 2H), 4.82 (s, 4H) ppm; ¹³ C NMR (100 MHz, DMSO- ₆ ) 6 184.1, 156.8, 133.1, 131.8, 130.8, 129.5 , 121.0, 119.6, 115.4, 67.6 ppm.

</ RTI><RTIgt; m, 2H), 6.90 (t, J = 7.2 Hz, 2H), 2.77-2.67 (m, 4H), 1.98-1.84 (m, 4H) ppm; ¹³ C NMR (100 MHz, acetone- ₆ ) δ 198.1, 155.1, 142.5, 131.8, 129.7, 129.3, 122.5, 118.6, 114.9, 28.9, 26.5 ppm.

The compound 30a prepared in Example 35 was a hydrogenated substrate, and the compound 7a was used as a catalyst (catalyst 7a) to prepare a chiral aromatic

The reaction was carried out as follows: 30a (46.4 mg, 0.1 mmol), Catalyst 7a (1.6 mg, EtOAc, EtOAc) After replacing the hydrogen three times, hydrogen gas was charged to 50 atm, and reacted at room temperature for 24 hours. After the hydrogen gas was vented, the reaction vessel was opened, the solvent was removed under reduced pressure, and the product was determined by the nuclear magnetic coarse spectrum. The residue was separated by column chromatography. The yield of (^J?)-5a was 93% and the ee value was >99%.

Fig. 2 is an X-ray crystal diffraction pattern of the compound obtained in the present example, and the obtained compound was confirmed from Fig. 2

The absolute configuration of -5a is (foot-size?), and the absolute configuration of the chiral aromatic spiroketal compound 5b-5j prepared in the following examples is determined by comparison with the Cotton effect of (scale)? .

(R ii)-5a, white solid, mp 97-98 °C; [a] _D ²⁰ = -85.2 (c 0.80, CHC1 ₃ ), >99% ee [Determination of chiral AD-H column by high performance liquid chromatography ; n-hexane/isobutanol = 99: 1, 0.5 mL/min, 230 nm; t _R (major) = 1 1.74 min; t _R (minor) = 13.10 min]. 1H NMR (300 MHz, CDC1 ₃ ) δ 7.36 (dd, J = 8.1, 0.9 Hz, 2H), 7.03 (dd, J = 7.5, 0.6 Hz, 2H), 6.77 (t, J = 7.5 Hz, 2H), 3.05 (dd, J = 16.8, 6.3 Hz, 2H), 2.70 (dd, J = 16.8 Hz, 7.2 Hz, 2H), 2.40-2.36 (m, 2H), 1.85-1.80 (m, 2H), 1.62-1.50 (m, 4H) ppm; ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 148.5, 131.0, 128.3, 122.6, 121.7, 110.8, 101.9, 33.3, 27.8, 27.3, 19.1 ppm; IR (neat) v 3058, 2924, 2853, 1566, 1447, 1358, 1329 , 1223, 1178, 1149, 1117, 960, 879, 774, 717, 464624 cm"¹; HRMS-EI (m/z) M+ calcd. for C ₂₍₎ H ₁₈ 0 ₂ Br ₂ 447.9674 found 447.9678.

Catalyst 7a was prepared by the method of Angew. Chem. Int. Ed. 2009, 48, 5345.

The compound 30b prepared in Example 35 was a hydrogenated substrate, and the compound 7a was used as a catalyst to prepare a chiral aromatic snail ketal compound (i?J?J?)-5b. The reaction was as follows: 30b (49.2 mg, 0.1 mmol), Catalyst 7a (4.8 mg, 0.003 mmol), 2 mL of anhydrous dichloromethane was added to a hydrogenated flask and transferred to a high pressure reaction kettle in a glove box. After replacing the hydrogen three times, it was charged with hydrogen to 50 atm and reacted at room temperature for 24 hours. After venting the hydrogen, the reactor was opened, the solvent was removed under reduced pressure, and the product was determined by nuclear magnetic resonance. In contrast, the residue was separated by column chromatography. The yield of (^^-5b was 85% and the ee value was >99%.

(R ii)-5b, white solid, mp 237-238 ° C, [a] _D ²⁰ = -98.8 (c 1.26, CHC1 ₃ ), >99% ee [Determination of chiral AD-H column by high performance liquid chromatography ; n-hexane/isobutanol = 99: 1, 1.0 mL/min, 230 nm; 3⁄4 (major) = 4.95 min; 3⁄4 (minor) = 7.17 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ 7.17 ( s, 2H), 6.82 (s, 2H), 2.99 (dd, J = 16.4, 6.0 Hz, 2H), 2.63 (dd, J = 16.4, 7.2 Hz, 2H), 2.35-2.32 (m, 2H), 2.24 (s, 6H), 1.83-1.79 (m, 2H), 1.59-1.46 (m, 4H) ppm; ¹³ C NMR (75 MHz, CDCI3) δ 146.2, 131.3, 131.2, 128.8, 122.1, 110.3, 101.8, 33.2 , 27.7, 27.2, 20.2, 19.0 ppm.

The compound 30c prepared in Example 35 was a hydrogenated substrate, and Compound 7a was used as a catalyst to prepare a chiral aromatic snail ketal compound (i?J?J?)-5c. The reaction was carried out as follows: 30c (53.3 mg, 0.1 mmol), Catalyst 7a (4.8 mg, 0.003 mmol), 2 mL of water-free methylene chloride was placed in a hydrogenated bottle and transferred to a high pressure reaction kettle in a glove box. After replacing the hydrogen three times, it was charged with hydrogen to 50 atm and reacted at room temperature for 24 hours. After the hydrogen gas was vented, the reaction vessel was opened, the solvent was removed under reduced pressure, and the product was determined by the nuclear magnetic coarse spectrum. The residue was separated by column chromatography. The yield obtained was 86% and the 66 value was >99%.

(R ii)-5c, white solid, mp 200-202 ° C; [a] _D ²⁰ = -75.8 (c 0.90, CHCI3), >99% ee [Chiral AD-H column determined by high performance liquid chromatography; n-Hexane/isobutanol = 98: 2, 1.0 mL/min, 230 nm; t _R (major) = 5.37 min; t _R (minor) = 5.97 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ 7.36 (d, J = 2.8 Hz, 2H), 7.03 (d, J = 2.4 Hz, 2H), 3.00 (dd, J = 16.8 Hz, 6.0 Hz, 2H), 2.67 (dd, J = 16.8 Hz, 7.2 Hz, 2H), 2.36-2.32 (m, 2H), 1.85-1.80 (m, 2H), 1.61-1.47 (m, 4H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 147.2, 130.5, 128.0, 126.0, 123.6, 111.2, 102.2, 33.1, 27.6, 27.2, 18.9 ppm.

The compound 30d prepared in Example 35 was a hydrogenated substrate, and a chiral aromatic snail ketal compound (i?J?J?)-5d was prepared using the compound 7a as a catalyst. The reaction was carried out as follows: 30d (49.2 mg, 0.1 mmol), Catalyst 7a (3.2 mg, 0.002 mmol), 2 mL of water-free chloroform was added to a hydrogenated bottle and transferred to a high pressure reaction kettle in a glove box. After replacing the hydrogen three times, it was charged with hydrogen to 50 atm and reacted at room temperature for 24 hours. After the hydrogen gas was vented, the reaction vessel was opened, the solvent was removed under reduced pressure, and the product was determined by the nuclear magnetic coarse spectrum. The residue was separated by column chromatography. The yield of (^^-5d was 88%, and the value of 66 was >99%.

(R,R,R)-5d, white solid, mp 160-161 °C; [a] _D ²⁰ = -33.1 (c 1.00, CHC1 ₃ ), >99% ee [Determination of chiral AD by high performance liquid chromatography -H column; n-hexane/isobutanol = 90: 10, 1.0 mL/min, 230 nm; t _R (minor) = 4.99 min; t _R (major) = 7.57 min]. 1H NMR (300 MHz, CDCI3 δ 7.20-7.18 (m, 2H), 6.82-6.78 (m, 2H), 2.90 (dd, J= 16.5, 6.0 Hz, 2H), 2.65 (dd, J = 17.1, 7.5 Hz, 2H), 2.32 ( s, 6H), 2.29-2.26 (m, 2H), 1.83-1.77 (m, 2H), 1.61-1.47 (m, 4H) ppm; ¹³ C NMR (75 MHz, CDCI3) δ 150.9, 131.8, 130.2, 123.0 , 118.5, 113.0, 100.8, 33.1, 27.9, 26.8, 20.1, 19.1 ppm.

The compound prepared in Example 35 was a hydrogenated substrate, and the optically active chiral aromatic spiroke compound ^^^)-51 was prepared using Compound 7a as a catalyst. The reaction was carried out as follows: 30 h (45.0 mg, 0.1 mmol), catalyst 7a (4.8 mg, 0.003 mmol), 2 mL of anhydrous dichloromethane was added to a hydrogenated bottle and transferred to a high pressure reaction kettle in a glove box. After replacing the hydrogen three times, it was charged with hydrogen to 50 atm and reacted at room temperature for 24 hours. After the hydrogen gas was vented, the reaction vessel was opened, the solvent was removed under reduced pressure, and the residue was separated by column chromatography. Yield (^^)-5h, yield 60%. The ee value is 95%. After one step of recrystallization, it can reach >99% ee.

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(R, R, R)-Lb, white solid, 40% yield. Mp 125-127. C, [a] _D = +143.5 (c 1.00, CHC1 ₃ ). 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.24-7.12 (m, 8H), 7.05 (t, J = 7.2 Hz, 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; ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 153.5 (d, J = 15.2 Hz), 143.2 (d, J _(P , _C ) = 28.3 Hz), 142.7 (d, J ₍ = 25.9 Hz), 135.3 (d, J (= 11.4 Hz), 134.9 (d, J _(RC) = 13.8 Hz), 133.5 (d, J _(P . _C) = 40.1 Hz), 131.0 (d, J _(P , c) = 2.9 Hz), 130.0-129.6 (m), 128.3 (d, J _(P , _C) = 15.8 Hz), 125.8 (d, J _(P , _{C )} = 24.0 Hz), 123.3 (d, J ₍ = 12.7 Hz), 120.6-120.5 (m), 101.4, 33.3, 27.7, 26.6, 21.2 (d, J ₍ = 21.1 Hz), 21.0 (d, J ₍ = 23.7 Hz), 19.3 ppm; ^?1 P (121 MHz, CDCl ₃ ) δ -33.4 ppm.

The same test method as above was used except that bis(3,5-dimethylphenyl)phosphine chloride was used instead of diphenylphosphine chloride to prepare a chiral aromatic snail ketone bone.

(R,R,R)- c, white solid,

1.00, CHC1 ₃ ). 1H NMR (300 MHz, CDCI3) δ = 6.93-6.84 (m, 14H), 6.73 (t, J = 6.9 Hz, 2H), 6.47 (t, J = 4.8 Hz, 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; ¹³ C NMR (75 MHz, CDCh) δ = 153.1 (d, J _(P , _C) = 14.7 Hz), 137.3 (d, J _(P , _C ) = 7.4 Hz), 137.2 (d, J ₍ = 7.8 Hz) ), 136.9 (d, J _(P , c) = 10.2 Hz), 136.5 (d, J _(P , _c) = 10.9 Hz), 132.1 (s), 131.8 (s), 131.5 (s), 130.8 (d , J _(P , _c) = 1.5 Hz), 130.2 (s), 129.8 (d, J _(P , _C) = 41.7 Hz), 125.5 (d, J _(P , _C) = 14.2 Hz), 120.1 (s ), 120.1 (d, J _(RC) = 1.7 Hz), 101.1, 33.4, 27.3, 26.7, 21.3, 21.2, 19.5 ppm; ¹ P (121 MHz, CDCl _? ) 6 -15.2 ppm.

The same test method as above was used except that bis(3,5-di-tert-butylphenyl)phosphine chloride was used instead of diphenylphosphine chloride to prepare a chiral aromatic snail ketone bone.

(R,R,R)- d, white solid,

1.00, CHC1 ₃ ). 1H NMR (400 MHz, CDCI3) δ = 6.91-6.82 (m, 14H), 6.69 (t, J = 6.6 Hz, 2H), 6.37 (t, J = 5.0 Hz, 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), 1.1 1-1.09 (m, 4H) ppm ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 155.1 (d, J _(P , _C) = 15.0 Hz), 139.5 (d, J _(P , _C) = 8.4 Hz), 137.7 (d, J ( = 8.0 Hz) , 136.1 (d, J( _P ,c) = 10.8 Hz), 135.4 (d, J _(P , _C) = 11.2 Hz), 133.4 (s), 131.8 (s), 130.9 (s), 130.8 (d, J _(P , _c) = 12.0 Hz), 130.4 (s), 129.6 (d, J _(P , _C) = 42.2 Hz), 126.5 (d, J _(P , _C) = 16.2 Hz), 120.9 (s) , 120.4 (d, J _(P , _C) = 2.2 Hz), 99.1, 33.4, 29.8, 27.3, 26.7, 25.6, 21.3, 21.2, 19.5 ppm; ³¹ P (121 MHz, CDCl ₃ ) δ -17.8 ppm.

The same test method as above was used except that bis(p-methylphenyl)phosphine chloride was used instead of diphenylphosphine chloride to prepare a chiral aromatic snail ketone skeleton (i?, i?, i?). -Le.

(foot rule?)-Le, white solid,

CHC1 ₃ ). 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.21-7.14 (m, 8H), 7.10-7.07 (m, 8H), 6.87 (d, J = 7.2 Hz, 2H), 6.73 (t, J = 7.6 Hz, 2H), 6.54 (t, J= 5.6 Hz, 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; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 153.1 (d, J _(P , _C ) = 14.5 Hz), 138.2 (s), 137.8 (s), 134.3-133.8 (m), 133.4 (d, J( _P ,c) = 10.4 Hz), 130.8 (d, J _(P , _C) = 2.6 Hz), 129.7 (s), 129.0-128.9 (m), 125.5 (d, J _(P , _C) = 14.0 Hz), 120.3-120.2 (m), 101.2, 33.4, 27.6, 26.7, 21.3, 19.4 ppm; ³¹ P NMR (162 MHz, CDCl ₃ ) δ -17.9 ppm. Using the same test method described above, different The chiral aromatic spirokeketone skeleton (i?, i?, i? Lf) was prepared by substituting di(p-fluorophenyl)phosphine chloride for diphenylphosphonium chloride.

(R, R, R)-U, white solid, 80% yield. Mp 76-77. C, [a] _D ²⁰ = +88.0 (c 1.00, CHC1 ₃ ). 1H NMR (400 MHz, CDCI3) δ = 7.27-7.20 (m, 8H), 6.99-6.93 (m, 10H), 6.76 (t, J = 7.6 Hz, 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; ³¹ P NMR (162 MHz, CDCl ₃ ) δ -17.8 ppm; ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -112.3, -112.5 ppm.

The same test method as above was used except that bis(p-methoxyphenyl)phosphine chloride was used instead of diphenylphosphine chloride to prepare a chiral aromatic snail ketone skeleton bisphosphine ligand (i?, i ?,i?)-L _g .

(foot rule?)-Lg, white solid, 65% yield. Mp 91-92. C, [a] _D ²⁰ = +122.5 (c 1.00, CHC1 ₃ ). 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.26-7.19 (m, 8H), 6.88-6.87 (m, 2H), 6.84-6.81 (m, 8H), 6.73 (t, J = 7.2 Hz, 2H), 6.51 (t, J = 5.2 Hz, 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; ¹³ C NMR (100 MHz, CDCI3) δ = 159.8 (d, J _(P , _C) = 38.8 Hz), 152.8 (d, J _(P , _C) = 13.9 Hz), 135.5-135.0 (m), 130.4 (s), 129.5 (s), 128.3 (d, J ₍ = 8.1 Hz), 127.6 (d, J ₍ = 9.0 Hz), 125.8 (d, J( _P ,c) = 13.3 Hz), 120.1 (d, J ₍ = 1.6 Hz), 113.8-113.7 (m), 101.0, 55.0, 54.9, 33.4, 27.6, 26.6, 19.3 ppm; ³¹ PNMR (162 MHz, CDCl ₃ ) δ -18.8 ppm.

The same test method as above was used except that dicyclohexylphosphine chloride was used instead of diphenylphosphonium chloride to prepare

(foot rule?)-Lh, white solid, 55% yield. Mp 95-96. C, [a] _D ² ° = +88.5 (c 1.00, CHC1 ₃ ). 1H NMR (400 MHz, CDCI3) 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, 20 H) ppm; ³¹ PNMR (162 MHz, CDCl ₃ ) δ -21.6 ppm.

The same test method as above was used except that di-tert-butylphosphine chloride was used instead of diphenylphosphine chloride to prepare a chiral aromatic snail ketone skeleton bisphosphine ligand (?,

(R,R,R)-U, white solid, 81% yield. [A] _D ²⁰ = +78.1 (c 1.00, CHC1 ₃ ). 1H NMR (400 MHz, CDCI3) 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; ³¹ PNMR (162 MHz, CDCl ₃ ) δ -22.8 ppm.

The same test method as above was used, except that the chiral aromatic snail ketone skeleton bisphosphine ligand (foot-size?)-Lj was prepared by using the ruler 5b as a raw material.

(foot rule?)-Lj, white solid, 70% yield. Mp 98-100. C, [a] _D ²⁰ = +109.3 (c 1.00, CHC1 ₃ ). 1H NMR (400 MHz, CDCI3) δ 7.31-7.24 (m, 20H), 6.69 (s, 2H), 6.35 (d, J= 5.6 Hz, 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; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 151.2, 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, 19.4 ppm; ³¹ P(162 MHz, CDCl ₃ ) δ -15.3 ppm.

The same test method as above was used except that the chiral aromatic snail ketone skeleton bisphosphine ligand (foot-size?)-Lk was prepared using (scale)?-5c as a raw material.

(foot rule?)-Lk, white solid,

(c 1.00, CHC1 ₃ ). 1H NMR (400 MHz, CDC1 ₃ ) δ 7.33-7.24 (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; ¹³ C NMR (100 MHz, CDCI3) 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, 19.2 ppm; 31 P (162 MHz, CDCl ₃ ) δ -15.5 ppm.

The same test method as above was used, except that the chiral aromatic snail ketone skeleton bisphosphine ligand (foot-size?)-Ll was prepared by using the ruler 5d as a raw material.

(R,R,R)-U, white solid,

(c 0.90, CHC1 ₃ ). 1H NMR (400 MHz, CDCI3) δ 7.31-7.24 (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; ³¹ P (162 MHz, CDCl ₃ ) δ -14.6 Ppm. The same test method as above was used except that the chiral aromatic snail ketone skeleton bisphosphine ligand (foot-size?)-Lm was prepared from (foot-scale?)-5h.

(foot rule?)-Lm, white solid, 75% yield. Mp 109-111. C, [a] _D ² ° = +83.1 (c 1.00, CHCI3). 1H NMR (400 MHz, CDCI3) δ 7.42-7.17 (m, 20H), 6.95 (d, J = 7.2 Hz, 2H), 6.76 ( t, J = 7.6 Hz, 2H), 6.58 (t, J = 7.2 Hz, 2H), 2.45 (dd, J = 16.0 Hz, 6.4 Hz, 2H), 2.28 (dd, J = 16.0 Hz, 6.8 Hz, 2H ), 1.98-1.95 (m, 2H), 1.47-1.43 (m, 2H), 1.12-1.08 (m, 2H) ppm; ³¹ P (162 MHz, CDCl ₃ ) δ -15.5 ppm.

The same test method as above was used except that (&S-5i was used as a raw material to prepare a chiral aromatic snail ketone skeleton bisphosphine ligand (&&)-Ln. Pph ₂ Ph ₂ p (s,S,R)- n

(S, S, R)-l^n, white solid, 79% yield. Mp 111-112. C, [a] _D ²⁰ = +75.2 (c 1.10, CHC1 ₃ ). 1H NMR (400 MHz, CDC1 ₃ ) δ 7.45-7.16 (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; ³¹ P (162 MHz, CDCl ₃ ) δ -17.3 ppm.

The same test method as above was used, except that the chiral aromatic snail ketone skeleton bisphosphine ligand (foot-size?)-Lo was prepared by using the ruler 5j as a raw material.

(foot rule?)-Lo, white solid, 81% yield. Mp 89-92. C, [a] _D ²⁰ = +112.2 (c 1.30, CHC1 ₃ ). 1H NMR (400 MHz, CDCI3) δ 7.35-7.14 (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; ³¹ P (162 MHz, CDCl ₃ ) δ -13.4 ppm.

Real

• ^{) Ua} (S, S, S)-5a Catalyst 7b

The compound 30a prepared in Example 35 was a hydrogenated substrate, and the compound 7b was used as a catalyst to prepare a chiral aromatic spiroke compound (&&5)-5a. The reaction was carried out as follows: 30a (46.4 mg, O.lmmol), catalyst 7b (1.6 mg, 0.001 mmol), 2 mL of water-free chloroform was added to a hydrogenated bottle, and transferred to a high pressure reaction kettle in a glove box. After replacing the hydrogen three times, it was charged with hydrogen to 50 atm and reacted at room temperature for 24 hours. After the hydrogen gas was vented, the reaction vessel was opened, the solvent was removed under reduced pressure, and the product was determined by the nuclear magnetic coarse spectrum. The residue was separated by column chromatography. The yield of 0^,5)-5a was found to be 91%, and the ee value was >99%.

Catalyst 7b reference

(S,S,S)-5a (S,S,S)- a

After 50 mL schlenk tube was treated with anhydrous anaerobic treatment, add substrate (&&5)-5a (350 mg, 0.77 mmol), anhydrous tetrahydrofuran (6 mL), cool to -78 ° C, slowly add n-butyl lithium ( 0.8 mL, 2.5 M hexane, 1.9 mmol). After the reaction mixture was stirred at -78 ° C for half an hour, diphenylphosphonium chloride (0.36 mL, 1.9 mmol) was slowly added dropwise, and the mixture was allowed to warm to room temperature after the addition. Stir at room temperature for 10 hours. After the reaction was quenched by the addition of 15 mL of distilled water, the mixture was extracted with dichloromethane (3×20 mL). The organic phase was dried over anhydrous sodium sulfate. Mg, 72% yield).

Example 38 Referring to the method of Example 6, using p-fluoroaniline as a nucleophilic reagent, a bisphosphine ligand (&&5)-La and a metal salt [Pd(C ₃ H ₅ )Cl] _{: a} site-forming complex as a catalyst, a catalytic bottom Asymmetric allyl amination of substance lb gives the formula (-2).

(R)-2c, colorless oil, 86% yield, [a] _D ²⁰ = -78.6 (c 1.00, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral AD-H column; n-Hexane/Isopropanol = 99:1, 1.0 mL/min, 254 nm; t _R (minor) = 18.31 min; t _R (major) = 22.32 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.37 -7.25 (m, 5H), 6.86 (t, J= 8.8 Hz, 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 = 7.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 166.1, 155.9 (d, J _(F , _C) = 234.0 Hz), 143.0 (d, J _(F , _C) = 1.8 Hz), 140.4 (d, J _(F , C) = 23.4 Hz), 128.7 (s), 127.7 (s), 127.4 (s), 125.9 (s), 115.6 (s), 115.4 (s), 114.2 (d, J _(F , _C) = 7.4 Hz), 60.8, 59.5, 14.0 ppm; ¹⁹ F-NMR (376 MHz, CDC1 ₃ ) δ -127.4 ppm.

Reference Example 14 is a compound of the -3c compound.

(R)-3c, white solid, 84% yield. Mp 125-126 ° C, [a] _D ²⁰ = -95.5 (c 1.40, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexanol = isopropanol = 90:10, 1.0 mL/min, 254 nm; t _R (major) = 6.80 min; t _R (minor) = 7.56 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.37-7.28 (m, 7H), 6.91 (t, J = 8.8 Hz, 2H), 5.80 (t, J = 1.6 Hz, 1H), 5.37 (s, 1H), 5.13 (s, 1H) ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 160.4, 158.9 (d, J _(F , C) = 242 Hz), 149.6, 135.9, 133.6 (d, J _(F , _C) = 2.6 Hz), 129.0 (s), 128.7 (s), 126.4 (s), 118.3 (d, J _(F , _C) = 7.8 Hz), 115.7 (d, J _(F , c) = 22.7 Hz), 110.8 (s), 63.4 ppm; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -109.0 ppm. Example 39

Referring to the method of Example 6, using cyclohexylamine, n-butylamine and benzylamine as nucleophiles, bisphosphine ligands 0S, 5)-La and metal salts [Pd(C ₃ H ₅ )Cl] _{2 in} situ preparation The complex acts as a catalyst to catalyze the asymmetric allyl amination of substrate lb to give compounds of formula (i?)-2v, (R)-2w, (R)-2x, respectively.

(R)-2v (R)-2w (R)-2x

(R)-2v, colorless oil, 74% yield, [a] _D ²⁰ = -74.3 (c 1.30, CHC1 ₃ ), 94% ee [determined by high performance liquid chromatography, chiral AD-H column; Hexane/isopropanol = 99: 1, 1.0 mL/min, 230 nm; t _R (minor) = 6.46 min; t _R (major) = 7.29 min]. 1H NMR (400 MHz, CDCI3) 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, [a] _D ²⁰ = -83.1 (c 1.00, CHC1 ₃ ), 91% ee [determined by high performance liquid chromatography, chiral AD-H column; Hexane/isopropanol = 99: 1, 1.0 mL/min, 230 nm; t _R (minor) = 6.51 min; t _R (major) = 7.18 min]. 1H NMR (400 MHz, CDC1 ₃ ) 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 = 7.6 Hz, 3H) ppm.

(R)-2x, colorless oil, 71% yield, [a] _D ²⁰ = -74.3 (c 1.30, CHCI3), 91% ee [determined by high performance liquid chromatography, chiral OD-H column; Alkane/isopropanol = 95:5, 1.0 mL/min, 230 nm; t _R (minor) = 4.38 min; t _R (major) = 5.37 min]. 1H NMR (400 MHz, CDC1 ₃ ) 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 = 22.4 Hz, 13.2 Hz, 2H ), 1.16 (t, J = 6.8 Hz, 3H) ppm.

Example 40

Referring to the method of Example 14, the β-lactams of the formula (R)-2v, (R)-2w (R)-2x were respectively prepared as a substrate, and (R)-3v, (R)-3w, R)-3

(R)-3v (R)-3w (R)-3x

(R)-3v, 73% yield. EI-MS (70 eV) (m/z) 341 (M+). (i?)-3w, 79% yield. EI-MS (70 eV) (m/z) 215

(M+). (R) - 3x, 60% yield. 1H NMR (400 MHz, CDCI3) δ = 7.34-7.14 (m, 10H), 5.73 (s, 1H), 5.02 (s, 1H) _:

4.90 (d, J = 14.8 Hz, 1H), 4.81 (s, 2H), 4.88 (d, J = 15.2 Hz, 1H) ppm.

Example 41

(R)-2y

Referring to the method of Example 6, using p-benzyloxyaniline as a nucleophilic reagent, a bisphosphine ligand &5)-La and a metal [Pd(C ₃ H ₅ )Cl] _{2 in} situ preparation of a complex as a catalyst, a catalytic bottom Asymmetric allyl amination of the lg to give a compound of formula (i?)-2y.

(R)-2y, colorless oil, 87% yield, [a] _D ²⁰ = -78.9 (c 1.20, CHCI3), 94% ee [determined by high performance liquid chromatography, chiral OD-H column; Alkane/isopropanol = 90:10, 1.0 mL/min, 254 nm; t _R (minor) = 9.81 min; t _R (major) = 12.21 min]. EI-MS (70 eV) (m/z) 502 (M+).

Example 42

Referring to the method of Example 6, using m-tert-butoxycarbonylaminoaniline as a nucleophile, the bisphosphine ligand (&&5)-La and the metal salt [Pd(C ₃ H ₅ )Cl] ₂ were prepared in situ. It was used as catalyst, the catalytic substrate lh asymmetric allylic amination reaction formula _(-22 compound.

(R)-2z, colorless oil, 89% yield, [a] _D ²⁰ = -98.2 (c 1.15, CHC1 ₃ ), 93% ee [determined by high performance liquid chromatography, chiral AD-H column; n-Hexane/Isopropanol = 95:5, 1.0 mL/min, 254 nm; t _R (minor) = 13.83 min; t _R (major) = 15.34 min]. EI-MS (70 eV) (m/z) 454 (M+).

Example 43

Referring to the method of Example 14, a compound of the formula (R)-2y, (R)-2z was used as a substrate to prepare a β-lactam compound of the formula (R)-3y, (R)-3z.

BocHN

(R)-3y (R)-3z

(R) - 3y, 73% yield. EI-MS (70 eV) (m/z) 456 (M+). (R) -3z, 79% yield. EI-MS (70 eV) (m/z) 408 (M+).

Example 44

The tumor cell inhibiting effects of the compounds prepared in Examples 40 and 43 were tested by the method of Example 34.

The results showed that the inhibitory effects of the compounds prepared in Examples 40 and 43 on leukemia cell HL60 showed IC ₅ . The value is lower than 6 (^g/mL, and the two compounds (R)-3y and (R)-3z exhibit IC ₅ G values even lower than 10 μ§/ηύ, ·, prepared in Examples 40 and 43 The inhibitory effect of the compound on lung cancer cell Α549 showed IC ₅ . The value was lower than 55 g mL, while the (R)-3v, (R)-3w compound showed IC ₅ value. The value range was even lower than 15 g mL, which was better. Inhibition of tumor cells.

Example 45

Referring to the method of Example 6, using 3,4,5-trimethoxybenzylamine as a nucleophile, a bisphosphine ligand (foot-size?)-Lc and a metal salt [Pd^-C ₃ H ₅ )C1] ₂ On-site preparation of the catalyst to catalyze the asymmetric allyl amination of the substrate (reaction formula is as follows):

The reaction was as follows: [Pd(C ₃ H ₅ )Cl] ₂ (1.8 mg, 0.005 mmol) and (foot-size?)-Lc (9.6 mg, 0.0125 mmol) were added to a schlenk tube under argon atmosphere, respectively. Water CH ₂ C1 ₂ (5 mL), after stirring at room temperature for 10 min, then add substrate (0.5 mmol), K ₂ C0 ₃ (1.0 M aqueous solution, 1.5 mL, 1.5 mmol) and 3,4,5-trimethyl Oxybenzylamine (295 mg, 1.5 mmol). After stirring at room temperature for three hours, it was extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography The experimental results are as follows:

2aa, colorless oil, 84% yield, [a] _D ²⁰ = +76.3 (c 1.00, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/iso Propanol = 85:15, 1.0 mL/min, 254 nm; t _R (major) = 14.28 min; t _R (minor) = 16.32 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.48-7.26 (m , 4H), 6.22 (s, 1H), 5.91 (s, 1H), 5.82 (s, 1H), 5.42 (s, 1H), 4.12-4.08 (m, 2H), 3.99-3.91 (m, 9H), 3.87-3.76 (m, 2H), 1.32 (s, 3H), 1.23 (t, J = 7.8 Hz, 3H) ppm.

2ab, colorless oil, 89% yield, [a] _D ^2Q = +96.2 (c 1.00, CHC1 ₃ ), 97% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/different Propanol = 80:20, 1.0 mL/min, 254 nm; t _R (major) = 13.12 min; t _R (minor) = 15.55 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.51-7.32 (m , 4H), 6.12 (s, 1H), 5.82 (s, 1H), 5.80 (s, 2H), 5.45 (s, 1H), 4.22-4.12 (m, 12H), 3.98-3.81 (m, 2H), 3.89-3.71 (m, 2H), 1.21 (t, J = 8.4 Hz, 3H) ppm.

(S)-2ac

2ac, colorless oil, 81% yield, [a] _D ²⁰ = +73.1 (c 1.00, CHC1 ₃ ), 92% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/iso Propanol = 90:10, 1.0 mL/min, 254 nm; t _R (major) = 15.78 min; t _R (minor) = 17.23 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.61-7.28 (m , 4H), 6.15 (s, 1H), 5.81 (s, 1H), 5.79 (s, 2H), 5.48 (s, 1H), 4.31-4.22 (m, 9H), 3.97-3.86 (m, 2H), 3.82-3.75 (m, 2H), 1.25 (t, J = 9.2 Hz, 3H) ppm.

2ad, colorless oil, 78% yield, [a] _D ²⁰ = +63.9 (c 1.00, CHC1 ₃ ), 94% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexane/iso Propanol = 80:20, 1.0 mL/min, 254 nm; t _R (major) = 10.52 min; t _R (minor) = 13.42 min]. 1H NMR (400 MHz, CDCI3) δ = 7.66-7.28 (m, 3H), 7.14 (s, 1H), 6.16 (s, 1H), 5.89 (s, 1H), 5.80 (s, 2H), 5.51 (s, 1H), 4.33-4.24 (m, 9H), 3.95-3.81 (m, 2H), 3.79-3.71 (m, 2H), 1.30 (s, 9H), 1.25 (t, J = 9.2 Hz, 3H), 0.87 (s, 9H) ppm.

The ligand (&?)-lc can be used to prepare the compound (i?)-2aa, 2ab, 2ac, 2ad. The racemic compound 2aa, 2ab, 2ac, 2ad can be prepared correspondingly using racemic ligands.

Example 46

Referring to the method of Example 14, a compound of the formula (5)-2aa, 2ab, 2ac, 2ad was used as a substrate to prepare a β-lactam (S)-3aa, 3ab, 3ac, 3ad compound. The reaction was as follows: Substrate (1.0 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were placed in a Schlenk tube, anhydrous toluene (5 mL) was added, and cooled to room temperature. Reduction, column chromatography purification.

3aa, white solid, 79% yield. [a] _D ^2Q = +41.2 (c 1.00, CHC1 ₃ ), 94% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/isopropanol = 85:15, 1.0 mL/min, 254 nm; t _R (minor) = 11.23 min; t _R (major) = 13.05 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.45-7.39 (m, 2H ), 7.15-7.05 (m, 2H), 6.59 (s, 2H), 5.85 (s, 1H), 5.39 (s, 1H), 5.19 (s, 1H), 3.77-3.73 (m, 9H), 3.69- 3.61 (m, 2H), 1.54 (s, 3H) ppm.

3ab, white solid, 82% yield. [a] _D ²⁰ = +87.2 (c 1.00, CHC1 ₃ ), 93% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexane/isopropanol = 85:15, 1.0 mL/min, 254 nm; t _R (minor) = 15.21 min; t _R (major) = 17.11 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.51-7.38 (m, 2H ), 7.17-7.02 (m, 2H), 6.62 (s, 2H), 5.89 (s, 1H), 5.27 (s, 1H), 5.11 (s, 1H), 3.82-3.70 (m, 12H), 3.65- 3.60 (m, 2H) ppm.

(S)-3ac

3ac, white solid, 86% yield. [a] _D ²⁰ = +65.1 (c 1.10, CHC1 ₃ ), 92% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexane/isopropanol = 90:10, 1.0 mL/min, 254 nm; t _R (minor) = 11.14 min; t _R (major) = 13.24 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.61-7.46 (m, 4H ), 6.68 (s, 2H), 5.81 (s, 1H), 5.22 (s, 1H), 5.16 (s, 1H), 3.90-3.87 (m, 2H), 3.80 (s, 3H), 3.75 (s, 6H) ppm.

(S)-3ad

3ad, white solid, 79% yield. [a] _D ²⁰ = +77.2 (c 1.33, CHC1 ₃ ), 91% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexane/isopropanol = 80:20, 1.0 mL/min, 254 nm; t _R (minor) = 18.22 min; t _R (major) = 19.35 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.71-7.52 (m, 3H ), 7.13 (s, 1H), 6.68 (s, 2H), 5.87 (s, 1H), 5.25 (s, 1H), 5.19 (s, 1H), 3.91-3.82 (m, 2H), 3.78 (s, 6H), 3.77 (s, 3H), 1.72 (s, 9H), 0.9 (s, 6H) ppm.

Starting from the configuration of the compound (i?)-2aa, 2ab, 2ac, 2ad as a substrate, the products of the (?) configuration (i?)-3aa, 3ab, 3ac, 3ad can be prepared accordingly.

Starting from the racemic compound 2aa, 2ab, 2ac, 2ad as a substrate, the racemic product (i?)-3aa, 3ab, 3ac, 3ad can be prepared accordingly. Example 47

Referring to the method of Example 6, using 3,4,5-trimethoxyaniline as a nucleophile, a bisphosphine ligand (foot-size?)-Lc and a metal salt [Pd(T!-C ₃ H ₅ )Cl] ₂ Prepare the catalyst on site to catalyze the asymmetric allyl amination of the following substrates (reaction formula is as follows):

The reaction was as follows: [Pd(C ₃ H ₅ )Cl] ₂ (1.8 mg, 0.005 mmol) and (foot-size?)-Lc (9.6 mg, 0.0125 mmol) under argon atmosphere Add a separate schlenk tube, add anhydrous CH ₂ C1 ₂ (5 mL), stir at room temperature for 10 min, then add substrate (0.5 mmol), K ₂ C0 ₃ (1.0 M aqueous solution, 1.5 mL, 1.5 mmol) And 3,4,5-trimethoxyaniline (274 mg, 1.5 mmol). After stirring at room temperature for three hours, it was extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography The experimental results are as follows:

2ah 2ai 2aj

2ak 2al 2am

2an

2ao 2ap

2ae, colorless oil, 90% yield, [a] _D ²⁰ = +100.7 (c 1.10, CHC1 ₃ ), 96% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/iso Propanol = 90:10, 1.0 mL/min, 254 nm; t _R (major) = 12.19 min; t _R (minor) = 13.86 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.28-6.84 (m , 5H), 6.31 (s, 1H), 5.93 (s, 1H), 5.89 (s, 2H), 5.43 (s, 1H), 4.18-4.09 (m, 2H), 3.79-3.77 (m, 9H), 1.21 (t, J = 7.8 Hz, 3H) ppm.

2af, colorless oil, 81% yield, [a] _D ²⁰ = +95.2 (c 1.10, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexane/iso Propanol = 90: 10, 1.0 mL/min, 254 nm; t _R (major) = 11.16 min; t _R (minor) = 13.72 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.28 (s, 1H ), 7.12 (s, 1H), 6.98 (d, J = 6.8 Hz, 1H), 6.87 (d, J = 6.8 Hz, 1H), 6.82 (s, 1H), 5.93 (s, 1H), 5.89 (s , 2H), 5.43 (s, 1H), 4.17-4.01 (m, 2H), 3.81-3.79 (m, 9H), 3.69 (s, 3H), 1.23 (t, J = 7.6 Hz, 3H) ppm. 2ag, colorless oil, 78% yield, [a] _D ²⁰ = +92.2 (c 1.20, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexane/iso Propanol = 90:10, 1.0 mL/min, 254 nm; t _R (major) = 9.18 min; t _R (minor) = 10.61 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.28-7.12 (m , 3H), 6.98 (s, 1H), 6.81 (s, 1H), 5.99 (s, 1H), 5.79 (s, 2H), 5.40 (s, 1H), 4.19-4.03 (m, 2H), 3.79- 3.73 (m, 9H), 1.30 (t, J = 7.2 Hz, 3H) ppm.

2ah, colorless oil, 83% yield, [a] _D ²⁰ = +76.1 (c 0.90, CHC1 ₃ ), 92% ee [determined by high performance liquid chromatography, chiral AD-H column; Propanol = 90: 10, 1.0 mL/min, 254 nm; t _R (major) = 8.12 min; t _R (minor) = 9.50 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.29-7.11 (m , 3H), 6.97 (d, J = 4.2 Hz, 1H), 6.89 (d, J = 4.2 Hz, 1H), 6.83 (s, 1H), 5.82 (s, 1H), 5.73 (s, 2H), 5.41 (s, 1H), 4.17-4.02 (m, 2H), 3.84-3.80 (m, 9H), 1.23 (t, J = 7.2 Hz, 3H) ppm.

2ai, colorless oil, 77% yield, [a] _D ²⁰ = +56.7 (c 1.25, CHC1 ₃ ), 91% ee [determined by high performance liquid chromatography, chiral AD-H column; Propanol = 90: 10, 1.0 mL/min, 254 nm; t _R (major) = 7.15 min; t _R (minor) = 8.52 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.29 (s, 1H ), 7.11-6.97 (m, 3H), 6.81 (s, 1H), 5.81 (s, 1H), 5.79 (s, 2H) _: 5.45 (s, 1H), 4.12-4.00 (m, 2H), 3.78- 3.71 (m, 9H), 1.27 (t, J = 8.2 Hz, 3H) ppm.

2aj, colorless oil, 71% yield, [a] _D ²⁰ = +98.9 (c 1.20, CHC1 ₃ ), 94% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexyl isopropanol = 85: 15, 1.0 mL/min, 254 nm; t _R (major) = 11.5 min; t _R (minor) = 12.2 min]. 1H NMR (400 MHz, CDCI3) δ = 7.27 (s, 1H), 7.19 (d, J = 4.1 Hz, 1H), 7.10 (d, J = 4.1 Hz, 1H), 7.08 (s, 1H), 6.85 (s, 1H), 5.87 (s, 1H), 5.82 (s, 2H) , 5.48 (s, 1H), 4.17-4.01 (m, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.80 (s, 6H), 1.29 (t, J = 7.2 Hz, 3H) ppm .

2ak, colorless oil, 83% yield, [01] ₀ ^{2 ()} = +103.9 (£;1.20, [13⁄41 ₃ ), 94% ^ [determined by high performance liquid chromatography, chiral OD-H column;己 ^ / / isopropanol = 85: 15, 1.0 mL / min, 254 nm; t _R (major) = 17.8 min; t _R (minor) = 19.2 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.12 -7.09 (m, 3H), 6.81 (s, 1H), 5.86 (s, 1H), 5.80 (s, 2H), 5.42 (s, 1H) _: 4.12-4.02 (m, 2H), 3.80 (s, 3H ), 3.75 (s, 6H), 1.24 (t, J = 7.2 Hz, 3H) ppm.

2al, colorless oil, 80% yield, [a] _D ²⁰ = +101.4 (c 1.15, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral OD-H column; Propanol = 85: 15, 1.0 mL/min, 254 nm; t _R (major) = 20.8 min; t _R (minor) = 22.5 min]. 1H NMR (400 MHz, CDCI3) δ = 7.11-7.05 (m, 3H), 6.79 (s, 1H), 5.87 (s, 1H), 5.75 (s, 2H), 5.35 (s, 1H) _: 4.10-4.00 (m, 2H), 3.78 (s, 3H), 3.71 (s , 6H), 1.20 (t, J = 6.8 Hz, 3H) ppm.

2am, colorless oil, 71% yield, [a] _D ²⁰ = +77.2 (c 1.00, CHC1 ₃ ), 91% ee [determined by high performance liquid chromatography, chiral OD-H column; Propanol = 85: 15, 1.0 mL/min, 254 nm; t _R (major) = 20.4 min; t _R (minor) = 21.9 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.15-7.04 (m , 3H), 6.75 (s, 1H), 5.82 (s, 1H), 5.79 (s, 2H), 5.42 (s, 1H) _: 4.21-4.10 (m, 2H), 3.95 (s, 1H), 3.82 ( s, 3H), 3.77 (s, 6H), 1.21 (t, J = 7.4 Hz, 3H) ppm.

2an, colorless oil, 78% yield, [a] _D ²⁰ = +78.1 (c 1.00, CHC1 ₃ ), 94% ee [determined by high performance liquid chromatography, chiral AD-H column; Propanol = 85: 15, 1.0 mL/min, 254 nm; t _R (major) = 26.4 min; t _R (minor) = 28.9 min]. 1H NMR (400 MHz, CDC1 ₃ ) 5 = 7.13 (d, J = 4.2 Hz, 1H), 7.69 (d, J= 4.2 Hz, 1H), 6.80 (s, 1H), 5.80 (s, 1H), 5.71 (s, 2H), 5.41 (s, 1H), 4.20-4.09 (m, 2H), 3.87 (s, 3H), 3.82 (s, 6H), 2.30 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H) ppm.

2ao, colorless oil, 82% yield, [a] _D ^2Q = +88.1 (c 1.00, CHC1 ₃ ), 96% ee [determined by high performance liquid chromatography, chiral AD-H column; Propanol = 85: 15, 1.0 mL/min, 254 nm; t _R (major) = 13.5 min; t _R (minor) = 15.4 min]. 1H NMR (400 MHz, CDCI3) δ = 7.11 (s, 1H) , 7.60 (s, 1H), 6.82 (s, 1H), 5.75 (s, 1H), 5.68 (s, 2H), 5.37 (s, 1H), 4.19-4.03 (m, 2H), 3.79 (s, 3H ), 3.71 (s, 6H), 1.20 (t, J = 6.8 Hz, 3H) ppm.

2ap, colorless oil, 82% yield, [a] _D ² ° = +90.5 (c 1.00, CHCI3), 91% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexanol = isopropanol = 90:10, 1.0 mL/min, 254 nm; t _R (major) = 13.5 min; t _R (minor) = 15.4 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.13 (s, 1H), 7.66 (s, 1H), 6.80 (s, 1H), 5.71 (s, 1H), 5.69 (s, 2H), 5.30 (s, 1H), 4.11-4.02 ( m, 2H), 3.98 (s, 3H), 3.82-3.80 (m, 9H), 3.77 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H) ppm. Use ligand (&3⁄4 )-lc The corresponding configuration of the compound (i?)-2ae~2ap.

The racemic compound 2a _e ~2ap can be prepared correspondingly using racemic ligands.

Example 48

Referring to the method of Example 14, a compound of the formula (5)-2ae~2ap was used as a substrate to prepare a β-lactam compound of the formula (5)-3ae~3ap. The reaction was as follows: Substrate (10 mmol) and Sn[N(TMS) ₂ ] ₂ (659.2 mg, 1.5 mmol) were added to a Schlenk tube, anhydrous toluene (5 mL) was added, heated to reflux for 3-12 hours, cooled to After room temperature, it was concentrated and purified by column chromatography.

3a 3ai 3aj

3an 3ao 3ap

3ae, white solid, 79% yield. [a] _D ²⁰ = +73.5 (c 1.20, CHC1 ₃ ), 94% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexane/isopropanol = 85:15, 1.0 mL/min, 254 nm; t _R (minor) = 14.00 min; t _R (major) = 15.64 min]. 1H NMR (400 MHz, CDCI3) δ = 7.47-7.31 (m, 5H) , 6.66 (s, 2H), 5.80 (s, 1H), 5.32 (s, 1H), 5.17 (s, 1H), 3.82 (s, 3H), 3.78 (s, 6H) ppm.

3af, white solid, 77% yield. [a] _D ²⁰ = +90.1 (c 1.10, CHC1 ₃ ), 92% ee [determined by high performance liquid chromatography, hand OD-H column; n-hexane/isopropanol = 85:15, 1.0 mL/min, 254 nm; t _R (minor) = 11.90 min; t _R (major) = 12.54 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.42 (s, 1H), 7.37 (s, 1H), 7.12 (d, J = 4.6 Hz, 1H), 6.98 (d, J = 4.6 Hz, 1H), 6.74 (s, 2H), 5.82 (s, 1H), 5.39 (s, 1H), 5.11 (s, 1H), 3.81 (s, 3H), 3.79 (s, 6H), 3.73 (s, 3H) ppm.

3ag, white solid, 82% yield. [a] _D ²⁰ = +61.3 (c 1.00, CHC1 ₃ ), 92% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexane/isopropanol = 85: 15, 1.0 mL/min, 254 nm; t _R (minor) = 9.82 min; t _R (major) = 10.33 min]. 1H NMR (400 MHz, CDCI3) δ = 7.39 (s, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 4.6 Hz, 1H), 6.98 (d, J = 4.6 Hz, 1H), 6.74 (s, 2H), 5.82 (s, 1H), 5.39 (s, 1H), 5.11 (s, 1H), 3.79 (s, 3H), 3.71 (s, 6H), 3.73 (s, 3H) ppm.

3ah, white solid, 81% yield. [a] _D ^2Q = +41.2 (c 1.00, CHCI3), 90% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexane/isopropanol = 85: 15, 1.0 mL/min, 254 nm; t _R (minor) = 7.13 min; t _R (major) = 8.21 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.35-7.12 (m, 5H) , 6.62 (s, 2H), 5.81 (s, 1H), 5.37 (s, 1H), 5.19 (s, 1H), 3.87 (s, 3H), 3.82 (s, 6H), ppm.

3ai, white solid, 75% yield. [a] _D ²⁰ = +95.6 (c 1.00, CHC1 ₃ ), 95% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexane/isopropanol = 85: 15, 1.0 mL/min, 254 nm; t _R (minor) = 7.67 min; t _R (major) = 9.44 min]. 1H NMR (400 MHz, CDCI3) δ = 7.35 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H), 7.30 (d, J = 2.8 Hz, 1H), 7.15 (t, J = 2.8 Hz, 1H), 6.61 (s, 2H), 5.89 (s, 1H), 5.35 (s, 1H), 5.17 (s, 1H), 3.75 (s, 3H), 3.71 (s, 6H) ppm.

3aj, white solid, 83% yield. [a] _D ²⁰ = +83.5 (c 1.10, CHC1 ₃ ), 96% ee [determined by high performance liquid chromatography, chiral AD-H column; n-hexane/isopropanol = 85: 15, 1.0 mL/min, 254 nm; t _R (minor) = 17.55 min; t _R (major) = 19.78 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.37 (s, 1H), 7.30 (d, J = 2.8 Hz, 1H), 7.25 (d, J = 2.8 Hz, 1H), 7.10 (s, 1H), 6.59 (s, 2H), 5.81 (s, 1H), 5.40 (s, 1H) ), 5.14 (s, 1H), 3.80 (s, 3H), 3.74 (s, 6H), ppm.

3ak, white solid, 77% yield. [a] _D ²⁰ = +74.2 (c 1.30, CHC1 ₃ ), 93% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexane/isopropanol = 90:10, 1.0 mL/min, 254 nm; t _R (minor) = 16.50 min; t _R (major) = 17.45 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.25 (s, 1H), 7.17 (d, J = 3.2 Hz, 1H), 7.15 (d, J = 3.2 Hz, 1H), 6.63 (s, 2H), 5.89 (s, 1H), 5.42 (s, 1H), 5.32 (s, 1H) ), 3.70 (s, 3H), 3.65 (s, 6H) ppm.

3al, white solid, 82% yield. [a] _D ²⁰ = +86.5 (c 1.25, CHC1 ₃ ), 93% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexane/isopropanol = 80:20, 1.0 mL/min, 254 nm; t _R (minor) = 15.20 min; t _R (major) = 15.65 min]. 1H NMR (400 MHz, CDCI3) δ = 7.41 (d, J = 3.8 Hz , 1H), 7.30 (d, J= 3.8 Hz, 1H), 7.15 (s, 1H), 6.61 (s, 2H), 5.79 (s, 1H), 5.31 (s, 1H), 5.11 (s, 1H) , 3.89 (s, 3H), 3.87 (s, 6H) ppm.

3am, white solid, 79% yield. [a] _D ²⁰ = +57.1 (c 1.32, CHC1 ₃ ), 90% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexane/isopropanol = 90:10, 1.0 mL/min, 254 nm; t _R (minor) = 12.21 min; t _R (major) = 13.11 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.38 (d, J= 3.2 Hz, 1H), 7.22 (d, J= 3.2 Hz, 1H), 7.10 (s, 1H), 6.59 (s, 2H), 5.77 (s, 1H), 5.36 (s, 1H), 5.10 (s, 1H) ), 3.89 (s, 3H), 3.83 (s, 6H), 3.57 (s, 3H) ppm.

3an, white solid, 89% yield. [a] _D ^2Q = +89.2 (c 1.00, CHC1 ₃ ), 92% ee [determined by high performance liquid chromatography, chiral

OD-H column; n-hexane/isopropanol = 90: 10, 1.0 mL/min, 254 nm; t _R (minor) = 12.21 min; t _R (major) = 13.11 min]. 1H NMR (400 MHz, CDCI3 5 = 7.11 (d, J = 2.8 Hz, 1H), 7.02 (d, J = 2.8 Hz, 1H), 6.66 (s, 2H), 5.72 (s, 1H), 5.31 (s, 1H), 5.09 ( s, 1H), 3.88 (s, 3H), 3.82 (s, 6H), ppm.

3ao, white solid, 89% yield. [a] _D ²⁰ = +89.2 (c 1.15, CHC1 ₃ ), 92% ee [determined by high performance liquid chromatography, chiral OD-H column; n-hexane/isopropanol = 90: 10, 1.0 mL/min, 254 nm; t _R (minor) = 12.21 min; t _R (major) = 13.11 min]. 1H NMR (400 MHz, CDC1 ₃ ) 5 = 7.15 (s, 1H), 7.00 (s, 1H), 6.72 (s, 2H), 5.79 (s, 1H), 5.20 (s, 1H), 5.15 (s, 1H), 3.71 (s, 3H), 3.69 (s, 6H), 3.25 (br, 1H) ppm.

3ap, white solid, 81% yield. [a] _D ²⁰ = +81.7 (c 1.20, CHC1 ₃ ), 92% ee [determined by high performance liquid chromatography, chiral

OD-H column; n-hexane/isopropanol = 90: 10, 1.0 mL/min, 254 nm; t _R (minor) = 12.21 min; t _R (major) = 13.11 min]. 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.23 (s, 1H), 7.14 (s, 1H), 6.65 (s, 2H), 5.82 (s, 1H), 5.15 (s, 1H),

5.05 (s, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.80 (s, 3H), 3.74 (s, 6H), ppm.

Starting from the configuration of the compound (R)-2ae~2ap as a substrate, the product of the (i?) configuration (i?) -3ae~3ap can be prepared accordingly.

Starting from the racemic compound 2ae~2ap as a substrate, the racemic product 3ae~3ap can be prepared accordingly. Example 49

Compound 3aq was prepared starting from compound (5) - 3t. The procedure is as follows: 3t (485 mg, 1 mmol) is dissolved in 5 ml of THF, cooled to zero degrees Celsius, slowly added tetrabutylammonium fluoride in THF (1 ml, 1 M), and stirred at 0 ° C for 10 minutes. After concentration and column chromatography, the product is obtained.

3aq, 90% yield. 1H Li R (400 MHz, CDC1 ₃ ) δ = 6.98-6.83 (m, 3H), 6.61 (s, 2H), 5.96 (br, 1H) _: 5.81 (s, 1H), 5.28 (s, 1H), 5.15 (s, 1H), 3.87 (s, 3H), 3.76-3.73 (m, 9H) ppm. Example 50

The compound (S)-4s was prepared from the compound (S)-3s. The procedure was as follows: 3s (415 mg, 1 mmol) was added to the reaction vessel, and 5 ml of ethyl acetate, 10% Pd/C (40 mg) was added, and the reaction vessel was charged and charged with 5 atmospheres of hydrogen. After reacting at room temperature for 6 hours, the reaction kettle was opened, and after concentration, column chromatography was performed.

4s, 90% yield. [a] _D ²⁰ = +56.2 (c 1.00, CHC1 ₃ ). 1H NMR (400 MHz, CDC1 ₃ ) δ = 6.68-6.62 (m, 4Η) _: 5.21 (d, J= 6.4 Hz, 1H), 3.82-3.78 (m, 9H), 3.72-3.69 (m, 9H), 3.67-3.65 (m, 1H), 1.57 (d, J = 7.2 Hz, 3H) ppm. Example 51

Compound (S)-4s was prepared starting from compound (S)-3s. The procedure is as follows: Add 3s (325 mg, 1 mmol), acetone 5 ml, N-methyl-N-oxidized morpholine C175 mg, 1.5 mol) and osmium tetroxide in a 25 ml reaction flask (0.1 ml, 2%) Stir at room temperature for 12 hours. Quenched with saturated aqueous sodium thiosulfate, extracted with dichloromethane, partitioned and evaporated.

(S)-3h (S)-4h

4h, 95% _{^{yield. [A] D 20 = +101.3}} (c 1.10, CHC1 3). 1H NMR (400 MHz, CDC1 3) δ = 7.42-7.32 (m, 5H), 6.59 (s, 2H), 5.54 (br, 1H), 5.17 (br, 1H), 3.82 (s, 3H), 3.73 (s, 6H), 3.69 (s, 2H) ppm. Example 52

Compound 0S)-4ab was prepared starting from compound 0S)-3ab. The procedure is as follows: Add 3ab (369 mg, 1 mmol), tetrahydrofuran 5 ml to 50 ml of Schlenk, cool to zero degrees Celsius, slowly add borane in tetrahydrofuran solution (1.2 ml, 1 M), return to room temperature, continue stirring for 5 hours. . Aqueous sodium hydroxide solution (2 ml, 1 M), hydrogen peroxide (30%, 3 ml) was added, and the mixture was stirred at room temperature for 2 hr.

(S)-3ab (S)-4ab

4ab, 77% yield. [a] _D ²⁰ = +87.2 (c 1.00, CHC1 ₃ ). 1H NMR (400 MHz, CDCI3) δ = 7.32 (d, J = 7.2 Hz, 2H), 7.28 (d, J = 7.2 Hz, 2H), 6.63 (s, 2H), 5.42 (d, J = 6.4 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 3.79 (s, 6H), 3.73 (s , 2H), 3.68-3.52 (m, 1H), 3.44-3.42 (m, 2H) ppm. Example 53

Compound 0S)-4u was prepared starting from compound 0S)-3u. The procedure was as follows: 3 ml (343 mg, 1 mmol), anhydrous toluene 5 ml, Ν-α-diphenylnitrone (240 mg, 1.2 mmol) were added to 50 ml of Schlenk, and heated under reflux for 6 hours. After cooling to room temperature, concentrate and purify by column chromatography.

3u 4u

4u, 82% yield. [a] _D ²⁰ = +65.1 (c 1.16, CHC1 ₃ ). 1H NMR (400 MHz, CDCI3) δ = 7.35-7.31 (m, 4H), 6.69 (s, 2H), 5.17 (s, 1H), 4.78-4.74 (m, 1H), 3.82 (s, 6H), 3.73 (s, 3H), 2.88-2.86 (m, 1H), 2.23-2.20 (m, 1H) ppm. Example 54

Compound (5)-4r was prepared starting from compound 0S)-3r. The procedure is as follows: 50 ml of Schlenk is added 3r (355 mg, 1 mmol), anhydrous tetrahydrofuran 5 ml, m-chloroperoxybenzoic acid (282 mg, 1.5 mmol), and reacted at room temperature for 5 hours, saturated sodium thiosulfate water Solution quenching, dichloromethane extract, organic phase concentration, column chromatography

3r 4r

4r, 86% yield. [a] _D ² . = +94.2 (c 1.20, CHC1 ₃ ). 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.34-7.28 (m, 4H) _: 6.72 (s, 2H), 5.24 (s, 1H), 3.98 (s, 3H ), 3.82 (s, 3H), 3.78 (s, 6H), 3.35 (s, 2H) ppm.

Example 55

Compound 0S)-4aa was prepared starting from compound 0S)-3aa. The procedure is as follows: Add 3aa (353 mg, 1 mmol), tetrahydrofuran 5 ml, hydrobromic acid (2 ml) to a 25 ml round bottom flask, react at room temperature for 5 hours, neutralize with saturated aqueous sodium hydrogencarbonate, and extract with dichloromethane. Liquid, organic.

(S)-3aa 4aa

4aa, 77% yield. [a] _D ² . = +54.1 (c 0.90, CHC1 ₃ ). 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.31-7.25 (m, 4H), 6.31 (s, 2H), 5.24 (d, J = 7.2 Hz, 1H), 3.87 (m, 9H), 3. 39 (m, 1H), 2.51 (d, J = 7.2 Hz, 2H), 2.12 (s _: 3H) ppm.

Example 56

Compound 5r was prepared starting from compound 4r. The procedure is as follows: 4 ml (371 mg, 1 mmol), 5 ml of anhydrous tetrahydrofuran in a 25 ml Schlenk tube, cooled to -78 ° C, and slowly added phenyl magnesium bromide (1.5 ml, 1 M tetrahydrofuran solution), and returned to room temperature. Stirring was continued for 2 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride, extracted with dichloromethane and partitioned.

4r 5r

5r, 72% yield. [a] _D ²⁰ = +66.1 (c 1.10, CHC1 ₃ ). ^ NMR (400 MHz, CDC1 ₃ ) δ = 7.32 (d, J = 7.2 Hz, 2H), 7.24 (d, J = 7.2 Hz, 2H), 7.20-7.15 (m, 5H), 6.78 (s, 2H), 5.15 (s, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.86 (s, 6H ), 2.53 (s, 2H) ppm.

Example 57

Compound 5ab was prepared starting from compound 4ab. The procedure was as follows: 3 ml (369 mg, 1 mmol), tetrahydrofuran 5 ml was added to 50 ml of Schlenk, and the mixture was cooled to zero degrees Celsius. A solution of boron hydride in tetrahydrofuran (1.2 ml, 1 M) was added dropwise. After returning to room temperature, stirring was continued for 5 hours. . Add sodium hydroxide aqueous solution (2ml, 1M), hydrogen peroxide (30%, 3 ml), stir at room temperature for 2 hours, quench with saturated aqueous sodium thiosulfate, extract with dichloromethane, partition, organic phase and column chromatography purification.

5ab, 92% yield. [a] _D ²⁰ = +96.1 (c 1.00, CHC1 ₃ ). 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.41-7.38 (m, 5H), 7.35-7.28 (m, 4H ), 6.72 (s, 2H), 5.48 (d, J = 7.4 Hz, 1H), 3.97 (s, 3H), 3.88 (s, 2H), 3.80 (d, J = 7.4 Hz, 2H), 3.74-3.71 (m, 9H), 3.40-3.38 (m, 1H) ppm.

Example 58

Compound 5aa was prepared starting from compound 4aa. The procedure is as follows: 4aa (434 mg, 1 mmol), anhydrous tetrahydrofuran 5 ml, n-butylamine (109 mg, 1.5 mmol), and heated under reflux for 5 hours. The organic phase is concentrated and purified by column chromatography.

4aa 5aa

5aa, 79% yield. [a] _D ² . = +109.7 (c 0.80, CHC1 ₃ ). 1H NMR (400 MHz, CDCI3) δ = 7.29-7.18 (m, 4H), 6.28 (s, 2H), 5.21 (d, J = 7.8 Hz, 1H), 3.72 (s, 2H), 3.65-3.60 (m, 1H), 3.38-3.22 (m, 4H), 2.42 (t, J = 6.8 Hz, 3H), 1.98-1.82 (m, 4H), 1.53 (t, J = 8.2 Hz, 3H), ppm.

Example 59

Compound 5u was prepared starting from compound 3u. The procedure is as follows: Add 3u (343 mg, 1 mmol), anhydrous toluene 5 ml, palladium acetate (22 mg, 0.1 mmol), triphenylphosphine (57 mg, 0.22 mmol), potassium carbonate (207 mg, 50 ml) to a 50 ml Schlenk tube. 1.5 mmol), phenylboronic acid C 146 mg, 1.2 mmol), heated under reflux for 5 hours, and the organic phase was concentrated and purified by column chromatography.

3u 5u

5u, white solid, 77% yield. [a] _D ² . = +133.2 (c 1.10, CHCI3). 1H NMR (400 MHz, CDCI3) δ =

7.36-7.28 (m, 4H), 7.11-6.99 (m, 5H), 6.55 (s, 2H), 5.81 (s, 1H), 5.72 (s, 1H), 3.79 (s, 3H), 3.71 (s, 6H) ppm.

Example 60

Compound 5u was prepared starting from compound 3u. The procedure was as follows: 5u (419 mg, 1 mmol) was added to the reaction vessel, and 5 ml of ethyl acetate, 10% Pd/C (40 mg) was added, and the reaction vessel was charged and charged with 5 atmospheres of hydrogen. The reaction was allowed to proceed for 6 hours at room temperature, the reaction vessel was opened, and the column was concentrated to give a product.

6u, white solid, 77% yield. [a] _D ²⁰ = +93.1 (c 1.00, CHC1 ₃ ). 1H NMR (400 MHz, CDC1 ₃ ) δ = 7.42-7.30 (m, 2H), 7.23-6.90 ( m, 7H), 6.59 (s, 2H), 5.88 (d, J = 7.2 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 6H), 3.71-3.69 (m, 1H), 2.53 (d , J = 7.4 Hz, 2H) ppm.

In Examples 49-60, the opposite of the absolute configuration was used to obtain the product of the opposite absolute configuration; using the racemic material, the racemic product was obtained.

Example 61

The tumor cell inhibiting effects of the compounds prepared in Examples 46, 48 and 49 to 60 were tested by the method of Example 34. The results showed that the inhibitory effects of the compounds prepared in Examples 46, 48 and 49-60 on leukemia cell HL60 showed an IC ₅₀ value of less than 20 gmL, while (5)-3ah~(5)-3ap, racemic 5aa, 5ab , 5u and (i?)-3aa-3ad exhibit IC ₅ o values even below 10 gmL; the compounds prepared in Examples 46, 48 and 49-60 inhibited lung cancer cell A549 and showed IC _5Q values lower than 15 g/mL, and (5)-4u, (S)-4r, (5)-5 and (i?)-3al! The ~(i?)-3ap compound exhibits an IC ₅ Q value range of even less than 10 ^mL, which has a good inhibitory effect on tumor cells.

All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it is to be understood that various modifications and changes may be made by those skilled in the art in the form of the present invention.

Claims

Claim

A β-lactam compound characterized by having the structure of Formula I:

I

Wherein R ¹ and R ² are each independently selected from the group consisting of substituted or unsubstituted: CM thiol, Cw. Cyclodecyl, C ₆ _-20 aryl; the substitution is substituted by a substituent selected from the group consisting of: halogen, d- ₆ fluorenyl, d ₆ methoxy, d ₆ haloalkyl, -OR ¹¹ Or -NR ¹² , wherein R ^u and R ¹² are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, untert Butyldimethylsilyl, tert-butyldiphenylsilyl or diphenylmethylsilyl;

* indicates a stereoisomer center, the compound of formula I is a configuration or an S configuration; or * indicates that the compound of formula I is a racemate.

2. The compound of claim 1, wherein, R, R ² are not simultaneously phenyl; or when one of the RR ² is phenyl, the other is not p-methoxyphenyl.

3. A method of preparing a compound according to claim 1, wherein the method comprises the steps of:

(b) in an organic solvent, the compound of the formula 2 is ring-closed under the action of a base to obtain the compound of claim 1.

1 2 ¹ wherein: R, R ² , * are as defined in claim 1;

R ³ is methyl, ethyl, isopropyl, n-butyl, tert-butyl, benzyl or adamantyl;

LG is an acetyl group, a tert-butoxycarbonyl group, a methoxycarbonyl group, or a bis(ethoxy)phosphino group.

The method according to claim 3, wherein the transition metal catalyst precursor is a palladium catalyst precursor, which is Pd(OAc) ₂ , PdCl ₂ , Pd ₂ (dba) ₃ , Pd ₂ (dba) ₃ 'CHCl ₃ , Pd(dba) ₂ , [Pd(C ₃ H ₅ )Cl] ₂ , Pd(PPh ₃ ) ₄ , Pd(PPh ₃ ) ₂ Cl ₂ , Pd(CH ₃ CN)Cl ₂ One or two or more.

The method according to claim 3, wherein the chiral phosphine ligand has the following structure: Wherein R ⁴ , R ⁵ , R ⁶ and RR\ R ⁹ are each independently selected from the group consisting of hydrogen, halogen and substituted or unsubstituted groups: C ₁₀ alkyl, Ci~C ₄ alkoxy, C a cycloalkyl or aryl group of _{3 to} C ₃ o;

R ^1Q and R ¹¹ are each independently selected from the group consisting of a substituted or unsubstituted group: a C ₃ -C _1Q cyclodecyl group, a C Cu) fluorenyl group, a 2-furyl group or an aryl group;

X is selected from CH ₂ , NH, NCH ₃ , 0 or S; n=0 to 4;

Wherein the substitution is substituted by the following substituent: halogen, d- ₆ fluorenyl, d- ₆ haloindolyl or d- ₆ decyloxy.

The preparation method according to claim 3, wherein in the step (a), the molar ratio of the base, R ² -NH ₂ to the compound of the formula 1 is 1 to 10: 1 to 10: 1;

The method according to claim 3 or 6, wherein the base is potassium carbonate, potassium phosphate, cesium carbonate, triethylamine, diisopropylethylamine, N, O-double ( One or more of trimethylsilyl)acetamide and tetra-n-butylammonium difluorotriphenylsilicate.

The preparation method according to claim 3, wherein in the step (b), the molar ratio of the base to the compound of the formula 2 is from 1 to 10:1.

The preparation method according to claim 3 or 8, wherein in the step (b), the base is bis(hexamethyldisilazide)tin or hexamethyldisilazide. One or more of lithium, lithium diisopropylamide, t-butylmagnesium chloride, t-butylmagnesium bromide, isopropyl magnesium chloride, and isopropyl magnesium bromide.

The preparation method according to claim 3, wherein the organic solvent is benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether. At least one of tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide or dimethyl sulfoxide.

11. A compound of formula 2,

2

Where: * represents a stereogenic center, in a configuration or an S configuration;

R ¹ and R ² are each independently selected from the group consisting of substituted or unsubstituted: d- ₆ fluorenyl, C^. Cyclodecyl, C ₆ _ ₂ . Aryl group It refers to the substituent selected from the group of substituents: halogen, d- ₆ alkyl, d- ₆ alkoxy or - ₆ haloalkyl, -OR ^U,

R ³ is methyl, ethyl, isopropyl, n-butyl, tert-butyl, benzyl or adamantyl.

12. A method of preparing a compound of formula 2, characterized in that the method comprises the steps of:

In each formula: * represents a stereogenic center, in a configuration or an S configuration;

RR ^{2 is} independently selected from the group consisting of substituted or unsubstituted groups: d- ₆ fluorenyl, C^. Cyclodecyl, C ₆ _ ₂ . The aryl group; the substitution means substitution with a substituent selected from the group consisting of halogen, C _R6 alkyl, d- ₆ alkoxy or d- ₆ haloalkyl, -OR ^U , -N ¹² , wherein R ^U And R ¹² are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, uncle Butyl diphenylsilyl or diphenylmethylsilyl;

R ³ is methyl, ethyl, isopropyl, n-butyl, tert-butyl, benzyl or adamantyl.

13. A β-lactam compound having the specific structure shown in Formula II:

Wherein Ar is selected from substituted or unsubstituted C ₆ _ ₂ . The aryl group; the substitution means substitution with a substituent selected from the group consisting of halogen, d- ₆ alkyl, CM alkoxy, C haloalkyl, -OR ¹¹ or -NR ¹² , wherein R ^U , R ¹² Each is independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxy, benzyl, oxy-oxyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl or diphenylmethylsilyl;

A β-lactam compound characterized by having the structure as shown in Formulas III, IV and V: Wherein R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are each independently selected from the group consisting of substituted or unsubstituted: CM alkyl. Cycloalkyl, C ₆ _ ₂ . Aryl; refers to a substituent selected from the group of substituents: halogen, d- ₆ alkyl, CM alkoxy, CM haloalkyl, -OR ^11, or -NR ^12, wherein R ^U, R ¹² are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl or diphenylmethylsilyl;

X is taken from a nitrogen, oxygen or sulfur atom;

* indicates a stereogenic center, and the compound of the formula III, IV, V is a configuration or an S configuration; or * indicates that the compound of the formula III, IV, V is a racemate.

A β-lactam compound characterized by having the structure shown in Formula VI:

Wherein Ar is selected from substituted or unsubstituted C ₆ _ ₂ . Aryl; refers to a substituent selected from the group of substituents: halogen, C ^ alkyl, CM alkoxy, CM haloalkyl, -OR ^11, or -NR ^12, wherein R ^U, R ¹² Each is independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyl Phenylsilyl or diphenylmethylsilyl;

* indicates a stereogenic center, and the compound of formula VI is in the R configuration or the S configuration; or * indicates that the compound of formula VI is a racemate.

A β-lactam compound characterized by having the structure shown in Formula VII:

Wherein: = 0 or 1; Ar is selected from substituted or unsubstituted C ₆ _ ₂ . The aryl group; the substitution means substitution with a substituent selected from the group consisting of halogen, C _R6 alkyl, CM alkoxy, CM haloalkyl, -OR ¹¹ or -NR ¹² wherein R ^U and R ¹² are each Independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenyl Silyl or diphenylmethylsilyl; R ²² , R ²³ , R ²⁴ , R ²⁵ are each independently selected from the group consisting of substituted or unsubstituted: CM fluorenyl, . Cyclodecyl, C ₆ _ ₂ . Aryl, hydroxy or amino; said substitution is substituted by a substituent selected from the group consisting of halogen, d- ₆ alkyl, CM alkoxy, CM haloalkyl, -OR ¹¹ or -NR ¹² , wherein R ^U ,

* indicates a stereoisomer center, the compound of formula VII is a configuration or an S configuration; or * indicates that the compound of formula VII is a racemate.

17. A compound of formula VIII, Where: * represents a stereogenic center, in a configuration or an S configuration; or as a racemate.

Wherein Ar is selected from substituted or unsubstituted C ₆ _ ₂ . The aryl group; the substitution means substitution with a substituent selected from the group consisting of halogen, d- ₆ alkyl, CM alkoxy, CM haloalkyl, -OR ¹¹ , or -NR ¹² , wherein R ^u , R ¹² are each independently selected from the group consisting of hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl or diphenylmethylsilyl;

R ³ is methyl, ethyl, isopropyl, n-butyl, tert-butyl, benzyl or adamantyl.

Use of a compound according to Claim 1, 13, 14, 15, or 16 for the preparation of a medicament for preventing and/or treating a tumor.