CN115108961A

CN115108961A - Indole-substituted cyclohexadienone hydrazone compound and synthesis method thereof

Info

Publication number: CN115108961A
Application number: CN202210551328.7A
Authority: CN
Inventors: 谭斌; 朱帅; 毛建辉
Original assignee: Southwest University of Science and Technology
Current assignee: Southwest University of Science and Technology
Priority date: 2022-05-18
Filing date: 2022-05-18
Publication date: 2022-09-27

Abstract

The invention belongs to the field of synthesis of axial chiral compounds, and discloses an indole-substituted cyclohexadienone hydrazone compound which has a structure shown in a general formula I or an enantiomer and a diastereomer shown in the general formula I:

wherein M is COOR ¹ Or CONHR ¹ ，R ¹ Selected from alkyl, benzyl, R ² Is alkyl, R ³ Selected from hydrogen, alkyl, alkoxy, halogen, cyano, hydroxyl, amino, phenyl, ester group, aldehyde group, trifluoromethyl, alkenyl, alkynyl, carboxyl, nitro and amido, n is 1-4, R is ⁴ Selected from alkyl groups. The invention also discloses a synthesis method of the compound. The invention can efficiently obtain an indole-substituted cyclohexadienone hydrazone compound with novel and various structures and good three-dimensional control through an asymmetric dearomatization strategy catalyzed by chiral phosphoric acid, not only enlarges an axial chiral compound library, but alsoLays a foundation for developing a new axial chiral framework.

Description

Indole-substituted cyclohexadienone hydrazone compound and synthesis method thereof

Technical Field

The invention belongs to the field of synthesis of axial chiral compounds, and particularly relates to an indole-substituted cyclohexadienone hydrazone compound and a synthesis method thereof.

Background

The non-planar arrangement of four substituents paired around the chiral axis produces a unique class of stereoisomers, namely axial chirality. Since axial chirality is widely existed in natural products, bioactive molecules, functional materials, especially chiral ligands and catalysts, research on axial chirality has become an important branch of modern chemistry, especially in the field of asymmetric catalysis, and in the last decades, isometric chiral compounds such as atropisomers, allenes, spiro molecules, etc. have been reported. Axial chiral backbones are generally characterized by the nature of the stereoaxis, and as the most representative class of axial chiral compounds, the chirality of biaryl atropisomers arises from a rotationally constrained C-C σ bond, whereas allenes can arise from the perpendicular arrangement of two pi-orbitals around a central carbon atom.

Nevertheless, most research has centered around the catalytic asymmetric synthesis and use of existing axial chiral compounds, particularly atropisomers and allene molecules, in contrast to the less exploratory new axial chiral backbones, which has hindered the overall progress in the field. Therefore, there is a need to construct structurally novel axial chiral backbones.

Disclosure of Invention

The inventors have designed a novel axial chiral backbone: one C ═ C double bond in the allene molecule is replaced by a planar cyclohexadiene molecule, with axis chirality preserved. In such a structure, the cyclohexadiene and exocyclic double bonds would be in the same plane, and axial chirality may be generated when the E/Z geometry of the terminal substituents of the double bond is fixed. Structurally, this new scaffold is similar to axially chiral alkylene cycloalkanes and cyclohexylidene oximes and is difficult to synthesize stereoselectively by catalysis, because it causes the C ═ C (or C ═ N) bond to break.

The inventors believe that there are two ways in which axial chirality can be introduced: a) by controlling the enantioselectivity during the formation of the cyclohexadiene subunit, or b) by controlling the E/Z geometry of the double bond. For the first method, which uses azo-substituted benzene as electrophile to perform catalytic asymmetric dearomatization, several conditions must be satisfied to achieve stereocontrol: 1) identifying a suitable catalytic system and compatible nucleophiles; 2) chemical site selectivity is favorable for remote para-position, because the nucleophilic reagent has a plurality of reaction sites; 3) the chiral catalyst and the substrate are effectively interacted to realize good three-dimensional control. For the second method, i.e. control of the E/Z geometry of the double bond, an enantioselective condensation reaction between cyclohexadienone and hydroxylamine is considered.

The invention aims to provide an indole-substituted cyclohexadienone hydrazone compound.

The invention also aims to provide a synthesis method of the cyclohexadienone hydrazone compound.

In order to achieve one of the purposes, the invention adopts the following technical scheme:

an indole-substituted cyclohexadienone hydrazone compound having the structure of formula i or an enantiomer, a diastereomer of formula i:

wherein M is COOR ¹ Or CONHR ¹ ，R ¹ Is selected from the group consisting of alkyl, benzyl,

R ² is an alkyl group, and is,

R ³ selected from hydrogen, alkyl, alkoxy, halogen, cyano, hydroxyl, amino, phenyl, ester group, aldehyde group, trifluoromethyl, alkenyl, alkynyl, carboxyl, nitro and amido, n is 1-4,

R ⁴ is an alkyl group.

Further, M is COOR ¹ Or CONHR ¹ ，R ¹ Selected from (C1-C6) alkyl and benzyl.

Further, M is COOR ¹ Or CONHR ¹ ，R ¹ Selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl and benzyl.

Further, M is selected from COOMe, COOEt, COO ⁱ Pr、COO ^t Bu、COOBn、CONH ⁿ Pr。

Further, said R ² Is (C1-C6) alkyl.

Further, said R ² Is methyl or ethyl.

Further, said R ³ Selected from hydrogen, alkyl, alkoxy, halogen, cyano, hydroxyl, amino.

Further, said R ³ Selected from hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, halogen, cyano, hydroxyl and amino.

Further, said R ³ Selected from hydrogen, methyl, methoxy, fluorine, chlorine, bromine, cyano, hydroxyl and amino.

Further, n is 1.

Further, said R ⁴ Is (C1-C6) alkyl.

Further, said R ⁴ Is methyl or ethyl.

Further, the cyclohexadienone hydrazone compound is selected from the following compounds or enantiomers and diastereomers thereof:

a method for synthesizing cyclohexadienone hydrazone compounds comprises the following steps: the chiral phosphoric acid is used as a catalyst, and the compound 1 and the compound 2 react as follows:

the chiral phosphoric acid is at least one of the following compounds or enantiomers thereof:

wherein R is selected from the group consisting of 3, 5-dimethyl-phenyl, 3, 5-diphenyl-phenyl, 4-phenyl, triphenylsilyl, 3,4, 5-trimethyl-phenyl, 1-naphthyl, 3, 5-bistrifluoromethyl-phenyl, 9-phenanthryl, phenyl, 2-naphthyl, 9-anthryl, 3, 5-ditertiary butyl-phenyl, 2,4, 6-trimethylphenyl, 2,4, 6-triisopropylphenyl, 4-trifluoromethyl-phenyl.

Further, the chiral phosphoric acid is at least one of the following compounds or enantiomers thereof:

wherein R is selected from the group consisting of 3, 5-dimethyl-phenyl, 3, 5-diphenyl-phenyl, 4-phenyl, triphenylsilyl, 3,4, 5-trimethyl-phenyl, 1-naphthyl, 3, 5-bistrifluoromethyl-phenyl, 9-phenanthryl.

further, the amount of the chiral phosphoric acid is at least 0.5 mol%.

Further, the molar ratio of compound 1 to compound 2 is 1: (1-4).

Further, the reaction uses dichloromethane, dichloroethane, ethyl acetate, toluene, acetonitrile, tetrahydrofuran or chloroform as a solvent.

Further, the reaction takes dichloromethane, ethyl acetate, toluene, acetonitrile or tetrahydrofuran as a solvent.

Further, the temperature of the reaction is 15 ℃ or higher.

Further, the reaction time is more than 5 h.

As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-methylpentyl.

As used herein, "alkoxy" refers to-O- (alkyl), wherein alkyl is defined as described herein, and non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-methylpentyloxy. Alkoxy groups typically have 1 to 6 carbon atoms connected by an oxygen bridge. Alkoxy also includes substituted alkoxy, which may be optionally substituted one or more times with halo.

As used herein, "alkenyl" refers to an unsaturated branched or straight chain alkyl group having at least one carbon-carbon double bond derived by the removal of one molecule of hydrogen from an adjacent carbon atom of the parent alkyl group. Alkenyl groups having 2 to 20 carbon atoms are preferred, and alkenyl groups having 2 to 6 carbon atoms are more preferred. The groups may be in either the cis or trans configuration with respect to one or more double bonds. Typical alkenyl groups include, but are not limited to, vinyl; propenyl, such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl; butenyl, such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl.

As used herein, "alkynyl" refers to an unsaturated, branched or straight chain alkyl group having at least one carbon-carbon triple bond derived by the removal of two molecules of hydrogen from adjacent carbon atoms of the parent alkyl group. Alkynyl groups having 2 to 20 carbon atoms are preferred, and alkynyl groups having 3 to 6 carbon atoms are more preferred. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl groups such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyl, e.g. but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl.

As used herein, "halogen" refers to fluorine, chlorine, bromine and iodine.

As used herein, "trifluoromethyl" refers to-CF ₃ 。

As used herein, "phenyl" refers to

"benzyl" as used herein refers to PhCH ₂ -。

As used herein, "amino" refers to-NH ₂ 。

As used herein, "cyano" refers to-CN.

As used herein, "ester group" refers to-C (O) O (alkyl), wherein alkyl is as defined herein, and said alkyl contains 1 to 20 carbon atoms.

As used herein, "hydroxy" refers to the group-OH.

As used herein, "aldehyde" refers to the group-CHO.

As used herein, "carboxy" refers to the group-COOH.

As used herein, "nitro" refers to-NO ₂ 。

As used herein, "amido" refers to the group-CONR ^b R ^c Wherein R is ^b Selected from hydrogen, alkyl, R ^c Selected from hydrogen, alkyl groups, as defined herein, said alkyl groups containing from 1 to 20 carbon atoms.

For substituents R on indole ³ When there are more than 2, the substituent R ³ May be the same or different.

The amount of the chiral phosphoric acid is based on the amount of the compound 1, and for example, the amount of the chiral phosphoric acid is written in the form of 0.5 mol%, which means that 0.005mol of the chiral phosphoric acid is used per 1mol of the compound 1.

The invention has the following beneficial effects:

the invention can efficiently obtain a compound skeleton, namely an indole-substituted cyclohexadienone hydrazone compound with novel and various structures and good three-dimensional control through a simple and direct synthesis strategy, namely an asymmetric dearomatization strategy catalyzed by chiral phosphoric acid, thereby not only expanding an axial chiral compound library, but also laying a foundation for developing a new axial chiral skeleton. The method takes indole as a nucleophilic reagent and performs dearomatization of an azobenzene compound catalyzed by chiral phosphoric acid to obtain an axial chiral product with a rotation hindered C-N bond, and has excellent chemoselectivity, site selectivity and stereoselectivity control.

The synthesis method is suitable for gram-scale reaction, and can keep excellent yield and enantioselectivity; the compound of the invention is easy to be converted into other axis chiral derivatives, and the chirality is not influenced.

Detailed Description

All solvents and reagents were purchased from commercial products and no further purification was required unless otherwise indicated. Thin Layer Chromatography (TLC) using 60GF254 silica gel plates; the silica gel column chromatography uses Qingdao marine silica gel (60, the particle size is 0.040-0.063 mm); TLC color development was performed using UV light (254,365 nm). NMR spectra were characterized using a Bruker DPX 400 nuclear magnetic resonance apparatus, ¹ the H NMR was 400MHz and the molecular weight of the polymer, ¹³ c NMR is 100MHz, solvent is DMSO-d ₆ 、CDCl ₃ Or DMF-d ₇ Tetramethylsilane (TMS) is used as an internal standard; chemical shifts are in ppm and coupling constants are in Hz. In that ¹ In HNMR, δ represents chemical shift, s represents singlet, d represents doublet, t represents triplet, q represents quartet, p represents quintet, m represents multiplet, br represents broad. The enantiomeric excess was determined by Agilent HPLC or Shimadzu HPLC using CHIRALPAK and CHIRALCEL chromatography columns.

Example 1

Synthesis of a substrate

Benzenediazotetrafluoroborate (15mmol) was added portionwise to SnCl in an ice-brine-water bath ₂ (8.53g,45mmol) in hydrochloric acid (6N, 80 mL). After stirring at room temperature for 8 hours, the reaction mixture was quenched with CH ₂ Cl ₂ Diluted (80mL), cooled to 0 ℃ and then basified with KOH (12M, 80 mL); separating the organic phase with CH ₂ Cl ₂ The aqueous phase was extracted (40mL) and the combined organic phases were combined with Na ₂ SO ₄ Dried, filtered through a pad of celite and concentrated under reduced pressure to give crude phenylhydrazine.

To phenylhydrazine or phenylhydrazine hydrochloride (15mmol) in CH at 0 deg.C ₂ Cl ₂ To a solution (40mL) were added pyridine (18 mmol for phenylhydrazinopyridine, 36mmol for phenylhydrazinopyridine hydrochloride) and chloroformate (15mmol) in that order. After stirring at 0 ℃ for 4 hours and at room temperature for a further 4 hours, the solution was cooled to 0 ℃ and PCC (3.23g, 15mmol) was added portionwise to the solution. The reaction was stirred at room temperature until starting materialThe material was completely consumed (detected by TLC). The reaction mixture was diluted, filtered through a pad of celite and dried under reduced pressure to give the crude product, and the residue was purified by silica gel column chromatography eluting with PE/EA (50/1 to 10/1) to give the corresponding product.

Starting from 3,4, 5-trimethoxybenzenediazotetrafluoroborate and methyl chloroformate, 1b was obtained in 85% yield.

¹ H NMR(400MHz,CDCl ₃ )δ7.29(s,2H),4.09(s,3H),3.97(s,3H),3.93(s,6H)。 ¹³ C NMR(100MHz,CDCl ₃ ) δ 162.14,153.46,147.25,143.51,101.85,61.15,56.29, 54.93. HRMS (ESI) accurate mass C ₁₁ H ₁₅ N ₂ O ₅ ⁺ ([M+H] ⁺ ) M/z 255.0975, found 255.0973.

Starting from 3,4, 5-trimethoxybenzenediazotetrafluoroborate and ethyl chloroformate, 1c was obtained in 51% yield.

¹ H NMR(400MHz,CDCl ₃ )δ7.29(s,2H),4.53(q,J＝7.1Hz,2H),3.97(s,3H),3.93(s,6H),1.48(t,J＝7.1Hz,3H)。 ¹³ C NMR(100MHz,CDCl ₃ ) δ 161.81,153.46,147.29,143.37,101.80,64.46,61.13,56.29, 14.21. HRMS (ESI) accurate mass C ₁₂ H ₁₇ N ₂ O ₅ ⁺ ([M+H] ⁺ ) M/z 269.1132, found 269.1130.

3,4, 5-trimethoxy benzene diazo tetrafluoroborate and isopropyl chloroformate are used as starting materials to obtain 1d with a yield of 45%.

¹ H NMR(400MHz,CDCl ₃ )δ7.28(s,2H),5.28(hept,J＝6.4Hz,1H),3.96(s,3H),3.92(s,6H),1.47(d,J＝6.3Hz,6H)。 ¹³ C NMR(100MHz,CDCl ₃ ) δ 161.56,153.46,147.33,143.22,101.75,72.77,61.12,56.29,21.75, 21.73. HRMS (ESI) accurate mass C ₁₃ H ₁₉ N ₂ O ₅ ⁺ ([M+H] ⁺ ) M/z 283.1288, found 283.1287.

With 3,4, 5-trimethoxy benzenediazotetrafluoroborate and (Boc) ₂ O as starting material gave 1e in 40% yield.

¹ H NMR(400MHz,CDCl ₃ )δ7.25(s,2H),3.95(s,3H),3.92(s,6H),1.67(s,9H)。 ¹³ C NMR(100MHz,CDCl ₃ ) δ 161.00,153.43,147.27,142.82,101.51,84.83,61.08,56.26, 27.85. HRMS (ESI) accurate mass C ₁₄ H ₂₁ N ₂ O ₅ ⁺ ([M+H] ⁺ ) M/z 297.1445, found 297.1444.

Starting from 3,4, 5-trimethoxybenzenediazotetrafluoroborate and benzyl chloroformate, 1f was obtained in 45% yield.

¹ H NMR(400MHz,CDCl ₃ )δ7.57–7.43(m,2H),7.43–7.31(m,3H),7.28(s,2H),5.47(s,2H),3.96(s,3H),3.90(s,6H)。 ¹³ C NMR(100MHz,CDCl ₃ ) δ 161.74,153.44,147.31,143.47,134.55,128.87,128.78,128.73,101.86,69.87,61.10, 56.26. HRMS (ESI) accurate mass C ₁₇ H ₁₉ N ₂ O ₅ ⁺ ([M+H] ⁺ ) M/z 331.1288, found 331.1291.

Propylamine was added to a solution of 1f (0.536g,2mmol) in EtOH (10mL), the mixture was warmed to 80 ℃ and stirred for 1 hour, then the mixture was evaporated to dryness and purified by silica gel column chromatography eluting with PE/EA to give 1g, 92% yield.

¹ H NMR(400MHz,CDCl ₃ )δ7.31(s,2H),3.98(s,3H),3.94(s,6H),3.54–3.42(m,2H),1.80–1.67(m,2H),1.04(t,J＝7.4Hz,3H)。 ¹³ C NMR(100MHz,CDCl ₃ ) δ 160.54,153.49,146.65,142.98,101.85,61.10,56.29,42.41,22.80, 11.35. HRMS (ESI) accurate mass C ₁₃ H ₂₀ N ₃ O ₄ ⁺ ([M+H] ⁺ ) m/z 282.1448, found 282.1447.

Starting with 3,4, 5-triethoxybenzenediazonium tetrafluoroborate and ethyl chloroformate, 1h was obtained with a yield of 71%.

¹ H NMR(400MHz,CDCl ₃ )δ7.25(s,2H),4.51(q,J＝7.2Hz,2H),4.19(q,J＝7.0Hz,2H),4.13(q,J＝7.0Hz,4H),1.46(td,J＝7.1,5.8Hz,9H),1.38(t,J＝7.0Hz,3H)。 ¹³ C NMR(101MHz,CDCl ₃ ) δ 161.91,153.12,147.20,143.26,102.81,69.25,64.71,64.32,15.63,14.73, 14.18. HRMS (ESI) accurate mass C ₁₅ H ₂₂ N ₂ O ₅ ⁺ ([M+H] ⁺ ) M/z 311.1601, found 311.1598.

Example 2

Axial chiral products 3b can be obtained by using 3,4, 5-trimethoxy-substituted azobenzene 1b and 2-methylindole 2a as starting materials and using chiral phosphoric acid with different axial chiral skeletons as a catalyst, wherein the enantioselectivity of the SPINOL skeleton chiral phosphoric acid is superior to that of BINOL skeleton chiral phosphoric acid, and particularly, the best result (96 percent yield,>99% ee); screening of the solvent, CH ₂ Cl ₂ Is the best solvent; catalyst dosage is reducedAs low as 0.5 mol%, good yields and enantiomeric control are also maintained.

Reaction conditions are as follows: 1b (0.10mmol), 2a (0.12mmol) and chiral phosphoric acid catalyst (2 mol%) were reacted in a solvent (1.0mL) at room temperature. a: 0.5 mol% of catalyst was used.

¹ H NMR(500MHz,DMSO-d ₆ )δ10.83(s,1H),10.49(s,1H),7.35(s,1H),7.19(d,J＝8.0Hz,1H),6.92(t,J＝7.5Hz,1H),6.80(t,J＝7.5Hz,1H),6.49(s,1H),5.79(s,1H),3.71(s,3H),3.60(s,3H),3.55(s,3H),3.04(s,3H),2.37(s,3H)。

¹³ C NMR(125MHz,DMSO-d ₆ )δ163.24,158.62,155.05,144.64,134.99,134.09,127.25,120.05,119.54,118.69,110.67,108.54,101.09,91.79,78.80,56.42,55.68,52.22,50.47,13.97。

HRMS (ESI) accurate mass C ₂₀ H ₂₄ N ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 386.1710, found 386.1699.

HPLC analysis HPLC DAICEL CHIRALCEL AD-3, n-hexane/isopropanol 80/20,1.0mL/min, λ 254nm, t _R (major)＝12.5min,t _R (minor)＝16.4min,ee＝>99.5％。

The absolute configuration of Compound 3b was determined by X-ray diffraction analysis and the relevant data was obtained at Cambridge crystallography data center (http:// www.ccdc.cam.ac.uk/data _ request/cif) under accession number CCDC 2027074, and the detailed information is shown in the following table:

after the optimal reaction conditions are obtained, 3-27 is carried out to expand the substrate, azobenzene with different ester groups obtains the required products (3c, 3d and 3f) with 99% ee, the tertiary butyl ester (3e) with larger space causes slight reduction of the ee value, and if the product is an amide group (3g) with weaker electron-withdrawing ability, the yield is reduced. The 2-methylindole substituents (3 h-3 q) have limited effect on the reaction, the electron donating groups favor the yield (3h,3i), the electron withdrawing groups cause yield reduction (3l), the indole with hydroxyl and amine is converted into the product with good yield and has excellent antipodal control (3m, 3n and 3q), the halogen substituents also have good tolerance, and the subsequent functional group conversion (3j, 3k, 3o and 3p) is facilitated. Good reaction results were maintained when the methoxy group was replaced with ethoxy (3 s-3 u) substitution. The successful synthesis of the axial chiral compounds 3 v-3 aa shows that the method has a large space in the aspect of expanding the types of the compounds.

Indole 2(0.24mmol,1.2equiv) was added to the azobenzene 1(0.20mmol,1.0equiv) and (S) -C10(0.5 mol%) CH at room temperature ₂ Cl ₂ (2.0mL), the reaction was stopped when 1 disappeared (TLC monitoring) and product 3 crystallized from the reaction mixture. The reaction suspension was directly applied to silica gel column chromatography and eluted with CH in 30 minutes ₂ Cl ₂ EA (8/1 to 1/2) gave pure product 3 as a white solid.

Synthesis of racemic Compound 3

Indole 2(0.12mmol) was added to azobenzene 1(0.10mmol) and (rac) -C10(2 mol%) in CH at room temperature ₂ Cl ₂ (1.0mL), after completion of the reaction (1 disappeared, TLC monitor), PE (1.0mL) was added to the reaction suspension, and the pure white product, PE/CH, was collected directly by filtration ₂ Cl ₂ (1/1, 2mL) was washed.

Example 3

3c (24h) was obtained in 92% yield, 99% ee.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.80(s,1H),10.43(s,1H),7.33(s,1H),7.17(d,J＝8.0Hz,1H),6.91(t,J＝7.5Hz,1H),6.79(t,J＝7.5Hz,1H),6.48(s,1H),5.77(s,1H),4.16(q,J＝7.0Hz,2H),3.59(s,3H),3.53(s,3H),3.03(s,3H),2.36(s,3H),1.25(t,J＝7.0Hz,3H)。

¹³ C NMR(100MHz,DMSO-d ₆ )δ163.16,158.56,154.59,144.41,135.01,134.09,127.28,120.04,119.55,118.69,110.67,108.58,101.15,91.87,78.81,60.79,56.44,55.68,50.45,15.16,13.97。

HRMS (ESI) accurate mass C ₂₁ H ₂₆ N ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 400.1867, found 400.1865.

HPLC DAICEL CHIRALCEL ID, 65/35 (n-hexane/isopropanol), 1.0mL/min, 254nm lambda, t _R (major)＝6.7min,t _R (minor)＝10.2min,ee＝99％。

Example 4

3d (24h) was obtained in 96% yield, 99% ee.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.82(s,1H),10.40(s,1H),7.34(s,1H),7.17(d,J＝8.0Hz,1H),6.91(t,J＝7.5Hz,1H),6.79(t,J＝7.5Hz,1H),6.48(s,1H),5.76(s,1H),4.94(hept,J＝6.3Hz,1H),3.59(s,3H),3.53(s,3H),3.02(s,3H),2.35(s,3H),1.26(d,J＝6.3Hz,6H)。

¹³ C NMR(100MHz,DMSO-d ₆ )δ163.03,158.44,154.13,144.24,134.99,134.09,127.26,120.03,119.52,118.68,110.66,108.58,101.18,91.93,78.79,68.08,56.45,55.68,50.42,22.53,13.97。

HRMS (ESI) accurate mass C ₂₂ H ₂₈ N ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 414.2023, found 414.2011.

HPLC DAICEL CHIRALCEL ID, 80/20 (n-hexane/isopropanol), 0.8mL/min (λ 273 nm), t _R (major)＝18.1min,t _R (minor)＝37.4min,ee＝99％。

Example 5

3e was obtained in 89% yield, 97% ee (24h) using 2 mol% of (S) -C10.

¹ H NMR(400MHz,DMF-d ₇ )δ10.86(s,1H),10.35(s,1H),7.48(s,1H),7.23(d,J＝8.2Hz,1H),6.94(t,J＝7.4Hz,1H),6.84(t,J＝7.5Hz,1H),6.70(s,1H),5.88(s,1H),3.68(s,3H),3.61(s,3H),3.14(s,3H),2.47(s,3H),1.50(s,9H)。

¹³ C NMR(100MHz,DMF-d ₇ )δ163.30,158.49,153.62,143.77,135.42,134.13,127.62,119.89,119.59,118.46,110.44,108.94,101.29,91.63,79.31,79.17,55.90,55.16,49.98,28.00,13.41。

HRMS (ESI) accurate mass C ₂₃ H ₃₀ N ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 428.2180, found 428.2164.

HPLC analysis is HPLC DAICEL CHIRALCEL AD-3, n-hexane/isopropanol 90/10,0.8mL/min, lambda 270nm, t _R (major)＝42.5min,t _R (minor)＝52.1min,ee＝97％。

Example 6

3f (12h) was obtained in 96% yield, 99% ee.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.82(s,1H),10.58(s,1H),7.54–7.22(m,6H),7.17(d,J＝8.0Hz,1H),6.91(t,J＝7.5Hz,1H),6.79(t,J＝7.6Hz,1H),6.48(d,J＝1.7Hz,1H),5.78(s,1H),5.19(s,2H),3.58(s,3H),3.53(s,3H),3.03(s,3H),2.36(s,3H)。

¹³ C NMR(100MHz,DMSO-d ₆ )δ163.30,158.70,154.45,144.82,137.22,135.00,134.10,128.94,128.73,128.56,127.26,120.06,119.56,118.71,110.68,108.54,101.11,91.87,78.80,66.38,56.45,55.71,50.47,13.99。

HRMS (ESI) accurate mass C ₂₆ H ₂₈ N ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 462.2023, found 462.2008.

HPLC analysis is HPLC DAICEL CHIRALCEL AD-3, n-hexane/isopropanol 80/20,0.7mL/min, lambda 254nm, t _R (major)＝22.6min,t _R (minor)＝34.9min,ee＝99％。

Example 7

3g (36h) was obtained in 66% yield, 92% ee.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.82(s,1H),9.89(s,1H),7.34(s,1H),7.18(d,J＝8.0Hz,1H),6.98–6.84(m,2H),6.80(t,J＝7.5Hz,1H),6.51(s,1H),5.79(s,1H),3.59(s,3H),3.53(s,3H),3.12(q,J＝6.8Hz,2H),3.04(s,3H),2.37(s,3H),1.60–1.37(m,2H),0.88(t,J＝7.4Hz,3H)。

¹³ C NMR(100MHz,DMSO-d ₆ )δ162.59,157.78,156.63,140.21,134.99,134.02,127.29,120.01,119.53,118.64,110.65,108.71,101.25,91.93,78.92,56.41,55.55,50.39,41.24,23.74,13.99,11.82。

HRMS (ESI) accurate mass C ₂₂ H ₂₉ N ₄ O ₄ ⁺ ([M+H] ⁺ ) M/z 413.2183, found 413.2191.

HPLC analysis is HPLC DAICEL CHIRALCEL AD-3, n-hexane/isopropanol 75/25,0.7mL/min, lambda 254nm, t _R (minor)＝13.7min,t _R (major)＝22.6min,ee＝92％。

Example 8

3h (5h) was obtained in 96% yield, 97% ee.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.68(s,1H),10.51(s,1H),7.07(d,J＝8.7Hz,1H),6.84(s,1H),6.59(dd,J＝8.7,2.5Hz,1H),6.50(s,1H),5.80(s,1H),3.71(s,3H),3.62(s,6H),3.56(s,3H),3.04(s,3H),2.35(s,3H)。

¹³ C NMR(100MHz,DMSO-d ₆ )δ163.26,158.66,155.04,153.03,144.64,135.03,130.20,127.52,111.05,109.16,108.21,102.33,101.04,91.82,78.76,56.45,55.72,55.54,52.22,50.53,14.16。

HRMS (ESI) accurate mass C ₂₁ H ₂₆ N ₃ O ₆ ⁺ ([M+H] ⁺ ) M/z 416.1816, found 416.1803.

HPLC analysis is HPLC DAICEL CHIRALCEL AD-3, n-hexane/isopropanol 80/20,0.7mL/min, lambda 254nm, t _R (major)＝19.5min,t _R (minor)＝25.1min,ee＝97％。

Example 9

3i (16h) was obtained in 95% yield, 98% ee.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.68(s,1H),10.49(s,1H),7.19(s,1H),7.06(d,J＝8.1Hz,1H),6.74(d,J＝7.8Hz,1H),6.46(s,1H),5.78(s,1H),3.70(s,3H),3.59(s,3H),3.53(s,3H),3.02(s,3H),2.30(s,3H),2.25(s,3H)。

¹³ C NMR(100MHz,DMSO-d ₆ )δ163.27,158.64,155.07,144.72,133.93,133.32,127.66,126.72,121.53,119.59,110.34,108.13,101.06,91.74,78.84,56.40,55.66,52.22,50.43,22.09,13.89。

HRMS (ESI) accurate mass C ₂₁ H ₂₆ N ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 400.1867, found 400.1856.

HPLC analysis is HPLC DAICEL CHIRALCEL AD-3, n-hexane/isopropanol 80/20,0.7mL/min, lambda 273nm, t _R (major)＝16.2min,t _R (minor)＝21.5min,ee＝98％。

Example 10

3j (24h) was obtained in 86% yield, 98% ee.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.12(s,1H),10.54(s,1H),7.64(s,1H),7.16(d,J＝8.5Hz,1H),7.04(dd,J＝8.5,2.0Hz,1H),6.50(s,1H),5.80(s,1H),3.70(s,3H),3.61(s,3H),3.56(s,3H),3.04(s,3H),2.25(s,3H)。

¹³ C NMR(100MHz,DMSO-d ₆ )δ162.68,158.06,155.00,144.23,134.97,133.62,129.49,122.67,122.50,112.63,111.44,108.80,101.29,91.90,78.65,56.53,55.79,52.26,50.50,13.46。

HRMS (ESI) accurate mass C ₂₀ H ₂₃ BrN ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 464.0816, found 464.0805.

HPLC analysis is HPLC DAICEL CHIRALCEL AD-3, n-hexane/isopropanol 80/20,0.8mL/min, lambda 254nm, t _R (major)＝19.3min,t _R (minor)＝31.9min,ee＝98％。

Example 11

3k (32h) was obtained in 90% yield, 99% ee.

¹ H NMR(500MHz,DMSO-d ₆ )δ11.00(s,1H),10.44(s,1H),7.40(s,1H),7.12(d,J＝8.6Hz,1H),6.86(d,J＝8.6Hz,1H),6.42(s,1H),5.73(s,1H),3.63(s,3H),3.54(s,3H),3.48(s,3H),2.97(s,3H),2.20(s,3H)。

¹³ C NMR(126MHz,DMSO-d ₆ )δ162.92,158.29,155.23,144.54,135.40,133.41,128.69,123.37,120.02,119.44,112.16,108.80,101.12,91.80,78.63,56.48,55.73,52.32,50.47,13.46。

HRMS (ESI) accurate mass C ₂₀ H ₂₃ ClN ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 420.1321, found 420.1316.

HPLC analysis is carried out with DAICEL CHIRALPAK AZ-3, 80/20 n-hexane/isopropanol, 0.8mL/min flow rate, 254nm lambda, t _R (major)＝9.5min,t _R (minor)＝12.6min,ee＝99％。

Example 12

3l (72h) were obtained in 66% yield with 95% ee.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.54(s,1H),10.57(s,1H),7.95(s,1H),7.37(d,J＝8.4Hz,1H),7.31(dd,J＝8.3,1.7Hz,1H),6.53(s,1H),5.84(s,1H),3.71(s,3H),3.63(s,3H),3.57(s,3H),3.07(s,3H),2.27(s,3H)。

¹³ C NMR(100MHz,DMSO-d ₆ )δ162.38,157.84,155.03,144.19,136.83,135.69,127.59,126.17,123.05,121.64,112.09,110.15,101.40,100.78,92.09,78.56,56.59,55.86,52.28,50.54,13.22。

HRMS (ESI) accurate mass C ₂₁ H ₂₃ N ₄ O ₅ ⁺ ([M+H] ⁺ ) M/z 411.1663, found 411.1652.

HPLC analysis is HPLC DAICEL CHIRALCEL AD-3, n-hexane/isopropanol 80/20,0.9mL/min, lambda 254nm, t _R (major)＝15.1min,t _R (minor)＝24.2min,ee＝95％。

Example 13

3m (8h) was obtained in 81% yield, 99% ee.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.43(s,1H),10.41(s,1H),8.35(s,1H),6.89(d,J＝8.5Hz,1H),6.66(s,1H),6.40–6.36(m,2H),5.72(s,1H),3.65(s,3H),3.55(s,3H),3.49(s,3H),2.96(s,3H),2.26(s,3H)。

¹³ C NMR(126MHz,DMSO-d ₆ )δ163.3,158.6,154.9,150.3,144.7,134.3,129.5,110.7,110.1,107.7,104.4,101.1,98.9,91.7,78.8,56.4,55.6,52.2,50.4,14.2。

HRMS (ESI) accurate mass C ₂₀ H ₂₄ N ₃ O ₆ ⁺ ([M+H] ⁺ ) M/z 402.1660, found 402.1657.

HPLC analysis is carried out at DAICEL CHIRALPAK AD-3, 80/20 of n-hexane/isopropanol, 0.8mL/min of flow rate, 254nm of lambda, t _R (major)＝21.7min,t _R (minor)＝18.5min,ee＝99％。

Example 14

The reaction temperature was 0 ℃ and 3n (16h) was obtained in 73% yield and 98% ee.

¹ H NMR(500MHz,DMSO-d ₆ )δ10.35(s,1H),10.26(s,1H),6.79(d,J＝8.4Hz,1H),6.52(s,1H),6.34(s,1H),6.26(d,J＝8.3Hz,1H),5.68(s,1H),4.23(s,2H),3.62(s,3H),3.53(s,3H),3.47(s,3H),2.92(s,3H),2.20(s,3H)。

¹³ C NMR(126MHz,DMSO-d ₆ )δ163.42,158.70,155.09,144.98,140.50,134.00,128.86,128.23,110.71,110.57,107.27,104.04,101.04,91.63,78.85,56.33,55.56,52.20,50.37,14.13。

HRMS (ESI) accurate mass C ₂₀ H ₂₅ N ₄ O ₅ ⁺ ([M+H] ⁺ ) M/z 401.1819, found 401.1817.

HPLC analysis is carried out by DAICEL CHIRALPAK AZ-3, 80/20 of n-hexane/isopropanol, 0.8mL/min of flow rate, 254nm of lambda and t _R (major)＝33.7min,t _R (minor)＝49.7min,ee＝98％。

Example 15

3o (32h) was obtained in 84% yield, 99% ee.

¹ H NMR(500MHz,DMSO-d ₆ )δ10.97(s,1H),10.42(s,1H),7.28–7.28(m,2H),6.88(d,J＝8.2Hz,1H),6.41(s,1H),5.72(s,1H),3.63(s,3H),3.52(s,3H),3.47(s,3H),2.95(s,3H),2.23(s,3H)。

¹³ C NMR(126MHz,DMSO-d ₆ )δ162.84,158.24,155.16,144.48,135.89,134.81,126.58,121.78,121.52,113.17,112.83,109.16,101.23,91.89,78.61,56.49,55.74,52.25,50.48,13.67。

HRMS (ESI) accurate mass C ₂₀ H ₂₃ BrN ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 464.0816, found 464.0815.

HPLC analysis is carried out by DAICEL CHIRALPAK AZ-3, 80/20 of n-hexane/isopropanol, 0.8mL/min of flow rate, 254nm of lambda and t _R (major)＝11.5min,t _R (minor)＝23.7min,ee＝99％。

Example 16

3p (29h) was obtained in 87% yield and 99% ee.

¹ H NMR(500MHz,DMSO-d ₆ )δ10.83(s,1H),10.41(s,1H),7.29(s,1H),6.87(d,J＝9.6Hz,1H),6.61(t,J＝10.0Hz,1H),6.40(s,1H),5.70(s,1H),3.61(s,3H),3.52(s,3H),3.45(s,3H),2.94(s,3H),2.22(s,3H)。

¹³ C NMR(126MHz,DMSO-d ₆ )δ163.03,158.43,158.37(d,J＝231Hz),154.88,144.61,134.81(d,J＝11.3Hz),134.18,124.25,120.79,108.87,106.88(d,J＝23.8Hz),101.15,96.66(d,J＝25.0Hz),91.84,78.69,56.45,55.70,52.22,50.47,13.68。

¹⁹ F NMR(376MHz,DMSO-d ₆ )δ-123.8。

HRMS (ESI) accurate mass C ₂₀ H ₂₃ FN ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 404.1616, found 404.1615.

HPLC analysis is carried out at DAICEL CHIRALPAK AD-3, 80/20 of n-hexane/isopropanol, 0.8mL/min of flow rate, 254nm of lambda, t _R (major)＝14.6min,t _R (minor)＝21.0min,ee＝99％。

Example 17

3q (8h) was obtained in 80% yield, 97% ee.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.35(s,1H),10.31(s,1H),8.63(s,1H),7.02(s,1H),6.47(s,1H),6.35(s,1H),6.25(d,J＝8.7Hz,1H),5.66(s,1H),3.61(s,3H),3.51(s,3H),3.45(s,3H),2.92(s,3H),2.19(s,3H)。

¹³ C NMR(101MHz,DMSO-d ₆ )δ163.46,158.83,155.10,152.30,144.64,136.03,131.60,120.74,119.93,108.91,108.22,100.89,96.04,91.61,78.81,56.37,55.63,52.21,50.45,13.79。

HPLC analysis is carried out by DAICEL CHIRALPAK AZ-3, 80/20 of n-hexane/isopropanol, 0.8mL/min of flow rate, 254nm of lambda and t _R (major)＝31.6min,t _R (minor)＝27.2min,ee＝97％。

Example 18

3r (12h) was obtained in 95% yield, 99% ee.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.76(s,1H),10.43(s,1H),7.30(s,1H),7.15(d,J＝8.0Hz,1H),6.88(t,J＝7.5Hz,1H),6.75(t,J＝7.6Hz,1H),6.43(s,1H),5.74(s,1H),3.66(s,3H),3.55(s,3H),3.49(s,3H),2.99(s,3H),2.78(s,2H),1.12(t,J＝7.5Hz,3H)。

¹³ C NMR(101MHz,DMSO-d ₆ )δ163.29,158.70,155.69,144.38,138.74,135.30,129.23,126.82,120.11,118.60,110.78,107.73,100.99,91.71,78.94,56.40,55.66,52.22,50.39,20.84,15.02。

HRMS (ESI) accurate mass C ₂₁ H ₂₆ N ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 400.1867, found 400.1866.

HPLC analysis is carried out by DAICEL CHIRALPAK AZ-3, 80/20 of n-hexane/isopropanol, 0.8mL/min of flow rate, 254nm of lambda and t _R (major)＝10.0min,t _R (minor)＝14.7min,ee＝99％。

Example 19

3s (12h) was obtained in 93% yield, 99% ee.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.76(s,1H),10.31(s,1H),7.39(d,J＝7.6Hz,1H),7.14(d,J＝8.0Hz,1H),6.87(t,J＝7.5Hz,1H),6.76(t,J＝7.6Hz,1H),6.36(s,1H),5.65(s,1H),4.12(q,J＝7.1Hz,2H),3.93–3.74(m,4H),3.24–3.15(m,2H),2.39(s,3H),1.22(t,J＝7.0Hz,3H),1.15–1.06(m,9H)。

¹³ C NMR(101MHz,DMSO-d ₆ )δ163.18,158.54,154.57,144.76,134.91,134.41,127.25,119.91,119.75,118.48,110.54,108.92,100.85,91.47,78.08,64.32,63.55,60.70,58.02,15.83,15.15,14.67,14.53,14.16。

HRMS (ESI) accurate mass C ₂₄ H ₃₂ N ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 442.2336, found 442.2335.

HPLC analysis is carried out by DAICEL CHIRALPAK AZ-3, 80/20 of n-hexane/isopropanol, 0.8mL/min of flow rate, 254nm of lambda and t _R (major)＝8.9min,t _R (minor)＝17.4min,ee＝99％。

Example 20

3t (36h) was obtained in 89% yield, 97% ee.

¹ H NMR(500MHz,DMSO-d ₆ )δ11.00(s,1H),10.36(s,1H),7.42(s,1H),7.34(s,1H),6.95(d,J＝8.6Hz,1H),6.39(s,1H),5.69(s,1H),4.15(q,J＝7.1Hz,2H),3.97–3.81(m,4H),3.28–3.16(m,2H),2.37(s,3H),1.25(t,J＝7.1Hz,3H),1.18–1.09(m,9H)。

¹³ C NMR(126MHz,DMSO-d ₆ )δ162.73,158.10,154.46,144.67,135.83,135.22,126.45,122.16,121.31,113.05,112.69,109.53,101.02,91.59,77.88,64.39,63.62,60.73,58.07,15.81,15.16,14.68,14.54,13.91。

HRMS (ESI) accurate mass C ₂₄ H ₃₁ BrN ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 520.1442, found 520.1443.

HPLC analysis is carried out by DAICEL CHIRALPAK AZ-3, 80/20 of n-hexane/isopropanol, 0.8mL/min of flow rate, 254nm of lambda and t _R (major)＝8.7min,t _R (minor)＝30.0min,ee＝97％。

Example 21

3u (12h) was obtained in 92% yield, 98% ee.

¹ H NMR(500MHz,CDCl ₃ )δ9.06(s,1H),7.97(s,1H),7.54(s,1H),7.16(d,J＝8.1Hz,1H),7.00(t,J＝7.6Hz,1H),6.90(t,J＝7.7Hz,1H),5.85(s,2H),4.31–4.30(m,2H),3.92–3.77(m,4H),3.32(dt,J＝41.4,7.7Hz,2H),2.99(s,2H),1.34–1.14(m,15H)。

¹³ C NMR(126MHz,CDCl ₃ )δ165.24,159.18,155.67,146.49,139.67,134.68,126.96,120.44,119.00,109.94,108.37,100.77,88.60,78.52,64.21,63.73,62.16,58.48,21.13,15.44,14.70,14.18,14.15,14.09。

HRMS (ESI) accurate mass C ₂₅ H ₃₄ N ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 456.2493, found 456.2491.

HPLC analysis is carried out by DAICEL CHIRALPAK AZ-3, 80/20 of n-hexane/isopropanol, 0.8mL/min of flow rate, 254nm of lambda and t _R (major)＝7.8min,t _R (minor)＝12.8min,ee＝98％。

Example 22

3v (30h) was obtained in 89% yield, 98% ee.

¹ H NMR(500MHz,DMSO-d ₆ )δ11.02(s,1H),10.43(s,1H),7.42(s,1H),7.14(d,J＝8.5Hz,1H),6.88(dd,J＝8.5,2.2Hz,1H),6.45(s,1H),5.75(s,1H),4.11(q,J＝7.1Hz,2H),3.56(s,3H),3.50(s,3H),2.99(s,3H),2.21(s,3H),1.20(t,J＝7.1Hz,3H)。

¹³ C NMR(126MHz,DMSO-d ₆ )δ162.64,158.05,154.45,144.18,135.52,133.43,128.84,123.29,119.94,118.90,112.10,108.90,101.32,91.98,78.66,60.83,56.53,55.76,50.46,15.14,13.53。

HRMS (ESI) accurate mass C ₂₁ H ₂₅ N ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 434.1477, found 434.1476.

HPLC analysis is carried out by DAICEL CHIRALPAK AZ-3, 80/20 of n-hexane/isopropanol, 0.8mL/min of flow rate, 254nm of lambda and t _R (major)＝10.3min,t _R (minor)＝13.2min,ee＝98％。

Example 23

3w (36h) was obtained in 87% yield, 99% ee.

¹ H NMR(500MHz,DMSO-d ₆ )δ11.02(s,1H),10.46(s,1H),7.35–7.35(m,2H),6.96(dd,J＝8.6,1.9Hz,1H),6.49(s,1H),5.79(s,1H),4.17(q,J＝7.1Hz,2H),3.60(s,3H),3.55(s,3H),3.03(s,3H),2.31(s,3H),1.26(t,J＝7.1Hz,3H)。

¹³ C NMR(126MHz,DMSO-d ₆ )δ162.72,158.14,154.40,144.30,135.89,134.88,126.50,121.97,121.51,113.15,112.82,109.20,101.29,91.96,78.61,60.81,56.50,55.74,50.46,15.16,13.67。

HRMS (ESI) accurate mass C ₂₁ H ₂₅ BrN ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 478.0972, found 478.0973.

HPLC analysis is carried out by DAICEL CHIRALPAK AZ-3, 80/20 of n-hexane/isopropanol, 0.8mL/min of flow rate, 254nm of lambda and t _R (major)＝12.6min,t _R (minor)＝40.4min,ee＝99％。

Example 24

3X (16h) was obtained in 95% yield, 99% ee.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.57(s,1H),10.41(s,1H),7.16(s,1H),6.92(s,1H),6.58(d,J＝8.3Hz,1H),6.41(s,1H),5.72(s,1H),3.65(s,3H),3.54(s,3H),3.48(s,3H),2.97(s,3H),2.28-2.26(m,6H)。

¹³ C NMR(101MHz,DMSO-d ₆ )δ163.35,158.72,155.12,144.51,135.40,133.23,128.90,125.19,120.35,119.22,110.52,108.37,101.00,91.69,78.80,56.38,55.64,52.21,50.46,21.65,13.91。

HRMS (ESI) accurate mass C ₂₁ H ₂₆ N ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 400.1867, found 400.1864.

HPLC analysis is carried out by DAICEL CHIRALPAK AZ-3, 80/20 of n-hexane/isopropanol, 0.8mL/min of flow rate, 254nm of lambda and t _R (major)＝13.7min,t _R (minor)＝28.5min,ee＝99％。

Example 25

3y (16h) was obtained in 96% yield, 99% ee.

¹ H NMR(500MHz,DMSO-d ₆ )δ10.56(s,1H),10.37(s,1H),7.14(s,1H),6.89(s,1H),6.56(dd,J＝8.4,1.6Hz,1H),6.39(s,1H),5.69(s,1H),4.10(q,J＝7.1Hz,2H),3.52(s,3H),3.46(s,3H),2.95(s,3H),2.26(s,3H),2.24(s,3H),1.19(t,J＝7.1Hz,3H)。

¹³ C NMR(126MHz,DMSO-d ₆ )δ163.25,158.63,154.67,144.56,135.39,133.36,128.90,125.19,120.35,119.29,110.52,108.38,101.04,91.75,78.79,60.79,56.40,55.64,50.45,21.66,15.16,13.91。

HRMS (ESI) accurate mass C ₂₂ H ₂₈ N ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 414.2023, found 414.2021.

HPLC analysis is carried out by DAICEL CHIRALPAK AZ-3, 80/20 of n-hexane/isopropanol, 0.8mL/min of flow rate, 254nm of lambda and t _R (major)＝15.0min,t _R (minor)＝53.4min,ee＝99％。

Example 26

3y (20h) was obtained in 92% yield, 99% ee.

¹ H NMR(500MHz,DMSO-d ₆ )δ10.60(s,1H),10.35(s,1H),7.18(s,1H),6.93(s,1H),6.59(d,J＝8.2Hz,1H),6.43(s,1H),5.72(s,1H),4.94–4.89(m,1H),3.56(s,3H),3.50(s,3H),2.99(s,3H),2.30–2.28(m,6H),1.24–1.23(m,6H)。

¹³ C NMR(126MHz,DMSO-d ₆ )δ163.12,158.52,154.05,144.31,135.39,133.13,128.88,125.24,120.33,119.62,110.51,108.41,101.09,91.83,78.79,68.07,56.42,55.64,50.42,22.53,21.67,13.92。

HRMS (ESI) accurate mass C ₂₃ H ₃₀ N ₃ O ₅ ⁺ ([M+H] ⁺ ) M/z 428.2180, found 428.2179.

HPLC analysis is carried out at DAICEL CHIRALPAK AS-3, 80/20 for n-hexane/isopropanol, 0.8mL/min for flow rate and 25 for lambda4nm,t _R (major)＝10.5min,t _R (minor)＝34.0min,ee＝99％。

Example 27

3aa (39h) was obtained in 72% yield, 93% ee.

¹ H NMR(500MHz,DMSO-d ₆ )δ10.63(s,1H),9.88(s,1H),7.22(s,1H),6.97(s,1H),6.87(t,J＝6.1Hz,1H),6.63(dd,J＝8.3,1.5Hz,1H),6.49(s,1H),5.78(d,J＝1.4Hz,1H),3.59(s,3H),3.53(s,3H),3.13(dt,J＝9.5,7.0Hz,2H),3.03(s,3H),2.34–2.32(m,6H),1.54–1.46(m,2H),0.88(t,J＝7.4Hz,3H)。

¹³ C NMR(126MHz,DMSO-d ₆ )δ162.70,157.87,156.66,140.29,135.40,133.05,128.86,125.25,120.31,119.34,110.51,108.55,101.17,91.84,78.92,56.38,55.52,50.39,41.24,23.74,21.67,13.94,11.82。

HRMS (ESI) accurate mass C ₂₃ H ₃₁ N ₄ O ₅ ⁺ ([M+H] ⁺ ) M/z 427.2295, found 427.2337.

HPLC analysis is carried out by DAICEL CHIRALPAK AZ-3, 80/20 of n-hexane/isopropanol, 0.8mL/min of flow rate, 254nm of lambda and t _R (major)＝19.4min,t _R (minor)＝15.5min,ee＝93％。

Example 28

Amplification test

Compound 3b was synthesized on a gram scale by simple filtration (product in CH) ₂ Cl ₂ Poor solubility) to give the product in 99% yield with an ee of 99.6%.

2a (0.629g,4.8mmol,1.2equiv.) was added to 1b (1.016g,4.0mmol), (S) -C10(15.9mg,0.5 mol%) of CH at room temperature ₂ Cl ₂ (40mL) in solution. After 11 hours the reaction of 1b was complete,the product crystallized out of the reaction mixture. To the reaction suspension was added 40mL of PE, and the white product was collected by filtration.

Example 29

Kinetic racemization experiment

By calculation, K racemization is 1.989833x10 ^-6 S ^-1

K-enantiomer 9.94967x10 ^-7 S ^-1

Δ G enantiomeric isomerization 135.0kj. mol ^-1

Half life t _1/2 348327s (5805min,96.8h,1.61 days)

T＝25℃,t _1/2 439.4 years old

The energy barrier for the enantiomeric isomerization of the compound 3b was up to 135.0kJ/mol (100 ℃, iPrOH), which indicates that the axial chiral structure of the backbone has high stability.

The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims

1. An indole-substituted cyclohexadienone hydrazone compound, characterized in that it has the structure of formula I or the enantiomers and diastereomers thereof:

R ² is an alkyl group, and is,

R ³ selected from hydrogen, alkyl, alkoxy, halogen, cyano, hydroxyl, amino, phenyl, ester group, aldehyde group, trifluoromethyl, alkenyl, alkynyl, carboxyl, nitro and acylamino, wherein n is 1-4,

R ⁴ is an alkyl group.

2. The cyclohexadienone hydrazone compound according to claim 1, wherein M is COOR ¹ Or CONHR ¹ ，R ¹ Selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl and benzyl.

3. The cyclohexadienone hydrazone compound according to claim 1, wherein R is ² Is (C1-C6) alkyl; the R is ⁴ Is (C1-C6) alkyl.

4. The cyclohexadienone hydrazone compound according to claim 2 or 3, wherein M is selected from the group consisting of COOMe, COOEt, COO ⁱ Pr、COO ^t Bu、COOBn、CONH ⁿ Pr; the R is ² Is methyl or ethyl; the R is ⁴ Is methyl or ethyl.

5. The cyclohexadienone hydrazone compound according to claim 1, wherein R is ³ Selected from hydrogen, alkyl, alkoxy, halogen, cyano, hydroxyl, amino.

6. The cyclohexadienone hydrazone compound according to claim 5, wherein R is ³ Selected from hydrogen, methyl, methoxy, fluorine, chlorine, bromine, cyano, hydroxyl, amino; and n is 1.

7. The cyclohexadienone hydrazone compound according to claim 1, characterized in that it is selected from the following compounds or enantiomers, diastereomers thereof:

8. the method for synthesizing the cyclohexadienone hydrazone compound according to any one of claims 1 to 7, comprising the steps of: the chiral phosphoric acid is used as a catalyst, and the compound 1 and the compound 2 react as follows:

9. The synthesis method according to claim 8, characterized in that the chiral phosphoric acid is at least one of the following compounds or enantiomers thereof:

10. a synthesis process according to claim 8 or 9, characterized in that the amount of chiral phosphoric acid used is at least 0.5 mol%; the molar ratio of the compound 1 to the compound 2 is 1: (1-4); the reaction takes dichloromethane, dichloroethane, ethyl acetate, toluene, acetonitrile, tetrahydrofuran or chloroform as a solvent; the reaction temperature is above 15 ℃, and the reaction time is above 5 h.