CN115109020A

CN115109020A - Spirolactone substituted cyclohexadienone oxime compound and synthesis method thereof

Info

Publication number: CN115109020A
Application number: CN202210551241.XA
Authority: CN
Inventors: 谭斌; 朱帅; 向少华
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 discloses a spirolactone-substituted cyclohexadienone oxime compound, which has a structure shown in a general formula I or an enantiomer and a diastereomer shown in the general formula I:

wherein R is ¹ Selected from alkoxy, halogen, alkyl, cyano, amino, ester, aldehyde, trifluoromethyl, carboxyl, nitro, -CH ═ CHCO ₂ Me, -SCN; a is O or S; m is selected from-CO ₂ R ² A phenyl group,

R ² Is alkyl, R ³ Selected from alkyl, alkoxy, halogen, cyano, hydroxyl, amino, phenyl, ester group, aldehyde group, trifluoromethyl, alkenyl, alkynyl, carboxyl, nitro and amide group, wherein n is 1-5; q is selected from phenyl,

Benzyl group, -CH ₂ CH＝CHCl，R ⁴ Is nitro, halogen, trifluoromethyl, cyano, phenyl, alkyl, alkoxy, hydroxyl, amino, ester group, aldehyde group, alkenyl, alkynyl, carboxyl and amido, and m is 1-5. The invention also discloses a synthesis method thereof, constructs a compound framework with novel and various structures and good three-dimensional control, and enlarges an axial chiral compound library.

Description

Spirolactone substituted cyclohexadienone oxime compound and synthesis method thereof

Technical Field

The invention belongs to the field of synthesis of axial chiral compounds, and particularly relates to a spirolactone-substituted cyclohexadienone oxime 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, which can result in axial chirality when the E/Z geometry of the terminal substituents of the double bond is fixed. In terms of structure, this new framework is similar to the axial chiral alkylene cycloalkanes and cyclohexylidene oximes and is difficult to synthesize stereoselectively by catalysis, since 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 effectively interact 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 a spirolactone-substituted cyclohexadienone oxime compound.

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

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

spirolactone-substituted cyclohexadienone oximes, further having the structure of formula i or enantiomers, diastereomers thereof:

wherein R is ¹ Selected from alkoxy, halogen, alkyl, cyano, amino, ester, aldehyde, trifluoromethyl, carboxyl, nitro, -CH ═ CHCO ₂ Me、-SCN；

A is O or S;

m is selected from-CO ₂ R ² A phenyl group,

R ² Is alkyl, R ³ Selected from alkyl, alkoxy, halogen, cyano, hydroxyl, amino, phenyl, ester group, aldehyde group, trifluoromethyl, alkenyl, alkynyl, carboxyl, nitro and amide group, wherein n is 1-5;

q is selected from phenyl,

Benzyl group, -CH ₂ CH＝CHCl，R ⁴ Is nitro, halogen, trifluoromethyl, cyano, phenyl, alkyl, alkoxy, hydroxyl, amino, ester group, aldehyde group, alkenyl, alkynyl, carboxyl and amido, and m is 1-5.

Further, said R ¹ Selected from alkoxy, halogen, alkyl, trifluoromethyl, -CH ═ CHCO ₂ Me、-SCN。

Further, said R ¹ Selected from alkoxy, halogen, -CH ═ CHCO ₂ Me、-SCN。

Further, said R ¹ Selected from (C1-C6) alkoxy, halogen, -CH ═ CHCO ₂ Me、-SCN。

Further, said R ¹ Selected from methoxy, ethoxy, isopropoxy, n-butoxy, iodine, bromine, -CH ═ CHCO ₂ Me、-SCN。

Further, A is O.

Further, M is selected from-CO ₂ R ² A phenyl group,

R ² Is alkyl, R ³ Selected from alkyl, alkoxy or halogen, and n is 1-5.

Further, M is selected from-CO ₂ R ² A phenyl group,

R ² Is (C1-C6) alkyl, R ³ Selected from (C1-C6) alkyl, (C1-C6) alkoxy or halogen, and n is 1-5.

Further, M is selected from-CO ₂ R ² A phenyl group,

R ² Is (C1-C6) alkyl, R ³ Selected from (C1-C6) alkyl, (C1-C6) alkoxy or halogen, and n is 1-2.

Further, M is selected from-CO ₂ R ² A phenyl group,

R ² Is methyl, ethyl, tert-butyl or n-butyl, R ³ Is selected from methyl, bromine and methoxy, and n is 1-2.

Further, M is selected from-CO ₂ Me、-CO ₂ Et、-CO ₂ ⁱ Pr、-CO ₂ ⁿ Bu, phenyl, p-bromophenyl, m-methoxyphenyl and 2, 6-dimethylphenyl.

Further, Q is selected from phenyl,

Benzyl group, -CH ₂ CH＝CHCl，R ⁴ Is selected from nitro, halogen, trifluoromethyl, cyano, phenyl and alkyl, and m is 1-5.

Further, Q is selected from phenyl,

Benzyl group, -CH ₂ CH＝CHCl，R ⁴ Is selected from nitro, halogen, trifluoromethyl, cyano, phenyl and (C1-C6) alkyl, and m is 1-5.

Further, Q is selected from phenyl,

Benzyl group, -CH ₂ CH＝CHCl，R ⁴ Is selected from nitro, halogen, trifluoromethyl, cyano, phenyl and (C1-C6) alkyl, and m is 1.

Further, Q is selected from phenyl,

Benzyl group, -CH ₂ CH＝CHCl，R ⁴ Selected from nitro, fluoro, trifluoromethyl, cyano, phenyl, tert-butyl, and m is 1.

Further, Q is selected from phenyl, benzyl, -CH ₂ CH ═ CHCl, p-nitrophenyl, o-nitrophenyl, m-nitrophenyl, p-fluorophenyl, p-trifluoromethylphenyl, p-cyanophenyl, p-phenylphenyl, p-t-butylphenyl.

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

a synthetic method of cyclohexadienone oxime compounds comprises the following steps: the chiral phosphoric acid is used as a catalyst, and the compound 4 and the compound 5 react as follows:

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

wherein Ar 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-anthracenyl, 3, 5-ditertbutyl-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:

further, the reaction adds sodium sulfate, magnesium sulfate, or molecular sieves as additives.

Further, the amount of the chiral phosphoric acid is at least 1 mol%.

Further, the molar ratio of compound 4 to compound 5 is 1: (1-4).

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

Further, the reaction takes dichloromethane, dichloroethane, diethyl ether, toluene or acetonitrile as a solvent.

Further, the reaction temperature is above-60 ℃.

Further, the reaction time is more than 3 h.

Further, the reaction temperature is-60 ℃, -50 ℃, -40 ℃, -30 ℃, -20 ℃, -10 ℃,0 ℃ or room temperature.

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 the group consisting of hydrogen, alkyl groups, as defined herein, said alkyl groups containing from 1 to 20 carbon atoms.

For the

When the number of substituents on the benzene ring is 2 or more, the substituents may be the same or different.

The amount of the chiral phosphoric acid is based on the amount of the compound 4, and for example, the amount of the chiral phosphoric acid is written in the form of 5 mol%, which means that 0.05mol of the chiral phosphoric acid is used per 1mol of the compound 4.

The invention has the following beneficial effects:

the invention can efficiently obtain a compound skeleton with novel and various structures and good three-dimensional control, namely the spiro-lactone substituted cyclohexadienone oxime compound, through a simple and direct synthesis strategy, namely a chiral phosphoric acid catalyzed enantioselective condensation strategy, thereby not only expanding an axial chiral compound library, but also laying a foundation for developing a new axial chiral skeleton.

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 plate; 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 a chemical shift, s represents a singlet, d represents a doublet, t represents a triplet, q represents a quartet, p represents a quintet, m represents a multiplet, and br represents a broad peak. Enantiomeric excess values were determined by Agilent HPLC or Shimadzu HPLC using CHIRALPAK and CHIRALCEL chromatography columns.

Example 1

By a screw [4.5 ]]Trienone 4a and O- (4-nitrophenyl) hydroxylamine 5a as starting materials, using chiral phosphoric acid (R) -C10 as a catalyst, gave an axial chiral product 6a having a cyclohexadiene skeleton with an ee of 47%, the reaction conditions were screened, using CH at room temperature ₂ Cl ₂ As solvent, Na ₂ SO ₄ As an additive, chiral phosphoric acid (R) -C16 can obtain the best enantioselectivity (82% ee) after 3h of reaction, and when the temperature is reduced to-40 ℃ and the reaction time is prolonged to 24h, the enantioselectivity is further improved to 93% ee.

Reaction conditions are as follows: 4a (0.10mmol), 5a (0.12mmol) and chiral phosphoric acid catalyst (0.01mmol), additive (30mg, if any) were reacted in solvent (2.0mL) at room temperature. a: the reaction temperature is-20 ℃; b: the reaction temperature is-40 ℃; c: the reaction temperature is-60 ℃; d: 5 mol% chiral phosphoric acid was used; e: 1 mol% chiral phosphoric acid was used.

¹ H NMR(400MHz,CDCl ₃ )δ8.27(d,J＝9.3Hz,2H),7.52–7.32(m,3H),6.73(dd,J＝9.9,1.8Hz,1H),6.12(dd,J＝10.1,2.4Hz,1H),6.03(dd,J＝10.0,2.4Hz,1H),4.33(s,3H),3.76(s,3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ165.09,163.29,160.86,149.46,149.19,143.00,135.58,132.04,126.99,125.75,121.99,119.10,114.62,78.46,60.11,52.31。

HRMS (ESI) accurate mass C ₁₈ H ₁₅ N ₂ O ₈ ⁺ ([M+H ⁺ ]) M/z 387.0823, found 387.0823。

HPLC analysis is CHIRALCEL OD-3, n-hexane/isopropanol 80/20,0.8mL/min, lambda 254nm, t _R (major)＝7.2min,t _R (minor)＝8.6min,ee＝93％。

After the optimal reaction conditions are obtained, the substrates are expanded in the examples 2-14, the using amount of the substrates is increased to 0.2mmol, the reaction yield is slightly increased to 95%, and the substituent groups on the unsaturated spironolactone basically have no influence on the reaction (6 b-6 d); the hydroxylamine with o-nitro group gives the target product with similar results (6e), and if the nitro group is in the meta position, the ee value of the product 6f is reduced; screening of a series of para-substituted hydroxylamines shows that substrates with electron withdrawing (6 g. about.6 i) or charge neutral (6j) substituents have better enantiomeric control than substrates with electron donating substituents (6 k); o-benzylhydroxylamine was suitable for the reaction to give a product of 6m in 93% yield with enantioselectivity identical to O-phenylhydroxylamine 6 l; allylhydroxylamine gave the product 6n in excellent yield.

(R) -C16(5 mol%), spironolactone 4(0.20mmol) and Na in a 10mL Schlenk tube ₂ SO ₄ (60mg) to the mixture was added CH ₂ Cl ₂ (4.0mL), after cooling to-40 deg.C, hydroxylamine 5(0.22mmol) was added and the reaction mixture was stirred vigorously at-40 deg.C until the starting material 4 was completely consumed, the resulting reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give the corresponding product 6.

Synthesis of racemic Compound 6

To a 10mL Schlenk tube of C1(10 mol%), spironolactone 4(0.20mmol), hydroxylamine 5(0.22mmol) and Na ₂ SO ₄ (60mg) to the mixture was added CH ₂ Cl ₂ (4.0mL), the reaction mixture was then vigorously stirred at room temperature until complete consumption of starting material 4 (monitored by TLC)Test), after which the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give the corresponding racemic product 6.

Example 2

(R) -6b was obtained in 95% yield and 94% ee.

¹ H NMR(400MHz,CDCl ₃ )δ8.27(d,J＝9.3Hz,2H),7.40-7.36(m,3H),6.72(d,J＝10.1Hz,1H),6.13(dd,J＝10.1,2.3Hz,1H),6.04(dd,J＝10.0,2.5Hz,1H),4.71(q,J＝7.0Hz,2H),4.19(q,J＝7.1Hz,2H),1.45(t,J＝7.1Hz,3H),1.21(t,J＝7.1Hz,3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ165.31,163.31,160.44,149.66,148.95,143.00,135.98,132.42,126.75,125.76,122.33,118.95,114.61,78.54,69.03,61.39,15.45,13.78。

HRMS (ESI) accurate mass C ₂₀ H ₁₉ N ₂ O ₈ ⁺ ([M+H ⁺ ]) M/z 415.1136, found 415.1136.

HPLC analysis CHIRALCEL OD-H, n-hexane/isopropanol 60/40,1.0mL/min, λ 254nm, t _R (major)＝10.7min,t _R (minor)＝7.9min,ee＝94％。

Example 3

(R) -6c was obtained in 95% yield and 91% ee.

¹ H NMR(400MHz,CDCl ₃ )δ8.34–8.23(m,2H),7.47–7.33(m,3H),6.70(dd,J＝9.9,1.8Hz,1H),6.13(dd,J＝10.1,2.4Hz,1H),6.04(dd,J＝9.9,2.4Hz,1H),5.56(p,J＝6.1Hz,1H),5.04(p,J＝6.2Hz,1H),1.40(d,J＝6.1Hz,6H),1.19(t,J＝6.2Hz,6H)。

¹³ C NMR(101MHz,CDCl ₃ )δ165.60,163.33,159.87,149.80,148.61,142.98,136.21,132.64,126.60,125.75,125.67,123.97,118.85,114.61,113.30,78.58,76.00,69.23,22.77,21.55。

HRMS (ESI) accurate mass C ₂₂ H ₂₃ N ₂ O ₈ ⁺ ([M+H ⁺ ]) M/z 443.1449, found 443.1451.

HPLC analysis CHIRALCEL OD-H, n-hexane/isopropanol 60/40,1.0mL/min, λ 254nm, t _R (major)＝6.4min,t _R (minor)＝5.4min,ee＝91％。

Example 4

(R) -6d was obtained in 96% yield and 93% ee.

¹ H NMR(400MHz,CDCl ₃ )δ8.33–8.18(m,2H),7.46–7.29(m,3H),6.70(dd,J＝9.9,1.9Hz,1H),6.13(dd,J＝10.1,2.4Hz,1H),6.03(dd,J＝10.0,2.4Hz,1H),4.65(t,J＝6.5Hz,2H),4.12(t,J＝6.4Hz,2H),1.83–1.71(m,2H),1.61–1.41(m,4H),1.36-1.26(m,2H),0.97(t,J＝7.4Hz,3H),0.84(t,J＝7.4Hz,3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ165.32,163.31,160.59,149.61,149.28,142.96,135.97,132.41,126.73,125.75,122.40,118.91,114.58,78.45,72.68,65.24,31.82,30.33,19.17,18.74,13.70,13.58。

HRMS (ESI) accurate mass C ₂₄ H ₂₇ N ₂ O ₈ ⁺ ([M+H ⁺ ]) M/z 471.1762, found 471.1761.

HPLC analysis CHIRALCEL OD-H, n-hexane/isopropanol 60/40,1.0mL/min, λ 254nm, t _R (major)＝9.0min,t _R (minor)＝6.8min,ee＝93％。

Example 5

(R) -6e was obtained in 92% yield, 93% ee.

¹ H NMR(400MHz,CDCl ₃ )δ8.00(dd,J＝8.2,1.6Hz,1H),7.82(dd,J＝8.5,1.3Hz,1H),7.61(ddd,J＝8.7,7.4,1.7Hz,1H),7.48(dd,J＝10.1,1.8Hz,1H),7.15(ddd,J＝8.4,7.3,1.3Hz,1H),6.71(dd,J＝9.9,1.8Hz,1H),6.11(dd,J＝10.1,2.5Hz,1H),6.02(dd,J＝10.0,2.5Hz,1H),4.31(s,3H),3.74(s,3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ165.14,160.82,152.42,150.07,149.24,137.29,135.68,134.82,132.34,126.69,125.70,122.28,122.01,120.00,116.77,78.50,60.14,52.32。

HRMS (ESI) accurate mass C ₁₈ H ₁₅ N ₂ O ₈ ⁺ ([M+H ⁺ ]) M/z 387.0823, found 387.0825.

HPLC analysis CHIRALCEL OD-H, n-hexane/isopropanol 60/40,1.0mL/min, λ 254nm, t _R (major)＝11.2min,t _R (minor)＝9.5min,ee＝93％。

Example 6

(R) -6f was obtained in 90% yield and 83% ee.

¹ H NMR(400MHz,CDCl ₃ )δ8.17(t,J＝2.3Hz,1H),7.94(ddd,J＝7.9,2.2,1.2Hz,1H),7.56(ddd,J＝8.3,2.4,1.2Hz,1H),7.50(t,J＝8.1Hz,1H),7.37(dd,J＝10.1,1.8Hz,1H),6.73(dd,J＝10.0,1.9Hz,1H),6.09(dd,J＝10.1,2.4Hz,1H),6.00(dd,J＝10.0,2.4Hz,1H),4.31(s,3H),3.74(s,3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ165.15,160.88,159.24,149.18,149.09,149.03,135.23,131.59,129.98,127.13,122.10,120.89,119.15,117.70,109.99,78.57,60.12,52.31。

HPLC analysis is carried out at DAICEL CHIRALPAK OD-H, 60/40 n-hexane/isopropanol, 1.0mL/min of flow rate, 254nm of lambda, t _R (major)＝10.6min,t _R (minor)＝9.3min,ee＝83％。

Example 7

(R) -6g was obtained in 91% yield and 87% ee.

¹ H NMR(400MHz,CDCl ₃ )δ7.38(dd,J＝10.1,1.8Hz,1H),7.24–7.21(m,2H),7.07–7.02(m,2H),6.70(dd,J＝9.9,1.8Hz,1H),6.04(dd,J＝10.1,2.4Hz,1H),5.94(dd,J＝10.0,2.4Hz,1H),4.31(s,3H),3.75(s,3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ165.25,160.96,159.85,157.46,154.98,154.96,149.06,148.10,134.02,130.38,127.59,122.42,119.38,116.26,116.18,115.91,115.68,78.85,60.09,52.26。

HRMS (ESI) accurate mass C ₁₈ H ₁₅ FNO ₈ ⁺ ([M+H ⁺ ]) M/z 360.0878, found 360.0882.

DAICEL CHIRALPAK IH, 60/40 (normal hexane/isopropanol), 1.0mL/min (flow rate), 254nm (lambda), t _R (major)＝12.4min,t _R (minor)＝23.4min,ee＝87％。

Example 8

Obtained in 95% yield, 90% ee (R) -6 h.

¹ H NMR(400MHz,CDCl ₃ )δ7.60(d,J＝8.6Hz,2H),7.49–7.29(m,3H),6.71(dd,J＝10.0,1.8Hz,1H),6.07(dd,J＝10.1,2.5Hz,1H),5.97(dd,J＝10.0,2.5Hz,1H),4.30(s,3H),3.73(s,3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ165.18,161.09,160.91,149.13,148.76,134.76,131.18,127.35,(126.90,126.86,126.82,126.78,q,J＝4),(125.41,125.13,124.80,124.48,q,J＝32),122.90,122.21,119.30,114.67,78.67,60.10,52.29。

HRMS (ESI) precisionMass C ₁₉ H ₁₅ F ₃ NO ₆ ⁺ ([M+H ⁺ ]) M/z 410.0846, found 410.0848.

HPLC analysis is carried out at DAICEL CHIRALPAK OD-H, 60/40 n-hexane/isopropanol, 1.0mL/min of flow rate, 254nm of lambda, t _R (major)＝11.6min,t _R (minor)＝9.4min,ee＝90％。

Example 9

(R) -6i was obtained in 95% yield and 91% ee.

¹ H NMR(400MHz,CDCl ₃ )δ7.65(d,J＝8.8Hz,2H),7.45–7.31(m,3H),6.70(dd,J＝10.0,1.8Hz,1H),6.09(dd,J＝10.2,2.5Hz,1H),5.99(dd,J＝10.0,2.4Hz,1H),4.31(s,3H),3.74(s,3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ165.12,161.78,160.87,149.17,135.31,133.92,131.74,127.09,122.04,119.15,118.94,115.28,106.14,78.52,60.11,52.30。

HRMS (ESI) accurate mass C ₁₉ H ₁₅ F ₃ NO ₆ ⁺ ([M+H ⁺ ]) M/z 367.0925, found 367.0927.

HPLC analysis is carried out at DAICEL CHIRALPAK OD-H, 60/40 n-hexane/isopropanol, 1.0mL/min of flow rate, 254nm of lambda, t _R (major)＝10.9min,t _R (minor)＝9.0min,ee＝91％。

Example 10

(R) -6j was obtained in 95% yield and 90% ee.

¹ H NMR(400MHz,CDCl ₃ )δ8.04–7.52(m,4H),7.54–7.40(m,3H),7.43–7.31(m,3H),6.75(dd,J＝9.9,1.8Hz,1H),6.05(dd,J＝10.1,2.5Hz,1H),5.95(dd,J＝9.9,2.5Hz,1H),4.33(s,3H),3.76(s,3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ165.28,160.98,158.46,149.09,148.18,140.64,136.15,133.94,130.30,128.76,128.08,127.73,126.95,126.88,122.48,119.52,115.18,78.92,60.11,52.28。

HRMS (ESI) accurate mass C ₂₄ H ₂₀ NO ₆ ⁺ ([M+H ⁺ ]) M/z 418.1285, found 418.1289.

HPLC analysis, DAICEL CHIRALPAK OD-3, 80/20 n-hexane/isopropanol, 0.8mL/min flow rate, 254nm lambda, t _R (major)＝17.1min,t _R (minor)＝28.0min,ee＝90％。

Example 11

(R) -6k was obtained in 94% yield and 83% ee.

¹ H NMR(400MHz,CDCl ₃ )δ7.52–7.28(m,3H),7.17(d,J＝8.8Hz,2H),6.70(dd,J＝10.0,1.8Hz,1H),5.99(dd,J＝10.1,2.4Hz,1H),5.89(dd,J＝10.0,2.5Hz,1H),4.29(s,3H),3.72(s,3H),1.32(s,9H)。

¹³ C NMR(101MHz,CDCl ₃ )δ165.31,160.99,156.74,149.06,147.87,146.00,133.55,129.90,127.86,126.18,122.56,119.57,114.57,79.01,60.10,52.24,34.29,31.52。

HRMS (ESI) accurate mass C ₂₂ H ₂₄ NO ₆ ⁺ ([M+H ⁺ ]) M/z 398.1598, found 398.1606.

HPLC analysis, DAICEL CHIRALPAK OD-3, 80/20 n-hexane/isopropanol, 0.8mL/min flow rate, 254nm lambda, t _R (major)＝15.1min,t _R (minor)＝11.0min,ee＝83％。。

Example 12

(R) -6l was obtained in 90% yield and 88% ee.

¹ H NMR(400MHz,CDCl ₃ )δ7.39(dd,J＝10.1,1.8Hz,1H),7.37–7.28(m,2H),7.26(m,2H),7.08(tt,J＝7.3,1.2Hz,1H),6.71(dd,J＝10.0,1.8Hz,1H),6.01(dd,J＝10.1,2.4Hz,1H),5.91(dd,J＝10.0,2.5Hz,1H),4.29(s,3H),3.72(s,3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ165.29,160.98,158.90,149.07,148.06,133.82,130.19,129.39,127.77,123.07,122.49,119.53,114.88,78.94,60.10,52.26。

HRMS (ESI) accurate mass C ₁₈ H ₁₆ NO ₆ ⁺ ([M+H ⁺ ]) M/z 342.0972, found 342.0975.

HPLC analysis is carried out at DAICEL CHIRALPAK OD-H, 60/40 n-hexane/isopropanol, 1.0mL/min of flow rate, 254nm of lambda, t _R (major)＝7.3min,t _R (minor)＝6.6min,ee＝88％。。

Example 13

(R) -6m was obtained in 93% yield and 88% ee.

¹ H NMR(400MHz,CDCl ₃ )δ7.67–7.30(m,5H),7.24–6.98(m,1H),6.79–6.27(m,1H),5.85(dd,J＝10.1,2.4Hz,1H),5.76(dd,J＝9.9,2.5Hz,1H),5.23(s,2H),4.26(s,3H),3.68(s,3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ165.40,161.07,148.89,146.47,137.00,132.15,128.47,128.40,128.23,128.18,128.13,122.85,119.56,79.27,77.11,60.04,52.16。

HRMS (ESI) accurate mass C ₁₉ H ₁₈ NO ₆ ⁺ ([M+H ⁺ ]) M/z 356.1129, found 356.1133.

HPLC analysis is carried out at DAICEL CHIRALPAK OD, 90/10 n-hexane/isopropanol, 0.8mL/min lambda-254 nm, t _R (major)＝21.8min,t _R (minor)＝19.5min,ee＝88％。。

Example 14

(R) -6n was obtained in 93% yield and 81% ee.

¹ H NMR(400MHz,CDCl ₃ )δ7.13(dd,J＝10.1,1.8Hz,1H),6.53(dd,J＝10.0,1.8Hz,1H),6.32(d,J＝13.3Hz,1H),6.13(dt,J＝13.3,6.6Hz,1H),5.88(dd,J＝10.1,2.5Hz,1H),5.79(dd,J＝10.0,2.5Hz,1H),4.67(dd,J＝6.5,1.4Hz,2H),4.27(s,3H),3.73(s,3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ165.36,161.04,148.90,146.61,132.55,128.85,128.76,127.93,122.77,122.75,119.29,79.12,72.87,60.03,52.21。

HRMS (ESI) accurate mass C ₁₅ H ₁₅ ClNO ₆ ⁺ ([M+H ⁺ ]) M/z 340.0582, found 340.0589.

DAICEL CHIRALPAK IH, 60/40 (normal hexane/isopropanol), 1.0mL/min (flow rate), 254nm (lambda), t _R (major)＝14.1min,t _R (minor)＝16.1min,ee＝81％。

Example 15

The compound 7a of which the ester group of the compound 4a is replaced by an aromatic ring is used as a substrate, the enantioselectivity (8a, 53% ee) is adversely affected, and the chiral phosphoric acid (R) -C14 is used through condition optimization, so that the enantiomeric control (92% ee) can be remarkably improved.

Reaction conditions are as follows: 7a (0.10mmol), 5a (0.12mmol), Na at room temperature ₂ SO ₄ (30mg) and chiral phosphoric acid catalyst (0.01mmol) in CH ₂ Cl ₂ (2.0 mL). a: 5 mol% chiral phosphoric acid was used; b: 1 mol% chiral phosphoric acid was used.

¹ H NMR(400MHz,CDCl ₃ )δ8.24(d,J＝9.1Hz,2H),7.71–7.31(m,8H),6.74(dd,J＝10.0,1.8Hz,1H),6.29(dd,J＝10.2,2.4Hz,1H),6.21(dd,J＝10.0,2.4Hz,1H)。

¹³ C NMR(101MHz,CDCl ₃ )δ168.75,167.54,163.09,149.06,143.07,134.97,131.51,130.98,130.73,128.92,127.42,127.39,125.77,119.55,114.60,87.33,86.30。

HRMS (ESI) accurate mass C ₂₁ H ₁₄ IN ₂ O ₅ ⁺ ([M+H ⁺ ]) M/z 500.9942, found 500.9950.

HPLC analysis, DAICEL CHIRALPAK OD-3, 80/20 n-hexane/isopropanol, 0.8mL/min flow rate, 254nm lambda, t _R (major)＝27.2min,t _R (minor)＝34.5min,ee＝92％。

After optimal reaction conditions were obtained, examples 16-25 extended the substrate. When iodine is substituted by bromine, the enantioselectivity is reduced (8b), acrylate and thiocyanate groups have good tolerance, corresponding products (8c and 8d) can be generated, the enantioselectivity is not influenced by an electron-donating group on a benzene ring (8f and 8g), the enantioselectivity is slightly reduced due to an electron-withdrawing substituent (8e), the axial chiral product is obtained by the spirothiolactone substrate for 8h, the yield is 93%, the ee value is 90%, and different para-substituent hydroxylamine substrates can be obtained with good results, namely 8 i-8 k.

(R) -C14(5 mol%), Compound 7(0.20mmol) and Na in a 10mL Schlenk tube ₂ SO ₄ (60mg) to the mixture was added CH ₂ Cl ₂ (4.0 mL). After cooling to-40 ℃ hydroxylamine 5(0.22mmol) was added. The mixture was stirred vigorously at-40 ℃ until the starting material 7 was completely consumed. Thereafter, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give the corresponding product (R) -8.

Synthesis of racemic Compound 8

To a 10mL Schlenk tube of C1(10 mol%), Compound 7(0.20mmol), hydroxylamine 5(0.22mmol) and Na ₂ SO ₄ (60mg) to the mixture was added CH ₂ Cl ₂ (4mL), the reaction mixture was stirred vigorously at room temperature until complete consumption of starting material 7 (monitored by TLC). The resulting mixture was then concentrated under reduced pressure and purified by silica gel column chromatography to give the corresponding racemic product 8.

Example 16

(R) -8b was obtained in 95% yield and 90% ee.

¹ H NMR(400MHz,CDCl ₃ )δ8.26(d,J＝8.8Hz,2H),7.59(d,J＝7.3Hz,2H),7.51-7.36(m,6H),6.79(d,J＝10.0Hz,1H),6.30(dd,J＝10.1,2.4Hz,1H),6.22(dd,J＝10.0,2.5Hz,1H)。

¹³ C NMR(101MHz,CDCl ₃ )δ167.13,163.06,160.28,148.89,143.14,135.01,131.56,131.23,129.16,128.97,127.66,125.78,119.74,114.62,111.45,84.25。

HRMS (ESI) accurate mass C ₂₁ H ₁₄ BrN ₂ O ₅ ⁺ ([M+H ⁺ ]) M/z 453.0081, found 453.0080.

HPLC analysis, DAICEL CHIRALPAK OD-3, 80/20 n-hexane/isopropanol, 0.8mL/min flow rate, 254nm lambda, t _R (major)＝24.3min,t _R (minor)＝30.0min,ee＝90％。

Example 17

(R) -8c was obtained in 94% yield and 91% ee.

¹ H NMR(400MHz,CDCl ₃ )δ8.23(d,J＝8.8Hz,2H),7.77–7.10(m,10H),6.74(d,J＝10.0Hz,1H),6.27(d,J＝10.3Hz,1H),6.19(d,J＝10.1Hz,1H),3.77(s,3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ169.18,166.96,164.54,163.12,149.03,143.02,135.41,131.89,131.32,131.08,129.56,129.18,128.25,127.40,125.85,125.74,123.14,119.65,114.57,82.38,51.99。

HRMS (ESI) accurate mass C ₂₅ H ₁₉ N ₂ O ₇ ⁺ ([M+H ⁺ ]) M/z 459.1187, found 459.1194.

HPLC analysis, DAICEL CHIRALPAK OD-3, 80/20 n-hexane/isopropanol, 0.8mL/min flow rate, 254nm lambda, t _R (major)＝15.2min,t _R (minor)＝30.0min,ee＝91％。

Example 18

(R) -8d was obtained in 93% yield and 95% ee.

¹ H NMR(400MHz,CDCl ₃ )δ8.24(d,J＝8.9Hz,2H),7.54–7.35(m,8H),6.82(d,J＝10.1Hz,1H),6.33(d,J＝10.2Hz,1H),6.24(d,J＝10.1Hz,1H)。

¹³ C NMR(101MHz,CDCl ₃ )δ166.64,166.29,163.02,148.65,143.15,133.95,132.11,130.51,129.37,128.24,128.16,127.83,125.78,120.30,115.05,114.65,105.81,84.41。

HRMS (ESI) accurate mass C ₂₂ H ₁₄ N ₃ O ₅ S ⁺ ([M+H ⁺ ]) M/z 432.0649, found 432.0656.

HPLC analysis is carried out with DAICEL CHIRALPAK OD-3, 80/20 n-hexane/isopropanol, 0.8mL/min flow rate, 254nm lambda, t _R (major)＝62.7min,t _R (minor)＝89.2min,ee＝95％。

Example 19

(R) -8e was obtained in 93% yield and 87% ee.

¹ H NMR(400MHz,CDCl ₃ )δ8.37–8.16(m,2H),7.82–7.51(m,2H),7.50–7.33(m,5H),6.76(dd,J＝10.0,1.8Hz,1H),6.25(dd,J＝10.1,2.4Hz,1H),6.17(dd,J＝9.9,2.4Hz,1H)。

¹³ C NMR(101MHz,CDCl ₃ )δ168.41,166.23,163.00,148.81,143.18,134.64,132.32,131.19,129.53,128.92,127.63,125.78,125.69,119.72,114.61,87.96,86.10。

HRMS (ESI) accurate mass C ₂₁ H ₁₂ BrIN ₂ O ₅ Na ⁺ ([M+Na ⁺ ]) M/z 600.8866, found 600.8854.

HPLC analysis, DAICEL CHIRALPAK OD-3, 80/20 n-hexane/isopropanol, 0.8mL/min flow rate, 254nm lambda, t _R (major)＝30.2min,t _R (minor)＝38.8min,ee＝87％。

Example 20

(R) -8f was obtained in 93% yield and 96% ee.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.23(d,J＝9.3Hz,2H),7.57–7.31(m,2H),7.32–7.21(m,1H),7.16(t,J＝7.5Hz,1H),7.07(t,J＝7.5Hz,2H),6.84(dd,J＝10.2,2.2Hz,1H),6.67(qd,J＝10.0,2.0Hz,2H),2.17(s,3H),2.15(s,3H)。

¹³ C NMR(101MHz,DMSO-d ₆ )δ170.28,169.32,163.16,150.05,142.84,137.90,135.84,134.37,130.32,129.57,128.33,126.35,126.16,125.25,118.05,115.15,113.97,94.13,89.36,20.96。

HRMS (ESI) accurate mass C ₂₃ H ₁₈ IBrN ₂ O ₅ ⁺ ([M+H ⁺ ]) M/z 529.0255, found 529.0256.

HPLC analysis, DAICEL CHIRALPAK OD-3, 80/20 n-hexane/isopropanol, 0.8mL/min flow rate, 254nm lambda, t _R (major)＝25.1min,t _R (minor)＝37.4min,ee＝96％。

Example 21

(R) -8g was obtained in 93% yield and 93% ee.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.27(d,J＝9.3Hz,2H),7.49–7.41(m,2H),7.40–7.34(m,2H),7.12–7.00(m,1H),6.99–6.92(m,2H),6.77(dd,J＝10.0,1.9Hz,1H),6.72(dd,J＝10.2,2.4Hz,1H),6.59(dd,J＝10.0,2.4Hz,1H),3.73(s,3H)。

¹³ C NMR(101MHz,CDCl ₃ )δ168.75,167.25,163.09,159.54,149.13,143.04,135.05,131.82,131.59,130.14,127.36,125.77,119.63,119.53,116.49,114.61,113.11,87.32,86.28,55.41。

HRMS (ESI) accurate mass C ₂₂ H ₁₆ IN ₂ O ₆ ⁺ ([M+H ⁺ ]) M/z 531.0048, found 531.0059.

HPLC analysis, DAICEL CHIRALPAK OD-3, 80/20 n-hexane/isopropanol, 0.8mL/min flow rate, 254nm lambda, t _R (major)＝31.0min,t _R (minor)＝39.5min,ee＝93％。

The absolute configuration of compound 8g 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 2126887, and the detailed information is shown in the following table:

example 22

Obtained in 93% yield, 90% ee (R) -8 h.

¹ H NMR(400MHz,CDCl ₃ )δ8.23(d,J＝9.2Hz,2H),7.65–7.39(m,3H),7.31–7.29(m,2H),7.24–7.21(m,3H),6.57(dd,J＝9.9,1.9Hz,1H),6.46(dd,J＝10.0,2.3Hz,1H),6.36(dd,J＝9.9,2.3Hz,1H)。

¹³ C NMR(101MHz,CDCl ₃ )δ190.33,169.98,163.28,149.19,142.84,137.25,134.54,133.66,130.08,128.70,127.43,125.73,125.06,117.70,114.45,104.74,64.65。

HRMS (ESI) accurate mass C ₂₁ H ₁₄ IN ₂ O ₄ S ⁺ ([M+H ⁺ ]) M/z 516.9713, found 516.9720.

HPLC analysis, DAICEL CHIRALPAK OD-3, 80/20 n-hexane/isopropanol, 0.8mL/min flow rate, 254nm lambda, t _R (major)＝16.8min,t _R (minor)＝18.8min,ee＝90％。

Example 23

(R) -8i was obtained in 93% yield and 91% ee.

¹ H NMR(400MHz,CDCl ₃ )δ7.75–7.56(m,2H),7.45(m,5H),7.40–7.30(m,3H),6.72(dd,J＝10.0,1.8Hz,1H),6.26(dd,J＝10.1,2.4Hz,1H),6.18(dd,J＝10.0,2.5Hz,1H)。

¹³ C NMR(101MHz,CDCl ₃ )δ168.76,167.58,161.59,148.78,134.70,133.95,131.21,130.96,130.74,128.91,127.48,127.42,119.59,118.87,115.24,106.31,87.30,86.35。

HRMS (ESI) accurate mass C ₂₂ H ₁₄ IN ₂ O ₃ ⁺ ([M+H ⁺ ]) M/z 481.0044, found 481.0053.

HPLC analysis, DAICEL CHIRALPAK OD-3, 80/20 n-hexane/isopropanol, 0.8mL/min flow rate, 254nm lambda, t _R (major)＝24.2min,t _R (minor)＝29.9min,ee＝91％。

Example 24

(R) -8j was obtained in 93% yield and 90% ee.

¹ H NMR(400MHz,CDCl ₃ )δ7.65–7.48(m,4H),7.44–7.27(m,5H),6.73(dd,J＝10.0,1.8Hz,1H),6.19(dd,J＝10.2,2.5Hz,1H),6.10(dd,J＝10.0,2.5Hz,1H)。

¹³ C NMR(101MHz,CDCl ₃ )δ168.53,166.44,160.87,148.16,133.85,132.28,130.35,129.60,128.96,127.99,(126.95,126.91,126.88,126.84；q,J＝3.8),(126.71,126.67,126.63,126.60,q,J＝1.6),125.65,125.53,(125.70,125.38,125.06,124.73,q,J＝13.2),122.84,119.92,114.66,113.20,87.79,86.31。

HRMS (ESI) accurate mass C ₂₂ H ₁₃ BrF ₃ NO ₃ +([M+H+]) M/z 601.9070, found 601.9080.

HPLC analysis is carried out at DAICEL CHIRALPAK OD-H, 80/20 n-hexane/isopropanol, 1.0mL/min flow rate, 254nm lambda, t _R (major)＝12.6 min,t _R (minor)＝17.3 min,ee＝90％。

Example 25

(R) -8k was obtained in 94% yield, 90% ee.

¹ H NMR(400 MHz,CDCl ₃ )δ7.54–7.30(m,8H),7.19–7.09(m,2H),6.70(dd,J＝10.0,1.8 Hz,1H),6.13(dd,J＝10.2,2.5 Hz,1H),6.04(dd,J＝10.0,2.4 Hz,1H),1.30(s,9H)。

¹³ C NMR(101 MHz,CDCl ₃ )δ168.91,167.91,156.58,147.51,146.18,132.97,130.90,130.88,129.39,128.83,128.25,127.48,126.22,120.00,114.46,86.93,86.78,34.31,31.51。

HRMS (ESI) accurate mass C ₂₅ H ₂₃ INO ₃ +([M+H+]) M/z 512.0717, found 512.0729.

HPLC analysis is carried out at DAICEL CHIRALPAK OD-H, 80/20 n-hexane/isopropanol, 1.0mL/min flow rate, 254nm lambda, t _R (major)＝12.8 min,t _R (minor)＝21.5 min,ee＝90％。

Example 26

Amplification test

The gram-scale synthesis of compounds 6a and 8g maintains excellent yield and enantioselectivity, and the method of the invention is suitable for large-scale production

(R) -C16(5 mol%), 4a (3.0mmol) and Na in a 250mL Schlenk tube ₂ SO ₄ (400mg) of the mixture was added to CH ₂ Cl ₂ (60 mL). After cooling to-40 ℃ 5a (3.3 mmol) was added. The reaction mixture was then stirred vigorously at-40 ℃ until 4a was completely consumed. Thereafter, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give the corresponding product (R) -6a (1.1g, 95% yield, 93% ee).

(R) -C14(5 mol%), 7g (3.0mmol) and Na in a 250mL Schlenk tube ₂ SO ₄ (400mg) of the mixture CH was added ₂ Cl ₂ (60 mL). After cooling to-40 ℃ 5a (3.3 mmol) was added. The reaction mixture was then stirred vigorously at-40 ℃ until 7g was completely consumed. Thereafter, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give the corresponding product (R) -8g (1.44g, 96% yield, 92% ee).

Example 27

Subsequent transformation

Phenylacetylene was reacted with compound 8d under copper catalysis to give 8l of the alkynylated product in 86% yield and 87% ee, while 8g was cross-coupled with methyl acrylate under palladium catalysis to give 8m in good yield.

To 8d (0.1mmol) of CH ₃ Adding CuI (0.02 mmol) and Cs to CN (4mL) solution ₂ CO ₃ (0.2mmol) followed by phenylacetylene (0.1 mL). The resulting mixture was stirred at room temperature and after completion of the reaction (TLC monitoring), the crude product was purified by silica gel column chromatography to give 8l (86% yield, 87% ee).

¹ H NMR(400 MHz,CDCl ₃ )δ8.24(d,J＝9.2 Hz,2H),7.55–7.31(m,8H),7.31–7.18(m,3H),7.16–7.00(m,2H),6.73(dd,J＝10.0,1.8 Hz,1H),6.28(dd,J＝10.1,2.4 Hz,1H),6.20(dd,J＝10.0,2.4 Hz,1H)。

¹³ C NMR(101 MHz,CDCl ₃ )δ167.80,163.11,159.08,149.02,143.10,135.52,132.05,131.63,130.73,129.04,128.89,128.52,128.26,128.13,127.39,125.77,122.01,121.97,119.56,114.58,97.98,83.83,70.84。

HRMS (ESI) accurate mass C ₂₉ H ₁₉ N ₂ O ₅ S+([M+H+]) M/z 507.1009, found 507.1026.

HPLC analysis, DAICEL CHIRALPAK OD-3, 80/20 n-hexane/isopropanol, 0.8mL/min flow rate, 254nm lambda, t _R (major)＝22.7 min,t _R (minor)＝36.3 min,ee＝87％。

To a solution of 8g (0.1mmol) in THF (4mL) was added Pd (OAc) ₂ (0.02 mmol) and K ₂ CO ₃ (0.2mmol) followed by the addition of methyl acrylate (0.1 mL). The mixture was stirred at 80 ℃ and after completion of the reaction (monitored by TLC), the resulting mixture was cooled to room temperature. The mixture was then dissolved in ethyl acetate (10mL), washed with a saturated saline solution, and washed with anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure,the crude product was purified by column chromatography on silica gel to give 8m (78% yield, 90% ee).

¹ H NMR(400 MHz,CDCl ₃ )δ8.24(d,J＝9.2 Hz,2H),7.52–7.29(m,6H),6.99(dd,J＝8.4,2.6 Hz,1H),6.86(d,J＝7.7 Hz,1H),6.81(s,1H),6.74(dd,J＝9.9,1.8 Hz,1H),6.24(dd,J＝10.2,2.4 Hz,1H),6.17(dd,J＝10.0,2.4 Hz,1H),3.78(s,3H),3.77(s,3H)。

¹³ C NMR(101 MHz,CDCl ₃ )δ169.16,167.00,164.26,163.11,159.76,149.07,143.08,135.43,131.93,131.32,130.67,130.37,127.37,125.90,125.77,123.24,120.64,119.63,116.43,114.58,113.83,82.33,55.36,52.02。

HRMS (ESI) accurate mass C ₂₆ H ₂₂ N ₂ O ₈ +([M+H+]) M/z 489.1292, found 489.1302.

HPLC analysis is carried out at DAICEL CHIRALPAK OD-H, 80/20 n-hexane/isopropanol, 1.0mL/min of flow rate, 254nm of lambda, t _R (major)＝13.1 min,t _R (minor)＝9.3 min,ee＝90％。

Example 28

Stability test

When 10 mg of Compound 6a was heated (100 ℃ C.) in a different solvent (2 mL) for 24 hours, the ee value of Compound 6a did not decrease, indicating that the stereochemical stability of this backbone compound was high.

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. Spirolactone-substituted cyclohexadienone oximes characterized by the general formula I structure or enantiomers, diastereomers thereof:

A is O or S;

m is selected from-CO ₂ R ² A phenyl group,

q is selected from phenyl,

2. The cyclohexadienone oxime compound according to claim 1, wherein R is ¹ Selected from alkoxy, halogen, -CH ═ CHCO ₂ Me、-SCN。

3. The cyclohexadienone oxime compound according to claim 1 or 2, wherein R is ¹ Selected from methoxy, ethoxy, isopropoxy, n-butoxy, iodine, bromine, -CH ═ CHCO ₂ Me, -SCN; and A is O.

4. The cyclohexadienone oxime compound according to claim 1The compound, wherein M is selected from the group consisting of-CO ₂ R ² A phenyl group,

5. The cyclohexadienone oxime compound according to claim 4, wherein M is selected from the group consisting of-CO ₂ R ² A phenyl group,

6. The cyclohexadienone oxime compound according to claim 1, wherein Q is selected from the group consisting of phenyl group,

7. The cyclohexadienone oxime compound according to claim 6, wherein Q is selected from the group consisting of phenyl group,

8. The cyclohexadienone oxime compound according to claim 1, which is selected from the following compounds or enantiomers, diastereomers thereof:

9. the method for synthesizing cyclohexadienone oximes according to any one of claims 1 to 8, characterized by comprising the steps of: the chiral phosphoric acid is used as a catalyst, and the compound 4 and the compound 5 react as follows:

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

sodium sulfate, magnesium sulfate or a molecular sieve is added in the reaction to be used as an additive; the amount of the chiral phosphoric acid is at least 1 mol%; the molar ratio of the compound 4 to the compound 5 is 1: (1-4); the reaction takes dichloromethane, dichloroethane, diethyl ether, toluene, acetonitrile, tetrahydrofuran or chloroform as a solvent; the reaction temperature is above-60 ℃, and the reaction time is above 3 h.