Synthesis method of chiral helicenone compound

Abstract

The invention provides a synthesis method of a chiral helicenone compound, and belongs to the technical field of chemical synthesis. According to the invention, racemic helico-ketene compounds and alpha-benzyl-alpha-diazonium ester are used as raw materials, and a series of chiral helico-ketene compounds are obtained through a catalytic reaction of a chiral dinitrogen oxygen metal complex. The invention provides a green, simple and cheap new method for synthesis of various substituted chiral helicenone compounds. Meanwhile, the invention proves that a series of synthesized chiral helicenone compounds have excellent electronic circular dichroism and have very high application value in the field of chiral optical materials.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing chiral spiroketone compounds. Background Art

[0002] Spiroketone compounds are a class of ketone compounds with a spatial helical structure. Their structural features include a twisted π system formed due to the steric repulsion between terminal aromatic rings. This structure endows them with unique optical and electrical properties, including optical rotation (OR), electronic circular dichroism (ECD), circularly polarized luminescence (CPL), etc. Therefore, they have attracted much attention in the fields of nonlinear optical materials, chiral optical materials, liquid crystal materials, supramolecular materials, molecular recognition, chiral catalysis, and asymmetric synthesis. Due to the structural complexity of spiroketone compounds, the construction of their rigid helical backbone requires multiple steps of reactions, and each step of cyclization or coupling reaction may lead to a decrease in yield due to steric hindrance, usually requiring special catalysts, which increases the process complexity. The chirality of spiroketones comes from the left-handed (M) or right-handed (P) helical direction, but traditional synthesis methods are prone to generating racemic mixtures. Efficient asymmetric synthesis strategies (such as chiral auxiliaries, asymmetric catalysis) still need to be optimized, and currently, the yield and enantiomeric excess value (ee value) are still not ideal. If a single enantiomer cannot be directly synthesized, subsequent resolution depends on chiral chromatography or crystallization methods, which are costly and time-consuming. In addition, the conjugated rigid structure of spiroketones leads to poor solubility, and they are prone to aggregation or precipitation during the reaction, affecting the reaction efficiency. Therefore, the precise synthesis of chiral spiroketone compounds with various structures has become one of the hot issues in the fields of chemistry and materials science research.

[0003] Currently, there are few examples of the synthesis of chiral spiroketone compounds. The literature "Rhodium-Catalyzed Enantioselective Synthesis, Crystal Structures, and Photophysical Properties of Helically Chiral 1,1'-Bitriphenylenes" discloses the highly enantioselective synthesis of helically chiral 1,1'-bitriphenylene through a rhodium-catalyzed bis[2 + 2 + 2] cycloaddition reaction, but the substrate scope is limited and it uses an expensive chiral rhodium catalyst. In addition, the electronic effect and steric effect of spiro substituents will significantly affect the optical properties of spiroenes. Therefore, developing a simple, efficient, environmentally friendly, low-cost, and substrate-universal method for synthesizing chiral spiroketone compounds and exploring their chiral optics has potential application value. Summary of the Invention

[0004] The purpose of the present invention is to provide a method for synthesizing chiral spiroketone compounds.

[0005] The present invention provides a method for synthesizing chiral spiroenone compounds, which comprises the following steps:

[0006]

[0007] In an organic solvent, using a chiral bis(oxazoline) ligand and a metal compound as catalysts, reacting a racemic spiroenone compound and an α-benzyl-α-diazoester as raw materials to obtain two chiral spiroenone compounds shown in Formula I and Formula II;

[0008] Wherein,

[0009] Ring A1 and A2 are each independently selected from 6- to 12-membered aryl, 5- to 12-membered heteroaryl, 5- to 12-membered heterocycloalkyl; Ring A1 and A2 are the same or different;

[0010] n1 and n2 are each independently selected from 0, 1, 2, 3, 4 or 5; n1 and n2 are the same or different;

[0011] m1 and m2 are each independently selected from 0, 1, 2, 3, 4 or 5; m1 and m2 are the same or different;

[0012] R 1a 、R 1b are substituents at any position on the benzene ring; each independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, 6- to 12-membered aryl; the substituents of the alkyl and alkoxy are selected from one or more halogens; R 1a and R 1b are the same or different;

[0013] R 4a is a substituent at any position on Ring A1, and R 4b is a substituent at any position on Ring A2; R 4a 、R 4b are each independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, 6- to 12-membered aryl; the substituents of the alkyl and alkoxy are selected from one or more halogens; R 4a and R 4b are the same or different;

[0014] R 2 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted 6- to 12-membered aryl, substituted or unsubstituted 5- to 12-membered heteroaryl, ferrocenyl; the substituents of the alkyl, alkenyl and alkynyl are selected from one or more of the following groups: substituted or unsubstituted 6- to 12-membered aryl, substituted or unsubstituted 5- to 12-membered heteroaryl, -C(O)OR 5; The substituents of the aryl and heteroaryl are selected from one or more of the following substituents: C1-C6 alkyl, halo-C1-C6 alkyl, C2-C6 alkenyl, halo-C2-C6 alkenyl, -C(O)OR 5 Substituted C2-C6 alkenyl, C2-C6 alkynyl, halo-C2-C6 alkynyl, halogen, C1-C6 alkoxy, C1-C6 alkylthio, 6-12-membered aryl, -C(O)OR 5 、-NR 6 R 7 、cyano, nitro, carboxyl, amino;

[0015] R 5 、R 6 、R 7 are each independently selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl;

[0016] R 3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, 3-8-membered cycloalkyl; The alkyl substituents in R 3 are selected from one or more of the following groups: 3-8-membered cycloalkyl, 6-12-membered aryl.

[0017] Furthermore,

[0018] Ring A1 and A2 are each independently selected from phenyl, naphthyl, thiophenyl, furyl, dihydrofuryl; Ring A1 and A2 are the same or different;

[0019] n1 and n2 are each independently selected from 0, 1, 2 or 3; n1 and n2 are the same or different;

[0020] m1 and m2 are each independently selected from 0, 1, 2 or 3; m1 and m2 are the same or different;

[0021] R 1a 、R 1b are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, trifluoromethyl, C1-C6 alkoxy, halogen, phenyl; R 1a and R 1b are the same or different;

[0022] R 4a 、R 4b are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, trifluoromethyl, C1-C6 alkoxy, halogen, phenyl; R 4a and R 4b are the same or different;

[0023] R 2Selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted substituted or unsubstituted substituted or unsubstituted substituted or unsubstituted pyridyl, ferrocenyl; the substituents of the alkenyl are selected from one or more of the following groups: phenyl, -C(O)OR 5 ; the phenyl, naphthyl, pyridyl, the substituents are selected from one or more of the following substituents: C1-C6 alkyl, halo C1-C6 alkyl, C2-C6 alkenyl, halo C2-C6 alkenyl, -C(O)OR 5 substituted C2-C6 alkenyl, C2-C6 alkynyl, halo C2-C6 alkynyl, halogen, C1-C6 alkoxy, C1-C6 alkylthio, phenyl, -C(O)OR 5 、-NR 6 R 7 、cyano, nitro, carboxyl, amino;

[0024] R 5 、R 6 、R 7 are each independently selected from hydrogen, C1-C6 alkyl, halo C1-C6 alkyl;

[0025] R 3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, cyclopentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, 1-adamantylmethyl.

[0026] Furthermore, the racemic spiroenone compounds are selected from one of the following structures:

[0027]

[0028] and / or, the α-benzyl-α-diazoester is selected from one of the following structures:

[0029]

[0030]

[0031] Furthermore, the structure of the chiral bis(dioxo) ligand is:

[0032]

[0033] and / or, the metal compound is selected from scandium trifluoromethanesulfonate, yttrium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, indium trifluoromethanesulfonate;

[0034] And / or, the organic solvent is selected from halogenated hydrocarbon solvents.

[0035] Furthermore,

[0036] The chiral bis(oxazoline) ligand is L3-PiMe2CH(2Nap)2;

[0037] And / or, the metal compound is selected from scandium trifluoromethanesulfonate;

[0038] And / or, the organic solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane;

[0039] Preferably, the organic solvent is selected from 1,1,2,2-tetrachloroethane.

[0040] Furthermore,

[0041] The molar ratio of the racemic spiroenone compound to the α-benzyl-α-diazoester is 1:(0.5 - 2);

[0042] And / or, the molar ratio of the chiral bis(oxazoline) ligand to the metal compound is 1:(1 - 2);

[0043] And / or, the chiral bis(oxazoline) ligand is 10 - 20% of the molar amount of the racemic spiroenone compound;

[0044] And / or, the molar ratio of the racemic spiroenone compound to the organic solvent is (0.01 - 0.1) mmol:1 mL;

[0045] Preferably,

[0046] The molar ratio of the racemic spiroenone compound to the α-benzyl-α-diazoester is 1:1.25;

[0047] And / or, the molar ratio of the chiral bis(oxazoline) ligand to the metal compound is 1:1.3;

[0048] And / or, the chiral bis(oxazoline) ligand is 10% of the molar amount of the racemic spiroenone compound;

[0049] And / or, the molar ratio of the racemic spiroenone compound to the organic solvent is 0.025 mmol:1 mL.

[0050] Furthermore, the chiral bis(oxazoline) ligand and the metal compound are activated before use. The activation method is: dissolving the chiral bis(oxazoline) ligand and the metal compound in tetrahydrofuran, stirring, and then drying the tetrahydrofuran to obtain.

[0051] Furthermore, the aforementioned synthesis method includes the following steps:

[0052] (1) Dissolve the chiral bis(oxazoline) ligand and the metal compound in tetrahydrofuran, stir, and then evaporate the tetrahydrofuran to dryness;

[0053] (2) Add the racemic spiroketone compound, an organic solvent, and an α-benzyl-α-diazoester, and carry out the reaction;

[0054] (3) Separate and purify the two chiral spiroketone compounds shown in Formula I and Formula II by column chromatography.

[0055] Furthermore, the temperature of the reaction is 0 to 40 °C; and / or, the reaction time is 1 to 100 h;

[0056] Preferably, the temperature of the reaction is 0 °C; and / or, the reaction time is 6 to 8 h.

[0057] The present invention also provides a chiral spiroketone compound and its derivatives, and the compound and its derivatives are selected from one of the following structures:

[0058]

[0059]

[0060]

[0061] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) naming system.

[0062] Definition of terms used in the present invention: Unless otherwise specified, the initial definitions provided for the groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, their meanings should be given by those skilled in the art according to the disclosure and context.

[0063] "Substituted" means that a hydrogen atom in a molecule is replaced by other different atoms or molecules.

[0064] The minimum and maximum carbon atom contents in a hydrocarbon group are indicated by a prefix. For example, the prefix C a ~C b alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, "C1-C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, specifically C1, C2, C3, C4, C5, C6 alkyl; "C1-C6 alkoxy" refers to an alkoxy group containing 1 to 6 carbon atoms, specifically C1, C2, C3, C4, C5, C6 alkoxy.

[0065] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of carbon atoms. For example, C1-C6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, i.e., an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group can be straight-chain or branched-chain. Representative branched-chain alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl, etc.

[0066] "Alkenyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. The alkenyl can be straight-chain or branched-chain.

[0067] "Alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl can be straight-chain or branched-chain.

[0068] "Halogen" is fluorine, chlorine, bromine, or iodine.

[0069] "Cycloalkyl" refers to a saturated or unsaturated all-carbon monocyclic or polycyclic (including fused rings, spiro rings, or bridged rings) that does not have a conjugated π-electron system, such as including but not limited to: etc.

[0070] "Heterocycloalkyl" means that at least one carbon atom on the ring of cycloalkyl is replaced by a heteroatom, and the heteroatom is O, N, or S, and it is a saturated or unsaturated monocyclic or polycyclic (including fused rings, spiro rings, or bridged rings) that does not have a conjugated π-electron system, such as including but not limited to:

[0071] etc.

[0072] "Aryl" refers to an all-carbon monocyclic or polycyclic (including fused rings, spiro rings, or bridged rings) having a conjugated π-electron system, such as including but not limited to phenyl, naphthyl, phenanthryl, anthryl, fluorenyl, and indenyl, etc. The aromatic ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N, or S, and the point connecting to the parent must be on a carbon atom of the ring having a conjugated π-electron system, such as including but not limited to etc.

[0073] "Heteroaryl" refers to an aryl in which at least one carbon atom on the ring having a conjugated π-electron system is replaced by a heteroatom, and the heteroatom is O, N, or S, such as including but not limited to thienyl, furyl, isothiazolyl, etc.

[0074] For the compounds of the present invention, in order to more intuitively represent the spatial structure of the spiroenone compounds, gray and bold black chemical bonds are used to represent the helical chirality. When observing from the top of the molecular structure, the front part is represented by bold black chemical bonds, and the rear part is represented by gray chemical bonds.

[0075] Compared with the prior art, the present invention has achieved the following beneficial effects:

[0076] (1) Using chiral bis(oxazoline) ligands and metal compounds as catalysts, and racemic spiroenone compounds and α-benzyl-α-diazo esters as raw materials, it is possible to achieve the high-yield and high enantioselective synthesis of two types of spiroenones in a one-pot reaction, with good substrate generality and smooth conversion of various substituted substrates.

[0077] (2) The product is easily separated from the catalyst and raw materials.

[0078] (3) Compared with the previous methods, the catalyst used in this method avoids the use of precious metals, greatly reduces the cost and is more environmentally friendly, providing an efficient and green new synthesis method.

[0079] In summary, the present invention provides a method for synthesizing chiral spiroenone compounds. The present invention uses racemic spiroenone compounds and α-benzyl-α-diazo esters as raw materials, and through the catalytic reaction of chiral bis(oxazoline) metal complexes, a series of chiral spiroenone compounds are obtained. The present invention provides a green, simple and inexpensive new method for the synthesis of various substituted chiral spiroenone compounds. At the same time, the present invention proves that a series of synthesized chiral spiroenone compounds have excellent electronic circular dichroism and have strong application value in the field of chiral optical materials.

[0080] Obviously, based on the above content of the present invention, according to the common general knowledge and conventional means in the art, without departing from the above basic technical idea of the present invention, other various forms of modifications, substitutions or changes can be made.

[0081] The following is a further detailed description of the above content of the present invention through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention. Description of the Drawings

[0082] Figure 1 are the ultraviolet-visible absorption spectrum, circular dichroism spectrum and dissymmetry absorption factor of M-A1.

[0083] Figure 2 are the ultraviolet-visible absorption spectrum, circular dichroism spectrum and dissymmetry absorption factor of M-A2.

[0084] Figure 3 The UV-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A3.

[0085] Figure 4 The UV-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A4.

[0086] Figure 5 The UV-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A5.

[0087] Figure 6 The UV-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A6.

[0088] Figure 7 The UV-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A7.

[0089] Figure 8 The UV-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A8.

[0090] Figure 9 The UV-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A9.

[0091] Figure 10 The UV-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A10.

[0092] Figure 11 The UV-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A11.

[0093] Figure 12 The UV-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A12.

[0094] Figure 13 The UV-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A13.

[0095] Figure 14 The UV-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A14.

[0096] Figure 15 The UV-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A15.

[0097] Figure 16 The UV-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A16.

[0098] Figure 17 The UV-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A17.

[0099] Figure 18 The ultraviolet-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A18.

[0100] Figure 19 The ultraviolet-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A19.

[0101] Figure 20 The ultraviolet-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-A20.

[0102] Figure 21 The ultraviolet-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-E6.

[0103] Figure 22 The ultraviolet-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-E3.

[0104] Figure 23 The ultraviolet-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M-E4.

[0105] Figure 24 The ultraviolet-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of P,S-C1.

[0106] Figure 25 The ultraviolet-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M,R-C1.

[0107] Figure 26 The ultraviolet-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of M,S-C1.

[0108] Figure 27 The ultraviolet-visible absorption spectrum, circular dichroism spectrum, and dissymmetry absorption factor of P,R-C1.

[0109] Figure 28 The dissymmetry absorption factor g of chiral spiroketone compounds with different structures abs . Detailed implementation mode

[0110] Unless otherwise specified, the raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products. The purchased 1,1,2,2-tetrachloroethane is dried and distilled using calcium hydride and then added with rod-shaped molecular sieve dried at 500 °C for more than 3 hours and stored in the dark for use.

[0111] In the present invention, the prefix "race" represents a racemic structure.

[0112] The specific structures of the metal salts, bis(oxazoline) ligands, and α-benzyl-α-diazo esters involved in the specific embodiments of the present invention are as follows:

[0113] (1) Metal salts: Sc(OTf)3, Y(OTf)3, La(OTf)3, Yb(OTf)3, In(OTf)3

[0114] (2) Bis(oxazoline) ligands:

[0115] The structures of the chiral bis(oxazoline) ligands are as follows:

[0116]

[0117] The structures of the racemic bis(oxazoline) ligands are as follows:

[0118]

[0119] (3) α-Benzyl-α-diazo esters:

[0120]

[0121]

[0122] Example 1. Selection of metal salts in the preparation of spiroenone compounds of the present invention

[0123] This example studies the asymmetric homologation ring-expansion reaction of α-benzyl-α-diazo ester (B35, Ph-CH2-C(N)2C(O)OCH3) with racemic spiroenone catalyzed by different metal salts and racemic bis(oxazoline) ligand race-L3-PiEt2.

[0124] The reaction route of this example is as follows:

[0125]

[0126] Weigh racemic spiroenone race-A1 (0.05 mmol), bis(oxazoline) ligand race-L3-PiEt2 (0.005 mmol), and metal salt (0.0065 mmol) into a test tube in a glove box in sequence. The amount of the bis(oxazoline) ligand is 10% mmol of the amount of racemic spiroenone. Add 1.0 mL of dichloromethane. After stirring at 35 °C for 0.5 h, add α-benzyl-α-diazo ester B35 (0.025 mmol), and continue the reaction for 12 h. Then, separate and purify by column chromatography with petroleum ether / ethyl acetate (9:1, v:v) to obtain product C35, and at the same time, recycle the raw material race-A1. The enantiomeric excess (ee) of product C35 is determined by high-performance liquid chromatography (Daicel chiralcel IA, V 正己烷 :V 异丙醇= 90:10, flow rate 1.0 mL / min), and the enantiomeric excess (ee) of the recovered A1 was determined by supercritical carbon dioxide liquid chromatography (Daicel chiralcel AD-3, V 二氧化碳 :V 甲醇 = 70:30, flow rate 1.5 mL / min). The selection of metal salts is shown in Table 1.

[0127] Table 1. Kinetic resolution results of different metal salts

[0128]

[0129] Note: In the table, N.R. represents no reaction occurred, so no product C35 was formed, and thus both the d.r. and e.e. data are represented by -; d.r. of C35 represents the diastereomeric ratio of product C35; ee represents enantiomeric excess. The meanings of relevant identifiers in subsequent tables are the same.

[0130] As can be seen from Table 1: Only scandium trifluoromethanesulfonate (Sc(OTf)3) as the metal salt can catalyze this reaction, so Sc(OTf)3 is the best, and Sc(OTf)3 was selected for subsequent research. At the same time, the enantiomeric excess of the product C35 obtained using the racemic bisoxazoline ligand was 0 (race-C35), and during the reaction, there was no selective conversion of the starting material A1 of a certain configuration, so the enantiomeric excess of the recovered starting material A1 was also 0 (race-A1).

[0131] Example 2. Selection of chiral bisoxazoline ligands in the preparation of spiroenone compounds of the present invention

[0132] This example studied the asymmetric homologation ring-expansion reaction of α-benzyl-α-diazoester (B35, Ph-CH2-C(N)2C(O)OCH3) with racemic spiroenone catalyzed by scandium trifluoromethanesulfonate and chiral bisoxazoline ligands with different structures to achieve the kinetic resolution of racemic spiroenone.

[0133] As can be seen from Example 1, when the racemic bisoxazoline ligand was selected, all the obtained products were racemic products. In this example, a chiral bisoxazoline ligand was selected for the reaction to prepare chiral spiroenone compounds.

[0134] The reaction route of this example is as follows:

[0135]

[0136] In a glove box, racemic spiroenone race-A1 (0.05 mmol), chiral bis(oxazoline) ligand Ligand (0.005 mmol), and scandium(III) trifluoromethanesulfonate (0.0065 mmol) were successively weighed into a test tube. 1.0 mL of dichloromethane was added, and after stirring at 35 °C for 0.5 h, α-benzyl-α-diazoester B35 (0.025 mmol) was added. After continuing the reaction for 12 h, the product C35 was obtained by column chromatography purification with petroleum ether / ethyl acetate (9:1, v:v), and at the same time, the raw material race-A1 was recovered. The enantiomeric excess (ee) of the product C35 was determined by high-performance liquid chromatography (Daicel chiralcel IA, V 正己烷 :V 异丙醇 = 90:10, flow rate 1.0 mL / min), and the enantiomeric excess (ee) of the recovered A1 was determined by supercritical carbon dioxide liquid chromatography (Daicel chiralcel AD-3, V 二氧化碳 :V 甲醇 = 70:30, flow rate 1.5 mL / min). The selection of the chiral bis(oxazoline) ligand Ligand is shown in Table 2.

[0137] Table 2. Kinetic resolution results of different chiral bis(oxazoline) ligands

[0138]

[0139] As can be seen from Table 2: Except that the reaction cannot proceed when using the chiral bis(oxazoline) ligand L3-Pi i Pr2, the reaction can occur with other chiral bis(oxazoline) ligands, thereby generating chiral products (P,S-C35), and the selective conversion of the P-configured raw material (P-A1) can be achieved during the reaction. Recycling the raw material A1 can obtain A1 with an excess of the M configuration (M-A1). Among them, the chiral bis(oxazoline) ligand L3-PiMe2CH(2Nap)2 is the best because when L3-PiMe2CH(2Nap)2 is used as the ligand, the selective conversion of the P-configured raw material (P-A1) can be better achieved, and both the enantioselectivity and diastereoselectivity of the obtained product P,S-C35 can reach better results.

[0140] Example 3. Selection of reactant ratio and solvent dosage when preparing spiroenone compounds in the present invention

[0141] This example studies the influence of the reactant ratio and solvent dosage on the reaction results in the asymmetric homologation ring-expansion reaction catalyzed by scandium(III) trifluoromethanesulfonate and the chiral bis(oxazoline) ligand L3-PiMe2CH(2Nap)2 to achieve the kinetic resolution of racemic spiroenone.

[0142] The reaction route of this example is as follows:

[0143]

[0144] In a glove box, racemic spiroenone race-A1 (0.05 mmol), chiral bis(dioxo) ligand L3-PiMe2CH(2Nap)2 (0.005 mmol), and scandium(III) trifluoromethanesulfonate (0.0065 mmol) were successively weighed into a test tube. X mL of dichloromethane was added. After stirring at 35 °C for 0.5 h, α-benzyl-α-diazoester B35 (Y mmol) was added, and the reaction was continued for Z h. Then, the product C35 was obtained by column chromatography separation and purification with petroleum ether / ethyl acetate (9:1, v:v), and at the same time, the raw material race-A1 was recovered. The enantiomeric excess (ee) of product C35 was determined by high performance liquid chromatography (Daicel chiralcel IA, V 正己烷 :V 异丙醇 = 90:10, flow rate 1.0 mL / min), and the enantiomeric excess (ee) of the recovered A1 was determined by supercritical carbon dioxide liquid chromatography (Daicel chiralcel AD-3, V 二氧化碳 :V 甲醇 = 70:30, flow rate 1.5 mL / min). The selection of the reactant ratio and the solvent dosage is shown in Table 3.

[0145] Table 3. Kinetic resolution results with different reactant ratios and solvent dosages

[0146]

[0147] As can be seen from Table 3, choosing different reactant ratios and solvent dosages has a great influence on the reaction results. Among them, when 2 mL of dichloromethane is used as the solvent and the molar ratio of the reactants race-A1 to B35 is 1:1.25, the reaction can obtain better results in a shorter time.

[0148] Example 4. Selection of diazoester in the preparation of spiroenone compounds of the present invention

[0149] This example studies the asymmetric homologation ring-expansion reaction of scandium(III) trifluoromethanesulfonate and chiral bis(dioxo) ligand L3-PiMe2CH(2Nap)2 catalyzing different structures of α-benzyl-α-diazoesters and racemic spiroenone to achieve the kinetic resolution of racemic spiroenone.

[0150] The reaction route of this example is as follows:

[0151]

[0152] In a glove box, racemic spiroenone race-A1 (0.05 mmol), chiral bis(oxazoline) ligand L3-PiMe2CH(2Nap)2 (0.005 mmol) and scandium(III) trifluoromethanesulfonate (0.0065 mmol) were successively weighed into a test tube. 2.0 mL of dichloromethane was added, and the mixture was stirred at 35 °C for 0.5 h. Then, α-benzyl-α-diazoester B (0.0625 mmol) was added, and the reaction was continued for 12 h. After separation and purification by column chromatography, product C was obtained, and at the same time, the raw material race-A1 was recovered. The enantiomeric excess (ee) of product C was determined by high performance liquid chromatography (Daicel chiralcel IK, IA, OJ-3, V 正己烷 :V 异丙醇 = 90:10, flow rate 1.0 mL / min), and the enantiomeric excess (ee) of the recovered A1 was determined by supercritical carbon dioxide liquid chromatography (Daicel chiralcel AD-3, V 二氧化碳 :V 甲醇 = 70:30, flow rate 1.5 mL / min). The selection of α-benzyl-α-diazoester B is shown in Table 4. Different products C can be obtained by using different α-benzyl-α-diazoesters B.

[0153] Table 4. Kinetic resolution results of α-benzyl-α-diazoesters with different structures

[0154]

[0155] As can be seen from Table 4: Different chiral spiroenone compounds can be successfully prepared by selecting different α-benzyl-α-diazoesters. Among them, when R is i Bu (α-benzyl-α-diazoisobutyrate), the obtained product (P,S)-C has higher enantioselectivity and diastereoselectivity.

[0156] Example 5. Selection of reaction temperature, time and solvent in the preparation of spiroenone compounds of the present invention

[0157] This example studies the asymmetric homologation ring-expansion reaction of α-benzyl-α-diazoester and racemic spiroenone catalyzed by scandium(III) trifluoromethanesulfonate and chiral bis(oxazoline) ligand L3-PiMe2CH(2Nap)2 at different reaction temperatures, times and solvents to achieve the kinetic resolution of racemic spiroenone.

[0158] The reaction route of this example is as follows:

[0159]

[0160] In a glove box, racemic spiroenone race-A1 (0.05 mmol), chiral bis(oxazoline) ligand L3-PiMe2CH(2Nap)2 (0.005 mmol), and scandium(III) trifluoromethanesulfonate (0.0065 mmol) were successively weighed into a test tube. 2.0 mL of a solvent was added, and after stirring for 0.5 h at different temperatures, α-benzyl-α-diazoester B1 (0.0625 mmol) was added. After reacting for a certain time at this temperature, the product C1 was obtained by column chromatography purification with petroleum ether / dichloromethane (2:1, v:v), and at the same time, the raw material race-A1 was recovered. The enantiomeric excess (ee) of the product C1 was determined by high performance liquid chromatography (Daicel chiralcel IK, V 正己烷 :V 异丙醇 = 90:10, flow rate 1.0 mL / min), and the enantiomeric excess (ee) of the recovered A1 was determined by supercritical carbon dioxide liquid chromatography (Daicel chiralcel AD-3, V 二氧化碳 :V 甲醇 = 70:30, flow rate 1.5 mL / min). The reaction temperature, time, and solvent selection are shown in Table 5.

[0161] Table 5. Kinetic resolution results at different reaction temperatures, times, and solvents

[0162]

[0163]

[0164] In Table 5, [1] is replacing α-benzyl-α-diazoester B1 with α-benzyl-α-diazoester B37; [2] is changing the chiral bis(oxazoline) ligand from 10% mmol of the amount of racemic spiroenone to 20% mmol, that is, L3-PiMe2CH(2Nap)2 is 0.01 mmol and scandium(III) trifluoromethanesulfonate is 0.013 mmol; [3] is activating scandium(III) trifluoromethanesulfonate and chiral bis(oxazoline) ligand L3-PiMe2CH(2Nap)2 in tetrahydrofuran first, then drying the solvent and using it (then adding the solvent, racemic spiroenone, and diazoester for reaction). The activation method is adding 1 mL of tetrahydrofuran to scandium(III) trifluoromethanesulfonate and chiral bis(oxazoline) ligand L3-PiMe2CH(2Nap)2, stirring at 35 °C for 0.5 h, and then drying the tetrahydrofuran.

[0165] As can be seen from Table 5, when the temperature is 0 °C, the solvent is Cl2CHCHCl2, the reaction time is 6 h, the chiral bis(oxazoline) ligand is 10% mmol of the amount of racemic spiroketene, and Sc(OTf)3 and the chiral bis(oxazoline) ligand are first activated in tetrahydrofuran and then the solvent is dried and used, the reaction conditions are optimal. At the same time, α-benzyl-α-diazoester B1 is the best. Under these reaction conditions, the product P,S-C1 can be obtained with more ideal enantioselectivity and diastereoselectivity in terms of yield, and optically pure M-A1 can also be recovered with a good yield and e.e. value.

[0166] Example 6. Standard reaction of the present invention

[0167] According to Examples 1-5 above, the optimal conditions for the reaction of the present invention are as follows: the metal salt is Sc(OTf)3, the chiral bis(oxazoline) ligand is L3-PiMe2CH(2Nap)2, the reaction solvent is 1,1,2,2-tetrachloroethane, the reaction temperature is 0 °C, the reaction time is 6 h, the chiral bis(oxazoline) ligand is 10% mmol of the amount of racemic spiroketene, the molar ratio of the chiral bis(oxazoline) ligand to the metal salt is 1:1.3, the molar ratio of racemic spiroketene to α-benzyl-α-diazoester is 1:1.25, and the molar ratio (volume ratio) of racemic spiroketene to the reaction solvent is 0.025 mmol:1 mL; Sc(OTf)3 and the chiral bis(oxazoline) ligand are first activated in tetrahydrofuran and then the solvent is dried and used.

[0168] The reaction route of this example is as follows:

[0169]

[0170] Weigh L3-PiMe2CH(2Nap)2 (0.005 mmol) and scandium trifluoromethanesulfonate (0.0065 mmol) into a test tube in a glove box, add 1.0 mL of tetrahydrofuran, stir at 35 °C for 0.5 h, and then dry the tetrahydrofuran. Weigh racemic spiroketene race-A1 (0.05 mmol) in a glove box, add 2.0 mL of 1,1,2,2-tetrachloroethane, add α-benzyl-α-diazoester B1 (0.0625 mmol) at 0 °C, react for 6 h, and then separate and purify by column chromatography to obtain the product P,S-C1, and at the same time recover the raw material race-A1. The enantiomeric excess (ee) of the product P,S-C1 is measured by high performance liquid chromatography (Daicel chiralcel IK, V 正己烷 :V 异丙醇 = 90:10, flow rate 1.0 mL / min), and the enantiomeric excess (ee) of the recovered M-A1 is measured by supercritical carbon dioxide liquid chromatography (Daicel chiralcel AD-3, V 二氧化碳 :V 甲醇= 70:30, flow rate 1.5 mL / min) measurement.

[0171]

[0172] In the glove box, ent-L3-PiMe2CH(2Nap)2 (0.005 mmol) and scandium trifluoromethanesulfonate (0.0065 mmol) were successively weighed into a test tube, 1.0 mL of tetrahydrofuran was added, and after stirring at 35 °C for 0.5 h, the tetrahydrofuran was dried by evaporation. In the glove box, racemic spiroenone race-A1 (0.05 mmol) was weighed, 2.0 mL of 1,1,2,2-tetrachloroethane was added, and α-benzyl-α-diazoester B1 (0.0625 mmol) was added at 0 °C. After reacting for 6 h, it was separated and purified by column chromatography to obtain products M,R-C1 and P-A1. The enantiomeric excess (ee) of product M,R-C1 was measured by high performance liquid chromatography (Daicel chiralcel IK, V 正己烷 :V 异丙醇 = 90:10, flow rate 1.0 mL / min), and the enantiomeric excess (ee) of the recovered P-A1 was measured by supercritical carbon dioxide liquid chromatography (Daicel chiralcel AD-3, V 二氧化碳 :V 甲醇 = 70:30, flow rate 1.5 mL / min) measurement.

[0173]

[0174] In the glove box, ent-L3-PiMe2CH(2Nap)2 (0.005 mmol) and scandium trifluoromethanesulfonate (0.0065 mmol) were successively weighed into a test tube, 1.0 mL of tetrahydrofuran was added, and after stirring at 35 °C for 0.5 h, the tetrahydrofuran was dried by evaporation. In the glove box, spiroenone P-A1 (0.05 mmol) was weighed, 2.0 mL of 1,1,2,2-tetrachloroethane was added, and α-benzyl-α-diazoester B1 (0.0625 mmol) was added at 0 °C. After reacting for 48 h, it was separated and purified by column chromatography to obtain product P,R-C1. The enantiomeric excess (ee) of product P,R-C1 was measured by high performance liquid chromatography (Daicel chiralcel IK, V 正己烷 :V 异丙醇 = 90:10, flow rate 1.0 mL / min) measurement.

[0175]

[0176] In a glove box, L3-PiMe2CH(2Nap)2 (0.005 mmol) and scandium trifluoromethanesulfonate (0.0065 mmol) were successively weighed into a test tube, 1.0 mL of tetrahydrofuran was added, and after stirring at 35 °C for 0.5 h, the tetrahydrofuran was dried by evaporation. Spiroenone M-A1 (0.05 mmol) was weighed in a glove box, 2.0 mL of 1,1,2,2-tetrachloroethane was added, and α-benzyl-α-diazoester B1 (0.0625 mmol) was added at 0 °C. After reacting for 48 h, the product M,S-C1 was obtained by column chromatography purification. The enantiomeric excess (ee) of the product M,S-C1 was determined by high performance liquid chromatography (Daicel chiralcel IK, V 正己烷 :V 异丙醇 = 90:10, flow rate 1.0 mL / min).

[0177] According to the above reaction, by changing the structures of the racemic spiroenone and the α-benzyl-α-diazoester, chiral spiroenone compounds with different structures were prepared, and different chiral starting materials spiroenone were recovered. The structures, yields and enantioselectivities of the chiral spiroenone compounds, and the recovery yields and enantioselectivities of the chiral starting materials spiroenone are shown in Table 6.

[0178] Table 6. Chiral spiroenone compounds prepared by the above method and their yields and enantioselectivities

[0179]

[0180]

[0181]

[0182] In Table 6, the structures of the starting materials race-A1 to race-A20 are as follows:

[0183]

[0184] In Table 6, the structures of the product chiral spiroenone compounds are as follows:

[0185]

[0186]

[0187]

[0188] In Table 6, the structures of the obtained starting material chiral spiroenone compounds are as follows:

[0189]

[0190] Example 7. Preparation of derivatives of chiral spiroenone compounds of the present invention

[0191]

[0192] Weigh M-A1 (0.1 mmol) and Lawesson's reagent (0.5 mmol) successively into a pressure-resistant reaction tube, add 5.0 mL of toluene, react at 100 °C for 6 h, detect the reaction by thin-layer chromatography. After the raw material M-A1 is completely consumed, cool the reaction solution to room temperature, separate and purify it by column chromatography with petroleum ether / dichloromethane (10:1, v:v) to obtain the product M-E1 (yield > 99%).

[0193]

[0194] Weigh methyltriphenylphosphonium iodide (0.5 mmol) into a dry test tube, evacuate and replace with nitrogen, add 2.0 mL of tetrahydrofuran, add n-butyllithium (0.6 mL, 1.0 mol / L) at -78 °C and react for 0.5 h, then add M-A1 (0.1 mmol) and warm the reaction to room temperature. Detect the reaction by thin-layer chromatography. After the raw material M-A1 is completely consumed, quench the reaction with saturated ammonium chloride aqueous solution, extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and separate and purify it by column chromatography with petroleum ether / dichloromethane (3:1, v:v) to obtain the product M-E2 (yield 82%).

[0195]

[0196] Weigh M-A1 (0.1 mmol) and O-methylhydroxylamine hydrochloride (0.5 mmol) successively into a dry test tube, add 2.0 mL of pyridine, react at 45 °C for 8 h, detect the reaction by thin-layer chromatography. After the raw material M-A1 is completely consumed, remove the solvent under reduced pressure, and separate and purify it by column chromatography with petroleum ether / ethyl acetate (9:1, v:v) to obtain the product M-E3 (yield > 99%).

[0197]

[0198] Weigh M-A1 (0.1 mmol), hydrazine hydrate (1.0 mmol) and glacial acetic acid (0.5 mmol) successively into a dry test tube, add 2.0 mL of pyridine, react at 45 °C for 20 h, detect the reaction by thin-layer chromatography. After the raw material M-A1 is completely consumed, remove the solvent under reduced pressure, and separate and purify it by column chromatography with petroleum ether / ethyl acetate (4:1, v:v) to obtain the product M-E4 (yield > 99%).

[0199]

[0200] Weigh M-E4 (0.1 mmol) and anhydrous magnesium sulfate (0.2 mmol) successively into a dry test tube, add 5.0 mL of dichloromethane, add manganese dioxide (0.35 mmol) at 0 °C, warm up to room temperature and react for 1 h. Monitor the reaction by thin-layer chromatography. After the raw material M-E4 is completely consumed, filter off the insoluble matter by suction filtration with diatomaceous earth. After removing the solvent under reduced pressure, purify by column chromatography on petroleum ether / ethyl acetate (4:1, v:v) to obtain the product M-E5 (yield 60%).

[0201]

[0202] Weigh M-A1 (0.1 mmol), triethylsilane (0.5 mmol) and water (0.2 mmol) into a dry test tube, add 2.0 mL of dichloromethane, add boron trifluoride diethyl ether complex (0.4 mmol) at 0 °C, warm up to 45 °C and react for 8 h. Monitor the reaction by thin-layer chromatography. After the raw material M-A1 is completely consumed, remove the solvent under reduced pressure, purify by column chromatography on petroleum ether / ethyl acetate (9:1, v:v) to obtain the product M-E6 (yield 78%).

[0203]

[0204] Weigh M-A1 (0.1 mmol) and methanol (0.1 mmol) into a dry test tube, add 2.0 mL of tetrahydrofuran, add sodium borohydride (0.5 mmol) at 0 °C, react for 20 min. Monitor the reaction by thin-layer chromatography. After the raw material M-A1 is completely consumed, add water to quench the reaction, extract with ethyl acetate, wash the organic phase with saturated sodium chloride, and dry with anhydrous sodium sulfate. After removing the solvent under reduced pressure, purify by column chromatography on petroleum ether / ethyl acetate (9:1, v:v) to obtain the product M-E7 (yield >99%).

[0205]

[0206] Weigh M-A1 (0.1 mmol) into a dry test tube, add 2.0 mL of tetrahydrofuran, add methylmagnesium bromide (0.2 mmol, 1.0 mol / L) at 0 °C, react for 5 min. Monitor the reaction by thin-layer chromatography. After the raw material M-A1 is completely consumed, add ammonium chloride to quench the reaction, extract with ethyl acetate, wash the organic phase with saturated sodium chloride, and dry with anhydrous sodium sulfate. After removing the solvent under reduced pressure, purify by column chromatography on petroleum ether / ethyl acetate (9:1, v:v) to obtain the product M-E8 (yield >99%).

[0207]

[0208] Weigh M-A1 (0.1 mmol) into a dry test tube, add 2.0 mL of tetrahydrofuran, add phenylmagnesium bromide (0.2 mmol, 1.0 mol / L) at 0 °C, react for 5 min, monitor the reaction by thin-layer chromatography. After the raw material M-A1 is completely consumed, quench the reaction with ammonium chloride, extract with ethyl acetate, wash the organic phase with saturated sodium chloride, and dry with anhydrous sodium sulfate. After removing the solvent under reduced pressure, purify by column chromatography with petroleum ether / ethyl acetate (9:1, v:v) to obtain the product M-E9 (yield > 99%).

[0209]

[0210] Weigh M-A1 (0.1 mmol) into a dry test tube, add 2.0 mL of dichloromethane, add trimethylsilyldiazomethane (0.4 mmol) at -40 °C, then add boron trifluoride diethyl ether complex (0.2 mmol) and react for 2 min. Monitor the reaction by thin-layer chromatography. After the raw material M-A1 is completely consumed, quench the reaction with water, extract with dichloromethane, wash the organic phase with saturated sodium chloride, and dry with anhydrous sodium sulfate. After removing the solvent under reduced pressure, directly use the crude product in the next step. Transfer the crude product into a dry test tube, add triethylamine (0.2 mmol), 4-dimethylaminopyridine (0.01 mmol) and 5.0 mL of dichloromethane, add isopropyl chloroformate (0.15 mmol) at 0 °C, react for 20 min, add water to quench the reaction, extract with dichloromethane, wash the organic phase with saturated sodium chloride, and dry with anhydrous sodium sulfate. After removing the solvent under reduced pressure, purify by column chromatography with petroleum ether / ethyl acetate (9:1, v:v) to obtain the product M-E10 (yield 81%).

[0211] The beneficial effects of the present invention are demonstrated by the following specific test examples.

[0212] Test Example 1. Determination of ECD, UV-absorption and asymmetric absorption factor G of the chiral heliacene ketone compounds and their derivatives of the present invention abs Determination

[0213] I. Experimental method

[0214] Determine the ECD, UV-absorption and asymmetric absorption factor G of the chiral heliacene ketone compounds and their derivatives prepared in Examples 6 and 7 abs Determination.

[0215] 1. Electronic Circular Dichroism (ECD) Test of Chiral Spiroketone Compounds and Their Derivatives: 0.005 mmol of each chiral spiroketone compound and its derivative spiroketone compound were separately added to 5 mL of dichloromethane to prepare solutions, which were then filled into quartz cuvettes with a thickness of 1 mm. The samples were scanned from 280 nm to 420 nm using the Chirascan V100 circular dichroism spectrometer from Applied Photophysics Ltd. in the UK, and the millidegree (mdeg) data at different wavelengths were collected.

[0216] 2. UV-Absorption Test of Chiral Spiroketone Compounds and Their Derivatives: 0.005 mmol of each chiral spiroketone compound and its derivative were separately added to 5 mL of dichloromethane to prepare solutions, which were then filled into quartz cuvettes with a thickness of 1 mm. The samples were scanned from 280 nm to 420 nm using the Chirascan V100 circular dichroism spectrometer from Applied Photophysics Ltd. in the UK, and the absorbance (A) data at each wavelength, i.e., the absorption intensity data, were collected.

[0217] 3. Asymmetric Absorption Factor G of Chiral Spiroketone Compounds and Their Derivatives abs Determination: The g-factor in Circular Dichroism (CD) is an important parameter for measuring the optical activity of chiral molecules, and it is related to the absorption intensity of the circular dichroism spectrum, etc. The value of the g-factor reflects the strength and characteristics of the optical activity of chiral molecules. The larger the g-factor, the greater the difference in the absorption of left-handed and right-handed circularly polarized light by the chiral molecule, and the more obvious its chiral characteristics; conversely, the smaller the g-factor, the weaker the chiral characteristics. The positive or negative sign of the g-factor indicates the relative order of the absorption of left-handed and right-handed circularly polarized light by the chiral molecule. A positive g-factor indicates that the absorption of left-handed circularly polarized light is greater than that of right-handed circularly polarized light, and a negative g-factor is the opposite.

[0218] The following is the calculation formula and derivation of the g-factor:

[0219] For Electronic Circular Dichroism (ECD), the calculation formula of the g-factor is:

[0220] g = Δε / ε

[0221] Among them: Δε is the molar circular dichroism, and there is a mathematical relationship of [θ] = 3298Δε between it and the molar ellipticity [θ]. 32980 is a constant, which is related to factors such as unit conversion. It is derived from the relationship between the molar extinction coefficient and the molar ellipticity and relevant physical constants, and is used to convert experimental measurement data such as ellipticity into a dimensionless g factor. The molar ellipticity [θ] can be calculated from the millidegree (mdeg) data measured in the electronic circular dichroism spectrum test according to [θ] = mdeg / (l1×c). ε is the molar extinction coefficient, which can be calculated from the absorbance data (A) measured in the ultraviolet absorption test according to ε = A / (l2×c). c is the concentration of the sample, and l1 and l2 are the optical path lengths of the sample cell, with the units being millimeters (mm) and centimeters (cm) respectively.

[0222] According to the above mathematical relationship, the following equation can be obtained:

[0223] g = [mdeg / (l1×c×3298)] / [A / (l2×c)]

[0224] g = (mdeg / 32980) / A

[0225] g = mdeg / 32980×A

[0226] By processing the millidegree data (mdeg) and absorbance data (A) measured at each wavelength of each sample according to the above method, a curve graph of the asymmetric absorption factor and wavelength of each sample can be obtained.

[0227] II. Experimental Results

[0228] Through the above tests, it can be known that: the asymmetric absorption factors of the chiral spiroketone compounds and their derivatives obtained in the present invention are basically between 10 -3 -10 -2 orders of magnitude, indicating that the chiral spiroketone compounds and their derivatives synthesized by the method of the present invention have excellent electronic circular dichroism ( Figures 1 to 28 ).

[0229] In summary, the present invention provides a method for synthesizing chiral spiroketone compounds. The present invention uses racemic spiroketone compounds and α-benzyl-α-diazo esters as raw materials, and through a chiral bisoxazoline metal complex-catalyzed reaction, a series of chiral spiroketone compounds are obtained. The present invention provides a new green, simple and inexpensive method for the synthesis of various substituted chiral spiroketone compounds. At the same time, the present invention proves that a series of chiral spiroketone compounds synthesized have excellent electronic circular dichroism and have strong application value in the field of chiral optical materials.

Claims

1. A method for synthesizing a chiral spirone compound, characterized in that: It includes the following steps: In an organic solvent, a chiral dinitrogen oxide ligand and a metal compound are used as catalysts, and a racemic spiroenone compound and an α-benzyl-α-diazo ester are used as raw materials to react to obtain two chiral spiroenone compounds represented by formula I and formula II; in, Ring A1 and A2 are independently selected from 6- to 12-membered aryl, 5- to 12-membered heteroaryl, and 5- to 12-membered heterocycloalkyl; Ring A1 and A2 are the same or different; n1 and n2 are independently selected from 0, 1, 2, 3, 4 or 5; n1 and n2 are the same or different; m1 and m2 are independently selected from 0, 1, 2, 3, 4 or 5; m1 and m2 are the same or different; R 1a , R 1b is a substituent at any position on the benzene ring; each independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, 6-12 membered aryl; the substituent of the alkyl or alkoxy is selected from one or more halogens; R 1a and R 1b the same or different; R 4a is a substituent at any position on ring A1, R 4b is a substituent at any position on ring A2; R 4a , R 4b are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, 6-12 membered aryl; the substituents of the alkyl and alkoxy are selected from one or more halogens; R 4a and R 4b the same or different; R 2 The alkyl radical is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted 6-12-membered aryl, substituted or unsubstituted 5-12-membered heteroaryl, and ferrocenyl; the substituents of the alkyl, alkenyl, and alkynyl radical are selected from one or more of the following groups: substituted or unsubstituted 6-12-membered aryl, substituted or unsubstituted 5-12-membered heteroaryl, -C(O)OR 5 The substituents of the aryl and heteroaryl groups are selected from one or more of the following substituents: C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, halogenated C2-C6 alkenyl, -C(O)OR 5 Substituted C2-C6 alkenyl, C2-C6 alkynyl, halogenated C2-C6 alkynyl, halogen, C1-C6 alkoxy, C1-C6 alkylthio, 6-12 membered aryl, -C(O)OR 5 、-NR 6 R 7 , cyano, nitro, carboxyl, amino; R 5 , R 6 , R 7 are independently selected from hydrogen, C1-C6 alkyl, and halogenated C1-C6 alkyl; R 3 R is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, 3-8 membered cycloalkyl; 3 The alkyl substituents are selected from one or more of the following groups: 3-8 membered cycloalkyl, 6-12 membered aryl.

2. The synthesis method according to claim 1, characterized in that: Ring A1 and A2 are independently selected from phenyl, naphthyl, thienyl, furanyl, dihydrofuranyl; Ring A1 and A2 are the same or different; n1 and n2 are independently selected from 0, 1, 2 or 3; n1 and n2 are the same or different; m1 and m2 are independently selected from 0, 1, 2 or 3; m1 and m2 are the same or different; R 1a , R 1b R is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, trifluoromethyl, C1-C6 alkoxy, halogen, and phenyl; 1a and R 1b the same or different; R 4a , R 4b R is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, trifluoromethyl, C1-C6 alkoxy, halogen, and phenyl; 4a and R 4b the same or different; R 2 is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted pyridyl, ferrocenyl; the substituent of the alkenyl is selected from one or more of the following groups: phenyl, -C(O)OR 5 ; The phenyl, naphthyl, pyridyl, The substituent is selected from one or more of the following substituents: C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, halogenated C2-C6 alkenyl, -C(O)OR 5 Substituted C2-C6 alkenyl, C2-C6 alkynyl, halogenated C2-C6 alkynyl, halogen, C1-C6 alkoxy, C1-C6 alkylthio, phenyl, -C(O)OR 5 、-NR 6 R 7 , cyano, nitro, carboxyl, amino; R 5 , R 6 , R 7 are independently selected from hydrogen, C1-C6 alkyl, and halogenated C1-C6 alkyl; R 3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, Cyclopentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, 1-adamantylmethyl.

3. The synthesis method according to claim 1, characterized in that: The racemic spironol compound is selected from one of the following structures: And / or, the α-benzyl-α-diazo ester is selected from one of the following structures:

4. The synthesis method according to claim 1, characterized in that: The structure of the chiral dinitrogen oxide ligand is: and / or, the metal compound is selected from scandium trifluoromethanesulfonate, yttrium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, indium trifluoromethanesulfonate; And / or, the organic solvent is selected from halogenated hydrocarbon solvents.

5. The synthesis method according to claim 4, characterized in that: The chiral dinitrogen oxide ligand is L3-PiMe2CH(2Nap)2; and / or, the metal compound is selected from scandium trifluoromethanesulfonate; and / or, the organic solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane; Preferably, the organic solvent is selected from 1,1,2,2-tetrachloroethane.

6. The synthesis method according to any one of claims 1 to 5, characterized in that: The molar ratio of the racemic spironone compound to the α-benzyl-α-diazo ester is 1:(0.5-2); and / or, the molar ratio of the chiral dinitrogen oxide ligand to the metal compound is 1:(1-2); And / or, the chiral dinitrogen oxide ligand is 10-20% of the molar amount of the racemic spironenone compound; and / or, the molar volume ratio of the racemic spirenone compound to the organic solvent is (0.01-0.1) mmol:1 mL; Preferably, The molar ratio of the racemic spironone compound to the α-benzyl-α-diazo ester is 1:1.25; and / or, the molar ratio of the chiral dinitrogen oxide ligand to the metal compound is 1:1.3; and / or, the chiral dinitrogen oxide ligand is 10% of the molar amount of the racemic spironenone compound; And / or, the molar volume ratio of the racemic spirenone compound to the organic solvent is 0.025 mmol:1 mL.

7. The synthesis method according to any one of claims 1 to 5, characterized in that: The chiral dinitrogen oxide ligand and the metal compound are activated before use. The activation method is: dissolving the chiral dinitrogen oxide ligand and the metal compound in tetrahydrofuran, stirring, and then draining the tetrahydrofuran to obtain the obtained product.

8. The synthesis method according to claim 7, characterized in that: It includes the following steps: (1) dissolving a chiral dinitrogen oxide ligand and a metal compound in tetrahydrofuran, stirring, and then draining the tetrahydrofuran; (2) adding a racemic spironone compound, an organic solvent and α-benzyl-α-diazo ester to react; (3) Separating and purifying the two chiral spironone compounds represented by Formula I and Formula II by column chromatography.

9. The synthesis method according to claim 8, characterized in that: The reaction temperature is 0 to 40°C; and / or the reaction time is 1 to 100 hours; Preferably, the reaction temperature is 0°C; and / or the reaction time is 6 to 8 hours.

10. A chiral spirone compound and its derivatives, characterized in that: The compound and its derivatives are selected from one of the following structures:

Images