Preparation method of chiral hydrogenated carbazole skeleton compound

Abstract

The invention discloses a preparation method of a chiral hydrogenated carbazole skeleton compound, an asymmetric Diels-Alder reaction is catalyzed by a catalyst, an asymmetric catalytic system is a secondary amine-acid catalytic system, a dienophile is nitrogen-substituted-2 or 3-alkenyl indole, and a dienophile is beta-substituted-alpha, beta-unsaturated aldehyde, alpha-alkyl-alpha, beta-unsaturated aldehyde or alpha-alkyl-alpha, beta-unsaturated aldehyde. The invention also relates to a method for preparing the compound. The asymmetric Diels-Alder reaction of low-activity 3-alkenyl indole and 2-alkenyl indole with wide alpha, beta-unsaturated aldehyde is realized for the first time, so that a chiral hydrogenated carbazole skeleton containing a continuous chiral center and a full-carbon quaternary carbon chiral center and a polycyclic hydrogenated carbazole skeleton can be rapidly constructed; the method has the advantages of high yield, high stereoselectivity, mild conditions and the like, and is helpful for promoting research of synthetic methodology and pharmaceutical chemistry in related fields.

Description

A method for preparing chiral hydrogenated carbazole skeleton compounds Technical Field

[0001] This invention belongs to the technical field of organocatalysis and asymmetric synthesis, and in particular relates to a method for preparing chiral hydrogenated carbazole skeleton compounds. Background Technology

[0002] The hydrogenated carbazole skeleton is widely found in indole alkaloids and synthetic drugs. Many of its natural products and drug molecules exhibit excellent biological activity. For example, aspidospermidine has antiparasitic activity against Leishmaniasis and Trypanosoma cruzi; strychnine selectively excites the spinal cord and enhances skeletal muscle tone, but is also highly toxic to humans; alstilobanine A has a certain relaxing effect on phenylephrine-induced contraction of the aortic annulus in rats; GSK983 shows strong anti-EBV and anti-HPV activity; and Ramatroban shows great potential in the treatment of coronary artery disease and asthma. The structural formula is shown below:

[0003] Meanwhile, hydrogenated carbazole is also a key intermediate in the synthesis of complex natural products.

[0004] Using structurally simple 2-alkenylindole and 3-alkenylindole as substrates, and inexpensive chemicals such as alkenes, a one-step Diels-Alder reaction is one of the most efficient methods for synthesizing chiral hydrogenated carbazoles. The reported asymmetric Diels-Alder reaction between 3-alkenylindole and α,β-unsaturated aldehydes is only one example of a tandem reaction involving Diels-Alder / aza-Michael / Adol condensation, which cannot proceed to the chiral hydrogenated carbazole stage (DOI:10.1002 / chem.201302127), and the substrates are limited to 3-alkenylindole with no substituents on the nitrogen atom and β-aromatic-α,β-unsaturated aldehydes. The reported asymmetric Diels-Alder reactions of 2-alkenylindoles and α,β-unsaturated aldehydes and ketones are limited to two cases involving 2-alkenylindoles with alkyl terminal substitution of the aromatic ring. However, the product structures in these reports all have indole fragments after double bond isomerization, which makes it impossible to achieve regioselectivity of the aldehyde group in the Diels-Alder reaction and to obtain dearomatized products by maintaining the double bond after the reaction.

[0005]

[0006] In addition to the problems mentioned above, the existing preparation methods cannot generate optically pure chiral hydrogenated carbazole compounds from the reaction of 3-alkenylindole and α,β-unsaturated aldehydes; cannot construct chiral hydrogenated carbazole skeletons containing all-carbon quaternary carbon chiral centers and polycyclic hydrogenated carbazole skeletons by using 3-alkenylindole and α-alkyl-substituted acrolein or cyclic enaldehydes (e.g., 1-cyclopentenaldehyde) via asymmetric Diels-Alder reactions; cannot construct regioselective Diels-Alder hydrogenated carbazole skeletons from the reaction of 2-alkenylindole and α,β-unsaturated aldehydes; and cannot maintain indole dearomatization without shifting the double bond position.

[0007] The reasons for the above problems and defects are as follows: existing organic catalytic systems are not catalytically active enough to achieve this type of reaction with high stereoselectivity and universality; or the catalytic system makes it impossible to obtain Diels-Alder reaction products with different regioselectivity, or to maintain the double bond position after the Diels-Alder reaction, thus making it impossible to obtain indole dearomatization products.

[0008] Therefore, developing methods to rapidly construct chiral centers with multiple chiral centers or all-carbon and quaternary-carbon chiral centers, to synthesize hydrogenated carbazole skeletons containing indole dearomatization fragments, and to develop regioselective Diels-Alder reaction products has significant research and application value. Summary of the Invention

[0009] To address the problem in existing technologies that lack methods for synthesizing hydrogenated carbazole skeletons from low-activity 3-enylindole and universal α,β-unsaturated aldehydes, α-alkyl-α,β-unsaturated aldehydes, and 1-cyclopentenaldehyde, this patent invention provides a method for achieving this reaction. This invention provides a method for preparing chiral hydrogenated carbazole skeleton compounds, based on the asymmetric Diels-Alder reaction of low-activity 2-enylindole, 3-enylindole, and universal α,β-unsaturated aldehydes, α-alkyl-α,β-unsaturated aldehydes, and 1-cyclopentenaldehyde, constructing chiral hydrogenated carbazole skeletons containing continuous chiral centers, all-carbon and quaternary-carbon chiral centers, and polycyclic hydrogenated carbazole skeletons. To achieve the above technical objectives, the present invention provides the following technical solution: As the first aspect of the present invention, it provides a method for preparing chiral hydrogenated carbazole skeleton compounds, which is carried out through a catalytic asymmetric Diels-Alder reaction. The asymmetric catalytic system used in the present invention is a secondary amine catalyst and an acid catalytic system. The diene is nitrogen-substituted-2 or 3-enylindole, and the dienophile is β-substituted-α,β-unsaturated aldehyde, α-alkyl-α,β-unsaturated aldehyde, or 1-cyclopentenaldehyde. The synthesis of chiral hydrogenated carbazole skeletons containing continuous chiral centers, all-carbon and quaternary carbon chiral centers and polycyclic hydrogenated carbazole skeletons is achieved under conditions of -20℃–120℃.

[0010] Specifically, the preparation method includes the following steps: reacting the compound represented by Formula I with the α,β-unsaturated aldehyde represented by Formula V in a secondary amine catalyst and an acid catalytic system to obtain a chiral hydrogenated carbazole skeleton compound. I; V; where R 4 and R 5 Selected from H or CH=CH2 respectively; the reaction formula is as follows:

[0012] In the secondary amine catalyst and acid catalysis system, the secondary amine catalyst is at least one of formulas A to L: .

[0013] In the secondary amine catalyst and acid catalytic system, the acid is trifluoromethanesulfonic acid, boron trifluoride ether, bis(trifluoromethanesulfonamide) (Tf2NH), trimethylsilyltrifluoromethanesulfonate (TMSOTf), trifluoroacetic acid, hydrochloric acid, or perchloric acid.

[0014] In the secondary amine catalyst and acid catalytic system, the solvent is dichloromethane (DCM), dichloroethane (DCE), chloroform (CHCl3), chlorobenzene (PhCl), tetrahydrofuran (THF), acetonitrile (CH3CN), toluene (Tol), trifluoroethanol (TFE, CF3CH2OH), ethyl tert-butyl ether (ETBE), or methyl tert-butyl ether (MTBE).

[0015] The preparation method includes the following steps: dissolving secondary amine catalysts A to L in a solvent, cooling to -78℃ to room temperature (rt), adding acid dropwise to the system, wherein the molar amounts of the secondary amine catalyst and the acid are 1-30 mol% relative to the alkenyl indole compound, and the molar ratio of the secondary amine catalyst and the acid is 3:1 to 1:3; after stirring, adding α,β-unsaturated aldehydes of formula V dropwise, stirring, and then adding alkenyl indole compounds of formula I dropwise; the system reacts between -78℃ and 120℃, and the reaction is monitored by TLC.

[0016] Furthermore, the preparation method further includes: after the 2-enylindole or 3-enylindole compound has completely disappeared, quenching the reaction with saturated sodium bicarbonate solution, separating the phases, extracting the aqueous phase twice with ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, filtration and elution, and then evaporating the organic phase to dryness. Purification by petroleum ether / ethyl acetate column chromatography yields the target Diels-Alder reaction product. The diastereoselectivity (dr) value of the product is determined by 1H NMR spectroscopy, and the enantioselectivity (ee) value is determined by chiral high-performance liquid chromatography (HPLC). HPLC analysis is performed using chiral IA, IB, IC, ID, IE, or IK columns. Racemic products are obtained by catalyzing the corresponding substrate with a racemic catalyst.

[0017] As a second aspect of the present invention, it is provided to provide a chiral hydrogenated carbazole skeleton compound prepared based on the first aspect of the present invention, having a structure as shown in Formula II, III or IV: II; III; IV; where R 1 For COOBn, COOMe, COOEt, Boc, Ms, or Ts; R 2 H, a C1-C4 alkyl group optionally substituted at the 4-7 positions, a C1-C4 alkoxy group optionally substituted at the 4-7 positions, a halogen-containing substituent optionally substituted at the 4-7 positions, such as -CF3, CH2CF3, or a halogen optionally substituted at the 4-7 positions, said halogen being F, Cl, or Br; in some embodiments of the invention, R 2 is H, 4-Me, 5-Me, 6-Me, 7-Me, 4-MeO, 5-MeO, 6-MeO, 7-MeO, 4-BnO, 5-BnO, 6-BnO, 7-BnO, 4-F, 5-F, 6-F, 7-F, 4-Cl, 5-Cl, 6-Cl, 7-Cl, 4-Br, 5-Br, 6-Br or 7-Br; R 3 Methyl (Me), ethyl (Et), isopropyl ( i Pr), -(CH2) m i Pr, m=1-7, C5-C6 cycloalkyl, -(CH2) m Ph, m = 1-7, aryl, optionally substituted aryl, including alkane-substituted aryl, halogen-substituted aryl, haloalkanes-substituted aryl, or optionally substituted 5- to 10-membered heterocycles or heteroaromatic rings, wherein the 5- to 10-membered heterocycles or heteroaromatic rings optionally contain one or more heteroatoms selected from N, O, or S as ring members; in one embodiment of the present invention, the 5- to 10-membered heterocycles or heteroaromatic rings are furanyl.

[0018] R 6 It is H, C1-C8 alkyl.

[0019] Or, R 3 and R 6 Together with the carbon atoms to which they are attached, they form 3 to 8-membered carbon rings, preferably 5-membered carbon rings.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. The present invention realizes for the first time the asymmetric Diels-Alder reaction of low-activity 3-enylindole substrates, 2-enylindole and widely α,β-unsaturated aldehydes, thereby enabling the rapid construction of chiral hydrogenated carbazole skeletons containing continuous chiral centers, all-carbon and quaternary carbon chiral centers and polycyclic hydrogenated carbazole skeletons. It has the advantages of high yield, high stereoselectivity and mild conditions, which helps to promote the research of synthetic methodology and medicinal chemistry in related fields.

[0021] 2. Based on the preparation method provided by this invention, it is possible to prepare polycyclic hydrogenated carbazole skeletons with different substituents on each ring, providing a new idea for the synthesis and preparation of similar structures in the future. It can be used for structural modification processes to prepare drugs with chiral hydrogenated carbazole skeletons and polycyclic hydrogenated carbazole skeletons. Detailed Implementation

[0022] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0023] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0024] This invention provides a method for preparing chiral hydrogenated carbazole skeleton compounds with structures as shown in Formula II, III, or IV: II; III; IV; In one or more embodiments of the present invention, the reaction formula is:

[0025] In the formula, R 1 R 2 R 3 R 4 R 5 R 6 The definitions are the same as those in general formulas I~V; cat represents catalyst, and acid represents acid.

[0026] Implementation Case 1: Preparation: 13.0 mg of (R)-α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidine was weighed at room temperature and dissolved in dichloromethane. 5.6 mg (20 mol%) of bis(trifluoromethyl)sulfonylimide was added at -78°C. After stirring for 10 minutes, 17.5 mg of crotonaldehyde (0.25 mmol) was added, followed by 1-benzyloxycarbonyl-3-vinylindole (0.10 mmol). The mixture was heated to 55°C and reacted for 20 hours. The reaction was quenched with saturated sodium bicarbonate solution. The mixture was separated, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, washed, and then evaporated to dryness. The organic phase was purified by column chromatography with petroleum ether / ethyl acetate (10:1) to obtain the target Diels-Alder reaction product, yielding 30.0 mg of a pale yellow oil with a yield of 86% and a diastereoselectivity of 10:1.

[0027] 1 H NMR (600 MHz, CDCl3)δ 9.54 (s, 1H), 7.95 (s, 1H), 7.47 – 7.32 (m,6H), 7.23 (s, 1H), 7.02 (q,J= 8.8, 8.2 Hz, 1H), 6.08 (q,J= 3.7 Hz, 1H), 5.33(s, 2H), 4.91 (s, 1H), 3.32 (s, 1H), 2.56 (d,J= 18.9 Hz, 1H), 2.45 (s, 1H), 1.86 (d,J= 18.3 Hz, 1H), 1.14 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 202.04, 153.36, 135.82, 134.70, 129.41, 128.84, 128.82, 128.61, 128.34, 123.58, 120.13, 118.36, 117.71, 116.10, 68.04, 63.76, 59.08, 30.32, 26.75, 21.25. MS (m / z): 347; Optical purity analysis: the enantioselectivity of the product was 99% excess. Chiral IK column (n-hexane:isopropanol:diethylamine 90:10:0.1, v / v) 0.8 mL / min, 40 °C, retention time t1= 12.914 min, t2 = 31.721 min. Example using a different catalyst: In another example, the catalyst used was 15.0 mg of (R)-α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanoltrimethylsilyl ether (B), and other conditions were the same as in Example 1, to produce the above product, yielding 28.0 mg of a pale yellow oil, with a yield of 81%, diastereoselectivity of 10:1, and an enantioselectivity of 99% excess.

[0028] In another embodiment, the catalyst used was 5.3 mg of (R)-2-(methoxydiphenylmethyl)pyrrolidine (K), and other conditions were the same as in Example 1, to produce the above product, yielding 10.2 mg of a pale yellow oily substance in 30% yield, with a diastereoselectivity of 2:1 and an enantioselectivity of 94% excess.

[0029] In another embodiment, the catalyst used was 4.9 mg of (2R,5R)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolinone (I), and other conditions were the same as in Example 1, to prepare the above product, yielding 21.6 mg of a pale yellow oil with a yield of 62%, diastereoselectivity >20:1, and an enantioselectivity of 93% excess.

[0030] In another embodiment, the catalyst used was 5.1 mg (R)-α,α-diphenylprolyl (L), and other conditions were the same as in Example 1, to obtain the above product, yielding 7.0 mg of a pale yellow oily substance with a yield of 20%, diastereoselectivity of 3:1, and an enantioselectivity excess of 96%.

[0031] In another embodiment, the catalyst used was 6.2 mg of (R)-α,α-bis(3,5-dimethylphenyl)proline (E), and other conditions were the same as in Example 1, to produce the above product, yielding 6.5 mg of a pale yellow oily substance in 19% yield, with a diastereoselectivity of 4:1 and an enantioselectivity excess of 88%.

[0032] In another embodiment, the catalyst used was 7.1 mg (R)-di-2-naphthylprolyl (D), and other conditions were the same as in Example 1, to produce the above product, yielding 5.8 mg of a pale yellow oily substance with a yield of 17%, diastereoselectivity of 7:1, and an enantioselectivity excess of 87%.

[0033] Example using a different acid: In another example, the acid used was trifluoromethanesulfonic acid (20 mol%), and other conditions were the same as in Example 1. The above product was prepared to obtain 14.7 mg of a pale yellow oily substance with a yield of 42%, a diastereoselectivity of 11:1, and an enantioselectivity of 98% excess.

[0034] In another embodiment, the acid used was trifluoroacetic acid (20 mol%), and other conditions were the same as in Example 1, to prepare the above product, yielding 15.4 mg of a pale yellow oily substance with a yield of 44%, diastereoselectivity of 5:1, and an enantioselectivity of 98% excess.

[0035] In another embodiment, the acid used was boron trifluoride ether (20 mol%), and other conditions were the same as in Example 1, to prepare the above product, yielding 20.5 mg of a pale yellow oily substance with a yield of 58%, diastereoselectivity of 7:1, and an enantioselectivity of 98% excess.

[0036] In another embodiment, the solvent used was tetrahydrofuran (20 mol%), and the other conditions were the same as in Embodiment 1. The above product was prepared to obtain 9.9 mg of a pale yellow oily substance with a yield of 29%, a diastereoselectivity of 5:1, and an enantioselectivity of 97% excess.

[0037] In another embodiment, toluene (20 mol%) was used as the solvent, and other conditions were the same as in Example 1, to obtain the above product, yielding 20.3 mg of a pale yellow oily substance with a yield of 58%, diastereoselectivity of 5:1, and an enantioselectivity of 98% excess.

[0038] In another embodiment, acetonitrile (20 mol%) was used as the solvent, and other conditions were the same as in Example 1, to prepare the above product, yielding 10.1 mg of a pale yellow oily substance with a yield of 29%, diastereoselectivity of 10:1, and enantioselectivity of the product exceeding 98%.

[0039] In another embodiment, the solvent used was 1,4-dioxane (20 mol%), and other conditions were the same as in Example 1, to prepare the above product, yielding 9.5 mg of a pale yellow oily substance with a yield of 27%, diastereoselectivity of 12:1, and an enantioselectivity excess of 55%.

[0040] In another embodiment, methanol (20 mol%) was used as the solvent, and other conditions were the same as in Example 1. The above product was prepared to obtain 12.3 mg of a light yellow oily substance with a yield of 35%, diastereoselectivity of 4:1, and enantioselectivity of the product of 97%.

[0041] In another embodiment, ethanol (20 mol%) was used as the solvent, and other conditions were the same as in Example 1, to prepare the above product, yielding 5.8 mg of a pale yellow oily substance with a yield of 17%, diastereoselectivity of 2:1, and an enantioselectivity of 95% excess.

[0042] Implementation Case 2: Preparation: The reactant was 0.10 mmol of 1-methoxycarbonyl-3-vinylindole. The reaction was carried out at 55°C for 24 hours, with other conditions the same as in Example 1, to obtain the above product, yielding 14.3 mg of a pale yellow oil, with a yield of 53% and a diastereoselectivity of 9:1. MS (m / z): 271; Optical purity analysis: the enantioselectivity of the product was 97% excess.

[0043] Implementation Case 3: Preparation: The reactant was 0.10 mmol of 1-ethoxycarbonyl-3-vinylindole. The reaction was carried out at 55°C for 24 hours, with other conditions the same as in Example 1, to obtain the above product, yielding 17.3 mg of a pale yellow oil, with a yield of 61% and a diastereoselectivity of 8:1. MS (m / z): 285; optical purity analysis: the enantioselectivity of the product was 98% excess.

[0044] Implementation Case 4: Preparation: The reactant was 0.10 mmol of 1-tert-butyloxycarbonyl-3-vinylindole. The reaction was carried out at 55°C for 24 hours, with other conditions the same as in Example 1, to obtain the above product, yielding 18.1 mg of a pale yellow oil in 58% yield with a diastereoselectivity of 6:1. MS (m / z): 313; Optical purity analysis: the enantioselectivity of the product was 98% excess.

[0045] Implementation Case 5: Preparation: The reactant was 0.10 mmol of 1-tert-butyloxycarbonyl-3-vinylindole. The reaction was carried out at 55°C for 24 hours, with other conditions the same as in Example 1, to obtain the above product, yielding 26.2 mg of a pale yellow oil with a yield of 91% and a diastereoselectivity of 7:1. MS (m / z): 291; Optical purity analysis: the enantioselectivity of the product was 97% excess.

[0046] Implementation Case Six: Preparation: The reactant was 1-p-toluenesulfonyl-3-vinylindole (0.10 mmol). The reaction was carried out at 55°C for 24 hours, with other conditions the same as in Example 1, to obtain the above product. A pale yellow oil of 33.9 mg was obtained, with a yield of 92% and a diastereoselectivity of 17:1. MS (m / z): 367; Optical purity analysis: the enantioselectivity of the product was 96% excess.

[0047] Implementation Case Seven: Preparation: The reactants consisted of 21.0 mg of the corresponding aldehyde (0.25 mmol), followed by the addition of 1-benzyloxycarbonyl-3-vinylindole (0.10 mmol). The reaction was carried out at 55°C for 24 hours, under the same conditions as in Example 1, yielding 33.3 mg of a pale yellow oil with a yield of 92% and a diastereoselectivity of 7:1. MS (m / z): 361; Optical purity analysis: the enantioselectivity of the product was 98% excess.

[0048] Implementation Case 8: Preparation: The reactant was 24.5 mg of the corresponding aldehyde (0.25 mmol), and other conditions were the same as in Example 1. The above product was prepared to yield 33.4 mg of a pale yellow oil, with a yield of 89% and a diastereoselectivity of 9:1. MS (m / z): 375; Optical purity analysis: the enantioselectivity of the product was 98% excess.

[0049] Implementation Case Nine: Preparation: The reactant was 31.0 mg of the corresponding aldehyde (0.25 mmol), and other conditions were the same as in Example 1. The above product was prepared to yield 27.5 mg of a pale yellow oil, with a yield of 68% and a diastereoselectivity of 4:1. MS (m / z): 401; Optical purity analysis: the enantioselectivity of the product was 96% excess.

[0050] Implementation Case 10: Preparation: The reactants consisted of 34.5 mg of the corresponding aldehyde (0.25 mmol), followed by the addition of 1-benzyloxycarbonyl-3-vinylindole (0.10 mmol). The reaction was carried out at 55°C for 36 hours, with other conditions identical to those in Example 1. The above product was obtained as 17.8 mg of a pale yellow oil, yielding 43% with a diastereoselectivity of 5:1. S (m / z): 415; Optical purity analysis showed an enantioselectivity of 97% for the product.

[0051] Implementation Case Eleven: Preparation: The reactants consisted of 36.5 mg of the corresponding aldehyde (0.25 mmol), followed by the addition of 1-benzyloxycarbonyl-3-vinylindole (0.10 mmol). The reaction was carried out at 55°C for 36 hours, with other conditions identical to those in Example 1. The above product was obtained as 19.9 mg of a pale yellow oil, yielding 47% with a diastereoselectivity of 9:1. MS (m / z): 423; Optical purity analysis: the enantioselectivity of the product was 96% excess.

[0052] Implementation Case Twelve: Preparation: The reactants consisted of 43.5 mg of the corresponding aldehyde (0.25 mmol), followed by the addition of 1-benzyloxycarbonyl-3-vinylindole (0.10 mmol). The mixture was heated to 55°C and reacted for 24 hours under the same conditions as in Example 1. The above product was obtained as 36.7 mg of a pale yellow oil, with a yield of 81% and a diastereoselectivity of 11:1. MS (m / z): 451; Optical purity analysis: the enantioselectivity of the product was 99% excess.

[0053] Implementation Case Thirteen: Preparation: The reactants consisted of 21.0 mg of the corresponding aldehyde (0.25 mmol), followed by the addition of 0.10 mmol of 1-benzyloxycarbonyl-3-vinyl-4-methylindole. Other conditions were the same as in Example 1. The above product was obtained, yielding 22.0 mg of a pale yellow oil with a yield of 59% and a diastereoselectivity of 5:1. MS (m / z): 375; Optical purity analysis: the product showed an enantioselectivity of 99%.

[0054] Implementation Case Fourteen: Preparation: The reaction was carried out using 21.0 mg of the corresponding aldehyde (0.25 mmol), followed by the addition of 1-benzyloxycarbonyl-3-vinyl-5-methylindole (0.10 mmol). The reaction was heated to 55°C and reacted for 36 hours under the same conditions as in Example 1, yielding the above product. A pale yellow oil of 31.3 mg was obtained, with a yield of 83% and a diastereoselectivity of 5:1. MS (m / z): 375; optical purity analysis: the enantioselectivity of the product was 99% excess.

[0055] Implementation Case 15: Preparation: The reactants consisted of 17.5 mg of the corresponding aldehyde (0.25 mmol), followed by the addition of 1-benzyloxycarbonyl-3-vinyl-7-methylindole (0.10 mmol). The reaction was carried out at 55°C for 36 hours, with other conditions identical to those in Example 1. The above product was obtained as 27.3 mg of a pale yellow oil, yielding 76% and a diastereoselectivity of 7:1. MS (m / z): 361; Optical purity analysis: the enantioselectivity of the product was 96% excess.

[0056] Implementation Case Sixteen: Preparation: The reactants consisted of 17.5 mg of the corresponding aldehyde (0.25 mmol), followed by the addition of 1-benzyloxycarbonyl-3-vinyl-4-methoxyindole (0.10 mmol). The reaction was carried out at 55°C for 27 hours, under the same conditions as in Example 1, yielding 24.6 mg of a pale yellow oil in 65% yield with a diastereoselectivity of 7:1. MS (m / z): 377; Optical purity analysis: the enantioselectivity of the product was 96% excess.

[0057] Implementation Case Seventeen: Preparation: 21.0 mg of the corresponding aldehyde (0.25 mmol) was added to the reactants, followed by the addition of 1-benzyloxycarbonyl-3-vinylindole (0.10 mmol). The reaction was carried out at 55°C for 24 hours, under the same conditions as in Example 1, yielding 19.5 mg of a pale yellow oil, with a yield of 50% and a diastereoselectivity of 6:1. MS (m / z): 391; Optical purity analysis: the enantioselectivity of the product was 98% excess.

[0058] Implementation Case 18: Preparation: The reactants consisted of 17.5 mg of the corresponding aldehyde (0.25 mmol), followed by the addition of 1-benzyloxycarbonyl-3-vinyl-5-methoxyindole (0.10 mmol). The reaction was carried out at 55°C for 27 hours, with other conditions identical to those in Example 1. The above product was obtained as 29.8 mg of a pale yellow oil, yielding 79% and a diastereoselectivity of 8:1. MS (m / z): 377; Optical purity analysis: the enantioselectivity of the product was 98% excess.

[0059] Implementation Case 19: Preparation: The reactants consisted of 21.0 mg of the corresponding aldehyde (0.25 mmol), followed by the addition of 0.10 mmol of 1-benzyloxycarbonyl-3-vinyl-6-methoxyindole. Other conditions were the same as in Example 1. The above product was obtained as 11.9 mg of a pale yellow oil, with a yield of 30% and a diastereoselectivity of 6:1. MS (m / z): 391; Optical purity analysis: the enantioselectivity of the product was 97% excess.

[0060] Implementation Case 20: Preparation: The reactants consisted of 17.5 mg of the corresponding aldehyde (0.25 mmol), followed by the addition of 0.10 mmol of 1-benzyloxycarbonyl-3-vinyl-4-chloroindole. The reaction was carried out at 55°C for 30 hours under the same conditions as in Example 1, yielding 26.7 mg of a pale yellow oil in 70% yield with a diastereoselectivity of 4:1. MS (m / z): 381; Optical purity analysis: the enantioselectivity of the product was 93% excess.

[0061] Implementation Case 21: Preparation: The reactants consisted of 17.5 mg of the corresponding aldehyde (0.25 mmol), followed by the addition of 1-benzyloxycarbonyl-3-vinyl-5-chloroindole (0.10 mmol). The reaction was carried out at 55°C for 45 hours, with other conditions identical to those in Example 1. The above product was obtained, yielding 21.4 mg of a pale yellow oil in 56% yield with a diastereoselectivity of 8:1. MS (m / z): 381; Optical purity analysis: the enantioselectivity of the product was 96% excess.

[0062] Implementation Case 22: Preparation: The reactants consisted of 17.5 mg of the corresponding aldehyde (0.25 mmol), followed by the addition of 1-benzyloxycarbonyl-3-vinylindole (0.10 mmol). The reaction was carried out at 55°C for 70 hours, with other conditions identical to those in Example 1. The above product was obtained as 29.0 mg of a pale yellow oil, yielding 76% and a diastereoselectivity of 5:1. MS (m / z): 381; Optical purity analysis: the enantioselectivity of the product was 95% excess.

[0063] Implementation Case 23: Preparation: The reactants consisted of 21.0 mg of the corresponding aldehyde (0.25 mmol), followed by the addition of 0.10 mmol of 1-benzyloxycarbonyl-3-vinyl-4-bromoindole. The reaction was carried out at 55°C for 24 hours, with other conditions identical to those in Example 1. The above product was obtained as 33.2 mg of a pale yellow oil, yielding 75% with a diastereoselectivity of 3:1. MS (m / z): 439; Optical purity analysis: the enantioselectivity of the product was 97% excess.

[0064] Implementation Case 24: Preparation: The reactants consisted of 17.5 mg of the corresponding aldehyde (0.25 mmol), followed by the addition of 1-benzyloxycarbonyl-3-vinyl-5-bromoindole (0.10 mmol). The reaction was carried out at 55°C for 70 hours, with other conditions identical to those in Example 1, yielding 28.5 mg of a pale yellow oil in 67% yield and diastereoselectivity of 6:1. MS (m / z): 425; Optical purity analysis: the enantioselectivity of the product was 95% excess.

[0065] Implementation Case 25: Preparation: 17.5 mg of the corresponding aldehyde (0.25 mmol) was added to the reactants, followed by the addition of 0.10 mmol of 1-benzyloxycarbonyl-3-vinyl-6-bromoindole. The mixture was reacted at 55°C for 70 hours to yield 29.5 mg of a pale yellow oil, with a yield of 69% and a diastereoselectivity of 5:1. MS (m / z): 425; Optical purity analysis: the enantioselectivity of the product was 93% excess.

[0066] Implementation Case 26: Preparation: 21.0 mg of the corresponding aldehyde (0.25 mmol) was added to the reactants, followed by 0.10 mmol of 1-benzyloxycarbonyl-3-vinyl-4-fluoroindole. The mixture was reacted at 55°C for 24 hours to yield 24.9 mg of a pale yellow oil, with a yield of 66% and a diastereoselectivity of 8:1. MS (m / z): 379; Optical purity analysis: the enantioselectivity of the product was 97% excess.

[0067] Implementation Case 27: Preparation: The reactants consisted of 17.5 mg of the corresponding aldehyde (0.25 mmol), and 1-benzyloxycarbonyl-3-vinyl-5-fluoroindole (0.10 mmol) was added. The mixture was heated to 55 degrees Celsius and reacted for 60 hours. Other conditions were the same as in Example 1. The above product was obtained, yielding 28.7 mg of a light yellow oil with a yield of 79% and a diastereoselectivity of 6:1.

[0068] MS (m / z): 365; Optical purity analysis: enantioselectivity of the product was 96% excess.

[0069] Implementation Case 28: Preparation: The reactants were 33.0 mg of the corresponding aldehyde (0.25 mmol), and 1-benzyloxycarbonyl-3-vinylindole (0.10 mmol). The reaction was carried out at 55 degrees Celsius for 39 hours. Other conditions were the same as in Example 1. The above product was obtained, yielding 27.9 mg of a light yellow oil with a yield of 68% and diastereoselectivity >20:1.

[0070] MS (m / z): 409; Optical purity analysis: enantioselectivity of the product was 96% excess.

[0071] Implementation Case 29: Preparation: 41.7 mg of the corresponding aldehyde (0.25 mmol) was added to the reactants, followed by the addition of 1-benzyloxycarbonyl-3-vinylindole (0.10 mmol). The reaction was carried out at 55°C for 80 hours, with other conditions identical to those in Example 1. The above product was obtained, yielding 21.4 mg of a pale yellow oil in 48% yield, with a diastereoselectivity >20:1. MS (m / z): 443; Optical purity analysis: the enantioselectivity of the product was 97% excess.

[0072] Implementation Case 30: Preparation: The reactants consisted of 52.8 mg of the corresponding aldehyde (0.25 mmol), followed by the addition of 1-benzyloxycarbonyl-3-vinylindole (0.10 mmol). The reaction was carried out at 55°C for 80 hours, with other conditions identical to those in Example 1. The above product was obtained as 35.1 mg of a pale yellow oil, yielding 72% with a diastereoselectivity >20:1. MS (m / z): 487; Optical purity analysis: the enantioselectivity of the product was 94% excess.

[0073] Implementation Case 31: Preparation: The reactants were 37.5 mg of the corresponding aldehyde (0.25 mmol), and 1-benzyloxycarbonyl-3-vinylindole (0.10 mmol). The reaction was carried out at 55 degrees Celsius for 41 hours. Other conditions were the same as in Example 1. The above product was obtained, yielding 22.1 mg of a light yellow oil with a yield of 52% and diastereoselectivity >20:1.

[0074] MS (m / z): 427; Optical purity analysis: enantioselectivity of the product was 97%.

[0075] Implementation Case 32: Preparation: 44.3 mg of the corresponding aldehyde (0.25 mmol) was used as the reactant, and 1-benzyloxycarbonyl-3-vinylindole (0.10 mmol) was added. The reaction was heated to 55 degrees and carried out for 24 hours. Other conditions were the same as in Example 1. The above product was obtained, yielding 34.9 mg of a light yellow oil with a yield of 77% and diastereoselectivity >20:1.

[0076] MS (m / z): 454; Optical purity analysis: enantioselectivity of the product was 99%.

[0077] Implementation Case 33: Preparation: 50.0 mg of the corresponding aldehyde (0.25 mmol) was used as the reactant, and 1-benzyloxycarbonyl-3-vinylindole (0.10 mmol) was added. The reaction was heated to 55 degrees and carried out for 21 hours. Other conditions were the same as in Example 1. The above product was obtained, yielding 23.6 mg of a light yellow oil with a yield of 49% and diastereoselectivity >20:1.

[0078] MS (m / z): 477; Optical purity analysis: enantioselectivity of the product was 97%.

[0079] Implementation Case 34: Preparation: 41.8 mg of the corresponding aldehyde (0.25 mmol) was used as the reactant, and 1-benzyloxycarbonyl-3-vinylindole (0.10 mmol) was added. The reaction was heated to 55 degrees and carried out for 20 hours. Other conditions were the same as in Example 1. The above product was obtained, yielding 23.1 mg of a light yellow oil with a yield of 52% and diastereoselectivity >20:1.

[0080] MS (m / z): 444; Optical purity analysis: enantioselectivity of the product was 97%.

[0081] Implementation Case 35: Preparation: The reactants were 36.5 mg of the corresponding aldehyde (0.25 mmol), and 1-benzyloxycarbonyl-3-vinylindole (0.10 mmol) were added. The mixture was heated to 55 degrees Celsius and reacted for 65 hours. Other conditions were the same as in Example 1. The above product was obtained, yielding 27.7 mg of a light yellow oil with a yield of 65% and diastereoselectivity >20:1.

[0082] MS (m / z): 423; Optical purity analysis: enantioselectivity of the product was 96% excess.

[0083] Implementation Case 36: Preparation: 41.7 mg of the corresponding aldehyde (0.25 mmol) was used as the reactant, and 1-benzyloxycarbonyl-3-vinyl-4-bromoindole (0.10 mmol) was added. The reaction was heated to 55 degrees and carried out for 48 hours. Other conditions were the same as in Example 1. The above product was obtained, yielding 18.3 mg of a light yellow oil with a yield of 35% and diastereoselectivity >20:1.

[0084] MS (m / z): 521; Optical purity analysis: enantioselectivity of the product was 94% excess.

[0085] Implementation Case 37: Preparation: 50.0 mg of the corresponding aldehyde (0.25 mmol) was used as the reactant, and 1-benzyloxycarbonyl-3-vinyl-5-fluoroindole (0.10 mmol) was added. The reaction was heated to 55 degrees and carried out for 70 hours. Other conditions were the same as in Example 1. The above product was obtained, yielding 40.2 mg of a light yellow oil with a yield of 81% and diastereoselectivity >20:1.

[0086] MS (m / z): 495; Optical purity analysis: enantioselectivity of the product was 93%.

[0087] Implementation Case 38: Preparation: 25.9 mg of the corresponding aldehyde (0.37 mmol) was used as the reactant, and 1-benzyloxycarbonyl-3-vinylindole (0.15 mmol) was added. The reaction was heated to 55 degrees and carried out for 18 hours. Other conditions were the same as in Example 1. The above product was obtained, yielding 53.3 mg of a light yellow oil with a yield of 95% and diastereoselectivity >20:1.

[0088] MS (m / z): 373; Optical purity analysis: enantioselectivity of the product was 95% excess.

[0089] Implementation Case 39: Preparation: 25.9 mg of the corresponding aldehyde (0.37 mmol) was used as the reactant, and 1-methoxycarbonyl-3-vinylindole (0.15 mmol) was added. The reaction was heated to 55 degrees and carried out for 19 hours. Other conditions were the same as in Example 1. The above product was obtained, yielding 25.5 mg of a light yellow oil with a yield of 57% and diastereoselectivity >20:1.

[0090] MS (m / z): 297; Optical purity analysis: enantioselectivity of the product was 92% excess.

[0091] Implementation Case 40: Preparation: 25.9 mg of the corresponding aldehyde (0.37 mmol) was added to the reactants, followed by 0.15 mmol of 1-ethoxycarbonyl-3-vinylindole. The mixture was reacted at 55°C for 16 hours to yield 24.6 mg of a pale yellow oil, with a yield of 53% and a diastereoselectivity >20:1. MS (m / z): 311; Optical purity analysis: the enantioselectivity of the product was 96% excess.

[0092] Implementation Case 41: Preparation: 25.9 mg of the corresponding aldehyde (0.37 mmol) was used as the reactant, and 1-tert-butoxycarbonyl-3-vinylindole (0.15 mmol) was added. The reaction was heated to 55 degrees and carried out for 18 hours. Other conditions were the same as in Example 1. The above product was obtained, yielding 40.6 mg of a light yellow oil with a yield of 80% and diastereoselectivity >20:1.

[0093] MS (m / z): 339; Optical purity analysis: enantioselectivity of the product was 95% excess.

[0094] Implementation Case 42: Preparation: 17.5 mg of the corresponding aldehyde (0.25 mmol) was used as the reactant, and 1-p-toluenesulfonyl-3-vinylindole (0.10 mmol) was added. The reaction was heated to 40 degrees and carried out for 33 hours. Other conditions were the same as in Example 1. The above product was obtained, yielding 21.6 mg of a light yellow oil with a yield of 59% and diastereoselectivity >20:1.

[0095] MS (m / z): 367; Optical purity analysis: enantioselectivity of the product was 91%.

[0096] Implementation Case 43: Preparation: 17.5 mg of the corresponding aldehyde (0.25 mmol) was used as the reactant, and 1-tert-butoxycarbonyl-3-vinylindole (0.10 mmol) was added. The reaction was heated to 40 degrees and carried out for 24 hours. Other conditions were the same as in Example 1. The above product was obtained, yielding 26.5 mg of a light yellow oil with a yield of 85% and diastereoselectivity >20:1.

[0097] MS (m / z): 313; Optical purity analysis: enantioselectivity of the product was 90% excess.

[0098] Implementation Case 44: Preparation: 21.0 mg of the corresponding aldehyde (0.25 mmol) was used as the reactant, and 1-p-toluenesulfonyl-3-vinylindole (0.10 mmol) was added. The reaction was heated to 40 degrees and carried out for 33 hours. Other conditions were the same as in Example 1. The above product was obtained, yielding 12.9 mg of a light yellow oil with a yield of 34% and diastereoselectivity >20:1.

[0099] MS (m / z): 381; Optical purity analysis: enantioselectivity of the product was 82% excess.

[0100] Implementation Case of 2-Alkenylindole: Implementation Case 45: Preparation: 15.0 mg of (R)-α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanoltrimethylsilyl ether (B) was weighed at room temperature and dissolved in trifluoroethanol. 5.6 mg (20 mol%) of bistrifluoromethylsulfonylimide was added at -78°C. After stirring for 10 minutes, 17.5 mg of crotonaldehyde (0.25 mmol) was added, followed by 1-p-toluenesulfonyl-2-vinylindole (0.10 mmol). The mixture was heated to 45°C and reacted for 7 hours. The reaction was quenched with saturated sodium bicarbonate solution. The mixture was separated, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, washed, and then evaporated to dryness. The organic phase was purified by column chromatography with petroleum ether / ethyl acetate (10:1) to obtain the target Diels-Alder reaction product, yielding 28.0 mg of a pale yellow oil with a yield of 76% and diastereoselectivity >10:1.

[0101] 1 H NMR (600 MHz, CDCl3)δ 9.15 (s, 1H), 7.80 (d,J= 8.2 Hz, 1H), 7.57 –7.49 (m, 2H), 7.28 (d,J= 7.8 Hz, 1H), 7.15 (d,J= 7.9 Hz, 2H), 7.10 (t,J= 7.4Hz, 1H), 7.05 (d,J= 7.3 Hz, 1H), 6.10 (q,J= 3.5 Hz, 1H), 3.46 (s, 1H), 2.70 (dd,J= 5.6, 2.8 Hz, 1H), 2.45 (dp,J= 17.8, 3.6 Hz, 1H), 2.40 (dt,J= 9.6, 4.8Hz, 1H), 2.35 (s, 3H), 1.94 (dt,J= 18.1, 2.9 Hz, 1H), 1.00 (d,J= 7.0 Hz, 3H). 13C10 NMR (151 MHz, CDCl3) δ 202.09, 144.57, 142.65, 138.12, 134.82, 130.90, 129.51, 128.51, 127.15, 125.45, 123.56, 117.66, 113.77, 51.99, 37.58, 28.86, 27.37, 21.69, 20.64. MS (m / z): 367; Optical purity analysis: the enantioselectivity of the product was 99% excess. Chiral ID column (n-hexane:isopropanol 94:6, v / v) 0.8 mL / min, 40 °C, retention times were t1 = 44.752 min, t2 = 50.538. Implementation Case 46: Preparation: 21.0 mg of the corresponding aldehyde (0.25 mmol) was added, followed by the addition of 1-p-toluenesulfonyl-2-vinylindole (0.10 mmol). The mixture was reacted at 55°C for 12 hours. Other preparation methods were the same as in Example 45, yielding 28.8 mg of a pale yellow oily substance with a yield of 75% and a diastereoselectivity >10:1. MS (m / z): 381; Optical purity analysis: the enantioselectivity of the product was 97% excess.

[0102] Implementation Case 47: Preparation: 28.0 mg of the corresponding aldehyde (0.25 mmol) was added, followed by the addition of 1-p-toluenesulfonyl-2-vinylindole (0.10 mmol). The mixture was reacted at 55°C for 7 hours. Other preparation methods were the same as in Example 45, yielding 29.0 mg of a pale yellow oily substance with a yield of 71% and a diastereoselectivity >10:1. MS (m / z): 409; Optical purity analysis: the enantioselectivity of the product was 99% excess.

[0103] Implementation Case 48: Preparation: 24.0 mg of the corresponding aldehyde (0.25 mmol) was added, followed by the addition of 1-p-toluenesulfonyl-2-vinylindole (0.10 mmol). The mixture was reacted at 45°C for 7 hours. Other preparation methods were the same as in Example 45, yielding 28.7 mg of a pale yellow oily substance with a yield of 73% and a diastereoselectivity >10:1. MS (m / z): 393; Optical purity analysis: the enantioselectivity of the product was 98% excess.

[0104] Implementation Case 49: Preparation: 20.0 mg of the corresponding aldehyde (0.15 mmol) was added, followed by the addition of 1-p-toluenesulfonyl-2-vinylindole (0.10 mmol). The mixture was heated to 75°C and reacted for 24 hours. Other preparation methods were the same as in Example 45, yielding 25.6 mg of a pale yellow oily substance in 60% yield with diastereoselectivity >10:1. MS (m / z): 429; Optical purity analysis: the enantioselectivity of the product was 92% excess.

[0105] Implementation Case 50: Preparation: Chlorobenzene (20 mol%) was used as the solvent, and other preparation methods were the same as in Example 45, yielding 20.3 mg of a pale yellow oily substance with a yield of 55% and diastereoselectivity >10:1. MS (m / z): 367; Optical purity analysis: the enantioselectivity of the product was 91% excess.

[0106] Implementation Case 51: Preparation: Using 21.0 mg of the corresponding aldehyde (0.25 mmol), the other preparation methods were the same as in Example 50, yielding 30.3 mg of a pale yellow oily substance with a yield of 79% and diastereoselectivity >10:1. MS (m / z): 381; Optical purity analysis: the enantioselectivity of the product was 96% excess.

[0107] Implementation Case 52: Preparation: Using 24.0 mg of the corresponding aldehyde (0.25 mmol), the other preparation methods were the same as in Example 60, yielding 33.0 mg of a pale yellow oily substance with a yield of 85% and diastereoselectivity >10:1. MS (m / z): 393; Optical purity analysis: the enantioselectivity of the product was 97% excess.

[0108] Implementation Case 53: Preparation: The reactant was 1-methanesulfonyl-2-vinylindole (0.10 mmol). Other preparation methods were the same as in Example 1, yielding 18.4 mg of a pale yellow oily substance with a yield of 63% and a diastereoselectivity of 10:1. MS (m / z): 291; Optical purity analysis: the enantioselectivity of the product was 95% excess.

[0109] Implementation Case 54 (Gram-scale Preparation Case): Gram-level preparation: 105.0 mg of (R)-α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidine was weighed at room temperature and dissolved in dichloromethane. 0.014 mmol (20 mol%) of bis(trifluoromethyl)sulfonylimide was added at -78°C. After stirring for 10 minutes, 8.75 mmol of the corresponding aldehyde was added, followed by 3.5 mmol of 1-p-toluenesulfonyl-3-vinylindole. The mixture was heated to 95°C and reacted for 15 hours. The reaction was quenched with saturated sodium bicarbonate solution. The mixture was separated, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, washed, and then evaporated to dryness. The organic phase was purified by column chromatography with petroleum ether / ethyl acetate (10:1) to obtain the target Diels-Alder reaction product, yielding 1.23 g of a pale yellow oil with a yield of 86%, diastereoselectivity of 6:1, and enantioselectivity of 98%.

[0110] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing a chiral hydrogenated carbazole skeleton compound, characterized in that, Using a secondary amine catalyst and an acid catalytic system, the diene is nitrogen-substituted-2-enylindole or nitrogen-substituted-3-enylindole, and the dienophile is β-substituted-α,β-unsaturated aldehyde, α-alkyl-α,β-unsaturated aldehyde, or 1-cyclopentenaldehyde. Chiral hydrogenated carbazole skeletons containing continuous chiral centers, all-carbon and quaternary carbon chiral centers are synthesized under conditions of -78℃–120℃.

2. The method for preparing chiral hydrogenated carbazole skeleton compounds according to claim 1, characterized in that, The preparation method includes the following steps: reacting an alkenylindole compound of Formula I with an α,β-unsaturated aldehyde of Formula V in a secondary amine catalyst and an acid catalytic system to obtain a chiral hydrogenated carbazole skeleton compound. I； V; where R 1 For COOBn, COOMe, COOEt, Boc, Ms, or Ts; R 2 H, a C1-C4 alkyl group optionally substituted at the 4-7 positions, a C1-C4 alkoxy group optionally substituted at the 4-7 positions, or a halogen optionally substituted at the 4-7 positions, wherein the halogen is F, Cl, or Br; R 3 It can be methyl, ethyl, isopropyl, or -(CH2). m i Pr, m=1-7, C5-C6 cycloalkyl, -(CH2) m Ph, m = 1-7, aryl, optionally substituted aryl, including alkane-substituted aryl, halogen-substituted aryl, haloalkane-substituted aryl, or optionally substituted 5- to 10-membered heterocycles or heteroaromatic rings, wherein the 5- to 10-membered heterocycles or heteroaromatic rings optionally contain one or more heteroatoms selected from N, O, or S as ring members; R 6 H, C1-C8 alkyl; or, R 3 and R 6 Together with the carbon atoms to which they are attached, they form 3 to 8-membered carbon rings; R 4 and R 5 Selected from H or CH=CH2 respectively; the reaction formula is as follows: 。 3. The method for preparing chiral hydrogenated carbazole skeleton compounds according to claim 1, characterized in that, In the secondary amine catalyst and acid catalysis system, the secondary amine catalyst is at least one of formulas A to L:

4. The method for preparing chiral hydrogenated carbazole skeleton compounds according to claim 1, characterized in that, In the secondary amine catalyst and acid catalytic system, the acid is trifluoromethanesulfonic acid, boron trifluoride ether, bis(trifluoromethanesulfonamide), trimethylsilyltrifluoromethanesulfonate, trifluoroacetic acid, hydrochloric acid, or perchloric acid.

5. The method for preparing chiral hydrogenated carbazole skeleton compounds according to claim 1, characterized in that, In the secondary amine catalyst and acid catalysis system, the solvent is dichloromethane, dichloroethane, trichloromethane, chlorobenzene, tetrahydrofuran, acetonitrile, toluene, trifluoroethanol, ethyl tert-butyl ether, or methyl tert-butyl ether.

6. The method for preparing chiral hydrogenated carbazole skeleton compounds according to claim 2, characterized in that, The preparation method includes the following steps: dissolving a secondary amine catalyst in a solvent, cooling to -78℃ to room temperature, adding acid dropwise to the system, wherein the molar amounts of the secondary amine catalyst and the acid are 1-30 mol% relative to the alkenyl indole compound, and the molar ratio of the secondary amine catalyst to the acid is 3:1 to 1:3; after stirring, adding an α,β-unsaturated aldehyde of formula V dropwise, and after stirring, adding an alkenyl indole compound of formula I dropwise; the system reacts between -78℃ and 120℃, and the reaction is monitored by TLC.

7. The method for preparing chiral hydrogenated carbazole skeleton compounds according to claim 2, characterized in that, The preparation method further includes: after the alkenyl indole compound represented by Formula I has completely disappeared, quenching the reaction with saturated sodium bicarbonate solution, separating the liquid phase, extracting the aqueous phase with ethyl acetate, combining the organic phases, adding anhydrous sodium sulfate to dry, filtering and washing, evaporating the organic phase to dryness, and purifying by column chromatography with petroleum ether / ethyl acetate to obtain the target Diels-Alder reaction product.

8. The chiral hydrogenated carbazole skeleton compound prepared by the method of claim 1, characterized in that, The structure is shown in equations II, III, or IV: II; III; IV; where R 1 For COOBn, COOMe, COOEt, Boc, Ms, or Ts; R 2 H, a C1-C4 alkyl group optionally substituted at the 4-7 positions, a C1-C4 alkoxy group optionally substituted at the 4-7 positions, a halogen-containing substituent optionally substituted at the 4-7 positions, such as -CF3, CH2CF3, or a halogen optionally substituted at the 4-7 positions, said halogen being F, Cl, or Br; R 3 It can be methyl, ethyl, isopropyl, or -(CH2). m i Pr, m=1-7, C5-C6 cycloalkyl, -(CH2) m Ph, m = 1-7, aryl, optionally substituted aryl, including alkane-substituted aryl, halogen-substituted aryl, haloalkane-substituted aryl, or optionally substituted 5- to 10-membered heterocycles or heteroaromatic rings, wherein the 5- to 10-membered heterocycles or heteroaromatic rings optionally contain one or more heteroatoms selected from N, O, or S as ring members; R 6 H, C1-C8 alkyl; or, R 3 and R 6 Together with the carbon atoms to which they are attached, they form 3 to 8-membered carbon rings.

9. The chiral hydrogenated carbazole skeleton compound according to claim 8, characterized in that, One of them has the following chemical structure: 。 10. The chiral hydrogenated carbazole skeleton compound according to claim 8, characterized in that, One of them has the following chemical structure: 。

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