Synthetic method of natural product Pyrroloazocine indole alkaloid skeleton

Abstract

The invention belongs to the field of organic chemical synthesis, and relates to a method for synthesizing a natural product Pyrroloazocine indole alkaloid skeleton. According to the method, a commercially available compound 1 and phenylhydrazine are taken as synthesis starting points, and a [2.2. 2] bridge ring system is constructed through key Fischer indole synthesis, Stille coupling reaction and intermolecular Diels-Alder reaction. The preparation method comprises the following steps: carrying out a cyclopropanation reaction mediated by carbene, carrying out a Ley-Griffith oxidation reaction, and carrying out a Beckmann rearrangement and an intramolecular SN2 cyclization cascade reaction so as to realize the construction of the core skeleton of the Pyrroloazocine indole alkaloid. According to the method, a material basis can be provided for activity testing of the Pyrroloazocine indole alkaloid and the analogue thereof, and a thought is provided for synthesis route design of more complex cage-shaped indole alkaloid basic frameworks.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis, and in particular to a method for synthesizing the skeleton of the natural product Pyrroloazocine indole alkaloid. Background Technology

[0002] Indole alkaloids are diverse and structurally complex, with most possessing certain physiological activities and unique, complex biosynthetic pathways, making them a research hotspot in the field of natural product chemistry. Plants of the genus *Kopsia* arborea are an important source of indole alkaloids, and the alkaloids isolated from them mostly possess polycyclic systems, multiple chiral centers, and complex cage-like structures. These alkaloids also exhibit a wide variety of pharmacological activities. Pyrroloazocine indole alkaloids are a class of structurally unique indole alkaloids isolated from *Kopsia grandifolia* DJMiddleton, a plant in the Apocynaceae family. Structurally, these alkaloids possess a unique 6 / 5 / 8 / 6 / 5 pentacyclic core skeleton, along with a [4.2.2] azirone-azo-octagonal strained bridged ring structure and four chiral centers; alkaloids Lapidilectine B and Grandilodine C also possess a unique bridged ring lactone structure. Therefore, the synthesis of Pyrroloazocine indole alkaloids presents a significant challenge. In terms of activity, Pyrroloazocine indole alkaloids have anti-B16 melanoma cells and anti-vincristine-resistant KB cell line activities, which makes this class of alkaloids have potential anti-tumor medicinal value and good prospects for drug conversion.

[0003] Due to the complex and novel structural features and excellent physiological activities of Pyrroloazocine indole alkaloids, these alkaloids have become a hot topic in the field of natural product synthesis in recent years. Several total syntheses of these indole alkaloids have been reported, among which the most representative are the racemic total synthesis of Lapidilectine B by Pearson's group and the cluster-based asymmetric total synthesis of Pyrroloazocine-type indole alkaloids by Echavarren's team. Pearson's team constructed a key spirocyclic intermediate through a denitrification gas cyclization reaction of an azidoketone followed by an imine condensation tandem [3+2] cycloaddition reaction, and finally synthesized the intermediate via intramolecular S... N The 2-reaction closed the eight-membered ring to complete the construction of the natural product skeleton; Echavarren's team used a gold-catalyzed indole alkyne cyclization reaction to construct an eight-membered ring, followed by a photoinduced radical cyclization reaction to construct a bridged ring skeleton. In addition to the above synthetic examples, Nishida, Tamba, Qin Yong, Ma Dawei, Zhai Hongbin, and Zu Liansuo, among others, have also reported on the total synthesis of this type of alkaloid.

[0004] Although there have been several reports of total synthesis of Pyrroloazocine indole alkaloids, the known routes all suffer from problems such as lengthy routes, high costs, limited synthetic strategies, and low efficiency. In addition, Pyrroloazocine indole alkaloids are of low abundance in nature and their sources are limited. Traditional separation and extraction methods cannot meet the needs of subsequent bioactivity research. Therefore, there is still a need to develop a novel and efficient synthetic strategy. Summary of the Invention

[0005] To overcome the shortcomings of existing methods for synthesizing Pyrroloazocine indole alkaloids, this invention provides a novel skeletal synthesis strategy that utilizes Beckmann rearrangement / intramolecular S... N The synthesis of the core skeleton of Pyrroloazocine indole alkaloids via a 2-cyclization tandem reaction can provide a material basis for the activity testing of Pyrroloazocine indole alkaloids and their analogues, and provide ideas for the design of synthetic routes for the basic skeletons of more complex cage-like indole alkaloids.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A method for synthesizing the Pyrroloazocine indole alkaloid skeleton includes the following steps:

[0008] 1) Compound 1 was condensed with phenylhydrazine to obtain a phenylhydrazone compound, and then a tetrahydrocarbazole compound 2 was prepared by Fischer indole synthesis under heating conditions;

[0009] 2) Compound 3 was prepared by introducing benzenesulfonyl group into tetrahydrocarbazole compound 2 under alkaline conditions, and then compound 4 was prepared by hydrolyzing ketal protecting group under acidic and heating conditions;

[0010] 3) Compound 5 was prepared by introducing trifluoromethanesulfonyl group into compound 4 under low temperature and alkaline conditions;

[0011] 4) Compound 6 was prepared by Stille coupling reaction under transition metal catalysis using compound 5, and then bridged ring compound 7 was prepared by intermolecular Diels-Alder reaction under Lewis acid.

[0012] 5) Using compound 7, a primary alcohol compound 8 was prepared by a borohydride oxidation reaction in a system of 9-boronbicyclo[3.3.1]nonane and sodium hydroxide hydrogen peroxide;

[0013] 6) Compound 9 was prepared by introducing a silyl ether protecting group using compound 8 in the presence of imidazole and tert-butyldimethylchlorosilane;

[0014] 7) Compound 10 was prepared by carbene-mediated cyclopropanation under alkaline conditions using compound 9, followed by rearrangement under acidic conditions to prepare compound 11.

[0015] 8) Compound 12 was prepared by hydrolyzing the ester group of compound 11 under alkaline conditions;

[0016] 9) Compound 13 was prepared by the Ley-Griffith oxidation reaction of compound 12 in the presence of tetrapropylammonium perruthenate and N-methylmorpholine oxide;

[0017] 10) Compound 14 was prepared by using compound 13 in the presence of zinc powder and calcium chloride via a free radical dechlorination reaction;

[0018] 11) Using compound 14, oxime compound 15 was prepared by condensation reaction under alkaline and heating conditions;

[0019] 12) Using oxime compound 15, Beckmann rearrangement / intramolecular S occurs under acidic conditions. N Compound 16, the core skeleton of the natural product Pyrroloazocine indole alkaloid, was prepared by a 2-cyclization tandem reaction.

[0020] The chemical structures of each compound are shown below:

[0021]

[0022] The synthesis of the core skeleton of the natural product Pyrroloazocine indole alkaloid started with inexpensive and readily available commercial raw materials, compound 1 and phenylhydrazine, and was achieved through 12 transformation steps. Compared with previous synthetic strategies, this method uses widely available and inexpensive raw materials, which can greatly reduce the synthesis cost; at the same time, the synthetic route is concise and novel, and the construction of the core skeleton of the natural product Pyrroloazocine indole alkaloid can be completed in only 12 steps, which greatly improves the overall synthetic efficiency. In addition, the synthetic routes reported in the literature all adopt the method of first constructing a spirocyclic system and then carrying out intramolecular S-transformation. N The strategies employed in this study, such as closing the eight-membered ring or constructing an eight-membered ring first and then introducing a bridged ring system via a radical reaction, suffer from limitations due to their singular approach. This technique, however, employs a completely different strategy from existing literature, utilizing key carbene-mediated cyclopropanation / ring-opening rearrangement reactions and Beckmann rearrangement / intramolecular S... NThe core skeleton of the natural product Pyrroloazocine indole alkaloid was directly constructed through a tandem cyclization reaction followed by two ring expansions. Therefore, this synthetic method provides a concise and novel strategy for constructing an eight-membered bridged ring skeleton, offering new insights for the design of routes for more natural products with bridged ring skeletons. Furthermore, this synthetic method also synthesized nine new substances, including compounds 7, 8, 9, 11, 12, 13, 14, 15, and 16.

[0023] In one embodiment, the main steps of condensing compound 1 with phenylhydrazine to form a phenylhydrazone compound, followed by a Fischer indole synthesis reaction to obtain compound 2, include: condensing compound 1 with phenylhydrazine at room temperature (25°C) using anhydrous ethanol as a solvent to obtain a phenylhydrazone compound; then removing the solvent and using ethylene glycol as a solvent, undergoing a Fischer indole synthesis reaction of the phenylhydrazone compound under reflux conditions (200°C) to obtain tetrahydrocarbazole compound 2.

[0024] In one embodiment, the main steps of preparing compound 4 by introducing a benzenesulfonyl group into tetrahydrocarbazole compound 2 under alkaline conditions and then hydrolyzing the ketal protecting group under acidic and heated conditions include: at room temperature (25°C), using dichloromethane as a solvent, the active hydrogen on the nitrogen atom of tetrahydrocarbazole compound 2 is removed by a base, which then attacks benzenesulfonyl chloride to undergo a nucleophilic substitution reaction to obtain compound 3; subsequently, at 85°C, using acetonitrile and water as a mixed solvent, the ketal protecting group is hydrolyzed in the presence of p-toluenesulfonic acid to obtain compound 4.

[0025] In one embodiment, the main steps for preparing compound 5 by introducing trifluoromethanesulfonyl group into compound 4 under low temperature and alkaline conditions include: using tetrahydrofuran and hexamethylphosphoric triamine as a mixed solvent, adding bis(trimethylsilylamino)lithium at -78°C to remove the carbonyl α-H of compound 4, and then attacking N-phenylbis(trifluoromethanesulfonyl)imide to introduce trifluoromethanesulfonyl group to obtain compound 5.

[0026] In one embodiment, compound 5 undergoes a Stille coupling reaction under transition metal catalytic cross-coupling conditions to prepare compound 6, followed by an intermolecular Diels-Alder reaction under Lewis acid to prepare [2.2.2] bridged ring compound 7. The main steps include: using tetrahydrofuran as solvent, under reflux conditions (80°C), compound 5 undergoes a Stille coupling reaction with allyltributyltin in the presence of tetra(triphenylphosphine)palladium and lithium chloride to obtain compound 6; then using toluene as solvent, at 50°C, compound 6 undergoes an intermolecular Diels-Alder reaction with methyl acrylate in the presence of diethylaluminum chloride to obtain compound 7.

[0027] In one embodiment, the main steps for preparing primary alcohol compound 8 by the hydroboration oxidation reaction of compound 7 in a system of 9-boronbicyclo[3.3.1]nonane and sodium hydroxide hydrogen peroxide include: using tetrahydrofuran as solvent, compound 7 undergoes a hydroboration reaction with 9-boronbicyclo[3.3.1]nonane under heating conditions (50°C), followed by an oxidation reaction at low temperature conditions (0°C) with 3M sodium hydroxide aqueous solution and 30% hydrogen peroxide aqueous solution to obtain compound 8.

[0028] In one embodiment, the main steps for preparing compound 9 by introducing a silyl ether protecting group into compound 8 under the action of imidazole and tert-butyldimethylchlorosilane include: using N,N-dimethylformamide as a solvent, at room temperature (25°C), the alcohol hydroxyl group of compound 8 attacks tert-butyldimethylchlorosilane under the action of imidazole to undergo a nucleophilic substitution reaction to introduce a silyl ether protecting group and obtain compound 9.

[0029] In one embodiment, the main steps of preparing compound 10 by carbene-mediated cyclopropanation under alkaline conditions and subsequent rearrangement under acidic conditions to prepare compound 11 include: generating dichlorocarbene in 50% sodium hydroxide aqueous solution at room temperature (25°C), which then undergoes cyclopropanation with the double bond of compound 9 to obtain compound 10; and then, under heating conditions (50°C) using acetonitrile and acetic acid as a mixed solvent, rearranging compound 10 in the presence of silver acetate to open the three-membered ring and form a seven-membered bridged ring compound 11.

[0030] In one embodiment, the main steps of preparing compound 12 by hydrolyzing the ester group of compound 11 under alkaline conditions include: using dichloromethane, methanol and water as a mixed solvent, under heating conditions (50°C), compound 11 undergoes an ester group hydrolysis reaction in the presence of potassium hydroxide to obtain compound 12.

[0031] In one embodiment, the main steps of preparing compound 13 by the Ley-Griffith oxidation reaction of compound 12 with tetrapropylammonium perruthenate and N-methylmorpholine oxide include: using dichloromethane as a solvent, at room temperature (25°C), compound 12... Ketone compound 13 was obtained by Ley-Griffith oxidation reaction under the action of molecular sieve, N-methylmorpholine oxide and tetrapropylammonium perruthenate.

[0032] In one embodiment, the main steps for preparing compound 14 by the free radical dechlorination reaction of compound 13 under the action of zinc powder and calcium chloride include: using anhydrous methanol as solvent, compound 13 undergoes a free radical dechlorination reaction under the action of zinc powder and calcium chloride at room temperature (25°C) to prepare compound 14.

[0033] In one embodiment, the main steps for preparing oxime compound 15 by condensation reaction of compound 14 under alkaline and heated conditions include: using pyridine as a base and solvent, compound 14 undergoes a condensation reaction with hydroxylamine hydrochloride under reflux conditions (110°C) to obtain oxime compound 15.

[0034] In one embodiment, compound 15 undergoes a Beckmann rearrangement / intramolecular S under acidic conditions. N The main steps of the 2-cyclization tandem reaction to prepare compound 16 include: using tetrahydrofuran as a solvent, at room temperature (25°C), compound 15 undergoes a Beckmann rearrangement reaction in the presence of sulfoxide to form a lactam, while simultaneously removing the silyl ether protecting group in an acidic system. Subsequently, the lactam attacks the carbon atom attached to the hydroxyl group, resulting in an intramolecular S-reaction. N The reaction removes one molecule of water to give compound 16, which is the core skeleton of the natural product Pyrroloazocine-type indole alkaloid.

[0035] In summary, the synthesis of the core skeleton of the natural product Pyrroloazocine indole alkaloid began with commercially available compound 1 and phenylhydrazine as the starting point. First, tetrahydrocarbazole compound 2 was prepared via the Fischer indole synthesis reaction. Then, the nitrogen atom of the tetrahydrocarbazole was protected, the ketal protecting group was removed, and a trifluoromethanesulfonyl group was introduced to obtain compound 5. An allyl side chain was then introduced via Stille coupling reaction, followed by an intermolecular Diels-Alder reaction under Lewis acid conditions to construct a bridged ring system, yielding compound 7. Compound 7 underwent hydroboration oxidation and silane protection to obtain compound 9. Subsequently, a carbene-mediated cyclopropanation reaction under basic conditions followed by rearrangement under acidic conditions yielded compound 11. Compound 11 underwent ester hydrolysis, Ley-Griffith oxidation, and free radical dechlorination to obtain compound 14. Compound 14 was condensed with hydroxylamine hydrochloride, followed by Beckmann rearrangement / intramolecular S... N Compound 16, the core skeleton of the natural product Pyrroloazocine indole alkaloid, was prepared by a 2-cyclization tandem reaction. This invention constructs the core skeleton of the natural product Pyrroloazocine indole alkaloid in a concise and efficient manner in 12 steps, providing insights for the design of synthetic routes for this type of natural product and its analogues. It also lays the foundation for constructing libraries of this type of natural product and its analogues, as well as for medicinal chemistry and chemical biology research such as activity screening, structure-activity relationship analysis, and target validation.

[0036] Beneficial technical effects:

[0037] 1) The raw materials used in this technology, such as compound 1, phenylhydrazine and benzenesulfonyl chloride, are all commercially available and inexpensive, which can greatly reduce the synthesis cost;

[0038] 2) This technique is applicable to the divergent total synthesis of the natural product Pyrroloazocine indole alkaloid. Compared with the natural product skeleton construction strategies reported in the literature, the synthetic route adopted by this technique is simpler and more efficient, and the synthesis of the natural product skeleton can be completed in only 12 steps.

[0039] 3) This technology employs a novel synthetic strategy, utilizing key carbene-mediated cyclopropanation / ring-opening rearrangement reactions and Beckmann rearrangement / intramolecular S... N The 2-cyclization tandem reaction directly constructs the core skeleton of the natural product Pyrroloazocine indole alkaloid through two ring expansions, which can provide new ideas for the route design of more natural products with bridged ring skeletons.

[0040] 4) The synthetic route of this technology is simple to operate and highly reproducible. It can provide a basis for constructing libraries of natural product Pyrroloazocine indole alkaloids and their analogues, and is of great help in screening lead drug molecules and structural modification. Detailed Implementation

[0041] To facilitate understanding of the invention, a more comprehensive description is given below. However, the invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that the disclosure of the invention will be thorough and complete. Unless otherwise defined, 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. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0042] The method for synthesizing the skeleton of the natural product Pyrroloazocine indole alkaloid, as described in the embodiments, mainly includes steps 1 to 12.

[0043] Step 1: Compound 2 is synthesized from commercially available compound 1 and phenylhydrazine.

[0044] Specifically, compound 1 condenses with phenylhydrazine to form a phenylhydrazone compound, which then undergoes a Fischer indole synthesis reaction to yield compound 2.

[0045] In this embodiment, the reaction formula for synthesizing compound 2 from commercially available compound 1 and phenylhydrazine is as follows:

[0046]

[0047] Further, at 25°C, compound 1 undergoes a condensation reaction with phenylhydrazine to obtain a phenylhydrazone compound; preferably, anhydrous ethanol is used as a solvent, and compound 1 and phenylhydrazine are reacted at a molar ratio of 1:1.05 to generate the phenylhydrazone compound; preferably, the reaction time is 0.5 h; since the phenylhydrazone compound has poor stability in air, the reaction should be strictly controlled in an oxygen-free environment, and the generated phenylhydrazone compound is used directly in the next step of the reaction without separation.

[0048] Further, anhydrous ethanol is rapidly removed, and at 180–220°C, the phenylhydrazone compound undergoes Fischer indole synthesis to yield compound 2; preferably, ethylene glycol is used as the solvent; preferably, the reaction time is 12 hours, and the reaction temperature should be controlled above 180°C, otherwise the phenylhydrazone compound cannot be completely converted into compound 2 within 12 hours.

[0049] Of course, after obtaining compound 2, the process also includes purifying compound 2. Specifically, water is added to quench the reaction, compound 2 is extracted, the organic phases are combined, dried, and then purified by silica gel column chromatography to obtain compound 2. Of course, the reagent used to quench this reaction is not limited to water; it can also be a saturated aqueous solution of sodium bicarbonate.

[0050] Step 2: Use compound 2 to synthesize compound 4.

[0051] Specifically, compound 2 was prepared by introducing a benzenesulfonyl group under alkaline conditions, and then compound 4 was prepared by hydrolyzing the ketal protecting group under acidic and heating conditions.

[0052] In this embodiment, the reaction formula for synthesizing compound 4 from compound 2 is as follows:

[0053]

[0054] Furthermore, at 25°C, compound 2 undergoes condensation with benzenesulfonyl chloride under alkaline conditions to obtain compound 3. Preferably, sodium hydroxide is used as the alkaline reagent, and tetrabutylammonium hydrogen sulfate is used as the phase transfer catalyst to participate in the reaction. The molar ratio of compound 2, benzenesulfonyl chloride, sodium hydroxide, and tetrabutylammonium hydrogen sulfate is 1:1.2:3:0.1, and the reaction time is 3 hours. The resulting compound 3 can be used directly in the next step of the reaction without separation.

[0055] Furthermore, the organic solvent is dichloroethane, and the alkaline reagent used is not limited to sodium hydroxide, but can also be other alkaline reagents commonly used in the field, such as potassium hydroxide, lithium hydroxide, and sodium hydride.

[0056] Further, the solvent dichloromethane is removed, and compound 3 is hydrolyzed under acidic conditions at 80–100 °C to prepare compound 4; preferably, compound 3 and p-toluenesulfonic acid are reacted in a molar ratio of 1:1.1 to generate compound 4, and the reaction time is 12 h.

[0057] Furthermore, the organic solvent is a mixture of acetonitrile and water, with a ratio of acetonitrile:water = 5:1 to 15:1. The acidic reagent used is not limited to p-toluenesulfonic acid, but can also be p-toluenesulfonic acid monohydrate.

[0058] Of course, after obtaining compound 4, the process also includes purifying compound 4. Specifically, a saturated sodium bicarbonate aqueous solution is added to quench the reaction, compound 4 is extracted, the organic phases are combined, dried, and then purified by silica gel column chromatography to obtain compound 4. Of course, the reagent used to quench this reaction is not limited to a saturated sodium bicarbonate aqueous solution; it can also be a saturated sodium carbonate or saturated potassium carbonate aqueous solution.

[0059] Step 3: Use compound 4 to synthesize compound 5.

[0060] Specifically, compound 4 was prepared by introducing a trifluoromethanesulfonyl group under low temperature and alkaline conditions.

[0061] In this embodiment, the reaction formula for synthesizing compound 5 from compound 4 is as follows:

[0062]

[0063] Furthermore, at -78°C, compound 4 undergoes a nucleophilic substitution reaction with N-phenylbis(trifluoromethanesulfonyl)imide to remove the hydrogen at the α-position of the carbonyl group. The molar ratio of compound 4 to LiHMDS is 1:1.3. The resulting carbanion then undergoes a nucleophilic substitution reaction with N-phenylbis(trifluoromethanesulfonyl)imide at -78°C, successfully introducing a trifluoromethanesulfonyl group to yield compound 5. Preferably, the molar ratio of compound 4, LiHMDS, and N-phenylbis(trifluoromethanesulfonyl)imide is 1:1.3:1.1.

[0064] Furthermore, the organic solvent is a mixture of ultra-dry tetrahydrofuran and hexamethylphosphoric triamine, with a mixing ratio of tetrahydrofuran:hexamethylphosphoric triamine = 10:1. The basic reagent used is not limited to LiHMDS, but can also be other basic reagents commonly used in the field, such as NaHMDS and KHMDS.

[0065] Of course, after obtaining compound 5, the process also includes purifying compound 5. Specifically, water is added to quench the reaction, compound 5 is extracted, the organic phases are combined, dried, and then purified by silica gel column chromatography to obtain purified compound 5. Of course, the reagent used to quench this reaction is not limited to water; it can also be a saturated ammonium chloride aqueous solution.

[0066] Step 4: Use compound 5 to synthesize compound 7.

[0067] Specifically, compound 5 undergoes a Stille coupling reaction under transition metal catalytic cross-coupling conditions to prepare compound 6, and then undergoes an intermolecular Diels-Alder reaction under the action of Lewis acid to prepare [2.2.2] bridged ring compound 7.

[0068] In this embodiment, the reaction formula for synthesizing compound 7 from compound 5 is as follows:

[0069]

[0070] Further, at 80°C, compound 5 undergoes a Stille coupling reaction with allyltributyltin in the presence of tetra(triphenylphosphine)palladium and lithium chloride to yield compound 6; preferably, the molar ratio of compound 5, tetra(triphenylphosphine)palladium, lithium chloride, and allyltributyltin is 1:0.02:2:3, the reaction time is 12 h, and the organic solvent is ultra-dry tetrahydrofuran. Because compound 6 has poor stability in air, the resulting compound 6 is used directly in the next reaction without separation.

[0071] Further, at 50°C, compound 6 undergoes an intermolecular Diels-Alder reaction with methyl acrylate under the action of Lewis acid to obtain [2.2.2] bridged ring compound 7; preferably, compound 6, diethylaluminum chloride and methyl acrylate are generated in a molar ratio of 1:1:10, the reaction time is 24 h, and the organic solvent is ultra-dry toluene.

[0072] Of course, after obtaining compound 7, the process also includes purifying compound 7. Specifically, the compound 7 is obtained by filtration through diatomaceous earth, washing the diatomaceous earth with dichloromethane, combining the organic phases, drying, and then performing silica gel column chromatography.

[0073] Step 5: Use compound 7 to synthesize compound 8.

[0074] Specifically, compound 7 was prepared into primary alcohol compound 8 by a borohydride oxidation reaction in a system of 9-boronbicyclo[3.3.1]nonane and sodium hydroxide hydrogen peroxide.

[0075] In this embodiment, the reaction formula for synthesizing compound 8 from compound 7 is as follows:

[0076]

[0077] Furthermore, at 50°C, compound 7 undergoes a hydroboration reaction with a 1.0 M tetrahydrofuran solution of 9-boronbicyclo[3.3.1]nonane; preferably, the molar ratio of compound 7 to 9-boronbicyclo[3.3.1]nonane is 1:2.5, the reaction time is 3 h, and the organic solvent is ultra-dry tetrahydrofuran.

[0078] Further, the reaction system was cooled to 0°C, and the borohydride reaction intermediate was oxidized with a 30% hydrogen peroxide aqueous solution under alkaline conditions to obtain compound 8. Preferably, the alkaline was a 3M sodium hydroxide aqueous solution, and the reaction time was 1 hour.

[0079] Of course, after obtaining compound 8, the process also includes purifying compound 8. Specifically, a saturated ammonium chloride aqueous solution is added to quench the reaction, compound 8 is extracted, the organic phases are combined, dried, and then purified by silica gel column chromatography to obtain compound 8.

[0080] Step 6: Use compound 8 to synthesize compound 9.

[0081] Specifically, compound 8 was prepared by introducing a silyl ether protecting group into compound 9 under the action of imidazole and tert-butyldimethylchlorosilane.

[0082] In this embodiment, the reaction formula for synthesizing compound 9 from compound 8 is as follows:

[0083]

[0084] Furthermore, at 25°C, compound 8 undergoes a nucleophilic substitution reaction with tert-butyldimethylchlorosilane under the action of imidazole to generate compound 9; preferably, the molar ratio of compound 8, imidazole and tert-butyldimethylchlorosilane is 1:5:4, and the reaction time is 2h.

[0085] Furthermore, the organic solvent is N,N-dimethylformamide. It is understood that in other embodiments, the solvent is not limited to N,N-dimethylformamide, but may be other commonly used solvents in the art, such as dichloromethane and dichloroethane.

[0086] Of course, after obtaining compound 9, the process also includes purifying compound 9. Specifically, a saturated aqueous sodium bicarbonate solution is added to quench the reaction, compound 9 is extracted, the organic phases are combined, dried, and then purified by silica gel column chromatography to obtain compound 9. Of course, the reagent used to quench this reaction is not limited to a saturated aqueous sodium bicarbonate solution; water can also be used.

[0087] Step 7: Use compound 9 to synthesize compound 11.

[0088] Specifically, compound 9 undergoes a carbene-mediated cyclopropanation reaction under alkaline conditions to give compound 10, which is then rearranged under acidic conditions to prepare compound 11.

[0089] In this embodiment, the reaction formula for synthesizing compound 11 from compound 9 is as follows:

[0090]

[0091] Furthermore, at 25°C, chloroform generates dichlorocarbene under strongly alkaline conditions, which then undergoes a cyclopropanation reaction with compound 9 to generate compound 10. Preferably, a 50% sodium hydroxide aqueous solution is used as the alkaline reagent, and benzyltriethylammonium chloride is used as a phase transfer catalyst to participate in the reaction. The molar ratio of compound 9 to benzyltriethylammonium chloride is 1:1, and the reaction time is 8 hours. Since compound 10 has poor stability on a silica gel column, the generated compound 10 is not separated and is directly used in the next step of the reaction.

[0092] Furthermore, at 50°C, compound 10 undergoes a rearrangement reaction under the action of silver acetate to generate compound 11; preferably, the molar ratio of compound 10 to silver acetate is 1:2, the organic solvent is a mixed solvent of ultra-dry acetonitrile and acetic acid, the ratio of the mixed solvent is acetonitrile:acetic acid = 2.5:1, and the reaction time is 12h.

[0093] Of course, after obtaining compound 11, the step of purifying compound 11 is also included. Specifically, saturated brine is added to quench the reaction, compound 11 is extracted, the organic phases are combined, dried, and purified by silica gel column chromatography to obtain compound 11.

[0094] Step 8: Use compound 11 to synthesize compound 12.

[0095] Specifically, compound 11 was hydrolyzed under alkaline conditions to prepare compound 12.

[0096] In this embodiment, the reaction formula for synthesizing compound 12 from compound 11 is as follows:

[0097]

[0098] Furthermore, at 50°C, compound 11 is hydrolyzed under alkaline conditions to generate compound 12; preferably, the molar ratio of compound 11 to potassium hydroxide is 1:10, and the reaction time is 5 h.

[0099] Furthermore, the solvent is a mixture of methanol, dichloromethane and water, with a ratio of methanol:dichloromethane:water = 4:4:1. The alkaline reagent used is not limited to potassium hydroxide, but can also be other alkaline reagents commonly used in the field, such as lithium hydroxide and sodium hydroxide.

[0100] Of course, after obtaining compound 12, the process also includes purifying compound 12. Specifically, water is added to quench the reaction, compound 12 is extracted, the organic phases are combined, dried, and then purified by silica gel column chromatography to obtain compound 12.

[0101] Step 9: Use compound 12 to synthesize compound 13.

[0102] Specifically, compound 12 was prepared by a Ley-Griffith oxidation reaction in the presence of tetrapropylammonium perruthenate and N-methylmorpholine oxide to produce compound 13.

[0103] In this embodiment, the reaction formula for synthesizing compound 13 from compound 12 is as follows:

[0104]

[0105] Furthermore, at 50°C, compound 12 undergoes a Ley-Griffith oxidation reaction with tetrapropylammonium perruthenate and N-methylmorpholine oxide to generate compound 13; preferably, the molar ratio of compound 12, tetrapropylammonium perruthenate, and N-methylmorpholine oxide is 1:0.2:2. The amount of molecular sieve used was 500 mg / mmol, and the reaction time was 5 h.

[0106] Furthermore, the organic solvent is dichloromethane. It is understood that in other embodiments, the solvent is not limited to dichloromethane, but may be other commonly used solvents in the art, such as dichloroethane and toluene.

[0107] Of course, after obtaining compound 13, the step of purifying compound 13 is also included. Specifically, the compound 13 is obtained by filtration through diatomaceous earth, washing the diatomaceous earth with dichloromethane, combining the organic phases, drying, and then performing silica gel column chromatography.

[0108] Step 10: Use compound 13 to synthesize compound 14.

[0109] Specifically, compound 13 undergoes a free radical dechlorination reaction with zinc powder and calcium chloride to prepare compound 14.

[0110] In this embodiment, the reaction formula for synthesizing compound 14 from compound 13 is as follows:

[0111]

[0112] Furthermore, at 25°C, compound 13 undergoes a free radical dechlorination reaction in the presence of zinc powder and calcium chloride to generate compound 14; preferably, the molar ratio of compound 13, zinc powder and calcium chloride is 1:5:3, the organic solvent is anhydrous methanol, and the reaction time is 8h.

[0113] Of course, after obtaining compound 14, the step of purifying compound 14 is also included. Specifically, the compound 14 is obtained by filtration through diatomaceous earth, washing the diatomaceous earth with ethyl acetate, combining the organic phases, drying, and then performing silica gel column chromatography.

[0114] Step 11: Synthesize compound 15 using compound 14.

[0115] Specifically, compound 14 undergoes a condensation reaction under alkaline and heated conditions to prepare oxime compound 15.

[0116] In this embodiment, the reaction formula for synthesizing compound 15 from compound 14 is as follows:

[0117]

[0118] Furthermore, at 110°C, compound 14 undergoes a condensation reaction with hydroxylamine hydrochloride under the action of pyridine to generate compound 15; preferably, the molar ratio of compound 14 to hydroxylamine hydrochloride is 1:8, pyridine acts as both a basic reagent and an organic solvent in the system, and the reaction time is 8 hours.

[0119] Of course, after obtaining compound 15, the process also includes purifying compound 15. Specifically, water is added to quench the reaction, compound 15 is extracted, the organic phases are combined, dried, and then purified by silica gel column chromatography to obtain compound 15.

[0120] Step 12: Use compound 15 to synthesize compound 16.

[0121] Specifically, compound 15 undergoes Beckmann rearrangement / intramolecular S under acidic conditions. N Compound 16, the core skeleton of the natural product Pyrroloazocine indole alkaloid, was prepared by a 2-cyclization tandem reaction.

[0122] In this embodiment, the reaction formula for synthesizing compound 16 from compound 15 is as follows:

[0123]

[0124] Furthermore, at 25°C, compound 15 undergoes a Beckmann rearrangement reaction in the presence of thionyl chloride to form a lactam. Simultaneously, the silyl ether protecting group is removed in an acidic system, and subsequently, the lactam attacks the carbon atom attached to the hydroxyl group, resulting in an intramolecular S-reaction. N2. The reaction removes one molecule of water to give compound 16; preferably, the molar ratio of compound 15 to sulfoxide is 1:5, the organic solvent is ultra-dry tetrahydrofuran, and the reaction time is 12 h. It is worth noting that this reaction cannot be monitored by thin-layer chromatography (TLC) and compound 16 can only be detected after quenching and extraction.

[0125] Of course, after obtaining compound 16, the step of purifying compound 16 is also included. Specifically, water and saturated sodium bicarbonate aqueous solution are added sequentially to quench the reaction, compound 16 is extracted, the organic phases are combined, dried, and purified by silica gel column chromatography to obtain compound 16. Specific Implementation

[0127] The following detailed description is provided with reference to specific embodiments. Unless otherwise specified, the embodiments do not include components other than unavoidable impurities. Experimental methods not specifically described in the embodiments are implemented under conventional conditions, such as those described in literature, books, or methods recommended by the manufacturer.

[0128] Example 1

[0129] Synthesis of Compound 2

[0130]

[0131] Compound 1 (23.4 g, 150 mmol) was added to a 1000 mL inclined two-necked flask, and anhydrous ethanol (250 mL) was added under a nitrogen atmosphere to completely dissolve it. Phenylated hydrazine (17.0 g, 157.5 mmol, 1.05 equiv.) was added dropwise at room temperature, and the mixture was stirred at room temperature for 0.5 h. The solvent was then removed under reduced pressure to obtain the phenylhydrazone intermediate. Separately, a 2000 mL inclined two-necked flask was prepared, and the crude phenylhydrazone intermediate was added. Ethylene glycol (500 mL) was added under a nitrogen atmosphere, and the system was heated to 200 °C and refluxed for 12 h. After the reaction was complete, the system was cooled to room temperature, and the reaction was quenched by adding water (500 mL) in an ice-water bath. The aqueous phase was extracted with ethyl acetate (200 mL × 3), the organic phases were combined and washed once with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude compound 2. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound 2 (30.3 g, 132 mmol), a white powder solid, with a yield of 88%.

[0132] The purified compound 2 was subjected to nuclear magnetic resonance (NMR) detection, and the results are as follows:

[0133] R f =0.67 (petroleum ether: ethyl acetate = 3:1)

[0134] 1 H NMR (400MHz, CDCl3) δ7.74(br,1H),7.41(d,J=7.6Hz,1H),7.24(d,J=7.6Hz,1H),7.11(t,J=7.6Hz,1H ),7.06(t,J=7.6Hz,1H),4.09-4.03(m,4H),2.97(s,2H),2.91(t,J=6.9Hz,2H),2.08(t,J=6.9Hz,2H);

[0135] 13 C NMR (101MHz, CDCl3) δ136.5,132.2,127.5,121.1,119.1,117.5,110.5,109.1,107.9,64.5,64.3,31.9,31.7,21.3.

[0136] Example 2

[0137] Synthesis of Compound 4

[0138]

[0139] Compound 2 (9.17 g, 40 mmol) was added to a 500 mL round-bottom flask, and dichloromethane (140 mL) was added to dissolve it completely. Tetrabutylammonium bisulfate (TBAHS, 1.36 g, 4 mmol, 0.1 equiv.) and NaOH (4.80 g, 120 mmol, 3.0 equiv.) were added at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Benzenesulfonyl chloride (6.13 mL, 48 mmol, 1.2 equiv.) was slowly added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 3 h. The reaction was quenched with water (140 mL), and the organic phase was separated. The remaining aqueous phase was extracted with dichloromethane (70 mL × 3). All organic phases were combined, washed once with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of compound 3. The crude product of compound 3 and p-toluenesulfonic acid (7.58 g, 44 mol, 1.1 equiv.) were added to a 1000 mL inclined two-necked flask. Acetonitrile (210 mL) and water (21 mL) were added under a nitrogen atmosphere to obtain a suspension. The system was then heated to 85 °C and refluxed for 12 h until the reaction was complete. The system was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the reaction was quenched by adding saturated sodium bicarbonate aqueous solution (200 mL). The aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of compound 4. The crude product of compound 4 was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound 4 (7.94 g, 28.4 mmol), a white powder solid, with a yield of 61%.

[0140] The purified compound 4 was subjected to nuclear magnetic resonance (NMR) detection, and the results are as follows:

[0141] R f =0.70 (Petroleum ether:ethyl acetate = 3:1)

[0142] 1 H NMR (400MHz, CDCl3) δ8.18(d,J=8.4Hz,1H),7.77(d,J=8.4Hz,2H),7.54(t,J=7.6Hz,1H), 7.42(t,J=7.6Hz,2H),7.36-7.27(m,3H),3.48(s,2H),3.47(s,2H),2.75(t,J=7.2Hz,2H);

[0143] 13 C NMR (101MHz, CDCl3) δ207.5,138.9,137.1,134.1,133.0,129.6,129.2,126.4,125.2,124.0,118.3,116.4,114.8,38.7,36.2,23.9

[0144] Example 3

[0145] Synthesis of Compound 5

[0146]

[0147] Compound 4 (9.1 g, 28 mmol) was added to a 500 mL inclined two-necked flask. Under a nitrogen atmosphere, ultra-dry tetrahydrofuran (160 mL) and HMPA (16 mL) were added to completely dissolve compound 4. The system was then cooled to -78 °C, and LiHMDS (1.0 M in THF) (36.4 mL, 36.4 mmol, 1.3 equiv.) was slowly added dropwise while maintaining the temperature at -78 °C and stirring for 0.5 h. Then, N-phenylbis(trifluoromethanesulfonyl)imide (PhNTf2) (11.0 g, 30.8 mmol, 1.1 equiv.) was dissolved in ultra-dry tetrahydrofuran (30.8 mL), and the tetrahydrofuran solution of N-phenylbis(trifluoromethanesulfonyl)imide was slowly added dropwise to the reaction system. After the addition was complete, the temperature of the reaction system was slowly raised to room temperature (heating rate approximately 0.85℃ / min). Then, water (150 mL) was added to quench the reaction, tetrahydrofuran was removed under reduced pressure, and the remaining aqueous phase was extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 5. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1-10:1) to give compound 5 (9.1 g, 19.9 mmol), a white powder solid, with a yield of 71%.

[0148] The purified compound 5 was subjected to nuclear magnetic resonance (NMR) detection, and the results are as follows:

[0149] R f =0.42 (petroleum ether: ethyl acetate = 10:1)

[0150] 1 H NMR(400MHz, (CD3)2CO) δ8.19(d,J=7.6Hz,1H),8.03(d,J=8.4Hz,2H),7.75-7.60(m,2H),7.63(t,J=7.6Hz, 2H),7.39(t,J=7.6Hz,1H),7.33(t,J=7.6Hz,1H),6.93(s,1H),3.68(t,J=9.8Hz,2H),3.04(t,J=9.8Hz,2H).

[0151] 13 C NMR (101MHz, (CD3)2CO) δ147.6,139.0,137.5,135.4,133.8,130.5,130.4,127.9,127.4,125.4,124.9,119.1

[0152] Example 4

[0153] Synthesis of Compound 7

[0154]

[0155] Compound 5 (5.2 g, 11.4 mmol), tetra(triphenylphosphine)palladium (266 mg, 0.23 mol, 0.02 equiv.), and lithium chloride (966 mg, 22.8 mmol, 2.0 equiv.) were added to a 250 mL inclined two-necked flask. Under a nitrogen atmosphere, ultra-dry tetrahydrofuran (45 mL) was added to completely dissolve compound 5. Then, allyltributyltin (10.6 mL, 34.2 mmol, 3.0 equiv.) was slowly added dropwise. The reaction system was heated to 80 °C and refluxed for 12 h. The mixture was cooled to room temperature, diluted with ethyl acetate (45 mL), followed by the addition of saturated potassium fluoride aqueous solution (45 mL) and stirred at room temperature for 6 h. The organic phase was separated, and the remaining aqueous phase was extracted with ethyl acetate (20 mL × 3). All organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 6. The crude compound was washed with eluent (petroleum ether: ethyl acetate = 10:1) on a short silica gel column and concentrated in a 250 mL inclined two-necked flask. Under a nitrogen atmosphere, ultra-dry toluene (38 mL) was added to completely dissolve compound 6. The reaction system was cooled to 0 °C, and diethylaluminum chloride (1.0 M in toluene) (11.4 mL, 11.4 mmol, 1.0 equiv.) and methyl acrylate (10.3 mL, 114 mmol, 10.0 equiv.) were slowly added dropwise. The reaction system was heated to 50 °C and stirred for 24 h. The diatomaceous earth was filtered, washed with dichloromethane (50 mL), and the organic phase was concentrated to obtain crude compound 7. The crude compound 7 was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give compound 7 (2.1 g, 4.8 mmol), a white foamy solid, with a yield of 42%.

[0156] The purified compound 7 was subjected to nuclear magnetic resonance (NMR) detection, and the results are as follows:

[0157] R f =0.35 (petroleum ether: ethyl acetate = 10:1)

[0158] 1H NMR (500MHz, CDCl3) δ7.96(t,J=1.2Hz,1H),7.95(d,J=1.5Hz,1H),7.63(d,J=7.5Hz,1H),7.56-7.49(m,1H),7.48 -7.39(m,3H),7.21(ddd,J=8.5,7.4,1.4Hz,1H),7.01(td,J=7.5,0.9Hz,1H),6.33(s,1H),5.90(ddt,J=17.4,10. 1,7.3Hz,1H),5.19-5.10(m,2H),3.79(dd,J=10.3,5.3Hz,1H),3.47(s,3H),2.77-2.67(m,1H),2.36(ddt,J=7.2, 4.6,1.2Hz,2H),1.85-1.77(m,1H),1.53-1.446(m,1H),1.46-1.36(m,1H),1.23-1.11(m,1H),0.91-0.80(m,1H).

[0159] 13 C NMR (126MHz, CDCl3) δ173.55,144.95,141.39,139.95,134.37,132.97,129.12,129.11,127.04,125. 85,123.16,121.02,120.89,118.14,113.53,72.16,51.79,46.86,42.44,38.40,35.13,30.26,28.88.

[0160] Example 5

[0161] Synthesis of Compound 8

[0162]

[0163] Compound 7 (1.7 g, 3.9 mmol) was added to a 250 mL inclined two-necked flask. Under a nitrogen atmosphere, 20 mL of ultra-dry tetrahydrofuran was added to completely dissolve compound 7. The reaction system was then cooled to 0 °C, and 9-BBN (0.5 M inTHF) (19.5 mL, 9.75 mmol, 2.5 equiv.) was slowly added dropwise. The system was then heated to 50 °C and stirred for 3 h. After compound 7 was completely converted to the borohydride product, the reaction system was cooled to 0 °C, and 11.7 mL of 3 M sodium hydroxide aqueous solution and 11.7 mL of 30% hydrogen peroxide aqueous solution were slowly added dropwise. The system was stirred at 0 °C for 1 h. The reaction was quenched by adding saturated ammonium chloride aqueous solution (25 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 8. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 8 (1.7 g, 3.7 mmol), a white foamy solid with a yield of 95%.

[0164] The purified compound 8 was subjected to nuclear magnetic resonance (NMR) detection, and the results are as follows:

[0165] R f =0.20 (Petroleum ether:ethyl acetate = 1:1)

[0166] 1 H NMR(400MHz, CDCl3)δ7.96(d,J=7.8Hz,2H),7.63(d,J=8.3Hz,1H),7.56-7.49(m,1H) ,7.43(dd,J=18.6,7.7Hz,3H),7.22(d,J=7.8Hz,1H),7.00(t,J=7.5Hz,1H),6.30(s, 1H),3.79(dd,J=10.3,5.3Hz,1H),3.71(t,J=5.9Hz,2H),3.47(s,3H),2.72(t,J=8.8 Hz,1H),1.82-1.75(m,1H),1.74-1.59(m,2H),1.52-1.40(m,3H),1.28-1.10(m,3H).

[0167] 13 C NMR (101MHz, CDCl3) δ173.5,144.8,141.3,139.9,132.9,129.0,127.0,125.8,123. 1,121.1,120.9,113.5,72.0,63.4,51.7,46.7,38.2,35.0,34.1,30.1,28.8,28.0.

[0168] Example 6

[0169] Synthesis of Compound 9

[0170]

[0171] Compound 8 (2.3 g, 5.1 mmol) was added to a 100 mL round-bottom flask, followed by N,N-dimethylformamide (25 mL). The reaction system was cooled to 0 °C, and imidazole (1.7 g, 25.5 mmol, 5.0 equiv.) and tert-butyldimethylchlorosilane (TBSCl) (3.1 g, 20.4 mmol, 4.0 equiv.) were added. The reaction system was then heated to room temperature and stirred for 2 h. After the reaction was complete, the system temperature was lowered to 0 °C, and the reaction was quenched by slowly adding saturated sodium bicarbonate aqueous solution (25 mL). The aqueous phase was extracted with ethyl acetate (25 mL × 3), and the organic phases were combined. The organic phase was washed three times with water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 9. The crude compound 9 was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 9 (2.9 g, 5.05 mmol), a white foamy solid, with a yield of 99%.

[0172] The purified compound 9 was subjected to nuclear magnetic resonance (NMR) detection, and the results are as follows:

[0173] R f =0.27 (petroleum ether: ethyl acetate = 20:1)

[0174] 1 H NMR (400MHz, CDCl3) δ7.96(d,J=7.9Hz,2H),7.63(d,J=8.2Hz,1H),7.52(t,J=7.5Hz,1H),7 .43(dd,J=16.6,8.0Hz,3H),7.21(t,J=7.8Hz,1H),7.00(t,J=7.5Hz,1H),6.31(s,1H),3.78 (dd,J=10.3,5.3Hz,1H),3.69-3.62(m,2H),3.47(s,3H),2.72(t,J=8.8Hz,1H),1.86-1.72 (m,1H),1.68-1.56(m,3H),1.50-1.38(m,2H),1.26-1.10(m,3H),0.91(s,9H),0.07(s,6H).

[0175] 13C NMR (101MHz, CDCl3) δ173.6,144.8,141.3,139.8,132.9,129.0,127.0,125.9,123.1,121.5 ,120.9,113.5,72.0,63.6,51.7,46.7,38.2,35.1,34.1,30.2,28.8,28.2,26.0,18.4,-5.2.

[0176] Example 7

[0177] Synthesis of Compound 11

[0178]

[0179] Compound 9 (2.44 g, 4.3 mmol) and benzyltriethylammonium chloride (TEBA) (979 mg, 4.3 mmol, 1.0 equiv.) were added to a 250 mL inclined two-necked flask. Under a nitrogen atmosphere, chloroform (43 mL) was added to completely dissolve compound 9. Then, 21.5 mL of 50% sodium hydroxide aqueous solution was slowly added at room temperature in the dark, and the mixture was stirred for approximately 8 hours. The reaction system was placed at 0 °C, and water (100 mL) was added to quench the reaction. The organic phase was separated, and the remaining aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of compound 10. Prepare a separate 250 mL inclined two-necked flask, add crude compound 10 and silver acetate (1.44 g, 8.6 mmol, 2.0 equiv.), and under a nitrogen atmosphere, add ultra-dry acetonitrile (43 mL) and acetic acid (17 mL) to completely dissolve compound 10. Then, raise the reaction system to 50 °C and stir for 12 h in the dark. After the reaction is complete, cool the reaction system to room temperature, add saturated brine (60 mL) to quench the reaction, extract the aqueous phase with ethyl acetate (60 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate to obtain crude compound 11. Purify by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1-5:1) to obtain compound 11 (1.62 g, 2.41 mmol), a white foamy solid, with a yield of 56%.

[0180] The purified compound 11 was subjected to nuclear magnetic resonance (NMR) detection, and the results are as follows:

[0181] R f =0.56 (petroleum ether: ethyl acetate = 5:1)

[0182] 1H NMR (400MHz, CDCl3) δ8.40(d,J=8.0Hz,1H),7.92(d,J=7.8Hz,2H),7.59(t,J=7.7Hz,1H),7.55-7.39(m,3 H),7.24(t,J=7.8Hz,1H),7.06(t,J=7.7Hz,1H),5.84(s,1H),4.02(t,J=9.3Hz,1H),3.65(dt,J=10.9,5.7 Hz,1H),3.60-3.50(m,1H),3.48(s,3H),3.20-3.10(m,1H),2.15(s,3H),2.13-2.01(m,1H),1.98(d,J=8. 5Hz,2H),1.93-1.83(m,1H),1.81-1.63(m,2H),1.49(m,1H),1.39-1.22(m,2H),0.93(s,9H),0.08(s,6H).

[0183] 13 C NMR (101MHz, CDCl3) δ172.8,170.1,144.3,141.7,140.8,133.1,130.7,129.3,126.5,126.1,125.6,123.1,1 23.0,112.8,81.3,74.1,63.2,52.1,46.2,38.0,36.3,32.9,30.1,27.1,26.7,26.0,20.9,18.3,-5.2,-5.3.

[0184] Example 8

[0185] Synthesis of Compound 12

[0186]

[0187] Compound 11 (1.21 g, 1.8 mmol) was added to a 250 mL round-bottom flask, followed by the addition of methanol (36 mL), dichloromethane (36 mL), and water (9 mL) to completely dissolve it. Potassium hydroxide (1.0 g, 18 mmol, 10.0 equiv.) was added at room temperature, and the reaction mixture was then heated to 50 °C and refluxed for 5 h. After cooling to 0 °C, the mixture was quenched by slow addition of water (50 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 12. This crude compound 12 was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1–5:1) to give compound 12 (1.0 g, 1.58 mmol), a white, foamy solid, in 88% yield.

[0188] The purified compound 12 was subjected to nuclear magnetic resonance (NMR) detection, and the results are as follows:

[0189] R f =0.50 (Petroleum ether:ethyl acetate = 5:1)

[0190] 1 H NMR(400MHz, CDCl3) δ8.35(d,J=8.0Hz,1H),7.87(d,J=7.8Hz,2H),7.58-7.50(m,1H),7.5 0-7.38(m,3H),7.19(t,J=7.9Hz,1H),7.02(t,J=7.7Hz,1H),4.27(s,1H),3.99(t,J=9.2Hz ,1H),3.61(t,J=5.6Hz,2H),3.44(s,3H),3.06(t,J=10.9Hz,1H),2.6(d,J=4.3Hz,1H),2. 00-1.94(m,2H),1.90-1.88(d,J=9.2Hz,2H),1.68-1.37(m,4H),0.90(s,9H),0.06(s,6H).

[0191] 13 C NMR (101MHz, CDCl3) δ173.1,144.2,141.6,138.5,133.0,130.4,129.3,126.7,126.5,125.9,125.7 ,122.9,112.8,81.9,74.3,63.5,51.9,46.6,37.9,36.7,32.8,30.7,26.9,26.0,25.7,18.4,-5.3.

[0192] Example 9

[0193] Synthesis of Compound 13

[0194]

[0195] Compound 12 (914 mg, 1.44 mmol) was added to a 50 mL round-bottom flask, and dichloromethane (15 mL) was added to completely dissolve compound 12. N-methylmorpholine oxide (NMO) (337 mg, 2.88 mmol, 2.0 equiv.) was then added at room temperature. Molecular sieve (720 mg, 500 mg / mmol) and tetrapropylammonium perruthenate (TPAP) (101 mg, 0.288 mmol, 0.2 equiv.) were stirred at room temperature for 5 h. The mixture was filtered through diatomaceous earth, washed with dichloromethane (30 mL), and the organic phase was concentrated to obtain crude compound 13. This crude compound 13 was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1-5:1) to give compound 13 (895 mg, 1.42 mmol), a yellow-green foamy solid, in 99% yield.

[0196] The purified compound 13 was subjected to nuclear magnetic resonance (NMR) detection, and the results are as follows:

[0197] R f =0.46 (petroleum ether: ethyl acetate = 5:1)

[0198] 1 H NMR (400MHz, CDCl3) δ8.61(d,J=8.1Hz,1H),7.94(d,J=7.3Hz,2H),7.59(t,J=7.4Hz,1H),7.55- 7.46(m,3H),7.38(t,J=7.9Hz,1H),7.12(t,J=7.8Hz,1H),4.28(dd,J=9.0,6.5Hz,1H),3.71-3. 59(m,2H),3.35(s,3H),3.24(ddd,J=13.5,9.4,4.6Hz,1H),2.17-2.01(m,2H),1.95-1.83(m,1H ),1.83-1.69(m,3H),1.69-1.60(m,1H),1.48(dt,J=14.6,6.7Hz,2H),0.90(s,9H),0.06(s,6H).

[0199] 13 C NMR(101MHz,Chloroform-d)δ196.5,172.0,150.5,146.0,141.1,133.5,133.0,129.4,128.4,126.7 ,124.8,123.3,113.2,77.3,76.9,63.4,52.1,48.9,46.1,35.6,31.0,29.6,27.6,26.0,18.5,-5.3.

[0200] Example 10

[0201] Synthesis of Compound 14

[0202]

[0203] Compound 13 (80 mg, 0.127 mmol), zinc powder (42 mg, 0.635 mmol, 5.0 equiv.), and calcium chloride (42 mg, 0.381 mmol, 3.0 equiv.) were added to a 10 mL Schlenk flask. Anhydrous methanol (1.5 mL) was added under a nitrogen atmosphere to completely dissolve Compound 13. The mixture was stirred at room temperature in the dark for 8 h. The solution was filtered through diatomaceous earth, washed with ethyl acetate (15 mL), and the organic phase was concentrated to obtain crude compound 14. This crude compound 14 was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1–5:1) to give compound 14 (66 mg, 0.111 mmol), a yellow-green foamy solid, in 87% yield.

[0204] The purified compound 14 was subjected to nuclear magnetic resonance (NMR) detection, and the results are as follows:

[0205] R f =0.42 (petroleum ether: ethyl acetate = 5:1)

[0206] 1 H NMR (400MHz, CDCl3) δ7.92(d,J=7.6Hz,2H),7.62-7.43(m,5H),7.37(t,J=7.2Hz,1H),7.08(t,J=7.5Hz,1H),6.53(s,1H),4.19(dd,J=9.3,7.1Hz,1 H),3.63(td,J=6.3,2.5Hz,2H),3.36(s,3H),3.22-3.05(m,1H),2.19-1.9 7(m,2H),1.96-1.83(m,1H),1.79-1.43(m,6H),0.90(s,9H),0.06(s,6H).

[0207] 13 C NMR (101MHz, CDCl3) δ203.2,172.4,156.5,145.3,141.1,133.3,132.9,129.3,126.7,125.5,123.6 ,122.2,117.7,113.8,76.1,63.6,51.9,49.3,46.3,34.9,31.0,30.4,27.7,26.6,26.0,18.4,-5.2.

[0208] Example 11

[0209] Synthesis of Compound 15

[0210]

[0211] Compound 14 (50 mg, 0.084 mmol) and hydroxylamine hydrochloride (47 mg, 0.672 mmol, 8.0 equiv.) were added to a 10 mL round-bottom flask. Pyridine (0.85 mL) was added to completely dissolve compound 14. The system was refluxed at 110 °C for 8 h. After cooling to room temperature, ethyl acetate (2 mL) was added for dilution, followed by quenching the reaction with water (5 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). All organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 15. The crude compound 15 was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1–5:1) to give compound 15 (32 mg, 0.053 mmol), a yellow-green foamy solid, with a yield of 63%.

[0212] The purified compound 15 was subjected to nuclear magnetic resonance (NMR) detection, and the results are as follows:

[0213] R f =0.40 (petroleum ether: ethyl acetate = 5:1)

[0214] 1 H NMR(400MHz, (CD3)2CO) δ8.01(d,J=7.5Hz,2H),7.65(dd,J=7.5,3.7Hz,2H),7.58(t,J=7.7Hz,2H ),7.49(d,J=8.3Hz,1H),7.36-7.23(m,2H),7.06(t,J=7.6Hz,1H),4.10(t,J=8.2Hz,1H),3.61(d ,J=6.6Hz,2H),3.26(s,3H),3.13(ddd,J=13.4,9.9,4.2Hz,1H),2.83(d,J=13.2Hz,1H),2.10(d, J=8.2Hz,2H),1.99-1.87(m,1H),1.86-1.71(m,2H),1.70-1.50(m,3H),0.90(s,9H),0.06(s,6H).

[0215] 13 C NMR(101MHz,(CD3)2CO)δ172.2,158.4,146.8,144.3,141.5,133.2,130.5,129.4,127.2,126.8,123. 1,121.1,113.5,106.1,74.8,63.6,50.8,47.2,40.9,35.5,34.0,32.2,30.9,27.6,25.5,17.9,-6.0.

[0216] Example 12

[0217] Synthesis of Compound 16

[0218]

[0219] Compound 15 (30 mg, 0.049 mmol) was added to a 10 mL Schlenk flask. Anhydrous tetrahydrofuran (1.0 mL) was added under a nitrogen atmosphere to completely dissolve compound 15. The reaction system was cooled to 0 °C, and thionyl chloride (18 μL, 0.245 mmol, 5.0 equiv.) was slowly added dropwise. The reaction system was then heated to room temperature and stirred for 12 h. The reaction was quenched by slowly adding water (3.0 mL) and saturated sodium bicarbonate aqueous solution (3.0 mL) at 0 °C. The aqueous phase was extracted with dichloromethane (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 16. This crude compound 16 was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1–1:3) to give compound 16 (7 mg, 0.0147 mmol), a yellow-green powder, in 30% yield.

[0220] The purified compound 16 was subjected to nuclear magnetic resonance (NMR) detection, and the results are as follows:

[0221] R f =0.16 (petroleum ether: ethyl acetate = 1:3)

[0222] 1 H NMR(400MHz,CD3OD)δ8.01(d,J=6.7Hz,2H),7.70-7.48(m,4H),7.32(d,J=7.5Hz,2H),7. 09(d,J=6.7Hz,1H),6.38(s,1H),4.41(dd,J=8.3,4.0Hz,1H),3.66(qd,J=12.9,12.3,4.8 Hz,2H),3.30(s,3H),3.05(dt,J=14.1,8.4Hz,1H),2.84(d,J=14.9Hz,1H),2.44(dt,J=15 .9,7.8Hz,1H),2.22-2.14(m,1H),2.14-1.90(m,5H),1.86(ddd,J=13.6,6.8,4.2Hz,1H).

[0223] 13C NMR (101MHz, CD3OD) δ172.4,164.2,146.5,143.4,141.4,133.3,131.5,131.0,129.2,126. 5,123.3,121.3,113.8,111.5,74.8,60.8,50.9,48.8,44.8,42.5,32.5,30.4,29.6,19.5.

[0224] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them. Those skilled in the art can modify or make equivalent substitutions to the technical solutions of the present invention without departing from the spirit and scope of the present invention. The scope of protection of the present invention should be determined by the claims.

Claims

1. A method for synthesizing the skeleton of Pyrroloazocine indole alkaloids, characterized in that, Includes the following steps: 1) Compound 1 was condensed with phenylhydrazine to form a phenylhydrazone compound, which was then subjected to the Fischer indole synthesis reaction to give compound 2; 2) Compound 2 was given by introducing a benzenesulfonyl group under alkaline conditions to obtain compound 3, and then compound 4 was prepared by hydrolyzing the ketal protecting group under acidic and heating conditions; 3) Compound 4 was prepared by introducing a trifluoromethanesulfonyl group under low temperature and alkaline conditions; 4) Compound 5 was prepared by Stille coupling reaction under transition metal catalysis; then, compound 6 was prepared by intermolecular Diels-Alder reaction under Lewis acid. [2.2.2] Bridged ring compound 7 was prepared. 5) Compound 7 was subjected to a hydroboration oxidation reaction to give primary alcohol compound 8; 6) Protect the alcohol hydroxyl group in compound 8 with a silyl ether to obtain compound 9; 7) Compound 9 was prepared by carbene-mediated cyclopropanation under basic conditions, followed by rearrangement under acidic conditions to obtain compound 11; 8) Compound 12 was prepared by hydrolyzing the ester group of compound 11 under alkaline conditions; 9) Compound 12 was prepared by undergoing a Ley-Griffith oxidation reaction in the presence of tetrapropylammonium perruthenate; 10) Compound 13 was prepared by undergoing a free radical dechlorination reaction with zinc powder and calcium chloride; 11) Compound 14 was condensed under alkaline and heating conditions to prepare oxime compound 15; 12) Compound 15 undergoes Beckmann rearrangement / intramolecular S under acidic conditions. N Compound 16, the core skeleton of the natural product Pyrroloazocine indole alkaloid, was prepared by a 2-cyclization tandem reaction.

2. The method for synthesizing the Pyrroloazocine indole alkaloid skeleton according to claim 1, characterized in that, In step 1), Compound 1 undergoes a condensation reaction with phenylhydrazine at room temperature to generate a phenylhydrazone compound (the molar ratio of compound 1 to phenylhydrazine is 1:1 to 1:1.5, preferably 1:1.05); the generated phenylhydrazone compound is directly heated under reflux to undergo a Fischer indole synthesis reaction to obtain tetrahydrocarbazole compound 2 (the heating conditions are 180 to 220°C, preferably 200°C).

3. The method for synthesizing the Pyrroloazocine indole alkaloid skeleton according to claim 1, characterized in that, In step 2), Compound 2 reacts with benzenesulfonyl chloride under alkaline conditions at room temperature, introducing a benzenesulfonyl group onto the nitrogen atom of carbazole to obtain compound 3 (the base is sodium hydroxide, potassium hydroxide, sodium hydride, or lithium hydroxide, preferably sodium hydroxide or potassium hydroxide). Subsequently, without separation, the crude product of compound 3 is heated under acidic conditions and refluxed to hydrolyze the ketal protecting group to obtain compound 4. The hydrolysis reaction solvent is a mixed solvent of acetonitrile and water (the acid is p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, or 1M hydrochloric acid aqueous solution, preferably p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate; the heating conditions are 80-100°C, preferably 85°C; the mixed solvent ratio is acetonitrile:water = 5:1-15:1, preferably acetonitrile:water = 10:1).

4. The method for synthesizing the Pyrroloazocine indole alkaloid skeleton according to claim 1, characterized in that, In step 3), Compound 4 was reacted with N-phenylbis(trifluoromethanesulfonyl)imide under low-temperature alkaline conditions to introduce a trifluoromethanesulfonyl group to obtain compound 5 (the low-temperature conditions were -78 to -60°C, preferably -78°C; the base was bistrimethylsilylaminolithium, bistrimethylsilylaminosodium, or bistrimethylsilylaminolithium, preferably bistrimethylsilylaminolithium).

5. The method for synthesizing the Pyrroloazocine indole alkaloid skeleton according to claim 1, characterized in that, In step 4), Compound 5 was heated under reflux with allyltributyltin in the presence of transition metal palladium to generate compound 6 via a Stille coupling reaction (heating conditions: 70-90°C, preferably 80°C; preferred metal catalyst: tetra(triphenylphosphine)palladium; molar ratio of compound 5 to tetra(triphenylphosphine)palladium: 1:0.01-1:0.05, preferably 1:0.02; molar ratio of compound 5 to allyltributyltin: 1:2.5-1:5, preferably 1:3); after simple filtration through a short silica gel column, compound 6 was reacted with methyl acrylate in the presence of Lewis acid to prepare [2.2.2] bridged ring compound 7 (Lewis acid is diethylaluminum chloride, dimethylaluminum chloride, or dichloroethylaluminum, preferably diethylaluminum chloride or dimethylaluminum chloride; molar ratio of compound 6 to methyl acrylate: 1:8-1:12, preferably 1:10; reaction temperature: 23-80°C, preferably 50°C).

6. The method for synthesizing the Pyrroloazocine indole alkaloid skeleton according to claim 1, characterized in that, In step 5), Compound 7 undergoes a hydroboration reaction with 9-BBN under heating conditions (preferably, the reaction temperature is 50°C, and the molar ratio of compound 7 to 9-BBN is 1:2.5); then it is cooled to 0°C and oxidized with a 30% aqueous hydrogen peroxide solution under alkaline conditions to give primary alcohol compound 8 (preferably, the base is an aqueous sodium hydroxide solution with a concentration of 3M).

7. The method for synthesizing the Pyrroloazocine indole alkaloid skeleton according to claim 1, characterized in that, In step 6), Compound 8 reacts with tert-butyldimethylchlorosilane under alkaline conditions at room temperature to protect the alcohol hydroxyl group and give silane compound 9 (preferably with imidazole as the base).

8. The method for synthesizing the Pyrroloazocine indole alkaloid skeleton according to claim 1, characterized in that, In step 7), Compound 9 undergoes a carbene-mediated cyclopropanation reaction under alkaline conditions at room temperature to give compound 10 (preferably, the base is a 50% aqueous sodium hydroxide solution); subsequently, it undergoes a rearrangement reaction under the action of silver acetate to give compound 11. The reaction solvent is a mixed solvent of acetonitrile and acetic acid (preferably, the heating temperature is 50°C, the ratio of the mixed solvent is acetonitrile:acetic acid = 5:2, and the molar ratio of compound 9 to silver acetate is 1:1.5 to 1:4, preferably 1:2).

9. The method for synthesizing the Pyrroloazocine indole alkaloid skeleton according to claim 1, characterized in that, In step 8), Compound 11 was heated under alkaline conditions and refluxed to hydrolyze the ester group to obtain compound 12. The reaction solvent was a mixed solvent of dichloromethane, methanol and water (preferably, the base was potassium hydroxide or sodium hydroxide, the heating temperature was 50°C, and the ratio of the mixed solvent was dichloromethane:methanol:water = 4:4:1).

10. The method for synthesizing the Pyrroloazocine indole alkaloid skeleton according to claim 1, characterized in that, In step 9), Compound 12 in tetrapropylammonium perruthenate, N-methylmorpholine oxide and The Ley-Griffith oxidation reaction under the action of molecular sieves yields compound 13.

11. The method for synthesizing the Pyrroloazocine indole alkaloid skeleton according to claim 1, characterized in that, In step 10), Compound 13 undergoes a free radical dechlorination reaction with zinc powder and calcium chloride to yield compound 14.

12. The method for synthesizing the Pyrroloazocine indole alkaloid skeleton according to claim 1, characterized in that, In step 11), Compound 14 undergoes a condensation reaction with hydroxylamine hydrochloride under alkaline heating conditions to give oxime compound 15 (preferably, the base is pyridine and is used as a solvent; the reaction temperature is 110°C).

13. The method for synthesizing the Pyrroloazocine indole alkaloid skeleton according to claim 1, characterized in that, In step 12), Compound 15 undergoes Beckmann rearrangement / intramolecular S under acidic conditions at room temperature. N Compound 16, the core skeleton of the natural product Pyrroloazocine indole alkaloid, was prepared by a 2-cyclization tandem reaction (preferably, the acid is thionyl chloride).

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