阅读说明：本技术 一种天然产物Pancratinine B和C的合成方法 (Method for synthesizing natural products Pannoncatinine B and C ) 是由 杨旸 王方 严炀忝 徐晓寒 张加洋 彭彤辉 于 2021-05-19 设计创作，主要内容包括：本发明公开了一种天然产物Pancratinine B和C及其中间体的制备方法。关键中间体化合物8的制备方法包括步骤：1)化合物1与与氮碘化合物反应,得到化合物2；2)化合物2与硅基保护基R-(1)保护的化合物2’发生环加成反应,得到化合物3；3)化合物3形成烯醇硅醚,然后发生Saegusa-Ito氧化反应,得到化合物4；4)化合物4发生还原反应,得到化合物5；5)化合物5经羟基保护,得到化合物6；6)化合物6脱保护基R,得到化合物7；7)化合物7经Pictet-spengler缩合反应,得到化合物8。然后由化合物8分别经由化合物9和10制得Pancratinine C和B。该方法是全新的合成方法,反应路线简洁,反应条件温和,易于操作。(The invention discloses a preparation method of natural products Panceratinine B and C and intermediates thereof. The preparation method of the key intermediate compound 8 comprises the following steps: 1) reacting the compound 1 with a nitrogen iodine compound to obtain a compound 2; 2) compound 2 and silicon-based protecting group R 1 Carrying out cycloaddition reaction on the protected compound 2' to obtain a compound 3; 3) forming enol silyl ether by the compound 3, and then carrying out Saegusa-Ito oxidation reaction to obtain a compound 4; 4) carrying out reduction reaction on the compound 4 to obtain a compound 5; 5) protecting the compound 5 with hydroxyl to obtain a compound 6; 6) removing the protecting group R from the compound 6 to obtain a compound 7; 7) and carrying out a Pictet-spengler condensation reaction on the compound 7 to obtain a compound 8. Pancratinine C and B were then prepared from compound 8 via compounds 9 and 10, respectively. The method is a brand new synthesis method, has simple reaction route, mild reaction conditions and easy operation.)

1. A method of synthesizing compound 8, comprising the steps of:

1) reacting the compound 1 with a nitrogen iodine compound to obtain a compound 2;

2) performing cycloaddition reaction on the compound 2 and the compound 2' under the catalysis of Lewis acid to obtain a compound 3;

3) forming enol silyl ether by the compound 3, and then carrying out Saegusa-Ito oxidation reaction to obtain a compound 4;

4) carrying out reduction reaction on the compound 4 to obtain a compound 5;

5) protecting the compound 5 with hydroxyl to obtain a compound 6;

6) removing the protecting group R from the compound 6 to obtain a compound 7;

7) carrying out a Pictet-spengler condensation reaction on the compound 7 to obtain a compound 8;

the reaction route is as follows:

wherein R represents p-toluenesulfonyl or p-nitrobenzenesulfonyl, R₁、R₂Each represents a hydroxyl protecting group.

2. The method of claim 1, wherein the method comprises one or more of the following features:

1) in the step 1), reacting the compound 1 with a nitrogen iodine compound in the presence of copper acetylacetonate to obtain a compound 2; the azoiodine compound is p-methyl benzenesulfonylimide iodobenzene or p-nitrobenzenesulfonylimide iodobenzene;

2) in the step 2), the compound 2 and the compound 2' are subjected to a [3+2] cycloaddition reaction under the catalysis of Lewis acid to obtain a compound 3; the Lewis acid is selected from at least one of copper tetra (acetonitrile) tetrafluoroborate, copper trifluoromethanesulfonate, copper tetra (acetonitrile) trifluoromethanesulfonate, copper tetraacetonitrilate, copper acetate, scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, cuprous iodide, copper chloride, copper trifluoroacetate hydrate, silver tetrafluoroborate, silver perchlorate, silver trifluoromethanesulfonate, silver acetate and silver trifluoroacetate;

3) in the step 3), the compound 3 forms silyl enol ether in the presence of alkali and trimethylsilyl trifluoromethanesulfonate, and then undergoes Saegusa-Ito oxidation reaction under the action of an oxidant to obtain a compound 4; the base is diisopropylethylamine; the oxidant is at least one selected from 2-iodoxybenzoic acid, pyridinium chlorochromate and palladium acetate;

4) in the step 4), the compound 4 is subjected to a reduction reaction under the action of a reducing agent to obtain a compound 5; the reducing agent is selected from at least one of sodium borohydride, aluminum lithium hydride, diisobutyl aluminum hydride, cerium trichloride and sodium borohydride;

5) in the step 5), the compound 5 is subjected to hydroxyl protection reaction under the action of a hydroxyl protection reagent to obtain a compound 6; the hydroxyl protecting reagent is selected from at least one of chloromethyl methyl ether, trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, tert-butyl dimethyl silyl trifluoromethanesulfonate and the like;

6) in the step 6), removing a protecting group R from the compound 6 under the action of sodium naphthalene or lithium aluminum hydride to obtain a compound 7;

7) in the step 7), the compound 7 is subjected to a Pictet-spengler reaction in the presence of paraformaldehyde and formic acid to obtain a compound 8.

3. A method for synthesizing Pancratinine C comprises the following steps:

1) the compound 8 of claim 1 is subjected to hydroxyl protection and oxidation to obtain a compound 9,

2) removing a hydroxyl protecting group from the compound 9, and then carrying out oxidation and reduction reactions to obtain Pancratinine C;

the reaction route is as follows:

wherein R is₃Represents a hydroxyl protecting group.

4. The method of claim 3, wherein the method comprises one or more of the following features:

1) carrying out hydroxyl protection reaction on the compound 8 under the action of a hydroxyl protection reagent, and then carrying out oxidation reaction under the action of an oxidant to obtain a compound 9; wherein the hydroxyl protecting reagent is selected from at least one of trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, chloromethyl ether and methanesulfonate; the oxidant is selected from at least one of pyridinium chlorochromate, ruthenium trichloride, sodium periodate and selenium dioxide;

2) removing a hydroxyl protecting group from the compound 9 under the action of acid, then performing oxidation reaction under the action of an oxidizing agent, and then performing reduction reaction under the action of a reducing agent to obtain Pancratinine C; wherein the acid is at least one selected from hydrofluoric acid, trifluoroacetic acid and ammonium bifluoride; the oxidant is manganese dioxide; the reducing agent is selected from at least one of sodium borohydride, aluminum lithium hydride and diisobutyl aluminum hydride.

5. A method for synthesizing Panceratinine B comprises the following steps:

1) subjecting compound 8 according to claim 1 to a nucleophilic substitution reaction to give compound 10;

2) carrying out oxidation reaction on the compound 10 to obtain Panceratinine B;

the reaction route is as follows:

6. the method of claim 5, wherein the method comprises one or more of the following features:

1) carrying out nucleophilic substitution reaction on the compound 8 in the presence of a methylating agent to obtain a compound 10; the methylating agent is selected from at least one of methyl iodide/sodium cyanide, methyl trifluoromethanesulfonate/hexamethyldisilazane diazonium sodium, methyl iodide/bis (trimethylsilyl) amide lithium, methyl iodide/silver oxide, trimethyloxonium tetrafluoroborate, phosgene/sodium methoxide and sulfuryl chloride/sodium methoxide;

2) oxidizing the compound 10 by an oxidant to obtain Pancratinine B; the oxidant is selected from at least one of pyridinium chlorochromate, ruthenium trichloride, sodium periodate and selenium dioxide.

7. Intermediate compound 5, the structural formula is shown below:

8. intermediate compound 8, the structural formula is shown below:

9. intermediate compound 9, the structural formula is shown below:

wherein R is₃Represents a hydroxyl protecting group.

10. Intermediate compound 10, the structural formula is shown below:

Technical Field

The invention belongs to the field of organic chemical synthesis, and particularly relates to a total synthesis method of natural products Pannoncatinine B and C.

Background

Panceratinine B and C are alkaloids which are firstly separated from Panceratinine canariense of Amaryllidaceae in 2009, have physiological activities such as anti-tumor, anti-virus and anti-bacterial activities, and belong to Mengtianine (montanine) type alkaloids in molecular skeleton structures. The alkaloid has a 5, 11-methylene morphidine structure, contains common five-membered heterocyclic rings (shown as formula I), and is mainly characterized in that substituent groups on an E ring are different from a stereo configuration.

Montanine, cocinine and manthine were first isolated from Haemanthus in 1955 by Wildam subjects, and numerous chemists isolated a number of montanine-type alkaloids in sequence during the next decades. Due to the abundant physiological activity, novel and complex structure and challenge, chemists are attracted to research the synthesis of montanine type natural products. The first total synthesis was reported by the Overman project group in 1991, followed by many chemists to study the synthesis of such natural products. Their recent reports were made in 2013 by Fan topic group and in 2017 by Dian topic group by utilizing Rh-catalyzed cycloaddition reaction to complete the core-backbone synthesis of montanine-type alkaloids. And after Panceratinine B and C are separated from 2009 for the first time, no relevant reports of synthesis of Panceratinine B and C exist so far.

Disclosure of Invention

The invention aims to provide a method for synthesizing natural products Pancritinine B and C. The method is a novel method for completing the total synthesis of Pannoncatinine B and C for the first time, and has the advantages of concise synthesis route, mild reaction conditions and easy operation. The invention also provides a preparation method of the novel intermediate compound of Panceratinine B and C.

The invention provides the following technical scheme:

in a first aspect, the present invention provides a method of synthesizing intermediate compound 8 of Pancratinine B and C, comprising the steps of:

1) reacting the compound 1 with a nitrogen iodine compound to obtain a compound 2;

2) performing cycloaddition reaction on the compound 2 and a compound 2' (six-membered ring diene) to obtain a compound 3;

3) forming enol silyl ether by the compound 3, and then carrying out Saegusa-Ito oxidation reaction to obtain a compound 4;

4) carrying out reduction reaction on the compound 4 to obtain a compound 5;

5) protecting the compound 5 with hydroxyl to obtain a compound 6;

6) removing the protecting group R from the compound 6 to obtain a compound 7;

7) carrying out a Pictet-spengler condensation reaction on the compound 7 to obtain a compound 8;

the reaction formula is as follows:

wherein R represents a p-methylbenzenesulfonyl group (Ts) or a p-nitrobenzenesulfonyl group (Ns); r₁、R₂Represents a hydroxyl protecting group.

In one embodiment, the method may include one or more of the following features with respect to steps 1) -7):

wherein, in the step 1), the compound 1 reacts with nitrogen iodine compound in the presence of copper acetylacetonate to obtain a compound 2. The azoiodine compound can be p-methyl benzenesulfonyliminoiodobenzene or p-nitrobenzenesulfonyliminoiodobenzene. Accordingly, the protecting group R attached to N in compounds 2-6 is p-toluenesulfonyl (Ts) or p-nitrobenzenesulfonyl (Ns).

Wherein, in step 1), the reaction solvent may be acetonitrile.

Wherein, in the step 1), the molar ratio of the nitrogen iodine compound to the olefin is in the range of 1 (1-4); the molar ratio of the nitrogen iodine compound to the copper acetylacetonate is 1 (0.03-0.08), and the preferred molar ratio is: 1:0.08.

Wherein, in the step 1), the azoiodide compound can be prepared by reacting p-methyl benzene sulfonamide or p-nitrobenzene sulfonamide with iodobenzene diacetic acid in the presence of alkali (such as potassium hydroxide).

In the step 2), the compound 2 and the compound 2' undergo a [3+2] cycloaddition reaction under the catalysis of Lewis acid to obtain a compound 3. The Lewis acid can be selected from at least one of tetraacetonitrile copper tetrafluoroborate, copper trifluoromethanesulfonate, tetraacetonitrile copper hexafluorophosphate, copper acetate, scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, cuprous iodide, copper chloride, copper trifluoroacetate hydrate, silver tetrafluoroborate, silver perchlorate, silver trifluoromethanesulfonate, silver acetate and silver trifluoroacetate.

Wherein, in the step 2), the hydroxyl protecting group R in the compound 2₁May be selected from silicon-based protecting groups such as triisopropylsilicon-based (TIPS), tert-butyldimethylsilyl (TBS), triethylsilicon-based (TES), etc.; preferably Triisopropylsilyl (TIPS).

In step 2), the reaction solvent may be at least one selected from dichloromethane, tetrahydrofuran, chloroform, dioxane and toluene, and preferably dichloromethane.

In the step 2), the molar ratio of the compound 2 to the six-membered ring diene compound 2' is 1 (1-2), and the molar ratio of the compound 2 to the Lewis acid is: 1, (0.1-0.5); the reaction temperature is 25-80 ℃.

Among them, in one embodiment, the preparation method of compound 2' may be: cyclohexenone reacts in the presence of bis (trimethylsilyl) amido Lithium (LiHMDS) and a silyl protecting group reagent to obtain (cyclohexa-1, 3-diene-1-yloxy) triisopropylsilane, namely a compound 2'; wherein the silicon-based protecting group reagent (enolsilyl ether protecting group reagent) can be: isopropylsilyltrifluoromethanesulfonate (TIPSOTf), triethylsilyltrifluoromethanesulfonate (TESOTf), tert-butyldimethylsilyltrifluoromethanesulfonic acid (TBSOTf) and the like, and triisopropylsilyltrifluoromethanesulfonate (TIPSOTf) is preferred. The reaction temperature is a low temperature, for example-78 ℃. The reaction solvent may be tetrahydrofuran.

Wherein, in the step 3), the compound 3 forms silyl enol ether in the presence of alkali and trimethylsilyl trifluoromethanesulfonate, and then undergoes Saegusa-Ito oxidation reaction under the action of an oxidant to obtain a compound 4. The base may be diisopropylethylamine. The oxidant can be selected from at least one of high-valence iodine reagent 2-iodoxybenzoic acid, pyridinium chlorochromate, palladium acetate and the like, and is preferably palladium acetate.

Wherein, in the step 3), the reaction solvent can be at least one selected from toluene, dichloromethane, acetonitrile and tetrahydrofuran; the reaction temperature may range from-78 deg.C to 65 deg.C.

Wherein, in the step 4), the compound 4 is subjected to a reduction reaction under the action of a reducing agent to obtain a compound 5. The reducing agent is selected from at least one of sodium borohydride, aluminum lithium hydride, diisobutyl aluminum hydride, cerium trichloride, sodium borohydride and the like; preferably, the Luche reduction reaction is carried out under the action of cerous trichloride and sodium borohydride.

In step 4), the reaction solvent may be selected from alcohol solvents (including methanol, ethanol, isopropanol, n-propanol, etc.), or dichloromethane, tetrahydrofuran, and a mixed solvent of dichloromethane and ethanol, preferably methanol.

In the step 5), the compound 5 is subjected to hydroxyl protection reaction under the action of a hydroxyl protection reagent to obtain a compound 6. The hydroxyl protecting reagent can be selected from at least one of chloromethyl methyl ether, trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, tert-butyl dimethyl silyl trifluoromethanesulfonate and the like; chloromethyl methyl ether is preferred. Hydroxy protecting group R in Compound 6₂Represents a methoxymethyl group (MOM), a trimethylsilyl group (TMS), a triethylsilyl group (TES), a tert-butyldimethyl group (TBS), etc., and is preferably a methoxymethyl group (MOM).

Wherein, in the step 5), the reaction solvent can be selected from common solvents such as dichloromethane, tetrahydrofuran and the like.

Wherein, in the step 6), the compound 6 is subjected to the removal of the protecting group R under the action of sodium naphthalene or lithium aluminum hydride to obtain a compound 7. Preferably, compound 6 is deprotected under the action of sodium naphthalene to give compound 7, under conditions at a reaction temperature of-78 ℃.

In the step 7), the compound 7 is subjected to a Pictet-spengler reaction in the presence of paraformaldehyde and formic acid to obtain a compound 8.

Wherein, in the step 7), the reaction solvent can be selected from methanol, formic acid, acetonitrile and N, N-dimethylformamide, and the reaction temperature can be 50-90 ℃, for example 80 ℃. Compound 8 is an important intermediate for the synthesis of Pancratinine B and C.

In a second aspect, the present invention further provides a method for synthesizing Pancratinine C, comprising the steps of:

8) the compound 8 is subjected to hydroxyl protection and then oxidation reaction to obtain a compound 9,

9) removing a hydroxyl protecting group from the compound 9, and then carrying out oxidation and reduction reactions to obtain Pancratinine C;

the reaction formula is as follows:

wherein, the compound 8 is subjected to hydroxyl protection reaction under the action of a hydroxyl protection reagent and then is subjected to oxidation reaction under the action of an oxidant to obtain a compound 9 (tertiary hydroxyl compound). The hydroxyl protecting reagent is selected from at least one of trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, chloromethyl ether, methanesulfonate and the like, and preferably triisopropylsilyl trifluoromethanesulfonate. In the compound 9, R₃The hydroxyl-protecting group may be methoxymethyl (MOM), Trimethylsilyl (TMS), Triethylsilyl (TES), tert-butyldimethyl (TBS), etc., and is preferably methoxymethyl (MOM). Wherein the oxidant is selected from at least one of pyridinium chlorochromate, ruthenium trichloride, sodium periodate, selenium dioxide and the like, and is preferably selenium dioxide, and the reaction temperature is 100 ℃. The reaction solvent can be selected from common solvents such as dichloromethane, tetrahydrofuran, dioxane, etc.

Wherein, the compound 9 is subjected to hydroxyl protecting group removal under the action of acid, then is subjected to oxidation reaction (hydroxyl is oxidized into carbonyl) under the action of an oxidizing agent, and then is subjected to reduction reaction (hydroxyl configuration inversion is realized) under the action of a reducing agent, so that Pancratinine C is obtained. Wherein the acid is at least one selected from hydrofluoric acid, trifluoroacetic acid, ammonium bifluoride, etc., preferably ammonium bifluoride. The oxidizing agent is preferably manganese dioxide. The reducing agent is selected from at least one of sodium borohydride, aluminum lithium hydride, diisobutyl aluminum hydride and the like, and diisobutyl aluminum hydride is preferred. The reaction temperature ranges from 0 ℃ to 50 ℃. The reaction solvent may be selected from tetrahydrofuran, pyridine, dichloromethane, water or their mixture.

The invention also provides a method for synthesizing Pancratinine B, which comprises the following steps:

1) nucleophilic Substitution (SN) by the above-mentioned compound 8₂) Reacting to obtain a compound 10;

2) carrying out oxidation reaction on the compound 10 to obtain Panceratinine B;

the reaction route is as follows:

wherein the compound 8 is nucleophilic-Substituted (SN) in the presence of a methylating agent₂) Reaction to give compound 10. The methylating agent is selected from methyl iodide/sodium cyanide, methyl trifluoromethanesulfonate/hexamethyldisilazane diazonium sodium, methyl iodide/bis (trimethylsilyl) aminolithium, methyl iodide/silver oxide, trimethyloxonium tetrafluoroborate, phosgene/sodium methoxide, sulfuryl chloride/sodium methoxide, etc., preferably sulfuryl chloride/sodium methoxide. For example, compounds 8 in SOCl₂Generation of SN under the condition of sodium methoxide₂The reaction was carried out to obtain compound 10 under the condition that the reaction temperature was 70 ℃. The reaction solvent is selected from common solvents such as dichloromethane, methanol, chloroform, tetrahydrofuran, and the like.

Wherein, the compound 10 is oxidized by an oxidant to obtain Panceratinine B (tertiary hydroxyl compound). The oxidant is selected from pyridinium chlorochromate, ruthenium trichloride, sodium periodate and selenium dioxide; selenium dioxide is preferred, under which conditions the reaction temperature is 100 ℃. The reaction solvent can be selected from common solvents such as dichloromethane, tetrahydrofuran, dioxane, etc.

In a third aspect, the present invention further provides intermediate compounds for the preparation of Pancratinine B and C. The intermediate compounds are all newly synthesized compounds, including compound 2, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, and compound 10, as described above. The invention also provides the use of said intermediate compounds 2 to 8, 9 and 10 for the synthesis of Pancratinine B or C.

The invention has the beneficial effects that: 1) the invention provides a brand new method for preparing Pancratinine B and C by chemical total synthesis, and the synthetic route is new and short; 2) the raw materials are cheap and easy to obtain, and the used reagents are all common industrial reagents; 3) the reaction condition is mild, and the operation is simple and convenient; 4) the key intermediate compound 3 is synthesized by one-step construction of a tetracyclic skeleton through a Lewis acid catalyzed [3+2] cycloaddition reaction, is simple and efficient, and is suitable for mass preparation.

Detailed Description

The features and advantages of the present invention are further described below by way of examples. The examples are for illustrative purposes only and should not be construed as limiting the scope of the summary and claims. The reaction conditions (such as reaction temperature, time, material feeding ratio, etc.) which are not specified in the summary of the invention are all routine operations which can be completed by a person skilled in the art according to common knowledge or referring to the examples. The starting materials used in the examples are all known available compounds. The abbreviated forms of chemical groups or chemical structures used in the specification are well known to those of ordinary skill. For example, Me-methyl, Et-ethyl, Ac-acetyl, Ph-phenyl, MOM-methoxymethyl, TBS-tert-butyldimethylsilyl, TIPS-triisopropylsilyl, TMS-trimethylsilyl, Ts-p-toluenesulfonyl and the like.

EXAMPLE 1 preparation of Compound 1

Under the protection of argon, p-methylbenzenesulfonamide (4g), potassium hydroxide (2.5eq) and methanol (39 ml) are added into a dry round-bottom flask, stirred for 10 minutes under ice bath, after the solution becomes solid, iodobenzene diacetic acid (1.1eq) is added in portions to dissolve, stirred for 1 hour under ice bath and then reacted for 1 hour at room temperature. 93ml of ice water was added thereto, followed by ice-bath reaction for 1 hour. The reaction solution was filtered with a buchner funnel, and the obtained solid was washed with 60ml of ice water, 60ml of methanol, and 60ml of ether in this order, and the solvent was dried with suction, whereby 6.52g of p-toluenesulfonylimide iodobenzene PhI ═ NTs (compound 1') was obtained in a yield of 76%.

EXAMPLE 2 preparation of Compound 2

To a dry round bottom flask was added acetonitrile-dissolved p-toluenesulfonyliminoiodobenzene (PhI ═ NTs) (653.11mg,1.75mmol) under argon protection, followed by addition of compound 1(1g,6.99mmol) and copper acetylacetonate (36.64mg, 0.14mmol), and the reaction was stirred at room temperature for 30min, whereupon the solution became clear, after addition of triethylamine, filtration through celite, and separation by column chromatography (petroleum ether, ethyl acetate system 8:1 → 2:1, with triethylamine) to give 388mg of 2- (benzo [ d ] [1,3] dioxa-5-yl) -1-toluenesulfonylizidine (compound 2) in 70% yield.

Compound 2:¹H NMR(400MHz,Acetone–d₆)δ:7.86(d,J＝8.4Hz,2H),7.45(d,J＝8.0Hz, 2H),6.84(dd,J＝8.0,2.0Hz,1H),6.77(d,J＝8.0Hz,1H),6.72(d,J＝2.0Hz,1H),5.97(s,2H), 3.71(dd,J＝7.2,4.4Hz,1H),2.90(m,1H),2.49(d,J＝4.4Hz,1H),2.43(s,3H)；HRMS(ESI, m/z)calcd for C₁₆H₁₅NNaO₄S[M+Na]⁺:340.0614,found 340.0634.

EXAMPLE 3 preparation of Compound 2

Under the protection of argon, adding a solution of cyclohexenone (2g) and tetrahydrofuran (0.4M), adding hexamethylphosphoric triamide (HMPA, 2.5eq) at-78 ℃, dropwise adding lithium bis (trimethylsilyl) amide (LiHMDS, 1eq) dissolved in tetrahydrofuran (1M), and stirring for reacting for 1 hour. After 1 hour at 0 ℃ and the reaction was carried out, triisopropylsilyltrifluoromethanesulfonate (TIPSOTf, 1.1eq) was added dropwise at-78 ℃ and the reaction was stirred for 0.5 hour. After the reaction solution was returned to room temperature, the reaction solution was quenched with sodium bicarbonate, extracted with dichloromethane, dried, and concentrated, and the crude product was separated by column chromatography (eluent) to obtain 4.77g of (cyclohexa-1, 3-dien-1-yloxy) triisopropylsilane (compound 2'), with a yield of 91%.

The compound 2':¹HNMR(400MHz,CDCl3)δ:5.84-5.80(m,1H),5.43-5.39(m,1H),5.13(d,J＝ 5.6Hz,1H),2.30-2.26(m,4H),1.22-1.18(m,3H),1.10(d,J＝6.8Hz,18H).

EXAMPLE 4 preparation of Compound 3

After addition of copper triflate (43.4mg,0.12mmol) and dry dichloromethane to a dry round bottom flask under argon protection, 2- (benzo [ d ] [1,3] dioxa-5-yl) -1-toluenesulfonylaziridine (478mg, 1.51mmol) and (cyclohexa-1, 3-dien-1-yloxy) triisopropylsilane (579mg,2.26mmol) dissolved in dichloromethane were added dropwise and the reaction was stirred at room temperature for 2.5 h (TLC monitoring). After addition of potassium carbonate (15.1mmol) and ethanol (30ml), the reaction was allowed to warm to 60 ℃ for 10 hours (TLC monitoring). After the reaction, water was added to terminate the reaction, and after extraction with dichloromethane, the product was dried, filtered, concentrated, and separated by column chromatography (petroleum ether and ethyl acetate system 6:1 → 2:1)) to obtain 3413mg of the compound in 77% yield.

Compound 3:¹H NMR(400MHz,CDCl3)δ:7.73(d,J＝8.4Hz,2H),7.36(d,J＝8.4Hz,2H), 6.72(d,J＝8.0Hz,1H),6.56(dd,J＝8.0,2.0Hz,1H),6.49(d,J＝1.6Hz,1H),5.93(s,2H),3.99 (td,J＝10.0,6.0Hz,1H),3.82(dd,J＝9.6,6.8Hz,1H),3.24(td,J＝10.8,6.8Hz,1H),3.07(dd,J ＝10.8,9.6Hz,1H),2.98(dd,J＝15.6Hz,5.6Hz,1H),2.70(dd,J＝16.0Hz,10.4Hz,1H),2.47(s, 3H),2.37(dt,J＝8.4,5.2Hz,1H),2.25-2.17(m,1H),2.15-2.08(m,1H),1.91-1.83(m,1H), 1.72-1.63(m,1H)；HRMS(ESI,m/z)calcd for C₂₂H₂₃NNaO₅S[M+Na]⁺:436.1189,found 436.1222.

EXAMPLE 5 preparation of Compound 4

To a dry round bottom flask, under argon, was added dry dichloromethane-dissolved compound 3(800mg, 1.94mmol) and DIPEA (N, N-diisopropylethylamine) (3.36mL,19.4mmol) and reacted at room temperature with trimethylsilyl triflate (TMSOTf, 1.76mL,9.68mmol) dropwise for 4 hours. Adding saturated sodium bicarbonate at 0 ℃ for quenching, and extracting by n-pentane. The combined organic phases are washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated to obtain a crude product.

Dissolving the crude product in the first step in acetonitrile, adding palladium acetate (Pd (OAc) at room temperature₂568mg,2.52mmol) was stirred for 4 hours. Adding saturated sodium bicarbonate solution for quenching, extracting with ethyl acetate, washing with saturated saline, adding magnesium sulfate for drying, filtering, and concentrating to obtain crude product. The crude product was isolated by column chromatography (5: 1 → 3:1 system of petroleum ether and ethyl acetate) to give 4632mg of compound in 78% yield.

Compound 4: 1H NMR (400MHz, CDCl3) δ:7.75(d, J ═ 8.0Hz,2H),7.37(d, J ═ 8.0Hz,2H), 6.73(d, J ═ 7.6Hz,1H),6.57(dd, J ═ 8.0,1.6Hz,1H),6.50(d, J ═ 1.6Hz,1H), 6.48-6.46 (m,1H), 6.00(d, J ═ 10.4Hz,1H),5.95(s,2H),4.38(td, J ═ 11.6,6.8Hz,1H),3.89(dd, J ═ 9.6,7.2Hz, 1H),3.37(td, J ═ 10.4,7.2, 1H),3.8 (t, 3.8H), 3.89(dd, J ═ 9.6,7.2Hz, 1H),3.37 (dd, 8H, 1H), 3.47 (dd, 8H, 3.8H), 3.8H, 1H, 3.47 (dd, 1H, 3.8H, 1H, 16H, 1H, 3.47H, 1H, 3.8H, 1H, and 1H); HRMS (ESI, m/z) calcd for C₂₂H₂₁NNaO₅S[M+Na]⁺:434.1033,found 434.0898.

EXAMPLE 6 preparation of Compound 5

After addition of dry methanol and dichloromethane (2:1) to a dry round bottom flask under argon protection, compound 4 (551mg,1.34mmol) and CeCl were added₃(cerium trichloride) (990mg,4.02mmol), stirred at room temperature for 20min, and NaBH added at 0 deg.C₄(sodium borohydride) (101mg,2.68mol) was reacted at room temperature for 30 min. Adding saturated sodium bicarbonate solution for quenching, extracting with ethyl acetate, washing with saturated saline, adding magnesium sulfate for drying, filtering, and concentrating to obtain crude product. The crude product was isolated by column chromatography (petroleum ether and ethyl acetate system 4:1 → 2:1) to give 5405mg of compound in 73% yield.

Compound 5:¹H NMR(400MHz,CDCl₃)δ:7.76(d,J＝8.0Hz,2H),7.36(d,J＝8.0Hz,2H), 6.71(d,J＝8.0Hz,1H),6.52(dd,J＝8.0,1.6Hz,1H),6.45(d,J＝1.6Hz,1H),5.92(s,2H),5.74 (d,J＝10.0Hz,1H),5.36-5.32(m,1H),4.35(d,J＝4.4Hz,1H),4.04-3.98(m,1H),3.79(td,J＝ 6.0,2.4Hz 1H),3.15-3.07(m,2H),2.60-2.55(m,1H),2.46(s,3H),2.25(t,J＝7.2Hz,1H),1.93(s, 1H),1.72-1.63(m,1H)；HRMS(ESI,m/z)calcd for C₂₂H₂₃NNaO₅S[M+Na]⁺:436.1189,found 436.0880.

EXAMPLE 7 preparation of Compound 6

After addition of dry dichloromethane-dissolved compound 5(332mg,0.8 mmol) to a dry round-bottomed flask under argon, DIPEA (N, N-diisopropylethylamine) (0.7mL,4.0mmol) and MOMCl (0.18mL, 2.4mmol) were added sequentially at 0 deg.C, and the reaction was stirred at room temperature for 6 hours. Adding saturated sodium bicarbonate solution for quenching, extracting by dichloromethane, washing by saturated saline, adding magnesium sulfate for drying, filtering and concentrating to obtain a crude product. The crude product was isolated by column chromatography (petroleum ether and ethyl acetate system 10:1 → 5:1) to give 6342mg, 93% yield.

Compound 6:¹H NMR(400MHz,CDCl₃)δ:7.76(d,J＝8.0Hz,2H),7.37(d,J＝8.0Hz,2H), 6.71(d,J＝8.0Hz,1H),6.51(dd,J＝7.6,1.6Hz,1H),6.42(d,J＝2.0Hz,1H),5.93(s,2H),5.75 (dd,J＝10.4,1.2Hz,1H),5,38-5.34(m,1H),4.73(dd,J＝20.8,6.8Hz,2H),4.27-4.23(m,1H), 4.03-3.97(m,1H),3.79(td,J＝6.0,2.0Hz 1H),3.40(s,3H),3.18-3.07(m,2H),2.63-2.58(m,1H), 2.47(s,3H),2.25-2.21(m,1H),1.73-1.64(m,1H)；HRMS(ESI,m/z)calcd for C₂₄H₂₇NNaO₆S [M+Na]⁺:480.1451,found 480.1471.

EXAMPLE 8 preparation of Compound 7

After addition of dry dichloroethane-dissolved compound 6(170mg,0.37 mmol) to a dry round-bottomed flask under argon protection, sodium naphthalene was added at-78 ℃ until the solution appeared dark green and stirred for 30min, saturated ammonium chloride solution was added at the same temperature and stirred for two minutes, and after returning to room temperature, potassium carbonate (1.6g,11.5mmol) was added and stirred for 30 min. Extracting with dichloromethane, washing with saturated ammonium chloride solution and brine respectively, drying with magnesium sulfate, filtering, and concentrating to obtain crude product. The compound 7112mg is separated by column chromatography (dichloromethane and methanol system 20:1), the yield is 89%, and the compound is directly used for the next step of reaction.

EXAMPLE 9 preparation of Compound 8

To a dry round-bottomed flask, formic acid-dissolved compound 7(112mg,0.37mmol) was added under an argon atmosphere, and paraformaldehyde (110.7mg,3.69mmol) was added at room temperature, followed by warming to 80 ℃ for 2 hours. After cooling to room temperature, add saturated aqueous sodium bicarbonate solution and quench until the solution pH is 7-8, dichloromethane and chloroform: isopropanol 10:1, extracting, washing with saturated salt solution, adding magnesium sulfate, drying, filtering and concentrating to obtain a crude product. Dissolving the crude product in methanol, adding potassium carbonate (77 mg,0.55mmol) at room temperature, stirring for 30min, filtering, concentrating, and separating by column chromatography (dichloromethane and methanol system 20:1) to obtain 883 mg of compound with yield 83%.

Compound 8:¹HNMR(600MHz,CDCl₃)δ:6.56(s,1H),6.46(s,1H),6.05(ddd,J＝6.0,4.2,2.4 Hz,1H),5.88(s,2H),5.73(dd,J＝9.6,2.4Hz,1H),4.21–4.19(m,2H),3.75(d,J＝18.6Hz,1H), 3.34(dd,J＝11.4,2.4Hz,1H),3.29(dd,J＝12.0,5.4Hz,1H),2.82(d,J＝7.2Hz,1H),2.79-2.76 (m,2H),2.03-1.98(m,1H),1.95-1.91(m,1H)；HRMS(ESI,m/z)calcd for C₁₆H₁₇NO₃[M+H]⁺: 272.1281,found 272.1301.

EXAMPLE 10 preparation of Compound 9

To a dry round bottom flask was added dichloromethane-dissolved compound 8(90mg,0.332 mmol) under argon protection, and triethylamine (0.15mL,0.664mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf, 0.14mL, 0.996mmol) were added at room temperature and the reaction was stirred for 1 hour. After addition of saturated sodium bicarbonate solution, the mixture was quenched, extracted with dichloromethane, washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The product is obtained by column chromatography separation, 118mg is obtained, the yield is 92 percent, and the next step is carried out.

To a dry round bottom flask, under argon, the product of the previous step (58mg,0.15mmol) dissolved in dioxane was added, and selenium dioxide (SeO) was added at room temperature₂50mg,0.45mmol), and reacted for 8 hours after heating to 100 ℃. Adding saturated sodium bicarbonate solution, quenching, extracting with dichloromethane, filtering with diatomaceous earth, washing with dichloromethane, concentrating, and purifying with columnChromatography (dichloromethane and methanol system 20:1 → 10:1) isolated 936mg of compound, yield 60%.

Compound 9:¹HNMR(400MHz,CDCl₃)δ:6.57(s,1H),6.53(s,1H),6.12(dd,J＝10.0,2.0Hz, 1H),5.93(s,2H),5.80(dd,J＝10.0,2.0Hz,1H),4.40(d,J＝17.6Hz,1H),4.36-4.32(m,1H), 3.88(d,J＝17.2Hz,1H),3.37(dd,J＝12.0,2.0Hz,1H),3.02(t,J＝7.6Hz,1H),2.88(dd,J＝ 12.0,2.4Hz,1H),2.69(d,J＝2.8Hz,1H),2.34-2.28(m,1H),1.67-1.59(m,1H),0.90(s,9H),0.09 (s,6H)；HRMS(ESI,m/z)calcd for C₂₂H₃₂NO₄Si[M+H]⁺:402.2095,found 402.2127.

EXAMPLE 11 preparation of the Compound PancretinieC

Tetrahydrofuran dissolved compound 9(15mg,0.037 mmol) was added to a dry round bottom flask under argon and NH was added at room temperature₄HF₂(ammonium hydrogen fluoride) (32mg,0.56mmol), and the reaction was carried out after heating to 50 ℃ for 5 hours. After cooling to room temperature, the product was purified on preparative thin-layer plates to give 9mg of product, which was put into the next step.

To a dry round bottom flask, the product of the previous step (8.1mg,0.028 mmol) dissolved in dichloromethane and manganese dioxide (49mg,0.56mmol) were added under argon and the reaction stirred at room temperature for 30 min. Adding dichloromethane for dilution, and filtering with diatomite to obtain crude product. Adding tetrahydrofuran, adding diisobutylaluminum hydride (DIBAL-H,35uL,1.2M in toluene, 0.04mmol) at-78 deg.C, stirring for 10min, adding methanol, quenching, extracting with dichloromethane, washing with saturated saline, adding magnesium sulfate, drying, filtering, and concentrating. Pancratinine C3.6 mg is obtained by column chromatography (chloroform, methanol, ammonia water system: 80:4:1) separation, and the yield is 44%.

Pancratinine C：¹H NMR(600MHz,CD₃OD)δ:6.60(s,1H),6.55(s,1H),6.00(d,J＝10.4 Hz,1H),5.89(s,2H),5.74(d,J＝10.0Hz,1H),4.29(m,1H),4.24(d,J＝16.8Hz,1H),3.86(d,J ＝16.4Hz,1H),2.98(dd,J＝12.4,2.8Hz,1H),2.84(d,J＝11.6Hz,1H),2.67(d,J＝2.4Hz,1H), 2.25(d,J＝13.2Hz,1H),1.58(m,1H)。HRMS(ESI,m/z)calcd for C₁₆H₁₈NO₄[M+H]⁺:288.1236, found 288.1237.

EXAMPLE 12 preparation of Compound 10

To a dry round bottom flask, under argon, was added dichloromethane-dissolved compound 8(40mg,0.147mmol) and SOCl₂(75uL,1.03mmol), stirred at room temperature for 30min and concentrated. After dissolving in methanol, sodium methoxide (0.28mL,1.47mmol) was added thereto at room temperature, and the reaction mixture was stirred at 100 ℃ for 8 hours. The mixture was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. Column chromatography (dichloromethane and methanol system 30:1 → 10:1) isolated 109.7mg, 23% yield.

Compound 10:¹H NMR(600MHz,CDCl₃)δ:6.56(s,1H),6.46(s,1H),5.99(dd,J＝10.2,1.2Hz, 1H),5.89(s,2H),5.71(ddd,J＝6.0,4.2,2.4Hz,1H),4.24(d,J＝16.2Hz,1H),3.89-3.87(m,1H), 3.80(d,J＝16.2Hz,1H),3.42(s,3H),3.33-3.32(m,1H),2.90(s br,1H),2.83(s,2H),2.75(s,1H), 2.47(d,J＝12.0Hz,1H),1.46-1.41(m,1H)；HRMS(ESI,m/z)calcd for C₁₇H₂₀NO₃[M+H]⁺: 286.1438,found 286.1446.

the compound Pancratinine of example 13 Preparation of B

To a dry round bottom flask, under argon, was added dioxane dissolved compound 13(5.5mg,0.02 mmol) and SeO was added at room temperature₂(6.4mg,0.058mmol) and then heated to 100 ℃ followed by stirring for 8 hours, celite filtration, dichloromethane washing, concentration and column chromatography (dichloromethane and methanol system 20:1 → 10:1) to isolate Pancratinine B3.5 mg, yield 60%.

Pancratinine B：¹H NMR(600MHz,CDCl₃)δ:6.63(s,1H),6.55(s,1H),6.15(d,J＝10.2Hz, 1H),5.94(s,2H),5.78(d,J＝10.8Hz,1H),4.29(d,J＝16.8Hz,1H),3.96(m,1H),3.84(d,J＝ 16.8Hz,1H),3.44(s,3H),3.00(d,J＝12.0Hz,1H),2.93(s,1H),2.86(d,J＝11.4Hz,1H),2.65(s, 1H),2.37(d,J＝12.6Hz,1H),1.59(dt,J＝4.8,12.6Hz,1H)；HRMS(ESI,m/z)calcd for C₁₇H₂₀NO₄[M+H]⁺:302.1387,found 302.1396.

The foregoing description is for the purpose of illustration and explanation only, and it is within the scope of the invention that various modifications and changes may be made to the disclosure and examples by those skilled in the art without departing from the spirit of the invention.