Asymmetric total synthesis method of natural product (-)-Lucidutone

Abstract

The invention belongs to the field of total synthesis of natural products, and relates to an asymmetric total synthesis method of a natural product (-)-Lucidutone. The total synthesis of the natural product takes known compounds S1 and S2 as synthesis starting points, and a basic skeleton of (-)-Lucidutone is constructed through key reactions such as key Lewis acid catalyzed intramolecular Diels-Alder, hydroboration oxidation, Suzuki coupling, acid catalyzed deprotection / Prins reaction / cyclic etherification series connection and the like. The asymmetric total synthesis method of the (-)-Lucidumone is successfully invented at a relatively high total yield by carrying out a series of functional group conversion such as Fleming-Tamao oxidation, Grieco elimination and Wacker oxidation on the (-)-Lucidumone and then carrying out a series of functional group conversion such as the Fleming-Tamao oxidation, the Grieco elimination and the Wacker oxidation. The synthesis method is relatively simple to operate, can be widely popularized and used, and lays a solid foundation # imgabs0 # for deeper pharmacological and physiological activity research of (-)-Lucidutone

Description

Technical Field

[0001] The present invention belongs to the field of total synthesis of natural products, and particularly relates to an asymmetric total synthesis method of a natural product (-)-Lucidumone. Background Art

[0002] In recent years, many natural product chemists have isolated many kinds of meroterpenoids from Ganoderma, including compounds such as lingzhiols, sinensilactam A, applanatumol B, and cochlearin A. In 2019, Professor Yongxian Cheng of Shenzhen University isolated and identified a novel meroterpenoid (±)-Lucidumone from the fruiting bodies of Ganoderma cultivated in Yongsheng County, Yunnan Province, China, and confirmed its absolute configuration as (-)-Lucidumone by X-ray single crystal diffraction. It has an unprecedented 6-5-6-6-5 cage-like pentacyclic structure, containing a hydroquinone, a chiral secondary alcohol, and two ketones, with six adjacent stereocenters on the bicyclo[2.2.2]octyl group, further highlighting the complexity of the Lucidumone structure. According to the research of Professor Yongxian Cheng's research group, Lucidumone selectively inhibits COX-2 by directly binding to Tyr385 and Ser530 residues, making it have potential in the treatment of inflammation. More interestingly, the team also found that although Ganoderma produces Lucidumone in the form of an enantiomeric mixture, only (-)-Lucidumone can exhibit selective COX-2 inhibitory activity (IC 50= 5.62 μM). Due to the association of inflammation with many diseases and the numerous adverse reactions of steroidal anti-inflammatory drugs, developing a non-steroidal anti-inflammatory drug with moderate inhibition and selectivity for COX-2 has become an important strategy for discovering new anti-inflammatory drugs. However, through traditional separation methods, only sub-milligram amounts of (+)-Lucidumone can be obtained, seriously hindering further research on the biological activity of this molecule. Therefore, realizing its total synthesis is extremely urgent. Currently, the artificial synthesis of the natural product Lucidumone mainly includes the following technical routes: 1) The team of Aurélien de la Torre at the University of Paris-Saclay in France completed the first enantioselective total synthesis of the natural product (+)-lucidumone in 13 steps with a total yield of 25.8% on a gram scale. 2) The team of Professor Hisanaka Ito at the University of Tokyo achieved the total synthesis of Lucidumone by preparing the key intermediate tetracyclic skeleton in one pot through Claisen rearrangement and intramolecular Aldol reaction. 3) The team of Professor She Xuegong at Lanzhou University achieved the synthesis of the Lucidumone molecular skeleton through oxidative dearomatization / intramolecular Diels-Alder (IMDA) reaction, Cu-mediated remote C-H hydroxylation, allylic oxidation, acid-promoted dynamic kinetic resolution (DKR) cyclization, and benzyl oxidation. Summary of the Invention

[0003] To achieve a more efficient and concise asymmetric total synthesis of (-)-Lucidumone, the present invention provides a technical route for asymmetric total synthesis by constructing the basic skeleton of (-)-Lucidumone through key reactions such as intramolecular Diels-Alder catalyzed by a key Lewis acid, hydroboration-oxidation, Suzuki coupling, and acid-catalyzed deprotection / Prins reaction / etherification cascade. Subsequently, a series of functional group transformations such as Fleming-Tamao oxidation, Grieco elimination, Wacker oxidation reaction, and Lewis acid-mediated demethylation reaction are carried out to lay a foundation for further pharmacological value research and the development of new skeletons of highly active and highly selective COX-2 inhibitors.

[0004] To achieve the above object, the present invention adopts the following technical routes and technical solutions:

[0005]

[0006] A method for asymmetric synthesis of (-)-Lucidumone, characterized by comprising the following steps:

[0007] 1) React compound S1 with triphenylsilane through a coupling reaction to obtain compound 1;

[0008] 2) The nucleophilic substitution reaction of compound 1 and S2 gives compound 2;

[0009] 3) The intramolecular Diels - Alder reaction of compound 2 catalyzed by Lewis acid gives compound (+)-3;

[0010] 4) The nucleophilic substitution of the oxazolidinone in compound (+)-3 is carried out, followed by hydrolysis reaction to obtain compound (+)-4;

[0011] 5) Compound (+)-4 is hydroborated and then oxidized to obtain a diol compound intermediate, and the generated primary alcohol is selectively protected, and the generated secondary alcohol is oxidized again to obtain compound (+)-5;

[0012] 6) The deprotonation reaction of compound (+)-5 is carried out and then a substitution reaction is carried out to obtain the trifluoromethanesulfonate compound (+)-6;

[0013] 7) The coupling reaction of compound (+)-6 and compound S3 gives compound (+)-7;

[0014] 8) Compound (+)-7 undergoes an acid - catalyzed deprotection / Prins reaction / ring etherification cascade reaction under acidic conditions to obtain an intermediate containing a secondary alcohol, and the generated secondary alcohol is oxidized to obtain the core skeleton (-)-8 of (-)-Lucidumone;

[0015] 9) The oxidation reaction of compound (-)-8 gives the diol compound (-)-9;

[0016] 10) The elimination reaction of compound (-)-9 through a selenoether intermediate gives the terminal olefin compound (-)-10;

[0017] 11) The oxidation reaction of compound (-)-10 gives compound (-)-11;

[0018] 12) The Lewis acid - mediated demethylation reaction of compound (-)-11 gives the natural product (-)-Lucidumone 12.

[0019] The asymmetric total synthesis of the above (-)-Lucidumone starts from S1 and S2 and realizes its total synthesis through 12 - step transformation. Compared with the previous synthetic strategies, the route is more concise and more operable; at the same time, this synthetic strategy also provides 9 new compounds, namely 1, 2, (+)-3, (+)-4, (+)-5, (+)-6, (+)-7, (-)-8, (-)-9.

[0020] In one embodiment, the main steps for obtaining compound 1 after the coupling reaction of compound S1 with triphenylsilane include: compound S undergoes a coupling reaction with triphenylsilane under the catalytic condition of metal cobalt to obtain compound 1.

[0021] In one embodiment, the main steps for obtaining compound 2 by the nucleophilic substitution reaction of compound 1 and known compound S2 include: compound 1 is protonated under the action of trifluoromethanesulfonic acid (TfOH) to form a trifluoromethanesulfonate, and then undergoes a silicon-oxygen nucleophilic substitution reaction with compound S2 under basic conditions to obtain the silicon-oxygen nucleophilic product 2.

[0022] In one embodiment, the main steps for obtaining compound (+)-3 by the intramolecular Diels-Alder reaction of compound 2 catalyzed by a Lewis acid include: in the presence of a Lewis acid and a BOX ligand, compound 2 is catalyzed to undergo an intramolecular Diels-Alder reaction to obtain compound (+)-3.

[0023] In one embodiment, the main steps for obtaining compound (+)-4 by the nucleophilic substitution of the oxazolidinone in compound (+)-3 followed by hydrolysis include: the peroxide formed by the reaction of hydrogen peroxide with a base acts as a nucleophile to attack the carbonyl group to obtain a peroxyacid compound intermediate, and then undergoes hydrolysis under acidic conditions to obtain compound (+)-4.

[0024] In one embodiment, the main steps for obtaining compound (+)-5 by the hydroboration-oxidation reaction of compound (+)-4 with borane-tetrahydrofuran complex (BH3·THF), followed by the selective protection of the resulting primary alcohol with TBSCl and the oxidation of the resulting secondary alcohol include: under low-temperature conditions, compound (+)-4 is hydroborated with borane-tetrahydrofuran complex, and then undergoes oxidation under the action of sodium perborate tetrahydrate (NaBO3·4H2O) to obtain a diol compound. After the selective protection of the primary alcohol therein, the resulting secondary alcohol is oxidized to a ketone under the action of a DMP oxidant to obtain compound (+)-5.

[0025] In one embodiment, the main steps for obtaining compound (+)-6 by the deprotonation reaction of compound (+)-5 followed by the substitution reaction with N-phenylbis(trifluoromethanesulfonyl)imide (PhNTf2) include: deprotonation with potassium bis(trimethylsilyl)amide (KHMDS) at low temperature to generate an enolate anion, and then the addition of N-phenylbis(trifluoromethanesulfonyl)imide (PhNTf2) for a nucleophilic substitution reaction to obtain compound (+)-6.

[0026] In one embodiment, the main steps for obtaining compound (+)-7 after the Suzuki coupling reaction of compound (+)-6 with compound S3 include: under high-temperature conditions, compound (+)-6 and S3 undergo a Suzuki coupling reaction under the action of palladium dichloride bis(diphenylphosphino)ferrocene (Pd(dppf)Cl2), potassium phosphate (K3PO4), 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl (S-Phos), etc. to obtain compound (+)-7.

[0027] In one embodiment, the main steps for obtaining the secondary alcohol compound after the acid-catalyzed deprotection / Prins reaction / ring etherification tandem reaction of compound (+)-7 under acidic conditions and then oxidizing the resulting secondary alcohol to obtain the core skeleton (-)-8 of (-)-Lucidumone include: under low-temperature conditions, hydrochloric acid protonates the carbonyl group of compound (+)-7 and then undergoes an electrophilic addition with the double bond to initiate an intramolecular oxa-Prins tandem cyclization reaction and remove the primary alcohol protection to obtain the secondary alcohol compound. Subsequently, the secondary alcohol is oxidized to construct the core skeleton (-)-8 of (-)-Lucidumone in one step.

[0028] In one embodiment, the main steps for obtaining the diol compound (-)-9 by Fleming-Tamao oxidation of compound (-)-8 include: under heating conditions, the silicon-oxygen bond in compound (-)-8 is cleaved under the action of potassium fluoride (KF) to obtain a fluorine-substituted silane salt and a primary alcohol. Then, hydrogen peroxide (H2O2) is added, and the peroxy group attacks the silicon atom of the fluorosilane salt, followed by a [1,2] alkyl migration and hydrolysis to obtain a secondary alcohol, namely the diol compound (-)-9.

[0029] In one embodiment, the main steps for obtaining the terminal olefin compound (-)-10 by Grieco elimination reaction of compound (-)-9 through a selenoether intermediate include: the primary alcohol of compound (-)-9 undergoes a nucleophilic substitution reaction with o-nitrobenzeneselenonitrile and tributylphosphine on the electron-deficient selenium atom to generate a selenoether intermediate. Then, the selenoether is oxidized to selenoxide by hydrogen peroxide, and an elimination reaction similar to Cope elimination occurs to generate the terminal olefin compound (-)-10.

[0030] In one embodiment, the main steps for oxidizing compound (-)-10 to obtain compound (-)-11 include: the terminal olefin in compound (-)-10 generates a radical under the catalysis of metallic iron or the olefin inserts into an iron-containing complex, and then the bond is broken to obtain the compound methyl ketone (-)-11.

[0031] In one of the embodiments, the main steps for the asymmetric total synthesis of (-)-Lucidumone by subjecting compound (-)-11 to a Lewis acid-mediated demethylation reaction are as follows: at 0 °C to 25 °C, compound (-)-11 undergoes demethoxylation under the action of a Lewis acid to achieve the asymmetric total synthesis of (-)-Lucidumone.

[0032] In summary, for the total synthesis of the natural product (-)-Lucidumone, starting from the known compounds S1 and S2, the basic skeleton of (-)-Lucidumone was constructed through key reactions such as intramolecular Diels-Alder catalyzed by Lewis acid, hydroboration-oxidation, Suzuki coupling, and one-pot oxa-Prins tandem cyclization. Subsequently, through a series of functional group transformations such as Fleming-Tamao oxidation, Grieco elimination, and Wacker oxidation, an asymmetric total synthesis method for (-)-Lucidumone was successfully invented in 12 steps with high efficiency and simplicity. This synthesis method is relatively simple to operate, can be widely promoted and used, and lays a solid foundation for further pharmacological and physiological activity studies of (-)-Lucidumone. In addition, in view of its known inhibitory effect on COX-2 and the novelty of its structural skeleton, the modular effect of the Suzuki coupling reaction can be further utilized to change its pharmacokinetic group, pharmacodynamic group, etc., to deeply understand its structure-activity relationship and pharmacological activity, and contribute to the development of the next generation of COX-2 inhibitors. Detailed implementation mode

[0033] To facilitate the understanding of the present invention, the present invention will be described more comprehensively below. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, these embodiments are provided to make the disclosure of the present invention more thorough and comprehensive. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which the present invention belongs. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0034] The total synthesis method of the natural product (-)-Lucidumone in the implementation mode mainly includes steps 1 to 12. The synthetic route has relatively simple steps and is easy to operate, and the yield of the compounds in the synthetic route is 50% to 95%.

[0035] Step 1: Synthesize compound 1 using the known compound S1 and triphenylsilane.

[0036] Specifically, compound S1 undergoes a coupling reaction with triphenylsilane under the catalytic condition of metal cobalt to obtain the said compound 1.

[0037] In this embodiment, the reaction formula for synthesizing Compound 1 using the known compound S1 and triphenylsilane is as follows:

[0038]

[0039] Furthermore, at 0 - 30 °C, Compound S1 undergoes a coupling reaction under metal-catalyzed conditions to obtain Compound 1; preferably, at 25 °C, Compound S1 and triphenylsilane undergo a coupling reaction at a molar ratio of 1:5; preferably, octacarbonyldicobalt is used as the metal catalyst to catalyze the occurrence of this reaction, and the molar ratio of Compound S1, triphenylsilane, and octacarbonyldicobalt is 1:5:0.04, and the reaction time is 12 h.

[0040] Furthermore, the organic solvent is toluene. It can be understood that in other embodiments, the solvent is not limited to toluene and can also be other commonly used solvents in the art, such as tetrahydrofuran, ethanol, and dichloromethane. As long as Compound S1, triphenylsilane, and octacarbonyldicobalt can dissolve in it and do not interfere with subsequent reactions, it is acceptable. Of course, in other embodiments, the metal catalyst used is not limited to octacarbonyldicobalt and can also be other commonly used metal catalysts in the art, such as palladium and copper.

[0041] Of course, after the step of obtaining Compound 1, there is also a step of purifying Compound 1. Specifically, the reaction is quenched by adding a saturated ammonium chloride solution, the organic phase is combined after extracting Compound 1, and after drying, purified Compound 1 is obtained by silica gel column chromatography. Of course, the reagent for quenching this reaction is not limited to a saturated ammonium chloride solution and can also be water.

[0042] Step 2: Synthesize Compound 2 using the said Compound 1 and the known compound S2.

[0043] Specifically, after Compound 1 is protonated under the action of an acid, the excess acid is neutralized under basic conditions and a silicon-oxygen nucleophilic substitution reaction occurs with Compound S2 to obtain the silicon-oxygen nucleophilic product 2.

[0044] In this embodiment, the reaction formula for synthesizing Compound 2 using the said Compound 1 and the known compound S2 is as follows:

[0045]

[0046] Further, at -20°C to 25°C, compound 1 is protonated for 1 h to 5 h under the action of trifluoromethanesulfonic acid (TfOH) to form a trifluoromethanesulfonate. The molar ratio of compound 1 to trifluoromethanesulfonic acid is 1:2 to 2.5. Preferably, at 0°C, compound 1 is protonated for 3 h under the action of trifluoromethanesulfonic acid (TfOH) to form a trifluoromethanesulfonate with a molar ratio of 1:2.2. The resulting trifluoromethanesulfonate reacts with compound S1 through a silicon-oxygen nucleophilic substitution reaction for 2 h to 12 h under the action of pyridine or 2,6-dimethylpyridine, potassium tert-butoxide, and triethylamine base and stirring at -78°C to 0°C for 0 to 3 h to obtain an intermediate. Preferably, the trifluoromethanesulfonate reacts with compound S1 through a silicon-oxygen nucleophilic substitution reaction for 2 h after stirring with 2,6-dimethylpyridine at -78°C for 5 min to obtain compound 2. Preferably, in the above steps, the molar ratio of compound 1, S2, TfOH, and 2,6-dimethylpyridine is 1:1.1:2.2:2.4.

[0047] In this embodiment, the organic solvent is dichloromethane. It can be understood that in other embodiments, the solvent is not limited to dichloromethane and can also be other solvents commonly used in the art, such as tetrahydrofuran, toluene, and methanol, as long as compound 1 and S2 can dissolve in them and do not interfere with subsequent reactions. Of course, in other embodiments, the acid used for protonating compound 1 is not limited to TfOH and can also be other strong acids commonly used in the art; of course, the base used for neutralizing the excess acid is not limited to 2,6-dimethylpyridine and can also be bases commonly used in the art, such as pyridine, potassium tert-butoxide, and triethylamine.

[0048] Of course, after the step of obtaining compound 2, it also includes the step of purifying compound 2. Specifically, the reaction is quenched by adding a saturated ammonium chloride solution, and compound 2 is extracted and the organic phases are combined. After drying, purified compound 2 is obtained by silica gel column chromatography. Of course, the reagent for quenching this reaction is not limited to a saturated ammonium chloride solution and can also be water or a saturated sodium bicarbonate solution.

[0049] Step 3, synthesize compound (+)-3 using compound 2.

[0050] Specifically, compound 2 is catalyzed to undergo an intramolecular Diels-Alder reaction in the presence of a Lewis acid and a BOX ligand to obtain compound (+)-3.

[0051] In this embodiment, the reaction formula for synthesizing compound (+)-3 using compound 2 is:

[0052]

[0053] Further, at 0 - 30 °C, the BOX ligand and the Lewis acid are stirred for 0.5 - 5 h to form a complex. Preferably, at 25 °C, stirring Cu(OTf)₂ and (4S,4′S)-(-)-2,2′-(3-pentylidene)bis(4-phenyloxazoline) ligand for 3 h can form the desired complex; further, compound 2 is added to the prepared complex, and the mixture is stirred at 30 - 100 °C for 6 h - 12 h to catalyze the intramolecular asymmetric Diels - Alder reaction to obtain the compound (+)-3. Preferably, the reaction temperature is 50 °C, and the molar ratio of compound 2, Cu(OTf)₂ and (4S,4′S)-(-)-2,2′-(3-pentylidene)bis(4-phenyloxazoline) ligand is 1:0.1:0.11.

[0054] In this embodiment, the organic solvent is dichloromethane. It can be understood that in other embodiments, the solvent is not limited to dichloromethane, and can also be other solvents commonly used in the art, such as tetrahydrofuran, toluene, dioxane, acetonitrile, as long as compound 2, the Lewis acid and the ligand can dissolve in it and do not interfere with the subsequent reaction. Of course, in other embodiments, the Lewis acid selected is not limited to Cu(OTf)₂, and can also be other Lewis acids commonly used in the art, such as copper hexafluoroantimonate, diethylaluminum monochloride, copper tetrafluoroborate. Further, the ligand used in this reaction is not limited to (4S,4′S)-(-)-2,2′-(3-pentylidene)bis(4-phenyloxazoline), and can also be other BOX ligands commonly used in the art, such as (4S,4'S)-2,2'-(cyclopentane-1,1-diyl)-bis(4-benzyl-4,5-dihydrooxazole), (4R,4'R)-2,2'-isopropylidene bis(4-isopropyl-2-oxazoline), (4S,4'S)-2,2'-cyclopentylidene bis[4,5-dihydro-4-phenyloxazole, (S,S)-2,2'-isopropylidene bis(4-phenyl-2-oxazoline), (4S,4'S)-2,2,-cyclobutylidene bis[4,5-dihydro-4-phenyloxazole, etc.

[0055] Of course, after the step of obtaining the compound (+)-3, it also includes the step of purifying the compound (+)-3. Specifically, saturated ammonium chloride solution is added to quench the reaction, the compound (+)-3 is extracted and the organic phases are combined, and after drying, silica gel column chromatography is used to obtain the purified compound (+)-3. Of course, the reagent for quenching this reaction is not limited to saturated ammonium chloride solution, and can also be water, saturated sodium bicarbonate solution.

[0056] Step 4, synthesize compound (+)-4 using compound (+)-3.

[0057] Specifically, the oxazolidinone in the compound (+)-3 is subjected to nucleophilic substitution, and then a hydrolysis reaction occurs to obtain the compound (+)-4.

[0058] In this embodiment, the reaction formula for synthesizing compound (+)-4 from compound (+)-3 is as follows:

[0059]

[0060] Furthermore, at -20°C to 0°C, compound (+)-3, hydrogen peroxide (30 wt.%), and lithium hydroxide are reacted at a molar ratio of 1:5 to 20:3 to 5 for a reaction time of 3 h to 12 h. Preferably, at 0°C, compound (+)-3, hydrogen peroxide (30 wt.%), and lithium hydroxide are reacted at a molar ratio of 1:8.8:3 for 5 h to obtain a peroxy acid intermediate. Preferably, the pH value is adjusted to 1 using 1 M HCl, and finally the compound (+)-4 is obtained.

[0061] Furthermore, the solvent is THF:H2O = 2:1. It can be understood that in other embodiments, the solvent is not limited to THF:H2O = 2:1, and can also be other common solvents and ratios in the art, such as dichloromethane, dichloroethane, methanol, ethanol, etc., as long as compound (+)-3 can dissolve in it and does not interfere with subsequent reactions. Of course, in other embodiments, the base used is not limited to lithium hydroxide, and can also be other common bases in the art such as potassium hydroxide and sodium hydroxide.

[0062] Of course, after the step of obtaining compound (+)-4, it further includes the step of purifying compound (+)-4. Specifically, the reaction is quenched by adding a saturated sodium thiosulfate solution, the organic phase is extracted after extracting compound (+)-4, and the purified compound (+)-4 is obtained by silica gel column chromatography after drying. Of course, the reagent for quenching this reaction is not limited to a saturated sodium thiosulfate solution, and can also be a saturated sodium sulfite solution.

[0063] Step 5, synthesize compound (+)-5 from compound (+)-4.

[0064] Specifically, under low-temperature conditions, compound (+)-4 is borohydrated with borane tetrahydrofuran complex (1.0 mol / L in THF), then oxidized under the action of sodium perborate tetrahydrate to obtain a diol compound, and then the primary alcohol therein is selectively protected, and the secondary alcohol is oxidized to a ketone under the action of a DMP oxidant to obtain compound (+)-5.

[0065] In this embodiment, the reaction formula for synthesizing compound (+)-5 from compound (+)-4 is as follows:

[0066]

[0067] Furthermore, at -78°C to -20°C, borane-tetrahydrofuran complex (1.0 mol / L in THF) was added and stirred for 6 h to 12 h to hydroborate compound (+)-4. The molar ratio of compound (+)-4 to borane-tetrahydrofuran complex (1.0 mol / L in THF) was 1:3 to 10. Preferably, at -30°C, borane-tetrahydrofuran complex was added to hydroborate compound (+)-4, the reaction time was 12 h, and the molar ratio of compound (+)-4 to borane-tetrahydrofuran complex (1.0 mol / L in THF) was 1:5. Then, at -20°C to 0°C, sodium perborate tetrahydrate was added and reacted for 1 h to 2 h to oxidize the hydroboration product. The molar ratio of compound (+)-4 to sodium perborate tetrahydrate was 1:5 to 20. Preferably, at 0°C, sodium perborate tetrahydrate was added and reacted for 1 h to oxidize the hydroboration product, and the molar ratio of compound (+)-4 to sodium perborate tetrahydrate was 1:10, thereby obtaining a diol compound. At 0°C to 30°C, TBSCl and imidazole were added successively and reacted for 1 h to 2 h to selectively protect the primary alcohol. Preferably, at 25°C, TBSCl and imidazole were added successively and reacted for 2 h to selectively protect the primary alcohol. The molar ratio of compound (+)-4 to TBSCl and imidazole was 1:3:5 successively. The above reaction solution was placed at 0°C to 30°C and an appropriate oxidant was added and reacted for 1 h to 2 h to oxidize the secondary alcohol to a ketone to obtain compound 5. Preferably, the above reaction solution was placed at 25°C and DMP oxidant was added and reacted for 2 h. The molar ratio of compound (+)-4, DMP oxidant, and base was 1:2:10, and the secondary alcohol could be oxidized to a ketone to obtain compound (+)-5.

[0068] Furthermore, the solvent used in the step of obtaining the diol compound was tetrahydrofuran. It can be understood that in other embodiments, the solvent is not limited to tetrahydrofuran, and other common solvents in the art can also be used, such as dichloromethane, dichloroethane, toluene, as long as compound (+)-4 can dissolve in it and does not interfere with subsequent reactions. Of course, in other embodiments, the reagents used for hydroboration oxidation are not limited to borane-tetrahydrofuran complex and sodium perborate tetrahydrate, and other common hydroboration reagents and oxidants in the art can also be used. Further, in other embodiments, the solvent used in the step of protecting the primary alcohol was dichloromethane. It can be understood that other common solvents in the art such as tetrahydrofuran, methanol, and ether can also be used. Of course, in other embodiments, the reagents for protecting the primary alcohol are not limited to TBSCl and imidazole, and other common reagents in the art such as TMSCl and pyridine can also be used. Furthermore, the choice of oxidant in the step of oxidizing the secondary alcohol is not limited to DMP, and other oxidants that can oxidize the secondary alcohol to a ketone such as PCC, PDC, etc. or oxidation methods such as the Swern reaction can also be used as long as other functional groups are not affected.

[0069] Of course, after the step of obtaining compound (+)-5, it also includes the step of purifying compound (+)-5. Specifically, a saturated sodium thiosulfate solution is added to quench the reaction. After extracting compound (+)-5, the organic phases are combined, dried, and then purified compound (+)-5 is obtained by silica gel column chromatography. Of course, the reagent for quenching this reaction is not limited to a saturated sodium thiosulfate solution, and it can also be other solutions such as a saturated sodium sulfite solution or a saturated ammonium chloride solution.

[0070] Step 6: Synthesize compound (+)-6 using compound (+)-5.

[0071] Specifically, after deprotonation with a strong base at low temperature to generate an enolate anion, N-phenylbis(trifluoromethanesulfonyl)imide (PhNTf2) is added to the reaction solution to react to obtain compound (+)-6.

[0072] In this embodiment, the reaction formula for synthesizing compound (+)-6 using compound (+)-5 is:

[0073]

[0074] Furthermore, the reaction time for deprotonation with a strong base at -78°C to -40°C to generate an enolate anion is 15 min to 1 h, where the molar ratio of compound (+)-5 to the strong base is 1:1.1 to 1.5. Preferably, deprotonation is carried out with potassium bis(trimethylsilyl)amide (KHMDS, 1 mol / L in THF) at -78°C to generate an enolate anion, and the reaction time is 15 min, where the molar ratio of compound (+)-5 to the strong base is 1:1.4. Then, N-phenylbis(trifluoromethanesulfonyl)imide (PhNTf2) is added to the reaction solution at -78°C to -40°C and reacted for 30 min to 1 h to obtain compound (+)-6. Preferably, the reaction temperature is -78°C, the reaction time is 30 min, and the molar ratio of compound (+)-5 to N-phenylbis(trifluoromethanesulfonyl)imide (PhNTf2) is 1:1.4.

[0075] Furthermore, the solvent is tetrahydrofuran. It can be understood that in other embodiments, the solvent is not limited to tetrahydrofuran, and it can also be other commonly used solvents in the art, such as dichloromethane, dichloroethane, methanol, etc., as long as compound (+)-5 can dissolve in it and does not interfere with subsequent reactions. Of course, in other embodiments, the strong base used for deprotonation is not limited to KHMDS, and it can also be other commonly used strong bases in the art such as LiHMDS or n-butyllithium. Furthermore, the electrophilic reagent used is not limited to N-phenylbis(trifluoromethanesulfonyl)imide (PhNTf2), and it can also be other commonly used reagents in the art such as Comins' Reagent.

[0076] Of course, after the step of obtaining compound (+)-6, it also includes the step of purifying compound (+)-6. Specifically, the reaction is quenched by adding a saturated ammonium chloride solution, and after extracting compound (+)-6, the organic phases are combined, dried, and then purified compound (+)-6 is obtained by silica gel column chromatography. Of course, the reagent for quenching this reaction is not limited to a saturated ammonium chloride solution, and it can also be other substances such as water or a saturated sodium bicarbonate solution.

[0077] Step 7: Synthesize compound (+)-7 using compound (+)-6.

[0078] Specifically, under high-temperature conditions, compound (+)-6 and S3 undergo a Suzuki coupling reaction to obtain compound 7.

[0079] In this embodiment, the reaction formula for synthesizing compound (+)-7 using compound (+)-6 is as follows:

[0080]

[0081] Furthermore, at 80°C to 120°C, compound (+)-6, organoboride S3, palladium catalyst, base, etc. are reacted at a molar ratio of 1:1 to 2:0.05 to 0.2:1 to 2 for 1 to 3 h, and after the Suzuki coupling reaction, compound (+)-7 is obtained. Preferably, at 80°C, compound (+)-6, organoboride S3, dichlorobis(diphenylphosphino)ferrocene palladium(II) (Pd(dppf)Cl2), potassium phosphate (K3PO4), etc. are reacted at a molar ratio of 1:1.5:0.05:1.5 for 1.5 h, and after the Suzuki coupling reaction, compound (+)-7 is obtained. Preferably, S-Phos is added in this step to increase the stability of the boride.

[0082] Furthermore, the solvent is N,N-dimethylformamide (DMF). It can be understood that in other embodiments, the solvent is not limited to DMF, and it can also be other commonly used solvents in the art, such as toluene, N,N-dimethylformamide / water, acetonitrile, etc., as long as compound (+)-6 and S3 can dissolve in it and do not interfere with subsequent reactions. Of course, in other embodiments, the palladium catalyst used is not limited to Pd(dppf)Cl 2， It can also be other commonly used palladium catalysts in the art such as Pd(PPh3)4, Pd(OAc)2; the base used is not limited to K3PO 4， It can also be other commonly used bases in the art such as sodium carbonate, triethylamine, sodium ethoxide.

[0083] Of course, after the step of obtaining the compound (+)-7, it also includes the step of purifying the compound (+)-7. Specifically, the reaction is quenched by adding a saturated sodium bicarbonate solution. After extracting the compound (+)-7, the organic phases are combined, dried, and then purified by silica gel column chromatography to obtain the purified compound (+)-7. Of course, the reagent for quenching this reaction is not limited to saturated sodium bicarbonate, and it can also be other substances such as water, saturated ammonium chloride solution, etc.

[0084] Step 8: Synthesize the compound (-)-8 using the compound (+)-7.

[0085] Specifically, under low-temperature conditions, the acid protonates the carbonyl group of the compound (+)-7, followed by an electrophilic addition with the double bond, triggering an intramolecular oxa-Prins tandem cyclization and the removal of the primary alcohol protection to obtain a secondary alcohol intermediate. Subsequently, the secondary alcohol is oxidized to construct the core skeleton (-)-8 of (-)-Lucidumone in one step.

[0086] In this embodiment, the reaction formula for synthesizing the compound (-)-8 using the compound (+)-7 is:

[0087]

[0088] Furthermore, under the conditions of -78°C to -40°C, the strong acid protonates the carbonyl group of the compound (+)-7, followed by an electrophilic addition with the double bond, triggering an intramolecular oxa-Prins tandem cyclization and the removal of the primary alcohol protection to obtain a secondary alcohol intermediate. The reaction time is 12h to 36h, and the molar ratio of the compound (+)-7 to the acid used is 1:5 to 15. Preferably, the reaction temperature is -78°C, the strong acid used is HCl (2M in EtOAc), the reaction time is 24h, and the molar ratio of the compound (+)-7 to HCl (2M in EtOAc) is 1:10. After this step, the secondary alcohol is oxidized to a ketone at 0°C to 25°C to construct the core skeleton (-)-8 of (-)-Lucidumone in one step. Preferably, the reaction temperature is 0°C, the oxidant used is DMP, the reaction time is 30 min, and the molar ratio of the compound (+)-7 to the DMP oxidant is 1:2.

[0089] Further, the solvent is dichloromethane (DCM). It can be understood that in other embodiments, the solvent is not limited to DCM and can also be other common solvents in the art, such as toluene, tetrahydrofuran, diethyl ether, as long as the compound (+)-7 can dissolve therein and does not interfere with subsequent reactions. Of course, in other embodiments, the strong protonic acid used is not limited to HCl and can also be other common protonic acids or Lewis acids in the art, such as p-toluenesulfonic acid, aluminum trichloride, boron trifluoride, etc. In the step of oxidizing secondary alcohol to ketone, the oxidant used is not limited to DMP and can also be other common oxidants in the art for oxidizing secondary alcohol to ketone, such as PCC, PDC, etc., or oxidation methods such as Swern reaction, as long as other functional groups are not affected.

[0090] Of course, after the step of obtaining the compound (-)-8, a step of purifying the compound (-)-8 is further included. Specifically, the reaction is quenched by adding a saturated sodium thiosulfate solution, the organic phase is combined after extracting the compound (-)-8, and the purified compound (-)-8 is obtained by silica gel column chromatography after drying. Of course, the reagent for quenching this reaction is not limited to the saturated sodium thiosulfate solution and can also be other solutions such as saturated sodium sulfite solution.

[0091] Step 9: Synthesize the compound (-)-9 from the compound (-)-8.

[0092] Specifically, under heating conditions, the compound (-)-8 and the halogenated salt convert the stable phenylsilane into a relatively more active halogenated silane through aryl electrophilic substitution, and then after oxidation under the action of peroxide, [1,2] alkyl migration occurs and hydrolysis occurs to obtain a secondary alcohol, that is, the diol compound (-)-9.

[0093] In the present embodiment, the reaction formula for synthesizing the compound (-)-9 from the compound (-)-8 is:

[0094]

[0095] Further, at 20°C to 50°C, compound (-)-8 and a halogenated salt convert a stable phenylsilane into a relatively more reactive halogenated silane through aryl electrophilic substitution, i.e., an intermediate containing a halogenated silane salt and a primary alcohol is obtained. Then, [1,2] alkyl migration occurs under the action of a peroxide and hydrolysis gives a secondary alcohol, i.e., the diol compound (-)-9. The reaction time is 8 h to 24 h, and the molar ratio of compound (-)-8, the halogenated salt, and hydrogen peroxide is 1:3 to 10:20 to 50. Preferably, at 50°C, compound (-)-8 and potassium fluoride (KF) convert a stable phenylsilane into a relatively more reactive fluorinated silane through aryl electrophilic substitution, i.e., an intermediate containing a fluorinated silane salt and a primary alcohol is obtained. Then, [1,2] alkyl migration occurs under the action of hydrogen peroxide and hydrolysis gives a secondary alcohol, i.e., the diol compound (-)-9. The reaction time is 12 h, and the molar ratio of compound (-)-8, KF, and hydrogen peroxide is 1:5:20.

[0096] Further, the solvent is methanol / tetrahydrofuran = 1:1 (MeOH / THF = 1:1). It can be understood that in other embodiments, the solvent is not limited to MeOH / THF, and the volume ratio is not limited to 1:1 either. It can also be other common solvents or mixed solvents in the art, such as toluene, dichloromethane, ether, N,N-dimethylformamide, etc. As long as compound (-)-8 can dissolve in it and does not interfere with subsequent reactions. Of course, in other embodiments, the halogenated salt used is not limited to KF, and it can also be other fluorides commonly used in the art, such as KHF2, etc. Further, the peroxide in the oxidation step is not limited to hydrogen peroxide, and it can be other peroxides commonly used in the art, such as m-chloroperoxybenzoic acid (m-CPBA).

[0097] Of course, after the step of obtaining compound (-)-9, it also includes the step of purifying compound (-)-9. Specifically, a saturated sodium thiosulfate solution is added to quench the reaction. After extracting compound (-)-9, the organic phases are combined, dried, and purified by silica gel column chromatography to obtain purified compound (-)-9. Of course, the reagent for quenching this reaction is not limited to a saturated sodium thiosulfate solution, and it can also be other substances such as a saturated sodium sulfite solution, water.

[0098] Step 10, synthesize compound (-)-10 using compound (-)-9.

[0099] Specifically, the primary alcohol of compound (-)-9 undergoes a nucleophilic substitution reaction with o-nitrobenzeneselenocyanide and tributylphosphine on the electron-deficient selenium atom to form a selenoether intermediate. Then, the selenoether is oxidized to a selenosulfoxide by hydrogen peroxide and an elimination reaction occurs to form the terminal olefin compound (-)-10.

[0100] In this embodiment, the reaction formula for synthesizing compound (-)-10 from compound (-)-9 is:

[0101]

[0102] Further, at 0 °C to 30 °C, the primary alcohol of compound (-)-9 undergoes a nucleophilic substitution reaction with o-nitrobenzeneselenocyanide and tributylphosphine on the electron-deficient selenium atom to form a selenoether intermediate. The reaction time is 1 h to 12 h, and the molar ratios of compound (-)-9, o-nitrobenzeneselenocyanide, pyridine, and tributylphosphine are 1:1.1 - 1.5:1.1 - 1.5:1.1 - 1.5, respectively. Preferably, the reaction temperature is 25 °C, the reaction time is 6 h, and the molar ratios of compound (-)-9, o-nitrobenzeneselenocyanide, pyridine, and tributylphosphine are 1:1.2:1.2:1.2, respectively. In the next elimination reaction, the molar ratio of compound (-)-9 to hydrogen peroxide is 1:24, and the reaction time is 12 h.

[0103] Further, the solvent is tetrahydrofuran. It can be understood that in other embodiments, the solvent is not limited to tetrahydrofuran and can also be other commonly used solvents in the art, such as toluene, dichloromethane, ether, N,N-dimethylformamide. As long as compound (-)-9 can be dissolved therein and does not interfere with subsequent reactions, it is acceptable. Of course, in other embodiments, the peroxide used is not limited to hydrogen peroxide and can be other commonly used peroxides in the art, such as m-chloroperoxybenzoic acid.

[0104] Of course, after the step of obtaining compound (-)-10, it also includes the step of purifying compound (-)-10. Specifically, a saturated sodium thiosulfate solution is added to quench the reaction. After extracting compound (-)-10, the organic phases are combined, dried, and then purified compound (-)-10 is obtained by silica gel column chromatography. Of course, the reagent for quenching this reaction is not limited to a saturated sodium thiosulfate solution and can also be other substances such as a saturated sodium sulfite solution or water.

[0105] Step 11: Synthesize compound (-)-11 using compound (-)-10.

[0106] Specifically, the terminal olefin in compound (-)-10 generates a radical under the catalysis of metallic iron or the olefin inserts into the iron-containing complex, and then the bond is broken to obtain the methyl ketone compound (-)-11.

[0107] In this embodiment, the reaction formula for synthesizing compound (-)-11 from compound (-)-10 is:

[0108]

[0109] Further, at 0 °C to 30 °C, the terminal olefin in compound (-)-10 generates free radicals under the catalysis of metallic iron or the olefin inserts into the iron-containing complex, and then the bond is broken to obtain the compound methyl ketone (-)-11. Preferably, at 25 °C, the terminal olefin in compound (-)-10 first reacts with ferric chloride and dibenzoylmethane under air or oxygen conditions for 2 min to generate free radicals, and then triphenylsilane is added in batches and reacted at 25 °C for 2 h. Among them, the molar ratio of compound (-)-10, ferric chloride, dibenzoylmethane to triphenylsilane is 1:0.1:0.1:10.

[0110] Further, the solvent is ethanol. It can be understood that in other embodiments, the solvent is not limited to ethanol, and can also be other commonly used solvents in the art, such as methanol, etc. As long as compound (-)-10 can be dissolved therein and can activate metallic iron without interfering with subsequent reactions. Of course, in other embodiments, the iron reagent used is not limited to Fe(dam)3, and can be other iron-containing reagents commonly used in the art such as Fe(dmm)3, Fe(ddm)3, Fe(ab)3, FeBr2.

[0111] Of course, after the step of obtaining compound (-)-11, it also includes the step of purifying compound (-)-11. Specifically, distilled water is added to quench the reaction, the organic phase is combined after extracting compound (-)-11, and after drying, the purified compound (-)-11 is obtained by silica gel column chromatography. Of course, the reagent for quenching this reaction is not limited to distilled water, and can also be other substances such as saturated ammonium chloride solution.

[0112] Step 12, synthesize compound (-)-12 with compound (-)-11.

[0113] Specifically, the methoxy protection of compound (-)-11 is removed under a Lewis acid to finally complete the asymmetric total synthesis of 12(-)-Lucidumone.

[0114] In this embodiment, the reaction formula for the synthesis of compound 12(-)-Lucidumone from compound (-)-11 is as follows:

[0115]

[0116] Further, at 0 °C to 25 °C, compound (-)-11 is activated by a Lewis acid to activate the methoxy group, and after being attacked by the nucleophile dodecanethiol, the protection is removed to obtain 12(-)-Lucidumone. Preferably, the reaction temperature is 0 °C, and the molar ratio of compound (-)-11, aluminum trichloride, to dodecanethiol is 1:50:50, and the reaction time is 5 h.

[0117] Further, the solvent is dichloromethane (DCM). It can be understood that in other embodiments, the solvent is not limited to DCM and can also be other commonly used solvents in the art, such as toluene, tetrahydrofuran, diethyl ether, etc., as long as the compound (-)-11 can dissolve therein and does not interfere with subsequent reactions. Of course, in other embodiments, the Lewis acid used is not limited to aluminum trichloride and can also be ferric chloride, boron trifluoride, magnesium bromide, boron tribromide, aluminum tribromide commonly used in the art; further, the thiol used is not limited to n-dodecyl mercaptan and can be other thiols commonly used in the art such as dithiol.

[0118] Of course, after the step of obtaining the compound (-)-12, it further includes the step of purifying the compound (-)-12. Specifically, distilled water is added to quench the reaction, the compound (-)-12 is extracted, and the organic phases are combined. After drying, silica gel column chromatography is used to obtain the purified compound (-)-12. Of course, the reagent for quenching this reaction is not limited to distilled water and can also be other substances such as saturated sodium chloride solution and saturated ammonium chloride solution. Specific Examples

[0120] The following is a detailed description in combination with specific examples. Unless otherwise specified in the following examples, they do not include other components except inevitable impurities. For the experimental methods without specific conditions noted in the examples, they are carried out under conventional conditions, such as the conditions described in the literature, books, or the methods recommended by the manufacturers.

[0121] Example 1

[0122] The reaction formula for synthesizing Compound 1 is:

[0123]

[0124] Under the protection of an inert gas or nitrogen, Compound S1 (7.05 g, 50 mmol), triphenylsilane (2.6 g, 10 mmol), and dicobalt octacarbonyl (136.0 mg, 0.4 mmol) are dissolved in toluene (50 ml). After reacting at room temperature for 12 h, saturated ammonium chloride solution is added at 0 °C to quench the reaction. The mixture is extracted with ethyl acetate (100 ml × 3), the organic phases are combined and washed with 25 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of Compound 1. Then, silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) is used to obtain the purified yellow solid Compound 1 with a yield of 45%.

[0125] The purified Compound 1 is respectively subjected to nuclear magnetic resonance, mass spectrometry and other detections, and the obtained detection results are as follows:

[0126] Rf: (petroleum ether / ethyl acetate, 5:1 v / v): Rf = 0.3

[0127] 1 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 18.5 Hz, 1H), 7.68 (d, J = 18.5 Hz, 1H), 7.57 - 7.51 (m, 6H), 7.48 - 7.36 (m, 9H), 4.41 (t, J = 7.9 Hz, 2H), 4.07 (t, J = 8.0 Hz, 2H).

[0128] 13 13C NMR (100 MHz, CDCl3): δ 164.6, 153.3, 145.0, 136.9, 136.0, 132.7, 130.1, 128.1, 62.2, 42.7.

[0129] HRMS (ESI / [M+H + ): C 24 H 22 NO3Si, molecular weight calculated value is 400.1369: measured value is 400.1364

[0130] Example 2

[0131] The reaction formula for synthesizing Compound 2 is as follows:

[0132]

[0133] Under the protection of inert gas or nitrogen at 0 °C, dissolve Compound 1 (1.62 g, 4.05 mmol) in ultradry dichloromethane (50 ml). At this temperature, add trifluoromethanesulfonic acid (0.79 ml, 8.91 mmol) and react for 3 h. Then place the reaction solution at -78 °C and slowly dropwise add 2,6-dimethylpyridine (1.12 ml, 9.8 mmol). After stirring for 5 min, slowly dropwise add the known Compound S2 (554.7 mg, 4.5 mmol), and raise the temperature to 0 °C. Then quench the reaction with saturated ammonium chloride solution (20 ml) at room temperature, extract with dichloromethane (100 ml × 3), combine the organic phases, wash with 50 ml of saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product of Compound 2. Then, purify the crude product by silica gel column chromatography to obtain the purified Compound 2 with a yield of 91%.

[0134] Take the purified Compound 2 and conduct tests such as nuclear magnetic resonance, mass spectrometry, and polarimeter. The test results are as follows:

[0135] Rf: (petroleum ether / ethyl acetate, 5:1 v / v): Rf = 0.2

[0136] 1 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 18.6 Hz, 1H), 7.67 - 7.58 (m, 5H), 7.46 - 7.36 (m, 6H), 5.90 - 5.81 (m, 1H), 5.66 (m, 2H), 4.42 (t, J = 8.0 Hz, 2H), 4.08 (t, J = 8.0 Hz, 2H), 3.88 (t, J = 7.0 Hz, 2H), 2.38 (t, J = 7.0 Hz, 2H), 2.16 - 2.08 (m, 2H), 2.08 - 1.99 (m, 2H).

[0137] 13 13C NMR (100 MHz, CDCl3): δ 164.5, 153.3, 144.0, 136.4, 136.0, 135.0, 132.9, 130.5, 128.1, 124.6, 124.0, 120.6, 62.8, 62.2, 42.7, 40.4, 26.5, 22.8.

[0138] HRMS (ESI / [M + H + ): C 26 H 28 NO4Si, molecular weight calculated value is 446.1788: measured value is 446.1782

[0139] Example 3

[0140] The reaction formula for synthesizing compound (+)-3 is:

[0141]

[0142] Under the protection of inert gas or nitrogen, Cu(OTf)2 (109.5 mg, 0.3 mmol), (4S,4′S)-(-)-2,2′-(3-pentylidene)bis(4-phenyloxazoline) (120.1 mg, 0.33 mmol) were dissolved in dichloromethane (20 ml). After stirring for 3 h, a copper complex was formed. Then compound 2 (1.324 g, 3.0 mmol) was dissolved in dichloromethane (20 ml), and the mixture was stirred at 50 °C for 12 h. Then the reaction was quenched with saturated ammonium chloride solution (20 ml) at room temperature, extracted with dichloromethane (100 ml × 3), the combined organic phases were washed with 50 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of compound (+)-3. The purified pure product of compound (+)-3 was obtained by silica gel column chromatography, and the yield was 95%.

[0143] The purified compound (+)-3 was respectively detected by nuclear magnetic resonance, mass spectrometry, polarimeter, etc., and the detection results are as follows:

[0144] Rf: (petroleum ether / ethyl acetate, 4:1 v / v): Rf = 0.2

[0145] Optical rotation: [α] D 20 = +42 (c = 1.0, MeOH)

[0146] 1 H NMR (400 MHz, CDCl3): δ 7.75 (dd, J = 6.4, 3.2 Hz, 2H), 7.46 (tt, J = 6.0, 2.7 Hz, 5H), 7.34 - 7.25 (m, 3H), 6.24 (d, J = 8.2 Hz, 1H), 6.00 (dd, J = 8.3, 6.4 Hz, 1H), 4.42 (td, J = 13.3, 12.6, 2.4 Hz, 1H), 4.36 - 4.30 (m, 1H), 4.29 - 4.15 (m, 3H), 3.95 - 3.79 (m, 2H), 2.83 (dd, J = 6.1, 2.6 Hz, 1H), 2.39 (td, J = 13.5, 5.1 Hz, 1H), 2.09 (dd, J = 7.5, 3.1 Hz, 1H), 1.82 (dq, J = 13.3, 3.9, 3.1 Hz, 2H), 1.32 - 1.26 (m, 1H), 1.19 (tt, J = 12.2, 3.9 Hz, 1H), 0.84 (tq, J = 12.1, 4.3, 3.4 Hz, 1H).

[0147] 13 C NMR (100 MHz, CDCl3): δ 174.8, 153.2, 142.8, 135.3, 134.8, 134.6, 134.1, 130.2, 130.0, 128.4, 128.1, 127.8, 61.8, 61.6, 43.0, 42.5, 38.8, 36.9, 35.1, 28.7, 26.3, 25.8.

[0148] HRMS (ESI / [M+H + ): C 26 H 28 O4Si, the calculated molecular weight is 446.1788: the measured value is 446.1771

[0149] Example 4

[0150] The reaction formula for synthesizing compound (+)-4 is:

[0151]

[0152] At 0 °C, the compound (+)-3 (448.6 mg, 1 mmol), hydrogen peroxide (30 wt.% in H2O) (1 ml, 8.8 mmol) were dissolved in THF:H2O = 2:1 (10 ml / 5 ml), then LiOH (72.2 mg, 3 mmol) was added, and the mixture was stirred for 5 h. The reaction was quenched with saturated sodium thiosulfate solution, and the pH was adjusted to 1 with 1 M HCl. The mixture was extracted with ethyl acetate (20 ml × 3), the combined organic phases were washed with 10 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product of compound (+)-4. The purified pure product of compound (+)-4 was obtained by silica gel column chromatography with a yield of 94%.

[0153] The purified compound (+)-4 was respectively detected by nuclear magnetic resonance, mass spectrometry, polarimeter, etc., and the detection results are as follows:

[0154] Rf: (petroleum ether / ethyl acetate, 5:1 v / v): Rf = 0.4

[0155] Optical rotation: [α] D 20 = +10 (c = 1.0, MeOH)

[0156] 1 1H NMR (500 MHz, CDCl3): δ 7.72 - 7.69 (m, 2H), 7.57 - 7.54 (m, 2H), 7.48 - 7.41 (m, 3H), 7.37 - 7.33 (m, 1H), 7.30 - 7.26 (m, 2H), 6.20 (d, J = 7.8 Hz, 1H), 6.14 (dd, J = 8.2, 6.3 Hz, 1H), 4.45 (ddd, J = 13.0, 11.5, 2.6 Hz, 1H), 4.23 (ddd, J = 11.5, 5.2, 1.7 Hz, 1H), 2.93 - 2.89 (m, 1H), 2.81 (dd, J = 7.6, 2.0 Hz, 1H), 2.36 - 2.27 (m, 1H), 1.88 (ddd, J = 12.1, 9.6, 4.3 Hz, 1H), 1.81 (ddd, J = 14.3, 2.6, 1.7 Hz, 2H), 1.76 (dd, J = 7.6, 3.0 Hz, 1H), 1.21 (tt, J = 12.3, 4.2 Hz, 1H), 1.10 - 1.04 (m, 1H), 0.95 - 0.87 (m, 1H).

[0157] 1313C NMR (125 MHz, CDCl3): δ 179.9, 142.5, 135.6, 134.8, 134.8, 134.4, 130.2, 130.0, 129.9, 128.0, 127.5, 61.8, 44.9, 38.5, 36.8, 34.2, 30.5, 26.3, 25.7.

[0158] HRMS (ESI / [M+H + ): C 23 H 25 O3Si, calculated for C18H25O3Si [M+H]+ 377.1573; found 377.1568

[0159] Example 5

[0160] The reaction scheme for the synthesis of compound (+)-5 is as follows:

[0161]

[0162] Under the protection of an inert gas or nitrogen, borane tetrahydrofuran complex (1 M in THF, 5 mL, 5 mmol) was slowly added to a solution of compound (+)-4 (376.5 mg, 1 mmol) in THF (10 mL) at -30 °C, and then the mixture was slowly warmed to room temperature and stirred for 12 h. Then the reaction mixture was cooled to 0 °C, and a solution of sodium perborate tetrahydrate (1.53 g, 10 mmol) dissolved in 15 mL of water was slowly added and stirred for 1 h. The reaction was quenched with 10 mL of saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude diol intermediate. At room temperature, imidazole (340 mg, 5 mmol) was added to the crude diol solution dissolved in dichloromethane (20 mL), and then TBSCl (453.6 mg, 3 mmol) was added. After reacting for 5 h, the reaction was quenched with water. The mixture was extracted with dichloromethane (25 mL × 3). The combined organic phases were washed with 15 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of selectively protected primary alcohol. At 0 °C, sodium bicarbonate (840 mg, 10 mmol) was added to the crude product of selectively protected primary alcohol dissolved in dichloromethane (20 mL), and then DMP oxidant (830 mg, 2 mmol) was added at this temperature. After reacting for 2 h, the reaction was quenched with saturated sodium thiosulfate solution (10 mL). The mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with 15 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of compound (+)-5. Further purification by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1 - 10:1) gave the purified white solid compound (+)-5 with a yield of 89%.

[0163] The purified compound (+)-5 was respectively detected by nuclear magnetic resonance, mass spectrometry, polarimeter, etc., and the test results are as follows:

[0164] Rf: (petroleum ether / ethyl acetate, 10:1 v / v): Rf = 0.35.

[0165] Optical rotation: [α] D 20 = +53 (c = 1.0, MeOH).

[0166] 1 H NMR (500 MHz, CDCl3): δ 7.72 - 7.69 (m, 2H), 7.60 - 7.56 (m, 2H), 7.48 - 7.39 (m, 4H), 7.37 - 7.32 (m, 2H), 4.37 (ddd, J = 12.9, 11.6, 2.4 Hz, 1H), 4.17 (ddd, J = 11.6, 5.1, 1.9 Hz, 1H), 3.44 (dd, J = 10.0, 2.7 Hz, 1H), 3.28 (dd, J = 10.0, 5.1 Hz, 1H), 2.29 - 2.24 (m, 2H), 2.10 (d, J = 1.5 Hz, 2H), 2.01 - 1.93 (m, 2H), 1.69 - 1.63 (m, 1H), 1.56 - 1.50 (m, 2H), 1.47 - 1.41 (m, 1H), 1.21 (m, 1H), 0.85 (s, 9H), –0.058 (s, 3H), –0.064 (s, 3H).

[0167] 13 C NMR (125 MHz, CDCl3): δ 214.7, 135.6, 135.1, 134.8, 134.0, 130.5, 130.1, 128.14, 128.08, 65.9, 61.4, 55.0, 46.9, 41.2, 40.3, 36.6, 28.9, 26.4, 26.0, 23.8, 18.5, –5.70, –5.73.

[0168] HRMS (ESI / [M + H + ): C 29 H 41 O3Si2, the calculated molecular weight is 493.2594: the measured value is 493.2582

[0169] Example 6

[0170] The reaction formula for synthesizing compound (+)-6 is:

[0171]

[0172] Under the protection of inert gas or nitrogen, dissolve compound (+)-5 (300.2 mg, 0.6 mmol) in 8 ml of ultra-dry tetrahydrofuran. Then, slowly drop KHMDS (1 M in THF, 0.84 mL, 0.84 mmol) into the reaction solution at -78 °C and stir for 15 min. At the same temperature, dissolve PhNTf2 (300.0 mg, 0.84 mmol) in 2 ml of THF and slowly drop it into the mixture for reaction for 30 min. Then, quench the reaction with 5 ml of saturated ammonium chloride solution, extract with ethyl acetate (20 ml × 3), combine the organic phases, wash with 10 ml of saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product of compound (+)-6. Further purify it by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain the purified pure product compound (+)-6 with a yield of 94%.

[0173] Take the purified compound (+)-6 and conduct tests such as nuclear magnetic resonance, mass spectrometry, and polarimeter. The test results are as follows:

[0174] Rf: (petroleum ether / ethyl acetate, 30:1 v / v): Rf = 0.30

[0175] Optical rotation: [α] D 20 = +53 (c = 1.0, MeOH);

[0176] 1 1H NMR (500 MHz, CDCl3): δ 7.78 - 7.73 (m, 2H), 7.54 - 7.50 (m, 2H), 7.50 - 7.44 (m, 3H), 7.42 - 7.37 (m, 1H), 7.36 - 7.30 (m, 2H), 5.84 (d, J = 2.5 Hz, 1H), 4.41 - 4.33 (m, 1H), 4.20 (ddd, J = 11.8, 5.0, 1.9 Hz, 1H), 3.15 (dd, J = 10.2, 4.0 Hz, 1H), 3.03 - 2.96 (m, 1H), 2.92 (p, J = 2.4 Hz, 1H), 2.35 - 2.21 (m, 2H), 1.86 (dt, J = 14.3, 2.2 Hz, 1H), 1.82 - 1.75 (m, 1H), 1.54 (tt, J = 12.2, 3.7 Hz, 1H), 1.15 (tdd, J = 9.8, 4.3, 2.5 Hz, 1H), 0.97 (tt, J = 12.2, 3.8 Hz, 1H), 0.82 (s, 9H), 0.72 (dd, J = 7.2, 3.1 Hz, 1H), –0.09 (s, 6H).

[0177] 13 13C NMR (125 MHz, CDCl3): δ 149.7, 135.2, 134.7, 134.5, 133.7, 130.4, 130.1, 128.1, 128.0, 126.1, 118.6 (q, JC-F = 318.7 Hz), 65.8, 61.3, 43.8, 40.2, 38.9, 37.2, 31.1, 26.8, 26.2, 25.8, 18.3, –5.69, –5.71.

[0178] HRMS (ESI / [M+H + ): C 30 H 40 F3O5SSi2, calculated molecular weight: 625.2087; found: 625.2072

[0179] Example 7

[0180] The reaction equation for synthesizing compound (-)-7 is as follows:

[0181]

[0182] Under the protection of inert gas or nitrogen, dissolve compound (+)-6 (213.3 mg, 1.0 mmol) in 10 ml of DMF, then successively add Pd(dppf)Cl2 (36.5 mg, 0.05 mmol), K3PO4 (0.97 g, 1.5 mmol), S-Phos (41.2 mg, 0.1 mmol), and S3 (312.2 mg, 0.5 mmol). Then heat the mixture at 80 °C for 1.5 h. After cooling to 0 °C, quench the reaction with saturated sodium bicarbonate solution. Extract with ethyl acetate (20 ml × 3), combine the organic phases, wash with 10 ml of saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product of compound (-)-7. Further purify it by silica gel column chromatography (petroleum ether / ethyl acetate / triethylamine = 100:10:1) to obtain the purified pure product of compound (-)-7 with a yield of 69%.

[0183] Take the purified compound (-)-7 and conduct tests such as nuclear magnetic resonance, mass spectrometry, and polarimeter. The test results are as follows:

[0184] Rf: (petroleum ether / ethyl acetate, 4:1 v / v): Rf = 0.32

[0185] Optical rotation: [α] D 20 = +38 (c = 1.0, MeOH);

[0186] 1 1H NMR (400 MHz, CD3OD): δ 10.20 (s, 1H), 7.83 - 7.79 (m, 2H), 7.56 - 7.49 (m, 5H), 7.41 - 7.32 (m, 3H), 7.14 (d, J = 9.1 Hz, 1H), 6.99 (d, J = 9.1 Hz, 1H), 5.96 (d, J = 1.6 Hz, 1H), 4.42 (ddd, J = 13.0, 11.6, 2.2 Hz, 1H), 4.15 (ddd, J = 11.6, 4.9, 1.9 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.13 - 2.99 (m, 3H), 2.35 - 2.25 (m, 2H), 1.93 - 1.70 (m, 3H), 1.21 - 1.14 (m, 1H), 0.98 - 0.90 (m, 1H), 0.89 - 0.86 (m, 1H), 0.64 (s, 9H), –0.31 (s, 3H), –0.36 (s, 3H).

[0187] 13 13C NMR (100 MHz, CD3OD): δ 192.7, 153.5, 151.7, 145.6, 136.9, 136.0, 134.6, 134.5, 134.0, 133.4, 130.0, 129.8, 127.8, 127.6, 125.3, 116.0, 110.9, 66.4, 61.2, 55.5, 55.1, 43.3, 38.7, 38.2, 37.6, 32.4, 26.7, 26.6, 25.0, 17.7, –6.8, –6.9.

[0188] HRMS (ESI / [M + H + ): C 38 H 49 O5Si2, calculated molecular weight: 641.3119; found: 641.3104

[0189] Example 7

[0190] The reaction equation for synthesizing compound (-)-8 is as follows:

[0191]

[0192] Under the protection of inert gas or nitrogen, dissolve compound 5 (210.0 mg, 0.33 mmol) in 5 ml of ultradry dichloromethane. Slowly add HCl (2 M in EA, 1.7 mL, 3.4 mmol) dropwise to the reaction solution at -78 °C and stir at this temperature for 24 h. Then quench the reaction with 5 ml of water, extract with dichloromethane (10 ml × 3), combine the organic phases, wash with 5 ml of saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product of the secondary alcohol intermediate. At 0 °C, add sodium bicarbonate (277.0 mg, 10 mmol) to the crude product of the secondary alcohol intermediate dissolved in 10 ml of dichloromethane. Then add DMP oxidant (279.2 mg, 0.66 mmol) at this temperature and react for 30 min. Quench with saturated sodium thiosulfate solution, extract with dichloromethane (10 ml × 3), combine the organic phases, wash with 5 ml of saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product of compound (-)-8. Further purify it by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1 - 1:1) to obtain the purified pure product compound (-)-8 with a yield of 80%.

[0193] Take the purified compound (-)-8 and conduct tests such as nuclear magnetic resonance, mass spectrometry, and polarimeter respectively. The test results are as follows:

[0194] Rf: (petroleum ether / ethyl acetate, 1:1 v / v): Rf = 0.35

[0195] Optical rotation: [α] D 20 = -13 (c = 1.0, MeOH)

[0196] 11H NMR (500 MHz, CDCl3): δ 7.77 - 7.75 (m, 2H), 7.59 - 7.57 (m, 2H), 7.47 - 7.34 (m, 6H), 7.05 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 4.33 (td, J = 12.4, 2.4 Hz, 1H), 4.20 (ddd, J = 11.7, 5.1, 1.8 Hz, 1H), 4.14 - 4.12 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.62 (d, J = 7.4 Hz, 1H), 2.76 (q, J = 3.4 Hz, 1H), 2.72 (dt, J = 14.5, 2.2 = Hz, 1H), 2.59 (q, J = 3.3 Hz, 1H), 2.28 (d, J = 2.3 Hz, 1H), 1.99 - 1.92 (m, 1H), 1.67 - 1.59 (m, 1H), 1.47 (t, J = 3.0 Hz, 1H), 1.23 - 1.19 (m, 1H), 1.18 - 1.12 (m, 1H), 0.87 - 0.81 (m, 1H).

[0197] 13 13C NMR (125 MHz, CDCl3): δ 201.1, 151.42, 151.41, 140.6, 135.7, 135.3, 134.6, 134.6, 130.4, 130.0, 128.2, 128.1, 127.9, 118.6, 111.8, 86.0, 77.2, 67.5, 61.9, 56.4, 56.1, 38.7, 38.5, 37.0, 36.6, 35.4, 21.2, 15.8.

[0198] HRMS (ESI / [M + H + ): C 32 H 33 O5Si, calculated molecular weight: 525.2097; found: 525.2079

[0199] Example 9

[0200] The reaction formula for synthesizing compound (-)-9 is as follows:

[0201]

[0202] At room temperature, compound (-)-8 was dissolved in tetrahydrofuran / methanol = 1:1, and then potassium fluoride (72.5 mg, 1.25 mmol), potassium bicarbonate (40.1 mg, 0.4 mmol) and hydrogen peroxide (30% wt with H2O, 0.64 mL, 5 mmol) were added respectively. The mixture was slowly heated to 50 °C and stirred at this temperature for 12 h. After cooling to 0 °C, it was quenched with saturated sodium thiosulfate solution, extracted with ethyl acetate (10 ml × 3), the combined organic phases were washed with 5 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product of compound (-)-9. The crude product was further purified by silica gel column chromatography (ethyl acetate) to obtain the purified compound (-)-9 with a yield of 91%.

[0203] The purified compound (-)-9 was respectively subjected to nuclear magnetic resonance, mass spectrometry, polarimeter and other detections, and the detection results are as follows:

[0204] Rf: (pure ethyl acetate): Rf = 0.4

[0205] Optical rotation: [α] D 20 = -24 (c = 1.0, MeOH)

[0206] 1 1H NMR (500 MHz, CDCl3): δ 7.06 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.15 (dd, J = 7.9, 4.4 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.81 (dd, J = 6.1, 3.2 Hz, 1H), 3.77 - 3.72 (m, 2H), 3.61 (s, 1H), 2.65 - 2.63 (m, 1H), 2.41 (ddd, J = 15.6, 6.0, 2.4 Hz, 1H), 2.33 (t, J = 4.2 Hz, 1H), 2.19 (d, J = 1.8 Hz, 1H), 1.96 (ddd, J = 15.6, 9.3, 3.2 Hz, 1H), 1.79 - 1.69 (m, 2H), 1.05 - 0.96 (m, 2H).

[0207] 13 13C NMR (125 MHz, CDCl3): δ 201.7, 151.4, 151.3, 139.9, 128.0, 118.8, 112.0, 86.1, 78.1, 73.6, 59.5, 58.5, 56.4, 56.0, 46.0, 39.3, 37.5, 36.4, 17.9, 15.8.

[0208] HRMS (ESI / [M + H+ ):C 20 H 25 O6, the calculated molecular weight is 361.1651: the measured value is 361.1638 Example 10

[0209] The reaction formula for synthesizing compound (-)-10 is as follows:

[0210]

[0211] Under the protection of an inert gas or nitrogen, dissolve compound (-)-9 (73.5 mg, 0.2 mmol) in 5 ml of tetrahydrofuran. At room temperature, add o-nitrobenzeneselenocyanide (55 mg, 0.24 mmol) and pyridine (20 μL, 0.24 mmol, 1.2 eq) respectively, and slowly dropwise add tributylphosphine (60 μL, 0.24 mmol) and react for 30 min; then add hydrogen peroxide at room temperature and stir for 12 h. Quench with saturated sodium thiosulfate solution at 0 °C, extract with ethyl acetate (10 ml × 3), combine the organic phases and wash with 5 ml of saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude product of compound (-)-10. Then, through silica gel column chromatography ((petroleum ether / ethyl acetate = 2:1)), the purified white solid compound (-)-10 is obtained with a yield of 50%.

[0212] Take the purified compound (-)-10 and conduct tests such as nuclear magnetic resonance, mass spectrometry, and polarimeter. The test results are as follows:

[0213] Rf: (petroleum ether / ethyl acetate, 1:1 v / v): Rf = 0.15

[0214] Optical rotation: [α] D 20 =-40 (c = 1.0, CHCl3)

[0215] 11H NMR (500 MHz, CDCl3): δ 7.07 (d, J = 8.9 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.01 (dd, J = 17.6, 10.9 Hz, 1H), 5.35 (dd, J = 10.9, 1.0 Hz, 1H), 5.13 (dd, J = 17.6, 1.1 Hz, 1H), 4.22 (dd, J = 8.1, 4.5 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.79 - 3.76 (d, J = 7.6 Hz, 1H), 3.55 (s, 1H), 2.70 (q, J = 3.2 Hz, 1H), 2.42 (t, J = 4.2 Hz, 1H), 2.33 (d, J = 1.8 Hz, 1H), 1.92 (d, J = 1.6 Hz, 1H), 1.83 - 1.74 (m, 2H), 1.23 - 1.17 (m, 1H), 1.10 - 1.02 (m, 1H).

[0216] 13 13C NMR (125 MHz, CDCl3): δ 199.6, 151.52, 151.45, 142.4, 139.6, 128.1, 118.8, 116.0, 112.4, 85.8, 73.5, 61.9, 56.5 (2C), 56.1, 44.8, 42.6, 37.8, 15.48, 15.47.

[0217] HRMS (ESI / [M + H + ): C 20 H 23 O5, calculated molecular weight: 343.1545; found: 343.1534 Example 11

[0218] The reaction formula for synthesizing compound (-)-11 is as follows:

[0219]

[0220] Compound (-)-10 (34.0 mg, 0.1 mmol) was dissolved in ethanol (3 ml) at room temperature. Then, ferric chloride (1.7 mg, 0.01 mmol) and dibenzoylmethane (2.3 mg, 0.01 mmol) were added. After stirring in air for 5 minutes, triphenylsilane (120 μl, 1.0 mmol) was added and the mixture was stirred at room temperature for 2 h. Then, it was quenched with distilled water, extracted with ethyl acetate (5 ml × 3), and the combined organic phases were washed with 5 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of compound (-)-11. The purified white solid compound (-)-11 was obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) with a yield of 65%.

[0221] The purified compound (-)-11 was respectively detected by nuclear magnetic resonance, mass spectrometry, polarimeter, etc., and the test results are as follows:

[0222] Rf: (pure ethyl acetate): Rf = 0.25

[0223] Optical rotation: [α] D 20 =-41 (c = 1.0, CHCl3)

[0224] 1 1H NMR (500 MHz, CDCl3): δ 7.10 (d(d, J = 8.2 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.21 (dd, J = 8.3, 4.6 Hz, 1H), 3.97 - 3.95 (m, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.79 (d, J = 8.2 Hz, 1H), 2.92 (d, J = 2.3 Hz, 1H), 2.71 (q, J = 3.4 Hz, 1H), 2.38 (s, 4H), 2.19 - 2.12 (m, 1H), 2.01 (q, J = 6.8 Hz, 1H), 1.83 (ddt, J = 14.4, 12.1, 3.9 Hz, 1H), 1.45 - 1.40 (m, 1H), 1.07 (ddd, J = 14.3, 5.1, 2.6 Hz, 1H).

[0225] 13 13C NMR (125 MHz, CDCl3): δ 213.7, 199.4, 151.52, 151.46, 139.5, 127.5, 119.2, 112.4, 85.4, 77.8, 73.1, 61.5, 56.5, 56.1, 51.3, 47.4, 37.7, 28.8, 15.4, 14.8.

[0226] HRMS (ESI / [M + H + ): C 20 H 23 O6, the calculated molecular weight is 359.1495: the measured value is 359.1551 Example 12

[0227] The reaction formula for synthesizing the compound (-)-12 is:

[0228]

[0229] Under the protection of inert gas or nitrogen at 0 °C, dissolve compound (-)-11 (17.5 mg, 0.05 mmol) in dichloromethane (2 ml), add aluminum trichloride (330.2 mg, 2.5 mmol) and n-dodecyl mercaptan (0.6 ml, 2.5 mmol). After reacting for 5 h, remove the methoxy group, quench the reaction with distilled water (5 ml), extract with ethyl acetate (5 ml × 3), combine the organic phases and wash with 5 ml of saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude product of compound (-)-12. Then, through silica gel column chromatography ((petroleum ether / ethyl acetate = 1:1)), the purified brown solid compound (-)-12 is obtained, realizing the asymmetric total synthesis of the natural product (-)-Lucidumone with a yield of 70%.

[0230] Take the purified compound (-)-12 and conduct tests such as nuclear magnetic resonance, mass spectrometry, and polarimeter. The test results are as follows:

[0231] Rf: (petroleum ether / ethyl acetate, 1:1 v / v): Rf = 0.10

[0232] Optical rotation: [α] D 20 = -62 (c = 1.0, CH3OH)

[0233] 1 1H NMR (500 MHz, CD3OD): δ 7.02 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 4.26 (dd, J = 8.3, 4.9 Hz, 1H), 3.92 - 3.90 (m, 1H), 3.78 (d, J = 8.4 Hz, 1H), 2.89 (d, J = 2.3 Hz, 1H), 2.70 (q, J = 3.3 Hz, 1H), 2.36 (t-like, (4.5)1H), 2.29 (s, 3H), 2.21 - 2.15 (m, 1H), 1.92 - 1.83 (m, 1H), 1.37 - 1.32 (m, 1H), 1.07 (dddd, J = 14.7, 11.9, 4.9, 2.7 Hz, 1H).

[0234] 13 13C NMR (125 MHz, CD3OD): δ 214.8, 204.2, 150.7, 149.5, 135.4, 126.4, 125.4, 118.6, 87.4, 79.5, 74.3, 62.3, 52.7, 48.7, 39.1, 28.5, 16.2, 15.8.

[0235] HRMS (ESI / [M+H+ ):C 18 H 19 O6, the calculated molecular weight is 331.1182: the measured value is 331.1177. The above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit them. Those of ordinary skill in the art can modify the technical solutions of the present invention or make equivalent replacements without departing from the spirit and scope of the present invention. The protection scope of the present invention shall be subject to what is described in the claims.

Claims

1. A method for asymmetric synthesis of (-)-Lucidumone, characterized in that, Comprising the following steps: 1) After the coupling reaction of compound S1 with triphenylsilane, compound 1 is obtained; 2) The nucleophilic substitution reaction of compound 1 and S2 gives compound 2; 3) The intramolecular Diels - Alder reaction of compound 2 catalyzed by Lewis acid gives compound (+)-3; 4) The oxazolidinone in compound (+)-3 undergoes nucleophilic substitution and then hydrolysis reaction to obtain compound (+)-4; 5) Compound (+)-4 is hydroborated and then oxidized to obtain a diol compound intermediate, the generated primary alcohol is selectively protected, and the generated secondary alcohol is oxidized again to obtain compound (+)-5; 6) Compound (+)-5 undergoes a deprotonation reaction and then a substitution reaction to obtain a trifluoromethanesulfonate compound (+)-6; 7) The coupling reaction of compound (+)-6 with compound S3 gives compound (+)-7; 8) Compound (+)-7 undergoes an acid - catalyzed deprotection / Prins reaction / ring etherification tandem reaction under acidic conditions to obtain an intermediate containing a secondary alcohol, and the generated secondary alcohol is oxidized to obtain the core skeleton (-)-8 of (-)-Lucidumone; 9) Compound (-)-8 undergoes an oxidation reaction to obtain a diol compound (-)-9; 10) Compound (-)-9 undergoes an elimination reaction through a selenoether intermediate to obtain a terminal olefin compound (-)-10; 11) Compound (-)-10 undergoes an oxidation reaction to obtain compound (-)-11; 12) Compound (-)-11 undergoes a Lewis acid - mediated demethylation reaction to obtain the natural product 12 (-)-Lucidumone.

2. The method for asymmetric synthesis of (-)-Lucidumone according to claim 1, characterized in that, In step 1), Compound S undergoes a coupling reaction with triphenylsilane under the catalysis of metallic cobalt to obtain compound 1.

3. The method for asymmetric synthesis of (-)-Lucidumone according to claim 1, characterized in that, In step 2), After being protonated under the action of an acid (the preferred acids are trifluoromethanesulfonic acid, hydrochloric acid, p - toluenesulfonic acid, acetic acid), compound S2 is neutralized with an excess of acid under basic conditions (the preferred basic compounds for the basic conditions are pyridine or 2,4 - dimethylpyridine or potassium tert - butoxide, triethylamine) (the equivalent ratio of acid to base is 1:1 - 1.2, preferably 1:1.09) and undergoes a silicon - oxygen nucleophilic substitution reaction with compound S1 to obtain a silicon - oxygen nucleophilic product 2.

4. The method for asymmetric synthesis of (-)-Lucidumone according to claim 1, wherein, In step 3), Compound 2 catalyzes the intramolecular asymmetric Diels - Alder reaction under the conditions of Lewis acid and BOX ligand to obtain the said compound (+)-3.

5. The method for asymmetric synthesis of (-)-Lucidumone according to claim 1, characterized in that, In step 4), The peroxide formed by the reaction of hydrogen peroxide with a base (the preferred bases are potassium hydroxide, lithium hydroxide, sodium hydroxide, sodium carbonate) is used as a nucleophile to attack the carbonyl group to obtain a peroxyacid compound intermediate, and then undergoes a hydrolysis reaction under acidic conditions (the preferred acids are hydrochloric acid, p - toluenesulfonic acid) to obtain the said compound (+)-4.

6. The method for asymmetric synthesis of (-)-Lucidumone according to claim 1, characterized in that, In step 5), Under low temperature conditions (the low temperature conditions are -78 to -20 °C, preferably -30 °C), the compound (+)-4 is hydroborated with a borane reagent, and then an oxidation reaction occurs under the action of an oxidant to obtain a diol compound. The primary alcohol formed is selectively protected, and then the secondary alcohol is oxidized to a ketone under the action of an oxidant to obtain the compound (+)-5.

7. The method for asymmetric synthesis of (-)-Lucidumone according to claim 1, characterized in that, In step 6), Under low temperature conditions (the low temperature conditions are -78 to -40 °C, preferably -78 °C), a strong base is used to abstract a proton to generate an enolate anion, and a trifluoromethanesulfonyl reagent is added to the reaction solution for a substitution reaction to obtain the compound (+)-6.

8. The method for asymmetric synthesis of (-)-Lucidumone according to claim 1, wherein, In step 7), Under high temperature conditions (the high temperature conditions are 80 to 120 °C, preferably 80 °C), the compound (+)-6 and S3 undergo a Suzuki coupling reaction under the action of a palladium reagent, a base, 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl (S-Phos), etc. to obtain the compound (+)-7.

9. The method for asymmetric synthesis of (-)-Lucidumone according to claim 1, characterized in that, In step 8), Under low temperature conditions (the low temperature conditions are -78 to -40 °C, preferably -40 °C), a strong acid protonates the carbonyl group of the compound (+)-7 and then undergoes an electrophilic addition with the double bond to initiate an intramolecular tandem cyclization reaction and remove the protection of the primary alcohol to obtain an intermediate containing a secondary alcohol. Then, the secondary alcohol is oxidized to construct the core skeleton (-)-8 of (-)-Lucidumone in one step.

10. The method for asymmetric synthesis of (-)-Lucidumone according to claim 1, characterized in that, In step 9), Under heating conditions (the heating conditions are 20 to 50 °C, preferably 50 °C), the siloxane bond in the compound (-)-8 is cleaved under the action of a fluoride to obtain a fluorine-substituted silane salt and a primary alcohol. Then, hydrogen peroxide (H2O2) is added, and the peroxide attacks the silicon atom of the fluorosilane salt, followed by a [1,2] alkyl migration and hydrolysis to obtain a secondary alcohol, that is, the diol compound (-)-9.

11. The method for asymmetric synthesis of (-)-Lucidumone according to claim 1, characterized in that, In step 10), The primary alcohol of the compound (-)-9 undergoes a nucleophilic substitution reaction with o-nitrobenzeneselenonitrile and tributylphosphine (PBu3) on the electron-deficient selenium atom to form a selenoether intermediate. Then, the selenoether is oxidized to a selenoxide with hydrogen peroxide and undergoes an elimination reaction similar to a Cope elimination to obtain the terminal olefin compound (-)-10.

12. The method for asymmetric synthesis of (-)-Lucidumone according to claim 1, characterized in that, In step 11), The terminal olefin in the compound (-)-10 generates a radical under the catalysis of metallic iron or the olefin inserts into an iron-containing complex, and then the bond is broken to obtain the compound methyl ketone (-)-11.

13. The method for asymmetric synthesis of (-)-Lucidumone according to claim 1, characterized in that, In step 12), The compound (-)-11 undergoes a demethoxylation reaction under the action of a Lewis acid to achieve the asymmetric total synthesis of (-)-Lucidumone.

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