WO2016037566A1

WO2016037566A1 - Use of antroqiononol for treating obesity, and process for preparation of antroquinonol

Info

Publication number: WO2016037566A1
Application number: PCT/CN2015/089224
Authority: WO
Inventors: Ching-Feng Weng; Chin-Piao Chen; Sulake Rohidas Shivaji; Zi-Ling HUANG
Original assignee: Ching-Feng Weng
Priority date: 2014-09-09
Filing date: 2015-09-09
Publication date: 2016-03-17
Also published as: TW201632491A

Abstract

Provided is the use of antroquinonol for manufacturing a composition or medicament for treating obesity. In addition, new processes for the total synthesis of antroquinonol and new compounds produced during the processes are disclosed.

Description

USE OF ANTROQIONONOL FOR TREATING OBESITY, AND PROCESS FOR PREPARION OF ANTROQUINONOL

FIELD OF THE INVENTION

The present invention relates to the use of antroqiononol for manufacturing a medicament for treating obesity, and also relates to a new process for preparing antroqiononol.

BACKGROUND OF THE INVENTION

In recent years, obesity has become a public health issue in the modern society that cannot be neglected. Because of imbalance of food intake and energy expenditure, obesity is thought of the condition that the excess energy is converted into fat, which is then accumulated in adipose tissues to cause gradual weight gain. Adipogenesis, the differentiation process that produces in adipocytes, is a complex process that involves various changes including gene expression, hormone sensitivity, and cellular morphology (Farmer, Cell Metabolism, 2006, 4: 263-273； Rosen et al., Nature Reviews Molecular Cell Biology, 2006, 7: 885-896) . Conversion of fat into fatty acids and glycerol is to rely on digestion of pancreatic lipase, secreted by the pancreas into the duodenum, and then decompose is absorbed into the body via diffusion. Liver, bile salts first released, attached to the surface of fat droplets, making them more likely to be decomposed by lipase. Lipase (Lipase, EC 3.1.1.3) , is a triglyceride hydrolases (triacylglycerol ester hydrolyaes) , are α/β hydrolase family of enzymes, the enzymatic activity is mainly for triglycerides (triacylglycerolester) digestive reaction. Most of the lipase is produced by the pancreas, while other parts of the body are also produced including the stomach, liver, and salivary glands.

Orlistat (Xenical) is the saturated derivative of lipstatin, a potent natural inhibitor of pancreatic lipases isolated from the bacterium Streptomyces toxytricini and is used as an oral treatment for obesity (Drent et al., Internatinal Journal of Obesity, 1993, 12: 241-244； Barbier et al., Helvetica ChimicaActa, 1987, 70: 196-202) . Orlistat is the only legal anti-obesity drug which can reduce the intestinal lipid absorption from the diet by lipase inhibition. Orlistat is very hydrophobic: (logP 7.6-8.1) and binds covalently to the active site serine of pancreatic lipase (Hadvary et al., The Journal of Biological Chemistry, 1991, 12: 2021-2027) . The primary side effects of orlistat are gastrointestinal related, and include steatorrhea (oily, loose stools with excessive flatus due to unabsorbed fats reaching the large intestine) , fecal incontinence and frequent or urgent bowel movements. Also the absorption of fat-soluble vitamins and other fat-soluble nutrients is inhibited by the use of orlistat. Current research for the treatment of obesity, taking the cost of drug development and adverse side effects into consideration, is exploring anti-obesity studies towards natural compounds to inhibit the activity of lipase, and thus achieve its occurrence lipid-lowering efficacy and reduce side effect caused by the commercial drug orlistat and chronic diseases.

It is still desirable to develop new drugs for treating obesity.

BREIF SUMMARY OF THE INVENTION

It is unexpectedly found in the invention that synthetic antroqiononols are effective in the treatment of obesity.

In one aspect, the invention provides a method for treating obesity in a subject comprising administering the subject with a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of general formula (I) :

wherein X, Y, and Z are the same or different, independently hydrogen, oxygen, sulfur, selenium, or NH, each of R¹, R², R³, and R⁴ are the same or different, independently, hydrogen, alkyl, aryl, or alkoxyl.

In one embodiment of the invention, the compound of general formula (I) is antroquinonol, particularly (+) or (-) -antroquinonol.

In other embodiments of the invention, (+) or (-) -antroquinonol is effective for inhibiting lipase activity.

In another aspect, the invention provides a pharmaceutical composition for treating obesity comprising a therapeutically effective amount of the compound of general formula (I) , together with a pharmaceutically acceptable carrier. Example of the the compound of general formula (I) is antroquinonol, particularly (+) or (-) -antroquinonol.

In one further aspect, the invention provides the use of the compound of general formula (I) for manufacturing a composition or mediciment for treating obesity. Example of the the compound of general formula (I) is antroquinonol, particularly (+) or (-) -antroquinonol.

In one yet aspect, the invention provides a new process for preparation of (+) or (-) -antroquinonol comprising the steps of Suzuki-Miyaura cross coupling, Barton-McCombie reaction, and selenylation/oxidation.

In addition, the invention further provides a process for preparation of (±) -antroquinonol D comprising the steps of chelation and substrate controlled diastereoselective reduction of cyclohexenone and lactonization, Michael addition of dimethyl malonate on cyclohexadienone, dihydroxylation, Wittig olefination, and sesquiterpene side chain through coupling with geranyl phenyl sulfide and Bouveault-Blanc reduction.

In a further yet aspect, the invention provides some new compounds prepared during the processes for preparation of antroquinonol according to the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown.

In the drawings:

Figure 1 shows the potential inhibition activities of Antroquinonol on the lipase activity as compared with commercial drug Orlistat and Simvastatin, including (A) lipase activity, (B) serum lipase, and (C) fecal triglycerides； wherein*means P<0.05, the significant difference in comparison with the controls.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the case of conflict, the present document, including definitions will be controlled.

As used herein, the singular forms “a” , “an” , and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a sample” includes a plurality of such samples and equivalents thereof known to those skilled in the art.

As used herein, the term “subject” refers to a human or a mammal, such as a patient, a companion animal (e.g., dog, cat, and the like) , a farm animal (e.g., cow, sheep, pig, horse, and the like) or a laboratory animal (e.g., rat, mouse, rabbit, and the like) .

Unexpectedly, it is evidenced in the present invention that antroquinonol is effective for treating obesity, as similar to or better than the commonly used drugs for treating obesity, such as Orlistat and Simvastatin. Accordingly, the present invention provides a new method/pharmaceutical composition for treatment of obesity, inhibiting lipase activity and increasing fecal triglycerides in the fat induced mice.

In the invention, the method for treating obesity in a subject comprises administering the subject with a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of general formula (I) :

One example of the compound is antroquinonol, which has a general formula (II) below:

Antroquinonol is a well-known compound only found in the fermentation of A. camphorate (Kuo et al., Novel compounds from antrodia camphorata, US20100130584A1) . In the conventional methods, the purification of antroquinonol from ferments costs highly but gets low recovery. Antroquinonol includes (+) and (-) -antroquinonol. The (+) -antroquinonol has the general formula (III) :

On the other hand, the (-) -antroquinonol has the general formula (IV) , which is first synthesized in the present invention:

In addition, the invention provides a new process for preparation of (+) or (-) -antroquinonol comprising the steps of Suzuki-Miyaura cross coupling, Barton-McCombie reaction, and selenylation/oxidation. In particular, the process comprises the steps of

(1) adding compound 1

into the lithium trimethylsilyl acetylide, and treating with potassium carbonate (K₂CO₃) /methanol (MeOH) to produce compound 2

(2) treating the compound 2 with tert-butyldimethylsilyl chloride (TBSCl) in dichloromethane (DCM, CH₂Cl₂) , and triethyl amine to produce compound 3

(3) transforming the compound 3 to compound 4

by Barton-McCombie deoxygenation with excess phenyl chloro thionoformate and pyridine in DCM, then treating the compound 4 with tributyltin hydride (Bu₃SnH) and azobisisobutyronitrile (AIBN) in cyclopentyl methyl ether by deoxygenative radical cyclization to produce compound 5

(4) treating the compound 5 with pyridinium p-toluenesulfonate (PPTS) in MeOH to afford compound 6

followed by iodination and treatment of methoxymethyl (MOM) ether to give compound 7,

(5) allowing the compound 7

and compound 8

subject to Marshall protocol for a Suzuki-Miyaura cross coupling reaction to give the compound 9

followed by deprotection of tert-butyldimethylsilyl (TBS) ether with tetra-n-butylammonium fluoride (TBAF) and oxidation of the resultant alcohol with Dess-Martin periodinane to give compound 10

(6) treating the compound 10 with Raney nickel, then treating with cerium (III) chloride (CeCl₃) and oxalic acid in acetonitrile, followed by dimethylation with Purdie reagent (Ag₂O, MeI) to produce compound 11

(7) treating the compound 11 with lithium bis (trimethylsilyl) amide (LiHMDS) in tetrahydrofuran (THF) , followed by oxidative elimination with hydrogen peroxide (H₂O₂) to give compound 12

then treating the compound 12 with dry zinc bromide (ZnBr₂) and ethanethiol in DCM to produce (+) or (-) -antroquinonol.

For example, the process for preparation of (+) -antroquinonol comprises the steps as shown in the scheme I below:

In another example, the process comprises the steps of

(1) treating the compound 14

with trimethylsilylacetylene and n-butyl lithium to give compound 15

then treating the compound 15 with ethyl chloroformate in DCM and pyridine to give compound 16

(2) treating the compound 16 with phenyl chlorothionoformate and pyridine in DCM to give compound 17

then treating the compound 17 with Bu₃SnH and AIBN in cyclopentyl methyl ether by deoxygenative radical cyclization to produce compound 18

and compound 19

treating the compound 18 with hydrochloric acid (HCl) in methanol to give compound 20

(3) treating the compound 20 with tosyl chloride and N, N-diisopropylethylamine in DCM followed by iodination with sodium iodide by refluxing in acetone, and treating with MOM ether to give compound 21

(4) conjugating the compound 21 with compound 8 by heating the THF solution with activated zinc at 50℃, then treated with bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (PdCl₂ (Amphos) ₂) and tetramethylethylenediamine (TMEDA) in THF to give the compound 22

followed by treating with K₂CO₃ in MeOH to give the compound 23

(5) treating the compound 23 with Dess-Martin periodinane (DMP) and followed by Raney nickel to give compound 24

then treating the compound 24 with LiHMDS in THF followed by oxidative elimination with H₂O₂ to give compound 12, then treating the compound 12 with ZnBr₂ and ethanethiol in DCM to obtain (+) or (-) -antroquinonol.

For example, the process for preparation of (+) -antroquinonol comprises the steps as shown in the scheme II below:

The invention also provides a new process for preparation of (±) -antroquinonol D comprises the steps of chelation and substrate controlled diastereoselective reduction of cyclohexenone and lactonization, Michael addition of dimethyl malonate on cyclohexadienone, dihydroxylation, Wittig olefination, and sesquiterpene side chain through coupling with geranyl phenyl sulfide and Bouveault-Blanc reduction. In particular, the process comprises the steps of:

(1) reacting 4-methoxy phenol

with methanol to prepare compound 25

adding the compound 25 to dimethyl malonate to give compound 26

then allowing the compound 26 subject to Luche condition followed by lactonization to give compound 27

(2) allowing the compound 27 subject to Krapcho decarboxylation by 1, 4-diazabicyclo [2.2.2] octane (DABCO) in toluene and water to give compound 28

and treating the compound 28 with HCl to give compound 29

(3) treating the compound 29 with sodium borohydride (NaBH₄) and CeCl₃ in MeOH to give compound 30

then treating the compound 30 with MOM ether and dihydroxylation followed by treating with osmium tetroxide (OsO₄) and N-methylmorpholine N-oxide (NMO) in acetone-H₂O to give the compound 31

(4) treating the compound 31 with Purdie’s reagent (methyl iodide, silver oxide) to give compound 32

then reducing the compound 32 to lactol with diisobutylaluminium hydride (DIBAL-H) , and then condensing with triphenylphosphonium ylid (Ph₃PC (Me) CO₂Et) in benzene followed by a treatment with TBS ether to give compound 33

(5) treating the compound 33 by bromination with Appel reaction condition (CBr₄/PPh₃, DCM, 0℃) to give compound 34

and coupling the compound 34 with lithioanion of compound 35

in the presence of TMEDA to give compound 36

then treating the compound 36 with TBAF in THF followed by oxidation of the intermediate alcohol with Dess-Martin periodinane to give compound

(6) treating the compound 37 with lithium diisopropylamide (LDA) or LiHMDS in THF to give compound 38

or compound 39

and followed by treatment with TFA in DCM to give the (±) -antroquinonol D (compound 40)

For example, the process for preparation of (±) -antroquinonol D comprises the steps as shown in the scheme III below:

According to the invention, some new compounds are found in the above described processes for preparation of antroquinonol. The new compounds obtained in the process of the scheme I includes any one selected from the group consisting of:

The new compound obtained in the process of the scheme II is any one selected from the group consisting of:

The new compounds obtained in the process of the scheme III includes any oen selected from the group consisting of:

In addition, the invention provides a new use of the compound of general formula (I) for manufacturing a composition or medicament for treating obesity.

The invention also provides a pharmaceutical composition for treating obesity comprising a therapeutically effective amount of the compound of general formula (I) , together with a pharmaceutically acceptable carrier.

In one example of the pharmaceutical composition according to the invention, the compound of general formula (I) is antroquinonol, particularly (+) or (-) -antroquinonol.

The term “therapeutically effective amount" as used herein refers to an amount of an agent sufficient to achieve the intended purpose for treatment. The therapeutically effective amount of a given agent will vary with factors such as the nature of the agent, the route of administration, the size and species of the animal to receive the agent, and the purpose of the administration. The therapeutically effective amount in each individual case may be determined empirically by a skilled artisan according to the disclosure herein and established methods in the art.

The term “alkyl” as used herein, represents a branched or linear alkyl group having from one to the specified number of carbon atoms. Typically, C₁-C₆ alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like.

As used herein the term “aryl” refers to an optionally substituted mono-or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, benzyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.

The term “alkoxyl” as used herein, represents a branched or linear alkyl group having from one to the specified number of carbon atoms with oxygen. Typically, C₁-C₆ alkoxyl groups include, but are not limited to, methoxyl, ethoxyl, n-propoxyl, iso-propoxyl, butoxyl, iso-butoxyl, sec-butoxyl, tert-butoxyl, pentoxyl, hexoxyl, and the like.

The pharmaceutical composition of the invention may be administered in any route that is appropriate, including but not limited to parenteral or oral administration. The pharmaceutical compositions for parenteral administration include solutions, suspensions, emulsions, and solid injectable compositions that are dissolved or suspended in a solvent immediately before use. The injections may be prepared by dissolving, suspending or emulsifying one or more of the active ingredients in a diluent. Examples of said diluents are distilled water for injection, physiological saline, vegetable oil, alcohol, and a combination thereof. Further, the injections may contain stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives, etc. The injections are sterilized in the final formulation step or prepared by sterile procedure.

According to the invention, the composition may be administered through oral route, wherein the composition may be in a solid or liquid form. The solid compositions include tablets, pills, capsules, dispersible powders, granules, and the like. The oral compositions also include gargles which are to be stuck to oral cavity and sublingual tablets. The capsules include hard capsules and soft capsules. In such solid compositions for oral use, one or more of the active compound (s) may be admixed solely or with diluents, binders, disintegrators, lubricants, stabilizers, solubilizers, and then formulated into a preparation in a conventional manner. When necessary, such preparations may be coated with a coating agent, or they may be coated with two or more coating layers. On the other hand, the liquid compositions for oral administration include pharmaceutically acceptable aqueous solutions, suspensions, emulsions, syrups, elixirs, and the like. In such compositions, one or more of the active compound (s) may be dissolved, suspended or emulsified in a commonly used diluent (such as purified water, ethanol or a mixture thereof, etc.) . Besides such diluents, said compositions may also contain wetting agents, suspending agents, emulsifiers, sweetening agents, flavoring agents, perfumes, preservatives and buffers and the like.

The specific examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent.

Examples

Example 1 Preparation I of antroquinonol from lactol

1.1 Scheme I for (+) -Antroquinonol

The total synthesis of (+) -antroquinonol was performed according to the scheme I below:

The synthesis of antroquinonol commenced with the addition of lithium trimethylsilyl acetylide to the lactol compound (1) , which can be synthesized in single step from D-mannose (Gelas, and Horton, Carbohydr. Res. 1978, 67, 371-387) , with slight modification of the process developed by Lopez (Lopes et al., Eur. J. Org. Chem. 2004, 1830-1840) . The n-BuLi (131.43 mmol, 65.71 mL 2.0 M solution in cyclohexane) was added in the solution of trimethylsilylacetylene (19.70 mL, 138.36 mmol) and 150 mL dry THF at-78℃, and stirred for 5 min. A solution of compound 1 (9 g, 34.59 mmol) was dropping in 30 mL dry THF and the reaction mixture was stirred for 1 h at-78℃, then allowed to reach room temperature, after that stirring was continued for 12 h. The reaction mixture was then concentrated and residue obtained was dissolved in 50 mL MeOH. The K₂CO₃ (4.7 g, 34.6 mmol) was added and stirred for 1 h at room temperature. Methanol was removed, and the residue was diluted with 200 mL Et₂O then it was washed with water. The organic layer was separated, dried and concentrated, and the residue was purified by flash chromatography (hexane/EtOAc, 4:1) to give the diol compound (2) as inseparable mixture of diastereomers (7.5 g, 76％) .

TBSCl (2.10 g, 13.97 mmol) and Et₃N (2.11 g, 20.92 mmol) were added in the solution of compound 2 (4.0 g, 13.97 mmol) in 50 mL CH₂Cl₂, and stirred for 3 h at room temperature. Reaction mixture was washed twice with 50 mL water brine and dried by MgSO₄. CH₂Cl₂ was removed and the residue was purified with flash column chromatography (hexane/EtOAc, 4:1) to give the mono OTBS compound (3) (4.46 g, 78％) .

The pyridine (2.01 mL, 25.03 mmol) and phenyl chlorothionoformate (5.18 mL, 37.52 mmol) were added in the compound 3 (5.0 g, 12.50 mmol) in 50 mL CH₂Cl₂. The mixture was stirred at room temperature for 3 h. The solution was washed with brine and dried by anhydrous MgSO₄. After concentration, the residue was purified by flash chromatography on silica gel (hexane/EtOAc, 4/1) to give thiocarbonate compound (4) (5.23 g, 78％) .

The degassed solution of the compound 4 (5.0 g, 9.33 mmol) in 250 mL CPME at 90℃under argon atmosphere was added in solution of tri-n-butyltin hydride (3.76 mL, 13.99 mmol) and AIBN (153 mg, 0.93 mmol) in 15 mL CPME over 3 h. The reaction mixture was stirring for 6 h, and concentrated under reduced pressure. The deoxygenative radical cyclisation gave rise to the exo-methylene cyclohexane compound (5) , and was purified by flash chromatography (hexane/EtOAc, 19/1) to get separable cis-fused diastereomers major (2.25 g, 63％) , minor diastereomer (1.0 g, 28％) .

A solution of compound 5 (2.25 g, 5.86 mmol) in 20 mL MeOH was treated with pyridinium para-toluenesulfonate (PPTS) (219 mg, 0.48 mmol) , and the solution was stirred for 48 h. The mixture was concentrated, and diluted with 30 mL EtOAc , then washed by saturated aqueous solution of sodium bicarbonate and brine. EtOAc was removed and the residue was purified with flash chromatography (hexane/EtOAc, 3:2) to yield diol compound (6) (1.63 g, 81％) .

TsCl (0.91 g, 4.79 mmol) was added in the solution of compound 6 (1.50 g, 4.35 mmol) with pyridine (0.71 mL, 8.70 mmol) in 20 mL CH₂Cl₂ at 0℃. The reaction mixture was then stirred at room temperature for 10 h. It was washed by 1 M HCl and saturated aqueous solution of sodium bicarbonate. CH₂Cl₂ was removed and the residue was dissolved in 20 mL acetone. NaI (1.17 g, 7.80 mmol) was added in the solution and refluxed for 15 h. Acetone was removed and the residue diluted with ether, then washed by water and dried by MgSO₄, and concentrated to give residue which was used as it is for further steps. The crude residue was dissolved in 20 mL EDC, diisopropylethylamine (1.53 mL, 8.80 mmol) and bromomethyl methyl ether (0.83 g, 6.60 mmol) which added under argon atmosphere at 0℃. After stirring at 70℃for 5 h, the solution was separated with dichloromethane and 0.5 M aqueous hydrochloric acid solution. The organic layer was washed with brine, and dried by MgSO₄. The solvent was evaporated, and the resulting residue was purified with flash column chromatography (hexane/EtOAc, 9:1) to obtained iodo compound (7) (1.65 g, 76％) .

The zirconocene dichloride (6.63 g, 22.69 mmol) in 20 mL CH₂Cl₂ at room temperature under argon atmosphere was dropped in a solution of trimethylaluminum with heptane (2 M in heptane, 12.48 mL, 24.96 mmol) . After 15 min, the solution was cooled to 0℃, and a solution of (E) -6, 10-dimethylundeca-5, 9-dien-1-yne (2.00 g, 11.34 mmol) dissolved in 10 mL CH₂Cl₂ was added to the above solution. The reaction mixture was stirred at 0℃for 6 h and then cooled to-30℃. Iodine (1.80 g, 14.18 mmol) in 15 mL THF was added. The resulting brown slurry was raised to 0℃and poured slowly with stirring into an icecold saturated aqueous NaHCO₃. The aqueous layer was extracted with 100 mL ether (3×) . The combined organic layer was washed with saturated aqueous NaHCO₃ and dried by MgSO₄. Concentration followed by flash chromatography on silica gel with 2:1 hexane/ether as eluent provided the desired product, vinyl iodide compound (8) , as a colorless oil (2.89 g, 80％) .

The 9-MeO-9-BBN (4.81 mL, 1.0 M solution in hexane) was added in the solution of compound 7 (0.60 g, 1.20 mmol) with 10 mL Et₂O, and the mixture was cooled to-78℃. The solution was rapidly added tert-butyllithium (2.48 mL, 1.7 M solution in pentane) . The mixture was stirred for 5 min, then 5.0 mL THF was added and the reaction mixture was warmed to 25℃for 1 h. In a separate flask, added in the solution of compound 8 (0.38 g, 1.20 mmol) with 5 mL DMF, Pd (dppf) Cl₂ (44 mg, 0.6 mmol) , AsPh₃ (55 mg, 0.18 mmol) , CsCO₃ (1.56 g, 4.81 mmol) and water (0.52 mL, 28.8 mmol) . The ethereal mixture of the alkylboronate was cannulated into the DMF solution and stirred overnight. The reaction mixture was then diluted with water and extracted with Et₂O. The organic extracts were washed with brine, worked up as usual and the residue was purified by column chromatography on silica gel (hexane/EtOAc, 19:1) to give coupled compound (9) (1.01 g, 90％) .

The solution of compound 9 (0.60 g, 1.07 mmol) with 10 mL THF was treated with TBAF (2.13 mL, 1 M in THF, 21.4 mmol) at room temperature. The reaction mixture was stirred for 3 h at room temperature and the THF was removed. The residue was diluted with 20 mL ether, and washed with water, brine, and dried by anhydrous MgSO₄. Then, the residue was filtered, and concentrated to afford crude product which was subjected to oxidation. Dess-Martin periodinane (0.67 g, 1.60 mmol) was added in the solution of the above crude product with 10 mL CH₂Cl₂ and the mixture was stirring at room temperature for 2 h. The reaction mixture was diluted with CH₂Cl₂, quenched with a saturated aqueous solution of sodium bicarbonate, and washed with brine. Usual work up and flash column chromatography (hexane/EtOAc, 9:1) afforded keto compound (10) (0.41 g, 87％over two steps) .

Under vigorous stirring, 0.5 mL 50％suspension of Raney Ni in water were added in a 0℃solution of compound 10 (0.3 g, 0.67 mmol) with 10 mL THF. The mixture was stirred at 0℃for 30 min. 20 mL Ether was added and the residue was washed with brine, dried by MgSO₄, and concentrated to give product which was used as it is for further steps. The oxalic acid (4 mg, 0.05 mmol) and CeCl₃·7H₂O (0.75 g, 2.02 mmol) were added in a stirred solution of above crude product with 5 mL acetonitrile at ambient temperature. The mixture was stirred for 3 h at room temperature and was cooled to 0℃. The solid sodium bicarbonate was added to neutralize the pH of the reaction mixture, which was then concentrated in vacuo. The residue was treated with 10 mL EtOAc and filtered through celite. The filtrate was concentrated to get diol compound. The diol compound was dissolved in 5 mL iodomethane, and Ag₂O (0.47 g, 2.02 mmol) was added and stirred for 12 h at reflux. Reaction mixture was diluted with 10 mL CH₂Cl₂ and filtered through celite. The filtrate was then concentrated, and the resulting product was subjected to flash chromatography (hexane/EtOAc, 4:1) to afford keto compound (11) (196 mg, 67％) .

The LiHMDS (1 M solution in THF, 0.43 mL) was dropped in a cold (-78℃) solution of compound 11 (0.19 g, 0.43 mmol) with 5 mL THF. After stirring for 20 mins, the phenylselenenyl bromide (0.10 g, 0.43 mmol) with 1 mL THF was added. The mixture was stirred for 40 mins at–78℃, and then quenched with a saturated ammonium chloride solution. The aqueous layer was extracted with Et₂O. The combined organic phases were washed with brine, dried by MgSO₄ and the solvents were evaporated. The crude product was used as it is for the next step. Above crude product was dissolved in 10 mL THF. The mixture was treated with 3 mL NaHCO₃ and 1 mL hydrogen peroxide (30 wt. ％solution in water) was added in slowly. The reaction mixture was allowed to warm and then stirred for 2 h at room temperature. Reaction was quenched with a Na₂S₂O₃ solution and the aqueous layer was extracted with Et₂O. The combined organic phases were washed with brine, dried by MgSO₄, and the solvents were evaporated. Purification by flash chromatography on silica gel (hexane/EtOAc, 19:1) afforded unsaturated ketone compound (12) (0.11 g, 55％) .

The dry ZnBr₂ (57 mg, 0.25 mmol) and EtSH (36 μL, 0.50 mmol) were added in a stirred solution of compound 12 (0.1 g, 0.23 mmol) with 5 mL dry CH₂Cl₂. After stirring for 1 h at room temperature, the resulting mixture was diluted with 10 mL CH₂Cl₂. 5 mL NaHCO₃ was added in slowly at 0℃and the mixture was filtered through Celite. The aqueous layer was separated and further extracted with 10 mL CH₂Cl₂. The combined organic layer was washed with 3 mL brine, dried by MgSO₄, and concentrated under reduced pressure. The mixture was purified by flash column chromatography on silica gel (hexane/EtOAc, 4/1) to afford antroquinonol (13) (72 mg, 80％) .

1.2 Characterization of the synthesized compounds

In the process for preparing antroquinonol, the following new compounds are found:

the spectral data are given as follows:

R_f (hexane/EtOAc, 3:2) 0.3. IR (film) : 3306, 2118, 1634, 1372, 1222 cm^-1. ¹H-NMR (400 MHz, CDCl₃) : δ 7.34 (m, 5H) , 5.11 (s, 1H) , 4.70 (d, J ＝ 11.72 Hz, 1H) , 4.52 (d, J ＝ 11.72 Hz, 1H) , 4.22 (d, J ＝ 5.64 Hz, 1H) , 4.16 (m, 1H) , 4.12 (m, 1H) , 3.84 (m, 1H) , 3.76 (m, 2H) , 3.63 (m, 1H) , 1.55 (s, 3H) , 1.52 (s, 3H) , 1.43 (s, 3H) , 1.34 (s, 3H) . ¹³C-NMR (100.6 MHz, CDCl₃) : δ 109.70, 108.95, 99.07, 98.53, 82.56, 80.98, 79.93, 78.38, 75.04, 74.34, 74.09, 73.86, 72.05, 71.51, 64.46, 64.32, 62.31, 62.11, 61.00, 60.81, 60.38, 28.28, 28.21, 26.19, 26.18, 25.68, 25.38, 20.82, 19.00, 13.88. HRMS-EI (m/z) [M] ⁺ calcd for C₁₄H₂₂O₆ 286.1416, found 286.1421；

the spectral data are given as follows:

R_f (hexane/EtOAc, 19:1) 0.5. IR (film) : 2930, 2119, 1781, 1591, 1490, 1248 cm^-1. ¹H-NMR (400 MHz, CDCl₃) : δ 7.30 (m, 5H) , 5.56 (m, 1H) , 4.75 (m, 1H) , 4.29 (m, 3H) , 3.93 (m, 2H) , 3.68 (m, 1H) , 2.61 (m, 1H) , 1.55 (s, 3H) , 1.52 (s, 3H) , 1.42 (m, 6H) , 0.92 (m, 9H) , 0.26 (s, 3H) , 0.23 (s, 3H) . ¹³C-NMR (100.6 MHz, CDCl₃) : δ 194.4, 153.3, 129.5, 126.4, 121.7, 110.4, 99.7, 83.3, 79.4, 76.3 75.5, 75.2, 68.5, 61.9, 61.4, 26.1, 26.1, 25.9, 25.7, 22.1, 18.1, -3.2, -4.3. HRMS-EI (m/z) [M] ⁺ calcd for C27H40O₇SSi 536.2264, found 536.2265；

the spectral data are given as follows:

Major R_f (hexane/EtOAc, 15:1) 0.7. [α] _D ²⁵ ＝ +160.0° (c ＝ 1.3 in CHCl₃) . ¹H-NMR (400 MHz, CDCl₃) : δ 5.46 (s, 1H) , 5.10 (s, 1H) , 5.05 (m, 1H) , 4.41 (dd, J ＝ 7.66 Hz, J ＝ 2.78 Hz, 1H) , 4.26 (dd, J ＝ 7.42 Hz, J ＝ 2.32 Hz, 1H) , 4.13 (dd, J ＝ 11.62 Hz, J ＝ 3.58 Hz, 1H) , 4.08 (t, J ＝ 3.04 Hz, 1H) , 3.89 (dd, J ＝ 11.67 Hz, J ＝ 2.32 Hz, 1H) , 2.51 (m, 1H) , 1.43 (s, 3H) , 1.39 (s, 3H) , 1.33 (s, 3H) , 1.32 (s, 3H) , 0.95 (s, 9H) , 0.16 (s, 3H) , 0.13 (s, 3H) . ¹³C-NMR (100.6 MHz, CDCl₃) : δ 144.96, 110.65, 109.11, 98.64, 75.83, 70.57, 67.66, 65.86, 35.04, 29.16, 26.21, 26.08, 23.98, 18.96, 18.73, -4.54, -5.19. HRMS-EI (m/z) [M] ⁺ calcd for C₂₀H₃₆O₅Si 384.2332, found 384.2338；

Minor R_f (hexane/EtOAc, 15:1) 0.8. [α] _D ²⁵ ＝ +68.0° (c ＝ 1.05 in CHCl₃) . ¹H-NMR (400 MHz, CDCl₃) : δ 5.46 (m, 1H) , 5.33 (m, 1H) , 4.49 (m, 1H) , 4.12 (m, 2H) , 4.02 (m, 2H) , 3.89 (dd, J ＝ 7.48 Hz, J ＝ 5.45 Hz, 1H) , 2.18, (m, 1H) , 1.51 (s, 3H) , 1.46 (s, 3H) , 1.36 (s, 3H) , 1.33 (s, 3H) , 0.94 (s, 9H) , 0.12 (s, 3H) , 0.05 (s, 3H) . ¹³C-NMR (100.6 MHz, CDCl₃) : δ 143.11, 110.80, 108.04, 99.02, 82.34, 77.42, 75.96, 69.27, 60.77, 36.41, 29.45, 28.41, 26.24, 25.92, 18.73, 18.32, -4.51, -4.79. HRMS-EI (m/z) [M] ⁺ calcd for C₂₀H₃₆O₅Si 384.2332, found 384.2330；

the spectral data are given as follows:

Major R_f (hexane/EtOAc, 9:1) 0.80. [α] _D ²⁵ ＝ +65.6° (c ＝ 1.4 in CHCl₃) . IR (film) : 2904, 1755, 1658, 1446, 1259, 787 cm^-1. ¹H-NMR (400 MHz, CDCl₃) : δ 5.46 (s, 1H) , 5.11 (s, 1H) , 4.80 (m, 3H) , 4.52 (dd, J ＝ 7.67 Hz, J ＝ 3.54 Hz, 1H) , 4.38 (dd, J ＝ 7.32 Hz, J ＝ 3.20 Hz, 1H) , 4.02 (t, J ＝ 3.40 Hz, 1H) , 3.59 (dd, J ＝ 10.04 Hz, J ＝ 5.60 Hz, 1H) , 3.51 (t, J ＝ 10.73 Hz, 1H) , 3.37 (s, 3H) , 3.05 (m, 1H) , 1.40 (s, 3H) , 1.31 (s, 3H) , 0.92 (s, 9H) , 0.12 (s, 3H) , 0.09 (s, 3H) . ¹³C-NMR (100.6 MHz, CDCl₃) : δ 143.82, 112.71, 109.54, 98.36, 77.06, 75.48, 74.89, 69.84, 55.72, 42.15, 32.92, 26.33, 24.23, 18.55, 7.00, -4.68, -5.10. HRMS-EI (m/z) [M] ⁺ calcd for C₁₉H₃₅IO₅Si 598.1298, found 598.1292；

Minor R_f (hexane/EtOAc, 9:1) 0.80. [α] _D ²⁵ ＝ +61.73° (c ＝ 1.1 in CHCl₃) . IR (film) : 2928, 1654, 1576, 1450, 1170, 1079 cm^-1. ¹H-NMR (400 MHz, CDCl₃) : δ 5.34 (s, 1H) , 4.88 (s, 1H) , 4.73 (m, 2H) , 4.25 (m, 2H) , 4.10 (d, J ＝ 6.34 Hz, 1H) , 3.95 (t, J ＝ 5.96 Hz, 1H) , 3.47 (m, 2H) , 3.44 (s, 3H) , 2.71 (m, 1H) , 1.52 (s, 3H) , 1.38 (s, 3H) , 0.93 (s, 9H) , 0.13 (s, 3H) , 0.07 (s, 3H) . ¹³C-NMR (100.6 MHz, CDCl₃) : δ 144.69, 110.44, 109.12, 97.27, 82.74, 76.78, 75.83, 75.66, 55.97, 45.09, 28.43, 26.43, 25.89, 18.23, 4.10, -4.60, -4.76. HRMS-EI (m/z) [M] ⁺ calcd for C₁₉H₃₅IO₅Si 598.1298, found 598.1294；

the spectral data are given as follows:

Major R_f (hexane/EtOAc, 15:1) 0.60. [α] _D ²⁵ ＝ +25.83° (c ＝ 1.2 in CHCl₃) . IR (film) : 2929, 1645, 1464, 1090, 1035 cm^-1. ¹H-NMR (400 MHz, CDCl₃) : δ 5.35 (s, 1H) , 5.10 (m, 4H) , 4.68 (m, 2H) , 4.37 (d, J ＝ 2.80, 1H) , 3.71 (m, 1H) , 3.37 (s, 3H) , 2.72 (m, 1H) , 2.32 (m, 1H) , 2.19 (m, 1H) , 1.95-2.05 (m, 8H) , 1.68 (s, 3H) , 1.60 (s, 6H) , 1.57 (s, 3H) , 1.46 (s, 3H) , 1.33 (s, 3H) , 0.94 (s, 9H) , 0.14 (s, 3H) , 0.11 (s, 3H) . ¹³C-NMR (100.6 MHz, CDCl₃) : δ 146.03, 136.41, 135.10, 131.25, 124.40, 124.12, 122.34, 110.85, 109.39, 97.24, 81.25, 77.62, 77.48, 76.11, 69.75, 55.55, 41.48, 39.76, 39.68, 29.69, 27.62, 27.02, 26.74, 26.65, 25.98, 25.69, 24.86, 18.58, 17.67, 16.27, 15.99, -4.57, -5.03. HRMS-EI (m/z) [M] ⁺ calcd for C₃₃H₅₈O₅Si 562.4054, found 562.4059；

Minor R_f (hexane/EtOAc, 15:1) 0.30. [α] _D ²⁵ ＝ +25.14° (c ＝ 0.7 in CHCl₃) . IR (film) : 2930, 1640, 1610, 1584, 1471, 1154, 837 cm^-1. ¹H-NMR (400 MHz, CDCl₃) : δ 5.32 (s, 1H) , 5.18 (m, 1H) , 5.10 (m, 2H) , 4.89 (s, 1H) , 4.69 (d, J ＝ 6.68 Hz, 1H) , 4.61 (d, J ＝ 6.68 Hz, 1H) , 4.25 (dd, J ＝ 5.25 Hz, J ＝ 2.78 Hz, 1H) , 4.10 (dt, J ＝6.94 Hz, J ＝ 1.94 Hz, 1H) , 3.99 (t, J ＝ 2.60 Hz, 1H) , 3.94 (dd, J ＝ 6.52 Hz, J ＝ 5.40 Hz, 1H) , 3.36 (s, 3H) , 2.39 (m, 2H) , 2.28 (m, 1H) , 1.97-2.09 (m, 8H) , 1.68 (s, 3H) , 1.64 (s, 3H) , 1.60 (s, 6H) , 1.53 (s, 3H) , 1.38 (s, 3H) , 0.93 (s, 9H) , 0.13 (s, 3H) , 0.06 (s, 3H) . ¹³C-NMR (100.6 MHz, CDCl₃) : δ 146.25, 136.41, 135.07, 131.22, 124.39, 124.08, 122.37, 112.17 108.87, 97.22, 83.21, 76.88, 76.41, 76.38, 55.75, 41.49, 39.75, 39.68, 28.46, 26.73, 26.60, 26.45, 25.91, 25.80, 25.68, 18.27, 17.67, 16.32, 15.98, -4.50, -4.84. HRMS-EI (m/z) [M] ⁺ calcd for C₃₃H₅₈O₅Si 562.4054, found 562.4057；

the spectral data are given as follows:

R_f (hexane/EtOAc, 4:1) 0.40. [α] _D ²⁵ ＝ IR (film) : 2928, 1736, 1455, 1375, 1259, 1095, 919 cm^-1. ¹H-NMR (400 MHz, CDCl₃) : δ 6.62 (s, 1H) , 5.45 (s, 1H) , 5.16 (m, 1H) , 5.09 (m, 2H) , 4.69 (d, J ＝ 6.68 Hz, 1H) , 4.67 (dd, J ＝ 7.45 Hz, J ＝ 4.16 Hz, 1H) , 4.63 (d, J ＝ 6.68 Hz, 1H) , 4.46 (d, J ＝ 7.68 Hz, 1H) , 3.86 (dd, J ＝ 3.72 Hz, J ＝ 1.98 Hz, 1H) , 3.34 (s, 3H) , 2.99 (m, 1H) , 2.35 (m, 2H) , 1.97-2.08 (m, 8H) , 1.68 (s, 3H) , 1.61 (s, 3H) , 1.60 (s, 6H) , 1.49 (s, 3H) , 1.38 (s, 3H) . ¹³C-NMR (100.6 MHz, CDCl₃) : δ 143.57, 137.66, 135.23, 131.27, 124.31, 123.89, 121.42, 110.95, 96.97, 77.02, 76.70, 76.26, 55.80, 40.01, 39.70, 39.67, 29.67, 27.09, 26.71, 26.51, 26.48, 25.68, 17.66, 16.26, 16.00. HRMS-EI (m/z) [M] ⁺ calcd for C₂₇H₄₂O₅ 446.3032, found 446.3038；

the spectral data are given as follows:

R_f (hexane/EtOAc, 7:3) 0.50. [α] _D ²⁵ ＝ -67.7° (c ＝ 1.3 in CHCl₃) . IR (film) : 2927, 1726, 1655, 1457, 1119, 1031, 919 cm^-1. ¹H-NMR (400 MHz, CDCl₃) : δ 5.09 (m, 3H) , 4.74 (d, J ＝ 6.76 Hz, 1H) , 4.69 (d, J ＝ 6.76 Hz, 1H) , 4.25 (d, J ＝ 2.84 Hz, 1H) , 4.10 (t, J ＝ 3.72 Hz, 1H) , 3.87 (t, J ＝ 3.28 Hz, 1H) , 3.48 (s, 3H) , 3.44 (s, 3H) , 3.41 (s, 3H) , 2.46 (m, 1H) , 2.19 (m, 2H) , 1.96-2.09 (m, 8 H) , 1.91 (m, 1H) , 1.36 (s, 3H) , 1.33 (s, 3H) , 1.32 (s, 6H) , 1.07 (d, J ＝ 6.52 Hz, 3H) ； ¹³C-NMR (100.6 MHz, CDCl₃) : δ 207.86, 136.84, 135.23, 131.28, 124.29, 123.96, 122.09, 98.30, 83.97, 83.04, 76.27, 59.00, 58.53, 56.09, 44.47, 44.03, 39.75, 39.71, 27.26, 26.74, 26.58, 25.66, 17.65, 16.21, 15.98, 11.09； HRMS-EI (m/z) [M] ⁺ calcd for C₂₆H₄₄O₅ 436.3189 found 436.3181.

Example 2 Preparation II of antroquinonol from lactol

2.1 Scheme II for (+) -Antroquinonol

The total synthesis of (+) -antroquinonol was performed according to the scheme II below:

To a solution of benzylacetal (6.0 g, 17.75 mmol) in MeOH (50 mL) was added triethyl amine (0.5 mL) , Pd/C (10 ％, 0.5 g) and was stirred under a hydrogen atmosphere at room temperature for 24 h. The catalyst was filtered off, the solvent evaporated under reduced pressure, to give the mixture of anomeric alcohols (14) in quantitative yield.

n-BuLi (61.22 mmol, 30.61 mL 2.0 M solution in cyclohexane) was added in the solution of trimethylsilylacetylene (9.17 mL, 64.45 mmol) with 100 mL dry THF at-78℃and stirred for 5 min. The solution of lactol 14 (4 g, 16.11 mmol) with 30 mL dry THF was dropped in the reaction mixture, and the reaction mixture was stirred at-78℃for 1 h, then allowed to reach room temperature after stirring for 12 h. The reaction mixture was concentrated and the residue was dissolved in 50 mL MeOH. The K₂CO₃ (4.7 g, 34.6 mmol) was added in the mixture and stirred for 1 h at room temperature. Methanol was removed and the residue was diluted with 100 mL Et₂O, and it was washed with water. The organic layer was separated, dried by MgSO₄ and concentrated. The residue was purified by flash chromatography (hexane/EtOAc, 4:1) to give the diol compound (15) as inseparable mixture of diastereomers (3.57 g, 81％) .

Pyridine (2.05 mL, 25.52 mmol) and ethyl chloroformate (1.33 mL, 14.04 mmol) were added in the solution of compound 15 (3.5 g, 12.76 mmol) with 50 mL dry CH₂Cl₂ under argon at-20℃. The solution was stirred at-20℃for 1 h, and the temperature was increased to 0℃and stirred for 1 h. The mixture was diluted with CH₂Cl₂ and washed by 10％HCl, aqueous sodium hydrogen carbonate, water and brine. The organic layer was dried by MgSO₄ and concentrated, giving a residue that was purified by flash chromatography (hexane/EtOAc, 4:1) to give the carbonates compound (16) (3.71 g, 84％) as the mixture of two diastereomers at C-1) .

The pyridine (1.63 mL, 20.21 mmol) and phenyl chlorothionoformate (2.79 mL, 20.21 mmol) were added in the solution of compound 16 (3.50 g, 10.10 mmol) with 40 mL CH₂Cl₂. The mixture was stirred at room temperature for 3 h. The solution was washed with brine and dried by anhydrous MgSO₄. After concentration, the residue was purified by flash chromatography on silica gel (hexane/EtOAc, 4/1) to give thiocarbonate compound (17) (3.94 g, 81％) .

The degassed solution of the compound 17 (3.5 g, 6.53 mmol) with CPME (150 mL) at 90℃under argon atmosphere was added in the solution of tri-n-butyltin hydride (2.63 mL, 13.99 mmol) and AIBN (107 mg, 0.65 mmol) with 15 mL CPME, and stirred at least 3 h. After stirring for 12 h, and the reaction mixture was concentrated under reduced pressure. Resultant residue was purified by flash chromatography (hexane/EtOAc, 19/1) to get separable cis-fused diastereomers major compound (18) (1.46 g, 61％) and minor diastereomer along with transfused product (0,53 g) .

A solution of compound 18 (1.20 g, 2.49 mmol) with 15 mL MeOH was treated with 2 mL 1 M HCl, and the solution was stirred for 3 h. The mixture was concentrated, diluted with EtOAc (30 mL) , and washed by saturated aqueous solution of sodium bicarbonate and brine. EtOAc was removed under reduced pressure and residue obtained was purified with flash chromatography (hexane/EtOAc, 1:1) to yield diol compound (20) (0.97 g, 92％) .

The TsCl (0.69 g, 3.60 mmol) was added in a solution of compound 20 (0.95 g, 3.28 mmol) and N, N-diisopropylethylamine (0.86 mL, 4.91 mmol) with 10 mL CH₂Cl₂ at 0℃. The reaction mixture was stirred at room temperature for 12 h. It was washed by 1 M HCl and saturated aqueous solution of sodium bicarbonate. CH₂Cl₂ was removed and the residue was dissolved in 15 mL acetone. NaI (1.23 g, 8.18 mmol) was added and the solution was refluxed for 15 h. Acetone was removed, and the residue was diluted with ether, washed with water, dried by MgSO₄ and concentrated to give crude product which was purified with column chromatography to give ethyl (3R, 4R, 5S, 6S) -4-hydroxy-3- (iodomethyl) -5, 6-dimethoxy-2-methylenecyclohexyl carbonate (1.12 g, 86％) . The above compound (1.1 g, 2.75 mmol) was dissolved in 20 mL EDC, and diisopropylethylamine (0.958 mL, 5.50 mmol) and bromomethyl methyl ether (0.27 mL, 3.30 mmol) were added under argon atmosphere at 0℃. After stirring at 70℃for 5 h, the solution was separated with dichloromethane and 0.5 M aqueous hydrochloric acid solution. The organic layer was washed by brine, and dried by MgSO₄. The solvent was evaporated, and the resulting residue was purified with flash column chromatography (hexane/EtOAc, 4:1) to afford iodo compound (21) (1.13 g, 93％) .

The activated zinc (44 mg, 0.68 mmol) was added in the solution of compound 21 (0.2 g, 0.45 mmol) with 2 mL THF and stirred at 50℃for 8 h. The vinyl iodo compound (8) (0.286 g, 0.90 mmol) and TMEDA (0.074 mL, 0.49 mmol) were added in the solution of PdCl₂ (Amphos) ₂ (6 mg) with 2 mL THF. Then the above prepared zinc iodide solution was dropped in the resulting solutionm, and was stirred for 24 h at room temperature. The reaction mixture was quenched with saturated NH₄Cl solution and the product was extracted with EtOAc. The organic layer was washed by water and brine, then dried by MgSO₄. The solvent was evaporated, and the resulting residue was purified with flash column chromatography (hexane/EtOAc, 9:1) to afford coupled compound (22) (0.118 g, 52％) .

A solution of compound 22 (0.23 g, 0.42 mmol) with 10 mL THF was treated by TBAF (0.6 mL, 1 M in THF, 0.60 mmol) at 50℃for 5 h. After completion of deprotection THF was removed and the residue obtained was diluted with 20 mL ether, washed by water and brine, dried by anhydrous MgSO₄, then filtered and concentrated to afford crude product which was purified with column chromatography (hexane/EtOAc, 4:1) to afford alcohol compound (23) (0.167 g, 92％) .

Dess-Martin periodinane (0.19 g, 0.45 mmol) was added in the solution of compound 23 (0.15 g, 0.34 mmol) with 10 mL CH₂Cl₂ and stirring at room temperature for 2 h. The reaction mixture was diluted with CH₂Cl₂, quenched with a saturated aqueous solution of sodium bicarbonate, and was stirred for 2 h at room temperature. Organic layer was separated, washed by water and brine and dried by MgSO₄. It was filtered and concentrated to give residue which was purified with flash column chromatography (hexane/EtOAc, 9:1) afforded vinyl keto compound (0.134 g, 90％) . Under vigorous stirring, 0.3 mL 50％suspension of Raney Ni in water were added to a cold (0℃) solution of above keto compound (0.12 g, 0.28 mmol) in 5 mL THF. The mixture was stirred for at 0℃30 min. 20 mL Ether was added and was washed with brine, dried by MgSO₄, and concentrated to give crude product which was purified with flash column chromatography (hexane/EtOAc, 9:1) afforded cyclohexanone compound (24) as thick oil (84 mg, 70％) .

The LiHMDS (1 M solution in THF, 0.20 mL, 0.20 mmol) was dropped in a cold (-78℃) solution of compound 24 (80 mg, 0.18 mmol) with 5 mL THF. After stirring for 20 min, the solution of phenylselenenyl bromide (43 mg, 0.18 mmol) with 1 mL THF was added. The mixture was stirred at-78℃for 1 h and quenched with a saturated ammonium chloride solution. The aqueous layer was extracted with Et₂O. The combined organic phases were washed by brine, dried by MgSO₄ and the solvents were evaporated. The crude product was used as it is for the next step. Above crude product was dissolved in 5 mL THF. The mixture was treated with 3 mL NaHCO₃ and 1 mL of hydrogen peroxide (30 wt. ％solution in water) was added in slowly. The reaction mixture was allowed to warm and stirred for 2 h at room temperature. Reaction was quenched with a Na₂S₂O₃ solution and the aqueous layer was extracted with Et₂O, and the combined organic phases were washed with brine, dried by MgSO₄ and the solvents were evaporated. Purification by flash chromatography on silica gel (hexane/EtOAc, 19:1) afforded unsaturated ketone compound (12) (37 mg, 47％) .

To a stirred solution of MOM ether 12 (30 mg, 0.07 mmol) in dry CH₂Cl₂ (3 mL) were added dry ZnBr₂ (16 mg, 0.07 mmol) and EtSH (36 μL, 0.50 mmol) . After stirring for 1 h at room temperature, the resulting mixture was diluted with CH₂Cl₂ (10 mL) . Sat. NaHCO₃ (5 mL) was added slowly at 0℃and the mixture was filtered through Celite. The aqueous layer was separated and further extracted with CH₂Cl₂ (10 mL) . The combined organic layer was washed with brine (3 mL) , dried over MgSO₄, and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography on silica gel (hexane/EtOAc, 4/1) to afford antroquinonol (13) (72 mg, 80％) .

2.2 Characterization of the synthsized compounds

the spectral data are given as follows:

R_f (hexane/ethyl acetate 3:2) 0.35. [α] _D ²⁵ ＝ +8.1° (c ＝ 1.15 in CHCl₃) . IR (film) : 3437, 2115, 1704, 1610, 1510, 1034, 811 cm^-1. ¹H-NMR (400 MHz, CDCl₃) : δ 4.56 (m, 1H) , 3.85 (m, 3H) , 3.61 (m, 8H) , 3.30 (d, J ＝ 8.16 Hz, 1H) , 2.53 (m, 2H) , 1.77 (brs, 1H) , 1.46 (s, 3H) , 1.38 (s, 3H) . ¹³C-NMR (100.6 MHz, CDCl₃) : δ 99.10, 83.11, 82.89, 82.27 81.57, 81.21, 80.49, 74.55, 73.74, 72.61, 64.65, 64.18, 63.74, 62.20, 62.06, 61.00, 60.94, 60.40, 60.34, 59.55, 28.27, 28.13, 19.42, 19.28. HRMS-EI (m/z) [M+Na] ⁺ calcd for C₁₃H₂₂O₆Na 297.1314, found 297.1323；

the spectral data are given as follows:

R_f (hexane/ethyl acetate 4:1) 0.7. [α] _D ²⁵ ＝ -11.1° (c ＝ 1.5 in CHCl₃) . IR (film) : 3289, 2987, 2125, 1754, 1748, 1590, 1259, 1095 cm^-1. ¹H-NMR (400 MHz, CDCl₃) : δ 7.38 (m, 2H) , 7.27 (m, 1H) , 7.05 (m, 2H) , 5.58 (m, 1H) , 5.41 (m, 1H) , 4.17 (m, 1H) , 3.88 (m, 1H) , 3.60 (m, 7H) , 2.61 (m, 1H) , 1.49 (s, 3H) , 1.48 (s, 3H) , 1.39 (m, 3H) . ¹³C-NMR (100.6 MHz, CDCl₃) : δ 193.84, 193.76, 154.04, 153.88, 153.11, 153.09, 129.41, 126.52, 121.62, 121.56, 100.20, 100.15, 81.93, 81.44, 79.62, 79.27, 77.94, 77.44, 76.86, 76.14, 75.91, 69.53, 69.15, 67.71, 67.50, 64.47, 61.32, 61.12, 61.06, 61.01, 60.74, 26.07, 25.90, 21.24, 20.79, 14.04, 14.00. HRMS-EI (m/z) [M] ⁺ calcd for C₂₃H₃₀O₉S 482.1611, found 482.1627；

the spectral data are given as follows:

R_f (hexane/ethyl acetate 4:1) 0.35. [α] _D ²⁵ ＝ +42.4° (c ＝ 1.5 in CHCl₃) . IR (film) : 2924, 1750, 1604, 1459, 1372, 1259 cm^-1. ¹H-NMR (400 MHz, CDCl₃) : δ 5.66 (m, 1H) , 5.28 (s, 1H) , 5.12 (s, 1H) , 4.22 (q, J ＝ 7.02 Hz, 2H) , 4.19 (t, J ＝ 4.72 Hz, 1H) , 4.05 (dd, J ＝ 11.84 Hz, J ＝ 4.96 Hz, 1H) , 3.87 (dd, J ＝ 11.84 Hz, J ＝ 4.40 Hz, 1H) , 3.48 (s, 3H) , 3.44 (s, 3H) , 3.38 (t, J ＝ 4.08 Hz, 1H) , 3.32 (dd, J ＝ 7.82 Hz, J ＝ 4.00 Hz, 1H) , 2.60 (m, 1H) , 1.44 (s, 3H) , 1.40 (s, 3H) , 1.32 (t, J ＝ 7.25 Hz, 3H) . ¹³C-NMR (100.6 MHz, CDCl₃) : δ 154.56, 141.39, 112.84, 99.00, 83.19, 82.88, 78.38, 69.43, 64.10, 62.76, 58.51, 58.04, 36.34, 28.17, 20.37, 14.22. HRMS-EI (m/z) [M] ⁺ calcd for C₁₆H₂₆O₇ 330.1679, found 330.1686；

the spectral data are given as follows:

R_f (hexane/ethyl acetate 4:1) 0.50. [α] _D ²⁵ ＝ +20.3° (c ＝ 1.25 in CHCl₃) . IR (film) : 2933, 1752, 1655, 1374, 1153, 1034, 917 cm^-1. ¹H-NMR (400 MHz, CDCl₃) : δ 5.21 (s, 1H) , 5.13 (d, J ＝ 9.36 Hz, 1H) , 5.04 (s, 1H) , 4.74 (d, J ＝ 6.76 Hz, 1H) , 4.69 (d, J ＝ 6.76 Hz, 1H) , 4.24 (m, 2H) , 3.67 (dd, J ＝ 9.80 Hz, J ＝ 3.80 Hz, 1H) , 3.56 (dd, J ＝ 9.20 Hz, J ＝ 5.60 Hz, 1H) , 3.56 (s, 3H) , 3.54 (s, 3H) , 3.40 (s, 3H) , 3.34 (t, J ＝ 9.80 Hz, 1H) , 3.05 (m, 3H) , 1.32 (t, J ＝ 7.12 Hz, 3H) . ¹³C-NMR (100.6 MHz, CDCl₃) : δ 154.29, 138.98, 114.15, 96.78, 84.85, 82.56, 78.16, 75.85, 64.28, 60.73, 60.69, 55.73, 49.70, 14.18, 3.11. HRMS-EI (m/z) [M] ⁺ calcd for C₁₅H₂₅IO₇ 444.0645, found 444.0641；

the spectral data are given as follows:

R_f (hexane/ethyl acetate 7:1) 0.6. [α] _D ²⁵ ＝ +3.75° (c ＝ 0.8 in CHCl₃) . IR (film) : 2897, 2856, 1742, 1635, 1471, 1253, 1154, 1036, 837 cm^-1. ¹H-NMR (400 MHz, CDCl₃) : δ 5.22 (d, J ＝ 10.36 Hz, 1H) , 5.08 (m, 4H) , 4.90 (s, 1H) , 4.74 (d, J ＝ 6.56 Hz, 1H) , 4.71 (d, J ＝ 6.56 Hz, 1H) , 4.24 (m, 2H) , 3.61 (s, 3H) , 3.57 (s, 3H) , 3.53 (dd, J ＝ 8.82 Hz, J ＝ 4.60 Hz, 1H) , 3.44 (m, 1H) , 3.41 (s, 3H) , 3.04 (t, J ＝ 9.21 Hz, 1H) , 2.61 (m, 1H) , 2.49 (m, 1H) , 2.03 (m, 8H) , 1.67 (s, 3H) , 1.61 (s, 3H) , 1.59 (s, 3H) , 1.58 (s, 3H) , 1.33 (t, J ＝ 7.08, 3H) . ¹³C-NMR (100.6 MHz, CDCl₃) : δ 154.48, 140.72, 136.60, 134.84, 131.21, 124.36, 124.19, 121.46, 111.30, 96.28, 85.41, 83.49, 78.70, 76.76, 64.15, 60.95, 60.86, 55.54, 47.12, 39.77, 39.70, 26.77, 26.66, 25.65, 24.91, 17.64, 16.17, 15.92, 14.23 HRMS-EI (m/z) [M] ⁺ calcd for C₂₉H₄₈O₇ 508.3400, found 508.3410；

the spectral data are given as follows:

R_f (hexane/ethyl acetate 4:1) 0.45. [α] _D ²⁵ ＝ +4.5° (c ＝ 1.0 in CHCl₃) . IR (film) : 2925, 1734, 1456, 1377, 1260, 1041, 919, 803.¹H-NMR (400 MHz, CDCl₃) : δ 5.10 (m, 3H) , 4.70 (d, J ＝ 6.78 Hz, 1H) , 4.60 (d, J ＝ 6.78 Hz, 1H) , 3.87 (d, J ＝ 5.78 Hz, 1H) , 3.82 (dd, J ＝ 3.87 Hz, J ＝ 2.00 Hz, 1H) , 3.50 (d, J ＝ 5.70 Hz, J ＝ 3.87 Hz, 1H) , 3.49 (s, 3H) , 3.48 (s, 3H) , 3.36 (s, 3H) , 2.41 (m, 1H) , 2.49 (m, 1H) , 2.21 (m, 1H) , 2.03 (m, 10H) , 1.68 (s, 3H) , 1.60 (s, 9H) , 1.19 (d, J ＝ 7.38 Hz, 3H) . ¹³C-NMR (100.6 MHz, CDCl₃) : δ 210.77, 137.50, 135.19, 131.30, 124.35, 124.00, 121.80, 96.59, 84.78, 84.69, 75.30, 58.88, 58.45, 55.79, 44.98, 43.15, 39.82, 39.73, 27.59, 26.77, 26.65, 25.69, 17.68, 16.42, 16.21, 15.99. HRMS-EI (m/z) [M] ⁺ calcd for C₂₆H₄₄O₅ 436.3189, found 436.3181.

Example 3 Preparation of (±) -antroquinonol D from 4-methoxyphenol

3.1 Scheme III for (±) -antroquinonol D

The total synthesis of (±) -antroquinonol D was performed according to the scheme III below:

The Diacetoxyiodobenzene (25.95 g, 80.55 mmol) was dissolved in 150 mL CH₂Cl₂ and cooled to 0℃. 4-methoxyphenol (10.00 g, 80.55 mmol) with 80 mL MeOH was added slowly and allowed to reach room temperature, then stirred for 2 h. After completion of reaction, 50 mL saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with CH₂Cl₂. The combined organic phase was dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and distilled under high vacuum to remove iodobenzene. The resulting crude product (25) was dissolved in THF (80 mL) , and DBU (12.02 mL, 80.55 mmol) and dimethyl malonate (9.25 mL, 80.55 mmol) were added and stirred for 24 h at room temperature. Reaction mixture was concentrated and residue was purified with column chromatography on Silica gel (Hexane/EtOAc, 9:1) to give compound 26 (dimethyl 2- (2, 2-dimethoxy-5-oxocyclohex-3-enyl) malonate) (18.90 g, 66.52 mmol) , 2-step yield 82.6％.

The NaBH₄ (0.09 g, 2.38 mmol) was added in a stirred solution of compound 26 (0.67 g, 2.35 mmol) and CeCl₃·7H₂O (0.88 g, 2.35 mmol) in 20 mL MeOH at 0℃. After completion of reaction, saturated aqueous 5 mL NaHCO₃ solution was added. Methanol was removed and the residue was diluted with water and extracted with 10 mL CH₂Cl₂ (2×) . The combined organic phase was dried by anhydrous sodium sulfate, then filtered and concentrated. The resulting crude product was dissolved in 5 mL DMF, and NaH (0.40 g, 8.3 mmol) was added and stirred at 70℃for 1 h. After completion of the reaction, it was cooled, and quenched with saturated NH₄Cl solution , and extracted with 10 mL CH₂Cl₂ (2×) , the organic phase was dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product. The residue obtained was purified by column chromatography on Silica gel (Hexane/EtOAc, 7:3) to give the compound (27) (Methyl-6, 6-dimethoxy-3-oxo-2-oxa-bicyclo [3.3.1] non-7-ene-4-carboxylate) (0.60 g, 2.34 mmol) , 2-step yield of 98.9％.

DABCO (3.10 g, 27.60 mmol) and H₂O (0.10 mL) were added in a solution of compound 27 (1.76 g, 6.90 mmol) with 50 mL toluene, then was heated at reflux for 24 h. Reaction mixture (28) was cooled and acidified with 1 N HCl and stirred for 30 min. Reaction mixture was diluted with water, organic layer was separatedand, aqueous layer was extracted with EtOAc, the combined organic phase was dried by anhydrous sodium sulfate, filtered and concentrated. The residue was purified with column chromatography on Silica gel (Hexane/EtOAc, 4:1) to give the compound 29 (2-oxa-bicyclo [3.3.1] non-7-ene-3, 6-dione) (0.68 g, 4.44 mmol) , yield 64.3％.

The NaBH₄ (5.80 mg, 0.15 mmol) was added in a solution of compound 29 (0.023 g, 0.15 mmol) and CeCl₃·7H₂O (0.06 g, 0.15 mmol) with 5 mL MeOH at-20℃and stirred for 10 min. Reaction mixture was quenched with saturated aqueous NH₄Cl solution and extracted with 5 mL EtOAc (2×) . The organic phase was dried by anhydrous magnesium sulfate, filtered and concentrated, and the crude product was purified with column chromatography on Silica gel (Hexane/EtOAc, 4:1) to give endo alcohol compound (30) (6-hydroxy-2-oxa-bicyclo [3.3.1] non-7-en-3-one) (0.022 g, 0.14 mmol) , yield 93.7％.

DIPEA (2 mL, 11.48 mmol) and MOMBr (1.07 g, 8.61 mmol) were added in a solution of compound 30 (0.884 g, 5.74 mmol) with 10 mL EDC, and heated to 70℃for 2 h. Reaction mixture was cooled, diluted with 10 mL CH₂Cl₂ and washed with 1 N HCl followed by saturated aqueous NaHCO₃ solution. The organic phase was dried by anhydrous magnesium sulfate, filtered and concentrated. The residue was purified with column chromatography on Silica gel (Hexane/EtOAc, 7:3) to give the 6- (methoxymethoxy) -2-oxa-bicyclo [3.3.1] non-7-en-3-one (0.99 g, 5.00 mmol) , yield 86.6％.

The OsO₄ (0.12 g, 0.49 mmol) and NMO (0.58 g, 5.00 mmol) were added in the solution of 6- (methoxymethoxy) -2-oxa-bicyclo [3.3.1] non-7-en-3-one (0.99 g, 4.98 mmol) with acetone/H₂O (33 mL, 10:1) at room temperature and stirred for 24 h. Reaction mixture was quenched with 10％Na₂S₂O₃·5H₂O, stirred for 30 min, and then extracted with 10 mL EtOAc (3×) . The combined organic phase was dried by anhydrous magnesium sulfate, filtered and concentrated. Crude product was then purified with column chromatography on Silica gel (MeOH /EtOAc, 1:9) to give the diol compound 31 (7, 8-dihydroxy-6- (methoxymethoxy) -2-oxa-bicyclo [3.3.1] nonan-3-one) (1.09 g, 4.72 mmol, dr>15:1) , yield 94.8％.

The Ag₂O (1.5 g, 6.45 mmol) was added in the solution of compound 31 (0.5 g, 2.15 mmol) with 5 mL MeI in seal tube. Reaction mixture was stirred for 48 h at 70℃then it was cooled and filtered through celite, washed with EtOAc, and concentrated under reduced pressure. The crude product was then purified with column chromatography on Silica gel (Hexane/EtOAc, 7:3) to give compound 32 (7, 8-dimethoxy-6- (methoxymethoxy) -2-oxa-bicyclo [3.3.1] nonan-3-one) (437 mg, 1.68 mmol) , yield 77.8％.

Compound 32 (0.35 g, 1.35 mmol) was dissolved in 5 mL CH₂Cl₂ and cooled to-78℃under argon atmosphere. DIBAL-H (1.1 M solution in cyclohexane) (1.35 mL, 1.48 mmol) was added and stirred at-78℃for 1 h. Reaction was quenched with MeOH and warmed to room temperature. 5 mL 1 M Sodium potassium tartrate solution was added and stirred for 2 h. The mixture was extracted with 10 mL CH₂Cl₂ (3×) , and the combined organic phase was dried by anhydrous magnesium sulfate, then filtered and concentrated. The resulting crude product was then dissolved in 10 mL benzene, ylide Ph₃PCH (CH₃) COOEt was added at 80℃and then stirred heating at reflux for 6 h. After the reaction, the solvent was concentrated under reduced pressure and crude product was purified with column chromatography on silica gel (Hexane/EtOAc, 4:1) to give the (E) -ethyl 4- (5-hydroxy-3, 4-dimethoxy-2-(methoxymethoxy) cyclohexyl) -2-methylbut-2-enoate (400 mg, 1.16 mmol) , yield 86％.

TBSCl (0.225 g, 1.50 mmol) , imidazole (0.157 g, 2.31 mmol) and DMAP (1.7 mg, 0.01 mmol) were added in the solution of (E) -ethyl 4- (5- (tert-butyldimethylsilyloxy) -3, 4-dimethoxy-2- (methoxymethoxy) cyclohexyl) -2-methylbut-2-e noate (0.40 g, 1.16 mmol) with 5 mL DMF. Reaction mixture was stirred for 24 h at room temperature, and then quenched with saturated aqueous NaHCO₃, and extracted with ether (3×, 10 mL) , the combined organic phase was dried by anhydrous sodium sulfate, filtered and concentrated. The crude product was purified with column chromatography on Silica gel (Hexane/EtOAc, 9:1) to give compound 33 ( (E) -ethyl 4- (5- (tert-butyldimethylsilyloxy) -3, 4-dimethoxy-2- (methoxymethoxy) cyclohexyl) -2-met hylbut-2-enoate) (0.51 g, 1.11 mmol) , yield of 96％.

DIBAL-H (2.15 mL, 2.37 mmol) was added in the solution of compound 33 (436 mg, 0.95 mmol) with 10 mL CH₂Cl₂ at-78℃. After completion of the reaction, MeOH was added to terminate the reaction, and 5 mL 1.2 M sodium potassium tartrate was added and allowed to reach room temperature. The mixture was extracted with 10 mL CH₂Cl₂ (2×) , and the combined organic phase was dried by anhydrous sodium sulfate and concentrated, then it was purified by column chromatography on Silica gel (Hexane/EtOAc, 4:1) to give alcohol compound (346 mg, 0.83 mmol) , yield 87.3％.

PPh₃ (0.240 g, 0.90 mmol) and CBr₄ (0.30 g, 0.90 mmol) were added in the solution of above alcohol compound (346 mg, 0.83 mmol) with 8 mL CH₂Cl₂ at 0℃and stirred for 10 min. The mixture was quenched with saturated aqueous NaHCO₃ solution and organic layer was separated. The solvent was concentrated under reduced pressure and then purified by column chromatography on Silica gel (Hexane/EtOAc, 9:1) to give bromo compound 34 ( (E) - (5- (4-bromo-3-methylbut-2-enyl) -2, 3-dimethoxy-4- (methoxymethoxy) cyclohexyloxy) (tert-butyl) dimethylsilane) (381 mg, 0.80 mmol) , yield 96％.

n-BuLi (0.06 mL, 0.13 mmol) was added in the solution of compound 35 (28.0 mg, 0.12 mmol) with 5 mL THF at-78℃, and stirred for 1 h at the same temperature. Then compound 34 (41.8 mg , 0.09 mmol) with 1 mL THF was added and stirred for 1 h. The mixture was quenched with saturated aqueous NH₄Cl solution and allowed to reach room temperature. The mixture was extracted with 10 mL ether (2×) , and the organic phase was dried by anhydrous magnesium sulfate, then filtered and concentrated. The residue was used for next step. Li (0.7 mg, 1 mmol) was added in the liquid NH₃ at-78℃, which gives dark blue color to the solution. Then above coupled product with 2 mL ether was added and stirred for 30 min at-60℃. The mixture was quenched with MeOH and slowly warmed to room temperature during which ammonia evaporates. The mixture was diluted with saturated NH₄Cl solution and extracted with 10 mL ether (2×) , and the organic phase was dried by anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by chromatography on Silica gel (Hexane/EtOAc, 15:1) to give the compound 36 (tert-butyl (2, 3-dimethoxy-4- (methoxymethoxy) -5- ( (2E, 6E) -3, 7, 11-trimethyldodeca-2, 6, 1 0-trienyl) cyclohexyloxy) dimethylsilane) (41.2 mg, 0.08 mmol) , yield 84.4％.

TBAF (0.15 mL, 0.15 mmol) was added in the solution of compound 36 (41.2 mg, 0.077 mmol) with 3 mL THF and was stirred for 24 h at reflux. After the reaction, the solvent was concentrated under reduced pressure, and then purified by column chromatography on Silica gel (Hexane/EtOAc, 3:2) to give alcohol compound.

Dess-Martin periodinane (0.045 g, 0.10 mmol) was added in the solution of the above alcohol compound with 5 mL CH₂Cl₂ and stirring continued at room temperature for 2 h. The reaction mixture was then diluted with CH₂Cl₂, quenched with a saturated aqueous solution of sodium bicarbonate and washed by brine. Usual work up and flash column chromatography (hexane/EtOAc, 9:1) afforded keto compound (37) (2, 3-dimethoxy-4- (methoxymethoxy) -5- ( (2E, 6E) -3, 7, 11-trimethyldodeca-2, 6, 10-trienyl) cyclohexanone) (28 mg, 0.066 mmol) 87％over two steps.

LiHMDS (1 M solution in THF) (0.148 mL, 0.15 mmol) was added in the solution of compound 37 (25 mg, 0.059 mmol) with 1 mL THF at-40℃and stirred for 30 min. Reaction mixture was cooled to-78℃, and methyl iodide (9 μL, 0.065 mmol) was added, then the temperature was increased to 0℃and stirred for 1 h. The mixture was quenched with NH₄Cl solution and extracted with 5 mL ether (2×) , and the organic phase was dried by anhydrous magnesium sulfate, then filtered and concentrated. The crude product was purified with column chromatography on Silica gel (Hexane/EtOAc, 9:1) to give the compound 38 (2-methoxy-4- (methoxymethoxy) -6-hydrogen-5- ( (2E, 6E) -3, 7, 11-trimethyldodeca-2, 6, 10-trienyl) cyclohex-2-enone) and the compound 39 (2-methoxy-4- (methoxymethoxy) -6-methyl-5- ( (2E, 6E) -3, 7, 11-trimethyldodeca-2, 6, 10-trienyl) cyclohex-2-enone) (18.4 mg, 0.045 mmol) , yield 77％.

The 40％trifluoroacetic acid was added in the solution of compound 39 (10 mg, 0.024 mmol) with 1 mL CH₂Cl₂ at 0℃. After being stirred at room temperature for 2 h, the reaction mixture was concentrated and residue was purified with column chromatography on Silica gel (Hexane/EtOAc, 4:1) to give the (±) -antroquinonol D (40) (4-hydroxy-2-methoxy-6-methyl-5- ( (2E, 6E) -3, 7, 11-trimethyldodeca-2, 6, 10-trienyl) cyclo hex-2-enone) (5.7 mg, 0.016 mmol) , yield 64％.

3.2 Characterization of the synthsized compounds

In the process for preparing (±) -antroquinonol, the following new compounds are found:

whose spectral data are given as follows:

IR (KBr) : 3630, 2955, 2839, 1737, 1691, 1629, 1506, 1437, 1380, 1290, 1260, 1228, 1197, 1156, 1110, 1076, 1052, 965, 924, 794 cm^–1； ¹H NMR (400 MHz, CDCl₃) : δ 6.75–6.72 (d, J ＝ 10.4 Hz, 1H ) , 6.02–5.99 (d, J ＝ 10.3 Hz, 1H) , 3.64 (s, 3H) , 3.61–3.59 (m, 1H) , 3.57 (s, 3H) , 3.25–3.24 (m, 1H) , 3.20 (s, 3H) , 3.19 (s, 3H) , 2.68–2.63 (dd, J₁ ＝ 17.6 Hz, J₂ ＝ 4.7 Hz, 1H) , 2.57–2.51 (dd, J₁ ＝ 17.5 Hz, J₂ ＝ 6.0 Hz, 1H) ； ¹³C NMR (100.6 MHz, CDCl₃) : δ 196.57, 168.59, 168.46, 145.55, 131.81, 98.01, 52.65, 52.28, 50.53, 50.28, 49.45, 40.17, 37.51； HRMS-EI (m/z) [M] ⁺ calcd for C₁₃H₁₈O₇ 286.1053 found 286.1058；

whose spectral data are given as follows:

IR (KBr) : 2964, 2836, 2361, 1749, 1730, 1437, 1398, 1368, 1345, 1302, 1268, 1240, 1210, 1154, 1114, 1060, 1030, 983, 952 cm^–1； ¹H NMR (400 MHz, CDCl₃) : δ 6.11–6.08 (m, 1H) , 5.87–5.85 (d, J ＝ 10.1 Hz, 1H) , 4.74–4.73 (t, J ＝ 1.0 Hz, 1H) , 3.72–3.71 (t, J ＝1.0 Hz, 3H) , 3.66–3.65 (d, J ＝ 2.2 Hz, 1H) , 3.17–3.15 (m, 6H) , 2.66 (s, 1H) , 2.25–2.24 (d, J ＝ 2.4 Hz, 2H) ； ¹³C NMR (100.6 MHz, CDCl₃) : δ 170.03, 166.89, 130.72, 129.39, 98.02, 70.20, 52.99, 49.48, 48.15, 47.50, 36.56, 25.49； HRMS-EI (m/z) [M] ⁺ calcd for C₁₂H₁₆O₆ 256.0947 found 256.0940；

whose spectral data are given as follows:

¹H NMR (400 MHz, CDCl₃) : δ 7.21–7.17 (q, J ＝ 6.0 Hz, 1H) , 6.16–6.14 (d, J ＝ 9.8 Hz, 1H) , 5.06–5.05 (t, J ＝ 1.6 Hz, 1H) , 3.02–2.96 (m, 2H) , 2.73–2.69 (m, 1H) , 2.41 (s, 2H) ； ¹³C NMR (100.6 MHz, CDCl₃) : δ 199.14, 167.97, 144.92, 130.15, 69.05, 40.17, 34.18, 29.. 67； HRMS-EI (m/z) [M] ⁺ calcd for C₈H₈O₃ 152.0473 found 152.0468；

whose spectral data are given as follows:

IR (KBr) : 3398, 3038, 2930, 2867, 2361, 1716, 1449, 1374, 1319, 1257, 1208, 1172, 1107, 1066, 1036, 997, 978, 959, 918, 847, 783, 741, 667, 634, 612, 519 cm^–1； ¹H NMR (400 MHz, CDCl₃) : δ 5.95–5.92 (m, 1H) , 5.83–5.80 (d, J ＝ 9.9 Hz, 1H) , 4.68–4.68 (d, J ＝ 2.4 Hz, 1H) , 4.42 (s, 1H) , 3.64–6.62 (d, J ＝ 10.2 Hz, 1H) , 2.94–2.89 (d, J ＝ 19.5 Hz, 1H) , 2.56–2.49 (dd, J₁ ＝ 19.5 Hz, J₂ ＝ 8.4 Hz, 1H) , 2.45 (br, 1H) , 2.16–2.13 (d, J ＝ 14.2 Hz, 1H) , 1.92–1.88 (dd, J₁ ＝ 14.0 Hz, J₂ ＝ 0.9 Hz, 1H) ； ¹³C NMR (100.6 MHz, CDCl₃) : δ 172.95, 134.70, 126.47, 69.70, 69.41, 31.08, 28.56, 28.24； HRMS-EI (m/z) [M] ⁺ calcd for C₈H₁₀O₃ 154.063 found 154.0625；

whose spectral data are given as follows:

IR (KBr) : 3901, 3747, 3675, 3615, 3421, 2940, 2904, 2829, 1724, 1649, 1541, 1517, 1455, 1419, 1378, 1339, 1251, 1212, 1095, 1035, 919, 618 cm^–1； ¹H NMR (400 MHz, CDCl₃) : δ 4.71–4.67 (q, J ＝ 7.0 Hz, 2H) , 4.61 (s, 1H) , 4.18–4.16 (d, J ＝ 9.9 Hz, 1H) , 3.68–3.64 (dd, J₁ ＝ 5.6 Hz, J₂ ＝ 4.2 Hz, 1H) , 3.57–3.55 (m, 2H) , 3.37 (s, 3H) , 2.92–2.87 (d, J ＝ 18.9 Hz, 1H) , 2.52–2.45 (dd, J₁ ＝ 19.1 Hz, J₂ ＝ 7.4 Hz, 1H) , 2.40 (s, 1H) , 2.18–2.15 (d, J ＝ 14.2 Hz, 1H) , 1.90–1.86 (d, J ＝ 14.4 Hz, 1H) ； ¹³C NMR (100.6 MHz, CDCl3) : δ 170.35, 97.18, 80.64, 76.82, 70.11, 68.30, 55.86, 30.88, 30.70, 23.54. HRMS-EI (m/z) [M] ⁺ calcd for C₁₀H₁₆O₆ 232.0947 found 232.0940；

whose spectral data are given as follows:

IR (KBr) : 2935, 2828, 1738, 1650, 1541, 1452, 1378, 1291, 1248, 1206, 1125, 1106, 1078, 1039, 916, 765, 692, 646, 608, cm^–1； ¹H NMR (400 MHz, CDCl₃) : δ 4.78–4.76 (d, J ＝ 6.8 Hz, 1H) , 4.68–4.65 (d, J ＝ 6.7 Hz, 2H) , 3.87–3.82 (m, 2H) , 3.47 (s, 3H) , 3.45 (s, 3H) , 3.35 (s, 3H) , 3.23–3.20 (dd, J₁ ＝ 10.1 Hz, J₂ ＝ 3.6 Hz, 1H) , 3.02–2.97 (dd, J₁ ＝ 18.9 Hz, J₂ ＝ 1.8 Hz, 1H) , 2.54–2.47 (dd, J₁ ＝ 19.0 Hz, J₂ ＝ 7.3 Hz, 1H) , 2.41 (s, 1H) , 2.12–2.09 (d, J ＝ 14.3 Hz, 1H) , 1.89–1.85 (d, J ＝ 14.4 Hz, 1H) ； ¹³C NMR (100.6 MHz, CDCl₃) : δ 169.99, 96.93, 78.22, 77.22, 76.88, 74.77, 59.50, 58.54, 55.61, 30.94, 30.82；

whose spectral data are given as follows:

IR (KBr) : 2932, 2897, 2824, 2362, 1713, 1650, 1462, 1198, 1175, 1128, 1039, 1007, 991, 935, 919, 836, 777, 747, 670 cm^–1； ¹H NMR (400 MHz, CDCl₃) : δ 6.77–6.74 (t, J ＝ 7.0 Hz, 1H) , 4.69–4.67 (d, J ＝ 6.9 Hz, 1H) , 4.62–4.60 (d, J ＝ 6.9 Hz, 1H) , 4.21–4.16 (q, J ＝ 7.1 Hz, 2H) , 3.87–3.81 (m, 1H) , 3.76–3.75 (t, J ＝ 3.4 Hz, 1H) , 3.68 (s, 1H) , 3.46 (s, 3H) , 3.43 (s, 3H) , 3.41 (s, 3H) , 3.24–3.21 (dd, J₁ ＝ 9.1 Hz, J₂ ＝ 2.8 Hz, 1H) , 2.28–2.23 (m, 1H) , 2.19–2.11 (m, 1H) , 2.01–1.95 (m, 1H) , 1.83 (s, 3H) , 1.65–1.58 (m, 1H) , 1.48–1.39 (m, 1H) , 1.30–1.27 (t, J ＝ 7.1 Hz, 3H) , 0.88 (s, 9H) , 0.08 (s, 3H) , 0.06 (s, 3H) ； ¹³C NMR (100.6 MHz, CDCl₃) : δ 168.06, 140.31, 128.78, 97.69, 83.67, 78.57, 77.19, 70.10, 60.47, 58.92, 58.73, 55.94, 35.15, 32.24, 3.055, 25.88, 18.12, 14.28, 12.58, -4.49, -4.71； HRMS-EI (m/z) [M] ⁺ calcd for C₂₃H₄₄O₇Si 460.2856 found 460.2859；

whose spectral data are given as follows:

IR (KBr) : 2931, 2823, 1700, 1650, 1541, 1521, 1393, 1253, 1208, 1152, 1129, 1100, 1039, 1007, 919, 879, 777 cm^–1； ¹H NMR (400 MHz, CDCl₃) : δ 5.62–5.58 (t, J ＝ 6.8 Hz, 1H) , 4.69–4.67 (d, J ＝ 6.9 Hz, 1H) , 4.63–4.61 (d, J ＝ 7.0Hz, 1H) , 3.97 (s, 2H) , 3.85–3.79 (m, 1H) , 3.75 (s, 1H) , 3.67 (s, 1H) , 3.46 (s, 3H) , 3.42, (s, 3H) , 3.41 (s, 3H) , 3.23–3.20 (dd, J₁ ＝ 9.1 Hz, J₂ ＝ 2.7 Hz, 1H) , 2.12–1.97 (m, 2H) , 1.87–1.85 (m. 1H) , 1.76 (s, 3H) , 1.62–1.56 (m, 1H) , 1.43–1.34 (m, 1H) , 0.88 (s, 9H) , 0.08 (s, 3H) , 0.07 (s, 3H) ；

whose spectral data are given as follows:

IR (KBr) : 2930, 1650, 1540, 1524, 1390, 1254, 1140, 1103, 1008 cm^–1； ¹H NMR (400 MHz, CDCl₃) : δ 5.29–5.28 (d, J ＝ 3.3 Hz, 1H) , 5.11–5.09 (d, J ＝ 6.5 Hz, 3H) , 4.67–4.60 (dd, J₁ ＝ 21.8 Hz, J₂ ＝ 6.8 Hz, 2H) , 3.83–3.79 (m, 1H) , 3.73–3.71 (d, J ＝ 9.7 Hz, 2H) , 3.47 (s, 3H) , 3.41 (s, 3H) , 3.40 (s, 3H) , 3.24–3.22 (d, J ＝ 7.4 Hz, 1H) , 2.06–1.97 (m, 12H) , 1.68 (s, 6H) , 1.43–1.36 (m, 4H) , 1.25 (s, 9H) , 0.88 (s, 9H) , 0.08 (s, 3H) , 0.06 (s, 3H)； ¹³C NMR (100.6 MHz, CDCl₃) : δ 136.40, 135.07, 131.27, 124.37, 124.17, 122.67, 97.72, 83.90, 78.87, 70.45, 58.79, 58.63, 55.79, 40.00, 39.86, 39.74, 35.16, 34.84, 29.71, 26.86, 26.77, 25.89, 25.69, 18.13, 17.68, 16.24, 15.97, -4.49, -4.68； HRMS-EI (m/z) [M] ⁺ calcd for C₃₁H₅₈O₅Si 538.4054 found 538.4058；

whose spectral data are given as follows:

IR (KBr) : 2924, 2854, 1716, 1456, 1383, 1254, 1145, 1008 cm^–1； ¹H NMR (400 MHz, CDCl₃) : δ 5.11–5.07 (m, 3H) , 4.79–4.77 (d, J ＝ 6.8 Hz, 1H) , 4.73-4.71 (d, J ＝ 6.8 Hz, 1H) , 4.22-4.21 (d, J ＝ 3.0 Hz, 1H) , 4.06-4.05 (d, J ＝ 3.6, 1H) , 3.88 (m, 1H) , 3.49 (s, 3H) , 3.45 (s, 3H) , 3.44 (s, 3H) , 2.64 (m, 1H) , 2.33–1.95 (m, 12H) , 1.67 (s, 3H) , 1.59 (s, 3H) , 1.58 (s, 3H) , 1.57 (s, 3H) ； ¹³C NMR (100.6 MHz, CDCl₃) : δ 206.72, 138.16, 137.24, 135.19, 124.33, 123.96, 121.47, 97.79, 84.00, 82.89, 76.81, 59.21, 58.62, 56.08, 41.89, 39.71, 39.68, 38.25, 26.73, 26.57, 25.66, 22.66, 17.65, 16.22, 15.98, 14.08； HRMS-EI (m/z) [M] ⁺ calcd for C₂₅H₄₂O₅ 422.3032 found 422.3034；

whose spectral data are given as follows:

R_f (hexane/EtOAc, 4:1) 0.53. IR (film) : 2921, 2851, 1682, 1640, 1456, 1365, 1148, 976 cm^–1； ¹H-NMR (400 MHz, CDCl₃) : δ 5.87 (d, J ＝ 5.48 Hz, 1H) , 5.10 (m, 3H) , 4.72 (d, J ＝ 6.84 Hz, 1H) , 4.66 (d, J ＝ 6.76 Hz, 1H) , 4.33 (m, 1H) , 3.62 (s, 3H) , 3.36 (s, 3H) , 2.75 (m, 1H) , 2.30-1.92 (m, 9H) , 1.67 (s, 3H) , 1.56 (s, 6H) , 1.52 (s, 3H) , 1.16 (d, J ＝ 7.20 Hz, 3H) . ¹³C-NMR (100.6 MHz, CDCl₃) : δ 190.51, 151.35, 137.35, 135.19, 131.31, 124.33, 124.00, 121.70, 113.42, 96.38, 71.00, 55.48, 54.92, 45.74, 42.78, 39.82, 39.71, 27.13, 26.75, 26.54, 25.68, 17.67, 16.18, 16.04, 12.90. HRMS-EI (m/z) [M] ⁺ calcd for C₂₅H₄₀O₄ 404.2927 found 404.2924；

whose spectral data are given as follows:

R_f (hexane/EtOAc, 7:3) 0.4. IR (film) : 2920, 2851, 1685, 1637, 1442, 1376, 1247, 1148, 1080 cm^-1； ¹H-NMR (400 MHz, CD₃OD) : δ 5.92 (d, J ＝ 5.60 Hz, 1H) , 5.22 (t, J ＝ 7.30 Hz, 1H) , 5.10 (m, 2H) , 4.49 (dd, J₁ ＝ 5.24 Hz, J₂ ＝ 3.80 Hz, 1H) , 3.61 (s, 3H) , 2.68 (m, 1H) , 2.27-1.97 (m, 9H) , 1.80 (m, 1H) , 1.67 (s, 3H) , 1.63 (s, 3H) , 1.61 (s, 3H) , 1.60 (s, 3H) , 1.16 (d, J ＝ 7.00 Hz, 3H) ； ¹³C-NMR (100.6 MHz, CDCl₃) : δ 198.84, 152.06, 138.11, 136.02, 132.12, 125.44, 125.34, 123.29, 116.67, 65.07, 55.34, 47.48, 43.40, 40.93, 40.86, 28.13, 27.82, 27.40, 25.87, 17.75, 16.19, 16.14, 13.09； HRMS-EI (m/z) [M] ⁺ calcd for C₂₃H₃₆O₃ 360.2664 found 360.2668.

Example 4 Inhibitory lipase activity of antroquinonol

4.1 Lipase activity assay

Lipase activity of antroquinonol was determined by a modified procedure described by Winkler by measuring the increase in the absorbance at 410 nm caused by the release of p-nitrophenol after hydrolysis of p-nitrophenylpalmitate (p-NPP) . The soluton which used in the assay comprising Solution I: 5 mg of p-NPP dissolved in 3 mL isopropanol, Solution II: 88 mg Triton X-100 and 22.4 mg Gun Arabic dissolved in 20 mL 50 mM Tris buffer (pH 8.0) , and Solution III: the reaction mixture consisting of solution I and solution II (1:9) was prepared fresh before the assay. A reaction mixture containing 75 μL of the antroquinonol (0.1 uM, 0.5 uM, 1 uM) or 46 nM Orlistat, or 0.5 mg Simvastatin in the Tris buffer (50 mM, pH 8.0) , 50 μL of lipase enzyme solution (8 mg/mL) (Lipase from porcine pancreas type II, 100-400 units/mg protein, using olive oil (30 min incubation) , 30-90 units/mg protein (triacetin, Sigma, St. Louis, MO, USA) and 75 μL of solution III as substrate were mixed in a vial and incubated at 37℃for 1 h. Orlistat taken as a positive control was performed to compare the inhibition of enzyme activity of antroquinonol (0.1 uM, 0.5 uM, 1 uM) .

4.2 Animals

C57BL/6 mouse was obtained from National Laboratory Animal Center (Taipei, Taiwan) and kept at controlled environmental conditions with room temperature (22 ± 2℃) and humidity (60 ± 10％) . The 12 h light and 12 h dark photoperiod (0600 am-1800 pm) was maintained throughout the study. Mice had free access to feed and water and maintained on a standard laboratory diet (carbohydrates 60％； protein 28％； lipid 12％； vitamin 3％) .

4.3 Lipase of Fat induced

10 weeks old male C57BL/6 mice were induced via oral gavaged (p.o.once daily) with 100 uL conventional lard (23％total saturated fatty acids and 77％total unsaturated fatty acids, Chinshan oil, Wei Lih Foods Co., Changhua, Taiwan) combined test drug 50 mg/kg Bwt Antroquinonol； 2.2 mg/kg Bwt Orlistat (GlaxoSmithKline Consumer Healthcare, L.P., Aiken South Carolina, USA) ； 12 mg/kg Bwt Simvastatin (Sigma-Aldrich) for 7 days. The experimental mice were allotted into 5 groups (n ＝ 6) including the groups as normal control, treated with fat-induced, 2.2 mg/kg Bwt of Orlistat, 50 mg /kg Bwt of Antroquinonol, and 12 mg/kg Bwt of Simvastatin.

4.4 Blood biochemical detect

After 7 days induction, blood samples of the mice were collected from piercing facial veins. The blood samples were centrifuged at 3000 rpm 4℃for 10 min to obtain serum samples. The serum was separated and analyzed for lipase and triglyceride (TG) using an automatic analyzer (ARTAX Menarini Diagnostics, Florence, Italy) with enzymatic colorimetric assay reagent strips (Human, Wiesbaden, Germany) .

4.5 Fecal triglycerides test

0.5 g feces of each mouse was added into 10 mL of chloroform/methanol/H₂O (1:2:0.8) solution, completely vortexed for 30 min at room temperature and centrifuged at 6000 rpm for 10 min. The 500 μL of supernatant was removed and added 500 μL of chloroform and H₂O, respectively. After mixed, the sample was centrifuged at 6000 rpm at room temperature for 10 min. The upper supernatant was discarded and 500 μL of chloroform layer was taken into the new eppendorf vial. This vial was put at Fume Hood to volatilize chloroform. After evaporated dry, 200 μL of isopropanol/triton X-100 (9:1) solution was added. Then solution was analyzed for triglyceride (TG) using an automatic analyzer (ARTAX Menarini Diagnostics, Florence, Italy) with enzymatic colorimetric assay reagent strips.

4.6 Statistical analyses

All data were expressed as means with standard deviations (mean ± SD) and the data were analyzed using one-way ANOVA with Tukey test. All statistical procedures were performed with GraphPad Prism version 5.01 (GraphPad Software, Inc., La Jolla, CA, USA) .

The results were given in Figure 1, including (A) lipase activity, (B) serum lipase, and (C) fecal triglycerides. In view of the results as provided in Figure 1, it is concluded that antroquinonol is potential for inhibiting lipase activity and increasing fecal triglycerides, which is similar to or better than Orlistat or Simvastatin. Accordingly, antroquinonol can be developed as a drug for treating obesity.

It is believed that a person of ordinary knowledge in the art where the present invention belongs can utilize the present invention to its broadest scope based on the descriptions herein with no need of further illustration. Therefore, the descriptions and claims as provided should be understood as of demonstrative purpose instead of limitative in any way to the scope of the present invention.

Claims

A use of a compound for manufacturing a composition or medicament for treating obesity, wherein said compound is of general formula (I) :

wherein X, Y, and Z are the same or different, independently hydrogen, oxygen, sulfur, selenium, or NH, each of R¹, R², R³, and R⁴ are the same or different, independently, hydrogen, alkyl, aryl, or alkoxyl.
The use of claim 1, wherein the compound of general formula (I) is antroquinonol.
The use of claim 1, wherein the compound of general formula (I) is (+) -antroquinonol.
The use of claim 1, wherein the compound of general formula (I) is (-) -antroquinonol
The use of claim 1, 2, 3 or 4, wherein the compound of general formula (I) is effective for inhibiting lipase activity.
The use of claim 1, 2, 3 or 4, wherein the compound of general formula (I) is effective for increasing fecal triglycerides.
A method for treating obesity in a subject, comprising administering the subject with a composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of general formula (I) :

wherein X, Y, and Z are the same or different, independently hydrogen, oxygen, sulfur, selenium, or NH, each of R¹, R², R³, and R⁴ are the same or different, independently, hydrogen, alkyl, aryl, or alkoxyl.
The method of claim 7, wherein the compound of general formula (I) is antroquinonol.
The method of claim 7, wherein the compound of general formula (I) is (+) -antroquinonol.
The method of claim 7, wherein the compound of general formula (I) is (-) -antroquinonol
A process for preparation of antroquinonol comprises the steps of Suzuki-Miyaura cross coupling, Barton-McCombie reaction, and selenylation/oxidation.
The process of claim 11, which comprises the steps of:

(1) adding compound 1
into the lithium trimethylsilyl acetylide, and treating with potassium carbonate (K₂CO₃) /methanol (MeOH) to produce compound 2

(2) treating the compound 2 with tert-butyldimethylsilyl chloride (TBSCl) in dichloromethane (DCM, CH₂Cl₂) , and triethyl amine to produce compound 3

(3) transforming the compound 3 to compound 4
by Barton-McCombie deoxygenation with excess phenyl chloro thionoformate and pyridine in DCM, then treating the compound 4 with tributyltin hydride (Bu₃SnH) and azobisisobutyronitrile (AIBN) in cyclopentyl methyl ether by deoxygenative radical cyclization to produce compound 5

(4) treating the compound 5 with pyridinium p-toluenesulfonate (PPTS) in MeOH to afford compound 6
followed by iodination and treatment of methoxymethyl (MOM) ether to give compound 7,

(5) allowing the compound 7
and compound 8
subject to Marshall protocol for a Suzuki-Miyaura cross coupling reaction to give the compound 9
followed by deprotection of tert-butyldimethylsilyl (TBS) ether with tetra-n-butylammonium fluoride (TBAF) and oxidation of the resultant alcohol with Dess-Martin periodinane to give compound 10

(6) treating the compound 10 with Raney nickel, then treating with cerium (III) chloride (CeCl₃) and oxalic acid in acetonitrile, followed by dimethylation with Purdie reagent (Ag₂O, MeI) to produce compound 11

(7) treating the compound 11 with lithium bis (trimethylsilyl) amide (LiHMDS) in tetrahydrofuran (THF) , followed by oxidative elimination with hydrogen peroxide (H₂O₂) to give compound 12
then treating the compound 12 with dry zinc bromide (ZnBr₂) and ethanethiol in DCM to produce (+) or (-) -antroquinonol.
The process of claim 12, which comprises the steps as shown in the scheme I below:
The process of claim 11, which comprises the steps of:

(1) treating the compound 14
with trimethylsilylacetylene and n-butyl lithium to give compound 15
then treating the compound 15 with ethyl chloroformate in DCM and pyridine to give compound 16

(2) treating the compound 16 with phenyl chlorothionoformate and pyridine in DCM to give compound 17
then treating the compound 17 with Bu₃SnH and AIBN in cyclopentyl methyl ether by deoxygenative radical cyclization to produce compound 18
and compound 19
treating the compound 18 with hydrochloric acid (HCl) in methanol to give compound 20

(3) treating the compound 20 with tosyl chloride and N, N-diisopropylethylamine in DCM followed by iodination with sodium iodide by refluxing in acetone, and treating with MOM ether to give compound 21

(4) conjugating the compound 21 with compound 8 by heating the THF solution with activated zinc at 50 ℃, then treated with bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (PdCl₂ (Amphos) ₂) and tetramethylethylenediamine (TMEDA) in THF to give the compound 22
followed by treating with K₂CO₃ in MeOH to give the compound 23

(5) treating the compound 23 with Dess-Martin periodinane (DMP) and followed by Raney nickel to give compound 24
then treating the compound 24 with LiHMDS in THF followed by oxidative elimination with H₂O₂ to give compound 12, then treating the compound 12 with ZnBr₂ and ethanethiol in DCM to obtain (+) or (-) -antroquinonol.
The process of claim 14, comprising the steps as shown in the scheme II below:
A process for preparation of antroquinonol comprising the steps of chelation and substrate controlled diastereoselective reduction of cyclohexenone and lactonization, Michael addition of dimethyl malonate on cyclohexadienone, dihydroxylation, Wittig olefination, and sesquiterpene side chain achieved through coupling with geranyl phenyl sulfide and Bouveault-Blanc reduction.
The process of claim 16, which comprises the steps of

(1) reacting 4-methoxy phenol
with methanol to prepare compound 25
adding the compound 25 to dimethyl malonate to give compound 26
then allowing the compound 26 subject to Luche condition followed by lactonization to give compound 27

(2) allowing the compound 27 subject to Krapcho decarboxylation by 1,4-diazabicyclo [2.2.2] octane (DABCO) in toluene and water to give compound 28
and treating the compound 28 with HCl to give compound 29

(3) treating the compound 29 with sodium borohydride (NaBH₄) and CeCl₃ in MeOH to give compound 30
then treating the compound 30 with MOM ether and dihydroxylation followed by treating with osmium tetroxide (OsO₄) and N-methylmorpholine N-oxide (NMO) in acetone-H₂O to give the compound 31

(4) treating the compound 31 with Purdie’s reagent (methyl iodide, silver oxide) to give compound 32
then reducing the compound 32 to lactol with diisobutylaluminium hydride (DIBAL-H) , and then condensing with triphenylphosphonium ylid (Ph₃PC (Me) CO₂Et) in benzene followed by a treatment with TBS ether to give compound 33

(5) treating the compound 33 by bromination with Appel reaction condition (CBr₄/PPh₃, DCM, 0 ℃) to give compound 34
and coupling the compound 34 with lithioanion of compound 35
in the presence of TMEDA to give compound 36
then treating the compound 36 with TBAF in THF followed by oxidation of the intermediate alcohol with Dess-Martin periodinane to give compound 37

(6) treating the compound 37 with lithium diisopropylamide (LDA) or LiHMDS in THF to give compound 38
or compound 39
and followed by treatment with TFA in DCM to give the (±) -antroquinonol D (compound 40)
The process of claim 17, comprising the steps of the scheme III below:
A compound, which is selected from the group consisting of:
A pharmaceutical composition comprising the compound of claim 19.
A compound, which is selected from the group consisting of:
A pharmaceutical composition comprising the compound of claim 21.
A compound, which is selected from the group consisting of:
A pharmaceutical composition comprising the compound of claim 23.
A composition or pharmaceutical composition for treating obesity comprising a therapeutically effective amount of the compound of general formula (I) as set forth in claim 1, together with a pharmaceutically acceptable carrier.
The pharmaceutical composition of claim 25, wherein the the compound of general formula (I) is antroquinonol.
The pharmaceutical composition or the use of claim 26, wherein the compound of general formula (I) is (+) -antroquinonol.
The pharmaceutical composition of claim 26, wherein the compound of general formula (I) is (-) -antroquinonol.