CN101982451A - Asymmetric synthesis of chiral muskone and other 3-methyl cyclic ketone - Google Patents
Asymmetric synthesis of chiral muskone and other 3-methyl cyclic ketone Download PDFInfo
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Abstract
The invention relates to asymmetric synthesis of chiral muskone and other 3-methyl cyclic ketone. The asymmetric synthesis comprises the following steps: generating a Michael addition product by taking cyclic ketene and dual-sulfonyl methane as raw materials, the chiral catalyst containing one or more functional groups of primary amine, tertiary amine, urea or thiourea or salt thereof as a catalytic system and an organic solvent as a reaction carrier and conducting reaction at 0 to 100 DEG C for 2 and 10 days; and performing carbonyl protection, selective dual-sulfonyl removal and decarbonylation protection by taking the Michael addition product as a start raw material to synthesize the chiral muskone and other 3-methyl cyclic ketone. The invention realizes high-conversion and high-selectivity synthesis of the chiral muskone and other 3-methyl cyclic ketone for the first time, ensures that the synthesized muskone has the same structure as the natural muskone and overcomes the shortcomings of small content and high price of the natural muskone; and moreover, as the reaction conditions are mild, the operation is simple and the raw materials are cheap and readily available, the invention is suitable for industrial production and application.
Description
[technical field]
The present invention relates to technical field of chemistry, relate to the asymmetric synthesis of chirality muskone and other 3-methyl cyclic ketones, specifically, is a kind of method of using the synthetic R-muskone of asymmetric Michael addition reaction and other 3-methyl cyclic ketones.
[background technology]
Natural musk ketone is (R)-3-methyl exaltone, is a kind of famous and precious spices, has sweet giving off a strong fragrance, and fragrance value of explaining extremely low (0.01-0.001ppm) and lasting are lasting, cost an arm and a leg in the international market.Natural musk still is famous and precious Chinese medicine, originates from the sachet of the male musk deer of Cervidae musk deer genus animal, and wherein the content of muskone is 1.2～1.4%.China's pharmacopeia record, Moschus has excitor nerve maincenter, respiratory centre and heart, promote the effect of multiple glandular secretion, it is the delirious important drugs of treatment, simultaneously again with logical all keys, open passages through which vital energy circulates, saturating flesh bone, in control apoplexy, middle gas, middle evil and infantile convulsion, control diseases such as wound and epidemic disease poison outward and be celebrated.Because the resource of natural musk is very limited, kill musk deer get that perfume (or spice) become can not (musk deer be China wildlife under first class protection), therefore, the synthetic muskone is extensively paid attention to.So the synthetic of muskone has very important significance.
Document has the crucial chirality step of synthetic (R)-3-muskone of report to have at present: asymmetric hydrogenation, asymmetric Michael addition reaction etc.Nineteen ninety, people such as Tanaka utilize chiral amino alcohol ligand and CuI, and MeLi carries out asymmetric Michael addition to 2-cyclopentadecylene ketone in toluene solution, and the R configuration muskone optical purity that obtains is 89%, productive rate is 80% (Chem.Commun.1990,795).2002, people such as Yamamoto are from 2,15-16 diketone set out, adopt classical Aldol reaction dehydration to obtain the 3-muscone, adopt hydrogenation under the catalysis of p-sulfonic acid base-BINAP-Ru (II) complex compound can obtain the muskone product of chirality then, this method yield and stereoselectivity be better (Tetrahedron, 2002 all, 58,9209).But, the catalyzer costliness that this method is used, also undesirable to the recycle of catalyzer.2006, people such as Pfaltz became dienone by IBX oxidation cyclopentadecanone, carried out the asymmetric conjugated reaction of asymmetric zinc methide then, obtained the product up to 98% optical purity, obtained (R)-muskone (Synlett, 2006,7,1031) after the hydrogenation.2007, people such as Knopff disclosed Aldol generation chiral centre in the use unsymmetric molecule, carry out (R)-muskone (Angew.Chem.Int.Ed.2007 that Eschenmoser ruptures, hydrogenation obtains 76%ee then, 46,1307), still, this method enantioselectivity is low excessively.2005, people such as Takabe use the method for chiral separation, under the effect of tartaric acid derivatives, racemization 3-methyl pentadecanone is split into (R), (S)-muskone, the enantioselectivity of (the R)-muskone that obtains with this method is more than 98%, cis-selectivity was greater than 99: 1 (Tetrahedron Letters, 2005,46,3457), but the yield of this method is lower and cause the waste of another enantiomorph easily.Therefore, explore the complete synthesis novel method of (R)-muskone, reduce cost, the optical purity that improves product has significance.
[summary of the invention]
The method that the purpose of this invention is to provide the asymmetric synthesis of a kind of chirality muskone and other 3-methyl cyclic ketones.
For achieving the above object, the technical scheme taked of the present invention is:
The asymmetric synthesis of chirality muskone and other 3-methyl cyclic ketones is characterized in that, its step comprises:
(1) generates asymmetric Michael adduct
With ring-type ketenes and two sulfuryl (alkylsulfonyl) methane is raw material, to contain chiral catalyst or its salt that one or more primary amine, tertiary amine, urea or thiocarbamide are functional group respectively is catalyst system, with the organic solvent is reaction carriers, temperature of reaction is 0～100 ℃, and the reaction times is 2～10 days; After reaction transforms fully, with reaction solution concentrating under reduced pressure, separation, generate the Michael adduct, its reaction expression is:
In the formula: n is a carbon atom number in the ring-type ketenes, R
1, R
2Be identical or different substituting group;
(2) synthesis of chiral muskone and other 3-methyl cyclic ketones
The Michael adduct that generates with step (1) is as starting raw material, through carbonyl-protection, optionally take off two sulfuryls and three steps of decarbonylation base protection, and synthesis of chiral muskone and other 3-methyl cyclic ketones, its reaction expression is:
In the formula: n is the number of carbon atom in the ring-type ketenes, and n=1-20, m are the number of carbon atom in the carbonyl-protection group, m=1-2.
The described ring-type ketenes of step (1) is an alpha, beta-unsaturated ketone, and its structure is:
In the formula: n is a carbon atom number in the ring-type ketenes, n=1-20.
The structure of described pair of sulfuryl methane of step (1) is:
In the formula: R
1, R
2Be identical or different alkyl substituent or aryl substituent or heterocyclic substituent.
The structure of the described chiral catalyst of step (1) is in the following structural or (5) or (6) or (7) or (8) or (9) or (10) or (11) or (12) or (13) or (14) a kind of:
In the formula: the carbon atom that indicates * number is a chiral carbon atom;
R
3, R
4Be respectively the alkyl substituent or the aryl substituent of straight or branched;
R
5Be hydrogen atom, hydroxyl or methoxyl group;
R
6Be ethyl or vinyl;
R
7, R
8Be identical or different hydrogen atom or alkyl substituent, acid salifiable with it is organic acid or mineral acid.
The described organic solvent of step (1) is methylene dichloride, ethyl acetate, ethanol, methyl alcohol, toluene, acetonitrile, 1,4-dioxane, ether, methyl tertiary butyl ether, chloroform and 1, one or more in 2-ethylene dichloride and the tetrahydrofuran (THF).
The mol ratio of the described ring-type ketenes of step (1) and two sulfuryl methane reactions is: 5: 1～1: 5, the consumption of chiral catalyst or its salt was 0～100% of a ring-type ketenes, and the molecular volume of ring-type ketenes in organic solvent is 0～100mol/L.
The described carbonyl-protection step of step (2) is: two mercaptan or the glycol of Michael adduct (1) and 1～5 molar equivalent are reacted the compound (2) that obtains carbonyl-protection; blocking group is ethylene glycol, dithioglycol, 1; ammediol or 1; the 3-dimercaptopropane; temperature of reaction is 0～100 ℃; reaction solvent is anhydrous methylene chloride, trichloromethane, 1, one or more in 2-ethylene dichloride, tetrahydrofuran (THF), dioxane, acetone, the acetonitrile, and its reaction expression is:
In the formula: X is Sauerstoffatom or sulphur atom, and n is the number of carbon atom in the ring-type ketenes, n=1～20, and m is the number of carbon atom in the blocking group, m=1-2;
The described pair sulfuryl steps of optionally taking off of step (2) are: the compound (2) of carbonyl-protection is optionally taken off muskone and other 3-methyl cyclic ketones (3) that two sulfuryls obtain carbonyl-protection; temperature of reaction is 0～150 ℃; reaction solvent is one or more in benzene,toluene,xylene, methyl alcohol, ethanol, the tetrahydrofuran (THF), and its reaction expression is:
In the formula: X is Sauerstoffatom or sulphur atom, and n is the number of carbon atom in the ring-type ketenes, n=1～20, and m is the number of carbon atom in the blocking group, m=1-2;
The described decarbonylation base protection of step (2) step is: muskone and other 3-methyl cyclic ketones (3) of carbonyl-protection are taken off the carbonyl-protection base, obtain final product chirality muskone and other 3-methyl cyclic ketones (4), its reaction expression is:
In the formula: X is Sauerstoffatom or sulphur atom, and n is the number of carbon atom in the ring-type ketenes, n=1～20, and m is the number of carbon atom in the blocking group, m=1-2.
The described concrete reaction conditions of optionally taking off two sulfuryls of step (2) can be:
Compound (2) selectivity under the effect of methyl alcohol/magnesium of carbonyl-protection is taken off two sulfuryls, and temperature of reaction is 0～100 ℃, and solvent for use is one or more in methyl alcohol, ethanol, the tetrahydrofuran (THF);
Or under the effect of three normal-butyl stannic hydrides and Diisopropyl azodicarboxylate, optionally take off two sulfuryls, and temperature of reaction is 0～100 ℃, solvent for use is one or more in toluene, benzene, the dimethylbenzene;
Or selectivity is taken off two sulfuryls under Raney's nickel/alcoholic acid effect, and temperature of reaction is 0～100 ℃, and solvent for use is one or more in ethanol, the methyl alcohol;
Or selectivity is taken off two sulfuryls under the effect of zinc/saturated ammonium chloride, and temperature of reaction is 0～100 ℃, and solvent for use is a tetrahydrofuran (THF);
Or selectivity is taken off two sulfuryls under the effect of zinc/acid, and temperature of reaction is 0～100 ℃, and used acid is organic acid or mineral acid;
Or at means of samarium iodide (SmI
2) effect under selectivity take off two sulfuryls, temperature of reaction is 0～100 ℃, solvent for use is tetrahydrofuran (THF), methylene dichloride, trichloromethane, ethanol, 1, one or more in 4-dioxane, the acetonitrile.
The concrete reaction conditions of the described decarbonylation base protection of step (2) can be:
Muskone and other 3-methyl cyclic ketones (3) decarbonylation base blocking group under the effect of two (trifluoroacetyl oxygen base) iodobenzene with carbonyl-protection, obtain chirality muskone and other 3-methyl cyclic ketones (4), the reaction solvent for use is one or more in methyl alcohol, water, methylene dichloride, the tetrahydrofuran (THF);
Or under the effect of iodine/sodium bicarbonate decarbonylation base blocking group, obtain chirality muskone and other 3-methyl cyclic ketones (4), the reaction solvent for use is one or more in acetone, the water;
Or under the effect of Oxone/ Potassium Bromide decarbonylation base blocking group, obtain chirality muskone and other 3-methyl cyclic ketones (4), the reaction solvent for use is one or more in acetonitrile, the water.
Positively effect of the present invention is:
(1) realized that first carrying out asymmetric Michael addition reaction with cyclopentadecane ketenes and other ring-type ketenes with two sulfuryl methane comes synthesis of chiral muskone and other 3-methyl cyclic ketones.
(2) the synthetic muskone is identical with natural musk ketone configuration, and optical purity height, enantioselectivity have remedied rare, the expensive deficiency in natural musk source up to 98%, provide convenience for utilizing muskone.
(3) this reaction conversion ratio height, selectivity are good, and the reaction conditions gentleness, and simple to operate, reaction reagent is cheap and easy to get, the suitability for industrialized production application.
[embodiment]
Below introduce the specific embodiment of the asymmetric synthesis of chirality muskone of the present invention and other 3-methyl cyclic ketones, 17 embodiment are provided.Should be pointed out that enforcement of the present invention is not limited to following examples.
Embodiment 1
Reaction formula is:
At 0.5mL 1, in the 4-dioxane, add two benzenesulfonyl methane (322mg, 0.75mmol), the pentadecane ketenes (111mg, 0.5mmol), phenylformic acid (24.4mg, 0.2mmol), catalyzer (9) (R
5Be methoxyl group, R
6Be vinyl) (32.3mg, 0.1mmol), feeding intake finishes is placed on 35 ℃ of stirrings 4 days, after reaction transforms fully, reaction solution concentrating under reduced pressure, silica gel column chromatography are separated (petrol ether/ethyl acetate=10: 1) separate the adduct 192mg that obtains white solid, yield is 74%, and fusing point is 142～144 ℃, specific rotation [α]
24 D=-20.0 ° of (c=1.00, CH
2Cl
2);
1H NMR (400MHz, CDCl
3): δ (ppm) 7.94 (dd, J=7.6,5.2Hz, 4H), 7.71-7.65 (m, 2H), 7.60～7.53 (m, 4H), 4.72 (s, 1H), 3.11～3.06 (m, 1H), 3.02～3.00 (m, 2H), 2.52～2.45 (m, 1H), 2.30～2.23 (m, 1H), 1.87～1.69 (m, 3H), 1.36～1.17 (m, 19H).
13CNMR (100MHz, CDCl
3): δ (ppm) 209.8,140.3,138.3,134.5,134.3,129.7,129.1,129.0,84.9,43.7,42.2,33.7,33.0,27.5,26.6,26.4,26.3,26.1,23.1.HRMS (ESI): theoretical [M+H]
+(C
28H
42NO
5S
2) be 536.2504, real that 536.2500. obtain chiral analysis by HPLC, actual conditions is [IC post, 220nm, Hexane: EtOH=4: 1,0.8mL/min]: 13.7min (master), 18.3min (inferior), ee=98%.
Embodiment 2
Be that with the difference of embodiment 1 used ring-type ketenes is 3-tetrahydrobenzene-2-ketone, temperature of reaction is 4 ℃, and other experimental techniques and condition obtain the adduct of white solid with embodiment 1, and yield is 81%, 176～177 ℃ of fusing points, specific rotation [α]
23 D=-8.5 ° of (c=1.0, CH
2Cl
2);
1H NMR (400MHz, CDCl
3): δ (ppm) 7.95～7.91 (m, 4H), 7.74～7.70 (m, 2H), 7.61～7.56 (m, 4H), 4.45 (s, 1H), 3.19 (t, J=13.6Hz, 1H), 2.79 (t, J=12.8Hz, 1H), 2.45～2.28 (m, 4H), 2.11～2.06 (m, 1H), 1.93 (d, J=13.2Hz, 1H), 1.55～1.43 (m, 1H).
13C NMR (100MHz, CDCl
3): δ (ppm) 208.3,139.1,138.4,134.7,134.6,129.4,129.2,86.0,45.6,40.8,38.8,27.8,25.0; HRMS (ESI): theoretical value [M+NH
4]
+(C
19H
24NO
5S
2) 410.1096, get 410.1091 in fact; Obtain chiral analysis by HPLC, actual conditions is: [the IA post, 220nm, n-Hexane: DCM=2: 1,0.8mL/min]: 27.5min (master), 31.7min (inferior), ee=95%.
Embodiment 3
Be that with the difference of embodiment 1 used ring-type ketenes is 3-suberene-2-ketone, other experimental techniques and condition obtain the adduct of white solid with embodiment 1, and yield is 92%, 212～214 ℃ of fusing points; Specific rotation [α]
23 D=-43.6 ° of (c=0.50, CH
2Cl
2);
1H NMR (400MHz, CDCl
3): δ (ppm) 7.95～7.92 (m, 4H), 7.73～7.69 (m, 2H), 7.60～7.56 (m, 4H), 4.51 (s, 1H), 3.34 (dd, J=12,2.8Hz, 1H), 2.86 (t, J=11.2Hz, 1H), 2.57～2.41 (m, 3H), 2.23～2.10 (m, 2H), 1.68～1.59 (m, 1H), 1.33～1.24 (m, 2H), 0.90～0.85 (m, 1H).
13C?NMR(100MHz，CDCl
3)：δ(ppm)211.3，138.9，138.8，134.7，134.6，129.5，129.4，129.2，88.3，47.3，43.6，37.1，34.2，29.4，23.7。HRMS (ESI): theoretical value [M+NH
4]
+(C
20H
26NO
5S
2) be 424.1252, get 424.1250 in fact; Obtain chiral analysis by HPLC, actual conditions is: [IA column, 220nm, Hexane: DCM=2: 1,0.8mL/min]: 20.9min (inferior), 24.3min (master), ee=92%.
Embodiment 4
Reaction formula is:
(219mg 0.38mmol) is dissolved in the 2mL anhydrous methylene chloride, and (0.07mL 0.76mmol), under the ice-water bath, adds the BF of catalytic amount again to add dithioglycol with compound (1-a)
3Et
2O places stirring at room with reaction, and TLC detects to reacting completely.In reaction solution, add 0.5mL NaOH (5%), dichloromethane extraction, organic phase is washed with saturated common salt, anhydrous sodium sulfate drying, concentrating under reduced pressure, residue obtains white solid 214mg with silica gel column chromatography separating purification (petrol ether/ethyl acetate=20: 1).Yield is 95%.Fusing point 148-150 ℃; Specific rotation [α]
22 D=+22.2 ° of (c=0.51, CH
2Cl
2);
1H NMR (400MHz, CDCl
3): δ (ppm) 8.01 (d, J=7.6Hz, 2H), 7.89 (d, J=7.6Hz, 2H), 7.69～7.65 (m, 3H), 7.58～7.52 (m, 4H), 6.28 (s, 1H), 3.35～3.28 (m, 3H), 3.23～3.18 (m, 1H), 2.94 (dd, J=9.6Hz, 1H), 2.55 (t, J=10.0Hz, 1H), 2.15 (d, J=15.6Hz, 1H), 2.06～1.99 (m, 1H), 1.83～1.75 (m, 1H), 1.71～1.64 (m, 1H), 1.60～1.51 (m, 2H), 1.33～1.19 (m, 19H).
13C NMR (100MHz, CDCl
3): δ (ppm) 141.7,138.2,134.4,133.9,129.7,129.2,128.8,128.7,83.8,70.3,42.8,42.1,39.7,38.5,36.7,30.4,27.8,27.6,27.4,27.2,27.0,26.7,26.4,26.3,26.0,25.9.HRMS (ESI): theoretical value [M+NH
4]
+(C
30H
46NO
4S
4) be 612.2310, get 612.2308 in fact.
Embodiment 5
Be that with the difference of embodiment 2 used carbonyl-protection group is respectively ethylene glycol, 1,3-dimercaptopropane and 1, ammediol, other conditions are identical with embodiment 2.
Embodiment 6
Reaction formula is:
With compound (2-a) (204mg, 0.34mmol) be dissolved in the 12mL anhydrous methanol, under agitation condition, with magnesium (312mg, 13mmol) join in the above-mentioned solution, with reaction system by the room temperature transposition in 50 ℃, add thermal booster reaction, treated reaction to be placed stirring at room 0.5 hour again when a large amount of bubbles produce, reflux detects to reaction end to TLC.After being cooled to room temperature, add 2N HCl (5mL), use dichloromethane extraction, merge organic phase, with saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, the resistates silica gel column chromatography separating purification gets colourless oil liquid (3-a) 99mg altogether, and yield is 92%.Specific rotation [α]
23 D=-2.7 ° of (c=0.49, CH
2Cl
2);
1H NMR (400MHz, CDCl
3): δ (ppm) 3.34～3.21 (m, 4H), 2.17 (dd, J=3.6,10.8Hz, 1H), 2.09～2.01 (m, 1H), 1.92～1.80 (m, 2H), 1.49～1.25 (m, 23H), 1.04 (d, J=6.8Hz, 3H).
13C?NMR(100MHz，CDCl
3)：δ(ppm)71.3，50.1，42.6，39.2，38.3，36.4，30.6，27.2，27.1，26.8，26.7，26.3，25.9，25.8，25.7，25.4，24.8，21.0。HRMS (ESI): theoretical value [M+H]
+(C
18H
35S
2) be 316.2214, get 316.2202 in fact.
Embodiment 7
Be with the difference of embodiment 6, the used reagent of optionally taking off two sulfuryls is three normal-butyl stannic hydride and Diisopropyl azodicarboxylates, concrete operations are: at room temperature with compound (2-a) (204mg, 0.34mmol) be dissolved in the 15mL toluene, to wherein splashing into three normal-butyl stannic hydrides (495mg, (2mL) solution of toluene 1.7mmol) and Diisopropyl azodicarboxylate (5mg) gradually; Reaction is heated to refluxed 1 hour, be cooled to room temperature after, add 10%HCl and regulate pH to acid, stirring at room half an hour, reaction solution is used ethyl acetate extraction respectively, other conditions are with embodiment 6.
Embodiment 8
Be with the difference of embodiment 6, the used reagent of optionally taking off two sulfuryls is zinc/saturated ammonium chloride, concrete operations are: with compound (2-a) (119.8mg, 0.2mmol) be dissolved in the 6mL tetrahydrofuran (THF), (0.8g is 12mmol) with saturated ammonium chloride solution 6mL to add zinc powder, reflux 6 hours, be cooled to suction filtration after the room temperature, use ethyl acetate extraction behind the filtrate thin up, other conditions are identical with embodiment 6.
Embodiment 9
Be that with the difference of embodiment 8 the used reagent of optionally taking off two sulfuryls is Raney's nickel/ethanol, other conditions are identical with embodiment 8.
Embodiment 10
Be that with the difference of embodiment 8 the used reagent of optionally taking off two sulfuryls is zinc/acetate, other conditions are identical with embodiment 8.
Embodiment 11
Be with the difference of embodiment 8; the used reagent of optionally taking off two sulfuryls is means of samarium iodide; actual conditions is: under the nitrogen protection with compound (2-a) (59.4mg 0.1mmol) is dissolved in the 5mL tetrahydrofuran (THF), in ice-water bath to the hexane solution (2mL that wherein slowly drips means of samarium iodide; 0.2mmol; 2equiv), be stirred to TLC and detect, in reaction solution, add saturated sodium bicarbonate solution 10mL to reaction end; use extracted with diethyl ether, other conditions are identical with embodiment 8.
Embodiment 12
When the carbonyl-protection group is respectively ethylene glycol, 1,3-dimercaptopropane and 1, during ammediol, the condition of optionally taking off two sulfuryls is identical with embodiment 6～11.
Embodiment 13
Reaction formula is:
(188.4mg 0.6mmol) is dissolved in 3mL CH with compound (3-a) under the ice-water bath condition
3COCH
3-H
2O (5: 1v/v), add NaHCO
3(428.4mg, 5mmol) and I
2(533.0mg, 3.5mmol), be stirred to TLC and detect reaction end, add saturated sodium thiosulfate (2mL), continue to stir after 15 minutes, use ethyl acetate extraction, use saturated sodium thiosulfate, water, saturated common salt water washing respectively, anhydrous sodium sulfate drying, concentrating under reduced pressure, the resistates silica gel column chromatography separating purification obtains yellow-white oily liquids R-muskone (4-a) 102.9mg altogether, and yield is 72%.Specific rotation [α]
25 D=-11.3 ° (c=1.13, MeOH);
1HNMR (400MHz, CDCl
3): δ (ppm) 2.44～2.38 (m, 3H), 2.18 (dd, J=5.2,9.6Hz, 1H), 2.08～2.00 (m, 1H), 1.71～1.54 (m, 2H), 1.30～1.21 (m, 20H), 0.93 (d, J=6.8Hz, 3H).
13C?NMR(100MHz，CDCl
3)：δ(ppm)211.9，50.4，42.0，35.5，29.0，27.5，27.1，26.7，26.6，26.5，26.4，26.2，26.1，25.0，23.0，21.1。HRMS (ESI): theoretical value [M+NH
4]
+(C
16H
34NO) be 256.2640, get 256.2638 in fact.
Embodiment 14
Be with the difference of embodiment 13; the reagent of used decarbonylation base protecting group is two (trifluoroacetyl oxygen base) iodobenzenes; actual conditions is: under the room temperature with compound (3-a) (62.8mg; 0.2mmol) be dissolved in 2mL methyl alcohol, 0.25mL water and the 1mL methylene dichloride mixing solutions; to wherein adding 0.2mL tetrahydrofuran (THF) and two-trifluoroacetic acid base iodobenzene (129mg; 0.3mmol); behind the stirring reaction 10 minutes; in reaction solution, add the 1.5mL saturated sodium bicarbonate solution; extracted with diethyl ether, other conditions are with embodiment 13.
Embodiment 15
Be that with the difference of embodiment 13 reagent of used decarbonylation base protecting group is the Oxone/ Potassium Bromide, actual conditions is: (73.9mg 0.235mmol) is dissolved in 1mL CH with compound (3-a)
3CN-H
2O (1: 1v/v), add equimolar Potassium Bromide (28mg, 0.235mmol), with Oxone reagent (68mg, 0.235mmol) be dissolved in the 1mL water, under the agitation condition it is added drop-wise in the above-mentioned solution, be stirred to TLC and detect reaction end, use ethyl acetate extraction, other conditions are with embodiment 13.
Embodiment 16
When the carbonyl-protection group is respectively ethylene glycol, 1,3-dimercaptopropane and 1, during ammediol, the condition of optionally taking off the carbonyl-protection group is identical with embodiment 13～15.
Embodiment 17
React with 3-cyclopentadecylene-2-ketone (0.1mmol) and two benzenesulfonyl methane (0.15mmol), reaction expression is:
The structure of used catalyzer is:
Shown in the catalytic result of different catalysts sees the following form:
| Numbering | Catalyzer | Additive/phenylformic acid | 48 hours GC transformation efficiency % | Ee value % |
| 1 | 5-a | - | 70 | 40 |
| 2 | 5-a | 1equiv. | 75 | 56 |
| 3 | 5-a | 2equiv. | 60 | 75 |
| 4 | 6-a | - | 32 | 40 |
| 5 | 6-a | 1equiv. | 42 | 19 |
| 6 | 6-a | 2equiv. | 26 | 17 |
| 7 | 7-a | - | 47 | 89 |
| 8 | 7-a | 1equiv. | 21 | 80 |
| 9 | 8-a | - | 15 | 76 |
| 10 | 9-a | - | 71 | 88 |
| 11 | 9-a | 1equiv. | 82 | 95 |
| 12 | 9-a | 2equiv. | 79 | 98 |
| 13 | 9-b | - | 65 | 83 |
| 14 | 9-c | - | 69 | 81 |
| 15 | 11-a | - | 90 | 50 |
| 16 | 11-a | 1equiv. | 67 | 36 |
| 17 | 11-a | 2equiv. | 19 | 27 |
| 18 | 11-b | - | 85 | 47 |
| 19 | 11-c | - | 82 | 49 |
Claims (9)
1. the asymmetric synthesis of chirality muskone and other 3-methyl cyclic ketones is characterized in that its step comprises:
(1) generates asymmetric Michael adduct
With ring-type ketenes and two sulfuryl (alkylsulfonyl) methane is raw material, to contain chiral catalyst or its salt that one or more primary amine, tertiary amine, urea or thiocarbamide are functional group respectively is catalyst system, with the organic solvent is reaction carriers, temperature of reaction is 0～100 ℃, and the reaction times is 2～10 days; Reaction with reaction solution concentrating under reduced pressure, separation, obtains the Michael adduct after transforming fully, and its reaction expression is:
In the formula: n is a carbon atom number in the ring-type ketenes, R
1, R
2Be identical or different substituting group;
(2) synthetic musk ketone and other 3-methyl cyclic ketones
The Michael adduct that generates with step (1) is as starting raw material, through carbonyl-protection, optionally take off two sulfuryls and three steps of decarbonylation base protection, and synthesis of chiral muskone and other 3-methyl cyclic ketones, its reaction expression is:
In the formula: n is the number of carbon atom in the ring-type ketenes, and n=1-20, m are the number of carbon atom in the carbonyl-protection group, m=1-2.
2. the asymmetric synthesis of chirality muskone according to claim 1 and other 3-methyl cyclic ketones is characterized in that, the described ring-type ketenes of step (1) is an alpha, beta-unsaturated ketone, and its structure is:
In the formula: n is a carbon atom number in the ring-type ketenes, n=1-20.
3. the asymmetric synthesis of chirality muskone according to claim 1 and other 3-methyl cyclic ketones is characterized in that, the structure of described pair of sulfuryl methane of step (1) is:
In the formula: R
1, R
2Be identical or different alkyl substituent or aryl substituent or heterocyclic substituent.
4. the asymmetric synthesis of chirality muskone according to claim 1 and other 3-methyl cyclic ketones, it is characterized in that the structure of the described chiral catalyst of step (1) is in the following structural or (5) or (6) or (7) or (8) or (9) or (10) or (11) or (12) or (13) or (14) a kind of:
In the formula: the carbon atom that indicates * number is a chiral carbon atom;
R
3, R
4Be respectively the alkyl substituent or the aryl substituent of straight or branched;
R
5Be hydrogen atom, hydroxyl or methoxyl group;
R
6Be ethyl or vinyl;
R
7, R
8Be identical or different hydrogen atom or alkyl substituent, acid salifiable with it is organic acid or mineral acid.
5. the asymmetric synthesis of chirality muskone according to claim 1 and other 3-methyl cyclic ketones, it is characterized in that, the described organic solvent of step (1) is methylene dichloride, ethyl acetate, ethanol, methyl alcohol, toluene, acetonitrile, 1,4-dioxane, ether, methyl tertiary butyl ether, chloroform and 1, one or more in 2-ethylene dichloride and the tetrahydrofuran (THF).
6. according to the asymmetric synthesis of the described chirality muskone of claim 1-5 and other 3-methyl cyclic ketones, it is characterized in that, the mol ratio of the described ring-type ketenes of step (1) and two sulfuryl methane reactions is: 5: 1～1: 5, the consumption of chiral catalyst or its salt is 0～100% of a ring-type ketenes, and the molecular volume of ring-type ketenes in organic solvent is 0～100mol/L.
7. the asymmetric synthesis of chirality muskone according to claim 1 and other 3-methyl cyclic ketones; it is characterized in that; the described carbonyl-protection step of step (2) is: two mercaptan or the glycol of Michael adduct (1) and 1～5 molar equivalent are reacted the compound (2) that obtains carbonyl-protection; blocking group is an ethylene glycol; dithioglycol; 1; ammediol or 1; the 3-dimercaptopropane; temperature of reaction is 0～100 ℃; reaction solvent is an anhydrous methylene chloride; trichloromethane; 1; the 2-ethylene dichloride; tetrahydrofuran (THF); dioxane; acetone; in the acetonitrile one or more, its reaction expression is:
In the formula: X is Sauerstoffatom or sulphur atom, and n is the number of carbon atom in the ring-type ketenes, n=1～20, and m is the number of carbon atom in the blocking group, m=1-2;
The described pair sulfuryl steps of optionally taking off of step (2) are: the compound (2) of carbonyl-protection is optionally taken off muskone and other 3-methyl cyclic ketones (3) that two sulfuryls obtain carbonyl-protection; temperature of reaction is 0～150 ℃; reaction solvent is one or more in benzene,toluene,xylene, methyl alcohol, ethanol, the tetrahydrofuran (THF), and its reaction expression is:
In the formula: X is Sauerstoffatom or sulphur atom, and n is the number of carbon atom in the ring-type ketenes, n=1～20, and m is the number of carbon atom in the blocking group, m=1-2;
The described decarbonylation base protection of step (2) step is: muskone and other 3-methyl cyclic ketones (3) of carbonyl-protection are taken off the carbonyl-protection base, obtain final product chirality muskone and other 3-methyl cyclic ketones (4), its reaction expression is:
In the formula: X is Sauerstoffatom or sulphur atom, and n is the number of carbon atom in the ring-type ketenes, n=1～20, and m is the number of carbon atom in the blocking group, m=1-2.
8. the asymmetric synthesis of chirality muskone according to claim 7 and other 3-methyl cyclic ketones is characterized in that, the described concrete reaction conditions of optionally taking off two sulfuryl steps of step (2) can be:
Compound (2) selectivity under the effect of methyl alcohol/magnesium of carbonyl-protection is taken off two sulfuryls, and temperature of reaction is 0～100 ℃, and solvent for use is one or more in methyl alcohol, ethanol, the tetrahydrofuran (THF);
Or under the effect of three normal-butyl stannic hydrides and Diisopropyl azodicarboxylate, optionally take off two sulfuryls, and temperature of reaction is 0～100 ℃, solvent for use is one or more in toluene, benzene, the dimethylbenzene;
Or selectivity is taken off two sulfuryls under Raney's nickel/alcoholic acid effect, and temperature of reaction is 0～100 ℃, and solvent for use is one or more in ethanol, the methyl alcohol;
Or selectivity is taken off two sulfuryls under the effect of zinc/saturated ammonium chloride, and temperature of reaction is 0～100 ℃, and solvent for use is a tetrahydrofuran (THF);
Or selectivity is taken off two sulfuryls under the effect of zinc/acid, and temperature of reaction is 0～100 ℃, and used acid is organic acid or mineral acid;
Or at means of samarium iodide (SmI
2) effect under selectivity take off two sulfuryls, temperature of reaction is 0～100 ℃, solvent for use is tetrahydrofuran (THF), methylene dichloride, trichloromethane, ethanol, 1, one or more in 4-dioxane, the acetonitrile.
9. the asymmetric synthesis of chirality muskone according to claim 7 and other 3-methyl cyclic ketones is characterized in that, the concrete reaction conditions of the described decarbonylation base protection of step (2) step can be:
Muskone and other 3-methyl cyclic ketones (3) decarbonylation base blocking group under the effect of two (trifluoroacetyl oxygen base) iodobenzene with carbonyl-protection, obtain chirality muskone and other 3-methyl cyclic ketones (4), the reaction solvent for use is one or more in methyl alcohol, water, methylene dichloride, the tetrahydrofuran (THF);
Or under the effect of iodine/sodium bicarbonate decarbonylation base blocking group, obtain chirality muskone and other 3-methyl cyclic ketones (4), the reaction solvent for use is one or more in acetone, the water;
Or under the effect of Oxone/ Potassium Bromide decarbonylation base blocking group, obtain chirality muskone and other 3-methyl cyclic ketones (4), the reaction solvent for use is one or more in acetonitrile, the water.
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| CN101362100A (en) * | 2008-09-12 | 2009-02-11 | 复旦大学 | Chiral amine-(sulphur)urea double functional catalyst and synthesis method and use thereof |
| CN101597286A (en) * | 2008-06-04 | 2009-12-09 | 中国科学院大连化学物理研究所 | A kind of organic catalyst and preparation thereof that contains primary amine, tertiary amine and urea or thiocarbamide |
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| CN101597286A (en) * | 2008-06-04 | 2009-12-09 | 中国科学院大连化学物理研究所 | A kind of organic catalyst and preparation thereof that contains primary amine, tertiary amine and urea or thiocarbamide |
| CN101362100A (en) * | 2008-09-12 | 2009-02-11 | 复旦大学 | Chiral amine-(sulphur)urea double functional catalyst and synthesis method and use thereof |
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| CN104689849A (en) * | 2015-02-11 | 2015-06-10 | 华东师范大学 | Phosphamide-(di) secondary amine dual-functional catalyst and synthesis method thereof |
| CN104689849B (en) * | 2015-02-11 | 2017-03-01 | 华东师范大学 | One class phosphamide (primary) secondary amine bifunctional catalyst and its synthetic method |
| CN105753679A (en) * | 2016-03-31 | 2016-07-13 | 常州大学 | Synthesis method for 1-chloro-1-hydroxyl-4,4-diphenyl butyl-2-ketone |
| CN108358780A (en) * | 2018-03-14 | 2018-08-03 | 广东工业大学 | The method for synthesizing α-acyloxylation ring ketone compounds of high cis-selectivity |
| CN108358780B (en) * | 2018-03-14 | 2022-04-19 | 广东工业大学 | Method for synthesizing alpha-acyloxo cyclic ketone compound with high diastereoselectivity |
| CN110903177A (en) * | 2019-12-16 | 2020-03-24 | 万华化学集团股份有限公司 | Method for preparing levo muscone |
| CN110903177B (en) * | 2019-12-16 | 2022-07-12 | 万华化学集团股份有限公司 | Method for preparing levo muscone |
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