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Asymmetric synthesis of chiral muskone and other 3-methyl cyclic ketone

A technology of methyl cyclic ketone and muskone, applied in the chemical field, can solve the problems of waste, low yield, low enantioselectivity, etc., and achieve the effects of high conversion rate, good selectivity, and high optical purity

Inactive Publication Date: 2011-03-02
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 2007, Knopff et al disclosed the use of asymmetric intramolecular Aldol to generate a chiral center, followed by Eschenmoser cleavage and hydrogenation to obtain (R)-musketone with 76% ee (Angew.Chem.Int.Ed.2007, 46, 1307), however, the enantioselectivity of this method is too low
In 2005, people such as Takabe applied the method of chiral resolution, and under the effect of tartaric acid derivatives, racemic 3-methylpentadecanone was resolved into (R), (S)-muscone, with this method The enantioselectivity of (R)-muscone that obtains is more than 98%, and the diastereoselectivity is greater than 99: 1 (Tetrahedron Letters, 2005,46,3457), but, the yield of this method is lower and easily causes waste of the other enantiomer

Method used

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  • Asymmetric synthesis of chiral muskone and other 3-methyl cyclic ketone
  • Asymmetric synthesis of chiral muskone and other 3-methyl cyclic ketone
  • Asymmetric synthesis of chiral muskone and other 3-methyl cyclic ketone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] The reaction formula is:

[0057]

[0058] In 0.5 mL of 1,4-dioxane, add bisphenylsulfonylmethane (322 mg, 0.75 mmol), pentadecenone (111 mg, 0.5 mmol), benzoic acid (24.4 mg, 0.2 mmol), catalyst ( 9)(R 5 is methoxy, R 6 Vinyl) (32.3mg, 0.1mmol), placed at 35°C and stirred for 4 days after the feeding was completed. After the reaction conversion was complete, the reaction liquid was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate=10: 1) 192mg of the addition product was isolated as a white solid with a yield of 74%, a melting point of 142-144°C, and an optical rotation [α] 24 D =-20.0° (c=1.00, CH 2 Cl 2 ); 1 H 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). 13 CNMR (100MHz, CDCl 3 ): δ (ppm) 209.8, 140.3, 138.3, 134....

Embodiment 2

[0060] The difference from Example 1 is that the cyclic enone used is 3-cyclohexen-2-one, the reaction temperature is 4°C, other experimental methods and conditions are the same as in Example 1, and the addition product of white solid is obtained , the yield is 81%, the melting point is 176~177℃, the optical rotation [α] 23 D =-8.5° (c=1.0, CH 2 Cl 2 ); 1 H 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). 13 C 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 19 h 24 NO 5 S 2 ) 410.1096, actually obtained 410.1091; obtain chiral analysis by HPLC, concrete conditions are: [IA column, 220nm, n-Hexane: DCM=2: 1, 0.8mL / min]: 27.5min (primary), 31.7min (secondary ), ee=95%.

Embodiment 3

[0062] The difference from Example 1 is that the cyclic enone used is 3-cyclohepten-2-one, other experimental methods and conditions are the same as in Example 1, and the addition product of a white solid is obtained with a yield of 92%. , melting point 212~214℃; optical rotation [α] 23 D =-43.6° (c=0.50, CH 2 Cl 2 ); 1 H 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). 13 C 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 20 h 26 NO 5 S 2 ) is 424.1252, and the actual result is 424.1250; chiral analysis is obtained by HPLC, and the specific conditions are: [IA column, 220nm, Hexane: DCM=2: 1, 0.8mL / min]: 20.9min (time), 24.3min (main) , ee=92%.

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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】 [0001] The invention relates to the field of chemical technology, and relates to the asymmetric synthesis of chiral muskone and other 3-methyl cyclic ketones, specifically, a method for synthesizing R-muskone and other 3-methyl cyclic ketones by using asymmetric Michael addition reaction. cyclic ketone method. 【Background technique】 [0002] Natural muskone is (R)-3-methylcyclopentadecanone, which is a kind of precious spice with a sweet and strong aroma, very low aroma value (0.01-0.001ppm) and long-lasting fragrance. expensive. Natural musk is also a valuable traditional Chinese medicine. It is produced in the sachets of male musk deer musk deer, and the content of muskone is 1.2-1.4%. According to Chinese Pharmacopoeia, musk has the functions of stimulating the nerve center, respiratory center and heart, and promoting the secretion of various glands. It is an important drug for the treatment of coma. It is famous for treating middle-qi, middle-evil an...

Claims

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Application Information

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IPC IPC(8): C07C49/385C07C45/56C07C45/59C07C45/60C07B53/00B01J31/02
CPCY02P20/55
Inventor 叶金星孙小敏
Owner EAST CHINA UNIV OF SCI & TECH
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