Synthesis method of (1R, 4aR, 6S, 8aS)-6-(benzyloxy)-5, 5, 8a-trimethyl-2-methylene decahydronaphthalene-1-methanol

Abstract

The invention discloses a synthesis method of (1R, 4aR, 6S, 8aS)-6-(benzyloxy)-5, 5, 8a-trimethyl-2-methylene decahydronaphthalene-1-methanol, and belongs to the technical field of organic synthesis. The method comprises the following steps: carrying out [2, 3]-Wittig rearrangement reaction on a (4aR, 6S, 8aR)-6-(benzyloxy)-2-[[(tributyltin alkyl) methoxyl] methyl]-5, 5, 8a-trimethyl-3, 4, 4a, 5, 6, 7, 8, 8a-octahydronaphthalene compound in a reactor in an inert atmosphere under the action of n-butyllithium, and carrying out subsequent separation and purification after the reaction is finished, so as to obtain the (1R, 4aR, 6S, 8aS)-6-(benzyloxy)-5, 5, 6, 7, 8, 8a-octahydronaphthalene compound. The method comprises the following steps: adding 2, 3, 5, 8, 8a-trimethyl-2-methylene decahydronaphthalene-1-methanol into a The method provided by the invention has the advantages of simple steps, safe operation, non-toxic and easily available raw materials, simple and easy process and small pollution, and accords with the idea of green chemistry.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a ( 1R , 4aR , 6S , 8aS A method for synthesizing 6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedehydronaphthalene-1-methanol. Background Technology

[0002] ( 1R , 4aR , 6S , 8aS 6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedehydronaphthalene-1-methanol is an important synthetic intermediate for natural products, and its core C5, C10, and C9... trans-syn- The 6 / 6 trans-cyclic skeleton structure is widely found in various biological and pharmaceutically active natural products and is frequently used as a raw material for the synthesis of various diterpenes (Takamasa O., Watanabe K., Ohkubo K., et al.). Chemistry A European Journal ,2009,15(12): 2826-2845.). Starting from this type of compound, a variety of natural products with different biological activities can be synthesized, such as oleanolic acid, lupeol, and betulinic acid. More importantly, because they may exhibit drastically different pharmacological, pharmacokinetic, metabolic, and toxicological activities in vivo, the synthesis of analytically pure ( 1R , 4aR , 6S , 8aS The determination of )-6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedehydronaphthalene-1-methanol is of great significance. 1R , 4aR , 6S , 8aS There are few reports on )-6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-methanol. In 2010, EJ Corey's group reported the synthesis of its skeletal analog epimer (2S,4aS,5R,8aR)-5-hydroxymethyl-1,1,4a-trimethyl-6-methylenedecahydronaphthalene-2-ol (Ryan A. Shenvi, EJ Corey). Organic Letters December 2010 (15)(3548-3551.) This method requires a polyene cyclization reaction induced by highly toxic and flammable ethyl aluminum chloride, and the synthesis produces a wide variety of products. One byproduct is (2S,4aS,5R,8aR)-5-hydroxymethyl-1,1,4a-trimethyl-1,2,3,4,4a,5,8,8a-octahydronaphthalene-2-ol, with a maximum yield of only 47%, which significantly affects the efficiency of total synthesis of natural products. Summary of the Invention

[0003] To address the shortcomings and defects of existing technologies, the purpose of this invention is to provide a simple and efficient ( 1R , 4aR , 6S , 8aS A method for synthesizing 6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedehydronaphthalene-1-methanol.

[0004] The objective of this invention is specifically achieved through the following technical solution: A sort of( 1R , 4aR , 6S , 8aS The method for synthesizing 6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedehydronaphthalene-1-methanol includes the following steps: (1) In a reactor, under an inert atmosphere, compound 1 was dissolved in an organic solvent, cooled, n-butyllithium was added, and the mixture was heated to carry out the reaction. (2) After the reaction is complete, the reaction solution is separated and purified to obtain ( 1R , 4aR , 6S , 8aS )-6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedehydronaphthalene-1-methanol.

[0005] The structural formula of compound 1 is:

[0006] Wherein, Bn is benzyl.

[0007] Further, the organic solvent mentioned in step (1) is n-hexane.

[0008] Further, the inert atmosphere described in step (1) is a nitrogen atmosphere.

[0009] Furthermore, the cooling temperature in step (1) is -50℃. Furthermore, the temperature for heating in step (1) is 0~15℃, and the reaction time at this temperature is 6h.

[0010] Further, the molar ratio of compound 1 to n-butyllithium in step (1) is 1:2 to 1:10.

[0011] Further, the specific steps of separation and purification in step (2) are as follows: dilute the reaction system with n-hexane, quench the reaction with saturated ammonium chloride aqueous solution, extract with ethyl acetate, backwash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate the organic phase, and separate and purify by column chromatography.

[0012] Furthermore, the product obtained from the above reaction ( 1R , 4aR , 6S , 8aS )-6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methanol, compound 2((1R,4aR,6S,8aS)-6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methanol, has the following structural formula:

[0013] Wherein, Bn is benzyl.

[0014] The synthetic route of the synthesis method of the present invention is as follows:

[0015] Wherein, Bn is benzyl.

[0016] Compared with the prior art, the present invention has the following advantages: (1) The present invention is based on ( 4aR , 6S , 8aR Using 6-(benzyloxy)-2-[[(tributyltinalkyl)methoxy]methyl]-5,5,8a-trimethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalene as the raw material and n-butyllithium as the base, the raw materials are non-toxic and readily available, the synthesis steps are simple, and the operation is safe.

[0017] (2) The synthesized by this invention ( 1R , 4aR , 6S , 8aS The structural formula of 6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-methanol contains a trans-decahydronaphthalene ring, a gem-dimethyl group, and C5, C10, and C9 groups. trans-synThe relative configuration is essential in many natural products and can be further derived through various functional group transformations and cyclization reactions, such as the synthesis of the natural product oleanolic acid (Pan, D., Qu, Y., Shi, C. et al.). Chin Med ,2024,19, 74), lupeol and betulinic acid (Gebrehiwot, H., Ensermu, U., Dekebo, A. et al. Appl. Biol. Chem. 2024, 67, 48.).

[0018] (3) Compared with the prior art, the present invention significantly improves the reaction yield, and the product yield can reach 85%, which significantly improves the efficiency of subsequent natural product synthesis.

[0019] (4) In this invention, n-butyllithium is added to an organic solvent of compound 1 under an inert atmosphere, and the temperature is raised to induce a [2,3]-Wittig rearrangement reaction. After the reaction, the product is synthesized ( 1R , 4aR , 6S , 8aS )-6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedehydronaphthalene-1-methanol. 1R , 4aR , 6S , 8aS 6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedehydronaphthalene-1-methanol can be used to synthesize the natural products oleanolic acid, lupeol, and betulinic acid, which are a class of substances with anti-inflammatory activity. Attached Figure Description

[0020] Figure 1 The hydrogen spectrum of compound 1 of the present invention is shown below; Figure 2 This is the hydrogen spectrum of compound 2 of the present invention. Detailed Implementation

[0021] The present invention will be further described below with reference to specific embodiments and accompanying drawings, but the implementation of the present invention is not limited thereto.

[0022] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the reagents, solvents, etc., used in the following examples are commercially available products.

[0023] The products prepared in the following examples were all stored below 0°C.

[0024] Example 1 ( 1R , 4aR , 6S , 8aS The method for synthesizing 6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedehydronaphthalene-1-methanol includes the following steps: Compound 1 (50.0 mg, 0.081 mmol) was weighed into a 4 mL reaction flask, evacuated with a vacuum pump, and then purged with nitrogen. Hexane (2 mL) was added. The mixture was cooled to -50 °C, and then butyllithium (1.6 M in hexane, 0.10 mL, 0.162 mmol) was added to the flask. The mixture was heated to 15 °C and reacted for 6 h. The reaction mixture was diluted with hexane, the reaction was quenched with saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate, and the combined organic phases were backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated using a preparative silica gel column (petroleum ether / ethyl acetate = 20:1) to give compound 2 (yellow oil, 5.3 mg, yield: 20%).

[0025] The synthesis route is as follows:

[0026] Example 2 ( 1R , 4aR , 6S , 8aS The method for synthesizing 6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedehydronaphthalene-1-methanol includes the following steps: Compound 1 (50.0 mg, 0.081 mmol) was weighed into a 4 mL reaction flask, evacuated with a vacuum pump, and then purged with nitrogen. Hexane (2 mL) was added. The mixture was cooled to -50 °C, and then butyllithium (1.6 M in hexane, 0.25 mL, 0.405 mmol) was added to the flask. The mixture was heated to 15 °C and reacted for 6 h. The reaction mixture was diluted with hexane, the reaction was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, and the combined organic phases were backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated using a preparative silica gel column (petroleum ether / ethyl acetate = 20:1) to give compound 2 (yellow oil, 16.2 mg, yield: 61%).

[0027] The synthesis route is as follows:

[0028] Example 3 ( 1R , 4aR , 6S ,8aS The method for synthesizing 6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedehydronaphthalene-1-methanol includes the following steps: Compound 1 (50.0 mg, 0.081 mmol) was weighed into a 4 mL reaction flask, evacuated with a vacuum pump, and then purged with nitrogen. Anhydrous n-hexane (2 mL) was added. The mixture was cooled to -50 °C, and then n-butyllithium (1.6 M in hexane, 0.51 mL, 0.81 mmol) was added to the reaction flask. The mixture was heated to 15 °C and reacted for 6 h. The reaction mixture was diluted with n-hexane, the reaction was quenched with saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate, and the combined organic phases were backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated using a preparative silica gel column (petroleum ether / ethyl acetate = 20:1) to give compound 2 (yellow oil, 22.6 mg, yield: 85%).

[0029] The synthesis route is as follows:

[0030] Example 4 ( 1R , 4aR , 6S , 8aS The method for synthesizing 6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedehydronaphthalene-1-methanol includes the following steps: Compound 1 (50.0 mg, 0.081 mmol) was weighed into a 4 mL reaction flask, evacuated with a vacuum pump, and then purged with nitrogen. Hexane (2 mL) was added. The mixture was cooled to -50 °C, and then butyllithium (1.6 M in hexane, 0.51 mL, 0.81 mmol) was added. The mixture was heated to 0 °C and reacted for 6 h. The reaction mixture was diluted with hexane, the reaction was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, and the combined organic phases were backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated using a preparative silica gel column (petroleum ether / ethyl acetate = 20:1) to give compound 2 (yellow oil, 19.1 mg, yield: 72%).

[0031] The synthesis route is as follows:

[0032] The yield of compound 2 synthesized in Examples 1-4 varied considerably due to the influence of the n-butyllithium equivalent and the reaction temperature. Analysis of the above results indicates that using n-hexane as a solvent and reacting at 15 °C yields a better product.

[0033] The structures of all compounds in Examples 1-4 above were confirmed by nuclear magnetic resonance spectroscopy. Figure 1 The hydrogen spectrum of compound 1 is shown below. Figure 2 The following is the proton NMR spectrum of compound 2. Identification data are as follows: Compound 1: 1 H NMR (400 MHz, Chloroform- d ) δ 7.38 – 7.30 (m, 4H), 7.29 – 7.27 (m,1H), 5.30 (d, J = 3.4 Hz, 1H), 4.68 (d, J = 11.8 Hz, 1H), 4.44 (d, J = 11.8 Hz,1H), 3.70 – 3.61 (m, 4H), 2.97 (dd, J = 11.5, 4.4 Hz, 1H), 2.09 (dd, J = 17.6,6.3 Hz, 1H), 2.00 – 1.85 (m, 2H), 1.74 (dd, J = 13.2, 7.0 Hz, 1H), 1.67 – 1.60(m, 1H), 1.53 – 1.46 (m, 6H), 1.36 – 1.23 (m, 9H), 1.06 (dd, J = 12.5, 2.0 Hz,1H), 1.01 (s, 3H), 0.97 (s, 3H), 0.92 – 0.86 (m, 18H). Compound 2: 1 H NMR (400 MHz, Chloroform- d ) δ 7.38 – 7.30 (m, 4H), 7.31 – 7.22 (m,1H), 4.94 (t, J = 2.3 Hz, 1H), 4.77 (t, J = 2.2 Hz, 1H), 4.67 (d, J = 11.9 Hz, 1H), 4.43 (d, J = 11.8 Hz, 1H), 3.73 (dd, J = 10.0, 5.1 Hz, 1H), 3.56 (t, J=10.4 Hz, 1H), 2.92 (dd, J = 11.5, 4.2 Hz, 1H), 2.34-2.26 (m, 1H), 2.16-2.03 (m, 1H), 1.96-1.84 (m, 2H), 1.72-1.64 (m, 1H), 1.65-1.53 ​​(m, 1H),1.50 – 1.39 (m, 2H), 1.36 – 1.28 (m, 2H), 1.01 (s, 3H), 0.98 (s, 3H), 0.85 (s, 3H). The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A kind of ( 1R , 4aR , 6S , 8aS The method for synthesizing 6-(benzyloxy)-5,5,8a-trimethyl-2-methylenedehydronaphthalene-1-methanol is characterized by, comprising the steps of: (1) dissolving compound 1 in an organic solvent in a reactor under an inert atmosphere, cooling, adding n-butyllithium, and then warming to react; (2) After the reaction is completed, the reaction solution is separated and purified, to obtain 1R , 4aR , 6S , 8aS )-6-(benzyloxy)-5,5,8a-trimethyl-2-methylene-decahydronaphthalen-1-methanol; The structural formula of the compound 1 is wherein Bn is benzyl.

2. The method of claim 1 wherein the compound is 1R , 4aR , 6S , 8aS The synthesis of (2S, 5S, 6S, 7R, 8aS)-6-(benzyloxy)-5,5,8a-trimethyl-2- methylenetetrahydro-2H-pentalen-1 -methanol is characterized by The synthetic route is as follows: 。 3. The method of claim 1, 1R , 4aR , 6S , 8aS A process for the synthesis of (3R,4S,5S,6S)-6-(benzyloxy)-5,5,8a- trimethyl-2-methylenedecahydro-1-naphthalenemethanol, characterized in that, The organic solvent in step (1) is n-hexane.

4. The method of claim 1, 1R , 4aR , 6S , 8aS A process for the synthesis of (E)-6-(benzyloxy)-5,5,8a-trimethyl-2- methylenetetrahydro naphthalene-1 -methanol, characterized by, The inert atmosphere in step (1) is a nitrogen atmosphere.

5. The method of claim 1, 1R , 4aR , 6S , 8aS The synthesis of (5S)-6-(benzyloxy)-5,5,8a-trimethyl-2-methylenetetrahydro- naphthalene-1 -methanol is characterized by, The molar ratio of compound 1 to n-butyllithium in step (1) is 1:2-1:

10.

6. The method of claim 1, 1R , 4aR , 6S , 8aS A process for the synthesis of (E)-6-(benzyloxy)-5,5,8a-trimethyl-2- methylenetetrahydro naphthalene-1 -methanol, characterized by, The temperature of cooling in step (1) is -50°C.

7. The method of claim 1, 1R , 4aR , 6S , 8aS A process for the synthesis of (R)-6-(benzyloxy)-5,5,8a-trimethyl-2- methylenetetrahydro naphthalene-1 -methanol, characterized by, The temperature of warming in step (1) is 0-15°C, and the reaction time at this temperature is 6 h.

8. The method of claim 1, 1R , 4aR , 6S , 8aS A process for the synthesis of (R)-6-(benzyloxy)-5,5,8a-trimethyl-2- methylenetetrahydro naphthalene-1 -methanol, characterized by, The specific steps of separation and purification in step (2) are as follows: diluting the reaction system with n-hexane, quenching the reaction with saturated ammonium chloride aqueous solution, extracting with ethyl acetate, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating the organic phase, and column chromatography separation and purification.

9. A compound synthesized according to the method of any one of claims 1-8 1R , 4aR , 6S , 8aS )-6-(benzyloxy)-5,5,8a-trimethyl-2-methylenetetrahydro- naphthalene-1 -methanol.

10. The compound of claim 9 1R , 4aR , 6S , 8aS Application of 6-(benzyloxy)-5,5,8a-trimethyl-2-methylene-decahydronaphthalene-1- methanol in the synthesis of oleanolic acid, lupeol, betulinic acid.

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