Enantiomorphous-kaurene diterpene and derivative and preparation method thereof

Abstract

The invention belongs to the field of chemical synthesis, and particularly relates to a method for transforming an alpha-methylene cyclopentanone structural unit in enantiomorphous-kaurene diterpene containing the alpha-methylene cyclopentanone structural unit into a cyclobutyl ortho-diketone structural unit, enantiomorphous-kaurene diterpene containing the alpha-methylene cyclopentanone structural unit obtained with the method, and an enantiomorphous-kaurene diterpene 'natural' derivative derived from the type of compound. The enantiomorphous-kaurene diterpene containing the alpha-methylene cyclopentanone structural unit and the derived enantiomorphous-kaurene diterpene 'natural' derivative keep the antitumor bioactivity of the original enantiomorphous-kaurene diterpene, and can be used for preparing an antitumor medicament.

Description

technical field

[0001] The invention belongs to the field of chemical synthesis, more specifically, relates to a kind of α-methylene cyclopentane in the enantio-kaurane type (ent-kaurane) diterpene containing α-methylene cyclopentanone structural unit Method for converting ketone structural unit into cyclobutanedione structural unit, and enantio-kaurane-type diterpenes containing cyclobutanedione structural unit obtained therefrom and enantio-kaurene diterpenes derived from such compounds "Natural-like" derivatives of diterpenoids of the chanane type. Ent-kaurane-type diterpenes containing cyclobutane-dione structural units and derived ent-kaurane-type diterpenes "natural" derivatives, retaining the original ent-kaurene-type diterpenes The antitumor biological activity of the terpene can be used to prepare antitumor drugs. Background technique

[0002] Natural products play an important role in the field of drug discovery. Their extensive biological activities are derived ...

Examples

Embodiment 1

[0125] Example 1 Synthesis of Oridonin A Cyclobutanedione

[0126] (1) Synthesis of oridonin cyclobutanedione (i.e. compound 1)

[0127]

[0128] Get Rubescensine A (1.5g, 4.12mmol; Specification: 95%, purchased from Xi'an Haoxuan Biotechnology Co., Ltd.) and dissolve it in dichloromethane (100mL) and methanol (20mL), cool in an ice-salt bath and control the internal temperature. Temperature (-5-15°C), blow oxygen containing ozone under the liquid surface of the above system at a speed of 2-4L / min (BGF-YQ type ozone generator, 2g / h, 60W, Beijing Beili Guoke Ozone Application Technology Co., Ltd.), and continue blowing for 0.5-1.5h. At this time, the color of the system is a yellow solution, and TLC detects that the raw materials have reacted completely (the developer is: chloroform / acetone / methanol=8 / 1 / 1(v / v / v), 10 wt% phosphomolybdic acid color). Then, excess ozone in the reaction system was removed by bubbling nitrogen gas, and dimethyl sulfide (1.5 mL) was added to the ...

Embodiment 2

[0136] Example 2 Synthesis of Oridonin Pyrazine Derivatives

[0137]

[0138] Compound 1 (200mg, 0.55mmol) was dissolved in methanol (15mL), o-phenylenediamine (300mg, 2.78mmol) was added to the resulting solution at room temperature, and reacted overnight with stirring, the system became a brownish yellow solution, and the reaction of raw materials was detected by TLC. completely. After the reaction system was concentrated, the residue obtained was purified by silica gel column chromatography (chloroform / methanol=25 / 1, 20 / 1, by volume ratio), and the eluent from the product point was collected and concentrated to obtain compound 2 as a light yellow solid. (180 mg), molar yield: 75%.

[0139] 1 H NMR (300MHz, DMSO-d 6 ): δ1.17(s, 3H), 1.20(s, 3H), 1.92(m, 1H), 2.43(m, 2H), 3.26(m, 2H), 3.67(dd, J=6.0, 9.9Hz, 1H), 3.97, 4.27(2d, J=9.9Hz, each 1H), 4.34(d, J=4.8Hz, 1H), 5.17(s, 1H), 6.22(s, 1H), 6.84(s, 1H) , 7.71 (d, J = 10.2 Hz, 1H), 7.79 (m, 2H), 7.92 (m, 1H), 8.03 (m...

Embodiment 3

[0178] Example 3 Synthesis of Rubescensine A Dihydropyrazine Derivatives

[0179]

[0180] Using ethylenediamine as a raw material, referring to the operation of Example 2 (1), Compound 15 was obtained.

[0181] 1 H NMR (300MHz, CDCl 3 ): δ1.03-1.08(2s, 6H), 1.88(m, 1H), 2.05, 2.44(2m, 2H), 2.87(d, J=10.5Hz, 1H), 3.43-3.67(m, 6H), 3.71 (d, J=6.6Hz, 1H), 4.09, 4.29 (2d, J=10.2Hz, each 1H), 4.89 (s, 1H), 5.05, 6.00, 7.98 (3br s, 3H). ESI-MS (m / z): 391.2 (M+H)+ (C 21 h 31 N 2 o 5 , theoretical value: 391.22).

[0182]

[0183] Using o-diaminocyclohexane as a raw material, refer to the operation of Example 2 (1) to obtain compound 16.

[0184] 1 H NMR (300MHz, DMSO-d 6 ): δ1.02-1.08(2s, 6H), 2.06(m, 1H), 2.58-2.61(m, 2H), 3.17-3.25(m, 2H), 3.40-3.48(m, 3H), 3.86, 4.11 (2d, J=9.9Hz, each 1H), 4.31-4.33 (m, 1H), 4.73 (s, 1H), 5.86-6.03 (m, 1H), 6.63-7.51 (m, 2H). ESI-MS (m / z): 445.2 (M+H) + (C 25 h 37 N 2 o 5 , theoretical value: 445.27).

technical field

[0001] The invention belongs to the field of chemical synthesis, more specifically, relates to a kind of α-methylene cyclopentane in the enantio-kaurane type (ent-kaurane) diterpene containing α-methylene cyclopentanone structural unit Method for converting ketone structural unit into cyclobutanedione structural unit, and enantio-kaurane-type diterpenes containing cyclobutanedione structural unit obtained therefrom and enantio-kaurene diterpenes derived from such compounds "Natural-like" derivatives of diterpenoids of the chanane type. Ent-kaurane-type diterpenes containing cyclobutane-dione structural units and derived ent-kaurane-type diterpenes "natural" derivatives, retaining the original ent-kaurene-type diterpenes The antitumor biological activity of the terpene can be used to prepare antitumor drugs. Background technique

[0002] Natural products play an important role in the field of drug discovery. Their extensive biological activities are derived ...

Examples

Embodiment 1

[0125] Example 1 Synthesis of Oridonin A Cyclobutanedione

[0126] (1) Synthesis of oridonin cyclobutanedione (i.e. compound 1)

[0127]

[0128] Get Rubescensine A (1.5g, 4.12mmol; Specification: 95%, purchased from Xi'an Haoxuan Biotechnology Co., Ltd.) and dissolve it in dichloromethane (100mL) and methanol (20mL), cool in an ice-salt bath and control the internal temperature. Temperature (-5-15°C), blow oxygen containing ozone under the liquid surface of the above system at a speed of 2-4L / min (BGF-YQ type ozone generator, 2g / h, 60W, Beijing Beili Guoke Ozone Application Technology Co., Ltd.), and continue blowing for 0.5-1.5h. At this time, the color of the system is a yellow solution, and TLC detects that the raw materials have reacted completely (the developer is: chloroform / acetone / methanol=8 / 1 / 1(v / v / v), 10 wt% phosphomolybdic acid color). Then, excess ozone in the reaction system was removed by bubbling nitrogen gas, and dimethyl sulfide (1.5 mL) was added to the ...

Embodiment 2

[0136] Example 2 Synthesis of Oridonin Pyrazine Derivatives

[0137]

[0138] Compound 1 (200mg, 0.55mmol) was dissolved in methanol (15mL), o-phenylenediamine (300mg, 2.78mmol) was added to the resulting solution at room temperature, and reacted overnight with stirring, the system became a brownish yellow solution, and the reaction of raw materials was detected by TLC. completely. After the reaction system was concentrated, the residue obtained was purified by silica gel column chromatography (chloroform / methanol=25 / 1, 20 / 1, by volume ratio), and the eluent from the product point was collected and concentrated to obtain compound 2 as a light yellow solid. (180 mg), molar yield: 75%.

[0139] 1 H NMR (300MHz, DMSO-d 6 ): δ1.17(s, 3H), 1.20(s, 3H), 1.92(m, 1H), 2.43(m, 2H), 3.26(m, 2H), 3.67(dd, J=6.0, 9.9Hz, 1H), 3.97, 4.27(2d, J=9.9Hz, each 1H), 4.34(d, J=4.8Hz, 1H), 5.17(s, 1H), 6.22(s, 1H), 6.84(s, 1H) , 7.71 (d, J = 10.2 Hz, 1H), 7.79 (m, 2H), 7.92 (m, 1H), 8.03 (m...

Embodiment 3

[0178] Example 3 Synthesis of Rubescensine A Dihydropyrazine Derivatives

[0179]

[0180] Using ethylenediamine as a raw material, referring to the operation of Example 2 (1), Compound 15 was obtained.

[0181] 1 H NMR (300MHz, CDCl 3 ): δ1.03-1.08(2s, 6H), 1.88(m, 1H), 2.05, 2.44(2m, 2H), 2.87(d, J=10.5Hz, 1H), 3.43-3.67(m, 6H), 3.71 (d, J=6.6Hz, 1H), 4.09, 4.29 (2d, J=10.2Hz, each 1H), 4.89 (s, 1H), 5.05, 6.00, 7.98 (3br s, 3H). ESI-MS (m / z): 391.2 (M+H)+ (C 21 h 31 N 2 o 5 , theoretical value: 391.22).

[0182]

[0183] Using o-diaminocyclohexane as a raw material, refer to the operation of Example 2 (1) to obtain compound 16.

[0184] 1 H NMR (300MHz, DMSO-d 6 ): δ1.02-1.08(2s, 6H), 2.06(m, 1H), 2.58-2.61(m, 2H), 3.17-3.25(m, 2H), 3.40-3.48(m, 3H), 3.86, 4.11 (2d, J=9.9Hz, each 1H), 4.31-4.33 (m, 1H), 4.73 (s, 1H), 5.86-6.03 (m, 1H), 6.63-7.51 (m, 2H). ESI-MS (m / z): 445.2 (M+H) + (C 25 h 37 N 2 o 5 , theoretical value: 445.27).

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