CN115677711A - Method for preparing spirocycloxyindole natural product spirotriptatin A - Google Patents

Method for preparing spirocycloxyindole natural product spirotriptatin A Download PDF

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CN115677711A
CN115677711A CN202211201485.1A CN202211201485A CN115677711A CN 115677711 A CN115677711 A CN 115677711A CN 202211201485 A CN202211201485 A CN 202211201485A CN 115677711 A CN115677711 A CN 115677711A
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compound
natural product
preparing
spirooxindole
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CN115677711B (en
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彭天凤
沈先福
陈梦华
童曼婷
徐文璐
晏欣
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Qujing Normal University
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Abstract

The invention discloses a method for preparing a spiro-epoxidised indole natural product spirotrpostatin A, belonging to the technical field of organic synthesis. The preparation method takes an o-iodo aniline compound as a starting material to prepare the spirooxindole natural product spirootrystatin A. The preparation method provided by the invention has mild reaction conditions, adopts cheap metal cuprous iodide as a catalyst, has low energy consumption, is beneficial to environmental protection and is beneficial to preparing a large amount of spirotropic indole natural product spirotropic statin A; the method also has the characteristics of better atom economy and high product yield; the method has the advantages of short synthetic route and simple reaction operation process.

Description

Method for preparing spirocycloxyindole natural product spirotriptatin A
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for preparing a spiro-epoxidized indole natural product spirotrpostatin A.
Background
In recent years, the structural unit of spiro-oxindole is a key synthon or intermediate for synthesizing a plurality of natural products and bioactive molecules, and has wide pharmacological activities such as tumor resistance, anxiety resistance, inflammation diminishing, blood pressure reduction, fever reduction, pain easing and the like. The spiro oxindole skeleton is widely present in indole alkaloids, is a common dominant skeleton of hundreds of natural products, and has good medicinal value or potential pharmaceutical properties. In recent years, the synthesis and biological activity research of the compounds attract more and more interests of synthetic chemists and medicinal chemists. Due to the special structure and important biological activity of the compounds, the development of a new reaction for efficiently synthesizing the spiro-oxindole compound is particularly important, is always a hotspot in the field of organic synthetic chemistry, and has important significance for drug research and development. In 1996, spirooxindole natural product spirootrystatin A was first isolated from the fermentation broth of the fungus Aspergillus fumigatus by Osada and colleagues, and it showed inhibitory activity on the progression of the G2/M phase mammalian cell cycle, suggesting that it may be used as a lead compound of clinical candidate anticancer drugs.
At present, the preparation method of the spiro oxindole natural product spirootrystatin A has the advantages of longer total synthetic route, lower total reaction yield and the need of noble metal palladium as a catalyst, and most of the existing synthetic routes need indole or oxindole compounds as starting materials, so that the preparation of the compounds is seriously influenced, and the further research on the compounds and analogues thereof is limited.
Disclosure of Invention
The invention aims to provide a method for preparing a spiro-epoxidised indole natural product spirotriptostatin A. The preparation method disclosed only uses cheap metal cuprous iodide as a catalyst, and has the advantages of little pollution to the environment, few reaction steps and high yield.
In order to achieve the purpose, the invention provides the following technical scheme:
provides a method for preparing a spiro-epoxidised indole natural product spirotriptostatin A, which comprises the following steps:
(1) Mixing an o-iodoaniline compound, cuprous iodide and lithium bis (trimethylsilyl) amide, adding a solvent, heating to react under the protection of inert gas, and then adding acetylenic ketone to prepare an oxindole compound containing a chiral quaternary carbon center;
(2) Dissolving the oxindole compound containing the chiral quaternary carbon center, and adding a hydrochloric acid solution for reaction to prepare a chiral spiro oxindole compound;
(3) Removing the p-methoxybenzyl of the chiral spiro oxoindole compound to prepare an oxoindole compound;
(4) Dissolving the indole oxide compound, adding osmium tetroxide and N-methyl morpholine oxide for reaction, and then adding sodium periodate to prepare an aldehyde compound;
(5) Oxidizing the aldehyde compound into a carboxylic acid compound, and then adding (trimethylsilane) diazomethane to prepare a methyl ester compound;
(6) Removing benzyl protection from the methyl ester compound to prepare an amino compound;
(7) Mixing the amino compound with N- (9-fluorenylmethoxycarbonyl) -L-proline, adding a condensing agent for condensation reaction, then removing the protection of fluorenylmethoxycarbonyl, and further carrying out ammonolysis reaction to obtain a spiro indole diketopiperazine compound;
(8) Reacting the spiro indole diketopiperazine compound with methyl magnesium bromide to prepare a hydroxyl compound;
(9) And reacting the hydroxyl compound with p-toluenesulfonic acid to obtain a spirooxindole natural product spirootryprostatin A.
Preferably, the solvent in step (1) is tetrahydrofuran; the heating reaction temperature is 70 ℃, and the time is 7-8h.
Preferably, the concentration of the hydrochloric acid solution in the step (2) is 1mol/L.
Preferably, the reactant used for the removal of the p-methoxybenzyl group in step (3) is trifluoromethanesulfonic acid.
Preferably, the oxidizing agent used in the oxidation in step (5) is sodium chlorite.
Preferably, the removal of benzyl protection in step (6) is carried out in hydrogen over a palladium/carbon catalyst.
Preferably, the condensing agent in step (7) is bis (2-oxo-3-oxazolidinyl) phosphoryl chloride; the removal of fluorenylmethyloxycarbonyl protection is carried out in piperidine.
Preferably, the steps (1) to (9) further comprise a purification step.
The invention has the following beneficial technical effects:
1. the preparation method provided by the invention has mild reaction conditions, adopts cheap metal cuprous iodide as a catalyst, has low energy consumption, is beneficial to environmental protection and is beneficial to preparing a large amount of spirotropic indole natural product spirotropic statin A.
2. The preparation method provided by the invention has better atom economy and high product yield.
3. The preparation method provided by the invention has the advantages of short synthetic route and simple reaction operation process.
Drawings
FIG. 1 is a flow chart of the preparation of spirooxindole natural product spirootryprostatin A in example 1 of the present invention.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every intervening value, to the extent any stated value or intervening value in a stated range, and any other stated or intervening value in a stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, 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 belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.
As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including, but not limited to.
The invention provides a method for preparing a spiro-epoxidised indole natural product spirotrpostatin A, which comprises the following steps:
(1) Mixing an o-iodoaniline compound, cuprous iodide and lithium bis (trimethylsilyl) amide, adding a solvent, heating to react under the protection of inert gas, and then adding acetylenic ketone to prepare an oxindole compound containing a chiral quaternary carbon center;
taking the alkynone in the step (1) as a tandem reagent;
(2) Dissolving the oxindole compound containing the chiral quaternary carbon center, and adding a hydrochloric acid solution for reaction to prepare a chiral spiro oxindole compound;
adding a hydrochloric acid solution into the step (2) to perform a reaction of firstly removing sulfinyl of the oxindole oxide compound containing the chiral quaternary carbon center and then performing aza-Michael addition reaction;
(3) Removing the p-methoxybenzyl of the chiral spiro oxoindole compound to prepare an oxoindole compound;
(4) Dissolving the indole oxide compound, adding osmium tetroxide and N-methylmorpholine oxide for reaction, and then adding sodium periodate to prepare an aldehyde compound;
adding osmium tetroxide and N-methylmorpholine oxide in the step (4) to perform a dihydroxylation reaction; the sodium periodate is added to cut off the vicinal diol compound;
(5) Oxidizing the aldehyde compound into a carboxylic acid compound, and then adding (trimethylsilane) diazomethane to prepare a methyl ester compound;
(6) Removing benzyl protection from the methyl ester compound to prepare an amino compound;
(7) Mixing the amino compound with N- (9-fluorenylmethoxycarbonyl) -L-proline, adding a condensing agent for condensation reaction, then removing the protection of fluorenylmethoxycarbonyl, and further carrying out ammonolysis reaction to obtain a spiro indole diketopiperazine compound;
(8) Reacting the spiro indole diketopiperazine compound with methyl magnesium bromide to obtain a hydroxyl compound;
(9) And reacting the hydroxyl compound with p-toluenesulfonic acid to obtain a spiro-oxindole natural product spirotyrostatin A.
Further, the solvent in the step (1) is tetrahydrofuran; the heating reaction temperature is 70 ℃, and the time is 7-8h.
Further, the concentration of the hydrochloric acid solution in the step (2) is 1mol/L.
Further, the reactant used for removing the p-methoxybenzyl group in the step (3) is trifluoromethanesulfonic acid.
Further, the oxidizing agent used in the oxidation in the step (5) is sodium chlorite.
Further, the benzyl group removal protection in the step (6) is carried out in hydrogen, and the catalyst is palladium/carbon catalyst.
Further, the condensing agent in the step (7) is bis (2-oxo-3-oxazolidinyl) phosphoryl chloride; the removal of fluorenylmethyloxycarbonyl protection is carried out in piperidine.
Further, the steps (1) to (9) further include a purification step.
The specific embodiment is as follows:
example 1
Preparation of spirooxindole natural product spirotriptatin A (the preparation flow chart is shown in figure 1):
(1) Synthesis of Compound 2, the reaction scheme is as follows:
Figure BDA0003872202120000061
cuprous iodide (CuI, 380mg,2.0mmol, 0.1 equiv) and compound 1 (13.5g, 20.0mmol) were weighed in a 500mL double-necked round-bottomed flask, degassed three times under the protection of high-purity nitrogen gas, anhydrous tetrahydrofuran (300 mL) was added, and stirred at room temperatureBis-trisilyl lithium (1.0M in THF,40mL,40mmol,2.0 equiv), degassed three more times, and reacted for 7 hours under oil bath heating at 70 deg.C, with high purity nitrogen protection required throughout the reaction. Then, the heating was stopped, the temperature was returned to room temperature, cooled to 0 ℃ again, and 3-butyn-2-one (3.9mL, 50 mmol, 2.5equiv) was added and reacted at 0 ℃ for 5 hours. And (3) post-treatment: adding saturated Na 2 S 2 O 3 The solution (40 mL) and a saturated ammonium chloride solution (40 mL) were stirred for 30 minutes, then 100mL of water was added, ethyl acetate (3 × 200 mL) was extracted, dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and silica gel column chromatography (petroleum ether 60-90 ℃: ethyl acetate =2:1 → 1:1) gave compound 2, which compound 2 consisted of compound 2a (7.37g, 60%) which is a pale yellow liquid of formula E and compound 2b (2.45g, 20%) which is a yellow liquid of formula Z.
Characterization data for compound 2a of formula E are as follows:
[α] 20 D -40.4(c 0.55,CHCl 3 ).FTIR(KBr,thin film)cm -1 :3306, 2925,1699,1651,1645,1505,1378,1249,1167. 1 H NMR(400MHz, CDCl 3 )δ7.40–7.25(m,6H),6.96(d,J＝8.6Hz,2H),6.93(d,J＝8.2 Hz,1H),6.85(d,J＝16.2Hz,1H),6.66(d,J＝8.6Hz,2H),6.44(d,J＝ 8.2,2.2Hz,1H),6.25(d,J＝2.2Hz,1H),5.94(d,J＝16.1Hz,1H),5.41 –5.29(m,1H),4.76(d,J＝15.2Hz,1H),4.58(d,J＝17.0Hz,1H),4.46 (s,1H),4.41(d,J＝4.9Hz,1H),4.11(d,J＝17.0Hz,1H),3.87(d,J＝ 17.0Hz,1H),3.76(s,3H),3.78–3.72(m,1H),3.72(s,3H),3.21(t,J＝ 9.7Hz,1H),2.78(dd,J＝13.5,1.4Hz,1H),2.59(dd,J＝13.5,11.0Hz, 1H),2.27(s,3H),1.15(s,9H). 13 C NMR(100MHz,CDCl 3 )δ198.53, 175.94,160.49,159.08,146.51,143.83,137.86,137.61,130.55,129.11, 128.98,128.69,128.57,127.79,127.62,127.23,125.82,120.44,116.90, 114.23,106.09,97.76,61.81,58.26,55.57,55.34,53.34,46.23,43.64, 38.97,27.26,23.45.HRMS(ESI-TOF)m/z[M+H] + calcd for C 36 H 43 N 2 O 5 S：615.2887,found 615.2888.
characterization data for compound 2b of formula Z are as follows:
[α] 20 D -48.2(c 0.32,CHCl 3 ).FTIR(KBr,thin film)cm -1 :3290, 2957,2837,1694,1660,1514,1247,1034,736. 1 H NMR(400MHz, CDCl 3 )δ7.38–7.20(m,6H),6.95(d,J＝8.5Hz,2H),6.82(d,J＝8.1 Hz,1H),6.65(d,J＝8.6Hz,2H),6.32(dd,J＝8.2,2.2Hz,1H),6.22– 6.10(m,3H),5.37–5.26(m,1H),5.01(d,J＝15.2Hz,1H),4.54(d,J＝ 16.9Hz,1H),4.37(d,J＝10.2Hz,1H),4.30(d,J＝15.2Hz,1H),4.07 (d,J＝16.8Hz,1H),3.78(s,3H),3.83–3.69(m,2H),3.67(s,3H),3.21 (t,J＝9.1Hz,1H),2.79(d,J＝12.9Hz,1H),2.61(t,J＝12.4Hz,1H), 2.03(s,3H),1.13(s,9H). 13 C NMR(100MHz,CDCl 3 )δ198.34,177.12, 160.04,158.83,145.78,142.95,137.99,137.34,129.37,129.28,128.95, 128.69,128.47,127.91,127.25,123.52,122.73,116.50,114.10,113.98, 105.70,96.92,61.08,58.24,55.40,55.35,51.78,46.27,44.30,43.16, 30.86,30.86,23.46.HRMS(ESI-TOF)m/z[M+H] + calcd for C 36 H 43 N 2 O 5 S：615.2887,found 615.2888.
(2) Synthesis of Compound 3, the reaction scheme is as follows:
Figure BDA0003872202120000081
compound 2 (614mg, 1.0 mmol) was dissolved in 20mL of dimethyl sulfoxide, followed by slow addition (1 mL/min) of HCl (1N, 2.0mL,2.0mmol,2.0 equiv.) and reaction at room temperature for 5 hours. And (3) post-treatment: saturated sodium bicarbonate solution was added until its pH >7, the solvent was evaporated to dryness, diluted with 10mL of water, most of the organic solvent evaporated to dryness, then extracted with ethyl acetate (3 × 30 mL), the organic phases combined, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, then chromatographed on silica gel column (petroleum ether 60-90 ℃: ethyl acetate = 3:1) to give light yellow liquid, compound 3 (255mg, 50%).
Characterization data for compound 3 are as follows:
[α] 20 D -89.0(c 0.31,CHCl 3 ).FTIR(KBr,thin film)cm -1 :2922, 2850,1715,1660,1651,1645,1514,1379,1247,1159. 1 H NMR(400 MHz,CDCl 3 )δ7.28–7.10(m,9H),6.77–6.71(m,2H),6.46(dd,J＝ 8.0,2.3Hz,1H),6.17(d,J＝2.2Hz,1H),5.76–5.65(m,1H),5.21(dd, J＝17.0,1.0Hz,1H),5.06(dd,J＝10.1,1.4Hz,1H),4.84(d,J＝15.4 Hz,1H),4.58(d,J＝15.4Hz,1H),4.00(d,J＝15.0Hz,1H),3.70(s,3H), 3.64(s,3H),3.62–3.58(m,1H),3.53–3.46(m,1H),3.43(d,J＝15.0 Hz,1H),2.39(dd,J＝13.0,7.3Hz,1H),2.14–2.00(m,2H),1.78(dd,J ＝13.0,9.4Hz,1H),1.22(s,3H). 13 C NMR(100MHz,CDCl 3 )δ206.10, 180.85,159.94,159.05,144.46,140.36,140.17,128.88,128.51,128.36, 128.27,126.82,125.27,124.41,118.07,114.15,105.96,97.01,68.20, 68.05,55.85,55.49,55.34,54.55,45.50,43.64,43.55,29.83.HRMS (ESI-TOF)m/z[M+H] + calcd for C 32 H 35 N 2 O 4 ：511.2592,found 511.2579.
(3) Synthesis of Compound 4, the reaction scheme is as follows:
Figure BDA0003872202120000091
compound 3 (510mg, 1mmol) was dissolved in 20mL of anhydrous dichloromethane, and then trifluoromethanesulfonic acid (0.48mL, 6.0mmol, 6 equiv) was slowly added (1 mL/min) in an ice-water bath to react for 2 hours, and then the reaction was slowly returned (1 mL/min) to room temperature for 12 hours. And (3) post-treatment: then 10mL of saturated sodium carbonate solution was added, stirred for 10 minutes, then extracted with dichloromethane (3 × 20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and then chromatographed on silica gel (petroleum ether 60-90 ℃: ethyl acetate = 1:1) to give compound 4 (316mg, 81%) as a pale yellow liquid.
Characterization data for compound 4 are as follows:
[α] 20 D -21.6(c 0.15,CHCl 3 ).FTIR(KBr,thin film)cm -1 :3280, 2930,1176,1626,1505,1344,1155,736. 1 H NMR(400MHz,CDCl 3 )δ 8.33(s,1H),7.36–7.18(m,6H),6.58(dd,J＝8.4,2.4Hz,1H),6.43(d, J＝2.4Hz,1H),5.83–5.70(m,1H),5.28(dd,J＝17.2,1.2Hz,1H), 5.13(dd,J＝10.0,1.6Hz,1H),4.07(d,J＝15.2Hz,1H),3.79(s,3H), 3.64(t,J＝6.8Hz,1H),3.51(t,J＝8.4Hz,1H),3.47(d,J＝15.6Hz, 1H),2.48(dd,J＝13.2,7.6Hz,1H),2.21–2.17(m,2H),1.85(dd,J＝ 12.8,9.2Hz,1H),1.32(s,3H). 13 C NMR(100MHz,CDCl 3 )δ206.54, 183.00,160.05,142.44,140.44,140.14,128.45,128.28,126.81,125.63, 124.85,118.12,107.29,96.83,68.24,68.19,55.76,55.61,55.07,45.39, 43.39,29.86.HRMS(ESI-TOF)m/z[M+H] + calcd for C 24 H 27 N 2 O 3 ： 391.2016Found 391.2015.
(4) Synthesis of Compound 5, the reaction scheme is as follows:
Figure BDA0003872202120000101
compound 4 (390mg, 1.0 mmol) was dissolved in a mixed solvent of tetrahydrofuran/water (9mL, 3mL, volume ratio), and N-methylmorpholine oxide (234mg, 2.0mmol,2.0 equiv) and OsO were added thereto 4 (20 mg/mL in water,1.3mL,0.1mmol, 0.1equiv), followed by reaction at room temperature for 20 hours, and addition of NaIO 4 (428mg, 2.0mmol,2.0 equiv), and reacted at room temperature for 3 hours. And (3) post-treatment: then adding saturated NaHSO 3 The solution (5 mL) was stirred for 10 min, then extracted with ethyl acetate (3 × 20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and then chromatographed on silica gel (petroleum ether 60-90 ℃: ethyl acetate = 1:1) to give pale yellow compound 5 (314mg, 80%).
Characterization data for compound 5 are as follows:
[α] 20 D -27.6(c 0.31,CHCl 3 ).FTIR(KBr,thin film)cm -1 :3281, 2835,1176,1626,1455,1344,1028,736. 1 H NMR(400MHz,CDCl 3 )δ 9.11(d,J＝4.0Hz,1H),7.38–7.27(m,5H),7.22(d,J＝8.3Hz,1H), 6.59(dd,J＝8.3,2.4Hz,1H),6.49(d,J＝2.3Hz,1H),3.96(d,J＝13.2 Hz,1H),3.80(s,3H),3.84–3.75(m,2H),3.61(d,J＝13.2Hz,1H), 3.58–3.53(m,1H),2.63–2.52(m,2H),2.50–2.41(m,1H),1.98(dd,J ＝13.6,7.6Hz,1H),1.67(s,3H). 13 C NMR(100MHz,CDCl 3 )δ206.29, 200.79,181.41,160.39,142.40,137.84,129.65,128.70,128.07,125.53, 123.11,107.47,97.28,71.75,67.41,58.28,55.65,55.53,45.30,37.30, 30.24.HRMS(ESI-TOF)m/z[M+H] + calcd for C 24 H 25 N 2 O 4 :393.1809 Found 393.1806.
(5) Synthesis of Compound 6, the reaction scheme is as follows:
Figure BDA0003872202120000111
compound 5 (314mg, 0.8mmol) was dissolved in (THF: H) 2 t-BuOH = 4mL to 1ml) of the mixed solution, and then 2-methyl-2-butene (3 mL), KH 2 PO 4 (544mg,4.0mmol,5equiv)，NaClO 2 (80% by volume, purity,180mg,1.6 mmol,2.0 equiv), and then reacted at room temperature for 2 hours. And (3) post-treatment: adding saturated NH 4 The Cl solution (4 mL) was extracted with ethyl acetate (3X 10 mL), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and evaporated to dryness to give the crude product (294 mg) which was used directly in the next reaction. The carboxylic acid compound was dissolved in 5mL of anhydrous methanol, and (trimethylsilane) diazomethane (0.58mL, 2.5M in THF, 1.44mmol, 2equiv) was added to react at room temperature for 5 hours, then the reaction was concentrated under reduced pressure to dryness, and then subjected to silica gel column chromatography (petroleum ether 60-90 ℃ C.: ethyl acetate = 1:1) to give a pale yellow compound 6 (240mg, 71%).
Characterization data for compound 6 are as follows:
[α] 20 D -29.2(c 0.33,CHCl 3 ).FTIR(KBr,thin film)cm -1 :2951, 1715,1660,1651,1645,1514,1463,1380,1162. 1 H NMR(400MHz, CDCl 3 )δ8.63(s,1H),7.55(d,J＝8.2Hz,1H),7.41(d,J＝7.3Hz,2H), 7.33–7.20(m,3H),6.61(dd,J＝8.3,2.3Hz,1H),6.46(d,J＝2.3Hz, 1H),3.90–3.87(m,1H),3.87–3.55(m,6H),3.54(s,3H),2.70(dd,J＝ 13.3,9.5Hz,1H),2.40–2.30(m,1H),2.25–2.09(m,2H),1.48(s,3H). 13 C NMR(100MHz,CDCl 3 )δ206.38,181.57,173.88,160.23,142.10, 138.57,129.12,128.31,127.25,126.44,123.69,107.50,97.00,67.06, 65.53,57.49,55.62,52.00,44.95,39.62,30.08.[α] 20 D -20.6(c 0.43, CHCl 3 ).HRMS(ESI-TOF)m/z[M+H] + calcd for C 24 H 27 N 2 O 5 ：423.1915 Found 423.1911.
(6) Synthesis of Compound 7, the reaction scheme is as follows:
Figure BDA0003872202120000121
compound 6 (127mg, 0.3 mmol) was dissolved in 3mL of anhydrous methanol, followed by addition of palladium on carbon (20% on carbon, 13mg), then the reaction was placed under a hydrogen balloon and stirred at room temperature for 15 hours, then the reaction was concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography (petroleum ether 60-90 ℃ c: ethyl acetate = 1:1) to give compound 7 (96 mg, 96%) as a colorless liquid.
Characterization data for compound 7 are as follows:
[α] 20 D -27.5(c 0.33,CHCl 3 ).FTIR(KBr,thin film)cm -1 :3287, 2959,2853,1716,1629,1505,1460,1312,1155,1106,801. 1 H NMR (400MHz,CDCl 3 )δ8.86(s,1H),7.24(d,J＝8.3Hz,1H),6.57(dd,J＝ 8.2,2.3Hz,1H),6.52(d,J＝2.4Hz,1H),4.21(dd,J＝10.2,6.3Hz,1H), 3.85(dd,J＝8.6,4.5Hz,1H),3.81(s,3H),3.78(s,3H),2.82(dd,J＝ 13.6,10.2Hz,1H),2.29(dd,J＝12.5,8.6Hz,1H),2.19(dd,J＝13.6,6.3 Hz,1H),1.96(s,3H). 13 C NMR(100MHz,CDCl 3 )δ207.00,181.21, 174.08,160.16,141.56,125.75,123.64,107.52,97.37,63.06,58.36, 56.19,55.63,52.49,44.76,40.68,30.21.HRMS(ESI-TOF)m/z[M+H] + calcd for C 17 H 21 N 2 O 5 ：333.1445Found 333.1444.
(7) Synthesis of Compound 8, the reaction scheme is as follows:
Figure BDA0003872202120000122
to a 10mL round bottom flask were added FMOC-L-proline (67mg, 0.2mmol, 2.0equiv), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (BOP-Cl, 51mg,0.2mmol, 2.0 equiv) and anhydrous dichloromethane (3 mL), followed by addition of Compound 7 (33.2mg, 0.1mmol) and triethylamine (33.3. Mu.L, 0.25mmol, 2.5equiv). The reaction mixture was degassed 3 times under nitrogen and allowed to react at room temperature for a further 24 hours. After the reaction was complete, saturated aqueous sodium bicarbonate solution (3 mL) was added, the mixture was separated and extracted with dichloromethane (3X 5 mL), the organic phases were combined and then washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, the reaction solvent was evaporated to dryness, and the product was used in the next step without further purification. The resulting product was dissolved in THF (3 mL), treated with piperidine (0.2 mL) at room temperature for 3 hours, and after removal of the solvent and excess piperidine, the residue was chromatographed on silica gel (petroleum ether 60-90 ℃ c: ethyl acetate = 1) to give product 8 (34.9 mg, 88%) as a colorless oil.
Characterization data for compound 8 are as follows:
[α] 20 D -95.3(c 0.10,CHCl 3 ).FTIR(KBr,thin film)cm -1 :3280, 2927,1715,1667,1506,1422,1345,1158. 1 H NMR(400MHz,CDCl 3 ) δ8.52(s,1H),6.90(d,J＝8.1Hz,1H),6.49–6.44(m,2H),4.86(t,J＝ 8.7Hz,1H),4.69(dd,J＝9.0,4.1Hz,1H),4.25(t,J＝8.0Hz,1H),3.76 (s,1H),3.59(dd,J＝8.4,5.4Hz,1H),3.27(dd,J＝18.0,4.1Hz,1H), 2.71(dd,J＝18.0,9.2Hz,1H),2.60(dd,J＝13.6,9.9Hz,1H),2.46(dd, J＝13.6,7.5Hz,1H),2.20–1.92(m,3H),1.88(s,3H). 13 C NMR(100 MHz,CDCl 3 )δ204.65,181.12,167.84,166.40,160.71,142.54,124.72, 119.74,107.14,97.62,61.13,59.02,55.49,54.14,45.25,43.43,34.66, 29.80,27.84,23.55.HRMS(ESI-TOF)m/z[M+H] + calcd for C 21 H 24 N 3 O 5 ：398.1711Found 398.1713.
(8) Synthesis of Compound 9, the reaction scheme is as follows:
Figure BDA0003872202120000141
compound 8 (20mg, 0.05mmol) is weighed into a two-neck round-bottom flask, and then anhydrous dichloromethane (3 mL) is added, and the mixture is removed under the protection of nitrogenAfter three times, cooling to-78 ℃ and stirring for 5 minutes, a solution of methylmagnesium bromide in THF (1.0M, 0.1mL,0.1mmol,2.0 eq.) was added to the solution. Then the reaction mixture is reacted for 6 hours at-78 ℃, then the temperature is raised to the room temperature, after the reaction is completed, saturated NH is added 4 Aqueous Cl (3 mL) and then dichloromethane (3 × 3 mL) were used for extraction, the organic phases were combined and dried over anhydrous sodium sulfate, then the reaction was concentrated to dryness under reduced pressure and subjected to silica gel column chromatography (petroleum ether 60-90 ℃: ethyl acetate = 1:5) to give compound 9 (20.7 mg, 88%) as a pale yellow liquid.
Characterization data for compound 9 are as follows:
[α] 21 D -97.8(c 0.41,CHCl 3 ).FTIR(KBr,thin film)cm -1 :3271, 2962,2925,2853,1716,1660,1651,1463,1192,1157,1030. 1 H NMR (400MHz,CDCl 3 )δ8.07(s,1H),6.98(d,J＝8.4Hz,1H),6.56(d,J＝ 8.4Hz,1H),6.48(s,1H),4.90(t,J＝8.2Hz,1H),4.37(t,J＝3.8Hz, 1H),4.33(t,J＝8.0Hz,1H),3.80(s,3H),3.61(dd,J＝8.2,5.8Hz,1H), 2.65(dd,J＝13.5,9.1Hz,1H),2.47(dd,J＝13.4,7.8Hz,1H),2.41– 2.33(m,1H),2.27–2.17(m,1H),2.09–1.84(m,5H),1.12(s,3H),0.61 (s,3H). 13 C NMR(100MHz,CDCl 3 )δ180.41,168.70,166.33,160.83, 142.33,126.29,119.41,107.20,97.67,69.00,61.17,59.42,59.11,55.66, 55.47,45.36,43.39,33.95,31.64,27.78,26.97,23.74.HRMS(ESI-TOF) m/z[M+H] + calcd for C 22 H 28 N 3 O 5 ：414.2023Found 414.2027.
(9) Synthesis of compound 10, reaction formula:
Figure BDA0003872202120000151
compound 9 (12.4mg, 0.03mmol) and anhydrous Na were weighed into a round-bottomed flask at room temperature 2 SO 4 (15.0 mg), toluene (3.0 mL) was then added, p-toluenesulfonic acid monohydrate (18mg, 0.090mmol) was added, degassing was performed three times under nitrogen, and the mixture was stirred at reflux at 115 ℃ for 19 hours. With saturated sodium bicarbonate solutionThe reaction mixture was quenched (0.5 mL), and the residue was subjected to flash chromatography on silica gel (ethyl acetate) to give compound 10 (spirotrpostatin A) (10.7mg, 90%) as a clear oil.
Characterization data for compound 10 are as follows:
[α] 21 D -96.9(c 0.21,CHCl 3 ).FTIR(KBr,thin film)cm -1 :2923, 1715,1660,1455,1193,1157,801. 1 H NMR(400MHz,CDCl 3 )δ7.70 (brs,1H),6.92(d,J＝8.4Hz,1H),6.50(dd,J＝8.4,2.4Hz,1H),6.43(d, J＝2.4Hz,1H),5.03(d,J＝7.6,1.2Hz,1H),5.00(dd,J＝10.8,7.2Hz, 1H),4.78(d,J＝9.2Hz,1H),4.29(t,J＝8.0Hz,1H),3.80(s,3H),3.64 –3.53(m,2H),2.60(dd,J＝13.2,10.8Hz,1H),2.39(dd,J＝13.2,6.8 Hz,1H),2.36–2.29(m,1H),2.29–2.22(m,1H),2.09–1.90(m,2H), 1.65(s,3H),1.16(s,3H). 13 C NMR(100MHz,CDCl 3 )δ180.90,167.23, 167.07,160.47,141.79,138.57,127.42,121.45,118.80,106.84,96.76, 61.18,60.26,58.62,55.61,55.61,45.33,34.44,27.55,25.67,23.81, 18.15.HRMS(ESI-TOF)m/z[M+H] + calcd for C 22 H 26 N 3 O 4 ：396.1918 Found 396.1916.
the above-described embodiments are only intended to illustrate the preferred embodiments of the present invention, and not to limit the scope of the present invention, and various modifications and improvements made to the technical solution of the present invention by those skilled in the art without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims (8)

1. A method for preparing spirocyclic indole natural product spirotropic statin A is characterized by comprising the following steps:
(1) Mixing an o-iodoaniline compound, cuprous iodide and lithium bis (trimethylsilyl) amide, adding a solvent, heating to react under the protection of inert gas, and then adding acetylenic ketone to prepare an oxindole compound containing a chiral quaternary carbon center;
(2) Dissolving the oxindole compound containing the chiral quaternary carbon center, and adding a hydrochloric acid solution for reaction to prepare a chiral spiro oxindole compound;
(3) Removing the p-methoxybenzyl of the chiral spiro oxoindole compound to prepare an oxoindole compound;
(4) Dissolving the indole oxide compound, adding osmium tetroxide and N-methylmorpholine oxide for reaction, and then adding sodium periodate to prepare an aldehyde compound;
(5) Oxidizing the aldehyde compound into a carboxylic acid compound, and then adding (trimethylsilane) diazomethane to prepare a methyl ester compound;
(6) Removing benzyl protection from the methyl ester compound to prepare an amino compound;
(7) Mixing the amino compound with N- (9-fluorenylmethoxycarbonyl) -L-proline, adding a condensing agent for condensation reaction, then removing the protection of fluorenylmethoxycarbonyl, and further carrying out ammonolysis reaction to obtain a spiro indole diketopiperazine compound;
(8) Reacting the spiro indole diketopiperazine compound with methyl magnesium bromide to obtain a hydroxyl compound;
(9) And reacting the hydroxyl compound with p-toluenesulfonic acid to obtain a spirooxindole natural product spirootryptastatin A.
2. The process for preparing spirooxindole-based natural product, spirotyrostantina, according to claim 1, wherein in step (1) the solvent is tetrahydrofuran; the heating reaction temperature is 70 ℃, and the time is 7-8h.
3. The process for preparing spirooxindole-based natural product, spirotyrostantina, according to claim 1, wherein the concentration of the hydrochloric acid solution in step (2) is 1mol/L.
4. The method for preparing spirooxindole-based natural product spirotropic statin A according to claim 1, wherein the reactant used in the step (3) for removing the p-methoxybenzyl group is trifluoromethanesulfonic acid.
5. The process for preparing spirooxindole-based natural product spirotriptatina as claimed in claim 1, wherein the oxidizing agent used in the oxidation in step (5) is sodium chlorite.
6. The method for preparing spirooxindole-based natural product spirotryptostatin A according to claim 1, wherein the debenzylation protection in step (6) is performed in hydrogen and the catalyst is palladium/carbon catalyst.
7. The process for preparing spirooxindole-based natural product spirotriptatina as claimed in claim 1, wherein the condensing agent in step (7) is bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride; the removal of fluorenylmethyloxycarbonyl protection is carried out in piperidine.
8. The method for preparing spirooxindole-based natural product spirotriptatina as claimed in claim 1, wherein the steps (1) to (9) further comprise a purification step.
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CN112430236A (en) * 2020-11-27 2021-03-02 暨南大学 Synthesis method of chiral spiro [ pyrrolidone-3, 3 '-oxindole ] ring system and application of chiral spiro [ pyrrolidone-3, 3' -oxindole ] ring system in synthesis of natural product
CN114105978A (en) * 2021-11-04 2022-03-01 江西师范大学 Oxindole compound and preparation method and application thereof

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* Cited by examiner, † Cited by third party
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CN112430236A (en) * 2020-11-27 2021-03-02 暨南大学 Synthesis method of chiral spiro [ pyrrolidone-3, 3 '-oxindole ] ring system and application of chiral spiro [ pyrrolidone-3, 3' -oxindole ] ring system in synthesis of natural product
CN114105978A (en) * 2021-11-04 2022-03-01 江西师范大学 Oxindole compound and preparation method and application thereof

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