CN115677711B - Method for preparing spiro oxindole natural product Spirotryprostatin A - Google Patents

Method for preparing spiro oxindole natural product Spirotryprostatin A Download PDF

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CN115677711B
CN115677711B CN202211201485.1A CN202211201485A CN115677711B CN 115677711 B CN115677711 B CN 115677711B CN 202211201485 A CN202211201485 A CN 202211201485A CN 115677711 B CN115677711 B CN 115677711B
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compound
natural product
oxindole
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CN115677711A (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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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a method for preparing spiro oxindole natural product spirogyryprostatine A, belonging to the technical field of organic synthesis. According to the preparation method, an o-iodo-aniline compound is used as a starting material to prepare a spirooxindole natural product spirogyryprostatine A. The preparation method provided by the invention has mild reaction conditions, adopts low-cost metal cuprous iodide as a catalyst, has low energy consumption, is favorable for environmental protection and is favorable for preparing spirooxindole natural products spirogyryprostatine A in a large scale; the method 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 spiro oxindole natural product Spirotryprostatin A
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for preparing spiro oxindole natural products Spirotryprostatin A.
Background
In recent years, the spirooxindole structural unit is a key synthon or intermediate for synthesizing a plurality of natural products and bioactive molecules, and has wide pharmacological activities, such as anti-tumor, anti-anxiety, anti-inflammatory, antihypertensive, antipyretic, analgesic and the like. The spiro oxindole skeleton widely exists in indole alkaloids, is a dominant skeleton shared by hundreds of natural products, and has good medicinal value or potential patent medicine characteristics. In recent years, the synthesis and biological activity research of the compounds attracts more and more interests of synthesis chemists and pharmaceutical chemists. Because of their special structure and important biological activity, the development of new reactions for efficiently synthesizing spiro oxindole compounds is important, and is also always a hotspot in the field of organic synthetic chemistry, and has more important significance for drug development. In 1996, the spiro oxindole natural product Spirotryprostatin A was first isolated from the fermentation broth of the fungus Aspergillus fumigatus by Osada and colleagues, and showed inhibitory activity against the progression of the G2/M mammalian cell cycle, indicating that it could be used as a lead compound for clinical candidate anticancer drugs.
At present, the preparation method of spiro oxindole natural products Spirotryprostatin A has the advantages of longer overall synthetic route, lower overall yield of reaction, and the need of noble metal palladium as a catalyst, and most of the current synthetic routes need to use indole or oxindole compounds as starting materials, thereby seriously affecting the preparation of the compounds in diversity and limiting the further research of the compounds and analogues thereof.
Disclosure of Invention
The invention aims to provide a method for preparing spiro oxindole natural product Spirotryprostatin A. The preparation method disclosed only uses low-cost metal cuprous iodide as a catalyst, and has the advantages of less environmental pollution, less reaction steps and high yield.
In order to achieve the above purpose, the present invention provides the following technical solutions:
a process for preparing a spiro oxindole natural product Spirotryprostatin A is provided comprising the steps of:
(1) Mixing an o-iodo-aniline compound, cuprous iodide and lithium bis (trimethylsilyl) amide, adding a solvent, heating under the protection of inert gas for reaction, and then adding propargyl 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 hydrochloric acid solution for reaction to prepare a chiral spiro oxindole compound;
(3) Removing p-methoxybenzyl of the chiral spiro oxindole compound to prepare an oxindole compound;
(4) Dissolving the oxindole 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 (trisilane) 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, removing fluorenylmethoxycarbonyl protection, and further carrying out ammonolysis reaction to prepare 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 spiro oxindole natural product Spirotryprostatin A.
Preferably, the solvent in step (1) is tetrahydrofuran; the temperature of the heating reaction 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 in step (3) to remove p-methoxybenzyl 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, the catalyst being a palladium on carbon catalyst.
Preferably, the condensing agent in step (7) is bis (2-oxo-3-oxazolidinyl) phosphinic chloride; the removal of the fluorenylmethoxycarbonyl group protection is performed in piperidine.
Preferably, the steps (1) to (9) further comprise a purification step.
The beneficial technical effects of the invention are as follows:
1. the preparation method provided by the invention has mild reaction conditions, adopts low-cost metal cuprous iodide as a catalyst, has low energy consumption, is favorable for environmental protection and is favorable for preparing spiro oxindole natural products Spirotryprostatin A in a large quantity.
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 shorter synthetic route and simpler reaction operation process.
Drawings
FIG. 1 is a flow chart of the preparation of spiro oxindole natural products Spirotryprostatin A according to example 1 of the invention.
Detailed Description
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions 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.
In addition, for numerical ranges in this disclosure, it is understood that each intermediate value between the upper and lower limits of the ranges is also specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, 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 intended to be inclusive and mean an inclusion, but not limited to.
The invention provides a method for preparing spiro oxindole natural products Spirotryprostatin A, which comprises the following steps:
(1) Mixing an o-iodo-aniline compound, cuprous iodide and lithium bis (trimethylsilyl) amide, adding a solvent, heating under the protection of inert gas for reaction, and then adding propargyl ketone to prepare an oxindole compound containing a chiral quaternary carbon center;
the alkynone in step (1) is used as a tandem reagent;
(2) Dissolving the oxindole compound containing the chiral quaternary carbon center, and adding hydrochloric acid solution for reaction to prepare a chiral spiro oxindole compound;
step (2), adding hydrochloric acid solution to perform a reaction, namely firstly removing sulfinyl groups of an oxindole compound containing chiral quaternary carbon centers, and then performing an aza-Michael addition reaction;
(3) Removing p-methoxybenzyl of the chiral spiro oxindole compound to prepare an oxindole compound;
(4) Dissolving the oxindole compound, adding osmium tetroxide and N-methylmorpholine oxide for reaction, and then adding sodium periodate to prepare an aldehyde compound;
the reaction of adding osmium tetroxide and N-methylmorpholine oxide in the step (4) is a dihydroxylation reaction; the effect of adding sodium periodate is to cut off the vicinal diol compound;
(5) Oxidizing the aldehyde compound into a carboxylic acid compound, and then adding (trisilane) 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, removing fluorenylmethoxycarbonyl protection, and further carrying out ammonolysis reaction to prepare 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 spiro oxindole natural product Spirotryprostatin A.
Further, in the step (1), the solvent is tetrahydrofuran; the temperature of the heating reaction 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 step (5) is sodium chlorite.
Further, the benzyl removal protection in step (6) is performed in hydrogen, and the catalyst is a palladium/carbon catalyst.
Further, the condensing agent in step (7) is bis (2-oxo-3-oxazolidinyl) hypophosphorous acid chloride; the removal of the fluorenylmethoxycarbonyl group protection is performed in piperidine.
Further, the steps (1) to (9) further comprise a purification step.
Specific examples are as follows:
example 1
Preparation of spiro oxindole natural product Spirotryprostatin A (preparation scheme see fig. 1):
(1) The synthesis of compound 2 is represented by the following formula:
cuprous iodide (CuI, 380mg,2.0mmol, 0.1 equiv) and compound 1 (13.5 g,20.0 mmol) were weighed into a 500mL double-neck round bottom bottle, degassed three times under the protection of high-purity nitrogen, anhydrous tetrahydrofuran (300 mL) was added, lithium bis (trimethylsilyl) amide (1.0M in THF,40mL,40mmol,2.0equiv) was added under stirring at room temperature, degassed three times again, and then reacted for 7 hours under the heating of 70 ℃ oil bath, wherein high-purity nitrogen is required for the whole course of the reaction. Then, the heating was stopped, the temperature was returned to room temperature, cooled to 0℃again, 3-butyn-2-one (3.9mL,50 mmol,2.5equiv) was added, and then the reaction was carried out at 0℃for 5 hours. Post-treatment: adding saturated Na 2 S 2 O 3 The solution (40 mL) and saturated ammonium chloride solution (40 mL) were stirred for 30 min, then 100mL of water was added, ethyl acetate (3X 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 ℃ C.: ethyl acetate=2:1→1:1) gave compound 2, compound 2 consisted of E-type pale yellow liquid compound 2a (7.37 g, 60%) and Z-type yellow liquid compound 2b (2.45 g, 20%).
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 Z compound 2b 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) The synthesis of compound 3 is represented by the following formula:
compound 2 (614 mg,1.0 mmol) was dissolved in 20mL of dimethyl sulfoxide, and then HCl (1N, 2.0mL,2.0mmol,2.0 equiv.) was slowly added (1 mL/min) and reacted at room temperature for 5 hours. Post-treatment: saturated sodium bicarbonate solution was added until its pH >7, the solvent was evaporated to dryness, 10mL of water was added to dilute, most of the organic solvent was evaporated to dryness, then extracted with ethyl acetate (3×30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and then column-chromatographed over silica gel (petroleum ether 60-90 ℃ C.: ethyl acetate=3:1) to give a pale yellow liquid, compound 3 (255 mg, 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＝15.4Hz,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＝15.0Hz,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) The synthesis of compound 4 is as follows:
compound 3 (510 mg,1 mmol) was dissolved in 20mL of anhydrous dichloromethane, then trifluoromethanesulfonic acid (0.48 mL,6.0mmol, 6 equiv) was slowly added (1 mL/min) under ice-water bath to react for 2 hours, and then the reaction was slowly resumed (1 mL/min) to room temperature to react for 12 hours. 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 under reduced pressure and evaporated to dryness, then purified by column chromatography on silica gel (petroleum ether 60-90 ℃ C.: ethyl acetate=1:1) to give compound 4 (316 mg, 81%).
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) The synthesis of compound 5 is as follows:
compound 4 (390 mg,1.0 mmol) was dissolved in a mixed solvent of tetrahydrofuran/water (9 mL:3mL, volume ratio), and N-methylmorpholine oxide (234 mg,2.0mmol,2.0 equiv) and OsO were further added 4 (20 mg/mL in water,1.3mL,0.1mmol,0.1 equiv) then reacted at room temperature for 20 hours before adding NaIO 4 (428mg,2.0mmol,2.0 equiv), at room temperature for 3 hours. Post-treatment: then adding saturated NaHSO 3 The solution (5 mL) was stirred for 10 minutes, then extracted with ethyl acetate (3×20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and evaporated to dryness, then purified by column chromatography over silica gel (petroleum ether 60-90 ℃ C.: ethyl acetate=1:1) to give pale yellow compound 5 (314 mg, 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＝13.2Hz,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) The synthesis of compound 6 is as follows:
compound 5 (314 mg,0.8 mmol) was dissolved in (THF: H) 2 O: t-BuOH=4 mL:4mL:1 mL) and 2-methyl-2-butene (3 mL), KH, were added thereto 2 PO 4 (544mg,4.0mmol,5equiv)，NaClO 2 (80%purity,180mg,1.6 mmol,2.0equiv) and then reacted at room temperature for 2 hours. Post-treatment: adding saturated NH 4 Cl solution (4 mL), then extracted with ethyl acetate (3X 10 mL), the organic phases were combined, then 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. Carboxylic acid compound was dissolved in 5mL of anhydrous methanol, and (trimethylsilyl) diazomethane (0.58mL,2.5M in THF, 1.44mmol,2 eq) was addeduiv), at room temperature, followed by concentrating the reaction under reduced pressure and evaporating to dryness, followed by column chromatography on silica gel (petroleum ether 60-90 ℃ C.: ethyl acetate=1:1) to give pale yellow compound 6 (240 mg, 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) The synthesis of compound 7 is as follows:
compound 6 (127 mg,0.3 mmol) was dissolved in 3mL of anhydrous methanol, then palladium on carbon (20%on carbon,13mg) was added, then the reaction was left under hydrogen balloon conditions and stirring at room temperature was continued for 15 hours, then the reaction was concentrated under reduced pressure and evaporated to dryness, and a colorless liquid, compound 7 (96 mg, 96%) was obtained by column chromatography on silica gel (petroleum ether 60-90 ℃ C.: ethyl acetate=1:1).
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) The synthesis of compound 8 is shown in the following reaction formula:
FMOC-L-proline (67 mg,0.2mmol,2.0 equiv), bis (2-oxo-3-oxazolidinyl) hypophosphorous acid chloride (BOP-Cl, 51mg,0.2mmol, 2.0 equiv) and anhydrous dichloromethane (3 mL) were added to a 10mL round bottom flask, then Compound 7 (33.2 mg,0.1 mmol) was added to the round bottom flask, followed by triethylamine (33.3. Mu.L, 0.25mmol,2.5 equiv). The reaction mixture was degassed 3 times under nitrogen and allowed to continue at room temperature for 24 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (3 mL) was added, the mixture was separated and extracted with dichloromethane (3×5 mL), the organic phases were combined, then washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, and the reaction solvent was evaporated to dryness, and the product was directly used in the next step without further purification. The resulting product was dissolved in THF (3 mL) and treated with piperidine (0.2 mL) at room temperature for 3 hours, after which the solvent and excess piperidine were removed, the residue was chromatographed on silica gel (petroleum ether 60-90 ℃ c: ethyl acetate=1:15) to give product 8 (34.9 mg, 88%) as a colourless 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) The synthesis of compound 9 is as follows:
compound 8 (20 mg,0.05 mmol) was weighed into a two-necked round bottom flask, then anhydrous dichloromethane (3 mL) was added, deaerated three times under nitrogen protection, then cooled to-78 ℃ and stirred for 5 minutes, then a THF solution of methylmagnesium bromide (1.0M, 0.1mL,0.1mmol,2.0 eq.) was added to the solution. Then the reaction mixture is reacted for 6 hours at the temperature of minus 78 ℃, then the temperature is raised to the room temperature, and after the reaction is completed, saturated NH is added 4 Aqueous Cl (3 mL) then extracted with dichloromethane (3 x 3 mL), the organic phases combined, dried over anhydrous sodium sulfate, then concentrated to dryness under reduced pressure and chromatographed on silica gel (petroleum ether 60-90 ℃ C.: 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) The synthesis of compound 10 is as follows:
compound 9 (12.4 mg,0.03 mmol) and anhydrous Na were weighed in a round bottom flask at room temperature 2 SO 4 (15.0 mg) then toluene (3.0 mL) and p-toluenesulfonic acid monohydrate (18 mg,0.090 mmol) were added, degassed three times under nitrogen and the mixture was stirred at 115℃under reflux for 19 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (0.5 mL) and the residue was flash chromatographed on silica gel (ethyl acetate) to give compound 10 (Spirotryprostatin A) (10.7 mg, 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 embodiments are only illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solutions of the present invention should fall within the protection scope defined by the claims of the present invention without departing from the design spirit of the present invention.

Claims (8)

1. A process for preparing spirooxindole natural product spiratyryprostatine a comprising the steps of:
(1) Mixing an o-iodo-aniline compound, cuprous iodide and lithium bis (trimethylsilyl) amide, adding a solvent, heating under the protection of inert gas for reaction, and then adding propargyl 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 hydrochloric acid solution for reaction to prepare a chiral spiro oxindole compound;
(3) Removing p-methoxybenzyl of the chiral spiro oxindole compound to prepare an oxindole compound;
(4) Dissolving the oxindole 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 (trisilane) 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, removing fluorenylmethoxycarbonyl protection, and further carrying out ammonolysis reaction to prepare a spiro indole diketopiperazine compound;
(8) Reacting the spiro indole diketopiperazine compound with methyl magnesium bromide to prepare a hydroxyl compound;
(9) Reacting the hydroxyl compound with p-toluenesulfonic acid to prepare spirooxindole natural product spirogyryprostatine A;
the structural formula of the o-iodo-aniline compound in the step (1) is as follows:
the alkynone in step (1) is 3-butyn-2-one;
the structural formula of the oxindole compound containing the chiral quaternary carbon center in the step (1) is as follows:
the structural formula of the chiral spiro oxindole compound in the step (2) is as follows:
the structural formula of the oxindole compound in the step (3) is as follows:
the structural formula of the aldehyde group compound in the step (4) is as follows:
the structural formula of the methyl ester compound in the step (5) is as follows:
the structural formula of the amino compound in the step (6) is as follows:
the structural formula of the spiro indole diketopiperazine compound in the step (7) is as follows:
the structural formula of the hydroxyl compound in the step (8) is as follows:
the structural formula of the spiro oxindole natural product spirogyryprostatine A in the step (9) is as follows:
2. the process for preparing spirooxindole natural product spirogyryprostatina according to claim 1, wherein in step (1) the solvent is tetrahydrofuran; the temperature of the heating reaction is 70 ℃ and the time is 7-8h.
3. The process for preparing spirooxindole natural product spirogyryprostatine a according to claim 1, wherein the concentration of the hydrochloric acid solution in step (2) is 1mol/L.
4. The process for preparing spirooxindole natural product spirogyryprostatine a according to claim 1, wherein the reactant used for removing p-methoxybenzyl group in step (3) is trifluoromethanesulfonic acid.
5. The process for preparing spirooxindole natural product spirogyryprostatine a according to claim 1, wherein the oxidizing agent used in the oxidation in step (5) is sodium chlorite.
6. The process for preparing spirooxindole natural product spirogyryprostatine a according to claim 1, wherein said debenzylation protection in step (6) is carried out in hydrogen, and the catalyst is a palladium on carbon catalyst.
7. The process for preparing spirooxindole natural product spirogyryprostatine a according to claim 1, wherein said condensing agent in step (7) is bis (2-oxo-3-oxazolidinyl) hypophosphorous acid chloride; the removal of the fluorenylmethoxycarbonyl group protection is performed in piperidine.
8. The process for preparing spirooxindole natural product spirogyryprostatine a according to claim 1, wherein the steps (1) to (9) comprise a purification step.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
Publication number Priority date Publication date Assignee Title
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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