CN111423465A - Synthesis method of Scabrosins/Ambewelamides framework structure - Google Patents

Synthesis method of Scabrosins/Ambewelamides framework structure Download PDF

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CN111423465A
CN111423465A CN201910020544.7A CN201910020544A CN111423465A CN 111423465 A CN111423465 A CN 111423465A CN 201910020544 A CN201910020544 A CN 201910020544A CN 111423465 A CN111423465 A CN 111423465A
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贺耘
刘玉印
王志鹏
斯瑞尼瓦斯·班尼
郭键
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Chongqing University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888

Abstract

The invention relates to a synthesis method of a Scabrosins/Ambewelamides framework structure. The synthesis method utilizes Negishi coupling reaction, reductive amination reaction, asymmetric epoxidation reaction, Mitsunobu reaction and intramolecular nucleophilic substitution reaction to complete the construction of the backbone structure of the Scabrosins/Ambewelamides. The synthesis method has the advantages of simple operation, mild reaction conditions, low cost and high yield, and lays a foundation for the total synthesis of the natural product.

Description

Synthesis method of Scabrosins/Ambewelamides framework structure
Technical Field
The invention belongs to the technical field of organic synthesis and pharmaceutical chemistry, and relates to a synthesis method of a Scabrosisn/Ambewelamides framework.
Background
Active natural products are an important source of drug development. However, many microorganisms and plants containing medicinal ingredients are not only limited in their distribution in nature, but also have very low contents of effective ingredients. Thus, it is clearly not sufficient to satisfy such a huge human need only by naturally occurring natural products. It is appreciated that chemical synthesis provides us with an effective approach to solving this practical problem. The dithiodiketopiperazine compounds are widely distributed in the natural world, are natural products with unique structures and containing disulfide bridges, and since the discovery of gliotoxin by Weidling and Emerson in 1936, more than twenty different dithiodiketopiperazine family compounds are successively discovered by scientists. The compounds have wide and good biological activity, such as antibacterial activity, antiviral activity, antifungal activity, anti-phagocytosis activity, immunosuppression activity and the like, and provide a possibility for drug development.
The natural products, Scabrosins A-C and Ambewelamides A-B, are members of the dithiodiketopiperazine family. William R.Begg et al in 1978 first reported isolation of the natural product, Scabrosins, from Xanthoparmelia scabrosa, but its structure was not determined by single crystal diffraction by Michael A.Ernst-Russell et al until 1999. David E.Williams et al in 1998 reported the isolation and extraction of Ambewelamides A-B. Scabrosins and Ambewelamides have the same cyclohexenotetrahydropyrrole cyclohexanedione piperazine parent structure and have symmetrical epoxy structures, which differ by the length of the ester side chain. The Scabrosins has good biological activity for resisting mouse P815 mastoma cells and MCF7 human breast cancer cells. The unique chemical structure and excellent biological activity attract the attention of many synthetic chemists.
In 2006, Steven T. Diver (Tetrahedron 2006, 62, 10528-10540) subject group studied the total synthesis of Scabrosins by using ruthenium carbene catalyzed tandem metathesis reaction and palladium metal catalyzed cyclization reaction, but unfortunately, the final product thereof cannot successfully introduce an epoxy structure.
Figure BDA0001940554910000011
In 2014, the Erick m.carreira professor of the switzerland federal institute of technology reports a research on synthesis of the sabrosins ester (Org. L ett.2014,16,2854-2857), which uses bromoacrolein as a starting material, synthesizes a bridged ring compound through multi-step conversion, prepares a diketopiperazine structure through functional group conversion and intermolecular nucleophilic reaction, and successfully prepares a dimer compound through multi-step reactions such as constructing a tetrahydropyrrole ring.
Figure BDA0001940554910000021
In the next year, complete synthesis of the Scabrosin ester was attempted again by Erick m.carreira group (chem.eur.j.2015,21, 12475-12480), which successfully prepared a 6-5-6-5-6-diketopiperazine structure by ring closure reaction using an intermediate tetraene compound, followed by deprotection and epoxidation reactions, but in the final double bond formation stage, the authors tried various conditions and still did not complete the construction of the natural product backbone.
Figure BDA0001940554910000022
Although there have been many attempts to fully synthesize Scabrosins, there have been no reports of complete backbone synthesis.
Disclosure of Invention
The invention relates to a synthesis method of a Scabrosisn/Ambewelamides framework and a monomer framework thereof as well as a non-corresponding isomer framework and a monomer framework thereof.
Figure BDA0001940554910000023
Natural products
Figure BDA0001940554910000031
Skeleton structure
Figure BDA0001940554910000032
Monomer skeleton
Wherein:
compounds 2 and 4 are also known as Ambewelamides A and Ambewelamides B, respectively.
Compounds i-8, i-16 and iii-2 are the backbone structures of Scabrosisn/Ambewelamides.
Compounds i-6 and ii-13 are the monomeric backbone structures of Scabrosisn/Ambewelamides.
The invention aims to provide a method for simply preparing a natural product Scabrosisn/Ambewelamides framework structure.
The invention takes a compound i-1 as an initial raw material, a Negishi coupling reaction and a reductive amination reaction are carried out to prepare a monomer compound i-6, and a Scabrosisn/Ambewelamides isomer skeleton structure i-8 is obtained through hydrolysis and condensation reaction.
The method comprises the steps of taking 3-hydroxybenzyl alcohol as an initial raw material, carrying out selective hydroxyl protection, benzene ring dearomatization reaction and asymmetric epoxidation reaction to obtain α -unsaturated ketone ii-4, carrying out multiple reactions such as asymmetric reduction, functional group protection and deprotection to obtain a compound ii-8, carrying out Mitsunobu reaction with a glycine derivative, carrying out functional group conversion, carrying out intramolecular nucleophilic substitution and other reactions to obtain a monomer compound ii-3, and carrying out ester hydrolysis, condensation reaction, configuration conversion and deprotection reaction keyi to obtain the framework structures ii-16 and iii-2 of the Scabrosisn/Ambewellamides.
Detailed Description
The first embodiment is as follows:
Figure BDA0001940554910000041
synthesis of Compound i-2:
zinc powder (7.0g,107.02mmol) is added to 8m L dried N, N-dimethylformamide at room temperature, 1, 2-dibromoethane (507.6mg,2.7mmol) is slowly added dropwise and reacted at 60 ℃ for 30 minutes, then trimethylchlorosilane (58.6mg,0.54mmol) is added to the reaction solution and stirred for 30 minutes Compound i-2(3.0g,8.99mmol) is dissolved in 5m L dried N, N-dimethylformamide and added to the reaction solution, the reaction is reacted at room temperature for 4 hours Compound i-1(1.3g,3.44mmol), cuprous bromide dimethyl sulfide (72.0mg,0.34 mmol), tris (dibenzylideneacetone) dipalladium (634.0mg,0.69mmol), tris (o-methylphenyl) phosphorus (1.3g,4.15mmol) is dissolved in 10m L dried N, N-dimethylformamide, then zinc is prepared, the reaction solution is added to a column chromatography, dried solution is separated at 10m, dried over ethyl acetate is added to obtain a saturated solution, dried over sodium chloride solution, dried over sodium sulfate is added to obtain a column chromatography, reaction solution, dried over sodium chloride is added to obtain a saturated solution, and reaction solution is addedThe substance i-3(1.2g, 67%).1H NMR(400MHz,CDCl3)5.34(s,2H),4.58(s,1H),4.33-4.23(m,3H),4.06-3.98(m,3H),3.72(s,3H),3.42(m,1H),2.63-2.55(m,2H),2.26-2.14(m,1H),1.50(d,J＝13.2,1H)1.42(s,9H),0.91(s,9H),0.12(s,6H)ppm；13C NMR(100MHz,C DCl3,)173.0,155.4,132.2,129.1,93.4,79.5,65.7,61.2,60.7,54.3,53.4,52.0,48.4,31.4,28.3,25.8,24.6,18.2,-4.6ppm。
Synthesis of Compound i-4:
the compound i-3(100.0mg,0.20mmol) was dissolved in 5m L dichloromethane, montmorillonite K10(300.0mg) was added to the solution, stirred at room temperature for 12 hours, and the reaction was checked for completion by T L C, filtered through celite, the solvent was concentrated, and the product i-4(80.0mg, 90%) was isolated by column chromatography.1H NMR(400MHz,CDCl3):6.23(s,1H),5.20(d,J＝7.1Hz,1H),4.76(s,1H),4.32(d,J＝6.1Hz,1H),3.74(s,3H),3.66(d,J＝3.3Hz,1H),3.42(d,J＝4.0Hz,1H),2.72(dd,J＝13.7,4.7Hz,1H),2.55(dd,J＝13.8,7.8Hz,1H),1.42(s,9H),0.95(s,9H),0.18(s,6H)ppm；13C NMR(100MHz,CDCl3):194.0,172.1,155.0,144.8,130.6,79.9,66.2,54.0,53.1,52.9,52.4,32.0,28.3,25.7,18.2,-4.6ppm。
Synthesis of Compound i-6:
dissolving the compound i-4 in trifluoroacetic acid dichloromethane (0.4m L: 5m L) at 0 ℃, stirring for 30 minutes, detecting T L C, the raw material disappears, quenching with saturated sodium bicarbonate solution, extracting with dichloromethane three times, drying with anhydrous sodium sulfate, filtering, concentrating to obtain the compound i-5, dissolving the compound i-5 in dry dichloromethane again at room temperature, adding sodium triacetoxyborohydride (54.7mg,0.26 mmol), acetic acid (15.5 mg,0.26mmol), stirring for 3 hours, quenching with saturated sodium bicarbonate solution, extracting with dichloromethane three times, combining the organic phases, drying with anhydrous sodium sulfate, filtering, spin-drying the solvent, and separating by column chromatography to obtain the product i-6(30.0mg, 71%).1H NMR(400MHz,CDCl3)5.22(d,J＝1.9Hz,1H),4.63(s,1H),3.89-3.85(m,1H),3.74(s,3H),3.59-3.55(m,2H),3.40(dt,J＝4.2,2.1Hz,1H),2.84-2.78(m,1H),2.52(dd,J＝16.7,7.8Hz,1H),1.96(s,1H),0.93(s,9H),0.14(s,6H)ppm；13C NMR(100MHz,CDCl3)172.9,136.0,119.2,67.7,58.6,58.1.55.3,52.3,50.5,35.0,25.9,18.3,-4.6ppm。
Synthesis of Compound i-8:
compound i-6(10.0mg,0.03mmol) was dissolved in 1.5m L tetrahydrofuran, lithium hydroxide monohydrate (2.6mg,0.06mmol, dissolved in 1.5m L water) was added dropwise thereto, and stirred at room temperature for 30 minutes, T L C detected the disappearance of the starting material, PH 6 was adjusted with sodium dihydrogen phosphate and potassium hydrogen sulfate buffer solution at PH 2.5, extracted with ethyl acetate several times, dried with anhydrous sodium sulfate and filtered, the solvent was dried, 2- (7-benzotriazole oxide) -N, N' -tetramethylurea hexafluorophosphate (46.7mg,0.123mmol) was added, and 5m L dried N, N-dimethylformamide was added as a solvent, N-diisopropylethylamine (16.0mg,0.123mmol) was added to the reaction solution, and stirred at room temperature for 3 hours, the solvent was dried, and product i-8(6mg, 67%) was isolated by column chromatography.1H NMR(400MHz,CDCl3)5.39(d,J＝1.7Hz,1H),4.61(s,1H),4.41(dd,J＝4.4,1.6Hz,1H),4.31(s,1H),4.30-4.25(m,1H),3.35-3.33(m,1H),3.26-3.20(m,1H),2.91-2.84(m,1H),0.92(s,9H),0.13(s,6H)ppm；13C NMR(100MHz,CDCl3)167.6,130.5,123.067.6,59.1,58.7,54.3,48.4,29.3,25.8,18.2,-4.7ppm。
Example two:
Figure BDA0001940554910000061
synthesis of Compound ii-2:
dissolving compound ii-1(18.6g,149.83mmol) and imidazole (13.26g,194.78mmol) in 130m L dry N, N-dimethylformamide, adding tert-butyldimethylsilyl chloride (23.7g, 157.32mmol, dissolved in 30m L N, N-dimethylformamide) to the reaction solution at 0 deg.C, stirring the reaction at room temperature for 30 minutes, detecting the reaction completion by T L C, adding water for quenching, extracting with ethyl acetate for multiple times, combining the organic phases, drying with anhydrous sodium sulfate, filtering, spin-drying the solvent, and separating by column chromatography to obtain product ii-2(30.6g, 86%).1H NMR(400MHz,CDCl3)7.19(t,J＝7.8Hz,1H),6.86(d,J＝7.6Hz,1H),6.83(s,1H),6.70(dd,J＝8.0,2.2Hz,1H),4.91(s,1H),4.70(s,2H),0.94(s,9H),0.10(s,6H)ppm；13C NMR(100MHz,CDCl3)155.7,143.0,129.4,118.3,114.0,113.1,64.8,26.0,18.5,-5.2ppm。
Synthesis of Compound ii-3:
compound ii-2(2.0g,8.38mmol) was dissolved in 30m L methanol at 0 deg.C and added dropwise to iodobenzene diacetate (5.4g,16.76mmol, suspended in 50m L methanol) and after stirring for 40 min, the T L C detection reaction was complete, quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate several times, dried over anhydrous sodium sulfate, filtered, the solvent dried by spinning off and isolated by column chromatography to give product ii-3(1.6g, 65%).1H NMR(400MHz,CDCl3)6.71(d,J＝10.3Hz,1H),6.51(q,J＝2.1Hz,1H),6.37(dd,J＝10.3,2.2Hz,1H),4.37(d,J＝2.1Hz,2H),3.20(s,6H),0.88(s,9H),0.05(s,6H)ppm；13C NMR(100MHz,CDCl3)185.0,158.2,143.0,132.4,126.0,95.2,59.4,51.0,25.8,18.2,-5.6ppm。
Synthesis of Compound ii-4:
compound ii-3(30.0g,100.52mmol) was dissolved in 804m L ethylene glycol dimethyl ether, 1, 3-propanediol (30.6g,402.07mmol) was added thereto at 0 ℃, then boron trifluoride diethyl ether (12.8m L, 105.54mmol) was added dropwise, stirring was carried out for 30 minutes, the reaction was terminated by T L C detection, quenched with saturated solution of sodium bicarbonate, extracted with ethyl acetate several times, dried over anhydrous sodium sulfate, filtered, the solvent was dried by spinning, and the product ii-4(21.5g, 69%) was isolated by column chromatography.1H NMR(400MHz,CDCl3)7.67(d,J＝10.4Hz,1H),6.35(q,J＝2.1Hz,1H),6.21(dd,J＝10.6,2.1Hz,1H),4.58(d,J＝2.2Hz,2H),4.20(td,J＝12.7,2.4Hz,2H),3.98-3.94(m,2H),2.26-2.13(m,1H),1.52(d,J＝13.6Hz,1H),0.92(s,9H),0.09(s,6H)ppm；13C NMR(100MHz,CDCl3)185.1,159.5,137.6,128.3,123.0,90.3,60.9,59.5,25.8,24.9,18.3,-5.5ppm。
Synthesis of Compound ii-5:
triphenylmethylperoxyalcohol (17.8g,64.42mmol, in 159m L dry toluene) was added to a reaction flask containing dry molecular sieves and stirred for 15 minutes, and sodium bis (trimethylsilyl) amide (2N,51.54mmol,25.8m L) was added dropwise thereto, stirred at room temperature for 25 minutes, and L- (+) -diisopropyl tartrate (6.0g,25.76mmol) was added to the reaction solution and stirredStirring for 25 minutes, then placing the reaction liquid at-78 ℃, dropwise adding a compound ii-4(4.0g,12.88mmol, dissolved in 15m L dry toluene) into the reaction liquid, reacting for 48 hours at-55 ℃, detecting the reaction completion by T L C, quenching the reaction by using a saturated ammonium chloride solution, extracting by ethyl acetate, drying by using anhydrous sodium sulfate, filtering, drying the solvent by spinning, and separating by column chromatography to obtain a product ii-5(2.87g, 69%).1H NMR(400MHz,CDCl3)6.13(q,J＝2.1Hz,1H),4.45(dd,J＝4.4,2.1Hz,2H),4.41(d,J＝4.1Hz,1H),4.36-4.28(m,2H),4.08-3.99(m,2H),3.48(dd,J＝4.0,2.1Hz,1H),2.20-2.15(m,1H),1.58(d,J＝13.6Hz,1H),0.89(s,9H),0.06(s,6H)ppm；13C NMR(100MHz,CDCl3)192.3,157.9,120.4,93.1,61.0,60.8,59.6,53.0,50.7,25.8,24.6,18.2,-5.5ppm。
Synthesis of Compound ii-6:
compound ii-5(6.0g,18.37mmol) was dissolved in 184m L dry tetrahydrofuran and placed at-78 ℃, lithium triethylborohydride (22.0m L,1N, 22.0mmol) was slowly added dropwise to the reaction solution, stirred for 30 minutes, T L C detected the reaction was complete, saturated ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, the solvent was spin dried, and separated by column chromatography to give α -unsaturated alcohol (5.43g, 90%).1H NMR(400MHz,CDCl3)5.74-5.73(m,1H),4.48(d,J＝10.2Hz,1H),4.30(t,J＝2.3Hz,2H),4.26(dd,J＝12.1,2.2Hz,2H),4.17(d,J＝4.3Hz,1H),3.97(td,J＝12.9,5.2Hz,2H),3.63-3.61(m,1H),2.12(tdd,J＝18.0,12.7,5.2Hz,1H),1.93(d,J＝11.1Hz,1H),1.50(d,J＝13.5Hz,1H),0.89(s,9H),0.06(s,6H)ppm；13C NMR(100MHz,CDCl3)137.5,121.8,93.4,64.7,61.1,60.7,59.4,54.7,50.2,25.9,24.8,18.3,-5.4ppm。
α -unsaturated alcohol (17.0g,51.75mmol) and imidazole (14.1g,207.01mmol) were dissolved in 258m L dry N, N-dimethylformamide solution, triisopropylchlorosilane (13.0g,67.27mmol) was added, stirring was carried out overnight at 50 ℃ to complete the reaction at T L C, a saturated ammonium chloride solution was added to the reaction solution, extraction was carried out with ethyl acetate, drying was carried out with anhydrous sodium sulfate, filtration was carried out, the solvent was dried by spin drying, and the product ii-6(25g, 100%) was obtained by column chromatography.1H NMR(400MHz,CDCl3)5.72(s,1H),4.73(s,1H),4.29-4.22(m,4H),4.07(d,J＝4.2Hz,1H),3.99-3.96(m,2H),3.51(s,1H),2.11(ddd,J＝23.0,15.3,8.9Hz,1H),1.50(d,J＝13.2Hz,1H),1.10(s,18H),1.08(s,3H),0.91(d,J＝7.6Hz,9H),0.05(s,6H)ppm；13C NMR(100MHz,CDCl3)136.0,123.1,94.0,65.8,61.1,60.4,59.5,54.7,48.6,25.9,24.9,18.2,18.0,12.3,-5.5ppm。
Synthesis of Compounds ii-7:
compound ii-6(100.0mg,0.21mmol) was dissolved in 184m L dichloromethane and montmorillonite K10(300mg) was added thereto, stirred at room temperature overnight, and the reaction was checked for completion by T L C, filtered through celite, the solvent was dried by spinning, and the product ii-7(86.0mg, 88%) was isolated by column chromatography.1H NMR(400MHz,CDCl3)6.56-6.54(m,1H),4.91-4.90(m,1H),4.46-4.41(m,1H),4.18(dt,J＝15.8,2.0Hz,1H),3.75(dd,J＝6.6,2.8Hz,1H),3.40(d,J＝4.0Hz,1H),1.13(s,18H),1.12(s,3H),0.90(s,9H),0.06(d,J＝2.2Hz,6H)ppm；13C NMR(100MHz,CDCl3)193.3,139.8,134.2,66.2,59.2,54.1,53.2,25.8,18.1,18.0,12.2,-5.6ppm。
Synthesis of Compounds ii-8:
compound ii-7(9.0g,20.94mmol) was dissolved in 105m L dry tetrahydrofuran and placed at-78 deg.c, lithium triethylborohydride (25.1m L,1N in THF,25.13mmol) was slowly added dropwise to the reaction solution, stirred for 30 minutes, T L C detected the reaction was complete, saturated ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, the solvent was dried, and product ii-8(8.0g, 89%) was isolated by column chromatography.1H NMR(400MHz,CDCl3)5.53(s,1H),4.64(d,J＝1.3Hz,1H,),4.39(d,J＝9.3Hz,1H),4.29(d,J＝13.6Hz,1H),4.20(d,J＝13.6Hz,1H),3.54(s,2H),2.38(d,J＝9.6Hz,1H),1.11(s,18H),1.09(s,3H)0.90(s,9H),0.07(s,6H)ppm；13C NMR(100MHz,CDCl3)135.7,122.8,66.1,65.7,63.6,55.6,54.8,25.8,18.2,18.0,12.3,-5.5ppm。
Synthesis of Compounds ii-10:
the compounds ii-8(142.0mg,0.33mmol), ii-9(91.7mg,0.40mmol) and triphenylphosphine (130.0mg,0.49mmol) were dissolved in 6.6m L dry tetrahydrofuran solution and reacted at 0 deg.CDiisopropyl azodicarboxylate (100.0mg,0.49mmol) was added to the solution, and the mixture was stirred for 40 minutes, and the reaction was terminated by T L C detection, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was dried by spin-drying, and separated by column chromatography to give ii-10(192.0mg, 91%).1H NMR(400MHz,CDCl3)7.94(d,J＝7.5Hz,2H),7.64-7.60(m,1H),7.54(t,J＝7.5Hz,2H),5.78(s,1H),4.60(s,1H),4.45(s,1H),3.90(q,J＝17.9Hz,2H),3.66(s,3H),3.58(d,J＝14.9Hz,1H),3.49(d,J＝14.8Hz,1H),3.34(d,J＝8.4Hz,2H),1.08(s,18H),1.06(s,3H),0.83(s,9H),-0.07(s,6H)ppm；13C NMR(100MHz,CDCl3)169.8,139.8,133.2,131.0,129.1,127.6,125.8,65.8,62.1,54.6,52.4,52.3,52.0,44.9,25.7,18.1,18.0,12.2,-5.6ppm。
Synthesis of Compounds ii-11:
compound ii-10(503.0mg,0.79mmol) was dissolved in acetonitrile: 0.1N hydrochloric acid (vol., 30m L/3 m L) and stirred at room temperature for 6 hours, the reaction was quenched with saturated sodium bicarbonate solution after T L C detection, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, the solvent was dried, and the product α -unsaturated alcohol (404.0mg, 98%) was isolated by column chromatography.1H NMR(400MHz,CDCl3)7.96(d,J＝7.7Hz,2H),7.63(t,J＝7.3Hz,1H),7.53(t,J＝7.4Hz,2H),5.67(s,1H),4.68(s,1H),4.60(s,1H),3.92(s,2H),3.78(d,J＝5.4Hz,2H),3.67(s,3H),3.33(s,1H),3.20(s,1H),2.08(t,J＝6.5Hz,1H),1.08(s,18H),1.07(s,3H)ppm；13C NMR(100MHz,CDCl3)170.2,139.6,133.4,131.9,129.2,128.1,127.6,65.6,63.3,54.5,52.4,52.1,51.7,45.0,18.0,12.3ppm。
α -unsaturated alcohol (369.0mg,0.70mmol) is dissolved in 5.6m L dry tetrahydrofuran solution, placed at-20 ℃, added with triethylamine (355.0mg,3.51mmol) and methanesulfonyl chloride (241.0mg,2.10mmol), stirred for 30 minutes, added with lithium bromide (609.0mg,7.02mmol) to the reaction solution and placed at 0 ℃ for reaction for 4 hours, the reaction is detected by T L C, quenched with saturated solution of sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, the solvent is dried, and separated by column chromatography to obtain the product ii-11(393.0mg, 93%).1H NMR(400MHz,CDCl3)7.99(d,J＝7.6Hz,2H),7.64(t,J＝7.3Hz,1H),7.56(t,J＝7.5Hz,2H),5.76(s,1H),4.82(s,1H),4.61(s,1H),4.02(d,J＝18.1Hz,1H),3.84(d,J＝18.1Hz,1H),3.67(s,3H),3.60(q,J＝10.7Hz,2H),3.36(s,1H),3.31(s,1H),1.09(s,18H),1.08(s,3H)ppm；13C NMR(100MHz,CDCl3)169.9,139.5,133.4,132.5,129.3,127.7,65.8,54.0,52.4,52.1,51.8,45.4,32.6,18.0,12.3ppm。
Synthesis of Compounds ii-12:
compound ii-11(318.0mg,0.54mmol) was dissolved in 30m L dry N, N-dimethylformamide solution, placed at-60 ℃, slowly added dropwise with potassium bis (trimethylsilyl) amide (1.1m L,1N, 1.1mmol) to the reaction solution, stirred for 1 hour, T L C detected reaction was completed, quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, solvent dried, and isolated by column chromatography to give compound ii-12(193.0mg, 70%).1H NMR(400MHz,CDCl3)7.92(d,J＝7.9Hz,2H),7.66(t,J＝7.2Hz,1H),7.57(t,J＝7.5Hz,2H),5.49(s,1H),4.69(s,1H),4.39(d,J＝9.8Hz,1H),4.12(s,1H),3.82(s,1H),3.73(s,3H),3.43(s,1H),2.38(d,J＝14.0Hz,1H),2.27-2.21(m,1H),1.09(m,21H)ppm；13C NMR(100MHz,CDCl3)171.0,136.0,134.6,133.6,129.5,127.9,122.2,64.2,60.4,58.2,56.5,54.0,52.7,34.7,18.0,12.3ppm。
Synthesis of Compounds ii-13:
compound ii-12(266.0mg,0.52mmol) and magnesium powder (127.0mg,5.24mmol) were placed in a round bottom flask, 30m L dry methanol was added as solvent, sonicated for 40 min, quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, the solvent was spun off, and isolated by column chromatography to give monomeric compound ii-13(164.0mg, 85%).1H NMR(400MHz,CDCl3)5.37(s,1H),4.70(s,1H),3.97(dd,J＝10.6,4.6Hz,1H),3.73(s,3H),3.63(s,1H),3.55(d,J＝3.3Hz,1H),3.41(t,J＝3.6Hz,1H),2.88-2.82(m,1H),2.46(dd,J＝15.6,4.5Hz,1H),2.19(s,1H),1.10(s,18H),1.09(s,3H)ppm；13C NMR(100MHz,CDCl3)174.1,138.7,118.1,65.3,57.0,56.5,55.3,54.3,52.3,34.2,18.0,12.4ppm。
Synthesis of Compounds ii-15:
compound ii-13(30.0mg, 8)1.62. mu. mol) was dissolved in 1.4m L tetrahydrofuran, lithium hydroxide monohydrate (6.8mg, 163.24. mu. mol, dissolved in 1.4m L water) was added dropwise thereto, the mixture was stirred for 15 minutes, and the reaction was terminated by T L C, the pH was adjusted to 6 with a buffer solution of sodium dihydrogenphosphate and potassium hydrogensulfate having a pH of 2.5, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and then filtered, and the solvent was dried to obtain compound ii-14, a 3m L solution of dried N, N-dimethylformamide was added, 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (124.0mg, 326.47. mu. mol) was added dropwise, N, N-diisopropylethylamine (42.0mg, 326.47. mu. mol) was added to the reaction solution, the reaction was terminated by T L C, and the solvent was dried by rotary drying to obtain product ii-15(23.3mg, 85%).1H NMR(400MHz,CDCl3)5.54(s,1H),4.85(d,J＝3.5Hz,1H),4.67(s,1H),4.29(dd,J＝11.1,2.9Hz,1H),4.23(s,1H),3.40(t,J＝3.2Hz,1H),3.15(dd,J＝15.7,2.7Hz,1H),2.82-2.75(m,1H),1.10(s,18H),1.09(s,3H)ppm；13C NMR(100MHz,CDCl3)166.7,134.5,121.2,64.7,59.5,56.3,54.7,53.6,29.1,18.0,12.3ppm。
Synthesis of Compounds ii-16:
compound ii-15(30.0mg, 44.70. mu. mol) was dissolved in 3m L tetrahydrofuran, glacial acetic acid (8.0mg, 134.12. mu. mol) was added, tetrabutylammonium fluoride (35.0mg,1N in THF, 134.12. mu. mol) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours, after completion of the reaction was checked by T L C, followed by spin-drying and column chromatography to give product ii-16(16.0mg, 100%).1H NMR(400MHz,CDCl3)5.67-5.66(m,1H),4.92(d,J＝3.5Hz,1H),4.47(s,1H),4.31(dd,J＝11.1,3.3Hz,1H),4.17(s,1H),3.52(t,J＝3.5Hz,1H),3.19(dd,J＝16.0,3.2Hz,1H),2.85-2.78(m,1H),1.93(d,1H)；ppm13C NMR(100MHz,CDCl3)166.9,135.6,121.1,63.0,59.5,56.2,55.6,54.3,29.0ppm。
Example three:
Figure BDA0001940554910000091
synthesis of Compound iii-1:
compound ii-15(50mg, 74.51. mu. mmol) was dissolved in 10m L dry methanol, and sodium methoxide solution (45.0. mu. L, 30 wt% in methanol) was added dropwise to the reactionLiquid), stirred at room temperature for 4 hours, T L C detected the reaction was complete, quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, the solvent dried, and isolated by column chromatography to give compound iii-1(45.0mg, 90%).1H NMR(400MHz,CDCl3)5.69(s,1H),4.71(s,1H),4.39(s,1H),4.29(dd,J＝10.3,6.9Hz,1H),4.19(d,J＝3.3Hz,1H),3.38(t,J＝3.5Hz,1H),2.87–2.81(m,1H),2.75(dd,J＝14.0,6.8Hz,1H),1.12(s,18H),1.10(s,6H)ppm；13C NMR(100MHz,CDCl3)166.4,135.2,122.1,64.4,60.8,55.7,54.9,53.8,33.6,18.0,12.4ppm。
Synthesis of Compound iii-2:
compound iii-1(14mg, 20.86. mu. mol) was dissolved in 2m L tetrahydrofuran, glacial acetic acid (4mg, 62.59. mu. mol) was added, tetrabutylammonium fluoride (62.59. mu. mol,1N in THF) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 3 hours, and the reaction was checked for completion by T L C, followed by spin-drying and column chromatography to give product iii-2(6.0mg, 80%).1H NMR(400MHz,DMSO)5.66(s,1H),5.02(d,J＝7.1Hz,1H),4.48-4.41(m,2H),4.19(s,1H),3.94(d,J＝3.5Hz,1H),2.66-2.64(m,,2H)；13C NMR(100MHz,DMSO)166.4,135.2,121.9,61.9,60.0,55.9,54.3,53.3,32.9ppm。
It is noted herein that the above-mentioned embodiments illustrate rather than limit the technical solution of the present invention, and although the present invention has been described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present invention.

Claims (4)

1. Synthesis method of Scabrosins/Ambewelamides framework structure with structure
Figure FDA0001940554900000011
Wherein:
R1、R4、R7、R8、R9、R10、R11、R12respectively independently selectFrom hydrogen, alkyl, alkoxycarbonyl, silyl;
R2、R5each independently selected from hydrogen and alkyl;
R3、R6are respectively and independently selected from hydrogen, formate, phenylsulfonyl and sulfonyl.
The method is characterized by comprising the following steps of;
step one, preparing i-6 and i-8 from i-1;
Figure FDA0001940554900000012
step two, preparing ii-13 and ii-16 from ii-1 respectively;
Figure FDA0001940554900000013
step three, preparing iii-2 from i-15 respectively;
Figure FDA0001940554900000021
2. the synthesis method as claimed in claim 1, wherein the compound i-1 is used as a starting material, the target compound i-6 is prepared through a plurality of reactions such as Negishi coupling reaction, deprotection, reductive amination and the like, and the target compound i-8 is obtained through ester hydrolysis and condensation reaction.
3. The synthesis method as claimed in claim 1, wherein the target compound ii-13 is prepared from the compound ii-1 as a starting material by a plurality of reactions such as selective hydroxyl protection, dearomatization, ketal exchange, asymmetric epoxidation, selective reduction, hydroxyl protection, deprotection, reduction, Mitsunobu, selective deprotection, bromination, intramolecular nucleophilic cyclization, and ultrasonic deprotection, and the target compound ii-16 is obtained by condensation and hydroxyl deprotection.
4. A synthesis process according to claim 1, characterized in that the fragment ii-15 obtained is reacted with sodium methoxide solution and then subjected to deprotection reaction of hydroxyl group to obtain the target compound iii-2.
CN201910020544.7A 2019-01-09 2019-01-09 Synthesis method of Scabrosins/Ambewelamides framework structure Pending CN111423465A (en)

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