CN114890932A - First total synthesis process of indole alkaloid Luteoride A - Google Patents
First total synthesis process of indole alkaloid Luteoride A Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 22
- WYTGDNHDOZPMIW-RCBQFDQVSA-N alstonine Chemical compound C1=CC2=C3C=CC=CC3=NC2=C2N1C[C@H]1[C@H](C)OC=C(C(=O)OC)[C@H]1C2 WYTGDNHDOZPMIW-RCBQFDQVSA-N 0.000 title claims abstract description 16
- 229930005303 indole alkaloid Natural products 0.000 title claims abstract description 16
- 238000006257 total synthesis reaction Methods 0.000 title claims abstract description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 12
- PKLFICDRWXSEJK-UHFFFAOYSA-N B.C1(=CC=CC2=CC=CC=C12)O Chemical compound B.C1(=CC=CC2=CC=CC=C12)O PKLFICDRWXSEJK-UHFFFAOYSA-N 0.000 claims abstract description 6
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 239000000758 substrate Substances 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 10
- HNVRRHSXBLFLIG-UHFFFAOYSA-N 3-hydroxy-3-methylbut-1-ene Chemical compound CC(C)(O)C=C HNVRRHSXBLFLIG-UHFFFAOYSA-N 0.000 claims description 9
- RDSVSEFWZUWZHW-UHFFFAOYSA-N 7-bromo-1h-indole Chemical compound BrC1=CC=CC2=C1NC=C2 RDSVSEFWZUWZHW-UHFFFAOYSA-N 0.000 claims description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 9
- 229940125782 compound 2 Drugs 0.000 claims description 9
- 229940125898 compound 5 Drugs 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 239000012074 organic phase Substances 0.000 claims description 9
- 238000002390 rotary evaporation Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 7
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000000741 silica gel Substances 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- -1 compound cuprous cyanide Chemical class 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- BZAZNULYLRVMSW-UHFFFAOYSA-N 2-Methyl-2-buten-3-ol Natural products CC(C)=C(C)O BZAZNULYLRVMSW-UHFFFAOYSA-N 0.000 claims description 3
- GRJZJFUBQYULKL-UHFFFAOYSA-N 4-bromo-1h-indole Chemical compound BrC1=CC=CC2=C1C=CN2 GRJZJFUBQYULKL-UHFFFAOYSA-N 0.000 claims description 3
- VXWVFZFZYXOBTA-UHFFFAOYSA-N 5-bromo-1h-indole Chemical compound BrC1=CC=C2NC=CC2=C1 VXWVFZFZYXOBTA-UHFFFAOYSA-N 0.000 claims description 3
- MAWGHOPSCKCTPA-UHFFFAOYSA-N 6-bromo-1h-indole Chemical compound BrC1=CC=C2C=CNC2=C1 MAWGHOPSCKCTPA-UHFFFAOYSA-N 0.000 claims description 3
- 238000007341 Heck reaction Methods 0.000 claims description 3
- GSCCALZHGUWNJW-UHFFFAOYSA-N N-Cyclohexyl-N-methylcyclohexanamine Chemical compound C1CCCCC1N(C)C1CCCCC1 GSCCALZHGUWNJW-UHFFFAOYSA-N 0.000 claims description 3
- 238000005899 aromatization reaction Methods 0.000 claims description 3
- ACONPURZGJUVLW-UHFFFAOYSA-N chloroform;palladium Chemical compound [Pd].[Pd].ClC(Cl)Cl ACONPURZGJUVLW-UHFFFAOYSA-N 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 229940126214 compound 3 Drugs 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 claims description 3
- BJHXPQCXQWQHIW-UHFFFAOYSA-N ethyl 3-iodo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CI BJHXPQCXQWQHIW-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 238000011065 in-situ storage Methods 0.000 claims description 3
- MQONVZMIFQQQHA-UHFFFAOYSA-N methyl 3-bromo-2-oxopropanoate Chemical compound COC(=O)C(=O)CBr MQONVZMIFQQQHA-UHFFFAOYSA-N 0.000 claims description 3
- IAYZPEQQJKKMJK-UHFFFAOYSA-N methyl 3-iodo-2-oxopropanoate Chemical compound COC(=O)C(=O)CI IAYZPEQQJKKMJK-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- YUIULFRCMVKNKV-UHFFFAOYSA-N propyl 3-iodo-2-oxopropanoate Chemical compound CCCOC(=O)C(=O)CI YUIULFRCMVKNKV-UHFFFAOYSA-N 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 238000007142 ring opening reaction Methods 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 2
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 9
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 abstract description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 4
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical group CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 abstract description 4
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 125000006239 protecting group Chemical group 0.000 abstract description 2
- 238000002444 silanisation Methods 0.000 abstract 2
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 5
- 239000007983 Tris buffer Substances 0.000 description 4
- CSCPPACGZOOCGX-MICDWDOJSA-N 1-deuteriopropan-2-one Chemical compound [2H]CC(C)=O CSCPPACGZOOCGX-MICDWDOJSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 2
- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
-
- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a first total synthesis process of indole alkaloid Luteoride A in the Luteoride A synthesis field, wherein an isoprene group is introduced into the 7 th site of indole, so that the use of toxic reagents (trimethyl silanization diazomethane, cuprous cyanide, 2-methyl-1-butene-3-alkyne and the like), highly flammable reagents (n-butyllithium, tri-n-butyltin hydride and the like) and expensive reagents (trimethyl silanization diazomethane, child naphthol borane, 2-methyl-1-butene-3-alkyne and the like) is avoided, and the operation without a protective group is also used, so that the process has redox economy and atomic economy; and realizes the first total synthesis of indole alkaloid luteorideA.
Description
Technical Field
The invention relates to the technical field of LuteorideA synthesis, in particular to a first total synthesis process of indole alkaloid LuteorideA.
Background
At present, no precedent for directly introducing an isoprene group at the 7-position of indole under the operation without a protecting group exists, and the traditional method has certain limitation in the process of introducing the isoprene group, and generally needs harsh reaction conditions such as strong acid and strong base, highly toxic reagents (trimethylsilylated diazomethane, cuprous cyanide, 2-methyl-1-butene-3-alkyne and the like), highly flammable reagents (n-butyllithium, tri-n-butyltin hydride, catechol borane and the like) and expensive reagents (trimethylsilylated diazomethane, naphthol borane, 2-methyl-1-butene-3-alkyne and the like). Atom economy is poor, preparation cost is high, total yield is low, and no relevant report on the synthesis of indole alkaloid luteorideA exists at present.
Based on the technical scheme, the invention designs a first total synthesis process of indole alkaloid LuteorideA to solve the problems.
Disclosure of Invention
The invention aims to provide a first total synthesis process of indole alkaloid Luteoridea A, so as to solve the problems in the background technology.
In order to achieve the purpose, the invention provides the following technical scheme: the primary total synthesis process of indole alkaloid LuteorideA comprises the following steps:
s1: a substrate 4 is taken as a starting material and undergoes a hydroxylamination reaction with hydroxylamine hydrochloride to obtain a compound 5 with a yield of 87%; the method specifically comprises the following steps: 335mL CHC13, and 221mL CH3OH were added to a dry reaction flask under nitrogen, 417.7mL (165.8mmol) of substrate was added at room temperature, stirring was uniform, and 10.7g HCl-amine (165.8mmol) was added; the mixture was stirred overnight at room temperature and then concentrated by rotary evaporation at 30 ℃ to remove most of the solvent, with little solvent remaining; the residue was dissolved in 300mL of dichloromethane, washed successively with 0.1N of 30mL HC1, 230mL of water, and 30mL of saturated sodium chloride solution, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 28.3g of Compound 5 as white crystals (87% yield); no further purification was required.
S2, adding excess initial raw material 2-methyl-1-butene-3-alkyne 1 into naphthol borane to obtain a compound 2;
the compound 3 is obtained by adding cuprous cyanide, flammable compounds n-butyl lithium and tri-n-butyl tin hydride into 2-methyl-1-butene-3-alkyne 1.
Preparation of prenyl Compounds
The compound 5 and a 7-bromoindole substrate 6 undergo a heteroatom D-A reaction and then undergo ring opening and aromatization to obtain a compound 7 with a yield of 82%, specifically: under nitrogen protection, 10g of compound 2(51mmol) was dissolved in 110mL of dichloromethane and added dropwise to 20g of 7-bromoindole 3(102mmol) dissolved in 110mL of dichloromethane and treated with 10.8g of Na2CO3(102mmol), the mixture was stirred at room temperature for 10h and then extracted with 200mL of dichloromethane, washed successively with 220mL of water and 20mL of saturated sodium chloride solution, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and the solvent was removed by rotary evaporation at 30 ℃ to give compound 2, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate ═ 5:1 to 3:1) to give 13g of compound 4 (yield 82%).
S3: the compound 7 and 2-methyl-3-butene-2-ol 8 are subjected to Heck reaction in the presence of a palladium catalyst, and the tertiary hydroxyl is eliminated in situ to obtain LuteorideA with a yield of 94%; the method specifically comprises the following steps: under nitrogen protection, 1.12g of compound 4(3.6mol), 64.8mg of catalyst (0.288mmo1), 219.6mg of tris (o-methylphenyl) phosphine (0.72mmol), 79.2mg of BHT (0.36mmol), DMF 19.2mL, 772 μ L N-methyldicyclohexylamine (3.6mmol) and 1.7mL of 2-methyl-3-buten-2-ol 5(54mmol) are put into a sealed tube in succession, mixed uniformly and reacted in an oil bath at 115 ℃ for 6 hours, after cooling, stirred with 10mL of sodium bicarbonate solution for 5 minutes, the insoluble matter is filtered through silica gel and the filter cake is washed with 150mL of ethyl acetate, the filtrate is washed once with (5X 30mL) of water and 30mL of saturated sodium chloride solution, the organic phases are combined and dried over anhydrous sodium sulfate, filtered and then concentrated at 30 ℃ by rotary evaporation to remove the solvent; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 5:1-1:1) to give 978mg of Luteoride A (yield 92%).
As a further scheme of the invention, in the first step, the substrate 4 is methyl bromopyruvate, ethyl bromopyruvate, methyl chlorophytonate, ethyl chlorophytonate, propyl chlorophytonate, methyl iodopyruvate, ethyl iodopyruvate or propyl iodopyruvate.
As a further embodiment of the invention, the catalyst in the third step is palladium acetate, palladium chloride, tetratriphenylphosphine palladium, tris (diylideneacetone) dipalladium-chloroform adduct, tris (diylideneacetone) dipalladium, palladium trifluoroacetate, bis (tri-tert-butylphosphine) palladium, palladium on carbon or no catalyst is added.
As a further embodiment of the present invention, in the second step, the substrate 6 is 7-bromoindole, 4-bromoindole, 5-bromoindole or 6-bromoindole.
Compared with the prior art, the invention has the beneficial effects that:
1. according to the invention, an isoprene group is introduced into the 7 th position of indole for the first time, so that the use of toxic reagents (trimethylsilylated diazomethane, cuprous cyanide, 2-methyl-1-butene-3-alkyne and the like), highly flammable reagents (n-butyllithium, tri-n-butyltin hydride and the like) and expensive reagents (trimethylsilylated diazomethane, naphthol borane, 2-methyl-1-butene-3-alkyne and the like) is avoided, and the use of a protecting group-free operation is adopted, so that the preparation method has redox economy and atomic economy; and realizes the first total synthesis of indole alkaloid luteorideA; generally, the synthesis method has the advantages of simple and direct route, simple and easily obtained raw materials, low preparation cost, high product yield, simple and convenient operation and the like.
Drawings
FIG. 1 is a schematic nuclear magnetic resonance hydrogen spectrum of a substrate 5 of the present invention;
FIG. 2 is a schematic nuclear magnetic resonance carbon spectrum of a substrate 5 of the present invention;
FIG. 3 is a schematic nuclear magnetic resonance hydrogen spectrum of a substrate 7 of the present invention;
FIG. 4 is a schematic nuclear magnetic resonance carbon spectrum of a substrate 7 of the present invention;
FIG. 5 is a schematic illustration of the hydrogen nuclear magnetic resonance spectrum of LuteorideA according to the present invention;
FIG. 6 is a schematic nuclear magnetic resonance carbon spectrum of LuteorideA according to the present invention.
Detailed Description
Referring to fig. 1-6, the present invention provides a technical solution: the first total synthesis process of the indole alkaloid Luteoridea A comprises the following steps:
s1: a substrate 4 is taken as a starting material and undergoes a hydroxylamination reaction with hydroxylamine hydrochloride to obtain a compound 5 with a yield of 87%; the method specifically comprises the following steps: 335mL of CHC13 and 221mLCH3OH were added to a dry reaction flask under nitrogen, 417.7mL (165.8mmol) of substrate was added at room temperature, the mixture was stirred well, and then 10.7g of hydrochloric acid and amine (165.8mmol) were added; the mixture was stirred overnight at room temperature and then concentrated by rotary evaporation at 30 ℃ to remove most of the solvent, with little solvent remaining; the residue was dissolved in 300mL of dichloromethane, washed successively with 0.1N of 30mL HC1, 230mL of water, and 30mL of saturated sodium chloride solution, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 28.3g of Compound 5 as white crystals (87% yield); no further purification was required.
White solid, total yield 87%, 1 H NMR(400MHz,Acetone-d 6 )δ4.39(d,2H),3.82(s,3H); 13 C NMR(101MHz,Acetone-d 6 )δ162.73,147.57,51.92,15.97.
s2, adding excess initial raw material 2-methyl-1-butene-3-alkyne 1 into naphthol borane to obtain a compound 2;
and then adding a compound cuprous cyanide, a flammable compound n-butyl lithium and tri-n-butyl tin hydride into the 2-methyl-1-butene-3-alkyne 1 to obtain a compound 3.
Preparation of prenyl Compounds
The compound 5 and a 7-bromoindole substrate 6 undergo a heteroatom D-A reaction and then undergo ring opening and aromatization to obtain a compound 7 with a yield of 82%, specifically: under nitrogen protection, 10g of compound 2(51mmol) was dissolved in 110mL of dichloromethane and added dropwise to 20g of 7-bromoindole 3(102mmol) dissolved in 110mL of dichloromethane and treated with 10.8g of Na2CO3(102mmol), the mixture was stirred at room temperature for 10h and then extracted with 200mL of dichloromethane, washed successively with 220mL of water and 20mL of saturated sodium chloride solution, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and the solvent was removed by rotary evaporation at 30 ℃ to give compound 2, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate ═ 5:1 to 3:1) to give 13g of compound 4 (yield 82%).
The solid content, the total yield is 82 percent, 1 H NMR(400MHz,CDCl 3 )δ9.47(s,1H),8.22(s,1H),7.72(dt,J=7.9,0.8Hz,1H),7.34(dd,J=7.7,0.8Hz,1H),7.21(d,J=2.4Hz,1H),7.01(t,J=7.8Hz,1H),4.09(d,J=0.9Hz,2H),3.82(s,3H); 13 C NMR(101MHz,CDCl 3 )δ163.78,151.23,134.55,128.39,124.42,124.17,120.77,118.54,110.77,104.67,52.81,20.45.
s3: the compound 7 and 2-methyl-3-butene-2-ol 8 are subjected to Heck reaction in the presence of a palladium catalyst, and the tertiary hydroxyl is eliminated in situ to obtain LuteorideA with a yield of 94%; the method comprises the following specific steps: under nitrogen protection, 1.12g of compound 4(3.6mol), 64.8mg of catalyst (0.288mmo1), 219.6mg of tris (o-methylphenyl) phosphine (0.72mmol), 79.2mg of BHT (0.36mmol), DMF 19.2mL, 772 μ L N-methyldicyclohexylamine (3.6mmol) and 1.7mL of 2-methyl-3-buten-2-ol 5(54mmol) are put into a sealed tube in succession, mixed uniformly and reacted in an oil bath at 115 ℃ for 6 hours, after cooling, stirred with 10mL of sodium bicarbonate solution for 5 minutes, the insoluble matter is filtered through silica gel and the filter cake is washed with 150mL of ethyl acetate, the filtrate is washed once with (5X 30mL) of water and 30mL of saturated sodium chloride solution, the organic phases are combined and dried over anhydrous sodium sulfate, filtered and then concentrated at 30 ℃ by rotary evaporation to remove the solvent; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1-1:1) to give 978mg of Luteoride A (92% yield).
The solid content, the total yield is 92 percent, 1 H NMR(400MHz,Acetone-d6)δ11.48(s,1H),10.44(s,1H),7.66(d,J=7.9Hz,1H),7.37(d,J=7.4Hz,1H),7.19(d,J=2.3Hz,1H),7.07(d,J=4.0Hz,2H),7.03(d,J=7.7Hz,1H),5.15(d,J=2.3Hz,1H),5.06(dt,J=2.9,1.4Hz,1H),4.06(s,2H),3.70(s,3H); 13 C NMR(101MHz,Acetone-d 6 )δ164.40,151.07,142.58,134.45,131.54,128.19,124.55,123.88,121.24,119.19,118.50,118.36,116.37,109.74,51.43,19.98,17.88;IR(KBr):3332,3050,2944,2346,1705,1438,1340,1206,1106,1013,894,799,728,670,466cm -1 ;HRMS(ESI)m/z calcd for C 17 H 17 N 2 O 3 [M-H] + 297.1246,found297.1245.
as a further scheme of the invention, in the first step, the substrate 4 is methyl bromopyruvate, ethyl bromopyruvate, methyl chlorophytonate, ethyl chlorophytonate, propyl chlorophytonate, methyl iodopyruvate, ethyl iodopyruvate or propyl iodopyruvate.
As a further embodiment of the invention, the catalyst in the third step is palladium acetate, palladium chloride, tetratriphenylphosphine palladium, tris (diylideneacetone) dipalladium-chloroform adduct, tris (diylideneacetone) dipalladium, palladium trifluoroacetate, bis (tri-tert-butylphosphine) palladium, palladium on carbon or no catalyst is added.
As a further embodiment of the present invention, in the second step, the substrate 6 is 7-bromoindole, 4-bromoindole, 5-bromoindole or 6-bromoindole.
Claims (4)
1. A primary total synthesis process of indole alkaloid Luteoride A is characterized in that: the primary total synthesis process of the indole alkaloid Luteoride A comprises the following steps:
s1: a substrate 4 is taken as a starting material and undergoes a hydroxylamination reaction with hydroxylamine hydrochloride to obtain a compound 5 with a yield of 87%; the method specifically comprises the following steps: 335mL of CHC13 and 221mLCH3OH were added to a dry reaction flask under nitrogen, 417.7mL (165.8mmol) of substrate was added at room temperature, the mixture was stirred well, and then 10.7g of hydrochloric acid and amine (165.8mmol) were added; the mixture was stirred overnight at room temperature and then concentrated by rotary evaporation at 30 ℃ to remove most of the solvent, with little solvent remaining; the residue was dissolved in 300mL of dichloromethane, washed successively with 0.1N of 30mL HC1, 230mL of water, and 30mL of saturated sodium chloride solution, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 28.3g of Compound 5 as white crystals (87% yield); no further purification was required.
S2, adding excess initial raw material 2-methyl-1-butene-3-alkyne 1 into naphthol borane to obtain a compound 2;
and then adding a compound cuprous cyanide, a flammable compound n-butyl lithium and tri-n-butyl tin hydride into the 2-methyl-1-butene-3-alkyne 1 to obtain a compound 3.
Preparation of prenyl Compounds
The compound 5 and a 7-bromoindole substrate 6 undergo a heteroatom D-A reaction and then undergo ring opening and aromatization to obtain a compound 7 with a yield of 82%, specifically: under nitrogen protection, 10g of compound 2(51mmol) was dissolved in 110mL of dichloromethane and added dropwise to 20g of 7-bromoindole 3(102mmol) dissolved in 110mL of dichloromethane and treated with 10.8g of Na2CO3(102mmol), the mixture was stirred at room temperature for 10h and then extracted with 200mL of dichloromethane, washed successively with 220mL of water and 20mL of saturated sodium chloride solution, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and the solvent was removed by rotary evaporation at 30 ℃ to give compound 2, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate ═ 5:1 to 3:1) to give 13g of compound 4 (yield 82%).
S3: the compound 7 and 2-methyl-3-butene-2-ol 8 are subjected to Heck reaction in the presence of a palladium catalyst, and the tertiary hydroxyl is eliminated in situ to obtain Luteoride A with a yield of 94%; the method specifically comprises the following steps: under nitrogen protection, 1.12g of compound 4(3.6mol), 64.8mg of catalyst (0.288mmo1), 219.6mg of tris (o-methylphenyl) phosphine (0.72mmol), 79.2mg of BHT (0.36mmol), DMF 19.2mL, 772 μ L N-methyldicyclohexylamine (3.6mmol) and 1.7mL of 2-methyl-3-buten-2-ol 5(54mmol) are put into a sealed tube in succession, mixed uniformly and reacted in an oil bath at 115 ℃ for 6 hours, after cooling, stirred with 10mL of saturated sodium bicarbonate solution for 5 minutes, the insoluble matter is filtered through silica gel and the filter cake is washed with 150mL of ethyl acetate, the filtrate is washed once with (5 × 30mL) of water and 30mL of saturated sodium chloride solution, the organic phases are combined and dried over anhydrous sodium sulfate, filtered and then concentrated by rotary evaporation at 30 ℃ to remove the solvent; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1-1:1) to give 978mg of Luteoride A (92% yield).
2. The process for the first total synthesis of indole alkaloid Luteoride A according to claim 1, wherein: in the first step, the substrate 4 is methyl bromopyruvate, ethyl bromopyruvate, methyl chlorophyruvate, ethyl chlorophyruvate, propyl chlorophyruvate, methyl iodopyruvate, ethyl iodopyruvate or propyl iodopyruvate.
3. The process for the first total synthesis of indole alkaloid Luteoride A according to claim 1, wherein: the catalyst in the third step is palladium acetate, palladium chloride, tetratriphenylphosphine palladium, a tri (diylideneacetone) dipalladium-chloroform adduct, tri (diylideneacetone) dipalladium, palladium trifluoroacetate, di (tri-tert-butylphosphine) palladium, palladium carbon or no catalyst is added.
4. The process for the first total synthesis of indole alkaloid Luteoride A according to claim 1, wherein: in the second step, the substrate 6 is 7-bromoindole, 4-bromoindole, 5-bromoindole or 6-bromoindole.
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CN114539123A (en) * | 2022-02-28 | 2022-05-27 | 大理大学 | Method for synthesizing TMC-205 in one step |
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CN114539123A (en) * | 2022-02-28 | 2022-05-27 | 大理大学 | Method for synthesizing TMC-205 in one step |
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