CN111187186B - Intermediate SA-01 of active natural product Solanoeclepin A and preparation method thereof - Google Patents
Intermediate SA-01 of active natural product Solanoeclepin A and preparation method thereof Download PDFInfo
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- CN111187186B CN111187186B CN202010035466.0A CN202010035466A CN111187186B CN 111187186 B CN111187186 B CN 111187186B CN 202010035466 A CN202010035466 A CN 202010035466A CN 111187186 B CN111187186 B CN 111187186B
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- 229930014626 natural product Natural products 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- RJGYDIIDNSNYIB-AVXUVGQDSA-N solanoeclepin a Chemical compound C([C@H]1[C@]23C[C@H](O)[C@]4(C3=O)C3=C(CC[C@]42C)[C@H](O)[C@]24O[C@@H](C(C4)=O)C(C)(C)C2=C(C3=O)OC)[C@H]1C(O)=O RJGYDIIDNSNYIB-AVXUVGQDSA-N 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 12
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims abstract description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 10
- -1 diallyl alcohol compound Chemical class 0.000 claims abstract description 9
- 239000003446 ligand Substances 0.000 claims abstract description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 5
- CHLCPTJLUJHDBO-UHFFFAOYSA-M sodium;benzenesulfinate Chemical compound [Na+].[O-]S(=O)C1=CC=CC=C1 CHLCPTJLUJHDBO-UHFFFAOYSA-M 0.000 claims abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000007032 Staudinger Ketene cycloaddition reaction Methods 0.000 claims abstract description 4
- 238000005888 cyclopropanation reaction Methods 0.000 claims abstract description 4
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical group O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 238000007239 Wittig reaction Methods 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 150000002148 esters Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 1
- TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 claims 1
- 230000000382 dechlorinating effect Effects 0.000 claims 1
- 241001442497 Globodera rostochiensis Species 0.000 abstract description 16
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 7
- 230000012447 hatching Effects 0.000 abstract description 7
- 230000006698 induction Effects 0.000 abstract description 7
- 238000006722 reduction reaction Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 4
- HIGQPQRQIQDZMP-DHZHZOJOSA-N geranyl acetate Chemical compound CC(C)=CCC\C(C)=C\COC(C)=O HIGQPQRQIQDZMP-DHZHZOJOSA-N 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 abstract 1
- 239000000758 substrate Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 239000007832 Na2SO4 Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 5
- 125000004185 ester group Chemical group 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 5
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 5
- 241001489135 Globodera pallida Species 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 4
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 235000002595 Solanum tuberosum Nutrition 0.000 description 3
- 244000061456 Solanum tuberosum Species 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 2
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 2
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 2
- 229910019213 POCl3 Inorganic materials 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 238000006298 dechlorination reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 239000006272 natural pesticide Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012053 oil suspension Substances 0.000 description 2
- 235000012015 potatoes Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- ZMJOVJSTYLQINE-UHFFFAOYSA-N Dichloroacetylene Chemical compound ClC#CCl ZMJOVJSTYLQINE-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 241000208292 Solanaceae Species 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- IPSRAFUHLHIWAR-UHFFFAOYSA-N zinc;ethane Chemical compound [Zn+2].[CH2-]C.[CH2-]C IPSRAFUHLHIWAR-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N41/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom
- A01N41/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom containing a sulfur-to-oxygen double bond
- A01N41/10—Sulfones; Sulfoxides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
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Abstract
The invention relates to a preparation method of a GE ring system intermediate SA-01 of a natural product Solanoeclepin A with extremely strong induction activity in a hatching process of potato cyst nematodes, which comprises the following steps: uses geraniol acetate as a starting material to quickly synthesize SA-03 according to a method reported by a literature, wherein the SA-03 generates SN through reacting with sodium phenylsulfinate2After the substitution reaction, removing acetyl protection by potassium carbonate to obtain a compound SA-05; the compound SA-05 is subjected to active manganese dioxide oxidation, HWE reaction to prolong a carbon chain and excessive DIBAL-H reduction to obtain a diallyl alcohol compound SA-08; and the compound SA-08 is subjected to chemoselective asymmetric cyclopropanation reaction induced by a Charette ligand and asymmetric Staudinger cycloaddition reaction induced by substrate chirality to finally complete the synthesis of the intermediate compound SA-01. The preparation method is novel, the raw materials are easy to obtain, the operation is simple, the yield of the product is high, and the mass preparation is easy.
Description
Technical Field
The invention relates to an intermediate (GE ring system) SA-01 of a natural product Solanoeclepin A with extremely strong induction activity in a hatching process of potato cyst nematodes (PCN; Globodera rostochiensis and G.pallida) and a preparation method thereof.
Background
The natural product Solanoeclepin a (fig. 13) was isolated from potato roots of the solanaceae family by the dutch scientist Mulder in 1986 and has a very unique high tensile core skeleton (DEFG ring system) in its structure, while the chiral cyclopropane, cyclobutane and side chain functional moieties in the intermediate compound SA-01 have structures consistent with their GE ring systems and are also important functional fragments of the natural product exhibiting biological activity (CN 105326825 a, against lung cancer metastasis). In addition, the natural product is found to have extremely strong induction activity (0.3 g/hectare of land) on the hatching process of potato cyst nematode (PCN; Globodera rostochiensis and G.pallida) which causes a large reduction in yield of potatoes. Therefore, based on the unique chemical structure, the biological activity with great application value and limited sources of solaoeclepin A (figure 13), the method realizes the mass preparation of the key part (intermediate SA-01) in the structure by developing a novel synthesis methodology and an efficient synthesis strategy, is an important basis for breaking through the source limitation of the natural product and realizing further biological activity research, and has important significance for searching novel anti-lung cancer metastasis and developing natural pesticides.
Disclosure of Invention
The invention aims to: a natural product Solanoeclepin A intermediate (GE ring system) SA-01 with extremely strong induction activity (0.3 g/hectare land) on the hatching process of Potato Cyst Nematodes (PCN), Globodera rostochiensis and G.pallida and a preparation method thereof are important synthetic raw materials of the active natural product, have important application value on developing further drug discovery, and are very economical and simple.
The invention is realized by the following steps:
an active natural product Solanoeclepin A intermediate SA-01, the compound has the structure shown in formula (1)
In the formula, R1Is an alkyl protecting group such as benzyl, p-methoxybenzyl, or a silyl ether protecting group such as TBDPS, TBS, TIPS, TMS, or an ester group such as acetate, benzoate, sulfonate; r2Is H or alkyl or halogen or hydroxy; x is O or CH2. The intermediate SA-01 has strong induction activity on the hatching process of potato cyst nematodes: 0.3 g/ha of land.
The preparation method of the intermediate SA-01 of the active natural product Solanoeclepin A is characterized by comprising the following steps:
firstly, geraniol acetate is taken as a starting material, and the starting material is Mori, K. reported in the literature; nakazono, Y.Liebigs Ann.chem.1988,167, large-scale preparation of compound SA-03;
A. the compound SA-03 and sodium phenylsulfinate undergo substitution reaction under the catalysis of NaI to obtain a compound SA-04;
performing ester exchange on SA-04 under the conditions of potassium carbonate and methanol to remove acetyl protecting groups to obtain a compound SA-05;
C. the compound SA-05 is prepared by oxidizing allyl alcohol into unsaturated aldehyde by active manganese dioxide, reacting with HWE to prolong the carbon chain to obtain a compound SA-07, and reducing by a certain amount of DIBAL-H to obtain a diallyl alcohol compound SA-08;
SA-08 produces chemoselective asymmetric cyclopropanation reaction under the catalytic action of a Charette chiral ligand to obtain a compound SA-09;
SA-09 is protected with an alkyl protecting group, such as benzyl, p-methoxybenzyl, or a silyl ether protecting group, such as TBDPS, TBS, TIPS, TMS, or an ester group, such as acetate, benzoate, sulfonate, to prepare compound SA-10;
SA-10 adopts Staudinger ketene cycloaddition reaction to construct cyclobutanone structure to obtain a compound SA-11;
g, performing Zn/Cu reduction dechlorination on the SA-11 to obtain a compound SA-12;
H. converting cyclobutanone into a terminal double-bond compound SA-13 by a compound SA-12 through a Wittig reaction;
I. removing alpha hydrogen of sulfuryl from the compound SA-13 by n-butyl lithium, and introducing R through oxidation reaction or halogenation reaction or alkylation reaction2And finally obtaining the compound SA-01.
The synthetic route of the invention is as follows:
a.PhSO2Na,NaI,DMF,80℃；b.K2CO3,MeOH,rt；c.MnO2,DCM；d.NaH,(EtO)2P(O)CH2CO2Et,THF,0℃-r.t.；e.DIBAL-H,-78℃；f.ligand A,CH2I2,Et2Zn,DME/DCM,-20℃；g.base,R1X,DMF(X＝Cl or Br)；h.Zn/Cu,POCl3,CCl3COCl,Et2O,rt to reflux；i.Zn/Cu,NH4Cl,MeOH,50℃；j.Ph3PCH3Br,n-BuLi,THF,-78℃ to rt；k.n-BuLi,R2X,THF,-78℃(X＝Cl or Br).
wherein R is1Is an alkyl protecting group such as benzyl, p-methoxybenzyl, or a silyl ether protecting group such as TBDPS, TBS, TIPS, TMS, or an ester group such as acetate, benzoate, sulfonate; r2Is H or alkyl or halogen or hydroxy; x is O or CH2。
By adopting the technical scheme, the compound SA-03 is prepared in a large quantity by taking geraniol acetate as a starting material according to the literature report (Mori, K.; Nakazono, Y.LiebigsAnn. chem.1988, 167.); the compound SA-03 and sodium phenylsulfinate undergo substitution reaction under the catalysis of NaI to obtain a compound SA-04; then ester exchange is carried out under the conditions of potassium carbonate and methanol to remove acetyl protecting group, thus obtaining a compound SA-05; the compound SA-07 is obtained by oxidizing allyl alcohol into unsaturated aldehyde by active manganese dioxide and extending carbon chain through HWE reaction; reducing by a certain amount of DIBAL-H to obtain a bisallyl alcohol compound SA-08; the compound SA-08 has chemoselective asymmetric cyclopropanation reaction under the catalytic action of a Charette chiral ligand to obtain a compound SA-09; compounds SA-09 using alkyl-protecting groups, e.g. benzylProtecting group, p-methoxybenzyl, or silyl ether protecting group, such as TBDPS, TBS, TIPS, TMS, or ester group, such as acetate, benzoate, sulfonate, to prepare compound SA-10; constructing a cyclobutanone structure by adopting Staudinger ketene cycloaddition reaction to obtain a compound SA-11; SA-10 is subjected to Zn/Cu reduction dechlorination to obtain a compound SA-12; converting cyclobutanone into a terminal double-bond compound SA-13 by a compound SA-12 through a Wittig reaction; then n-butyl lithium is used for removing alpha hydrogen of sulfuryl, and then R is introduced through oxidation reaction or halogenation reaction or alkylation reaction2And finally obtaining the compound SA-01.
The compound SA-01 is a key part of a natural product Solanoeclepin A showing bioactivity, is an important basis for breaking through the source limitation of the natural product and realizing further bioactivity research, and has important significance for searching novel anti-lung cancer metastasis and developing natural pesticides. Meanwhile, the chemical reaction involved in the invention has the advantages of simple and easy operation, cheap and easily available raw material synthesis, environmental protection and no use of expensive metal catalysts.
Drawings
FIGS. 1-12 are NMR spectra of compounds of examples of the invention;
FIG. 13 shows the structural formula of Solanoeclepin A, a natural product.
Detailed Description
The invention is further described below by way of examples.
An active natural product Solanoeclepin A (figure 13) intermediate SA-01, the compound has a structure shown as formula (1)
In the formula, R1Is an alkyl protecting group such as benzyl, p-methoxybenzyl, or a silyl ether protecting group such as TBDPS, TBS, TIPS, TMS, or an ester group such as acetate, benzoate, sulfonate; r2Is H or alkyl or halogen or hydroxy; x is O or CH2. The intermediate SA-01 has strong induction activity on hatching process of potato cyst nematode: 0.3 g/ha of land.
The synthetic route of the invention is as follows:
1. synthesis of Compound SA-04:
the compound SA-03 (known compound reported in literature, see Mori, K.; Nakazono, Y. Liebigs Ann. chem.1988,167.) (39.6g,121.4mmol) was dissolved in DMF (200mL), and NaI (36.4g,242.8mmol), PhSO, were added sequentially at room temperature2Na (75.5g,459.9mmol) was added and the reaction stirred at 80 ℃ for 12 h. H2Quench the reaction with O (300mL), extract with EtOAc (150mL x 3), combine the organic phases, wash with saturated NaCl (100mL x 3), Na2SO4Drying, rotary removal of the solvent under reduced pressure, and column chromatography on silica gel (petroleum ether/EtOAc,8:1) afforded SA-04 as a pale yellow oil (28.7g, 80%). Rf＝0.3(petroleum ether/EtOAc,8:1)；1H NMR(400MHz CDCl3)δ7.89–7.87(m,2H),7.66–7.62(m,1H),7.57–7.53(m,2H),5.82–5.25(m,1H),4.52(d,J＝6.9Hz,1H),3.04–3.00(m,2H),2.10–2.06(m,2H),2.01(s,3H),1.85–1.80(m,2H),1.60(s,3H)；13C NMR(125MHz,CDCl3)δ170.89,139.57,139.21,133.67,133.67,129.29,129.29,128.00,128.00,120.31,60.97,55.39,37.59,20.93,20.39,15.99；HRMS(ESI)m/z:calculated for C16H23O5S[M+H]+327.4162,found 327.4158.
2. Synthesis of Compound SA-05:
compound SA-04(28.7g,97.1mmol) is dissolved in MeOH (150mL) and K is added at room temperature2CO3(7.3g,52.8mmol), reaction at room temperatureThe reaction was stirred for 2 h. H2The reaction was quenched with O (200mL), most of the MeOH removed under reduced pressure, extracted with EtOAc (150mL x 3), the combined organic phases washed with saturated NaCl (100mL x 3), Na2SO4Drying, rotary removal of the solvent under reduced pressure, and column chromatography on silica gel (petroleum ether/EtOAc,1:1) afforded SA-05(24.4g, 99%) as a colorless oil. Rf＝0.3(petroleum ether/EtOAc,1:1)；1H NMR(400MHz CDCl3)δ7.84–7.82(m,2H),7.61–7.57(m,1H),7.52–7.48(m,2H),5.29–5.26(m,1H),4.03(d,J＝6.9Hz,1H),3.02–2.98(m,2H),2.27(s,1H),2.02–1.98(m,2H),1.80–1.74(m,2H),1.50(s,3H)；13C NMR(125MHz,CDCl3)δ139.02,136.43,136.36,133.72,129.30,127.94,125.51,58.90,58.87,55.36,37.53,20.43,15.77；HRMS(ESI)m/z:calculated for C13H19O3S[M+H]+255.3534,found 255.3534.
3. Synthesis of Compound SA-08:
compound SA-05(24.4g,96.1mmol) is dissolved in CH2Cl2(200mL), MnO was added to the solution in portions at room temperature2(53.0g,124.9mmol) the reaction mixture was stirred at room temperature for a further 2h, filtered off with suction over celite under reduced pressure and the solvent was removed by rotation. The crude product was carried on to the next reaction without purification.
Triethyl phosphonoacetate (17.2mL,288.3mmol) is slowly added dropwise to a THF (200mL) suspension of NaH (11.5g,288.3mmol, 60% oil suspension) at 0 deg.C, after the reaction system stops generating gas, a THF (50mL) solution of the crude product from the previous step is slowly added dropwise to the reaction system, and the reaction is continued for 1h at room temperature. Saturated NH4The reaction was quenched with Cl (100mL), the solvent was spun off under reduced pressure to remove most of the THF, extracted with EtOAc (150 mL. times.3), and the organic phases combined, Na2SO4Drying, removing solvent under reduced pressure, adding CH2Cl2(50mL) was dissolved, filtered through silica gel with suction under reduced pressure, the silica gel was washed with (petroleum ether/EtOAc,3:1) and the solvent was removed by vortexing under reduced pressure to give a pale yellow oil.
The crude product of the previous step is dissolved in anhydrous CH2Cl2(300mL) DIBAL-H (120.1mL,240.3mmol,2M in CH) was slowly added dropwise at-78 deg.C2Cl2) The reaction mixture was allowed to continue at-78 ℃ for 30 min. The reaction was quenched with saturated Rochelle salt (300mL), warmed to room temperature, and stirred for 5 h. CH (CH)2Cl2(150 mL. times.3) extraction, combine the organic phases, Na2SO4Drying, rotary removal of the solvent under reduced pressure, and column chromatography on silica gel (petroleum ether/EtOAc,2:1) afforded SA-08(21.8g, 81%) as a colorless oil. Rf＝0.3(petroleum ether/EtOAc,2:1)；1H NMR(400MHz CDCl3)δ7.82–7.80(m,2H),7.59–7.56(m,1H),7.50–7.47(m,2H),6.32(dd,J＝15.1,11.9Hz,1H),5.69–5.60(m,2H),4.07(d,J＝5.8Hz,2H),2.98–2.94(m,2H),2.28(s,1H),2.03(m,2H),1.79–1.73(m,2H),1.57(s,3H)；13C NMR(125MHz,CDCl3)δ139.06,136.37,133.72,130.90,129.31,129.31,127.96,127.96,127.18,125.62,63.23,55.39,37.86,20.56,16.12；HRMS(ESI)m/z:calculated for C15H21O3S[M+H]+281.3907,found 281.3905.
4. Synthesis of Compound SA-10:
et at-20 deg.C2Zn (55.6mL,55.6mmol,1.0M in hexane) was added to anhydrous CH2Cl2(100mL), CH was slowly added dropwise2I2(8.96mL,111.1mmol), DME (5.8mL,55.6mmol) to give a clear cyclopropanating reagent solution. At-20 ℃ it was then slowly added dropwise to the mixture of SA-08(5.2g,18.5mmol) and ligand A[3](6.0g,22.2mmol) of CH2Cl2(50mL) and the reaction was continued at-20 ℃ for 2 h. Saturated NH4Cl (80mL) quench the reaction, CH2Cl2(50 mL. times.3) extraction, combine the organic phases, Na2SO4Drying, and rotary removing the solvent under reduced pressure to obtain a mixture of the monocyclopropanation and the dicyclopropylation, and directly carrying out the next reaction without purification.
A solution of the crude product from the previous step in anhydrous DMF (20mL) was slowly added dropwise to a suspension of NaH (1.4g,57.1mmol, 60% oil suspension) in DMF (20mL) at 0 ℃ to generate a large amount of bubbles, and after 0.5h of reaction continued at 0 ℃, benzyl bromide (4.52mL,38.08mmol) was slowly added dropwise to the reaction system and reaction continued at room temperature for 3 h. Adding saturated NH4Cl (80mL) quench reaction, Et2O (100mL x 3) extraction, saturated NaCl (100mL x 3) wash, Na2SO4Drying, rotary removal of the solvent under reduced pressure, and column chromatography on silica gel (petroleum ether/EtOAc,6:1) afforded SA-10(5.31g, 75%) as a colorless oil. Rf＝0.3(petroleum ether/EtOAc,6:1)；1H NMR(400MHz CDCl3)δ7.91–7.89(m,2H),7.64–7.63(m,1H),7.57–7.54(m,2H),7.34–7.24(m,5H),4.58–4.52(m,3H),3.38–3.35(m,2H),3.04–3.00(m,2H),2.00(m,2H),1.84–1.76(m,2H),1.62(s,3H),1.30(m,1H),1.03(m,1H),0.65(m,1H),0.52(m,1H)；13C NMR(125MHz,CDCl3)δ139.30,138.57,133.59,132.23,129.26,129.26,128.88,128.36,128.36,128.04,128.04,127.76,127.63,127.53,73.50,72.46,55.54,37.60,20.70,20.22,16.23,15.98,12.19；HRMS(ESI)m/z:calculated for C23H29O3S[M+H]+385.5402,found 385.5402.
5. Synthesis of Compound SA-12:
compound SA-10(49.5g,129.0mmol) was dissolved in anhydrous Et2To O (1500mL), Zn/Cu couple (17.0g,258.0mmol) was added, and Cl was added3CCOCl (22.0mL,193.0mmol) and POCl3(18.0mL,193.0mmol) in anhydrous Et2O (1500mL), was added slowly dropwise (4h) to the reaction system and refluxed at 37 ℃ for 12 h. Adding saturated NaHCO3The reaction was quenched (1000mL), suction filtered through celite under reduced pressure, and the filtrate was washed with saturated sodium chloride (800 mL. times.3), Na2SO4Drying, and removing the solvent under reduced pressure. The crude product is dissolved in saturated NH4A solution of Zn/Cu cobble (25.0g,385.0mmol) in Cl in methanol (500mL) was added and the mixture was heated to 50 deg.CAfter 0.5h of reaction. Suction filtration over silica gel, concentration of the filtrate, addition of EtOAc (1500mL) and water (500mL) to the concentrated crude product and continued washing of the organic phase with saturated sodium chloride (3X 500mL), Na2SO4Drying, rotary removal of the solvent under reduced pressure, and column chromatography on silica gel (petroleum ether/EtOAc,4:1) afforded SA-11(33.0g, 65%) as a colorless oil.
At-78 ℃ to PPh3CH3Br (33.5g,94.0mmol) in THF (200mL) was slowly added dropwise n-BuLi (44.0mL,70.0mmol,1.6M in THF), and after stirring the reaction for 30min, a solution of compound SA-11(10.0g,24.0mmol) in THF (100mL) was added and allowed to spontaneously warm to room temperature for 4 h. Adding saturated NH4The reaction was quenched with Cl (300mL), concentrated to remove most of the THF, extracted with EtOAc (500mL x 3), washed with saturated NaCl (500mL x 3), Na2SO4Drying, rotary removal of the solvent under reduced pressure, and column chromatography on silica gel (petroleum ether/EtOAc,10:1) afforded SA-12 as a colorless oil (6.6g, 65%). Rf＝0.3(petroleum ether/EtOAc,8:1)；1H NMR(400MHz CDCl3)δ7.91–7.78(m,2H),7.65–7.61(m,1H),7.56–7.51(m,2H),7.33–7.24(m,5H),4.90(s,1H),4.75(s,1H),4.51(m,2H),3.36–3.23(m,2H),3.05(m,2H),2.30–2.12(m,2H),1.88(m,1H),1.72–1.65(m,2H),1.55–1.42(m,2H),1.06(s,3H),0.75(m,1H),0.59(m,1H),0.47(m,2H)；13C NMR(125MHz,CDCl3)δ149.28,139.31,138.67,133.64,129.28,129.22,129.19,129.13,129.11,128.35,128.03,127.52,127.47,105.26,73.97,72.60,56.95,56.72,42.63,41.39,38.22,19.75,18.58,16.06,15.74,9.44；HRMS(ESI)m/z:calculated for C26H33O3S[M+H]+425.6041,found 425.6042.
6. Synthesis of Compound SA-01:
compound SA-12(20.0g,50.0mmol) was dissolved in anhydrous THF (2000mL), n-BuLi (40.0mL,60.0mmol,1.6M in THF) was slowly added dropwise thereto at-78 deg.C, the reaction was continued for 30min with stirring, allyl bromide (4.8mL,60.0mmol) was added thereto, and the mixture was allowed to naturally warm to room temperature,the reaction was stirred for an additional 6 h. Adding saturated NH4The reaction was quenched with Cl (300mL), concentrated to remove most of the THF, extracted with EtOAc (300mL x 3), washed with saturated NaCl (500mL x 3), Na2SO4Drying, rotary removal of the solvent under reduced pressure, and column chromatography on silica gel (petroleum ether/EtOAc,15:1) afforded SA-01(19.2g, 88%) as a colorless oil. Rf＝0.4(petroleum ether/EtOAc,10:1)；1H NMR(400MHz CDCl3)δ7.89–7.87(m,2H),7.64–7.61(m,1H),7.56–7.52(m,2H),7.34–7.26(m,5H),5.71(m,1H),5.07(s,1H),5.04(m,1H),4.90(d,J＝2.2Hz,1H),4.75(d,J＝2.2Hz,1H),4.51(m,2H),3.38–3.21(m,2H),2.95(m,1H),2.61(m,1H),2.41–2.10(m,3H),1.88–1.75(m,2H),1.65–1.41(m,3H),1.05(s,3H),0.77(m,1H),0.59(m,1H),0.48(m,2H)；13C NMR(125MHz,CDCl3)δ149.45,138.71,138.17,138.12,133.64,133.34,129.17,129.16,128.83,128.80,128.34,127.57,127.52,127.49,127.45,118.44,118.41,105.18,105.14,74.00,73.98,72.56,72.54,64.30,64.26,56.88,56.83,42.57,39.54,39.46,38.28,38.27,32.27,32.20,22.82,22.76,19.72,19.68,16.10,16.09,15.84,15.81,9.53,9.45；HRMS(ESI)m/z:calculated for C29H37O3S[M+H]+465.6681,found 465.6681。
Through inspection, the structures of chiral cyclopropane, cyclobutane and side chain functional group parts in the intermediate compound SA-01 synthesized by the invention are consistent with the GE ring system, and are consistent with the reported experimental results: is also an important functional group fragment of the natural product showing biological activity (CN 105326825A, resisting lung cancer metastasis), and the natural product has extremely strong induction activity (0.3 g/ha land) on the hatching process of potato cyst nematode (PCN; Globodera rostochiensis and G.pallida) causing mass reduction of potatoes.
The preparation method is novel, raw materials are easy to obtain, the operation is simple, the yield of the product is high, the large-scale preparation is easy, and the application of the product as a drug intermediate for resisting potato cyst nematodes can be expected.
Claims (1)
1. A preparation method of an intermediate SA-01 of an active natural product Solanoeclepin A is characterized by comprising the following steps: the method comprises the following steps: from the known compound SA-03 the following procedure was followed,
A. the compound SA-03 and sodium phenylsulfinate undergo substitution reaction under the catalysis of NaI to obtain a compound SA-04;
B. then ester exchange is carried out under the conditions of potassium carbonate and methanol to remove acetyl protecting group, thus obtaining a compound SA-05;
C. oxidizing the compound SA-05 with active manganese dioxide to obtain an unsaturated aldehyde compound SA-06, then, extending a carbon chain through HWE reaction to obtain a compound SA-07, and finally, reducing with excessive DIBAL-H to obtain a bis-allyl alcohol compound SA-08;
D. the compound SA-08 has chemoselective asymmetric cyclopropanation reaction under the catalytic action of a Charette chiral ligand to obtain a compound SA-09;
E. compound SA-09 protected with benzyl to prepare compound SA-10;
F. constructing a cyclobutanone structure by adopting Staudinger ketene cycloaddition reaction to obtain a compound SA-11;
g, reducing and dechlorinating SA-11 by adopting a zinc-copper reagent to obtain a compound SA-12;
H. converting cyclobutanone into a terminal double-bond compound SA-13 by a compound SA-12 through a Wittig reaction;
I. then n-butyl lithium is used for removing alpha hydrogen of sulfuryl, and then R is introduced by reacting with allyl bromide2Group, finally to obtain compound SA-01, wherein R1Is benzyl, R2Is allyl;
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