WO2021249545A1 - Procédé de préparation en une étape de polyéther ayant une structure de réseau d'éther polycyclique trans-fusionné - Google Patents

Procédé de préparation en une étape de polyéther ayant une structure de réseau d'éther polycyclique trans-fusionné Download PDF

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WO2021249545A1
WO2021249545A1 PCT/CN2021/099762 CN2021099762W WO2021249545A1 WO 2021249545 A1 WO2021249545 A1 WO 2021249545A1 CN 2021099762 W CN2021099762 W CN 2021099762W WO 2021249545 A1 WO2021249545 A1 WO 2021249545A1
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alkyl
formula
trans
carbon atom
fused polycyclic
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渠瑾
李风兴
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南开大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • 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

Definitions

  • the invention relates to a one-step method for preparing a polyether with a trans-fused polycyclic ether skeleton structure.
  • the cyclic ether (the size of the cyclic ether is five-membered cyclic ether, six-membered cyclic ether, seven-membered cyclic ether, eight-membered cyclic ether, and nine-membered cyclic ether). Because it contains multiple fused cyclic ethers, marine polyether toxins The molecular skeleton of the product is in the shape of a ladder, so it is also known as a trapezoidal thick polyether toxin.
  • Marine polyether toxins produced by marine algae generally have strong neurotoxicity. When marine algae multiply morbidly, the marine polyether toxins produced by them can cause a large number of deaths of marine organisms. Marine polyether toxins can also be concentrated in fish, shrimp or shellfish through the transmission of the food chain. If the contaminated fish, shrimp or shellfish is accidentally eaten by humans, it will cause a poisoning reaction, which can lead to death in severe cases (Toxicon 2001, 39). , Pp 97-106). But there are also some marine polyethers that have biological activity that can be developed as drugs (Chem. Res. Toxicol. 2004, 17, pp 1251-1257).
  • brevenal can also competitively bind to the protein receptors of breven pyridine toxin and ciguatoxin in the human body, thereby reducing the poisoning reaction caused by breven pyridine toxin and ciguatoxin (Cell.Mol .Neurobiol. 2004, 24, pp 553-563).
  • brevenal is a potential treatment option for chronic lung diseases such as cystic fibrosis
  • the daily use of brevenal or its derivatives will be very expensive for patients.
  • the content of brevenal produced by Lusoflagellate is very low, and it is difficult to obtain large amounts of brevenal only by extraction.
  • the brevenal containing the trans-fused 7/7/6/7/6 pentacyclic ether structure can also be obtained by artificial synthesis.
  • the total yield of total synthesis of 57 steps is 0.84% (Figure b, Org. Lett. 2009, 11, pp 2531-2534); In 2010, the second-generation total synthesis route of Professor Kadota’s research group required 53 steps, with a total yield of 1.8% (Tetrahedron 2010, 66, pp 5329-5344) ; In 2011, Professor Rainier's research group from the University of Utah used the key enester cyclization reaction to achieve the construction of the two-ring CD of brevenal. Their total synthesis route of brevenal was 38 steps, and the total yield was 0.99% (Figure c below) , J. Am. Chem. Soc. 2011, 133, pp 3208-3216).
  • long-chain polyepoxy compounds can be synthesized from long-chain polyene compounds by Shi asymmetric epoxidation in one step, and long-chain polyene compounds can be synthesized from commercially available small molecules.
  • the raw materials are prepared by organic reactions such as Wittig reaction and transition metal-catalyzed coupling reaction, so the precursor compound of the tandem reaction is easy to prepare in organic synthesis, but it is a one-step series connection of long-chain homochiral polyepoxy precursors.
  • the trans-fused polycyclic ether can be constructed through the intramolecular endo, endo-selective series epoxy ring-opening and cyclization reaction of the polyepoxy precursor compound. structure.
  • the Murai research group in Japan developed the intramolecular endo, endo-selective tandem epoxy ring-opening and cyclization reaction of homochiral polyepoxy precursor compounds catalyzed by lanthanum salt.
  • the McDonald research group in the United States found that when the homochiral polyepoxy precursor compound has a carbonyl group instead of a hydroxyl group as the terminating group, the polyepoxy precursor compound can undergo intramolecular endo, endo-selection under the catalysis of Lewis acid.
  • the serial epoxy ring-opening and cyclization reaction realizes the construction of polyethers in which all the trans-fused cyclic ethers are seven-membered rings.
  • the yield of polyethers containing four seven-membered rings is only 12% (J. Org. Chem. 2002, 67, pp 2515-2523).
  • the yields of the first two cases of these 3 cases are low, and these 3 cases can only produce all six-membered ring polyethers or all seven-membered ring polyethers, while the biologically active marine polyether toxin brevenal molecule It has a 7/7/6/7/6 five-ring structure mixed with six-membered cyclic ether and seven-membered cyclic ether.
  • many biologically active marine polyether toxins contain eight-membered cyclic ethers or nine-membered cyclic ethers.
  • the existing endo, endo-selective tandem epoxy ring-opening and cyclization method cannot be used to synthesize molecules containing eight-membered cyclic ethers. Cyclic ethers or polyethers of nine-membered cyclic ethers.
  • the technical problem to be solved by the present invention is that the preparation method of polyether with trans-fused polycyclic ether skeleton structure in the prior art is relatively simple, thereby providing a new one-step method for preparing polyether with trans-fused polycyclic ether skeleton Structured polyether (trans-fused polycyclic polyether) method.
  • This method uses easy-to-prepare long-chain homochiral polyepoxy compounds as raw materials, and can synthesize trans-fused polycyclic ether compounds through a one-step intramolecular endo, endo-selective serial epoxy ring-opening and cyclization reaction.
  • the cyclic ether in the formed polycyclic ether compound may be a six-membered cyclic ether, a seven-membered cyclic ether, an eight-membered cyclic ether, a nine-membered cyclic ether, or a combination thereof.
  • the present invention provides a method for preparing a trans-fused polycyclic ether compound represented by formula (I), which comprises the following steps: in the presence of a reaction medium and a salt containing a weak coordination anion, the formula (II)
  • the homochiral polyepoxy compound shown is prepared by a one-step cyclization reaction to obtain the trans-fused polycyclic ether compound represented by formula (I);
  • Each R is the same or different, and is independently selected from H, C 1-3 alkyl- or halogenated C 1-3 alkyl-; particularly preferably H, methyl, ethyl, propyl or isopropyl; most preferably H Or methyl
  • Each R 1 is the same or different, and is independently selected from H, C 1-10 alkyl-, C 1-10 alkyl-OC 1-10 alkyl-, C 6-10 aryl-C 1-10 alkyl- OC 1-10 alkyl-, halogenated C 1-10 alkyl-; preferably H, C 1-6 alkyl-, C 1-6 alkyl-OC 1-6 alkyl-, C 6-10 aryl -C 1-6 alkyl-OC 1-6 alkyl-, halogenated C 1-6 alkyl-; more preferably H, C 1-3 alkyl-, C 1-3 alkyl-OC 1-3 alkane Group-, phenyl-C 1-3 alkyl-OC 1-3 alkyl-, halogenated C 1-3 alkyl-; particularly preferably H, methyl, ethyl, propyl, isopropyl; most preferably H. Methyl;
  • Each R 2 is the same or different, and is independently selected from H, C 1-10 alkyl-, C 1-10 alkyl-OC 1-10 alkyl-, C 6-10 aryl-C 1-10 alkyl- OC 1-10 alkyl-, halogenated C 1-10 alkyl-; preferably H, C 1-6 alkyl-, C 1-6 alkyl-OC 1-6 alkyl-, C 6-10 aryl -C 1-6 alkyl-OC 1-6 alkyl-, halogenated C 1-6 alkyl-; more preferably H, C 1-3 alkyl-, C 1-3 alkyl-OC 1-3 alkane Group-, phenyl-C 1-3 alkyl-OC 1-3 alkyl-, halogenated C 1-3 alkyl-; particularly preferably H, methyl, ethyl, propyl, isopropyl; most preferably H, methyl; or, when R 2 is connected to a double-bonded carbon atom, R 2 does not exist;
  • n is the same or different, and is independently selected from 1, 2, 3, 4;
  • the carbon atoms in the fragments can be optionally substituted by the following groups: H, OH, C 1-4 alkyl- or halogenated C 1-4 alkyl-;
  • R 3 is H or an acid-sensitive hydroxyl protecting group
  • the acid-sensitive hydroxyl protecting group is for example an ether protecting group (such as THP (2-tetrahydropyranyl)), a silyl ether protecting group (such as TMS (three Methylsilyl) or TES (triethylsilyl)), preferably THP, TMS, most preferably THP;
  • the part represents the structure in which the x fragments and the y fragments appear alternately and repeatedly.
  • the structures of the trans-fused polycyclic ether compound and the homochiral polyepoxy compound are defined as follows:
  • each R is the same or different, and is independently selected from H, C 1-3 alkyl-, halogenated C 1-3 alkane Group -; H, methyl, ethyl, propyl, isopropyl are particularly preferred; H, methyl is most preferred.
  • Each R 1 is the same or different, and is independently selected from H, C 1-10 alkyl-, C 1-10 alkyl-OC 1-10 alkyl-, C 6-10 aryl-C 1-10 alkyl- OC 1-10 alkyl-, halogenated C 1-10 alkyl-; preferably H, C 1-6 alkyl-, C 1-6 alkyl-OC 1-6 alkyl-, C 6-10 aryl -C 1-6 alkyl-OC 1-6 alkyl-, halogenated C 1-6 alkyl-; more preferably H, C 1-3 alkyl-, C 1-3 alkyl-OC 1-3 alkane Group-, phenyl-C 1-3 alkyl-OC 1-3 alkyl-, halogenated C 1-3 alkyl-; particularly preferably H, methyl, ethyl, propyl, isopropyl; most preferably H. Methyl;
  • Each R 2 is the same or different, and is independently selected from H, C 1-10 alkyl-, C 1-10 alkyl-OC 1-10 alkyl-, C 6-10 aryl-C 1-10 alkyl- OC 1-10 alkyl-, halogenated C 1-10 alkyl-; preferably H, C 1-6 alkyl-, C 1-6 alkyl-OC 1-6 alkyl-, C 6-10 aryl -C 1-6 alkyl-OC 1-6 alkyl-, halogenated C 1-6 alkyl-; more preferably H, C 1-3 alkyl-, C 1-3 alkyl-OC 1-3 alkane Group-, phenyl-C 1-3 alkyl-OC 1-3 alkyl-, halogenated C 1-3 alkyl-; particularly preferably H, methyl, ethyl, propyl, isopropyl; most preferably H, methyl; or, when R 2 is connected to a double-bonded carbon atom, R 2 does not exist;
  • n is the same or different, and is independently selected from 1, 2, 3; or
  • the carbon atoms in the fragment can be optionally substituted by the following groups: H, OH, C 1-4 alkyl-, halo C 1-4 alkyl-; or
  • the Structure is (I.e. form with the structure on the right ), where the a terminal is connected to the epoxy group, and the b terminal is connected to the carbon atom marked with &; others
  • the structure is the same or different, which are independently The c terminal is connected to the left group, and the d terminal is connected to the right group;
  • Each hydrogen atom in the structure is independently optionally substituted by R 4 ;
  • R 4 is independently OH, C 1-4 alkyl- or halogenated C 1-4 alkyl-, preferably methyl, ethyl, propyl , Isopropyl, most preferably methyl.
  • each n is the same or different, and is independently selected from 1, 2 or 3. .
  • R 3 is H.
  • R 3 is an acid-sensitive hydroxyl protecting group, such as an ether protecting group
  • the group for example, THP (2-tetrahydropyranyl)
  • the silyl ether protecting group for example, TMS (trimethylsilyl) or TES (triethylsilyl)
  • THP 2,3-tetrahydropyranyl
  • TMS trimethylsilyl
  • TES triethylsilyl
  • the R connected to the carbon atom marked with * is a C 1-3 alkane Group-, preferably methyl, ethyl, propyl, isopropyl, most preferably methyl.
  • R 1 connected to the carbon atom marked with * is C 1-10 Alkyl-, preferably C 1-6 alkyl-, more preferably C 1-3 alkyl-, particularly preferably methyl, ethyl, propyl, isopropyl, and most preferably methyl.
  • R and R 1 connected to the carbon atom marked with * are the same .
  • R and R 1 connected to the carbon atom marked with * are both methyl base.
  • R in the u, v, x, and y fragments are independently H Or C 1-3 alkyl-, particularly preferably H, methyl, ethyl, propyl or isopropyl, most preferably H or methyl.
  • the Structure in the preparation method of the trans-fused polycyclic ether compound represented by formula (I) as described in any one of the preceding embodiments, the Structure is The a terminal is connected to the epoxy group, and the b terminal is connected to the carbon atom marked with &; others The structure is the same or different, which are independently Above Each hydrogen atom in the structure is independently optionally substituted by R 4.
  • the Structure in the preparation method of the trans-fused polycyclic ether compound represented by formula (I) as described in any one of the preceding embodiments, the Structure is The a terminal is connected to the epoxy group, and the b terminal is connected to the carbon atom marked with &; others The structure is the same or different, which are independently Above Each hydrogen atom in the structure is independently optionally substituted by R 4.
  • the leftmost compound of the general formula structure above Each hydrogen atom in the structure is independently optionally substituted by R 4 ; R 4 is independently OH, C 1-4 alkyl- or halogenated C 1-4 alkyl-, preferably C 1-3 alkyl-, Particularly preferred are methyl, ethyl, propyl, and isopropyl, and most preferred are OH and methyl.
  • the leftmost compound of the general formula Structure is
  • R 2 is H or C 1-10 alkyl-, preferably H Or C 1-6 alkyl-, more preferably H or C 1-3 alkyl-, particularly preferably H, methyl, ethyl, propyl or isopropyl, most preferably H or methyl; or, & marked When a double bond is connected to the carbon atom, R 2 connected to the carbon atom marked with & does not exist.
  • R 2 connected to the carbon atom labeled & is H, or, When a double bond is connected to the carbon atom labeled &, R 2 connected to the carbon atom labeled & does not exist.
  • the R connected to the carbon atom labeled & is H or C 1- 3 Alkyl-, preferably H, methyl, ethyl, propyl or isopropyl, most preferably H or methyl, such as H.
  • R 2 and R connected to the carbon atom labeled & are H, Alternatively, when a double bond is connected to the carbon atom labeled &, R 2 connected to the carbon atom labeled & does not exist.
  • the R connected to the carbon atom marked with # is H or C 1- 3 Alkyl-, preferably H, methyl, ethyl, propyl or isopropyl, most preferably H or methyl.
  • R 2 connected to the carbon atom marked with # is H or C 1 -10 alkyl-, preferably H or C 1-6 alkyl-, more preferably H or C 1-3 alkyl-, particularly preferably H, methyl, ethyl, propyl or isopropyl, most preferably H or methyl.
  • R 2 and R connected to the carbon atom labeled with # are the same .
  • R 2 and R connected to the carbon atom labeled with # are the same And is H or methyl.
  • the structures of the trans-fused polycyclic ether compound and the polyepoxy compound are as follows:
  • R, R 1 , R 2 , R 3 , and n are defined as described in any of the above schemes.
  • the structures of the trans-fused polycyclic ether compound and the polyepoxy compound are as follows:
  • R, R 1 , R 2 , R 3 , n The definition is as described in any of the above schemes.
  • the structures of the trans-fused polycyclic ether compound and the polyepoxy compound are as follows:
  • R, R 1 , R 2 , R 3 , n The definition is as described in any of the above schemes;
  • the structures of the trans-fused polycyclic ether compound and the polyepoxy compound are as follows:
  • R, R 1 , R 2 , R 3 , and n are as defined above.
  • the structures of the trans-fused polycyclic ether compound and the polyepoxy compound are as follows:
  • R, R 1 , R 2 , R 3 , n The definition is as described in any of the above schemes.
  • the structures of the trans-fused polycyclic ether compound and the polyepoxy compound are as follows:
  • R, R 1 , R 2 , R 3 , n The definition is as described in any of the above schemes;
  • the structure is independently
  • the structures of the trans-fused polycyclic ether compound and the polyepoxy compound are as follows:
  • R, R 1 , R 2 , R 3 , and n are as described in any of the above schemes.
  • the structures of the trans-fused polycyclic ether compound and the polyepoxy compound are as follows:
  • R, R 1 , R 2 , R 3 , n The definition is as described in any of the above schemes.
  • the structures of the trans-fused polycyclic ether compound and the polyepoxy compound are as follows:
  • R, R 1 , R 2 , R 3 , n The definition is as described in any of the above schemes;
  • the structure is independently
  • the structures of the trans-fused polycyclic ether compound and the polyepoxy compound are as follows:
  • R, R 1 , R 2 , R 3 , n The definition is as described in any of the above schemes;
  • the structure is independently
  • the structures of the trans-fused polycyclic ether compound and the polyepoxy compound are as follows:
  • R, R 1 , R 2 , R 3 , and n are defined as described in any of the above schemes.
  • the structures of the trans-fused polycyclic ether compound and the polyepoxy compound are as follows:
  • R, R 1 , R 2 , R 3 , n The definition is as described in any of the above schemes.
  • the structures of the trans-fused polycyclic ether compound and the polyepoxy compound are as follows:
  • R, R 1 , R 2 , R 3 , n The definition is as described in any of the above schemes;
  • the structure is independently
  • R in the u, v, x and y fragments are independently H or methyl
  • the a terminal is connected to the epoxy group, and the b terminal is connected to the carbon atom marked with &; others
  • the structure is the same or different, which are independently
  • R 2 and R connected to the carbon atom marked with # are the same and are H or methyl;
  • R 2 connected to the carbon atom labeled & is H, or when a double bond is connected to the carbon atom labeled &, R 2 connected to the carbon atom labeled & does not exist.
  • the structure of the trans-fused polycyclic ether compound and the polyepoxy compound is any one of the following groups:
  • the reaction medium may be a C 1-10 alkyl alcohol substituted by one or more halogens or its Mixed solvent with other solvents.
  • the C 1-10 alkyl alcohol substituted by one or more halogens is preferably C 1-8 alkyl alcohol substituted by one or more halogens , more preferably C 1 substituted by one or more halogens.
  • the other solvent may be selected from C 1-10 alkanes substituted with one or more halogens, C 1-10 ethers or cyclic ethers optionally substituted with one or more halogens, C 1-10 optionally substituted with one or more halogens 1-10 esters; preferably chloroform, dichloromethane, 1,2-dichloroethane, 1,1-dichloroethane ethyl ether, tetrahydrofuran, 1,4-dioxane.
  • the reaction medium is most preferably trifluoromethanol, trifluoroethanol, perfluoroethanol, trifluoropropanol (Including n-propanol, isopropanol), hexafluoropropanol (including n-propanol, isopropanol), perfluoropropanol (including n-propanol, isopropanol), trifluorobutanol (including n-butanol) , Isobutanol, tert-butanol), hexafluorobutanol (including n-butanol, isobutanol, tert-butanol), perfluorobutanol (including n-butanol, isobutanol, tert-butanol), trifluorobutanol Pentanol,
  • the reaction medium may specifically be 2,2,2-trifluoroethanol (TFE), 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), perfluoro tertiary Butanol (PFTB), most preferably perfluoro-tert-butanol (PFTB).
  • TFE 2,2,2-trifluoroethanol
  • HFIP 1,1,1,3,3,3-hexafluoro-2-propanol
  • PFTB perfluoro tertiary Butanol
  • PFTB perfluoro-tert-butanol
  • the weakly coordinating anion-containing salt is soluble in the reaction medium.
  • the anionic salt containing weakly coordinating anion is preferably a fluorine-containing weakly coordinating anion, it may be: tetrafluoroborate anion (BF 4 -), hexafluorophosphate anion (PF 6 -), six hexafluoro antimonate anion (SbF 6 -), trifluoromethanesulfonic acid anion (trifluoromethansulfonate, TfO-), tetrakis [3,5-bis (trifluoromethyl) phenyl] borate anion (tetrakis [3,5-bis ( trifluoromethyl) phenyl] borate, (BARF )), tetrakis (pentafluorophenyl) borate anion (tetrakis (pentafluorophenyl) borate); preferably tetrafluoroborate anion (BF 4 -), hexafluorophosphate anion (PF 6 -), he
  • the cation of the salt containing weak coordination anion can be selected from quaternary ammonium ion or quaternary phosphorus ion, for example, tetramethylammonium ion (Me 4 N + ), tetraethylammonium ion (Et 4 N + ), tetra-n-butylammonium ion ((n-Bu) 4 N + ), tetraphenyl quaternary phosphonium ion (Ph 4 P + ), 1-butyl-3-methylimidazole quaternary ammonium ion ([BMIM]) , 1-ethyl-3-methylimidazole quaternary ammonium ion ([EMIM]), 1-hexyl-3-methylimidazole quaternary ammonium ion ([HMIM]); preferably 1-butyl-3-methylimidazole quaternary Ammonium ion ([BMIM]),
  • the salt containing weak coordination anions may specifically be [BMIM]BF 4 , [BMIM]PF 6 , [EMIM]BF 4 , [EMIM]PF 6 , [HMIM]BF 4 , [HMIM ]PF 6 ; preferably [BMIM]BF 4 , [EMIM]BF 4 , [HMIM]BF 4 ; more preferably [EMIM]BF 4 .
  • the molar ratio of the salt containing the weakly coordinating anion to the homochiral polyepoxy compound represented by formula (II) may be 1:10-10:1, preferably 1:5-5:1, It is more preferably 1:2 to 2:1, most preferably 1:1.
  • the concentration of the homochiral polyepoxy compound represented by formula (II) in the cyclization reaction solution may be 0.01-2.0 mol/L, preferably 0.01-1.0 mol/L, more preferably 0.05 -0.5mol/L, most preferably 0.1-0.3mol/L.
  • the cyclization reaction can be carried out at 0-100°C (preferably 10-60°C; more preferably 20-45°C; most preferably 40°C).
  • the cyclization reaction time may be 0.5-24 hours, preferably 1-18 hours, more preferably 5-18 hours, particularly preferably 12-18 hours, and most preferably 15 hours.
  • halogen means fluorine, chlorine, bromine or iodine.
  • Alkyl represents a straight or branched chain saturated hydrocarbon group containing 1-10 carbon atoms; preferably a straight or branched chain saturated hydrocarbon group containing 1-8 carbon atoms; more preferably a straight chain or branched chain containing 1 to 6 carbon atoms Chain saturated hydrocarbon groups; most preferably straight or branched chain saturated hydrocarbon groups having 1 to 4 carbon atoms.
  • alkyl groups include methyl, ethyl, propyl (including n-propyl, isopropyl), butyl (including n-butyl, isobutyl, tert-butyl), pentyl (including n-pentyl, isopropyl), Pentyl, tert-pentyl, neopentyl) or hexyl, etc.
  • Alkyl alcohol means a compound in which one or more H atoms in the above-mentioned alkyl group is substituted by OH.
  • alkyl alcohols include methanol, ethanol, propanol (including n-propanol, isopropanol), butanol (including n-butanol, isobutanol, tert-butanol), pentanol (including n-pentanol, isoamyl alcohol) Alcohol, tert-amyl alcohol, neopentyl alcohol) or hexanol, etc.
  • Halohydrin refers to a compound in which one or more H atoms in the above-mentioned alkyl alcohol is substituted by halogen; wherein polyhalo refers to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 15 or more halogens are substituted. Polyhalogenation also means that all H on the alkyl group in the alkyl alcohol is substituted by halogen.
  • halogenated alcohols include trifluoromethanol, trifluoroethanol, perfluoroethanol, trifluoropropanol (including n-propanol, isopropanol), hexafluoropropanol (including n-propanol, isopropanol), perfluoropropanol Propanol (including n-propanol, isopropanol), trifluorobutanol (including n-butanol, isobutanol, tert-butanol), hexafluorobutanol (including n-butanol, isobutanol, tert-butanol) , Perfluorobutanol (including n-butanol, isobutanol, tert-butanol), trifluoropentanol (including n-pentanol, isoamyl alcohol, tert-amyl alcohol, neopen
  • weakly coordinating anions refer to a type of anion that has a very weak interaction force with the cation.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the preparation method of the invention has one or more advantages such as easy preparation of raw materials, short synthetic route, simple experimental operation, mild reaction conditions, rapid reaction and high yield.
  • the preparation method of the present invention can obtain a polyether with 2 trans-fused cyclic ethers at a yield of up to 55%, and obtain a polyether with 3 trans-fused cyclic ethers at a yield of up to 57%, A polyether with 4 trans-fused cyclic ethers was obtained at a yield of up to 40%, and a polyether with an eight-membered ring and 4 trans-fused cyclic ethers was obtained at a yield of up to 19%.
  • the yield is as high as 17% to obtain the polyether with the trans-fused 7/7/6/7/6 pentacyclic ether skeleton in the brevenal molecule, and all the above-mentioned synthesis reactions only have one step.
  • the present invention provides a simpler synthetic route for the industrial synthesis of polyethers with trans-fused polycyclic ether skeletons, which has significant social and economic effects, and can be industrialized. The potential is high.
  • FIG. 1 is a hydrogen nuclear magnetic resonance spectrum of a polyether with two trans-fused cyclic ethers obtained in Example 1.
  • FIG. 1 is a hydrogen nuclear magnetic resonance spectrum of a polyether with two trans-fused cyclic ethers obtained in Example 1.
  • FIG. 2 is a carbon nuclear magnetic resonance spectrum of the polyether with two trans-fused cyclic ethers obtained in Example 1.
  • FIG. 3 is a hydrogen nuclear magnetic resonance spectrum of the polyether with 3 trans-fused cyclic ethers obtained in Example 2.
  • FIG. 4 is a carbon nuclear magnetic resonance spectrum of the polyether with 3 trans-fused cyclic ethers obtained in Example 2.
  • FIG. 4 is a carbon nuclear magnetic resonance spectrum of the polyether with 3 trans-fused cyclic ethers obtained in Example 2.
  • FIG. 5 is a hydrogen nuclear magnetic resonance spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 3.
  • FIG. 5 is a hydrogen nuclear magnetic resonance spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 3.
  • FIG. 6 is a carbon nuclear magnetic resonance spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 3.
  • FIG. 6 is a carbon nuclear magnetic resonance spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 3.
  • FIG. 7 is a high-resolution mass spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 3.
  • FIG. 7 is a high-resolution mass spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 3.
  • FIG. 8 is a hydrogen nuclear magnetic resonance spectrum of a polyether containing an eight-membered ring and having 4 trans-fused cyclic ethers obtained in Example 4.
  • FIG. 8 is a hydrogen nuclear magnetic resonance spectrum of a polyether containing an eight-membered ring and having 4 trans-fused cyclic ethers obtained in Example 4.
  • FIG. 9 is a carbon nuclear magnetic resonance spectrum of a polyether containing an eight-membered ring and having 4 trans-fused cyclic ethers obtained in Example 4.
  • FIG. 9 is a carbon nuclear magnetic resonance spectrum of a polyether containing an eight-membered ring and having 4 trans-fused cyclic ethers obtained in Example 4.
  • FIG. 10 is a high-resolution mass spectrum of a polyether containing an eight-membered ring and having 4 trans-fused cyclic ethers obtained in Example 4.
  • FIG. 10 is a high-resolution mass spectrum of a polyether containing an eight-membered ring and having 4 trans-fused cyclic ethers obtained in Example 4.
  • FIG. 11 is a hydrogen nuclear magnetic resonance spectrum of the polyether having a trans-fused 7/7/6/7/6 pentacyclic ether skeleton in the brevenal molecule obtained in Example 5.
  • FIG. 11 is a hydrogen nuclear magnetic resonance spectrum of the polyether having a trans-fused 7/7/6/7/6 pentacyclic ether skeleton in the brevenal molecule obtained in Example 5.
  • Fig. 12 is a carbon nuclear magnetic resonance spectrum of the polyether having a trans-fused 7/7/6/7/6 pentacyclic ether skeleton in the brevenal molecule obtained in Example 5.
  • Example 13 is a high-resolution mass spectrum of the polyether having a trans-fused 7/7/6/7/6 pentacyclic ether skeleton in the brevenal molecule obtained in Example 5.
  • FIG. 14 is a hydrogen nuclear magnetic resonance spectrum of the polyether with 3 trans-fused cyclic ethers obtained in Example 6.
  • FIG. 14 is a hydrogen nuclear magnetic resonance spectrum of the polyether with 3 trans-fused cyclic ethers obtained in Example 6.
  • FIG. 15 is a carbon nuclear magnetic resonance spectrum of the polyether with 3 trans-fused cyclic ethers obtained in Example 6.
  • FIG. 15 is a carbon nuclear magnetic resonance spectrum of the polyether with 3 trans-fused cyclic ethers obtained in Example 6.
  • FIG. 16 is a high-resolution mass spectrum of the polyether with 3 trans-fused cyclic ethers obtained in Example 6.
  • FIG. 16 is a high-resolution mass spectrum of the polyether with 3 trans-fused cyclic ethers obtained in Example 6.
  • FIG. 17 is a hydrogen nuclear magnetic resonance spectrum of the polyether with 3 trans-fused cyclic ethers obtained in Example 7.
  • FIG. 17 is a hydrogen nuclear magnetic resonance spectrum of the polyether with 3 trans-fused cyclic ethers obtained in Example 7.
  • FIG. 18 is a carbon nuclear magnetic resonance spectrum of the polyether with 3 trans-fused cyclic ethers obtained in Example 7.
  • FIG. 18 is a carbon nuclear magnetic resonance spectrum of the polyether with 3 trans-fused cyclic ethers obtained in Example 7.
  • FIG. 20 is a hydrogen nuclear magnetic resonance spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 8.
  • FIG. 20 is a hydrogen nuclear magnetic resonance spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 8.
  • FIG. 21 is a carbon nuclear magnetic resonance spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 8.
  • FIG. 21 is a carbon nuclear magnetic resonance spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 8.
  • FIG. 22 is a high-resolution mass spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 8.
  • FIG. 22 is a high-resolution mass spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 8.
  • FIG. 23 is a hydrogen nuclear magnetic resonance spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 9.
  • FIG. 23 is a hydrogen nuclear magnetic resonance spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 9.
  • FIG. 24 is a carbon nuclear magnetic resonance spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 9.
  • FIG. 24 is a carbon nuclear magnetic resonance spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 9.
  • Example 25 is a high-resolution mass spectrum of the polyether with 4 trans-fused cyclic ethers obtained in Example 9.
  • the epoxidized compounds used in the examples of this application are all prepared from the corresponding olefinic compounds through the Shi asymmetric epoxidation reaction known in the art (for details, please refer to the document Angew.Chem.Int.Ed.2020, 59, pp 18473 -18478.; Org. Lett. 2012, 14, pp 3932-3935; Science 2007, 317, pp 1189-1192; J. Am. Chem. Soc. 2005, 127, pp 4586-4587), in which Shi asymmetric ring
  • the oxidation reaction conditions are all conventional reaction conditions in the art.
  • the diastereomer mixture of diepoxy alcohol obtained by Shi asymmetric epoxidation (48.4 mg, 0.2 mmol, according to the hydrogen nuclear magnetic spectrum analysis, the content of all diepoxy alcohols (R, R) is 89%, That is, 0.178mmol) was dissolved in perfluoro-tert-butanol (2mL), then 1-ethyl-3-methylimidazole tetrafluoroborate (40mg, 0.2mmol) was added to it, and the reaction was stirred at 40°C for 15 hours . After the reaction was completed, water (5mL) was added to quench the reaction. The reaction mixture was extracted three times with dichloromethane, 10mL each time. The organic phases from the three extractions were combined.
  • the diastereomer mixture of triepoxy alcohol obtained by Shi asymmetric epoxidation (59.6mg, 0.2mmol, according to the hydrogen nuclear magnetic spectrum analysis, the content of the substrate of triepoxy alcohol which is all (R, R) is 83%, ie 0.166mmol) was dissolved in perfluoro-tert-butanol (2mL), then 1-ethyl-3-methylimidazole tetrafluoroborate (40mg, 0.2mmol) was added to it, and stirred at 40°C React for 15 hours. After the reaction was completed, water (5mL) was added to quench the reaction. The reaction mixture was extracted three times with dichloromethane, 10mL each time.
  • the diastereomeric mixture of tetraepoxy alcohol containing cis-disubstituted olefins obtained by Shi asymmetric epoxidation (78.9 mg, 0.2 mmol, according to the analysis of hydrogen nuclear magnetic spectrum, all of which are (R, R) tetraepoxy
  • the content of the alcohol substrate is 75%, that is, 0.15mmol) is dissolved in perfluoro-tert-butanol (2mL), and then 1-ethyl-3-methylimidazole tetrafluoroborate (40mg, 0.2mmol) is added to it , The reaction was stirred at 40°C for 15 hours. After the reaction was completed, water (5mL) was added to quench the reaction.
  • the reaction mixture was extracted three times with dichloromethane, 10mL each time.
  • the organic phases from the three extractions were combined.
  • the organic phase was washed once with water (10mL) and then with brine (10mL) once.
  • the 4-ring trans-fused polycyclic ether of eight-membered cyclic ether After 1 H NMR, 13 C NMR and mass spectrometry analysis, the obtained proton nuclear magnetic resonance spectrum is shown in FIG. 8, the carbon nuclear magnetic resonance spectrum is shown in FIG. 9, and the high-resolution mass spectrum spectrum is shown in FIG. 10.
  • the diastereomer mixture of pentaepoxy alcohol obtained by Shi asymmetric epoxidation (90.5mg, 0.2mmol, according to the proton nuclear magnetic spectrum analysis, the content of all (R, R) pentaepoxy alcohol substrate is 71 %, that is, 0.142mmol) was dissolved in perfluoro-tert-butanol (2mL), then 1-ethyl-3-methylimidazole tetrafluoroborate (40mg, 0.2mmol) was added to it, and the reaction was stirred at 40°C. 15 hours. After the reaction was completed, water (5mL) was added to quench the reaction. The reaction mixture was extracted three times with dichloromethane, 10mL each time.
  • the diastereomeric mixture of triepoxy alcohol obtained by Shi asymmetric epoxidation (54.0 mg, 0.2 mmol, and the content of the substrate of triepoxy alcohol which is all (R, R) according to the proton nuclear magnetic spectrum analysis is 83%, ie 0.166mmol) was dissolved in perfluoro-tert-butanol (2mL), then 1-ethyl-3-methylimidazole tetrafluoroborate (40mg, 0.2mmol) was added to it, and stirred at 40°C React for 24 hours. After the reaction was completed, water (5mL) was added to quench the reaction. The reaction mixture was extracted three times with dichloromethane, 10mL each time.
  • the diastereomer mixture of triepoxy alcohol obtained by Shi asymmetric epoxidation (51.2 mg, 0.2 mmol, according to the proton nuclear magnetic spectrum analysis, the content of the substrate of triepoxy alcohol which is all (R, R) is 83%, ie 0.166mmol) was dissolved in perfluoro-tert-butanol (2mL), then 1-ethyl-3-methylimidazole tetrafluoroborate (40mg, 0.2mmol) was added to it, and stirred at 40°C React for 24 hours. After the reaction was completed, water (5mL) was added to quench the reaction. The reaction mixture was extracted three times with dichloromethane, 10mL each time.
  • the diastereomer mixture of THP-protected hydroxyl triepoxy obtained by Shi asymmetric epoxidation (68.0mg, 0.2mmol, according to the proton nuclear magnetic spectrum analysis, all of which are (R, R) triepoxy substrates
  • the content is 83%, that is, 0.166mmol
  • perfluoro-tert-butanol (2mL) perfluoro-tert-butanol
  • 1-ethyl-3-methylimidazole tetrafluoroborate 40mg, 0.2mmol
  • the product was analyzed by 1 H NMR, 13 C NMR and mass spectrometry.
  • the obtained proton nuclear magnetic resonance spectrum is shown in FIG. 17, the carbon nuclear magnetic resonance spectrum is shown in FIG. 18, and the high-resolution mass spectrum spectrum is shown in FIG. 19.
  • the diastereomer mixture of tetraepoxy alcohol obtained by Shi asymmetric epoxidation (70.8 mg, 0.2 mmol, according to the hydrogen nuclear magnetic spectrum analysis, the content of which is all (R, R) tetraepoxy alcohol substrate is 75 %, ie 0.15mmol) was dissolved in perfluoro-tert-butanol (2mL), then 1-ethyl-3-methylimidazole tetrafluoroborate (40mg, 0.2mmol) was added to it, and the reaction was stirred at 40°C 24 hours. After the reaction was completed, water (5mL) was added to quench the reaction. The reaction mixture was extracted three times with dichloromethane, 10mL each time.
  • the diastereomer mixture of tetraepoxy alcohol obtained by Shi asymmetric epoxidation (68.0mg, 0.2mmol, according to the hydrogen nuclear magnetic spectrum analysis, the content of all tetraepoxy alcohol substrates of (R, R) is 75 %, ie 0.15mmol) was dissolved in perfluoro-tert-butanol (2mL), then 1-ethyl-3-methylimidazole tetrafluoroborate (40mg, 0.2mmol) was added to it, and the reaction was stirred at 40°C 20 hours. After the reaction was completed, water (5mL) was added to quench the reaction. The reaction mixture was extracted three times with dichloromethane, 10mL each time.
  • the diastereomer mixture of THP-protected hydroxyl tetraepoxy obtained by Shi asymmetric epoxidation (84.9mg, 0.2mmol, according to the hydrogen nuclear magnetic spectrum analysis of the content of all (R, R) tetraepoxy substrates 75%, ie 0.15mmol) was dissolved in perfluoro-tert-butanol (2mL), and then 1-ethyl-3-methylimidazole tetrafluoroborate (40mg, 0.2mmol) was added to it, at 40°C The reaction was stirred for 20 hours. After the reaction was completed, water (5mL) was added to quench the reaction. The reaction mixture was extracted three times with dichloromethane, 10mL each time.
  • the product was analyzed by 1 H NMR, 13 C NMR and mass spectrometry, and the obtained proton nuclear magnetic resonance spectrum is shown in FIG. 23, the carbon nuclear magnetic resonance spectrum is shown in FIG. 24, and the high-resolution mass spectrum spectrum is shown in FIG. 25.
  • the synthesis method of the present invention can obtain a polyether with 2 trans-fused cyclic ethers at a yield of up to 55%, and obtain a polyether with 3 trans-fused cyclic ethers at a yield of up to 57%.
  • the polyether of the cyclic ether is obtained with a yield of up to 40%, and the polyether with 4 trans-fused cyclic ethers is obtained with a yield of up to 19%. It contains an eight-membered ring and has 4 trans-fused
  • the polyether of the cyclic ether is as high as 17% to obtain the polyether with the trans-fused 7/7/6/7/6 pentacyclic ether skeleton in the brevenal molecule.
  • the method for synthesizing a polyether with a trans-fused polycyclic ether skeleton structure from a long-chain homochiral polyepoxy compound through a one-step tandem reaction provided by the present invention has raw materials that can be conveniently prepared from cheap and readily available reagents.
  • the experimental operation is simple, the reaction conditions are mild, and the reaction is fast.

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Abstract

La présente invention concerne un procédé de préparation en une étape de polyéther ayant une structure de réseau d'éther polycyclique trans-fusionné. En particulier, la présente invention concerne un procédé de préparation d'un composé éther polycyclique trans-fusionné représenté par la formule (I), comprenant les étapes suivantes : en présence d'un milieu réactionnel et d'un sel contenant un anion faiblement coordonnant, préparer un composé éther polycyclique trans-fusionné représenté par la formule (I) par soumission d'un composé polyépoxy homochiral représenté par la formule (II) à une réaction de cyclisation en une étape. Le procédé de préparation selon la présente invention a un ou plusieurs avantages tels qu'une préparation facile de matières premières, une courte voie de synthèse, une simple opération expérimentale, des conditions de réaction modérées, une réaction rapide et un rendement élevé.
PCT/CN2021/099762 2020-06-12 2021-06-11 Procédé de préparation en une étape de polyéther ayant une structure de réseau d'éther polycyclique trans-fusionné WO2021249545A1 (fr)

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