CN114426511A - Method for preparing chiral spiro [2.4] heptane compounds through palladium-catalyzed asymmetric cycloaddition reaction - Google Patents
Method for preparing chiral spiro [2.4] heptane compounds through palladium-catalyzed asymmetric cycloaddition reaction Download PDFInfo
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- 238000006352 cycloaddition reaction Methods 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 23
- HEMCGZPSGYRIOL-UHFFFAOYSA-N spiro[2.4]heptane Chemical class C1CC11CCCC1 HEMCGZPSGYRIOL-UHFFFAOYSA-N 0.000 title claims description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 95
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 41
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000003446 ligand Substances 0.000 claims abstract description 30
- 239000003054 catalyst Substances 0.000 claims abstract description 29
- 239000002904 solvent Substances 0.000 claims abstract description 27
- 239000004202 carbamide Substances 0.000 claims abstract description 21
- 239000012970 tertiary amine catalyst Substances 0.000 claims abstract description 20
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 18
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims abstract description 17
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims abstract description 17
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims abstract description 15
- 125000003003 spiro group Chemical group 0.000 claims abstract description 9
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 7
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 6
- 230000003197 catalytic effect Effects 0.000 claims abstract description 5
- 230000002153 concerted effect Effects 0.000 claims abstract description 4
- 230000008569 process Effects 0.000 claims abstract description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract 7
- -1 4-chlorphenyl Chemical group 0.000 claims description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N CHCl3 Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 15
- 239000003208 petroleum Substances 0.000 claims description 15
- 239000002808 molecular sieve Substances 0.000 claims description 13
- 239000012043 crude product Substances 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- VHPHAXFRLQPAEU-UHFFFAOYSA-N 5-methylideneoxan-2-one Chemical compound C=C1CCC(=O)OC1 VHPHAXFRLQPAEU-UHFFFAOYSA-N 0.000 claims 1
- 230000008901 benefit Effects 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- 150000003413 spiro compounds Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 27
- 239000000047 product Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 238000012512 characterization method Methods 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- RZJUMQWTXIXIMY-VOTSOKGWSA-N 1-methyl-3-[(e)-2-nitroethenyl]indole Chemical compound C1=CC=C2N(C)C=C(\C=C\[N+]([O-])=O)C2=C1 RZJUMQWTXIXIMY-VOTSOKGWSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 238000007115 1,4-cycloaddition reaction Methods 0.000 description 1
- JFFYKITVXPZLQS-UHFFFAOYSA-N 2-methylidenepropane-1,3-diol Chemical compound OCC(=C)CO JFFYKITVXPZLQS-UHFFFAOYSA-N 0.000 description 1
- 229910014263 BrF3 Inorganic materials 0.000 description 1
- DGRGSXSFTRWFDD-UHFFFAOYSA-N C(Cl)Cl.P(Cl)(Cl)Cl Chemical compound C(Cl)Cl.P(Cl)(Cl)Cl DGRGSXSFTRWFDD-UHFFFAOYSA-N 0.000 description 1
- BGFTZKFVBSZFEQ-UHFFFAOYSA-N COC(C(CC(CO1)=C)(C2=CC=C(C(F)(F)F)C=C2)C1=O)=O Chemical compound COC(C(CC(CO1)=C)(C2=CC=C(C(F)(F)F)C=C2)C1=O)=O BGFTZKFVBSZFEQ-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000006579 Tsuji-Trost allylation reaction Methods 0.000 description 1
- 238000010958 [3+2] cycloaddition reaction Methods 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 150000001454 anthracenes Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical class ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000005888 cyclopropanation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical group C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000019256 formaldehyde Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- KICUISADAVMYCJ-UHFFFAOYSA-N methyl 2-ethylhexanoate Chemical compound CCCCC(CC)C(=O)OC KICUISADAVMYCJ-UHFFFAOYSA-N 0.000 description 1
- CLGFVBQMULAELJ-UHFFFAOYSA-N methyl 5-methylidene-2-oxo-3-phenyloxane-3-carboxylate Chemical compound C=1C=CC=CC=1C1(C(=O)OC)CC(=C)COC1=O CLGFVBQMULAELJ-UHFFFAOYSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 150000003953 γ-lactams Chemical class 0.000 description 1
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
- C07D209/20—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 substituted additionally by nitrogen atoms, e.g. tryptophane
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1845—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing phosphorus
- B01J31/1885—Ligands comprising two different formal oxidation states of phosphorus in one at least bidentate ligand, e.g. phosphite/phosphinite
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/824—Palladium
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a method for preparing chiral spiro [2.4] by palladium-catalyzed asymmetric cycloaddition reaction]A process for producing heptanes, comprising the steps of: in a solvent, under the concerted catalysis of a palladium catalysis system and an organic urea tertiary amine catalyst, a gamma-methylene-delta-valerolactone compound I and an indole nitroolefin compound II undergo a cycloaddition reaction to obtain chiral spiro [2.4]A heptane compound III; the palladium catalytic system consists of a palladium catalyst and a chiral ligand, and the chiral ligand has a structure shown in a formula IV; the organic urea tertiary amine catalyst has a structure shown in a formula V. The spiro compound is constructed by the palladium-catalyzed asymmetric cycloaddition reaction, and the method has the advantages of low catalyst cost, convenient operation, wide substrate application range, cheap and easily obtained reaction raw materials and the like.
Description
Technical Field
The invention relates to a method for preparing chiral spiro [2.4] heptane compounds by palladium-catalyzed asymmetric cycloaddition reaction, belonging to the technical field of organic synthesis.
Background
Transition metal-catalyzed intermolecular cycloaddition reactions are one of the most effective methods for synthesizing cyclic frameworks. Transition metal-catalyzed dipolar cycloaddition reactions between active zwitterionic intermediates and unsaturated acceptors have been widely used in the construction of multifunctional cyclic compounds since the first report in 1979 by Trost and Chan of the formation of 1, 3-dipolar intermediates from 2-acetoxymethyl-3-allyltrimethylsilane (Trost, B, M.; Chan, D, M, T.J.am.chem.Soc.,1979,101, 6429-. In 2007, Shintani and Hayashi reported for the first time that the reaction precursor gamma-methylene-delta-valerolactone (GMDVs) can be decarboxylated under the action of zero-valent palladium to generate 1, 4-dipoles (Shintani, R.; Murakami, M.; Hayashi, T.J.Am.chem.Soc.,2007,129,12356-12357.), and therefore, GMDVs becomes a reliable and powerful zwitterionic intermediate for constructing various carbocycles and heterocycles. Most of the current research is mainly focused on Tsuji-Trost type intramolecular nucleophilic attack of activated unsaturated olefin on one of the two terminal carbons of the pi-allylpalladium intermediate, resulting in a [4+2] cycloaddition product.
In contrast, asymmetric [3+2] cycloaddition reactions are rarely reported in which the central carbon of a pi-allylpalladium intermediate is attacked by an anion to form a polysubstituted chiral spiro ring. In 2012, Shintani and Hayashi reported that palladium-catalyzed cycloaddition of GMDVs to isocyanates to [3+2]/[4+2] yielded 2-pyrrolidones (Shintani, r.; Ito, T.; Hayashi, T. org. lett.,2012,14, 2410-2413; Shintani, r.; Ito, T.; Nagamoto, m.; Otomo, h.; Hayashi, T. chem. commu., 2012,48,9936-9938.), but the substrates were limited to isocyanate-based compounds and the functional group tolerance range was small. In 2020, the Trost subject group reports two unique asymmetric cycloaddition routes involving 1, 4-dipoles of fat species, and chiral spiro [2.4] heptanes compounds (Trost, B, M.; Jiao, Z.; Liu, Y.; Min C.; Hung, C, -I.J.am.chem.Soc.,2020,142,18628 and 18636) are successfully synthesized, however, only 4 successful synthetic product cases are reported in the article, and the application value is low. In 2021, our group reported the synthesis of tetrahydrobenzo [ b ] mustard derivatives (Gao, C.; Wang, X.; Liu, J.; Li, X.ACS Cat. 2021,11, 2684) -one) by palladium catalyzed asymmetric [4+4] cycloaddition of GMDVs to form 1, 4-dipolar zwitterions with anthracenes.
As is clear from the above, since the application range of the conventional synthesis method is small, it is very necessary to develop an asymmetric cyclopropanation reaction catalyzed by palladium in order to search for a new reaction mode of a 1, 4-dipole to prepare a chiral spiro [2.4] heptane compound.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a method for preparing chiral spiro [2.4] heptane compounds by palladium-catalyzed asymmetric cycloaddition reaction. The invention uses the palladium catalyst with simple structure and low price and the chiral ligand which is simple and easy to synthesize to complete the high-efficiency asymmetric synthesis of the chiral spiro [2.4] heptane compounds.
The technical scheme of the invention is as follows:
a process for the preparation of chiral spiro [2.4] heptanes by palladium catalysed asymmetric cycloaddition comprising the steps of:
in a solvent, under the concerted catalysis of a palladium catalysis system and an organic urea tertiary amine catalyst, performing cycloaddition reaction on a gamma-methylene-delta-valerolactone compound I and an indole nitroolefin compound II to obtain a chiral spiro [2.4] heptane compound III; the palladium catalytic system consists of a palladium catalyst and a chiral ligand, and the chiral ligand has a structure shown in a formula IV; the organic urea tertiary amine catalyst has a structure shown in a formula V;
wherein in the structural formula of the compound of the formula I, R1Selected from C1-C3 alkyl or benzyl; ar is phenyl or substituted phenyl, and the substituent of the substituted phenyl is trifluoromethyl, halogen or methyl formate;
in the structural formula of the compound of formula II, R2Is hydrogen, cyano, halogen or C1-C3 alkyl;
in the formula of the compound of formula III, the substituent R1Ar is the same as the structural formula of the compound shown in the formula I; substituent R2And the substitution position is the same as that in the structural formula of the compound shown in the formula II.
Preferred according to the invention are compounds of the formula I in which R is1Is methyl, ethyl or benzyl; ar is phenyl, 4-trifluoromethylphenyl and 4-chlorphenyl4-bromophenyl, 4-carbomethoxyphenyl or 3-carbomethoxyphenyl.
Preferably, according to the invention, the solvent is tetrahydrofuran, anisole or N, N-dimethylformamide; the ratio of the volume of the solvent to the mole number of the indole nitroolefin compound II is 1mL: 0.05-0.5 mmol; the solvent is an anhydrous and oxygen-free solvent.
According to a preferred embodiment of the invention, the palladium catalyst is Pd2(dba)3·CHCl3Or Pd (PPh)3)4(ii) a The molar ratio of palladium in the palladium catalyst to the indole nitroolefin compound II is 0.1-0.11: 1; the molar ratio of palladium to the chiral ligand in the palladium catalyst is 1: 2-2.2.
According to the invention, the molar ratio of the organic urea tertiary amine catalyst to the palladium in the palladium catalyst is preferably 1: 1.
According to the invention, the mol ratio of the gamma-methylene-delta-valerolactone compound I to the indole nitroolefin compound II is 1-1.2: 1.
According to the invention, the reaction system is preferably added
A molecular sieve; the described
The ratio of the mass of the molecular sieve to the mole number of the indole nitroolefin compound II is 2-5 g:1mmol, and the function is to further remove a trace amount of water in the reaction system.
Preferably, according to the invention, the cycloaddition reaction is carried out under a protective gas atmosphere, the protective gas being nitrogen or argon.
According to the invention, the temperature of the cycloaddition reaction is preferably-30-0 ℃, and more preferably-10-0 ℃.
According to the invention, the time of the cycloaddition reaction is preferably 1-14 h, the reaction process is monitored by TLC in the reaction process, and the reaction is completed when the indole nitroolefin compound II disappears.
According to the invention, after the cycloaddition reaction of the gamma-methylene-delta-valerolactone I and the indole nitroolefin compound II, the product can be separated and characterized by a conventional separation and purification method. Preferably, the post-treatment steps of the reaction liquid obtained after the cycloaddition reaction of the gamma-methylene-delta-valerolactone I and the indole nitroolefin compound are as follows: removing the solvent from the reaction liquid, and performing silica gel column chromatography separation on the obtained crude product to obtain a chiral spiro [2.4] heptane compound III, wherein the eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether in the mixed solvent is 0.01-0.5: 1.
According to the invention, the preparation method of the chiral ligand is the prior art and can be prepared by reference (chem.Sci.2018,3, 2628-2632.).
According to the invention, the gamma-methylene-delta-valerolactone compound I is synthesized by a known method from 2-methylene-1, 3-propanediol and corresponding aryl carboxylic ester (see a document: J.Am.chem.Soc.2007,129,12356-12357), and the reaction route is shown as follows:
in the above formula, the substituent R1Ar is as described above.
According to the invention, the indole nitroolefin compound II is synthesized by a known method from 3-indole formaldehydes with different substituents (see the literature: RSC adv.,2018,8,5702-5713.), and the reaction route is shown as follows:
in the above formula, the substituent R2As described above.
The invention has the following technical characteristics and beneficial effects:
1. the invention takes gamma-methylene-delta-valerolactone compound I and indole nitroolefin compound II substituted by different substituents as raw materials, takes an organic catalyst as a synergistic catalyst, and generates asymmetric [3+2] cycloaddition reaction under the action of a palladium catalyst and a chiral ligand to generate a cycloaddition product chiral spiro [2.4] heptane compound III with high selectivity. The method can generate chiral spiro [2.4] heptane compounds with high stereoselectivity and regioselectivity, and carry out efficient asymmetric synthesis on the chiral spiro [2.4] heptane compounds.
2. According to the invention, a large number of chiral ligands and catalysts with different skeletons are screened, so that the palladium catalyst with a simple structure and low price and the chiral ligand which is simple and easy to synthesize are finally confirmed to be used as a catalytic system, and the catalyst has the advantages of low cost, high efficiency and small using amount of the catalyst; the invention adopts a palladium chiral ligand catalytic system and an organic urea tertiary amine catalyst to carry out concerted catalytic reaction, has the advantage of controlling reaction selectivity, has good diastereoselectivity (dr is more than 12: 1) and high corresponding selectivity (ee can be more than 95%); the method has the advantages of cheap and easily-obtained reaction raw materials, good atom economy, wide substrate application range, mild reaction conditions, convenient and simple operation and high yield.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
The experimental methods described in the examples are all conventional methods unless otherwise specified; the reagents and starting materials, unless otherwise specified, are commercially available or may be prepared according to known methods.
The solvents used in the examples were treated with anhydrous and oxygen-free treatment, which was carried out according to the prior art.
The organic urea tertiary amine catalyst V used in the examples can be synthesized by known methods.
The chiral ligand IV (11bS) -N- (di (naphthalene-2-yl) methyl) -N-methyldiphthalene [2,1-d:1',2' -f ] [1,3,2] phosphohept-4-amine used in the examples was prepared as follows:
slowly dripping 6.9mL of triethylamine into 50mL of 0.2mol/L phosphorus trichloride dichloromethane solution at the temperature of 0-5 ℃, wherein the dripping time is 20min, heating to room temperature after finishing dripping, then adding 3.0g of a compound shown in the formula VII, continuously stirring for 5h at room temperature, then adding 2.9g of a compound shown in the formula VI, stirring for 12h at room temperature, and finishing the reaction; removing the solvent from the obtained reaction liquid by rotary evaporation, purifying by using a silica gel chromatographic column to obtain a chiral ligand IV with an ee value of 99 percent, wherein an eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether in the mixed solvent is 0.02: 1; the reaction scheme is as follows:
example 1
Synthesis of benzyl (5R,6S,7R) -6- (1-methyl-1H-indol-3-yl) -7-nitro-5-phenylspiro [2.4] heptane-5-carboxylate IIIaa
The reaction route is as follows:
to a 5mL round bottom flask, under nitrogen, was added 5-methylene-2-oxo-3-phenyltetrahydro-2H-pyran-3-carboxylic acid benzyl ester Ia (39mg), 1-methyl-3- (2-nitrovinyl) -1H-indole IIa (20mg), palladium catalyst Pd2(dba)3·CHCl3(5.2mg), chiral ligand IV (13.4mg), organic urea tertiary amine catalyst V (4.4mg) and
300mg of molecular sieve, 1mL of tetrahydrofuran is added, the flask is then brought to-10 ℃ and stirred for 12h, and the completion of IIa reaction is detected by TLC. Removing the solvent from the reaction solution obtained by the reaction, and separating and purifying the obtained crude product by column chromatography (ethyl acetate: petroleum ether ═ 1: 20-1: 5v/v) to obtain a colorless oily substance IIIaa (5R,6S,7R) -6- (1-methyl-1H-indol-3-yl) -7-nitro-5-phenyl spiro [2.4]Benzyl heptane-5-carboxylate 35mg, yield 73%.
The characterization data of the product (IIIaa) obtained are as follows:
colorless oil, 35mg, 73% yield; dr ═ 6:1, 94% ee;
(0.1,CH2Cl2)；[Daicel
IC-U(0.46cm×25cm),n-hexane/2-propanol＝90/10,v＝1mL·min-1,λ＝254nm,t(major)＝13.3min,t(minor)＝14.2min]；
1H NMR(400MHz,CDCl3)δ0.73-0.81(m,1H),0.85-0.93(m,1H),1.07-1.14(m,1H),1.15-1.21(m,1H),2.63(d,J＝13.8Hz,1H),2.95(d,J＝13.8Hz,1H),3.55(s,3H),5.00-5.04(m,2H),5.18(d,J＝12.4Hz,1H),5.36(d,J＝10Hz,1H),6.11(s,1H),6.96(ddd,J＝8.0,6.7,1.2Hz,1H),7.04(d,J＝7.5Hz,2H),7.08–7.19(m,6H),7.20(dt,J＝9.3,3.3Hz,2H),7.28(dd,J＝5.9,2.6Hz,3H)；
13C NMR(100MHz,CDCl3)δ13C NMR(101MHz,CDCl3)δ14.4,17.6,23.2,32.7,44.5,50.2,60.9,67.0,97.5,108.9,109.00,119.2,119.8,121.4,127.0,127.4,127.8,128.1,128.2,128.5,128.6,128.8,135.7,136.5,138.9,174.2；
HRMS(ESI)m/z calcd.for C30H29N2O4[M+H]+:481.2122,found:481.2121。
example 2
Synthesis of (5R,6S,7R) -6- (6-fluoro-1-methyl-1H-indol-3-yl) -7-nitro-5-phenylspiro [2.4] heptane-5-carboxylic acid benzyl ester IIIab
The reaction route is as follows:
to a 5mL round bottom flask, under nitrogen, was added 5-methylene-2-oxo-3-phenyltetrahydro-2H-pyran-3-carboxylic acid benzyl ester Ia (39mg), 6-fluoro-1-methyl-3- (2-nitrovinyl) -1H-indole IIb (22mg), palladium catalyst Pd2(dba)3·CHCl3(5.2mg), chiral ligand IV (13.4mg), organic urea tertiary amine V (4.4mg) and
molecular sieves 300mg, then tetrahydrofuran 1mL, then the flask was brought to-10 ℃ and stirred for 12h, and IIb reaction was checked by TLC to be complete. Removing the solvent from the reaction solution obtained by the reaction, and separating and purifying the obtained crude product by column chromatography (ethyl acetate: petroleum ether: 1: 20-1: 5v/v) to obtain a colorless oily substance IIIab (5R,6S,7R) -6- (6-fluoro-1-methyl-1H-indol-3-yl) -7-nitro-5-phenyl spiro [ 2.4: (1-methyl-5-phenyl) spiro [2]Benzyl heptane-5-carboxylate 27mg, yield 54%.
The characterization data of the product (IIIab) obtained are as follows:
colorless oil, 27mg, 54% yield; dr 2:1, 88% ee;
(0.1,CH2Cl2)；[Daicel
IA-U(0.46cm×25cm),n-hexane/2-propanol＝95/5,v＝1mL·min-1,λ＝254nm,t(major)＝15.2min,t(minor)＝18.6min]；
1H NMR(400MHz,CDCl3)δ0.72–0.79(m,1H),0.83–0.89(m,1H),1.09-1.13(m,1H),1.16-1.20(m,1H),2.61(d,J＝13.8Hz,1H),2.91(d,J＝13.8Hz,1H),3.49(s,3H),4.96-5.03(m,2H),5.18(d,J＝12.4Hz,1H),5.29(d,J＝8.0Hz,1H),6.08(s,1H),6.49–6.59(m,1H),6.70(td,J＝9.2,2.4Hz,1H),6.78–6.84(m,1H),7.02(dd,J＝7.2,1.8Hz,2H),7.12–7.18(m,5H),7.25–7.30(m,3H)；
13C NMR(100MHz,CDCl3)δ14.4,17.6,23.1,32.8,44.5,50.2,60.7,67.0,95.3(d,J＝26.0Hz),97.3,108.0(d,J＝24.2Hz),109.2,120.7(d,J＝10.0Hz),126.9,127.5,127.9,128.2,128.3(d,J＝2.3Hz),128.4,128.5,128.6,135.7,136.5(d,J＝11.9Hz),138.8,159.7(d,J＝236.3Hz),174.1；
HRMS(ESI)m/z calcd.for C30H28FN2O4[M+H]+:499.2028,found:499.2023。
example 3
Synthesis of benzyl (5R,6S,7R) -6- (6-bromo-1-methyl-1H-indol-3-yl) -7-nitro-5-phenylspiro [2.4] heptane-5-carboxylate IIIac
The reaction route is as follows:
to a 5mL round bottom flask, under nitrogen, was added 5-methylene-2-oxo-3-phenyltetrahydro-2H-pyran-3-carboxylic acid benzyl ester Ia (39mg), 6-bromo-1-methyl-3- (2-nitrovinyl) -1H-indole IIc (28mg), palladium catalyst Pd2(dba)3·CHCl3(5.2mg), chiral ligand IV (13.4mg), organic urea tertiary amine catalyst V (4.4mg) and
molecular sieves 300mg, then tetrahydrofuran 1mL, then the flask was placed at-10 ℃ and stirred for 12h, and IIc reaction was complete by TLC. Removing the solvent from the reaction solution obtained by the reaction, and separating and purifying the obtained crude product by column chromatography (ethyl acetate: petroleum ether: 1: 20-1: 5v/v) to obtain a colorless oily substance IIIac (5R,6S,7R) -6- (6-bromo-1-methyl-1H-indol-3-yl) -7-nitro-5-phenyl spiro [ 2.4%]Benzyl heptane-5-carboxylate 36mg, yield 65%.
The characterization data of the product (IIIac) obtained are as follows:
colorless oil, 36mg, 65% yield; dr ═ 5:1, 94% ee;
(0.1,CH2Cl2)；[Daicel
IA-U(0.46cm×25cm),n-hexane/2-propanol＝97/3,v＝1mL·min-1,λ＝254nm,t(major)＝22.0min,t(minor)＝25.6min]；
1H NMR(400MHz,CDCl3)δ0.74-0.79(m,1H),0.85-0.89(m,1H),1.07-1.14(m,1H),1.17-1.22(m,1H),2.61(d,J＝13.8Hz,1H),2.91(d,J＝13.8Hz,1H),3.51(s,3H),4.97-5.03(m,2H),5.17(d,J＝12.4Hz,1H),5.28(d,J＝10.4Hz,1H),6.07(s,1H),7.00-7.04(t,J＝8.4Hz,3H),7.07-7.09(d,J＝8.6Hz,1H),7.14–7.19(m,4H),7.23(d,J＝7.4Hz,1H),7.27-7.28(m,2H),7.33-7.34(m,2H)
13C NMR(100MHz,CDCl3)δ14.5,17.5,23.1,32.8,44.5,50.1,60.6,67.1,97.1,109.3,112.1,115.2,121.1,122.5,126.7,126.9,127.5,127.9,128.2,128.3,128.5,129.5,135.6,137.3,138.8,174.1
HRMS(ESI)m/z calcd.for C30H28BrN2O4[M+H]+:559.1227,found:559.1224。
example 4
Synthesis of benzyl (5R,6S,7R) -6- (5-cyano-1-methyl-1H-indol-3-yl) -5- (4- (methoxycarbonyl) phenyl) -7-nitro-spiro [2.4] heptane-5-carboxylate IIIbd
The reaction route is as follows:
to a 5mL round bottom flask, under nitrogen, was added 5-methylene-2-oxo-3- (4- (methoxycarbonyl) phenyl) tetrahydro-2H-pyran-3-carboxylic acid benzyl ester Ib (46mg), 5-cyano-1-methyl-3- (2-nitrovinyl) -1H-indole IId (23mg), palladium catalyst Pd2(dba)3·CHCl3(5.2mg), chiral ligand IV (13.4mg), organic urea tertiary amine catalyst V (4.4mg) and
300mg of molecular sieve, 1mL of tetrahydrofuran is added, the flask is then brought to-10 ℃ and stirred for 12h, and the completion of IId reaction is detected by TLC. Removing the solvent from the reaction solution obtained by the reaction, and separating and purifying the obtained crude product by column chromatography (ethyl acetate: petroleum ether: 1: 20-1: 5v/v) to obtain a colorless oily substance III bd (5R,6S,7R) -6- (5-cyano-1-methyl-1H-indol-3-yl) -5- (4- (methoxycarbonyl) phenyl) -7-nitro spiro [ 2.4%]Benzyl heptane-5-carboxylate 38mg, yield 67%.
The characterization data of the product (III bd) obtained are as follows:
colorless oil, 38mg, 67% yield; dr 4:1, 86% ee;
(0.1,CH2Cl2)；[Daicel
IA-U(0.46cm×25cm),n-hexane/2-propanol＝80/20,v＝1mL·min-1,λ＝254nm,t(major)＝17.1min,t(minor)＝13.9min]；
1H NMR(400MHz,CDCl3)δ0.78-0.83(m,1H),0.86-0.93(m,1H),1.14-1.24(m,2H),2.62(d,J＝14.0Hz,1H),2.92(d,J＝14.0Hz,1H),3.59(s,3H),3.93(s,3H),4.95(d,J＝10.8Hz,1H),5.04(d,J＝12.2Hz,1H),5.17(d,J＝12.2Hz,1H),5.31(d,J＝10.0Hz,1H),6.33(s,1H),7.06(dd,J＝8.4,1.4Hz,2H),7.15(dd,J＝6.0,3.0Hz,2H),7.21(dd,J＝8.6,1.4Hz,1H),7.26-7.30(m,3H),7.34(dt,J＝8.6,1.4Hz,1H),7.47(s,1H),7.78–7.89(m,2H)；
13C NMR(100MHz,CDCl3)δ14.5,17.6,23.0,33.0,44.3,50.0,52.3,60.7,67.4,96.5,102.7,109.8,110.1,120.6,124.6,125.5,127.2,128.3,128.4,128.5,128.6,129.3,129.6,131.0,135.2,138.0,143.6,166.5,173.3；
HRMS(ESI)m/z calcd.for C33H30N3O6[M+H]+:564.2129,found:564.2126。
example 5
Synthesis of (5R,6S,7R) -6- (6-bromo-1-methyl-1H-indol-3-yl) -5- (4- (methoxycarbonyl) phenyl) -7-nitro-spiro [2.4] heptane-5-carboxylic acid benzyl ester III bc
The reaction route is as follows:
to a 5mL round bottom flask, under nitrogen, was added 5-methylene-2-oxo-3- (4- (methoxycarbonyl) phenyl) tetrahydro-2H-pyran-3-carboxylic acid benzyl ester Ib (46mg), 6-bromo-1-methyl-3- (2-nitrovinyl) -1H-indole IIc (28mg), palladium catalyst Pd2(dba)3·CHCl3(5.2mg), chiral ligand IV (13.4mg), organic urea tertiary amine catalystReagent V (4.4mg) and
molecular sieves 300mg, then tetrahydrofuran 1mL, then the flask was placed at-10 ℃ and stirred for 12h, and IIc reaction was complete by TLC. Removing the solvent from the reaction solution obtained in the reaction, and separating and purifying the obtained crude product by column chromatography (ethyl acetate: petroleum ether ═ 1: 20-1: 5v/v) to obtain a colorless oily substance III bc (5R,6S,7R) -6- (6-bromo-1-methyl-1H-indol-3-yl) -5- (4- (methoxycarbonyl) phenyl) -7-nitro spiro [ 2.4-]Heptane-5-carboxylic acid benzyl ester 39mg, yield 63%.
The characterization data of the product obtained (III bc) are as follows:
colorless oil, 39mg, 63% yield; dr ═ 6:1, 92% ee;
(0.1,CH2Cl2)；[Daicel
IC-U(0.46cm×25cm),n-hexane/2-propanol＝80/20,v＝1mL·min-1,λ＝254nm,t(major)＝16.9min,t(minor)＝15.1min]；
1H NMR(400MHz,CDCl3)δ0.75-0.80(m,1H),0.85-0.93(m,1H),1.10-1.14(m,1H),1.16-1.21(m,1H),2.62(d,J＝14.0Hz,1H),2.95(d,J＝14.0Hz,1H),3.50(s,3H),3.91(s,3H),4.92(d,J＝10.0Hz,1H),5.02(d,J＝12.2Hz,1H),5.16(d,J＝12.2Hz,1H),5.36(d,J＝10.0Hz,1H),6.10(s,1H),7.04-7.10(m,3H),7.12–7.16(m,2H),7.21(d,J＝8.6Hz,1H),7.25–7.28(m,3H),7.33(d,J＝1.5Hz,1H),7.79–7.84(m,2H)；
13C NMR(100MHz,CDCl3)δ14.2,17.5,23.1,32.9,44.3,49.9,52.3,61.0,67.4,97.1,109.2,112.3,115.5,121.0,122.7,126.5,128.2,128.5,128.5,128.6,129.0,129.1,129.2,135.3,137.4,143.8,166.7,173.5；
HRMS(ESI)m/z calcd.for C32H30BrN2O6[M+H]+:617.1282,found:617.1287。
example 6
Synthesis of benzyl (5R,6S,7R) -6- (6-bromo-1-methyl-1H-indol-3-yl) -5- (3- (methoxycarbonyl) phenyl) -7-nitro-spiro [2.4] heptane-5-carboxylate IIIcc
The reaction route is as follows:
to a 5mL round bottom flask, under nitrogen, was added 3- (3- (methoxycarbonyl) phenyl) -5-methylene-2-oxotetrahydro-2H-pyran-3-carboxylic acid benzyl ester ic (46mg), 6-bromo-1-methyl-3- (2-nitrovinyl) -1H-indolic (28mg), palladium catalyst Pd2(dba)3·CHCl3(5.2mg), chiral ligand IV (13.4mg), organic urea tertiary amine V (4.4mg) and
molecular sieves 300mg, then tetrahydrofuran 1mL, then the flask was placed at-10 ℃ and stirred for 12h, and IIc reaction was complete by TLC. Removing the solvent from the reaction solution obtained by the reaction, and separating and purifying the obtained crude product by column chromatography (ethyl acetate: petroleum ether: 1: 20-1: 5v/v) to obtain a colorless oily substance IIIcc (5R,6S,7R) -6- (6-bromo-1-methyl-1H-indol-3-yl) -5- (3- (methoxycarbonyl) phenyl) -7-nitro spiro [ 2.4%]Benzyl heptane-5-carboxylate 41mg, yield 67%.
The characterization data of the product obtained (IIIcc) are as follows:
41mg of a colorless oil, 67% yield; dr ═ 6:1, 85% ee;
(0.1,CH2Cl2)；[Daicel
IA-U(0.46cm×25cm),n-hexane/2-propanol＝90/10,v＝1mL·min-1,λ＝254nm,t(major)＝16.1min,t(minor)＝19.4min]；
1H NMR(400MHz,CDCl3)δ0.76-0.82(m,1H),0.86-0.94(m,1H),1.13-1.19(m,1H),1.26-1.32(m,1H),2.63(d,J＝14.0Hz,1H),2.98(d,J＝14.0Hz,1H),3.51(s,3H),3.87(s,3H),4.93(d,J＝10.0Hz,1H),5.04(d,J＝12.2Hz,1H),5.16(d,J＝12.2Hz,1H),5.36(d,J＝10.0Hz,1H),6.17(s,1H),6.87–6.92(m,1H),7.00–7.07(m,2H),7.08(d,J＝7.8Hz,1H),7.11–7.16(m,2H),7.24–7.29(m,3H),7.32(d,J＝1.5Hz,1H),7.88(dt,J＝7.8,1.3Hz,1H),7.97(d,J＝2.2Hz,1H)；
13C NMR(100MHz,CDCl3)δ14.0,17.9,23.3,32.8,44.2,50.3,52.2,52.3,60.9,97.1,109.2,112.2,115.4,121.0,122.6,126.4,127.7,128.2,128.4,128.5,128.7,128.9,129.4,129.9,133.7,135.4,137.4,138.9,166.8,173.6；
HRMS(ESI)m/z calcd.for C32H30BrN2O6[M+H]+:617.1282,found:617.1281；
example 7
Synthesis of methyl (5R,6S,7R) -6- (6-bromo-1-methyl-1H-indol-3-yl) -7-nitro-5- (4- (trifluoromethyl) phenyl) spiro [2.4] heptane-5-carboxylate IIIdc
The reaction route is as follows:
to a 5mL round bottom flask, under nitrogen, was added 5-methylene-2-oxo-3- (4- (trifluoromethyl) phenyl) tetrahydro-2H-pyran-3-carboxylic acid methyl ester Id (38mg), 6-bromo-1-methyl-3- (2-nitrovinyl) -1H-indolic (28mg), palladium catalyst Pd2(dba)3·CHCl3(5.2mg), chiral ligand IV (13.4mg), organic urea tertiary amine catalyst V (4.4mg) and
molecular sieves 300mg, then tetrahydrofuran 1mL, then the flask was placed at-10 ℃ and stirred for 12h, and IIc reaction was complete by TLC. Removing the solvent from the reaction solution obtained by the reaction, and separating and purifying the obtained crude product by column chromatography (ethyl acetate: petroleum ether: 1: 20-1: 5) to obtain a colorless oily substance IIIdc (5R,6S,7R) -6- (6-bromo-1-methyl-1H-indol-3-yl) -7-nitro-5- (4- (trifluoromethyl) phenyl) spiro [ 2.4%]Heptane-5-carboxylic acid methyl ester 41mg, yield 75%.
The characterization data of the product (IIIdc) obtained are as follows:
colorless oil, 41mg, 75% yield; dr ═ 5:1, 88% ee;
(0.1,CH2Cl2)；[Daicel
IA-U(0.46cm×25cm),n-hexane/2-propanol＝95/5,v＝1mL·min-1,λ＝254nm,t(major)＝14.2min,t(minor)＝13.5min]；
1H NMR(400MHz,CDCl3)δ0.79-0.85(m,1H),0.91-0.97(m,1H),1.10-1.24(m,2H),2.61(d,J＝14.0Hz,1H),3.00(d,J＝14.0Hz,1H),3.54(s,3H),3.67(s,3H),4.92(d,J＝10.0Hz,1H),5.36(d,J＝10.0Hz,1H),6.17(s,1H),7.06-7.18(m,4H),7.35(d,J＝1.8Hz,1H),7.38–7.46(m,2H)；
13C NMR(100MHz,CDCl3)δ14.3,17.8,23.1,32.8,44.4,50.2,52.9,60.9,96.8,108.9,112.4,115.6,120.9,122.8,124.0(q,J＝270.6Hz),124.8(q,J＝3.7Hz),126.4,128.8,129.2,129.9(q,J＝32.5Hz),137.4,142.8,174.2；
HRMS(ESI)m/z calcd.for C25H23BrF3N2O4[M+H]+:551.0788,found:551.0783。
example 8
Synthesis of methyl (5R,6S,7R) -6- (6-bromo-1-methyl-1H-indol-3-yl) -5- (4-bromophenyl) -7-nitrospiro [2.4] heptane-5-carboxylate III ee
The reaction route is as follows:
to a 5mL round bottom flask, under nitrogen, was added 3- (4-bromophenyl) -5-methylene-2-oxotetrahydro-2H-pyran-3-carboxylic acid methyl ester ie (39mg), 6-chloro-1-methyl-3- (2-nitrovinyl) -1H-indoliie (24mg), palladium catalyst Pd2(dba)3·CHCl3(5.2mg), chiral ligand IV (13.4mg), organic urea tertiary amine catalyst V (4.4mg) and
300mg of molecular sieve, 1mL of tetrahydrofuran is added, the flask is then brought to-10 ℃ and stirred for 12h, and the reaction of IIe is detected to be complete by TLC. Removing the solvent from the reaction solution obtained in the reaction, and separating and purifying the obtained crude product by column chromatography (ethyl acetate: petroleum ether: 1: 20-1: 5v/v) to obtain a colorless oily substance III ee (5R,6S,7R) -6- (6-bromo-1-methyl-1H-indol-3-yl) -5- (4-bromophenyl) -7-nitro spiro [2.4] spiro]29mg of methyl heptane-5-carboxylate in 56% yield.
The characterization data of the product (III ee) obtained are as follows:
colorless oil, 29mg, 52% yield; dr 4:1, 87% ee;
(0.1,CH2Cl2)；[Daicel
IC-U(0.46cm×25cm),n-hexane/2-propanol＝90/10,v＝1mL·min-1,λ＝254nm,t(major)＝9.6min,t(minor)＝11.2min]；
1H NMR(400MHz,CDCl3)δ0.70-0.76(m,1H),0.83-0.88(m,1H),1.02-1.08(m,1H),1.10-1.15(m,1H),2.49(d,J＝13.8Hz,1H),2.90(d,J＝13.8Hz,1H),3.51(s,3H),3.59(s,3H),4.85(d,J＝10.0Hz,1H),5.26(d,J＝10.0Hz,1H),6.12(s,1H),6.81(d,J＝8.6Hz,2H),7.08(dd,J＝8.6,1.7Hz,1H),7.18(d,J＝8.6Hz,1H),7.20–7.26(m,2H)7.30(d,J＝1.7Hz,1H)；
13C NMR(100MHz,CDCl3)δ14.3,17.6,23.0,32.9,44.5,50.0,52.8,60.5,97.0,109.2,112.4,115.6,121.0,121.8,122.8,126.6,129.2,130.2,131.0,137.4,137.8,174.4；
HRMS(ESI)m/z calcd.for C24H23BrClN2O4[M+H]+:517.0530,found:517.0535。
example 9
Synthesis of methyl (5R,6S,7R) -6- (1-methyl-1H-indol-3-yl) -7-nitro-5-phenylspiro [2.4] heptane-5-carboxylate IIIfa
The reaction route is as follows:
to a 5mL round bottom flask, under nitrogen, was added 5-methylene-2-oxo-3-phenyltetrahydro-2H-pyran-3-carboxylic acid methyl ester if (30mg), 1-methyl-3- (2-nitrovinyl) -1H-indole IIa (20mg), palladium catalyst Pd2(dba)3·CHCl3(5.2mg), chiral ligand IV (13.4mg), organic urea tertiary amine catalyst V (4.4mg) and
300mg of molecular sieve, 1mL of tetrahydrofuran is added, the flask is then brought to-10 ℃ and stirred for 12h, and the completion of IIa reaction is detected by TLC. Removing the solvent from the reaction solution obtained by the reaction, and separating and purifying the obtained crude product by column chromatography (ethyl acetate: petroleum ether ═ 1: 20-1: 5v/v) to obtain a colorless oily substance IIIfa (5R,6S,7R) -6- (1-methyl-1H-indol-3-yl) -7-nitro-5-phenyl spiro [ 2.4-]Heptane-5-carboxylic acid methyl ester 23mg, yield 57%.
The characterization data of the product (IIIfa) obtained are as follows:
colorless oil, 23mg, 57% yield; dr ═ 12:1, 87% ee;
(0.1,CH2Cl2)；[Daicel
IB-U(0.46cm×25cm),n-hexane/2-propanol＝95/5,v＝1mL·min-1,λ＝254nm,t(major)＝8.5min,t(minor)＝8.2min]；
1H NMR(400MHz,CDCl3)δ0.77-0.82(m,1H),0.89-0.95(m,1H),1.09-1.16(m,1H),1.18-1.23(m,1H),2.63(d,J＝13.8Hz,1H),2.98(d,J＝13.8Hz,1H),3.56(s,3H),3.66(s,3H),5.01(d,J＝10.0Hz,1H),5.39(d,J＝10.0Hz,1H),6.10(s,1H),6.98-7.07(m,3H),7.11-7.24(m,5H),7.37(d,J＝8.0Hz,1H)
13C NMR(100MHz,CDCl3)δ14.3,17.6,23.0,32.9,44.5,50.0,52.8,60.4,96.9,109.2,112.3,115.5,121.0,122.7,126.6,128.0,129.2,129.8,133.6,137.2,137.4,174.4
HRMS(ESI)m/z calcd.for C24H25N2O4[M+H]+:405.1809,found:405.1811。
comparative example 1
Synthesis of benzyl (5R,6S,7R) -6- (1-methyl-1H-indol-3-yl) -7-nitro-5-phenylspiro [2.4] heptane-5-carboxylate IIIaa as in example 1 except that: the chiral ligand IV and the organic urea tertiary amine catalyst V are not added, the yield of the obtained target product is 58 percent, the dr value is 1:1, and the ee value is 0.
In the comparative example, chiral ligand IV and organic urea tertiary amine catalyst V are not added, the yield of the obtained target product is low, stereoselectivity is avoided, and a racemic product is obtained.
Comparative example 2
Synthesis of benzyl (5R,6S,7R) -6- (1-methyl-1H-indol-3-yl) -7-nitro-5-phenylspiro [2.4] heptane-5-carboxylate IIIaa as in example 1 except that: no tertiary amine catalyst V was added, and the yield of the obtained target product was 67%, dr value was 1:1, and ee value was 85%.
In the comparative example, a mobile phone tertiary amine catalyst V is not added, so that the enantioselectivity of the obtained target product is reduced, and the diastereoselectivity is poor.
Comparative example 3
Synthesis of benzyl (5R,6S,7R) -6- (1-methyl-1H-indol-3-yl) -7-nitro-5-phenylspiro [2.4] heptane-5-carboxylate IIIaa as in example 1 except that: toluene was used as a solvent, and the yield of the objective product was 60%, dr value was 2:1, and ee value was 55%.
In the comparative example, the solvent is toluene, the yield of the obtained target product is low, the enantioselectivity is reduced, and the diastereoselectivity is poor.
Comparative example 4
Synthesis of benzyl (5R,6S,7R) -6- (1-methyl-1H-indol-3-yl) -7-nitro-5-phenylspiro [2.4] heptane-5-carboxylate IIIaa as in example 1 except that: the chiral ligand VI-1 is used to replace the chiral ligand IV, the yield of the target product is 40 percent, the dr value is 1:1, and the ee value is 39 percent.
In the comparative example, the chiral ligand VI-1 is used as the solvent, so that the yield of the obtained target product is obviously reduced, the enantioselectivity is reduced, and the diastereoselectivity is poor.
The above embodiments are only some examples of the present invention, and the present invention is not limited thereto in any way, and any simple modification, equivalent change and modification to the above embodiments according to the technical spirit of the present invention are within the technical scope of the present invention.
Claims (10)
1. A process for the preparation of chiral spiro [2.4] heptanes by palladium catalysed asymmetric cycloaddition comprising the steps of:
in a solvent, under the concerted catalysis of a palladium catalysis system and an organic urea tertiary amine catalyst, performing cycloaddition reaction on a gamma-methylene-delta-valerolactone compound I and an indole nitroolefin compound II to obtain a chiral spiro [2.4] heptane compound III; the palladium catalytic system consists of a palladium catalyst and a chiral ligand, and the chiral ligand has a structure shown in a formula IV; the organic urea tertiary amine catalyst has a structure shown in a formula V;
wherein in the structural formula of the compound of the formula I, R1Selected from C1-C3 alkyl or benzyl; ar is phenyl or substituted phenyl, and the substituent of the substituted phenyl is trifluoromethyl, halogen or methyl formate;
in the structural formula of the compound of formula II, R2Is hydrogen, cyano, halogen or C1-C3 alkyl;
in the formula of the compound of formula III, the substituent R1Ar is the same as the structural formula of the compound shown in the formula I; substituent R2And the substitution position is the same as that in the structural formula of the compound shown in the formula II.
2. Preparation of chiral spiro [2.4] according to claim 1]The method for preparing the heptane compounds is characterized in that in the structural formula of the compound shown in the formula I, R is1Is methyl, ethyl or benzyl; ar is phenyl, 4-trifluoromethylphenyl, 4-chlorphenyl, 4-bromophenyl, 4-carbomethoxyphenyl or 3-carbomethoxyphenyl.
3. The process for preparing chiral spiro [2.4] heptanes according to claim 1, wherein the solvent is tetrahydrofuran, anisole or N, N-dimethylformamide; the ratio of the volume of the solvent to the mole number of the indole nitroolefin compound II is 1mL: 0.05-0.5 mmol; the solvent is an anhydrous and oxygen-free solvent.
4. Preparation of chiral spiro [2.4] according to claim 1]The method for preparing heptane compounds is characterized in that the palladium catalyst is Pd2(dba)3·CHCl3Or Pd (PPh)3)4(ii) a The molar ratio of palladium in the palladium catalyst to the indole nitroolefin compound II is 0.1-0.11: 1; the molar ratio of palladium to the chiral ligand in the palladium catalyst is 1: 2-2.2.
5. The process for preparing chiral spiro [2.4] heptanes according to claim 1, wherein the molar ratio of the organic urea tertiary amine catalyst to palladium in the palladium catalyst is 1: 1.
6. The method for preparing chiral spiro [2.4] heptane compounds according to claim 1, wherein the molar ratio of the gamma-methylene-delta-valerolactone compound I and the indole nitroolefin compound II is 1-1.2: 1.
7.Preparation of chiral spiro [2.4] according to claim 1]The method for producing heptane compounds is characterized in that the reaction system is added with
A molecular sieve; the above-mentioned
The ratio of the mass of the molecular sieve to the number of moles of the indole nitroolefin compound II is 2-5 g:1 mmol.
8. The method of claim 1, wherein the cycloaddition reaction is performed under a protective gas atmosphere, wherein the protective gas is nitrogen or argon.
9. The process for the preparation of chiral spiro [2.4] heptanes according to claim 1, characterized in that the temperature of the cycloaddition reaction is-30 ℃ to 0 ℃, preferably-10 ℃ to 0 ℃; the time of the cycloaddition reaction is 1-14 h.
10. The method for preparing chiral spiro [2.4] heptanes according to claim 1, wherein the post-treatment step of the reaction solution obtained after cycloaddition reaction of γ -methylene- δ -valerolactone i and indole nitroolefin compound is as follows: removing the solvent from the reaction liquid, and performing silica gel column chromatography separation on the obtained crude product to obtain a chiral spiro [2.4] heptane compound III, wherein the eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether in the mixed solvent is 0.01-0.5: 1.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732550A (en) * | 2014-12-09 | 2016-07-06 | 中国科学院大连化学物理研究所 | Preparing method of chiral 3-methylene-2,3-dihydro-furan compound |
| CN112430236A (en) * | 2020-11-27 | 2021-03-02 | 暨南大学 | Synthesis method of chiral spiro [ pyrrolidone-3, 3 '-oxindole ] ring system and application of chiral spiro [ pyrrolidone-3, 3' -oxindole ] ring system in synthesis of natural product |
| CN113200905A (en) * | 2021-03-31 | 2021-08-03 | 中山大学 | Chiral indolone derivative and synthesis method thereof |
| CN113620918A (en) * | 2021-08-18 | 2021-11-09 | 山东大学 | Method for synthesizing spiro compound through Lewis acid catalyzed [3+2] cycloaddition reaction |
| CN113666862A (en) * | 2021-08-18 | 2021-11-19 | 山东大学 | Method for preparing chiral 3-nitroindole compound by nickel-catalyzed asymmetric nitration reaction |
-
2021
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732550A (en) * | 2014-12-09 | 2016-07-06 | 中国科学院大连化学物理研究所 | Preparing method of chiral 3-methylene-2,3-dihydro-furan compound |
| CN112430236A (en) * | 2020-11-27 | 2021-03-02 | 暨南大学 | Synthesis method of chiral spiro [ pyrrolidone-3, 3 '-oxindole ] ring system and application of chiral spiro [ pyrrolidone-3, 3' -oxindole ] ring system in synthesis of natural product |
| CN113200905A (en) * | 2021-03-31 | 2021-08-03 | 中山大学 | Chiral indolone derivative and synthesis method thereof |
| CN113620918A (en) * | 2021-08-18 | 2021-11-09 | 山东大学 | Method for synthesizing spiro compound through Lewis acid catalyzed [3+2] cycloaddition reaction |
| CN113666862A (en) * | 2021-08-18 | 2021-11-19 | 山东大学 | Method for preparing chiral 3-nitroindole compound by nickel-catalyzed asymmetric nitration reaction |
Non-Patent Citations (1)
| Title |
|---|
| B. M. TROST等: "Palladium-Catalyzed Enantioselective Cycloadditions of Aliphatic 1, 4-Dipoles: Access to Chiral Cyclohexanes and Spiro [2.4] heptanes", 《J. AM. CHEM. SOC.》, vol. 142, no. 43, pages 18628 * |
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