CN101812046B - Furan compound, synthetic method and applications - Google Patents
Furan compound, synthetic method and applications Download PDFInfo
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- CN101812046B CN101812046B CN201010114566.9A CN201010114566A CN101812046B CN 101812046 B CN101812046 B CN 101812046B CN 201010114566 A CN201010114566 A CN 201010114566A CN 101812046 B CN101812046 B CN 101812046B
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- furan compound
- reductive agent
- herba clerodendri
- clerodendri indici
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- ZCBQZDMJIVJQLX-JGVFFNPUSA-N O[C@@]1(CCC(C2)=O)[C@H]2OCC1 Chemical compound O[C@@]1(CCC(C2)=O)[C@H]2OCC1 ZCBQZDMJIVJQLX-JGVFFNPUSA-N 0.000 description 1
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Abstract
The invention relates to a chiral 1,4-oxa-compound and a furan compound which are synthesized in high efficiency and high enantioselectivity by an intramolecular oxa-Michael reaction of cyclohexadienone derivatives catalyzed by chiral phosphoric acid. The furan compound can be used for preparing a clerodendrum indicum extract natural product. The method has mild reaction conditions and simple operation. In addition, any metal salt compound is not added during the reaction, which is beneficial to producing and treating potential biological active compounds. The method has good reaction yield (71% to 93% generally) and high enantioselectivity (61% to >99% generally).
Description
Technical field
The present invention relates to a kind of chirality furan compound, system carries out oxa-Michael reaction high-level efficiency in molecule, high enantioselectivity ground synthesis of chiral furan compound by the acid catalyzed cyclohexadiene ketone derivatives of chiral phosphorus, and this furan compound can be for the preparation of Herba Clerodendri Indici element class natural product.
background technology
In recent years, organocatalysis is because the advantages such as it is synthetic easily, and structural modification is convenient, and heavy metal free is residual have caused extensive concern [(a) Seayad, the J. of academia and industry member in worldwide; List, B.Org.Biomol.Chem.2005,3,719-724. (b) Dalko, P.I.; Moisan, L.Angew.Chem.Int.Ed.2004,43,5138-5175.], the asymmetry catalysis of wherein being realized as catalyzer by chiral phosphoric acid has been obtained development [(a) Akiyama, T. rapidly in recent years especially; Itoh, J.; Yokota, K.; Fuchibe, K.Angew.Chem.Int.Ed.2004,43,1566-1568. (b) Uraguchi, D.; Terada, M.J.Am.Chem.Soc.2004,126,5356-5357. (c) Uraguchi, D.; Sorimachi, K.; Terada, M.J.Am.Chem.Soc.2004,126,11804-11805.].In this field, we have developed by oxa-Michael in the molecule of the acid catalyzed cyclohexadiene ketone derivatives of chiral phosphorus and have reacted, this reaction can high-level efficiency, the synthesis of chiral ring-type oxa-compound of high enantioselectivity, as Isosorbide-5-Nitrae-oxa-compound and furan compound.Oxa-ring compound is present in a large amount of [(a) Tang, Y. in bioactive natural product and drug molecule of having; Oppenheimer, J.; Song, Z.-L.; You, L.-F.; Zhang, X.-J.; Hsung, R.P.Tetrahedron2006,62,10785. (b) Shi, Y.-L.Shi, M.Org.Biomol.Chem.2007,5,1499.], but because oxa-Michael reaction often exists certain reversibility, hindered development [Nising, the C.F. of its asymmetric methodology aspect;
s., Chem.Rev.2008,37,1218.].Thereby develop a kind of easy to operately, particularly the asymmetric oxa-Michael of high-level efficiency, high enantioselectivity reaction is the Focal point and difficult point of this respect.Our this organic micromolecule catalyst of development utilization chiral phosphoric acid, oxa-Michael reaction in catalytic molecular in several minutes to a few hours, has great significance as Isosorbide-5-Nitrae-oxa-compound and furan compound to synthesis of chiral oxa-ring compound.In addition, oxa-Michael product is if furan compound is by further transforming, can synthesize simply efficiently Herba Clerodendri Indici chlorins compound, this compounds can extract acquisition from plant Herba Clerodendri Indici, this plant is usually used for treating malaria and rheumatosis [(a) Tian, J. in China; Zhao, Q.-S.; Zhang, H.-J.; Lin, Z.-W.; Sun, H.-D.J.Nat.Prod.1997,60,766. (b) Cheng, H.-H.; Wang, H.-K.; Ito, J.; Bastow, K.F.T.Y.; Nakanishi, Y.; Xu, Z.; Luo, T.-Y.; Lee, K.-H.J.Nat.Prod.2001,64,915.].But only have a small amount of report about the asymmetric synthesis of Herba Clerodendri Indici chlorins compound, and step cumbersome [(a) Honzumi, M.; Kamikubo, T.; Ogasawara, K.Synlett1998,1001. (b) Canto, M.; DeMarch, P.; Figueredo, M.; Font, J.; Rodriguez, S.; Alarez-Larena, A.; Piniella, J.F.Tetrahedron:Asymmetry2002,13,455. (c) You, Z.; Hoveyda, A.H.; Snapper, M.L.Angew.Chem.Int.Ed.2009,48,547. (d) Wenderski, T.A.; Huang, S.-L.; Pettus, T.R.R.J.Org.Chem.2009,74,4104.].We use the method student movement in synthesizing of these natural products, have synthesized simply efficiently and have had optically active Herba Clerodendri Indici element class compounds.
summary of the invention
The object of this invention is to provide a kind of furan compound that contains;
Object of the present invention or a kind of effectively method of synthetic above-mentioned furan compound is provided;
Another object of the present invention is to provide a kind of asymmetric synthesis Herba Clerodendri Indici chlorins compound method.
A kind of furan compound of method of the present invention, has following structural formula:
R wherein
1be selected from arbitrarily H, the alkyl of C1-C16; R wherein
2be selected from arbitrarily OH, OOH, C
3-C
16cycloalkyl, C
4-C
10the aryl that replaces of the heterocyclic radical containing N, O or S, aryl, R; Described aryl is phenyl or naphthyl; R is C
1-C
4alkyl, C
1-C
4perfluoroalkyl, halogen or C
1-C
4alkoxyl group; Wherein X is selected from arbitrarily CH
2or OCH
2.
A kind of furan compound that contains of the present invention is to take cyclohexadiene ketone derivatives as raw material, and under the existence of organic solvent, the chiral phosphoric acid of take makes as catalyst reaction, and available following reaction formula represents:
The further description of this reaction is to be-78 ℃ to 100 ℃ at organic solvent neutral temperature, cyclohexadiene ketone derivatives is raw material, take chiral phosphoric acid as catalyst reaction 5 minutes-48 hours, described cyclohexadiene ketone derivatives and the mol ratio of chiral phosphoric acid are 1: 0.01-0.5, the mol ratio of recommendation response is: cyclohexadiene ketone derivatives: chiral phosphoric acid=1: 0.05-0.2. recommendation response temperature is :-60 ℃ to 25 ℃.The general structure of catalyzer is (be any optically pure structure, not limit by diagram):
r wherein
8, R
9, R
10,
R
11, R
12the aryl that the alkyl, the triphenyl that are selected from arbitrarily H, C1-C16 are silica-based, aryl, R replace; Described aryl is phenyl, naphthyl, anthryl or phenanthryl; R is C
1-C
4alkyl, C
1-C
4perfluoroalkyl, halogen or C
1-C
4alkoxyl group.
In the inventive method, described water is distilled water.Described organic solvent can be polarity or non-polar solvent, as benzene, tetracol phenixin, sherwood oil, tetrahydrofuran (THF), dimethyl formamide, ether, methylene dichloride, trichloromethane, toluene, dimethylbenzene, hexanaphthene, normal hexane, normal heptane, dioxane or acetonitrile etc.
Adopt the inventive method products therefrom can pass through recrystallization, thin-layer chromatography, the in addition separation and purification of the methods such as column chromatography underpressure distillation.As the method with recrystallization, recommending solvent is the mixed solvent of polar solvent and non-polar solvent.Recommend solvent to can be methylene dichloride---normal hexane, Virahol---sherwood oil, ethyl acetate---sherwood oil, ethyl acetate---normal hexane, Virahol---ethyl acetate---mixed solvents such as sherwood oil.With thin-layer chromatography and column chromatography method, developping agent used is the mixed solvent of polar solvent and non-polar solvent.Recommend solvent to can be Virahol---sherwood oil, ethyl acetate---sherwood oil, ethyl acetate---normal hexane, Virahol---ethyl acetate---mixed solvents such as sherwood oil, its volume ratio can be respectively: polar solvent: non-polar solvent=1: 0.1-500. for example: ethyl acetate: sherwood oil=1: 0.1-50, Virahol: sherwood oil=1: 0.1-500.
Furan compound of the present invention can be for the preparation of Herba Clerodendri Indici chlorins compound, and its structural formula is as follows:
Herba Clerodendri Indici element F, Herba Clerodendri Indici element C or Herba Clerodendri Indici element D.
Further specifically describe method of the present invention as follows: in organic solvent and under room temperature, foregoing furan compound of the present invention and reductive agent reaction obtain Herba Clerodendri Indici element F compound for 1-72 hour, and described furan compound and the mol ratio of reductive agent are 1: 1-5; Described reductive agent is S-WAT, Sulfothiorine, triphenyl phosphite or triphenyl phosphorus.
In organic solvent and under room temperature, Herba Clerodendri Indici element F compound as above obtains Herba Clerodendri Indici element C compound, described Herba Clerodendri Indici element F compound and palladium carbon 1: 0.01-0.2 for 1-72 hour in the reaction of palladium hydrocarbonize.
In organic solvent and under room temperature, foregoing furan compound reacts 1-72 hour with salt of wormwood, sodium carbonate or benzyltrimethylammonium hydroxide, then reacts with reductive agent and within 1-72 hour, obtains Herba Clerodendri Indici element D compound; Described reductive agent is triethyl-boron aluminum hydride, aluminium amalgam or Lithium Aluminium Hydride; The mol ratio of described furan compound and salt of wormwood, sodium carbonate or benzyltrimethylammonium hydroxide is 1: 0.1-0.5; Described furan compound and the mol ratio of reductive agent are 1: 1-10.
The invention provides a kind of effectively by chiral phosphoric acid as catalyzer, by cyclohexadiene ketone derivatives, be the synthesis of chiral oxa-ring compound of raw material high-level efficiency, high enantioselectivity, as the method for Isosorbide-5-Nitrae-oxa-compound and furan compound; Wherein furans product can efficiently be prepared Herba Clerodendri Indici chlorins compound through simple conversion.This synthetic method catalyzer is easy to get relatively, catalytic activity is high, wide application range of substrates, product enantioselectivity are high, and reaction conditions is gentle, easy and simple to handle.In addition, in reaction without adding any metal salt compound, thereby be conducive to production and the processing of medicine.And the productive rate of reaction is better (being generally 71%-93%) also, enantioselectivity high (being generally 61%-99%).
Embodiment
By following embodiment, will contribute to understand the present invention, but not limit content of the present invention.
Embodiment 1: the preparation of chiral phosphoric acid
Under room temperature argon shield; in a dry reaction tubes, the derivative of BINOL (0.5mmol) is dissolved in the pyridine that 1mL is dry; under the condition of rapid stirring, the phosphorus oxychloride of (1.0mmol) is added drop-wise in system slowly to stirring at room 3 hours.1mL water is added drop-wise in system slowly, then stirring at room 30 minutes.Add methylene dichloride to dissolve, with 1N aqueous hydrochloric acid (3 * 10mL) washing, organic layer anhydrous sodium sulfate drying, desolventizing is revolved in decompression, and residue column chromatography for separation obtains product.
(S)-3,3 '-[3,5-bis-(trifluoromethyl) phenyl] 2-1,1 '-binaphthol phosphoric acid
(S)-3，3′-[3，5-Bis(trifluoromethyl)phenyl]2-1，1′-binaphthyl?phosphate
Solid, 89% productive rate (yield) .IR (CHCl
3) 1620,1501,1474,1379,1325,1281,1246,1178,1140,1109,1084,1024,988,964,891,870,867cm
-1.
1h NMR (400MHz, CDCl3) δ=8.01 (s, 8H), 7.61-7.58 (m, 4H), 7.42-7.39 (m, 4H).
31p NMR (189MHz, CDCl
3) δ=4.61.
13c NMR (100MHz, CDCl
3) δ=143.5 (d, J
p-C=9.3Hz), 138.6,132.3,132.0,131.4,131.4 (q, J
c-F=33.4Hz), 131.1 (d, J
p-C=3.1Hz), 129.9,128.7,127.6,127.1,126.8,123.1 (q, J
c-F=272.9Hz), 122.5 (d, J
p-C=1.9Hz), 121.5.
19f NMR (376MHz, CDCl
3) δ=96.3.
Embodiment 2: oxa-Michael reaction in the acid catalyzed molecule of chiral phosphorus
Under argon shield, in a dry reaction tubes, add cyclohexadiene ketone derivatives (0.3mmol), chiral phosphoric acid catalyzer (22.8mg, 10mol%), activation
molecular sieve (150mg) and methylene dichloride (6mL).Under room temperature, react to raw material disappearance (TLC detection).Reaction solution is through diatomite filtration, solid washed with dichloromethane, filtrate decompression is revolved desolventizing, residue through plate layer chromatography separated product.
P1:(4aS, 8aR)-8a-methyl-2,3,4a, 5-tetrahydro benzo [b] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia-6 (8aH)-one
P1：(4aS，8aR)-8a-methyl-2，3，4a，5-tetrahydrobenzo[b][1，4]dioxin-6(8aH)-one
White solid, 91%yield, 94%ee[62%yield, 99%ee (ethyl acetate/petroleum ether, recrystallization)] .Analytical data for P1 (99%ee): [α]
d 20=+23.6 ° of (c=0.5, CHCl
3) .Mp=105-106 ℃.
1h NMR (300MHz, CDCl
3) δ 1.39 (s, 3H), 2.59 (dd, J=3.0,17.4Hz, 1H), 2.69 (dd, J=3.0,17.1Hz, 1H), 3.63-3.73 (m, 3H), 3.80-3.83 (m, 1H), 3.89-3.91 (m, 1H), 6.11 (d, J=10.5Hz, 1H), 6.70 (dd, J=3.0,10.5Hz, 1H);
13c NMR (75MHz, CDCl
3) δ 24.5,42.0,62.9,66.2,71.9,78.2,130.5,152.3,195.7; IR (KBr) 2977,2914,2863,1674,1414,1386,1350,1287,1233,1124,1097,1023,953,946,791,697cm
-1; HRMS (EI): high resolution mass spectrum calculating value C
9h
12o
3: 168.0786. measured value: 168.0786. chirality test condition: Daicel Chiralpak OB-H (25cm), normal hexane/Virahol=90/10,0.6mL/min
-1, λ=220nm, t
r(major)=22.04min, t
r(minor)=26.49min.
P2:(4aS, 8aR)-8a-ethyl-2,3,4a, 5-tetrahydro benzo [b] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia-6 (8aH)-one
P2：(4aS，8aR)-8a-ethyl-2，3，4a，5-tetrahydrobenzo[b][1，4]dioxin-6(8aH)-one
Semisolid, 91%yield, 78%ee.Analytical data for P2:[α]
d 20=+27.7 ° of (c=1.0, CHCl
3).
1h NMR (400MHz, CDCl
3) δ 1.04 (t, J=7.2Hz, 3H), 1.71-1.75 (m, 2H); 2.55-2.71 (m, 2H), 3.67-3.70 (m, 3H), 3.79-3.86 (m, 1H), 3.93-3.95 (m, 1H), 6.13 (dd, J=1.2,10.4Hz, 1H), 6.73 (dd, J=2.8,10.4Hz, 1H);
13c NMR (100MHz, CDCl
3) δ 7.2,31.4,41.8,62.8,66.2,73.8,76.9,130.9,152.3,195.8; IR (KBr) 2973,2920,2866,1686,1411,1382,1275,1126,1096,992,966,926,793,697cm
-1; HRMS (EI): high resolution mass spectrum calculating value C
10h
14o
3: 182.0943. measured value: 182.0941 chirality test conditions: DaicelChiralpak OB-H (25cm), normal hexane/Virahol=90/10,0.6mL/min
-1, λ=220nm, t
r(major)=22.21min, t
r(minor)=26.78min.
P3:(4aS, 8aR)-8a-sec.-propyl-2,3,4a, 5-tetrahydro benzo [b] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia-6 (8aH)-one
P3:(4aS, 8aR)-8a-isopropyl-2,3,4a, 5-tetrahydro benzo [b] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia-6 (8aH)-one
Faint yellow solid, 71%yield, 61%ee.Analytical data for P3:[α]
d 20=+1.6 ° of (c=0.6, CHCl
3) .Mp=65-67 ℃.
1h NMR (300MHz, CDCl
3) δ 1.03 (d, J=6.9Hz, 3H), 1.08 (d, J=6.9Hz, 3H), 1.95 (heptet, J=6.9Hz, 1H), 2.52-2.73 (m, 2H), 3.64-3.71 (m, 3H), 3.80-3.88 (m, 1H), 4.13-4.16 (m, 1H), 6.14 (d, J=10.5Hz, 1H), 6.82 (d, J=10.5Hz, 1H);
13c NMR (75MHz, CDCl
3) δ 16.8,17.2,35.6,41.3,62.6,66.2,75.0,75.5,130.6,153.8,195.8; IR (KBr) 2957,2918,2860,1683,1379,1279,1261,1222,1137,1101,998,922,802,774,690cm
-1; HRMS (EI): high resolution mass spectrum calculating value C
11h
16o
3: 196.1099. measured value: 196.1097. chirality test condition: Daicel Chiralpak OB-H (25cm), normal hexane/Virahol=90/10,0.6mL/min
-1, λ=220nm, t
r(major)=18.93min, t
r(minor)=21.81min.
P4:(4aS, 8aS)-8a-phenyl-2,3,4a, 5-tetrahydro benzo [b] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia-6 (8aH)-one
P4：(4aS，8aS)-8a-phenyl-2，3，4a，5-tetrahydrobenzo[b][1，4]dioxin-6(8aH)-one
White solid, 92%yield, 91%ee[68%yield, 99%ee (ethyl acetate/petroleum ether, recrystallization)] .Analytical data for P4 (99%ee): [α]
d 20=+171.6 ° of (c=0.39, CHCl
3) .Mp=123-124 ℃.
1h NMR (300MHz, CDCl
3) δ 2.45 (d, J=3.0Hz, 2H), 3.84-3.91 (m, 3H), 4.03-4.07 (m, 2H), 6.48 (d, J=10.5Hz, 1H), 6.78 (dd, J=3.0,10.5Hz, 1H), 7.35-7.43 (m, 3H), 7.54-7.57 (m, 2H);
13c NMR (75MHz, CDCl
3) δ 41.2,62.8,66.3,76.9,79.3,126.7,128.6,128.7,132.9,138.4,148.7,196.4; IR (KBr) 2968,2916,2868,1685,1490,1446,1401,1263,1218,1120,1087,979,917,777,758,696cm
-1; HRMS (EI): high resolution mass spectrum calculating value C
14h
14o
3: 230.0943. measured value: 230.0942. chirality test condition: Daicel ChiralpakAS-H (25cm), normal hexane/Virahol=80/20,1.0mL/min
-1, λ=220nm, t
r(major)=22.44min, t
r(minor)=34.19min.
P5:(4aS, 8aS)-8a-(4-fluorophenyl)-2,3,4a, 5-tetrahydro benzo [b] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia-6 (8aH)-one
P5：(4aS，8aS)-8a-(4-fluorophenyl)-2，3，4a，5-tetrahydrobenzo[b][1，4]dioxin-6(8aH)-one
White solid, 91%yield, 90%ee.Analytical data for P5:[α]
d 20=+137.1 ° of (c=0.5, CHCl
3) .Mp=159-160 ℃.
1h NMR (300MHz, CDCl
3) δ 2.53-2.37 (m, 2H), 3.84-3.89 (m, 3H), 3.99-4.10 (m, 2H), 6.48 (d, J=10.5Hz, 1H), 6.76 (dd, J=3.0,10.5Hz, 1H), 7.05-7.11 (m, 2H), 7.51-7.56 (m, 2H);
13c NMR (75MHz, CDCl
3) δ 41.1,62.9,66.3,76.5,79.3,115.5 (d, J=21.3Hz), 128.6 (d, J=8.2Hz), 133.1,134.3 (d, J=3.3Hz), 148.3,162.7 (d, J=246.6Hz), 196.15;
19f NMR (282MHz, CDCl
3) δ-113.42; IR (KBr) 3072,2970,2914,2865,1685,1604,1509,1491,1225,1161,1120,1102,1037,980,920,841,771,689cm
-1; HRMS (EI): high resolution mass spectrum calculating value C
14h
13o
3f:248.0849. measured value: 248.0846. chirality test condition: Daicel Chiralpak AS-H (25cm), normal hexane/Virahol=80/20,1.0mL/min
-1, λ=220nm, t
r(major)=72.04min, t
r(minor)=102.38min.
P6:(4aS, 8aS)-8a-(4-chloro-phenyl-)-2,3,4a, 5-tetrahydro benzo [b] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia-6 (8aH)-one
P6：(4aS，8aS)-8a-(4-chlorophenyl)-2，3，4a，5-tetrahydrobenzo[b][1，4]dioxin-6(8aH)-one
White solid, 90%yield, 91%ee.Analytical data for P6:[α]
d 20=+162.7 ° of (c=0.4, CHCl
3) .Mp=135-136 ℃.
1h NMR (300MHz, CDCl
3) δ 2.37-2.47 (m, 2H), 3.84-3.89 (m, 3H), 3.96-4.07 (m, 2H), 6.48 (d, J=10.5Hz, 1H), 6.75 (dd, J=2.7,10.5Hz, 1H), 7.37 (d, J=8.7Hz, 2H), 7.49 (d, J=8.7Hz, 2H);
13c NMR (75MHz, CDCl
3) δ 41.1,62.8,66.3,76.6,79.2,128.2,128.8,133.2,134.8,137.1,148.1,196.1; IR (KBr) 2966,2916,2863,1692,1486,1402,1283,1262,1123,1094,1014,977,923,826,728; HRMS (EI): high resolution mass spectrum calculating value C
14h
13o
3cl:264.0553. measured value: 264.0558. chirality test condition: Daicel Chiralpak AS-H (25cm), normal hexane/Virahol=80/20,1.0mL/min
-1, λ=220nm, t
r(major)=81.40min, t
r(minor)=105.82min.
P7:(4aS, 8aS)-8a-(4-bromophenyl)-2,3,4a, 5-tetrahydro benzo [b] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia-6 (8aH)-one
P7：(4aS，8aS)-8a-(4-bromophenyl)-2，3，4a，5-tetrahydrobenzo[b][1，4]dioxin-6(8aH)?-one
White solid, 84%yield, 90%ee[64%yield, 99%ee (ethyl acetate/petroleum ether, recrystallization] .Analytical data for P7 (99%ee): [α]
d 20=+187.0 ° of (c=0.5, CHCl
3) .Mp=146-147 ℃.
1h NMR (300MHz, CDCl
3) δ 2.37-2.53 (m, 2H), 3,84-3.87 (m, 3H), 4.09-4.93 (m, 2H), (6.49 d, J=10.5Hz, 1H), 6.74 (dd, J=3.0,10.5Hz, 1H), 7.42 (d, J=8.4Hz, 2H), 7.52 (d, J=8.4Hz, 2H);
13c NMR (75MHz, CDCl
3) δ 41.1,62.8,66.3,76.5,79.1,122.9,128.5,131.7,133.2,137.6,148.0,196.0; IR (KBr) 2916,2864,1695,1481,1398,1284,1263,1124,1115,1033,1002,977,824,677cm
-1; HRMS (EI): high resolution mass spectrum calculating value C
14h
13o
3br:308.0048. measured value: 308.0045. chirality test condition: Daicel Chiralpak AS-H (25cm), normal hexane/Virahol=80/20,1.0mL/min
-1, λ=220nm, t
r(major)=71.23min, t
r(minor)=98.27min.
P8:(4aS, 8aS)-8a-(4-aminomethyl phenyl)-2,3,4a, 5-tetrahydro benzo [b] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia-6 (8aH)-one
P8：(4aS，8aS)-8a-p-tolyl-2，3，4a，5-tetrahydrobenzo[b][1，4]dioxin-6(8aH)-one
White solid, 91%yield, 92%ee[72%yield, 99%ee (ethyl acetate/petroleum ether, recrystallization)] .Analytical data for P8 (99%ee): [α]
d 20=+212.6 ° of (c=1.1, CHCl
3) .Mp=164-165 ℃.
1h NMR (300MHz, CDCl
3) δ 2.36 (s, 3H), 2.45 (d, J=3.0Hz, 2H), 3.83-3.90 (m, 3H), 4.00-4.05 (m, 2H), 6.47 (d, J=10.5Hz, 1H), (6.77 dd, J=2.7,10.5Hz, 1H), 7.20 (d, J=8.4Hz, 2H), 7.42 (d, J=8.4Hz, 2H);
13c NMR (75MHz, CDCl
3) δ 21.0,41.3,62.8,66.4,76.8,79.4,126.6,129.3,132.8,135.5,138.6,148.9,196.6; IR (KBr) 2974,2916,2864,1681,1517,1447,1404,1263,1106,1083,978,921,821,687cm
-1; HRMS (EI): high resolution mass spectrum calculating value C
15h
16o
3: 244.1099. measured value: 244.1102; Chirality test condition: Daicel Chiralpak AS-H (25cm), normal hexane/Virahol=80/20,1.0mL/min
-1, λ=220nm, t
r(major)=24.12min, t
r(minor)=36.27min.
P9:(4aS, 8aS)-8a--(3-aminomethyl phenyl)-2,3,4a, 5-tetrahydro benzo [b] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia-6 (8aH)-one
P9：(4aS，8aS)-8a-m-tolyl-2，3，4a，5-tetrahydrobenzo[b][1，4]dioxin-6(8aH)-one
White solid, 91%yield, 91%ee[75%yield, 96%ee (ethyl acetate/petroleum ether, recrystallization)] .Analytical data for P9 (96%ee): [α]
d 20=+155.5 ° of (c=1.1, CHCl
3) .Mp=113-114 ℃.
1h NMR (300MHz, CDCl
3) δ 2.37 (s, 3H), 2.46 (d, J=3.0Hz, 2H), 3.83-3.91 (m, 3H), 4.01-4.06 (m, 2H), 6.48 (d, J=10.5Hz, 1H), 6.77 (dd, J=3.0,10.5Hz, 1H), 7.16 (d, J=6.9Hz, 1H), 7.25-7.37 (m, 3H); );
13c NMR (75MHz, CDCl
3) δ 21.5,41.3,62.8,66.3,76.9,79.3,123.8,127.3,128.4,129.5,132.8,138.3,138.4,148.9,196.6cm
-1; IR (KBr) 2958,2921,2866,1689,1608,1404,1206,1121,1111,1002,791,706,691,661; HRMS (EI): high resolution mass spectrum calculating value C
15h
16o
3: 244.1099. measured value: 244.1101; Chirality test condition: Daicel Chiralpak AS-H (25cm), normal hexane/Virahol=80/20,1.0mL/min
-1, λ=220nm, t
r(major)=12.22min, t
r(minor)=19.61min.
P10:(4aS, 8aS)-8a-(2-aminomethyl phenyl)-2,3,4a, 5-tetrahydro benzo [b] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia-6 (8aH)-one
P10：(4aS，8aS)-8a-o-tolyl-2，3，4a，5-tetrahydrobenzo[b][1，4]dioxin-6(8aH)-one
White solid, 92%yield, 95%ee.Analytical data for P10:[α]
d 20=+66.6 ° of (c=1.0, CHCl
3) .Mp=107-108 ℃.
1h NMR (300MHz, CDCl
3) δ 2.34-2.52 (m, 2H), 2.75 (s, 3H), 3.79-3.88 (m, 2H), 3.97-4.06 (m, 2H), 4.49-4.51 (m, 1H), 6.49 (d, J=10.2Hz, 1H), 6.79 (dd, J=3.0,10.2Hz, 1H), 7.12-7.15 (m, 1H), 7.24-7.32 (m, 3H);
13c NMR (75MHz, CDCl
3) δ 22.8,41.6,62.4,65.6,75.0,78.5,125.70,128.0,128.8,132.7,133.8,135.3,137.8,149.7,196.7; IR (KBr) 2858,1690,1447,1402,1280,1263,1208,1109,1086,1001,977,921,752,725,687cm
-1; HRMS (EI): high resolution mass spectrum calculating value C
15h
16o
3: 244.1099. measured value: 244.1102. chirality test condition: Daicel ChiralpakAS-H (25cm), normal hexane/Virahol=80/20,1.0mL/min
-1, λ=220nm, t
r(major)=19.98min, t
r(minor)=31.44min.
P11:(4aS, 8aS)-8a-(3,5-3,5-dimethylphenyl)-2,3,4a, 5-tetrahydro benzo [b] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia-6 (8aH)-one
P11：(4aS，8aS)-8a-(3，5-dimethylphenyl)-2，3，4a，5-tetrahydrobenzo[b][1，4]dioxin-6(8aH)-one
White solid, 81%yield, 90%ee.Analytical data for P11:[α]
d 20=+165.2 ° of (c=1.0, CHCl
3) .Mp=130-131 ℃.
1h NMR (300MHz, CDCl
3) δ 2.32 (s, 6H), 2.46 (d, J=2.1Hz, 2H), 3.82-3.91 (m, 3H), (4.04-4.06 m, 2H), 6.47 (d, J=10.5Hz, 1H), 6.76 (dd, J=3.0,10.5Hz, 1H), 6.98 (s, 1H), 7.14 (s, 2H);
13c NMR (75MHz, CDCl
3) δ 21.4,41.4,62.8,66.3,76.9,79.3,124.4,130.4,132.7,138.2,138.4,149.0,196.7; IR (KBr) 2970,2918,2887,1689,1602,1454,1401,1277,1209,1174,1112,1095,1017,1001,925,854,807,703,679cm
-1; HRMS (EI): high resolution mass spectrum calculating value C
16h
18o
3: 258.1256. measured value: 258.1254. chirality test condition: Daicel Chiralpak AS-H (25cm), normal hexane/Virahol=80/20,1.0mL/min
-1, λ=220nm, t
r(major)=8.94min, t
r(minor)=15.36min.
P12:(4aS, 8aS)-8a-(3,5-bis trifluoromethyl phenyl)-2,3,4a, 5-tetrahydro benzo [b] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia-6 (8aH)-one
P12：(4aS，8aS)-8a-(3，5-bis(trifluoromethyl)phenyl)-2，3，4a，5-tetrahydrobenzo[b][1，4]dioxin-6(8aH)-one
Faint yellow oily matter, 93%yield, 88%ee.Analytical data for P12:[α]
d 20=+94.3 ° of (c=1.0, CHCl
3).
1h NMR (400MHz, CDCl
3) δ 2.39-2.58 (m, 2H), 3.91-3.98 (m, 4H), 4.08-4.12 (m, 1H); 6.58 (d, J=10.4Hz, 1H), 6.74 (dd, J=2.4,10.4Hz, 1H), 7.90 (s, 1H), 8.01 (s, 2H);
13c NMR (100MHz, CDCl
3) δ 40.9,62.8,66.3,76.3,78.9,122.8 (m), 123.0 (q, J=272.9), 127.2 (m), 132.1 (q, J=33.5Hz), 134.2,141.6,146.5,195.2;
19f NMR (282MHz, CDCl
3) δ-63.2; IR (KBr) 2965,2924,2869,1698,1625,1464m 1374,1279,1124,1001,897,844,798,706,682,673cm
-1; HRMS (EI): high resolution mass spectrum calculating value: C
16h
12o
3f
6: 366.0691. measured value: 366.0694. chirality test condition: Daicel Chiralpak AS-H (25cm), normal hexane/Virahol=80/20,1.0mL/min
-1, λ=220nm, t
r(major)=7.15min, t
r(minor)=12.57min.
Embodiment 3: the conversion of oxa-Michael product P 4
P13:(4aS, 8aS)-8a-phenyl hexahydrobenzene [b] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia-6 (7H)-one also
P13：(4aS，8aS)-8a-phenylhexahydrobenzo[b][1，4]dioxin-6(7H)-one
Under argon shield, in a dry reaction tubes, add compound P4 (23.0mg, 0.1mmol), methyl alcohol (2mL), 10% palladium carbon (2.3mg). through hydrogen exchange three times, under 1 normal atmosphere, room temperature reaction to raw material disappears.Reaction solution is through diatomite filtration, and uses methanol wash.Desolventizing is revolved in decompression, and residue is through the separated product P 13 (19.7mg, 85%yield, 99%ee) that obtains of plate layer chromatography.
Analytical data for P13:[α]
d 20=+68.5 ° of (c=0.5, CHCl
3) .Mp=90-91 ℃.
1hNMR (300MHz, CDCl
3) δ 1.95-1.98 (m, 1H), 2.29-2.36 (m, 1H), 2.59-2.71 (m, 3H), 3.08 (dd, J=7.2,14.4Hz, 1H), 3.56-3.68 (m, 1H), 3.71-3.80 (m, 2H), 3.96-4.02 (m, 1H), 4.60 (t, J=6.0Hz, 1H), 7.35-7.46 (m, 3H), 7.56-7.59 (m, 2H);
13c NMR (75MHz, CDCl
3) δ 32.1,37.2,42.3,60.6,61.9,74.6,74.8,126.4,128.0,128.8,141.2,208.6; IR (KBr) 2968,2920,2872,1725,1495,1445,1417,1280,1227,1099,1066,966,901,760,705,643,537cm
-1; HRMS (EI): high resolution mass spectrum calculating value C
14h
16o
3: 232.1103. measured value: 232.1099. chirality test condition: Daicel ChiralpakAS-H (25cm), normal hexane/Virahol=80/20,1.0mL/min
-1, λ=220nm, t
r(major)=23.56min, t
r(minor)=36.30min.
P14:(4aS, 8aS)-8a-phenyl-2,3,4a, 5,6,8a-hexahydrobenzene is [b] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia also
P14：(4aS，8aS)-8a-phenyl-2，3，4a，5，6，8a-hexahydrobenzo[b][1，4]dioxine
In a dry reaction tubes, add compound P4 (54.0mg, 0.235mmol), methyl alcohol (3mL) and cerous compounds (106.0mg, 0.285mmol), be cooled to 0 ℃, adds sodium borohydride (18.0mg, 0.285mmol).At 0 ℃, react after 0.5 hour water cancellation, ethyl acetate extraction (3 * 10mL).Organic phase saturated common salt water washing, anhydrous sodium sulfate drying, filters.Decompression is revolved and is desolventized to obtain product alcohol, without purifying, is directly used in next step reaction.
In a dry reaction tubes, add successively compound sodium hydrogen (18.0mg, 0.75mmol) and tetrahydrofuran (THF) (3mL), at room temperature, to tetrahydrofuran (THF) (3mL) solution that drips above-mentioned product alcohol in above-mentioned system.At room temperature react after 30 minutes, add dithiocarbonic anhydride (90.0mg, 1.18mmol), continue reaction after 1 hour, add methyl iodide (64 μ L, 1.04mmol).At room temperature react after 3 hours, saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, merges organic phase, and anhydrous sodium sulfate drying is concentrated.Resistates is through column chromatography (ethyl acetate: sherwood oil=1: 5) separation obtains compound (50.3mg, two step 67% yields).Above-mentioned product is dissolved in dry toluene (4mL) to reflux under argon shield, the toluene solution (3mL) of dropping tributyl tin hydrogen (102 μ L, 0.37mmol) and Diisopropyl azodicarboxylate (5.0mg, 0.03mmol).After back flow reaction 5 hours, be cooled to room temperature, decompression is revolved and is desolventized, and resistates obtains compound P14 (30.2mg, 87%yield, 99%ee) through column chromatography purification (ethyl acetate/petroleum ether, 1: 10).
Analytical data for P14:[α]
d 20=+127.3 ° of (c=1.0, CHCl
3).
1h NMR (400MHz, CDCl
3) δ 1.53-1.61 (m, 1H), 1.66-1.73 (m, 1H), 1.95-2.03 (m, 1H), 2.23-2.33 (m, 1H), 3.69-3.73 (m, 2H), 3.80-3.92 (m, 2H), 3.99-4.06 (m, 1H), 5.59-5.63 (m, 1H), 6.26-6.31 (m, 1H), 7.26-7.35 (m, 3H), 7.55-7.58 (m, 2H);
13c NMR (75MHz, CDCl
3) δ 20.8,24.4,61.9,66.4,76.4,76.5,127.5,127.6,127.6,127.9,132.9,143.2; IR (KBr) 2955,2929,2858,1491,1447,1252,1123,1100,1026,946,908,757,700cm
-1; HRMS (EI): high resolution mass spectrum calculating value C
14h
16o
3: 216.1157. measured value: 216.1150. chirality test condition: Daicel Chiralcel OJ-H (25cm), normal hexane/Virahol=70/30,1.0mL/min
-1, λ=220nm, t
r(major)=13.61min, t
r(minor)=34.86min.
Embodiment 4: the asymmetric synthesis of Herba Clerodendri Indici element (C, D, F)
herba Clerodendri Indici element F
In 250mL reaction flask, add successively p-hydroxyphenylethanol 2 (276mg, 2mmol) and water (32mL), stirring at room is dissolved. slowly add potassium hydrogen persulfate (9.8g in batches, 16mmol) and the mixture of sodium bicarbonate (4.2g, 50mmol), at room temperature react to raw material and disappear. add shrend and go out, ethyl acetate extraction, merge organic phase, anhydrous sodium sulfate drying, filtering and concentrating.Resistates is through plate layer chromatography purifying (ethyl acetate: sherwood oil=2: 1) obtain compound P15 (130mg, 38% productive rate).
1H?NMR(300MHz，D
2O)δ1.98(t，J＝6.9Hz，2H)，3.55(t，J＝6.9Hz，2H)，6.34(d，J＝9.9Hz，2H)，7.09(d，J＝9.9Hz，2H)。
In dry reaction tubes, add successively above-mentioned product P 15 (51.0mg, 0.3mmol), CH
2cl
2(6mL), chiral phosphoric acid catalyzer (22.8mg, 10mol%) and activation
molecular sieve (150mg).At room temperature react 2 hours, through diatomite filtration, washed with dichloromethane.In above-mentioned methylene dichloride filtrate, add (triphenyl phosphite (140mg, 0.45mmol).At room temperature react 0.5h, decompression is revolved and is desolventized, and resistates is through plate layer chromatography purifying (ethyl acetate: sherwood oil=2: (two steps are totally 57% productive rate, 80%ee) 1) to obtain Herba Clerodendri Indici element F.
Analytical data for Herba Clerodendri Indici element F:[α]
d 20=+29 ° of (c=0.2, CH
3oH), [document (Wenderski, T.A.; Huang, S.L.; Pettus, T.R.R.J.Org.Chem.2009,74,4104-4109): [α]
d 20=+59 ° of (c=1.0, CH
3oH)].
1h NMR (300MHz, CDCl
3) δ 2.10-2.31 (m, 2H), 2.48-2.74 (m, 2H), 3.80 (br, 1H), 3.85 (dd, J=8.4,15.0Hz, 1H), 3.99 (dd, J=8.4,15.0Hz, 1H), 4.15 (t, J=4.5Hz, 1H), 5.92 (d, J=9.9Hz, 1H), 6.71 (d, J=9.9Hz, 1H);
13c NMR (75MHz, CDCl
3) δ 39.3,39.9,66.2,75.1,81.2,128.3,148.7,197.6; Chirality test condition: Daicel Chiralpak IC (25cm), normal hexane/Virahol=70/30,0.8mL/min
-1, λ=220nm, t
r(minor)=8.64min, t
r(major)=9.63min.
Under argon shield, in dry reaction pipe, add successively Herba Clerodendri Indici element F (30.3mg, 0.2mmol), methyl alcohol (2mL), 10% palladium carbon (6.0mg).Through hydrogen exchange three times, under 1 normal atmosphere, room temperature reaction to raw material disappears.Through diatomite filtration, and by methanol wash, desolventizing is revolved in decompression, residue through plate layer chromatography (ethyl acetate: sherwood oil=2: 1) purifying obtain product Herba Clerodendri Indici element C (94% productive rate, 81%ee).
Analytical data for Herba Clerodendri Indici element C:[α]
d 20=-50.0 ° of (c=1.0, CH
3oH), [document (Wenderski, T.A.; Huang, S.L.; Pettus, T.R.R.J.Org.Chem.2009,74,4104-4109): [α]
d 20=-79 ° of (c=0.1, CH
3oH)].
1h NMR (300MHz, CDCl
3) δ 2.09-2.13 (m, 4H), 2.22-2.32 (m, 1H), 2.45-2.61 (m, 3H), 2.71-2.78 (m, 1H), 3.87-3.99 (m, 3H);
13cNMR (75MHz, CDCl
3) δ 33.3,35.0,40.4,42.3,65.9,77.3,83.4,210.4; Chirality test condition: 60 ℃-180 ℃ of chiral GC analysis (Rt-β DEX 30m * 0.25mm * 0.25um), 5 ℃/min, 12psi) t
r(major)=51.91min, t
r(minor)=54.49min.
In dry reaction tubes, add successively compound P15 (51.0mg, 0.3mmol), methylene dichloride (6mL), chiral phosphoric acid catalyzer (22.8mg, 10mol%) and activation
molecular sieve (150mg). at room temperature react after 2 hours, be added dropwise to the methanol solution (30 μ L) of benzyltrimethylammonium hydroxide (40%). under room temperature, react after 30 minutes, through diatomite filtration, washed with dichloromethane, decompression is revolved and is desolventized to obtain epoxy compounds (containing chiral phosphoric acid catalyzer), without purifying, be directly used in next step reaction.
In reaction tubes, add successively above-mentioned epoxy compounds, tetrahydrofuran (THF) (4mL), ethanol (1.6mL), water (1.6mL) and saturated sodium bicarbonate (0.4mL), at room temperature add freshly prepd aluminium amalgam.Vigorous stirring reaction, disappears to raw material.Diatomite filtration, washing with alcohol, filtrate extracts through ethyl acetate, merges organic phase.Anhydrous sodium sulfate drying, filters, and under reduced pressure revolves and desolventizes, and resistates obtains compound Herba Clerodendri Indici element D (13.8mg, three steps are totally 27% productive rate) through column chromatography purification (ethyl acetate).
Analytical data for compound P16 (80%ee):
1h NMR (300MHz, CDCl
3) δ 2.12-2.19 (m, 1H), 2.28-2.34 (m, 1H), 2.67-2.97 (m, 2H), 3.98-4.03 (m, 2H), 4.56 (t, J=5.1Hz, 1H), 6.17 (d, J=10.2Hz, 1H), 6.84 (d, J=10.2Hz, 1H), 8.56 (br, 1H);
13cNMR (100MHz, CDCl
3) δ 36.4,41.2,66.1,78.8,86.6,130.7,146.7,197.2; Chirality test condition: Daicel Chiralpak AD-H (25cm), normal hexane/Virahol=80/20,1.0mL/min
-1, λ=220nm, t
r(major)=6.08min, t
r(minor)=7.01min.
Analytical data for Herba Clerodendri Indici element D:[α]
d 20=-63 ° of (c=0.2, CH
3oH), [document [α]
d 20=-38 ° of (c=0.5, CH
3oH); Wenderski, T.A.; Huang, S.L.; Pettus, T.R.R.J.Org.Chem.2009,74,4104-4109.].
1h NMR (400MHz, CDCl
3) δ 2.12-2.16 (m, 2H), 2.63-2.56 (m, 3H), 2.77 (br, 1H), 2.92 (dd, J=3.6,12.6Hz, 1H), 2.94 (br, 1H), (3.89-3.93 m, 1H), 3.99-4.02 (m, 2H), 4.13 (br, 1H);
13c NMR (75MHz, CDCl
3) δ 38.7,41.6,42.2,66.1,70.9,78.6,82.7,207.4.
Claims (8)
1. a furan compound, has following structural formula:
2. the synthetic method of a furan compound as claimed in claim 1, it is characterized in that in-78 ℃ to 100 ℃ and organic solvent, take cyclohexadiene ketone derivatives as raw material, the chiral phosphoric acid oxa-Michael in catalyzer carries out molecule of take reacts 30 minutes-48 hours, and described cyclohexadiene ketone derivatives and the mol ratio of chiral phosphoric acid are 1: 0.01-0.5; Wherein, described cyclohexadienone derivant structure formula is as follows:
the structural formula of described catalyzer is
or
R wherein
1, R
2or X as claimed in claim 1; R
8, R
9, R
10, R
11or R
12be selected from arbitrarily alkyl, thriaryl-silicon, the aryl of H, C1-C16; Described aryl is naphthyl, anthryl or phenanthryl.
3. the method for synthetic furan compound as claimed in claim 2, is characterized in that described organic solvent is benzene, tetracol phenixin, sherwood oil, tetrahydrofuran (THF), dimethyl formamide, ether, methylene dichloride, trichloromethane, toluene, dimethylbenzene, hexanaphthene, normal hexane, normal heptane, dioxane or acetonitrile.
4. the method for synthetic furan compound as claimed in claim 2, is characterized in that products therefrom is through in addition separation and purification of recrystallization, thin-layer chromatography, column chromatography or underpressure distillation.
5. a purposes for furan compound as claimed in claim 1, is characterized in that for the preparation of following structural formula
Compound: Herba Clerodendri Indici element F, Herba Clerodendri Indici element C or Herba Clerodendri Indici element D.
6. purposes as claimed in claim 5, it is characterized in that in organic solvent and room temperature under, described furan compound and reductive agent reaction obtain Herba Clerodendri Indici element F compound for 1-72 hour, described furan compound and the mol ratio of reductive agent are 1: 1-5; Described reductive agent is S-WAT, Sulfothiorine, triphenyl phosphite or triphenyl phosphorus.
7. purposes as claimed in claim 5, it is characterized in that in organic solvent and room temperature under, described furan compound and reductive agent reaction obtain Herba Clerodendri Indici element F compound for 1-72 hour, described furan compound and the mol ratio of reductive agent are 1: 1-5; Described reductive agent is S-WAT, Sulfothiorine, triphenyl phosphite or triphenyl phosphorus; In organic solvent and under room temperature, described Herba Clerodendri Indici element F compound obtains Herba Clerodendri Indici element C compound, described Herba Clerodendri Indici element F compound and palladium carbon 1: 0.01-0.2 for 1-72 hour in the reaction of palladium hydrocarbonize.
8. purposes as claimed in claim 5, it is characterized in that in organic solvent and room temperature under, described furan compound reacts 1-72 hour with salt of wormwood, sodium carbonate or benzyltrimethylammonium hydroxide, then reacts with reductive agent and within 1-72 hour, obtains Herba Clerodendri Indici element D compound; Described reductive agent is triethyl-boron aluminum hydride, aluminium amalgam or Lithium Aluminium Hydride; The mol ratio of described furan compound and salt of wormwood, sodium carbonate or benzyltrimethylammonium hydroxide is 1: 0.1-0.5; Described furan compound and the mol ratio of reductive agent are 1: 1-10.
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Non-Patent Citations (4)
| Title |
|---|
| Jin CHEN,et al..First Total Synthesis of Cleroindicin B, ( ) Cleroindicin C and E.《Chinese Chemical Letters》.2001,第12卷(第9期),771-774. * |
| JinCHEN，etal..FirstTotalSynthesisofCleroindicinB ( ) Cleroindicin C and E.《Chinese Chemical Letters》.2001 |
| Jun Tian,et al..New Cleroindicins from Clerodendrum indicum.《J. Nat. Prod.》.1997,第60卷(第8期),第766-769页. * |
| Todd A. Wenderski, et al..Enantioselective Total Synthesis of All of the Known Chiral Cleroindicins (C-F): Clarification Among Optical Rotations and Assignments.《J. Org. Chem.》.2009,第74卷(第11期),第4104–4109页. * |
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