CN103936753B - Natural products Daldinin and the like total synthesis method - Google Patents
Natural products Daldinin and the like total synthesis method Download PDFInfo
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- CN103936753B CN103936753B CN201410110154.6A CN201410110154A CN103936753B CN 103936753 B CN103936753 B CN 103936753B CN 201410110154 A CN201410110154 A CN 201410110154A CN 103936753 B CN103936753 B CN 103936753B
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- ZQWJRFGNGYRWBE-IAPIXIRKSA-N CCC[C@H](c1ccc(C(C(C(C)(C)O)O2)=O)c2c11)OC1=O Chemical compound CCC[C@H](c1ccc(C(C(C(C)(C)O)O2)=O)c2c11)OC1=O ZQWJRFGNGYRWBE-IAPIXIRKSA-N 0.000 description 1
- XJOQPVVSVUTXMN-SNVBAGLBSA-N CCC[C@H](c1ccc(C(CO2)=O)c2c11)OC1=O Chemical compound CCC[C@H](c1ccc(C(CO2)=O)c2c11)OC1=O XJOQPVVSVUTXMN-SNVBAGLBSA-N 0.000 description 1
- AAISPZDKNRTJAF-VXGBXAGGSA-N CCC[C@H](c1ccc(C[C@H](C(C)(C)O)O2)c2c11)OC1=O Chemical compound CCC[C@H](c1ccc(C[C@H](C(C)(C)O)O2)c2c11)OC1=O AAISPZDKNRTJAF-VXGBXAGGSA-N 0.000 description 1
- 0 CCC[C@](c1ccc([C@@]([C@](C(C)(C)*)O2)O)c2c11)OC1=O Chemical compound CCC[C@](c1ccc([C@@]([C@](C(C)(C)*)O2)O)c2c11)OC1=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
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Abstract
The present invention relates to a kind of natural products Daldinin A, B, C and the like general, simple and effective Enantioselective total synthesis method, in the ethylbenzo of synthesizing chiral compound 6 [1,2 b:5,6 c'] difuran 3,8 (2H, 6H) on the basis of dione, different groups are introduced in the ɑ positions of benzofuran ketone carbonyl by necleophilic reaction, again corresponding 2 can be constructed with chiral reducing agent by reduction reaction, 3 Dihydrobenzofuranes chiral centres, complete the Enantioselective total synthesis of such compound, the route can also pass through the reduction elimination reaction to compound A, optically pure Concentricolide and the like is obtained, and not by alkyl side chain generation racemization is influenceed on benzene peptide lactones in the reaction of benzofuran ring is built.The design of this synthetic method is easy to be reliable, reaction condition is gentle, it is suitable for a large amount of preparations, while the route has good versatility, the method is especially significant using the Dihydrobenzofuranes containing chiral functional group and benzofuranone lactone as the Enantioselective total synthesis of the compound of parent to building.
Description
Technical field
The invention belongs to the field of chemical synthesis, it is related to the two of a class natural products Daldinin A, B, C and its substitution containing chirality
The total synthesis method of the analog of hydrogen benzofuran precursor structure, once property is built the needs that are particularly suitable for use on benzofuran ring
The compound of two chiral radicals it is fully synthetic.
Background technology
2005, Chinese Academy of Sciences Kunming Institute of Zoology Liu Ji is opened etc. to be sent out first from the charcoal coccus for picking up from Lijiang Yunnan
Compound Concentricolide is showed, and has been found that it has significantly and unique anti HIV-1 virus activity in Primary Study
（X.D.Qing,Z.J.Dong,J.K.Liu,L.M.Yang,R.R.Wang,Y.T.Zheng,Y.Liu,Y.S.Wu,
Q.T.Zheng,Concentricolide,an Anti-HIV Agent from the Ascomycete Daldinia
concentrica,Helv.Chim.Acta.,2006,89,127-133）；2007, Shao Red Army of the seminar etc. was using by one
Kind of bacterial strain obtains the method (One strain many compounds, i.e. OSMAC) of a variety of secondary metabolites and from charcoal coccus
A series of isolated Concentricolide class noval chemical compounds in zymotic fluid[1]Daldinin A, B, C（H.J.Shao,X.D.Qin,
Z.J.Dong,et al.Induced Daldinin A,B,C with a New Skeleton from Cultures of
the Ascomycete Daldinia concentrica.J.Antibiot.,2008,61(3):115119.）.Such chemical combination
Thing has benzofuran and the two common drug effect functional groups of benzofuranone lactone simultaneously, and is the chemical combination of new framework types
Thing, there is no the total synthesis method of simple general use to report at present.Due to it is fully synthetic be medicament research and development must through approach and premise, it is this kind of
There is important synthetic methodology to start meaning and obvious potential using value for the fully synthetic research of compound.This Shen in 2013
Please inventor establish general, easy, the effective total synthesis method of such novel framework compound, and applied for charcoal coccus
Element and its fully synthetic patent of derivative.China application CN103159776A discloses a kind of natural products Concentricolide
（Concentricolide）And the like general, simple and effective racemization and Enantioselective total synthesis method.
On this basis, present inventor fully synthetic three Concentricolides analog Daldinin A, B, C again, and
The simple and effective method for synthesizing optically pure Dihydrobenzofuranes cycle compound by transfer hydrogenation process is established, at present
Such synthetic method has not been reported, so, the present invention has to the Dihydrobenzofuranes class compound of synthesis of chiral extremely to be weighed
The meaning wanted.It is noted that obtaining the two of chiral substituent by carrying out asymmetric hydrogenation reduction to benzofuran ring
Hydrogen benzofuran compounds, are this kind of chipal compounds of synthesis most direct and effective methods, also always one difficult point, especially
It is two chiral radicals for disposably obtaining single-minded configuration, extremely difficult.Only have several document reports excessively similar so far
The synthesis of thing, and condition is extremely harsh, is difficult under usual terms.（Sajal K D,Gautam P.β-Hydroxy-α-
osyloxy esters as chiral building blocks for the enantioselective synthesis
of benzo-annulated oxa-heterocycles:scope and limitations[J].Tetrahedron,
2008,64:4162-4173；Kuwano R,Sato K,Kurokawa T.et al.Catalytic Asymmetric
Hydrogenation of Heteroaromatic Compounds,Indoles[J].J.Am.Chem.Soc.,2000,122:
7614-7615.）
The content of the invention
It is an object of the invention to provide a kind of natural products Daldinin A, B, C and the like general fully synthetic side
Method, total synthesis method design route of the invention is succinct, and reaction raw materials are cheap and easily-available, easy to operate, and reaction condition is gentle, and production
Rate good stable, is adapted to fairly large preparation.
The total synthesis method of natural products Daldinin analogs, comprises the following steps：
（1）Compound 1 reacts under alkalescence condition or acid condition with electrophilic reagent, obtains compound 2；
（2）Compound 2 carries out carbonyl reduction reaction synthesis asymmetric compound A with chiral reducing agent, during completion is chiral
The foundation of the heart, obtains the natural products Daldinin analogs as shown in formula A；
Wherein, R1Selected from hydrogen, hydroxyl, alkoxy, carbonyls, sulfoxide group, phosphoryl, halogen, nitro, C1~C18Take
Generation or non-substituted alkyl, substituted or non-substituted aryl, substituted or non-substituted benzyl;
R2And R3Independently selected from hydrogen, hydroxyl, alkoxy, C1~C18It is substituted or non-substituted alkyl, substituted or non-substituted
Aryl, substituted or non-substituted benzyl；
R4And R5Independently selected from hydrogen, hydroxyl, alkoxy, carbonyls, sulfoxide group, phosphoryl, halogen or nitro；
The natural products Daldinin analogs are R/S configurations.
Further, can also further it be prepared such as formula C as the natural products Daldinin analogs as shown in formula A
Shown natural products Daldinin analogs and Concentricolide Concentricolide analogs, specific method is included such as
Lower step：
（3）Natural products Daldinin analogs as shown in formula A slough hydroxyl through reduction reaction again and obtain compound B；
（4）Open loop synthesizes natural products Daldinin analogs as shown in formula C to compound B in the basic conditions；
（5）Compound A carry out reduction elimination reaction, can obtain optically pure Concentricolide Concentricolide and
Its analog, and not by outside chiral alkyl side chain may occur on benzene peptide lactones during structure benzofuran functional group reactionses
The influence of racemization.
In formula II, wherein R1-R5Reference scope ibid；
R6Independently selected from carboxyl independently selected from alkoxy, hydroxyl, carboxyl, ester group, phosphoryl, aldehyde radical or carbonyl.
As the preferred embodiment of the present invention, described natural products is structure Daldinin A as follows,
Daldinin B and Daldinin C；
Wherein, Concentricolide structures are shown in China application CN103159776A.
Specifically, the total synthesis method of natural products Daldinin analogs of the present invention, comprises the following steps（Together
When obtain plurality of target product）：
（1）Compound 1 reacts under alkalescence condition or acid condition with electrophilic reagent, obtains compound 2；
（2）Compound 2 carries out carbonyl reduction reaction synthesis asymmetric compound A with chiral reducing agent, during completion is chiral
The foundation of the heart, obtains the natural products Daldinin analogs as shown in formula A；
（3）Natural products Daldinin analogs as shown in formula A slough hydroxyl through reduction reaction again and obtain compound B；
（4）Open loop synthesizes natural products Daldinin analogs as shown in formula C to compound B in the basic conditions；
（5）Compound A carry out reduction elimination reaction, can obtain optically pure Concentricolide Concentricolide and
Its analog.The step can directly prepare optically pure Concentricolide Concentricolide and its class with compound A
Like thing, particular compound A disappears in the presence of BFEE/triethyl silicane or trifluoroacetic acid/dichloromethane through reduction
Except obtaining Concentricolide Concentricolide and the like.
Wherein, another China's application CN103159776A that compound 1 of the present invention can be submitted according to applicant（It is public
Open a day 2013.6.19）Prepare, the present invention will not be repeated here.
Synthetic method of the present invention, wherein step 1 are specially：Under alkalescence condition or acid condition, compound 1 and parent
Electric reagent reacting, in ɑ introducing R of furanylcarbonyl5Base, obtains compound 2, and the electrophilic reagent is ketone carbonyl reagent, halogen, no
Saturation aldehyde ketone, alkene or alkynes, preferably described ketone carbonyl reagent are acetone, butanone or propione.
Reaction dissolvent used is methanol, isopropanol or ethers reagent in step 1, and the ethers reagent is selected from ether, tetrahydrochysene
Furans or dioxane；The reagent of the alkalescence condition is lithium diisopropylamine, sodium methoxide, sodium hydride or potassium hydroxide；Institute
It is p-methyl benzenesulfonic acid, perchloric acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid to state the reagent under acid condition.
The step 2 is specially：The chiral go back original reagent of compound 2 carries out carbonyl reduction reaction synthesis asymmetric compound
A, wherein chiral reducing agent used be Ipc2BH, Corey-Bakshi-Shibata reagent, Ipc2BCl, BINAL-H,
BINAP-Ru, RuCl (p-cymene) [(R, R)-Ts-DPEN] or RuCl (p-cymene) [(S, S)-Ts-DPEN].
Wherein, above-mentioned chiral reducing agent is commercially available prod disclosed in prior art, and the present invention does not make especially limit to this
It is fixed.
Step 2 agents useful for same is tetrahydrofuran, isopropanol, dichloromethane, formic acid/triethylamine, methanol or ethanol, compound
2 be 200 with the mol ratio of chiral reducing agent:1-20.
Step 3 is specially：Natural products Daldinin analogs as shown in formula A are in acid condition or neutrallty condition
Under, hydroxyl is sloughed, the fully synthetic of compound B is completed；Wherein reaction dissolvent be selected from methanol, ethanol, trifluoroacetic acid, dichloromethane,
Go back original reagent is selected from trifluoroacetic acid, triethyl silicane, tri-phenyl-silane, BFEE, palladium carbon, trifluoro acid anhydrides.
Wherein, the natural products Daldinin analogs as shown in formula DaldininA rub with reducing agent and Bronsted acid
You are than being 1：1.2：0-40;It is preferred that the natural products Daldinin analogs as shown in formula DaldininA and reducing agent and
Bronsted acid mol ratio is 1：1.2：1.5-40.
Described step 4 is specially：Under alkalescence condition, compound B completes the fully synthetic of compound C by open loop, wherein
Alkali used be Lithium Aluminium Hydride, potassium hydroxide, sodium hydroxide, sodium hydride, potassium tert-butoxide, sodium methoxide, reaction dissolvent is methanol, second
The mol ratio of alcohol, isopropanol, toluene, tetrahydrofuran, ether, compound B and alkali is 1:1.5-4.
The step 5 is specially：A carries out reduction elimination reaction, obtains optically pure Concentricolide
(Concentricolide) analog.Reagent is BFEE/triethyl silicane or trifluoroacetic acid/dichloromethane, and its is excellent
The ratio is selected to be：Boron trifluoride/triethyl silicane/substrate=1.3-8：1.3-15：1；Trifluoroacetic acid/dichloromethane=10-30：1.
The present invention is on the basis of the synthesis route of compound 1 disclosed in China application CN103159776A, by furanone ɑ
Position substitution reaction introduces various groups, and by the chiral reduction reaction of chiral reducing agent, synthesizes two substitutions two of chirality
Hydrogen furfuran compound Daldinin A, then it is to obtain to carry out dehydrogenation and the reaction of furanone lactonic ring hydrolysis to them respectively
Daldinin B and Daldinin C.
The total synthesis method learning aid has preferably logical adaptive, based on compound 1, can be contained by nucleophilic displacement of fluorine
The furanylcarbonyl compound 2 of different substituents, then by chiral reducing agent reduce can synthesize it is various containing chiral radicals 2,3
Dihydrobenzofuranes analog.Also optically pure Concentricolide can be obtained and similar by the reduction elimination reaction to compound A
Thing, and not by alkyl side chain generation racemization is influenceed on benzene peptide lactones in the reaction of benzofuran ring is built.The present invention is built
Vertical simple and direct efficient full legal manner, with the easy reliable, raw material of synthesis condition and reagent be easy to get inexpensively, synthesis of chiral produces
The characteristics of thing has high ee values（≥97%）, it is that the subsequently deep structure-activity relationship of such compound and activity research have established solid
Basis.
Embodiment
Embodiment 1：Prepare Daldinin A
（1）
Under the protection of room temperature argon gas, 6mL anhydrous THF and 180mg (0.80mmol) compound 1 is taken（Its prepare referring to
CN103159776A）In 50mL single port bottles, low-temp reaction instrument cooling and stirring is placed in.By 0.8mL diisopropyl amidos at -78 DEG C
Lithium solution is slowly dropped in reaction bulb, is continued to react 30min after completion of dropping, is then added 0.2mL acetone, continues to stir
Refrigeration is closed after 30min, is slowly increased to after room temperature 2h stop reaction.Add 10mL saturations NH4Cl solution, ether (3 × 10mL)
Extraction three times, organic layer is washed with saturated brine, anhydrous sodium sulfate drying.Solvent is evaporated off in filtering, and silica gel column chromatography is separated
174mg faint yellow solids 2, yield 79%；20mg faint yellow solids 3, yield 9%.
Compound 21H-NMR and13C-NMR data
1H-NMR(400MHz,CDCl3)δppm:1.01(3H,t,J=7.2Hz),1.26(6H,s),1.81(1H,m),2.10
(1H,m),4.46(1H,s),5.37(1H,s),5.42(1H,dd,J=4.4,7.2Hz),6.96(1H,d,J=7.6Hz),7.70
(1H,d,J=7.6Hz).
13C-NMR(100MHz,CDCl3)δppm:8.9,25.2,27.6,28.7,71.5,82.7,91.1,109.7,
114.3,131.9,132.3,152.7,156.8,168.4,196.5.
Compound 31H-NMR and13C-NMR data
1H-NMR(400MHz,CDCl3)δppm:1.00(3H,t,J=7.2Hz),1.76(6H,s),1.91(1H,m),2.10
(1H,m),5.40(1H,dd,J=4.4,7.2Hz),6.99(1H,d,J=7.6Hz),7.78(1H,d,J=7.6Hz).
13C-NMR(100MHz,CDCl3)δppm:8.9,25.2,27.6,28.7,82.7,109.4,114.7,131.6,
132.3,140.9,145.6,152.8,156.5,167.4,194.5.
（2）
Under argon gas protection, 14mg (0.022mmol) Ru (R)-BINAP, 60mg (0.22mmol) compound 2 is taken, 3mL is mixed
Close solution (HCOOH:Et3N=5:2) it is added in 50mL single port bottles, reacts 7 days at room temperature.TLC detection raw material reactions are finished, to
5mL H are added in reaction bulb2O, uses CH2Cl2(3 × 10mL) is extracted three times, saturated brine washing, anhydrous sodium sulfate drying, post layer
Analysis separates to obtain 40mg oily solid chemical compound Daldinin A, yield 65%, ee% value >=99%.
Daldinin A's1H NMR and13C-NMR data：
1H-NMR(400MHz,CDCl3)δppm:1.02(3H,t,J=7.2Hz),1.62(6H,s),1.81(1H,m),2.10
(1H,m),4.12(1H,m),4.46(1H,d),4.90(1H,s),5.37(1H,t,J=6.8Hz),5.42(1H,dd,J=4.4,
7.2Hz),6.96(1H,d,J=7.6Hz),7.70(1H,d,J=7.6Hz).
13C-NMR(100MHz,CDCl3)δppm:8.9,25.0,27.8,28.7,71.5,73.1,82.7,91.1,
109.7,114.3,131.9,132.3,152.7,156.8,168.4.
Embodiment 2：Prepare Daldinin B
Under argon gas protection, 70mg is taken（0.25mmol）The anhydrous CH of Daldinin A and 2mL2Cl2In 50mL single port bottles, put
In being slowly added to 0.4mL trimethyl silanes and 0.12mL BFEEs after cooling and stirring 10min under ice bath.React after 1h
TLC detection reactions are finished.Add 10mL saturated sodium bicarbonate solutions and reaction, CH is quenched2Cl2(3 × 10mL) is extracted three times, anhydrous
Sodium sulphate is dried, and column chromatography for separation obtains 46mg Daldinin B (70%)., ee% value >=98%.
Daldinin B's1H NMR and13C-NMR data：
1H-NMR(400MHz,CDCl3)δppm:0.97(3H,t,J=7.2Hz),1.25(3H,s),1.34(3H,s),
1.84-1.74(1H,m),2.18-2.09(1H,m),3.26(2H,d,J=8.8Hz),3.36(2H,d,J=8.8Hz),4.87
(1H,t,J=8.8Hz),5.50(1H,s),6.96(1H,d,J=7.2Hz),7.53(1H,d,J=7.2Hz).
13C-NMR(100MHz,CDCl3)δppm:9.1,25.1,25.4,28.9,30.5,72.6,84.5,93.6,
109.3,114.5,130.9,132.5,151.7,159.1,171.2.
Embodiment 3：Prepare Daldinin C
Under nitrogen environment, 85.0mg Daldinin B are added in dry 25mL single port bottles, and injection 5mL is dried
THF, is placed in cooling and stirring 30min in frozen water, adds 15mg (1.5equi) LiAlH4, stirring reaction 30min at 0 DEG C adds
5ml saturations NH4Reaction is quenched in Cl solution.CHCl3Extract three times (3 × 8ml), anhydrous sodium sulfate drying.Filtering, concentrated solvent, silicon
Glue chromatography obtains product 78mg Daldinin C (90%).
Daldinin C's1H NMR and13C-NMR data：
1H-NMR(400MHz,CDCl3)δppm:0.94(3H,t,J=7.4Hz),1.20(3H,s),1.30(3H,s),1.77
(2H,m),3.10(1H,dd,J=16.0,9.6Hz),3.25(1H,dd,J=8.5,16.0Hz),4.58(1H,dd,J=8.5,
9.4Hz),4.71(2H,s),4.88(1H,dd,J=6.3,7.2Hz),6.95(1H,d,J=7.6Hz),7.09(1H,d,J=
7.6Hz).
13C-NMR(100MHz,CDCl3)δppm:11.0,24.8,25.7,31.4,32.4,58.7,72.6,72.7,
90.2,119.2,120.0,125.3,127.0,144.4,159.8.
Embodiment 4：Prepare natural products Daldinin analog compounds 5
（1）
Under ar gas environment, by 44mg compounds 9,2mL ether, 2mL dioxane is added in 50mL single port bottles, is placed in 0
Stirred at DEG C.Br is slowly added dropwise after 15min2（32mg）, 1h completion of dropping, continuation, which is reacted, stops reaction after 30min.Filtering, plus
Enter 5mL water, chloroform extraction, anhydrous sodium sulfate drying, concentration obtains product 55mg through column chromatography for separation（93%）.
Compound 41H-NMR and13C-NMR data：
1H-NMR(400MHz,CDCl3)δppm:1.01(3H,t,J=7.2Hz),1.91(1H,m),2.08(1H,m),5.38
(1H,dd,J=4.4,7.2Hz),6.96(1H,d,J=7.6Hz),7.02(1H,s),7.70(1H,d,J=7.6Hz).
13C-NMR(100MHz,CDCl3)δppm:8.9,28.7,82.7,97.1,109.7,114.3,131.9,132.3,
152.7,156.8,168.4,196.5.
（2）
Use the operation of be the same as Example 10.
Compound 51H-NMR and13C-NMR data：
1H-NMR(400MHz,CDCl3)δppm:0.98(3H,t,J=7.2Hz),1.96(1H,m),2.08(1H,m),3.67
(1H,d,J=7.2Hz),5.37(1H,m),5.41(1H,dd,J=4.4,7.2Hz),6.10(1H,d,J=6.8Hz),6.96(1H,
d,J=7.6Hz),7.40(1H,d,J=7.6Hz).
13C-NMR(100MHz,CDCl3)δppm:9.9,28.7,82.3,87.1,87.8,119.7,124.3,131.9,
132.3,152.7,156.8,168.4.
Embodiment 5：Prepare natural products Daldinin analog compounds 6
Weigh Compound 560mg, Anhydrous potassium carbonate 138mg, are added in the single port bottle containing 3mL DMF, in 0 DEG C of addition
57mg iodomethane, then reacts 12h at normal temperatures, and TLC detection reactions are complete.10mL frozen water is added, ethyl acetate extraction is organic
Layer is washed with saturated sodium bicarbonate solution and saturated brine respectively, anhydrous sodium sulfate drying, and concentration, column chromatography for separation obtains product
57mg, yield 91%.
Compound 61H-NMR and13C-NMR data：
1H-NMR(400MHz,CDCl3)δppm:0.98(3H,t,J=7.2Hz),1.98(1H,m),2.08(1H,m),3.17
(3H,s),5.07(1H,d,J=7.2Hz),5.40(1H,dd,J=4.4,7.2Hz),6.34(1H,d,J=7.2Hz),6.98(1H,
d,J=7.6Hz),7.39(1H,d,J=7.6Hz).13C-NMR(100MHz,CDCl3)δppm:10.2,28.5,56.7,82.4,
84.1,97.8,114.7,117.3,121.9,132.3,145.7,156.8,168.4.
Embodiment 6：Prepare natural products Daldinin analog compounds 7
60mg compounds 5 are weighed, 32.8mg sodium acetates, 2mL acetic anhydride is warming up to backflow and continues anti-in 50mL single port bottles
Answer raw material after 30min to disappear, stop reaction.Saturated sodium bicarbonate solution washing is added, chloroform is extracted, anhydrous sodium sulfate drying,
Concentration.Product 63mg is obtained through column chromatography for separation（90%）.
Compound 71H-NMR and13C-NMR data：
1H-NMR(400MHz,CDCl3)δppm:0.95(3H,t,J=7.2Hz),1.98(1H,m),2.10(1H,m),2.27
(3H,s),5.42(1H,dd,J=4.4,7.2Hz),6.07(1H,d,J=7.2Hz),6.54(1H,d,J=7.2Hz),6.96(1H,
d,J=7.6Hz),7.41(1H,d,J=7.6Hz).
13C-NMR(100MHz,CDCl3)δppm:10.2,21.7,28.3,82.0,84.1,90.8,114.7,118.3,
124.9,132.3,145.5,160.8,168.4,170.3.
Embodiment 7：Prepare natural products Daldinin analog compounds 10 and 11
Compared with Examples 1 and 2, distinctive points are only that replaces starting compound 1 with compound 8, finally gives compound
11.The synthetic route of the present embodiment is following (each reactions steps and condition be the same as Example 1 and 2):
Compound 101H-NMR and13C-NMR data：1H-NMR(400MHz,CDCl3)δppm:0.98(3H,t,J=
7.2Hz),1.34(2H,m),1.37(3H,s),1.42(3H,s),1.81(1H,m),2.10(1H,m),4.12(1H,m),4.46
(1H,d),4.92(1H,s),5.33(1H,t,J=6.8Hz),5.42(1H,dd,J=4.4,7.2Hz),6.96(1H,d,J=
7.6Hz),7.40(1H,d,J=7.6Hz).
13C-NMR(100MHz,CDCl3)δppm:8.9,25.0,27.8,28.7,35.7,72.5,73.1,82.7,91.1,
109.7,114.3,131.9,132.3,152.7,156.8,168.4.
Compound 111H-NMR and13C-NMR data：
1H-NMR(400MHz,CDCl3)δppm:0.97(3H,t,J=7.2Hz),1.25(3H,s),1.34(3H,s),1.37
(2H,m),1.74-1.84(1H,m),2.09-2.18(1H,m),3.26(2H,d,J=8.8Hz),3.36(2H,d,J=8.8Hz),
4.87(1H,t,J=8.8Hz),5.50(1H,s),6.96(1H,d,J=7.2Hz),7.43(1H,d,J=7.2Hz).13C-NMR
(100MHz,CDCl3)δppm:9.1,18.9,25.1,25.4,28.9,37.5,72.6,84.5,93.6,109.3,114.5,
130.9,132.5,151.7,159.1,171.2.
Embodiment 8：Prepare natural products Daldinin analog compounds 14
Compared with Example 4, distinctive points are only that replaces starting compound 1, the synthesis road of the present embodiment with compound 12
Line is following (each reactions steps and condition be the same as Example 4):
Compound 141H-NMR and13C-NMR data：
1H-NMR(400MHz,CDCl3)δppm:0.91(3H,t,J=7.2Hz),1.26-1.30(6H,m),1.96(1H,
m),2.08(1H,m),3.67(1H,s),5.37(1H,m),5.41(1H,dd,J=4.4,7.2Hz),6.10(1H,d,J=
6.8Hz),7.40(1H,s).13C-NMR(100MHz,CDCl3)δppm:9.9,18.7,23.6,28.7,31.2,82.3,87.1,
87.8,119.7,124.3,134.9,142.3,152.7,158.8,167.8.
Embodiment 9：Prepare natural products Daldinin analog compounds 17 and 18
Compared with embodiment 4 and example 5, distinctive points are only that replaces starting compound 1 with compound 15, finally gives chemical combination
The synthetic route of the present embodiment of thing 18. is following (each reactions steps and condition be the same as Example 4 and example 5):
Compound 181H-NMR and13C-NMR data：
1H-NMR(400MHz,CDCl3)δppm:1.68(3H,m),2.34(3H,s),3.17(3H,s),5.07(1H,d,J=
7.2Hz),5.40(1H,dd,J=4.4,7.2Hz),6.34(1H,d,J=7.2Hz),6.98(1H,s).
13C-NMR(100MHz,CDCl3)δppm:18.2,20.5,52.4,79.8,84.7,96.4,114.7,117.3,
121.9,132.3,145.7,160.8,167.4.
Embodiment 10：Concentricolide. is prepared by natural products DaldininA
Under argon gas protection, 56mg is taken（0.2mmol）The anhydrous CH of Daldinin A and 2mL2Cl2In 50mL single port bottles, it is placed in
0.48mL trimethyl silanes and 0.18mL BFEEs are slowly added under ice bath after cooling and stirring 10min.React TLC after 1h
Detection reaction is finished.Add 10mL saturated sodium bicarbonate solutions and reaction, CH is quenched2Cl2(3 × 10mL) is extracted three times, anhydrous slufuric acid
Sodium is dried, and column chromatography for separation obtains 25mg Concentricolide (62%), ee% values 99.3%.
1H-NMR(400MHz,CDCl3)δppm:0.99(3H,t,J=7.2Hz),1.79-1.90(1H,m),2.14-2.20
(1H,m),5.56(1H,dd,J=4.0,7.2Hz),6.89(1H,d,J=2.2Hz),7.26(1H,d,J=2.2Hz),7.79(1H,
d,J=8.0Hz),7.90(1H,d,J=8.0Hz).13C-NMR(100MHz,CDCl3)δppm:8.9,28.0,82.9,106.6,
111.1,116.2,128.0,128.9,146.8,147.9,149.8,168.2.
Although above having made to retouch in detail to the present invention with general explanation, embodiment and experiment
State, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, are belonged to claimed
Scope.
Claims (16)
1. a kind of total synthesis method of natural products Daldinin analogs, it is characterised in that：Comprise the following steps：
(1) compound 1 reacts under alkalescence condition or acid condition with electrophilic reagent, obtains compound 2；
(2) compound 2 carries out carbonyl reduction reaction synthesis asymmetric compound A with chiral reducing agent, completes chiral centre
Set up, obtain the natural products Daldinin analogs as shown in formula A；
Wherein, R1Selected from C1~C18Alkyl；
R2And R3Independently selected from hydrogen or C1~C18Alkyl；
R4For hydroxyl, R5For halogen；
Described natural products Daldinin and the like can be R or S configurations；
The reagent of the alkalescence condition is lithium diisopropylamine, sodium methoxide, sodium hydride or potassium hydroxide；Under the acid condition
Reagent be p-methyl benzenesulfonic acid, perchloric acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid；The electrophilic reagent be ketone carbonyl reagent, halogen,
Unsaturated aldehyde ketone, alkene or alkynes；
Chiral reducing agent used is Ipc2BH, Corey-Bakshi-Shibata reagent, Ipc2BCl, BINAL-H, BINAP-
Ru, RuCl (p-cymene) [(R, R)-Ts-DPEN] or RuCl (p-cymene) [(S, S)-Ts-DPEN].
2. a kind of total synthesis method of natural products Daldinin analogs, it is characterised in that：Described natural products
Daldinin analogs are structure Daldinin A, Daldinin B as follows；
Synthetic route is as follows：
(1) compound 1 reacts under alkalescence condition or acid condition with electrophilic reagent, obtains compound 2；
(2) compound 2 carries out carbonyl reduction reaction with chiral reducing agent, completes the foundation of chiral centre, obtains Daldinin
A；
(3) Daldinin A slough hydroxyl through reduction reaction, obtain Daldinin B；
The reagent of the alkalescence condition is lithium diisopropylamine, sodium methoxide, sodium hydride or potassium hydroxide；Under the acid condition
Reagent be p-methyl benzenesulfonic acid, perchloric acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid；The electrophilic reagent be ketone carbonyl reagent, halogen,
Unsaturated aldehyde ketone, alkene or alkynes；
Chiral reducing agent used is Ipc2BH, Corey-Bakshi-Shibata reagent, Ipc2BCl, BINAL-H, BINAP-
Ru, RuCl (p-cymene) [(R, R)-Ts-DPEN] or RuCl (p-cymene) [(S, S)-Ts-DPEN].
3. a kind of total synthesis method of natural products Daldinin analogs, it is characterised in that：Described natural products
Daldinin analogs are structure Daldinin C as follows；
Its synthetic method is：
Under nitrogen environment, 85.0mg Daldinin B are added in dry 25mL single port bottles, and the THF that injection 5mL is dried is put
The cooling and stirring 30min in frozen water, adds 15mgLiAlH4, stirring reaction 30min at 0 DEG C adds 5ml saturations NH4Cl solution is quenched
Go out reaction, CHCl3Extraction three times, each 8ml, anhydrous sodium sulfate drying, filtering, concentrated solvent, silica gel column chromatography separates to obtain product
Daldinin C。
4. total synthesis method according to claim 1, it is characterised in that：Also comprise the following steps：
(3) the natural products Daldinin analog compounds A as shown in formula A sloughs hydroxyl through reduction reaction again and obtains compound
B；
(4) open loop synthesizes natural products Daldinin analogs as shown in formula C to compound B in the basic conditions；
(5) the natural products Daldinin analog compounds A as shown in formula A carries out reduction elimination reaction, obtains optically pure
Concentricolide Concentricolide and the like, and not by during benzofuran functional group reactionses are built in benzene peptide
The influence of racemization may occur for chiral alkyl side chain on ester；
In compound A, wherein R1-R5Reference scope with claim 1；
R6Independently selected from alkoxy, hydroxyl, ester group, phosphoryl, aldehyde radical or carbonyl.
5. total synthesis method according to claim 1 or 2, it is characterised in that：Described step 1 is specially：Alkalescence condition
Or under acid condition, compound 1 is reacted with electrophilic reagent, in ɑ introducing R of furanylcarbonyl5Base, obtains compound 2, described electrophilic
Reagent is ketone carbonyl reagent, halogen, unsaturated aldehyde ketone, alkene or alkynes.
6. total synthesis method according to claim 5, it is characterised in that：The ketone carbonyl reagent is acetone, butanone or 3-
Pentanone.
7. the total synthesis method according to any one of claim 1,2,4,6, it is characterised in that：It is used in step 1 to react
Solvent is methanol, isopropanol or ethers reagent, and the ethers reagent is selected from ether, tetrahydrofuran or dioxane.
8. total synthesis method according to claim 5, it is characterised in that：Reaction dissolvent used is methanol, isopropyl in step 1
Alcohol or ethers reagent, the ethers reagent are selected from ether, tetrahydrofuran or dioxane.
9. the total synthesis method according to claim 1 or 4, it is characterised in that：The step 2 is specially：Compound 2 is handled
Property go back original reagent carry out carbonyl reduction reaction synthesis asymmetric compound A.
10. the total synthesis method according to any one of claim 1,2,4,6 or 8, it is characterised in that：Step 2 institute
It is tetrahydrofuran, isopropanol, dichloromethane, formic acid/triethylamine, methanol or ethanol with solvent, compound 2 and chiral reducing agent
Mol ratio be 200:1-20.
11. total synthesis method according to claim 4, it is characterised in that：The step 3 is specially：Day as shown in formula A
Right product Daldinin analog compounds A sloughs hydroxyl under acid condition or neutrallty condition, completes the complete of compound B
Synthesis；Wherein reaction dissolvent is selected from methanol, and ethanol, trifluoroacetic acid, dichloromethane, go back original reagent is selected from trifluoroacetic acid, triethyl group
Silane, tri-phenyl-silane, BFEE, hydrogen/palladium carbon, trifluoro acid anhydrides.
12. total synthesis method according to claim 2, it is characterised in that：In reduction reaction described in step 3,
DaldininA is 1 with reducing agent and Bronsted acid mol ratio：1.2：0-40.
13. total synthesis method according to claim 12, it is characterised in that：In reduction reaction described in step 3,
DaldininA is 1 with reducing agent and Bronsted acid mol ratio：1.2：1.5-40.
14. the total synthesis method according to claim 4 or 11, it is characterised in that：Described step 4 is specially：Alkaline bar
Under part, compound B completes the fully synthetic of compound C by open loop, wherein alkali used is Lithium Aluminium Hydride, potassium hydroxide, hydroxide
Sodium, sodium hydride, potassium tert-butoxide, sodium methoxide, reaction dissolvent is methanol, ethanol, isopropanol, toluene, tetrahydrofuran, ether, chemical combination
The mol ratio of thing B and alkali is 1:1.5-4.
15. the total synthesis method according to claim 4 or 11, it is characterised in that：The step 5 is specially：As shown in formula A
Natural products Daldinin analog compounds A in BFEE/triethyl silicane or trifluoroacetic acid/dichloromethane
Under effect Concentricolide Concentricolide and the like is obtained through reducing elimination.
16. total synthesis method according to claim 14, it is characterised in that：The step 5 is specially：As shown in formula A
Natural products Daldinin analog compounds A is in BFEE/triethyl silicane or the work of trifluoroacetic acid/dichloromethane
With it is lower through reduce elimination obtain Concentricolide Concentricolide and the like.
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|---|---|---|---|---|
| CN1537855A (en) * | 2003-10-22 | 2004-10-20 | �й���ѧԺ����ֲ���о��� | Hypoxylonin and its preparation method and application |
| CN103159776A (en) * | 2013-03-11 | 2013-06-19 | 新乡医学院 | Total synthesis method of natural active product concentricolide and its analogue |
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2014
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1537855A (en) * | 2003-10-22 | 2004-10-20 | �й���ѧԺ����ֲ���о��� | Hypoxylonin and its preparation method and application |
| CN103159776A (en) * | 2013-03-11 | 2013-06-19 | 新乡医学院 | Total synthesis method of natural active product concentricolide and its analogue |
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| Angular tricyclic benzofurans and related natural products of fungal origin. Isolation, biological activity and synthesis;Sebasti´an O. Simonetti et al.;《Nat. Prod. Rep.》;20130530;第30卷;第941-969页 * |
| Induced Daldinin A, B, C with a New Skeleton from Cultures of the Ascomycete Daldinia concentrica;Hong-Jun Shao et al.;《J. Antibiot.》;20081231;第61卷(第3期);第115-119页 * |
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