CN103936753A - Total synthesis method of natural products Daldinin and analogues thereof - Google Patents
Total synthesis method of natural products Daldinin and analogues thereof Download PDFInfo
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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 invention relates to a universal, simple, and effective asymmetrical total synthesis method of natural products Daldinin A, B, and C and analogues thereof. The method comprises the following steps: synthesizing a chiral compound 6-ethylbenzo[1,2-b:5,6-c']difuran-3,8(2H,6H)-dione, introducing different groups to the alpha position of a benzofuran keto-carbonyl group through a nucleophilic reaction; and then carrying out a reduction reaction in the presence of a chiral reducing agent so as to construct a corresponding 2,3-dihydrobenzofuran chiral center to finish the asymmetrical total synthesis of the Daldinin. The synthesis can also be achieved through a route as follows: a compound A is subjected to a reductive elimination reaction so as to obtain optically-pure concentricolide and analogues thereof; and this route is not influenced by the racemization happening on the alkyl branch chains of phthalide lactone during the benzofuran ring establishment reactions. The synthesis method has the advantages of simple and reliable design, and mild reaction conditions, and is suitable for massive preparation. At the same time, the synthesis route has a very good universality. The synthesis method has a very important meaning for asymmetrical synthesis of compounds that take chiral functional groups namely dihydorbenzofuran and benzofuran keto-lactone as the matrix.
Description
Technical field
The invention belongs to the field of chemical synthesis, relate to a class natural product Daldinin A, B, the total synthesis method of the analogue of C and the Dihydrobenzofuranes precursor structure that replaces containing chirality thereof, be particularly useful for need to be on cumarone ring once property build compound complete synthesis of two chiral radicals.
Background technology
2005, the Kunming Institute of Zoology Liu Ji of the Chinese Academy of Sciences opens etc. from pick up from the charcoal coccus of Lijiang Yunnan and has found first Compound C oncentricolide, and in preliminary study, found that it has significantly and the active (X.D.Qing of unique anti HIV-1 virus, 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, a kind of method (One strain many compounds, i.e. OSMAC) that the employings such as Shao Red Army of this study group obtain multiple secondary metabolite by bacterial strain again from charcoal coccus fermented liquid separation obtained a series of hypoxylonin class new compounds
[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): 115 119.).This compounds has cumarone and these two common drug effect functional groups of benzofuranone lactone simultaneously, and is the compound of new framework types, there is no at present the total synthesis method report of simple general use.Due to complete synthesis be medicament research and development must through approach and prerequisite, the complete synthesis research of this compounds has important synthetic method and starts meaning and obvious potential using value.Present inventors in 2013 have set up general, easy, effective total synthesis method of such novel framework compound, and have applied for hypoxylonin and the complete synthesis patent of derivative thereof.China application CN103159776A discloses a kind of natural product hypoxylonin (Concentricolide) and general, the simple and effective racemization of analogue and asymmetric total synthesis method.
On this basis, present inventor is complete synthesis again three hypoxylonin analogue Daldinin A, B, C, and set up the simple and effective method that synthesizes optically pure Dihydrobenzofuranes cyclic cpds by transfer hydrogenation process, such synthetic method have not been reported at present, so the present invention is extremely important to the Dihydrobenzofuranes compounds of synthesis of chiral.It is worth mentioning that, by cumarone ring being carried out to asymmetric hydrogenation reduction, obtained the substituent Dihydrobenzofuranes compounds of chirality, to synthesize this class chipal compounds the most directly and effective means, also be a difficult point always, especially disposable two chiral radicals that obtain single-minded configuration, very difficulty.Only have up to now several pieces of bibliographical informations to cross the synthetic of analogue, and condition is very harsh, is difficult to realize 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.）
Summary of the invention
The object of this invention is to provide a kind of natural product Daldinin A, B, the total synthesis method that C and analogue thereof are general, total synthesis method design route of the present invention is succinct, and reaction raw materials is cheaply easy to get, easy and simple to handle, reaction conditions is gentle, and productive rate good stable, is applicable to fairly large preparation.
The total synthesis method of natural product Daldinin analogue, comprises the steps:
(1) compound 1 reacts with electrophilic reagent under alkaline condition or acidic conditions, obtains compound 2;
(2) compound 2 and chiral reduction reagent carry out carbonyl reduction and react synthetic asymmetric compound A, complete the foundation of chiral centre, obtain suc as formula the natural product Daldinin analogue shown in A;
Wherein, R
1be selected from hydrogen, hydroxyl, alkoxyl group, carbonyl compound, sulfoxide group, phosphoryl, halogen, nitro, C
1～C
18substituted or non-substituted alkyl, substituted or non-substituted aryl, substituted or non-substituted benzyl;
R
2and R
3independently selected from hydrogen, hydroxyl, alkoxyl group, C
1～C
18substituted or non-substituted alkyl, substituted or non-substituted aryl, substituted or non-substituted benzyl;
R
4and R
5independently selected from hydrogen, hydroxyl, alkoxyl group, carbonyl compound, sulfoxide group, phosphoryl, halogen or nitro;
Described natural product Daldinin analogue is R/S configuration.
Further, can also further be prepared suc as formula the natural product Daldinin analogue shown in C and hypoxylonin Concentricolide analogue by the natural product Daldinin analogue suc as formula shown in A, concrete grammar comprises the steps:
(3) suc as formula the natural product Daldinin analogue shown in A, through reduction reaction, slough hydroxyl again and obtain compd B;
(4) compd B under alkaline condition ring opening synthesis suc as formula the natural product Daldinin analogue shown in C;
(5) compd A reduces and eliminates reaction, can obtain optically pure hypoxylonin Concentricolide and analogue thereof, and not be subject in building cumarone functional group reactions process chirality alkyl group side chain on benzene peptide lactones that the impact of racemization may occur.
In general formula II, R wherein
1-R
5to refer to scope the same;
R
6independently selected from carboxyl independently selected from alkoxyl group, hydroxyl, carboxyl, ester group, phosphoryl, aldehyde radical or carbonyl.
As the preferred embodiment of the present invention, described natural product is structure Daldinin A as follows, Daldinin B and Daldinin C;
Wherein, Concentricolide structure is shown in China application CN103159776A.
Particularly, the total synthesis method of natural product Daldinin analogue of the present invention comprises the steps (obtaining plurality of target product) simultaneously:
(1) compound 1 reacts with electrophilic reagent under alkaline condition or acidic conditions, obtains compound 2;
(2) compound 2 and chiral reduction reagent carry out carbonyl reduction and react synthetic asymmetric compound A, complete the foundation of chiral centre, obtain suc as formula the natural product Daldinin analogue shown in A;
(3) suc as formula the natural product Daldinin analogue shown in A, through reduction reaction, slough hydroxyl again and obtain compd B;
(4) compd B under alkaline condition ring opening synthesis suc as formula the natural product Daldinin analogue shown in C;
(5) compd A reduces and eliminates reaction, can obtain optically pure hypoxylonin Concentricolide and analogue thereof.This step can directly prepare optically pure hypoxylonin Concentricolide and analogue thereof with compd A, and particular compound A eliminates and obtains hypoxylonin Concentricolide and analogue through reduction under the effect of boron trifluoride diethyl etherate/triethyl silicane or trifluoroacetic acid/dichloromethane.
Wherein, the open day 2013.6.19 of another China application CN103159776A(that compound 1 of the present invention can be submitted to according to applicant) prepare, the present invention does not repeat them here.
Synthetic method of the present invention, wherein step 1 is specially: under alkaline condition or acidic conditions, compound 1 reacts with electrophilic reagent, introduces R in furans carbonyl ɑ position
5base, obtains compound 2, and described electrophilic reagent is ketone carbonyl reagent, halogen, unsaturated aldehyde ketone, alkene or alkynes, and preferred described ketone carbonyl reagent is acetone, butanone or propione.
In step 1, reaction solvent used is methyl alcohol, Virahol or ethers reagent, and described ethers reagent is selected from ether, tetrahydrofuran (THF) or dioxane; The reagent of described alkaline condition is lithium diisopropylamine, sodium methylate, sodium hydride or potassium hydroxide; Reagent under described acidic conditions is tosic acid, perchloric acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid.
Described step 2 is specially: compound 2 carries out the synthetic asymmetric compound A of carbonyl reduction reaction through chiral reduction reagent, wherein chiral reduction reagent 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].
Wherein, above-mentioned chiral reduction reagent is the disclosed commercially available prod of prior art, and the present invention is not particularly limited this.
Step 2 agents useful for same is tetrahydrofuran (THF), Virahol, and methylene dichloride, formic acid/triethylamine, methyl alcohol or ethanol, compound 2 is 200:1-20 with the mol ratio of chiral reduction reagent.
Step 3 is specially: suc as formula the natural product Daldinin analogue shown in A, under acidic conditions or neutrallty condition, slough hydroxyl, complete the complete synthesis of compd B; Wherein reaction solvent is selected from methyl alcohol, ethanol, and trifluoroacetic acid, methylene dichloride, goes back original reagent and is selected from trifluoroacetic acid, triethyl silicane, tri-phenyl-silane, boron trifluoride diethyl etherate, palladium carbon, trifluoro acid anhydrides.
Wherein, described is 1:1.2:0-40 suc as formula the natural product Daldinin analogue shown in DaldininA and reductive agent and protonic acid mol ratio; Preferably described is 1:1.2:1.5-40 suc as formula the natural product Daldinin analogue shown in DaldininA and reductive agent and protonic acid mol ratio.
Described step 4 is specially: under alkaline condition, compd B completes the complete synthesis of Compound C through open loop, and wherein alkali used is Lithium Aluminium Hydride, potassium hydroxide, sodium hydroxide, sodium hydride, potassium tert.-butoxide, sodium methylate, reaction solvent is methyl alcohol, ethanol, Virahol, toluene, tetrahydrofuran (THF), ether, the mol ratio of compd B and alkali is 1:1.5-4.
Described step 5 is specially: A reduces and eliminates reaction, obtains optically pure hypoxylonin (Concentricolide) analogue.Reagent is boron trifluoride diethyl etherate/triethyl silicane or trifluoroacetic acid/dichloromethane, and its preferred proportion is: boron trifluoride/triethyl silicane/substrate=1.3-8:1.3-15:1; Trifluoroacetic acid/dichloromethane=10-30:1.
The present invention is on the China's application disclosed synthetic compound of CN103159776A 1 route basis, by to furanone ɑ position substitution reaction introduce various groups, and pass through chiral reduction reagent through chirality reduction reaction, the two substituted-dihydro furfuran compound Daldinin A that synthesize chirality, more respectively they are carried out to the reaction of dehydrogenation and furanone lactonic ring hydrolysis and obtain Daldinin B and Daldinin C.
This total synthesis method learning aid has preferably logical adaptive, take compound 1 as basis, can obtain the furans carbonyl compound 2 containing different substituents by nucleophilic substitution, then can synthesize various 2, the 3 Dihydrobenzofuranes analogues containing chiral radicals by the reduction of chiral reduction reagent.Also can obtain optically pure hypoxylonin and analogue by the reduction of compd A is eliminated to reaction, and not be subject to the impact of alkyl group side chain generation racemization on benzene peptide lactones in building the reaction of cumarone ring.The simple and direct complete legal methodology efficiently that the present invention sets up, there is be easy to get cheapness, synthesis of chiral product of easy reliable, the raw material of synthesis condition and reagent and there is the feature (>=97%) of high ee value, for the follow-up deep structure activity relationship of this compounds and activity research have been established solid foundation.
Embodiment
Embodiment 1: preparation Daldinin A
（1）
Under room temperature argon shield, get its preparation of the anhydrous THF of 6mL and 180mg (0.80mmol) compound 1(referring to CN103159776A) in 50mL single port bottle, be placed in low-temp reaction instrument cooling and stirring.At-78 ℃, 0.8mL lithium diisopropyl amido solution is slowly added drop-wise in reaction flask, dropwises rear continuation reaction 30min, and then add 0.2mL acetone, close refrigeration after continuing to stir 30min, slowly rise to stopped reaction after room temperature 2h.Add the saturated NH of 10mL
4cl solution, ether (3 * 10mL) extraction three times, organic layer washs with saturated brine, anhydrous sodium sulfate drying.Filter steaming and desolventize, separated 174mg faint yellow solid 2, the yield 79% of obtaining of silica gel column chromatography; 20mg faint yellow solid 3, yield 9%.
Compound 2
1h-NMR and
13c-NMR data
1H-NMR(400MHz,CDCl
3)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,CDCl
3)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 3
1h-NMR and
13c-NMR data
1H-NMR(400MHz,CDCl
3)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,CDCl
3)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 shield, get 14mg (0.022mmol) Ru (R) – BINAP, 60mg (0.22mmol) compound 2,3mL mixing solutions (HCOOH:Et
3n=5:2) join in 50mL single port bottle, under room temperature, react 7 days.It is complete that TLC detects raw material reaction, in reaction flask, adds 5mL H
2o, uses CH
2cl
2(3 * 10mL) extraction three times, saturated brine washing, anhydrous sodium sulfate drying, column chromatography for separation obtains 40mg oily solid chemical compound Daldinin A, productive rate 65%, ee% value>=99%.
Daldinin A's
1h NMR and
13c-NMR data:
1H-NMR(400MHz,CDCl
3)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,CDCl
3)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: preparation Daldinin B
Under argon shield, get 70mg(0.25mmol) Daldinin A and the anhydrous CH of 2mL
2cl
2in 50mL single port bottle, be placed in and under ice bath, after cooling and stirring 10min, slowly add 0.4mL trimethyl silane and 0.12mL boron trifluoride diethyl etherate.After reaction 1h, TLC detection reaction is complete.Add 10mL saturated sodium bicarbonate solution cancellation reaction, CH
2cl
2(3 * 10mL) extraction three times, anhydrous sodium sulfate drying, column chromatography for separation obtains 46mg Daldinin B (70%)., ee% value >=98%.
Daldinin B's
1h NMR and
13c-NMR data:
1H-NMR(400MHz,CDCl
3)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,CDCl
3)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: preparation Daldinin C
Under nitrogen environment, add 85.0mg Daldinin B in dry 25mL single port bottle, inject the dry THF of 5mL, be placed in frozen water cooling and stirring 30min, add 15mg (1.5equi) LiAlH
4, stirring reaction 30min at 0 ℃, adds the saturated NH of 5ml
4cl solution cancellation reaction.CHCl
3extract three times (3 * 8ml) anhydrous sodium sulfate drying.Filter concentrated solvent, the separated product 78mg Daldinin C (90%) that obtains of silica gel column chromatography.
Daldinin C's
1h NMR and
13c-NMR data:
1H-NMR(400MHz,CDCl
3)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,CDCl
3)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 product Daldinin analog compounds 5
（1）
Under ar gas environment, by 44mg compound 9,2mL ether, 2mL dioxane adds in 50mL single port bottle, and is placed in stirring at 0 ℃.After 15min, slowly drip Br
2(32mg), 1h dropwises, stopped reaction after continuation reaction 30min.Filter, add 5mL water, chloroform extraction, anhydrous sodium sulfate drying, concentrated, through column chromatography for separation, obtain product 55mg(93%).
Compound 4
1h-NMR and
13c-NMR data:
1H-NMR(400MHz,CDCl
3)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,CDCl
3)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 is with the operation of embodiment 10.
Compound 5
1h-NMR and
13c-NMR data:
1H-NMR(400MHz,CDCl
3)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,CDCl
3)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 product Daldinin analog compounds 6
Take compound 560mg, Anhydrous potassium carbonate 138mg, adds in the single port bottle that contains 3mL DMF, at 0 ℃, adds 57mg methyl iodide, then reacts at normal temperatures 12h, and TLC detection reaction is complete.Add 10mL frozen water, ethyl acetate extraction, organic layer is respectively with saturated sodium bicarbonate solution and saturated brine washing, and anhydrous sodium sulfate drying, concentrates, and column chromatography for separation obtains product 57mg, yield 91%.
Compound 6
1h-NMR and
13c-NMR data:
1H-NMR(400MHz,CDCl
3)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 product Daldinin analog compounds 7
Take 60mg compound 5,32.8mg sodium acetate, 2mL acetic anhydride in 50mL single port bottle, being warming up to reflux to continue reaction 30min after raw material disappear, stopped reaction.Add saturated sodium bicarbonate solution washing, chloroform extraction, anhydrous sodium sulfate drying, concentrated.Through column chromatography for separation, obtain product 63mg(90%).
Compound 7
1h-NMR and
13c-NMR data:
1H-NMR(400MHz,CDCl
3)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,CDCl
3)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 product Daldinin analog compounds 10 and 11
Compare with 2 with embodiment 1, distinctive points is only to replace starting compound 1 with compound 8, finally obtains compound 11.The synthetic route following (each reactions steps and condition are with embodiment 1 and 2) of the present embodiment:
Compound 10
1h-NMR and
13c-NMR data:
1h-NMR (400MHz, CDCl
3) δ ppm: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,CDCl
3)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 11
1h-NMR and
13c-NMR data:
1H-NMR(400MHz,CDCl
3)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,CDCl
3)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 product Daldinin analog compounds 14
Compare with embodiment 4, distinctive points is only to replace starting compound 1 with compound 12, the synthetic route following (each reactions steps and condition are with embodiment 4) of the present embodiment:
Compound 14
1h-NMR and
13c-NMR data:
1H-NMR(400MHz,CDCl
3)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,CDCl
3)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 product Daldinin analog compounds 17 and 18
Compare with example 5 with embodiment 4, distinctive points is only to replace starting compound 1 with compound 15, finally obtains the synthetic route following (each reactions steps and condition are with embodiment 4 and example 5) of compound 18. the present embodiment:
Compound 18
1h-NMR and
13the data of C-NMR:
1H-NMR(400MHz,CDCl
3)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,CDCl
3)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: by natural product, DaldininA prepares Concentricolide.
Under argon shield, get 56mg(0.2mmol) Daldinin A and the anhydrous CH of 2mL
2cl
2in 50mL single port bottle, be placed in and under ice bath, after cooling and stirring 10min, slowly add 0.48mL trimethyl silane and 0.18mL boron trifluoride diethyl etherate.After reaction 1h, TLC detection reaction is complete.Add 10mL saturated sodium bicarbonate solution cancellation reaction, CH
2cl
2(3 * 10mL) extraction three times, anhydrous sodium sulfate drying, column chromatography for separation obtains 25mg Concentricolide (62%), ee% value 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 used general explanation, embodiment and test, the present invention is described in detail, on basis of the present invention, can make some modifications or improvements it, and this will be apparent to those skilled in the art.Therefore, these modifications or improvements, all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (11)
1. a total synthesis method for natural product Daldinin analogue, is characterized in that: comprise the steps:
(1) compound 1 reacts with electrophilic reagent under alkaline condition or acidic conditions, obtains compound 2;
(2) compound 2 and chiral reduction reagent carry out carbonyl reduction and react synthetic asymmetric compound A, complete the foundation of chiral centre, obtain suc as formula the natural product Daldinin analogue shown in A;
Wherein, R
1be selected from hydrogen, hydroxyl, alkoxyl group, carbonyl compound, sulfoxide group, phosphoryl, halogen, nitro, C
1～C
18substituted or non-substituted alkyl, substituted or non-substituted aryl, substituted or non-substituted benzyl;
R
2and R
3independently selected from hydrogen, hydroxyl, alkoxyl group, C
1～C
18substituted or non-substituted alkyl, substituted or non-substituted aryl, substituted or non-substituted benzyl;
R
4and R
5independently selected from hydrogen, hydroxyl, alkoxyl group, carbonyl compound, sulfoxide group, phosphoryl, halogen or nitro;
Described natural product Daldinin and analogue can be R or S configuration.
2. total synthesis method according to claim 1, is characterized in that: also comprise the steps:
(3) suc as formula the natural product Daldinin analogue shown in A, through reduction reaction, slough hydroxyl again and obtain compd B;
(4) compd B under alkaline condition ring opening synthesis suc as formula the natural product Daldinin analogue shown in C;
(5) compd A reduces and eliminates reaction, can obtain optically pure hypoxylonin Concentricolide and analogue thereof, and not be subject in building cumarone functional group reactions process chirality alkyl group side chain on benzene peptide lactones that the impact of racemization may occur;
In general formula II, R wherein
1-R
5the scope that refers to claim 1;
R
6independently selected from carboxyl independently selected from alkoxyl group, hydroxyl, carboxyl, ester group, phosphoryl, aldehyde radical or carbonyl.
3. according to the total synthesis method described in claim 1,2 or 3, it is characterized in that, described natural product Daldinin analogue is structure Daldinin A as follows, Daldinin B and Daldinin C;
4. according to the total synthesis method described in any one in claim 1-3, it is characterized in that: described step 1 is specially: under alkaline condition or acidic conditions, compound 1 reacts with electrophilic reagent, in furans carbonyl ɑ position, introduce R
5base, obtains compound 2, and described electrophilic reagent is ketone carbonyl reagent, halogen, unsaturated aldehyde ketone, alkene or alkynes, and preferred described ketone carbonyl reagent is acetone, butanone or propione.
5. according to the total synthesis method described in any one in claim 1-4, it is characterized in that: in step 1, reaction solvent used is methyl alcohol, Virahol or ethers reagent, described ethers reagent is selected from ether, tetrahydrofuran (THF) or dioxane; The reagent of described alkaline condition is lithium diisopropylamine, sodium methylate, sodium hydride or potassium hydroxide; Reagent under described acidic conditions is tosic acid, perchloric acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid.
6. according to the total synthesis method described in any one in claim 1-5, it is characterized in that: described step 2 is specially: compound 2 carries out the synthetic asymmetric compound A of carbonyl reduction reaction through chiral reduction reagent, wherein chiral reduction reagent 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].
7. according to the total synthesis method described in any one in claim 1-6, it is characterized in that: described step 2 agents useful for same is tetrahydrofuran (THF), Virahol, methylene dichloride, formic acid/triethylamine, methyl alcohol or ethanol, compound 2 is 200:1-20 with the mol ratio of chiral reduction reagent.
8. according to the total synthesis method described in claim 2-7 any one, it is characterized in that: described step 3 is specially: suc as formula the natural product Daldinin analogue shown in A, under acidic conditions or neutrallty condition, slough hydroxyl, complete the complete synthesis of compd B; Wherein reaction solvent is selected from methyl alcohol, ethanol, and trifluoroacetic acid, methylene dichloride, goes back original reagent and is selected from trifluoroacetic acid, triethyl silicane, tri-phenyl-silane, boron trifluoride diethyl etherate, hydrogen/palladium carbon, trifluoro acid anhydrides.
9. according to the total synthesis method described in claim 1-8 any one, it is characterized in that: described is 1:1.2:0-40 suc as formula the natural product Daldinin analogue shown in DaldininA and reductive agent and protonic acid mol ratio; Preferably described is 1:1.2:1.5-40 suc as formula the natural product Daldinin analogue shown in DaldininA and reductive agent and protonic acid mol ratio.
10. according to the total synthesis method described in claim 2-9 item, it is characterized in that: described step 4 is specially: under alkaline condition, compd B completes the complete synthesis of Compound C through open loop, wherein alkali used is Lithium Aluminium Hydride, potassium hydroxide, sodium hydroxide, sodium hydride, potassium tert.-butoxide, sodium methylate, reaction solvent is methyl alcohol, ethanol, Virahol, toluene, tetrahydrofuran (THF), ether, the mol ratio of compd B and alkali is 1:1.5-4.
11. according to the total synthesis method described in claim 2-10, it is characterized in that: described step 5 is specially: compd A is eliminated and obtained hypoxylonin Concentricolide and analogue through reduction under the effect of boron trifluoride diethyl etherate/triethyl silicane or trifluoroacetic acid/dichloromethane.
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Citations (2)
| 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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| 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 |
Non-Patent Citations (4)
| Title |
|---|
| D. F. JONES ET AL.: "Microbial Modification of- MycophenoBic Acid", 《J . CHEM. SOC.》 * |
| HONG-JUN SHAO ET AL.: "Induced Daldinin A, B, C with a New Skeleton from Cultures of the Ascomycete Daldinia concentrica", 《J. ANTIBIOT.》 * |
| SAMUEL DANISHEFSKY ET AL.: "Synthesis of dl-Epigriseofulvin", 《J. ORG. CHEM.》 * |
| SEBASTI´AN O. SIMONETTI ET AL.: "Angular tricyclic benzofurans and related natural products of fungal origin. Isolation, biological activity and synthesis", 《NAT. PROD. REP.》 * |
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| CN111763216A (en) * | 2020-07-10 | 2020-10-13 | 新乡医学院 | Annulatins series natural products, preparation method and application thereof |
| CN111763216B (en) * | 2020-07-10 | 2022-10-25 | 新乡医学院 | Annullatins series natural products and preparation method and application thereof |
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