CN110156738A - A kind of total synthesis method of Yi Lu alkane type sequiterpene reaction intermediate and natural products - Google Patents
A kind of total synthesis method of Yi Lu alkane type sequiterpene reaction intermediate and natural products Download PDFInfo
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Abstract
The invention belongs to the synthesis fields of Yi Lu alkane type (Illudalane) sequiterpene, more particularly to a kind of Yi Lu alkane type sequiterpene reaction intermediate and the total synthesis method of natural products, the total synthesis method is for synthesizing Granulolactone, Echinolactone A, Radulactone and Riparol B in Yi Lu alkane type sequiterpene.The total synthesis method synthesizes a kind of Yi Lu alkane type sequiterpene reaction intermediate first, then reacts to obtain the EchinolactoneA through dialkyl using the reaction intermediate；It restores the Echinolactone A and obtains the Radulactone；Clemmensen reduction reaction is carried out to the ketone carbonyl of the Echinolactone A and obtains the Granulolactone；It finally restores the Granulolactone and obtains the Riparol B.The total synthesis method is " divergence expression " synthetic method, has synthesized four Yi Lu alkane type sequiterpene natural products, and has many advantages, such as few, easy to operate, the suitable industrialized production of reaction step.
Description
Technical field
The invention belongs to the synthesis fields of Yi Lu alkane type (Illudalane) sequiterpene, and in particular to a kind of Yi Lu alkane type times
The total synthesis method of hemiterpene reaction intermediate and natural products, the total synthesis method is for synthesizing in Yi Lu alkane type sequiterpene
Granulolactone, Echinolactone A, Radulactone and Riparol B.
Background technique
Yi Lu alkane type sequiterpene is the natural production of representativeness of Basidiomycetes fungi and Pteris Secondary metabolites
Object usually contains the five-membered ring fused benzene unique texture being functionalized, they are not only large number of, but also it is reported that the type day
Right product often have cytotoxicity (The Journal of Organic Chemistry, 2000,65,4482-4486；
Tetrahedron, 1999,55,12295-12300.), antispastic (European Journal of Medicinal
Chemistry, 1990,25,603.), antitumor (The Journal of Organic Chemistry, 2000,65,4482-
4486；Bioorganic&Medicinal Chemistry, 2006,14,1863-1870.) multiple biological activities such as.2016
Agar plate culture of the Raj Bahadur Singh et al. from wood-degrading fungi (Granulobasidium vellereum)
A series of natural products of separation and Extraction in base (Journal of Natural Products, 2016,79,1698-1701.),
In addition to four Yi Lu alkane type sequiterpene natural products being reported of discovery, this four natural products are respectively
Radulactone (Zeitschrift Fur Naturforschung C-A Journal of Biosciences, 1998,
53,939-945.), Echinolactone A (Phytochemistry, 2005,66,2329-2333.), Alcyopterosin
N (The Journal of Organic Chemistry, 2000,65,4482-4486.) and Riparol B (Zeitschrift
Fur Naturforschung C-A Journal of Biosciences, 2006,61,663-669.), an example is also obtained
New Yi Lu alkane type sequiterpene natural products Granulolactone passes through nuclear magnetic resonance, infrared and high resolution mass spectrum etc.
Technology identifies their structure, while preliminary biological activity test has also been carried out to it, it is found that they are showed
Different degrees of anti-mite and insecticidal activity.
Fully synthetic chemists are also keen to the fully synthetic research of Yi Lu alkane type terpene natural products, and earliest is to be seen in
The total synthesis method of Coprinol reports (Indian Journal of Chemistry Section B-Organic
Chemistry Including Medicinal Chemistry, 1987,26,914-916；Indian Journal of
Chemistry Section B-Organic Chemistry Including Medicinal Chemistry, 1987,26,
469-470.), as many as synthesis step up to 16 steps；Raj Bahadur Singh in 2016 et al. has developed new method, utilizes
Friedel-Crafts and dialkyl are that key reaction has synthesized phenylpropyl alcohol five-membered ring nuclear structure, finally complete with the synthesis step of 8 steps
At the fully synthetic of Coprinol, herein on basis they to report natural products Onitin in 2017 fully synthetic, close
It is 9 steps (Journal of Natural Products, 2018,81,2111-2114.) at step；Gregory B.Dudley
Et al. the 6 step synthetic methods of Alcyopterosin A were reported in 2016, key reaction is cyclisation/oxygen of Rh catalysis
Change aromatization tandem reaction (Organic Letters, 2016,18,3470-3473.)；It is noted that Fumie Satoy
And Bernhard Witulski et al. using modularization response strategy (Chemical Communications, 2002,
2984–2985；Journal of the American Chemical Society, 2002,124,9682-9683；Organic
Letters, 2010,12,5644-5647.), ene-alkyne [2+2+2] cyclization can occur under the catalysis of Rh, can successfully construct
Yi Lu alkane type terpene structural framework, and with this successfully synthesize natural products Alcyopterosin A, Alcyopterosin C,
Alcyopterosin E, Alcyopterosin I, Alcyopterosin L, Alcyopterosin M and
Alcyopterosin N, but fully synthetic step is more than 10 steps.
2019, Zhang Yandong seminar, Xiamen University first reported the four Yi Lu alkane type terpenes mentioned for the present invention
The total synthesis method of natural products Granulolactone, Echinolactone A, Radulactone and Riparol B
(Chemical Communications, 2019,55,4250-4253.), key reaction is the ene-alkyne [2+2 an of intramolecular
+ 2] cyclization aoxidizes isophorone from commercial reagents, has synthesized Granulolactone, reaction step at first
Need as many as ten steps, by subsequent hydrocarbon oxidation reaction and reduction reaction, it can be achieved that Echinolactone A,
Radulactone and Riparol B's is fully synthetic.
To sum up, in relation to the fully synthetic report of this type natural analog, longer, starting that largely all there is synthetic routes
The drawbacks such as raw material or reaction reagent are expensive, total recovery is low.In view of discussed above, develop it is a kind of it is succinct, efficiently, it is economical, be suitble to work
Industry metaplasia produce Yi Lu alkane type sequiterpene natural products Granulolactone, Echinolactone A, Radulactone and
" divergence expression " chemical synthesis process of Riparol B is just particularly important.
Summary of the invention
In order to achieve the above objectives, the present invention propose Granulolactone in a kind of Yi Lu alkane type sequiterpene,
The total synthesis method of Echinolactone A, Radulactone and Riparol B, the total synthesis method are " divergence expression " conjunction
At method, four Yi Lu alkane type sequiterpene natural products have been synthesized for the first time, and there is few, easy to operate, the suitable work of reaction step
The advantages that industry metaplasia produces.
The present invention is achieved by the following technical solutions:
Present invention firstly provides a kind of preparation method of Yi Lu alkane type sequiterpene reaction intermediate, the reaction intermediate is used
In preparation Granulolactone, Echinolactone A, Radulactone and Riparol B；The preparation method with 1,
3- cyclopentanedione is starting material, is connected through halogenating reaction, coupling reaction, esterification and Diels-Alder/ oxidizing aromatic
Reaction, obtains the reaction intermediate.
Further, the preparation method comprises the following steps:
S1, halogenating reaction: 1,3- cyclopentanedione and halogen are through halogenating reaction 3 halogenated cyclopentenones of generation；
S2, coupling reaction: 3 halogenated cyclopentenones and ene boric acid ester or alkenyl trialkyltin are raw through coupling reaction
At unsaturated dienone；
S3, esterification: the unsaturation dienone and propiolic acid through esterification obtain the first cyclization precursor；
S4, Diels-Alder/ oxidizing aromatic tandem reaction: first cyclization precursor is in sealing and inert gas item
Diels-Alder cyclization occurs under part, then oxidizing aromatic reaction is contacted and occurred in a heated condition with air, obtains
The reaction intermediate.
Further, the reaction intermediate is 5/6/6 and ring system.
Further, the structural formula of the reaction intermediate are as follows:
Further, the reaction condition of halogenating reaction described in S1 is: organic in halogenating reaction deoxidier and halogenating reaction
Under conditions of alkali additive, 1, the 3- cyclopentanedione reacts in the first solvent with halogen, and reaction temperature is room temperature, when reaction
Between be 10~15h.
Further, the halogenating reaction organic base additive is as acid binding agent.
Further, halogen described in S1 is Cl2、Br2Or I2。
Further, 1, the 3- cyclopentanedione, halogen, halogenating reaction deoxidier, halogenating reaction organic base additive
The ratio between amount of substance is 1:1.0~3.0:1.0~3.0:1.0~3.0.
Further, the halogenating reaction deoxidier is triphenylphosphine.
Further, the halogenating reaction organic base additive is in triethylamine, diisopropyl ethyl amine and tri-n-butylamine
More than one.
Further, first solvent is acetonitrile, methylene chloride, chloroform and 1, one or more of 2- dichloroethanes.
Further, the reaction condition of coupling reaction described in S2 is: adding in coupling reaction catalyst and coupling reaction alkali
Under the conditions of adding agent, 3 halogenated cyclopentenones react in the second solvent with ene boric acid ester or alkenyl trialkyltin, reaction
Temperature is 50-80 DEG C, and the reaction time is 5~8h.
Further, the coupling reaction catalyst is Pd (PPh3)4、Pd2(dba)3Or PdCl2(dppf)2。
Further, the coupling reaction alkali additive is Na2CO3、Ba(OH)2、K3PO4、Cs2CO3Or K2CO3。
Further, second solvent is that there are commonly the mixtures of one or more of solvent and water.
Further, described there are commonly solvent includes dioxane, tetrahydrofuran and ether.
Further, 3 halogenated cyclopentenones, ene boric acid ester or alkenyl trialkyltin, coupling reaction catalyst
The ratio between the amount of substance with coupling reaction alkali additive is 1:1.3~4.0:0.02~0.15:1.5~4.5.
Further, the coupling reaction is Suzuki cross-coupling reaction or Stille cross-coupling reaction.
Further, the reaction condition of esterification described in S3 is: in the condition of dehydrating agent and catalyst for esterification reaction
Under, the unsaturation dienone reacts in third solvent with propiolic acid, and reaction temperature is -5~0 DEG C, and the reaction time 1.5~
3.0h。
Further, esterification described in S3 is Keck esterification.
Further, the dehydrating agent is DCC or EDCI.
Further, the catalyst for esterification reaction is DMAP.
Further, the ratio between the unsaturated dienone, propiolic acid, dehydrating agent and amount of substance of catalyst for esterification reaction
It is 1:1.0~5.0:1.5~5.0:0.01~0.1.
Further, the third solvent is one or more of methylene chloride, 1,2- dichloroethanes and chloroform.
Further, the reaction condition of the Diels-Alder/ oxidizing aromatic tandem reaction of S4 is: in the 4th solvent
Reaction, reaction temperature are 140~170 DEG C, and total reaction time is 20~40h.
Further, the reaction time of the Diels-Alder cyclization is 15h；The reaction of oxidizing aromatic reaction
Time is 15h.
Further, the 4th solvent is one or more of DMSO, toluene and dimethylbenzene.
Another object of the present invention is to provide Granulolactone in a kind of Yi Lu alkane type sequiterpene,
The total synthesis method of Echinolactone A, Radulactone and Riparol B, the total synthesis method is using described above
Reaction intermediate react to obtain the Echinolactone A through dialkyl；The Echinolactone A is restored to obtain
The Radulactone；The ketone carbonyl progress Clemmensen reduction reaction of the Echinolactone A is obtained described
Granulolactone；It finally restores the Granulolactone and obtains the Riparol B.
Further, the total synthesis method specifically includes the following steps:
Step 1, prepare Echinolactone A: under basic conditions, the reaction intermediate and iodomethane are by double alkane
Glycosylation reaction obtains Echinolactone A；
Step 2, it prepares Radulactone: being obtained using the first go back original reagent reduction Echinolactone A
Radulactone；
Step 3, it prepares Granulolactone: Clemmensen reduction reaction being carried out to Echinolactone A and is obtained
Granulolactone；
Step 4, it prepares Riparol B: Riparol B is obtained using third go back original reagent reduction Granulolactone.
Further, step 1, which prepares the reaction condition of Echinolactone A, is: reacting in the 5th solvent, reaction temperature
- 10~10 DEG C of degree, 4~6h of reaction time.
Further, highly basic described in step 1 is LDA, KHMDS, LiHMDS, NaH or LiTMP.
Further, the 5th solvent is methylene chloride, tetrahydrofuran or ether.
Further, step 2, which prepares the reaction condition of Radulactone, is: reacting in the 6th solvent, reaction temperature
It is -78~0 DEG C, 10~15h of reaction time.
Further, the first go back original reagent described in step 2 is NaBH4Or BH4。
Further, the ratio between amount of substance of Echinolactone A described in step 2 and go back original reagent be 1:5.0~
15.0。
Further, the 6th solvent is ethyl alcohol, methanol or water.
Further, step 3, which prepares the reaction condition of Granulolactone, is: in the second go back original reagent and hydrogen source donor
Under conditions of, it is reacted in the 7th solvent, reaction temperature is -10 DEG C~room temperature, 10~15h of reaction time.
Further, second go back original reagent is active metal.
Further, the active metal includes one or more of Zn, Hg and Fe.
Further, the substance withdrawl syndrome of the hydrogen source donor is 6~12M.
Further, the ratio between amount of substance of Echinolactone A, the second go back original reagent and hydrogen source donor is 1:
100.0~450.0:20.0~80.0.
Further, the hydrogen source donor is strong acid.
Further, the strong acid includes hydrochloric acid and sulfuric acid.
Further, preferred Clemmensen reduction reaction conditions when step 3 preparation Granulolactone.
Further, step 4, which prepares the reaction condition of Riparol B, is: molten the 8th under the conditions of third go back original reagent
It is reacted in agent, reaction temperature is 0 DEG C, and the reaction time is 1~3h.
Further, the third go back original reagent is strong go back original reagent.
Further, the strong go back original reagent includes DIBAL-H, LiAlH4、LiHBEt3One or more of with red aluminum.
Further, the 8th solvent is methylene chloride, tetrahydrofuran or ether.
Further, the ratio between amount of substance of the Granulolactone and third go back original reagent is 1:4.0~8.0.
Another object of the present invention is to provide Granulolactone and Riparol B in a kind of Yi Lu alkane type sequiterpene
Synthetic method, the synthetic method be with 3,3- Dimethyl-cyclopentanone replace 1, the 3- cyclopentanedione, through above-mentioned S1~S4
Reaction obtains Granulolactone, then Granulolactone is restored to obtain Riparol B.
Further, the synthetic method includes the following steps:
6) halogenating reaction: 3,3- Dimethyl-cyclopentanones produce alkenyl halide through halogenating reaction and close object (R at this time2For Cl,
Br or I) or 3,3- Dimethyl-cyclopentanone with trifluoromethanesulfonic acid anhydride reactant, generates trifluoromethanesulfonic acid enol under alkaline condition
Ester (R at this time2For OTf)；
7) coupling reaction: alkenyl compound and reagent are through Suzuki cross-coupling reaction or Stille cross-coupling reaction
Generate diolefin compound；
8) esterification: diolefin compound and propiolic acid are through Keck esterification the second cyclization precursor of formation；
9) generation Diels- first Diels-Alder/ oxidizing aromatic tandem reaction: is heated in pressure-resistant seal pipe
Alder cyclization then contacts with air and occurs in a heated condition oxidizing aromatic reaction, finally passes through tandem reaction
Generate natural products Granulolactone；
10) it prepares Riparol B: can get natural products using third go back original reagent reduction Granulolactone
Riparol B。
Further, the reaction condition in the synthetic method and the total synthesis method corresponding step above-mentioned is anti-
Answer condition identical.
The present invention has following advantageous effects:
Total synthesis method of the invention compared with prior art, has the following characteristics that
1) from the commercialization iodo- cyclopentenone of raw material 3-, this method only needs 4-6 step reaction just to synthesize four Yi Lu alkane
Type terpene natural products has had both reaction step is short, source chemicals are cheap and easy to get, divergence expression synthesizes, is suitble to industrialized production etc.
Advantage；
2) in Suzuki coupling reaction, which is not necessarily to deoxygenation operation, and easy to operate, reaction is mild；
3) Keck esterification activity is high, and reaction speed is fast, convenient post-treatment；
3) new method that committed step uses one pot of Diels-Alder/ oxidizing aromatic operation has synthesized benzo five-membered
Ring skeleton, method is novel, and operation, post-processing are easy.
Detailed description of the invention
Fig. 1 is the nuclear magnetic resonance spectroscopy for the unsaturated dienone being prepared in the embodiment of the present invention 1.
Fig. 2 is the carbon-13 nmr spectra for the unsaturated dienone being prepared in the embodiment of the present invention 1.
Fig. 3 is the high resolution mass spectrum for the unsaturated dienone being prepared in the embodiment of the present invention 1.
Fig. 4 is the nuclear magnetic resonance spectroscopy for the first cyclization precursor being prepared in the embodiment of the present invention 1.
Fig. 5 is the carbon-13 nmr spectra for the first cyclization precursor being prepared in the embodiment of the present invention 1.
Fig. 6 is the high resolution mass spectrum for the first cyclization precursor being prepared in the embodiment of the present invention 1.
Fig. 7 is the nuclear magnetic resonance spectroscopy for the reaction intermediate being prepared in the embodiment of the present invention 1.
Fig. 8 is the carbon-13 nmr spectra for the reaction intermediate being prepared in the embodiment of the present invention 1.
Fig. 9 is the high resolution mass spectrum for the reaction intermediate being prepared in the embodiment of the present invention 1.
Figure 10 is the nuclear magnetic resonance spectroscopy for the Echinolactone A being prepared in the embodiment of the present invention 1.
Figure 11 is the carbon-13 nmr spectra for the Echinolactone A being prepared in the embodiment of the present invention 1.
Figure 12 is the high resolution mass spectrum for the Echinolactone A being prepared in the embodiment of the present invention 1.
Figure 13 is the nuclear magnetic resonance spectroscopy for the Radulactone being prepared in the embodiment of the present invention 1.
Figure 14 is the carbon-13 nmr spectra for the Radulactone being prepared in the embodiment of the present invention 1.
Figure 15 is the high resolution mass spectrum for the Radulactone being prepared in the embodiment of the present invention 1.
Figure 16 is the nuclear magnetic resonance spectroscopy for the Granulolactone being prepared in the embodiment of the present invention 1.
Figure 17 is the carbon-13 nmr spectra for the Granulolactone being prepared in the embodiment of the present invention 1.
Figure 18 is the high resolution mass spectrum for the Granulolactone being prepared in the embodiment of the present invention 1.
Figure 19 is the nuclear magnetic resonance spectroscopy for the Riparol B being prepared in the embodiment of the present invention 1.
Figure 20 is the carbon-13 nmr spectra for the Riparol B being prepared in the embodiment of the present invention 1.
Figure 21 is the high resolution mass spectrum for the Riparol B being prepared in the embodiment of the present invention 1.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to embodiments and specification
The present invention is explained in further detail in attached drawing.It should be appreciated that specific embodiment described herein is used only for explaining this
Invention, is not intended to limit the present invention.
On the contrary, the present invention covers any substitution done on the essence and scope of the present invention being defined by the claims, repairs
Change, equivalent teaching method and scheme.Further, in order to make the public have a better understanding the present invention, below to this hair
It is detailed to describe some specific detail sections in bright datail description.For a person skilled in the art without these details
The present invention can also be understood completely in partial description.
It will be appreciated that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Base
Embodiment in the present invention, it is obtained by those of ordinary skill in the art without making creative efforts it is all its
Its embodiment, shall fall within the protection scope of the present invention.
The term used in embodiments of the present invention is only to be not intended to be limiting merely for for the purpose of describing particular embodiments
The present invention.In the embodiment of the present invention and the "an" of singular used in the attached claims, " described " and "the"
It is also intended to including most forms, unless the context clearly indicates other meaning.
Embodiment 1
The present embodiment proposes a kind of preparation method of Yi Lu alkane type sequiterpene reaction intermediate, and the reaction intermediate is used for
Prepare Granulolactone, Echinolactone A, Radulactone and Riparol B；The preparation method is with 1,3-
Cyclopentanedione is starting material, is connected through halogenating reaction, coupling reaction, esterification and Diels-Alder/ oxidizing aromatic anti-
It answers, obtains the reaction intermediate.
The preparation method comprises the following steps:
S1, halogenating reaction: 1,3- cyclopentanedione and halogen are through halogenating reaction 3 halogenated cyclopentenones of generation；
S2, coupling reaction: 3 halogenated cyclopentenones and ene boric acid ester or alkenyl trialkyltin are raw through coupling reaction
At unsaturated dienone；
S3, esterification: the unsaturation dienone and propiolic acid through esterification obtain the first cyclization precursor；
S4, Diels-Alder/ oxidizing aromatic tandem reaction: first cyclization precursor is in sealing and inert gas item
Diels-Alder cyclization occurs under part, then oxidizing aromatic reaction is contacted and occurred in a heated condition with air, obtains
The reaction intermediate.
The reaction intermediate is 5/6/6 and ring system.
The structural formula of the reaction intermediate are as follows:
The reaction condition of halogenating reaction described in S1 is: in halogenating reaction deoxidier and halogenating reaction organic base additive
Under the conditions of, 1, the 3- cyclopentanedione reacts in the first solvent with halogen, and reaction temperature is room temperature, and the reaction time is 10~
15h。
The halogenating reaction organic base additive is as acid binding agent.
Halogen described in S1 is Cl2、Br2Or I2。
1, the 3- cyclopentanedione, halogen, halogenating reaction deoxidier, halogenating reaction organic base additive substance amount it
Than for 1:1.0~3.0:1.0~3.0:1.0~3.0.
The halogenating reaction deoxidier is triphenylphosphine.
The halogenating reaction organic base additive is one or more of triethylamine, diisopropyl ethyl amine and tri-n-butylamine.
First solvent is acetonitrile, methylene chloride, chloroform and 1, one or more of 2- dichloroethanes.
The reaction condition of coupling reaction described in S2 is: in coupling reaction catalyst and coupling reaction alkali additive condition
Under, 3 halogenated cyclopentenones react in the second solvent with ene boric acid ester or alkenyl trialkyltin, and reaction temperature is
50-80 DEG C, the reaction time is 5~8h.
The coupling reaction catalyst is Pd (PPh3)4、Pd2(dba)3Or PdCl2(dppf)2。
The coupling reaction alkali additive is Na2CO3、Ba(OH)2、K3PO4、Cs2CO3Or K2CO3。
Second solvent is that there are commonly the mixtures of one or more of solvent and water.
Described there are commonly solvent includes dioxane, tetrahydrofuran and ether.
3 halogenated cyclopentenones, ene boric acid ester or alkenyl trialkyltin, coupling reaction catalyst and coupling reaction
The ratio between the amount of substance of alkali additive is 1:1.3~4.0:0.02~0.15:1.5~4.5.
The coupling reaction is Suzuki cross-coupling reaction or Stille cross-coupling reaction.
The reaction condition of esterification described in S3 is: under conditions of dehydrating agent and catalyst for esterification reaction, it is described not
Saturation dienone reacts in third solvent with propiolic acid, and reaction temperature is -5~0 DEG C, 1.5~3.0h of reaction time.
Esterification described in S3 is Keck esterification.
The dehydrating agent is DCC or EDCI.
The catalyst for esterification reaction is DMAP.
The ratio between the unsaturation dienone, propiolic acid, dehydrating agent and amount of substance of catalyst for esterification reaction be 1:1.0~
5.0:1.5~5.0:0.01~0.1.
The third solvent is one or more of methylene chloride, 1,2- dichloroethanes and chloroform.
The reaction condition of the Diels-Alder/ oxidizing aromatic tandem reaction of S4 is: reacting, reacts in the 4th solvent
Temperature is 140~170 DEG C, and total reaction time is 20~40h.
The reaction time of the Diels-Alder cyclization is 15h；The reaction time of oxidizing aromatic reaction is 15h.
4th solvent is one or more of DMSO, toluene and dimethylbenzene.
The present embodiment also provide Granulolactone in a kind of Yi Lu alkane type sequiterpene, Echinolactone A,
The total synthesis method of Radulactone and Riparol B, the total synthesis method is using reaction intermediate described above through double
Alkylated reaction obtains the Echinolactone A；It restores the Echinolactone A and obtains the Radulactone；
Clemmensen reduction reaction is carried out to the ketone carbonyl of the Echinolactone A and obtains the Granulolactone；Most
After restore the Granulolactone and obtain the Riparol B.
The total synthesis method specifically includes the following steps:
Step 1, prepare Echinolactone A: under basic conditions, the reaction intermediate and iodomethane are by double alkane
Glycosylation reaction obtains Echinolactone A；
Step 2, it prepares Radulactone: being obtained using the first go back original reagent reduction Echinolactone A
Radulactone；
Step 3, it prepares Granulolactone: Clemmensen reduction reaction being carried out to Echinolactone A and is obtained
Granulolactone；
Step 4, it prepares Riparol B: Riparol B is obtained using third go back original reagent reduction Granulolactone.
The synthetic route of the total synthesis method is as follows:
The reaction condition that step 1 prepares Echinolactone A is: reacting in the 5th solvent, reaction temperature -10~10
DEG C, 4~6h of reaction time.
Highly basic described in step 1 is LDA, KHMDS, LiHMDS, NaH or LiTMP.
5th solvent is methylene chloride, tetrahydrofuran or ether.
The reaction condition that step 2 prepares Radulactone is: it is reacted in the 6th solvent, reaction temperature is -78~0 DEG C,
10~15h of reaction time.
First go back original reagent described in step 2 is NaBH4Or BH4。
The ratio between amount of substance of Echinolactone A described in step 2 and go back original reagent is 1:5.0~15.0.
6th solvent is ethyl alcohol, methanol or water.
The reaction condition that step 3 prepares Granulolactone is: under conditions of the second go back original reagent and hydrogen source donor,
It is reacted in the 7th solvent, reaction temperature is -10 DEG C~room temperature, 10~15h of reaction time.
Second go back original reagent is active metal.
The active metal includes Zn, Hg and Fe.
The substance withdrawl syndrome of the hydrogen source donor is 6~12M.
The ratio between amount of substance of Echinolactone A, the second go back original reagent and hydrogen source donor be 1:100.0~
450.0:20.0~80.0.
The hydrogen source donor is strong acid.
The strong acid includes hydrochloric acid and sulfuric acid.
Step 3 prepares preferred Clemmensen reduction reaction conditions when Granulolactone.
The reaction condition that step 4 prepares Riparol B is: under the conditions of third go back original reagent, reacted in the 8th solvent,
Reaction temperature is 0 DEG C, and the reaction time is 1~3h.
The third go back original reagent is strong go back original reagent.
The strong go back original reagent includes DIBAL-H, LiAlH4、LiHBEt3One or more of with red aluminum.
8th solvent is methylene chloride, tetrahydrofuran or ether.
The ratio between amount of substance of the Granulolactone and third go back original reagent is 1:4.0~8.0.
It is the halogen in halogenation that the present embodiment, which chooses elemental iodine, carries out following preparation process:
The synthesis of the iodo- cyclopentenone of 1.3- (6)
The iodo- cyclopentenone of 3- can be bought by commercial sources, and (Journal of the can also be synthesized according to known method
American Chemical Society, 2009,131,8,2993-3006).Elemental iodine (31g, 122.25mmol) is weighed to add
Enter into two mouthfuls of round-bottomed flasks of 1000mL, the second of triphenylphosphine (32g, 122.25mmol) is then slowly added dropwise into the two-mouth bottle
Nitrile solution (700mL).After 2 hours are stirred at room temperature under nitrogen protection, the acetonitrile that 1,3- cyclopentanedione (8g, 81.5mmol) is added is molten
Liquid (100mL) is then stirred at room temperature 12 hours, then heats to 90 DEG C of back flow reactions 13 hours, directly reaction solution is concentrated, column
Chromatographic purification (petroleum ether: ethyl acetate=8:1.), obtains faint yellow solid 12.5g, yield 74%.
2. the synthesis of unsaturated dienone (8)
In the mono- neck round-bottom flask of 150ml, the iodo- cyclopentenone of 3- (2g, 9.62mmol) is dissolved in Isosorbide-5-Nitrae-dioxane
The mixed liquor of (75mL) and water (15mL), successively by ene boric acid ester (4.1g, 19.2mmol), four (triphenyl phosphorus) palladiums
Reaction flask is added in (341mg, 0.289mmol) and tripotassium phosphate (6.1g, 28.9mmol).Oil bath is warming up at 80 DEG C and stirs instead
Answer, stop reaction after 6h, with suction filtered through kieselguhr, be removed under reduced pressure Isosorbide-5-Nitrae-dioxane, water phase be extracted with ethyl acetate (50mL ×
3), anhydrous sodium sulfate dries, filters, and concentration, column Chromatographic purification (petroleum ether: ethyl acetate=1:1.) obtains faint yellow solid
1.6g, yield 100%.Nuclear magnetic resonance spectroscopy1H NMR (600MHz, CDCl3) δ 6.18 (t, J=7.2Hz, 1H), 6.06 (s,
1H), 3.77 (dd, J=11.9,6.2Hz, 2H), 2.79 (dd, J=5.0,3.7Hz, 2H), 2.52 (q, J=6.7Hz, 2H),
2.48-2.37 (m, 2H), 1.93 (s, 3H), 1.88 (t, J=5.3Hz, 1H).Carbon-13 nmr spectra13C NMR (150MHz,
CDCl3) δ 210.2,175.8,134.0,132.4,127.4,61.8,35.1,32.4,27.7,14.6.High resolution mass spectrum HRMS
(ESI):m/z calcd for C10H14NaO2[M+Na]+189.0886 found 189.0880。
3. the synthesis of cyclization precursor (10)
Under nitrogen protection, DCC (8.7g, 42.2mmol) and DMAP (51mg, 0.42mmol) are added sequentially to 100mL
In two mouth flask, and 50mL methylene chloride is added and makes it dissolve, and is spare after so that it is stirred 30min at normal temperature.Separately take 150mL
Two mouth flask, and the dichloromethane solution (20mL) of cyclization precursor (10,3.5g, 21.1mmol) is added into bottle, and in room temperature
Then system is cooled to 0 DEG C by lower addition propiolic acid (9,2.2g, 31.5mmol), and by the dichloro of above-mentioned DCC-DMAP system
Dichloromethane is added drop-wise in 150mL two mouth flask, after being added dropwise to complete, is stopped reaction after so that it is reacted 2h at such a temperature, is passed through
It filtering and removes solid impurity, concentration, column Chromatographic purification (petroleum ether: ethyl acetate=2:1.) obtains white solid product 4.07g,
Yield 88%.Nuclear magnetic resonance spectroscopy1H NMR (600MHz, CDCl3) δ 6.10 (s, 1H), 6.08 (t, J=7.3Hz, 1H), 4.31
(t, J=6.6Hz, 2H), 2.91 (s, 1H), 2.81-2.75 (m, 2H), 2.65 (q, J=6.8Hz, 2H), 2.51-2.42 (m,
2H), 1.94 (s, 3H).Carbon-13 nmr spectra13C NMR (150MHz, CDCl3) δ 209.8,175.0,152.7,134.8,
129.6,128.1,75.3,74.6,64.8,35.1,28.2,27.7,14.6.High resolution mass spectrum HRMS (ESI): m/z calcd
for C13H14NaO3[M+Na]+241.0835 found 241.0835。
4. reaction intermediate --- the synthesis of 5/6/6 tricyclic key intermediate (11)
Under nitrogen protection, cyclization precursor (10,175mg, 0.8mmol) is dissolved in 4mL dry toluene, is then warming up to bath temperature
It 160 DEG C and is reacted in 25mL pressure-resistant seal pipe.After reaction 15 hours, opens seal pipe and add 2mL dry toluene, will react
System comes into full contact with air, is then shut off seal pipe continuation and reacts 15 hours at 160 DEG C.Reaction solution is directly concentrated, column
Chromatographic purification (petroleum ether: ethyl acetate=1:1.), obtains white solid product 106.8mg, yield 61%.Nuclear magnetic resonance spectroscopy1H
NMR (600MHz, CDCl3) δ 8.42 (s, 1H), 4.54 (t, J=6.0Hz, 2H), 3.18-3.00 (m, 4H), 2.86-2.67 (m,
2H), 2.34 (s, 3H) carbon-13 nmr spectra13C NMR (150MHz, CDCl3) δ 205.8,165.0,158.7,143.8,
136.2,133.2,125.4,124.5,66.4,36.3,25.9,25.7,14.3. high resolution mass spectrum HRMS (ESI): m/z
calcd for C13H12NaO3[M+Na]+239.0679 found 239.0677。
The synthesis of 5.Echinolactone A (1)
Under nitrogen protection, sodium hydride (purity: 60%, 184mg, 4.6mmol) is weighed in reaction tube, and drying is added
The methylene chloride of 5/6/6 tricyclic key intermediate (11,50mg, 0.23mmol) is added in tetrahydrofuran (2mL) after being cooled to 0 DEG C
Solution (1mL).Move to and be stirred at room temperature after twenty minutes, be cooled to 0 DEG C again, be added dropwise excessive iodomethane (0.14mL, 326.5mg,
2.3mmol).After 0 DEG C is reacted 4.5 hours, reaction solution is added drop-wise to the mixing of 5mL hydrochloric acid (concentration 1mol/mL) and 10mL water
Quenching reaction in liquid.Tetrahydrofuran is removed under reduced pressure, water phase successively uses ethyl acetate (20mL × 3), methylene chloride (20mL × 3) extraction
It taking, anhydrous sodium sulfate dries, filters, and concentration, column Chromatographic purification (petroleum ether: ethyl acetate=2:1.) obtains white solid 43mg,
Yield 77%.Nuclear magnetic resonance spectroscopy1H NMR (400MHz, CDCl3) δ 8.38 (s, 1H), 4.52 (t, J=6.0Hz, 2H), 3.07
(t, J=6.0Hz, 2H), 2.95 (s, 2H), 2.30 (s, 3H), 1.24 (s, 6H) carbon-13 nmr spectras13C NMR (100MHz,
CDCl3) δ 210.2,165.0,155.9,144.0,134.4,133.2,125.5,125.0,66.4,45.7,42.6,25.9,
25.4,14.3. high resolution mass spectrum HRMS (ESI): m/z calcd for C15H16NaO3[M+Na]+267.0992 found
267.0990。
The synthesis of 6.Radulactone (2)
Echinolactone A (10mg, 0.04mmol) is dissolved in 1mL anhydrous methanol, is cooled to -78 DEG C, boron is added
Sodium hydride (2.3mg 0.06mmol).Reaction is moved to after reaction being stirred at room temperature 12 hours, it is water-soluble that 10mL saturated ammonium chloride is added
Liquid quenching reaction, after methanol is removed under reduced pressure, water phase is extracted with ethyl acetate (20mL × 4), and anhydrous sodium sulfate dries, filters, dense
Contracting, column Chromatographic purification (petroleum ether: ethyl acetate=2:1.) obtain white solid 8.5mg, yield 85%.Nuclear magnetic resonance spectroscopy1H
NMR (600MHz, CDCl3) δ 8.01 (s, 1H), 4.70 (s, 1H), 4.50 (t, J=6.1Hz, 2H), 2.97 (t, J=6.0Hz,
2H), 2.80 (d, J=16.3Hz, 1H), 2.63 (d, J=16.3Hz, 1H), 2.20 (s, 3H), 1.18 (s, 3H), 1.06 (s,
3H) carbon-13 nmr spectra13C NMR (100MHz, CDCl3) δ 166.0,147.6,143.9,138.3,131.4,124.4,
83.2,66.8,44.4,44.3,29.8,26.9,25.4,21.6,15.1.High resolution mass spectrum HRMS (ESI): m/z calcd
for C15H18NaO3[M+Na]+269.1148 found 269.1150。
The synthesis of 7.Granulolactone (3)
Zinc powder (5g) is placed in 100mL round-bottomed flask, be added 50% hydrochloric acid solution (4.5mL) activation twice, then
Mercuric chloride (214.5mg), water (4.0mL) and concentrated hydrochloric acid (0.6mL) is added to the system, stirs 1 hour at room temperature.To above-mentioned
The toluene solution (2mL) of Echinolactone A (42.9mg, 0.18mmol) is added in Zn-Hg complex system, and adds again
Enter concentrated hydrochloric acid (3.2mL).After reaction being stirred at room temperature 10 hours, diatomite is filtered to remove impurity, and the dilution of 10mL water, acetic acid second is added
Ester (20mL × 4) extraction, anhydrous sodium sulfate dry, filter, and are concentrated, and column Chromatographic purification (petroleum ether: ethyl acetate=8:1.) obtains
White solid 38.8mg, yield 85%.Nuclear magnetic resonance spectroscopy1H NMR (600MHz, CDCl3) δ 7.78 (s, 1H), 4.49 (t, J=
6.1Hz, 2H), 2.94 (t, J=6.0Hz, 2H), 2.74 (d, J=30.8Hz, 4H), 2.18 (s, 3H), 1.15 (d, J=
9.3Hz, 6H).Carbon-13 nmr spectra13C NMR (100MHz, CDCl3) δ 166.4,149.5,142.6,136.3,130.9,
124.3,123.6,66.9,47.6,47.3,39.8,29.8,29.00,25.2,15.4.High resolution mass spectrum HRMS (ESI): m/z
calcd for C15H18NaO2[M+Na]+253.1199 found 253.1200。
The synthesis of 8.Riparol B (4)
Under nitrogen protection, Granulolactone (24mg, 0.1mmol) is dissolved in methylene chloride (1mL), is cooled to -78
DEG C, it is added DIBAL-H (hexane solution, concentration 1.6mmol/mL, 0.3mL).After reacting about 1 hour at -78 DEG C, by reaction solution
It is added drop-wise to quenching reaction in the aqueous solution of 15mL saturation sodium potassium tartrate tetrahydrate, then stirs 1 hour, is extracted with dichloromethane at room temperature
(20mL × 8) extraction, anhydrous sodium sulfate dry, filter, and are concentrated, and column Chromatographic purification (petroleum ether: ethyl acetate=1:1.) obtains white
Color solid 17.1mg, yield 73%.Nuclear magnetic resonance spectroscopy1H NMR (600MHz, CDCl3) δ 7.00 (s, 1H), 4.61 (d, J=
5.7Hz, 2H), 3.89-3.83 (m, 2H), 3.02 (t, J=5.9Hz, 3H), 2.72 (s, 2H), 2.67 (s, 2H), 2.20 (s,
3H), 1.15 (s, 6H).Carbon-13 nmr spectra13C NMR (150MHz, CDCl3) δ 143.7,141.8,139.6,138.0,
133.4,124.3,61.8,47.9,47.4,39.5,31.7,29.4,29.4.High resolution mass spectrum HRMS (ESI): m/z calcd
for C15H23O2[M+H]+235.1693 found 235.1695。
Embodiment 2
The present embodiment provides the synthetic method of Granulolactone and Riparol B in Yi Lu alkane type sequiterpene a kind of,
The synthetic method is to replace 1, the 3- cyclopentanedione with 3,3- Dimethyl-cyclopentanone, reacts to obtain through above-mentioned S1~S4
Granulolactone, then Granulolactone is restored to obtain Riparol B.
The synthetic method includes the following steps:
1) halogenating reaction: 3,3- Dimethyl-cyclopentanones produce alkenyl halide through halogenating reaction and close object (R at this time2For Cl,
Br or I) or 3,3- Dimethyl-cyclopentanone with trifluoromethanesulfonic acid anhydride reactant, generates trifluoromethanesulfonic acid enol under alkaline condition
Ester (R at this time2For OTf)；
2) coupling reaction: alkenyl compound and reagent are through Suzuki cross-coupling reaction or Stille cross-coupling reaction
Generate diolefin compound；
3) esterification: diolefin compound and propiolic acid are through Keck esterification the second cyclization precursor of formation；
4) generation Diels- first Diels-Alder/ oxidizing aromatic tandem reaction: is heated in pressure-resistant seal pipe
Alder cyclization then contacts with air and occurs in a heated condition oxidizing aromatic reaction, finally passes through tandem reaction
Generate natural products Granulolactone；
5) it prepares Riparol B: can get natural products using third go back original reagent reduction Granulolactone
Riparol B。
Reaction condition in the synthetic method and the reaction condition phase in total synthesis method corresponding steps described in embodiment 1
Together.
The synthetic route of the synthetic method is as follows:
Above description shows and describes several preferred embodiments of the present application, but as previously described, it should be understood that the application
Be not limited to forms disclosed herein, should not be regarded as an exclusion of other examples, and can be used for various other combinations,
Modification and environment, and the above teachings or related fields of technology or knowledge can be passed through in application contemplated scope described herein
It is modified.And changes and modifications made by those skilled in the art do not depart from spirit and scope, then it all should be in this Shen
It please be in the protection scope of the appended claims.
Claims (10)
1. a kind of Yi Lu alkane type sequiterpene reaction intermediate, which is characterized in that the reaction intermediate is used to prepare
Granulolactone, Echinolactone A, Radulactone and RiparolB；The structural formula of the reaction intermediate is such as
Under:
2. a kind of preparation method for preparing Yi Lu alkane type sequiterpene reaction intermediate as described in claim 1, which is characterized in that
The preparation method with 1,3- cyclopentanedione be starting material, through halogenating reaction, coupling reaction, esterification and Diels-
Alder/ oxidizing aromatic tandem reaction, obtains the reaction intermediate.
3. preparation method according to claim 2, which is characterized in that the preparation method comprises the following steps:
S1, halogenating reaction: 1,3- cyclopentanedione and halogen are through halogenating reaction 3 halogenated cyclopentenones of generation；
S2, coupling reaction: 3 halogenated cyclopentenones and ene boric acid ester or alkenyl trialkyltin generate not through coupling reaction
It is saturated dienone；
S3, esterification: the unsaturation dienone and propiolic acid through esterification obtain the first cyclization precursor；
S4, Diels-Alder/ oxidizing aromatic tandem reaction: first cyclization precursor is under sealing and inert gas conditions
Diels-Alder cyclization occurs, then oxidizing aromatic reaction is contacted and occurred in a heated condition with air, obtains described
Reaction intermediate.
4. a kind of preparation method of Yi Lu alkane type sequiterpene reaction intermediate according to claim 3, which is characterized in that S1
Described in the reaction condition of halogenating reaction be: under conditions of halogenating reaction deoxidier and halogenating reaction organic base additive, institute
It states 1,3- cyclopentanedione and is reacted in the first solvent with halogen, reaction temperature is room temperature, and the reaction time is 10~15h；
Halogen described in S1 is Cl2、Br2Or I2；
The ratio between 1, the 3- cyclopentanedione, halogen, halogenating reaction deoxidier, amount of substance of halogenating reaction organic base additive are
1:1.0~3.0:1.0~3.0:1.0~3.0.
5. a kind of preparation method of Yi Lu alkane type sequiterpene reaction intermediate according to claim 3, which is characterized in that S2
Described in the reaction condition of coupling reaction be: under the conditions of coupling reaction catalyst and coupling reaction alkali additive, 3 halogen
It is reacted in the second solvent for cyclopentenone with ene boric acid ester or alkenyl trialkyltin, reaction temperature is 50-80 DEG C, when reaction
Between be 5~8h；
3 halogenated cyclopentenones, ene boric acid ester or alkenyl trialkyltin, coupling reaction catalyst and coupling reaction alkali add
The ratio between the amount of substance for adding agent is 1:1.3~4.0:0.02~0.15:1.5~4.5.
6. a kind of preparation method of Yi Lu alkane type sequiterpene reaction intermediate according to claim 3, which is characterized in that S3
Described in the reaction condition of esterification be: under conditions of dehydrating agent and catalyst for esterification reaction, the unsaturation dienone
It is reacted in third solvent with propiolic acid, reaction temperature is -5~0 DEG C, 1.5~3.0h of reaction time；
The ratio between the unsaturation dienone, propiolic acid, dehydrating agent and amount of substance of catalyst for esterification reaction are 1:1.0~5.0:
1.5~5.0:0.01~0.1.
7. Granulolactone in a kind of Yi Lu alkane type sequiterpene, Echinolactone A, Radulactone and
The total synthesis method of RiparolB, which is characterized in that the total synthesis method is described in any item anti-using claim 1~6
Intermediate is answered to react to obtain the Echinolactone A through dialkyl；Restore the Echinolactone A obtain it is described
Radulactone；The ketone carbonyl progress Clemmensen reduction reaction of the Echinolactone A is obtained described
Granulolactone；It finally restores the Granulolactone and obtains the Riparol B.
8. Granulolactone in a kind of Yi Lu alkane type sequiterpene according to claim 7, Echinolactone A,
The total synthesis method of Radulactone and Riparol B, which is characterized in that the total synthesis method specifically includes the following steps:
Step 1, prepare Echinolactone A: under basic conditions, the reaction intermediate and iodomethane pass through dialkyl
Reaction, obtains Echinolactone A；
Step 2, it prepares Radulactone: Radulactone is obtained using the first go back original reagent reduction Echinolactone A；
Step 3, it prepares Granulolactone: Clemmensen reduction reaction being carried out to Echinolactone A and is obtained
Granulolactone；
Step 4, it prepares Riparol B: RiparolB is obtained using third go back original reagent reduction Granulolactone.
9. the synthetic method of Granulolactone and Riparol B in a kind of Yi Lu alkane type sequiterpene, which is characterized in that described
Synthetic method is that 1, the 3- cyclopentanedione is replaced with 3,3- Dimethyl-cyclopentanone, described in any item through claim 3~6
S1~S4 reacts to obtain Granulolactone, then Granulolactone is restored to obtain Riparol B.
10. the synthesis of Granulolactone and Riparol B in a kind of Yi Lu alkane type sequiterpene according to claim 9
Method, which is characterized in that the synthetic method includes the following steps:
1) halogenating reaction: 3,3- Dimethyl-cyclopentanones produce alkenyl halide through halogenating reaction and close object；
Or,
3,3- Dimethyl-cyclopentanones with trifluoromethanesulfonic acid anhydride reactant, generate trifluoromethanesulfonic acid enol ester under alkaline condition；
2) coupling reaction: alkenyl compound and reagent are generated through Suzuki cross-coupling reaction or Stille cross-coupling reaction
Diolefin compound；
3) esterification: diolefin compound and propiolic acid are through Keck esterification the second cyclization precursor of formation；
4) generation Diels-Alder ring first Diels-Alder/ oxidizing aromatic tandem reaction: is heated in pressure-resistant seal pipe
Change reaction, oxidizing aromatic reaction is then contacted and occurred in a heated condition with air, finally generates day by tandem reaction
Right product Granulolactone；
5) it prepares Riparol B: can get natural products RiparolB using third go back original reagent reduction Granulolactone.
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| CN102241593A (en) * | 2010-04-26 | 2011-11-16 | 中国医药研究所 | Protoilludance norsesquiterpenoid esters and uses thereof |
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