CN108659094A - A kind of synthetic method of mycoleptodiscin A - Google Patents
A kind of synthetic method of mycoleptodiscin A Download PDFInfo
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- CN108659094A CN108659094A CN201710212680.7A CN201710212680A CN108659094A CN 108659094 A CN108659094 A CN 108659094A CN 201710212680 A CN201710212680 A CN 201710212680A CN 108659094 A CN108659094 A CN 108659094A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0036—Nitrogen-containing hetero ring
- C07J71/0042—Nitrogen only
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The present invention relates to a kind of synthetic methods of marine natural products mycoleptodiscin A, belong to the field of chemical synthesis.The present invention is starting material with ketenes sequiterpene 2 and 7 methoxy-Indoles 3,Sequiterpene base indoles 4 is generated by ketenes sequiterpene 2 and the coupling of 7 methoxy-Indoles 3,Sequiterpene base indoles 4, which methylates, generates sequiterpene base indanol 5,Sequiterpene base indanol 5 is reacted with electrophilic blocking group,It is protected on NH,Generate the sequiterpene base indoles 6 of N EWG protections,Cyclization is occurring for the sequiterpene base indoles 6 of N EWG protections,Generate five rings sequiterpene base indoles 7,Five rings sequiterpene base indoles 7 removes N EWG protections,Generate the five rings NH sequiterpene base indoles 8,8 demethylating of the five rings NH sequiterpene base indoles,Generate the five rings NH sequiterpene base indoxyl 9,The five rings NH sequiterpene base indoxyl 9 finally generates final natural products mycoleptodiscin A through peroxidization.The present invention has the characteristics that few reaction step, easy to operate, good product selectivity, is suitble to industrialized production.
Description
Technical field
The present invention relates to a kind of synthetic methods of marine natural products mycoleptodiscin A.
Background technology
Marine natural products mycoleptodiscin A are in 2013 from endogenetic fungusMycoleptodiscusSp. in
Separation and Extraction obtains for the first time（Ortega H E, Graupner P R, Asai Y, et al. Journal of natural products, 2013, 76(4): 741-744.）.As shown in Fig. 1, the C-4 natural products for hydroxyl
Mycoleptodiscin B have the multiple biological activities such as anticancer, antibacterial（Ortega H E, Graupner P R, Asai
Y, et al. Journal of natural products, 2013, 76(4): 741-744；Dissanayake R K,
Ratnaweera P B, Williams D E, et al. Journal of Applied Pharmaceutical ScienceVol, 2016, 6(01): 001-006.）.In order to preferably study the bioactivity of mycoleptodiscin A,
Pharmaceutical research for the follow-up natural products provides material base, and there is an urgent need for a kind of efficient, succinct mycoleptodiscin A
Synthetic method.
It is less for the synthetic method report of mycoleptodiscin A, currently, only three reports, 2015, China
The Li Ang seminars of Chinese Academy of Sciences's Shanghai Institute of Organic Chemistry realize the fully synthetic of mycoleptodiscin A for the first time, synthetic route warp
25 steps are reacted, total recovery<1%（Zhou S, Chen H, Luo Y, et al. Angewandte Chemie International Edition, 2015, 54(23): 6878-6882.）.2016, India's science and industrial research institute
Chandrasekhar seminars reacted with 9 steps, 19% total recovery completes the semi-synthetic of the natural products（Nagaraju
K, Chegondi R, Chandrasekhar S. Organic letters, 2016, 18(11): 2684-2687.）.Together
Year, the Dethe seminars of your research institute of India's Kemp complete the bio-mimetic syntheses of mycoleptodiscin A, and the route is through 13
Step reaction, total recovery 20%（Dethe D H, Sau S K, Mahapatra S.Organic Letters, 2016.）.But
It is that the above method mostly has the drawbacks such as reaction route length, severe reaction conditions, is not appropriate for industrialized production.
In view of above-mentioned discussion, the ocean day that a kind of synthetic route is succinct, reaction condition is mild, is suitble to industrialized production is developed
The chemical synthesis process of right product mycoleptodiscin A just seems particularly necessary.The natural products that the present invention reports
Synthetic method i.e. have reaction step it is few, it is easy to operate, be suitble to industrialized production the advantages that.
Invention content
Present invention aims at provide a kind of synthetic method of marine natural products mycoleptodiscin A.Reaction step
Suddenly less, good product selectivity, be suitble to industrialized production.
1. to achieve the above object, the present invention includes attached following steps shown in Fig. 2：
A) with 7- methoxy-Indoles 3 under Louis acid catalysis coupling reaction occurs for ketenes sequiterpene 2, generates sequiterpene base Yin
Diindyl 4；
B) with methyl Grignard methylation reaction occurs for sequiterpene base indoles 4, generates sequiterpene base indanol 5；
C) sequiterpene base indanol 5 is reacted with electrophilic blocking group, is protected on-NH, and the sesquialter of N-EWG protections is generated
Terpene base indoles 6；
D) under lewis acid effect cyclization occurs for the sequiterpene base indoles 6 of N-EWG protections, generates five rings sequiterpene base
Indoles 7；
E) five rings sequiterpene base indoles 7 is in removing N-EWG protecting groups, the five rings generation-NH sequiterpene base indoles 8；
F) demethylating under halogenation hydroboration of the five rings-NH sequiterpene base indoles 8, the five rings generation-NH sequiterpene base indoxyl 9；
G) five rings-NH sequiterpene base indoxyl 9 generates final natural products mycoleptodiscin A through peroxidization.
2. the coupling reaction of ketenes sequiterpene 2 and 7- methoxy-Indoles 3 of the present invention, lewis acid catalyst three
Be fluorinated borate ether, gallium triflate, Bismuth triflate, trifluoromethanesulfonic acid tin, trifluoromethanesulfonic acid hafnium, silver trifluoromethanesulfonate,
Trifluoromethanesulfonic acid zinc, copper trifluoromethanesulfcomposite；Reaction dissolvent be dichloromethane, 1,2- dichloroethanes, chloroform, tetrahydrofuran, chlorobenzene,
Toluene；Reaction temperature is 0 °C and arrives reflux；Reaction time is 1-12 hours.
3. the methylation reaction of sequiterpene base indoles 4 of the present invention, methylating reagent is methyl-magnesium-bromide, methyl iodide
Change magnesium, lithium methide；Reaction dissolvent be toluene, 1,2- dichloroethanes, ether, tetrahydrofuran, dichloromethane, 1,4- dioxane,
N,N-dimethylformamide；Reaction temperature is -78 °C and arrives room temperature；Reaction time is 1-12 hours.
4. protection group reaction on sequiterpene base indanol 5 of the present invention, protecting group is trifyl, methyl sulphur
Acyl group, p-toluenesulfonyl, phenyl sulfonyl；Reaction dissolvent is toluene, tetrahydrofuran, dichloromethane, 1,2- dichloroethanes；Instead
It answers temperature to be -20 °C and arrives reflux；Reaction time is 1-6 hours.
5. the cyclization of the sequiterpene base indoles 6 of N-EWG of the present invention protection, cyclization reagent be boron trifluoride,
Ferric trichloride, butter of tin, gallium triflate, Bismuth triflate, trifluoromethanesulfonic acid tin；Reaction dissolvent be dichloromethane,
1,2- dichloroethanes, ether；Reaction temperature is -78 °C and arrives room temperature；Reaction time is 1-6 hours.
6. the N-EWG protecting group elimination reactions of five rings sequiterpene base indoles 7 of the present invention, deprotection based method are
Li- liquefied ammonia, Na- liquefied ammonia, HBr- phenol, Mg-MeOH, Na-Hg；Reaction dissolvent is methanol, ethyl alcohol, isopropanol, butanol, isobutyl
Alcohol, the tert-butyl alcohol；Reaction temperature is -20 °C and arrives reflux；Reaction time is 1-6 hours.
7. 8 demethylating reaction of the five rings-NH sequiterpene base indoles of the present invention, demethylation reagent is boron trifluoride, three
Boron chloride, triiodide boron；Reaction dissolvent is toluene, tetrahydrofuran, dichloromethane, 1,2- dichloroethanes, ether；Reaction temperature
It is -78 °C to reflux；Reaction time is 1-5 hours.
8. the oxidation reaction of the five rings-NH sequiterpene base indoxyl 9 of the present invention, oxidant DDQ, CAN, IBX；Reaction
Solvent is N,N-dimethylformamide, acetonitrile, tetrahydrofuran；Reaction temperature is 0 °C and arrives reflux；Reaction time is 1-6 hours.
Compared with related synthesis report before, the invention has the characteristics that：
1. the present invention is starting material with ketenes sequiterpene 2 and 7- methoxy-Indoles 3, reaction step is few, is suitble to industry metaplasia
Production.
2. total recovery is high, easy to operate.
Description of the drawings
Attached drawing 1：Mycoleptodiscin A and B structure formula figure
Attached drawing 2:The specific synthetic route chart of the present invention
Specific implementation mode
Embodiment 1：The synthesis of sequiterpene base indoles 4
Take 3.09 grams of ketenes sequiterpene（2,15.0 mmol）With 2.2 grams of 7- methoxy-Indoles（3,15.0 mmol）It is dissolved in 100 millis
It rises in 1,2- dichloroethanes, 0.63 gram of trifluoromethanesulfonic acid tin is added（1.5 mmol）, it is stirred to react at room temperature 3 hours, TLC detections
Reaction terminates.Add 100 milliliters of water, washing reaction liquid, the extraction of water phase dichloromethane（30 mL x 2）, merge organic phase saturation food
Salt water washing, anhydrous sodium sulfate drying, is filtered, concentration, and column chromatography purification obtains 5.09 grams of white solid, yield 96%.
Hydrogen nuclear magnetic resonance modal data：1H-NMR ((400 MHz, CDCl3): δ = 8.14 (br, s, 1 H), 7.20
(d, J = 7.9 Hz, 1 H), 7.04 (d, J = 7.7 Hz, 1 H), 7.00 (s, 1 H), 6.63 (d, J =
7.6 Hz, 1 H), 3.94 (s, 3 H), 3.19 (dd, J = 13.9, 10.1 Hz, 1 H), 2.68 (d, J =
14.1 Hz, 1 H), 2.49 (d, J = 9.7 Hz, 1 H), 2.38 (dd, J = 12.8, 2.4 Hz, 1 H),
2.21 (td, J = 13.1, 6.5 Hz, 1 H), 0.96 (s, 3 H) , 0.89 (s, 3 H), 0.86 (s, 3
H);
Carbon-13 nmr spectra data：13C NMR (100 MHz, CDCl3): 211.7, 146.2, 128.7, 126.4,
122.7, 119.3, 116.1, 111.3, 101.5, 65.4, 55.2, 54.2, 43.1, 42.6, 41.9, 39.5,
33.7, 33.4, 24.1, 21.6, 19.1, 17.1, 14.5.
Embodiment 2：The synthesis of sequiterpene base indanol 5
Take 4.24 grams of sequiterpene base indoles（4,12.0 mmol）It is dissolved in 100 milliliters of anhydrous tetrahydro furans, fills row's argon gas three repeatedly
It is secondary, drain air.- 10 °C are cooled to, 11.25 milliliters of lithium methide is slowly added dropwise（1.6 M, 18 mmol）It stirs at such a temperature
Reaction 2 hours is mixed, TLC detection reactions terminate.50 milliliters of saturated sodium carbonate solution, ether extraction are added into reaction system（50
mL x 3）, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying is filtered, concentration, and column chromatography purification obtains white
4.16 grams of solid, yield 94%.
Hydrogen nuclear magnetic resonance modal data：1H-NMR ((400 MHz, CDCl3): δ = 8.29 (br, s, 1 H), 7.33
(d, J = 7.9 Hz, 1 H), 7.07 (d, J = 7.8 Hz, 1 H), 6.94 (s, 1 H), 6.67 (d, J =
7.6 Hz, 1 H), 3.97 (s, 3 H), 2.97 (dd, J = 16.7, 5.7 Hz, 1 H), 2.79 (d, J =
16.6 Hz, 1 H), 1.83 (t, J = 12.3 Hz, 2 H), 1.14 (s, 3 H), 1.08 (s, 3 H) ,
0.94 (s, 3 H), 0.91 (s, 3 H);
Carbon-13 nmr spectra data：13C NMR (100 MHz, CDCl3): 145.9, 128.8, 126.6, 120.6,
119.6, 119.2, 111.7, 101.7, 73.3, 58.8, 56.0, 55.1, 42.6, 42.0, 39.7, 38.9,
33.4, 33.3, 31.3, 21.7, 20.3, 18.3, 18.2, 15.0.
Embodiment 3：The synthesis of the sequiterpene base indoles 6 of N- phenyl sulfonyls protection
Take 3.69 grams of sequiterpene base indanol（5,10.0 mmol）It is dissolved in 100 milliliters of toluene, is cooled to 0 °C, sequentially adds
0.68 gram of 4-butyl ammonium hydrogen sulfate（2 mmol）, 100 milliliters of 50 wt% sodium hydrate aqueous solutions, phenylsulfonylchloride is slowly added dropwise
1.54 milliliter（12 mmol）.It is warming up to room temperature, continues to be stirred to react 2 hours, TLC detection reactions terminate.Add into reaction system
Enter 50 milliliters of water, liquid separation, the extraction of water phase dichloromethane（50 mL x 3）, merge organic phase, saturated common salt water washing, anhydrous sulphur
Sour sodium drying, is filtered, concentration, and column chromatography purification obtains 4.89 grams of yellowish foaming solid, yield 96%.
Hydrogen nuclear magnetic resonance modal data：1H-NMR ((400 MHz, CDCl3): δ = 7.80 (d, J = 8.1 Hz, 1
H), 7.57 (s, 1 H), 7.52 (m, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.20 (d, J = 7.8
Hz, 1 H), 7.13 (t, J = 7.8 Hz, 1 H), 6.67 (d, J = 7.8 Hz, 1 H), 3.62 (s, 3
H), 2.90 (dd, J = 17.4, 5.8 Hz, 1 H), 2.65 (d, J = 17.4 Hz, 1 H), 1.79 (d, J
= 8.3 Hz, 1 H), 1.71 (d, J = 12.5 Hz, 1 H), 1.09 (s, 3 H), 1.06 (s, 3 H) ,
0.91 (s, 3 H), 0.87 (s, 3 H);
Carbon-13 nmr spectra data：13C NMR (100 MHz, CDCl3): 147.3, 140.5, 134.0, 132.9,
128.6, 126.9, 124.8, 123.7, 112.0, 107.0, 73.1, 57.7, 55.8, 55.3, 42.5, 41.8,
39.6, 38.9, 33.4, 33.3, 21.7, 20.9, 20.0, 19.1, 15.0.
Embodiment 4：The synthesis of five rings sequiterpene base indoles 7
4.08 grams of sequiterpene base indoles for taking N- phenyl sulfonyls to protect（6,8.0 mmol）It is dissolved in 100 milliliters of anhydrous methylene chlorides
In, -20 °C are cooled to, 9.36 milliliters of butter of tin is slowly added dropwise（80 mmol）, it is stirred to react 1 hour at such a temperature, TLC
Detection reaction terminates.Reaction solution is poured into 100 milliliters of ice, liquid separation, dichloromethane extraction（50 mL x 3）, merge organic
Phase, saturated common salt water washing, anhydrous sodium sulfate drying are filtered, concentration, and column chromatography purification obtains 3.24 grams of yellow oil, yield
It is 82%.
Hydrogen nuclear magnetic resonance modal data：1H-NMR ((400 MHz, CDCl3): δ = 7.90 (d, J = 7.6 Hz, 2
H), 7.51 (d, J = 7.3 Hz, 2 H), 7.44 (m , 3 H), 6.87 (d, J = 8.1 Hz, 1 H),
6.62 (d, J = 8.0 Hz, 1 H),3.68 (s, 3 H), 2.90 (dd, J = 15.8, 2.9 Hz, 1 H),
2.62 (d, J = 13.3 Hz, 1 H), 2.40 (d, J = 12.3 Hz, 1 H), 1.89-1.86 (m, 1 H),
1.79-1.73 (m, 2 H), 1.72-1.69 (m, 2 H), 1.59-1.52 (m, 2 H), 1.50-1.47 (m, 2
H), 1.42-1.38 (m, 1 H), 1.11 (s, 3 H), 1.04 (s, 3 H) , 0.94 (s, 3 H), 0.90
(s, 3 H);
Carbon-13 nmr spectra data：13C NMR (100 MHz, CDCl3): = 145.4, 140.7, 138.8, 133.1,
130.9, 128.9, 127.7, 122.6, 121.6, 118.8, 116.8, 108.3, 56.8, 56.6, 56.2,
42.1, 40.4, 39.1, 38.3, 37.5, 33.7, 33.6, 29.9, 25.2, 21.7, 19.0, 18.9, 18.2,
16.4.
Embodiment 5：The synthesis of the five rings-NH sequiterpene base indoles 8
Take 2.47 grams of five rings sequiterpene base indoles（7,5.0 mmol）It is dissolved in 50 milliliters of anhydrous tetrahydro furan-methanol（1:1）Mixing
In solution, row's argon gas is filled repeatedly three times, drains air.1.34 grams of sodium amalgam is added（50%, 6.0 mmol）, stirring is anti-at room temperature
It answers 1 hour, TLC detection reactions terminate.50 milliliters of ice water, ether extraction are added into reaction system（50 mL x 3）, it is associated with
Machine phase, saturated common salt water washing, anhydrous sodium sulfate drying are filtered, concentration, and column chromatography purification obtains 1.70 grams of yellowish solid, receives
Rate is 97%.
Embodiment 6：The synthesis of the five rings-NH sequiterpene base indoxyl 9
Take 1.05 grams of the five rings-NH sequiterpene base indoles（8,3.0 mmol）It is dissolved in 20 milliliters of anhydrous methylene chlorides, fills row repeatedly
Argon gas three times, drains air.- 78 °C are cooled to, 30 milliliters of the dichloromethane solution of triiodide boron is slowly added dropwise（1 M, 30
mmol）, it is to slowly warm up to room temperature, and be stirred to react at such a temperature 1 hour, TLC detection reactions terminate.Reaction solution is poured into
In 100 milliliters of ice, liquid separation, dichloromethane extraction（50 mL x 3）, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate
It is dry, it filters, concentration, column chromatography purification obtains 0.81 gram of khaki solid, yield 80%.
Hydrogen nuclear magnetic resonance modal data：1H-NMR ((400 MHz, CDCl3): δ = 8.09 (br, s, 1 H), 6.84
(s, 1 H), 6.81 (d, J = 7.7 Hz, 1 H), 6.64 (d, J = 7.7 Hz, 1 H), 3.98 (s, 3
H), 3.00 (dd, J = 15.2, 2.3 Hz, 1 H), 2.75 (t, J = 13.8 Hz, 1 H), 2.54 (d, J
= 12.6 Hz, 1 H), 1.94 (d, J = 12.4 Hz, 1 H), 1.81 (m, 2 H), 1.67 (m, 2 H),
1.48 (m, 2 H), 1.26 (s, 3 H), 1.14 (s, 3 H) , 0.96 (s, 6 H);
Carbon-13 nmr spectra data：13C NMR (100 MHz, CDCl3): 143.8, 138.2, 126.7, 123.7,
116.9, 114.2, 111.1, 102.6, 57.4, 56.6, 55.2, 41.9, 40.3, 38.8, 38.1, 37.4,
33.4, 33.3, 24.9, 21.6, 18.8, 18.6, 18.2, 16.4,.
Embodiment 7：The synthesis of natural products mycoleptodiscin A 1
Take 0.51 gram of the five rings-NH sequiterpene base indoxyl（9,1.5 mmol）It is dissolved in 50 milliliters of acetonitriles, fills row's argon gas three repeatedly
It is secondary, drain air.It is cooled to 0 °C of addition potassium dihydrogen phosphate aqueous solution（0.062 M）50 milliliters, 0.68 gram of DDQ (3 mmol).
It is warming up to room temperature, is stirred to react at such a temperature 2 hours, TLC detection reactions terminate.50 milli of ice water is added into reaction system
It rises, ethyl acetate extraction（50 mL x 3）, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying is filtered, dense
Contracting, column chromatography purification, obtains 0.40 gram of red solid, yield 76%.
Optically-active data： = -172 (c = 0.20 in MeOH);
Ir data：IR (film): νmax = 3202, 2947, 2927, 2852, 1653, 1467, 1442,
1387, 1265, 1069, 934, 871, 687 cm−1;
Hydrogen nuclear magnetic resonance modal data：1H NMR (400 MHz, CD3OD): δ = 7.00 (s, 1 H), 5.68 (s, 1
H), 2.73 (dd, J = 16.2, 3.5 Hz, 1 H), 2.49 (dd, J = 16.0, 12.2 Hz, 1 H),
2.13-2.11 (m, 1 H), 1.82-1.80 (m, 1 H), 1.76 - 1.73(m, 1 H), 1.72-1.68 (m, 1
H), 1.64-1.60 (m, 1 H), 1.59-1.49 (m, 2 H), 1.47-1.43 (m, 1 H), 1.41-1.39 (m,
1 H), 1.25 (s, 3 H), 1.20-1.16 (m, 1H), 1.08 (s, 3 H), 0.96-0.91 (m,2 H),
0.91 (s, 3 H), 0.89 (s, 3 H) ppm;
Carbon-13 nmr spectra data：13C NMR (100 MHz, CD3OD): δ = 187.3, 167.8, 166.4, 132.0,
129.3, 126.4, 125.1, 116.0, 58.2, 57.7, 43.2, 41.6, 40.0, 40.0, 38.6, 34.6,
34.3, 22.6, 22.4, 19.9, 19.9, 19.2, 17.5 ppm;
High resolution mass spectrum data：HRMS (ESI) m/z calcd. for C23H30NO2 [M + H]+ 352.2277; found
352.2271.
The present invention relates to 3 coupling reaction of ketenes sequiterpene 2 and 7- methoxy-Indoles, methylation reaction, EWG protections reaction, cyclisation
Reaction, deprotection reaction, demethylating reaction, the reaction of 7 step of oxidation reaction, total recovery 42% finally synthesize marine natural products
mycoleptodiscin A.Above-mentioned specific implementation citing is only the preferred embodiments of the present invention, is not to make it to the present invention
The limitation of its form.
Claims (8)
1. a kind of synthetic method of marine natural products mycoleptodiscin A as shown in Fig. 2, which is characterized in that packet
Include following synthesis step：
A) with 7- methoxy-Indoles 3 under Louis acid catalysis coupling reaction occurs for ketenes sequiterpene 2, generates sequiterpene base Yin
Diindyl 4；
B) with methyl Grignard methylation reaction occurs for sequiterpene base indoles 4, generates sequiterpene base indanol 5；
C) sequiterpene base indanol 5 is reacted with electrophilic blocking group, is protected on-NH, and the sesquialter of N-EWG protections is generated
Terpene base indoles 6；
D) under lewis acid effect cyclization occurs for the sequiterpene base indoles 6 of N-EWG protections, generates five rings sequiterpene base
Indoles 7；
E) five rings sequiterpene base indoles 7 is in removing N-EWG protecting groups, the five rings generation-NH sequiterpene base indoles 8；
F) demethylating under halogenation hydroboration of the five rings-NH sequiterpene base indoles 8, the five rings generation-NH sequiterpene base indoxyl 9；
G) five rings-NH sequiterpene base indoxyl 9 generates final natural products mycoleptodiscin A through peroxidization.
2. preparation method according to claim 1, it is characterised in that：The ketenes sequiterpene 2 and 7- methoxy-Indoles 3
Coupling reaction, lewis acid catalyst be boron trifluoride ether, gallium triflate, Bismuth triflate, trifluoromethanesulfonic acid
Tin, trifluoromethanesulfonic acid hafnium, silver trifluoromethanesulfonate, trifluoromethanesulfonic acid zinc, copper trifluoromethanesulfcomposite；Reaction dissolvent be dichloromethane, 1,
2- dichloroethanes, chloroform, tetrahydrofuran, chlorobenzene, toluene；Reaction temperature is 0 °C and arrives reflux；Reaction time is 1-12 hours.
3. preparation method according to claim 1, it is characterised in that：The methylation reaction of the sequiterpene base indoles 4,
Methylating reagent is methyl-magnesium-bromide, methylpyridinium iodide magnesium, lithium methide；Reaction dissolvent is toluene, 1,2- dichloroethanes, ether, four
Hydrogen furans, dichloromethane, 1,4- dioxane, N,N-dimethylformamide；Reaction temperature is -78 °C and arrives room temperature；Reaction time
It is 1-12 hours.
4. preparation method according to claim 1, it is characterised in that：Protecting group is anti-on the sequiterpene base indanol 5
It answers, protecting group is trifyl, methyl sulphonyl, p-toluenesulfonyl, phenyl sulfonyl；Reaction dissolvent is toluene, four
Hydrogen furans, dichloromethane, 1,2- dichloroethanes；Reaction temperature is -20 °C and arrives reflux；Reaction time is 1-6 hours.
5. preparation method according to claim 1, it is characterised in that：The sequiterpene base indoles 6 of the N-EWG protections
Cyclization, cyclization reagent are boron trifluoride, ferric trichloride, butter of tin, gallium triflate, Bismuth triflate, trifluoro
Tin methane sulfonate；Reaction dissolvent is dichloromethane, 1,2- dichloroethanes, ether；Reaction temperature is -78 °C and arrives room temperature；Reaction time
It is 1-6 hours.
6. preparation method according to claim 1, it is characterised in that：The N-EWG of the five rings sequiterpene base indoles 7 is protected
Base elimination reaction is protected, deprotection based method is Li- liquefied ammonia, Na- liquefied ammonia, HBr- phenol, Mg-MeOH, Na-Hg；Reaction dissolvent
For methanol, ethyl alcohol, isopropanol, butanol, isobutanol, the tert-butyl alcohol；Reaction temperature is -20 °C and arrives reflux；Reaction time is that 1-6 is small
When.
7. preparation method according to claim 1, it is characterised in that：8 demethylation of the five rings-NH sequiterpene base indoles
Reaction, demethylation reagent are boron trifluoride, boron chloride, triiodide boron；Reaction dissolvent be toluene, tetrahydrofuran, dichloromethane,
1,2- dichloroethanes, ether；Reaction temperature is -78 °C and arrives reflux；Reaction time is 1-5 hours.
8. preparation method according to claim 1, it is characterised in that：The oxygen of the five rings-NH sequiterpene base indoxyl 9
Change reaction, oxidant DDQ, CAN, IBX；Reaction dissolvent is N,N-dimethylformamide, acetonitrile, tetrahydrofuran；Reaction temperature is 0
°C to reflux；Reaction time is 1-6 hours.
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| CN201710212680.7A CN108659094B (en) | 2017-04-01 | 2017-04-01 | Synthesis method of mycodepiscin A |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114350524A (en) * | 2022-01-07 | 2022-04-15 | 暨南大学附属第一医院（广州华侨医院） | Mycoleptodiscin type indole sesquiterpene compound, biosynthesis method and application thereof |
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|---|---|---|---|---|
| CN105412065A (en) * | 2015-11-05 | 2016-03-23 | 淄博齐鼎立专利信息咨询有限公司 | Application of Mycoleptodiscin A in preparing aseptic inflammation resisting medicine |
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| CN105412065A (en) * | 2015-11-05 | 2016-03-23 | 淄博齐鼎立专利信息咨询有限公司 | Application of Mycoleptodiscin A in preparing aseptic inflammation resisting medicine |
Non-Patent Citations (3)
| Title |
|---|
| DATTATRAYA H. DETHE等: "Biomimetic Enantioselective Total Synthesis of (−)-Mycoleptodiscin A", 《ORG. LETT.》 * |
| KARRE NAGARAJU等: "Expanding Diversity without Protecting Groups: (+)-Sclareolide to Indolosesquiterpene Alkaloid Mycoleptodiscin A and Analogues", 《ORG. LETT.》 * |
| SHUPENG ZHOU等: "Asymmetric Total Synthesis of Mycoleptodiscin A", 《ANGEW. CHEM. INT. ED.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114350524A (en) * | 2022-01-07 | 2022-04-15 | 暨南大学附属第一医院（广州华侨医院） | Mycoleptodiscin type indole sesquiterpene compound, biosynthesis method and application thereof |
| CN114350524B (en) * | 2022-01-07 | 2024-04-23 | 暨南大学附属第一医院（广州华侨医院） | Mycolepothilone indole sesquiterpene compound, biosynthesis method and application thereof |
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