CN106588850A - Total synthetic method of Talienbisflavan A - Google Patents
Total synthetic method of Talienbisflavan A Download PDFInfo
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- CN106588850A CN106588850A CN201611138586.3A CN201611138586A CN106588850A CN 106588850 A CN106588850 A CN 106588850A CN 201611138586 A CN201611138586 A CN 201611138586A CN 106588850 A CN106588850 A CN 106588850A
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- dimerization
- dimeric
- epicatechin
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- catechin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
- C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to a total synthetic method of the proanthocyanidin natural product Talienbisflavan A and belongs to the field of chemical synthesis. The natural product Talienbisflavan A (see figures) is synthesized by: synthesizing dimeric catechin via acid catalyzed dimerization of formaldehyde, subjecting the dimeric catechin to DMP (Dess-Martin periodinane) oxidation and L-Selectride selective reduction to synthesize dimeric epicatechin, subjecting the dimeric epicatechin to coupling reaction with benzyl-protected gallic acid to synthesize dimeric epicatechin gallate, subjecting the dimeric epicatechin gallate to palladium/carbon debenzylation. The method of the invention has the advantages that reaction steps are few, total yield is high, product selectivity is good, and the method is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of total synthesis method of TalienbisflavanA.
Background technology
Procyanidin is one of composition of plant pigment, is the Polyphenols secondary generation that a class is widely present in various plants
Thank to product.Research finds that procyanidin class natural product has multiple biological activities, with antioxidation, antibacterial, antimutagenic, anti-
The different physiological roles such as hypertension（Curr. Med. Chem. 2010, 17, 1756）.In recent years, research shows procyanidin
Class natural product has important using value in terms of marine anti-pollution.In structure, procyanidin is by the youngster of varying number
Theine or epicatechin are combined into.Research discovery, procyanidin C8,8 dimer class compounds, with excellent antioxidation
And radical scavenging activity（Pharm. Biol. 2010, 48, 116）, such framework compound synthesis is reported less
（Tetrahedron Letters,55, 2014, 2484–2486）, reactions steps are long, are not suitable for commercial production.
TalienbisflavanA is the new procyanidin C8 of a class for extracting discovery from the tea of Dali first, 8 dimer classes
Compound（J. Agric. Food Chem.2012, 60, 12170 −12176）, there is presently no the conjunction with regard to this compound
Into report.The present invention with known O-Bn catechins as initiation material, with reactions steps it is few, total recovery is high, selectivity of product
The features such as good, suitable industrialized production.
The content of the invention
Present invention aim at providing a kind of complete synthesis side of procyanidin class natural product TalienbisflavanA
Method.Reactions steps are few, good product selectivity, suitable industrialized production.
For achieving the above object, the present invention is comprised the following steps：
A) O-Bn catechins synthesize dimeric-catechin through acid catalyzed formaldehyde dimerization reaction；
B) dimeric-catechin synthesizes dimerization epicatechin through DMP oxidations and L-Selectride Chemoselective reductions；
C) dimerization epicatechin and benzyl protection gallic acid coupling reaction, synthesize dimerization L-Epicatechin gallate；
D) the palladium carbon debenzylation of dimerization L-Epicatechin gallate, synthesis of natural product TalienbisflavanA.
2. step a prioritization scheme described in：Catechin through acid catalyzed formaldehyde dimerization reaction prioritizing selection sulphuric acid for acid, two
Six ring of oxygen is solvent, and reaction temperature is room temperature.
3. step b prioritization scheme described in：Dimeric-catechin DMP oxidation reaction prioritizing selection moistenings dichloromethane is solvent,
Reaction temperature is room temperature.Dimeric-catechin diketone L-Selectride Chemoselective reduction prioritizing selections tetrahydrofuran is molten
Agent, reaction temperature are -78 °C.
4. step c prioritization scheme described in：Dimerization epicatechin and benzyl protection gallic acid coupling reaction prioritizing selection
DMAP is alkali, and dichloromethane is solvent, and reaction temperature is room temperature.
5. step d prioritization scheme described in：The palladium carbon debenzylation prioritizing selection second of dimerization L-Epicatechin gallate
Acetoacetic ester is solvent, and reaction temperature is room temperature.
The present invention is the complete synthesis first of natural product TalienbisflavanA, the invention has the characteristics that：
1. it is with known O-Bn catechins as initiation material, few with reactions steps, it is adapted to industrialized production；
2. total recovery is high, good product selectivity.
Description of the drawings
Accompanying drawing：For concrete synthetic route chart of the invention
Specific embodiment
Embodiment 1：Dimeric-catechin（2, see accompanying drawing）Synthesis
O-Bz catechins（1,1.0 mmol）Add in reaction bulb with 5 milliliters of dioxane, add at ambient temperature
formalin（35.0uL）H dense with 50%2SO4（0.5 mL）, it is stirred at room temperature 24 hours, TLC detection reactions terminate.Add 20 millis
Rise water quenching to go out, point liquid after concussion, water are mutually extracted with ethyl acetate（20 mL x 3）, merging organic faciess, anhydrous sodium sulfate drying,
Filter, concentration, column chromatography purification obtains dimeric-catechin（2, see accompanying drawing）, yield is 50%.
Embodiment 2：Dimerization epicatechin ketone（3, see accompanying drawing）Synthesis
Dimeric-catechin（2,0.5 mmol）Add in reaction bulb with 5 milliliters of dichloromethane, add DMP at ambient temperature
（1.25mmol）, it is stirred at room temperature 16 hours, TLC detection reactions terminate.Add 5 milliliter of 10% hypo solution to be quenched, shake
After divide liquid, water to be mutually extracted with ethyl acetate（10 mL x 3）, merging organic faciess, anhydrous sodium sulfate drying is filtered, concentration, post layer
Analysis purification, obtains dimerization epicatechin ketone（3, see accompanying drawing）, yield is 87%.
Embodiment 3：Dimerization epicatechin（4, see accompanying drawing）Synthesis
Dimerization epicatechin ketone（3,0.5 mmol）Add in reaction bulb with 5 milliliters of tetrahydrofurans, be cooled to -78 °C, this temperature
Under be slowly added dropwise L-Selectride（1 mmol）, -78 °C are stirred 4 hours, and TLC detection reactions terminate.Add 5 milliliters of water quenchings
Go out, point liquid after concussion, water are mutually extracted with ethyl acetate（10 mL x 3）, merging organic faciess, anhydrous sodium sulfate drying is filtered, dense
Contracting, column chromatography purification, obtains dimerization epicatechin（4, see accompanying drawing）, yield is 75%.
Embodiment 4：Dimerization L-Epicatechin gallate（6, see accompanying drawing）Synthesis
Dimerization epicatechin（4,0.5 mmol）With O-Bz gallic acids（5,2.0 mmol）5 milliliters of dichloromethane are dissolved in, in room
DCC is added under the conditions of temperature（2.0 mmol）And DMAP（0.1 mmol）, it is stirred at room temperature 16 hours, TLC detection reactions terminate.Add
20 milliliters of water quenchings are gone out, and point liquid after concussion, water are mutually extracted with ethyl acetate（10 mL x 3）, merging organic faciess, anhydrous sodium sulfate is done
It is dry, to filter, concentration, column chromatography purification obtains dimerization L-Epicatechin gallate（6, see accompanying drawing）, yield is 60%.
Embodiment 5：TalienbisflavanA（7, see accompanying drawing）Synthesis
Dimerization L-Epicatechin gallate（6,0.1 mmol）2 milliliters of ethyl acetate are dissolved in, chromatograph is added at ambient temperature
Pure water（0.8 mL）With 20 % Pd (OH)2/C（10 mg）, it is stirred at room temperature 16 hours, TLC detection reactions terminate.Use ethyl acetate
Extraction（5 mL x 3）, merging organic faciess, anhydrous sodium sulfate drying is filtered, concentration, and column chromatography purification is obtained
TalienbisflavanA（7, see accompanying drawing）, yield is 90%.Proton nmr spectra1H NMR (400 MHz, CDCl3,)
6.91 (s, 4H), 6.85 (s, 2H), 6.67-6.64 (m, 4H), 6.02 (s, 2H), 5.40 (br, 2H),
4.80(br, 2H), 3.90 (s, 2H), 2.90 (dd, J = 17.4, 4.3 Hz, 2H), 2.80 (dd, J =
17.4,4.3 Hz, 2H), carbon-13 nmr spectra13CNMR(100MHz,CDCl3) 167.7,167.5,155.8,153.7,
146.3, 146.1, 145.9, 139.8, 130.9, 121.4, 19.7, 116.1, 115.2, 110.3, 106.8,
99.9,96.9,79.0,69.5,26.7,16.8, high resolution mass spectrum ESI sources (C45H36O20) m/ z 895.1734
[M − H] −(calculated for 895.1722)。
The present invention relates to formaldehyde dimerization reaction, DMP oxidation reactions, L-Selectride reduction reactions, dimerization epicatechin
With the reaction of 5 steps such as benzyl protection gallic acid coupling reaction, O-Bz deprotection reactions, synthesize procyanidin compounds
TalienbisflavanA.It is above-mentioned be embodied as illustrating be tightly the present invention preferred embodiments, be not to the present invention make its
The restriction of its form.
Claims (6)
1. a kind of total synthesis method of TalienbisflavanA, it is characterised in that including following synthesis step（See accompanying drawing）：
A) O-Bn catechins synthesize dimeric-catechin through acid catalyzed formaldehyde dimerization reaction；
B) dimeric-catechin synthesizes dimerization epicatechin through DMP oxidations and L-Selectride Chemoselective reductions；
C) dimerization epicatechin through with benzyl protection gallic acid coupling reaction, synthesize dimerization L-Epicatechin gallate；
D) dimerization L-Epicatechin gallate is through palladium carbon debenzylation, synthesis of natural product TalienbisflavanA.
2. catechin according to claim 1 is sour, dioxy through acid catalyzed formaldehyde dimerization reaction prioritizing selection sulphuric acid
Six rings are solvent, and reaction temperature is room temperature.
3. dimeric-catechin DMP oxidation reactions prioritizing selection moistening dichloromethane according to claim 1 be solvent, room temperature
Reaction condition.
4. dimeric-catechin diketone L-Selectride Chemoselective reduction prioritizing selection tetrahydrochysenes according to claim 1
Furan is solvent, and reaction temperature is -78 °C.
5. dimerization epicatechin according to claim 1 with benzyl protection gallic acid coupling reaction prioritizing selection DMAP is
Alkali, dichloromethane are solvent, and reaction temperature is room temperature.
6. the palladium carbon debenzylation prioritizing selection acetic acid second of dimerization L-Epicatechin gallate according to claim 1
Ester is solvent, room temperature reaction condition.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611138586.3A CN106588850B (en) | 2016-12-12 | 2016-12-12 | total synthesis method of TalienbisflavanA |
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| CN106588850A true CN106588850A (en) | 2017-04-26 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103857665A (en) * | 2011-08-09 | 2014-06-11 | 雀巢产品技术援助有限公司 | Synthesis of catechin and epicatechin conjugates |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103857665A (en) * | 2011-08-09 | 2014-06-11 | 雀巢产品技术援助有限公司 | Synthesis of catechin and epicatechin conjugates |
Non-Patent Citations (3)
| Title |
|---|
| LI-FANG ZHU ET AL.: "New Flavan-3-ol Dimer from Green Tea Produced from Camellia taliensis in the Ai-Lao Mountains of Southwest China", 《J. AGRIC. FOOD CHEM.》 * |
| PENG ZENG ET AL.: "Advances in studying of the pharmacological activities and structure–activity relationships of natural C-glycosyl flavonoids", 《ACTA PHARMACEUTICASINICAB》 * |
| QING LIU ET AL.: "Phenolic Antioxidants from Green Tea Produced from Camellia crassicolumna Var. multiplex", 《J. AGRIC. FOOD CHEM.》 * |
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