CN105481746A - Synthetic method for Dtena modified fragment of apratoxin marine natural product - Google Patents
Synthetic method for Dtena modified fragment of apratoxin marine natural product Download PDFInfo
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- CN105481746A CN105481746A CN201510804489.2A CN201510804489A CN105481746A CN 105481746 A CN105481746 A CN 105481746A CN 201510804489 A CN201510804489 A CN 201510804489A CN 105481746 A CN105481746 A CN 105481746A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention relates to a synthetic method for a Dtena modified fragment of an apratoxin marine natural product, which belongs to the field of chemical synthesis. The synthetic method comprises the following steps: subjecting boryl enol ether and aldehyde to adol reaction so as to prepare beta-hydroxyl ketone; preparing O-Troc alcohol through the Troc protection reaction of the hydroxyl group of beta-hydroxyl ketone and silyl ether deprotection reaction; subjecting the O-Troc alcohol and N-Fmoc proline to a coupling reaction to prepare o-O-Bz-yl ketone containing a proline constitutional unit; and carrying out O-Bz deprotection reaction of the o-O-Bz-yl ketone and oxidation reaction of newly generated o-hydroxyl ketone so as to prepare the Dtena modified fragment (as in a figure in the specification) of the apratoxin marine natural product. The synthetic method has the characteristics of a few reaction steps, high overall yield, good product selectivity, suitability for industrial production, etc.
Description
Technical field
The present invention relates to the synthetic method that a kind of apratoxin class marine natural product Dtena modifies fragment.
Background technology
Apratoxin class marine natural product is a kind of new type anticancer medicine of uniqueness, the cell fission of cancer cells can be made to stop at the G1 stage and rapid apoptosis, the migration (diffusion) of cancer cells secrete albumen can be stoped, the migration of normal human cell's secretory protein can not be stoped.The scientific research personnel in National Cancer research centre (http://dtp.nci.nih.gov/index.html) studies and finds that the biological activity of marine natural medicine apratoxin to 60 kinds of cancer cells shows special mechanism of action, all different from existing cancer therapy drug mechanism of action, the novel cancer therapy drug (Nat.Rev.Cancer of a class, 2006,6,813).Research finds that the active conformations of such marine natural product is its cis-configuration (with O-Me-Tyr-N-Me-Ala amido linkage for benchmark, seeing accompanying drawing, Bioorg.Med.Chem., 2002,10,1973).Intramolecular hydrogen bond (see photo) between the carbonylic oxygen atom of the hydroxyl hydrogen atom of No. 35 positions and No. 6 positions keeps its cis-configuration key factor (Bioorg.Med.Chem., 2002,10,1973).Easily there is enolization in the imines of No. 33 position (see photo) of Apratoxin class marine natural product, thus makes its 34 position chirality racemization (Chem.AsianJ., 2011,6,180), and then cause in its 34-35 position dehydration (see photo).The present invention changes the hydrogen atom of 34 positions of apratoxin class marine natural product into methyl (see photo), avoid the enolization of its No. 33 position imines, thus avoid its 34-35 position to dewater, be conducive to the intramolecular hydrogen bond keeping it corresponding in live body environment, and then be conducive to keeping its active conformations in live body environment, thus make its its antitumour activity of maintenance in live body environment.Therefore, the composition optimizes of Dtena modification fragment to such marine natural product of apratoxin class marine natural product is most important.
The synthesis of the Dtena modification fragment of this apratoxin class marine natural product only has a kind of report (J.Med.Chem.2014,57,3011) at present, and reactions steps is long, is not suitable for suitability for industrialized production.The present invention for starting raw material, has that reactions steps is few, total recovery is high with known enol boron ether and aldehyde, good product selectivity, be applicable to the features such as suitability for industrialized production.
Summary of the invention
The object of the invention is to provide a kind of apratoxin class marine natural product Dtena to modify the synthetic method of fragment.Reactions steps is few, good product selectivity, applicable suitability for industrialized production.
For achieving the above object, the present invention includes following steps:
A) with known enol boron ether and aldehyde for raw material, through adol reaction, synthesis beta-hydroxyketone;
B) beta-hydroxyketone is through perhydroxyl radical Troc protective reaction and silicon ether deprotection reaction, synthesis O-Troc alcohol;
C) linked reaction of O-Troc alcohol and N-Fmoc proline(Pro), synthesis is containing the adjacent O-Bz base ketone of proline structure unit;
D) adjacent O-Bz base ketone is through the O-Bz deprotection reaction of its ketone and the oxidizing reaction of newly-generated adjacent hydroxyketone, and the Dtena of synthesis apratoxin class marine natural product modifies fragment.
2. step a prioritization scheme described in: the adol of enol boron ether and aldehyde reacts prioritizing selection low-temp reaction system (-78 ° of C are to-20 ° of C), and ether is reaction solvent, and the reaction times is 16 hours.
3. step b prioritization scheme described in: the hydroxyl Troc protective reaction prioritizing selection DMAP of beta-hydroxyketone is alkali, and methylene dichloride is reaction solvent, room temperature reaction condition.Silicon ether deprotection reaction prioritizing selection water, methylene dichloride and methyl alcohol are mixed solvent, and acetic acid is promotor, room temperature reaction condition.
4. step c prioritization scheme described in: the linked reaction of O-Troc alcohol and N-Fmoc proline(Pro), first allows N-Fmoc proline(Pro) and 2,4,6-trichloro-benzoyl chloride at Et
3in N/PhMe reaction system, room temperature reaction generates nitration mixture acid anhydride, and this nitration mixture acid anhydride then reacts 6 hours with O-Troc alcohol under 90 ° of C temperature of reaction conditions, and synthesis synthesis is containing the adjacent O-Bz base ketone of proline structure unit.
5. steps d prioritization scheme described in: the O-Bz deprotection reaction prioritizing selection salt of wormwood of O-Bz base ketone is alkali, and methyl alcohol is solvent, and temperature of reaction is room temperature.The oxidizing reaction prioritizing selection of adjacent hydroxyketone take sodium periodate as oxygenant, tBuOH/H
2o is mixed solvent, and temperature of reaction is zero degree, and the reaction times is 0.5 hour.
Modify the existing synthetic method ratio (J.Med.Chem.2014,57,3011) of fragment with the Dtena of this apratoxin class marine natural product, the present invention has following characteristics:
1. with known enol boron ether and aldehyde for starting raw material, there is reactions steps few, be applicable to suitability for industrialized production;
2. high, the good product selectivity of total recovery.
Accompanying drawing explanation
Accompanying drawing: be the concrete synthetic route chart of the present invention
Embodiment
The synthesis of embodiment 1:beta-hydroxyketone (9, see accompanying drawing)
Add 20 milliliters of anhydrous diethyl ethers in reaction flask, be cooled to-78 ° of C, add enol boron ether 7(successively and see accompanying drawing, according to reference Synthesis, 1998,639 preparations, 10mmol) see accompanying drawing with aldehyde 8(, according to reference Org.Lett., 2003,5,3503 preparations, 10mmol) add in reaction flask, naturally rise to-20 ° of C, stir 16 hours at-20 ° of C, TLC detects esterification to be terminated.Add 20 ml water cancellation, separatory after concussion, aqueous phase is extracted with ethyl acetate (20mLx3), merges organic phase, anhydrous sodium sulfate drying, filters, concentrated, and column chromatography is purified, and obtain beta-hydroxyketone (9, see accompanying drawing), yield is 51%.
The synthesis of embodiment 2:O-Troc alcohol (10, see accompanying drawing)
Beta-hydroxyketone (10,10.0mmol) and 20 milliliters of methylene dichloride add in reaction flask, add TrocCl(12.0mmol at ambient temperature) and DMAP(13.0mmol), stirring at room temperature, TLC detects.After reaction terminates (about 6 hours), add 20 ml water cancellation, separatory after concussion, aqueous phase, with dichloromethane extraction (20mLx3), merges organic phase, anhydrous sodium sulfate drying, filters, concentrated, obtains beta-OTroc ketone (90%).Get this beta-OTroc ketone (5.0mmol), dissolve in 10 milliliters of H
2o/DCM/MeOH(1:1:1) in mixed solvent, add acetic acid (AcOH, 5.5mmol), stirring at room temperature under zero degree condition, TLC detects.After reaction terminates (about 8 hours), add 20 ml water cancellation, separatory after concussion, aqueous phase is with dichloromethane extraction (20mLx3), merge organic phase, anhydrous sodium sulfate drying, filter, concentrated, column chromatography is purified, and obtain O-Troc alcohol (10, see accompanying drawing), yield is 82%.
Embodiment 3: containing the synthesis of the adjacent O-Bz base ketone (12, see accompanying drawing) of proline structure unit
N-Fmoc proline(Pro) (11, see accompanying drawing, 2.0mmol) and 2,4,6-trichloro-benzoyl chlorides (2.0mmol) and Et
3n(2.0mmol) dissolve in 10 milliliters of toluene (PhMe), stirring at room temperature 2 hours, generate nitration mixture acid anhydride.O-Troc alcohol (10, see accompanying drawing, 2.0mmol) is added, stirring reaction 6 hours under 90 ° of C temperature of reaction conditions to this nitration mixture anhydride reactant system.TLC detection reaction terminates, add 20 milliliters of saturated sodium bicarbonate aqueous solution cancellation, separatory after concussion, aqueous phase is with dichloromethane extraction (20mLx3), merge organic phase, anhydrous sodium sulfate drying, filters, concentrated, column chromatography is purified, obtain the adjacent O-Bz base ketone (12, see accompanying drawing) containing proline structure unit, yield is 63%.
Embodiment 4:Apratoxin class marine natural product Dtena modifies the synthesis of fragment (6, see accompanying drawing)
Adjacent O-Bz base ketone (12, see accompanying drawing, 1.0mmol) dissolves in 5 ml methanol, and add 10 milliliter of 50% wet chemical, stirring at room temperature 4 hours, TLC detection reaction terminates.Add 20 ml waters, be extracted with ethyl acetate (20mLx3), merge organic phase, anhydrous sodium sulfate drying, filter, concentrated, obtain adjacent hydroxyketone (thick yield is 98%).Get this adjacent hydroxyketone (0.5mmol) and dissolve in 2 milliliters of tBuOH/H
2o(1:1) mixed solvent, add sodium periodate (2.0mmol) under zero degree condition, stir 0.5 hour at zero degree, TLC detection reaction terminates.Adjust ph to 6, is extracted with ethyl acetate (20mLx3), merges organic phase, anhydrous sodium sulfate drying, filters, concentrated, and column chromatography is purified, and obtain apratoxin class marine natural product Dtena and modify fragment (6, see accompanying drawing), yield is 76%.Optically-active [α]
d 20-52.5 ° of (c=0.1, CH
2cl
2), proton nmr spectra
1hNMR (400MHz, CDCl
3, mixtureofrotamers) δ 9.90 (br, 1H), 7.77 7.74 (m, 2H), 7.68 7.63 (m, 2H), 7.42 7.38 (m, 2H), 7.34 7.29 (m, 2H), 5.23 (d, J=10.4Hz, 0.4H), 5.13 (d, J=10.4Hz, 0.6H), 5.01 (d, J=12.0Hz, 0.6H), 4.90 (d, J=12.0Hz, 0.4H), 4.85 4.79 (m, 1H), 4.70 (d, J=12.0Hz, 0.4H), 4.63 (d, J=12.0Hz, 0.6H), 4.52 4.17 (m, 4H), 3.67 3.48 (m, 1H), 2.37 2.27 (m, 0.6H), 2.24 2.19 (m, 0.4H), 2.16 2.10 (m, 1H), 2.01 1.83 (m, 3H), 1.78 1.69 (m, 0.4H), 1.62 1.49 (M, 1.6H), 1.43 1.35 (m, 1H), 1.31 1.20 (m, 6H), 1.09 1.00 (m, 1H), 1.01 (d, J=6.4Hz, 1.2H), 0.94 (s, 5.4H), 0.87 (s, 3.6H), 0.69 (d, J=6.4Hz, 1.8H), carbon-13 nmr spectra
13cNMR (75MHz, CDCl
3, mixtureofrotamers) δ 181.1, 180.7, 172.8, 172.3, 154.8, 154.4, 154.2, 144.3, 144.1, 143.9, 143.7, 141.3, 141.3, 141.2, 141.2, 135.1, 135.0, 135.0, 130.6, 128.1, 128.1, 128.0, 127.7, 127.1, 127.1, 127.0, 125.5, 125.3, 125.2, 125.1, 120.0, 119.9, 94.9, 94.8, 80.5, 80.3, 79.8, 79.4, 77.0, 76.8, 68.0, 67.6, 59.8, 59.3, 47.2, 47.1, 46.9, 46.4, 38.1, 37.5, 37.1, 36.7, 34.9, 34.7, 34.6, 34.5, 31.6, 31.3, 30.0, 29.1, 29.1, 26.7, 26.5, 25.9, 25.3, 24.3, 23.5, 22.7, 22.2, 21.9, 20.8, 20.4, 19.9, 19.6, 19.4, 18.8, 14.2, 11.5, high resolution mass spectrum HRMS (TOFMSES
+) m/z:CalcdforC
37h
46cl
3nO
9na [M+Na]
+: 776.2130.Found:776.2151.
The present invention relates to the adol reaction of enol boron ether and aldehyde, the Troc protective reaction of its hydroxyl, silicon ether deprotection reaction, the linked reaction of O-Troc alcohol and N-Fmoc proline(Pro), O-Bz deprotection reaction and adjacent hydroxyketone 6 steps such as oxidizing reaction react, synthesize the Dtena modification fragment of apratoxin class marine natural product.Above-mentioned concrete implementation example is tightly preferred embodiments of the present invention, is not restriction the present invention being made to other form.
Claims (7)
1. apratoxin class marine natural product Dtena modifies a synthetic method for fragment, it is characterized in that, comprises following synthesis step (see photo):
A) with known enol boron ether and aldehyde for raw material, through adol reaction, synthesis beta-hydroxyketone;
B) beta-hydroxyketone is through perhydroxyl radical Troc protective reaction and silicon ether deprotection reaction, synthesis O-Troc alcohol;
C) linked reaction of O-Troc alcohol and N-Fmoc proline(Pro), synthesis is containing the adjacent O-Bz base ketone of proline structure unit;
D) adjacent O-Bz base ketone is through the O-Bz deprotection reaction of its ketone and the oxidizing reaction of newly-generated adjacent hydroxyketone, and the Dtena of synthesis apratoxin class marine natural product modifies fragment.
2. the adol of enol boron ether according to claim 1 and aldehyde reacts prioritizing selection low-temp reaction system (-78 ° of C are to-20 ° of C), and ether is reaction solvent, and the reaction times is 16 hours.
3. the hydroxyl Troc protective reaction prioritizing selection DMAP of beta-hydroxyketone according to claim 1 is alkali, and methylene dichloride is reaction solvent, room temperature reaction condition.
4. silicon ether deprotection reaction prioritizing selection water according to claim 1, methylene dichloride and methyl alcohol are mixed solvent, and acetic acid is promotor, room temperature reaction condition.
5. the linked reaction of O-Troc alcohol according to claim 1 and N-Fmoc proline(Pro), first allows N-Fmoc proline(Pro) and 2,4,6-trichloro-benzoyl chloride at Et
3in N/PhMe reaction system, room temperature reaction generates nitration mixture acid anhydride, and this nitration mixture acid anhydride then reacts 6 hours with O-Troc alcohol under 90 ° of C temperature of reaction conditions, and synthesis synthesis is containing the adjacent O-Bz base ketone of proline structure unit.
6. the O-Bz deprotection reaction prioritizing selection salt of wormwood of O-Bz base ketone according to claim 1 is alkali, and methyl alcohol is solvent, and temperature of reaction is room temperature.
7. the oxidizing reaction prioritizing selection of adjacent hydroxyketone according to claim 1 take sodium periodate as oxygenant, tBuOH/H
2o is mixed solvent, and temperature of reaction is zero degree, and the reaction times is 0.5 hour.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107344909A (en) * | 2016-05-07 | 2017-11-14 | 复旦大学 | A kind of method for preparing 3,7- dihydroxy -2,5,8,8- tetramethyl n-nonanoic acids |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140088016A1 (en) * | 2011-05-18 | 2014-03-27 | University Of Florida Research Foundation, Inc. | Macrocyclic therapeutic agents and methods of treatment |
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2015
- 2015-11-20 CN CN201510804489.2A patent/CN105481746A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140088016A1 (en) * | 2011-05-18 | 2014-03-27 | University Of Florida Research Foundation, Inc. | Macrocyclic therapeutic agents and methods of treatment |
Non-Patent Citations (3)
| Title |
|---|
| IAN PATERSON ET AL.,: "Polyketide Synthesis Using the Boron-Mediated, anti-Aldol Reactions of Lactate-Derived Ketones: Total Synthesis of (–)-ACRL Toxin IIIB", 《SYNTHESIS》 * |
| QI-YIN CHEN ET AL.,: "Improved Total Synthesis and Biological Evaluation of Potent Apratoxin S4 Based Anticancer Agents with Differential Stability and Further Enhanced Activity", 《J. MED. CHEM.》 * |
| TAKAYUKI DOI ET AL.,: "Total Synthesis of Apratoxin A", 《ORG. LETT.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107344909A (en) * | 2016-05-07 | 2017-11-14 | 复旦大学 | A kind of method for preparing 3,7- dihydroxy -2,5,8,8- tetramethyl n-nonanoic acids |
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