CN103113338B - Asymmetric full-synthesis method of Tanikolide - Google Patents

Asymmetric full-synthesis method of Tanikolide Download PDF

Info

Publication number
CN103113338B
CN103113338B CN201310038301.9A CN201310038301A CN103113338B CN 103113338 B CN103113338 B CN 103113338B CN 201310038301 A CN201310038301 A CN 201310038301A CN 103113338 B CN103113338 B CN 103113338B
Authority
CN
China
Prior art keywords
reaction
add
dissolved
anhydrous
concentrated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201310038301.9A
Other languages
Chinese (zh)
Other versions
CN103113338A (en
Inventor
杨华
孙默然
谢阳腊
周航
牛长岭
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhengzhou University
Original Assignee
Zhengzhou University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhengzhou University filed Critical Zhengzhou University
Priority to CN201310038301.9A priority Critical patent/CN103113338B/en
Publication of CN103113338A publication Critical patent/CN103113338A/en
Application granted granted Critical
Publication of CN103113338B publication Critical patent/CN103113338B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • 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

Landscapes

  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses an asymmetric full-synthesis method of a natural product ()-Tanikolide, belonging to the field of organic synthesis. The ()-Tanikolide has a structure shown in the specification; and chiral tertiary alcohol is created through a synthesis strategy which is completely different from that of the existing document, and the synthesis of ()-Tanikolide is correspondingly selectively finished. The synthesis path takes the optically active amino alcohol as a raw material and comprises the following steps of: performing an oxidation reaction to obtain amino aldehyde with maintained configuration; creating chiral quaternary carbon through three-step continuous reaction including Witting reaction, [2,3]-Meisenheimer rearrangement and catalytic hydrogenation; and finally performing functional group transformation to obtain a target product. The total yield is 35%. The operation is convenient, the reaction conditions are moderate, the method is suitable for large-scale preparation, and the optical rotation of the synthesis product is consistent with the optical rotation and optical rotation direction of the natural product ()-Tanikolide.

Description

The Enantioselective total synthesis method of Tanikolide
Technical field
The present invention relates to the Enantioselective total synthesis method of natural product (+)-Tanikolide, belong to organic synthesis field.
Background technology
The exploitation of Living marine resources are subject to the attention of country day by day, and marine organisms can produce due to special habitat the active substance that terrestrial life do not have, and have obtained the generally acknowledged of scientific circles.External many bibliographical informations, marine microorganism, even the genus kind similar to land, due to special living environment, also can produce the active substance different from land microorganism.Therefore, marine microorganism is considered to the valuable source obtaining new antibiotic and other active substance from now on, and becomes the focus of research both at home and abroad.
1999, Gernick group isolated natural product (+)-Tanikolide first from the tropical cyanobacteria Lyngbyamajusclula on Madagascan Tanikeli island.Biological activity test shows that (+)-Tanikolide has higher toxicity and fungicidal activity: to the LD of extra large shrimp 50be 3.6 μ g/mL; To the LD of snail 50be 9.0 μ g/ mL; To goldfish, there is obvious anesthetic action (10 μ g/mL), and to Candida albicans fungi, there is good restraining effect (100 μ g/disk).
Meanwhile, Gernick group by means of 2D NMR, 1h- 1the spectrum means that H COSY, HMBC etc. are advanced, utilize the anisotropy that generation derivative and introducing chiral auxiliary (such as generating the acid amides with chirality) produce afterwards, the absolute configuration determining C-5 is R configuration, as follows:
Although (+)-Tanikolide has significant biological activity, it is very difficult for only relying on and obtaining (+)-Tanikolide from occurring in nature.According to Gernick group, 70mg (+)-Tanikolide can only be extracted from every kilogram of marine cyanobacterium bacterium Lyngbya majuscula.Obviously, the amount of Natural Samples is only relied on to be difficult to meet the needs its chemical property and biological activity being done to further investigation further.Day by day deficient, exhausted due to natural matter resource, the method for seeking chemosynthesis obtains the interest that (+)-Tanikolide causes numerous synthetic organic chemist.
Up to the present; the synthetic great majority of (+)-Tanikolide concentrate on the structure to its chirality tertiary alcohol; its synthesis strategy comprises: Sharpless asymmetric Epoxidation (the Angew. Chem. Int. Ed. 2005,44,5857-5960 of vinyl carbinol; Org. Biomol. Chem. 2004,2,621-624; Bull. Chem. Soc. Jpn. 2005,78,1549-1554.); With optical purity D-erythrulose (Tetrahedron 2003,59,857-864) and D-erythrose (Tetrahedron Lett. 2003,44,2513-2516.) for starting raw material introduces chiral carbon; The stereospecificity C-H insertion reaction (Chem. Pharm. Bull. 2004,52,848-852) of the chiral secondary alcohol of dichlorocarbene; Asymmetric alpha-alkyl, the Bayer-Villiger of 'beta '-ketoester are oxidized successive reaction (Angew. Chem. Int. Ed. 2006,45,4301-4305); α-the metallization of ketone and olefin metathesis ring-closure reaction (Tetrahedron 2003,59,4085-4101); The Domino of epoxy alcohol and hypervalent iodine reagent reacts (Angew. Chem. Int. Ed.2005,44,5857-5860; Chem. Eur. J. 2007,13,5238-5248).
Summary of the invention
The present invention is intended to, by constructing the chirality tertiary alcohol with the diverse synthesis strategy of existing document, complete the complete synthesis of (+)-Tanikolide enantioselectivity, realize high yield, suitability for industrialized production.
For realizing the object of the invention, the present invention take optically active aminoalcohol as raw material, first the amino-aldehyde of retention of configuration is obtained through oxidizing reaction, again by Witting reaction, [2,3]-Meisenheimer rearrangement and catalytic hydrogenation three step successive reaction construct chirality quaternary carbon, obtain target product finally by functional group conversions.
Its concrete synthesis step is: with optical activity (L)-N-Boc-α-aminoalcohol 2for starting raw material, first explore the method for oxidation that chiral carbon configuration can be made to keep completely, and obtain (L)-N-Boc-alpha-amino group aldehyde 3, the latter and Witting reagent 4be obtained by reacting N-Boc-enamine 5, the more two benzyl enamine of precursor N-of Meisenheimer rearrangement reaction is obtained through two Benzylation, reduction, acetylization reaction 8.Compound 8oxynitride is generated under m-CPBA effect 9, obtain triol through hydrolysis, catalytic hydrogenation 11.Vicinal diamines obtains alcohol through the protection of propylidene base 12,one pot of successive reaction alcohol oxidation, hydrochloric acid Deprotection occurring afterwards and lactonizes, directly obtained delta-lactone (+)-Tanikolide( 1).
The synthesis step of compound 1 provided by the invention is:
The concrete synthesis step of above-mentioned route is:
Step one: (L)-N-Boc-α-aminoalcohol 2within the scope of-50 DEG C in organic solvent ~ 50 DEG C, under oxygenant effect, be transformed into (L)-N-Boc-alpha-amino group aldehyde 3, products therefrom is concentrated after extraction, does not need purifying to be directly used in next step reaction; Said organic solvent is one or more in methylene dichloride, DMSO and tetrahydrofuran (THF); Said oxygenant is Swern oxygenant, Parkin-Doering oxygenant, IBX oxygenant, Dess-Martin oxygenant or TEMPO oxygenant, is preferably Dess-Martin oxygenant and TEMPO oxygenant.
Step 2: amino-aldehyde 3in organic solvent within the scope of 50 ~ 150 DEG C, with Witting reagent 4be obtained by reacting compound 5, products therefrom carries out purifying through column chromatography; Said organic solvent is tetrahydrofuran (THF), toluene, methylene dichloride or benzene.
Step 3: alpha, beta-unsaturated esters 5in organic solvent within the scope of 0 ~ 100 DEG C, under trifluoroacetic acid effect, slough Boc protecting group.Thick product is not purified, under inert solvent and acid binding agent exist, obtains two benzyl alpha, beta-unsaturated esters with benzyl bromine reaction 6.Said organic solvent is methylene dichloride; Described acid binding agent is one or more in salt of wormwood, sodium carbonate, triethylamine, pyridine and DMAP (DMAP); Said inert solvent is acetonitrile, toluene, tetrahydrofuran (THF) or ethyl acetate.
Step 4: two benzyl alpha, beta-unsaturated esters 6in organic solvent within the scope of-50 DEG C ~ 50 DEG C, under reductive agent effect, be reduced to glycol 7, products therefrom carries out purifying through column chromatography; Said organic solvent be methyl alcohol, ethanol, the trimethyl carbinol, tetrahydrofuran (THF), anhydrous diethyl ether or methyl alcohol, ethanol, the trimethyl carbinol respectively with the mixing solutions of methylene dichloride, be preferably tetrahydrofuran (THF); Said reductive agent is lithium aluminium hydride, sodium borohydride.
Step 5: compound 7in anhydrous organic solvent, within the scope of-50 DEG C ~ 50 DEG C, under catalyst action, obtain diacetate esters with acylation reaction 8, products therefrom carries out purifying by column chromatography; Said anhydrous organic solvent is ethylene dichloride; Said acylating agent is diacetyl oxide, Acetyl Chloride 98Min. or methylvinyl acetate; Said catalyzer is DMAP, PPY or P (MeNCH 2cH 2) 3.
Step 6: compound 8in organic solvent within the scope of 0 ~ 100 DEG C, under oxygenant effect, rearrangement reaction occurs, products therefrom carries out purifying through column chromatography, obtains oxynitrides 9; Said organic solvent is preferably methylene dichloride; Said oxygenant is preferably m-CPBA; The amount of oxygenant used is compound 80.9 ~ 1.3 times of molar weight.
Step 7: compound 9in organic solvent within the scope of 0 ~ 100 DEG C, under alkali effect, there is ester hydrolysis reaction generate alcohol 10, products therefrom carries out purifying through column chromatography; Said organic solvent is preferably tetrahydrofuran (THF).Described alkali is potassium hydroxide or sodium hydroxide.
Step 8: compound 10in organic solvent within the scope of 0 ~ 100 DEG C, under catalyst action, there is hydro-reduction reaction, disconnect nitrogen-oxygen bond and obtain three alkylol cpds 11,products therefrom carries out purifying through column chromatography.Said catalyzer is preferably Pd/C; Said organic solvent is preferably methyl alcohol.
Step 9: compound 11in organic solvent within the scope of 0 ~ 100 DEG C, under catalyst action, the protection of propylidene base is carried out to vicinal diamines and generate compound 12, products therefrom carries out purifying through column chromatography.Said organic solvent is acetone, ether; Said catalyzer is tosic acid, boron trifluoride, iodine; Propylidene base protects reagent used to be acetone, 2,2-dimethoxypropane, is preferably 2,2-dimethoxypropane.
Step 10: compound 12in organic solvent within the scope of 0 ~ 100 DEG C, to there is under oxygenant effect one pot of successive reaction that alcoholic extract hydroxyl group is oxidized to carboxyl, hydrochloric acid takes off propylidene base and lactonize, directly obtain target product 1, products therefrom carries out purifying through column chromatography; Said organic solvent is preferably acetonitrile; Said oxygenant is KMnO 4/ NaOH, Jones oxygenant, TEMPO/NaClO/NaClO 2or H 5iO 6/ CrO 3, be preferably TEMPO/NaClO/NaClO 2.
Witting reagent described in step 2 of the present invention 4,its synthetic method is as follows:
By bromododecane and triphenylphosphine reflux in toluene 3 days, and be placed in vacuum drier dried overnight.Within the scope of-50 DEG C in organic solvent ~ 50 DEG C, under the effect of calculated amount alkali, in above-mentioned freshly prepd bromododecane base triphenylphosphine salt, dropwise add the anhydrous solution of Vinyl chloroformate.Products therefrom is concentrated after extraction, does not need purifying to be directly used in next step reaction.Said organic solvent is anhydrous tetrahydro furan, and said alkali is potassium tert.-butoxide.
This synthetic route possesses following advantage: 1. raw material is natural amino acid, cheap and easy to get, and each step agents useful for same is laboratory common agents; 2. except oxynitrides 10catalytic hydrogenation yield be 61%, other respectively step reaction be almost quantitative reaction, ten step total recoverys 35%.3. easy and simple to handle, reaction conditions is gentle, is applicable to a large amount of preparation; 4. the chirality of natural amino acid is shifted completely in Meisenheimer rearrangement reaction process, and the specific rotation of synthetics is consistent with the specific rotation of natural product (+)-Tanikolide and optical direction.
Embodiment
Below by the embodiment of embodiment form, foregoing of the present invention is described in further detail again, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only for following embodiment.All technology realized based on foregoing of the present invention all belong to the scope of Ben Fanming.
Be below embodiments of the invention, be divided into ten steps for sake of convenience.
Step 1:
By 332 mg (1.43 mmol) primary alconol 2be dissolved in 7 mL CH 2cl 2in, add 1 mL H 2o, then add 67 mg (0.43 mmol) TEMPO, 17 mg (0.14 mmol) KBr, 16 mg (0.18 mmol) NaHCO successively 3.After stirring at normal temperature 10min, 1.29 mL (1.7 mmol, 10%) NaClO is joined in reaction system in 40 min.Add rear 100mL CH 2cl 2diluting reaction system, uses 2 × 10 mL H successively 2o, 2 × 10 mL saturated common salt water washing organic phases.Anhydrous MgSO 4dry, concentrated, obtain 322 mg colorless oil, not purifiedly directly carry out Wittig reaction.
Step 2:
3229mg (6.31mmol) bromododecane base triphenylphosphine salt (bromododecane and triphenylphosphine reflux in toluene 3 days) is placed in 100mL two-mouth bottle, is positioned over dried overnight in vacuum drier, two-mouth bottle is replaced N 2after add the anhydrous THF of 25mL.Again replace N 2, stir 10min under condition of ice bath after, add 710mg (6.31mmol) fast tbuOK, and again replace N 2, reaction solution promptly becomes orange turbid solution by achromaticity and clarification.After stirring 2h under condition of ice bath, dropwise add anhydrous THF (5mL) solution of 0.30mL (3.15mmol) Vinyl chloroformate, along with adding of Vinyl chloroformate, mixture color gradually becomes light yellow by orange.After reaction 2h by reaction system filtered through silica gel, concentrated to obtain dark orange oily liquids.Not purified directly carry out next step reaction.
By 919mg (3.96mmol) the N-Boc-amino-aldehyde of above-mentioned preparation 3be dissolved in 20mL chloroform, under condition of ice bath, add 3981mg (7.92mmol) Wittig reagent 4, directly concentrate after 30min, column chromatography (PET:EA=10:1, r f =0.3) 1696mg colorless oil is obtained 5(94% yield).
[α] 20 D( c=1.30, CHCl 3); IR (KBr) 3374, 2923, 2854, 1747, 1648 cm _1; 1H NMR (400 MHz, CDCl 3): δ 6.59 (d, 1H, J= 9.40 Hz ), 5.23 (s, 1H), 4.81 (s, 1H), 4.19 (q, 2H, J= 7.08 Hz ), 3.70 (s, 3H), 2.66 (dd, 1H, J= 16.21 Hz , 4.32 Hz), 2.59 (dd, 1H, J= 16.21 Hz , 5.63 Hz), 2.48 – 2.27 (m, 2H), 1.43 (s, 9H), 1.35 – 1.23 (m, 21H), 0.88 (t, 3H, J= 7.12 Hz); 13C NMR (100 MHz, CDCl 3): δ 171.2, 167.6, 154.7, 138.3, 135.0, 79.7, 60.7, 51.8, 45.2, 39.5, 31.9, 29.6, 29.6, 29.4, 29.3, 28.3, 14.2, 14.1; HRMS (ESI-TOF) m/z[M + Na] +calcd for C 25H 45NO 6Na 473.3145, found 473.3146.。
Step 3:
By 1696mg (3.72mmol) alpha, beta-unsaturated esters 5be dissolved in the anhydrous CH of 15mL 2cl 2in, then 0.69 mLTFA (9.30mmol) is joined in reaction solution.Room temperature reaction 4h, drains solvent and unnecessary TFA.In enriched material, add 20ml anhydrous acetonitrile, then add 1540mg K successively 2cO 3(11.16mmol) with 1.10ml BrBn (9.30mmol).Decompressing and extracting solvent and unnecessary BrBn after room temperature reaction 30h, add water (20mL), and ethyl acetate (3 × 60mL) extracts, and organic phase merges, and saturated aqueous common salt (2 × 10ml) washs.Anhydrous magnesium sulfate drying, filtration, concentrated, column chromatography (PET:EA=25:1, r f =0.3) colorless oil is obtained 6(1793 mg), yield 90%.
[α] 20 D( c= - 4.11, CHCl 3); IR (KBr) 3062, 3027, 2925, 1743, 1713 cm _1; 1H NMR (400 MHz, CDCl 3): δ 7.40 - 7.30 (m, 8H), 7.29 - 7.23 (m, 2H), 6.79 (d, 1H, J= 10.31 Hz), 4.27 (q, 2H, J= 7.12 Hz), 4.06 (td, 1H, J= 9.82 Hz, 6.32 Hz), 3.89 (d, 2H, J= 13.79 Hz), 3.45 (d, 2H, J= 13.79 Hz), 3.68 (s, 3H), 2.86 (dd, 1H, J= 14.10 Hz, 9.03 Hz), 2.42 (dd, 1H, J= 14.12 Hz, 9.02 Hz), 1.37 (t, 3H, J= 7.21 Hz), 1.34 – 1.15 (m, 18H), 0.93 (t, 3H, J=6.42 Hz ); 13C NMR (100 MHz, CDCl 3): δ 171.3, 167.6, 139.4, 136.8, 136.8, 128.7, 128.2, 127.0, 77.7, 77.1, 76.8, 60.7, 53.8, 53.6, 51.6, 38.0, 32.0, 29.7, 29.6, 29.6, 29.4, 29.4, 29.2, 22.7, 14.3, 14.2; HRMS (ESI-TOF) m/z[M + Na] +calcd for C 34H 49NO 4Na 558.3559, found 558.3560.。
Step 4:
By 514mg (13.24mmol) LiAlH in 50mL two-mouth bottle 4be suspended in 25mL anhydrous diethyl ether, displacement N 2, stir 10min under condition of ice bath after, by 1432mg (3.31mmol) two benzyl compounds 6be dissolved in 10mL anhydrous diethyl ether, and drop in reaction system with syringe, under adding rear condition of ice bath, stir 10min, in reaction system, drip 0.514 mL water successively, 0.514 mL 15% NaOH solution, 1.5424 mL water.White particle is there is after stirring 30min under condition of ice bath, filter with sand core funnel, and with 3 × 15mL ethyl acetate washing solid, concentrate organic phase, obtain 1135mg (94.5%yield) colourless oil liquid through column chromatography (PET:EA=2:1) 7.
[α] 20 D( c= – 25,82, CHCl 3); IR (KBr) 3420, 3028, 2924, 2853 cm _1; 1H NMR (400 MHz, CDCl 3): δ 7.40 – 7.30 (m, 8H), 7.29 – 7.23 (m, 2H), 5.63 (d, 1H, J= 10.20 Hz), 4.19 (d, 1H, J= 13.68 Hz), 4.15 (d, 1H, J= 13.68 Hz), 3.99 (d, 2H, J= 13.52 Hz), 3.86 – 3.78 (m, 1H), 3.74 – 3.66 (td, 2H, J= 10.68 Hz, 3.56 Hz), 3.36 (d, 2H, J= 13.52 Hz), 2.21 – 2.12 (m, 1H), 2.07 – 1.98 (m, 1H), 1.95 – 1.88 (m, 2H), 1.42 – 1.14 (m, 20H), 0.92 (t, 3H, J=6.52 Hz ); 13C NMR (100 MHz, CDCl 3): δ 143.4, 139.3, 128.8, 128.5, 127.2, 121.3, 66.3, 62.4, 55.7, 53.9, 34.5, 31.9, 29.8, 29.6, 29.6, 29.4, 29.3, 28.7, 28.6, 22.7, 14.1; HRMS (ESI-TOF) m/z[M + Na] +calcd for C 31H 47NO 2Na 488.3504, found 488.3505.。
Step 5:
By 1406mg (3.08mmol) glycol 7be dissolved in the anhydrous CH of 15mL 2cl 2in, add 1.725mL(12.32mmol under normal temperature) anhydrous Et 3n, 0.750mL(7.70mmol) acetic anhydride, catalytic amount DMAP, by reaction system 100 mL CH after reaction 20min 2cl 2dilution, and be placed in separating funnel 2 × 10 mL 1N HCl and wash, then use the saturated NaHCO of 10mL 3, 2 × 10 mL saturated common salt water washings.Anhydrous MgSO 4drying, concentrated, through column chromatography (PET:EA=13:1, r f =0.3) 1609mg(95%yield is obtained) colorless oil 8.
[α] 20 D( c= – 8.73, CHCl 3); IR (KBr) 3027, 2925, 2853, 1741 cm _1; 1H NMR (400 MHz, CDCl 3): δ 7.41 – 7.29 (m, 8H), 7.26 – 7.21 (m, 2H), 5.56 (d, 1H, J= 10.12 Hz), 4.59 (d, 1H, J= 12.76 Hz), 4.58 (d, 1H, J= 12.76 Hz), 4.36 – 4.27 (m, 1H), 4.11 – 4.04 (m, 1H), 3.84 (d, 2H, J= 13.84 Hz), 3.62 – 3.55 (m, 1H), 3.39 (d, 2H, J= 13.84 Hz), 2.15 (s, 3H), 2.12 – 2.06 (m, 1H), 1.99 – 1.91 (m, 1H), 1.89 (s, 3H), 1.87 – 1.81 (m, 1H), 1.72 – 1.61 (m, 1H), 1.39 – 1.09 (m, 18H), 0.93 (t, 3H, J=6.52 Hz ); 13C NMR (100 MHz, CDCl 3): δ 171.0, 170.8, 140.1, 139.0, 128.6, 128.2, 126.9, 126.1, 67.9, 61.9, 53.8, 51.7, 31.9, 29.9, 29.7, 29.4, 29.3, 28.7, 28.5, 22.7, 21.1, 20.8, 14.2; HRMS (ESI-TOF) m/z[M + Na] +calcd for C 35H 51NO 4Na 572.3216, found 572.3217.。
Step 6:
By 2031mg (3.70mmol) compound 8be dissolved in the anhydrous CH of 15mL 2cl 2in, add 790mg (3.89mmol) m-CPBA under normal temperature condition, under reflux conditions, react 2h, reaction solution is used 100mL CH 2cl 2dilution, uses 2 × 10 mL 10% NaOH, 2 × 10 mL saturated common salt water washings successively.Anhydrous MgSO 4drying, concentrated, through column chromatography (PET:EA=2:1, r f =0.3) 1881mg(90%yield is obtained) compound 9.
[α] 20 D( c= –6.64, CHCl 3); IR (KBr) 3030, 2925, 2853, 1742 _1; 1H NMR (400 MHz, CDCl 3): δ 7.38 – 7.26 (m, 10H), 5.55 (dt, 1H, J= 16.24 Hz, 6.76 Hz), 5.35 (d, 1H, J= 16.28 Hz), 4.23 (d, 1H, J= 11.68 Hz), 4.19 (d, 1H, J= 11.68 Hz), 4.07 (t, 2H, J= 6.64Hz), 3.90 – 3.80 (m, 5H), 2.90 (q, 2H, J= 6.56 Hz), 2.06 (s, 3H), 2.01 (s, 3H), 1.60 – 1.45 (m, 2H), 1.35 – 1.15 (m, 18H), 0.92 (t, 3H, J=6.53 Hz ); 13C NMR (100 MHz, CDCl 3): δ 171.0, 170.9, 137.6, 133.7, 129.9, 129.5, 128.3, 128.2, 127.3, 126.6, 81.7, 65.1, 64.1, 63.6, 61.9, 32.3, 31.9, 30.1, 29.7, 29.7, 29.6, 29.5, 29.4, 23.5, 22.7, 21.0, 20.9, 14.2; HRMS (ESI-TOF) m/z[M + Na] +calcd for C 35H 51NO 5Na 588.3665, found 588.3666.。
Step 7:
By 1109mg (1.87mmol) compound 9be dissolved in 25mL THF, 210mg (3.74mmol) KOH be dissolved in MeOH (2 mL) and also dropwise add in reaction system, after 30min, in reaction system, add 10mL 1N HCl.Stirring at room temperature 10min, removes organic solvent under reduced pressure, with 3 × 50mL CH 2cl 2aqueous phase extracted, merges organic phase, and with 2 × 10 mL saturated common salt water washings.Anhydrous MgSO 4drying, concentrated, through column chromatography (PET:acetone=5:1, r f =0.3) 802mg (89%yield) colorless oil is obtained 10.
[α] 20 D( c= –12.01, CHCl 3); IR (KBr) 3421, 3029, 2924, 2852 cm _1; 1H NMR (400 MHz, CDCl 3): δ 7.39 – 7.29 (m, 10H), 5.72 (dt, 1H, J= 16.04 Hz, 6.84 Hz), 5.46 (d, 1H, J= 16.08 Hz), 4.11 (d, 1H, J= 12.56 Hz), 4.01 – 3.75 (m, 4H), 3.64 (t, 2H, J= 6.42 Hz), 3.43 (d, 1H, J= 12.04 Hz), 3.31 (d, 1H, J= 12.04 Hz),2.71 (brs, 1H), 2.30 (q, 2H, J= 6.48 Hz),1.61 – 1.43 (m, 2H), 1.37 – 1.16 (m, 18H), 0.92 (t, 3H, J=6.52 Hz ); 13C NMR (100 MHz, CDCl 3): δ 136.8, 133.8, 130.0, 128.4, 128.2, 127.8, 83.5, 66.9, 63.3, 62.8, 61.8, 36.4, 35.3, 32.0, 30.2, 29.7, 29.7, 29.6, 29.4, 23.7, 22.7, 14.2; HRMS (ESI-TOF) m/z[M + Na] +calcd for C 31H 47NO 3Na 504.3454, found 504.3455.。
Step 8:
By 2138mg(4.438mmol) oxynitride 10be placed in 250mL hydrogenation bottle, use 150mL CH 3oH dissolves substrate, adds 620mg(10%w/w) palladium carbon, on hydrogenation unit, first replace four hydrogen, under normal temperature 60psi hydrogen pressure condition, react 2h, increase the temperature to 60 DEG C of reaction 2h.Reaction system is filtered, and with methanol wash palladium carbon, concentrates organic phase, through column chromatography (EA, r f =0.3) 781mg(61%yield is obtained) powdery white solid 11.
mp 56.1 – 57.9 ℃ (EtOAc); [α] 20 D( c= 1.72, CHCl 3); IR (KBr) 3420 cm _1; 1H NMR (400 MHz, CDCl 3): δ 3.64 (t, 2H, J= 5.88 Hz), 3.62 – 3.47 (brs, 3H), 3.44 (t, 2H, J= 12.16 Hz), 1.60 – 1.53 (m, 2H), 1.50 – 1.35 (m, 6H), 1.33 – 1.22 (m, 18H), 0.89 (t, 3H, J=6.52 Hz ); 13C NMR (100 MHz, CDCl 3): δ 75.0, 67.8, 61.9, 35.9, 34.9, 32.7, 31.9, 30.4, 29.7, 29.7, 29.4, 23.5, 22.7, 19.5, 14.1; HRMS (ESI-TOF) m/z[M + Na] +calcd for C 17H 36NO 3Na 311.2562, found 311.2564.。
Step 9:
By 342mg (1.186mmol) triol 11be dissolved in 3.9mL acetone, add 0.39mL 2,2-dimethoxypropane and catalytic amount p-methyl benzenesulfonic acid, after 30min, solvent is divided exactly in decompression, adds the saturated NaHCO of 20mL 3,with 3 × 30mL extraction into ethyl acetate aqueous phase after stirring 30min, merge organic phase, with the water washing of 2 × 10mL saturated common salt.Anhydrous MgSO 4drying, concentrated, through column chromatography (PET:EA=5:1, r f =0.3) 390mg (100%yield) colorless oil is obtained 12.
[α] 20 D( c= 2.42, CHCl 3); IR (KBr) 3434 cm _1; 1H NMR (400 MHz, CDCl 3): δ 3.75 (s, 2H), 3.65 (t, 2H, J= 5.88 Hz), 1.77 – 1.67 (brs, 1H), 1.67 – 1.42 (m, 7H), 1.42 – 1.35 (m, 7H), 1.35 – 1.20 (m, 18H), 0.89 (t, 3H, J=6.52 Hz ); 13C NMR (100 MHz, CDCl 3): δ 108.8, 83.6, 72.8, 62.6, 37.4, 37.0, 33.1, 31.9, 30.2, 29.6, 29.6, 29.6, 29.3, 27.2, 27.1, 24.2, 22.7, 20.4, 14.1; HRMS (ESI-TOF) m/z[M + Na] +calcd for C 20H 40NO 3Na 351.2875, found 351.2876.。
Step 10:
By 220mg (0.70mmol) compound 12be dissolved in 3.6mLCH 3in CN, add phosphate buffer solution (0.67M, the 2091mg NaH of 2.72mL 2pO 4with 4799mg Na 2hPO 4be dissolved in 40mL H 2in O), add 33mg(0.21mmol) TEMPO, control temperature is at 35 DEG C, and in 2h, adding 1.11mL NaClO, (1.11mL 10% NaClO solution is dissolved in 1.69mL H by 1.40mmol 2and 159mgNaClO O), 2(1.40mmol, by 159mg NaClO 2be dissolved in 0.70mL H 2o) aqueous solution.After adding, under condition of ice bath, slowly drip 2mL concentrated hydrochloric acid, by 3 × 30 mL extraction into ethyl acetate reaction systems after 2h, anhydrous MgSO 4drying, concentrated, through column chromatography (PET:EA=8:1, r f =0.3) 190mg(95%yield is obtained) white solid 1.
mp 35.2 – 36.7 ℃ (EtOAc); [α] 20 D( c= 2.77, CHCl 3); IR (KBr) 3434, 1728 cm _1; 1H NMR (400 MHz, CDCl 3): 3.66 (d, 1H, J= 11.90 Hz), 3.55 (d, 1H, J= 11.90 Hz), 2.65 (brs, 1H), 2.48 (t, 2H, J= 6.23 Hz), 1.97 – 1.80 (m, 3H), 1.77 – 1.66 (m, 3H), 1.65 – 1.56 (m, 1H), 1.33 – 1.24 (m, 18H), 0.88 (t, 3H, J=6.32 Hz ); 13C NMR (100 MHz, CDCl 3): δ 172.1, 86.6, 67.4, 36.7, 31.9, 30.0, 29.8, 29.6, 29.6, 29.5, 29.5, 29.3, 26.6, 23.4, 22.7, 16.1, 14.1; HRMS (ESI-TOF) m/z[M + Na] +calcd for C 17H 32NO 3Na 307.2249, found 307.2250.。

Claims (1)

  1. The Enantioselective total synthesis method of 1.Tanikolide, it has structure shown in formula 1, it is characterized in that, synthesizes as follows:
    Step 1:
    By 332 mg, 1.43 mmol primary alconols 2be dissolved in 7 mL CH 2cl 2in, add 1 mL H 2o, then add 67 mg successively, 0.43 mmol TEMPO, 17 mg, 0.14 mmol KBr, 16 mg, 0.18 mmol NaHCO 3, after stirring at normal temperature 10min, by 1.29 mL, 1.7 mmol, 10%NaClO join in reaction system in 40 min; Add rear 100mL CH 2cl 2diluting reaction system, uses 2 × 10 mL H successively 2o, 2 × 10 mL saturated common salt water washing organic phases; Anhydrous MgSO 4dry, concentrated, obtain 322 mg colorless oil, not purifiedly directly carry out Wittig reaction;
    Step 2:
    3229mg, 6.31mmol bromododecane base triphenylphosphine salt is placed in 100mL two-mouth bottle, is positioned over dried overnight in vacuum drier, two-mouth bottle is replaced N 2after add the anhydrous THF of 25mL; Again replace N 2, stir 10min under condition of ice bath after, add 710mg fast, 6.31mmol, tbuOK, and again replace N 2, reaction solution promptly becomes orange turbid solution by achromaticity and clarification; After stirring 2h under condition of ice bath, dropwise add 0.30mL, the anhydrous THF solution 5mL of 3.15mmol Vinyl chloroformate, along with adding of Vinyl chloroformate, mixture color gradually becomes light yellow by orange; After reaction 2h by reaction system filtered through silica gel, concentrated to obtain dark orange oily liquids; Not purified directly carry out next step reaction; Bromododecane base triphenylphosphine salt is prepared from reflux in toluene by bromododecane and triphenylphosphine for 3 days;
    By the 919mg of above-mentioned preparation, 3.96mmol N-Boc-amino-aldehyde 3be dissolved in 20mL chloroform, under condition of ice bath, add 3981mg, 7.92mmol, Wittig reagent 4, directly concentrate after 30min, column chromatography, PET:EA=10:1, r f =0.3 obtains 1696mg colorless oil 5;
    Step 3:
    By 1696mg, 3.72mmol alpha, beta-unsaturated esters 5be dissolved in the anhydrous CH of 15mL 2cl 2in, then by 0.69 mL, 9.30mmol TFA, joining in reaction solution, room temperature reaction 4h, drains solvent and unnecessary TFA; In enriched material, add 20ml anhydrous acetonitrile, then add 1540mg successively, 11.16mmol K 2cO 3, and 1.10ml, 9.30mmol BrBn; After room temperature reaction 30h, decompressing and extracting solvent and unnecessary BrBn, add water 20mL, 3 × 60mL extraction into ethyl acetate, and organic phase merges, the water washing of 2 × 10ml saturated common salt; Anhydrous magnesium sulfate drying, filtration, concentrated, column chromatography, PET:EA=25:1, r f =0.3 obtains colorless oil 6;
    step 4:
    By 514mg, 13.24mmol LiAlH in 50mL two-mouth bottle 4be suspended in 25mL anhydrous diethyl ether, displacement N 2, stir 10min under condition of ice bath after, by two to 1432mg, 3.31mmol benzyl compounds 6be dissolved in 10mL anhydrous diethyl ether, and drop in reaction system with syringe, under adding rear condition of ice bath, stir 10min, in reaction system, drip 0.514 mL water successively, 0.514 mL 15% NaOH solution, 1.5424 mL water; Occur white particle after stirring 30min under condition of ice bath, filter with sand core funnel, and wash solid by 3 × 15mL ethyl acetate, concentrated organic phase, through column chromatography, PET:EA=2:1 obtains 1135mg colourless oil liquid 7;
    step 5:
    By 1406mg, 3.08mmol glycol 7be dissolved in the anhydrous CH of 15mL 2cl 2in, add 1.725mL under normal temperature, the anhydrous Et of 12.32mmol 3n, 0.750mL, 7.70mmol acetic anhydride, catalytic amount DMAP, by reaction system 100 mL CH after reaction 20min 2cl 2dilution, and be placed in separating funnel 2 × 10 mL 1N HCl and wash, then use the saturated NaHCO of 10mL 3, 2 × 10 mL saturated common salt water washings, anhydrous MgSO 4drying, concentrated, through column chromatography, PET:EA=13:1, r f =0.3 obtains 1609mg colorless oil 8;
    Step 6:
    By 2031mg, 3.70mmol compound 8be dissolved in the anhydrous CH of 15mL 2cl 2in, add 790mg under normal temperature condition, 3.89mmol m-CPBA, under reflux conditions, react 2h, reaction solution is used 100mL CH 2cl 2dilution, uses 2 × 10 mL 10% NaOH, 2 × 10 mL saturated common salt water washings successively; Anhydrous MgSO 4drying, concentrated, through column chromatography, PET:EA=2:1, r f =0.3 obtains 1881mg compound 9;
    Step 7:
    By 1109mg, 1.87mmol compound 9be dissolved in 25mL THF, 210mg, 3.74mmol KOH be dissolved in 2 mL MeOH and also dropwise add in reaction system, after 30min, in reaction system, add 10mL 1N HCl; Stirring at room temperature 10min, removes organic solvent under reduced pressure, with 3 × 50mL CH 2cl 2aqueous phase extracted, merges organic phase, and with 2 × 10 mL saturated common salt water washings, anhydrous MgSO 4drying, concentrated, through column chromatography, PET:acetone=5:1, r f =0.3 obtains 802mg colorless oil 10;
    Step 8:
    By 2138mg, 4.438mmol oxynitride 10be placed in 250mL hydrogenation bottle, use 150mL CH 3oH dissolves substrate, adds 620mg, 10%w/w palladium carbon, first replaces four hydrogen on hydrogenation unit, under normal temperature 60psi hydrogen pressure condition, react 2h, increases the temperature to 60 DEG C of reaction 2h; Reaction system is filtered, and with methanol wash palladium carbon, concentrates organic phase, EA column chromatography, r f =0.3 obtains 781mg powdery white solid 11;
    Step 9:
    By 342mg, 1.186mmol triol 11be dissolved in 3.9mL acetone, add 0.39mL 2,2-dimethoxypropane and catalytic amount p-methyl benzenesulfonic acid, after 30min, solvent is divided exactly in decompression, adds the saturated NaHCO of 20mL 3, with 3 × 30mL extraction into ethyl acetate aqueous phase after stirring 30min, merge organic phase, with the water washing of 2 × 10mL saturated common salt, anhydrous MgSO 4drying, concentrated, through column chromatography, PET:EA=5:1, r f =0.3 obtains 390mg colorless oil 12;
    step 10:
    By 220mg, 0.70mmol compound 12be dissolved in 3.6mLCH 3in CN, add the phosphate buffer solution of 2.72mL, add 33mg, the TEMPO of 0.21mmol, control temperature, at 35 DEG C, adds 1.11mL in 2h, 1.40mmol NaClO, and 159mg, 1.40mmol NaClO 2the aqueous solution; After adding, under condition of ice bath, slowly drip 2mL concentrated hydrochloric acid, by 3 × 30 mL extraction into ethyl acetate reaction systems after 2h, anhydrous MgSO 4drying, concentrated, through column chromatography, PET:EA=8:1, r f =0.3 obtains 190mg white solid 1; Phosphate buffer solution is by 0.67M, 2091mg NaH 2pO 4with 4799mg Na 2hPO 4be dissolved in 40mL H 2be prepared from O; NaClO is by being dissolved in 1.69mL H by 1.11mL 10% NaClO solution 2be prepared from O; NaClO 2by by 159mg NaClO 2be dissolved in 0.70mL H 2o is prepared from.
CN201310038301.9A 2013-01-31 2013-01-31 Asymmetric full-synthesis method of Tanikolide Expired - Fee Related CN103113338B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310038301.9A CN103113338B (en) 2013-01-31 2013-01-31 Asymmetric full-synthesis method of Tanikolide

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201310038301.9A CN103113338B (en) 2013-01-31 2013-01-31 Asymmetric full-synthesis method of Tanikolide

Publications (2)

Publication Number Publication Date
CN103113338A CN103113338A (en) 2013-05-22
CN103113338B true CN103113338B (en) 2015-04-15

Family

ID=48411758

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310038301.9A Expired - Fee Related CN103113338B (en) 2013-01-31 2013-01-31 Asymmetric full-synthesis method of Tanikolide

Country Status (1)

Country Link
CN (1) CN103113338B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112029738B (en) * 2020-08-18 2022-04-29 浙江省人民医院 Human parkin protein acetylation and application thereof in medicine preparation

Also Published As

Publication number Publication date
CN103113338A (en) 2013-05-22

Similar Documents

Publication Publication Date Title
Sasaki et al. A general strategy for the convergent synthesis of fused polycyclic ethers via B-alkyl Suzuki coupling: synthesis of the ABCD ring fragment of ciguatoxins
Fuwa et al. Synthetic studies on a marine polyether toxin, gambierol: stereoselective synthesis of the EFGH ring system via B-alkyl Suzuki coupling
CN112608296B (en) Synthesis method of Brazilane natural product Brazilane
McLeod et al. Synthetic approaches to [5, 6]-benzannulated spiroketal natural products
CN110922350B (en) N-acetyl-3-oxyindole compound and construction method of C-O bond at C2 position thereof
CN103087074A (en) Method of semi-synthesizing artemisinin
CN106083803B (en) A kind of synthetic method of marine natural products Puupehedione
Harris et al. Enantioselective synthesis of 5-substituted α, β-unsaturated δ-lactones: application to the synthesis of styryllactones
Liu et al. A new approach to asymmetric synthesis of infectocaryone
CN104892614A (en) Synthesis method of 6H-isoindolo[2, 1-alpha]indol-6-one derivative
CN105085168B (en) Wheat midge sex pheromone precursor and wheat midge sex pheromone
CN103113338B (en) Asymmetric full-synthesis method of Tanikolide
CN110627765B (en) Preparation method of ticagrelor key intermediate
Kinugasa et al. Desymmetrization of meso-1, 2-diols via chiral oxazaborolidine-mediated ring-cleavage of acetal derivatives with silyl ketene S, O-acetal
Sato et al. Convergent synthesis of the BCDEFGHIJ-ring polyether core of gambieric acids, potent antifungal polycyclic ethers
Yasumoto et al. Isolation and absolute configuration determination of aliphatic sulfates as the Daphnia kairomones inducing morphological defense of a phytoplankton—Part 2
Potopnyk et al. The synthesis of higher carbon sugars: a study on the rearrangement of higher sugar allylic alcohols
Kido et al. Carbocyclic construction by the [2, 3] sigmatropic rearrangement of cyclic sulfonium ylides. A new entry for the stereoselective synthesis of substituted cyclohexanones
Takamura et al. A convergent synthesis of the right-hand fragment of ciguatoxin CTX3C
Iwasaki et al. Stereoselective vinylogous Mukaiyama aldol reaction of α-haloenals
Yadav et al. Total synthesis of 8-methoxygoniodiol related compounds via chiron approach
IwATA et al. Synthetic Studies on Spiroketal Natural Products. V. Total Synthesis of (+)-Talaromycin A and (-)-talaromycin B
CN103547558B (en) Preparation is containing the method for 5-membered ring compounds
Ikejiri et al. A novel and efficient method for inside selective esterification of terminal vic-diols
CN101440076A (en) Process for synthesizing optical activity 2-(1'(Z) alkenyl iodo-alkyl) tetrahydrofuran

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20150415

Termination date: 20160131

EXPY Termination of patent right or utility model