CN104725193A - Marine natural product (+)-(4E, 15Z)-4, 15-docosadienoic-1- alkyne-3-alcohol and synthetic method of enantiomer thereof - Google Patents
Marine natural product (+)-(4E, 15Z)-4, 15-docosadienoic-1- alkyne-3-alcohol and synthetic method of enantiomer thereof Download PDFInfo
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Abstract
The invention discloses a marine natural product (+)-(4E, 15Z)-4, 15- docosadienoic-1- alkyne-3-alcohol and a synthetic method of an enantiomer thereof, and belongs to the field of chemical synthesis. With propargyl alcohol as an initial raw material, the method provided by the invention comprises multiple reactive synthesis steps, such as coupling, triple bond transposition, oxidation, selective reduction, asymmetric alkynylation, esterification and hydrolysis and the like, and the key step is to carry out an asymmetric addition reaction on trimethylsilylacetylene and aldehyde to directly obtain a chiral propargyl alcohol structure. The synthetic method disclosed by the invention has the advantages of simple steps, high total yield and high optical purity of the product.
Description
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to the synthetic method of a kind of marine natural product (+)-(4E, 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol and enantiomorph thereof.
Background technology
In the past twenty years, marine natural product studies (Nat.Prod.Rep.2013,30,237-323. widely because the structure of its uniqueness and biological activity have obtained; Nat.Prod.Rep.2012,29,144-222.), become an emerging research field and study hotspot at present.(4E, 15Z)-docosa-4,15-dien-1-yn-3-ol are class sponge kind natural product (J.Org.Chem.1990,55,6223-5.), there is a chiral carbon atom in the structure of this natural product, there is a pair enantiomer, there is different biological activitys respectively.Research shows: this natural product antiviral, bactericidal antiphlogistic, antitumor etc. in there is unique effect (J.Nat.Prod.1992,55,1275-80.).Therefore how efficiently and economically to synthesize such product and there is high novelty and using value.Current acquisition (4E, 15Z)-docosa-4,15-dien-1-yn-3-ol) only there are enzyme catalysis method (.J.Nat.Prod.1995,58,1801-7.; J.Chem.Soc., Perkin Trans.11996, (10), 961-962.; J.Chem.Soc., Perkin Trans.11999, (4), 513-51.).Enzyme catalysis method refers to the alkynol utilizing lipase Novozym-435 resolution of racemic, obtain high optically pure acetic acid alkynol ester, then through KOH hydrolysis, obtain high optically pure alkynol, but the efficiency that enzyme splits is lower, overall yield is caused to only have 5-6%, on this point, because yield is lower, such product cannot be synthesized on a large scale in reality synthesis, therefore practicality is poor, and enzyme catalysis method also has some drawbacks, as loaded down with trivial details in needs enzyme reagent, severe reaction conditions, reactions steps etc.The method of asymmetry catalysis is the most effective means of current synthesizing chiral compound, up to now, bibliographical information is not also had to utilize method synthesis marine natural product (+)-(4E of asymmetry catalysis, 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol and enantiomorph thereof, the present invention uses the asymmetric addition of trimethyl silicane ethyl-acetylene and two olefine aldehydrs efficiently to prepare marine natural product (+)-(4E, 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol and enantiomorph thereof.
Summary of the invention
The object of this invention is to provide the synthetic method of a kind of marine natural product (+)-(4E, 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol and enantiomorph thereof.The structural formula of described natural product and enantiomorph thereof is:
(+)-(4E, 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol) (-)-(4E, 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol)
Be starting raw material with propargyl alcohol, comprise the reactions such as coupling, triple bond transposition, oxidation, selective reduction, asymmetric alkynyl, esterification, hydrolysis.The committed step of this synthetic method is that the asymmetric reduction reaction of trimethyl silicane ethyl-acetylene and two olefine aldehydrs directly obtains chirality alkynol structure, and building-up reactions formula is as follows:
By compound 9 synthetic compound 12
Concrete synthetic method comprises the following steps:
First be synthesis material with propiolic alcohol, with propiolic alcohol 1 for synthesis material, the alkynyl lithium that propiolic alcohol and n-Butyl Lithium generate and halo n-nonane generation linked reaction obtain dodecyl alkynol compound 2, compound 3 is generated by carrying out triple bond transposition after hydroxyl protection with dihydro pyranyl, there is again linked reaction with bromohexane and generate compound 4, then under the catalysis of tosic acid, slough THP trtrahydropyranyl, obtain octadecyl alkynol compound 5; Octadecyl alkynes aldehyde cpd 6 is obtained again through iodobenzene diacetate and TEMPO oxidation; first there is Witing with phosphine acyl acetic acid three ethyl and react in this compound; obtain important intermediate eicosyl alkynol compound 7 through four isobutylaluminiumhydride process again, this alkynol is at NaBH
4with Ni (OAc)
2existence under, with hydrogen quantitative be reduced to eicosyl dienol compound 8, then be oxidized to key intermediate eicosyl diene aldehyde cpd 9 through iodobenzene diacetate and TEMPO; ; Last under different configuration Trost part and zinc methide catalysis; there is asymmetric reduction reaction and obtain R configuration respectively in trimethyl silicane ethyl-acetylene and two olefine aldehydrs 9; the alkynol compound 10 of S configuration; compound 11 is generated again through esterifying agent recrystallization; finally slough trimethyl silicane blocking group and obtain high optically pure marine natural product (+)-(4E; 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol and enantiomorph 12 thereof.
Described asymmetric alkynyl addition reaction is at (R; and (S R); S) under Trost chiral ligand catalysis; highly-solid selectively obtains chiral intermediate (S, 4E, 15Z)-1-trimethyl silicon based-4; 15-22 carbon diene-1-alkynes-3-alcohol and enantiomorph thereof; again respectively through recrystallization and slough protecting group and obtain marine natural product (+)-(4E, 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol and enantiomorph thereof.
The coupling step of described propargyl alcohol is by propiolic alcohol under n-Butyl Lithium and HMPA effect, in-78 DEG C and halo n-nonane generation linked reaction, generates corresponding product dodecyl alkynol compound; Wherein coupling reagent is selected from iodo n-nonane or bromo n-nonane, preferred iodo n-nonane.
Described triple bond indexing steps is that 2-dodecyne-1-alcohol, under NaH and the effect of 1,3-propylene diamine, triple bond translocation reaction is occurred, and generates transposition product 11-dodecyne-1-alcohol; Wherein translocation reaction temperature is 60 DEG C-90 DEG C, preferably 70 DEG C.
Described oxidation step be eicosyl dienol in methylene dichloride, be quantitatively oxidized to eicosyl two olefine aldehydr by iodobenzene diacetate.
In asymmetric alkynylation reaction, Trost part and the molar equivalent of two olefine aldehydrs are than being 0.05:1-0.4:1, preferred 0.2:1.
Solvent used in asymmetric alkynylation reaction is toluene, methylene dichloride, tetrahydrofuran (THF), preferred toluene.
Described recrystallization is by R configuration with sloughing protecting group, the alkynol compound of S configuration, by esterifying reagent esterification, use normal hexane recrystallization again, the optical purity of compound can be improved rapidly, then in salt of wormwood and anhydrous methanol, eliminative reaction occurs, obtain marine natural product (+)-(4E of high-optical-purity, 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol and enantiomorph thereof; Esterifying reagent wherein used in recrystallization is selected from Benzoyl chloride, 3,5-dinitrophenyl acyl chlorides or P-Toluoyl chlorides, preferably 3,5-dinitrophenyl acyl chlorides.
By asymmetric addition, recrystallization can obtain the marine natural product of two configurations easily with the step of sloughing protecting group.
After obtaining respective compound for every single step reaction, this area ordinary method can be adopted to process, such as adopt extraction, dry, solvent is sloughed in decompression, and the steps such as silica gel chromatography have been come.
Beneficial effect of the present invention: the present invention utilizes the method for asymmetry catalysis to successfully synthesize a kind of new marine natural product (+)-(4E, 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol and enantiomorph thereof, the shortcoming such as the method overcome that existing method overall yield is low, the harsh and yield of enzyme splitting condition is low is the synthetic method that a kind of step is easy, overall yield is higher, product optical purity is high.The method synthetic route overall yield is 15%, and product optical purity high (being greater than 95%ee), particularly importantly can obtain the natural product of two configurations easily.
Embodiment
The present invention relates to a kind of marine natural product (+)-(4E, 15Z)-4, the synthetic method of 15-22 carbon diene-1-alkynes-3-alcohol and enantiomorph thereof, now in conjunction with the building-up reactions formula in summary of the invention and embodiment, the present invention is further described.
Embodiment 1 prepares 2-dodecyne-1-alcohol
Under nitrogen protection, in 250mL Shrek pipe, add anhydrous THF (50mL), the propiolic alcohol (3.36g, 60mmol) newly distilled and HMPA (42mL, 240mmol), stir.Mixed solution is cooled to-78 DEG C, slowly drips n-butyllithium solution (48mL, 2.5mol/L in hexane, 120mol).After dropwising, mixed solution stirs 30min at-78 DEG C, is then warming up to-30 DEG C, continues to stir 3h.In mixed solution, slowly add iodo n-nonane (16.8g, 66mmol), continue stirring reaction 12h, reaction solution is warming up to room temperature naturally.After reaction terminates, add saturated NH
4the Cl aqueous solution (5mL) cancellation is reacted.Aqueous phase, with extracted with diethyl ether (40mL × 3), merges organic phase, anhydrous Na
2sO
4drying, decompression is sloughed solvent and is obtained crude product.Colourless liquid 2 (11.0g, 93%yield) is obtained finally by silica gel column chromatography (normal hexane: ethyl acetate=5:1 ~ 10:1) purifying.
1H NMR(300MHz,CDCl
3):δ4.25(dt,J＝6.0,2.1Hz,2H),2.24-2.18(m,2H),1.95(t,J＝6.0Hz,1H),1.55-1.46(m,2H),1.38-1.27(m,12H),0.88(t,J＝6.5Hz,3H).
13C NMR(75MHz,CDCl
3):δ86.5,78.2,51.2,31.8,29.4,29.2,29.1,28.8,28.6,22.6,18.7,14.0.
Embodiment 2 prepares 2-(11-dodecyne oxygen base) tetrahydropyrans
Under nitrogen protection; being furnished with mechanical stirring, in 500mL four-hole bottle that temperature takes into account reflux condensing tube; add 1; 3-propylene diamine (150mL); add NaH (4.6g, 60%in mineral oil, 115mmol) under ice bath cooling in batches; mixed solution is heated to 70 DEG C, continues after having a large amount of bubble to emerge to stir 1h.Then mixed solution is down to room temperature, slowly drips 2-dodecyne-1-alcohol (5.0g, 27.5mmol), reaction solution heating raised temperature to 55 DEG C, continues stirring reaction 12h.After reacting completely, add a small amount of frozen water (3mL) cancellation reaction.Organic phase ether (50mL × 3) extraction, merges organic phase, anhydrous Na
2sO
4drying, obtains colorless viscous shape liquid Terminal Acetylenes alcohol crude product after concentrating under reduced pressure, do not need purifying can be directly used in next step reaction.
Terminal Acetylenes alcohol crude product (1.1g is added in 100mL there-necked flask, 6mmol) and tetrahydrofuran (THF) (30mL), dihydropyrane (0.3g, 3.6mmol) and tosic acid (62mg, 0.3mmol) is added after stirring.Reaction mixture is continued stirring reaction 12h at 0 DEG C.After reaction terminates, the saturated NaHCO of reaction solution
3the aqueous solution (30mL) washs, aqueous phase ether (50mL) back extraction, merges organic phase.Anhydrous Na
2sO
4drying, decompression is sloughed solvent and is obtained crude product, obtains colourless liquid 3 (6.4g, two step total recoverys 88%) finally by silica gel column chromatography (normal hexane: ethyl acetate=20:1) purifying.
1H NMR(300MHz,CDCl
3):δ4.59-4.56(m,1H),3.90-3.84(m,1H),3.77-3.69(m,1H),3.52-3.48(m,1H),2.18(dt,J＝4.3,2.6Hz,2H),1.94(t,J＝2.6Hz,1H),1.84-1.82(m,1H),1.72-1.70(m,1H),1.62-1.48(m,8H),1.41-1.28(m,12H).
13C NMR(75MHz,CDCl
3):δ98.8,84.7,68.0,67.6,62.2,30.7,29.7,29.4,29.3,29.0,28.7,28.4,26.2,25.5,19.6,18.3.
Embodiment 3 prepares 2 – (11-octadecyne oxygen base) tetrahydropyrans
Under nitrogen protection; anhydrous THF (30mL), 2-(11-dodecyne oxygen base) tetrahydropyrans (1.3g is added in 100mL Shrek bottle; 5mmol) and HMPA (3.5mL, 20mol), stir.Mixed solution is cooled to-78 DEG C, slowly drips n-Butyl Lithium (4mL, 2.5mol/L in hexane, 10mmol), after dropwising, mixed solution is stirred 30min at-78 DEG C.Then be warming up to-30 DEG C, continue to stir 3h.Then slowly add bromo normal hexane (0.9g, 5.5mmol), continue stirring reaction 12h, reaction solution is warming up to room temperature naturally.After reaction terminates, add saturated NH
4the Cl aqueous solution (1mL) cancellation is reacted.Aqueous phase, with extracted with diethyl ether (40mL × 3), merges organic phase, anhydrous Na
2sO
4drying, decompression is sloughed solvent and is obtained crude product, obtains colourless liquid 4 (1.6g, 90%yield) finally by silica gel column chromatography (normal hexane: ethyl acetate=20:1) purifying.
1H NMR(300MHz,CDCl
3):δ4.58(t,J＝4.5Hz,1H),3.90-3.83(m,1H),3.77-3.69(m,1H),3.53-3.48(m,1H),3.42-3.34(m,1H),2.13(t,J＝6.8Hz,4H),1.86-1.68(m,2H),1.61-1.28(m,28H),0.88(t,J＝6.8Hz,3H).
13C NMR(75MHz,CDCl
3):δ98.7,80.1,80.0,67.5,62.1,31.3,30.7,29.7,29.5,29.4,29.3,29.1,29.0,29.0,28.7,28.4,26.2,25.4,22.5,19.6,18.7,13.9.HRMS(ESI-TOF)calcd for C
23H
43O
2[M+H]
+:351.3263,found:351.3274.
Embodiment 4 prepares 11-octadecyne-1-alcohol
Under room temperature, in 50mL single port flask, add methyl alcohol (20mL) and 2 – (11-octadecyne oxygen base) tetrahydropyrans (1.75g, 5mmol).Under stirring, in this mixed solution, add tosic acid (103mg, 0.5mmol).Then at room temperature continue stirring reaction 4 hours, after completion of the reaction, add deionized water (2mL) cancellation reaction.Aqueous phase ether (10mL × 5) extraction, merges organic layer, after anhydrous magnesium sulfate drying, obtains crude product after concentrating under reduced pressure.White solid alkynol (1.16g, 87% yield) is obtained finally by silica gel column chromatography (normal hexane: ethyl acetate=2:1) purifying.
1H NMR(300MHz,CDCl
3):δ3.64(q,J＝6.5Hz,2H),2.14(t,J＝6.8Hz,4H),1.59-1.28(m,25H),0.88(t,J＝6.8Hz,3H).
13C NMR(75MHz,CDCl
3):δ80.2,80.1,63.0,32.8,31.4,29.6,29.5,29.4,29.2,29.1,28.8,28.5,25.7,22.6,18.8,18.7,14.0.HRMS(ESI-TOF)calcd for C
18H
35O[M+H]
+:267.2688,found:267.2700.
Embodiment 5 prepares 11-octadecyne aldehyde
Under room temperature, in the 100mL there-necked flask being furnished with induction stirring, add iodobenzene diacetate (5.7g, 17.6mmol), anhydrous methylene chloride (30mL) and 11-octadecyne-1-alcohol (4.3g, 16mmol), slowly add TEMPO (276mg, 1.76mmol) under stirring in batches.After adding, continue stirring reaction under room temperature, TLC monitors reaction.After reaction terminates, reaction solution saturated aqueous sodium thiosulfate (10mL) washing, aqueous phase methylene dichloride (50mL) back extraction.Merge organic phase, anhydrous magnesium sulfate drying, after concentrating under reduced pressure, obtain crude product.White solid 11-octadecyne aldehyde (3.84g, 91%yield) is obtained finally by silica gel column chromatography (normal hexane: ethyl acetate=20:1) purifying.
1H NMR(300MHz,CDCl
3):δ9.76(t,J＝1.7Hz,1H),2.42(t,J＝7.3Hz,2H),2.14(t,J＝6.8Hz,4H),1.65-1.58(m,2H),1.47-1.30(m,20H),0.88(t,J＝6.7Hz,3H).
13C NMR(75MHz,CDCl
3):δ202.7,80.2,80.1,43.8,31.3,29.3,29.1,29.0,28.7,28.5,25.5,22.0,18.7,18.6,14.0.HRMS(ESI-TOF)calcd for C
18H
33O[M+H]
+:265.2531,found:265.2501.
Embodiment 6 prepares (E)-2-eicosylene-13-alkynes-1-alcohol
Under nitrogen protection, in 100mL Shrek bottle, add anhydrous THF (30mL) and NaH (0.24g, 60%in mineral oil, 6mmol).Then at 0 DEG C, slowly drip phosphonoacetate (1.2mL, 6mmol), mixed solution is stirred 15min.Slow dropping 11-octadecyne aldehyde (1.58g, 6mmol), after dropwising, stirring reaction 30min at 0 DEG C.Reaction solution is naturally warming up to room temperature and continues stirring reaction 1h.After reaction terminates, reaction solution saturated sodium carbonate solution (10mL) washing, aqueous phase ether (10mL) back extraction.Merge organic phase, anhydrous magnesium sulfate drying, concentrating under reduced pressure obtains white solid eneyne aldehyde crude product, does not need purifying to be directly used in next step reaction.
Under nitrogen protection, in 100mL Shrek bottle, add anhydrous THF (20mL) and eneyne aldehyde crude product, stirring and dissolving.Mixed solution is cooled to-78 DEG C, slowly drips DIBAL-H (12.0mL, 1.0M in hexanes, 12.0mmol), after dropwising, at-78 DEG C, continue stirring reaction 3h.After reaction terminates, add saturated NH
4the Cl aqueous solution (3mL) cancellation is reacted, and aqueous phase, with extracted with diethyl ether (20mL × 3), merges organic phase, anhydrous Na
2sO
4drying, decompression is sloughed solvent and is obtained crude product.Colourless liquid eneyne alcohol 7 (1.35g, two step overall yields are 77%) is obtained finally by silica gel column chromatography (normal hexane: ethyl acetate=2:1) purifying.
1H NMR(300MHz,CDCl
3):δ5.74-5.58(m,2H),4.08(s,2H),2.14(t,J＝6.8Hz,4H),2.02(dd,J＝13.0,6.4Hz,2H),1.47-1.28(m,23H),0.88(t,J＝6.8Hz,3H).
13C NMR(75MHz,CDCl
3):δ133.4,128.8,80.2,80.1,63.8,32.2,31.3,29.4,29.4,29.1,29.1,28.8,28.5,22.5,18.7,18.7,14.0.HRMS(ESI-TOF)calcd for C
20H
37O[M+H]
+:293.2844,found:293.2845.
Embodiment 7 prepares (2E, 13Z)-2,13-20 carbon diene-1-alcohol
Under hydrogen balloon protection, in the 50mL there-necked flask being furnished with induction stirring, add Ni (OAc)
2.4H
2o (0.99g, 4mmol) and dehydrated alcohol (10mL).NaBH is added after stirring
4(0.15g, 4mmol.), stirs 30min by mixed solution, then adds quadrol (0.97g, 16mmol) and (E)-2-eicosylene-13-alkynes-1-alcohol (1.18g, 4mmol).Under room temperature, continue stirring reaction 4h, TLC monitors reaction.After reaction terminates, by reaction solution suction filtration, filtrate, with ether (30mL × 3) extraction, merges organic phase, anhydrous sodium sulfate drying, obtains crude product after concentrating under reduced pressure.White solid (2E, 13Z)-2,13-20 carbon diene-1-alcohol (1.05g, 90%yield) is obtained finally by silica gel column chromatography (normal hexane: ethyl acetate=2:1) purifying.
1H NMR(300MHz,CDCl
3):δ5.72-5.58(m,2H),5.36(t,J＝4.5Hz,2H),4.07(d,J＝4.0Hz,2H),2.07-1.98(m,6H),1.51(s,1H),1.28(s,22H),0.88(t,J＝6.8Hz,3H).
13C NMR(75MHz,CDCl
3):δ133.5,129.9,129.8,128.8,63.8,32.2,31.7,29.7,29.7,29.5,29.5,29.5,29.3,29.2,29.1,29.0,27.2,27.1,22.6,14.1.HRMS(ESI-TOF)calcd for C
20H
39O[M+H]
+:295.3001,found:295.2937.
Embodiment 8 prepares (2E, 13Z)-2,13-20 carbon two olefine aldehydr
Under room temperature, in the 100mL there-necked flask being furnished with induction stirring, add iodobenzene diacetate (5.7g, 17.6mmol), anhydrous methylene chloride (30mL) and (2E, 13Z)-2,13-20 carbon diene-1-alcohol (4.3g, 16mmol), slowly add TEMPO (276mg, 1.76mmol) under stirring in batches.Continue stirring reaction under room temperature, TLC monitors reaction.After reaction terminates, by reaction solution thiosulfuric acid saturated aqueous solution of sodium (10mL) washing, aqueous phase methylene dichloride (20mL) back extraction, merges organic phase, anhydrous magnesium sulfate drying, obtains crude product after concentrating under reduced pressure.Colourless liquid (2E, 13Z)-2,13-20 carbon two olefine aldehydr (4.25g, 91%yield) is obtained finally by silica gel column chromatography (normal hexane: ethyl acetate=20:1) purifying.
1HNMR(300MHz,CDCl
3):δ9.51(d,J＝7.9Hz,1H),6.85(dt,J＝15.6,6.8Hz,1H),6.16-6.07(m,1H),5.35(d,J＝5.4Hz,2H),2.37-2.30(m,2H),2.09-1.98(m,4H),1.53-1.46(m,2H),1.28(s,20H),0.88(t,J＝6.8Hz,3H).
13C NMR(75MHz,CDCl
3):δ194.0,158.9,132.9,129.9,129.7,32.7,31.7,29.7,29.4,29.4,29.3,29.2,29.0,28.9,27.8,27.2,27.1,22.6,14.0.HRMS(ESI-TOF)calcd for C
20H
37O[M+H]
+:293.2844,found:293.2857.
Embodiment 9 prepares (S, 4E, 15Z)-1-trimethyl silicon based-4,15-22 carbon diene-1-alkynes-3-alcohol
Under nitrogen protection, in the Shlenk bottle of 100mL drying, under stirring, add trimethyl silicane ethyl-acetylene (0.078mL successively; 0.60mmol; 3equiv), dry toluene (2.0mL), (R; R)-ProPhenol part (25mg; 0.04mmol, 0.20equiv), triphenylphosphine oxide (22mg; 0.08mmol, 0.40equiv) and Me
2zn (0.5mL, 1.2M in toluene, 0.60mmol, 3equiv), is warming up to 30 DEG C by mixed solution, stir 90min.Then mixed solution is cooled to 0 DEG C, slowly drips (2E, 13Z)-2,13-20 carbon two olefine aldehydr (0.20mmol, 1equiv), after dropwising, continue stirring reaction 48h.After reaction terminates, use saturated NH
4the Cl aqueous solution (5mL) cancellation is reacted, and aqueous phase, with extracted with diethyl ether (10mL × 3), merges organic phase, anhydrous Na
2sO
4drying, decompression is sloughed solvent and is obtained crude product.Finally by silica gel column chromatography (normal hexane: ethyl acetate=10:1) purifying, obtain colourless oil liquid (S, 4E, 15Z)-1-trimethyl silicon based-4,15-22 carbon diene-1-alkynes-3-alcohol (0.0624g, 80%yield, 81%ee).
1H NMR(300MHz,CDCl
3):δ5.92-5.83(m,1H),5.60(dd,J＝15.2,6.1Hz,1H),5.35(t,J＝4.9Hz,2H),4.82(t,J＝5.8Hz,1H),2.09-1.98(m,6H),1.87(d,J＝5.9Hz,1H),1.27(s,22H),0.88(t,J＝6.7Hz,3H),0.18(s,9H).
13C NMR(75MHz,CDCl
3):δ134.3,129.9,129.8,128.7,105.0,90.6,63.4,31.9,31.8,29.8,29.7,29.6,29.5,29.4,29.3,29.2,29.0,28.9,27.2,22.6,14.1,0.2.HRMS(ESI-TOF)calcd for C
25H
50NOSi[M+NH
4]
+:408.3662,found:408.3657.
Embodiment 10 prepares (S, 4E, 15Z)-1 – trimethyl silicon based-4,15-22 carbon diene-1-alkynes-3,5-dinitrobenzene ester
In the 25mL single port flask being equipped with induction stirring, add (S, 4E, 15Z)-1-trimethyl silicon based-4,15-22 carbon diene-1-alkynes-3-alcohol (0.078g, 0.2mmol), anhydrous methylene chloride (5mL), triethylamine (0.2mL, 1.4mmol) and DMAP (2mg, 0.02mmol), stir.At 0 DEG C, dropwise add the CH of 3,5-nitrobenzoyl chloride (0.055g, 0.24mmol)
2cl
2solution (3mL).After dropwising, at room temperature continue stirring reaction.After TLC detection reaction is complete, add saturated NH
4the Cl aqueous solution (1mL) cancellation is reacted.Aqueous phase, with extracted with diethyl ether (10mL × 3), merges organic phase, anhydrous Na
2sO
4drying, decompression is sloughed solvent and is obtained crude product.Silica gel column chromatography (normal hexane: ethyl acetate=20:1) purifying is finally used to obtain white solid ester (S, 4E, 15Z)-1 – trimethyl silicon based-4,15-22 carbon diene-1-alkynes-3,5-dinitrobenzene ester (0.110g, 94%yield, 81%ee).This ester normal hexane recrystallization, optical purity of products brings up to 96%ee, and after recrystallization, productive rate is 59%.
1H NMR(300MHz,CDCl
3):δ9.23(t,J＝2.0Hz,1H),9.19(t,J＝2.0Hz,1H),9.14(t,J＝2.0Hz,1H),6.14(dt,J＝14.2,7.1Hz,2H),5.71-5.64(m,1H),5.35(t,J＝4.8Hz,2H),2.14(q,J＝6.8Hz,2H),1.99(q,J＝5.9Hz,4H),1.44-1.28(m,22H),0.22(s,9H).
13C NMR(75MHz,CDCl
3):δ161.3,148.7,138.8,133.9,129.9,129.8,129.6,123.8,122.4,99.6,93.6,67.5,32.0,31.7,29.7,29.5,29.5,29.4,29.2,29.1,28.9,28.5,27.2,27.1,22.6,14.1,0.3.HRMS(ESI-TOF)calcd for C
32H
48N
2O
6Si:584.3282,found:584.3269.
Embodiment 11 prepares (S, 4E, 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol
In the 25mL single port flask being furnished with induction stirring, add (S, 4E, 15Z)-1 – trimethyl silicon based-4,15-22 carbon diene-1-alkynes-3,5-dinitrobenzene ester (0.058g, 0.1mmol) successively, anhydrous methanol (7mL), K
2cO
3(0.027g, 2mmol), stirred at ambient temperature reaction 12h.After TLC detection reaction is complete, by reaction solution ether (5mL × 3) extraction, merge organic phase, anhydrous Na
2sO
4drying, decompression is sloughed solvent and is obtained crude product.Colourless liquid (S, 4E, 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol (0.0293g, 92%yield) is obtained finally by silica gel column chromatography (normal hexane: ethyl acetate=2:1) purifying.
1H NMR(300MHz,CDCl
3):δ5.94-5.87(m,1H),5.60(dd,J＝15.3,6.1Hz,1H),5.35(t,J＝4.7Hz,2H),4.85-4.81(m,1H),2.56(d,J＝2.1Hz,1H),2.10-1.93(m,6H),1.27(s,22H),0.88(t,J＝6.7Hz,3H).
13C NMR(75MHz,CDCl
3):δ134.5,129.9,128.8,128.4,83.4,73.9,62.8,31.9,31.8,29.7,29.5,29.4,29.3,29.2,29.0,28.8,27.2,27.1,22.6,14.1.HRMS(ESI-TOF)calcd for C
22H
39O[M+H]
+:319.3001,found:319.3013.
Embodiment 12 prepares (R, 4E, 15Z)-1 – TMS-4,15-22 carbon diene-1-alkynes-3-alcohol
Synthesis step is identical with step (9).By (2E, 13Z)-2,13-20 carbon two olefine aldehydr (0.20mmol, 1equiv), trimethyl silicane ethyl-acetylene (0.60mmol, 3equiv), (S, S)-ProPhenol part (25mg, 0.04mmol, 0.20equiv), triphenylphosphine oxide (22mg, 0.08mmol, 0.40equiv) and Me
2zn (0.5mL, 1.2M in toluene, 0.60mmol, 3equiv) obtain colourless oil liquid (R, 4E, 15Z)-1 – TMS-4,15-22 carbon diene-1-alkynes-3-alcohol (0.0608g, 78%yield, 82%ee).
1H NMR(300MHz,CDCl
3):δ5.92-5.83(m,1H),5.60(dd,J＝15.2,6.1Hz,1H),5.35(t,J＝4.9Hz,2H),4.82(t,J＝5.8Hz,1H),2.09-1.98(m,6H),1.87(d,J＝5.9Hz,1H),1.27(s,22H),0.88(t,J＝6.7Hz,3H),0.18(s,9H).
13C NMR(75MHz,CDCl
3):δ134.3,129.9,129.8,128.7,105.0,90.6,63.4,31.9,31.8,29.8,29.7,29.6,29.5,29.4,29.3,29.2,29.0,28.9,27.2,22.6,14.1,0.2.HRMS(ESI-TOF)calcd for C
25H
51NOSi[M+NH
4]
+:408.3662,found:408.3657.
That embodiment 13 prepares (R, 4E, 15Z)-1-is trimethyl silicon based-(4,15)-two 10 two carbon-diene-1-alkynes-3,5-dinitrobenzene ester
Synthesis step is identical with step (10).By (R, 4E, 15Z)-1 – TMS-4,15-22 carbon diene-1-alkynes-3-alcohol (0.078g, 0.2mmol) obtains white solid ester (R, 4E, 15Z)-1-trimethyl silicon based-(4,15)-two 10 two carbon-diene-1-alkynes-3,5-dinitrobenzene ester (0.106g, 91%yield, 82%ee).This ester normal hexane recrystallization, optical purity of products brings up to 95%ee, and after recrystallization, productive rate is 57%.
1H NMR(300MHz,CDCl
3):δ9.23(t,J＝2.0Hz,1H),9.19(t,J＝2.0Hz,1H),9.14(t,J＝2.0Hz,1H),6.14(dt,J＝14.2,7.1Hz,2H),5.71-5.64(m,1H),5.35(t,J＝4.8Hz,2H),2.14(q,J＝6.8Hz,2H),1.99(q,J＝5.9Hz,4H),1.44-1.28(m,22H),0.22(s,9H).
13C NMR(75MHz,CDCl
3):δ161.3,148.7,138.8,133.9,129.9,129.8,129.6,123.8,122.4,99.6,93.6,67.5,32.0,31.7,29.7,29.5,29.5,29.4,29.2,29.1,28.9,28.5,27.2,27.1,22.6,14.1,0.3.HRMS(ESI-TOF)calcd for C
32H
48N
2O
6Si:584.3282,found:584.3269.
Embodiment 14 prepares (R, 4E, 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol
Synthesis step is identical with step (11).By ester (R, 4E, 15Z)-1-trimethyl silicon based-(4,15)-two 10 two carbon-diene-1-alkynes-3,5-dinitrobenzene ester (0.058g, 0.1mmol) obtain colourless liquid (R, 4E, 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol (0.286g, 90%yield).
1H NMR(300MHz,CDCl
3):δ5.94-5.87(m,1H),5.60(dd,J＝15.3,6.1Hz,1H),5.35(t,J＝4.7Hz,2H),4.85-4.81(m,1H),2.56(d,J＝2.1Hz,1H),2.10-1.93(m,6H),2.56(d,J＝2.1Hz,1H),1.27(s,22H),0.88(t,J＝6.7Hz,3H).
13C NMR(75MHz,CDCl
3):δ134.5,129.9,128.8,128.4,83.4,73.9,62.8,31.9,31.8,29.7,29.5,29.4,29.3,29.2,29.0,28.8,27.2,27.1,22.6,14.1.HRMS(ESI-TOF)calcd for C
22H
39O[M+H]
+:319.3001,found:319.3013。
Claims (8)
1. the synthetic method of marine natural product (+)-(4E, a 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol and enantiomorph thereof, synthesis step is as follows:
Take propiolic alcohol as synthesis material, the alkynyl lithium that propiolic alcohol and n-Butyl Lithium generate and halo n-nonane generation linked reaction obtain dodecyl alkynol compound, triple bond transposition is carried out by after hydroxyl protection with dihydro pyranyl, linked reaction is again there is with bromohexane, then under the catalysis of tosic acid, slough THP trtrahydropyranyl, obtain octadecyl alkynol compound; Obtain octadecyl alkynes aldehyde cpd through iodobenzene diacetate and TEMPO oxidation again, first there is Witing with phosphine acyl acetic acid three ethyl and react in this compound, then obtains important intermediate eicosyl alkynol compound through four isobutylaluminiumhydride process, and this alkynol is at NaBH
4with Ni (OAc)
2existence under, with hydrogen quantitative be reduced to eicosyl dienol compound, then be oxidized to key intermediate eicosyl diene aldehyde cpd through iodobenzene diacetate and TEMPO; Finally this diene aldehyde cpd and trimethyl silicane ethyl-acetylene generation asymmetric reduction reaction obtain chirality alkynol, then obtain target molecule respectively through recrystallization and deprotection base;
It is characterized in that,
In described asymmetric reduction reaction step, intermediate two olefine aldehydr is respectively at (R, and (S R), S) under Trost chiral ligand catalysis, highly-solid selectively obtains chiral intermediate (+)-(4E, 15Z)-1-trimethyl silicon based-4, 15-22 carbon diene-1-alkynes-3-alcohol and enantiomorph (-)-(4E thereof, 15Z)-1-trimethyl silicon based-4, 15-22 carbon diene-1-alkynes-3-alcohol, again respectively through recrystallization and slough protecting group and obtain marine natural product (+)-(4E, 15Z)-4, 15-22 carbon diene-1-alkynes-3-alcohol and enantiomorph (-)-(4E thereof, 15Z)-4, 15-22 carbon diene-1-alkynes-3-alcohol.
2. synthetic method according to claim 1, it is characterized in that, the coupling step of described propargyl alcohol is by propiolic alcohol under n-Butyl Lithium and HMPA effect, in-78 DEG C and halo n-nonane generation linked reaction, generates corresponding product dodecyl alkynol compound; Wherein coupling reagent is selected from iodo n-nonane or bromo n-nonane.
3. synthetic method according to claim 1, is characterized in that, described triple bond indexing steps is that 2-dodecyne-1-alcohol, under NaH and the effect of 1,3-propylene diamine, triple bond translocation reaction is occurred, and generates transposition product 11-dodecyne-1-alcohol; Wherein translocation reaction temperature is 60 DEG C-90 DEG C.
4. synthetic method according to claim 1, is characterized in that: described oxidation step be eicosyl dienol in methylene dichloride, be quantitatively oxidized to eicosyl two olefine aldehydr by iodobenzene diacetate.
5. synthetic method according to claim 1, is characterized in that, in asymmetric reduction reaction, Trost part and the molar equivalent of two olefine aldehydrs are than being 0.05:1-0.4:1.
6. synthetic method according to claim 1 or 5, is characterized in that: solvent used in asymmetric alkynylation reaction is selected from toluene, methylene dichloride, tetrahydrofuran (THF).
7. synthetic method according to claim 1, it is characterized in that, described recrystallization is by R configuration with sloughing protecting group, the alkynol compound of S configuration, by esterifying reagent esterification, again by the optical purity improving rapidly compound after normal hexane recrystallization, then in salt of wormwood and anhydrous methanol, there is eliminative reaction, obtain marine natural product (+)-(4E of high-optical-purity, 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol and enantiomorph (-)-(4E, 15Z)-4,15-22 carbon diene-1-alkynes-3-alcohol thereof; Esterifying reagent wherein used in recrystallization is selected from Benzoyl chloride, 3,5-dinitrophenyl acyl chlorides or P-Toluoyl chlorides.
8. according to the synthetic method described in claim 1,5 or 7, it is characterized in that: by asymmetric addition, recrystallization and slough protecting group step after obtain the marine natural product of two configurations.
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