CN105884843B - Natural products Cocosolide and its analogue - Google Patents
Natural products Cocosolide and its analogue Download PDFInfo
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- CN105884843B CN105884843B CN201610231604.6A CN201610231604A CN105884843B CN 105884843 B CN105884843 B CN 105884843B CN 201610231604 A CN201610231604 A CN 201610231604A CN 105884843 B CN105884843 B CN 105884843B
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- 0 CCC1(C*)C(*CC2*[C@@](**O*)*(C)(*)*(*)C2)C1 Chemical compound CCC1(C*)C(*CC2*[C@@](**O*)*(C)(*)*(*)C2)C1 0.000 description 6
- VGZNHSKHVNYPOJ-RUASRDBBSA-N CCC(C1)[C@@H]1C(C)(C)CC(CC(C(C)(C)C(C)CCOCc1ccccc1)O)O Chemical compound CCC(C1)[C@@H]1C(C)(C)CC(CC(C(C)(C)C(C)CCOCc1ccccc1)O)O VGZNHSKHVNYPOJ-RUASRDBBSA-N 0.000 description 1
- JZEAWGSADDPGNJ-LUTHVSDMSA-N CCCCC([C@H](C[C@@H](C[C@@H](CCOCc1ccccc1)C1(C)C)C[C@@H]1O)OCc1ccccc1)C=N Chemical compound CCCCC([C@H](C[C@@H](C[C@@H](CCOCc1ccccc1)C1(C)C)C[C@@H]1O)OCc1ccccc1)C=N JZEAWGSADDPGNJ-LUTHVSDMSA-N 0.000 description 1
- FAZVSRGJPIFIJI-AWEZNQCLSA-N C[C@](CO/C(/C1)=S/c2ccccc2)(/C1=[O]/C)OC Chemical compound C[C@](CO/C(/C1)=S/c2ccccc2)(/C1=[O]/C)OC FAZVSRGJPIFIJI-AWEZNQCLSA-N 0.000 description 1
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- 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
Abstract
The present invention relates to the total synthesis methods of the isolated dimer Macrocyclic lactone compounds Cocosolide containing xylopyranoside structure and its analogue and they from the reef flat near Guam and the algae blueness strain Symploco sp. on Cocos rings Hu Jiao, and their excellent inhibitory activity for t cell growth factor IL 2 are demonstrated, the application prospect with very strong medical industry.
Description
Technical field
The present invention relates to dimer Macrocyclic lactone compounds Cocosolide and its structure containing xylopyranoside structure
The total synthesis method of analog and they belongs to organic and medicinal chemistry art.
Background technology
The correlative study of natural products is quickly grown in recent years, more and more natural small molecule compounds, the quilts such as polypeptide
The separation and Extraction from nature, and identify that there is various bioactivity, and may be developed into as pharmaceutical compound.
Immunological diseases are quickly grown in recent years, seriously affect human health, and excessive immune reaction will bring inflammation etc. various
Undesirable condition, however the research for being anchored to the oral drugs for the treatment of immunological diseases is still made slow progress, and it is immune to can be used in treatment
The natural products of disease is even more to be rarely reported in recent years.
As it can be seen that further investigation revealed that can be used in treating the natural products of immunological diseases being that technology urgently to be resolved hurrily is asked
Topic confirms its activity and finds that more analogues will also have the research of structure-activity relationship and the deposit of drug candidate
Very important value.
Therefore, it is based on foregoing description, finds the new natural products compound and its knot that can be used in treating immunological diseases
Structure analog is still current research hotspot and emphasis, is leaned on power where this basis that also exactly the present invention is accomplished.
Invention content
As described above, in order to find that the new natural products compound that can be used in treating immunological diseases and its structure are similar
Object, and to realize its industrial applicability, develop its total synthesis method, confirm its bioactivity, the present inventor has carried out this depth
The research entered, after paying a large amount of creative works, so as to complete the present invention.
The present invention relates to following four aspects, and more specifically, the first aspect, the present invention relates to such as following formula (I)
The compound and its pharmaceutically acceptable salt of shown structure, wherein R1-R8It is independent to be selected from H, C1-C6Alkyl, C1-C6's
Alkoxy, halogen, hydroxyl, amino, nitro, cyano, sulfydryl, R9-R10It is independent to be selected from C1-C6Alkyl, C1-C6Alkoxy,
Halogen, hydroxyl, amino, nitro, cyano, sulfydryl, R11-R12It is independent to be selected from H, C1-C6Alkyl, C1-C6Alkoxy, halogen,
Hydroxyl, amino, nitro, cyano, sulfydryl,
The present invention the compound in, unless otherwise prescribed, halogen or it is halogenated in halogen may be, for example, F, Cl, Br
Or I.
In the compound of the present invention, C1-C6The meaning of alkyl refer to the straight chain or branch for having 1-6 carbon atom
Alkyl group, may be, for example, in non-limiting manner methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, tertiary butyl,
N-pentyl, isopentyl or n-hexyl etc..
In the compound of the present invention, C1-C6Alkoxy refers to " C defined above1-C6Alkyl " is connected with O atom
Group afterwards.
The structure of compound shown in the preferred formula (I) is as follows：
The second aspect, the present invention relates to the synthetic methods of above compound.
The synthetic method of Cocosolide (1) includes the steps that by compound 22 by deprotection reaction preparation, wherein
Pg is independent selected from conventional hydroxyl protection base, further, preferably in the tetrabutyl fluorine the step of the preferred TBS of Pg, Deprotection
It is carried out in the presence of change ammonium (TBAF).
The compound 22 is prepared via compound 21 by being oxidized to carboxylic acid and being esterified coupling, further, the oxygen
Change preferably carries out in the presence of Tempo under alkaline condition, the esterification be coupled preferably 2,4,6- trichloro-benzoyl chlorides,
It is carried out in the presence of DIPEA, DMAP,
The compound 21 removes benzyl preparation, the condition of the reproducibility via compound 20 under conditions of reproducibility
Preferably hydrogen atmosphere further, under conditions of hydrogen reducing is preferably added Pd/C as catalyst
The compound 20 is prepared via compound 16 and 19 in the presence of NBS
The compound 19 is prepared via compound 18 under conditions of carbonyl reduction, preferably in NaBH4Presence
It is prepared by lower reduction.
The compound 18 is via compound 17 in OsO4、NMO、NaIO4In the presence of prepare.
Specifically, the whole route of the synthetic method of Cocosolide (1) is as follows：
In terms of third, the present invention relates to above-mentioned formula (I) compounds and/or its pharmaceutically acceptable salt to prepare treatment
Purposes in immunological disorder drug, the preferred immunological diseases are the immunological diseases that t cell growth factor IL-2 is mediated.
Fourth aspect, the present invention relates to above-mentioned formula (I) compound and/or the pharmaceutical compositions of its pharmaceutically acceptable salt
Object, preferred above-mentioned formula (I) compound and/or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier and/or other
The pharmaceutical composition of anti-immunity disease medicament composition.Described pharmaceutical composition may be used technology well known to organic field and prepare.
Description of the drawings
Fig. 1 is the single crystal diffraction collection of illustrative plates of Cocosolide.
Fig. 2A is influence of the compound 1 to Jurkat cell activity and IL-2 expression.
Fig. 2 B are influence of the compound 26 to Jurkat cell activity and IL-2 expression.
Fig. 2 C are the influences that compound 1 and the like expresses Jurkat cell IL-2 under PMA/PHA conditional stimulus.
Fig. 2 D are that compound 1 and the like expresses Jurkat cell IL-2 under PMA/ionomycin conditional stimulus
It influences.
Fig. 2 E are the influences that compound 1 is proliferated T cell.
Lines meaning is as follows in Fig. 2A -2B：
The expression (percentage %) of IL-2 under PMA/PHA conditional stimulus
Jurkat cell activity (percentage %) under PMA/PHA conditional stimulus
The expression (percentage %) of IL-2 under PMA/ionomycin conditional stimulus
Jurkat cell activity (percentage %) under PMA/ionomycin conditional stimulus
Specific implementation mode
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and
Purpose is only used for enumerating the present invention, not constitutes any type of any restriction to the real protection scope of the present invention, more non-to incite somebody to action
Protection scope of the present invention is confined to this.
Embodiment 1
The extraction separation method of natural products Cocosolide：
Natural products is isolated from the ocean algae blueness bacterium Symploca sp. being collected on reef.The object of freeze-drying
Material continuous use methylene chloride-methanol (1:And water-methanol (1 1):1) it is extracted, extract liquor is in ethyl acetate-aqueous systems
Layering, takes ethyl acetate phase to concentrate, gains are detached repeatedly with silica gel chromatographic column, then isolated with reverse phase C18 liquid chromatograies
Cocosolide compounds (1,8.0 milligram, account for extract weight percent 0.08%).
It is as follows that nuclear-magnetism parses data：
a1H-1H COSY and Hydrogen Proton.bNOESY relevance orders
Embodiment 2
Compound 4 (354mg, 1.3mmol) is dissolved in DCM (10mL) and be added 2,6-lutidine (0.35mL,
4.1mmol), TESOTf (0.31mL, 1.9mmol) is added at 0 DEG C, saturated sodium bicarbonate solution is used after stirring 1h at this temperature
Reaction is quenched in (10mL).(2 × 30mL) is extracted with ethyl acetate to merge organic phase and use saturated ammonium chloride solution (10mL) successively
It is washed with saturation saturated salt solution (10mL).Organic phase is dried with anhydrous sodium sulfate, is filtered and is concentrated under reduced pressure.Residue silica gel
Colorless oil compound 5 (428mg, 85%) is made in column chromatography (n-hexane/ether=95/5).[α]D 20=-10.2 (c 5.0,
DCM)；1H NMR(400MHz,CDCl3) δ 7.38-7.26 (m, 5H), 4.48 (t, J=11.9Hz, 2H), 4.08 (dd, J=8.6,
1.9Hz,1H),3.63(s,3H),3.53–3.46(m,2H),1.81–1.67(m,1H),1.67–1.55(m,1H),1.16(s,
3H), 1.08 (s, 3H), 0.92 (t, J=7.9Hz, 9H), 0.55 (q, J=8.0Hz, 6H)；13C NMR(100MHz,CDCl3)δ
177.53,138.41,128.34,127.71,127.53,74.09,72.88,67.65,51.64,48.31,33.55,21.14,
20.48,6.99,5.41；HRMS(ESI)m/z C21H36O4NaSi(+)[(M+Na)+]:403.2275,403.2273.
Embodiment 3
Compound 5 (5.3g, 13.90mmol) is dissolved in pentane (100mL), trimethyl silicon substrate is added after being cooled to 0 DEG C
Lithium methide (27.5mL, 27.50mmol, 1.0M in pentane), stirring are slowly added to MeOH (15mL) and continue after 5 hours
Stirring 2 hours.It is added after reaction is quenched in saturated sodium bicarbonate solution (30mL) and is extracted with ethyl acetate (2 × 60mL).It is associated with
Machine phase is simultaneously washed with saturated ammonium chloride (30ml) and saturated salt solution (30ml) successively.Organic phase is dried with anhydrous sodium sulfate, mistake
It is concentrated under reduced pressure after filter.Residue silica gel column chromatography (n-hexane/ether=95/5) be made colorless oil compound 6 (5.0g,
98%).[α]D 20=-10.4 (c 10.0, DCM)；1H NMR(500MHz,CDCl3)δ7.39–7.24(m,5H),4.54–4.44
(dd, J=11.83,14.75Hz, 2H), 4.08 (dd, J=8.5,2.6Hz, 1H), 3.51 (dd, J=7.8,5.4Hz, 2H),
2.14 (s, 3H), 1.79-1.67 (m, 1H), 1.61-1.51 (m, 1H), 1.12 (s, 3H), 1.07 (s, 3H), 0.95 (t, J=
7.9Hz, 9H), 0.60 (q, J=7.8Hz, 6H)13C NMR(125MHz,CDCl3)δ213.46,138.52,128.42,
127.77,127.62,74.25,73.00,67.55,53.30,34.21,26.95,21.78,20.15,7.11,5.54；HRMS
(ESI)m/z C21H36NaO3Si(+)[(M+Na)+]:387.2326,387.2323.
Embodiment 4
Compound 6 (2.6g, 7.1mmol) is dissolved in THF (35mL), KHMDS is slowly added to after being cooled to -78 DEG C
N- is slowly added dropwise after persistently stirring one hour at this temperature in (11.5mL, 9.2mmol, 0.8M in THF)
THF (10mL) solution of phenyltrifluoromethanesulfonimide (2.9g, 8.1mmol) and to continue stirring 2 small
When.Saturated ammonium chloride solution (20mL) is added reaction is quenched and is extracted with n-hexane (2 × 100mL).Merge organic phase and successively
It is washed with saturated sodium bicarbonate solution (50ml) and saturated salt solution (50ml), organic phase is dried with anhydrous sodium sulfate, after filtering
It is concentrated under reduced pressure.Colorless oil compound 7 (3.2g, 91%) is made with silica gel column chromatography (n-hexane/ether=96/4) in residue.
[α]D 20=-10.6 (c 2.0, DCM)；1H NMR(400MHz,CDCl3) δ 7.35-7.25 (m, 5H), 5.13 (d, J=4.3Hz,
1H), 5.01 (d, J=4.3Hz, 1H), 4.49 (dd, J=11.90,15.33Hz, 2H), 3.83 (dd, J=8.8,2.2Hz,
1H), 3.56-3.44 (m, 2H), 1.88 (dtd, J=14.1,8.0,2.2Hz, 1H), 1.63-1.51 (m, 2H), 1.57 (s,
1H), 1.15 (s, 3H), 1.09 (s, 3H), 0.92 (t, J=8.0Hz, 9H), 0.56 (q, J=7.9Hz, 6H)；13C NMR
(100MHz,CDCl3)δ162.09,138.34,128.33,127.67,127.54,102.59,72.92,72.87,67.55,
45.33,33.31,22.74,20.40,6.98,5.35；HRMS(ESI)m/z C22H35F3NaO5SSi(+)[(M+Na)+]:
519.1819,519.1820.
Embodiment 5
LiCl (900mg, 21.2mmol) and flame calcination drying at reduced pressure conditions are added in dry round-bottomed flask
Argon gas ventilation is used in combination three times.Ether (40mL) solution of compound 7 (2.5g, 5.1mmol) is added after cooling, is cooled to 0 DEG C
After sequentially add tetra-triphenylphosphine palladium (471mg, 0.4mmol) and trimethyl silicane ylmethyl magnesium chloride (13.0mL, 13.0mmol,
1.0M in Et2O), filtered using diatomite after being stirred 5 hours at a temperature of this and washed with ether (100mL).Merge organic phase
And it is washed successively with saturated sodium bicarbonate (50mL) and saturated salt solution (50mL).Organic phase is dried with anhydrous sodium sulfate, filtering
After be concentrated under reduced pressure.Residue with silica gel column chromatography (n-hexane/ether=99/1) obtain colorless oil compound 8 (1.8g,
81%).[α]D 20=-0.96 (c 2.4, DCM)；1H NMR(500MHz,CDCl3)δ7.40–7.20(m,5H),4.84(s,1H),
4.70 (s, 1H), 4.51 (dd, J=12.09,13.57Hz, 2H), 3.85 (dd, J=8.8,1.9Hz, 1H), 3.58-3.46 (m,
2H), 1.86 (dtd, J=14.3,8.1,2.0Hz, 1H), 1.65-1.44 (m, 3H), 1.02 (s, 3H), 1.02 (s, 3H), 0.99
(t, J=7.9Hz, 9H), 0.63 (q, J=7.6Hz, 6H), 0.07 (s, 9H)；13C NMR(125MHz,CDCl3)δ152.70,
138.83,128.39,127.69,127.51,109.21,75.07,72.88,68.37,45.16,33.69,25.85,21.41,
20.50,7.27,5.71,-0.32；HRMS(ESI)m/z C25H46NaO2Si2(+)[(M+Na)+]:457.2929,
457.2927.
Embodiment 6
Compound 8 (450mg, 1.04mmol) is dissolved in MeOH (5ml), camphorsulfonic acid is added at room temperature
MeOH (1.5mL) solution of (camphorsulfonic acid) (21mg, 0.09mmol).Et is added after 2 hours in stirring3N
Reaction is quenched in (1mL).Saturated ammonium chloride (20mL), unsaturated carbonate hydrogen are used successively after organic addition ethyl acetate (100ML) dilution
Sodium (50mL) and saturated salt solution (20mL) washing.Organic phase is dried with anhydrous sodium sulfate, is concentrated under reduced pressure after filtering.Residue is used
Colorless oil compound 9 (250mg, 75%) is made in silica gel column chromatography (n-hexane/ethyl acetate=6/1).[α]D 20=-7.3 (c
2.0,DCM)；1H NMR(500MHz,CDCl3) δ 7.37-7.27 (m, 5H), 4.86 (d, J=1.0Hz, 1H), 4.79 (d, J=
0.7Hz, 1H), 4.53 (dd, J=11.88,14.53Hz, 2H), 3.75-3.64 (m, 3H), 2.46 (d, J=2.1Hz, 1H),
1.76 (ddd, J=11.6,6.6,1.4Hz, 1H), 1.62 (s, 2H), 1.66-1.57 (m, 3H), 1.53 (s, 2H), 1.05 (s,
3H),1.00(s,3H),0.06(s,9H)；13C NMR(125MHz,CDCl3)δ152.61,138.38,128.48,127.76,
127.70,109.85,74.47,73.37,69.85,44.33,31.33,22.19,22.16,21.22,-0.42；HRMS(ESI)
m/z C19H32NaO2Si(+)[(M+Na)+]:343.2064,343.2064.
Embodiment 7
Sodium hydride (2.5g, 60mmol) is added in dry toluene and suspension is made, second is slowly added to after being cooled to 0 DEG C
Acyl tricresyl phosphate ester (13) (13mL, 65mmol).Be vigorously stirred be slowly added to after ten minutes epoxide 10 (4.2mL,
50mmol).30%NaOH solution 50mL is added after stirring being stirred at room temperature 6 hours.Liquid separation retains water after being heated to reflux two hours
Dilute hydrochloric acid is slowly added dropwise at 0 DEG C to system pH value to 2-3 for phase.With being used after ethyl acetate (2 × 200mL) extraction merging organic phase
Saturated salt solution (3 × 50mL) washs, and organic phase is dried with anhydrous sodium sulfate, is concentrated under reduced pressure after filtering.Residue silicagel column
Chromatography (n-hexane/ethyl acetate=1/1) obtains pale yellow oily liquid compound 11 (4.7g, 82).[α]D 20=-88.4 (c
1.0,DCM)；1H NMR(500MHz,CDCl3)δ11.30(b,1H),1.44–1.35(m,1H),1.35–1.24(m,3H),1.18
(dt, J=8.7,4.3Hz, 1H), 0.95 (t, J=7.3Hz, 3H), 0.75 (ddd, J=8.0,6.4,4.1Hz, 1H)；13C NMR
(125MHz,CDCl3)δ181.43,26.19,25.72,19.98,16.21,13.17；HRMS(ESI)m/z C6H9O2(-)
[M-]:113.0608,113.0608.
Embodiment 8
Compound 11 (1.5g, 40mmol) is dissolved in 100mL ether at 0 DEG C, LiAlH is added portionwise4(3.5g,
30mmol).It is slowly increased to persistently stir after room temperature 2 hours.Again MeOH (10mL) is slowly added dropwise after being cooled to 0 DEG C to be quenched instead
It answers.Saturation potassium sodium tartrate solution (Rochelle ' s) (100mL) is then added and is stirred at room temperature 4 hours.With ether (2
× 100mL) it extracts, organic phase is washed with saturated sodium bicarbonate solution (50mL) and saturated salt solution (50mL) successively.Organic phase
It is dried with anhydrous sodium sulfate, is filtered, and concentrated under reduced pressure to give yellowish oily compound 11-OH and is directly used in and react in next step
。1H NMR(500MHz,CDCl3) δ 3.40 (dd, J=7.1,2.5Hz, 2H), 1.64 (s, 1H), 1.27-1.19 (m, 2H), 0.92
(t, J=7.4Hz, 3H), 0.84-0.75 (m, 1H), 0.59-0.50 (m, 1H), 0.35-0.29 (m, 1H), 0.29-0.24 (m,
1H)；13C NMR(125MHz,CDCl3) δ=67.25,26.70,21.08,19.09,13.74,9.80.
Level-one alcoholic compound 11-OH (30mmol) is dissolved in ether (100mL) and be added sodium bicarbonate (7.6g,
90mmol) and TEMPO (468mg, 3.0mmol).TCCA (7.7g, 33mmol) is added after being cooled to 0 DEG C.1 is stirred at this temperature
0 DEG C of hour, reaction solution is directly filtered under diminished pressure through short silicagel column and is washed with ether (2 × 30mL).Organic phase uses saturated carbon successively
Sour hydrogen sodium solution (30mL), saturated ammonium chloride solution (30mL) and saturated salt solution (30mL) washing.Organic phase anhydrous slufuric acid
Sodium is dried, and filters and the aldehyde being concentrated under reduced pressure to give under low temperature is directly used in next step.
By (-)-B-Allyl bis (Isopinocampheyl) borane (35mmol) ether (50mL) solution of desalination
It is cooled to ether (30mL) solution (keeping temperature to be less than -80 DEG C during being added dropwise) that freshly prepared aldehyde is added after -82 DEG C.In the temperature
Stirring 2 was as a child slowly increased to room temperature under degree, and 3 moles every liter of NaOH (40mL) solution is added after being warmed to room temperature and is slowly added dropwise
H2O2(30%, 80mL).With using saturated carbon successively after di ether (2x 200ml) extraction merging organic phase after being stirred at room temperature 18 hours
Sour hydrogen sodium solution (50mL), saturated ammonium chloride solution (50mL) and saturated salt solution (50mL) washing.Organic phase anhydrous slufuric acid
Sodium is dried, and filters and the oily mixture that allyated products and (-)-isopinocampheol are made is concentrated under reduced pressure under low temperature.This is mixed
Conjunction object is dissolved in THF and (sodium hydride (6.0g, 150mmol) is added portionwise after being cooled to 0 DEG C in 300mL.Wait for reaction system without apparent
Gas is stirred for 0.5 hour after generating, sequentially add BnBr (16mL, 135mmol) and tetrabutylammonium iodide (3.5g,
9.5mmol).Again it is cooled to 0 DEG C after being stirred at room temperature 24 and is slowly added to MeOH (20mL) and reaction is quenched in water (30mL), uses ether
(2x 300mL merge organic interdependent time and are washed with saturated ammonium chloride solution (50mL) and saturated salt solution (50mL) for extraction.It is organic
It is mutually dried with anhydrous sodium sulfate, is concentrated under reduced pressure after filtering.Residue silica gel column chromatography (n-hexane/ether=95/5) removes big
The mixing oily liquids of target benzyl ether compound and (-)-isopinocampheol benzyl oxide is made in polar compound.
Gained oily liquids above is dissolved in the mixed solvent of (200mL) of water (60mL) and acetone, sequentially adds 2,6-
Lutidines (7.0mL, 60mmol), osmium tetroxide (50mL, 1mmol, 0.02M in t-BuOH) and sodium metaperiodate (8.5g,
40mmol).Stirring is filtered with diatomite and is washed with ethyl acetate (2 × 200mL) for 3 hours.Organic phase uses unsaturated carbonate successively
Hydrogen sodium solution (50mL) and saturated salt solution (50mL) washing.Organic phase is dried with anhydrous sodium sulfate, is concentrated under reduced pressure after filtering.It is residual
Excess with silica gel column chromatography (n-hexane/ether=90/15) obtains colorless oil compound 12, and (1.84g, 26%5 steps are always received
Rate).[α]D 20=-34.0 (c 2.0, DCM)；1H NMR(500MHz,CDCl3) δ 9.81 (t, J=2.4Hz, 1H), 7.38-7.24
(m, 5H), 4.67 (dd, J=126.1,11.6Hz, 2H), 3.29 (td, J=8.5,4.2Hz, 1H), 2.77 (ddd, J=15.9,
8.2,2.8Hz, 1H), 2.63 (ddd, J=15.9,4.1,2.0Hz, 1H), 1.45-1.33 (m, 1H), 1.33-1.22 (m, 1H),
1.03 (t, J=7.4Hz, 3H), 0.89-0.77 (m, 1H), 0.73 (ddd, J=13.4,8.9,4.8Hz, 1H), 0.34-0.21
(m,2H).13C NMR(125MHz,CDCl3)δ201.61,138.56,128.47,127.69,127.67,78.42,70.90,
49.47,26.71,22.30,21.43,13.51,8.03；HRMS(ESI)m/z C15H20O2Na(+)[(M+Na)+]:
255.1356,255.1355.
Embodiment 9
The ether of compound 12 (19mg, 82 μm of ol) is added in the molecular sieve that flame calcination drying is added in round-bottomed flask
Ether (2mL) solution of compound 9 (20mg, 62 μm of ol) is added in (2mL) solution after being cooled to -78 °.It stirs at such a temperature
It is slowly added to TMSOTf (17 μ L, 94 μm of ol) after 30 minutes and continues stirring 1 hour, saturated sodium bicarbonate solution is added
Reaction is quenched in (0.5mL).Mixture is extracted with ethyl acetate (2 × 25mL), and organic phase uses saturated ammonium chloride solution successively
(10mL), saturated salt solution (10mL) washing.Organic phase is dried with anhydrous sodium sulfate, is concentrated under reduced pressure after filtering.Residue silicon
Plastic column chromatography (n-hexane/ether=95/5) obtains colorless oil compound 17 (22mg, 76%).[α]D 20=-58.4 (c1.0,
DCM)；1H NMR(500MHz,CDCl3)；δ 7.37-7.24 (m, 10H), 4.73 (d, J=11.7Hz, 1H), 4.71 (s, 1H),
4.65 (s, 1H), 4.51 (d, J=11.7Hz, 1H), 4.47 (s, 2H), 3.59-3.53 (m, 1H), 3.53-3.46 (m, 2H),
3.12 (dd, J=10.7,1.7Hz, 1H), 2.90 (dt, J=8.5,6.7Hz, 1H), 2.24-2.16 (m, 1H), 2.08-2.00
(m, 2H), 1.85 (ddd, J=9.5,7.9,3.9Hz, 1H), 1.68 (ddd, J=9.1,6.5,2.1Hz, 2H), 1.44-1.34
(m,1H),1.27–1.18(m,2H),1.06–0.97(m,9H),0.74–0.66(m,1H),0.63–0.56(m,1H),0.28–
0.20(m,2H)；13C NMR(125MHz,CDCl3)δ153.97,139.32,138.76,128.41,128.38,127.73,
127.71,127.53,127.43,106.09,81.59,79.50,76.10,73.10,70.54,68.33,42.37,39.68,
39.48,30.23,26.90,22.58,22.47,20.59,20.14,13.65,8.36；HRMS(ESI)m/z C31H42O3Na
(+)[(M+Na)+]:485.3026,485.3027.
Embodiment 10
17 (193mg, 0.42mmol) are dissolved in the mixed solvent of water (6mL) and acetone (20.0mL).Sequentially add four oxygen
Change osmium (0.5mL, 0.05mmol, 0.1M in t-BuOH) and N-methyl morpholine oxide (467mg, 1.67mmol).Stirring 24
Water (10mL) solution of sodium metaperiodate (450mg, 2.10mmol) is added after hour.The yellow liquid of generation persistently stirs 3 hours
Reaction system is filtered with diatomite and is washed with ethyl acetate (2 × 50mL), and organic phase uses saturated sodium bicarbonate solution successively
(30mL), saturated salt solution (30mL) washing.Organic phase is dried with anhydrous sodium sulfate, is concentrated under reduced pressure after filtering.Residue silicon
Colorless oil compound 18 (164mg, 85%) is made in plastic column chromatography (n-hexane/ether=85/15).[α]D 20=-87.4 (c
1.0,DCM)；1H NMR(500MHz,CDCl3) δ 7.35-7.25 (m, 10H), 4.74 (d, J=11.6Hz, 1H), 4.45 (s,
2H), 4.45 (d, 2H), 3.86-3.75 (m, 1H), 3.61-3.47 (m, 2H), 3.39 (dd, J=8.6,3.8Hz, 1H), 2.87
(dt, J=8.6,6.5Hz, 1H), 2.47 (dd, J=14.2,11.9Hz, 1H), 2.24 (dd, J=14.2,2.6Hz, 1H),
2.10 (dt, J=13.9,7.0Hz, 1H), 1.82-1.75 (m, 2H), 1.75-1.65 (m, 1H), 1.42-1.31 (m, 1H),
1.26–1.15(m,1H),1.08(s,3H),1.02–0.96(m,6H),0.73–0.65(m,1H),0.65–0.51(m,1H),
0.28–0.15(m,2H)；13C NMR(125MHz,CDCl3)δ211.80,139.04,138.56,128.46,127.69,
127.66,127.64,127.56,80.63,79.28,74.59,73.12,70.67,67.58,49.15,44.70,42.50,
29.87,26.83,22.35,20.40,19.40,18.91,13.62,8.27；HRMS(ESI)m/z C30H40NaO4(+)[(M+
Na)+]:487.2819,487.2815.
Embodiment 11
It is slowly added to NaBH after methanol (1.5mL) solution of compound 18 (41mg, 88 μm of ol) is cooled to -40 DEG C4
After (10mg, 0.26mmol) is persistently stirred 30 minutes at this temperature plus reaction is quenched in saturated ammonium chloride solution (10mL).Mixture
It is extracted with ethyl acetate (2 × 50mL), merges organic phase and uses saturated sodium bicarbonate solution (15mL), saturated salt solution successively
(15mL) is washed.Organic phase is dried with anhydrous sodium sulfate, is concentrated under reduced pressure after filtering.Residue silica gel column chromatography (n-hexane/second
Acetoacetic ester=3/1) obtain colorless oil compound 19 (39mg, 92%).[α]D 20=-49.1 (c 1.0, DCM)；1H NMR
(500MHz,CDCl3) δ 7.38-7.27 (m, 10H), 4.75 (d, J=11.6Hz, 1H), 4.46 (d, J=11.5Hz, 3H),
3.60 (dd, J=11.2,5.6Hz, 1H), 3.58-3.53 (m, 1H), 3.53-3.46 (m, 1H), 3.39 (dd, J=11.4,
4.3Hz, 1H), 3.08 (d, J=9.5Hz, 1H), 2.88 (dd, J=15.2,6.7Hz, 1H), 2.02 (dt, J=14.1,
7.2Hz, 1H), 1.87-1.78 (m, 1H), 1.68-1.63 (m, 2H), 1.44-1.34 (m, 2H), 1.32 (d, J=12.0Hz,
1H), 1.25 (dt, J=14.0,7.6Hz, 2H), 1.01 (t, J=7.4Hz, 3H), 0.93 (s, 3H), 0.83 (s, 3H), 0.71
(dd, J=12.3,5.7Hz, 1H), 0.64-0.56 (m, 1H), 0.28-0.21 (m, 2H)；13C NMR(125MHz,CDCl3)δ
139.29,138.74,128.43,128.39,127.75,127.70,127.56,127.46,80.28,79.54,76.04,
73.08,73.04,70.62,68.13,42.04,38.85,37.13,29.53,26.90,22.42,20.24,13.65,
12.55,8.29；HRMS(ESI)m/z C30H42O4Na(+)[(M+Na)+]:489.2975,489.2974.
Embodiment 12
Flame calcination drying is added in dry round-bottomed flaskSimultaneously compound 16 is added in molecular sieve (90mg)
Acetonitrile (1mL) solution of (16mg, 42 μm of ol).1.5 hours postcoolings are stirred at room temperature to -25 DEG C, be slowly added to NBS (7.5mg,
42 μm of ol) acetone (0.5mL) solution.10 minutes acetone (0.5mL) solution that compound 19 (10mg, 21 μm of ol) is added.
It is slowly increased to room temperature after persistently stirring 30 minutes at this temperature.Saturated sodium bicarbonate solution (10mL) is added, reaction is quenched, uses second
Acetoacetic ester (2 × 50mL) extracts.Organic phase uses ammonium chloride (15mL), saturated salt solution (15mL), the anhydrous sulphur of organic phase successively
Sour sodium drying, filters and dry, is concentrated under reduced pressure to give the mixture (α of two configurations:β=3:5), with silica gel column chromatography (just oneself
Alkane/ethyl acetate=3/1) 9.4mg colorless oil beta comfiguration products (20) (60%yield) are made.[α]D 20=-51.8 (c
1.0,DCM)；1H NMR(500MHz,CDCl3) δ 7.37-7.27 (m, 10H), 4.74 (d, J=11.5Hz, 1H), 4.46 (s,
2H), 4.45 (d, J=11.6Hz, 1H), 4.23 (d, J=7.3Hz, 1H), 3.93 (dd, J=11.5,5.2Hz, 1H), 3.63-
3.57(m,2H),3.55(s,3H),3.52(m,1H),3.48(m,2H),3.44(s,3H),3.41–3.34(m,1H),3.30–
3.22 (m, 2H), 3.09 (dd, J=21.0,10.9Hz, 2H), 3.00 (t, J=8.7Hz, 1H), 2.92-2.86 (m, 1H),
2.05–1.98(m,1H),1.83(m,1H),1.78(m,1H),1.64(m,1H),1.42–1.33(m,1H),1.25–1.17(m,
1H), 1.01 (t, J=7.4Hz, 3H), 0.95 (s, 3H), 0.92 (s, 9H), 0.89 (m, 5H), 0.68 (m, 1H), 0.59 (m,
1H),0.28–0.22(m,2H),0.13(s,6H)；13C NMR(100MHz,CDCl3)δ139.23,138.61,128.32,
128.29,127.61,127.44,127.34,106.17,86.26,84.56,80.68,80.44,79.96,77.33,77.01,
76.69,74.31,72.95,70.71,67.92,63.13,61.01,58.34,41.97,38.97,36.66,29.69,
29.20,26.82,26.08,22.32,20.06,18.11,13.61,13.49,8.23,-3.70,-4.11；HRMS(ESI)m/z
C43H68O8NaSi(+)[(M+Na)+]:763.4576,763.4579.
Embodiment 13
Compound 20 (21mg, 28 μm of ol) is dissolved in MeOH (3mL) and 10%Pd/C (5mg) is added and uses reaction system
Hydrogen is replaced three times, is stirred 2 hours under an atmosphere of hydrogen, using argon gas displacement three times and with diatomite mistake after the completion of waiting reacting
Filter, filtrate decompression concentration residue obtain colorless oil compound 21 with silica gel column chromatography (n-hexane/ethyl acetate=2/1)
(13mg, 83%).[α]D 20=-25.8 (c 1.0, DCM)；1H NMR(500MHz,CDCl3) δ 4.21 (d, J=7.2Hz, 1H),
3.95 (dd, J=11.4,5.2Hz, 1H), 3.71 (dd, J=10.4,4.4Hz, 2H), 3.60 (dd, J=11.6,8.8Hz,
1H), 3.53 (s, 3H), 3.43 (s, 3H), 3.35 (dd, J=8.7,7.3Hz, 1H), 3.24 (ddd, J=11.8,8.2,
4.9Hz, 2H), 3.18-3.13 (m, 1H), 3.10 (dd, J=11.4,10.1Hz, 2H), 2.98 (t, J=8.7Hz, 1H), 2.58
(s, 2H), 1.85-1.75 (m, 2H), 1.65 (dd, J=11.3,6.4Hz, 3H), 1.29-1.16 (m, 3H), 0.93 (dd, J=
9.4,5.1Hz, 6H), 0.90 (d, J=1.7Hz, 12H), 0.65 (dd, J=13.3,8.1Hz, 1H), 0.60 (dt, J=12.9,
4.2Hz,1H),0.33–0.27(m,1H),0.27–0.21(m,1H),0.10(s,6H)；13C NMR(125MHz,CDCl3)δ
106.24,86.27,83.95,80.81,76.35,75.42,74.42,63.22,61.70,60.96,58.36,42.78,
39.06,37.06,31.08,26.80,26.17,25.60,22.44,18.88,18.19,13.74,13.62,9.32,0.06,-
3.65,-4.01；HRMS(ESI)m/z C29H56NaO8Si(+)[(M+Na)+]:583.3637,583.3534.
Embodiment 14
Compound 21 (13mg, 23 μm of ol) is dissolved in DCM (300 μ L), TEMPO (0.2mg, 1.2 μm of ol) and saturation are added afterwards
Sodium bicarbonate solution (130 μ L).KBr (50 μ L, 2.5 μm of ol, 0.05M aqueous solutions) and Bu is sequentially added after being cooled to 0 DEG C4NCl
(30 μ L, 1.5 μm of ol, 0.05M aqueous solutions) is vigorously stirred down is slowly added to sodium bicarbonate solution (33 μ L), saturated salt solution successively
(61 μ L) and sodium hypochlorite (40 μ L, 0.06mmol, 1.5M) persistently stir 30 minutes to the reaction was complete.Water (2mL) and DCM is added
With 10% acidified with citric acid to pH=3 after (2mL) dilution.It is saturated with ethyl acetate (2 × 30mL) extraction merging organic phase
Saline solution (15mL) washs, and organic phase is dried with anhydrous sodium sulfate, is filtered, and concentrated under reduced pressure to give carboxylic acid and is directly used in next
Step reaction.The carboxylic acid obtained above (8mg, 0.02mmol) is dissolved in toluene (2ml) and sequentially add DIPEA (30 μ L,
It 0.18mmol) is stirred 2 hours at room temperature with 2,4,6-trichlorobenzoyl chloride (20 μ L, 0.13mmol), by this
Reaction solution is added dropwise in DCM (8mL) solution of DMAP (35mg, 0.29mmol) after taking out in 3 hours.Persistently stir 10 hours
Saturated ammonium chloride solution (15mL) is added afterwards, reaction is quenched.It is extracted with ethyl acetate (2 × 40mL), organic phase uses saturated carbon successively
Sour hydrogen sodium solution (15mL), saturated salt solution (15mL) washing, organic phase are dried with anhydrous sodium sulfate, are concentrated under reduced pressure after filtering.
Residue obtains compound 22 (5.5mg, 43%) colorless oil with silica gel column chromatography (n-hexane/ethyl acetate=3/1)
[α]D 20=-67.6 (c 0.2, DCM)；1H NMR(500MHz,CD3CN) δ 4.30 (t, J=8.4Hz, 2H), 4.24 (d, J=
7.2Hz, 2H), 3.90 (dd, J=11.3,5.0Hz, 2H), 3.47 (s, 6H), 3.40-3.38 (m, 2H), 3.37 (s, 6H),
3.34 (dd, J=11.6,4.8Hz, 2H), 3.28 (dd, J=8.6,7.2Hz, 2H), 3.22-3.16 (m, 2H), 3.11 (dd, J
=11.2,9.7Hz, 2H), 2.95 (t, J=8.5Hz, 2H), 2.66 (s, 2H), 2.37 (dd, J=17.3,1.7Hz, 2H),
2.08-2.05 (m, 2H), 1.80 (dd, J=4.9,2.5Hz, 2H), 1.79-1.75 (m, 2H), 1.66 (dd, J=14.5,
2.9Hz, 2H), 1.39-1.32 (m, 4H), 0.93 (d, J=7.6Hz, 2H), 0.90 (s, 18H), 0.87 (s, 6H), 0.85 (t, J
=7.0Hz, 6H), 0.81 (s, 6H), 0.72 (dd, J=11.5,6.9Hz, 2H), 0.69-0.64 (m, 2H), 0.40-0.32 (m,
2H),0.26–0.18(m,2H),0.10(s,6H),0.09(s,6H)；13C NMR(125MHz,CD3CN)δ170.94,108.71,
105.74,89.27,85.95,84.05,83.39,81.51,80.62,80.27,79.95,77.24,76.86,76.60,
75.78,74.56,74.34,66.23,62.71,61.46,60.11,57.62,57.44,56.42,40.72,39.14,
38.51,38.15,36.89,36.08,35.11,27.12,26.37,26.27,25.61,24.40,23.98,21.95,
21.57,20.41,19.77,18.81,17.84,14.61,12.97,9.29,8.97,8.27,-4.32,-4.63；HRMS
(ESI)m/z C58H104NaO16Si2(+)[(M+Na)+]:1135.6755,1135.6753.
Embodiment 15
Compound 22 (2.0mg, 1.8 μm of ol) is dissolved in THF (1.5mL), tetrabutyl ammonium fluoride is added after being cooled to 0 DEG C
(TBAF)(300μL,1M in THF,300μmol).Ethyl acetate (20mL) is added after being stirred at room temperature 3 hours in reaction system
Merge organic interdependent secondary saturated sodium bicarbonate solution with water phase ethyl acetate (2x 20mL) extraction after water (10mL) liquid separations
(15mL), saturated ammonium chloride solution (15mL), saturated salt solution (15mL) washing, organic phase are dried with anhydrous sodium sulfate, are filtered
And it is evaporated under reduced pressure.Colorless oil compound (1) is made with silica gel column chromatography (n-hexane/ethyl acetate=1/1) in residue
(1.3mg, 82%).[α]D 20=-55.5 (c 0.4, DCM)；1H NMR(500MHz,CD3CN) δ 4.30 (t, J=8.3Hz, 2H),
4.23 (d, J=7.3Hz, 2H), 3.90 (dd, J=11.3,4.8Hz, 2H), 3.50 (s, 6H), 3.40 (dd, J=8.2,
1.5Hz, 2H), 3.39-3.38 (m, 2H), 3.38 (s, 6H), 3.34 (dd, J=11.6,4.9Hz, 6H), 3.32 (d, J=
4.7Hz, 6H), 3.21-3.18 (m, 2H), 3.18-3.15 (m, 2H), 3.10 (dd, J=11.2,9.7Hz, 2H), 3.02 (t, J
=8.5Hz, 2H), 2.39 (dd, J=17.2,1.7Hz, 2H), 2.07 (dd, J=17.2,8.3Hz, 2H), 1.84-1.81 (m,
2H),1.81–1.78(m,2H),1.69–1.64(m,2H),1.40–1.36(m,2H),1.35–1.31(m,2H),0.93–0.90
(m,2H),0.88(s,6H),0.87–0.84(m,6H),0.80(s,6H),0.75–0.70(m,2H),0.70–0.66(m,2H),
0.37 (dt, J=8.7,4.8Hz, 2H), 0.24 (dt, J=8.5,5.0Hz, 2H)；13C NMR(125MHz,CD3CN)δ
171.79,106.37,85.42,85.21,80.64,80.00,77.60,76.36,74.19,63.36,60.29,58.44,
41.52,39.26,37.49,35.98,27.18,24.73,22.23,20.60,13.78,13.48,9.78；HRMS(ESI)m/z
C46H76NaO16(+)[(M+Na)+]:907.5026,907.5023.
Embodiment 16
Compound 14 (1.3g, 5.2mmol) is dissolved in after DCM (50mL) is cooled to -45 DEG C, BF is slowly added dropwise successively3·
Et2O (980 μ L, 8mmol) and PhSH (650 μ L, 6.3mmol).Et is added after persistently stirring 2 hours at room temperature3N (5mL) is quenched
Reaction.It is diluted with water (50mL) and ethyl acetate (150mL), water phase is extracted with ethyl acetate (100mL) after liquid separation, is merged organic
Saturated sodium bicarbonate solution (30mL), ammonium chloride (30mL) and saturated salt solution (30mL) washing, organic phase is used mutually and successively to use
Anhydrous sodium sulfate is dried, and is concentrated under reduced pressure after filtering.Residue obtains nothing with silica gel column chromatography (n-hexane/ethyl acetate=1/1)
Color oily compound 15 (650mg, 36%).[α]D 20=-29.9 (c 1.0, DCM)；1H NMR(500MHz,CDCl3)δ7.60–
7.38 (m, 2H), 7.36-7.15 (m, 3H), 4.93 (t, J=7.9Hz, 1H), 4.76 (d, J=8.1Hz, 1H), 4.32-4.08
(m, 1H), 3.53 (s, 3H), 3.47 (s, 3H), 3.34 (ddd, J=24.0,14.0,5.7Hz, 3H), 2.14 (s, 3H)；13C
NMR(125MHz,CDCl3)δ169.72,133.78,131.96,129.01,127.71,86.75,82.61,78.30,71.03,
65.69,59.92,58.61,21.15；HRMS(ESI)m/z C19H32NaO2Si(+)[(M+Na)+]:343.2064,
343.2064；HRMS(ESI)m/z C19H32NaO2Si(+)[(M+Na)+]:335.0924,335.0922.
Embodiment 17
Compound 15 (142mg, 0.45mmol) is dissolved in MeOH (5mL), the NaOMe of catalytic amount is added at room temperature and is continued
Stirring 1 hour is concentrated under reduced pressure and removes MeOH.Residue is dissolved in dry DCM (15mL) postcoolings and is slowly added to 2 successively to 0 DEG C,
6-lutidine (0.18mL, 1.5mmol) and TBSOTf (0.22mL, 1.0mmol) is persistently stirred 1 hour at dry temperature, is used
Saturated sodium bicarbonate solution (10mL) is quenched reaction and is extracted with ethyl acetate (2 × 30mL), merges organic interdependent secondary saturation
Ammonium chloride (10mL) and saturated salt solution (10mL) washing, organic phase are dried with anhydrous sodium sulfate, are concentrated under reduced pressure after filtering.It is remaining
Object obtains colorless oil compound 16 (150mg, 86%) with silica gel column chromatography (n-hexane/ether=95/5).[α]D 20=-
42.7(c 1.0,DCM)；1H NMR(400MHz,CDCl3)δ7.56–7.38(m,2H),7.36–7.15(m,3H),4.57(d,J
=9.1Hz, 1H), 4.13-4.04 (m, 1H), 3.58 (s, 2H), 3.51-3.47 (m, 1H), 3.45 (d, J=6.3Hz, 3H),
3.35-3.28 (m, 1H), 3.17 (dd, J=11.4,9.9Hz, 1H), 3.08 (t, J=8.4Hz, 1H), 0.95 (s, 9H), 0.19
(s, 3H), 0.14 (d, J=6.9Hz, 3H)；13C NMR(100MHz,CDCl3)δ134.77,131.24,128.87,127.16,
90.38,87.12,80.30,73.20,66.55,60.93,58.27,26.10,18.31,-3.89,-4.34；HRMS(ESI)m/
z C19H32NaO2Si(+)[(M+Na)+]:407.1683,407.1684.
Embodiment 18
Flame calcination drying is added in dry round-bottomed flaskSimultaneously compound 16 is added in molecular sieve (60mg)
Dichloromethane (1mL) solution of (12mg, 31 μm of ol).It is stirred at room temperature 1.5 and is as a child cooled to -78 DEG C, 19 are added at this temperature
(10mg, 21 μm of ol) (in dry methylene chloride 0.5mL), is sufficiently stirred and is slowly added to NIS (7mg, 31 μ successively after ten minutes
Mol dichloromethane (0.5mL) and TfOH (0.30 μ L, 3.4 μm of ol)) is slowly increased to room temperature after persistently stirring 0.5 hour, adds
Enter water (15mL) to be added after reaction is quenched in TEA (2mL) and ethyl acetate (50mL) extracts liquid separation, water phase is with ethyl acetate (50mL)
Extraction.Saturated sodium bicarbonate solution (10mL), ammonium chloride (10mL) and saturated salt solution (10mL) are used successively after merging organic phase
Washing, organic phase are dried with anhydrous sodium sulfate, filter and be concentrated under reduced pressure, residue silica gel column chromatography (n-hexane/ethyl acetate
=10/1) colorless oil compound 23 (11mg, 71%) is obtained.[α]D 20=3.3 (c 1.0, DCM)；1H NMR(500MHz,
CDCl3) δ 7.37-7.22 (m, 10H), 4.73 (d, J=11.7Hz, 1H), 4.69 (d, J=3.7Hz, 1H), 4.48 (d, J=
12.0Hz, 1H), 4.47 (s, 2H), 3.68 (dd, J=11.0,5.7Hz, 1H), 3.58 (s, 3H), 3.54 (ddd, J=12.3,
8.5,3.0Hz, 3H), 3.49 (s, 3H), 3.48-3.42 (m, 1H), 3.36 (dd, J=11.4,4.4Hz, 1H), 3.30 (t, J=
9.1Hz, 1H), 3.22 (ddd, J=10.6,8.9,5.8Hz, 1H), 3.10 (d, J=9.3Hz, 1H), 2.85 (dd, J=15.3,
6.7Hz,1H),2.08–1.99(m,1H),1.89–1.80(m,1H),1.77–1.71(m,1H),1.68–1.62(m,1H),
1.38 (dt, J=21.2,7.0Hz, 1H), 1.21 (dd, J=14.5,9.2Hz, 2H), 1.00 (dd, J=14.2,6.8Hz,
6H), 0.90 (d, J=4.8Hz, 3H), 0.89-0.85 (m, 9H), 0.72-0.64 (m, 1H), 0.61-0.54 (m, 1H), 0.24
(ddd, J=8.4,6.6,4.2Hz, 2H), 0.08 (s, 3H), 0.00 (s, 3H)；13C NMR(125MHz,CDCl3)δ139.28,
138.78,128.41,128.39,127.73,127.67,127.52,127.47,94.90,83.35,80.55,80.51,
79.46,79.02,73.16,73.05,72.73,70.49,68.15,61.27,60.28,58.91,42.41,38.50,
32.61,29.78,29.50,26.88,25.92,23.31,22.35,20.12,18.08,13.63,13.43,8.28,-
4.57,-4.62；HRMS(ESI)m/z C43H68O8NaSi(+)[(M+Na)+]:763.4576,763.4579.
Embodiment 19
Compound 23 (72mg, 97 μm of ol) is dissolved in MeOH (6mL) and 10%Pd/C (10mg) is added by reaction system
Three times with hydrogen displacement, it stirs 2 hours under an atmosphere of hydrogen, using argon gas displacement three times and with diatomite mistake after the completion of waiting reacting
Filter, filtrate decompression concentration residue obtain colorless oil compound 24 with silica gel column chromatography (n-hexane/ethyl acetate=2/1)
(35mg, 64%).[α]D 20=33.6 (c 1.0, DCM)；1H NMR(500MHz,CDCl3) δ 4.73 (d, J=3.5Hz, 1H),
3.79-3.70 (m, 2H), 3.68 (dd, J=11.0,5.7Hz, 1H), 3.58 (s, 3H), 3.54-3.47 (m, 2H), 3.49 (s,
3H), 3.37 (dd, J=11.3,4.3Hz, 1H), 3.30 (t, J=9.1Hz, 1H), 3.25-3.16 (m, 2H), 3.15-3.05
(m,1H),1.88–1.80(m,2H),1.74–1.64(m,4H),1.60(b,3H),1.39–1.31(m,2H),1.24–1.19
(m,1H),0.98(s,3H),0.97–0.93(m,6H),0.91(s,9H),0.73–0.65(m,1H),0.65–0.58(m,1H),
0.35–0.31(m,1H),0.31–0.23(m,1H),0.10(s,3H),0.05(s,3H)；13C NMR(125MHz,CDCl3)δ
95.04,83.87,83.33,80.48,75.91,73.16,61.72,61.28,60.35,58.95,42.93,38.54,
32.81,29.77,26.79,25.89,25.58,23.22,18.89,18.09,13.72,13.46,9.34,-4.56,-4.62；
HRMS(ESI)m/z C29H56NaO8Si(+)[(M+Na)+]:583.3637,583.3534.
Embodiment 20
Diol compound 24 (35mg, 62 μm of ol) is dissolved in after DCM (0.7mL) and sequentially adds TEMPO (0.5mg, 3.2 μ
) and sodium bicarbonate (380 μ L) mol.Be vigorously stirred down after being cooled to 0 DEG C be slowly added to successively KBr (125 μ L, 6.2 μm of ol,
0.05M aqueous solutions), Bu4NCl (100 μ L, 5.0 μm of ol, 0.05M aqueous solutions), saturated sodium bicarbonate (90 μ L) solution, saturation food
Brine (165 μ L) and sodium hypochlorite (108 μ L, 0.16mmol, 1.5M).It is anti-that monitoring in 30 minutes and TLC is persistently stirred at this temperature
It answers.Water (2mL) and DCM (2mL) is added after the reaction was complete to dilute and citric acid (0.3mL, 10%wt aqueous solution) is used to be acidified to pH
=4.It with ethyl acetate (2 × 50mL), is washed with saturated salt solution (15mL) after merging organic phase, anhydrous sodium sulfate drying, mistake
It filters and is concentrated under reduced pressure to give objective carboxylic acid compound (22mg, 38 μm of ol) and be directly used in and react in next step.
Gained carboxylic acid compound above is dissolved in dry toluene and sequentially adds DIPEA (15 μ L, 90 μm of ol) and 2,4,6-
Trichlorobenzoyl chloride (10 μ L, 64 μm of ol) are simultaneously being stirred at room temperature 2 hours.By obtained Solutions Solution
Toluene (10mL) hot solution (80 DEG C) that DMAP (17mg, 0.14mmol) is slowly added to after taking-up persistently stirs 3 hours postcoolings
To room temperature, saturated ammonium chloride solution (15mL) is added, reaction is quenched.It is extracted with ethyl acetate (2 × 70mL), organic phase is used successively
Saturated sodium bicarbonate solution (15ml), saturated salt solution (15ml), organic phase is dried with anhydrous sodium sulfate, is depressurized after filtering dense
Contracting.Residue obtains colorless oil compound 25 (2.5mg, 40%) with silica gel column chromatography (n-hexane/ethyl acetate=3/1).
[α]D 20=29.4 (c 1.0, DCM)；1H NMR(500MHz,CD3CN) δ 4.74 (d, J=3.7Hz, 2H), 4.26 (t, J=
8.5Hz, 2H), 3.66 (dd, J=11.0,5.3Hz, 2H), 3.49 (d, J=4.6Hz, 6H), 3.51-3.46 (m, 2H), 3.46-
3.41 (m, 2H), 3.39 (s, 6H), 3.38 (d, J=7.5Hz, 4H), 3.33-3.27 (m, 2H), 3.21-3.10 (m, 4H),
2.40 (dd, J=16.2,1.4Hz, 2H), 2.09 (s, 2H), 1.95-1.85 (m, 4H), 1.68 (dd, J=13.6,5.3Hz,
2H), 1.34 (dt, J=20.0,6.5Hz, 2H), 1.20-1.12 (m, 2H), 1.00-0.93 (m, 2H), 0.91 (s, 6H), 0.90
(s, 18H), 0.87 (t, J=7.2Hz, 6H), 0.84 (s, 6H), 0.78-0.73 (m, 2H), 0.71 (dd, J=11.2,6.1Hz,
2H),0.40–0.30(m,2H),0.30–0.22(m,2H),0.08(s,6H),0.05(s,6H)；13C NMR(125MHz,
CD3CN)δ171.36,95.16,83.25,80.42,80.29,78.55,76.44,74.84,73.04,60.46,60.04,
57.98,41.18,38.03,35.41,32.83,26.36,25.42,23.68,22.26,19.85,17.81,12.98,
12.76,9.06,-5.26,-5.34；HRMS(ESI)m/z C58H104NaO16Si2(+)[(M+Na)+]:1135.6755,
1135.6753.
Embodiment 21
Compound 25 (2.0mg, 1.8 μm of ol) is dissolved in THF (1mL), TBAF (200 μ L, 1M in are slowly added at 0 DEG C
THF, 200 μm of ol) brown yellow solution is generated afterwards, ethyl acetate (20mL) and water is added after persistently stirring 3 hours at a temperature of this
(10mL) dilutes liquid separation, and water phase is extracted with ethyl acetate (2x 20mL).Organic phase uses saturated sodium bicarbonate solution successively
(15mL), ammonium chloride solution (15mL) and saturated salt solution (15mL) washing.Organic phase is dried with anhydrous sodium sulfate, after filtering
Be concentrated under reduced pressure residue with silica gel column chromatography (n-hexane/ethyl acetate=1/1) obtain compound as colourless oily 26 (1.2mg,
75%).[α]D 20=18.0 (c 1.0, DCM)；1H NMR(500MHz,CD3CN) δ 4.81 (d, J=3.8Hz, 2H), 4.32 (t, J
=8.1Hz, 2H), 3.69 (dd, J=11.0,4.9Hz, 2H), 3.54 (s, 6H), 3.50-3.42 (m, 6H), 3.41 (s, 6H),
3.39-3.32 (m, 4H), 3.24-3.12 (m, 4H), 2.70 (d, J=9.0Hz, 2H), 2.70 (b, 2H), 2.44 (dd, J=
16.8,1.5Hz, 2H), 1.92-1.84 (m, 4H), 1.73 (dd, J=14.8,3.1Hz, 2H), 1.38 (dd, J=14.9,
7.6Hz, 4H), 1.00-0.94 (m, 2H), 0.93 (s, 6H), 0.91-0.85 (m, 12H), 0.75 (dd, J=10.7,7.9Hz,
4H), 0.44-0.34 (m, 2H), 0.27 (dd, J=13.5,4.9Hz, 2H)；13C NMR(125MHz,CD3CN)δ171.12,
95.36,83.23,80.15,79.38,79.34,76.64,75.25,72.00,60.21,59.71,57.87,40.88,
37.89,35.33,32.80,29.43,26.38,23.84,22.23,19.80,12.98,12.84,9.01；HRMS(ESI)m/z
C46H76NaO16(+)[(M+Na)+]:907.5026,907.5023.
Embodiment 22
Compound 19 (37mg, 0.08mmol) is dissolved in DCM (1.5mL), 2,6- lutidines (2,6- is added afterwards
Lutidine TBSOTf (0.26mL, 0.12mmol) is added after) (0.30mL, 0.24mmol) is cooled to 0 DEG C to hold at such a temperature
Continuous stirring 1 hour.Sodium bicarbonate solution (10mL) is added, reaction is quenched, with ethyl acetate (2 × 30mL)；Organic phase is used successively
Saturated ammonium chloride solution (10mL) and saturated salt solution (10mL) washing, organic phase are dried with anhydrous sodium sulfate, are depressurized after filtering
Concentration.Target silica-ether compound (25mg, 54%) is made with silica gel column chromatography (n-hexane/ether=85/15) in residue.
Products therefrom above is dissolved in ethyl acetate (1mL) and 10%Pd/C (5mg) is added.By reaction system hydrogen
Displacement three times, is stirred 2 hours under an atmosphere of hydrogen, is waited filtering three times and with diatomite using argon gas displacement after the completion of reacting, be filtered
Liquid is concentrated under reduced pressure residue and colorless oil diol compound is made with silica gel column chromatography (n-hexane/ethyl acetate=3/1)
(17mg, 99%).
Diol compound above (17mg, 0.043 μm of ol) is dissolved in after DCM (300 μ L) sequentially add TEMPO (0.3mg, 2
μm ol), saturated sodium bicarbonate solution (115 μ L).KBr (10 μ L, 5 μm of ol, 0.05M aqueous solutions) is sequentially added after being cooled to 0 DEG C
And Bu4NCl (40 μ L, 3.2 μm of ol, 0.08M aqueous solutions) is vigorously stirred down is slowly added to sodium bicarbonate solution (31 μ L) successively, satisfies
30 minutes are persistently stirred with saline solution (60 μ L) and sodium hypochlorite (85 μ L, 0.136mmol, 1.6M) to the reaction was complete.Water is added
With 10% acidified with citric acid to pH=3 after (2mL) and DCM (2mL) dilution.Have with ethyl acetate (2 × 30mL) extraction merging
Machine is mutually washed with saturated salt solution (15mL), and organic phase is dried with anhydrous sodium sulfate, is filtered, and concentrated under reduced pressure to give carboxylic acid and straight
It connects for reacting in next step.
The carboxylic acid obtained above (8mg, 0.02mmol) is dissolved in DCM (0.6ml) and sequentially add DIPEA (40 μ L,
It 0.24mmol) is stirred 2 hours at room temperature with 2,4,6-trichlorobenzoyl chloride (20 μ L, 0.13mmol), by this
Reaction solution is added dropwise in DCM (8mL) solution of DMAP (35mg, 0.29mmol) after taking out in 3 hours.Persistently stir 10 hours
Saturated ammonium chloride solution (15mL) is added afterwards, reaction is quenched.It is extracted with ethyl acetate (2 × 40mL), organic phase uses saturated carbon successively
Sour hydrogen sodium solution (15mL), saturated salt solution (15mL) washing, organic phase are dried with anhydrous sodium sulfate, are concentrated under reduced pressure after filtering.
Residue obtains colorless oil compound 27 (2.8mg, 36%) with silica gel column chromatography (n-hexane/ethyl acetate=3/1).
[α]D 20=-14.7 (c 0.4, DCM)；1H NMR(400MHz,CDCl3) δ 4.43 (t, J=9.2Hz, 2H), 3.44 (d, J=
6.5Hz, 4H), 3.39 (dd, J=11.3,4.9Hz, 2H), 2.40 (dd, J=17.4,1.6Hz, 1H), 2.24 (dd, J=
17.4,8.2Hz, 2H), 1.95-1.84 (m, 2H), 1.69 (dd, J=14.9,3.5Hz, 2H), 1.55 (d, J=5.0Hz, 2H),
1.43–1.33(m,4H),1.33–1.27(m,2H),0.91–0.88(m,18H),0.86(s,6H),0.80(s,6H),0.79
(s, 6H), 0.67 (ddd, J=13.4,9.0,4.7Hz, 2H), 0.41-0.31 (m, 2H), 0.26 (dt, J=9.7,4.8Hz,
2H),0.04(s,6H),0.00(s,6H)；13C NMR(100MHz,CDCl3)δ171.3,79.6,77.2,75.7,75.6,
41.0,38.8,38.1,35.3,29.7,26.6,25.8,24.3,22.7,19.8,18.0,13.5,12.9,9.6,-3.9,-
5.0；HRMS(ESI)m/z C44H81O8Si2(+)[(M+H)+]:793.5464,793.5502.
Embodiment 23
Compound 27 (2.0mg, 2.5 μm of ol) is dissolved in THF (1mL), tetrabutyl ammonium fluoride is added after being cooled to 0 DEG C
(TBAF)(1mL,0.5mmol,0.5M in THF).Ethyl acetate is added after being stirred at room temperature 28 hours in reaction system
Water phase ethyl acetate (2x 20mL) extracts the organic interdependent secondary unsaturated carbonate hydrogen of merging after (20mL) and water (10mL) liquid separations
Sodium solution (15mL), saturated ammonium chloride solution (15mL), saturated salt solution (15mL) washing, organic phase are dry with anhydrous sodium sulfate
It is dry, it filters and is evaporated under reduced pressure.Residue obtains colorless oil compound with silica gel column chromatography (n-hexane/ethyl acetate=2/1)
28 (1.0mg, 71%).[α]D 20=5.0 (c 0.4, DCM)；1H NMR(300MHz,CDCl3) δ 4.41 (t, J=9.1Hz, 2H),
3.52–3.37(m,6H),2.45–2.24(m,4H),2.02–1.88(m,2H),1.83–1.69(m,4H),1.41–1.30(m,
4H), 1.00-0.93 (m, 2H), 0.90 (s, 6H), 0.87 (d, J=6.4Hz, 6H), 0.82 (s, 6H), 0.74-0.63 (m,
2H),0.40–0.31(m,2H),0.31–0.22(m,2H)；13C NMR(100MHz,CDCl3)δ171.3,79.9,77.2,
75.5,75.3,41.1,38.4,35.1,26.6,24.2,22.2,19.9,13.5,12.5,9.6；HRMS(ESI)m/z
C32H53O8(+)[(M+H)+]:565.3735,565.3732。
Embodiment 24
Compound Compound 1 (1.0mg) is dissolved in the ethyl alcohol of 1mL and the aqueous solution (hydrogen-oxygen of 0.1mL sodium hydroxides is added
Change sodium mass fraction 10%).Vacuum distillation in 1 hour is stirred at 65 DEG C and removes ethyl alcohol, and residue is used after being cooled to 5 DEG C in dilute hydrochloric acid
Be acidified and extracted with dichloromethane, organic phase drying after be spin-dried for obtaining white foam monomer acids (1.0mg).The list that will be obtained
Body acid (1.0mg) is dissolved in 1mL methanol and is cooled to 4 DEG C, and trimethyl silicane base diazomethane is added in solution after cooling
(TMSCH2N2, 50 μ L, 2.0M diethyl ether solutions) and it is evaporated under reduced pressure removing MeOH and excessive trimethyl silicane base diazomethane, residue
White foam compound 3 (1.0mg) is obtained with silica gel column chromatography (n-hexane/ethyl acetate=3/1).[α]D 25=-42.8 (c
0.17,MeOH)；IR(film)νmax 3520,2959,1741,1435,1370,1259,1162,1096,1073,991cm-1；1H
NMR(CD3CN) 4.23 (1H, d, J=7.6Hz), 3.90 (1H, dd, J=11.0,4.8Hz), 3.59 (3H, s), 3.55 (1H,
M), 3.50 (3H, s), 3.45 (1H, dd, J=8.2,2.0Hz), 3.37 (3H, s), 3.35 (1H, dd, J=11.4,4.8Hz),
3.18 (1H, m), 3.17 (1H, m), 3.10 (1H, dd, J=11.0,9.6Hz), 3.02 (1H, t, J=8.3Hz), 2.98 (1H,
M), 2.87 (1H, d, J=2.8Hz), 2.46 (1H, dd, J=17.2,2.0Hz), 2.27 (1H, dd, J=17.2,8.2Hz),
1.80 (1H, ddd, J=13.0,4.8,2.0Hz), 1.63 (1H, m, H-8a), 1.55 (1H, m, H-8b), 1.43 (1H, ddd, J
=13.0,11.4,11.0Hz), 1.20 (2H, m), 0.93 (3H, s), 0.93 (3H, t, J=6.9Hz), 0.82 (3H, s), 0.58
(1H,m),0.48(1H,m),0.30(1H,m),0.16(1H,m)；13C NMR(CD3CN),173.3,106.4,85.4,84.9,
81.4,79.9,75.9,74.1,73.9,63.3,60.3,58.4,52.0,43.8,39.3,37.3,35.6,27.4,25.6,
22.2,18.9,13.9,13.4,9.2；HRESI/APCIMS m/z C24H42O9Na[(M+Na)+]:497.2738,
497.2721。
Biological experiment：
Jurkat cell (1X10 is spread in 96 orifice plates5/ hole, the holes 150uL/), stand 1 hour.Then cell compound
1,3,26,28 with TCR- dependent forms stimulant (PMA 80nM in DMSO and PHA 10ug/mL in water) or non-TCR-
Dependent form stimulant (PHA80nM in DMSO and clothing song promise mycin 1uM in DMSO) is jointly processed by, and is made with ethyl alcohol/DMSO
For negative control.Due to the toxicity of PMA/PHA and PMA/ clothing song promise mycins, cell is also individually handled with compound.
The concentration of DMSO maintains 0.21% toxicity to reduce it to Jurkat cell.It is incubated 24 hours, the training of 50uL is taken out per hole
It supports base supernatant and is put into independent culture dish, IL-2 is measured with alphaLISA kits (PerkinElmer, Waltham, MA)
Concentration.Cell activity (mtt assay) is measured after 48 hours.
We are the model measurement immunoloregulation function of Cocosolide molecules with immortal T- cells (Jurkat).Stimulation
T- cells generate IL-2 and use two ways, and one is T-cell receptors (TCR) dependent form methods, and it is non-dependent that one is TCR
Type method.TCR dependent form methods are using phorbol -12- myristic acid -13- esters (PMA, 80nM) plus plant hemagglutinin
The condition of (PHA, 10ug/mL)；Non- TCR dependent forms method is stimulated using PMA (80nM) and clothing song promise mycin (1uM).
Cocosolide 1 and compound 26 can reduce the concentration of IL-2, the survival ability (Fig. 2A, B) without influencing cell.TCR
The sensibility of independent form is stronger, and is all dose-dependent under both of which.Big ring 28 and monomeric ester 3 show lower
Active (Fig. 2 C and D) shows that sugar and dimeric structure are extremely important to the identification of target protein and activity.
It is isolated to contain xylopyranoside structure in conclusion inventor has paid a large amount of creative work
Dimer Macrocyclic lactone compounds Cocosolide, and the total synthesis method of it and analogue is completed, demonstrate it
With good t cell growth factor IL-2 inhibitory activity and smaller cytotoxicity, can be used as immunosuppressor use
In the candidate compound of immunological diseases treatment, have for the research and development of immunological diseases medicine and its important meaning and industry
Application value.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limitation protection model of the invention
It encloses.In addition it will also be appreciated that after reading the technical contents of the present invention, those skilled in the art can make the present invention various
Change, modification and/or variation, all these equivalent forms are also fallen within the scope of the appended claims of the present application
It is interior.
Claims (9)
1. compound and its pharmaceutically acceptable salt with structure shown in logical formula (I)：Wherein R1-R8For H or C1-C3Alkane
Base, R9-R10For C1-C3Alkyl, R11-R12For H or C1-C3Alkyl,
2. compound according to claim 1, it is characterised in that：Wherein R1-R4For H, R5-R8For C1-C3Alkyl, R9-
R10For C1-C3Alkyl, R11-R12For H.
3. according to claim 1-2 any one of them compounds, it is characterised in that：The structure of the compound is as follows：
4. the synthetic method of compound Cocosolide (1) described in a kind of claim 3, which is characterized in that including by compound
22 the step of being prepared by deprotection reactions, wherein Pg is selected from TBS, the step of Deprotection in the presence of tetrabutyl ammonium fluoride
It carries out
5. according to the method described in claim 4, it is characterized in that：The compound 22 is via compound 21 by being oxidized to carboxylic
Acid is simultaneously esterified coupling preparation, and the oxidation carries out in the presence of Tempo under alkaline condition, and the esterification is coupled at 2,4,6- tri-
It is carried out in the presence of chlorobenzoyl chloride, DIPEA, DMAP,
6. according to the method described in claim 5, it is characterized in that：The compound 21 via compound 20 reproducibility item
It removes benzyl under part to prepare, the condition of the reproducibility is hydrogen atmosphere, and Pd/C is added under conditions of hydrogen reducing as catalysis
Agent,
7. the pharmaceutical composition comprising claim 1-3 any one of them compound or its pharmaceutically acceptable salt.
8. claim 1-3 any one of them compound or its pharmaceutically acceptable salt are preparing treatment immunological disorder drug
In purposes, the immunological diseases are the immunological diseases that t cell growth factor IL-2 is mediated.
9. the Cocosolide analogues having the following structure：
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| 《Cyanolide A, a Glycosidic Macrolide with Potent Molluscicidal Activity from the Papua New Guinea Cyanobacterium Lyngbya bouillonii》;Alban R. Pereira;《Journal of Natural Products》;20100204;第73卷(第2期);217，219 * |
| 《Suppression of Immunopathology in Schistosomiasis by Interleukin-2-Targeted Fusion Toxin, DAB389IL-2》;MOHAMED ANWAR RAMADAN;《CELLULAR IMMUNOLOGY》;19951231(第166期);全文 * |
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