CN109384675A - The Enantioselective total synthesis method of needle juniper celery alkane type diterpene and the like - Google Patents

The Enantioselective total synthesis method of needle juniper celery alkane type diterpene and the like Download PDF

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CN109384675A
CN109384675A CN201710704135.XA CN201710704135A CN109384675A CN 109384675 A CN109384675 A CN 109384675A CN 201710704135 A CN201710704135 A CN 201710704135A CN 109384675 A CN109384675 A CN 109384675A
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谢建华
刘运亭
王立新
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Nankai University
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Abstract

The present invention relates to the Enantioselective total synthesis methods of needle juniper celery alkane (Mulinane) type Diterpenes natural products and the like.Using 3- isopropyl -2- carbethoxyl group cyclopentenone as starting material, optically pure chiral alcohol is prepared by asymmetric catalytic hydrogenation method under the iridium catalyst effect of chiral spiro pyridine aminophosphine ligand first, and be oxidized as beta-ketoester.Quaternary carbon center is constructed by alkylated reaction, three-ring system is constructed in the Friedel-Crafts reaction of intramolecular.Again through Birch reduction, Isosorbide-5-Nitrae-conjugate addition, the reaction steps such as carburetting ring expansion construct 5-6-7 tricyclic basic framework.Constructing for carbon skeleton is completed by 1,2- addition, succinct, the efficient Enantioselective total synthesis of needle juniper celery alkane type Diterpenes natural products and the like is completed in last postmenstruation functional group conversions and modification.

Description

The Enantioselective total synthesis method of needle juniper celery alkane type diterpene and the like
Technical field
The present invention relates to the Enantioselective total synthesis of needle juniper celery alkane (Mulinane) type Diterpenes natural products and the like Method belongs to organic synthesis field.
Background technique
Needle juniper celery alkane (Mulinane) type terpene natural products is the diterpene compound with 5-6-7 three-ring system.Such Diterpene natural products is crouch from the flora of Andean celery subfamily plant sleeping apium (Azorella), pad apium (Bolax) and Du Isolated secondary metabolite in the umbelliferaes such as loose apium (Mulinum).These umbelliferaes are used by locals In diseases such as treatment diabetes, bronchitis, digestive discomforts.Nineteen ninety, Loyola etc. is from needle juniper apium plant Mulinum Isolated for the first time such diterpene compound (Loyola, L.A. in crassifolium；Et al.Tetrahedron 1990, 46,5413；Phytochemistry 1990,29,3950).So far, separated obtained family member reaches more than 30 A (I.S.Marcos, R.F.Moro, A. Gil-Mes ó n, D.D í ez, in Studies in natural products Chemistry, Atta-ur-Rahman, Ed.Elsevier, Amsterdam, 2016, Vol 48, pp137-207).Physiology is living Property measurement, needle juniper celery alkane type terpenoid have treatment gastric ulcer (Areche, C.；et Al.Bioorg.Med.Chem.2014,12,6406), treating pulmonery tuberculosis (Molina-Salinas, G.M.；et al. Fitoterapia 2010,81,219), antiplasmodial (Loyola, L.A.；Et al.Phytochemistry 2004,65, 1931.), antibacterial (G.A.；Et al.J.Nat.Prod.1999,62,1319) physiological activity such as.Research table recently Bright, the physiology that the analog of the needle juniper celery alkane type terpenoid obtained by semi-synthetic or bioconversion also performs better than is living Property (Molina-Salinas, G. M.；Et al.Phytochem Rev.2010,9,271；Sep ú lveda, B.；et Al.Bioorg.Med.Chem.Lett.2016,26,3220).Just because of this, the biology of needle juniper celery alkane type terpenoid turns Change etc. has obtained extensive concern.However, since such tricyclic diterpene compound has continuous chiral centre and full carbon quaternary carbon The structure of the complexity such as center, this brings challenge to fully synthetic.Currently, the only fully synthetic document report of an example.2015, Guerrero group is that committed step completes needle juniper celery alkane type diterpene with Michael addition reaction, oxy-Cope rearrangement reaction etc. Racemization for the first time fully synthetic (Reber, K.P.；Et al.J.Org. Chem.2015,80,2397).But synthetic route is longer, always Yield is relatively low.They have used 17-19 step reaction, have synthesized 4 needle juniper celery alkane type diterpene with the total recovery of 1.9-4.6% It is fully synthetic.Therefore, develop succinct, the efficient route of one kind to complete needle juniper celery alkane type Diterpenes natural products and the like Enantioselective total synthesis, to finding and develop the drugs such as completely new treating pulmonery tuberculosis disease to have a very important significance.Needle juniper celery alkane The representative molecule of type diterpene is shown below:
Summary of the invention
The purpose of the present invention is to provide a kind of asymmetric syntheses needle juniper celery alkane type Diterpenes natural products and the like Method, realize it is succinct, efficiently synthesize.
Purpose to realize the present invention, we pass through first using 3- isopropyl -2- carbethoxyl group cyclopentenone as starting material Asymmetric catalytic hydrogenation method that we develop early period prepares optically pure chiral alcohol, is then oxidized as beta-ketoester. Three-ring system is constructed by the Friedel-Crafts reaction of intramolecular, is then restored using Birch, carburetting ring expansion structure 5-6-7 tricyclic basic framework is built, finally needle juniper celery alkane type Diterpenes is completed by the functional group conversions in later period and modification and naturally produces The Enantioselective total synthesis of object and the like.
Its specific synthesis step are as follows: using 3- isopropyl -2- carbethoxyl group cyclopentenone as starting material, first in chiral spiral shell Optically pure chiral alcohol is prepared by asymmetric catalytic hydrogenation method under the iridium catalyst effect of ring pyridine aminophosphine ligand, is connect Not purified one kettle way direct oxidation obtain beta-ketoester.After constructing quaternary carbon center by alkylated reaction, through intramolecular Three-ring system is constructed in Friedel-Crafts reaction.Then, by reduction reaction, Birch reaction, Isosorbide-5-Nitrae-conjugate addition, bromine Generation, carburetting ring expansion step complete constructing for 5-6-7 tricyclic basic framework.The structure of carbon skeleton is completed finally by 1,2- addition Build and the functional group conversions in later period and modification complete needle juniper celery alkane type Diterpenes natural products and the like asymmetry it is complete Synthesis.
The asymmetric syntheses route of cadinane type Diterpenes natural products provided by the invention and the like such as following formula institute Show:
The specific synthesis step of above-mentioned route are as follows:
Step 1: ketene compound 1 under the effect of the catalyst, is obtained by asymmetric catalytic hydrogenation containing there are three continuous The chiral alcohol 2 of chiral centre, products therefrom is directly used in without purification to react in next step；Described catalyst is to be with general formula The chiral spiro pyridine aminophosphine ligand of V and iridium metals precursor scene complexing gained:
Wherein, R1For C1~C8Alkyl, phenyl, substituted-phenyl, 1- naphthalene, 2- naphthalene, heteroaryl or benzyl, it is described Substituent group on phenyl is C1~C8Alkyl, alkoxy, substituent group quantity be 1~5, heteroaryl be furyl, thienyl or pyrrole Piperidinyl；
R2、R3、R4、R5For H, C1~C8 alkyl, phenyl, substituted-phenyl, 1- naphthalene, 2- naphthalene, heteroaryl or benzyl, institute The substituent group on phenyl stated is C1~C8Alkyl, alkoxy, substituent group quantity be 1~5, heteroaryl be furyl, thienyl Or pyridyl group；Or C1~C8 alkoxy；Or R2~R3、R4~R5It and is C3~C7 cycloaliphatic ring, aromatic rings；R2、R3、 R4、R5It can be with It is identical to can also be different；
R6、R7For H, C1~C8 alkyl, C1~C8 alkoxy, C1~C8 fat amido, n=0~3；Or as n >=2, two A adjacent R6、R7It can and be C3~C7 cycloaliphatic ring or aromatic rings, R6、R7It can be the same or different；
R8、R9For H, C1~C8 alkyl, C1~C8 alkoxy, phenyl, substituted-phenyl, 1- naphthalene, 2- naphthalene, heteroaryl or Benzyl, the substituent group on the phenyl are C1~C8Alkyl, alkoxy, substituent group quantity be 1~5, heteroaryl is furans Base, thienyl or pyridyl group, m=0~3；Or as m >=2, adjacent R9Or R8And R9It can and be C3~C7 cycloaliphatic ring or fragrance Ring, R8、R9It can be the same or different；
R10For H, C1~C8Alkyl, phenyl, substituted-phenyl, 1- naphthalene, 2- naphthalene, heteroaryl or benzyl, the phenyl On substituent group be C1~C8Alkyl, alkoxy, substituent group quantity be 1~5, heteroaryl be furyl, thienyl or pyridine Base；
Chiral spiro amido pyridine Phosphine ligands in suitable chiral catalyst comprise the following structure shown in formula:
Wherein DTB is 3,5- di-tert-butyl-phenyl；Xyl is 3,5- 3,5-dimethylphenyl；tBu is tert-butyl；Chiral spiro amine The structure of yl pyridines Phosphine ligands both can be (R)-configuration and be also possible to (S)-configuration.Iridium metals precursor is [Ir (cod) Cl]2(cod =cyclo-octadiene), [Ir (cod)2]BF4、[Ir(cod)2]PF6、[Ir(cod)2]SbF6、[Ir(cod)2] OTf etc..
Step 2: chiral alcohol 2 within the scope of -60~100 DEG C, is converted into beta-keto acid under oxidant effect in organic solvent Ester 3.Described organic solvent is one or more of methylene chloride, dimethyl sulfoxide, tetrahydrofuran；Described oxidant is PCC, PDC, IBX, TEMPO, Swern oxidant, Dess-Martin oxidant or Parkin-Doering oxidant.
Step 3: beta-ketoester 3 within the scope of 0~150 DEG C, is reacted with iodide 4 in the presence of alkali in organic solvent Obtain compound 5.Described organic solvent is one or more of acetone, acetonitrile, toluene, ether, THF, DMSO, DMF；Institute The alkali said is K2CO3、Cs2CO3Or NaH.
Step 4: compound 5 within the scope of 0~100 DEG C, friedel-crafts reaction occurs under the action of an acid and obtains in organic solvent Compound 6.Described organic solvent is one or more of methylene chloride, tetrahydrofuran, methanesulfonic acid；Described acid is methylsulphur Acid, trifluoromethanesulfonic acid, concentrated hydrochloric acid, the concentrated sulfuric acid or polyphosphoric acids.
Step 5: compound 6 is in organic solvent within the scope of 0~100 DEG C, and catalytic hydrogenation obtains under the effect of the catalyst Compound 7.Described organic solvent is one or more of methanol, ethyl alcohol, ethyl acetate；Described catalyst be palladium carbon, Palladium dydroxide or Raney Ni.
Step 6: within the scope of -100~30 DEG C, under alkali metal effect birch reduction occurs for compound 7 in organic solvent Reaction, is then isomerized to ketenes 8 under the action of an acid.Described organic solvent is acetone, methylene chloride, tetrahydrofuran, second One or more of ether, methanol, ethyl alcohol, isopropanol, tert-butyl alcohol；Described alkali metal is lithium, sodium or potassium；Described acid is Hydrochloric acid, sulfuric acid or acetic acid.
Step 7: ketenes 8 within the scope of -100~50 DEG C, occurs 1 under the action of alkylmetal reagent in organic solvent, 4- conjugate addition obtains ketone 9.Described organic solvent is one or both of tetrahydrofuran, ether；Described alkyl gold Belonging to reagent is copper lithium reagent or cuprous iodide that cuprous iodide and lithium methide generate and the copper azoviolet that methyl Grignard generates.
Step 8: within the scope of -30~80 DEG C, under the action of bromide reagent bromo occurs for compound 9 in organic solvent Reaction obtains bromide 10.Described organic solvent is tetrahydrofuran, in ether, methylene chloride, chloroform, carbon tetrachloride It is one or more of；Described bromide reagent is bromine, phenyltrimethylammonium bromide (PTAB) or pyridinium tribromide drone salt.
Step 9: bromide 10 is in organic solvent within the scope of -100~80 DEG C, in diazomethane and boron trifluoride ether Under the action of ring expansion occurs, gained effect under desiliconization obtain compound 11.Described organic solvent is tetrahydrofuran, second One or more of ether, methylene chloride；Described acid is p-methyl benzenesulfonic acid, hydrochloric acid, trifluoromethanesulfonic acid or sulfuric acid.
Step 10: compound 11 within the scope of 0~180 DEG C, is eliminated hydrogen bromide in the presence of alkali and is obtained in organic solvent Ketenes 12.Described organic solvent is one or more of toluene, paraxylene, ortho-xylene, DMF, DMSO: described alkali For DBU or lithium bromide and lithium carbonate.
Step 11: ketenes 12 is in organic solvent within the scope of -100~80 DEG C, under the action of lewis acid with methyl Change reagent effect and generates compound 13-epi-mulinolic acid ethyl ester (13).Described organic solvent is four One or more of hydrogen furans, ether, methylene chloride；Described lewis acid is cerous chloride；Described methylating reagent For lithium methide or methyl Grignard.
Step 12: within the scope of 0~150 DEG C, hydrolysis occurs in the presence of alkali for compound 13 in organic solvent Obtain natural products 13-epi-mulinolic acid (14).Described organic solvent is DMSO；Described alkali is the tert-butyl alcohol Potassium.
Step 13: compound 14 is in organic solvent within the scope of 0~100 DEG C, and dehydration generates natural under the action of an acid Product mulin-11,13-dien-20-oic acid (15).Described organic solvent is benzene, in toluene, tetrahydrofuran, ether One or more；Described acid is p-methyl benzenesulfonic acid, hydrochloric acid, trifluoromethanesulfonic acid or sulfuric acid.
Step 14: compound 15 is in organic solvent within the scope of -20~30 DEG C, under illumination condition, in the work of catalyst Natural products mulinic acid (16) are generated with lower react with oxygen.Described organic solvent be methylene chloride, chloroform, One or more of carbon tetrachloride；Described illumination is ultraviolet light；Described catalyst is tetraphenylporphyrin (TPP).
Step 15: compound 16 within the scope of -20~30 DEG C, generates natural under the effect of the catalyst in organic solvent Product isomulinic acid (17).Described organic solvent be one of methylene chloride, chloroform, carbon tetrachloride or It is several；Described catalyst is RuCl2(PPh3)3。
Step 10 six: compound 15 within the scope of -20~150 DEG C, generates aldehyde under the action of oxidant in organic solvent, It is not purified, it is directly reduced to allyl alcohol under the action of reducing agent and obtains natural products 16-hydroxy mulin-11,13- dien-20-oic acid(18).Described organic solvent is one or more of methanol, ethyl alcohol, water, Isosorbide-5-Nitrae-dioxane； Described oxidant is selenium dioxide.Described reducing agent is sodium borohydride.
Step 10 seven: compound 13 is in organic solvent within the scope of -60~80 DEG C, under the action of reducing agent also by ester group It originally was that alcohol obtains compound 13-epi-mulinol (19).Described organic solvent is tetrahydrofuran, in ether, methylene chloride It is one or more of；Described reducing agent is Lithium Aluminium Hydride or diisobutyl aluminium hydride lithium.
Step 10 eight: compound 19 is in organic solvent within the scope of 0~100 DEG C, and dehydration generates natural under the action of an acid Product mulin-11,13-dien-20-ol (20).Described organic solvent is one of benzene, toluene, tetrahydrofuran, ether Or it is several；Described acid is p-methyl benzenesulfonic acid, hydrochloric acid, trifluoromethanesulfonic acid or sulfuric acid.
Step 10 nine: compound 20 is in organic solvent within the scope of 0~100 DEG C, under the action of alkali and catalyst with vinegar Anhydride reaction generates natural products 20-hydroxymulin-11,13-dienyl acetate (21).Described organic solvent is One or more of methylene chloride, tetrahydrofuran, ether, pyridine；Described alkali is triethylamine, pyridine or diisopropyl second Amine；Described catalyst is DMAP.
The invention has the following advantages that raw material is simple, is readily synthesized, and each step agents useful for same is the common examination in laboratory Agent；Most of intermediates can the preparation of gram-grade scale, and high income；7 needle junipers can with diversity be synthesized by the route Celery alkane type diterpene natural products and 2 analogs.
Specific embodiment
Above content of the invention is made further specifically by the specific embodiment of embodiment form again below It is bright, but the range that this should not be interpreted as to the above-mentioned theme of the present invention only limits embodiment below.It is all to be based on above content of the present invention The technology realized belongs to the scope of the present invention.
Embodiment 1
Weigh catalyst Ir- (R)-SpiroPAP (20mg, 0.2mmol) and potassium tert-butoxide respectively in glove box (560mg, 5 mmol) in 2 dry 25mL Schlenk pipes, take out glove box after respectively to two Schlenk Guan Zhongjia Enter dehydrated alcohol (10mL) to dissolve solid chemical compound.Weighed in 250mL hydrogenation inner tube hydrogenation substrate (10.0g, After 50mmol), reaction inner tube is put into hydrogenation reaction cauldron, and system is replaced into nitrogen, with syringe quickly to hydriding reactor Reaction inner tube in sequentially add dehydrated alcohol (60mL), catalyst solution and aqueous slkali, system is quickly replaced into nitrogen atmosphere It encloses and is flushed with hydrogen gas to 50 atm, be stirred to react under room temperature (25 DEG C) to no Hydrogen Vapor Pressure and dropped.Slow release hydrogen, into system It is added saturated ammonium chloride (30 mL), the stratification in separatory funnel, ethyl acetate extracts (50mL × 3) water layer, merges organic Phase, saturated salt solution (50mL) washing, anhydrous sodium sulfate is dry, filters precipitation and obtains crude product, column chromatography silica gel column, and (PE: EA =5: 1), obtaining 8.4g product, be colourless liquid, yield 92%, Rf=0.3 (PE: EA=5: 1).99%ee. 1H NMR (400MHz, CDCl3) δ 4.41-4.27 (m, 1H), 4.16 (dt, J=7.0, 2.1Hz, 2H), 2.88 (d, J=3.7Hz, 1H), 2.49 (dd, J=9.8,5.3Hz, 1H), 2.35-2.25 (m, 1H), 1.94 (dt, J=15.1,8.4Hz, 1H), 1.80-1.70 (m, 2H), 1.64-1.56 (m, 1H), 1.31 (d, J=7.2Hz, 1H), 1.26 (t, J=7.1Hz, 3H), 0.85 (t, J=7.3Hz, 6H)13C NMR (101MHz, CDCl3) δ 175.5,75.0, 60.8,52.8,47.8,34.4,31.7,25.9,21.2,19.3,14.3. HRMS (ESI) m/z calc ' d for C11H20NaO3[M+Na]+: 223.2747, found 223.1304.HPLC analysis (Chiralpak AD-H column, Hexane:2-propanol=95:5, flow rate=1.0mL/min, wavelength=220 nm): Rt=5.694 (major)and 7.646min(minor).
Embodiment 2
Raw material (2.0g, 10mmol) is added in the 250mL three neck round bottom flask equipped with magnetic stir bar, is added 100mL methylene chloride is dissolved, and 6g diatomite is added, and PCC (6.5g, 30mmol) then is added, and reacts at room temperature 16h, TLC monitoring, after completion of the reaction, by suction filtered through kieselguhr, acquired solution precipitation, column chromatography silica gel column, (PE: EA=4: 1) is obtained 1.8 g products are weak yellow liquid, yield 92%, Rf=0.5 (PE: EA=4: 1).92%yield, 1H NMR (400MHz, CDCl3) δ 4.19 (dd, J=7.1,2.3Hz, 2H), 2.88 (d, J= 11.6Hz, 1H), 2.39 (d, J=8.5Hz, 3H), 2.23-2.12 (m, 1H), 1.63 (dd, J=14.1,6.9Hz, 1H), 1.47 (dd, J=12.0,9.0Hz, 1H), 1.26 (t, J=7.1Hz, 3H), 0.93 (dd, J=14.7,6.7Hz, 6H)13C NMR (101MHz, CDCl3) δ 170.4,61.4,60.5,48.3,38.9,32.9,25.4,20.9,20.0,14.3.
Embodiment 3
Raw material 3 (1.4g, 7mmol) is added in the 250mL three neck round bottom flask equipped with magnetic stir bar, 45mL is added Anhydrous acetonitrile is dissolved.It is added cesium carbonate (6.8g, 21mmol), reacts at room temperature 30min.Add iodo object 4 (2.8g, 11mmol), 60 DEG C of reactions are risen to overnight, add iodo object 4 (1.4g, 5.5mmol) afterwards for 24 hours, the reaction was continued.TLC monitoring, reaction After, by suction filtered through kieselguhr, acquired solution precipitation, residue is dissolved with water, is extracted with ethyl acetate, and organic phase, nothing are merged Water magnesium sulfate is dry.It filters, precipitation, column chromatography silica gel column, (PE: EA=8: 1) obtains 1.5g product, is weak yellow liquid, yield For 65%, Rf=0.5 (PE: EA=4: 1). 1H NMR (400MHz, CDCl3)δ7.19 (dd, J=8.9,7.6Hz, 1H), 6.79-6.71 (m, 3H), 4.14 (dd, J=7.1,4.5Hz, 2H), 3.79 (s, 3H), 2.69-2.55 (m, 2H), 2.42-2.25 (m, 2H), 2.15 (dd, J=6.4,1.8Hz, 4H), 1.85 (d, J=2.8Hz, 1H), 1.63 (d, J=1.8Hz, 1H), 1.24 (t, J=7.1Hz, 3H), 1.07 (d, J=6.6Hz, 3H), 0.98 (d, J=6.6Hz, 3H).13C NMR (101MHz, CDCl3) δ 217.0,170.9,159.8,143.5,129.5,121.0,114.2,111.5, 63.3,61.1,55.3,50.6,39.1,35.1,31.1,31.0,25.4,22.2,21.6,14.3.HRMS (ESI) calcd for C20H28O4([M+H]+): 333.2066；Found:333.2064
Embodiment 4
Raw material 5 (1.5g, 4.5mmol) is added in the 100mL round-bottomed flask equipped with magnetic stir bar, 45mL bis- is added Chloromethanes is dissolved, and is down to 0 DEG C, and methanesulfonic acid (4mL) is slowly added dropwise, reacts 2h at this temperature.TLC monitoring, end of reaction Afterwards, it is extracted with dichloromethane, organic phase is washed with water respectively, and saturated sodium bicarbonate is washed, and saturated sodium-chloride is washed, and anhydrous magnesium sulfate is dry It is dry.It filters, precipitation, column chromatography silica gel column, (PE: EA=8: 1) obtains 1.4g product, is white solid, yield 91%, Rf= 0.6 (PE: EA=8: 1).Mp.80-82 DEG C, 1H NMR (400MHz, CDCl3)δ7.50 (d, J=8.6Hz, 1H), 6.71 (dd, J=8.6,2.5Hz, 1H), 6.60 (d, J=2.3Hz, 1H), 6.21- 6.08 (m, 1H), 4.13 (d, J=7.1Hz, 1H), 4.04 (d, J=7.1Hz, 1H), 3.77 (s, 3H), 3.17-3.03 (m, 1H), 2.84- 2.68 (m, 2H), 2.58-2.51 (m, 1H), 2.37 (dd, J=15.1,11.0Hz, 1H), 1.91-1.84 (m, 1H), 1.64- 1.59 (m, 2H), 1.18 (t, J=7.1Hz, 3H), 1.09 (d, J=6.5Hz, 3H), 0.93 (d, J=6.5Hz, 3H)13C NMR (101MHz, CDCl3) δ 173.8,158.9,141.7,137.1,126.2,124.4,122.5,112.9,112.8,60.5, 60.4,58.7,55.3,37.3,33.5,30.8,28.1,23.0,22.6,14.4.HRMS (ESI) calcd for C20H26O3 ([M+H]+): 315.1960；Found:315.1959.
Embodiment 5
Raw material 6 (3.1g, 10.0mmol) is added in the 100mL round-bottomed flask equipped with magnetic stir bar, 50mL is added Dehydrated alcohol is dissolved.10% palladium carbon (0.31g), replacing hydrogen, room temperature reaction is added.TLC monitoring, after completion of the reaction, By suction filtered through kieselguhr, acquired solution precipitation, column chromatography silica gel column, (PE: EA=8: 1) obtains 3.1g product, is colourless liquid, Yield is 99%, Rf=0.6 (PE: EA=5: 1) 1H NMR (400MHz, CDCl3)δ6.96 (d, J=8.1Hz, 1H), 6.72-6.49 (m, 2H), 3.97-3.80 (m, 2H), 3.75 (s, 3H), 3.09-2.79 (m, 4H), 2.31-2.13 (m, 2H), 2.11-2.01 (m, 1H), 1.76-1.56 (m, 3H), 1.48 (dd, J=11.5,5.0Hz, 1H), 1.04 (d, J=6.5Hz, 3H), 0.98 (t, J=7.1Hz, 3H), 0.90 (d, J=6.5Hz, 3H)13C NMR (101MHz, CDCl3) δ 173.9,157.8,137.8,132.1,125.6,113.3,110.9,59.6,58.0,57.2,55.2,51.3, 33.8,32.2,30.6,27.9,24.8,23.0,22.4,14.1.HRMS (ESI) calcd for C20H28O3([M+H]+): 317.2117；Found:317.2117.
Embodiment 6
Raw material 7 (3.2g, 10mmol) is added in the 500mL four round flask equipped with magnetic stir bar, is added 100mL anhydrous tetrahydro furan and 12mL ethyl alcohol are dissolved.- 78 DEG C are down to, liquefied ammonia 150mL is collected.Add in batches at this temperature Enter metallic sodium (4.6g, 200mmol), about 1h is added, and maintenance system is navy blue, continues to react 1h at this temperature after adding. It is slowly added to chloride solid to be quenched, takes off blue, be warmed to room temperature, fall Ammonia valatilization.Residual residue is dissolved with water, with two Chloromethanes extraction, organic phase are washed with saturated sodium-chloride, and anhydrous magnesium sulfate is dry.It filters, precipitation obtains yellow liquid.
Above-mentioned gained liquid is dissolved in 100mLTHF, under condition of ice bath, concentrated hydrochloric acid 10mL is added.Maintain 0 DEG C of reaction 2 H, TLC monitoring, after completion of the reaction, are diluted with water, are extracted with ethyl acetate.Organic phase saturated sodium bicarbonate, sodium chloride solution Washing, merges organic phase, and anhydrous magnesium sulfate is dry.It filters, precipitation, column chromatography silica gel column, (PE: EA=4: 1), obtains 2.4g production Product are yellow liquid, yield 80%, Rf=0.3 (PE: EA=3: 1). 1H NMR (400MHz, CDCl3) δ 5.82 (s, 1H), 4.18 (q, J=7.1Hz, 2H), 2.74-2.70 (m, 1H), 2.51-2.34 (m, 4H), 2.33-2.24 (m, 1H), 2.15-2.08 (m, 1H), 2.02-1.85 (m, 2H), 1.74-1.63 (m, 1H), 1.56- 1.45m, 3H), 1.43-1.26 (m, 6H), 1.02 (d, J=5.9Hz, 3H), 0.84 (d, J=6.0Hz, 3H)13C NMR (101MHz, CDCl3) δ 199.9,173.7,166.1,125.0,60.2,58.0,56.7,56.3,39.3,37.0,35.9, 33.1,32.0,29.3,27.7,25.0,22.9,22.4,14.4.HRMS (ESI) calcd for C19H28O3([M+H]+): 305.2117；Found:305.2115.
Embodiment 7
Cuprous iodide (5.7g, 30mmol) is added in the 250mL three neck round bottom flask equipped with magnetic stir bar, displacement 50mL anhydrous ether is added in nitrogen.It is down to 0 DEG C, the diethyl ether solution (37.5mL, 1.6M) of lithium methide is slowly added dropwise, is greater than 30min is dripped off.Solution has muddiness to become clarifying during dropwise addition, and color is become colorless by yellow.The reaction was continued after being added dropwise 1h.Then the diethyl ether solution 10mL of ketenes 8 (3.0g, 10mmol) is added dropwise, the 1h that is added dropwise that the reaction was continued.TLC monitoring, has reacted Bi Hou is added dropwise saturated ammonium chloride solution and is quenched, extracted with ether, and organic phase is washed with saturated sodium chloride solution, anhydrous sulphur Sour magnesium is dry.It filters, it is colourless liquid that precipitation, column chromatography silica gel column, (PE: EA=8: 1), which obtains 2.7g product, and yield is 85%, Rf=0.5 (PE: EA=5: 1). 1H NMR (400MHz, CDCl3) δ 4.15 (t, J= 7.0Hz, 2H), 2.73 (d, J=14.4Hz, 1H), 2.57-2.47 (m, 1H), 2.27-2.12 (m, 2H), 2.08-1.84 (m, 5H), 1.75-1.64 (m, 2H), 1.59 (d, J=12.1Hz, 1H), 1.54-1.45 (m, 3H), 1.39-1.30 (m, 2H), 1.29-1.23 (m, 4H), 1.03 (d, J=6.4Hz, 3H), 0.90 (s, 3H), 0.84 (d, J=6.5Hz, 3H)13C NMR (101MHz, CDCl3) δ 212.9,174.3,59.8,58.6,57.8,48.3,48.1,41.0,39.3,38.6,36.6,33.3, 32.1,29.1,28.4,25.0,24.8,23.0,22.4,14.4.HRMS (ESI) calcd for C20H32O3([M+NH4]+): 338.2695；Found:338.2690
Embodiment 8
Equipped with magnetic stir bar 250mL round-bottomed flask in be added raw material 9 (2.7g, 8.4mmol), be added 30mL without Water tetrahydrofuran is molten by its, is down to 0 DEG C.The tetrahydrofuran solution 30mL of PTAB (3.5g, 9.2mmol) is slowly added dropwise.It drips The reaction was continued 1h after finishing.TLC monitoring, after completion of the reaction, is quenched with saturated sodium thiosulfate solution, is extracted with ether, organic phase It is washed with saturated sodium chloride solution, merges organic phase, it is dry with anhydrous magnesium sulfate.It filters, precipitation, column chromatography silica gel column, (PE: EA=8: 1), obtaining 3.2g product, is white solid, yield 97%, Rf=0.5 (PE: EA=8: 1).Mp. 122-124 DEG C, 1H NMR (400MHz, CDCl3) δ 4.64 (dd, J=13.4,6.6Hz, 1H), 4.15 (q, J= 7.1Hz, 2H), 2.89 (d, J=14.0Hz, 1H), 2.60-2.49 (m, 1H), 2.48-2.33 (m, 2H), 2.09-1.88 (m, 4H), 1.77-1.64 (m, 2H), 1.55-1.42 (m, 3H), 1.37-1.25 (m, 6H), 1.02 (d, J=6.4Hz, 3H), 0.93 (s, 3H), 0.84 (d, J=6.5Hz, 3H)13C NMR (101MHz, CDCl3) δ 201.9,173.8,60.0,58.5,57.7, 53.3,48.6,47.6,43.8,40.1,38.1,38.0,33.2,32.0,29.0,28.1,25.1,22.9,22.4, 14.4.HRMS (ESI)calcd for C20H31BrO3([M+H]+): 339.1535；Found:399.1526and 401.1510.
Embodiment 9
Raw material 10 (1.2g, 2.9mmol) is added in the 100mL three neck round bottom flask equipped with magnetic stir bar, is added 25 mL anhydrous methylene chlorides are dissolved, and are down to -78 DEG C.Successively it is slowly added to BF3.Et2O (1.4g, 9.7mmol) and TMSCHN2(4.4mL, 2M).It is added dropwise, reacts 1h at this temperature.Unsaturated carbonate hydrogen is added after completion of the reaction in TLC monitoring Sodium solution is quenched, and is extracted with ethyl acetate, and merges organic phase, is washed with water respectively, and saturated sodium-chloride is washed, and anhydrous magnesium sulfate is dry. It filters, precipitation obtains yellow liquid.
Above-mentioned gained liquid is dissolved in methanol, is added PPTS (1.1g, 4.4mmol), 1h is reacted at room temperature.Precipitation, residue are used Methylene chloride dissolution, is washed with water respectively, and saturated sodium-chloride is washed, and anhydrous magnesium sulfate is dry.It filters, precipitation, column chromatography silica gel column, (PE: EA=8: 1) obtains 1.1g product, is white solid, yield 85%, Rf=0.7 (PE: EA=6: 1).Mp.74-76 DEG C, 1H NMR (400MHz, CDCl3) δ 4.38 (dd, J=11.0,6.3Hz, 1H), 4.12 (q, J =7.1Hz, 2H), 2.96 (td, J=13.4,2.5Hz, 1H), 2.49-2.23 (m, 4H), 2.06-1.88 (m, 3H), 1.76- 1.43 (m, 4H), 1.38-1.29 (m, 5H), 1.25 (t, J=7.1Hz, 4H), 1.00-0.98 (m, 6H), 0.80 (d, J= 6.2Hz, 3H) ..13C NMR (101MHz, CDCl3) δ 206.3,174.0,59.9,58.7,57.5,51.1,48.0,45.6, 40.6,36.3,34.8,33.1,32.3,31.9,31.7,28.8,27.5,24.8,22.9,22.4,14.4.HRMS (ESI) calcd for C21H33BrO3([M+H]+): 413.1691；Found:413.1682and 415.1689.
Embodiment 10
Raw material 11 (1.9g, 4.7mmol) is added in the 100mL three neck round bottom flask equipped with magnetic stir bar, is added 25 mL dry o-xylenes are dissolved.It is added DBU (0.85g, 5.6mmol), is heated to 140 DEG C of reactions.TLC monitoring, reaction After, it with 2M hydrochloric acid, is extracted with ethyl acetate, merges organic phase, anhydrous magnesium sulfate is dry.It filters, precipitation, column chromatography Silicagel column, (PE: EA=8: 1) obtain 1.3g product, are yellow liquid, yield 84%, Rf=0.4 (PE: EA=6: 1). 1H NMR (400MHz, CDCl3) δ 6.25 (dd, J=13.1,6.9Hz, 1H), 5.90 (d, J =13.1Hz, 1H), 4.15 (q, J=7.1Hz, 2H), 2.71-2.63 (m, 1H), 2.55-2.40 (m, 3H), 2.33 (s, 1H), 2.03-1.89 (m, 2H), 1.82-1.74 (m, 1H), 1.57-1.49 (m, 2H), 1.41-1.31 (m, 6H), 1.27 (t, J=7.1 Hz, 3H), 1.02-1.01 (m, 6H), 0.82 (d, J=6.0Hz, 3H)13C NMR (101MHz, CDCl3) δ 204.0,174.0, 146.3,130.6,59.9,58.3,57.3,52.0,50.9,42.3,39.7,35.6,32.3,32.0,29.0,28.9,27.0, 24.9,22.9,22.4,14.4.HRMS (ESI) calcd for C21H32O3([M+H]+): 333.2430；Found: 333.2428.
Embodiment 11
Anhydrous cerous chloride (4.9g, 20mmol) is added in the 250mL three neck round bottom flask equipped with magnetic stir bar, Nitrogen is replaced, 40mL anhydrous tetrahydro furan is added, is down to 0 DEG C of reaction 2h.Then -78 DEG C are down to, the second of lithium methide is slowly added dropwise Ethereal solution (1.6M, 12.5mL, 20mmol), reacts 30min at such a temperature.Raw material 12 (1.33g, 4.0mmol) is added dropwise Tetrahydrofuran solution 10mL.It is added dropwise, is slowly increased to 0 DEG C, continuation is reacted at this temperature.TLC monitoring, end of reaction Afterwards, it is quenched with saturated ammonium chloride solution, is extracted with ether, merge organic phase, anhydrous magnesium sulfate is dry.It filters, precipitation, column chromatography Silicagel column, (PE: EA=8: 1) obtain 1.18g product, are yellow liquid, yield 85%, Rf=0.3 (PE: EA=5: 1). 1H NMR (400MHz, CDCl3) δ 5.54 (dd, J=12.9,1.9Hz, 1H), 5.33 (dd, J=12.9,8.2Hz, 1H), 4.14 (q, J=7.1Hz, 2H), 2.45-2.41 (m, 1H), 2.24-2.17 (m, 1H), 2.08- 2.02 (m, 2H), 1.94-1.84 (m, 3H), 1.62-1.57 (m, 1H), 1.51-1.46 (m, 1H), 1.41-1.34 (m, 6H), 1.29-1.24 (m, 7H), 1.12 (dd, J=14.8,5.1Hz, 1H), 1.02 (d, J=6.2Hz, 3H), 0.97 (s, 3H), 0.83 (d, J=6.3Hz, 3H)13C NMR (101MHz, CDCl3) δ 174.3,138.5,127.6,74.6,59.7,58.2, 57.8,51.3,48.2,42.3,37.9,35.9,32.6,32.1,31.1,29.1,29.0,28.0,25.1,23.0,22.4, 14.4.IR (KBr): vmax 3460,2954,2925,2869,1716,1646,1457,1180,1153,748cm-1HRMS (ESI)calcd for C22H35O2([M-OH]+): 331.2632；Found:331.2646
Embodiment 12
Raw material 13 (696mg, 2.0mmol) is added in the 50mL Schlenk pipe equipped with magnetic stir bar, is added 20mL DMSO is dissolved, and is added potassium tert-butoxide (2.24g, 20mmol).Nitrogen is replaced, 95 DEG C of reactions are heated to.TLC monitoring, After completion of the reaction, it is down to room temperature, 20mL ice water is added.It is neutralized with the hydrochloric acid of 1.0M, is extracted with ether, merge organic phase, it is anhydrous Magnesium sulfate is dry.It filters, precipitation, column chromatography silica gel column, (PE: EA: MeOH=30: 10: 1) obtains 589mg product, solid for white Body body, yield 92%, Rf=0.2 (PE: EA: MeOH=30: 10: 1).Mp.238-240 DEG C, 1H NMR (400MHz, CD3OD) δ 5.53 (dd, J=13.0,1.6Hz, 1H), 5.29 (dd, J=13.0, 8.1Hz, 1H), 2.45-2.21 (m, 2H), 2.13-2.02 (m, 2H), 1.93 (d, J=6.7Hz, 3H), 1.58-1.33 (m, 8H), 1.27 (s, 3H), 1.13 (dd, J=14.8,4.6Hz, 1H), 1.04 (d, J=5.5Hz, 3H), 1.00 (s, 3H), 0.87 (d, J=5.6 Hz, 3H)13C NMR (101MHz, CD3OD) 177.9 δ, 140.0,127.9,75.1,59.2,58.7,52.3, 43.4,38.0,36.9,33.8,33.2,32.0,30.0,29.1,28.4,26.1,23.3,22.9.IR (KBr): vmax 3447,2953,2924,2360,1698,1237,742cm-1HRMS(ESI)calcd for C20H31O3([M-H]-): 319.2279；Found:319.2274
Embodiment 13
Raw material 13-epi-mulinolic acid is added in the 25mL Schlenk pipe equipped with magnetic stir bar (320mg, 1 mmol) is added 5mL dry toluene and is dissolved.It is added p-methyl benzenesulfonic acid (35mg, 0.2mmol), room temperature reaction, TLC monitoring, after completion of the reaction, precipitation, column chromatography silica gel column, (PE: EA=2: 1) obtains 272mg product, is weak yellow liquid, Yield is 90%, Rf=0.3 (PE: EA=2: 1).Mp.83-85 DEG C, 1H NMR(400 MHz, CDCl3) δ 11.36 (s, 1H), 5.64 (d, J=12.6Hz, 1H), 5.57 (dd, J=12.5,6.0Hz, 1H), 5.47 (d, J=8.1Hz, 1H), 2.68 (d, J=17.1Hz, 1H), 2.47-2.39 (m, 1H), 2.23-2.16 (m, 1H), 2.09-1.99 (m, 1H), 1.96-1.90 (m, 1H), 1.79 (s, 3H), 1.74-1.70 (m, 1H), 1.70-1.68 (m, 1H), 1.67-1.64 (m, 1H), 1.64-1.60 (m, 1H), 1.52-1.50 (m, 1H), 1.50-1.48 (m, 1H), 1.48-1.45 (m, 1H), 1.43- 1.41 (m, 1H), 1.41-1.39 (m, 1H), 1.02 (d, J=5.8Hz, 3H), 0.86 (d, J=3.4Hz, 6H)13C NMR (101MHz, CDCl3) δ 180.6,132.8,131.8,127.9,125.4,58.5,57.7,55.1,50.4,41.1,36.4, 34.9,32.7,31.8,28.8,27.1,25.7,24.7,22.8,22.4.IR (KBr): vmax 3446,2360,1647, 1541,1265,744cm-1HRMS(ESI)calcd for C20H29O2([M-H]+): 301.2168；Found:301.2178.
Embodiment 14
Raw material mulin-11,13-dien-20-oic are added in the 25mL Schlenk pipe equipped with magnetic stir bar Acid (15l mg, 0.5mmol) is added 5mL anhydrous methylene chloride and is dissolved.It is added tetraphenylporphyrin (TPP, 3.3mg), sets Change oxygen.System is placed under 300W mercury lamp and is irradiated, is reacted at room temperature, TLC monitoring, after completion of the reaction, and precipitation, column chromatography silica gel Column, (PE: EA=1: 1) obtain 109mg product, are white solid, yield 65%, Rf=0.2 (PE: EA=1: 1) .mp. 185-187 DEG C, 1H NMR (400MHz, CDCl3) δ 6.13 (d, J=7.4Hz, 1H), 4.63-4.55 (m, 1H), 4.40 (d, J=3.4Hz, 1H), 2.43-2.35 (m, 1H), 2.29 (d, J=15.0Hz, 1H), 2.17-2.09 (m, 1H), 2.00-1.94 (m, 1H), 1.94-1.90 (m, 1H), 1.89 (d, J=1.3Hz, 3H), 1.88-1.83 (m, 1H), 1.73 (dd, J=11.6,4.1Hz, 1H), 1.56-1.54 (m, 1H), 1.54-1.50 (m, 2H), 1.47-1.44 (m, 1H), 1.43-1.39 (m, 1H), 1.39-1.35 (m, 1H), 1.34-1.32 (m, 1H), 1.06 (d, J=6.5Hz, 6H), 0.86 (d, J=5.9 Hz, 3H)13C NMR (101MHz, CDCl3) δ 181.2,137.0,124.3,80.5,77.5,57.4, 57.0,49.4,49.1,42.5,41.6,33.8,33.6,32.7,31.6,28.4,25.4,22.7,22.6,20.6.IR (KBr): vmax 3445,2360,1467,1265,743cm-1HRMS(ESI)calcd for C20H29O4([M-H]+): 333.2071；Found:333.2070.
Embodiment 15
Equipped with magnetic stir bar 25 mL Schlenk pipes in be added raw material mulinic acid (67 mg, 0.2 Mmol), 3 mL anhydrous methylene chlorides are added to be dissolved.It is down to 0 DEG C, RuCl is added2(PPh3)3(19 mg, 0.02 mmol), It is slowly increased to react at room temperature, TLC monitoring, after completion of the reaction, precipitation, column chromatography silica gel column, (PE: EA=1: 1) obtains 54 mg production Product are white solid, yield 80%, Rf=0.15 .mp.180-182 DEG C of (PE: EA=1: 1), 1H NMR (400 MHz, CDCl3) δ 3.24 (d, J=2.8Hz 1H), 3.14 (t, 1H), 2.88 (t, J=7.1Hz, 1H), 2.38 (d, J=13.1Hz, 1H), 2.13-1.83 (m, 7H), 1.56 (dd, J=14.3, 8.0Hz, 1H), 1.50 (s, 3H), 1.44 (d, J=6.9 Hz, 4H), 1.20-1.14 (m, 1H), 1.04 (s, 6H), 0.86 (d, J =5.6Hz, 3H)13C NMR (101 MHz, CDCl3) δ 180.4,60.5,60.2,59.1,57.5,57.3,56.0,48.8, 45.6,43.1,33.7,32.5,32.5,31.7,28.4,27.7,24.4,22.7,22.5,22.4.IR (KBr): vmax 3445,2360,1636,1265,739 cm-1HRMS(ESI)calcd for C20H29O4([M-H]+): 333.2071；Found: 333.2069.
Embodiment 16
Raw material mulin-11,13-dien-20-oic are added in the 25 mL Schlenk pipes equipped with magnetic stir bar Acid (30 mg, 0.1 mmol), is added 2 mL ethyl alcohol and 0.2 mL water is dissolved.It is added at one time SeO2(55.5 mg, 0.5 mmol), it is heated to 80 DEG C of 24 h of reaction.It is down to room temperature, is filtered with diatomite, filter vacuum precipitation.It is residue obtained to use 2 The dissolution of mL methanol, is added NaBH4(7.6 mg, 0.20 mmol) reacts at room temperature 30 min.TLC monitoring, after completion of the reaction, with 1 M HCl quenching reaction, is extracted with ethyl acetate, and merges organic phase, and anhydrous magnesium sulfate is dry, filters, precipitation, column chromatography silica gel Column, (PE: EA=10: 1) obtain 29 mg products, are colourless liquid, yield 91%, Rf=0.15 (PE: EA=1: 1) 91% Yield, 1H NMR (400MHz, CDCl3) δ 5.78 (d, J=12.7Hz, 1H), 5.73 (d, J =5.4Hz, 1H), 5.70 (d, J=5.8Hz, 1H), 4.07 (s, 2H), 2.74 (d, J=17.3Hz, 1H), 2.44 (dt, J= 10.1,3.2Hz, 1H), 2.23 (dd, J=10.0,5.1Hz, 1H), 2.08-1.98 (m, 1H), 1.95-1.91 (m, 1H), 1.83-1.76 (m, 1H), 1.75-1.68 (m, 1H), 1.68-1.66 (m, 1H), 1.62-1.57 (m, 1H), 1.54-1.49 (m, 1H), 1.48-1.45 (m, 2H), 1.43-1.38 (m, 2H), 1.02 (d, J=5.8Hz, 3H), 0.85 (d, J=5.0Hz, 6H) .13C NMR (101MHz, CDCl3) δ 180.5,135.8,134.6,127.6,124.2,69.2,58.6,57.6,55.1, 50.4,41.1,36.3,34.8,32.7,31.8,28.8,27.1,24.6,22.7,22.4.IR (KBr): vmax 3649, 2360,1698,1541,1265,741cm-1HRMS(ESI)calcd for C20H29O3([M-H]+): 317.2122；Found: 317.2120.
Embodiment 17
Equipped with magnetic stir bar 25mL Schlenk pipe in be added raw material 13 (342mg, 1mmol, be added 5mL without Water tetrahydrofuran is dissolved.It is down to 0 DEG C, Lithium Aluminium Hydride (570mg, 15mmol) is added portionwise, back flow reaction is heated to and stays overnight. TLC monitoring, after completion of the reaction, is carefully added into ethyl acetate and is quenched, 2M hydrochloric acid is then added dropwise, is diluted with water, with acetic acid second Ester extraction, merges organic phase, and anhydrous magnesium sulfate is dry.It filters, precipitation, column chromatography silica gel column, (PE: EA=5: 1) obtains 260mg Product is colourless liquid, yield 85%, Rf=0.2 (PE: EA=2: 1).Mp.133-134 DEG C, 1H NMR (400MHz, CDCl3) δ 5.53 (dd, J=13.0,1.9Hz, 1H), 5.21 (dd, J=12.9, 8.1Hz, 1H), 3.75 (d, J=11.5Hz, 1H), 3.52 (d, J=11.6Hz, 1H), 2.26 (t, J=13.6Hz, 1H), 2.20-2.13 (m, 1H), 2.07-1.95 (m, 2H), 1.92-1.84 (m, 1H), 1.71-1.55 (m, 4H), 1.55-1.48 (m, 2H), 1.40-1.25 (m, 7H), 1.12-0.98 (m, 9H), 0.87 (d, J=6.5Hz, 3H)13C NMR (101MHz, CDCl3) δ 138.5,127.8,74.7,59.8,58.3,50.5,47.7,47.1,40.2,37.8,36.1,31.8,31.1,29.8, 29.3,28.4,28.2,24.3,23.5,23.4.IR (KBr): vmax 3446,2360,1636,1541,740cm-1HRMS (ESI)calcd for C20H33O ([M-OH]+): 289.2526；Found:289.2518
Embodiment 18
Equipped with magnetic stir bar 25mL Schlenk pipe in be added raw material 13-epi-mulinol (153mg, 0.5mmol), 3mL dry toluene is added to be dissolved.It is added p-methyl benzenesulfonic acid (8.6mg, 0.05mmol), room temperature reaction, TLC Monitoring, after completion of the reaction, precipitation, column chromatography silica gel column, (PE: EA=2: 1) obtains 272mg product, is colourless liquid, and yield is 88%, Rf=0.3 (PE: EA=2: 1). 1H NMR (400MHz, CDCl3) δ 5.63 (d, J =12.6Hz, 1H), 5.46 (dd, J=12.0,6.6Hz, 2H), 3.79 (d, J=11.5Hz, 1H), 3.57 (d, J=11.5Hz, 1H), 2.73 (d, J=17.3Hz, 1H), 2.17 (dt, J=6.5,3.5Hz, 1H), 2.05 (dd, J=11.3,5.9Hz, 1H), 1.91-1.84 (m, 1H), 1.79 (s, 3H), 1.70-1.66 (m, 1H), 1.65-1.62 (m, 1H), 1.62-1.59 (m, 1H), 1.59-1.57 (m, 1H), 1.50-1.45 (m, 1H), 1.43-1.38 (m, 1H), 1.33-1.28 (m, 1H), 1.26-1.24 (m, 1H), 1.16-1.13 (m, 1H), 1.11-1.07 (m, 1H), 1.04 (d, J=6.4Hz, 3H), 0.86 (d, J=8.3Hz, 6H) .13C NMR (101MHz, CDCl3) δ 133.1,131.8,128.0,125.7,60.2,58.1,54.2,49.3,48.3,39.2, 36.4,35.0,3l.8,30.0,28.5,27.4,25.8,24.0,23.5,23.4.IR (KBr): vmax 3446,2360, 2341,1647,746cm-1HRMS (ESI)calcd for C20H32O([M+H]+): 289.2526；Found:289.2515
Embodiment 19
Raw material mulin-11,13-dien-20-ol are added in the 25mL Schlenk pipe equipped with magnetic stir bar (29mg, 0.1 mmol) is added 2mL anhydrous methylene chloride and is dissolved.Sequentially add triethylamine (20mg, 0.2mmol), DMAP (1.2mg, 0.01mmol) and acetic anhydride (15mg, 0.15mmol) reacts at room temperature 2.5h.TLC monitoring takes off after completion of the reaction Molten, column chromatography silica gel column, (PE: EA=5: 1) obtains 31mg product, is colourless liquid, yield 94%, Rf=0.7 (PE: EA= 4∶1)。 1H NMR (400MHz, C6D6) δ 5.68 (d, J=12.5Hz, 1H), 5.48 (d, J=8.0Hz, 1H), 5.39 (dd, J=12.5,6.3Hz, 1H), 4.29 (d, J=11.9Hz, 1H), 3.91 (d, J= 11.8Hz, 1H), 2.68 (d, J=17.1Hz, 1H), 2.09 (dt, J=13.2,3.4Hz, 1H), 1.94 (dd, J=11.2, 6.3Hz, 1H), 1.81 (s, 3H), 1.71 (s, 3H), 1.68-1.63 (m, 1H), 1.62-1.57 (m, 1H), 1.55-1.51 (m, 1H), 1.51 (m, 1H), 1.50-1.47 (m, 1H), 1.35-1.31 (m, 1H), 1.20 (d, J=3.1Hz, 1H), 1.19-1.17 (m, 1H), 1.16-1.13 (d, J=3.6Hz, 1H), 1.04 (d, J=6.4Hz, 3H), 1.00-0.94 (m, 4H), 0.87- 0.80 (m, 4H)13C NMR (101 MHz, C6D6) δ 169.9,132.7,131.6,128.2,125.4,61.6,57.7, 53.8,48.9,46.6,38.9,36.4,34.7,31.4,30.6,28.1,27.1,25.6,23.6,23.3,22.8, 20.3.IR 3676,2924,2360,2341,1716,1541,1265,744 cm of (KBr): vmax-1HRMS(ESI)calcd for C22H34O2([M+H]+): 331.2637；Found:331.2633.

Claims (1)

1. a kind of Enantioselective total synthesis method of needle juniper celery alkane (mulinane) type diterpene and the like, which is characterized in that logical Following steps are crossed to be synthesized:
Step 1: ketene compound 1 under the effect of the catalyst, is obtained by asymmetric catalytic hydrogenation containing there are three continuous chiral The chiral alcohol 2 at center, products therefrom is directly used in without purification to react in next step；It is V that the catalyst, which has general formula, Chiral spiro pyridine aminophosphine ligand and iridium metals precursor scene complexing gained:
Wherein, R1For C1~C8Alkyl, phenyl, substituted-phenyl, 1- naphthalene, 2- naphthalene, heteroaryl or benzyl, the phenyl On substituent group be C1~C8Alkyl, alkoxy, substituent group quantity be 1~5, heteroaryl be furyl, thienyl or pyridine Base；
R2、R3、R4、R5For H, C1~C8 alkyl, phenyl, substituted-phenyl, 1- naphthalene, 2- naphthalene, heteroaryl or benzyl, the benzene Substituent group on base is C1~C8Alkyl, alkoxy, substituent group quantity be 1~5, heteroaryl be furyl, thienyl or pyridine Base；Or C1~C8 alkoxy；Or R2~R3、R4~R5It and is C3~C7 cycloaliphatic ring, aromatic rings；R2、R3、R4、R5Can it is identical can also With difference；
R6、R7For H, C1~C8 alkyl, C1~C8 alkoxy, C1~C8 fat amido, n=0~3；Or as n >=2, two phases Adjacent R6、R7It can and be C3~C7 cycloaliphatic ring or aromatic rings, R6、R7It can be the same or different；
R8、R9For H, C1~C8 alkyl, C1~C8 alkoxy, phenyl, substituted-phenyl, 1- naphthalene, 2- naphthalene, heteroaryl or benzyl, Substituent group on the phenyl is C1~C8Alkyl, alkoxy, substituent group quantity be 1~5, heteroaryl be furyl, thiophene Base or pyridyl group, m=0~3；Or as m >=2, adjacent R9Or R8And R9It can and be C3~C7 cycloaliphatic ring or aromatic rings, R8、R9 It can be the same or different；
R10For H, C1~C8Alkyl, phenyl, substituted-phenyl, 1- naphthalene, 2- naphthalene, heteroaryl or benzyl, taking on the phenyl Dai Jiwei C1~C8Alkyl, alkoxy, substituent group quantity be 1~5, heteroaryl be furyl, thienyl or pyridyl group；
Chiral spiro amido pyridine Phosphine ligands in suitable chiral catalyst comprise the following structure shown in formula:
Wherein DTB is 3,5- di-tert-butyl-phenyl；Xyl is 3,5- 3,5-dimethylphenyl；tBu is tert-butyl；Chiral spiro amido pyridine The structure of Phosphine ligands both can be (R)-configuration and be also possible to (S)-configuration；
Iridium metals precursor is [Ir (cod) Cl]2(cod=cyclo-octadiene), [Ir (cod)2]BF4、[Ir(cod)2]PF6、[Ir (cod)2]SbF6、[Ir(cod)2] OTf etc.；
Step 2: chiral alcohol 2 within the scope of -60~100 DEG C, is converted into beta-ketoester 3 under oxidant effect in organic solvent； The organic solvent is one or more of methylene chloride, dimethyl sulfoxide, tetrahydrofuran；The oxidant be PCC, PDC, IBX, TEMPO, Swern oxidant, Dess-Martin oxidant or Parkin-Doering oxidant；
Step 3: beta-ketoester 3 within the scope of 0~150 DEG C, reacts to obtain with iodide 4 in the presence of alkali in organic solvent Compound 5；The organic solvent is one or more of acetone, acetonitrile, toluene, ether, THF, DMSO, DMF；Described Alkali is K2CO3、Cs2CO3Or NaH；
Step 4: compound 5 within the scope of 0~100 DEG C, friedel-crafts reaction occurs under the action of an acid and obtains chemical combination in organic solvent Object 6；The organic solvent is one or more of methylene chloride, tetrahydrofuran, methanesulfonic acid；The acid be methanesulfonic acid, Trifluoromethanesulfonic acid, concentrated hydrochloric acid, the concentrated sulfuric acid or polyphosphoric acids；
Step 5: compound 6 is in organic solvent within the scope of 0~100 DEG C, and catalytic hydrogenation obtains chemical combination under the effect of the catalyst Object 7；The organic solvent is one or more of methanol, ethyl alcohol, ethyl acetate；The catalyst is palladium carbon, hydrogen-oxygen Change palladium or Raney Ni；
Step 6: compound 7 is in organic solvent within the scope of -100~30 DEG C, and generation birch reduction is anti-under alkali metal effect It answers, is then isomerized to ketenes 8 under the action of an acid；The organic solvent be acetone, methylene chloride, tetrahydrofuran, ether, One or more of methanol, ethyl alcohol, isopropanol, tert-butyl alcohol；The alkali metal is lithium, sodium or potassium；The acid is salt Acid, sulfuric acid or acetic acid；
Step 7: within the scope of -100~50 DEG C, Isosorbide-5-Nitrae-occurs under the action of alkylmetal reagent for ketenes 8 altogether in organic solvent Yoke addition obtains ketone 9；The organic solvent is one or both of tetrahydrofuran, ether；The alkylmetal reagent The copper azoviolet that the copper lithium reagent or cuprous iodide and methyl Grignard generated for cuprous iodide and lithium methide generates；
Step 8: within the scope of -30~80 DEG C, under the action of bromide reagent bromo-reaction occurs for compound 9 in organic solvent Obtain bromide 10；The organic solvent is one of tetrahydrofuran, ether, methylene chloride, chloroform, carbon tetrachloride Or it is several；The bromide reagent is bromine, phenyltrimethylammonium bromide (PTAB) or pyridinium tribromide drone salt；
Step 9: bromide 10 is in organic solvent within the scope of -100~80 DEG C, in the work of diazomethane and boron trifluoride ether With lower generation ring expansion, desiliconization obtains compound 11 under gained effect；The organic solvent be tetrahydrofuran, ether, One or more of methylene chloride；The acid is p-methyl benzenesulfonic acid, hydrochloric acid, trifluoromethanesulfonic acid or sulfuric acid；
Step 10: compound 11 within the scope of 0~180 DEG C, eliminates hydrogen bromide in the presence of alkali and obtains ketenes in organic solvent 12；The organic solvent is one or more of toluene, paraxylene, ortho-xylene, DMF, DMSO；The alkali is DBU or lithium carbonate；
Step 11: ketenes 12 within the scope of -100~80 DEG C, tries under the action of lewis acid with methylation in organic solvent Agent effect generates compound 13-epi-mulinolic acid ethyl ester (13)；The organic solvent is tetrahydro furan It mutters, one or more of ether, methylene chloride；The lewis acid is cerous chloride；The methylating reagent is first Base lithium or methyl Grignard；
Step 12: compound 13 within the scope of 0~150 DEG C, hydrolysis occurs in the presence of alkali and obtains in organic solvent Natural products 13-epi-mulinolic acid (14)；The organic solvent is DMSO；The alkali is potassium tert-butoxide；
Step 13: compound 14 is in organic solvent within the scope of 0~100 DEG C, and dehydration generates natural products under the action of an acid Mulin-11,13-dien-20-oic acid (15)；The organic solvent is benzene, toluene, tetrahydrofuran, one in ether Kind is several；The acid is p-methyl benzenesulfonic acid, hydrochloric acid, trifluoromethanesulfonic acid or sulfuric acid；
Step 14: compound 15 is in organic solvent within the scope of -20~30 DEG C, under illumination condition, under the effect of the catalyst It is reacted with oxygen and generates natural products mulinic acid (16)；The organic solvent is methylene chloride, chloroform, tetrachloro Change one or more of carbon；The illumination is ultraviolet light；The catalyst is tetraphenylporphyrin (TPP)；
Step 15: compound 16 within the scope of -20~30 DEG C, generates natural products in organic solvent under the effect of the catalyst isomulinic acid(17)；The organic solvent is one or more of methylene chloride, chloroform, carbon tetrachloride； The catalyst is RuCl2(PPh3)3；
Step 10 six: compound 15 within the scope of -20~150 DEG C, generates aldehyde under the action of oxidant in organic solvent, without Purification, allyl alcohol is directly reduced under the action of reducing agent and obtains natural products 16-hydroxymulin-11,13-dien- 20-oic acid(18)；The organic solvent is one or more of methanol, ethyl alcohol, water, Isosorbide-5-Nitrae-dioxane；It is described Oxidant be selenium dioxide.The reducing agent is sodium borohydride；
Step 10 seven: ester group within the scope of -60~80 DEG C, is reduced to by compound 13 under the action of reducing agent in organic solvent Alcohol obtains compound 13-epi-mulinol (19)；The organic solvent is one of tetrahydrofuran, ether, methylene chloride Or it is several；The reducing agent is Lithium Aluminium Hydride or diisobutyl aluminium hydride lithium；
Step 10 eight: compound 19 is in organic solvent within the scope of 0~100 DEG C, and dehydration generates natural products under the action of an acid Mulin-11,13-dien-20-ol (20)；The organic solvent is one of benzene, toluene, tetrahydrofuran, ether or several Kind；The acid is p-methyl benzenesulfonic acid, hydrochloric acid, trifluoromethanesulfonic acid or sulfuric acid；
Step 10 nine: compound 20 is in organic solvent within the scope of 0~100 DEG C, under the action of alkali and catalyst with acetic anhydride Reaction generates natural products 20-hydroxymulin-11,13-dienyl acetate (21)；The organic solvent is dichloro One or more of methane, tetrahydrofuran, ether, pyridine；The alkali is triethylamine, pyridine or diisopropylethylamine；Institute The catalyst stated is DMAP.
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CN109970795A (en) * 2019-05-05 2019-07-05 南开大学 4- substituted chiral spiro aminophosphine ligand preparation method and applications on pyridine ring
CN115197058A (en) * 2021-04-12 2022-10-18 南开大学 Anticancer natural product Dysideanone B analogue and preparation method thereof
CN115477581A (en) * 2022-09-13 2022-12-16 安徽金禾化学材料研究所有限公司 Preparation method of high-cis methyl dihydrojasmonate

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109970795A (en) * 2019-05-05 2019-07-05 南开大学 4- substituted chiral spiro aminophosphine ligand preparation method and applications on pyridine ring
CN109970795B (en) * 2019-05-05 2022-03-04 浙江九洲药业股份有限公司 Preparation method and application of 4-substituted chiral spiro aminophosphine ligand on pyridine ring
CN115197058A (en) * 2021-04-12 2022-10-18 南开大学 Anticancer natural product Dysideanone B analogue and preparation method thereof
CN115197058B (en) * 2021-04-12 2024-05-07 南开大学 Anticancer natural product Dysideanone B analogue and preparation method thereof
CN115477581A (en) * 2022-09-13 2022-12-16 安徽金禾化学材料研究所有限公司 Preparation method of high-cis methyl dihydrojasmonate

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