樟柳碱的全合成

Jourmal of Chinese Pharmaceutical Sciences 2005 , 14( 1 ):13- 173Total Synthesis of AnisodineWU Yan-fen , LU Qiang ,Li Wen , and ZHANG Wen-sheng( Deprtment of Medicinal Chemistry , School of Pharmaceutical Scienes , Peking Uninersity , Bejing 100083 , China)Abstract : Aim To design a practical synthetic route of anisodine. Methods Starting from 3a-hydroxy-6B- acetyltropine , anisodine was synthesized in 11 steps. Result Anisodine was obtainded withan overall yield of 2.6% . Conclusion Total synthetic route of anisodine was achieved which may afforda possible route for commercial preparation of anisodine .Key words : anisodine ; tropine alkaloid ; total synthesisCLC number : R916.41Document code : AArticle ID : 1003-1057 2005 )I -013-05IntroductionIn this paper , we report the synthesis of anisodineTropane alkaloids such as atropine , scopolamine ,by using 3 as the starting material , which affords not onlyand anisodamine have been widely used in clinical therapythe possible route for commercial preparation , but alsofor a long time. Anisodine'( 1 , Figure 1 ) is anotherprovides subsequent access to analogs of the parent struc-tropane alkaloid ，which was isolated from the plantture. Its quaterary ammonium salts will be potentiallyAnisodus tanguticus. It has many valuable pharmacologi-used as anticholinergic bronchodilators.cal activities , such as for the treatment of motion sick-ness ,migraine , and vascular spasm of fundus occuli. Re-Results and Discussionsearchers try to find an effective method to synthesize 1.The synthetic route is outlined in Scheme 1. Com-3-Hydroxytropene-6( 2 , Figure 1 ) is the key internediatepound 3 reacted with acetic anhydride to give 3a , 6-di-for the total synthesis of 1. Forder synesized compound 2acetyltropine 4 in 95% yield , which was then hydrolyzedwith very low yield21. R. Noyorf 3] gave a shorter routewith 1% NaOH in ethanol at 0 C to give the correspond-but the reagents were very expensive and very virulent .Xie et al synthesized anisodine via 3a-hydroxy- 6β-ing compound 5( 42% ) and 6( 26% ), respectively. Seacetytropine( 3 , Figure 1 ), but the overall yield waslected hydrolysis of two acetic esters was achieved by con-very low4]. Due to the low content of 1 in Anisodustrolling the reacting temperature , the amount of alkaline ,tanguticus and its difficulty in total synthesis , its has notand neutralizing the solution to pH 7 at 0 C before evap-widely been used elinically 2-4].oration under reduced pressure. Otherwise the two esterswere hydrolyzed simultaneously and only 6 was obtained..CH3.CH;..CH3The selectivity might be due to the neighboring group par-ticipation of the amine group. The hydroxyl group of com-AcO、pound 5 was then protected with tetrahydrofuran( THP )inPhCH2Cl2 in an ice- bath catalyzed by toluenesulfonic acid atCH2OHpH 3 to give compound 7 , which reacted with ethyl chlo-0 OOHrofon中国煤化工The THP group of com-Atisodinepoun;YHCN MH G elhanol atss c. After5 h, TLC showed that the reaction was accomplished.Figure 1 Structures of tropane alkaloid derivativesThe solution was evaporated under reduced pressure , theReceived date : 2004-10-30.residue was dissolved with chloroform ，and ether was* Corres(点政权据:Tel 81082801558added to the solution. After filtration , the mother liquid14Jourmal of Chinese Pharmaceutical Sciences 2005 , 14( 1 ):13- 17was evaporated to dryness under reduced pressure to giveand the thermometer was not corrected. Elemental analy-the corresponding compound 9 in 88% yield. Compoundsis, 'H NMR , and MS data were obtained with PE240C ,9 reacted with methanesulfonyl chloride in anhydrous pyri-VXR2300S( 300 MHz) , and KZ25( FAB ) , respectively.dine at 09C for an hour and then stirred at room tempera-3a , 6B-Diacetoxyl tropine hydrocholoride( 4)ture overnight , after workup to give compound 10 in 60%To a three- neck flask , 30 g of 3a-hydroxy-6-acetyl-yield , which was refluxed with DBU in 2 A 6-ollidine totropine , 60 mL of chloroform , and 60 mL of acetyl chlo-give the corresponding alkene compound 11 in 75.2%ride were added , and the solution was stirred at 50- 60yield. Reduction of compound 11 with LiAlH4 in THF atC for2 h. Then the solution was concentrated under re-room temperature for 6 hgave 6 ,7-dehydrotropine 2 induced pressure. The residue was recrystallized from anhy-80% yield , and after esterification with the correspondingdrous alcohol to give 19.7 g of pink solid , yield 95% ,acyl chloride to gave an oil compound 12. Selective oxi-mp98- 102 9C( lit1]105-112 C ).dation of the 67 )-double bond of compound 12 with hy-3a-AcetoxyI-6B-hydroxyl tropine( 5 )drogen peroxide in the existence of V2O5 gave the corre-To a solution of compound4( 17.9 g ,74 mmol ) insponding compound 13 with an exo-epoxy group27] ,water ,100 mLof 1 mol L- 1 potassium hydroxide solutionwhich was dihydroxylated with OsO4 and N-methylmorpho-was added , and the mixture was kept stirring at an ice-line N-oxide( NMO ) to give the racemic target compoundbath for 2 h. After the reaction was completed , 1 mot1 in 65% yield.L-1 HCl was dropped into the reaction solution until thesolution changed to neutral. Ethyl alcohol was removedExperimentalunder reduced pressure , and the solution was adjusted toUnless othervise mentioned , reagents were commer-be alkaline with 1 mot L~ 1 potassium hydroxide solutioncially obtained and used without further purification.and extracted with chloroform( 3x 50 mL). The organ-Melting points were determined with an X24 apparatusicphases were washed with ice water and brine , dried with.CH3."HO_11THPO、U95%84%.OAcOR5. R= Ac, 42%;6. R= H, 26%.74%|I,CH3CH,O~NC2Hs,CX_几WM80%75.2%OR,)R13x∈3, R=H; 40%1R= THHP: 88%-12.R= R|;vS9 R=H89.0% |xIvi( 10.R=Ms 60% .中国煤化工0CIAnisodineR=CH214=CHCNMHG:HsAcORcagents and condition: 1. Ac2O/Py;11. 1% NaOH in EIOH; u. DHP/TsOH/CH2Cl; IN. CICO2 EVBenzene, refux;V.PPTs/EIOH; VI MsCVPy; vwa. DBUollidine, reflux; y. LAIlL/THF; x.14/Py; x. H2O/V:O; x. NM0/OsO4Scheme 1 Synthetic route of anisodineWU Yan-fen , et al :Total Synthesis of Anisodine5anhydrous sodium sulfate , and the residue was purified by .tropine( 9 )chromatography on silica gel with chloroform-methanol toIn the existence of PPTS( 650 mg ), compound 8give compound 5(5.7 g , yield 32% ) and compound 6(4.1 g )was stirred at 55-60 C for5h in 110 mL of(6.2 g ,yield 42% ). 'H NMR( DMSO-d6 ,300 MHz)δ :anhydrous ethyl alcohol solution and then at room temper-1.34- 1.51 ( 2H, dd, J = 14.9 Hz, 2, 4-Heq ),ature ovemight. TLC showed that the reaction was com-1.76-1.942H ,m,2 A-Hax ),1.97 3H ,s, COCH3 ),pleted, and ethyl alcohol was removed under reduced2.07- 2.30[2H ,m ,7-H),2.39( 3H ,s ,N-CH3),2.82pressure. The residue was dissolved in chloroform , and(1H ,m,1-H),3.10( 1H ,m,5-H),4.39( 1H ,m,6-anhydrous ethyl ether was added to the solution. TheH),4.61(1H ,s ,6-0H),4.78( 1H ,m ,3-H).white solid was filtered and the filtrate was evaporated to3o.-Acetoxyl-6B-O-tetrahydropyranyl tropine ( 7 )dryness to give 2.6 g of yellow oil ,yield 88%. 'H NMRIna round bottom flask , compound 5( 6.2 g) was( DMSO-d6 ,300 MHz)δ :1.19( 3H,t,J=7.2 Hz ,dissolved in a mixture of 250 mL of dry dichloromethaneC00CH2CH3),1.59-2.01(5H ,m,2 ,4-H ,7-H.),and 20 mL of dihydropyran , and the solution was cooled1.99 3H ,s , C0CH3),2.53( 1H,dd,J= 13.5 ,6.9on an ice-bath. To the cold solution para-toluene sulfonicHz, 7-Hendo ),2.89( 1H, br,s, 0H ),4.0- 4.31acid was added , and the reaction solution reached pH 3.(5H ,m,1 ,5 ,6-H , CO0CH2),4.95 1H,t,J=4.5The reaction solution was stirred for additional half anHz ,3-H ).hour at0 C , the ice-bath was removed , and the reaction3o-Acetoxyl-6B-methylsulfonyl-8 acetoxyl demethy-mixture was kept stirring for ten hours at ambient tempe-ltropine( 10 )rature till the reaction was completed. The reacion solu-To the solution of compound9( 1.1 g,mol)in 10tion was washed with saturated sodium bicarbonate andmL of dry pyridine at 0 C ,0.6 mL of methylsulphonylwater , dried with anhydrous sodium sulfate , and was con-chloride was added dropwise. The mixture was stirred forcentrated to dryness under reduced pressure. The red oilan hour at0 C and then for 26 h at room temperature un-residue was purified by chromatography on silica gel withtil TLC showed that the reaction was completed. The darkchloroform-methanol( 30 :1 )to give 7.4 g of compound 4red solution was poured into ice water ，stirred and ex-as colorless oil , yield 84%. 'H NMR ( DMSO-d6 ,300tracted with chloroform( 3 x 20 mL ). The combined chlo-MHz)δ:1.39-2.13(12H,m),1.92(3H,s,roform phase was washed with 1 mot L- 1 hydrochlorideCOCH3), 2.62( 3H ,s , N-CH3), 3.25 - 4.55( 6H，saturated sodium bicarbonate and brine ，and then driedm),4.85( 1H ,m ,3-H).with anhydrous sodium sulfate , filtered and evaporated to .3o- Acetoxyl-6B-O- tetrapyranyl-8- ethoxycarbonyldryness. The residue was purified by chromatography ondemethyltropine( 8 )silica gel with petroleum ether-ethyl acetate( 12 )to give .The solution of compound 7 ( 7.4 g ) and ethyl0.8 g light yellow oil ,yield 60%. 'H NMR( DMSO-d6 ,chlorocarbonate( 16 mL)in 100 mL of dry benzene was300 MHz)δ :1.28(3H ,t,J=7.2 Hz ,C00CH2CH3),refluxed for 10 h , and then strred overmight at room tem-1.72-2.18(5H ,m,2 ,4-H ,7-H.),2.09(3H,s,perature. TLC showed that the reaction was completed ,COCH3).2.67 1H ,dd,J=14.1 ,7.2 Hz ,7-Hendo ),and the reaction mixture was poured into ice water. The3.05( 3H, s, CH,SO2 ),4.18( 2H, q, J=7.2 Hz ,organic phase was extracted and dried with Na2SO4 , fil-C0OCH2 ),4.45(2H ,m,1 ,5-H),5.09( 1H,t,J=tered and concentrated to dryness under reduced pressure .4.8 Hz ,3-H),5.44 1H ,m ,6-H).The yellow oil residue was purified by chromatography on30-AcetoxyI-8-ethoxvcarboy-6 , 7B-dehydrotropine中国煤化工silica gel with acetone-petroleum ether( 15)togive4.1 g(11of yllw-green oil , yield 74%. 'H NMR ( DMSO-d6 ,fYHCN M H G.8 g( mol )of compond300 MHz)δ :1.193H,t,J=7.2 Hz , C00CH2CH3 ),10 ,12 mLof dry 2 A ,6-ollidine and 0.4 mL of DBU1.46-2.53 ( 12H，m ), 1.96 ( 3H ,s ,C0CH3 ),were refluxed for 10 h. The reaction mixture was cooled to3.37-4.57( 6H ,m),4.97( 1H ,m ,3-H ).room temperature , then poured into ice water , stired and3a-AccX4p hydroxyl-8- acetoxy1demethy-extracted with chloroform( 3 x 30 mL ). The combined16Jourmal of Chinese Pharmaceutical Sciences 2005 , 14( 1 ):13- 17chloroformn phase was washed with 1 mot L- 1 hydrochlo-(2H ,dd,J=1.5 Hz, =CH2),5.97(2H ,br,s,6,ride , saturated sodium bicarbonate and brine , and then7-H),7.22-7.53 5H ,m,Ar-H).dried with anhydrous sodium sulfate , filtered and evapo-3o-Phenylacrylyl-6 , 7B-epoxytropine ester( 13)rated to dryness . The residue was purified by chromatog-Compound 12( 50 mg, mmol ) was dissolved in 5raphy on silica gel with petroleum ether-ethyl acetate( 2:mL of anhydrous acetonitrile ，and catalytic amount of1 )to give 0.46 g of light yellow oil , yield 75.2%. HV2Os ,0.3 mL of 30% H202 was added. The mixture wasNMR( DMSO-d6 ,300 MHz)δ :1.27(3H ,t,J=7.2heated to 40 9C and stired overmnight with a great amountHz , C00CH2CH3),1.68(2H ,br ,d,J= 15.3 Hz ,2 ,of green powder formed. The reaction mixture was filtered4-Hg),1.99( 3H ,s, COCH3),2.04-2.2(2H ,m,and condensed to give green oil. The residue was dis-2 ,4-H.),4.76( 2H ,q ,C00CH2),4.572H ,m,1 ,solved with water , alkalized with potassium carbonate5-H),5.02( 1H ,t,J=5.7 Hz ,3-H),6.19(2H ,br ,pH 10 , and extracted with chloroform(3x 10 mL). Thes ,6 ,7-H ).combined chloroform phase was washed with brine , dried6 , 7-Dehydrotropine( 2 )with anhydrous sodium sulfate , filtered , and evaporatedTo the suspension of lithium alumium hydride ( 400to dryness under reduced pressure. The residue was puri-mg ) in 6 mL of dry tetrahydrofuran at room temperature ,fied by chromatography on silica gel with chloroform-a solution of 400 mg of compound 11 in 4 mL dry tetrahy-methyl alcohol(5:1 )to give 50 mg of white solid , mprofuran was added , and the mixture was stirred at room96 °C ,yield 95%. 'H NMR( DMSO-do ,300 MHz)δ :temperature for 6 h. TLC showed that the reaction was1.622H ,d,J=15 Hz,2 ,4-H_q),2.19(2H ,m,2,completed . The reaction solution was cooled to0 C , and4-H.),2.51( 3H ,s,N-CH3 ),3.15(2H ,m,1 ,5-water was added dropwise to decompose lithium alumiumH),3.35(2H ,m,6, 7-H),5.13( 1H ,t,J=5.4hydride until all the LiAlH4 disappeared. After an addi-Hz ,3-H),6.31 ,5. 83(2H ,dd, =CH2 ),7.24-7.37tional 10 min stirring , the reaction mixture was filtered(5H ,m ,Ar-H )through diatomite , and the filtrate was evaporated to dry-Anisodine( 1 )ness under reduced pressure. The residue was purified onAt room temperature .2.5 g of compound 13 , 15 mLsilica gel column , eluted with petroleum ether-ethyl ac-of water ,30 mL of acetone ,5 mL of t-butyl alcohol , andetate( 1:2)to give0.21 g of oil , yield 80%. H NMR1.6 g of N-methylmorpholine-N-oxide were added to a( DMSO-d6 ,300 MHz)δ :1.72H ,d ,J= 15.6 Hz ,2，round bottom flask. The mixture was stirred to form a so-4-Hg),2.082H ,m,2 ,4H、),2.18 3H ,s ,N-CH3 ),lution. A few granules of OsO4 were added to the solution3.0(1H ,br ,0H),3.36(2H ,m,1 ,5-H ),3.75( 1H ,and the mixture was stired for 10 h. TLC showed that thet ,J=5.7 Hz ,3-H),6.12(2H ,br ,s ,6,7-H).reaction was completed. Five milliliters of water contain-3a-Phenylacrylic-6 , 7-dehydrotropine ester( 12 )ing 0.6 g of NaHSO3 was added to the solution. The mix-At room temperature , 210 mg of compound 2 wasture was filtered , and the filtrate was extracted by chloro-dissolved in 2 mL of anhydrous pyridine and 2 mL of an-form( 3 x 50 mL ). The combined organic phases werehydrous chloroform. A solution of 600 mg of 3a-pheny-washed with iced water and brine. The organic phaseslacrylyl chloride in chloroform was added dropwise , andwere dried( NaSO4 ) , filtered , and concentrated under re-then the reaction solution was refluxed overmight till TLCduced pressure. The residue was recrystallyzed from chlo-showed that the reaction was completed. The reactionroform to give 2.3 g of white solid , mp 158-160 C ,mixture was filtered and evaporated to dryness. Theyield 89.0%. 'H NMR( DMSO-d6 ,300 MHz)δ :1.45 .residue was purified by chromatography on silica gel with(2H中国煤化工),1.95( 2H,m,2,4petroleum ether-ethyl acetate( 1:2)to give 150 mg oil .YHC N MHG3.03-4.17( 6H ,3'-compound , yield 40%. 'H NMR( DMSO-d6 ,300 MHz )CH2 ,1 ,5,6,7-H),4.82( 1H,t, J=5.1 Hz ,3-δ :1.89(2H ,d,J=15.6Hz ,2 ,4-Hg),2.07(2H ,H), 5.09( 1H, m, 3'-0H( disappeared with D20 ),m,2 ,4-Hx),2.58( 3H ,s, N-CH3 ),2.72( 2H ,m ,5.68( 1H ,s ,2'-0H( disappeared with D2O ), 7.26 -1 ,5-H)月万教据,t,J=5.7 Hz ,3-H),6.32 ,5.877.5x 5H ,m ,Ar-H ). Anal. Calcd for C17H21NOz HBr :WU Yan-fen , et al :Total Synthesis of Anisodine17C,51.01 ;H ,5.48;N ,3.49. Found :C,51.34 ,H ,Am Chem Soc , 1974 , 96 10 )3336-3339.5.72 ,N ,3.57.[4]Xie JX , Jin J , Zhang CZ ,et al . New method of total synthesisof anisodine[J] Acta Acad Med Sin ,1982 ,4(2):92.References[5] Chu GH , Zhou QT. A new synthetic method of 6 ,7-dedy-drotropine[ J]. Chin J Med Chem , 1996 ,6( 1 ):7-10.[1]Xie JX , WangL,Liu YL, et al. Chemical structure of aniso-[6]Lohray BB , Kalantar TH , Kim BM , et al. Documenting thedind[J]. Chin Sci Bull , 1975 ,20( 1):52-53.scope of the catalytic asymmetric dihydroxylation[ J ]. Tetrahe-[2] Dobo P , Fodor DP. The stereochemisty of the tropine alka-dron Lett , 1989 ,30 : 2041-2044.loids , Part VII , the total synthesis of scopolamine[ J] J Chem[7] Institute of Materia Medica. Studies on the chemical structureSoc , 1959 ,11 : 3461-3463.and synthesis[J] Pharmn Ind , 1976 ,2 :59-62.[3] Noyori R. A new general synthesis of tropine alkaloids[J] J樟柳碱的全合成吴艳芬,卢强,吕雯,仉文升(北京大学药学院药物化学系,北京100083 )摘要:目的设计合成一 条樟 柳碱的全合成路线。方法以 3a-羟基-6p乙酰氧基托品为起始物, 经化学合成方法合成樟柳碱。结果经11步实现了樟柳碱的全合成, 该路线条件温和,收率高。结论获得了 -条樟柳碱的全合成路线,具有潜在的工业化价值。关键词:樟柳碱托品生物碱;全合成中国煤化工MHCNMHG