丁 偉，呂 霞，劉世領(lǐng)，朱瑞恒，施小新

(華東理工大學(xué) 藥學(xué)院 制藥工程系，上海 200237)

·研究簡報(bào)·

(S)-(-)-norlaudanosine和(S)-(-)-O,O-dimethylcoclaurine的合成*

丁 偉，呂 霞，劉世領(lǐng)，朱瑞恒，施小新

(華東理工大學(xué) 藥學(xué)院 制藥工程系，上海 200237)

N-Ts homoveratrylamine(2)was prepared byN-sulfonylation of 3,4-diemthoxydopamine.(±)-Norlaudanosine(5a)and (±)-O,O-dimethylcoclaurine(5b)were synthesized by Pictet-Spengler reaction of 2with styryl methyl ethers catalyzed by PTS and removal of Ts group.(S)-(-)-5aand (S)-(-)-5bwere obtained by half-equivalent resolution withN-Ac-L-phe.The structures were confirmed by1H NMR,13C NMR，IR,MS and HR-ESI-MS.

Pictet-Spengler reaction;norlaudanosine;O,O-dimethylcoclaurine;synthesis;resolution

芐基四氫異喹啉類化合物在自然界中廣泛存在[1-2]。相關(guān)研究表明這類結(jié)構(gòu)化合物具有廣泛的生理活性[3-5]，可方便地轉(zhuǎn)化成其它生物堿，如阿樸啡類生物堿、嗎啡類生物堿、小檗堿類生物堿、二芐基四氫異喹啉類生物堿等[6-7]。

norlaudanosine(5a)是合成多種藥物分子的關(guān)鍵中間體[3]，而O,O-dimethylcoclaurine(5b)是合成去甲烏藥堿的前體[8]。目前這兩個(gè)化合物的單一構(gòu)型主要通過不對稱合成或消旋體拆分制得。但是文獻(xiàn)報(bào)道的不對稱合成方法需要使用價(jià)格昂貴的手性催化劑[8-9]或手性輔基[10-11]，而傳統(tǒng)的全量拆分方法[12-13]需要用到高劑量的拆分劑，造成拆分劑的浪費(fèi)。

本文以高藜蘆胺(1)為起始原料，經(jīng)N-磺酰化反應(yīng)制得高藜蘆磺酰胺(2)；2分別與芳乙烯甲醚(3a和3b)經(jīng)對甲苯磺酸(PTS)催化的Pictet-Spengler反應(yīng)后用金屬鈉脫除Ts基團(tuán)合成了(±)-5a和(±)-5b；使用半量拆分法，以N-乙酰-L-苯丙氨酸(6)為拆分劑，將(±)-5a或(±)-5b拆分制得(S)-(-)-5a和(S)-(-)-5b(Scheme 1)，其結(jié)構(gòu)經(jīng)1H NMR,13C NMR，IR,MS和HR-ESI-MS確證。并對拆分條件進(jìn)行了優(yōu)化，首次報(bào)道了(S)-(-)-5b的拆分方法。

1 實(shí)驗(yàn)部分

1．1 儀器與試劑

SGW X-4型顯微熔點(diǎn)儀(溫度未校正)；WZZ-1S型自動旋光儀；Bruker ADVANCE 400MHz型核磁共振儀(CDCl3為溶劑，TMS為內(nèi)標(biāo))；NICOLET IR 550型紅外光譜儀(KBr壓片)；HP 5989A型質(zhì)譜儀；Shimadzu LC-20A型高效液相色譜儀[手性柱：Chiralcel OD；流動相：正己烷/異丙醇=80/20(V/V)，流速：1.0mL·min-1；UV檢測波長：220nm]。

所用試劑均為分析純。

1．2 合成

(1)2的合成

在反應(yīng)瓶中依次加入15.00g(27.59mmol),CH2Cl250mL和NEt34.18g(41.39mmol)，冰水浴冷卻，攪拌下分批(5次)加入對甲苯磺酰氯(TsCl)5.15g(27.04mmol)，自然升至室溫，反應(yīng)2h(TLC檢測)。加1mol·L-1鹽酸20mL，分液，有機(jī)層用10% K2CO3溶液(10mL)洗至堿性，無水MgSO4干燥，蒸干得淡黃色固體，用20%甲醇(3×15mL)洗滌，干燥得白色固體28.25g，產(chǎn)率91%，m.p.131℃～132℃；1H NMRδ: 2.40(s,3H),2.68(t,J=6.8Hz,2H),3.16(t,J=6.7Hz,2H),3.78(s,3H),3.83(s,3H),4.39(s,1H),6.54(d,J=1.7Hz,1H),6.60(dd,J=1.7Hz,1H),7.25(d,J=3.7Hz,1H),7.27(s,1H),7.65(d,J=8.2Hz,2H)；IRν：3110,2980,1590,1510,1330,1260,810,550cm-1；EI-MSm/z(%): 335[M+,36],184(15),151(100),91(29)。

(2)4的合成(以4a為例)

在反應(yīng)瓶中依次加入21.00g(2.98mmol)和甲苯15mL，攪拌下依次加入3，4-二甲氧基苯乙烯基甲醚(3a)0.70g(3.58mmol)和PTS 11mg(0.06mmol)，回流反應(yīng)2h。冷卻至室溫，用1mol·L-1K2CO3溶液(2mL)洗滌，無水MgSO4干燥，濃縮后用乙醇重結(jié)晶(加入少量晶種)得N-磺酰化norlaudanosine(4a)1.33g。

用類似的方法合成4b。

4a：白色固體，產(chǎn)率90%,m.p.143℃～145℃；1H NMRδ: 2.34(s,3H),2.34～2.43(m,1H),2.53～2.66(m,1H),3.01(dd,J=13.5Hz,7.2Hz,1H),3.12(dd,J=13.5Hz,5.8Hz,1H),3.28～3.39(m,1H),3.56～3.65(m,1H),3.66(s,3H),3.74(s,3H),3.79(s,3H),3.85(s,3H),5.08(dd,J=6.5Hz,1H),6.20(s,1H),6.43(s,1H),6.51(d,J=1.8Hz,1H),6.56(dd,J=8.1Hz,1.8Hz,1H),6.72(d,J=8.1Hz,1H),7.13(d,J=8.1Hz,2H),7.52(d,J=8.3Hz,2H);13C NMRδ: 21.5,26.9,39.8,43.9,55.7,55.8(2C),55.9,57.5,110.2,110.9,111.2,112.9,122.1,125.6,127.1,127.4,129.4,130.2,137.3,143.0,146.9,147.8(2C),148.6；IRν：2935,1612,1518,1462,1292,1231,1148,1112,1027,976,811,564cm-1；HR-ESI-MSm/z: Calcd for C27H32NO6S{[M+H]+}498.1950，found 498.1950。

N-磺?；疧,O-dimethylcoclaurine(4b): 白色固體，產(chǎn)率92%,m.p.129℃～131℃；1H NMRδ: 2.27(s,3H),2.31～2.42(m,1H),2.48～2.61(m,1H),2.90(dd,J=13.5Hz,7.6Hz,1H),3.05(dd,J=13.5Hz,5.9Hz,1H),3.26～3.37(m,1H),3.55(s,3H),3.56～3.62(m,1H),3.70(s,3H),3.72(s,3H),4.99(dd,J=6.8Hz,1H),6.04(s,1H),6.36(s,1H),6.65～6.75(m,2H),6.82～6.91(m,2H),7.05(d,J=8.1Hz,2H),7.45(d,J=8.3Hz,2H);13C NMRδ: 21.5,26.9,39.8,43.4,55.2,55.7,55.8,57.7,110.2,111.1,113.7,125.4,127.1,127.4,129.8,130.9,137.3,143.0,146.7,147.7,158.4；IRν：2935,1615,1519,1460,1321,1248,1156,1112,813,564cm-1；HR-ESI-MSm/z: Calcd for C26H30NO5S{[M+H]+}468.1845,found 468.1843。

(3)(±)-5的合成[以(±)-5a為例]

在反應(yīng)瓶中依次加入4a1.00g(2.01mmol)和混合溶劑[V(DME)∶V(iPrOH)=4∶1]20mL，攪拌使其溶解；加入小鈉絲0.92g (40mmol)，劇烈攪拌下于35℃～ 40℃反應(yīng)1h(TLC檢測)。冰水浴冷卻，加入碎冰5g破壞剩余小鈉絲，旋蒸除去有機(jī)溶劑，用乙酸乙酯(15mL)萃取，有機(jī)相用水(10mL)洗滌，洗液用乙酸乙酯(10mL)萃取，合并有機(jī)相，用無水MgSO4干燥，旋蒸除溶得無色油狀液體，用乙醇10mL溶解，滴加濃鹽酸0.3mL，于室溫?cái)嚢?0min，蒸干溶劑(析出固體)，用乙酸乙酯(2mL)洗滌，過濾，濾餅干燥得白色鹽酸鹽固體0.72g。用1mol·L-1的K2CO3溶液(10mL)中和，用乙酸乙酯(2×10mL)萃取，合并有機(jī)相，用無水MgSO4干燥，蒸干得無色油狀液體(±)-5a0.64g。

用類似方法合成(±)-5b。

(±)-5a：產(chǎn)率92%；1H NMRδ: 1.85(br s,1H),2.64～2.80(m,2H),2.81～2.97(m,2H),3.09～3.28(m,2H),3.84(s,3H),3.86(s,6H),3.88(s,3H),4.13(dd,J=9.1Hz,4.1Hz,1H),6.60(s,1H),6.67(s,1H),6.76(s,1H),6.78～6.86(m,2H);13C NMRδ: 29.5,40.9,42.2,55.81,55.84,55.9,56.0,56.8,109.3,111.2,111.8,112.3,121.4,127.4,130.3,131.4,147.0,147.4,147.6,148.9；IRν：3598,3331,2933,2831,1734,1608,1514,1463,1216,1113,1028,803cm-1；EI-MSm/z: 343[M+,1],206(1),192(100),176(7),151(3)。

(±)-5b: 無色油狀液體，產(chǎn)率91%；1H NMRδ: 1.95(s,1H),2.62～2.80(m,2H),2.80～2.95(m,2H),3.10～3.25(m,2H),3.79(s,3H),3.81(s,1H),3.85(s,3H),4.10(dd,J=9.4Hz,4.1Hz,1H),6.59(s,1H),6.63(s,1H),6.82～6.89(m,2H),7.13～7.20(m,2H);13C NMRδ: 29.5,40.7,41.8,55.2,55.8,55.9,56.9,109.4,111.8,114.0,127.3,130.3,130.6,131.0,146.9,147.4,158.2；IRν：3330,2935,2829,1610,1469,1300,1245,1179cm-1；HR-ESI-MSm/z: Calcd for C19H23NO3{[M+H]+}314.1756，found 314.1743。

(4)(S)-(-)-5的合成[以(S)-(-)-5a為例]

2 結(jié)果與討論

2.1 Pictet-Spengler反應(yīng)條件優(yōu)化

實(shí)驗(yàn)中我們首先嘗試了1和3的Pictet-Spengler反應(yīng)，發(fā)現(xiàn)反應(yīng)需過量酸催化且收率很低(20%～30%)；之后參考文獻(xiàn)[15]方法嘗試了高藜蘆羧酰胺與3的Pictet-Spengler反應(yīng)，發(fā)現(xiàn)反應(yīng)仍需過量三氟乙酸催化，收率中等(62%)；最后改用高藜蘆磺酰胺2與3進(jìn)行Pictet-Spengler反應(yīng)，收率很高，且只需2mol%PTS催化。

對于2與3的Pictet-Spengler反應(yīng)，若選用乙酸或苯甲酸等弱酸作催化劑，則反應(yīng)幾乎不能進(jìn)行；若用較強(qiáng)的Lewis酸，如三氟化硼乙醚、四氯化鈦、氯化鐵、氯化鋁等作催化劑，則原料3容易分解，反應(yīng)較亂；而選用中強(qiáng)酸PTS作催化劑，收率較高。

2.2 拆分條件優(yōu)化

對于(±)-5a的手性拆分，王保成[12]用1.06eq.N-乙酰-D-苯丙氨酸為拆分劑，以97%的純度和32%的產(chǎn)率制得(R)-(+)-5a；Hill等[13]用1.00eq.N-乙酰-L-亮氨酸作拆分劑，以97%的純度和40%的產(chǎn)率制得(R)-(+)-5a。本文用0.50eq.6為拆分劑，以99%的純度和34%的產(chǎn)率制得(S)-(-)-5a，相比文獻(xiàn)方法，減少拆分劑的用量，避免了浪費(fèi)。

考察了以6為拆分劑時(shí)不同溶劑對拆分效果的影響，結(jié)果見表1。從表1可以看出，用AcOEt作溶劑時(shí)，產(chǎn)率較高，但ee值不高；而用EtOH作溶劑時(shí)，產(chǎn)率不高，但ee值很高；而用EtOH/AcOEt(V/V=1/2)混合溶劑作溶劑時(shí)，產(chǎn)率和ee值均較高。

(±)-5b的手性拆分未見文獻(xiàn)報(bào)道，本文首次通過拆分制得(S)-(-)-5b。其最佳拆分條件與(±)-5a一致。

表1 溶劑對拆分(±)-5a的影響Table1 Effect of solvents on resolution of (±)-5a

aV/V=1/2;b由手性柱Chiralcel OD測定

3 結(jié)論

首次通過Pictet-Spengler反應(yīng)合成了(S)-(-)-norlaudanosine和(S)-(-)-O,O-dimethylcoclaurine。在文獻(xiàn)方法的基礎(chǔ)上對(±)-norlaudanosine的拆分進(jìn)行了改進(jìn)，并且首次對(±)-O,O-dimethylcoclaurine的手性拆分進(jìn)行了研究。

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2014-02-27

國家自然科學(xué)基金資助項(xiàng)目(20972048)；上海市教育發(fā)展基金資助項(xiàng)目(03SG27)

丁偉(1986-)，男，漢族，浙江紹興人，博士研究生，主要從事藥物合成的研究。

施小新，教授，博士生導(dǎo)師，Tel.021-64252052，E-mail: xxshi@ecust.edu.cn

以高藜蘆胺為起始原料，經(jīng)N-磺?；磻?yīng)制得高藜蘆磺酰胺(2)；2分別與芳乙烯甲醚經(jīng)對甲苯磺酸催化的Pictet-Spengler反應(yīng)后用金屬鈉脫除Ts基團(tuán)合成了(±)-norlaudanosine(5a)和(±)-O,O-dimethylcoclaurine(5b)；使用半量拆分法，以N-乙酰-L-苯丙氨酸為拆分劑，制得(S)-(-)-5a和(S)-(-)-5b，其結(jié)構(gòu)經(jīng)1H NMR,13C NMR，IR,MS和HR-ESI-MS確證。

Pictet-Spengler反應(yīng);norlaudanosine;O,O-dimethylcoclaurine;合成；拆分

O625.3;O626.3

A

1005-1511(2014)05-0679-04

Synthesisof(S)-(-)-norlaudanosineand(S)-(-)-O,O-dimethylcoclaurine

DING Wei, LU Xia, LIU Shi-ling, ZHU Rui-heng, SHI Xiao-xin

(Department of Pharmaceutical Engineering,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China)