(+)-Talaumidin的全合成

2008年第16卷合成化學(xué)Vol. 16, 2008第4期, 477 ~480Chinese Joumnal of Synthetic ChemistryNo.4, 477 ~ 480●制藥技術(shù)●( + )-Talaumidin的全合成姜英俊，焦曉臻,王麗萍,張力子，謝平， 梁曉天(中國醫學(xué)科學(xué)院北京協(xié)和醫學(xué)院藥物研究所,北京100050)摘要:以(S) 4.苯基-3-戊烯?；?-嘻唑烷酮為起始原料,以不對稱(chēng)的Aldol反式羥醛縮合反應和付-克反應為關(guān)鍵步驟,合成了( + )-Talaumidin,其結構經(jīng)'H NMR, "C NMR和ESI-MS表征。關(guān)鍵詞:( +)-Talaunidin; Aldol 羥醛縮合;付-克反應;藥物合成中圖分類(lèi)號: 0621.3; R914.5文獻標識碼: A文章編號: 105-1511(2008)0477-04Total Synthesis of ( + ) -TalaumidinJIANG Ying-jun，JIAO Xiao-zhen，WANG Li-ping,ZHANG Li-zi，XIE Ping，LIANG Xiao tian(Institute of Materia Medica, Chinese Academy of Medical Sciences,Peking Union Mdical College, Bejjng 1000, China)Abstract: ( + )-Talaumidin was synthesized from (S) -3-pentenoyl.4-phenyl-1 ,3 -oxazolidin-2 one byasymmetric Aldol reaction and F- C reaction as key steps. The structure was confirmed by 'H NMR,1C NMR and ESI-MS.Keywords: ( + )-Talaumidin; Aldol reaction; F - C reaction; drug synthesisTalaumidin(12)是從馬兜鈴中分離得到的2,8; 8在雙三甲基硅氨基鋰(LHMDS)存在下和碘甲5-二芳基-3 ,4-二甲基四氫呋喃新木脂素類(lèi)化合烷甲基化[°0]得9; 9經(jīng)二異丁基氫化鋁( DIBALH)物"。研究表明12具有對皮質(zhì)神經(jīng)元的向神經(jīng)還原,甲醚化得10; 10在SnCl,存在下和胡椒環(huán)進(jìn)作用,對阿爾茨海默病和帕金森病體外模型有神行付-克(F -C)反應["] ,并伴隨5位取代苯基的經(jīng)保護作用(] ,不僅增加存活神經(jīng)元的數量,而構型翻轉得11; 11經(jīng)Pd-C催化氫化得12(Scheme且促進(jìn)樹(shù)突的伸展,是一一個(gè)很有希望治療神經(jīng)退1)。12的結構經(jīng)'H NMR, "C NMR和SEI-MS表行性疾病的先導化合物。征,其數據與文獻("]值-致,旋光符號相反。本文以(S)4-苯基-3-戊烯?；?2-囈唑烷酮1實(shí)驗部分(1)為起始原料,在三乙胺氯化鎂和三甲基氯硅烷的存在下與3~甲氧基4芐氧基苯甲醛進(jìn)行不對稱(chēng)1.1 儀器與試劑Aldol反應“1得到反式產(chǎn)物2; 2經(jīng)硅醚保護得3; 3Yanaco 500D型顯微熔點(diǎn)儀(溫度未經(jīng)校正);經(jīng)硼氫化鋰還原[$)得4; 4經(jīng)甲烷磺酰氯(°],四氫Varian INOVA-500和MERCURY 400型核磁共振鋁鋰還原”得5; 5經(jīng)高碘酸鈉氧化吲得6; 6脫硅儀( CDCI,為溶劑，TMS為內標); Micromass Auto醚成半縮醛7; 7經(jīng)氯鉻酸吡啶鹽(PCC)氧化'得Spec Utima-TOF型質(zhì)譜儀;Perlin Elmer型旋光儀。中國煤化工收稿日期: 2008-01-26.CH.CNMH G作者簡(jiǎn)介:姜英俊(1982 -) ,男,權族,遼寧臺安人,在讀碩士.主要從事大m廠(chǎng)切的王日取x共組傳夢(mèng)評。通訊聯(lián)系人:謝平,研究員, Tel. 010-63165241, E-mail; pingie123@ vip. sohu. net合成化學(xué)Vol. 16, 2008 .OHC.OMes,OMe9只QTBS) on , TMSCIUIBH.2)TFAOBn- TBSCI3OTBSHO-, OMe1)MsCl;,. OMeNalO4 050+ 26-uidineg.OMeTBAF.2)UAIH"OBn0Bn^0BnPCC， OMeLHMDS. Mel.1) DIBALH:molecular sleve*-78C2) CH(OMe) TsOH'OBn~o0." OBn-78c“OBn12OHScheme 11~4按文獻方法合成; (S)4苯基2-嘎J=4.8 Hz, 1H, 1-H), 3. 87(s, 3H, 0CH),唑烷酮[ (S)-POA]和叔丁基二甲基氯硅烷(TB-2.15(m, 1H, 2-H), 1. 75(m, 2H, 3-H), 0.90SC1) ,工業(yè)品;三乙胺和咪唑,化學(xué)純,其余所用試[s, 9H, C(CH),], 0.85(d, J=6.4 Hz, 3H, 2-劑為Acros產(chǎn)品。薄層層析用硅膠和柱層析硅膠CH,), 0.06(s, 3H, SiCH,)，-0.21(s, 3H,160目~200目,青島海洋化工廠(chǎng)生產(chǎn)。SiCH,)。(2) 6的合成1.2 合成在圓底瓶中依次加入56.3 g(15 mmol),二(1)5的合成氧六環(huán)100 mL,水35 mL, 2,6-lutidine 3.2 mL,在圓底瓶中加入47.2 g( 16 mmol) ,無(wú)水高碘酸鈉10.2 g(50 mmol)及4%四氧化鋨溶液1CH2Cl, 50 mL和三乙胺5.8 mL,攪拌下(冰浴)滴mL,攪拌下于室溫反應3 h(反應液變白色粘稠)。加甲烷磺酰氯( MsCl)2.5 mL(32 mmol) ,滴畢,于加水100 mL和CH2Cl2 200 mL,分出有機層,水層室溫反應2 h。加入CH2C12 200 mL稀釋,依次用用CH2CL(3 x50 mL)萃取,合并有機層,依次用5%氫氧化鈉、水、飽和氯化鈉洗滌,無(wú)水硫酸鈉干飽和亞硫酸氫鈉,飽和碳酸氫鈉、水、飽和氯化鈉燥,過(guò)濾，蒸除溶劑得粗品。將粗品加入圓底瓶洗滌,無(wú)水硫酸鈉干燥,過(guò)濾,蒸除溶劑,殘余物經(jīng)中,攪拌下加入無(wú)水THF 150 mL,冰浴冷卻下分柱層析(洗脫劑:A=1 :5)分離得無(wú)色油狀液體6批加入四氫鋁鋰1.82 g(48 mmol) ,于室溫反應35.4g,收率80%，[a]B -20(e1.4); 'H NMRδ:h。加入飽和硫酸鈉終止反應,再攪拌1 h后抽9. 68(s, 1H, CHO), 7.55 ~7.29(m, 5H, ArH),濾,濾餅用乙酸乙酯洗濾。合并有機層,用飽和氯6.83(m, 3H, ArH), 5. 12(s, 2H, PhCH20),化鈉洗滌,無(wú)水硫酸鈉干燥,過(guò)濾,蒸除溶劑,殘余4.30(d, J=4.8 Hz, 1H, 1-H), 3.87(s, 3H,液經(jīng)柱層析[洗脫劑:A =V(乙酸乙酯) :V(石油CH,0), 2.92 ~3.01(m, 1H, 3-H), 2.32 ~2.444醚)=1:10]分離得無(wú)色油狀液體5 5.52 g,收率(m, 1H, 3-H), 2. 12(m, 1H, 2-H), 0. 86[s,86%，[a] -29(c 1.2, CHCI,,下同); 'H NMR.8 Hz, 3H, 2-中國煤化工8: 7.55~7.29(m, 5H, ArH), 6.83(m, 3H,CH,0.22(s, 3H,ArH), 5. 76(m, 1H, 4-H), 5. 12(s, 2H,SiCH,YCHCNMH GK), 313, 91PhCH20), 4. 97 (complex, 2H, 5-H), 4. 42(d,(100%)。第4期姜英俊等:( + )-Talaumidin的全合成- 479-(3)7的合成J=6.8 Hz, 3H, 4-CH,); ESI-MS m/z: 349(M +在圓底瓶中加入63.3 g(7.8 mmol), THF Na), 328, 327(M +H), 91(100%)。50 mL及四丁基氟化銨(TBAF)3.2 g( 10 mmol) ,(6) 10的合成攪拌下于室溫反應2 h。加入飽和氯化銨50 mL，在三頸瓶中加入90.83 g(2.5 mmol)和無(wú)水分出有機層,水層用乙酸乙酯提取(3 x50 mL)。CH2C2 8 mL,攪拌下于-78 C滴加DIBALH4 mL合并有機層,依次用水飽和氯化鈉洗滌,無(wú)水硫(4 mmol) ,滴畢,繼續反應1 h。加甲醇5 mL,升酸鈉干燥,過(guò)濾,蒸除溶劑，殘余物經(jīng)柱層析(洗溫至室溫,加飽和氯化銨。分出有機層,水層用脫劑:A=1 :3)分離得無(wú)色油狀液體7 2.2 g,收CH2Cl2(3 x50 mL)萃取,合并有機層,依次用水、率90%; ESI-MS m/z: 651(2M +Na), 337(M +飽和氯化鈉洗滌,無(wú)水硫酸鈉干燥,過(guò)濾,蒸除溶Na), 297(100%), 279, 91。劑,殘余液經(jīng)柱層析(洗脫劑:A=1 :5)分離得粗(4) 8的合成品。將粗品加入圓底瓶中,再加入甲醇5 mL,原在圓底瓶中加入75.0 g(15.9 mmol),無(wú)水甲酸三甲酯 0.39 g(3.7 mmol) 及對甲苯磺酸CH2Cl2 50 mL,分子篩粉末1.0g及PCC4.2g (Ts0H)0.1 g(0. 5 mmol) ,攪拌下于室溫反應30(19.5 mmol) ,攪拌下于室溫反應2 h。反應液過(guò)min。 加入飽和碳酸氫鈉( 10 mL)終止反應,蒸除硅膠短柱(洗脫劑:乙酸乙酯)除去鹽和分子篩,蒸甲 醇,殘余物用乙酸乙酯稀釋。分出有機層,水層除溶劑,殘余物經(jīng)柱層析(洗脫劑A=1 :5)分離得用乙酸乙酯(3x50 mL)萃取。合并有機層,用無(wú)色油狀液體8 3.9 g, 收率79%, [a] -26水飽和氯化鈉洗滌,無(wú)水硫酸鈉干燥,過(guò)濾,蒸除(c1.3); 'H NMR 8: 7.28 ~7.45(m, 5H, ArH)，溶劑 ,殘余物經(jīng)柱層析(洗脫劑:A=1 :10)分離6. 89(d,J=8.0 Hz, 1H, ArH), 6.78(d, J=2.0得無(wú)色油狀液體 100.74 g, 收率85%; ESI-MSHz, 1H, ArH), 6.70(ddd, J=8.0 Hz, 2.0 Hz，m/z: 365(M +Na), 311(100%), 312, 91。0.8 Hz, 1H, ArH), 5.54(d, J=5.6 Hz, 1H, 5-(7) 11的合成H), 5. 15(s, 2H, PhCH2)， 3. 89(s, 3H,在三頸瓶中加人10 200 mg(0. 58 mmol) ,胡CH,0), 2. 78~2.86(m, 2H, 2-H), 2.35(m，椒環(huán) 500 mg(4 mmol)及無(wú)水CH2C2 10 mL,于1H, 4-H), 0.71(d, J=7.2 Hz, 3H, 4-CH,);-78 C滴加四氯化錫0.07 mL(0. 58 mmol),滴ESI-MS m/z: 313(M +H, 100%), 297, 91。畢,繼續反應( -78 C)20 min。加飽和氯化銨,(5) 9的合成分出有機層,水層用CH2Cl2(3 x50 mL)萃取。合在三頸瓶中加人8 6.0 g(19 mmol),無(wú)水并有機層,依次用水、飽和氯化鈉洗滌,無(wú)水硫酸THF 100 mL,于-78 C滴加1 mol●L-' LHMDS鈉干燥,過(guò)濾,蒸除溶劑,殘余物經(jīng)柱層析(洗脫27 mL(25 mmol) ,攪拌下反應30 min( -78 C)。劑:A=1 : 10)分離得無(wú)色油狀液體11 210 mg,收加人CH,1 3mL(74mmol) ,再反應1 h。緩慢升溫率87%,[a]D +89(c0.9); 'H NMR 8: 7.27 ~至-20 C反應2 h,加入飽和氯化銨終止反應,攪7.45(m, 5H, ArH), 6.98(m, 6H, ArH), 5.94拌10 min后分出有機層,水層用乙酸乙酯(3 x50(s, 2H, PhCH20), 5.15(s, 2H, CH2), 4.61(d,mL)提取。合并有機層,用水和飽和氯化鈉洗滌,J=7.6 Hz, 2H, 2,5-H), 3. 92(s, 3H, CH,0),無(wú)水硫酸鈉干燥,過(guò)濾,蒸除溶劑,殘余物經(jīng)柱層1.71 ~1.84(m, 2H, 3,4-H), 1.04(d, J=4.8析(洗脫劑A=1 :5)分離得無(wú)色油狀液體94.7 g,Hz, 3H, CH,), 1.02(d, J=4.8 Hz, 3H, CH);收率75%，[a]R +30(c1.3); 'H NMR8:7.27~ ESI-MS m/z: 455(M +Na), 433(M +H), 4157.43(m, 5H, ArH), 6. 86(d, J=8.0 Hz, 1H，(100%)。ArH), 6.66(d, J=2.0 Hz, 1H, ArH), 6. 63(dd,(8) 12的合成J=8.0 Hz, 2.4 Hz, 1H, ArH), 5.48(d, J=7.6在圓底燒瓶中加人11, 100 mg,乙酸乙酯5Hz, 1H, 5-H), 5. 14(s, 2H, PhCH20), 3. 85(s,mI中國煤化工過(guò)濾蒸除溶劑，3H, CH,), 2.44(m, 1H, 3-H), 2. 32(m, 1H，殘余C N MH G1 :7)得白色粘4-H), 1.26(d, J=7.2 Hz, 3H, 3-CH), 0.74(d,稠油狀物 12 70 mg,收率90%，[a]B +85(c0.4);一480--合成化學(xué)Vol. 16, 2008MeO.SnC4."OBn~ dBn; dBn=- =)HMeO-, OMe,OWeSnCiP0HOHScheme 26.94 ~6. 78(m, 6H，ArH), 5. 95(s, 2H,lidinones and bormane-2, 10-8ulam[J].J Org Chem,0CH20), 5.59(s, 1H, 0H), 4.61(d, J=9.01995 ,60(7) :2271 -2273.Hz, 1H, 2,5-H), 3.91(s, 3H, CH,0), 1.72~5] Evans D A, Tedrow JS, ShawJT, et al. 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