●972●中國醫(yī)藥工業(yè)雜志Chinese Journal of Pharmaceuticals 2013, 44(10)Fridamycin E的合成陳遷'，宋光泉”(1.廣東工業(yè)大學輕工化工學院，廣東廣州510006; 2. 仲愷農(nóng)業(yè)工程學院化學化工學院，廣東廣州510225)摘要: 1,5- 二羥基蒽醌與3-氯-2-甲基丙烯經(jīng)取代反應得1-羥基-5-<(2- 甲基烯丙氧基)蔥醌，經(jīng)連=亞硫酸鈉還原后進行克萊森重排制成1,5-二羥基-2-(2-甲基烯丙基)蒽醌，與間氯過氧苯甲酸發(fā)生環(huán)氧化反應，再與氰化鉀進行區(qū)域選擇性環(huán)氧開環(huán)，最后經(jīng)水解得fridamycin E,總收率約14%。關鍵詞: fridamycin E; angucycline 類抗生素:蒽醌;合成中圖分類號: R978.1+9文獻標志碼: A文章編號: 1001-8255 (2013) 10-0972-03Synthesis of Fridamycin ECHEN Qian', SONG Guangquan2(1. School of Chemical Engineering and Light Indusr; Gruangdong University of Technology, Guangzhou 510006;2. College of Chemistry and Chemical Engineering, Zhongkai University of Agriculture and Engineering, Guangzhou 510225)ABSTRACT: Fridamycin E was synthesized from 1,-dihydroxyanthraquinone by mono-substitution with 3-chloro-2-methylpropene to give 1-hydroxy-5- (2-methlallyloxy) anthraquinone, which was subjected to reduction with Na2S2O4and Claisen rearrangement to afford 1,5-dihydroxy-2- (2-methylalyl) anthraquinone, followed by epoxidation withm-chloroperbenzoic acid, regioselective epoxide ring-opening reaction with potassium cyanide and then hydrolysis in14% overall yield.Key Words: fridamycin E; angucycline antibiotics; anthraquinone; synthesisAngucycline類抗生素是一類具有廣 泛生物活異構(gòu)體的全合成已有報道[,59。其中，Krohn 等[3]性的苯并蒽醌類化合物，具有抗腫瘤、抗菌、抗利用格氏反應構(gòu)筑叔丁醇側(cè)鏈作為關鍵步驟完成了病毒、酶抑制、血小板凝集抑制以及免疫調(diào)節(jié)等外消旋體的合成，但路線較長，總收率僅2.9%?；钚?12。其中fridamycin E,化學名4-(1,5-二羥.本研究參考相關文獻[10,以圖1所示路線制基-9,10-二氧-9,10-二氫蒽-2-基)-3-羥基-3-甲得1。以1,5-二羥基蒽醌(2)為原料，先用3-氯-基丁酸(1)，可從鏈霉菌Streptomyces parvulus菌2-甲基丙烯單取代2的酚羥基得1-羥基-5-(2-甲絲體中分離得到，對革蘭陽性菌具有顯著活性[1-3),基烯丙基氧基)蔥醌(3)，3經(jīng)連二亞硫酸鈉還原也是fidamycinA、B、D, vineomycin B2、C, hima-為蒽二酚中間體后，再經(jīng)熱驅(qū)動下的克萊森重排得lomycin A、B, amicenomycin B和grincamycin B、C、到1,5-二羥基-2-(2-甲基烯丙基)蒽醌(4)。4于D等angucycline類抗生素的重要糖苷配基[14)。最.室溫與間氯過氧苯甲酸(m-CPBA)發(fā)生環(huán)氧化反應新研究發(fā)現(xiàn)，1對革蘭陰性菌如大腸桿菌也有明顯得1,5-二羥基-2-(2-甲基環(huán)氧乙烷甲基)蒽醌(5),抑制作用(MIC=8 umol/L) 5s。其外消旋體及立體酚羥基可不受影響。5與氰化鉀發(fā)生區(qū)域選擇性的環(huán)氧開環(huán)反應得4-(1,5-二羥基-9,10-二氧代-9,10- .收稿日期: 2013-02-21基金項目:國家自然科學基金資助項目(2124202)二氫蒽-2-基)-3-羥基-3-甲基丁腈(6)，但由于5作者簡介:陳遷(1977-)， 男，博士，副教授，從事藥物合成研在堿性條件下不穩(wěn)定.會發(fā)生分子內(nèi)環(huán)氧開環(huán)反應,究Tel: 013822136153所以此步收中國煤化工經(jīng)氫氧化鈉水E-mail: qianchen@gdut.edu.cnDYHCNMH G解得1。此法不兒人公心，心認T為14%。.中國醫(yī)藥工業(yè)雜志Chinese Joumal of Pharmaceuticals 2013, 44(10),973●r CH38 OH?‘QHoQH OHH2CCH2_ NaSO4、CHreflux=CHK2CO3,KIlDMF/H2OCHsDMF, 75%C克萊森重排OH oOHOH OH? OHi OH8 QHq9 OHC0OH .eCH21. KCN,KINaOHCH，HzCDMSOHsC oH一 refuxHzC oHCH,Cl2, rt600COH 0H0H o.OH (5圖11 的合成路線實驗部分無水硫酸鈉千燥后過濾，濾液濃縮，剩余物經(jīng)硅膠1-羥基-5-(2-甲基烯丙氧基)蔥醌(3)[10]色譜柱(洗脫劑同3)分離，得橙色固體4(0.79 g,將2(購自Aldrich公司，純度85%，8.47 g,89% )，mp 154~ 156 C。R,0.35(展開劑:含30.0 mmol)、3-氯-2-甲基丙烯(購自Aldrich 公10%乙酸乙酯的環(huán)已烷)。'H NMR (600 MHz,司，純度90%，4.40 ml, 40.5 mmol)、無水碳酸鉀CDCIl)8: 13.05 (s, 1H), 12.70(s, 1H), 7.85 (dd,J=7.8、(22.9 g，166 mmol)和碘化鉀(1.76 g, 10.5 mmol) .1.2 Hz, 1H), 7.81 (d,J=7.2 Hz, 1H), 7.68 (dd, J=7.8、加入到DMF(400 ml)中，于75 C攪拌7h后過濾，7.8 Hz, 1H), 7.57(d,J=7.8 Hz, 1H), 7.32(dd, J=8.4、濾渣用丙酮(100 ml)洗滌。合并濾液及洗液，減0.6 Hz, 1H), 4.90(s, 1H), 4.74(s, 1H), 3.49(s, 2H),壓濃縮，剩余物經(jīng)硅膠色譜柱[洗脫劑:石油醚-1.78(s, 3H); 'C NMR(150 MHz, CDCI,)8: 188.2,乙酸乙酯(9 : 1)]分離，得橙色固體3(3.70 g, .187.8, 162.7, 161.2, 143.0, 137.0, 136.5, 133.3, 131.4,42%),mp160~ 162C (文獻10]: 161~162 C)。124.8, 119.3, 119.2, 119.0, 116.1, 15.5, 112.9, 37.4,R,0.5(展開劑:含20%乙酸乙酯的環(huán)己烷)。22.5。與文獻[5]報道一致。'H NMR (600 MHz, CDCl)8: 12.45(s, 1H), 7.94 (dd,1,5- 二羥基-2-(2-甲基環(huán)氧乙烷甲基)蒽醌(5)J=7.8、1.2 Hz, 1H), 7.76(dd, J=7.8、1.2 Hz, 1H),將4(0.75 g，2.55 mmol)溶于二氯甲烷(25 m1)7.68 ~ 7.62 (m, 2H), 7.31 (d, J=8.4 Hz, 1H), 7.22 (dd,中，室溫加入70%間氯過氧苯甲酸(0.94g,J=8.4、1.2 Hz, 1H), 5.35(s, 1H), 5.09(s, 1H), 4.63(s,3.81mmol)。攪拌3h后加入飽和碳酸氫鈉溶液2H), 1.92(s, 3H); 'C NMR(150 MHz, CDCI]) 8:(15 m1)淬滅反應。反應液用二氯甲烷(20 mlx3) .188.6, 181.3, 161.9, 159.5, 139.6, 136.8, 135.3, 135.0,萃取，經(jīng)無水硫酸鈉干燥后過濾，濾液濃縮，剩余134.8, 122.8, 121.7, 119.8, 119.5, 119.3, 115.6, 113.3,物經(jīng)硅膠色譜柱(洗脫劑同3)分離，得橙色固體72.8, 19.3。與文獻10)報道一致。5(0.67 g, 85%)，mp 136~ 138 C。R,0.21(展1,5-二羥基-2-(2-甲基烯丙基)蔥醌(4)[10]開劑同4)。EI-HRMS實測值(CiH2O,計算值):在氬氣保護下將連二亞硫酸鈉(1.04 g,310.083 2(310.083 6); 'H NMR (400 MHz, CDCI,)8:6.0 mmol)溶于水(200 ml)和DMF (100 ml)的混13.08(s, 1H), 12.68(s, 1H), 7.85(dd,J=8.0、1.2 Hz,合溶劑中。加熱至90 C加入3(0.88 g，3.0 mmol)1H), 7.81 (d, J=8.0 Hz, 1H), 7.70(d, J=8.4 Hz, 1H),的DMF (100 ml)溶液。加熱回流3 h后加入氫氧化7.66(dd,J=7.6、4.0 Hz, 1H), 7.32(dd,J=8.4、1.2 Hz, .鈉(0.30 g, 7.5 mmol)。繼續(xù)回流45 min,反應液.1H), 3.12(d,J=14.4 Hz, 1H), 3.04(d,J=14.0 Hz, 1H),冷卻至室溫，用乙酸乙酯(200 mlx3)萃取。合并2.67(d,J=4.8中國煤化 1H), 1.37(s,有機層，用飽和氯化鈉溶液(200 mlx5)洗滌，經(jīng)3H); I'C NYHCNMHG 188.2, 187.8,.●974●中國醫(yī)藥工業(yè)雜志Chinese Joumnal of Pharmaceuticals 2013, 44(10)162.7, 161.2, 138.4, 136.7, 134.1, 133.2, 131.8, 125.0,1H), 3.14(br s, 1H), 3.10(d, J=13.2 Hz, 1H), 3.05 (d,119.4, 118.9, 116.1, 115.8, 56.4, 53.4, 35.8, 21.4;J=13.2 Hz, 1H), 2.56(s, 2H), 1.30(s, 3H); "C NMRIR(KBr)v(cm): 3039, 2 924, 1633, 1 598, 1 390,(100 MHz, (CD)2CO)8: 189.2, 188.8, 173.9, 162.4,1 301, 1 245, 794, 777。162.3, 140.9, 137.9, 136.0, 134.2, 132.4, 125.5,4-(1,5-二羥基-9,10-二氧代-9,10-二氫蒽-2-120.0, 119.2, 116.9, 116.3, 72.2, 45.5, 40.8, 27.2;基)-3-羥基-3-甲基丁腈(6)IR(KBr)v(cm): 3412, 1 709, 1 632, 1 248。與文將5(0.31 g，1.0 mmol)溶于無水二甲亞砜獻13.S.9) 報道- -致。(10 ml)中，加入氰化鉀(0.32 g, 5.0 mmol)、碘化鉀(0.017 g, 0.1 mmol)和4A分子篩(500 mg)。參考文獻:60 C攪拌過夜后加水(10 m1)淬滅反應。反應液.1] Rohr J, Thicricke R. Angucycline group antibiotics [J]. Nat用二氯甲烷(50 mlx3)萃取，經(jīng)無水硫酸鈉干燥Prod Rep, 1992, 9(2): 103-137.后過濾，濾液濃縮，剩余物經(jīng)硅膠色譜柱[洗脫2] Kharel MK, Pahari P, Shepherd MD, et al. Angucyclines:biosynthesis, mode-of-action, new natural products, and劑:二氯甲烷-甲醇(40 : 1)]分離，得黃色固體synthesis [J]. Nat Prod Rep, 2012, 29(2): 264-325.6(0.19g，56%)， mp 176~ 178 C。R, 0.10(展開3] Krohn K, Baltus W. Synthesis of rac- and ent-fridamycin E劑同3)。ESI-HRMS實測值(CjH,OJN,計算值):[J]. Tetrahedron, 1988, 44(1): 49-54.338. 102 8(338.102 3); 'H NMR (400 MHz, CDCI])8:4] Huang H, Yang T, Ren X, et al. Cytotoxic angucycline class12.96(s, 1H), 12.42(s, lH), 7.88 ~ 7.85 (m, 2H),glycosides from the deep sea actinomycete Streptomyces lhusi-tamus SCsIo LR32 [J].J Nat Prod, 2012, 75(2): 202-208.7.73 ~ 7.65 (m, 2H), 7.35(d, J=8.0 Hz, 1H), 3.23 (d,5] Chen Q, Mulzer M, Shi P, et al. De novo asymmetricJ=14.4 Hz, 1H), 3.11(d, J=14.0 Hz, 1H), 2.62(d,synthesis of fridamycin E [J]. Org Lett, 2011, 13(24):J=16.8 Hz, 1H), 2.57(d,J=16.8 Hz, 1H), 1.45(s,6592-6595.3H); 'C NMR (100 MHz, CDCI3)δ: 188.4, 187.4,6] Pausler GM, Rutledge PS. Experiments directed towards the162.8, 160.8, 139.3, 136.8, 132.9(2C), 132.4, 125.4,synthesis of anthracyclinones. 23. A synthesis of fridamycin119.6, 119.3 (2C), 117.5, 116.0, 72.0, 41.0, 31.4, 27.2;E [J]. Aus.J Chem, 1994, 47(12): 2135-2147.IR(KBr)v(cm^'): 3 468,2 925, 1629, 1 600, 1 583,7] Pausler GM, Rutledge PS. Titanium mediation of aldolreactions in fridamycin and vineomycinone syntheses [J].1 429, 1372, 1 310, 1 258, 1 079, 786, 696。Tetrahedron Lett, 1994, 35(20): 3345-3348.Fridamycin E(1)8] Matsumoto T, Jona H, Katsuki M, et al. Effcient method將6(0.17 g, 0.50 mmol)溶于1 mol/L氫氧化for introducing vineomycin-fridamycin-type side chain.鈉溶液(18ml)中，加熱回流過夜。反應液冷卻Total synthesis of fridamycin E [J]. Tetrahedron Ler, 1991,至室溫，加入1 mol/L鹽酸(24 ml)，用二氯甲烷32 (38): 5103-5106.(50 mlx3)萃取，經(jīng)無水硫酸鈉干燥后過濾，濾9] Ueberbacher BJ, Osprian I, Mayer SF, et al. A chemo-液濃縮，剩余物經(jīng)硅膠色譜柱[洗脫劑:二氯甲enzymatic, enantioconvergent, asymmetric total synthesisof (R) fidamycin E [n]. Eur J Org Chem, 2005, 2005(7):烷-甲醇(10 : 1)] 分離，得橙色固體1(0.14 g,1266-1270.81% )，mp 142~ 144 C。R,0.10[ 展開劑:二10] Beauregard DA, Cambie RC, Higgs KC, et al. Experiments氯甲烷-甲醇(10 : 1)]。ESI-HRMS實測值directed towards the synthesis of ant bracyclinones. 21.(C,H。O,Na,計算值): 379.079 4(379.078 8);Claisen rearrangements of some mixed allyl ethers [J]. Aust'H NMR (400 MHz, (CD,) 2CO)8: 13.11(s, 1H),J Chem, 1994, 47(7): 1321-1333.12.59(s, 1H), 7.83 ~ 7.73 (m, 4H), 7.34 ~ 7.32 (m,中國煤化工MHCNMHG.