戴煥然, 方志杰
(南京理工大學,化工學院,江蘇 南京 210094)
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·研究論文·
新型碳苷糖類維生素D2衍生物的合成
戴煥然, 方志杰*
(南京理工大學,化工學院,江蘇 南京210094)
以D-葡萄糖為原料,經(jīng)碳苷化反應,酰化反應和脯氨酸-DIPEA催化的aldol反應制得2個碳苷糖[1-(4′-羥基苯基)-4-C-β-四乙?;咸烟腔?3-烯-2-酮(5a)和1-(3-羥基苯基)-4-C-β-四乙?;咸烟腔?3-烯-2-酮(5b)]; 5與琥珀酸維生素D2經(jīng)Steglich酯化反應合成了2個新型碳苷糖類維生素D2衍生物,其結(jié)構(gòu)經(jīng)1H NMR,13C NMR和HR-ESI-MS表征。
脯氨酸-DIPEA; aldol反應; 碳苷糖; 維生素D2衍生物; 合成
糖是具有重要生物活性的碳水化合物。糖分子中糖氧苷(O-glycosides)鍵中的氧被碳取代之后被稱為糖碳(C-glycosides)[1]。大多數(shù)碳苷糖均從天然產(chǎn)物中提取,人工合成的糖碳苷化合物是氧苷的類似物,但其具有區(qū)別于氧苷的特性,如對于酸和酶較穩(wěn)定,是重要的糖苷酶抑制劑[2]。由于糖碳苷具有良好的生物相容性,廣泛應用于生物醫(yī)藥方面,因此,碳苷化合物的研究與開發(fā)為近年來科研工作者們的工作熱點之一[3-4]。研究表明,部分乙?;架仗穷愃幬飳τ谌梭whuman CAⅡ細胞具有明顯的抑制活性[5-7]。
維生素是一類具有良好生物相容性,可被生物降解且無毒的天然產(chǎn)物,具有調(diào)節(jié)生物進程的重要作用。研究表明,以維生素D2為藥物載體通過琥珀酸酯鍵鍵連的乙二醇殼聚糖,能夠較好的分散在水溶液中,其釋放水平可根據(jù)酸堿度來調(diào)控[8-9]。此外,經(jīng)維生素D2通過琥珀酸酯鍵鍵連的紫杉醇、PI103、阿霉素等藥物已開發(fā)出來,具有良好的抗癌活性也已得到驗證[10]。
為完善本課題組對碳水化合物和維生素D2衍生物的研究[11-13],本文以D-葡萄糖為原料,與乙酰丙酮經(jīng)碳酸鈉催化碳苷化反應制得1-C-(β-D-吡喃葡萄糖基)-丙酮(2); 2經(jīng)?;磻?,在脯氨酸-DIPEA催化下與對(或間)羥基苯甲醛(4a或4b)經(jīng)aldol反應制得2個碳苷糖[1-(4′-羥基苯基)-4-C-β-四乙?;咸烟腔?3-烯-2-酮(5a)和1-(3′-羥基苯基)-4-C-β-四乙?;咸烟腔?3-烯-2-酮(5b)]; 5與琥珀酸維生素D2(1)經(jīng)Steglich酯化反應合成了兩個新型碳苷糖修飾的維生素D2衍生物(6a和6b, Scheme 1),其結(jié)構(gòu)經(jīng)1H NMR,13C NMR和HR-ESI-MS表征。并優(yōu)化了aldol反應的反應條件。
Scheme 1
1.1儀器與試劑
X-5型顯微熔點儀(溫度未校正); Bruker AV-500型, Varian XL-200型和Bruker AV-300型核磁共振儀(CDCl3為溶劑,TMS為內(nèi)標;D2O為溶劑時,無內(nèi)標); Agilent 1290 Infinity LC/6460 QQQ MS型高分辨質(zhì)譜儀; Waters Quattro Premier XE型質(zhì)譜儀。
[9-10]方法合成【收率64.10%;1H NMRδ:6.20(d,J=11.2 Hz, 1H), 6.02(d,J=11.2 Hz, 1H), 5.23~5.14(m, 2H), 5.05(s, 1H), 4.98(m, 1H), 4.83(s, 1H), 2.85~2.76(m, 1H), 2.69~2.60(m, 4H), 2.56(m, 1H), 2.43~2.32(m, 2H), 2.19(ddd,J=13.5 Hz, 9.0 Hz, 4.6 Hz, 1H), 2.04~1.93(m, 4H), 1.84(dt,J=13.1 Hz, 6.4 Hz, 1H), 1.78~1.62(m, 5H), 1.58~1.40(m, 5H), 1.33~1.26(m, 3H), 1.01(d,J=6.6 Hz, 3H), 0.91(d,J=6.8 Hz, 3H), 0.82(t,J=7.2 Hz, 6H), 0.54(s, 3H); ESI-MSm/z: 495.20 {[M-H]-}】;維生素D2(98%),四川省玉鑫藥業(yè)有限公司;N,N-二異丙基乙胺(DIPEA),天津希恩思生化科技有限公司;二氯甲烷和 THF,三乙胺用前經(jīng)干燥蒸餾純化;其余所用試劑均為分析純。
1.2合成
(1) 2的合成
在單口瓶中依次加入D-葡萄糖5.0 g(27 mmol),碳酸氫鈉3.7 g,乙酰丙酮6 mL和水30 mL,攪拌下回流(90 ℃)反應至終點(TLC跟蹤)。冷卻至室溫,用二氯甲烷洗去乙酰丙酮后用732陽離子交換樹脂調(diào)至pH 6,過濾,濾液旋蒸除溶得黃色黏稠物2 5.25 g,收率86%;1H NMRδ: 3.76(dd,J=12.3 Hz, 1.5 Hz, 1H), 3.70(ddd,J=9.5 Hz, 3.2 Hz, 3.2 Hz, 1H), 3.59(dd,J=12.3 Hz, 5.1 Hz, 1H), 3.40(t,J=8.7 Hz, 1H), 3.28~3.19(m, 2H), 3.14(t,J=9.3 Hz, 1H), 2.93(dd,J=16.5 Hz, 3.0 Hz, 1H), 2.63(dd,J=16.5 Hz, 9.0 Hz, 1H), 2.19(s, 3H); ESI-MSm/z: 221.2 {[M+H]+}。
(2) 3的合成
在反應瓶中依次加入2 3.0 g(13.6 mmol), DMAP 100 mg(0.82 mmol),三乙胺14 mL和二氯甲烷20 mL,攪拌使其溶解;冰浴冷卻下緩慢加入乙酸酐14 mL,加畢,緩慢升至室溫,反應過夜。加入碳酸氫鈉溶液50 mL淬滅反應,用二氯甲烷(3×30 mL)萃取,合并有機相,用無水硫酸鈉干燥,旋蒸除溶,用乙醇重結(jié)晶得白色粉末3 1.23 g,收率71%,m.p.47~49 ℃;1H NMRδ:5.33(dd,J=3.0 Hz, 1.0 Hz, 1H), 5.04~4.91(m, 2H), 4.04~3.78(m, 4H), 2.69(dd,J=16.5 Hz, 9.0 Hz, 1H), 2.40(dd,J=16.5 Hz, 3.0 Hz, 1H), 2.09(s, 3H), 2.06(s, 3H), 1.95(s, 3H), 1.94(s, 3H), 1.89(s, 3H);13C NMRδ:205.4, 170.5, 170.3, 170.2, 170.1, 74.5, 74.4, 72.0, 69.1, 67.8, 61.6, 45.6, 31.2, 20.9, 20.8, 20.7; ESI-MSm/z: 389.14 {[M+H]+}。
(3) 5的合成(以5a為例)
反應瓶中加入3 200 mg(0.515 mmol),脯氨酸12 mg(0.10 mmol), DIPEA 0.5 mL, 4a 120 mg(0.98 mmol)和甲醇25 mL,攪拌下于40 ℃反應過夜。用二氯甲烷(3×30 mL)萃取,合并有機相,旋蒸除溶后經(jīng)硅膠柱層析[洗脫劑:A=V(石油醚) ∶V(乙酸乙酯)=1 ∶1]純化得白色固體5a 222.5 g。
用類似方法合成白色固體5b。
5a:收率87.8%, m.p.176~177 ℃;1H NMR(200 MHz, CDCl3)δ: 7.50(d,J=16.1 Hz, 1H), 7.43(d,J=8.6 Hz, 2H), 6.97(s, 1H), 6.87(d,J=8.6 Hz, 2H), 6.59(d,J=16.1 Hz, 1H), 5.24(t,J=9.2 Hz, 1H), 5.10(d,J=9.8 Hz, 1H), 5.00(dd,J=13.6 Hz, 5.5 Hz, 1H), 4.27(dd,J=12.4 Hz, 4.8 Hz, 1H), 4.13(ddd,J=11.1 Hz, 9.1 Hz, 3.9 Hz, 1H), 4.03(dd,J=12.4 Hz, 2.1 Hz, 1H), 3.72(ddd,J=9.8 Hz, 4.8 Hz, 2.1 Hz, 1H), 3.01(dd,J=16.3 Hz, 8.3 Hz, 1H), 2.67(dd,J=16.3 Hz, 3.2 Hz, 1H), 2.03(s, 3H), 2.02(s, 3H), 2.01(s, 3H), 2.01(s, 3H);13C NMRδ: 196.84, 171.16, 170.59, 170.41, 169.94, 159.18, 144.42, 130.75, 126.67, 123.84, 116.34, 75.89, 74.45, 74.37, 71.98, 68.74, 62.31, 42.57, 20.95, 20.95, 20.85(2C); HR-ESI-MSm/z: Calcd for C24H28O11[M+] 492.163 2, found 492.163 0。
5b:收率 71%, m.p.152~153 ℃;1H NMRδ: 7.50(d,J=16.2 Hz, 1H), 7.27(dd,J=9.2 Hz, 6.5 Hz, 1H), 7.07(t,J=4.4 Hz, 2H), 6.91~6.82(m, 1H), 6.71(d,J=16.2 Hz, 1H), 6.69(s, 1H), 5.22(d,J=9.2 Hz, 1H), 5.11(d,J=9.8 Hz, 1H), 4.96(d,J=9.3 Hz, 1H), 4.27(dd,J=12.4 Hz, 4.7 Hz, 1H), 4.11(ddd,J=9.7 Hz, 8.6 Hz, 2.8 Hz, 1H), 4.05(dd,J=12.4 Hz, 2.2 Hz, 1H), 3.73(ddd,J=9.7 Hz, 4.7 Hz, 2.2 Hz, 1H), 3.02(dd,J=16.3 Hz, 8.6 Hz, 1H), 2.68(dd,J=16.3 Hz, 3.1 Hz, 1H), 2.04(s, 3H), 2.03(s, 3H), 2.02(s, 3H), 2.01(s, 3H);13C NMRδ: 196.99, 171.27, 170.63, 170.37, 169.95, 156.83, 144.22, 135.79, 130.44, 126.46, 121.29, 118.46, 114.86, 75.84, 74.40, 74.30, 71.84, 68.67, 62.29, 42.74, 20.96, 20.93, 20.88(2C); HR-ESI-MSm/z: Calcd for C24H28O11[M+] 492.163 2, found 492.165 1。
(4) 6的合成(以6a為例)
單口瓶中加入1 253 mg(0.51 mmol), 5a 250 mg(0.51 mmol),二環(huán)己基碳二亞胺(DCC)212 mg, DMAP 120 mg和二氯甲烷25 mL,攪拌使其溶解,于室溫反應過夜。旋蒸除溶后經(jīng)硅膠柱層析(洗脫劑:A=10 ∶1)得淡黃色固體6a 254 mg。
用類似方法合成淡黃色固體6b。
6a:收率50.1%, m.p.79~81 ℃;1H NMR(500 MHz, CDCl3)δ:7.61~7.54(m, 2H), 7.52(s, 1H), 7.16(d,J=8.3 Hz, 2H), 6.70(d,J=16.2 Hz, 1H), 6.21(d,J=11.3 Hz, 1H), 6.03(d,J=11.4 Hz, 1H), 5.28~5.12(m, 3H), 5.10~5.04(m, 4H), 4.84(s, 1H), 4.32~3.95(m, 6H), 3.73(d,J=6.8 Hz, 1H), 3.51(s, 2H), 3.11~3.02(m, 1H), 2.88(d,J=6.4 Hz, 2H), 2.92~2.71(m, 5H), 2.46~2.32(m, 2H), 2.02(dd,J=12.5 Hz, 6.1 Hz, 14H), 1.70(s, 7H), 1.35~1.30(m, 6H), 1.04~0.99(m, 3H), 0.92(d,J=6.7 Hz, 3H), 0.84(t,J=7.2 Hz, 6H), 0.56(s, 2H);13C NMR(126 MHz, CDCl3)δ:196.16, 171.66, 170.81, 170.42, 170.16, 169.74, 152.65, 144.67, 142.77, 142.68, 135.78, 134.30, 132.13, 129.74, 129.03, 126.47, 122.73, 122.42, 117.64, 112.99, 75.95, 74.38, 72.58, 71.89, 68.69, 62.22, 56.63, 49.31, 46.02, 42.99, 42.85, 42.26, 40.56, 34.18, 33.28, 32.28, 32.08, 31.62, 29.87, 29.55, 29.23, 27.97, 25.80, 25.13, 23.74, 22.87, 22.38, 21.28, 20.81, 20.13, 19.82, 19.34, 17.76, 14.29, 12.40; ESI-MSm/z: 1 005.50 {[M+Cl]-}。
6b:收率51.1%, m.p.77~80 ℃;1H NMRδ:7.72(dd,J=5.4 Hz, 3.4 Hz, 1H), 7.56~7.51(m, 1H), 7.40(d,J=4.9 Hz, 2H), 7.29(s, 1H), 7.15(d,J=4.3 Hz, 1H), 6.71(d,J=16.2 Hz, 1H), 6.20(d,J=11.1 Hz, 1H), 6.02(d,J=11.2 Hz, 1H), 5.20(m, 4H), 5.10~4.95(m, 4H), 4.83(s, 1H), 4.18~3.95(m, 6H), 3.73~3.68(m, 1H), 3.48(dd,J=10.9 Hz, 7.5 Hz, 2H), 2.98(d,J=8.4 Hz, 1H), 2.91~2.83(m, 2H), 2.76~2.69(m, 3H), 2.58(d,J=14.3 Hz, 2H), 2.43~2.35(m, 2H), 2.02~1.92(m, 14H), 1.69~1.55(m, 8H), 1.29 ~1.20(m, 3H), 0.98(d,J=6.7 Hz, 3H), 0.91(d,J=6.8 Hz, 2H), 0.82~0.75(m, 6H), 0.54(s, 3H);13C NMRδ:194.89, 170.50, 169.78, 169.63, 169.22, 168.93, 168.54, 155.79, 143.52, 141.48, 134.61, 133.13, 130.96, 129.91, 129.01, 127.85, 126.04, 125.01, 122.85, 121.55, 120.04, 116.47, 111.80, 74.78, 73.20, 73.09, 71.37, 70.79, 70.71, 67.52, 61.04, 55.46, 48.14, 44.84, 41.81, 41.09, 39.41, 32.95, 32.10, 31.10, 30.91, 28.68, 28.36, 28.05, 26.78, 24.63, 23.94, 23.70, 22.56, 21.20, 20.11, 19.62, 18.95, 18.64, 18.16, 16.58, 11.25; ESI-MSm/z: 993.58 {[M+Na]+}。
2.1aldol反應條件優(yōu)化
以合成5a的反應為例,對aldol反應條件進行優(yōu)化,探索反應時間、反應溶劑及催化劑等對收率的影響。
(1) 溶劑
3 0.515 mmol,其余反應條件同1.2(3),考察溶劑對收率的影響,結(jié)果見表1。由表1可見,在非質(zhì)子溶劑中反應很少或不反應,質(zhì)子溶劑更適合該反應,甲醇為溶劑時反應效果最好,收率85.7%。反應溶劑確定為甲醇。
表1 溶劑對5a收率的影響*
*3 0.515 mmol,其余反應條件同1.2(3)。
(2) 催化劑與反應時間
3 0.515 mmol,甲醇為溶劑,其余反應條件同2.1(1),考察催化劑與反應時間對收率的影響,結(jié)果見表2。由表2可見,以脯氨酸-DIPEA為催化劑,反應時間為8 h時,收率87.8%。文獻[14]方法采用的脯氨酸-TEA催化體系在反應時間8 h時,幾乎不反應,收率較低,只有當反應時間為72 h時,收率85.7%。因此,以脯氨酸-DIPEA為催化劑,反應時間為8 h。
表2 催化劑與反應時間對5a收率的影響*
*甲醇為溶劑,其余反應條件同表1。
綜上所述,合成5a的最佳反應條件為:3 0.515 mmol,脯氨酸-DIPEA為催化劑,甲醇為溶劑,反應時間為8 h,收率87.8%。
以D-葡萄糖為原料,經(jīng)碳苷化反應,?;磻蚢ldol反應,最后與維生素D2琥珀酸酯發(fā)生酯化反應合成了2個新型碳苷糖類維生素D2衍生物(5a和5b)。碳苷糖的引入可能會提高維生素D2靶向藥物的生物活性,這為開展該類化合物衍生化研究提供了一個新的思路。
合成5a的最佳反應條件為:3 0.515 mmol,脯氨酸-DIPEA為催化劑,甲醇為溶劑,反應時間為8 h,收率87.8%。該方法操作簡單,反應時間較短,催化劑簡單易得,提高了反應效率。
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Synthesis of NovelC-glycosides Vitamin D2Derivatives
DAI Huan-ran,FANG Zhi-jie*
(School of Chemical Enginering, Nanjing University of Science and Technology, Nanjing 210094, China)
TwoC-glycosides, 1-(4′-hydroxyphenyl)-4-C-(β-2′,3′,4′,6′ acetyl glucopyranosyl)-3-ene-2-ketone(5a) and 1-(3′-hydroxyphenyl)-4-C-(β-2′,3′,4′,6′ acetyl glucopyranosyl)-3-ene-2-ketone(5b), were prepared byC-glycosidation, acylation and aldol reaction catalyzed by proline-DIPE from D-glucose. Then 5 were esterified with vitamin D2succinate to give two novel vitamin D2derivatives. The structures were characterized by1H NMR,13C NMR and HR-ESI-MS.
proline-DIPEA; aldol reaction;C-glycoside; vitamin D2derivative; synthesis
10.15952/j.cnki.cjsc.1005-1511.2016.06.15234
2015-06-05;
2016-04-05
江蘇省產(chǎn)學研聯(lián)合創(chuàng)新資金前瞻性聯(lián)合研究項目(BY2013004-02); 南京理工大學研究生科研創(chuàng)新計劃項目
戴煥然(1990-),男,漢族,江蘇宿遷人,碩士研究生,主要從事藥物合成研究。 E-mail: daihuanran001@126.com
通信聯(lián)系人:方志杰,研究員,博士生導師, E-mail:zjfang@njust.edu.cn
O629.11; O621.3
A