垂盆草苷的合成*
作者：诸国华 周启霆 白东鲁
单位：(中国科学院上海药物研究所， 上海 200031)
关键词：垂盆草苷；谷丙转氨酶；全合成
药学学报990108.htm SYNTHESIS OF SARMENTOSIN*
Chu Guohua(Chu GH), Zhou Qiting(Zhou QT) and Bai Donglu(Bai DL)**
(Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031)
ABSTRACT AIM: The synthesis of sarmentosin. METHODS: Condensation of butane-1,2,4-triol-1,2-acetonide(3) with α-D-glucopyranosyl bromide tetraacetate in the presence of Ag2O and molecular sieves gave the desired β-glucoside 4, which was transformed into sarmentosin via a reaction sequence of 7 steps. RESULTS: The overall yield is 5.8%. CONCLUSION: The first synthesis of sarmentosin(1), a potent natural GPT lowering agent, was achieved.
, 百拇医药
KEY WORDS sarmentosin; glutamic-pyruvic transaminase(GPT); total synthesis
Sarmentosin(1) was isolated in 1978 by Fang et al[1] from the whole herb of Sedum sarmentosum Bunge which belongs to the family Crassulaceae. The herb is widely distributed in China and used for the treatment of hepatitis in folk medicine. Clinical trials showed that the herb had a significant effect in lowering the level of serum glutamic-pyruvic transaminase of the patients suffering from chronic virus hepatitis. Later on, sarmentosin was showen to be responsible for this effect[1,2]. Sarmentosin was also found to have immunomodulating activity[3]. Sarmentosin is a water soluble syrupy substance and its structure was elucidated by chemical and spectral methods as compound 1.
, 百拇医药
Although sarmentosin has promising bio-activity and its structure seems to be rather simple, there is still no report about its synthesis in the literature. To the best of our knowledge, several research groups have attempted to synthesize this compound. They all took the following strategy: to prepare the aglycone, compound 2 first, and then condense it with α-D-glucopyranosyl bromide tetraacetate or β-D-glucose pentaacetate to achieve the target molecule. Due to the instability of compound 2, this approach has not been successful yet. Recently, we accomplished the first total synthesis of sarmentosin[4]. In this paper the work is reported in detail.
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Butane-1,2,4-triol-1,2-acetonide(3) was used as the starting material, which could be prepared easily from commercially available butane-1,2,4-triol in one step[5]. Condensation of 3 with α-D-glucopyranosyl bromide tetraacetate in the presence of silver(I) oxide and molecular sieves 4
gave the desired β-glucoside 4(85.0%) and a small amount of the α-anomer(<10.0%). Cleavage of the acetonide 4 by MeOH/TsOH at room temperature furnished the diol 5(65.0%). Selective protection of diol 5 as trityl ether afforded the secondary alcohol 6(89.4%), which was oxidized with 4.5 equiv. of PCC in the presence of NaOAc to give the ketone 7(78.3%). Then compound 7 was converted into cyanohydrin 8(70.7%) by treatment with acetone cyanohydrin in methanol solution of sodium bicarbonate. 8 is a mixture of two diastereomers which was dehydrated without separation using thionyl chloride in pyridine at room temperature for 3 days. The desired E-olefin 9 was obtained as the only isomer in 40.2% yield. Selective removal of the trityl group in 9 with TMSI yielded the allylic alcohol 10(70.9%), and subsequent deacetylation of 10 with MeOH-Et3N-H2O(8∶1∶1)[6] led to sarmentosin(1, 74.2%), [α]30.5D=-17.96°(c 2.16, MeOH) [Lit1,2: [α]30D-17.4°(c 0.62, H2O); Lit7: [α]24D-18°(c 0.3, MeOH)]. The IR, MS, 1HNMR and 13CNMR data of the synthetic product are identical with those of the natural sarmentosin reported in the literature[1,2]. The E-configuration of the double bond in compounds 9,10 and 1 was determined by NOE experiments. Irradiation at C-3 proton of 9,10 and 1 produced 3.3%, 3.75% and 5.6% enhancement of the proton at C-1 respectively and vice versa.
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In conclusion, starting from butane-1,2,4-triol-1,2-acetonide(3), the first total synthesis of sarmentosin has been accomplished through a reaction sequence of 8 steps in an overall yield of 5.8%.
, 百拇医药
EXPERIMENTAL
IR spectra were obtained on a Perkin-Elmer-599B spectrometer. A JEOL-PS-100 or Bruker-AM-400 spectrometer was used for NMR measurement. Mass spectra were determined on a Varian-MAT-711 mass spectrometer. A JASCO CIP-181 spectrometer was used for the measurement of optical rotation.
1 4-β-D-Tetraacetylglucopyranosyloxy-1,2-butanediol acetonide (4)
To a solution of compound 3(1.46 g, 10 mmol) in dry chloroform(50 ml) was added powdered molecular sieves 4(5 g) and Ag2O(6.5 g), and the resulting mixture was stirred at room temperature for 1 h. Then a solution of α-D-glucopyranosyl bromide tetraacetate(6.2 g,15 mmol) in dry chloroform(50 ml) was added dropwise to the above mixture within 1 h. After stirring at room temperature for 20 h in the dark, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography using ether as eluent, affording the β-glucoside 4(4.06 g, 85.0%) as a gum. [α]11D-13.5°(c 0.067, CHCl3). IR(KBr)cm-1: 2980,2880,1750,1430,1370,1225,1160,1040,905. 1HNMR (CDCl3) δ: 1.28,1.32(6H,2s,2×CH3), 1.8(2H,m), 1.96,2.00,2.04(12H,3s,1∶2∶1,4×OAc), 3.44～4.2(8H,m), 4.46(1H,d,J=8 Hz,1′-H), 5.00(3H,m). m/z 461(8),331(25),169(100),145(23).
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2 4-β-D-Tetraacetylglucopyranosyloxy-1,2-butanediol(5)
Toluenesulfonic acid monohydrate(160 mg, 0.84 mmol) was added to a solution of compound 4(2.4 g, 5.04 mmol) in absolute methanol(70 ml). The reaction mixture was stirred at room temperature for 6 h. NaHCO3 was added to neutralize the acidic solution. After filtration and concentration of the filtrate in vacuo, the residue was subjected to column chromatography on silica gel with 1∶1 ethyl acetate-ether as eluent, yielding the diol 5(1.43 g, 65.0%) as a gum. [α]11D-7.91°(c 0.28, CHCl3). IR(KBr)cm-1: 3400,2940,2880,1750,1430,1375,1225,1040,910. 1HNMR (CDCl3) δ: 1.68(2H,m),1.96,2.00,2.04(12H,3s,1∶2∶1,4×OAc),2.90(2H,brs,2×OH),3.48～4.2(8H,m),4.48(1H,d,J=8 Hz,1′-H),5.00(3H,m). m/z: 331(23),169(66),117(100),159(17).
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3 1-Trityloxy-4-β-D-tetraacetylglucopyranosyloxy-2-butanol (6)
Dry triethylamine(2 ml, 14.38 mmol), triphenylmethyl chloride(2.3 g, 8.25 mmol) and 4-dimethylaminopyridine(122 mg, 1 mmol) were added successively to a solution of diol 5(3 g, 6.88 mmol) in dry methylene chloride(130 ml). The reaction mixture was refluxed for 18 h and then cooled to room temperature. The reaction mixture was washed with aqueous NaHCO3 and water. The organic layer was separated, dried with Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ether as eluent, giving compound 6(4.17 g, 89.4%) as a gum. [α]11D-16.93°(c 0.17, CHCl3). IR(KBr)cm-1: 3450,2960,2880,1755,1490,1450,1370,1225,1035,905. 1HNMR (CDCl3) δ: 1.6(2H,m),1.88,1.92,1.96(12H,3s,1∶2∶1,4×OAc),2.4(1H,brs,OH),2.97(2H,d,J=6.4 Hz),3.5～4.1(6H,m),4.36(1H,d,J=8 Hz,1′-H),4.92(3H,m),7.15～7.36(15H,m,Ar-H). m/z: 331(54),243(100),169(75).
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4 1-Trityloxy-4-β-D-tetraacetylglucopyranosyloxy-2-butanone (7)
To the slurry of PCC(4 g, 18.5 mmol), anhydrous sodium acetate(220 mg) and Celite(2.5 g) in dry methylene chloride(50 ml) was added in one portion a solution of the secondary alcohol 6(2.68 g, 3.95 mmol) in the same solvent(30 ml). The reaction mixture was stirred at room temperature for 27 h and then diluted with ether(100 ml). The reaction mixture was filtered through a Florisil pad and the pad was washed with ether repeatedly. The filtrate and washings were combined and concentrated in vacuo. The residue was subjected to column chromatography on silica gel using 3∶1 ether-petroleum ether as eluent, yielding the ketone 7(2.09 g, 78.3%) as a gum. [α]11D-15.87°(c 0.126, CHCl3). IR(KBr)cm-1: 2950,2880,1755,1490,1450,1370,1225,1040,905. 1HNMR (CDCl3) δ: 1.88,1.90,1.96(12H,3s,1∶2∶1,4×OAc),2.76(2H,t,J=6.8 Hz),3.66(2H,s),3.7～4.16(3H,m),4.4(1H,d,J=8 Hz,1′-H),4.96(3H,m),7.15～7.36(15H,m,Ar-H). m/z: 403(12),331(12),243(100),169(37),165(100).
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5 1-Trityloxy-4-β-D-tetraacetylglucopyranosyloxy-2-butanone cyanohydrin (8)
Ketone 7(340 mg, 0.5 mmol) was dissolved in a saturated methanolic solution of NaHCO3(5 ml). To this solution acetone cyanohydrin(0.14 ml, 1.5 mmol) was added. The reaction mixture was stirred at room temperature for 20 h and then concentrated in vacuo. The residue was purified by column chromatography on silica gel with 3∶1 ether-petroleum ether as eluent. The cyanohydrin 8(250 mg, 70.7%) was obtained as a gum. [α]11D-3.49°(c 0.2,CHCl3). IR(KBr)cm-1: 3480,2940,2870,1755,1490,1450,1370,1225,1040,905. 1HNMR (CDCl3) δ: 1.3(2H,m),1.96,2.06(12H,2s,1∶1,4×OAc),3.1～4.2(8H,m),4.54(1H,d,J=8 Hz,1′-H),5.06(3H,m),7.2～7.44(15H,m,Ar-H). m/z: 403(25),331(17),243(100),169(62),165(100).
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6 (E)-1-Trityloxy-2-cyano-4-β-D-tetraacetylglu-copyranosyloxy-2-butene (9)
An excess of freshly distilled thionyl chloride(0.25 ml, 3.43 mmol) was added dropwise to a solution of cyanohydrin 8(1.1 g, 1.56 mmol) in dry pyridine at 0℃. The reaction mixture was stirred at 0℃ for 2 h and then at room temperature for 68 h. The reaction mixture was poured into ice-water and extracted with chloroform. The extract was dried with Na2SO4 and concentrated in vacuo. The residue was dissolved in benzene and the solution was evaporated in vacuo. This process was repeated several times in order to remove the remaininng pyridine. Chromatography of the residue on silica gel with 3∶1 ether-petroleum ether as eluent gave the product 9(430 mg, 40.2%) as a gum. [α]11D-9.59°(c 0.089, CHCl3). IR(KBr)cm-1: 2950,2860,2218,1755,1608,1490,1448,1370,1225,1090～1040,905. 1HNMR (CDCl3) δ: 1.99,2.01,2.04(12H,3s,1∶2∶1,4×OAc),3.70(1H,m,5′-H),3.74(2H,s,1-H),4.12(1H,dd,J=12.5,2 Hz,6′-H),4.26(1H,dd,J=12.5,4.7 Hz,6′-H),4.48～4.54(3H,m,4,1′-H),4.99～5.19(3H,m,2′,3′,4′-H),6.50(1H,brt,J=6.4 Hz,3-H),7.30～7.41(15H,m,Ar-H). m/z: 331(3),259(1),243(100),169(3),165(9).
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7 (E)-2-Cyano-4-β-D-tetraacetylglucopyranosyloxy-2-buten-1-ol (10)
Trimethylsilyl iodide(0.03 ml, 0.21 mmol) was added dropwise to a solution of compound 9(120 mg, 0.175 mmol) in dry chloroform(2 ml) at room temperature under nitrogen atomosphere. After 5 min, methanol was added to quench the reaction. The reaction mixture was washed with aqueous Na2S2O3 and water. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was subjected to column chromatograpy on silica gel with 8∶1 ether-petroleum ether as eluent, yielding the allylic alcohol 10(55 mg, 70.9%) as a crystal, mp: 79℃～81℃. [α]29D-6.98°(c 0.153,CHCl3). IR(KBr)cm-1: 3490,2940,2880,2220,1750,1645,1430,1375,1250,1215,1086,1045,905. 1HNMR (CDCl3) δ: 1.7(1H,brs,OH),1.99,2.02,2.04,2.09(12H,4s,4×OAc),3.68(1H,m,5′-H),4.11(1H,dd,J=12.4,4.2 Hz,6′-H),4.24(2H,brs,1-H),4.34(1H,dd,J=12.4,2.3 Hz,6′-H),4.51(2H,m,4-H),4.55(1H,d,J=8 Hz,1′-H),4.97(1H,dd,J=9.4,8 Hz,2′-H),5.07,5.18(2H,2t,J=9.4 Hz,3′,4′-H),6.53(1H,brt,J=6.4 Hz,3-H). m/z: 383(4),346(7),323(6),243(23),200(37),169(38),157(78),145(55),140(45),115(100). Anal. C19H25NO11. Calcd: C 51.46, H 5.68, N 3.16; Found: C 51.24, H 5.64, N 2.98.
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Sarmentosin (1) Compound 10(50 mg, 0.113 mmol) was dissolved in a mixture of MeOH-Et3N-H2O(8∶1∶1, 6 ml) and the reaction solution was stirred at room temperature for 18 h. After evaporation of the solvent in vacuo, toluene was added to the residue and removed in vacuo again. This process was repeated several times to remove water. Chromatography of the residue on silica gel using 8∶3 chloroform-methanol as eluent furnished sarmentosin(23 mg, 74.2%) as a syrup, [α]30.5D-17.96°(c 2.16, MeOH). The IR, MS, 1HNMR and 13CNMR data of the synthetic product are identical with those of the natural sarmentosin reported in the literature[1,2]. IR(KBr)cm-1: 3540～3240,2227,1643,1100,1076,1050. 1HNMR (C5D5N) δ: 3.78～4.18(7H,m,1,4,5′,6′-H),4.38(1H,d,J=11.8 Hz,1′-H),4.50～4.80(3H,m,2′,3′,4′-H),6.80(1H,t,J=6.0 Hz,3-H). 13CNMR(D2O) δ: 62.0(6′-C), 63.0(4-C), 68.5(1-C), 70.9(4′-C), 74.3(2′-C), 77.1(5′-C), 77.4(3′-C), 103.2(1′-C), 117.5(2-C), 118.0(CN), 145.3(3-C). m/z (FAB): 276(M++1,10),207(17),185(62),93(100).
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Acknowledgement We thank Mr. Xu Rui and Miss Zhang Hong for valuable and stimulating discussions concerning this project.
REFERENCES
1 Fang SD, Yan XQ, Li JF, et al. The isolation and structure of the active principle sarmentosin. Kexue Tongbao, 1979,24∶431
2 Fang SD, Yan XQ, Li JF, et al. Studies on the chemical constituents of Sedum sarmentosum bunge IV. The structures of sarmentosin and iso-sarmentosin. Acta Chimica Sinica, 1982,40∶273
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3 Zhai SK, Shen ML, Xong YL, et al. A preliminary report on the immuno-suppressive activity of sarmentosin. Chin J Microbiol Immunol, 1982,2∶145
4 Chu GH, Zhou QT, Bai DL. The total synthesis of sarmentosin, a potent GPT lowering agent. Bioorg Med Chem Lett, 1993,3∶343
5 Mori K, Takigawa T, Matsuo T. Synthesis of optically active forms of ipsdienal and ipsenol. The pheromone components of ips bark beetles. Tetrahedron, 1979,35∶933
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6 Lubineau A, Queneau Y. Aqueous cycloadditions using glyco-organic substrates. 1. Stereochemical course of the reaction. J Org Chem, 1987,52∶1001
7 Nishida R, Rothschild M, Mummery R. A cyanoglucoside, sarmentosin, from the Magpie moth, Abraxas grossulariata, Geometridae: Lepidoptera. Phytochemistry, 1994,36∶37
*Project supported by State Key Laboratory of Drug Research
**To whom correspondence should be addressed
, 百拇医药
Tel:(021)64311833, Fax:(021)64370269,E-mail:dlbai.@server sh.cmc.ac.ca
Received: 1997-12-05
摘要 目的： 垂盆草苷(1)是从垂盆草(Sedum sarmentosum Bunge)中分得的，能降低慢性病毒性肝炎病人血清谷丙转氨酶的活性成分并有免疫调节作用。以1，2，4-丁三醇-1，2-丙缩酮(3)为原料，经8步反应完成其全合成。方法和结果： 溴化α-D-四乙酰基吡喃葡萄糖在氧化银和分子筛存在下，与3缩合生成β-葡糖苷4。去缩酮保护后，伯醇基用三苯甲基保护得化合物6。6的仲醇基用PCC氧化成酮7，羰基与丙酮合氰化氢交换得加成物8。氰醇8用氯化亚砜脱水，形成所需的E式双键化合物9。用三甲碘硅烷脱除三苯甲基得烯丙醇10，最后用三乙胺含水甲醇溶液除去乙酰基，得目标产物1。总产率5.8%。结论： 首次完成了天然产物垂盆草苷的人工合成。
*基金项目：国家重点实验室基金资助项目, http://www.100md.com
单位：(中国科学院上海药物研究所， 上海 200031)
关键词：垂盆草苷；谷丙转氨酶；全合成
药学学报990108.htm SYNTHESIS OF SARMENTOSIN*
Chu Guohua(Chu GH), Zhou Qiting(Zhou QT) and Bai Donglu(Bai DL)**
(Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031)
ABSTRACT AIM: The synthesis of sarmentosin. METHODS: Condensation of butane-1,2,4-triol-1,2-acetonide(3) with α-D-glucopyranosyl bromide tetraacetate in the presence of Ag2O and molecular sieves gave the desired β-glucoside 4, which was transformed into sarmentosin via a reaction sequence of 7 steps. RESULTS: The overall yield is 5.8%. CONCLUSION: The first synthesis of sarmentosin(1), a potent natural GPT lowering agent, was achieved.
, 百拇医药
KEY WORDS sarmentosin; glutamic-pyruvic transaminase(GPT); total synthesis
Sarmentosin(1) was isolated in 1978 by Fang et al[1] from the whole herb of Sedum sarmentosum Bunge which belongs to the family Crassulaceae. The herb is widely distributed in China and used for the treatment of hepatitis in folk medicine. Clinical trials showed that the herb had a significant effect in lowering the level of serum glutamic-pyruvic transaminase of the patients suffering from chronic virus hepatitis. Later on, sarmentosin was showen to be responsible for this effect[1,2]. Sarmentosin was also found to have immunomodulating activity[3]. Sarmentosin is a water soluble syrupy substance and its structure was elucidated by chemical and spectral methods as compound 1.
, 百拇医药
Although sarmentosin has promising bio-activity and its structure seems to be rather simple, there is still no report about its synthesis in the literature. To the best of our knowledge, several research groups have attempted to synthesize this compound. They all took the following strategy: to prepare the aglycone, compound 2 first, and then condense it with α-D-glucopyranosyl bromide tetraacetate or β-D-glucose pentaacetate to achieve the target molecule. Due to the instability of compound 2, this approach has not been successful yet. Recently, we accomplished the first total synthesis of sarmentosin[4]. In this paper the work is reported in detail.
, http://www.100md.com
Butane-1,2,4-triol-1,2-acetonide(3) was used as the starting material, which could be prepared easily from commercially available butane-1,2,4-triol in one step[5]. Condensation of 3 with α-D-glucopyranosyl bromide tetraacetate in the presence of silver(I) oxide and molecular sieves 4
gave the desired β-glucoside 4(85.0%) and a small amount of the α-anomer(<10.0%). Cleavage of the acetonide 4 by MeOH/TsOH at room temperature furnished the diol 5(65.0%). Selective protection of diol 5 as trityl ether afforded the secondary alcohol 6(89.4%), which was oxidized with 4.5 equiv. of PCC in the presence of NaOAc to give the ketone 7(78.3%). Then compound 7 was converted into cyanohydrin 8(70.7%) by treatment with acetone cyanohydrin in methanol solution of sodium bicarbonate. 8 is a mixture of two diastereomers which was dehydrated without separation using thionyl chloride in pyridine at room temperature for 3 days. The desired E-olefin 9 was obtained as the only isomer in 40.2% yield. Selective removal of the trityl group in 9 with TMSI yielded the allylic alcohol 10(70.9%), and subsequent deacetylation of 10 with MeOH-Et3N-H2O(8∶1∶1)[6] led to sarmentosin(1, 74.2%), [α]30.5D=-17.96°(c 2.16, MeOH) [Lit1,2: [α]30D-17.4°(c 0.62, H2O); Lit7: [α]24D-18°(c 0.3, MeOH)]. The IR, MS, 1HNMR and 13CNMR data of the synthetic product are identical with those of the natural sarmentosin reported in the literature[1,2]. The E-configuration of the double bond in compounds 9,10 and 1 was determined by NOE experiments. Irradiation at C-3 proton of 9,10 and 1 produced 3.3%, 3.75% and 5.6% enhancement of the proton at C-1 respectively and vice versa., http://www.100md.com
In conclusion, starting from butane-1,2,4-triol-1,2-acetonide(3), the first total synthesis of sarmentosin has been accomplished through a reaction sequence of 8 steps in an overall yield of 5.8%.
, 百拇医药
EXPERIMENTAL
IR spectra were obtained on a Perkin-Elmer-599B spectrometer. A JEOL-PS-100 or Bruker-AM-400 spectrometer was used for NMR measurement. Mass spectra were determined on a Varian-MAT-711 mass spectrometer. A JASCO CIP-181 spectrometer was used for the measurement of optical rotation.
1 4-β-D-Tetraacetylglucopyranosyloxy-1,2-butanediol acetonide (4)
To a solution of compound 3(1.46 g, 10 mmol) in dry chloroform(50 ml) was added powdered molecular sieves 4
(5 g) and Ag2O(6.5 g), and the resulting mixture was stirred at room temperature for 1 h. Then a solution of α-D-glucopyranosyl bromide tetraacetate(6.2 g,15 mmol) in dry chloroform(50 ml) was added dropwise to the above mixture within 1 h. After stirring at room temperature for 20 h in the dark, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography using ether as eluent, affording the β-glucoside 4(4.06 g, 85.0%) as a gum. [α]11D-13.5°(c 0.067, CHCl3). IR(KBr)cm-1: 2980,2880,1750,1430,1370,1225,1160,1040,905. 1HNMR (CDCl3) δ: 1.28,1.32(6H,2s,2×CH3), 1.8(2H,m), 1.96,2.00,2.04(12H,3s,1∶2∶1,4×OAc), 3.44～4.2(8H,m), 4.46(1H,d,J=8 Hz,1′-H), 5.00(3H,m). m/z 461(8),331(25),169(100),145(23)., http://www.100md.com
2 4-β-D-Tetraacetylglucopyranosyloxy-1,2-butanediol(5)
Toluenesulfonic acid monohydrate(160 mg, 0.84 mmol) was added to a solution of compound 4(2.4 g, 5.04 mmol) in absolute methanol(70 ml). The reaction mixture was stirred at room temperature for 6 h. NaHCO3 was added to neutralize the acidic solution. After filtration and concentration of the filtrate in vacuo, the residue was subjected to column chromatography on silica gel with 1∶1 ethyl acetate-ether as eluent, yielding the diol 5(1.43 g, 65.0%) as a gum. [α]11D-7.91°(c 0.28, CHCl3). IR(KBr)cm-1: 3400,2940,2880,1750,1430,1375,1225,1040,910. 1HNMR (CDCl3) δ: 1.68(2H,m),1.96,2.00,2.04(12H,3s,1∶2∶1,4×OAc),2.90(2H,brs,2×OH),3.48～4.2(8H,m),4.48(1H,d,J=8 Hz,1′-H),5.00(3H,m). m/z: 331(23),169(66),117(100),159(17).
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3 1-Trityloxy-4-β-D-tetraacetylglucopyranosyloxy-2-butanol (6)
Dry triethylamine(2 ml, 14.38 mmol), triphenylmethyl chloride(2.3 g, 8.25 mmol) and 4-dimethylaminopyridine(122 mg, 1 mmol) were added successively to a solution of diol 5(3 g, 6.88 mmol) in dry methylene chloride(130 ml). The reaction mixture was refluxed for 18 h and then cooled to room temperature. The reaction mixture was washed with aqueous NaHCO3 and water. The organic layer was separated, dried with Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ether as eluent, giving compound 6(4.17 g, 89.4%) as a gum. [α]11D-16.93°(c 0.17, CHCl3). IR(KBr)cm-1: 3450,2960,2880,1755,1490,1450,1370,1225,1035,905. 1HNMR (CDCl3) δ: 1.6(2H,m),1.88,1.92,1.96(12H,3s,1∶2∶1,4×OAc),2.4(1H,brs,OH),2.97(2H,d,J=6.4 Hz),3.5～4.1(6H,m),4.36(1H,d,J=8 Hz,1′-H),4.92(3H,m),7.15～7.36(15H,m,Ar-H). m/z: 331(54),243(100),169(75).
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4 1-Trityloxy-4-β-D-tetraacetylglucopyranosyloxy-2-butanone (7)
To the slurry of PCC(4 g, 18.5 mmol), anhydrous sodium acetate(220 mg) and Celite(2.5 g) in dry methylene chloride(50 ml) was added in one portion a solution of the secondary alcohol 6(2.68 g, 3.95 mmol) in the same solvent(30 ml). The reaction mixture was stirred at room temperature for 27 h and then diluted with ether(100 ml). The reaction mixture was filtered through a Florisil pad and the pad was washed with ether repeatedly. The filtrate and washings were combined and concentrated in vacuo. The residue was subjected to column chromatography on silica gel using 3∶1 ether-petroleum ether as eluent, yielding the ketone 7(2.09 g, 78.3%) as a gum. [α]11D-15.87°(c 0.126, CHCl3). IR(KBr)cm-1: 2950,2880,1755,1490,1450,1370,1225,1040,905. 1HNMR (CDCl3) δ: 1.88,1.90,1.96(12H,3s,1∶2∶1,4×OAc),2.76(2H,t,J=6.8 Hz),3.66(2H,s),3.7～4.16(3H,m),4.4(1H,d,J=8 Hz,1′-H),4.96(3H,m),7.15～7.36(15H,m,Ar-H). m/z: 403(12),331(12),243(100),169(37),165(100).
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5 1-Trityloxy-4-β-D-tetraacetylglucopyranosyloxy-2-butanone cyanohydrin (8)
Ketone 7(340 mg, 0.5 mmol) was dissolved in a saturated methanolic solution of NaHCO3(5 ml). To this solution acetone cyanohydrin(0.14 ml, 1.5 mmol) was added. The reaction mixture was stirred at room temperature for 20 h and then concentrated in vacuo. The residue was purified by column chromatography on silica gel with 3∶1 ether-petroleum ether as eluent. The cyanohydrin 8(250 mg, 70.7%) was obtained as a gum. [α]11D-3.49°(c 0.2,CHCl3). IR(KBr)cm-1: 3480,2940,2870,1755,1490,1450,1370,1225,1040,905. 1HNMR (CDCl3) δ: 1.3(2H,m),1.96,2.06(12H,2s,1∶1,4×OAc),3.1～4.2(8H,m),4.54(1H,d,J=8 Hz,1′-H),5.06(3H,m),7.2～7.44(15H,m,Ar-H). m/z: 403(25),331(17),243(100),169(62),165(100).
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6 (E)-1-Trityloxy-2-cyano-4-β-D-tetraacetylglu-copyranosyloxy-2-butene (9)
An excess of freshly distilled thionyl chloride(0.25 ml, 3.43 mmol) was added dropwise to a solution of cyanohydrin 8(1.1 g, 1.56 mmol) in dry pyridine at 0℃. The reaction mixture was stirred at 0℃ for 2 h and then at room temperature for 68 h. The reaction mixture was poured into ice-water and extracted with chloroform. The extract was dried with Na2SO4 and concentrated in vacuo. The residue was dissolved in benzene and the solution was evaporated in vacuo. This process was repeated several times in order to remove the remaininng pyridine. Chromatography of the residue on silica gel with 3∶1 ether-petroleum ether as eluent gave the product 9(430 mg, 40.2%) as a gum. [α]11D-9.59°(c 0.089, CHCl3). IR(KBr)cm-1: 2950,2860,2218,1755,1608,1490,1448,1370,1225,1090～1040,905. 1HNMR (CDCl3) δ: 1.99,2.01,2.04(12H,3s,1∶2∶1,4×OAc),3.70(1H,m,5′-H),3.74(2H,s,1-H),4.12(1H,dd,J=12.5,2 Hz,6′-H),4.26(1H,dd,J=12.5,4.7 Hz,6′-H),4.48～4.54(3H,m,4,1′-H),4.99～5.19(3H,m,2′,3′,4′-H),6.50(1H,brt,J=6.4 Hz,3-H),7.30～7.41(15H,m,Ar-H). m/z: 331(3),259(1),243(100),169(3),165(9).
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7 (E)-2-Cyano-4-β-D-tetraacetylglucopyranosyloxy-2-buten-1-ol (10)
Trimethylsilyl iodide(0.03 ml, 0.21 mmol) was added dropwise to a solution of compound 9(120 mg, 0.175 mmol) in dry chloroform(2 ml) at room temperature under nitrogen atomosphere. After 5 min, methanol was added to quench the reaction. The reaction mixture was washed with aqueous Na2S2O3 and water. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was subjected to column chromatograpy on silica gel with 8∶1 ether-petroleum ether as eluent, yielding the allylic alcohol 10(55 mg, 70.9%) as a crystal, mp: 79℃～81℃. [α]29D-6.98°(c 0.153,CHCl3). IR(KBr)cm-1: 3490,2940,2880,2220,1750,1645,1430,1375,1250,1215,1086,1045,905. 1HNMR (CDCl3) δ: 1.7(1H,brs,OH),1.99,2.02,2.04,2.09(12H,4s,4×OAc),3.68(1H,m,5′-H),4.11(1H,dd,J=12.4,4.2 Hz,6′-H),4.24(2H,brs,1-H),4.34(1H,dd,J=12.4,2.3 Hz,6′-H),4.51(2H,m,4-H),4.55(1H,d,J=8 Hz,1′-H),4.97(1H,dd,J=9.4,8 Hz,2′-H),5.07,5.18(2H,2t,J=9.4 Hz,3′,4′-H),6.53(1H,brt,J=6.4 Hz,3-H). m/z: 383(4),346(7),323(6),243(23),200(37),169(38),157(78),145(55),140(45),115(100). Anal. C19H25NO11. Calcd: C 51.46, H 5.68, N 3.16; Found: C 51.24, H 5.64, N 2.98.
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Sarmentosin (1) Compound 10(50 mg, 0.113 mmol) was dissolved in a mixture of MeOH-Et3N-H2O(8∶1∶1, 6 ml) and the reaction solution was stirred at room temperature for 18 h. After evaporation of the solvent in vacuo, toluene was added to the residue and removed in vacuo again. This process was repeated several times to remove water. Chromatography of the residue on silica gel using 8∶3 chloroform-methanol as eluent furnished sarmentosin(23 mg, 74.2%) as a syrup, [α]30.5D-17.96°(c 2.16, MeOH). The IR, MS, 1HNMR and 13CNMR data of the synthetic product are identical with those of the natural sarmentosin reported in the literature[1,2]. IR(KBr)cm-1: 3540～3240,2227,1643,1100,1076,1050. 1HNMR (C5D5N) δ: 3.78～4.18(7H,m,1,4,5′,6′-H),4.38(1H,d,J=11.8 Hz,1′-H),4.50～4.80(3H,m,2′,3′,4′-H),6.80(1H,t,J=6.0 Hz,3-H). 13CNMR(D2O) δ: 62.0(6′-C), 63.0(4-C), 68.5(1-C), 70.9(4′-C), 74.3(2′-C), 77.1(5′-C), 77.4(3′-C), 103.2(1′-C), 117.5(2-C), 118.0(CN), 145.3(3-C). m/z (FAB): 276(M++1,10),207(17),185(62),93(100).
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Acknowledgement We thank Mr. Xu Rui and Miss Zhang Hong for valuable and stimulating discussions concerning this project.
REFERENCES
1 Fang SD, Yan XQ, Li JF, et al. The isolation and structure of the active principle sarmentosin. Kexue Tongbao, 1979,24∶431
2 Fang SD, Yan XQ, Li JF, et al. Studies on the chemical constituents of Sedum sarmentosum bunge IV. The structures of sarmentosin and iso-sarmentosin. Acta Chimica Sinica, 1982,40∶273
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3 Zhai SK, Shen ML, Xong YL, et al. A preliminary report on the immuno-suppressive activity of sarmentosin. Chin J Microbiol Immunol, 1982,2∶145
4 Chu GH, Zhou QT, Bai DL. The total synthesis of sarmentosin, a potent GPT lowering agent. Bioorg Med Chem Lett, 1993,3∶343
5 Mori K, Takigawa T, Matsuo T. Synthesis of optically active forms of ipsdienal and ipsenol. The pheromone components of ips bark beetles. Tetrahedron, 1979,35∶933
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6 Lubineau A, Queneau Y. Aqueous cycloadditions using glyco-organic substrates. 1. Stereochemical course of the reaction. J Org Chem, 1987,52∶1001
7 Nishida R, Rothschild M, Mummery R. A cyanoglucoside, sarmentosin, from the Magpie moth, Abraxas grossulariata, Geometridae: Lepidoptera. Phytochemistry, 1994,36∶37
*Project supported by State Key Laboratory of Drug Research
**To whom correspondence should be addressed
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Tel:(021)64311833, Fax:(021)64370269,E-mail:dlbai.@server sh.cmc.ac.ca
Received: 1997-12-05
摘要 目的： 垂盆草苷(1)是从垂盆草(Sedum sarmentosum Bunge)中分得的，能降低慢性病毒性肝炎病人血清谷丙转氨酶的活性成分并有免疫调节作用。以1，2，4-丁三醇-1，2-丙缩酮(3)为原料，经8步反应完成其全合成。方法和结果： 溴化α-D-四乙酰基吡喃葡萄糖在氧化银和分子筛存在下，与3缩合生成β-葡糖苷4。去缩酮保护后，伯醇基用三苯甲基保护得化合物6。6的仲醇基用PCC氧化成酮7，羰基与丙酮合氰化氢交换得加成物8。氰醇8用氯化亚砜脱水，形成所需的E式双键化合物9。用三甲碘硅烷脱除三苯甲基得烯丙醇10，最后用三乙胺含水甲醇溶液除去乙酰基，得目标产物1。总产率5.8%。结论： 首次完成了天然产物垂盆草苷的人工合成。
*基金项目：国家重点实验室基金资助项目, http://www.100md.com
参见：首页 > 中医药 > 中药专业 > 中草药汇编 > 中药大典 > 全草类 > 垂盆草