榄香烯型分子母核的构建与莪术醇的结构修饰及活性研究
|
摘要
温莪术挥发油具有抗癌、抗病毒等多方面生物活性。过去的研究发现其中的榄香烯、莪术醇、莪术二酮等倍半萜类化合物为其主要活性成分。本论文针对榄香烯型分子骨架的构建和莪术醇的结构修饰及活性进行了研究。
第一部分：榄香烯型萜类分子中1,2-二烯基环己烷母核骨架的构建及合成研究
榄香烯型萜类化合物在自然界中广泛的存在,具有抗癌、抗炎、抗病毒等多种重要生物活性。在化学结构上,此类萜类天然产物分子普遍含有顺式或者反式1,2-二烯基环己烷母核骨架,类似于(±)-geijerone。本文以构建1,2-二烯基环己烷母核结构骨架为目的,并应用于(±)-geijerone的合成研究中,作为研究合成榄香烯型萜类分子的一部分。设计采用易得的geraniol为起始原料,运用Ireland-Claisen重排策略构建顺式和反式1,2-二烯基结构片断,并以分子内Barier反应环合作为关键反应步骤,进行了13步易于操作的反应步骤合成(±)-geijerone及(±)-5-epi-geijetone。本文丰富了1,2-二烯基环己烷结构片断及(±)-geijerone的合成方法,同时为研究合成榄香烯型化合物提供有价值的指导。
第二部分：萜类分子莪术醇的结构修饰及生物活性研究
萜类分子莪术醇是中药莪术的有效成分之一,其具有广泛的抗病毒、抗肿瘤、抗炎等活性,具有潜在的临床应用开发价值。目前,对于莪术醇的结构修饰及相应的生物活性研究的报道较少。本部分根据莪术醇的结构特点,通过化学方法对其结构的不同部位进行改造研究,合成了27个莪术醇衍生物,其中24个为未见报道的新化合物。采用MTT法对这些化合物进行初步体外抗肿瘤(细胞HeLa,HepG2,HT-1080,HCT116,A375-S2,MCF-7,A549,U-937, K562与HL60)活性筛选,结果发现卓酮化合物197对细胞HepG2与HCT116的抑制活性增强,分别为23.61与21.01μM；C7位引入羟基的ESC-01及环外双键末端引入亲水性的氨基硫脲片断的ESC-03对细胞HCT116的抑制活性增强,分别为22.42与16.35μM；桥环半缩醛还原开环化合物ESC-07对细胞A375-S2、细胞HT-1080的抑制活性增强,分别为34.45与32.71μM；6位羟基与α、β-不饱和肉桂酸系列成酯衍生化化合物ESC-09～ESC-23没有表现出明显的活性改善,且无明显的构效关系。其中,肉桂酸苯环上无取代基的ESC-09对细胞HL60的抑制活性提高明显,为10.46μM。此外,苯环上无取代基的ESC-09、对位为甲氧基取代的ESC-11、芳环为噻吩的ESC-22分别对细胞HT-1080、HL60、HCT116的抑制活性提高。而6位羟基与p-卤代酰胺成醚衍生物ESC-24与ESC-26对人肝癌细胞HepG2的抑制活性提高明显,分别为9.85与6.17μM。本部分不仅考察了莪术醇结构在不用化学环境体系下的稳定性,加深了对其结构特点的认识,而且可以通过体外抗肿瘤活性结果为我们进一步优化莪术醇的结构,开发具有临床应用价值的莪术醇类似物提供指引。
The essential oil extraced from Rhizoma Curcuma contains elemenes, curcumol, curdione and other sesquiterpenes has been reported to have many different biological activities, such as anti-cancer, anti-virus. This thesis aims to make a research on the construction of the mother nucleus of the elemene-type terpenoids and structural modification and bioactivity of curcumol derivatives:
1. Synthetic studies on the construction of the1,2-dialkenylcyclohexane framework of the elemene-type terpenoids.
The elemene-type terpenoids are widely existed in various natural products. These compounds or their racemic mixtures have been shown to inhibit tumor cell growth, anti-inflammatory and anti-virus in vitro and in vivo. Structurally, they contain a highly functionalized syn-or anti-1,2-dialkenylcyclohexane skeleton, which was similar to the strcuture of (±)-geijerone. Therefore,(±)-geijerone could be considered as a common precursor in the synthesis of elemene-type terpenoids. Here, we present a13-step for the synthesis of (±)-geijerone and a diastereoisomeric mixture with its5-epimer, which starting from the commercially available geraniol. Construction of the syn-and anti-1,2-dialkenylcyclohexane skeleton was achieved via Ireland-Claisen rearrangement of the (E)-allylic ester, and the cyclohexanone moiety was derived from the iodoaldehyde via intramolecular Barbier reaction. The newly formed syn-and anti-1,2-dialkenylcyclohexane strategy not only enrichs the synthetic methods of syn-and anti-1,2-dialkenylcyclohexane framework and (±)-geijerone, but also allows rapid access to various epimers and analogues of elemene-type products.
2. Structural modification and bioactivity of curcumol derivatives
Curcumol is an active ingredient of curcuma, a traditional Chinese medicine. It has present many important bioactivities, such as anti-virus, anti-tumor, anti-inflammatory and so on. At the present, the reports of the structural modification and bioactivity of curcumol are relatively rare. Here, on the base of the structural features, twenty-seven derivatives were synthesieed by modification of several active sites of curcumol. And the preliminary evaluation of these derivatives in vitro anti-tumor activity is screened using an MTT assay with HeLa, HepG2, HT-1080, HCT116, A375-S2, MCF-7, A549, U-937, K562and HL60. The results show that the IC50values of compound197, ESC-01, ESC-03, ESC-22for HCT116cells were21.01,22.42,16.35and21.51pM, which is stronger than curcumol. The IC50values of compound197, ESC-24, ESC-26for HepG2cells were23.61,9.85and6.17and the IC50values of compound ESC-07and ESC-09for HT-1080cells were32.71and27.71respectively. They are all stronger than curcumol. In addition, The IC50values of compound ESC-09and ESC-11for HL60cells were10.46and20.29μM, respectively, about five times stronger than curcumol. The structural modification of C6, C7and C8position and the decomposition of hemiacetal's bridge of curcumol was not effectively improve the inhibitory activities of tumor cells in vitro, and has no clear structure-activity relationship of curcumol derivatives. These not only investgate the stablization of curcumol in different chemical environments to deepen understanding of its structural characteristics, but also give us a guidance to exploit valuable curcumol derivatives in clinic according to the results of anti-tumor activity.
第一部分：榄香烯型萜类分子中1,2-二烯基环己烷母核骨架的构建及合成研究
榄香烯型萜类化合物在自然界中广泛的存在,具有抗癌、抗炎、抗病毒等多种重要生物活性。在化学结构上,此类萜类天然产物分子普遍含有顺式或者反式1,2-二烯基环己烷母核骨架,类似于(±)-geijerone。本文以构建1,2-二烯基环己烷母核结构骨架为目的,并应用于(±)-geijerone的合成研究中,作为研究合成榄香烯型萜类分子的一部分。设计采用易得的geraniol为起始原料,运用Ireland-Claisen重排策略构建顺式和反式1,2-二烯基结构片断,并以分子内Barier反应环合作为关键反应步骤,进行了13步易于操作的反应步骤合成(±)-geijerone及(±)-5-epi-geijetone。本文丰富了1,2-二烯基环己烷结构片断及(±)-geijerone的合成方法,同时为研究合成榄香烯型化合物提供有价值的指导。
第二部分：萜类分子莪术醇的结构修饰及生物活性研究
萜类分子莪术醇是中药莪术的有效成分之一,其具有广泛的抗病毒、抗肿瘤、抗炎等活性,具有潜在的临床应用开发价值。目前,对于莪术醇的结构修饰及相应的生物活性研究的报道较少。本部分根据莪术醇的结构特点,通过化学方法对其结构的不同部位进行改造研究,合成了27个莪术醇衍生物,其中24个为未见报道的新化合物。采用MTT法对这些化合物进行初步体外抗肿瘤(细胞HeLa,HepG2,HT-1080,HCT116,A375-S2,MCF-7,A549,U-937, K562与HL60)活性筛选,结果发现卓酮化合物197对细胞HepG2与HCT116的抑制活性增强,分别为23.61与21.01μM；C7位引入羟基的ESC-01及环外双键末端引入亲水性的氨基硫脲片断的ESC-03对细胞HCT116的抑制活性增强,分别为22.42与16.35μM；桥环半缩醛还原开环化合物ESC-07对细胞A375-S2、细胞HT-1080的抑制活性增强,分别为34.45与32.71μM；6位羟基与α、β-不饱和肉桂酸系列成酯衍生化化合物ESC-09～ESC-23没有表现出明显的活性改善,且无明显的构效关系。其中,肉桂酸苯环上无取代基的ESC-09对细胞HL60的抑制活性提高明显,为10.46μM。此外,苯环上无取代基的ESC-09、对位为甲氧基取代的ESC-11、芳环为噻吩的ESC-22分别对细胞HT-1080、HL60、HCT116的抑制活性提高。而6位羟基与p-卤代酰胺成醚衍生物ESC-24与ESC-26对人肝癌细胞HepG2的抑制活性提高明显,分别为9.85与6.17μM。本部分不仅考察了莪术醇结构在不用化学环境体系下的稳定性,加深了对其结构特点的认识,而且可以通过体外抗肿瘤活性结果为我们进一步优化莪术醇的结构,开发具有临床应用价值的莪术醇类似物提供指引。
The essential oil extraced from Rhizoma Curcuma contains elemenes, curcumol, curdione and other sesquiterpenes has been reported to have many different biological activities, such as anti-cancer, anti-virus. This thesis aims to make a research on the construction of the mother nucleus of the elemene-type terpenoids and structural modification and bioactivity of curcumol derivatives:
1. Synthetic studies on the construction of the1,2-dialkenylcyclohexane framework of the elemene-type terpenoids.
The elemene-type terpenoids are widely existed in various natural products. These compounds or their racemic mixtures have been shown to inhibit tumor cell growth, anti-inflammatory and anti-virus in vitro and in vivo. Structurally, they contain a highly functionalized syn-or anti-1,2-dialkenylcyclohexane skeleton, which was similar to the strcuture of (±)-geijerone. Therefore,(±)-geijerone could be considered as a common precursor in the synthesis of elemene-type terpenoids. Here, we present a13-step for the synthesis of (±)-geijerone and a diastereoisomeric mixture with its5-epimer, which starting from the commercially available geraniol. Construction of the syn-and anti-1,2-dialkenylcyclohexane skeleton was achieved via Ireland-Claisen rearrangement of the (E)-allylic ester, and the cyclohexanone moiety was derived from the iodoaldehyde via intramolecular Barbier reaction. The newly formed syn-and anti-1,2-dialkenylcyclohexane strategy not only enrichs the synthetic methods of syn-and anti-1,2-dialkenylcyclohexane framework and (±)-geijerone, but also allows rapid access to various epimers and analogues of elemene-type products.
2. Structural modification and bioactivity of curcumol derivatives
Curcumol is an active ingredient of curcuma, a traditional Chinese medicine. It has present many important bioactivities, such as anti-virus, anti-tumor, anti-inflammatory and so on. At the present, the reports of the structural modification and bioactivity of curcumol are relatively rare. Here, on the base of the structural features, twenty-seven derivatives were synthesieed by modification of several active sites of curcumol. And the preliminary evaluation of these derivatives in vitro anti-tumor activity is screened using an MTT assay with HeLa, HepG2, HT-1080, HCT116, A375-S2, MCF-7, A549, U-937, K562and HL60. The results show that the IC50values of compound197, ESC-01, ESC-03, ESC-22for HCT116cells were21.01,22.42,16.35and21.51pM, which is stronger than curcumol. The IC50values of compound197, ESC-24, ESC-26for HepG2cells were23.61,9.85and6.17and the IC50values of compound ESC-07and ESC-09for HT-1080cells were32.71and27.71respectively. They are all stronger than curcumol. In addition, The IC50values of compound ESC-09and ESC-11for HL60cells were10.46and20.29μM, respectively, about five times stronger than curcumol. The structural modification of C6, C7and C8position and the decomposition of hemiacetal's bridge of curcumol was not effectively improve the inhibitory activities of tumor cells in vitro, and has no clear structure-activity relationship of curcumol derivatives. These not only investgate the stablization of curcumol in different chemical environments to deepen understanding of its structural characteristics, but also give us a guidance to exploit valuable curcumol derivatives in clinic according to the results of anti-tumor activity.
引文
1. Newman, D. J. Natural products as leads to potential drugs:an old process or the new hone fnr drug discovery? J. Med. Chem.2008,51,2589-2599.
2. Wichtman, E.-M.; Stahl-Biskup, E. Composition of the essential oils from caraway herb and root. Flavour Fragrance J.1987,2,83-89.
3. Villanueva, M. A.; Torres, R. C.; Baser, K. H. C.; Ozek, T.; Kiirkciioglu, M. The composition of Manila elemi oil. Flavour Fragrance J.1993,8,35-37.
4. Herout, V.; Mod, O.; Sorm, F. Collect. Collech. Chem. Commun.1954,19,990-1001.
5. de Kraker, J.-W.; Franssen, M. C. R.; de Groot, A.; Shibata, T.; Bouwmeester, H. J. Germacrenes from fresh costus roots. Phytochemistry 2001,58,481-487.
6. Adio, A. M.; Paul, C.; Tesso, H.; Kloth, P.; Konig, W. A. Absolute configuration of helminthogermacrene. Tetrahedron:Asymmetry 2004,15,1631-1635.
7. Tesso,H.; Konig, W. A.; Son, P. T.; Giang, P. M. Composition of the essential oil of flowers of Chloranthus spicatus (Thunb.) Makino. Flavour Fragrance J.2006,21,592-597.
8. Jones, R. V. H.; Sutherland, M. D. Hedycaryol, the precursor of elemol.J. Chem. Soc., Chem. Commun.1968,1229-1230. doi:10.1039/C19680001229
9. Konig, W. A.; Rieck, A.; Saritas, Y.; Hardt, I. H.; Kubeczka, K.-H. Sesquiterpene hydrocarbons in the essential oil of Meum athamanticum. Phytochemistry 1996,42,461-464.
10. Wang, X. W. Elemene:antineoplastic. Drugs Future 1998,23,266-270.
11. Li, D. J.; Shao, J. L.; Zhang, Z. L.; Ao, J. H.; Zhang, Y.; Gu, M.; Chen, T. Pharmacological studies on elemene and the clinical application. Lishizhen Med. Mater. Med. Res.2001,12,1123-1124.
12. 华文峰；蔡绍晖.p-榄香烯抗肿瘤作用的基础与临.中草药2006,29,93-97.
13. 杨骅；王仙平；高力；张行；郑树.榄香烯诱导HL-60细胞程序死亡.中国肿瘤生物治疗杂志1995,2,351-352.
14.左云飞；张耀铮；魏巍；郑军.榄香烯对肝癌腹水瘤细胞系Hca-F25/CL-16A3的抗肿瘤作用及对细胞周期的影响.中药药理与临床1999,15,24-25.
15. 钱军.抗癌新药-榄香烯的药理及临床.中国肿瘤临床1996,23,453-455.
16. 邹丽娟；李杰；于丽敏；邵淑娟；杨佩满；卢步峰；张晨.p-榄香烯抗癌作用与诱发肿瘤细胞凋亡的研究.大连医科大学学报1998,20,9-12.
17. 秦叔逵；钱军；杨爱珍；王琳；乐美兆；何泽明；刘文虎.榄香烯乳抗肺癌细胞的实验研究.肿瘤防治研究1996,23,251-255.
18. 钱军；秦叔逵；乐美兆；杨爱珍；苏长青；刘文虎.榄香烯乳对体外培养人肺癌细胞株超微结构的影响.临床肿瘤学杂志1997,2,49-51.
19. 崔秀云；李德山.β-榄香烯对RNA聚合酶活性的抑制及与DNA的结合.中国药理学通报1991,7,228-231.
20.吕莉萍；刘丽华；李玉勤.榄香烯乳与阿霉素治疗恶性胸腔积液的疗效观察.临床内科杂志1998,16,94-95.
21. 张家骝；张静珊.榄香烯乳治疗中晚期肺癌的观察.云南中医中药杂志1998,19,21-23.
22.谭敏；郭智涛；宾晓农；石灵春；张维斌；何青莲.榄香烯乳区域动脉灌注对乳腺癌细胞凋亡和增殖的影响.中国肿瘤临床2001,28,267-269.
23.王俊红.榄香烯乳保留灌肠治疗老年晚期直肠癌.实用老年医学1998,12,137-138.
24. 常绍志；计永兰；吴学振；何科铭；罗兰.榄香烯乳膀胱内灌注治疗膀胱癌.中国肿瘤临床1999,26,70-71.
25.王晶；隋丽华；娄阁；徐峰.榄香烯治疗卵巢癌腹水疗效观察.中医药学报1999,27,35-36.
26.杨伯泵；翁方纪；金春丽.榄香烯与顺铂对癌性胸腔积液的疗效比较.实用肿瘤杂志2000,15,212-213.
27. de Kraker, J.-W.; Franssen, M. C. R.; de Groot, A.; Konig, W. A.; Bouwmeester, H. J. (+)-Germacrene a biosynthesis:The committed step in the biosynthesis of bitter sesquiterpene lacton. Plant Physiol.1998,117,1381-1392.
28. Sutherland, J. K. Regio- and stereo-specificity in the cyclisation of medium ring 1,5-dienes. Tetrahedron 1974,30,1651-1660.
29. Fisher, N. H.; Mabry, T. J. The structure of tamaulipin-B, a new germacranolide, and the thermal conversion of a trans-1,2-divinylcyclohexane derivative into a cyclodeca-1,5-diene system.J. Chem. Soc, Chem. Commun.1967,1235-1236. doi:10.1039/C19670001235.
30. Jain, T. C.; Banks, C. M.; McCloskey, J. E. Dehydrosaussurea lactone from costunolide and reversibility in the germacranolide-cope reaction. Tetrahedron Lett.1970,11,841-844.
31. Gopalan, A.; Magnus, P. Studies on terpenes.8. Total synthesis of (±)-linderalactone, (±)-isolinderalactone, and (±)-neolinderalactone, germacrane furanosesquiterpenes.J. Org. Chem. 1984,42,2317-2321.
32. Gajewski, J. J.; Conrad, N. D. The mechanism of the Cope rearrangement.J. Am. Chem. Soc. 1978, 100,6268-6269.
33. Brown, E. D.; Sam, T. W.; Sutherland, J. K.; Torre, A. Medium-ring 1,5-dienes. Part Ⅱ. The radical and electrophile-induced cyclisation of germacra-`(10),4,7(11)-triene.J. Chem. Soc., Perkin Trans.11975,2326-2332. doi:10.1039/P19750002326.
34. Gough, J. H.; Sutherland, M. D. Terpenoid chemistry. VIII. The structure of 8-elemene. Aust. J. Chem.1964,17,1270-1281.
35. Sutherland, M. D. Terpenoid chemistry. VII. The structure of geijerene. Aust. J. Chem.1964,17, 75-91.
36. Jones, R. V. H.; Sutherland, M. D. Terpenoid chemistry. XV. 1,5-Dimethylcyclodeca-1,5,7-triene, the precursor of geijerene in Geijera parviflora (Lindley). Aust. J. Chem.1968,21,2255-2264.
37. Baldovini, N.; Tomi, F.; Casanova, J. Identification and quantitative determination of furanodiene, a heat-sensitive compound, in essential oil by 13C-NMR. Phytochem. Anal.2001,12,58-63.
38. Miller, D. J.; Yu, F.; Allemann, R. K. Aristolochene synthase-catalyzed cyclization of 2-fluorofarnesyl-diphosphate to 2-fluorogermacrene A. ChemBioChem 2007,8,1819-1825.
39. Faraldos, J. A.; Zhao, Y.; O'Maille, P. E.; Noel, J. P.; Coates, R. M. Interception of the enzymatic conversion of farnesyl diphosphate to 5-epi-aristolochene by using a fluoro substrate analogue: 1-fluorogermacrene A from (2E,6Z)-6-fluorofarnesyl diphosphate. ChemBioChem 2007,8, 1826-1833.
40. Niwa, M.; Nishiyama, A.; Iguchi, M.; Yamamura, S. Sesquiterpenes from Acorus calamus L. Bull. Chem. Soc.Jpn.1975,48,2930-2934.
41. Jain, T. C.; Banks, C. M.; McCloskey, J. E. Novel cyclization of trans-1,2-divinylcyclohexane-3,4-trans-γ-lactone unit. Tetrahedron Lett.1970,11,2387-2390.
42. Rao, A. S.; Kelkar, G. R.; Battaacharyya, S. C. Terpenoids-ⅩⅪ:The structure of costunolide, a new sesquiterpene lactone from costus root oil. Tetrahedron 1960,9,275-283.
43. Takeda, K.; Minato, H.; Ishikawa, M. Components of the root of Lindera strychnifolia Vill. Part VIII. Structures of linderalactone and isolinderalactone.j. Chem. Soc.1964,11,4578-4582.
44. Hikino, H.; Konno, C.; Takemoto, T.; Tori, K.; Otsuru, M.; Horibe, I. Structure and conformation of the sesquiterpenoids furanodienone and isofuranodienone. Chem. Commun.1969, 662-663.
45. Hayashi, N.; Hayashi, S.; Matsuura, T. The structure of sericenine and sericenic acid, the new germacrane type sesquiterpenoids, isolated from Neolitsea sericea Koidz. Tetrahedron Lett.1968,9, 4957-4960.
46. Grandi, R.; Marchesini, A.; Pagnoni, U. M.; Trave, R. β-elemen-9β-ol from Achillea ageratum. Phytochemistry 1972,11,3363-3365.
47. Grandi, R.; Marchesini, A.; Pagnoni, U. M.; Trave, R. Reactions of quinolinium and pyridinium N-imines with cyclopentadienone derivatives. Tetrahedron Lett.1973,20,1765-1773.
48. Hackl, T.; Konig, W. A.; Muhle, H. Isogermacrene A, a proposed intermediate in sesquiterpene biosynthesis. Phytochemistry 2004,65,2261-2275.
49. Ognyanov, I.; Herout, V.; Horak, M.; Sorm, F. Uber terpene CIII. Uber die konstitution von (3-elemenon aus bulgarischem geranirno. Collect. Czech. Chem. Commun.1959,24,2371-2377.
50. Vlahov, R.; Holub, M.; Ognjanov, I.; Herout, V. On terpenes. CLⅩⅩⅩⅣ Sesquiterpenic hydrocarbons from the essential oil of Mentha piperita of Bulgarian origin. Collect. Czech. Chem. Commun.1967,32,808-821.
51. Wahidulla, S.; Govenkar, M. B.; Paknikar, S. K. Reaction of elemol with acetic Acid/perchloric acid:characterization of a novel oxide and (+)-β-cyperone. Helv. Chim. Acta 2006,89,496-501.
52. Ganter, V. C.; Wojtkiewicz, B. K. Pyrolysen- und hydrierungsversuche in der eletnol- und dihydrogeijeren-reihe. Helv. Chim. Acta 1971,54,183-206.
53. Blay, G.; Fernandez, I.; Garcia, B.; Pedro, J. R. Synthesis of various natural 8,12-elemanolides from artemisin. Tetrahedron 1989,45,5925-5934.
54. Lansbury, P. T.; Vacca, J. P. Total synthesis of pseudoguaianolides Ⅲ. (±)-Arornatin. Tetrahedron 1982,38,2797-2803.
55. Kato, M.; Watanabe, M.; Vogler, B.; Awen, B. Z.; Masuda, Y.; Tooyama, Y.; Yoshikoshi, A. The use of 4,4-disubstituted nopinones for natural-product synthesis. Synthesis of elemanoid sesquiterpenes.J. Org. Chem.1991,56,7071-7076.
56. Miyaoka, H.; Nishiyama, A.; Nagaoka, H.; Yamada, Y. A formal total synthesis of eleman-8b,12-olide with SmI2-induced cyclization. Synlett 2003,5,717-719.
57. Corey, E. J.; Roberts, B. E.; Dixon, B. R. Enantioselective total synthesis of β-elemene and fuscol based on enantiocontrolled Ireland-Claisen rearrangement.J. Am. Chem. Soc.1995,117,193-196.
58. Kim, D.; Lee, J.; Chang, J.; Kim, S. Stereoselective synthesis of (±)-b-elemene by a doubly diastereodifferentiating internal alkylation:a remarkable difference in the rate of enolization between syn and anti esters. Tetrahedron 2001,57,1247-1252.
59. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.; Faulkner, J.; Peterson, M.Simple stereoselective version of the Claisen rearrangement leading to trans-trisubstituted olefinic bonds. Synthesis of squalene.J. Am. Chem. Soc.1970,92,741-743.
60. Daub, G. W.; Edwards, J. P.; Okada, C. R.; Allen, J. W.; Maxey, C. T.; Wells, M. S.; Goldstein, A. S.; Dibley, M. J.; Wang, C. J.; Ostercamp, D. P.; Chung, S.; Cunningham, P. S.; Berliner, M. A. Acyclic stereoselection in the ortho ester Claisen rearrangement. J. Org. Chem.1997,62, 1976-1985.
61. Kato, M.; Kurihara, H.; Yoshikoshi, A. Total synthesis of racemic geijerone and y-elemene.J. Chem. Soc., Perkin Trans.11979,2740-2743. doi:10.1039/P19790002740.
62. Kato, M.; Kurihara, H.; Kosugi, H.; Watanabe, M.; Asuka, S.; Yoshikoshi, A. Synthesis of 4,4a-5,6,7,8-hexahydro-5β-hydroxy-4aβ,8α-dimethylnaphthalen-2(3 H)-one, a versatile intermediate for sesquiterpene synthesis.J. Chem. Soc., Perkin Trans.1 1977,2433-2436. doi: 10.1039/P19770002433.
63. Kim, D.; Kim, H. S. Stereoselective construction of functionalized cis-1,2-dialkyl cyclohexanecarboxylates:A novel synthesis of (±)-geijerone and γ-elemene.J. Org. Chem.1987,52, 4633-4634.
64. Zhao, R.; Zhao, Y.; Song, G.; Wu, Y. Double michael reaction of carvone and its derivatives. Tetrahedron Lett.1990,31,3559-3562.
65. Zhao, Y.; Zhao, R.; Wu, Y. Double michael reaction of carvone and its utilization in chiral synthesis of natural products. Acta Chim Sinica 1994,52,823-830.
66. Ireland, R. E.; Mueller, R. H. Claisen rearrangement of allyl esters.J. Am. Chem. Soc.1972,94, 5897-5898.
67. Ireland, R. E.; Willard, A. K. The stereoselective generation of ester enolates. Tetrahedron Lett. 1975,16,3975-3978.
68. Doering, W. E.; Roth, W. R. The overlap of two allyl radicals or a four-centered transition state in the cope rearrangement. Tetrahedron 1962,18,67-74.
69. Barbier, P. CR Acad. Sci. Paris 1899,128,110.
70. Killinger, T. A.; Boughton, N. A.; Runge, T. A.; Wolinsky, J. Alcohols as solvent for the generation and reaction of allylic zinc halides with aldehydes and ketones. J. Organomet. Chem. 1977,124,131-134.
71. Gyenes, F.; Bergmann, K. E.; Welch, J. T. Convenient access to primary amines by employing the Barbier-type reaction of N-(trimethylsilyl)imines derived from aromatic and aliphatic aldehydes.J. Org. Chem.1998,63,2824-2828.
72. Uneyama, K.; Kamaki, N.; Moriya, A.; Torii, S. Tin(Ⅱ)-aluminum-promoted allylation of aldehydes with allyl chloride in an aqueous solvent system.J. Org. Chem.1985,50,5396-5399.
73. Basu, K.; Banik, B. K. Samarium-mediated Barbier reaction of carbonyl compounds. Tetrahedron Lett 2001,42,187-189.
74. Molander, G. A.; Huerou, Y. L.; Brown, G. A. Sequenced reactions with samarium(Ⅱ) iodide. Sequential intramolecular Barbier cyclization/grob fragmentation for the synthesis of medium-sized carbocycles.J. Org. Chem.2001,66,4511-4516.
75. Ennis, D. S.; Lathbury, D. C.; Wanders, A.; Watts, D. Scale-up of an intermolecular Barbier reaction. Org. Proc. Res. Dev.1998,2,287-289.
76. Koch, G.; Janser, P.; Kottirsch, G.; Romero-Giron, E. Highly diastereoselective lewis acid promoted Claisen-Ireland rearrangement. Tetrahedron Lett.2002,43,4837-4840.
77. Baldwin, S. W.; Tomesch, J. C. Total synthesis of dl-cyclosativene by cationic olefinic and acetylenic cyclizations.J. Org. Chem.1980,45,1455-1462.
78. Wiley, G. A.; Hershkowitz, R. L.; Rein, B. M.; Chung, B. C. Studies in organophosphorus chemistry. I. Conversion of alcohols and phenols to halides by tertiary phosphine dihalides.J. Am. Chem. Soc.1964,86,964-965.
79. Kuwahara, S.; Liang, T.; Leal, W. S.; Ishikawa, J.; Kodama, O. Synthesis of all four possible stereoisomers of 5,9-dimethylpentadecane, the major sex pheromone component of the coffee leaf miner moth, Perileucoptera coffeella. Biosci. Biotechnol. Biochem.2000,64,2723-2726.
80. Yasui, H.; Hirai, K.; Yamamoto, S.; Takao, K.; Tadano, K. Total syntheses of (+)-1893B and its three diastereomers and evaluation of their biological activities.J. Antibiot.2006,59,456-463.
81. 姜建萍.莪术抗肿瘤研究概况.吉林中医药2000,2,62-64.
82.曾建红；陈旭；潘艳薇；舒丽清.莪术醇的研究进展.中药材2008,31,168-170.
83. 唐渊；李晓辉.莪术提取物对肝癌细胞系HepG2的抗癌作用及机制研究.中国药理学通报2007,23,790-794.
84. 林海；李晓辉.莪术醇诱导白血病L1210细胞凋亡作用研究.中国药房2008,19,2328-2329.
85.林海；李晓辉.莪术醇诱导慢性粒细胞白血病K562细胞分化的研究.现代生物学进展2007,7,1674-1676.
86. 徐立春；边可君；卜平；许祥裕；周娟；刘志敏；孙振华；陈平.莪术醇修饰的肿瘤疫苗抗MFC效应的研究.现代肿瘤医学2006,14,1357-1359.
87. 徐立春；边可君；刘志敏；周娟；Gohrke, W天然药物莪术醇抑制肿瘤细胞生长及RNA合成影响的初步研究.肿瘤2005,25,570-572.
88.李应东；李啸红；王毓美.中药莪术拮抗致突变作用的初步研究.中国优生与遗传杂志1999,7,22-23.
89. 徐立春；陈海燕；文洁；陶亚玲.莪术醇对人胃癌细胞凋亡、MMP2、NO影响的初步探讨.中国医药导报2012,34,19-21,
90. 王娟；陈旭；曾建红.莪术醇对鼻咽癌细胞CEN-2增殖与凋亡的影响.细胞与分子免疫学杂志2011,27,790-792.
91. Levidou, G.; Saetta, A. A.; Korkolopoulou, P.; Papanastasiou, P.; Gioti, K.; Pavlopoulos, P.; Diamantopoulou, K.; Thomas-Tsagli, E.; Xiromeritis, K.; Patsouris, E. Clinical significance of nuclear factor (NF)-(?)B levels in urothelial carcinoma of the urinary bladder. Virchows Arch.2008,452,295-304.
92.陈旭；王娟；蒋晓山；曾建红；黄凤香.莪术醇对肺癌A549细胞凋亡诱导因子、聚ADP核糖聚合酶及Caspase-3表达的影响.中国实用方剂学杂志2011,19,157-159.
93.曾建红；欧贤红；郭俊平；赵日良；刘淑清；赵斌.莪术醇原药对大鼠慢性毒性的实验研究.现代农业科学2008,15,21-23.
94. 郭永沺；杜晓鸣.11-氨甲基-2,6-二甲基-3,9-二异丙基三环[5.3.2.01,5]十二碳-5,9-二烯-8-醇的合成.药学学报1989,24,707-710.
95.孙汉杰；邹亚平；聂秀范；于润海.温莪术抗肿瘤作用研究—莪术醇磷酸酯单钠的合成.中国医药工业杂志1983,14,12-13.
96. 于润海；程蘅；张普明；聂秀范.温莪术抗肿瘤的研究6.莪术醇的结构改造(I)莪术醇邻苯二甲酸酸性酯的合成.沈阳药学院学报1978,10,25-27.
97. Fessler, W. A.; Shriner, R. L. Derivatives of tertiary alcohols. Acid phthalic esters.J. Am. Chem. Soc.1936,58,1384-1386.
98. 赵伟杰；王世盛；陈均；郭永沺；佟淑娟.新化合物3-异丙基-6-(1-甲基-1-乙酰胺基乙基)-9-甲基-2-氧代-1-氧杂螺[4.4]-壬烷化学结构的研究.中国药物化学杂志1995,5,40-43.
99. Ritter, J. J.; Minieri, P. P. Ritter reaction.J. Am. Chem. Soc.1948,70,4045-4048.
100. lnayama, S.; Gao, J. F.; Harimaya K. The absolute stereostructure of curcumol isolated from Curcuma Wenyujin. Chem. Pharm. Bull.1984,32,3783-3786.
101.王树龙；孟昭柯.新化合物莪术醇衍生物.CN1704417.2005.
102.梁广；李校堃；姚崇舜；杨树林.新的莪术醇糖苷类化合物及其制备与应用.CN 1995056.2007.07.11.
103.马旭.天然药物莪术醇的结构修饰.大连理工大学,硕士学位论文.2010.
104. Hiroshi, H.; Kanji, M.; Yojito, S.; Tsunematsu, T. Structure of curcumol. Chem. Pharm. Bull.1966, 14,1241-1249.
2. Wichtman, E.-M.; Stahl-Biskup, E. Composition of the essential oils from caraway herb and root. Flavour Fragrance J.1987,2,83-89.
3. Villanueva, M. A.; Torres, R. C.; Baser, K. H. C.; Ozek, T.; Kiirkciioglu, M. The composition of Manila elemi oil. Flavour Fragrance J.1993,8,35-37.
4. Herout, V.; Mod, O.; Sorm, F. Collect. Collech. Chem. Commun.1954,19,990-1001.
5. de Kraker, J.-W.; Franssen, M. C. R.; de Groot, A.; Shibata, T.; Bouwmeester, H. J. Germacrenes from fresh costus roots. Phytochemistry 2001,58,481-487.
6. Adio, A. M.; Paul, C.; Tesso, H.; Kloth, P.; Konig, W. A. Absolute configuration of helminthogermacrene. Tetrahedron:Asymmetry 2004,15,1631-1635.
7. Tesso,H.; Konig, W. A.; Son, P. T.; Giang, P. M. Composition of the essential oil of flowers of Chloranthus spicatus (Thunb.) Makino. Flavour Fragrance J.2006,21,592-597.
8. Jones, R. V. H.; Sutherland, M. D. Hedycaryol, the precursor of elemol.J. Chem. Soc., Chem. Commun.1968,1229-1230. doi:10.1039/C19680001229
9. Konig, W. A.; Rieck, A.; Saritas, Y.; Hardt, I. H.; Kubeczka, K.-H. Sesquiterpene hydrocarbons in the essential oil of Meum athamanticum. Phytochemistry 1996,42,461-464.
10. Wang, X. W. Elemene:antineoplastic. Drugs Future 1998,23,266-270.
11. Li, D. J.; Shao, J. L.; Zhang, Z. L.; Ao, J. H.; Zhang, Y.; Gu, M.; Chen, T. Pharmacological studies on elemene and the clinical application. Lishizhen Med. Mater. Med. Res.2001,12,1123-1124.
12. 华文峰；蔡绍晖.p-榄香烯抗肿瘤作用的基础与临.中草药2006,29,93-97.
13. 杨骅；王仙平；高力；张行；郑树.榄香烯诱导HL-60细胞程序死亡.中国肿瘤生物治疗杂志1995,2,351-352.
14.左云飞；张耀铮；魏巍；郑军.榄香烯对肝癌腹水瘤细胞系Hca-F25/CL-16A3的抗肿瘤作用及对细胞周期的影响.中药药理与临床1999,15,24-25.
15. 钱军.抗癌新药-榄香烯的药理及临床.中国肿瘤临床1996,23,453-455.
16. 邹丽娟；李杰；于丽敏；邵淑娟；杨佩满；卢步峰；张晨.p-榄香烯抗癌作用与诱发肿瘤细胞凋亡的研究.大连医科大学学报1998,20,9-12.
17. 秦叔逵；钱军；杨爱珍；王琳；乐美兆；何泽明；刘文虎.榄香烯乳抗肺癌细胞的实验研究.肿瘤防治研究1996,23,251-255.
18. 钱军；秦叔逵；乐美兆；杨爱珍；苏长青；刘文虎.榄香烯乳对体外培养人肺癌细胞株超微结构的影响.临床肿瘤学杂志1997,2,49-51.
19. 崔秀云；李德山.β-榄香烯对RNA聚合酶活性的抑制及与DNA的结合.中国药理学通报1991,7,228-231.
20.吕莉萍；刘丽华；李玉勤.榄香烯乳与阿霉素治疗恶性胸腔积液的疗效观察.临床内科杂志1998,16,94-95.
21. 张家骝；张静珊.榄香烯乳治疗中晚期肺癌的观察.云南中医中药杂志1998,19,21-23.
22.谭敏；郭智涛；宾晓农；石灵春；张维斌；何青莲.榄香烯乳区域动脉灌注对乳腺癌细胞凋亡和增殖的影响.中国肿瘤临床2001,28,267-269.
23.王俊红.榄香烯乳保留灌肠治疗老年晚期直肠癌.实用老年医学1998,12,137-138.
24. 常绍志；计永兰；吴学振；何科铭；罗兰.榄香烯乳膀胱内灌注治疗膀胱癌.中国肿瘤临床1999,26,70-71.
25.王晶；隋丽华；娄阁；徐峰.榄香烯治疗卵巢癌腹水疗效观察.中医药学报1999,27,35-36.
26.杨伯泵；翁方纪；金春丽.榄香烯与顺铂对癌性胸腔积液的疗效比较.实用肿瘤杂志2000,15,212-213.
27. de Kraker, J.-W.; Franssen, M. C. R.; de Groot, A.; Konig, W. A.; Bouwmeester, H. J. (+)-Germacrene a biosynthesis:The committed step in the biosynthesis of bitter sesquiterpene lacton. Plant Physiol.1998,117,1381-1392.
28. Sutherland, J. K. Regio- and stereo-specificity in the cyclisation of medium ring 1,5-dienes. Tetrahedron 1974,30,1651-1660.
29. Fisher, N. H.; Mabry, T. J. The structure of tamaulipin-B, a new germacranolide, and the thermal conversion of a trans-1,2-divinylcyclohexane derivative into a cyclodeca-1,5-diene system.J. Chem. Soc, Chem. Commun.1967,1235-1236. doi:10.1039/C19670001235.
30. Jain, T. C.; Banks, C. M.; McCloskey, J. E. Dehydrosaussurea lactone from costunolide and reversibility in the germacranolide-cope reaction. Tetrahedron Lett.1970,11,841-844.
31. Gopalan, A.; Magnus, P. Studies on terpenes.8. Total synthesis of (±)-linderalactone, (±)-isolinderalactone, and (±)-neolinderalactone, germacrane furanosesquiterpenes.J. Org. Chem. 1984,42,2317-2321.
32. Gajewski, J. J.; Conrad, N. D. The mechanism of the Cope rearrangement.J. Am. Chem. Soc. 1978, 100,6268-6269.
33. Brown, E. D.; Sam, T. W.; Sutherland, J. K.; Torre, A. Medium-ring 1,5-dienes. Part Ⅱ. The radical and electrophile-induced cyclisation of germacra-`(10),4,7(11)-triene.J. Chem. Soc., Perkin Trans.11975,2326-2332. doi:10.1039/P19750002326.
34. Gough, J. H.; Sutherland, M. D. Terpenoid chemistry. VIII. The structure of 8-elemene. Aust. J. Chem.1964,17,1270-1281.
35. Sutherland, M. D. Terpenoid chemistry. VII. The structure of geijerene. Aust. J. Chem.1964,17, 75-91.
36. Jones, R. V. H.; Sutherland, M. D. Terpenoid chemistry. XV. 1,5-Dimethylcyclodeca-1,5,7-triene, the precursor of geijerene in Geijera parviflora (Lindley). Aust. J. Chem.1968,21,2255-2264.
37. Baldovini, N.; Tomi, F.; Casanova, J. Identification and quantitative determination of furanodiene, a heat-sensitive compound, in essential oil by 13C-NMR. Phytochem. Anal.2001,12,58-63.
38. Miller, D. J.; Yu, F.; Allemann, R. K. Aristolochene synthase-catalyzed cyclization of 2-fluorofarnesyl-diphosphate to 2-fluorogermacrene A. ChemBioChem 2007,8,1819-1825.
39. Faraldos, J. A.; Zhao, Y.; O'Maille, P. E.; Noel, J. P.; Coates, R. M. Interception of the enzymatic conversion of farnesyl diphosphate to 5-epi-aristolochene by using a fluoro substrate analogue: 1-fluorogermacrene A from (2E,6Z)-6-fluorofarnesyl diphosphate. ChemBioChem 2007,8, 1826-1833.
40. Niwa, M.; Nishiyama, A.; Iguchi, M.; Yamamura, S. Sesquiterpenes from Acorus calamus L. Bull. Chem. Soc.Jpn.1975,48,2930-2934.
41. Jain, T. C.; Banks, C. M.; McCloskey, J. E. Novel cyclization of trans-1,2-divinylcyclohexane-3,4-trans-γ-lactone unit. Tetrahedron Lett.1970,11,2387-2390.
42. Rao, A. S.; Kelkar, G. R.; Battaacharyya, S. C. Terpenoids-ⅩⅪ:The structure of costunolide, a new sesquiterpene lactone from costus root oil. Tetrahedron 1960,9,275-283.
43. Takeda, K.; Minato, H.; Ishikawa, M. Components of the root of Lindera strychnifolia Vill. Part VIII. Structures of linderalactone and isolinderalactone.j. Chem. Soc.1964,11,4578-4582.
44. Hikino, H.; Konno, C.; Takemoto, T.; Tori, K.; Otsuru, M.; Horibe, I. Structure and conformation of the sesquiterpenoids furanodienone and isofuranodienone. Chem. Commun.1969, 662-663.
45. Hayashi, N.; Hayashi, S.; Matsuura, T. The structure of sericenine and sericenic acid, the new germacrane type sesquiterpenoids, isolated from Neolitsea sericea Koidz. Tetrahedron Lett.1968,9, 4957-4960.
46. Grandi, R.; Marchesini, A.; Pagnoni, U. M.; Trave, R. β-elemen-9β-ol from Achillea ageratum. Phytochemistry 1972,11,3363-3365.
47. Grandi, R.; Marchesini, A.; Pagnoni, U. M.; Trave, R. Reactions of quinolinium and pyridinium N-imines with cyclopentadienone derivatives. Tetrahedron Lett.1973,20,1765-1773.
48. Hackl, T.; Konig, W. A.; Muhle, H. Isogermacrene A, a proposed intermediate in sesquiterpene biosynthesis. Phytochemistry 2004,65,2261-2275.
49. Ognyanov, I.; Herout, V.; Horak, M.; Sorm, F. Uber terpene CIII. Uber die konstitution von (3-elemenon aus bulgarischem geranirno. Collect. Czech. Chem. Commun.1959,24,2371-2377.
50. Vlahov, R.; Holub, M.; Ognjanov, I.; Herout, V. On terpenes. CLⅩⅩⅩⅣ Sesquiterpenic hydrocarbons from the essential oil of Mentha piperita of Bulgarian origin. Collect. Czech. Chem. Commun.1967,32,808-821.
51. Wahidulla, S.; Govenkar, M. B.; Paknikar, S. K. Reaction of elemol with acetic Acid/perchloric acid:characterization of a novel oxide and (+)-β-cyperone. Helv. Chim. Acta 2006,89,496-501.
52. Ganter, V. C.; Wojtkiewicz, B. K. Pyrolysen- und hydrierungsversuche in der eletnol- und dihydrogeijeren-reihe. Helv. Chim. Acta 1971,54,183-206.
53. Blay, G.; Fernandez, I.; Garcia, B.; Pedro, J. R. Synthesis of various natural 8,12-elemanolides from artemisin. Tetrahedron 1989,45,5925-5934.
54. Lansbury, P. T.; Vacca, J. P. Total synthesis of pseudoguaianolides Ⅲ. (±)-Arornatin. Tetrahedron 1982,38,2797-2803.
55. Kato, M.; Watanabe, M.; Vogler, B.; Awen, B. Z.; Masuda, Y.; Tooyama, Y.; Yoshikoshi, A. The use of 4,4-disubstituted nopinones for natural-product synthesis. Synthesis of elemanoid sesquiterpenes.J. Org. Chem.1991,56,7071-7076.
56. Miyaoka, H.; Nishiyama, A.; Nagaoka, H.; Yamada, Y. A formal total synthesis of eleman-8b,12-olide with SmI2-induced cyclization. Synlett 2003,5,717-719.
57. Corey, E. J.; Roberts, B. E.; Dixon, B. R. Enantioselective total synthesis of β-elemene and fuscol based on enantiocontrolled Ireland-Claisen rearrangement.J. Am. Chem. Soc.1995,117,193-196.
58. Kim, D.; Lee, J.; Chang, J.; Kim, S. Stereoselective synthesis of (±)-b-elemene by a doubly diastereodifferentiating internal alkylation:a remarkable difference in the rate of enolization between syn and anti esters. Tetrahedron 2001,57,1247-1252.
59. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.; Faulkner, J.; Peterson, M.Simple stereoselective version of the Claisen rearrangement leading to trans-trisubstituted olefinic bonds. Synthesis of squalene.J. Am. Chem. Soc.1970,92,741-743.
60. Daub, G. W.; Edwards, J. P.; Okada, C. R.; Allen, J. W.; Maxey, C. T.; Wells, M. S.; Goldstein, A. S.; Dibley, M. J.; Wang, C. J.; Ostercamp, D. P.; Chung, S.; Cunningham, P. S.; Berliner, M. A. Acyclic stereoselection in the ortho ester Claisen rearrangement. J. Org. Chem.1997,62, 1976-1985.
61. Kato, M.; Kurihara, H.; Yoshikoshi, A. Total synthesis of racemic geijerone and y-elemene.J. Chem. Soc., Perkin Trans.11979,2740-2743. doi:10.1039/P19790002740.
62. Kato, M.; Kurihara, H.; Kosugi, H.; Watanabe, M.; Asuka, S.; Yoshikoshi, A. Synthesis of 4,4a-5,6,7,8-hexahydro-5β-hydroxy-4aβ,8α-dimethylnaphthalen-2(3 H)-one, a versatile intermediate for sesquiterpene synthesis.J. Chem. Soc., Perkin Trans.1 1977,2433-2436. doi: 10.1039/P19770002433.
63. Kim, D.; Kim, H. S. Stereoselective construction of functionalized cis-1,2-dialkyl cyclohexanecarboxylates:A novel synthesis of (±)-geijerone and γ-elemene.J. Org. Chem.1987,52, 4633-4634.
64. Zhao, R.; Zhao, Y.; Song, G.; Wu, Y. Double michael reaction of carvone and its derivatives. Tetrahedron Lett.1990,31,3559-3562.
65. Zhao, Y.; Zhao, R.; Wu, Y. Double michael reaction of carvone and its utilization in chiral synthesis of natural products. Acta Chim Sinica 1994,52,823-830.
66. Ireland, R. E.; Mueller, R. H. Claisen rearrangement of allyl esters.J. Am. Chem. Soc.1972,94, 5897-5898.
67. Ireland, R. E.; Willard, A. K. The stereoselective generation of ester enolates. Tetrahedron Lett. 1975,16,3975-3978.
68. Doering, W. E.; Roth, W. R. The overlap of two allyl radicals or a four-centered transition state in the cope rearrangement. Tetrahedron 1962,18,67-74.
69. Barbier, P. CR Acad. Sci. Paris 1899,128,110.
70. Killinger, T. A.; Boughton, N. A.; Runge, T. A.; Wolinsky, J. Alcohols as solvent for the generation and reaction of allylic zinc halides with aldehydes and ketones. J. Organomet. Chem. 1977,124,131-134.
71. Gyenes, F.; Bergmann, K. E.; Welch, J. T. Convenient access to primary amines by employing the Barbier-type reaction of N-(trimethylsilyl)imines derived from aromatic and aliphatic aldehydes.J. Org. Chem.1998,63,2824-2828.
72. Uneyama, K.; Kamaki, N.; Moriya, A.; Torii, S. Tin(Ⅱ)-aluminum-promoted allylation of aldehydes with allyl chloride in an aqueous solvent system.J. Org. Chem.1985,50,5396-5399.
73. Basu, K.; Banik, B. K. Samarium-mediated Barbier reaction of carbonyl compounds. Tetrahedron Lett 2001,42,187-189.
74. Molander, G. A.; Huerou, Y. L.; Brown, G. A. Sequenced reactions with samarium(Ⅱ) iodide. Sequential intramolecular Barbier cyclization/grob fragmentation for the synthesis of medium-sized carbocycles.J. Org. Chem.2001,66,4511-4516.
75. Ennis, D. S.; Lathbury, D. C.; Wanders, A.; Watts, D. Scale-up of an intermolecular Barbier reaction. Org. Proc. Res. Dev.1998,2,287-289.
76. Koch, G.; Janser, P.; Kottirsch, G.; Romero-Giron, E. Highly diastereoselective lewis acid promoted Claisen-Ireland rearrangement. Tetrahedron Lett.2002,43,4837-4840.
77. Baldwin, S. W.; Tomesch, J. C. Total synthesis of dl-cyclosativene by cationic olefinic and acetylenic cyclizations.J. Org. Chem.1980,45,1455-1462.
78. Wiley, G. A.; Hershkowitz, R. L.; Rein, B. M.; Chung, B. C. Studies in organophosphorus chemistry. I. Conversion of alcohols and phenols to halides by tertiary phosphine dihalides.J. Am. Chem. Soc.1964,86,964-965.
79. Kuwahara, S.; Liang, T.; Leal, W. S.; Ishikawa, J.; Kodama, O. Synthesis of all four possible stereoisomers of 5,9-dimethylpentadecane, the major sex pheromone component of the coffee leaf miner moth, Perileucoptera coffeella. Biosci. Biotechnol. Biochem.2000,64,2723-2726.
80. Yasui, H.; Hirai, K.; Yamamoto, S.; Takao, K.; Tadano, K. Total syntheses of (+)-1893B and its three diastereomers and evaluation of their biological activities.J. Antibiot.2006,59,456-463.
81. 姜建萍.莪术抗肿瘤研究概况.吉林中医药2000,2,62-64.
82.曾建红；陈旭；潘艳薇；舒丽清.莪术醇的研究进展.中药材2008,31,168-170.
83. 唐渊；李晓辉.莪术提取物对肝癌细胞系HepG2的抗癌作用及机制研究.中国药理学通报2007,23,790-794.
84. 林海；李晓辉.莪术醇诱导白血病L1210细胞凋亡作用研究.中国药房2008,19,2328-2329.
85.林海；李晓辉.莪术醇诱导慢性粒细胞白血病K562细胞分化的研究.现代生物学进展2007,7,1674-1676.
86. 徐立春；边可君；卜平；许祥裕；周娟；刘志敏；孙振华；陈平.莪术醇修饰的肿瘤疫苗抗MFC效应的研究.现代肿瘤医学2006,14,1357-1359.
87. 徐立春；边可君；刘志敏；周娟；Gohrke, W天然药物莪术醇抑制肿瘤细胞生长及RNA合成影响的初步研究.肿瘤2005,25,570-572.
88.李应东；李啸红；王毓美.中药莪术拮抗致突变作用的初步研究.中国优生与遗传杂志1999,7,22-23.
89. 徐立春；陈海燕；文洁；陶亚玲.莪术醇对人胃癌细胞凋亡、MMP2、NO影响的初步探讨.中国医药导报2012,34,19-21,
90. 王娟；陈旭；曾建红.莪术醇对鼻咽癌细胞CEN-2增殖与凋亡的影响.细胞与分子免疫学杂志2011,27,790-792.
91. Levidou, G.; Saetta, A. A.; Korkolopoulou, P.; Papanastasiou, P.; Gioti, K.; Pavlopoulos, P.; Diamantopoulou, K.; Thomas-Tsagli, E.; Xiromeritis, K.; Patsouris, E. Clinical significance of nuclear factor (NF)-(?)B levels in urothelial carcinoma of the urinary bladder. Virchows Arch.2008,452,295-304.
92.陈旭；王娟；蒋晓山；曾建红；黄凤香.莪术醇对肺癌A549细胞凋亡诱导因子、聚ADP核糖聚合酶及Caspase-3表达的影响.中国实用方剂学杂志2011,19,157-159.
93.曾建红；欧贤红；郭俊平；赵日良；刘淑清；赵斌.莪术醇原药对大鼠慢性毒性的实验研究.现代农业科学2008,15,21-23.
94. 郭永沺；杜晓鸣.11-氨甲基-2,6-二甲基-3,9-二异丙基三环[5.3.2.01,5]十二碳-5,9-二烯-8-醇的合成.药学学报1989,24,707-710.
95.孙汉杰；邹亚平；聂秀范；于润海.温莪术抗肿瘤作用研究—莪术醇磷酸酯单钠的合成.中国医药工业杂志1983,14,12-13.
96. 于润海；程蘅；张普明；聂秀范.温莪术抗肿瘤的研究6.莪术醇的结构改造(I)莪术醇邻苯二甲酸酸性酯的合成.沈阳药学院学报1978,10,25-27.
97. Fessler, W. A.; Shriner, R. L. Derivatives of tertiary alcohols. Acid phthalic esters.J. Am. Chem. Soc.1936,58,1384-1386.
98. 赵伟杰；王世盛；陈均；郭永沺；佟淑娟.新化合物3-异丙基-6-(1-甲基-1-乙酰胺基乙基)-9-甲基-2-氧代-1-氧杂螺[4.4]-壬烷化学结构的研究.中国药物化学杂志1995,5,40-43.
99. Ritter, J. J.; Minieri, P. P. Ritter reaction.J. Am. Chem. Soc.1948,70,4045-4048.
100. lnayama, S.; Gao, J. F.; Harimaya K. The absolute stereostructure of curcumol isolated from Curcuma Wenyujin. Chem. Pharm. Bull.1984,32,3783-3786.
101.王树龙；孟昭柯.新化合物莪术醇衍生物.CN1704417.2005.
102.梁广；李校堃；姚崇舜；杨树林.新的莪术醇糖苷类化合物及其制备与应用.CN 1995056.2007.07.11.
103.马旭.天然药物莪术醇的结构修饰.大连理工大学,硕士学位论文.2010.
104. Hiroshi, H.; Kanji, M.; Yojito, S.; Tsunematsu, T. Structure of curcumol. Chem. Pharm. Bull.1966, 14,1241-1249.