吡咯并[2，3-c]氮杂（艹卓）-4，8-二酮类化合物的合成
|
摘要
吡咯类生物碱是生物碱化学的重要分支之一,多种含吡咯并内酰胺环二酮结构单元的生物碱都具有显著的生理活性,例如抗菌、抗肿瘤及抗病毒等。本文在文献总结分析的基础上,以具有生物活性的1-烷基吡咯并[2,3-c]氮杂(?)-4,8-二酮类化合物的合成为主要研究内容。
本文以吡咯、β-丙氨酸、丙烯腈等为原料,经酰基化、酯化、缩合和Michael加成反应等步骤,制备了合成中间体N-(2-吡咯甲酰基)-β-丙氨酸甲酯(1A)及N-甲基-N-(2-吡咯甲酰基)-β-氨基丙腈(1B),并以之为底物进行烷基化,合成了12个相关烷基化产物N-(1-烷基-2-吡咯甲酰基)-β-丙氨酸酯及N-甲基-N-(1-烷基-2-吡咯甲酰基)-β-氨基丙腈(2a～21),收率68～91%。在该烷基化产物的合成过程中,本文对合成方法进行了创新：以无水碳酸钾为缚酸剂,TBAB相转移催化作用下,化合物1A或1B与烷基化试剂RX进行亲核取代反应,通过控制底物与RX的物质的量之比,可方便地合成不同的烷基化产物,避免了合成该类化合物时需制备和使用多种1-烷基-2-三氯乙酰吡咯。
以上述合成所得系列N-(1-烷基-2-吡咯甲酰基)-β-丙氨酸酯为原料,经水解酸化制备相应的酸(3a～3f),在PPA-P2O5作用下,N-(1-烷基-2-吡咯甲酰基)-β-丙氨酸经脱水关环,合成了6个目标化合物1-烷基-6,7-二氢-1H，5H-吡咯并[2,3-c]氮杂(?)-4,8-二酮(4a～4f),收率65%～77%。
本研究中所合成的化合物均通过重结晶或色谱技术分离纯化,大部分没有文献数据可作比较。主要通过红外光谱、核磁共振氢谱并结合化合物的理化性质对所获得中间体及目标产物进行结构表征,部分化合物还进行了X-射线单晶结构分析。论文中对合成反应条件、反应机理,各波谱数据均进行了讨论和解析。
Pyrrole alkaloids is one of the important branches of alkaloid chemistry, many kinds of alkaloids which include pyrrole lactam cyclodione structural element show notalbe bioactivities, such as anti-bacterium, anticancer antivirus, et. al. Based on consulting literature, this thesis describe the synthesis of series of bioactivity substances 1-alkyl-6,7-dihydropyrrolo [2,3-c]azepine-4,8(1H,5H)-diones,
N-(2-pyrrolecarbonyl)-β-alanine methyl esters(1A) and N-(2-cyanoethyl)-N-methyl-1H-pyrrole-2-carboxamide (1B) were synthesized as synthetic intermediates by refinement multi-step reactions including acylation, esterification, Michael addition, using the economic and convenient compouds such as pyrrole,β-alanine and acrylonitrile as starting materials. Inherited traditional methods, new idea was brought forth in synthetic method of the intermediates'alkylation.12 alkylation products (2a-21):N-(1-alkyl-2-pyrrolecarbonyl)-β-alanine methyl esters and N-(1-alkyl-2-cyanoethyl)-N-methyl-lH-pyrrole-2-carboxamide were facile synthesized by the nucleophilic substitution reaction using compounds (1A)& (1B) as reagents and RX as alkylates in the presence of anhydrous K2CO3 as alkaline catalyst, n-Bu4NBr (TBAB) as phase transfer catalyst in 68-91%yields, which avoid the preparation and use of 1-alkyl-2-(trichloroacetyl) pyrrol as synthetic intermediates.
Then series of 1-alkyl-6,7-dihydropyrrolo-[2,3-c]azepine-4,8(1H,5H)-diones (4a-4f) were obtained in 65-77% yields through cyclocondensation of the corres-ponding acids (3a-3f) that came out from the hydrolysis of the 3-(1-alky 1-1H-pyrrole-2-carbonyl)aminopropionates (2a-2f) and the N-methyl-3-(1-alkyl-1H-pyrrole-2-carbonyl) aminopropionitriles (2k-21) in the presence of PPA-P2O5.
Most of the above products prepared by the thesis are new compounds without document data existed for reference. All of the synthetic products were purified by crystallyzation or chromatography, and their structures were determined by means of 1HNMR, IR combination with the chemical & physical properties. Moreover, structures of some of these products were confirmed by single-crystal X-ray difraction. Reaction conditions and reaction mechanisms of the syntheses were discussed and explained in detail, and the spectral data also.
本文以吡咯、β-丙氨酸、丙烯腈等为原料,经酰基化、酯化、缩合和Michael加成反应等步骤,制备了合成中间体N-(2-吡咯甲酰基)-β-丙氨酸甲酯(1A)及N-甲基-N-(2-吡咯甲酰基)-β-氨基丙腈(1B),并以之为底物进行烷基化,合成了12个相关烷基化产物N-(1-烷基-2-吡咯甲酰基)-β-丙氨酸酯及N-甲基-N-(1-烷基-2-吡咯甲酰基)-β-氨基丙腈(2a～21),收率68～91%。在该烷基化产物的合成过程中,本文对合成方法进行了创新：以无水碳酸钾为缚酸剂,TBAB相转移催化作用下,化合物1A或1B与烷基化试剂RX进行亲核取代反应,通过控制底物与RX的物质的量之比,可方便地合成不同的烷基化产物,避免了合成该类化合物时需制备和使用多种1-烷基-2-三氯乙酰吡咯。
以上述合成所得系列N-(1-烷基-2-吡咯甲酰基)-β-丙氨酸酯为原料,经水解酸化制备相应的酸(3a～3f),在PPA-P2O5作用下,N-(1-烷基-2-吡咯甲酰基)-β-丙氨酸经脱水关环,合成了6个目标化合物1-烷基-6,7-二氢-1H，5H-吡咯并[2,3-c]氮杂(?)-4,8-二酮(4a～4f),收率65%～77%。
本研究中所合成的化合物均通过重结晶或色谱技术分离纯化,大部分没有文献数据可作比较。主要通过红外光谱、核磁共振氢谱并结合化合物的理化性质对所获得中间体及目标产物进行结构表征,部分化合物还进行了X-射线单晶结构分析。论文中对合成反应条件、反应机理,各波谱数据均进行了讨论和解析。
Pyrrole alkaloids is one of the important branches of alkaloid chemistry, many kinds of alkaloids which include pyrrole lactam cyclodione structural element show notalbe bioactivities, such as anti-bacterium, anticancer antivirus, et. al. Based on consulting literature, this thesis describe the synthesis of series of bioactivity substances 1-alkyl-6,7-dihydropyrrolo [2,3-c]azepine-4,8(1H,5H)-diones,
N-(2-pyrrolecarbonyl)-β-alanine methyl esters(1A) and N-(2-cyanoethyl)-N-methyl-1H-pyrrole-2-carboxamide (1B) were synthesized as synthetic intermediates by refinement multi-step reactions including acylation, esterification, Michael addition, using the economic and convenient compouds such as pyrrole,β-alanine and acrylonitrile as starting materials. Inherited traditional methods, new idea was brought forth in synthetic method of the intermediates'alkylation.12 alkylation products (2a-21):N-(1-alkyl-2-pyrrolecarbonyl)-β-alanine methyl esters and N-(1-alkyl-2-cyanoethyl)-N-methyl-lH-pyrrole-2-carboxamide were facile synthesized by the nucleophilic substitution reaction using compounds (1A)& (1B) as reagents and RX as alkylates in the presence of anhydrous K2CO3 as alkaline catalyst, n-Bu4NBr (TBAB) as phase transfer catalyst in 68-91%yields, which avoid the preparation and use of 1-alkyl-2-(trichloroacetyl) pyrrol as synthetic intermediates.
Then series of 1-alkyl-6,7-dihydropyrrolo-[2,3-c]azepine-4,8(1H,5H)-diones (4a-4f) were obtained in 65-77% yields through cyclocondensation of the corres-ponding acids (3a-3f) that came out from the hydrolysis of the 3-(1-alky 1-1H-pyrrole-2-carbonyl)aminopropionates (2a-2f) and the N-methyl-3-(1-alkyl-1H-pyrrole-2-carbonyl) aminopropionitriles (2k-21) in the presence of PPA-P2O5.
Most of the above products prepared by the thesis are new compounds without document data existed for reference. All of the synthetic products were purified by crystallyzation or chromatography, and their structures were determined by means of 1HNMR, IR combination with the chemical & physical properties. Moreover, structures of some of these products were confirmed by single-crystal X-ray difraction. Reaction conditions and reaction mechanisms of the syntheses were discussed and explained in detail, and the spectral data also.
引文
[1]Keiko H., Takaaki K., Masashi T., et al, Ma'edamines A and B, cytotoxic bromotyrosine alkaloids with a unique 2(1H) pyrazinone ring from sponge Suberea sp.[J].Tetrahedron,2000,56(41):8107.
[2]Jongheon S., Jung R. R., Seo Y. W., Sarcotragins A and B, new sesterterpenoid alkaloids from the sponge Sarcotragus sp. [J].Tetrahedron Letters,2001,42(16):3005.
[3]Romila D., Charan A., Tawnya C., Thorectandramine, a novel β-carboline alkaloid from the marine sponge Thorectandra sp.[J].Tetrahedron Letters,2002,43(30):5201.
[4]徐任生,天然产物化学[M].北京：科学出版社,2004：115.
[5]Aoki S., Wei H., Matsui K., et al, Pyridoacridine alkaloids inducing neuronal differentiation in a neuroblastoma cell line, from marine sponge Biemna fortis[J].Bio. org. Med. Chem.,2003,11(9):1969.
[6]Warabi K., Matsunaga S., Soest R.W., et al, Dictyodendrins A-E, the first telomerase inhibitory marine natural products from the sponge Dictyodendrilla verongiformis[J].J. Org. Chem.,2003,68(7): 2765.
[7]Endo T., Tsuda M., Okada T., et al, Nagelamides A-H, new dimeric bromopyrrole alkaloids from marine sponge Agelas species[J].J. Nat. Prod.,2004,67(8):1262.
[8]Furstner A., Domostoj M. M., Scheiper B., Total synthesis of dictyodendrin B[J]. J.Am. Chem. Soc.,2005,127(33):11620.
[9]Meijer L., Thunnissen A. M., White A. W., et al, Inhibition of cyclin-dependent kinases, GSK-3β and CK1 by Hymenialdisine, a marine sponge constituent[J]. Chem.& Biol., 2000,7(1):51.
[10]Rickards R. W., Rothschild J. M., Willis A. C., et al, novel pentacyclic metabolites from Calothrix cyanobacteria with potent activity against malaria parasites and human cancer cells[J].Tetrahedron,1999,55(47):13513.
[11]Francis J. S., Sarath P. G., Vijai L., et al, Marine natural products:Pyrrolo-lactams from several sponges[J].J. Nat. Prod.,1985,48(1):47.
[12]Portevin B., Golsteyn R. M., Pierre'A., et al, An expeditious multigram preparation of the marine protein kinase inhibitor Debromohymenialdisine[J]. Tetrahedron Lett.,2003,44(52):9263.
[13]Pettit G. R., McNulty J., Herald D. L., et al, Isolation and X-ray crystal structure of Dibromophakellstatin from the Indian Ocean sponge Phacellia mauritiana[J].J. Nat. Prod.,1997,60(2):180.
[14]Faulkner D. John., Marine natural products[J].Nat. Prod. Rep.,2002,19(1):1.
[15]刘家峰,郭松坡,姜标,海绵溴吡咯生物碱的研究进展[J].有机化学，2005,25(7)：788.
[16]唐孝礼,许实波,徐石海,海绵polymistia spongia提取物aldisin的抗脂质过氧化及清除自由基作用研究[J].中国药理学通报,1998,14(2)：148.
[17]曾向潮,徐石海,李毅群等,Aldisin及其衍生物的合成和α-葡萄糖苷酶抑制活性研究[J].有机化学，2005,25(8)：954.
[18]蒙其淼,梁洁,吴桂凡等,生物碱类化合物药理作用研究进展[J].时珍国医国药，2003,4(11)：700.
[19]Rao M. R., Venkatesham U., Venkateswarlu Y., Two bromo-compounds from the sponge Psammaplysilla purpurea. Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry,1999,38B(11):1301.
[20]Tasdemir D., Mallon R., Greenstein M., et al, Aldisine alkaloids from the Philippine sponge Stylissa mass are potent inhibitors of mitogen-activated Protein Kinase Kinase-1 (MEK-1)[J].J. Med. Chem.,2002,45(2):529.
[21]Nakagawa M., Hamamoto Y., Ishihama M., et al, Pharmacologically active homosesterterpenes from Palauan sponges[J].Tetrahedron Letters,1987,28(4):431.
[22]Cimino G., Rosa S. De., Stefano S. De., et al., Isolation and X-ray crystal structure of a novel bromo compound from two marine sponges[J].Tetrahedron Lett., 1982,23(7):767.
[23]Mattia C. A., Mazzarella L., Puliti R.,4-(2-Amino-4-oxo-2-imidazolin-5-ylidene)-2-bromo-4,5,6,7-tetrahydropyrrolo-[2,3-c]azepin-8-one methanol solvent:a new bromo compound from the sponge Acanthella aurantiaca[J]Acta Cryst.,1982, B38: 2513.
[24]KenjiroI., Hiroyasu S., Masashi T., et al, Spongiacidins A-D, new bromo-pyrrole alkaloids from hymeniacidon sponge[J].J. Nat. Prod.,1998,61(5):693.
[25]徐石海,曾陇梅,苏镜娱,两种吡咯并内酰胺生物碱的分离及结构[J].分析测试学报,1998,17(3)：32.
[26]李文林,毛士龙,易杨华等,棕色扁海绵化学成分研究[J].中国海洋药物,2001,79(1)：9.
[27]徐效华,姚广民,孔垂华等,海绵Phacellia fusca中含氮化合物的分离与结构鉴定[J].有机化学，2003,23(9)：953.
[28]Shamil L., Rogelio F., Emilio Q., et al,.The conformation of aldisin and analogues. A potential model for expanded nucleosides[J].Tetrahedron,1995,51(4): 1301.
[29]Sharma G. M., Buyer J. S., Pomerantz M. W., Characterization of a yellow compound isolated from the marine sponge Phakellia flabellata[J].Chem. Soc. Chem. Commun.,1980,10:435.
[30]Annoura H., Tatsuoka T., Total syntheses of hymenialdisine and debromo-hymenialdisine:stereospecific construction of the 2-amino-4-oxo-2-imidazolin-5(Z)-disubstituted ylidene ring system[J].Tetrahedron Letters,1995,36(1):413.
[31]Cho H., Matsuki S., Ring construction of several heterocycles with phosphorus pentoxide-methanesulfonic acid (PPMA)[J].Heterocycles,1996,43(1):127.
[32]Zeng X. C., Xu S. H., Method for the total synthesis of the pyrrole heterocyclic alkaloid aldisin, CN1554657A,20041215.
[33]Gianluca P., Helena P., Daniela B., et al, A New Glycociamidine Ring Precursor: Syntheses of (Z)-Hymenialdisine, (Z)-2-Debromohymenialdisine, and (±)-endo-2-Debromo-hymenialdisine[J].Organic Letters.,2005,7(25):5641.
[34]He Q. F., Chen W., Qin Y., Syntheses of 2-substituted endo-Hymenialdisine derivatives[J].Tetrahedron Lett.,2007,48(11):1899.
[35]曾向潮,徐石海,李毅群等,N-(2-吡咯甲酰基)氨基酸甲酯的合成[J].有机化学，2004,24(7)：802
[36]Bailey D. M., Johnson R. E., Albertson, N. F., Ethyl pyrrole-2-carboxylate [J].Organic Syntheses,1971,51:24
[37]徐石海,刘铂润,廖小建等,Aldisin及其衍生物的合成和表征[J].化学试剂，2007,29(2),65.
[38]Hidetsura C., Shinsuke M., Akira M., et al, Syntheses of Pyrroloazepines. Facile Synthesis of 2-Substituted Pyrrole Derivatives by the Phosgene Method[J].J. Heterocyclic Chem.,1997,34(1):87.
[39]Harry H., Steven V. L., N-alkylation of indole and pyrroles in dimethyl sulphoxide[J].J. Chem. Soc., Perkin Trans.1,1973,5:499.
[40]Candy C.F., Jones R. A., Pyrrole studies. XVII. Alkylation of pyrrylthallium(I) [J].J. Org. Chem.,1971,36(25):3993.
[41]Vasudha S., Theresa A. L., Guangyi J., et al, Inhibition of Cytokine Production by Hymenialdisine Derivatives [J] J. Med. Chem.,2004,47(14):3700.
[42]黄伟强,袁谷,肖军华,含六个杂环的寡聚酰胺的合成[J].化学通报，2001,7：425.
[43]Winfried L., Andrsas W.,Wilfried D., et al, Process for the Preparatoin of Phenylglyoxylic Acid Esters[P] US:4596885.1986-06-24.
[44]陈惠,刘志红,张生勇等,2-氨基-5-硝基苯甲腈水解条件的研究[J].化学试剂，2003,25(1)：35.
[45]Bachmann W. E., Horion W. J., The synthesis of 2-Hydroxy-17-equilenone[J].J. Am. Chem. Soc.,1947,69(1):58.
[46]Snyder H. R., Werber F. X., Polyphosphoric acid as a dehydrating agent. Ⅰ.The cyclodehydration of some a-acylamino-β-arylpropionic acids[J].J.Am. Chem. Soc., 1950,72(7):2962.
[47]Alirio P., Claudia C., Elena S., et al, Unexpected and novel synthesis of spirojulolidines via intramolecular cyclization of N-carbe-thoxymethyl spirotetra-hydroquinolines catalyzed by PPA[J].Tetrahedron Lett.,2001,42(36):6247.
[48]Wang X. J., Tan J., Crazinger K., A significantly improved condition for cyclization of phenethylcarbamates to N-alkylated-3,4-dihydroisoquinolones[J]. Tetrahedron Lett.,1998,39(37):6609.
[49]Phillips D. D., The Friedel-Crafts condensation between y-valerolactone and toluene[J] J. Am. Chem. Soc.,1955,77(13):3658.
[50]Wenner H., Stanley T., The synthesis of apoharmine[J].J. Am. Chem. Soc.,1955, 77(23):6355.
[51]钱旭红,张玉兰,徐晓勇等,四甲基萘并二呋喃的合成和DNA嵌入性能及其结构的分子模拟研究[J].高等学校化学学报,1996,17(9)：1399.
[52]Snyder H. R., Werber F. X., Polyphosphoric acid as a dehydrating agent. II.Intramolecular acylation[J] J. Am. Chem. Soc.,1950,72(7):2965.
[53]Klemm L. H., Mann R., Lind C. D., Syntheses of 3,3-dimethoxybenzophenone, ±-substitution in acylation of the organocadmium reagent from m-haloanisoles[J].J. Org. Chem.,1958,23(3):349.
[54]Gilmore R. C., Cyclization of aryl-aliphatic esters with phosphorus pentoxide in phosphoric acid[J].J. Am. Chem. Sco.,1951,73(12):5879.
[55]王葆仁,有机合成反应,科学出版社[M].1985年第一版,1304.
[2]Jongheon S., Jung R. R., Seo Y. W., Sarcotragins A and B, new sesterterpenoid alkaloids from the sponge Sarcotragus sp. [J].Tetrahedron Letters,2001,42(16):3005.
[3]Romila D., Charan A., Tawnya C., Thorectandramine, a novel β-carboline alkaloid from the marine sponge Thorectandra sp.[J].Tetrahedron Letters,2002,43(30):5201.
[4]徐任生,天然产物化学[M].北京：科学出版社,2004：115.
[5]Aoki S., Wei H., Matsui K., et al, Pyridoacridine alkaloids inducing neuronal differentiation in a neuroblastoma cell line, from marine sponge Biemna fortis[J].Bio. org. Med. Chem.,2003,11(9):1969.
[6]Warabi K., Matsunaga S., Soest R.W., et al, Dictyodendrins A-E, the first telomerase inhibitory marine natural products from the sponge Dictyodendrilla verongiformis[J].J. Org. Chem.,2003,68(7): 2765.
[7]Endo T., Tsuda M., Okada T., et al, Nagelamides A-H, new dimeric bromopyrrole alkaloids from marine sponge Agelas species[J].J. Nat. Prod.,2004,67(8):1262.
[8]Furstner A., Domostoj M. M., Scheiper B., Total synthesis of dictyodendrin B[J]. J.Am. Chem. Soc.,2005,127(33):11620.
[9]Meijer L., Thunnissen A. M., White A. W., et al, Inhibition of cyclin-dependent kinases, GSK-3β and CK1 by Hymenialdisine, a marine sponge constituent[J]. Chem.& Biol., 2000,7(1):51.
[10]Rickards R. W., Rothschild J. M., Willis A. C., et al, novel pentacyclic metabolites from Calothrix cyanobacteria with potent activity against malaria parasites and human cancer cells[J].Tetrahedron,1999,55(47):13513.
[11]Francis J. S., Sarath P. G., Vijai L., et al, Marine natural products:Pyrrolo-lactams from several sponges[J].J. Nat. Prod.,1985,48(1):47.
[12]Portevin B., Golsteyn R. M., Pierre'A., et al, An expeditious multigram preparation of the marine protein kinase inhibitor Debromohymenialdisine[J]. Tetrahedron Lett.,2003,44(52):9263.
[13]Pettit G. R., McNulty J., Herald D. L., et al, Isolation and X-ray crystal structure of Dibromophakellstatin from the Indian Ocean sponge Phacellia mauritiana[J].J. Nat. Prod.,1997,60(2):180.
[14]Faulkner D. John., Marine natural products[J].Nat. Prod. Rep.,2002,19(1):1.
[15]刘家峰,郭松坡,姜标,海绵溴吡咯生物碱的研究进展[J].有机化学，2005,25(7)：788.
[16]唐孝礼,许实波,徐石海,海绵polymistia spongia提取物aldisin的抗脂质过氧化及清除自由基作用研究[J].中国药理学通报,1998,14(2)：148.
[17]曾向潮,徐石海,李毅群等,Aldisin及其衍生物的合成和α-葡萄糖苷酶抑制活性研究[J].有机化学，2005,25(8)：954.
[18]蒙其淼,梁洁,吴桂凡等,生物碱类化合物药理作用研究进展[J].时珍国医国药，2003,4(11)：700.
[19]Rao M. R., Venkatesham U., Venkateswarlu Y., Two bromo-compounds from the sponge Psammaplysilla purpurea. Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry,1999,38B(11):1301.
[20]Tasdemir D., Mallon R., Greenstein M., et al, Aldisine alkaloids from the Philippine sponge Stylissa mass are potent inhibitors of mitogen-activated Protein Kinase Kinase-1 (MEK-1)[J].J. Med. Chem.,2002,45(2):529.
[21]Nakagawa M., Hamamoto Y., Ishihama M., et al, Pharmacologically active homosesterterpenes from Palauan sponges[J].Tetrahedron Letters,1987,28(4):431.
[22]Cimino G., Rosa S. De., Stefano S. De., et al., Isolation and X-ray crystal structure of a novel bromo compound from two marine sponges[J].Tetrahedron Lett., 1982,23(7):767.
[23]Mattia C. A., Mazzarella L., Puliti R.,4-(2-Amino-4-oxo-2-imidazolin-5-ylidene)-2-bromo-4,5,6,7-tetrahydropyrrolo-[2,3-c]azepin-8-one methanol solvent:a new bromo compound from the sponge Acanthella aurantiaca[J]Acta Cryst.,1982, B38: 2513.
[24]KenjiroI., Hiroyasu S., Masashi T., et al, Spongiacidins A-D, new bromo-pyrrole alkaloids from hymeniacidon sponge[J].J. Nat. Prod.,1998,61(5):693.
[25]徐石海,曾陇梅,苏镜娱,两种吡咯并内酰胺生物碱的分离及结构[J].分析测试学报,1998,17(3)：32.
[26]李文林,毛士龙,易杨华等,棕色扁海绵化学成分研究[J].中国海洋药物,2001,79(1)：9.
[27]徐效华,姚广民,孔垂华等,海绵Phacellia fusca中含氮化合物的分离与结构鉴定[J].有机化学，2003,23(9)：953.
[28]Shamil L., Rogelio F., Emilio Q., et al,.The conformation of aldisin and analogues. A potential model for expanded nucleosides[J].Tetrahedron,1995,51(4): 1301.
[29]Sharma G. M., Buyer J. S., Pomerantz M. W., Characterization of a yellow compound isolated from the marine sponge Phakellia flabellata[J].Chem. Soc. Chem. Commun.,1980,10:435.
[30]Annoura H., Tatsuoka T., Total syntheses of hymenialdisine and debromo-hymenialdisine:stereospecific construction of the 2-amino-4-oxo-2-imidazolin-5(Z)-disubstituted ylidene ring system[J].Tetrahedron Letters,1995,36(1):413.
[31]Cho H., Matsuki S., Ring construction of several heterocycles with phosphorus pentoxide-methanesulfonic acid (PPMA)[J].Heterocycles,1996,43(1):127.
[32]Zeng X. C., Xu S. H., Method for the total synthesis of the pyrrole heterocyclic alkaloid aldisin, CN1554657A,20041215.
[33]Gianluca P., Helena P., Daniela B., et al, A New Glycociamidine Ring Precursor: Syntheses of (Z)-Hymenialdisine, (Z)-2-Debromohymenialdisine, and (±)-endo-2-Debromo-hymenialdisine[J].Organic Letters.,2005,7(25):5641.
[34]He Q. F., Chen W., Qin Y., Syntheses of 2-substituted endo-Hymenialdisine derivatives[J].Tetrahedron Lett.,2007,48(11):1899.
[35]曾向潮,徐石海,李毅群等,N-(2-吡咯甲酰基)氨基酸甲酯的合成[J].有机化学，2004,24(7)：802
[36]Bailey D. M., Johnson R. E., Albertson, N. F., Ethyl pyrrole-2-carboxylate [J].Organic Syntheses,1971,51:24
[37]徐石海,刘铂润,廖小建等,Aldisin及其衍生物的合成和表征[J].化学试剂，2007,29(2),65.
[38]Hidetsura C., Shinsuke M., Akira M., et al, Syntheses of Pyrroloazepines. Facile Synthesis of 2-Substituted Pyrrole Derivatives by the Phosgene Method[J].J. Heterocyclic Chem.,1997,34(1):87.
[39]Harry H., Steven V. L., N-alkylation of indole and pyrroles in dimethyl sulphoxide[J].J. Chem. Soc., Perkin Trans.1,1973,5:499.
[40]Candy C.F., Jones R. A., Pyrrole studies. XVII. Alkylation of pyrrylthallium(I) [J].J. Org. Chem.,1971,36(25):3993.
[41]Vasudha S., Theresa A. L., Guangyi J., et al, Inhibition of Cytokine Production by Hymenialdisine Derivatives [J] J. Med. Chem.,2004,47(14):3700.
[42]黄伟强,袁谷,肖军华,含六个杂环的寡聚酰胺的合成[J].化学通报，2001,7：425.
[43]Winfried L., Andrsas W.,Wilfried D., et al, Process for the Preparatoin of Phenylglyoxylic Acid Esters[P] US:4596885.1986-06-24.
[44]陈惠,刘志红,张生勇等,2-氨基-5-硝基苯甲腈水解条件的研究[J].化学试剂，2003,25(1)：35.
[45]Bachmann W. E., Horion W. J., The synthesis of 2-Hydroxy-17-equilenone[J].J. Am. Chem. Soc.,1947,69(1):58.
[46]Snyder H. R., Werber F. X., Polyphosphoric acid as a dehydrating agent. Ⅰ.The cyclodehydration of some a-acylamino-β-arylpropionic acids[J].J.Am. Chem. Soc., 1950,72(7):2962.
[47]Alirio P., Claudia C., Elena S., et al, Unexpected and novel synthesis of spirojulolidines via intramolecular cyclization of N-carbe-thoxymethyl spirotetra-hydroquinolines catalyzed by PPA[J].Tetrahedron Lett.,2001,42(36):6247.
[48]Wang X. J., Tan J., Crazinger K., A significantly improved condition for cyclization of phenethylcarbamates to N-alkylated-3,4-dihydroisoquinolones[J]. Tetrahedron Lett.,1998,39(37):6609.
[49]Phillips D. D., The Friedel-Crafts condensation between y-valerolactone and toluene[J] J. Am. Chem. Soc.,1955,77(13):3658.
[50]Wenner H., Stanley T., The synthesis of apoharmine[J].J. Am. Chem. Soc.,1955, 77(23):6355.
[51]钱旭红,张玉兰,徐晓勇等,四甲基萘并二呋喃的合成和DNA嵌入性能及其结构的分子模拟研究[J].高等学校化学学报,1996,17(9)：1399.
[52]Snyder H. R., Werber F. X., Polyphosphoric acid as a dehydrating agent. II.Intramolecular acylation[J] J. Am. Chem. Soc.,1950,72(7):2965.
[53]Klemm L. H., Mann R., Lind C. D., Syntheses of 3,3-dimethoxybenzophenone, ±-substitution in acylation of the organocadmium reagent from m-haloanisoles[J].J. Org. Chem.,1958,23(3):349.
[54]Gilmore R. C., Cyclization of aryl-aliphatic esters with phosphorus pentoxide in phosphoric acid[J].J. Am. Chem. Sco.,1951,73(12):5879.
[55]王葆仁,有机合成反应,科学出版社[M].1985年第一版,1304.