具有生物活性杂环化合物的设计、合成及其研究
|
摘要
第一：在对Bcr-Abl激酶抑制剂进行综述的基础上,通过计算机辅助设计并结合已有的抑制剂建立了药效团模型；在对该模型分析的基础上,找到了这些抑制剂的共同特征,设计合成了三类Bcr-Abl激酶抑制剂(苯并咪唑、苯并噻吩和噻二唑类),并对这些抑制剂进行了活性测试,结果表明,苯并噻吩类化合物具有较好的活性。
第二：在对金属催化呋喃环及其衍生物合成方法综述的基础上,研究了K'OBu和Cu(OTf)2/PPh3体系催化2-炔丙基-1.3-二羰基化合物的分子内环化反应。使用易得的原料2-炔丙基-1.3-二羰基化合物、无机碱(KO'Bu),廉价催化剂(Cu2+)和配体(PPh3)在甲醇-二氯甲烷中高产率合成了2-亚甲基二氢呋喃,并将2-亚甲基二氢呋喃在CF3COOH-甲醇体系中转化为呋喃衍生物。该方法具有直接高效易于操作的特点。
第三：在对Nikkomycin B的N-端氨基酸片断合成综述的基础上,对Nikkomycin B的N-端氨基酸片断的不对称合成进行了探索。采用手性氧化腈和烯丙醇进行1,3-偶极环加成反应合成手性异噁唑啉为关键步骤；随后经多步官能团转化得到Nikkomycin B的N-端氨基酸内酯片段。但遗憾的是内酯的相对构型与天然产物构型不符。
第四：在对石蒜科生物碱Lycorane合成方法综述的基础上,对α-Lycorane的不对称合成进行了探索。通过手性奎宁硫脲催化硝基烯和不饱和酯的双迈克尔加成高效构筑了α-Lycorane的三个手性中心；随后经多步官能团转化得到重要前体101,为进行α-Lycorane不对称合成奠定了基础。
The thesis aims at the studies on four parts as following:
Part I The design, synthesis and activity assay of Bcr-Abl kinase inhibitors
Based on the review of Bcr-Abl kinase inhibitors, we were interested in building a pharmacophore model. A series of compounds (including benzo[d]imidazole, benzo[b]thiophene and thiadiazol) as potential inhibitors were designed and synthesized. For the inhibitor assay, some compounds were observed to have inhibitory activities, and the result indicated benzo[b]thiophene derivatives showed good inhibitory activities.
PartⅡCu(Ⅱ)-catalyzed cyclization reaction
Based on the review of synthetic method for furan derivatives, the intramolecular cyclization reaction of 2-propynyl-1,3-dicarbonyl compounds was explored. The reaction was performed using readily available materials (2-propynyl-1,3-dicarbonyl compounds), an inexpensive catalyst (Cu2+ salt) and ligand (PPh3) under very mild basic conditions in good to excellent yields. Then,5-methylene-4,5-dihydrofurans were easily converted into the corresponding furans under acidic conditions. The reaction provides a new approach to dihydrofurans in a direct, efficient and facile manner.
Part III Asymmetric synthesis of N-terminal amino acid component of Nikkomycin B
Based on the review of synthetic method for N-terminal amino acid component of Nikkomycin B, the asymmetric synthesis of N-terminal amino acid component of Nikkomycin B was explored.1,3-Dipolar cycloaddition reaction involving (E)-p-methoxycinnamyl alcohol and chiral nitrile oxide to construct the chiral isoxazoline was used as the key step. N-terminal amino acid component of Nikkomycin B was synthesized by subsequent functional group transformation. To our regret, the configuration is not consistent with the natural N-terminal amino acid component of Nikkomycin B.
Part IV Asymmetric total synthesis of a-Lycorane
Based on the review of synthetic method for Lycorane, the asymmetric synthesis of a-Lycorane was explored. Three stereogenic centers of a-Lycorane were effectively constructed with high diastereoselectivity and enantioselectivity via chiral thiourea catalyzing tandem Michael addition involving nitrostyrene and unsaturated ester. The key compound 101 was synthesized by subsequent functional group transformation, which established foundation for further asymmetric synthesis of a-Lycorane.
第二：在对金属催化呋喃环及其衍生物合成方法综述的基础上,研究了K'OBu和Cu(OTf)2/PPh3体系催化2-炔丙基-1.3-二羰基化合物的分子内环化反应。使用易得的原料2-炔丙基-1.3-二羰基化合物、无机碱(KO'Bu),廉价催化剂(Cu2+)和配体(PPh3)在甲醇-二氯甲烷中高产率合成了2-亚甲基二氢呋喃,并将2-亚甲基二氢呋喃在CF3COOH-甲醇体系中转化为呋喃衍生物。该方法具有直接高效易于操作的特点。
第三：在对Nikkomycin B的N-端氨基酸片断合成综述的基础上,对Nikkomycin B的N-端氨基酸片断的不对称合成进行了探索。采用手性氧化腈和烯丙醇进行1,3-偶极环加成反应合成手性异噁唑啉为关键步骤；随后经多步官能团转化得到Nikkomycin B的N-端氨基酸内酯片段。但遗憾的是内酯的相对构型与天然产物构型不符。
第四：在对石蒜科生物碱Lycorane合成方法综述的基础上,对α-Lycorane的不对称合成进行了探索。通过手性奎宁硫脲催化硝基烯和不饱和酯的双迈克尔加成高效构筑了α-Lycorane的三个手性中心；随后经多步官能团转化得到重要前体101,为进行α-Lycorane不对称合成奠定了基础。
The thesis aims at the studies on four parts as following:
Part I The design, synthesis and activity assay of Bcr-Abl kinase inhibitors
Based on the review of Bcr-Abl kinase inhibitors, we were interested in building a pharmacophore model. A series of compounds (including benzo[d]imidazole, benzo[b]thiophene and thiadiazol) as potential inhibitors were designed and synthesized. For the inhibitor assay, some compounds were observed to have inhibitory activities, and the result indicated benzo[b]thiophene derivatives showed good inhibitory activities.
PartⅡCu(Ⅱ)-catalyzed cyclization reaction
Based on the review of synthetic method for furan derivatives, the intramolecular cyclization reaction of 2-propynyl-1,3-dicarbonyl compounds was explored. The reaction was performed using readily available materials (2-propynyl-1,3-dicarbonyl compounds), an inexpensive catalyst (Cu2+ salt) and ligand (PPh3) under very mild basic conditions in good to excellent yields. Then,5-methylene-4,5-dihydrofurans were easily converted into the corresponding furans under acidic conditions. The reaction provides a new approach to dihydrofurans in a direct, efficient and facile manner.
Part III Asymmetric synthesis of N-terminal amino acid component of Nikkomycin B
Based on the review of synthetic method for N-terminal amino acid component of Nikkomycin B, the asymmetric synthesis of N-terminal amino acid component of Nikkomycin B was explored.1,3-Dipolar cycloaddition reaction involving (E)-p-methoxycinnamyl alcohol and chiral nitrile oxide to construct the chiral isoxazoline was used as the key step. N-terminal amino acid component of Nikkomycin B was synthesized by subsequent functional group transformation. To our regret, the configuration is not consistent with the natural N-terminal amino acid component of Nikkomycin B.
Part IV Asymmetric total synthesis of a-Lycorane
Based on the review of synthetic method for Lycorane, the asymmetric synthesis of a-Lycorane was explored. Three stereogenic centers of a-Lycorane were effectively constructed with high diastereoselectivity and enantioselectivity via chiral thiourea catalyzing tandem Michael addition involving nitrostyrene and unsaturated ester. The key compound 101 was synthesized by subsequent functional group transformation, which established foundation for further asymmetric synthesis of a-Lycorane.
引文
1. Chopra, R.; Pu, Q. Q.; Elefanty, A. G. Biology of BCR-ABL. Blood Rev.1999,13,211-229.
2. Nowell P. C; Hungerford D. A. A Minute Chromosome in Human Chronic Granulocytic Leukemia. Science 1960,132,1497-1501.
3. Rowley J. D. A New Consistent Chromosomal Abnormality in Chronic Myelogenous Leukaemia Identified by Quinacrine Fluorescence and Giemsa Staining. Nature 1973,243, 290-293.
4. a) Ren R. B. Mechanisms of BCR-ABL in the Pathogenesis of Chronic Myelogenous Leukemia Nat. Rev. Cancer,2005,5,172-183. b) Faderl S.; Talpaz M.; Estrov Z.; Kantarjian H. M. Chronic Myelogenous Leukemia:Biology and Therapy. Ann. Intern. Med.1999,131, 207-219.
5. a) Kantarjian H. M.; Talpaz M.; Santini V.; Murgo A.; Cheson B.; O'Brien S. M. Homoharringtonine:History, Current Research, and Future Direction. Cancer,2001,92, 1591-1605. b) Nagar B.; Bornmann W.G.; Pellicena P.; Schindler T.; Veach D.R.; Miller W.T.; Clarkson B.; Kuriyan J. Crystal Structures of the Kinase Domain of c-Abl in Complex with the Small Molecule Inhibitors PD173955 and Imatinib (STI-571). Cancer Res.2002,62, 4236-4243.
6. a) Druker B. J.; Talpaz M.; Resta D. J.; Peng B.; Buchdunger, E.; Ford J. M.; Lydon N. B.; Kantarjian H.; Capdeville R.; Ohno-Jones S.; Sawyers C. L. Efficacy and Safety of Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia. N. Engl. J. Med. 2001,344,1031-1037.b)O'Dwyer M.E.;Mauro M.J.；Druker B.J.Recent Advancements in the Treatment of Chronic Myelogenous Leukemial.Annu.Rev.Med.2002,53,369-381.c) Weisberg E.；Manley P.W.；Breitenstein W.;Bruggen J.；Cowan-Jacob S.W.；Ray A.;Huntly B.；Fabbro D.；Fendrich G.；Hall-Meyers E.；Kung A.L.；Mestan J.；Daley G.Q.;Callahan L.； Catley L.;Cavazza C.;Azam M.；Neuberg D.；Wright R.D.;Gilliland D.G.;Griffin J.D.； Characterization of AMN 107,a Selective Inhibitor of Native and Mutant Bcr-Abl.Cancer Cell 2005,7,129-141.d)Weisberg E.;Manley P.;Mestan J.;Cowan-Jacob S.;Ray A.;Griffin J.D.AMN 107 Nilotinib:A Novel and Selective Inhibitor of Bcr-Abl.Br.J.Cancer 2006,94, 1765-1769.
7.Yokota A.；Kimura S.;Masuda S.；Ashihara E.；Kuroda J.；Sato K.；Kamitsuji Y.;Kawata E.； Deguchi Y.；Urasaki Y.；Terui Y.；Ruthardt M.；Ueda T.;Hatake K.；Inui K.-i.;Maekawa T. INNO-406,A Novel BCR-ABL/Lyn Dual Tyrosine Kinase Inhibitor,Suppresses the Growth of Ph+Leukemia Cells in the Central Nervous System,and Cyclosporine A Augments its in Vivo Activity.Blood 2007,109,306-314.
8.a)Buchdunger E.；Cioffi C.L.;Law N.;Stover D.；Ohno-Jones S.;Druker B.J.；Lydon N.B. Abl Protein-tyrosine Kinase Inhibitor STI571 Inhibits in Vitro Signal Transduction.Mediated by c-Kit and Platelet-derived Growth Factor Receptors.J.Pharmacol.Exp.Ther.2000,295, 139-145.b)Horio T.； Hamasaki T.；Inoue T.；Wakayama T.；Itou S.；Naito H.；Asaki T.； Hayase H.;Niwa T.Structural Factors Contributing to the Abl/Lyn Dual Inhibitory Activity of 3-Substituted Benzamide Derivatives.Bioorg.Med. Chem.Lett.2007,17,2712-2717.
9. Puttini M.;Redaelli S.;Moretti L.；Brussolo S.；Gunby R.H.;Mologni L.;Marchesi E.;Cleris L.；Donella-Deana A.；Drueckes P.；Sala E.；Lucchini V.；Kubbutat M.；Formelli F.；Zambon A.；Scapozza L.;Gambacorti-Passerini C.Characterization of Compound 584,an Abl Kinase Inhibitor with Lasting Effects.Haematologica 2008,93,653-661.
10.a)Arnold W.D.;Bounaud P.;Goseberg A.；Mcdonald I.;Steensma R.W.;Wilson M.E. W02006015123.b)Zhou T.;Parillon L.；Li F.；Wang Y.;Keats J.;Lamore S.;Xu Q.； Shakespeare W.;Dalgarno D.;Zhu X.Crystal Structure of the T315I Mutant of Abl Kinase. Chem.Biol.Drug.Des.2007,70,171-181.
11.McBride C.M.；Renhowe P.A.；Gesner T.G.；Jansen J.M.；Lin J.；Ma S.；Zhou Y.；Shafer C. M.3-Benzimidazol-2-yl-1H-Indazoles as Potent c-ABL Inhibitors.Bioorg.Med.Chem.Lett.
2006,16,3789-3792.
12. Manetti F.; Falchi F.; Crespan E.; Schenone S.; Maga G.; Botta M. N-(Thiazol-2-yl)-2-thiophene Carboxamide Derivatives as Abl Inhibitors Identified by a Pharmacophore-based Database Screening of Commercially Available Compounds. Bioorg. Med. Chem. Lett.2008, 18,4328-4331.
13. Manley P. W.; Cowan-Jacob S. W.; Jurgen M. Advances in the Structural Biology, Design and Clinical Development of Bcr-Abl Kinase Inhibitors for the Treatment of Chronic Myeloid Leukaemia. Biochimica et Biophysica Acta,2005,1754,3-13.
14. Lombardo L. J.; Lee F. Y.; Chen P.; Norris D.; Barrish J.C.; Behnia K.; Castaneda S.; Cornelius L.A.; Das J.; Doweyko A.M.; Fairchild C.; Hunt J.T.; Inigo I.; Johnston K.; Kamath A.; Kan D.; Klei H.; Marathe P.; Pang S.; Peterson R.; Pitt S.; Schieven G.L.; Schmidt R.J.; Tokarski J.; Wen M. L.; Wityak J.; Borzilleri R. M. Discovery of N-(2-Chloro-6-methyl-phenyl)-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), A Dual Src/Abl Kinase Inhibitor with Potent Antitumor Activity in Preclinical Assays. J. Med. Chem.2004,47:6658-6661.
15. a) Shah N. P. Dasatinib. Drugs Today 2007,43,5-12. b) Veach D. R.; Namavari M.; Pillarsetty N.; Santos E. B.; Beresten-Kochetkov T.; Lambek C.; Punzalan B. J.; Antczak C.; Smith-Jones P. M.; Djaballah H.; Clarkson B.; Larson S. M. Synthesis and Biological Evaluation of a Fluorine-18 Derivative of Dasatinib. J. Med. Chem.2007,50,5853-5857.
16. Golas J. M.; Arndt K.; Etienne C.; Jennifer M.; et al. SKI-606, a 4-Aniline-3-quinoline-carbonitrile Dual Inhibitor of Src and Abl Kinases, is a Potent Antiproliferative Agent against Chronic Myelogenous Leukemia Cells in Culture and Causes Regression of K562 Xenografts in Nude Mice. Cancer Res.2003,63,375-381.
17. Boschelli D.H.; Ye F.; Wang Y. D.; Dutia M.; Johnson S.L.; Wu B.; Miller K.; Powell D.W.; Yaczko D.; Young M.; Tischler M.; Arndt K.; Discafani C.; Etienne C.; Gibbons J.; Grod J.; Lucas J.; Weber J. M.; Boschelli F.; Optimization of 4-Phenylamino-3-quinolinecarbonitriles as Potent Inhibitors of Src Kinase Activity. J. Med. Chem.2001,44,3965-3967.
18. Schenone S.; Manetti F.; Botta M. Synthetic Src-kinase Domain Inhibitors and Their Structural Requirements. Anti-cancer Agents Med. Chem.2007,7,660-680.
19. a) Puttini M.; Coluccia A.M.; Boschelli F.; Cleris L.; Marchesi E.; Donella-Deana A.; Ahmed S.; Redaelli S.; Piazza R.; Magistroni V.; Andreoni F.; Scapozza L.; Formelli F.; Gambacorti-Passerini C. In Vitro and in Vivo Activity of SKI-606, A Novel Src-Abl Inhibitor, against Imatinib-Resistant Bcr-Abl+Neoplastic Cells. Cancer Res.2006,66, 11314-11322. b) Redaelli S.; Piazza R.; Rostagno R.; Magistroni V.; Perini P.; Marega M.; Gambacorti-Passerini C.; Boschelli F. Activity of Bosutinib, Dasatinib, and Nilotinib against Imatinib-resistant BCR/ABL Mutants. J. Clin. Oncol.2009,27,469-471.
20. a) Boschelli D. H. Wang Y. D.; Johnson S.; Wu B.; Ye F.; Barrios Sosa A. C.; Golas J. M, Boschelli F.7-Alkoxy-4-phenylamino-3-quinolinecarbonitriles as Dual Inhibitors of Src and Abl Kinases. J. Med. Chem.2004,47,1599-1601. b) Boschelli D. H.; Wu B.; Barrios Sosa A. C.; Durutlic H.; Ye F.; Raifeld Y.; Golas J. M.; Boschelli F. Identification of 7-Phenylaminothieno[3,2-b]pyridine-6-carbonitriles as a New Class of Src Kinase Inhibitors. J. Med. Chem.2004,47,6666-6668.
21. O'Hare T.; Pollock R.; Stoffregen E. P.; Keats J. A.; Abdullah O. M.; Moseson E. M.; Rivera V. M.; Tang H.; Metcalf C. A.; Bohacek R. S. Wang Y.; Sundaramoorthi R.; Shakespeare W. C.; Dalgarno D.; Clackson T.; Sawyer T. K.; Deininger M. W.; Druker B. J. Inhibition of Wild-type and Mutant Bcr-Abl by AP23464, a Potent ATP-based Oncogenic Protein Kinase Inhibitor:Implications for CML. Blood,2004,104,2532-2539.
22. Connolly C. J. C.; Hamby J. M.; Schroeder M. C.; Barvian M.; Lu G. H.; Panek R. L.; Amar A.; Shen C.; Kraker A. J.; Fry D. W.; Klohs W. D.; Doherty A. M. Discovery and Structure-activity Studies of a Novel Series of Pyrido[2,3-d]pyrimidine Tyrosine Kinase Inhibitors. Bioorg. Med. Chem. Lett.1997,7,2415-2420.
23. Huron D. R.; Gorre M. E.; Kraker A. J.; Sawyers C. L.; Rosen N.; Moasser M. M. A Novel Pyridopyrimidine Inhibitor of Abl Kinase is a Picomolar Inhibitor of Bcr-abl-driven K562 Cells and is Effective against STI571-resistant Bcr-abl Mutants. Clin. Cancer Res.2003,9, 1267-1273.
24. La Rosee P.; Corbin A. S.; Stoffregen E. P.; Deininger M. W.; Druker B. J. Activity of the Bcr-Abl Kinase Inhibitor PD 180970 against Clinically Relevant Bcr-Abl Isoforms that Cause Resistance to Imatinib Mesylate (Gleevec, STI571). Cancer Res.2002,62,7149-7153.
25. Noronha G.; Barrett K.; Boccia A.; Brodhag T.; Cao J.; Chow C. P.; Dneprovskaia E.; Doukas J.; Fine R.; Gong X.; Gritzen C.; Gu H.; Hanna E.; Hood J. D.; Hu S.; Kang X.; Key J.;
Klebansky B.; Kousba A.; Li G.; Lohse D.; Mak C. C.; McPherson A.; Palanki M. S.; Pathak V. P.; Renick J.; Shi F.; Soll R.; Splittgerber U.; Stoughton S.; Tang S.; Yee S.; Zeng B.; Zhao N,; Zhu H. Discovery of [7-(2,6-Dichlorophenyl)-5-Methylbenzo[1,2,4]triazin-3-yl]-[4-(2-Pyrrolidin-1-ylethoxy)phenyl]amine-A Potent, Orally Active Src Kinase Inhibitor with Antitumor Activity in Preclinical Assays. Bioorg. Med. Chem. Lett.2007,17,602-608.
26. Hu S. X.; Soll R.; Yee S.; Lohse D. L.; Kousba A.; Zeng B.; Yu X.; McPherson A.; Renick J.; Cao J.; Tabak A.; Hood J.; Doukas J.; Noronha G.; Martin M. Metabolism and Pharmacokinetics of a Novel Src Kinase Inhibitor TG100435 [7-(2,6-Dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine) and Its Active N-Oxide Metabolite TG100855([7-(2,6-Dichloro-phenyl)-5-methylbenzo[1,2,4] triazin-3-yl]-{4-[2-(1-oxy-pyrrolidin-1-yl)-ethoxy]-phenyl}-amine). Drug Metab. Dispos. 2007,35,929-936.
27. Missbach M.; Jeschke M.; Feyen J.; Miiller K.; Glatt M.; Green J.; Susa M. A Novel Inhibitor of the Tyrosine Kinase Src Suppresses Phosphorylation of its Major Cellular Substrates and Reduces Bone Resorption in Vitro and in Rodent Models in Vivo. Bone,1999,24,437-449.
28. Recchia I.; Rucci N.; Funari A.; Migliaccio S.; Taranta A.; Longo M.; Kneissel M.; Susa M.; Fabbro D.; Teti A. Reduction of c-Src Activity by Substituted 5,7-Diphenyl-pyrrolo [2,3-d]pyrimidines Induces Osteoclast Apoptosis in Vivo and in Vitro. Involvement of ERK1/2 Pathway. Bone 2004,34,65-79.
29. Hanke J. H.; Gardner J. P.; Dow R. L.; Changelian P. S.; Brissette W. H.; Weringer E. J.; Pollok B. A.; Connelly P. A. Discovery of a Novel, Potent, and Src Family-selective Tyrosine Kinase Inhibitor. Study of Lck-and FynT-dependent T Cell Activation. J. Biol. Chem.1996,271:695-701.
30. Tatton L.; Morley G. M.; Chopra R.; Khwaja A. The Src-selective Kinase Inhibitor PP1 also Inhibits Kit and Bcr-Abl Tyrosine Kinases.J. Biol. Chem.2003,278,4847-4853.
31. a) Harrington E.A.; Bebbington D.; Moore J.; Rasmussen R. K.; Ajose-Adeogun A. O.; Nakayama T.; Graham J. A.; Demur C.; Hercend T.; Diu-Hercend A.; Su M.; Golec J. M. C.; Miller K. M. VX-680, a Potent and Selective Small-molecule Inhibitor of the Aurora Kinases, Suppresses Tumor Growth in Vivo. Nat. Med.2004,10,262-267. b) Akahane D; Tauchi T; Okabe S; Nunoda K; Ohyashiki K. Activity of a Novel Aurora Kinase Inhibitor against the
T315I Mutant Form of BCR-ABL:in Vitro and in Vivo Studies. Cancer Sci.2008,99, 1251-1257.
32. Manetti F.; Brullo C.; Magnani M.; Mosci F.; Chelli B.; Crespan E.; Schenone S.; Naldini A.; Bruno O.; Trincavelli M. L.; Maga G.; Carraro F.; Martini C.; Bondavalli F.; Botta M. Structure-based Optimization of Pyrazolo[3,4-d]pyrimidines as Abl Inhibitors and Antiproliferative Agents Toward Human Leukemia Cell Lines. J. Med. Chem.2008,51, 1252-1259.
33. a) Gumireddy K; Baker S. J; Cosenza S. C.; John P.; Kang A. D.; Robell K.A.; Reddy M. V. R.; Reddy E. P. A Non-ATP-competitive Inhibitor of BCR-ABL Overrides Imatinib Resistance. Proc. Natl. Acad. Sci.2005,102,1992-1997.
34. a) Adria'n F. J.; Ding Q.; Sim T.; Velentza A.; Sloan C.; Liu Y.; Zhang G.; Hur W.; Ding S.; Manley P.; Mestan J.; Fabbro D.; Gray N. S. Allosteric Inhibitors of Bcr-abl-dependent Cell Proliferation. Nat. Chem. Biol.2006,2,95-102. b) Owers J. T.; Azam M.; Gray S. N.; Daley G. Q. Dissection of Bcr-abl Structural Domains Relating Tokinase Auto-inhibition Using a Forward Mutational Screen with the Non-ATP Competitive Inhibitor GNF-2. Blood (ASH Annual Meeting Abstracts),2007,10,021.
35. Bhatia R.; Holtz M.; Niu N.; Gray R.; Snyder D. S.; Sawyers C. L.; Arber D. A.; Slovak M. L.; Forman S. J. Persistence of Malignant Hematopoietic Progenitors in Chronic Myelogenous Leukemia Patients in Complete Cytogenetic Remission Following Imatinib Mesylate Treatment. Blood,2003,101,4701-4707.
36. Thomas J.; Wang L.; Clark R. E.; Pirmohamed M. Active Transport of Imatinib into and out of Cells:Implications for Drug Resistance. Blood,2004,104,3739-3745.
37. a) La R. P.; Corbin A. S.; Stoffregen E. P.; Deininger M. W.; Druker B. J. Activity of the Bcr-Abl Kinase Inhibitor PD 180970 against Clinically Relevant Bcr-Abl Isoforms that Cause Resistance to Imatinib Mesylate (Gleevec, STI571). Cancer Res.2002,62,7149-7153. b) Corbin A. S.; Buchdunger E.; Pascal F.; Druker B. J. Analysis of the Structural Basis of Specificity of Inhibition of the Abl Knase by STI571. J. Biol. Chem.2002,277, 32214-32219.
38. Lu J.; Yang B.; Bai Y. Microwave Irradiation Synthesis of 2-Substituted Benzimidazoles Using PPA as a Catalyst under Solvent-free Conditions. Synth. Commum.2002,32,3703-3709.
39. Nadipuram A. K.; David W. M.; Kumar D.; Kerwin S. M. Synthesis and Thermolysis of Heterocyclic 3-Aza-3-ene-1,5-diynes. Org. Lett.2002,4,4543-4546.
40. Siva A.; Murugan E. Synthesis and Characterization of Novel Multi-site Phase Transfer Catalyst and Its Catalytic Efficiency for Dichlorocarbene Addition to Citral. Journal of Molecular Catalysis A:Chemical 2005,241101-110.
41. Phillips W. G.; Ratts K. W. Chemistry of a, a-Dichlorosulfenyl Chlorides.J. Org. Chem.1972, 37,1526-1531.
42. Tatsuo H. Oxidations by Thionyl Chloride. VI. Mechanism of the Reaction with Cinnamic Acids. J. Org. Chem.1975,40,3037-3045.
1. Nakanishi, K. Natural Products Chemistry 1974, Kodansha, Ltd.:Tokyo.
2. a) Maeda S.; Masuda H.; Tokoroyama T. Studies on the Preparation of Bioactive Lignans by Oxidative Coupling Reaction. III. Synthesis of Polyphenolic Benzofuran and Coumestan Derivatives by Oxidative Coupling Reaction of Methyl (E)-3-(4-Hydroxy-2-methoxyphenyl) propenoate and Their Inhibitory Effect on Lipid Peroxidation. Chem. Pharm. Bull.1994,42, 2536-2545. b) Huang H. C.; Chamberlain T. S.; Seibert K.; Koboldt C. M.; Isakson P. C.; Reitz D. B. Diaryl Indenes and Benzofurans:Novel Classes of Potent and Selective Cyclooxygenase-2 Inhibitors. Bioorg. Med. Chem. Lett.1995,5,2377-2380. c) Sato M.; Grese T. A.; Dodge J. A.; Henry U. B.; Charles H. T. Emerging Therapies for the Prevention or Treatment of Postmenopausal Osteoporosis. J. Med. Chem.1999,42,1-24.
3. a) Marshall J. A.; Robinson E. D. A Mild Method for the Synthesis of Furans. Application to 2,5-Bridged Furano Macrocyclic Compounds. J. Org. Chem.1990,55,3450-3451. b) Marshall J. A.; Wang X.-J. Synthesis of Furans by Silver(Ⅰ)-promoted Cyclization of Allenyl
Ketones and Aldehydes.J. Org. Chem.1991,56,960-969. c) Marshall J. A.; Bartley G. S. Observations Regarding the Ag(I)-catalyzed Conversion of Allenones to Furans. J. Org. Chem.1994,59,7169-7171.
4. Marshall J. A.; Wang X.-J. Synthesis of 2,5-Furanocycles through Intraannular Cyclization of Macrocyclic Allenones. J. Org. Chem.1992,57,3387-3396.
5. a) Hashmi A. S. K. Transition Metal Catalyzed Dimerization of Allenyl Ketones. Angew. Chem. Int. Ed.1995,34,1581-1583. b) Hashmi A. S. K.; Ruppert T.L.; Knofel T.; Bats J. W. C-C-Bond Formation by the Palladium-Catalyzed Cycloisomerization/Dimerization of Terminal Allenyl Ketones:Selectivity and Mechanistic Aspects. J. Org. Chem.1997,62, 7295-7304.
6. Hashmi A. S. K.; Schwarz L.; Choi J. H.; Frost T. M. A New Gold-catalyzed C-C Bond Formation. Angew. Chem. Int. Ed.2000,39,2285-2288.
7. Ma S. M.; Zhang J. L.; Lu L. H. Pd0-catalyzed Coupling Cyclization Reaction of Aryl or lAlkenyl Halides with 1,2-Allenyl Ketones:Scope and Mechanism. An Efficient Assembly of 2,3,4-,2,3,5-Tri-and 2,3,4,5-Tetra-substituted Furans. Chem. Eur. J.2003,9,2447-2456.
8. Peng L.-L.; Zhang X.; Ma M.; Wang J.-B. Transition-metal-catalyzed Rearrangement of Allenyl Sulfides:A Route to Furan Derivatives. Angew. Chem., Int. Ed.2007,46,1905-1908.
9. Sieller B.; Bruneau C.; Dixneuf P. H. Novel Ruthenium-catalysed Synthesis of Furan Derivatives via Intramolecular Cyclization of Hydroxy Enynes.J. Chem. Soc. Chem. Commun.1994,493-494.
10. Sieller B.; Bruneau C.; Dixneuf P. H. Synthesis of Furans by Cyclization of 2-En-4-yn-l-ols in the presence of Ruthenium and Palladium Catalysts. Tetrahedron 1995,51,13089-13102.
11. Marshall J. A.; Sehon C. A. Synthesis of Furans and 2,5-Dihydrofurans by Ag(I)-Catalyzed Isomerization of Allenones, Alkynyl Allylic Alcohols, and Allenylcarbinols.J. Org. Chem. 1995,60,5966-5968.
12. Gabriele B.; Salerno G.; De Pascali F.; Costa M.; Chiusoli G. P. An Efficient and General Synthesis of Furan-2-Acetic Esters by Palladium-catalyzed Oxidative Carbonylation of (Z)-2-En-4-yn-l-ols.J. Org. Chem.1999,64,7693-7699.
13. Qing F. L.; Gao W, Z.; Ying J. W. Synthesis of 3-Trifluoroethylfurans by Palladium-catalyzed Cyclization-isomerization of (Z)-2-Alkynyl-3-trifluoromethyl Allylic Alcohols. J. Org. Chem.2000,65,2003-2006.
14. Liu Y.; Song F.; Liu M.; Yan B. Gold-catalyzed Cyclization of (Z)-2-en-4-yn-l-ols:Highly Efficient Synthesis of Fully Substituted Dihydrofurans and Furans. Org. Lett.2005,7, 5409-5412.
15. Utimoto K. Palladium Catalyzed Synthesis of Heterocycles. Pure Appl. Chem.1983,55, 1845-1852.
16. Pale P.; Chuche J. Silver Assisted Heterocyclization of Acetylenic Compounds. Tetrahedron Lett.1987,28,6447-6448.
17. McDonald F. E.; Connolly C. B.; Gleason M. M.; Towne T. B.; Treiber K. D. A New Synthesis of 2,3-Dihydrofurans:Cycloisomerization of Alkynyl Alcohols to Endocyclic Enol Ethers. J. Org. Chem.1993,58,6952-6953.
18. McDonald F. E.; Schultz C. C. Mechanism of Molybdenum Pentacarbonyl-catalyzed Cyclizations of Alkynols and Epoxyalkynes. J. Am. Chem. Soc.1994,116,9363-9364.
19. a) Dulcere J.-P.; Dumez E. Tandem Oxa-Michael Addition-SN2 Substitution of 4-Chlorobut-2-yn-l-ol with Nitroalkenes:a Total Allylic 1,3-Strain-controlled Diastereoselective Synthesis of 3-Vinylidenetetrahydrofurans. Chem. Commun.1997, 971-972. b) Dumez E.; Rodriguez J.; Dulcere J.-P. Studies towards a New One-pot Heterocyclization:Bu'OK-promoted Oxa-and Aza-Michael Addition-intramolecular Carbocyclization of Prop-2-ynyl alcohols and Amines with a, β-Disubstituted Nitroalkenes. Chem. Commun.1997,1831-1832.
20. Clique B.; Monteiro N.; Balme G. A One Pot Synthesis of Various Pyrrolidines via a Tandem Michael Addition-transition Metal-catalysed Cyclisation Reaction. Tetrahedron Lett.1999, 40,1301-1304.
21. Morikawa S.; Yamazaki S.; Furusaki Y.; Amano N.; Zenke K.; Kakiuchi K. Zinc-and Indium-promoted Conjugate Addition-cyclization Reactions of Ethenetricarboxylates with Propargylamines and Alcohol:Novel Methylenepyrrolidine and Methylenetetrahydrofuran Syntheses. J. Org. Chem.2006,71,3540-3544.
22. Cadierno V.; Gimeno J.; Nebra N. A Novel Propargylation/Cycloisomerization Tandem Process Catalyzed by a Ruthenium(II)/Trifluoroacetic Acid System:One-pot Entry to Fully Substituted Furans from Readily Available Secondary Propargylic Alcohols and 1,3-Dicarbonyl Compounds. Adv. Synth. Catal.2007,349,382-394.
23. a) Tsuji J.; Watanabe H.; Minami I.; Shimizu I. Novel Palladium-catalyzed Reactions of Propargyl Carbonates with Carbonucleophiles under Neutral Conditions. J. Am. Chem. Soc. 1985,107,2196-2198. b) Minami I.; Yuhara M.; Watanabe H.; Tsuji J. A New Furan Annulation Reaction by the Palladium-catalyzed Reaetion of 2-Alkynyl Carbonates or 2-(1-Alkynyl)oxiranes with β-Keto Esters. J. Organomet. Chem.1987,334,225-242.
24. Aurrecoechea J. M.; Solay-Ispizua M. Synthesis of Furans from Epoxypropargyl Esters. Heterocycles 1994,37,223-226.
25 Aurrecoechea J. M.; Perez E.; Solay M. Synthesis of Trisubstituted Furans from Epoxypropargyl Esters by Sequential SmI2-Promoted Reduction-elimination and Pd(II)-catalyzed Cycloisomerization. J. Org. Chem.2001,66,564-569
26. Hashmi A. S. K.; Sinha P. Gold Catalysis:Mild Conditions for the Transformation of Alkynyl Epoxides to Furans. Adv. Synth. Catal.2004,346,432-438.
27. Fukuda Y.; Shiragami H.; Utimoto K.; Nozaki H. Synthesis of Substituted Furans by Palladium-catalyzed Cyclization of Acetylenic Ketones. J. Org. Chem.1991,56,5816-5819.
28. Arcadi A.; Cacchi S.; Laroek R. C.; Marinelli F. The Palladium-catalysed Synthesis of 2,3,5-Trisubstituted Furans from 2-Propargyl-1,3-dicarbonyl Compounds and Vinylic or Aryl Triflates or Halides. Tetrahedron Lett.1993,34,2813-2816.
29. Cacchi S.; Fabrizi G.; Moro L. Synthesis of 3,5-Disubstituted Furans via Palladium-Catalyzed Annulation of Alkyl 3-Oxo-6-heptynoates. J. Org. Chem.1997,62,5327-5332.
30. Arcadi A.; Rossi E. Palladium-catalyzed Domino Reaction of 3-Acetyl-5-hexyn-2-one with Aryl Iodides under Carbon Monoxide. Tetrahedron Lett.1996,37,6811-6814.
31. Arcadi A.; Cerichelli G.; Chiarini M.; Giuseppe S. D.; Marinelli F. Sequential Alkylation/Transition Metal Catalyzed Annulation Reactions of 1,3-Dicarbonyl Compounds with Propargyl Bromide. Tetrahedron Lett.2000,41,9195-9198.
32. Kato K.; Yamamoto Y.; Akita H. Palladium(II)-mediated Cyclization-carbonylation of 4-yn-l-ones:Facile Access to 2-Cyclopentenone Carboxylates. Tetrahedron Lett.2002,43, 4915-4917.
33. Wipf P.; Soth M. J. Synthesis of the C(1)-C(18) Segment of Lophotoxin and Pukalide. Control of 2-Alkenylfuran (E/Z)-configuration. Org. Lett.2002,4,1787-1790
34. Imagawa H.; Kurisaki T.; Nishizawa M. Mercuric Triflate-catalyzed Synthesis of 2-Methylfurans from 1-Alkyn-5-ones. Org. Lett.2004,6,3679-3681.
35. Asao N.; Nogami T.; Takahashi K.; Yamamoto Y. Pd(II) Acts Simultaneously as a Lewis Acid and as a Transition-metal Catalyst:Synthesis of Cyclic Alkenyl Ethers from Acetylenic Aldehydes. J. Am. Chem. Soc.2002,124,764-765.
36. Ma S.; Gao W. Efficient Synthesis of 4-(2'-Alkenyl)-2,5-dihydrofurans via PdCl2-catalyzed Coupling-cyclization Reaction of 2,3-Allenols with Allylic Halides. Tetrahedron Lett.2000, 41,8933-8936.
37. Ma S.; Zhao S. Pd(0)-Catalyzed Insertion-cyclization Reaction of 2,3-Allenols with Aryl or Alkenyl Halides. Diastereoselective Synthesis of Highly Optically Active trans-2,3-Disubstituted Vinylic Oxiranes.J. Am. Chem. Soc.1999,121,7943-7944.
38. Tsuji J.; Watanabe H.; Minami I.; Shimizu I. Novel Palladium-catalyzed Reactions of Propargyl Carbonates with Carbonucleophiles under Neutral Conditions.J. Am.Chem. Soc. 1985,107,2196-2198.
39. Greeves N.; Torode J. S. Synthesis of Phenylthiomethyl Substitution Furans by Lewis Acid Catalysed Substitution. Synthesis 1993,11,1109-1112.
40. Wang H.-F.; Yang T.; Xu P.-F.; Dixon D. J. Base and Copper (I) Catalyzed Mannich, Alkyne Hydroamination Cascades for the Direct Synthesis of 2-Methylenepyrrolidines. Chem. Commun.2009,3916-3918
1. Isono K. Nucleoside Antibiotics, Structure, Biological Activity and Biosynthesis. J Antibiot. 1988,41,1711-1739.
2. Dahn U; Hagenmaier H; Hohne H; Konig, W. A.; Wolf, G.; Zahner, H. Stoffwechselprodukte von Mikroorganismen.154. Mitt. Nikkomycin, ein neuer Hemmstoff der Chitinsynthese bei Pilzen. Arch Microbiol.1976,107,143-160.
3. (a) Hagenmaier H.; Keckeisen A.; Zahner H.; Konig W. A. Stoffwechselprodukte von Mikroorganismen,182. Aufklarung der Struktur des Nucleosidantibiotikums Nikkomycin X. Liebigs Ann. Chem.1979,1494-1502. (b) Konig W. A.; Hass W.; Dehler W.; Fiedler H. P.; Zahner H. Strukturaufkarung und Partialsynthese des Nucleosidantibiotikums Nikkomycin B. Liebigs Ann. Chem.1980,622-628. (c) Hagenmaier H.; Keckeisen A.; Dehler W.; Fiedler H. P.; Zahner H.; Konig W. A. Stoffwechselprodukte von Mikroorganismen,199. Konstitutionsaufklarung der Nikkomycine I, J, M und N. Liebigs Ann. Chem.1981, 1018-1024.
4. a) Fiedler H -P.; Kurth R.; Langharig J.; Delzer J.; Zahner H. Nikkomycins:Microbial Inhibitors of Chitin Synthase. J. Chem. Technol. Biotechno.1982,32,271-280. b) Cabib E. Differential Inhibition of Chitin Synthetases 1 and 2 from Saccharomyces Cerevisiae by Polyoxin D and Nikkomycins. Antimicrob Agents Chemoth 1991,35,170-173.
5. Hector R.; Zimmer B.; Pappagianis D. Evaluation of Nikkomycins X and Z in Murine Models of Coccidiomycosis, Histoplasmosis, and Blastomycosis. Antimicrob Agents Chemothe.1990,
34,587-593.
6. Zimmermann G.; Hass W.; Faasch H.; Schmalle H.; Konig W. A. Synthese reiner Stereoisomerer der N-terminalen Aminosaure von Nikkomycin B. Leibegs Ann. Chem.1985, 2165-2177.
7. Jager V.; Grund H.; Buss V.; Schwab W.; Muller I.; Schohe R.; Franz R.; Ehrler R. Isoxazolines Key Intermediates for Synthesis of some Naturally Occuring Amino Compounds. Bull. Soc. Chim. Belg.1983,92,1039-1054.
8. Jager V.; Buβ V.; Schwab W. Synthesis via Isoxazolines Ⅲ. Diasereoselective Synthesis of y-Amino-alcohols with 2 and 3 Chrial Centres. Tetrahedron Lett.1978,3133-3136
9. Michael J. M.; Steven M. W. Intramolecular Cycloaddition Reactions of N-Acyl Imines. A Stereoselective Approach to the N-Terminal Amino Acid Component of Nikkomycin B.J. Org. Chem.1988,53,850-854
10. Brown H. C.; Bhat K. S. Chiral Synthesis via Organoboranes.7. Diastereoselective and Enantioselective Synthesis of Erythro-and Threo-.Beta.-Methylhomoallyl Alcohols via Enantiomeric (Z) and (E)-Crotylboranes. J. Am. Chem. SOC.1986,108,5919-5923.
11. a) Anthony G. M.; Barrett J.; Suzanne A. L. The Total Synthesis of Nikkomycin B. J. Org. Chem.1990,55,5818-5820. b) Barrett A. G. M.; Lebold S. A. Applications of Crotyldiisopinocampheylboranes in Synthesis:The Total Synthesis of Nikkomycin B. J. Org. Chem.1991,56,4875-4884.
12. Barrett A. G. M.; Dhanak D.; Lebold S. A.; Russell M. A. Alpha.-Oximino Amide Trianions in the Stereoselective Synthesis of Isoxazolines and Gamma.-Hydroxy Alpha.-Amino acids. J. Org. Chem.1991,56,1894-1901.
13. Barluenga J.; Olano B.; Fustero S.; Foces-Foces M. C.; Cano F. H. Diastereo-and Enantio-selective Synthesis of Dihydro-and Tetrahydro-pyrimidines. A New Strategy for the Asymmetric Synthesis of β-Amino Ketones and γ-Amino Alcohols. J. Chem. Soc. Chem. Commun.1988,410b.
14. Barluenga J.; Viado A. L.; Aguilar E.; Fustero S.; Olano B.1,3-Amino Alcohols from 4-Amino-l-aza Dienes. Diastereo-and Enantioselective Approach to the Four Diastereoisomers of the N-Terminal Amino Acid Component of Nikkomycins B and Bx. J. Org. Chem.1993,58,5972-5975
15. Palomo C.; Aizpurua J. M.; Garcia J. M.; Iturburu M.; Odriozola J. M. Concise General Synthesis of.alpha., gamma.-Disubstituted beta.-Amino Ketones from beta.-Lactams. J. Org. Chem.1994,59,5184-5188
16. Kronenthal D. R.; Han C. Y.; Taylor M. K. Oxidative N-Dearylation of 2-Azetidinones. p-Anisidine as a Source of Azetidinone Nitrogen. J. Org. Chem.1982,47,2765-2768.
17. Baldwin J. E.; Adlington R. M.; Gollins D. W.; Schofield C. J. Stereospecific Synthesis of Dealanylalahopcin. Tetrahedron 1990,46,4733-4748.
18. Akita H.; Chen C. Y.; Uchida K. A Formal Total Synthesis of Nikkomycin B Based on Enzymatic Resolution of a Primary Alcohol Possessing Two Stereogenic Centers. Tetrahedron:Asymmetry 1995,6,2131-2134.
19. Kapeller H.; Jary W. G.; Hayden W.; Griengl H. A Chemo-enzymatic Synthesis of the N-Terminal Amino acid Lactone of Nikkomycin B. Tetrahedron:Asymmetry 1997,8, 245-251.
20. Tamura O.; Mita N.; Kusaka N.; Suzuki H.; Sakamoto M. Intramolecular Cycloaddition of a-Allyloxycarbonylnitrone Bearing a Chiral Sugar Auxiliary:A Short-step Synthesis of the N-Terminal Amino Acid Component of Nikkomycin Bz. Tetrahedron Letter 1997,38, 429-432.
21. Palomo C.; Maizpurua J.; Gracenea J. J. Diastereoselective Conjugate Reduction and Enolate Trapping with Glyoxylate Imines:A Concise Approach to α-Lactams that Involves a Ternary Combination of Components. J. Org. Chem.1999,64,1693-1698
22. Hayashi Y.; Tsuboi W.; Ashimine I.; Urushima T.; Shoji M.; Sakai K. The Direct and Enantioselective, One-pot, Three-component, Cross-Mannich Reaction of Aldehydes. Angew. Chem., Int. Ed.2003,42,3677-3680.
23. Hayashi Y.; Urushima T.; Shin M.; Shoji M. The Stereoselective Synthesis of α-Substituted β-Amino Secondary Alcohols Based on the Proline-mediated, Asymmetric, Three-component Mannich Reaction and Its Application to the Formal Total Synthesis of Nikkomycins B and Bx. Tetrahedron 2005,61,11393-11404.
1.梁生旺.生物碱类成分分析,1999,学苑出版社,北京.
2. Lizuka N.; Miyamoto K.; Okita K.; Tangoku A.; Hayashi H.; Yosino S.; Abe T.; Morioka T.; Hazama S.; Oka M. Inhibitory Effect of Coptidis Rhizoma and Berberine on the Proliferation of Human Esophageal Cancer Cell Lines. Cancer Letters 2000,148,19-25.
3.洪山海,马广恩.石蒜科生物碱的研究Ⅱ.紫花石蒜和其他两种石蒜中的生物碱及新生物碱紫花石蒜碱.药学学报,1964,11,1-14.
4. a) Gabrielsen B.; Monath T. P.; Huggins J. W.; Kefauver D. F.; Pettit G. R.; Groszek G.; Hollingshead M.; Kirsi J. J.; Shannon W. M.; Schubert E. M.; DaRe J.; Ugarkar B.; Ussery M. A.; Phelan M. J. Antiviral (RNA) Activity of Selected Amaryllidaceae Isoquinoline Constituents and Synthesis of Related Substances.J. Nat. Prod.1992,55,1569-1581. b) Renard Nozaki J.; Kim T.; Imakura Y.; et al. Effect of Alkaloids Isolated from Amaryllidaceae on Herpes Simplex Virus. Res. Virol.1989,140,115-128.
5.贾献慧；周铜水；郑颖；刘汉清.石蒜科植物生物碱成分的药理学研究.中医药学刊.2001,19,573-574.
6. Matveenko M.; Kokas O. J.; Banwell M. G.; Willis A.; Chemoenzymatic Approaches to Lycorine-type Amaryllidaceae Alkaloids:Total Syntheses of ent-Lycoricidine, 3-epi-ent-Lycoricidine, and 4-Deoxy3-epi-ent-lycoricidine. Org Lett.2007,9,3683-3685.
7. Backvall J. E.; Andersson P. G.; Stone G. B.; GoZoll A. Syntheses of (+/-)-alpha.-and (+/-)-gamma.-Lycorane via a Stereocontrolled Organopalladium Route.J. Org. Chem.1991, 56,2988-2993.
8. Oppolzer W.; Spivey A. C.; Bochet C. G. Suprafaciality of Thermal N-4-Alkenylhydroxy lamine Cyclizations:Syntheses of (+/-)-alpha.-Lycorane and (+)-Trianthine. J. Am. Chem. SOC.1994,116,3139-3140.
9. Rigby J. H.; Mateo M. E. Total Synthesis of (±)-a-Lycorane and 4,5-Dehydroanhydrolycorine. Tetrahedron 1996,52,10569-10582.
10. Tamura O.; Matsukida H.; Toyao A.; Takeda Y.; Ishibashi H.. Is an Iodine Atom Almighty as
a Leaving Group for Bu3SnH-Mediated Radical Cyclization? The Effect of a Halogen Atom on the 5-Endo-trig Radical Cyclization of N-Vinyl-a-Halo Amides. J. Org. Chem.2002,67, 5537-5545.
11. Miranda L. D.; Zard S. Z. A Short Synthesis of the Erythrina Skeleton and of (±)-a-Lycorane. Org. Lett.2002,4,1135-1138.
12. Yasuhara T.; Nishimura K.; Yamashita M.; Fukuyama N.; Yamada K.-I.; Muraoka O.; Tomioka K. Total Synthesis of (±)-a-and β-Lycoranes by Sequential Chemoselective Conjugate Addition-Stereoselective Nitro-Michael Cyclization of an ω-Nitro-α,β,ψ,ω-unsaturated Ester. Org. Lett.2003,5,1123-1126.
13. Dong L.; Xu Y.-J.; Yuan W.-C.; Cui X.; Cun L.-F.; Gong L.-Z. Rhodium-catalyzed Asymmetric Nitroallylation of Arylmetallics with Cyclic nitroallyl Acetates and Applications in Organic Synthesis. Eur. J. Org. Chem.2006,4093-4105.
14. Banwell M. G.; Harvey J. E.; Wu D. C. R. H. W. Electrocyclic Ring-opening/π-Allyl Cation Cyclization Reaction Sequences Involving gem-Dihalocyclopropanes as Substrates: Application to Syntheses of (±)-, (+)-, and (-)-γ-Lycorane. J. Org. Chem.2000,65, 4241-4250.
15. Gao S.; Tu Y. Q.; Song Z.; Wang A.; Fan X.; Jiang Y. A General and Efficient Strategy for 7-Aryloctahydroindole and cis-3a-Aryloctahydroindole Alkaloids:Total Syntheses of ((+/-)-r-Lycorane and ((+/-)-Crinane. J. Org. Chem.2005,70,6523-6525.
16. Dong L.; Xu Y.-J.; Cun L.-F.; Cui X.; Mi A.-Q.; Jiang Y.-Z.; Gong L.-Z. Asymmetric Nitroallylation of Arylboronic Acids with Nitroallyl Acetates Catalyzed by Chiral Rhodium Complexes and Its Application in a Concise Total Synthesis of Optically Pure (+)-r-Lycorane. Org. Lett.2005,7,4285-4288.
17. Chapsal B. D.; Ojima I. Total Synthesis of Enantiopure (+)-r-Lycorane Using Highly Efficient Pd-Catalyzed Asymmetric Allylic Alkylation. Org. Lett.2006,8,1395-1398.
18. Fujioka H.; Murai K.; Ohba Y.; Hirose H.; Kita Y. Intramolecular Bromo-amination of 1,4-Cyclohexadiene Aminal:One-pot Discrimination of Two Olefins and Concise Asymmetric Synthesis of (-)-r-Lycorane. Chem. Commun.2006,832-834.
2. Nowell P. C; Hungerford D. A. A Minute Chromosome in Human Chronic Granulocytic Leukemia. Science 1960,132,1497-1501.
3. Rowley J. D. A New Consistent Chromosomal Abnormality in Chronic Myelogenous Leukaemia Identified by Quinacrine Fluorescence and Giemsa Staining. Nature 1973,243, 290-293.
4. a) Ren R. B. Mechanisms of BCR-ABL in the Pathogenesis of Chronic Myelogenous Leukemia Nat. Rev. Cancer,2005,5,172-183. b) Faderl S.; Talpaz M.; Estrov Z.; Kantarjian H. M. Chronic Myelogenous Leukemia:Biology and Therapy. Ann. Intern. Med.1999,131, 207-219.
5. a) Kantarjian H. M.; Talpaz M.; Santini V.; Murgo A.; Cheson B.; O'Brien S. M. Homoharringtonine:History, Current Research, and Future Direction. Cancer,2001,92, 1591-1605. b) Nagar B.; Bornmann W.G.; Pellicena P.; Schindler T.; Veach D.R.; Miller W.T.; Clarkson B.; Kuriyan J. Crystal Structures of the Kinase Domain of c-Abl in Complex with the Small Molecule Inhibitors PD173955 and Imatinib (STI-571). Cancer Res.2002,62, 4236-4243.
6. a) Druker B. J.; Talpaz M.; Resta D. J.; Peng B.; Buchdunger, E.; Ford J. M.; Lydon N. B.; Kantarjian H.; Capdeville R.; Ohno-Jones S.; Sawyers C. L. Efficacy and Safety of Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia. N. Engl. J. Med. 2001,344,1031-1037.b)O'Dwyer M.E.;Mauro M.J.；Druker B.J.Recent Advancements in the Treatment of Chronic Myelogenous Leukemial.Annu.Rev.Med.2002,53,369-381.c) Weisberg E.；Manley P.W.；Breitenstein W.;Bruggen J.；Cowan-Jacob S.W.；Ray A.;Huntly B.；Fabbro D.；Fendrich G.；Hall-Meyers E.；Kung A.L.；Mestan J.；Daley G.Q.;Callahan L.； Catley L.;Cavazza C.;Azam M.；Neuberg D.；Wright R.D.;Gilliland D.G.;Griffin J.D.； Characterization of AMN 107,a Selective Inhibitor of Native and Mutant Bcr-Abl.Cancer Cell 2005,7,129-141.d)Weisberg E.;Manley P.;Mestan J.;Cowan-Jacob S.;Ray A.;Griffin J.D.AMN 107 Nilotinib:A Novel and Selective Inhibitor of Bcr-Abl.Br.J.Cancer 2006,94, 1765-1769.
7.Yokota A.；Kimura S.;Masuda S.；Ashihara E.；Kuroda J.；Sato K.；Kamitsuji Y.;Kawata E.； Deguchi Y.；Urasaki Y.；Terui Y.；Ruthardt M.；Ueda T.;Hatake K.；Inui K.-i.;Maekawa T. INNO-406,A Novel BCR-ABL/Lyn Dual Tyrosine Kinase Inhibitor,Suppresses the Growth of Ph+Leukemia Cells in the Central Nervous System,and Cyclosporine A Augments its in Vivo Activity.Blood 2007,109,306-314.
8.a)Buchdunger E.；Cioffi C.L.;Law N.;Stover D.；Ohno-Jones S.;Druker B.J.；Lydon N.B. Abl Protein-tyrosine Kinase Inhibitor STI571 Inhibits in Vitro Signal Transduction.Mediated by c-Kit and Platelet-derived Growth Factor Receptors.J.Pharmacol.Exp.Ther.2000,295, 139-145.b)Horio T.； Hamasaki T.；Inoue T.；Wakayama T.；Itou S.；Naito H.；Asaki T.； Hayase H.;Niwa T.Structural Factors Contributing to the Abl/Lyn Dual Inhibitory Activity of 3-Substituted Benzamide Derivatives.Bioorg.Med. Chem.Lett.2007,17,2712-2717.
9. Puttini M.;Redaelli S.;Moretti L.；Brussolo S.；Gunby R.H.;Mologni L.;Marchesi E.;Cleris L.；Donella-Deana A.；Drueckes P.；Sala E.；Lucchini V.；Kubbutat M.；Formelli F.；Zambon A.；Scapozza L.;Gambacorti-Passerini C.Characterization of Compound 584,an Abl Kinase Inhibitor with Lasting Effects.Haematologica 2008,93,653-661.
10.a)Arnold W.D.;Bounaud P.;Goseberg A.；Mcdonald I.;Steensma R.W.;Wilson M.E. W02006015123.b)Zhou T.;Parillon L.；Li F.；Wang Y.;Keats J.;Lamore S.;Xu Q.； Shakespeare W.;Dalgarno D.;Zhu X.Crystal Structure of the T315I Mutant of Abl Kinase. Chem.Biol.Drug.Des.2007,70,171-181.
11.McBride C.M.；Renhowe P.A.；Gesner T.G.；Jansen J.M.；Lin J.；Ma S.；Zhou Y.；Shafer C. M.3-Benzimidazol-2-yl-1H-Indazoles as Potent c-ABL Inhibitors.Bioorg.Med.Chem.Lett.
2006,16,3789-3792.
12. Manetti F.; Falchi F.; Crespan E.; Schenone S.; Maga G.; Botta M. N-(Thiazol-2-yl)-2-thiophene Carboxamide Derivatives as Abl Inhibitors Identified by a Pharmacophore-based Database Screening of Commercially Available Compounds. Bioorg. Med. Chem. Lett.2008, 18,4328-4331.
13. Manley P. W.; Cowan-Jacob S. W.; Jurgen M. Advances in the Structural Biology, Design and Clinical Development of Bcr-Abl Kinase Inhibitors for the Treatment of Chronic Myeloid Leukaemia. Biochimica et Biophysica Acta,2005,1754,3-13.
14. Lombardo L. J.; Lee F. Y.; Chen P.; Norris D.; Barrish J.C.; Behnia K.; Castaneda S.; Cornelius L.A.; Das J.; Doweyko A.M.; Fairchild C.; Hunt J.T.; Inigo I.; Johnston K.; Kamath A.; Kan D.; Klei H.; Marathe P.; Pang S.; Peterson R.; Pitt S.; Schieven G.L.; Schmidt R.J.; Tokarski J.; Wen M. L.; Wityak J.; Borzilleri R. M. Discovery of N-(2-Chloro-6-methyl-phenyl)-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), A Dual Src/Abl Kinase Inhibitor with Potent Antitumor Activity in Preclinical Assays. J. Med. Chem.2004,47:6658-6661.
15. a) Shah N. P. Dasatinib. Drugs Today 2007,43,5-12. b) Veach D. R.; Namavari M.; Pillarsetty N.; Santos E. B.; Beresten-Kochetkov T.; Lambek C.; Punzalan B. J.; Antczak C.; Smith-Jones P. M.; Djaballah H.; Clarkson B.; Larson S. M. Synthesis and Biological Evaluation of a Fluorine-18 Derivative of Dasatinib. J. Med. Chem.2007,50,5853-5857.
16. Golas J. M.; Arndt K.; Etienne C.; Jennifer M.; et al. SKI-606, a 4-Aniline-3-quinoline-carbonitrile Dual Inhibitor of Src and Abl Kinases, is a Potent Antiproliferative Agent against Chronic Myelogenous Leukemia Cells in Culture and Causes Regression of K562 Xenografts in Nude Mice. Cancer Res.2003,63,375-381.
17. Boschelli D.H.; Ye F.; Wang Y. D.; Dutia M.; Johnson S.L.; Wu B.; Miller K.; Powell D.W.; Yaczko D.; Young M.; Tischler M.; Arndt K.; Discafani C.; Etienne C.; Gibbons J.; Grod J.; Lucas J.; Weber J. M.; Boschelli F.; Optimization of 4-Phenylamino-3-quinolinecarbonitriles as Potent Inhibitors of Src Kinase Activity. J. Med. Chem.2001,44,3965-3967.
18. Schenone S.; Manetti F.; Botta M. Synthetic Src-kinase Domain Inhibitors and Their Structural Requirements. Anti-cancer Agents Med. Chem.2007,7,660-680.
19. a) Puttini M.; Coluccia A.M.; Boschelli F.; Cleris L.; Marchesi E.; Donella-Deana A.; Ahmed S.; Redaelli S.; Piazza R.; Magistroni V.; Andreoni F.; Scapozza L.; Formelli F.; Gambacorti-Passerini C. In Vitro and in Vivo Activity of SKI-606, A Novel Src-Abl Inhibitor, against Imatinib-Resistant Bcr-Abl+Neoplastic Cells. Cancer Res.2006,66, 11314-11322. b) Redaelli S.; Piazza R.; Rostagno R.; Magistroni V.; Perini P.; Marega M.; Gambacorti-Passerini C.; Boschelli F. Activity of Bosutinib, Dasatinib, and Nilotinib against Imatinib-resistant BCR/ABL Mutants. J. Clin. Oncol.2009,27,469-471.
20. a) Boschelli D. H. Wang Y. D.; Johnson S.; Wu B.; Ye F.; Barrios Sosa A. C.; Golas J. M, Boschelli F.7-Alkoxy-4-phenylamino-3-quinolinecarbonitriles as Dual Inhibitors of Src and Abl Kinases. J. Med. Chem.2004,47,1599-1601. b) Boschelli D. H.; Wu B.; Barrios Sosa A. C.; Durutlic H.; Ye F.; Raifeld Y.; Golas J. M.; Boschelli F. Identification of 7-Phenylaminothieno[3,2-b]pyridine-6-carbonitriles as a New Class of Src Kinase Inhibitors. J. Med. Chem.2004,47,6666-6668.
21. O'Hare T.; Pollock R.; Stoffregen E. P.; Keats J. A.; Abdullah O. M.; Moseson E. M.; Rivera V. M.; Tang H.; Metcalf C. A.; Bohacek R. S. Wang Y.; Sundaramoorthi R.; Shakespeare W. C.; Dalgarno D.; Clackson T.; Sawyer T. K.; Deininger M. W.; Druker B. J. Inhibition of Wild-type and Mutant Bcr-Abl by AP23464, a Potent ATP-based Oncogenic Protein Kinase Inhibitor:Implications for CML. Blood,2004,104,2532-2539.
22. Connolly C. J. C.; Hamby J. M.; Schroeder M. C.; Barvian M.; Lu G. H.; Panek R. L.; Amar A.; Shen C.; Kraker A. J.; Fry D. W.; Klohs W. D.; Doherty A. M. Discovery and Structure-activity Studies of a Novel Series of Pyrido[2,3-d]pyrimidine Tyrosine Kinase Inhibitors. Bioorg. Med. Chem. Lett.1997,7,2415-2420.
23. Huron D. R.; Gorre M. E.; Kraker A. J.; Sawyers C. L.; Rosen N.; Moasser M. M. A Novel Pyridopyrimidine Inhibitor of Abl Kinase is a Picomolar Inhibitor of Bcr-abl-driven K562 Cells and is Effective against STI571-resistant Bcr-abl Mutants. Clin. Cancer Res.2003,9, 1267-1273.
24. La Rosee P.; Corbin A. S.; Stoffregen E. P.; Deininger M. W.; Druker B. J. Activity of the Bcr-Abl Kinase Inhibitor PD 180970 against Clinically Relevant Bcr-Abl Isoforms that Cause Resistance to Imatinib Mesylate (Gleevec, STI571). Cancer Res.2002,62,7149-7153.
25. Noronha G.; Barrett K.; Boccia A.; Brodhag T.; Cao J.; Chow C. P.; Dneprovskaia E.; Doukas J.; Fine R.; Gong X.; Gritzen C.; Gu H.; Hanna E.; Hood J. D.; Hu S.; Kang X.; Key J.;
Klebansky B.; Kousba A.; Li G.; Lohse D.; Mak C. C.; McPherson A.; Palanki M. S.; Pathak V. P.; Renick J.; Shi F.; Soll R.; Splittgerber U.; Stoughton S.; Tang S.; Yee S.; Zeng B.; Zhao N,; Zhu H. Discovery of [7-(2,6-Dichlorophenyl)-5-Methylbenzo[1,2,4]triazin-3-yl]-[4-(2-Pyrrolidin-1-ylethoxy)phenyl]amine-A Potent, Orally Active Src Kinase Inhibitor with Antitumor Activity in Preclinical Assays. Bioorg. Med. Chem. Lett.2007,17,602-608.
26. Hu S. X.; Soll R.; Yee S.; Lohse D. L.; Kousba A.; Zeng B.; Yu X.; McPherson A.; Renick J.; Cao J.; Tabak A.; Hood J.; Doukas J.; Noronha G.; Martin M. Metabolism and Pharmacokinetics of a Novel Src Kinase Inhibitor TG100435 [7-(2,6-Dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine) and Its Active N-Oxide Metabolite TG100855([7-(2,6-Dichloro-phenyl)-5-methylbenzo[1,2,4] triazin-3-yl]-{4-[2-(1-oxy-pyrrolidin-1-yl)-ethoxy]-phenyl}-amine). Drug Metab. Dispos. 2007,35,929-936.
27. Missbach M.; Jeschke M.; Feyen J.; Miiller K.; Glatt M.; Green J.; Susa M. A Novel Inhibitor of the Tyrosine Kinase Src Suppresses Phosphorylation of its Major Cellular Substrates and Reduces Bone Resorption in Vitro and in Rodent Models in Vivo. Bone,1999,24,437-449.
28. Recchia I.; Rucci N.; Funari A.; Migliaccio S.; Taranta A.; Longo M.; Kneissel M.; Susa M.; Fabbro D.; Teti A. Reduction of c-Src Activity by Substituted 5,7-Diphenyl-pyrrolo [2,3-d]pyrimidines Induces Osteoclast Apoptosis in Vivo and in Vitro. Involvement of ERK1/2 Pathway. Bone 2004,34,65-79.
29. Hanke J. H.; Gardner J. P.; Dow R. L.; Changelian P. S.; Brissette W. H.; Weringer E. J.; Pollok B. A.; Connelly P. A. Discovery of a Novel, Potent, and Src Family-selective Tyrosine Kinase Inhibitor. Study of Lck-and FynT-dependent T Cell Activation. J. Biol. Chem.1996,271:695-701.
30. Tatton L.; Morley G. M.; Chopra R.; Khwaja A. The Src-selective Kinase Inhibitor PP1 also Inhibits Kit and Bcr-Abl Tyrosine Kinases.J. Biol. Chem.2003,278,4847-4853.
31. a) Harrington E.A.; Bebbington D.; Moore J.; Rasmussen R. K.; Ajose-Adeogun A. O.; Nakayama T.; Graham J. A.; Demur C.; Hercend T.; Diu-Hercend A.; Su M.; Golec J. M. C.; Miller K. M. VX-680, a Potent and Selective Small-molecule Inhibitor of the Aurora Kinases, Suppresses Tumor Growth in Vivo. Nat. Med.2004,10,262-267. b) Akahane D; Tauchi T; Okabe S; Nunoda K; Ohyashiki K. Activity of a Novel Aurora Kinase Inhibitor against the
T315I Mutant Form of BCR-ABL:in Vitro and in Vivo Studies. Cancer Sci.2008,99, 1251-1257.
32. Manetti F.; Brullo C.; Magnani M.; Mosci F.; Chelli B.; Crespan E.; Schenone S.; Naldini A.; Bruno O.; Trincavelli M. L.; Maga G.; Carraro F.; Martini C.; Bondavalli F.; Botta M. Structure-based Optimization of Pyrazolo[3,4-d]pyrimidines as Abl Inhibitors and Antiproliferative Agents Toward Human Leukemia Cell Lines. J. Med. Chem.2008,51, 1252-1259.
33. a) Gumireddy K; Baker S. J; Cosenza S. C.; John P.; Kang A. D.; Robell K.A.; Reddy M. V. R.; Reddy E. P. A Non-ATP-competitive Inhibitor of BCR-ABL Overrides Imatinib Resistance. Proc. Natl. Acad. Sci.2005,102,1992-1997.
34. a) Adria'n F. J.; Ding Q.; Sim T.; Velentza A.; Sloan C.; Liu Y.; Zhang G.; Hur W.; Ding S.; Manley P.; Mestan J.; Fabbro D.; Gray N. S. Allosteric Inhibitors of Bcr-abl-dependent Cell Proliferation. Nat. Chem. Biol.2006,2,95-102. b) Owers J. T.; Azam M.; Gray S. N.; Daley G. Q. Dissection of Bcr-abl Structural Domains Relating Tokinase Auto-inhibition Using a Forward Mutational Screen with the Non-ATP Competitive Inhibitor GNF-2. Blood (ASH Annual Meeting Abstracts),2007,10,021.
35. Bhatia R.; Holtz M.; Niu N.; Gray R.; Snyder D. S.; Sawyers C. L.; Arber D. A.; Slovak M. L.; Forman S. J. Persistence of Malignant Hematopoietic Progenitors in Chronic Myelogenous Leukemia Patients in Complete Cytogenetic Remission Following Imatinib Mesylate Treatment. Blood,2003,101,4701-4707.
36. Thomas J.; Wang L.; Clark R. E.; Pirmohamed M. Active Transport of Imatinib into and out of Cells:Implications for Drug Resistance. Blood,2004,104,3739-3745.
37. a) La R. P.; Corbin A. S.; Stoffregen E. P.; Deininger M. W.; Druker B. J. Activity of the Bcr-Abl Kinase Inhibitor PD 180970 against Clinically Relevant Bcr-Abl Isoforms that Cause Resistance to Imatinib Mesylate (Gleevec, STI571). Cancer Res.2002,62,7149-7153. b) Corbin A. S.; Buchdunger E.; Pascal F.; Druker B. J. Analysis of the Structural Basis of Specificity of Inhibition of the Abl Knase by STI571. J. Biol. Chem.2002,277, 32214-32219.
38. Lu J.; Yang B.; Bai Y. Microwave Irradiation Synthesis of 2-Substituted Benzimidazoles Using PPA as a Catalyst under Solvent-free Conditions. Synth. Commum.2002,32,3703-3709.
39. Nadipuram A. K.; David W. M.; Kumar D.; Kerwin S. M. Synthesis and Thermolysis of Heterocyclic 3-Aza-3-ene-1,5-diynes. Org. Lett.2002,4,4543-4546.
40. Siva A.; Murugan E. Synthesis and Characterization of Novel Multi-site Phase Transfer Catalyst and Its Catalytic Efficiency for Dichlorocarbene Addition to Citral. Journal of Molecular Catalysis A:Chemical 2005,241101-110.
41. Phillips W. G.; Ratts K. W. Chemistry of a, a-Dichlorosulfenyl Chlorides.J. Org. Chem.1972, 37,1526-1531.
42. Tatsuo H. Oxidations by Thionyl Chloride. VI. Mechanism of the Reaction with Cinnamic Acids. J. Org. Chem.1975,40,3037-3045.
1. Nakanishi, K. Natural Products Chemistry 1974, Kodansha, Ltd.:Tokyo.
2. a) Maeda S.; Masuda H.; Tokoroyama T. Studies on the Preparation of Bioactive Lignans by Oxidative Coupling Reaction. III. Synthesis of Polyphenolic Benzofuran and Coumestan Derivatives by Oxidative Coupling Reaction of Methyl (E)-3-(4-Hydroxy-2-methoxyphenyl) propenoate and Their Inhibitory Effect on Lipid Peroxidation. Chem. Pharm. Bull.1994,42, 2536-2545. b) Huang H. C.; Chamberlain T. S.; Seibert K.; Koboldt C. M.; Isakson P. C.; Reitz D. B. Diaryl Indenes and Benzofurans:Novel Classes of Potent and Selective Cyclooxygenase-2 Inhibitors. Bioorg. Med. Chem. Lett.1995,5,2377-2380. c) Sato M.; Grese T. A.; Dodge J. A.; Henry U. B.; Charles H. T. Emerging Therapies for the Prevention or Treatment of Postmenopausal Osteoporosis. J. Med. Chem.1999,42,1-24.
3. a) Marshall J. A.; Robinson E. D. A Mild Method for the Synthesis of Furans. Application to 2,5-Bridged Furano Macrocyclic Compounds. J. Org. Chem.1990,55,3450-3451. b) Marshall J. A.; Wang X.-J. Synthesis of Furans by Silver(Ⅰ)-promoted Cyclization of Allenyl
Ketones and Aldehydes.J. Org. Chem.1991,56,960-969. c) Marshall J. A.; Bartley G. S. Observations Regarding the Ag(I)-catalyzed Conversion of Allenones to Furans. J. Org. Chem.1994,59,7169-7171.
4. Marshall J. A.; Wang X.-J. Synthesis of 2,5-Furanocycles through Intraannular Cyclization of Macrocyclic Allenones. J. Org. Chem.1992,57,3387-3396.
5. a) Hashmi A. S. K. Transition Metal Catalyzed Dimerization of Allenyl Ketones. Angew. Chem. Int. Ed.1995,34,1581-1583. b) Hashmi A. S. K.; Ruppert T.L.; Knofel T.; Bats J. W. C-C-Bond Formation by the Palladium-Catalyzed Cycloisomerization/Dimerization of Terminal Allenyl Ketones:Selectivity and Mechanistic Aspects. J. Org. Chem.1997,62, 7295-7304.
6. Hashmi A. S. K.; Schwarz L.; Choi J. H.; Frost T. M. A New Gold-catalyzed C-C Bond Formation. Angew. Chem. Int. Ed.2000,39,2285-2288.
7. Ma S. M.; Zhang J. L.; Lu L. H. Pd0-catalyzed Coupling Cyclization Reaction of Aryl or lAlkenyl Halides with 1,2-Allenyl Ketones:Scope and Mechanism. An Efficient Assembly of 2,3,4-,2,3,5-Tri-and 2,3,4,5-Tetra-substituted Furans. Chem. Eur. J.2003,9,2447-2456.
8. Peng L.-L.; Zhang X.; Ma M.; Wang J.-B. Transition-metal-catalyzed Rearrangement of Allenyl Sulfides:A Route to Furan Derivatives. Angew. Chem., Int. Ed.2007,46,1905-1908.
9. Sieller B.; Bruneau C.; Dixneuf P. H. Novel Ruthenium-catalysed Synthesis of Furan Derivatives via Intramolecular Cyclization of Hydroxy Enynes.J. Chem. Soc. Chem. Commun.1994,493-494.
10. Sieller B.; Bruneau C.; Dixneuf P. H. Synthesis of Furans by Cyclization of 2-En-4-yn-l-ols in the presence of Ruthenium and Palladium Catalysts. Tetrahedron 1995,51,13089-13102.
11. Marshall J. A.; Sehon C. A. Synthesis of Furans and 2,5-Dihydrofurans by Ag(I)-Catalyzed Isomerization of Allenones, Alkynyl Allylic Alcohols, and Allenylcarbinols.J. Org. Chem. 1995,60,5966-5968.
12. Gabriele B.; Salerno G.; De Pascali F.; Costa M.; Chiusoli G. P. An Efficient and General Synthesis of Furan-2-Acetic Esters by Palladium-catalyzed Oxidative Carbonylation of (Z)-2-En-4-yn-l-ols.J. Org. Chem.1999,64,7693-7699.
13. Qing F. L.; Gao W, Z.; Ying J. W. Synthesis of 3-Trifluoroethylfurans by Palladium-catalyzed Cyclization-isomerization of (Z)-2-Alkynyl-3-trifluoromethyl Allylic Alcohols. J. Org. Chem.2000,65,2003-2006.
14. Liu Y.; Song F.; Liu M.; Yan B. Gold-catalyzed Cyclization of (Z)-2-en-4-yn-l-ols:Highly Efficient Synthesis of Fully Substituted Dihydrofurans and Furans. Org. Lett.2005,7, 5409-5412.
15. Utimoto K. Palladium Catalyzed Synthesis of Heterocycles. Pure Appl. Chem.1983,55, 1845-1852.
16. Pale P.; Chuche J. Silver Assisted Heterocyclization of Acetylenic Compounds. Tetrahedron Lett.1987,28,6447-6448.
17. McDonald F. E.; Connolly C. B.; Gleason M. M.; Towne T. B.; Treiber K. D. A New Synthesis of 2,3-Dihydrofurans:Cycloisomerization of Alkynyl Alcohols to Endocyclic Enol Ethers. J. Org. Chem.1993,58,6952-6953.
18. McDonald F. E.; Schultz C. C. Mechanism of Molybdenum Pentacarbonyl-catalyzed Cyclizations of Alkynols and Epoxyalkynes. J. Am. Chem. Soc.1994,116,9363-9364.
19. a) Dulcere J.-P.; Dumez E. Tandem Oxa-Michael Addition-SN2 Substitution of 4-Chlorobut-2-yn-l-ol with Nitroalkenes:a Total Allylic 1,3-Strain-controlled Diastereoselective Synthesis of 3-Vinylidenetetrahydrofurans. Chem. Commun.1997, 971-972. b) Dumez E.; Rodriguez J.; Dulcere J.-P. Studies towards a New One-pot Heterocyclization:Bu'OK-promoted Oxa-and Aza-Michael Addition-intramolecular Carbocyclization of Prop-2-ynyl alcohols and Amines with a, β-Disubstituted Nitroalkenes. Chem. Commun.1997,1831-1832.
20. Clique B.; Monteiro N.; Balme G. A One Pot Synthesis of Various Pyrrolidines via a Tandem Michael Addition-transition Metal-catalysed Cyclisation Reaction. Tetrahedron Lett.1999, 40,1301-1304.
21. Morikawa S.; Yamazaki S.; Furusaki Y.; Amano N.; Zenke K.; Kakiuchi K. Zinc-and Indium-promoted Conjugate Addition-cyclization Reactions of Ethenetricarboxylates with Propargylamines and Alcohol:Novel Methylenepyrrolidine and Methylenetetrahydrofuran Syntheses. J. Org. Chem.2006,71,3540-3544.
22. Cadierno V.; Gimeno J.; Nebra N. A Novel Propargylation/Cycloisomerization Tandem Process Catalyzed by a Ruthenium(II)/Trifluoroacetic Acid System:One-pot Entry to Fully Substituted Furans from Readily Available Secondary Propargylic Alcohols and 1,3-Dicarbonyl Compounds. Adv. Synth. Catal.2007,349,382-394.
23. a) Tsuji J.; Watanabe H.; Minami I.; Shimizu I. Novel Palladium-catalyzed Reactions of Propargyl Carbonates with Carbonucleophiles under Neutral Conditions. J. Am. Chem. Soc. 1985,107,2196-2198. b) Minami I.; Yuhara M.; Watanabe H.; Tsuji J. A New Furan Annulation Reaction by the Palladium-catalyzed Reaetion of 2-Alkynyl Carbonates or 2-(1-Alkynyl)oxiranes with β-Keto Esters. J. Organomet. Chem.1987,334,225-242.
24. Aurrecoechea J. M.; Solay-Ispizua M. Synthesis of Furans from Epoxypropargyl Esters. Heterocycles 1994,37,223-226.
25 Aurrecoechea J. M.; Perez E.; Solay M. Synthesis of Trisubstituted Furans from Epoxypropargyl Esters by Sequential SmI2-Promoted Reduction-elimination and Pd(II)-catalyzed Cycloisomerization. J. Org. Chem.2001,66,564-569
26. Hashmi A. S. K.; Sinha P. Gold Catalysis:Mild Conditions for the Transformation of Alkynyl Epoxides to Furans. Adv. Synth. Catal.2004,346,432-438.
27. Fukuda Y.; Shiragami H.; Utimoto K.; Nozaki H. Synthesis of Substituted Furans by Palladium-catalyzed Cyclization of Acetylenic Ketones. J. Org. Chem.1991,56,5816-5819.
28. Arcadi A.; Cacchi S.; Laroek R. C.; Marinelli F. The Palladium-catalysed Synthesis of 2,3,5-Trisubstituted Furans from 2-Propargyl-1,3-dicarbonyl Compounds and Vinylic or Aryl Triflates or Halides. Tetrahedron Lett.1993,34,2813-2816.
29. Cacchi S.; Fabrizi G.; Moro L. Synthesis of 3,5-Disubstituted Furans via Palladium-Catalyzed Annulation of Alkyl 3-Oxo-6-heptynoates. J. Org. Chem.1997,62,5327-5332.
30. Arcadi A.; Rossi E. Palladium-catalyzed Domino Reaction of 3-Acetyl-5-hexyn-2-one with Aryl Iodides under Carbon Monoxide. Tetrahedron Lett.1996,37,6811-6814.
31. Arcadi A.; Cerichelli G.; Chiarini M.; Giuseppe S. D.; Marinelli F. Sequential Alkylation/Transition Metal Catalyzed Annulation Reactions of 1,3-Dicarbonyl Compounds with Propargyl Bromide. Tetrahedron Lett.2000,41,9195-9198.
32. Kato K.; Yamamoto Y.; Akita H. Palladium(II)-mediated Cyclization-carbonylation of 4-yn-l-ones:Facile Access to 2-Cyclopentenone Carboxylates. Tetrahedron Lett.2002,43, 4915-4917.
33. Wipf P.; Soth M. J. Synthesis of the C(1)-C(18) Segment of Lophotoxin and Pukalide. Control of 2-Alkenylfuran (E/Z)-configuration. Org. Lett.2002,4,1787-1790
34. Imagawa H.; Kurisaki T.; Nishizawa M. Mercuric Triflate-catalyzed Synthesis of 2-Methylfurans from 1-Alkyn-5-ones. Org. Lett.2004,6,3679-3681.
35. Asao N.; Nogami T.; Takahashi K.; Yamamoto Y. Pd(II) Acts Simultaneously as a Lewis Acid and as a Transition-metal Catalyst:Synthesis of Cyclic Alkenyl Ethers from Acetylenic Aldehydes. J. Am. Chem. Soc.2002,124,764-765.
36. Ma S.; Gao W. Efficient Synthesis of 4-(2'-Alkenyl)-2,5-dihydrofurans via PdCl2-catalyzed Coupling-cyclization Reaction of 2,3-Allenols with Allylic Halides. Tetrahedron Lett.2000, 41,8933-8936.
37. Ma S.; Zhao S. Pd(0)-Catalyzed Insertion-cyclization Reaction of 2,3-Allenols with Aryl or Alkenyl Halides. Diastereoselective Synthesis of Highly Optically Active trans-2,3-Disubstituted Vinylic Oxiranes.J. Am. Chem. Soc.1999,121,7943-7944.
38. Tsuji J.; Watanabe H.; Minami I.; Shimizu I. Novel Palladium-catalyzed Reactions of Propargyl Carbonates with Carbonucleophiles under Neutral Conditions.J. Am.Chem. Soc. 1985,107,2196-2198.
39. Greeves N.; Torode J. S. Synthesis of Phenylthiomethyl Substitution Furans by Lewis Acid Catalysed Substitution. Synthesis 1993,11,1109-1112.
40. Wang H.-F.; Yang T.; Xu P.-F.; Dixon D. J. Base and Copper (I) Catalyzed Mannich, Alkyne Hydroamination Cascades for the Direct Synthesis of 2-Methylenepyrrolidines. Chem. Commun.2009,3916-3918
1. Isono K. Nucleoside Antibiotics, Structure, Biological Activity and Biosynthesis. J Antibiot. 1988,41,1711-1739.
2. Dahn U; Hagenmaier H; Hohne H; Konig, W. A.; Wolf, G.; Zahner, H. Stoffwechselprodukte von Mikroorganismen.154. Mitt. Nikkomycin, ein neuer Hemmstoff der Chitinsynthese bei Pilzen. Arch Microbiol.1976,107,143-160.
3. (a) Hagenmaier H.; Keckeisen A.; Zahner H.; Konig W. A. Stoffwechselprodukte von Mikroorganismen,182. Aufklarung der Struktur des Nucleosidantibiotikums Nikkomycin X. Liebigs Ann. Chem.1979,1494-1502. (b) Konig W. A.; Hass W.; Dehler W.; Fiedler H. P.; Zahner H. Strukturaufkarung und Partialsynthese des Nucleosidantibiotikums Nikkomycin B. Liebigs Ann. Chem.1980,622-628. (c) Hagenmaier H.; Keckeisen A.; Dehler W.; Fiedler H. P.; Zahner H.; Konig W. A. Stoffwechselprodukte von Mikroorganismen,199. Konstitutionsaufklarung der Nikkomycine I, J, M und N. Liebigs Ann. Chem.1981, 1018-1024.
4. a) Fiedler H -P.; Kurth R.; Langharig J.; Delzer J.; Zahner H. Nikkomycins:Microbial Inhibitors of Chitin Synthase. J. Chem. Technol. Biotechno.1982,32,271-280. b) Cabib E. Differential Inhibition of Chitin Synthetases 1 and 2 from Saccharomyces Cerevisiae by Polyoxin D and Nikkomycins. Antimicrob Agents Chemoth 1991,35,170-173.
5. Hector R.; Zimmer B.; Pappagianis D. Evaluation of Nikkomycins X and Z in Murine Models of Coccidiomycosis, Histoplasmosis, and Blastomycosis. Antimicrob Agents Chemothe.1990,
34,587-593.
6. Zimmermann G.; Hass W.; Faasch H.; Schmalle H.; Konig W. A. Synthese reiner Stereoisomerer der N-terminalen Aminosaure von Nikkomycin B. Leibegs Ann. Chem.1985, 2165-2177.
7. Jager V.; Grund H.; Buss V.; Schwab W.; Muller I.; Schohe R.; Franz R.; Ehrler R. Isoxazolines Key Intermediates for Synthesis of some Naturally Occuring Amino Compounds. Bull. Soc. Chim. Belg.1983,92,1039-1054.
8. Jager V.; Buβ V.; Schwab W. Synthesis via Isoxazolines Ⅲ. Diasereoselective Synthesis of y-Amino-alcohols with 2 and 3 Chrial Centres. Tetrahedron Lett.1978,3133-3136
9. Michael J. M.; Steven M. W. Intramolecular Cycloaddition Reactions of N-Acyl Imines. A Stereoselective Approach to the N-Terminal Amino Acid Component of Nikkomycin B.J. Org. Chem.1988,53,850-854
10. Brown H. C.; Bhat K. S. Chiral Synthesis via Organoboranes.7. Diastereoselective and Enantioselective Synthesis of Erythro-and Threo-.Beta.-Methylhomoallyl Alcohols via Enantiomeric (Z) and (E)-Crotylboranes. J. Am. Chem. SOC.1986,108,5919-5923.
11. a) Anthony G. M.; Barrett J.; Suzanne A. L. The Total Synthesis of Nikkomycin B. J. Org. Chem.1990,55,5818-5820. b) Barrett A. G. M.; Lebold S. A. Applications of Crotyldiisopinocampheylboranes in Synthesis:The Total Synthesis of Nikkomycin B. J. Org. Chem.1991,56,4875-4884.
12. Barrett A. G. M.; Dhanak D.; Lebold S. A.; Russell M. A. Alpha.-Oximino Amide Trianions in the Stereoselective Synthesis of Isoxazolines and Gamma.-Hydroxy Alpha.-Amino acids. J. Org. Chem.1991,56,1894-1901.
13. Barluenga J.; Olano B.; Fustero S.; Foces-Foces M. C.; Cano F. H. Diastereo-and Enantio-selective Synthesis of Dihydro-and Tetrahydro-pyrimidines. A New Strategy for the Asymmetric Synthesis of β-Amino Ketones and γ-Amino Alcohols. J. Chem. Soc. Chem. Commun.1988,410b.
14. Barluenga J.; Viado A. L.; Aguilar E.; Fustero S.; Olano B.1,3-Amino Alcohols from 4-Amino-l-aza Dienes. Diastereo-and Enantioselective Approach to the Four Diastereoisomers of the N-Terminal Amino Acid Component of Nikkomycins B and Bx. J. Org. Chem.1993,58,5972-5975
15. Palomo C.; Aizpurua J. M.; Garcia J. M.; Iturburu M.; Odriozola J. M. Concise General Synthesis of.alpha., gamma.-Disubstituted beta.-Amino Ketones from beta.-Lactams. J. Org. Chem.1994,59,5184-5188
16. Kronenthal D. R.; Han C. Y.; Taylor M. K. Oxidative N-Dearylation of 2-Azetidinones. p-Anisidine as a Source of Azetidinone Nitrogen. J. Org. Chem.1982,47,2765-2768.
17. Baldwin J. E.; Adlington R. M.; Gollins D. W.; Schofield C. J. Stereospecific Synthesis of Dealanylalahopcin. Tetrahedron 1990,46,4733-4748.
18. Akita H.; Chen C. Y.; Uchida K. A Formal Total Synthesis of Nikkomycin B Based on Enzymatic Resolution of a Primary Alcohol Possessing Two Stereogenic Centers. Tetrahedron:Asymmetry 1995,6,2131-2134.
19. Kapeller H.; Jary W. G.; Hayden W.; Griengl H. A Chemo-enzymatic Synthesis of the N-Terminal Amino acid Lactone of Nikkomycin B. Tetrahedron:Asymmetry 1997,8, 245-251.
20. Tamura O.; Mita N.; Kusaka N.; Suzuki H.; Sakamoto M. Intramolecular Cycloaddition of a-Allyloxycarbonylnitrone Bearing a Chiral Sugar Auxiliary:A Short-step Synthesis of the N-Terminal Amino Acid Component of Nikkomycin Bz. Tetrahedron Letter 1997,38, 429-432.
21. Palomo C.; Maizpurua J.; Gracenea J. J. Diastereoselective Conjugate Reduction and Enolate Trapping with Glyoxylate Imines:A Concise Approach to α-Lactams that Involves a Ternary Combination of Components. J. Org. Chem.1999,64,1693-1698
22. Hayashi Y.; Tsuboi W.; Ashimine I.; Urushima T.; Shoji M.; Sakai K. The Direct and Enantioselective, One-pot, Three-component, Cross-Mannich Reaction of Aldehydes. Angew. Chem., Int. Ed.2003,42,3677-3680.
23. Hayashi Y.; Urushima T.; Shin M.; Shoji M. The Stereoselective Synthesis of α-Substituted β-Amino Secondary Alcohols Based on the Proline-mediated, Asymmetric, Three-component Mannich Reaction and Its Application to the Formal Total Synthesis of Nikkomycins B and Bx. Tetrahedron 2005,61,11393-11404.
1.梁生旺.生物碱类成分分析,1999,学苑出版社,北京.
2. Lizuka N.; Miyamoto K.; Okita K.; Tangoku A.; Hayashi H.; Yosino S.; Abe T.; Morioka T.; Hazama S.; Oka M. Inhibitory Effect of Coptidis Rhizoma and Berberine on the Proliferation of Human Esophageal Cancer Cell Lines. Cancer Letters 2000,148,19-25.
3.洪山海,马广恩.石蒜科生物碱的研究Ⅱ.紫花石蒜和其他两种石蒜中的生物碱及新生物碱紫花石蒜碱.药学学报,1964,11,1-14.
4. a) Gabrielsen B.; Monath T. P.; Huggins J. W.; Kefauver D. F.; Pettit G. R.; Groszek G.; Hollingshead M.; Kirsi J. J.; Shannon W. M.; Schubert E. M.; DaRe J.; Ugarkar B.; Ussery M. A.; Phelan M. J. Antiviral (RNA) Activity of Selected Amaryllidaceae Isoquinoline Constituents and Synthesis of Related Substances.J. Nat. Prod.1992,55,1569-1581. b) Renard Nozaki J.; Kim T.; Imakura Y.; et al. Effect of Alkaloids Isolated from Amaryllidaceae on Herpes Simplex Virus. Res. Virol.1989,140,115-128.
5.贾献慧；周铜水；郑颖；刘汉清.石蒜科植物生物碱成分的药理学研究.中医药学刊.2001,19,573-574.
6. Matveenko M.; Kokas O. J.; Banwell M. G.; Willis A.; Chemoenzymatic Approaches to Lycorine-type Amaryllidaceae Alkaloids:Total Syntheses of ent-Lycoricidine, 3-epi-ent-Lycoricidine, and 4-Deoxy3-epi-ent-lycoricidine. Org Lett.2007,9,3683-3685.
7. Backvall J. E.; Andersson P. G.; Stone G. B.; GoZoll A. Syntheses of (+/-)-alpha.-and (+/-)-gamma.-Lycorane via a Stereocontrolled Organopalladium Route.J. Org. Chem.1991, 56,2988-2993.
8. Oppolzer W.; Spivey A. C.; Bochet C. G. Suprafaciality of Thermal N-4-Alkenylhydroxy lamine Cyclizations:Syntheses of (+/-)-alpha.-Lycorane and (+)-Trianthine. J. Am. Chem. SOC.1994,116,3139-3140.
9. Rigby J. H.; Mateo M. E. Total Synthesis of (±)-a-Lycorane and 4,5-Dehydroanhydrolycorine. Tetrahedron 1996,52,10569-10582.
10. Tamura O.; Matsukida H.; Toyao A.; Takeda Y.; Ishibashi H.. Is an Iodine Atom Almighty as
a Leaving Group for Bu3SnH-Mediated Radical Cyclization? The Effect of a Halogen Atom on the 5-Endo-trig Radical Cyclization of N-Vinyl-a-Halo Amides. J. Org. Chem.2002,67, 5537-5545.
11. Miranda L. D.; Zard S. Z. A Short Synthesis of the Erythrina Skeleton and of (±)-a-Lycorane. Org. Lett.2002,4,1135-1138.
12. Yasuhara T.; Nishimura K.; Yamashita M.; Fukuyama N.; Yamada K.-I.; Muraoka O.; Tomioka K. Total Synthesis of (±)-a-and β-Lycoranes by Sequential Chemoselective Conjugate Addition-Stereoselective Nitro-Michael Cyclization of an ω-Nitro-α,β,ψ,ω-unsaturated Ester. Org. Lett.2003,5,1123-1126.
13. Dong L.; Xu Y.-J.; Yuan W.-C.; Cui X.; Cun L.-F.; Gong L.-Z. Rhodium-catalyzed Asymmetric Nitroallylation of Arylmetallics with Cyclic nitroallyl Acetates and Applications in Organic Synthesis. Eur. J. Org. Chem.2006,4093-4105.
14. Banwell M. G.; Harvey J. E.; Wu D. C. R. H. W. Electrocyclic Ring-opening/π-Allyl Cation Cyclization Reaction Sequences Involving gem-Dihalocyclopropanes as Substrates: Application to Syntheses of (±)-, (+)-, and (-)-γ-Lycorane. J. Org. Chem.2000,65, 4241-4250.
15. Gao S.; Tu Y. Q.; Song Z.; Wang A.; Fan X.; Jiang Y. A General and Efficient Strategy for 7-Aryloctahydroindole and cis-3a-Aryloctahydroindole Alkaloids:Total Syntheses of ((+/-)-r-Lycorane and ((+/-)-Crinane. J. Org. Chem.2005,70,6523-6525.
16. Dong L.; Xu Y.-J.; Cun L.-F.; Cui X.; Mi A.-Q.; Jiang Y.-Z.; Gong L.-Z. Asymmetric Nitroallylation of Arylboronic Acids with Nitroallyl Acetates Catalyzed by Chiral Rhodium Complexes and Its Application in a Concise Total Synthesis of Optically Pure (+)-r-Lycorane. Org. Lett.2005,7,4285-4288.
17. Chapsal B. D.; Ojima I. Total Synthesis of Enantiopure (+)-r-Lycorane Using Highly Efficient Pd-Catalyzed Asymmetric Allylic Alkylation. Org. Lett.2006,8,1395-1398.
18. Fujioka H.; Murai K.; Ohba Y.; Hirose H.; Kita Y. Intramolecular Bromo-amination of 1,4-Cyclohexadiene Aminal:One-pot Discrimination of Two Olefins and Concise Asymmetric Synthesis of (-)-r-Lycorane. Chem. Commun.2006,832-834.