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Efforts toward the first enantioselective total synthesis of praziquantel and synthetic model studies on ecteinascidin 743 by novel aromatic C-H insertion methodology
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Chen, Chiliu
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tetrahydroisoquinoline
heterocycle
isoquinolone
ecteinascidin
praziquantel
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government publication (state, provincial, terriorial, dependent)   ( marcgt )
bibliography   ( marcgt )
theses   ( marcgt )
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ABSTRACT: The thesis is composed of three chapters. The aim of this thesis is to apply the novel dirhodium perfluorobutyrate-catalyzed intramolecular aromatic C-H insertion methodology to the enantioselective total synthesis of praziquantel and synthetic model studies on ecteinascidin 743, which belongs to the important tetrahydroisoquinoline family. The first introductory chapter deals with the biological significance and previous synthetic methodologies. Our novel methodology is based on dirhodium perfluorobutyrate-catalyzed intromolecular aromatic C-H insertion reaction, which is crucial in the pivotal carbon-carbon bond formation when constructing isoquinolone moiety, which is ubiquitous in numerous natural products of significant biological and pharmacological activities. The second chapter takes on the first enantioselective total synthesis of praziquantel, an antihelmintic drug. Praziquantel is used worldwide to treat schistosomiasis, which has tremendous impact on the global fight on this disease affecting 150 million people. We believe this is the first asymmetric total synthesis to date, which is distinct from previous racemic syntheses reported. We also shed light on the mechanistic aspect of this key reaction to rationalize the superb regioselectivity and stereoselectivity achieved. The third chapter explores the synthetic model studies on ecteinascidin 743, a tetrahydroisoquinolone family natural product with significant antitumor and antimicrobial activities. Several different synthetic routes were attempted, including the N-Methyl and the N-Boc routes, and the results achieved contributed significantly to our final synthetic plan of the target molecule.
Thesis:
Thesis (M.S.)--University of South Florida, 2004.
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by Chiliu Chen.
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Efforts toward the First Enantioselective Tota l Synthesis of Praziqua ntel and Synthetic Model Studies on Ecteinascidin 743 by N ovel Aromatic C-H Insertion Methodology by Chiliu Chen A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science Department of Chemistry College of Arts and Sciences University of South Florida Major Professor: K yung Woon Jung, Ph.D. Bill Baker, Ph.D. Kirpal Bisht, Ph.D. Edward Turos, Ph.D. Date of Approval: March 18, 2004 Keywords: Praziquantel, Ecteinas cidin, Isoquinolone, Heterocycle, Tetrahydroisoquinoline Copyright 2004, Chiliu Chen

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Dedication I would like to dedicate this thesis to my wife Yu Ch en, for her love and support.

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Acknowledgments I would like to take this opportunity to e xpress my eternal gratitude to my Advisor professor Kyung Woon Jung. As a brilliant organic chemist, he transformed the structures of a lot of compounds; as an inspir ational mentor, he also transformed the lives of a lot of students. I am lucky and proud to be one of them. I enjoyed my organic chemistry study and research under Dr. Jung’s firm leadership and nimble guidance. I would also like to thank all my comm ittee members: Dr. Bill Baker, Dr. Kirpal Bisht, and Dr. Edward Turos for their kind support, critical comments, and valuable suggestions. In addition, I would also wa nt to thank Dr. Yoon, Advait Nagle, David Flanigan, and Young Chun Jung for sharing th eir valuable knowledge and providing me with encouragement and support during so many ups and downs in my chemistry odyssey. Finally, I would also like to expr ess my appreciation to my fellow graduate students and colleagues Sung Wook Yi, Robert Huigens, Dr. Yoo, and Ki Soo Park for the help and advice they constantly re ndered. These invaluable and rewarding experiences will always enrich my li fe and be etched into my memory.

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i Table of Contents List of Tables ii List of Figures iii Abstract iv List of Abbreviations and Acronyms vi Chapter One Introduction 1 References 5 Chapter Two Efforts toward the First Enan tioselective Total Synthesis of Praziquantel 7 Introduction 7 Results and Discussion 9 Isoquinolone Formation by Intramolecular Aromatic C-H Insertion 10 Coupling with 2-(Cyclohexyl carbonylamino) Acetic Acid 13 Intramolecular Cyclization 14 Conclusion 16 Experimental Section 17 References 25 Chapter Three Synthetic Model Studies on Ecteinascidin 743 27 Introduction 27 Results and Discussion 32 Conclusion 39 Experimental Section 40 References 56 Appendices 59 Appendix A: Selected 1H and 13C NMR Spectra 60

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ii List of Tables Table 2-01 Effect of Protic Acids 12

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iii List of Figures Figure 1-01. Various Natural Products 1 Figure 1-02. Pictet-Spengler Approach 2 Figure 1-03. Formation of Cycloheptatriene 3 Figure 1-04. Formation of Indole via Electrophilic Aromatic Substitution 3 Figure 1-05. Formation of Isoquinolones via Electrophilic Substitution 4 Figure 2-01. Previous Sy nthetic Strategies 8 Figure 2-02. Retrosynthetic Analys is of Chiral Praziquantel 9 Figure 2-03. Isoquinolone Formation by Aromatic C-H Insertion 11 Figure 2-04. Mechanism of Formal Aromatic C-H Insertion 13 Figure 2-05. Coupling with 2-(Cyclo hexylcarbonylamino) Acetic Acid 14 Figure 2-06. Intramolecular Cyclization 15 Figure 3-01. Ecteinascidin 743 28 Figure 3-02. Corey’s Total Synt hesis of Ecteinascidin 743 29 Figure 3-03. Cuevas’ Formal Synthesis of Ecteinascidin 743 30 Figure 3-04. Fukuyama’s Synthesis of Ecteinascidin 743 31 Figure 3-05. Jung’s Synthetic Stra tegy of Ecteinascidin 743 32 Figure 3-06. N -Methyl Derivatives of Pyroglutamic Acid 33 Figure 3-07. Failure of Diazo Transfer 35 Figure 3-08. N -Boc Derivatives of Pyroglutamic Acid 36 Figure 3-09. Selective Reduction of N-Boc Protected Pyrrolidone Methyl Ester 37

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iv Efforts toward the First Enantioselectiv e Total Synthesis of Praziquantel and Synthetic Model Studies on Ecteinascidin 743 by Novel Aromatic C-H Insertion Methodology Chiliu Chen ABSTRACT The thesis is composed of three chapters. The aim of this thesis is to apply the novel dirhodium perfluorobutyrate-catalyzed intramolecular aromatic C-H insertion methodology to the enantioselective total synt hesis of praziquantel and synthetic model studies on ecteinascidin 743, which belongs to the impor tant tetrahydroisoquinoline family. The first introductory chapte r deals with the biological significance and previous synthetic methodologies. Our novel methodology is based on dirhodium perfluorobutyrate-catalyzed in tromolecular aromatic C-H insertion reaction, which is crucial in the pivotal ca rbon-carbon bond formation when constructing isoquinolone moiety, which is ubiquitous in numerous na tural products of signi ficant biological and pharmacological activities. The second chapter takes on the first enantioselective to tal synthesis of praziquantel, an antihelmintic drug. Pr aziquantel is used worldwide to treat schistosomiasis, which has tremendous im pact on the global fight on this disease affecting 150 million people. We believe this is the first asymmetric total synthesis to date, which is distinct from previous racemic syntheses reported. We also shed light on

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v the mechanistic aspect of this key reaction to rationalize the superb regioselectivity and stereoselectivity achieved. The third chapter explores the synthetic model studies on ecteinascidin 743, a tetrahydroisoquinolone family natural product with significant antitumor and antimicrobial activities. Several different sy nthetic routes were attempted, including the N -Methyl and the N -Boc routes, and the results achieve d contributed significantly to our final synthetic plan of the target molecule.

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vi List of Abbreviations and Acronyms ABSA 4-Acetamido benzenesulfonyl azide Ar aryl Bn benzyl BnBr benzyl bromide Boc t -Butyloxycarbonyl CDCl3 deuterated chloroform CH2Cl2 dichloromethane CH3CN acetonitrile DBU 1, 8-diazabicyclo[5.4.0]undec-7-ene DMAP 4-dimethylaminopyridine DMF N, N -dimethylformamide EDCI 1-(3-dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride EtOAc ethyl acetate EtOH ethanol HOBT 1-hydroxybenzotriazole hydrate LiAlH4 lithium aluminum hydride Me methyl MeI iodomethane MeOH methanol

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vii MOM methoxymethyl MPMCl 3-methoxybenzyl chloride Ms methanesulfonyl NaOH sodium hydroxide Pd/C palladium on carbon pfb perfluorobutyric acid Ph phenyl Rh2(OAc)4 dirhodium acetate Rh2(pfb)4 dirhodium perfluorobutyrate TBDMS tert -butyldimethylsilyl TEA triethylamine TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran TLC thin layer chromatography UV ultraviolet

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1 Chapter One Introduction The antitumor antibiotics belonging to the tetrahydroisoquinoline family have been investigated thoroughly over the past 25 years starting with the isolation of naphthyridinomycin in 1974. To date, 55 natu ral products in this family have been isolated1. Due to their stereochemically intr icate structure, potent antitumor, antimicrobial activities, and enormous potenti al as promising drug ca ndidates, they have become one of the most sought -after synthetic targets of a number of research groups. Figure 1-01 shows various natural products possessing tetrahydroisoquinoline moiety. Figure 1-01: Various Natural Products N NMe HOH H AcO Me S O NH HO MeO O HO OMe Me O O Ecteinascidin 743 (anticancer) OH H MeO OMe N N O H Praziquantel ( S )-calycotomine NH O Although the syntheses of tetrahydroisoquinolines have been known for almost a century, chiral syntheses of tetrahydroisoquino lines have been rarely reported, and still remain a daunting challenge to organic chemists. The primary pathway employed in the pa st of synthesizing this family of compounds is via Pictet-Spengler approach a nd its variants, as shown in Figure 1-02.

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2 One of the most serious dr awbacks arising from the in termolecular Pictet-Spengler reaction is its nonstereoselectiv ity, usually resulting in diffe rent diastereomers even under mild conditions2. For instance, A1 which possesses one stereogenic center, would be converted into different diastereomers A2 and A3 under the intermolecular PictetSpengler approach. Also shown in Figur e 1-02, alternatively, E.J.Corey achieved stereoselectivity, converting A4 to a single stereoisomer A5 of tetrahydroisoquinoline via intramolecular Pictet-Spengler approach3, but regioselectivity was compromised. Figure 1-02: Pictet-Spengler Approach HN H CHO X N H X H N H X H + A1 A2 A3 NHCBZ H N H A5 H O O O O H CBZ R R R R R -H2O -H2O A4 Intermolecular approach Intramolecular approach Aromatic C-H insertion has been investig ated by numerous research groups with mediocre results.4 The main hurdle encountered was the formation of side product cycloheptatriene A7 when aromatic C-H insertion was carried out with diazo precursor A6 Formation of cycloheptatriene can be explained by cyclopropanation followed by

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3 ring expansion, as shown in Figure 1-03. Figure 1-03: Formation of Cycloheptatriene N O N2 100% N O tBu tBu A6 A7 Rh2(OAc)4, CH2Cl2 Employing diazo precursors, electrophilic ar omatic substitution is another general route to gain access to the heterocyclic com pounds. For example, in the presence of nafion-H(an acid), electrophili c aromatic substitution of diazo precursors such as A8 gives rise to the formation of indole A9 along with -lactam A10 .5 Figure 1-04: Formation of Indole via Electrophilic Aromatic Substitution N MeO O O N2 OMe N CO2Me MeO O N O PMP MeO2C Nafion-H PhCH3+ A8A9A10 Isoquinolone formation via electrophilic arom atic substitution of diazo precursors such as A11 is also known, as shown in Figure 1-05. However, the harsh conditions employed and concomitant regioisomer fo rmations often pose serious problems.6

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4 Figure 1-05: Formation of Isoquinolo nes via Electrophilic Substitution N R' O N2 R TFA CCl4A11A12 N O R R' The drawbacks of previous methodologies were tackled by our investigation of novel Rh (II) catalyzed formal aromatic CH insertion methodology and its applications to the first enantioselective synthesis of praziquantel and synthetic model studies on Ecteinascidin 743.

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5 References 1) For a comprehensive account of the chem istry and biology of these compounds, see: (a) Scott, J.D.; Williams, R.M. Chem. Rev. 2002, 102, 1669. (b) Myers, A.G.; Kung, D.W. J. Am. Chem. Soc. 1999, 121, 10828. (c) Myers, A.G.; Kung, D.W.; Z hong, B.; Movassaghi, M.; Kwon, S. J. Am. Chem. Soc. 1999, 121, 8401. (d) Kubo, A.; Saito, N.; Yamato, H.; Masubuchi, K.; Nakamura, M. J. Org. Chem. 1988, 53, 4295. (e) Saito, N.; Harada, S.; Yamashita, M.; Saito, T.; Yamaguchi, K.; Kubo, A. Tetrahedron 1995, 51, 8213. (f) Fukuyama, T.; Sachleben, R.A. J. Am. Chem. Soc. 1982, 104, 4957. (g) Fukuyama, T.; Yang, L.; Ajeck, K.L.; Sachleben, R.A. J. Am. Chem. Soc. 1990, 112, 3712. (h) Zhou, B.; Edmondson, S.; Padron, J.; Danishefsky, S.J. Tetrahedron Lett. 2000, 41, 2039. (i) Zhou, B.; Guo, J.; Danishefsky, S.J. Tetrahedron Lett. 2000, 41, 2043. (j) Zhou, B.; Guo, J.; Danishefsky, S.J. Org Lett. 2002, 4, 43. 2) Magnus, P.; Matthews, K.S.; Lynch, V. Org Lett 2003, 5, 2181.

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6 3) Corey, E.J.; Gin, D.Y.; Kania, R.S. J. Am. Chem. Soc. 1996, 118, 9202 4) Padwa, A.P.; Austin, D.J.; Price, A.T. ; Semones, M.A.; Doyle, M.P.; Protopopova, M.N.; Winchester, W.R.; Tran, A. J. Am. Chem. Soc. 1993, 115, 8669. Wee, A.G.; Liu, B. Tetrahedron 1994, 50, 609. Rishton, G.M.; Schwartz, M.A. Tetrahedron Lett 1988, 29, 2643. (a) Pedrosa, R.; Andres, C.; Iglesias, J.M. J. Org. Chem. 2001, 66, 243. (b) Shah, R.; Vaghani, D.; Merchant, J. J. Org. Chem. 1961, 26, 3533. (c) Bennington, F.; Morin, R.D. J. Org. Chem. 1961, 26, 194. 5) Silveira, C.C.; Bernardi, C.R.; Braga, A.L.; Kaufman, T.S. Tetrahedron Lett. 1999, 40, 4969 6) Morimoto, T.; Suzuki, N.; Achiwa, K. Tetrahedron Asymm. 1998, 9, 183

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7 Chapter Two Efforts toward the First Enantioselect ive Total Synthesis of Praziquantel Introduction Praziquantel is a well-known effective antihelmintic drug,1 used worldwide in the treatment of schistosomiasis. Current st astistics suggest that 150 million people are infected with schistosomiasis,2 and praziquantel plays crucial role in curbing this disease. Although several synt hetic strategies 3 have emerged in literature, the results are still a far cry from being ideal, as show n in Figure 2-01. Original synthesis of praziquantel was achieved by the formation of piperazine ring from 1-aminomethyltetrahydroisoquinoline ring B2 the main disadvantage of this synthetic strategy was the requirement of a catalytic hydrogenation step with high pressure (ca. 100 atm) to construct the tetrahydroisoquinoline B2 from isoquinoline 4. Another strategy employed hydroxypiperazinones B3 which were prepared by the pa rtial reduction of piperazine-2, 6-dione, to form an isoquinoline ring system 5, however, multi-step synthetic sequences or vigorous reaction co nditions were required.

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8 Figure 2-01: Previous Synthetic Strategies NH NH R N N O R N N O R HO B1 B2 B3 Predicated on our investigation of Rh (II) catalyzed intramolecular C-H insertion leading to regioselective and stereoselective formation of -lactams,6 we decided to expand this methodology to the construction of isoquinolones, in which crucial C-C bond formation would involve intramolecular aromatic C-H insertion.

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9 Results and Discussion Our synthetic strategy of chiral praziqua ntel took advantage of diazo precursor that can be easily obtained fr om chiral L-alpha-phenylglycine B4 as shown in figure 202. We expected that the el ectrophilic metallocarbenoid de rived from diazo precursor would lead to the intramolecualr aromatic C-H insertion product B6 by virtue of being less reactive, due to the elegant installation of -phenylsulfonyl group which fine-tunes the reactivity of the metallocarbenoid center. In addition, N, O-ke tal ring would provide the requisite rigidity to the system so as to prevent the formation of regioisomers. The key reactions in our novel synthesis of ch iral praziquantel include: intramolecular aromatic C-H insertion of diazo precursor B5 coupling of secondary amine B7 with 2(Cyclohexylcarbonylamino) acetic acid, a nd final intramolecu lar cyclization. Figure 2-02: Retrosynthetic Anal ysis of Chiral Praziquantel CO2H NH2 PhO2S N O N2 O N O O PhO2S N N O O H N H N O O OMs NH OTBDMS B4B5B6 B7 B8 B9 CyclizationCoupling Aromatic C-H Insertion Diazo Transfer H H H

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10 Isoquinolone formation by Intramolecular Aromatic C-H Insertion We launched our synthesis of praziquante l with chiral L-alpha-phenylglycine. Reduction of L-alpha-phenylglycine B10 by LAH in THF afforded L-alphaphenylglycinol B11 followed by ketalization to give N, O-ketal B12 N-acylation of secondary amine with -bromoacetyl bromide followed by the treatment with benzenesulfinic acid sodium salt afforded -phenylsulfonylacetamide B13 Diazo transfer by p -ABSA and DBU yielded -diazo-phenylsulfonylacetamide B14 which underwent intramolecular aromatic C-H insertio n smoothly with the assistance of catalyst dirhodium perfluorobutyrate in refluxing dichloromethane to give isoquinolone B15 as a single diastereomer, as shown in figure 2-03. The stereochemistry of the newly formed stereogenic center was unequivocally determined by X-ray crystallography.

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11 Figure 2-03: Isoquinolone Formation by Intramolecular Aromatic C-H Insertion CO2H NH2 LiAlH4 THF NH2 OH O HN Acetone:DCE (1:1) reflux for 8h 1) BrCH2COBr 0C to r.t. TEA, CH2Cl22) PhSO2Na, DMF O N PhO2S O reflux for 8h O N PhO2S O N2 p-ABSA, DBU CH3CN, 0C N O O PhO2S H cat. Rh2(pfb)4CH2Cl2, reflux for 8h quantitative yield quantitative yield 70%, for two steps 90% 90% B10 B11 B12 B13 B14 B15 One of the important issues of this novel methodology is the mechanism of the reaction. In order to rule out the possibil ity that the reaction pr oceeds via electrophilic aromatic substitution, reactions were carried out using different protic acids, also the electron-donating 3-OMe group wa s installed to further enha nce the electron density of the aromatic ring. Use of 10 mol% protic aci d at higher temperature led to the formation of isoquinolone in small amount, but it wa s accompanied by considerable product decomposition (entry 1). However, the reac tion did not proceed at all in low boiling solvents like dichloromethane (entry 2). Furthermore, the r eaction did not go to completion when a smaller amount of catalyst was used (entry 3), as shown in Table 201.

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12 Table 2-01: Effect of Protic Acids O N PhO2S O N2 N O O PhO2S OMe OMe Yield 25% conditions 10 mol% pfb 10 mol% pfb No reaction solvent CH2Cl22 mol% Rh2(OAc)4, 5 mol% pfb63 % CH2Cl22 mol% Rh2(OAc)468 % CH2Cl2C6H6B16B17 time 1 h 24 h 0.5 h 0.75 h 2 mol% Rh2(OAc)4, 5 mol% AcOH92 % CH2Cl20.5 h entry 1 2 3 4 5 Based on these results, we postulated that the reaction proceeded via formation of electrophilic rhodium carbenoid B19 which was then attacked by the electron-rich aromatic ring. The phenylsulfonyl group th en rearranged itself into a more thermodynamically stable position, so as to make C-H and C-Rh bond syn-periplanar to each other, and hence facilitating hydr ogen transfer, as shown in Figure 2-04.

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13 Figure 2-04: Mechanism of Formal Aromatic C-H Insertion O N PhO2S O N2 O N O O N H O PhO2S O N H O PhO2S Rh H H H PhO2S Rh H N H PhO2S O H O B18B19B20 B21 B22 Rh Coupling with 2-(Cyclohexylca rbonylamino) Acetic Acid Dephenylsulfonylation followed by deketalization of isoquinolone B23 afforded acetate B25 Amido acetate was then completely reduced to give amino alcohol B26 In order to set the stage for th e crucial coupling with 2-(c yclohexylcarbonylamino) acetic acid, the hydroxyl group of the amino alcohol has to be selectively protected over the amino group. In the course of our synthesis, we first tried to prot ect the hydroxyl group with TBDMSCl and imidazole, only a trace amount of de sired product was observed. The use of a more reactive silylating agent TBDMS triflate resulted in the protection of both amino and hydroxyl groups. The selectiv e protection problem was circumvented by fine-tuning the reactivity of the silylating ag ent. Selective prot ection of the hydroxyl group was achieved by employing TBDMSCl in the presence of TEA to give the protected amino alcohol B27 Finally, the crucial coupl ing of the protected amino

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14 alcolhol B27 with 2-(cyclohexylcarbonylamino) acetic acid was accomplished on treatment with HOBT, EDCI, a nd TEA, as shown in Figure 2-05. Figure 2-05: Coupling with 2-(Cyclo hexylcarbonylamino) Acetic Acid N O O H N O O H PhO2S Activated Zn TiCl4,THF HBr/HOAc NH O H OAc LiAlH4THF NH H OH TBDMSCl TEA,DMAP CH2Cl2NH H OTBDMS HO H N O O HOBT EDCI TEA DMF N H H N O O OTBDMS B23 B24B25 B26B27 B28 95% 70% 85% 0C to r.t. reflux for 8h 80% Intramolecular Cyclization TBDMS deprotection of the coupling product B28 by TBAF afforded alcohol B29 we were poised to explore the final intramolecular cycliz ation. We considered that two competing factors would come into pl ay to effect the final outcome of the intramolecular cyclization: the tendency to form six-membered ring would be the favorable factor, and the weak nucleophilic ity of the amide nitrogen would be the unfavorable factor. We tried to cyclize B29 by using methanesulfonyl chloride and TEA, but it failed to afford the desired intram olecular cyclization pr oduct praziquantel, as shown in Figure 2-06. Efforts to clear the fina l hurdle of cyclization will be continued in

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15 our research group. Figure 2-06: Intramolecular Cyclization N H H N O O OTBDMS B28 TBAF N H H N O O OH B29 MsCl TEA CH2Cl2N H O N O B30

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16 Conclusion In conclusion, we have developed a novel and efficient methodology for the synthesis of isoquinolones via intramolecular aromatic C-H insertion. The isoquinolone was obtained as a single regi oand diastereomer. This methodology can be applied to construct various chiral isoquinolones, and these isoquinolones can be further functionalized to synthesize a slew of biologically important natural products.

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17 Experimental Section General Methods All experiments were performed under nitrogen atmosphere, using glassware dried by oven or flame. All reagents were purchased from ACROS and Aldrich chemical Co. Dichloromethane was distilled over calciu m hydride prior to use. Analytical thinlayer chromatography (TLC) was performed on precoated glass-backed 60 silica gel (0.25 mm thickness) and visualized with a 254 nm UV light. TLC pl ates were further visualized with I2 and/or ninhydrin solu tion (0.4 gm in 100 ml n -butanol + 1 ml acetic acid). All reactions were worked up after the complete consumption of starting materials unless specified otherwise. Flash chromatogr aphy was carried out using silica gel 60 (particle size 200 mesh). Unless otherwise st ated, all NMR spectra were recorded on 250 or 360 MHz Bruker spectrometers, using CHCl3 ( H = 7.26 ppm) or C = 77.00 ppm) as an internal standard.

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18 O N PhO2S O B13 p-ABSA, DBU CH3CN, 0C 90% O N PhO2S O N2 B14 Formation of -Diazo-(phenylsulfonyl)acetamide B14 Into a solution of 2-benzenesulfonyl-1-(2,2dimethyl-4-phenyl-oxazo lidin-3-yl)ethanone (359 mg, 1.00 mmol) in acetonitrile (5.00 ml 0.2 M) were added successively ABSA (360 mg, 1.5 mmol, 1.5 eq.) and DBU (0.38 ml, 2.5 mmol., 2.5 eq.) and stirred under nitrogen atmosphere for 1.5 hrs at 0 C. At the end of the reaction, the solvent was removed under reduced pressure and the resi due was dissolved in diethyl ether. The organic layer was successively washed with 1 N NaOH followed by water. The organic layer was dried over anhydrous sodium sulfate and concentr ated under reduced pressure. The crude diazo compound was subjected to flash column chromatography to yield analytically pure diazo compound B14 (300 mg, 78%) as a yellow solid. 1H NMR (250 MHz) 1.50 (s, 3 H), 1.68 (s, 3 H), 3.67 (t, J = 8.5 Hz, 1 H), 4.22 (t, J = 7.1 Hz, 1 H), 4.71 (t, J = 6.2 Hz, 1 H), 7.40 (m, 10 H). 13C NMR (62 MHz) 24.36, 61.48, 72.12, 74.43, 97.38, 125.31, 127.63, 128.38, 128.81, 129.06, 133.48, 137.95, 141.67, 154.86

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19 O N PhO2S O N2 N O O PhO2S H cat. Rh2(pfb)4CH2Cl2, reflux for 8h 90% B14B15 Formation of Isoquinolone B15 via Intram olecular Aromatic C-H Insertion of -Diazo(phenylsulfonyl)acetamide B14 Rh2(pfb)4 (22 mg, 5 mol%) was a dded to a solution of -diazo-(phenylsulfonyl)acetamide B14 (0.15 g, 0.41 mmol) in dry dichloromethan e (17 mL, C = 0.025 M). The mixture was refluxed for 8 hrs under N2, cooled to r.t., and concentrated. The residue was chromatographed to give isoquinolone B15 as a white crystal. (144 mg, 90%). 1H NMR (250 MHz) 1.45 (s, 3 H), 1.62 (s, 3 H), 3.74 (ABX JAB = 9.2 Hz, JAX = 8.4 Hz, 1 H), 4.53 ( JABX, JA B = 9.2 Hz, JBX = 6.3 Hz, 1 H), 4.86 (s, 1 H), 4.98 (dd, J1 = 6.2 Hz, J2= 10.1 Hz, 1 H ), 6.98 (m, 1 H), 7–7.77 (m, 8 H).13C NMR (62 MHz) 23.21, 25.08, 58.16, 68.19, 74.49, 95.73, 123.96, 125.44, 128.32, 129.04, 129.23, 129.69, 130.94, 134.97, 137.11, 157.69.

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20 N O O H N O O H PhO2S Activated Zn TiCl4,THF B23 B24 95% 0C to r.t. Formation of Dephenylsulfonated Isoquinolone B24 S.M. B23 was dissolved in THF (C=0.2 M) at 0 C, then 6.0 eq. of activated zinc was added to the solution, followed by the addition of 2.0 eq. of titanium tetrachloride in 1M dichloromethane solution, kept vi gorously stirring at 0C for 30 min, and the ice bath was removed, and kept stirring at room temperat ure under nitrogen atmosphere for 4 h. At the end of the reaction, a small amount of water was added to the reaction mixture, then extracted three times with dichloromethane, the organic layer wa s dried over anhydrous sodium sulfate and concentrated under re duced pressure. The crude mixture was subjected to flash column chromatography to give the dephenylsulfonated isoquinolone B24 (95%) as a green solid. 1H NMR (250 MHz) 1.48 (s, 3 H), 1.67 (s, 3 H), 3.51 (q, J= 18.3 Hz, 2 H), 3.88 (t, J = 8.7 Hz, 1 H), 4.56 (t, J= 6.4 Hz, 1 H), 4.78 (m, 1 H), 6.927.43 (m, 4 H). 13C NMR (62 MHz) 23.50, 25.40, 39.62, 57.60, 67.60, 77.24, 94.71, 123.12, 126.68, 127.09, 127.85, 132.95, 133.17, 165.50.

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21 N O O H HBr/HOAc NH O H OAc B24B25 70% Formation of Acetate B25 via Deketa lization of the N, O-Ketal Ring Into S.M. B24 was added hydrobromic acid with acetic acid, kept vigorously stirring at room temperature for 8 h. At the end of the reaction, air-blew mo st of the hydrobromic acid. Then the brown reaction mixture was ke pt at 0C, into which saturated sodium bicarbonate solution was added cautiously, and when the reaction mixture solution turned into weakly basic, extracted with ethyl aceta te three times. The organic layer was dried over anhydrous sodium sulfate and concentr ated under reduced pressure. The crude mixture was then subjected to flash column chromatography to give the pure acetate B25 (70%) as a brown solid. 1H NMR (250 MHz) 2.06 (s, 3 H), 3.55 (m, 2 H), 4.11 (m, 1 H), 4.33 (dd, J1=3.8 Hz, J2=11.1Hz, 1 H), 4.73 (m, 1 H), 6.93-8.05 (m, 4 H). 13C NMR (62 MHz) 20.66, 35.59, 54.91, 67.90, 76.91, 125.98, 126.74, 127.96, 130.07, 131.61, 170.52, 171.63.

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22 NH O H OAc LiAlH4THF B25 85% reflux for 8h NH H OH B26 Formation of Complete Reduction Product Amino Alcohol B26 Acetate B25 was dissolved in THF (C=0.4 M) at 0C, and then 4.0 eq. of lithium aluminum hydride was added to the solution, kept vigorously stirri ng at 0C for 30 min, and then the ice bath was removed, and kept refluxing for 8h. Let the reaction mixture cool down to room temperature, and then ke pt at 0C, small amount of sodium sulfate decahydrate was added to quench the reacti on. The resulting reaction mixture was filtered by vacuum filtration, and the solid was washed three times with THF, the organic layer was dried over anhydrous sodium sulfate and concentrat ed under reduced pressure. The resulting mixture was subjected to flas h column chromatography to give the amino alcohol B26 (85%) as a light yellow oil. 1H NMR (250 MHz) 2.74-2.79 (m, 2 H), 3.053.10 (m, 2 H), 3.59-3.81 (m, 2 H), 4.014.05 (m, 1 H), 7.06-7.33 (m, 4 H).

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23 NH H OH TBDMSCl TEA,DMAP CH2Cl2NH H OTBDMS B26B27 80% Formation of TBDMS Protected Amino Alcohol B27 Amino alcohol B26 was dissolved in anhydrous dich loromethane, 2.5 eq. of TEA was added, then 1.2 eq. of t-butyl-dimethylchloro silane and catalytic amount of DMAP was added, and kept vigorously stirring at room temperature for 24 h. At the end of the reaction, a small amount of water was added into the reaction mixture, and extracted with dichloromethane three times. The organic la yer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, then the crude mixture was subjected to flash column chromatography to give th e TBDMS protected amino alcohol B27 (80%) as a light yellow solid. 1H NMR (250 MHz) 0.048 (d, J=7.6 Hz, 6 H), 0.88 (s, 9 H), 2.652.81 (m, 2 H), 2.88-2.97 (m, 1 H), 3.16-3.20 (m 1 H), 3.70-3.85 (m, 2 H), 4.03-4.05 (m, 1 H), 7.10-7.56 (m, 4 H).

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24 NH H OTBDMS HO H N O O HOBT EDCI TEA DMF N H H N O O OTBDMS B27 B28 Formation of the Coupled Product B28 via Coupling Reaction of the TBDMS Protected Amino Alcohol with 2-(Cyclohexyl carbonylamino) Acetic Acid 1.2 eq. of 2-(Cyclohexylcarbonylamino) acetic acid was dissolved in DMF (C=0.2 M), then 1.44 eq. of HOBt was added, followed by addition of 1.44 eq. of TEA, then addition of 1.44 eq. of EDCI, kept vigorously stirri ng for 1h, finally, the solution of TBDMS protected amino alcohol B27 (dissolved in small amount of DMF) was added to the reaction mixture. The reaction mixture was ke pt vigorously stirring fo r 4h. At the end of the reaction, a small amount of water was added, and extract ed with ethyl acetate three times, the organic layer was dried over anhydr ous sodium sulfate a nd concentrated under reduced pressure, then the crude mixture wa s subjected to flash column chromatography to give the coupling product B28 as a white solid. 1H NMR (250 MHz) -0.15 (d, J=8.3 Hz, 6 H), -0.03 (d, J=10.6 Hz, 6 H), 0.68 (s 9 H), 0.80 (s, 9 H), 1.22-2.15 (m, 11 H), 2.85 (s, 2 H), 2.92 (s, 2 H), 3.52-4.38 (m, 5 H), 4.81-4.95 (m, 2 H), 7.06-7.97 (m, 4 H).

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25 References 1) Sharma, S.; Dubey, S.K.; Iyer, R.N. Progress in Drug Research Jacker, E., Eds, Birkhauser Verlag, Basel, 1980, Vol. 24, p 217 2) (a) Redman, C.A.; Robertson, A.; Fallon, P.G.; Modha, J.; Kusel, J.R.; Doenhoff, M.J.; Martin, R.J. Parasitology Today 1996, 12, 14. (b) Bennett, J.L.; Day, T.; Feng-Tao, L.; Ismail, M.; Farghaly, A. Exp. Parasitol 1997, 87, 260. (c) Kusel, J.; Hagan, P. Parasitology Today 1999, 15, 352. (d) Doenhoff, M.J.; Kimani, G.; Cioli, D. Parasitology Today 2000, 16, 364 (e) Day, T.A.; Bennett, J.L.; Pax, R.A. Parasitology Today 1992, 8, 342 3) (a) Seubert, J.; Pohlke, R.; Loebich, F. Experientia 1977, 33, 1036 (b) Yuste, F.; Pallas, Y.; Barrios, H.; Ortiz, B.; Sanchez-Obregon, R. J. Heterocycl. Chem 1986, 23, 189. (c) Frehel, D.; Maffrand, J.-P. Heterocycles 1983, 20, 1731. 4) Seubert, J.; Pohlke, R.; Loebich, F. Experientia 1977, 33, 1036

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26 5) (a) Yuste, F.; Pallas, Y.; Barrios, H.; Ortiz, B.; Sanchez-Obregon, R. J. Heterocycl. Chem 1986, 23, 189. (b) Frehel, D.; Maffrand, J.-P. Heterocycles 1983, 20, 1731. 6) (a) Yoon, C.H.; Zaworotko, M.J.; Moulton, B.; Jung, K.W. Org Lett. 2001, 3, 3539. (b) Yoon, C.H.; Nagle, A.; Chen, C.; Gandhi, D.; Jung, K.W. Org Lett. 2003, 5, 2259.

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27 Chapter Three Synthetic Model Studies on Ecteinascidin 743 Introduction Ecteinascidin 743 is an extremely potent antitumor agent isolated from a marine tunicate, Ecteinascidia turbinate. 1 The isolation of the ectei nascidins was first reported by Rinehart et al. in 1990. Ecteinascidin 743 is currently undergoing phase II clinical trials and attracting considerable attention due to its remarkable biological activities. The mechanism of action of the ecte inascidins has been studied by several groups. It has been shown that Ecteinascidin 743 has a similar stru cture to that of saframycin S, indicating that DNA alkylation should be indeed possible. 2 The alkylation takes place in the minor groove, as does alkylation with the saframyc ins. The alkylated DNA substrate exhibits a bend or widening of the minor groove, pr esumably due to the C-subunit of the ecteinascidins. The C-subunit, which is perpen dicular to the rest of the molecule, makes the ecteinascidins unique from the saframyc ins, which are fairly flat. It has been postulated that this bend in DNA disrupts DNAprotein binding and may be, in part, the source of the enhanced biologi cal activities of the ecteinasc idins. The novelty of its structure, the meager availability from natural sources, and th e unique mechanism of action 3 has made Ecteinascidin 743 a very attrac tive and important synthetic target, as shown in Figure 3-01.

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28 Figure 3-01: Ecteinascidin 743 N NMe HOH H AcO Me S O NH HO MeO O HO OMe Me O O Ecteinascidin 743 (antitumor) The first total synthesis of Ecteinascidin 743 4 was accomplished by E. J. Corey in 1996 employing the coupling of two optically active fragments as seen in their saframycin A synthesis. Starting with hexacycle C1 a selective hydroxylation was accomplished using phenylselenic anhydride. Removal of the silyl ether followed by esterification with a diprotected cysteine derivative provided C2 Elimination of the tertiary alcohol under Swern conditions allowe d for cyclization of the thiol to form C3 Removal of the Alloc carbamate followed by transamination afforded -keto lactone C4 The final three steps to Ecteinascidin 743 were the condensation of the homobenzylic amine C5 on the ketone followed by removal of the MOM group with TFA and finally conversion of the aminonitrile to the carbinolamine using si lver nitrate and water, as shown in Figure 3-02.

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29 Figure 3-02: Corey’s Total Synthesis of Ecteinascidin 743 N NMe HOH H AcO Me S O NH HO MeO O HO OMe Me O O Ecteinascidin 743 N NMe CN H OH Me MOMO OMe Me O O OTBS H 1)(PhSeO)2O 2)TBAF 3)Alloc-Cys(CH2FI)-OH EDCI, DMAP FI=9-fluorenyl N NMe CN H Me MOMO OMe Me O O H O NHAlloc O S FI DMSO, Tf2O iPr2NEt, t-BuOH (Me2N)2C=N-t-Bu Ac2O N NMe HCN H AcO Me S O NHAlloc O OMe Me O O 1)PdCl2(PPh3)2, Bu3SnH 2)(N-methylpyridinium-4carboxaldehyde)+I-, DBU, (CO2H)2N NMe HCN H AcO Me S O O OMe Me O O O MOMO MOMO 1) 2)TFA, H2O 3)AgNO3, H2O HO MeO NH2 SiO2C1C2 C3 C4 O OH H C5 Carmen Cuevas’ group 5 was able to synthesi ze Ecteinascidin 743 in a semisynthetic fashion star ting from cyanosafracin B 6, which is an antibiotic of bacterial origin, available through fermentation of the bacterial Pseudomonas fluorescens 7. Optimization of the fermentation process has allowed for the synthesis of cyanosafracin B on a kilogram scale, providing a robust, s ophisticated, and cheap starting material for the synthesis of Ecteinascidin compounds, as shown in Figure 3-03.

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30 Figure 3-03: Cuevas’ Formal Sy nthesis of Ecteinascidin 743 N NMe HOH H AcO Me S O NH HO MeO O HO OMe Me O O Ecteinascidin 743 N NMe CN H Me HO OMe Me NH O NH2 O O MeO Cyanosafracin B In 2002, Tohru Fukuyama’s group 8 accomplished an enantioselective total synthesis of Ecteinascidin 743. Their s ynthesis features Ugi’s four-component condensation for a ready access to diketopiperazine C9 and the intramolecular Heck reaction of the cyclic enamide C10 to give tricycle C11 as shown in Figure 3-04.

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31 Figure 3-04: Fukuyama’s Synthesis of Ecteinascidin 743 N NMe HOH H AcO Me S O NH HO MeO O HO OMe Me O O Ecteinascidin 743 N Me NH OH Me Me OMe OBn O O O AcO I NH2OMOM Me O O OTBDPS BnO OMe Me I CO2H BocHN + NC MeO CH3CHO 1)MeOH,reflux(90%) 2)TBAF,THF,r.t.(89%) 3)Ac2O,pyridine,DMAP,r.t.(93%) 4)TFA,anisole,CH2Cl2,r.t. 5)EtOAc,reflux(87% in two steps) C6 N Me HN NH Boc OMOM Me Me OMe OBn O O O TBDPSO I PMP O C7C8 O N Me N OMs Me Me OMe OBn O O O AcO I Boc Pd2(dba)3(5mol%) P(o-tol)3(20mol%) TEA,CH3CN,reflux(83%) N N OMs Me BnO OMe Me O O O AcO I Boc C9 C10 C11

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32 Results and Discussion Despite some progress made in the tota l synthesis of ecteinascidin 743, there is still of vast interest to find a more efficien t synthesis, and we have felt that a convergent synthetic strategy may become a more practical solution. Efficient synthesis of chiral building blocks is crucial for a convergen t synthetic strategy to succeed, and we are ambitious to apply our novel intramolecular aromatic C-H insertion methodology to serve this aim. Ecteinascidin 743 is composed of three tetrahydroisoqui noline moieties, which resemble the three building blocks designed in our synthetic strate gy, the three fragments C12 C13 and C14 will be prepared in an asymmetric manner, and coupled in the order of ( C12 + C13 ) + C14 to secure the Ecteinascidin 743 skeleton, as depicted in Figure 305. Figure 3-05: Jung’s Synthetic Strategy of Ecteinascidin 743 SH NBoc TBSO MeO HO2C N AcO Me O O SO2Ph O O N O OTBS OMe Me SO2Ph H O C12C13 C14 H N NMe HOH H AcO Me S O NH HO MeO O HO OMe Me O O Ecteinascidin 743 One of the strategies we are currently pursuing is the late stage cyclization of

PAGE 43

33 diazo precursor. In order to achieve this goal, we have coupled pyroglutamic acid derivative to phenylglycine methyl ester. Cu rrently, we are inves tigating various diazo transfer conditions as well as different pyroglutamic acid de rivatives to ac hieve optimum conditions for fused ring system. The first route attempted in our synthe tic model studies on Ecteinascidin 743 was with the N -methyl derivative of pyroglutamic acid, as shown in Figure 3-06. Figure 3-06: N -Methyl Derivatives of Pyroglutamic Acid NH OH O O BnBr K2CO3CH3CN reflux NH OBn O O N OBn O O Me MeI NaH,THF at 0C Pd/C MeOH N OH O O Me (COCl)2CH2Cl2N Cl O O Me H2N OMe O Ph TEA,CH2Cl2at 0C N H N O O Me OMe Ph O NaBH4:LiCl (1:1) THF:MeOH(1:1) N H N O O Me OH Ph TEA,CH2Cl2at -20C MsCl N H N O O Me OMs Ph reflux for 30 mins NaOH,EtOH N O Me N O Ph Cl Cl O NaBH4,THF reflux NaI Acetone PhSO2Na DMF N O Me N O Ph PhO2S O H N2 H N O Me N O Ph PhO2S O H H N O Me N O Ph I O H H C12 C13C14 C15 C16 C17 C18 C19C20 C21C22 C23 97% 65% quantitative yield N O Me N O Ph Cl O H H 74% 90% quantitative yield for two steps 85% 80% 80%

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34 Esterification of L-2-pyrroli done-5-carboxylic acid with benzyl bromide afforded benzyl ester C13 N -methylation of pyrrolidone with iodomethane afforded the N methylated benzyl ester C14 hydrogenolysis of the benzyl ester with palladium on carbon afforded the resulting carboxylic acid C15 Generation of acid chloride in situ, followed by coupling with (S)-(+)-2-phenylglyc ine methyl ester hydrochloride, afforded the coupled methyl ester C16 Selective reduction of the coupled methyl ester with sodium borohydride: lithium chlori de (1:1) afforded the alcohol C17 Then we were poised to do the intramolecula r cyclization to install th e crucial oxazoline skeleton. Treatment of the alcohol C17 with methanesulfonyl ch loride and TEA, followed by reluxing in sodium hydroxide in ethanol afforded the oxazoline C19 smoothly. Next three steps were mainly functional group ma nipulations to install the phenylsulfonyl group to the oxazoline ring nitr ogen, so as to set the st age for diazo transfer. N -Acylation and in situ reduction of the resulting N -acylium ion with sodium borohydride afforded the reduced oxazoline C20 with N -( -chloro)-acetyl group at the proper position. The primary chloride C20 was treated with sodium iodide in acetone, namely, Finkelstein reaction, followed by treatment with benzenes ulfinic acid sodium salt, afforded the phenylsulfone C22 Frustratingly, several diazo tran sfer conditions failed to obtain the desired diazo transfer product C23 which was the requisite precursor for our next intramolecular C-H insertion, as shown in Figure 3-07.

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35 Figure 3-07: Failure of Diazo Transfer N O Me N O Ph PhO2S O H N2 H N O Me N O Ph PhO2S O H H C22C23 p-ABSA, DBU CH3CN, 0C 1. p-ABSA, TEA CH3CN, 0C 2. TsN3, DBU CH3CN, 0C 3. TsN3, Pyridine CH3CN, 0C 4. MsN3, TEA CH3CN, 0C 5. Unsuccessful Reaction Conditions Include: The second route was with the N -Boc derivative of pyroglutamic acid, as shown in Figure 3-08.

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36 Figure 3-08: N -Boc Derivatives of Pyroglutamic Acid NH OH O O N OMe O O NaHCO3 quenching at -10C,1h H2N OMe O Ph TEA,CH2Cl2at 0C N H N O Boc OMe Ph O TEA,CH2Cl2at 0C MsCl reflux NaOH,EtOH C12C24 C25 C26 1)SOCl2,MeOH 2)(Boc)2O,DMAP CH3CN Boc 80% for two steps NaBH4,MeOH N OMe O Boc OH (CF3CO)2O TEA,CH2Cl2at -5C N OMe O Boc NaOH,MeOH N OH O Boc HOBt, EDCI NaBH4:LiCl (1:1) THF:MeOH(1:1) N H N O Boc OH Ph N H N O Boc OMs Ph C27 C28 C29 C30 N Boc N O Ph C31 at r.t. for 5h 97% at 0C 90% Esterification of L-2-pyrrolidone-5-ca rboxylic acid by thionyl chloride in methanol afforded methyl ester. N -Boc protection of pyrrolid one with di-tert-butyl dicarbonate afforded the N -Boc protected methyl ester C24 Selective reduction of the resulting N -Boc protected amide with s odium borohydride afforded the N -Boc protected amino alcohol C25 conscientious monitoring and stri ngent control of temperature was crucial in achieving the desired selectivel y reduced amino alcohol, otherwise, side products may ensue, as shown in Figure 3-09.

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37 Figure 3-09: Selective Reduction of N -Boc Protected Pyrrolidone Methyl Ester N OMe O O NaHCO3 quenching at -10C,1h C24 C25 Boc NaBH4,MeOH N OMe O Boc OH NaHCO3 quenching at 0C,1h NaBH4,MeOH N OMe O Boc H2O quenching at -10C,1h NaBH4,MeOH N OMe O Boc OMe After we obtained the N -Boc protected amino alcohol C25 we were ready to do the elimination reaction. Treat ment of the amino alcohol C25 with trifluoroacetic anhydride and TEA in dichloromethan e afforded the elimination product C26 followed by hydrolysis with sodium hydroxide in meth anol gave the resulting carboxylic acid. Coupling of the carboxylic acid with (S)-(+)-2-phenylglycin e methyl ester hydrochloride by treatment with HOBt, EDCI, and TEA in dichloromethane afforded the coupled methyl ester C28 Selective reduction of the c oupled methyl ester with sodium borohydride: lithium chloride (1:1) afforded the alcohol C29 Then we were poised to do the intramolecular cyclization to install the crucial oxazolin e skeleton. Treatment of the alcohol C29 with methanesulfonyl chloride a nd TEA yielded the methanesulfonate C30 but the resulting intramolecular cycli zation failed to give the oxazoline C31 by reluxing

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38 the methanesulfonate C30 in sodium hydroxide in ethanol.

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39 Conclusion In conclusion, we have developed a novel and efficient methodology for the construction of isoquinolones via intramolecula r aromatic C-H insertion. Our audacious and pioneering research in this field will ma ke huge impact on the ingenious syntheses of various natural product s with tetrahydroisoquinoline skel etons, including saframycine, tetrazomine, and ecteinascidin 743, which are considered as possible anticancer drugs. The synthetic model studies on Ecteinascidin 743 helped explore new routes to apply the methodology to the fused ring system and gain insight on how to design a more suitable strategy to accomplish the total synthesis, especially when the intramolecular aromatic CH insertion would take place in the contex t of a big, complicated molecule with diabolical disposition of vari ous functional groups. We are dedicated to further refining and applying this novel methodology to the to tal syntheses of various natural products with tetrahydroisoquinoline skeletons.

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40 Experimental Section General Methods All experiments were performed under nitrogen atmosphere, using glassware dried by oven or flame. All reagents were purchased from ACROS and Aldrich chemical Co. Dichloromethane was distilled over calciu m hydride prior to use. Analytical thinlayer chromatography (TLC) was performed on precoated glass-backed 60 silica gel (0.25 mm thickness) and visualized with a 254 nm UV light. TLC pl ates were further visualized with I2 and/or Ninhydrin solu tion (0.4 gm in 100 ml n -butanol + 1 ml acetic acid). All reactions were worked up after the complete consumption of starting materials unless specified otherwise. Flash chromatogr aphy was carried out using silica gel 60 (particle size 200 mesh). Unless otherwise st ated, all NMR spectra were recorded on 250 or 360 MHz Bruker spectrometers, using CHCl3 ( H = 7.26 ppm) or C = 77.00 ppm) as an internal standard.

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41 NH OH O O BnBr K2CO3CH3CN reflux NH OBn O O C12 C13 97% Formation of Benzyl-(2S)-1-Pyroglutamate C13 L-2-pyrrolidone-5-c arboxylic acid C12 was dissolved in acetonitrile (C=0.2 M), and 1.1 eq. of potassium carbonate was added, then 1.1 eq. of benzyl bromide was added dropwise, kept vigorously stirring under reflux for 8h. At the end of the reaction, acetonitrile was evaporated under reduced pres sure, the resulting mixture was subjected to flash column chromatography to give the benzyl ester C13 (97%). 1H NMR (250 MHz) 2.17-2.44 (m, 4 H), 4.21 (dd, J1=5.4 Hz, J2=8.3 Hz, 1 H), 5.13 (s, 2 H), 5.93 (s, 1 H), 7.24 (m, 5 H).

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42 NH OBn O O N OBn O O Me MeI NaH,THF at 0C C13C14 65% Formation of Benzyl-(2S)-1-Methyl Pyroglutamate C14 Benzyl ester C13 was dissolved in THF (C=0.4 M) at 0C, 1.2 eq. of sodium hydride was added, then 1.3 eq. of iodomethane was added dropwise, kept vigorously stirring for 2h. At the end of the reaction, THF was evaporat ed under reduced pressure. Into the resulting reaction mixture was added a small amount of water, and extracted with ethyl acetate three times, dried over anhydrous sodium su lfate, and concentrated under reduced pressure. The mixture was subjected to flash column chromatography to give the Benzyl(2S)-1-Methyl Pyroglutamate C14 (65%). 1H NMR (250 MHz) 2.10-2.33 (m, 4 H), 2.77 (s, 3 H), 4.07 (dd, J1=5.4 Hz, J2=8.3 Hz, 1 H), 5.14 (s, 2 H), 7.24 (m, 5 H).

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43 N OBn O O Me Pd/C MeOH N OH O O Me C14 C15 quantitative yield Formation of 1-Methyl-(2S )-Pyroglutamic Acid C15 Benzyl-(2S)-1-Methyl Pyroglutamate C14 was dissolved in Methanol (C=0.4 M), catalytic amount of palladium on carbon was added, then put into hydrogenator and subjected to hydrogenolysis for 12 h. At th e end of the reaction, the palladium on carbon was filtered out by vacuum filtration and washed with dichloromethane three times. The organic layer was concentrated under reduced pressure to give the 1-Methyl-(2S) Pyroglutamic acid C15 in quantitative yield. 1H NMR (250 MHz) 2.09-2.58 (m, 4 H), 2.88 (s, 3 H), 4.14 (dd, J1=1.8 Hz, J2=8.2 Hz, 1 H).

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44 (COCl)2CH2Cl2N Cl O O Me H2N OMe O Ph TEA,CH2Cl2at 0C N H N O O Me OMe Ph O C16 74% N OH O O Me C15 Formation of the Coupled Product C16 vi a Coupling Reaction of 1-Methyl-(2S)Pyroglutamic Acid C15 with (S)-(+)-2-Phenylglycine Methyl ester Hydrochloride The carboxylic acid C15 was dissolved in anhydrous di chloromethane (C=0.2 M), and 1.1 eq. of oxalyl chloride was added, and kept vigorously stirring at room temperature for 8 h to form the acid chloride. 1.2 eq. of (S)-(+)-2-phenylglycine methyl ester hydrochloride was dissolved in anhydrous dichloromethane (C=0.4 M), 3.5 eq. of TEA was added, and cooled to 0C, followed by add ition of of the acid chloride mixture. The reaction mixture was kept vigorous ly stirring at 0C for 4 h. At the end of the reaction, a small amount of water was added, and extract ed with dichloromethane three times, the organic layer was dried over anhydrous sodium sulfate and concen trated under reduced pressure, then the crude mixture was subjecte d to flash column chromatography to give the coupling product C16 (74%) as a white solid. 1H NMR (250 MHz) 1.87-2.52 (m, 4 H), 2.68 (s, 3 H), 3.63 (s, 3 H), 4.04 (m, 1 H, ), 5.49 (dd, J1=3.1 Hz, J2=7.2 Hz, 1 H), 7.14-7.80 (m, 5 H).

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45 N H N O O Me OMe Ph O NaBH4:LiCl (1:1) THF:MeOH(1:1) N H N O O Me OH Ph C16 C17 90% Formation of the Reduction Product Phenylglycinol C17 Methyl ester C16 was dissolved in THF (C=0.4 M) at 0C, 3.0 eq. of lithium chloride was added, and the mixture was kept stirring at 0 C for 5 mins, then 3.0 eq. of sodium borohydride was added portionwise, and equal volume of methanol was added dropwise, and the mixture was kept vigorously stirring at 0C for 5 h. At th e end of the reaction, solvents were evaporated under reduced pressure, into the white reaction mixture, a small amount of water was added, and extracted with ethyl acetate th ree times. The organic layer wa s dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the reduced product phenylglycinol C17 (90%) as a white solid.

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46 TEA,CH2Cl2at -20C MsCl N H N O O Me OMs Ph reflux for 30 mins NaOH,EtOH N O Me N O Ph C18 C19 quantitative yield for two steps N H N O O Me OH Ph C17 Formation of Oxazoline C19 vi a Intramolecular Cyclization The phenylglycinol C17 was dissolved in anhydrous dichloromethane (C=0.4 M), then cooled to -20C, and 5.0 eq. of TEA was added, followed by the addition of 2.3 eq. of methanesulfonyl chloride, and kept vigorously stirring for 4 h. At the end of the reaction, a small amount of water was added, and extracted with dichloromethane three times, the organic layer was dried over anhydr ous sodium sulfate a nd concentrated under reduced pressure. The crude mixture was di ssolved in ethanol (C=0.4M), and 5.0 eq. of sodium hydroxide was added, then kept refluxin g for 30 mins. At the end of the reaction, a small amount of water was added, and ex tracted with ethyl acetate three times, the organic layer was dried over anhydrous sodium sulfate and concen trated under reduced pressure to give the oxazoline C19 ( quantitative yield for two st eps) as a light yellow oil. 1H NMR (250 MHz) 1.95-2.33 (m, 4 H), 2.82 (s, 3 H), 4.01-4.14 (m, 1 H), 4.26-4.31 (m, 1 H), 4.57-4.63 (m, 1 H), 5.155.16 (m, 1 H), 7.11-7.30 (m, 5 H).

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47 reflux NaI Acetone N O Me N O Ph I O H H C21 80% Cl Cl O NaBH4,THF C20 N O Me N O Ph Cl O H H 85% N O Me N O Ph C19 Formation of N -Iodoacetyl Oxazoline C21 via N -Acylation and Reduct ion, and Finkelstein Reaction The oxazoline C19 was dissolved in anhydrous THF (C =0.3 M), then cooled to -78C, and 1.1 eq. of chloroacetyl chloride was adde d, kept stirring at -78C for 3 h, followed by portionwise addition of 3.0 eq. of sodium borohy dride at -78C, then the reaction mixture was slowly warmed up to room temperature, and kept vigorously stirring at room temperature for 45 min. At the end of th e reaction, THF was eva porated under reduced pressure, and a small amount of saturated so dium bicarbonate soluti on was added into the reaction mixture, and extracted with ethyl a cetate three times, the organic layer was dried over anhydrous sodium sulfate and concentrat ed under reduced pressure to give the reduced N-chloroacetylated oxazoline C20 Then C20 was dissolved in acetone (C=0.3 M), and 5.0 eq. of sodium iodide was added, re fluxing for 2 h. At the end of the reaction, the reaction mixture was filtere d by vacuum filtration, the orga nic layer was collected and concentrated under reduced pressure to give N -iodoacetyl oxazoline C21

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48 PhSO2Na DMF N O Me N O Ph PhO2S O H H N O Me N O Ph I O H H C21C22 80% Formation of Phenylsulfone C22 The N -iodoacetyl oxazoline C21 was dissolved in DMF (C=0.2 M), and 1.2 eq. of benzene sulfinic acid sodium salt was added, ke pt vigorously stirring at room temperature for 4 h. At the end of the reaction, a sma ll amount of water was added, and extracted with ethyl acetate thr ee times, the organic layer was dr ied over anhydrous sodium sulfate and concentrated under reduced pressure. The crude mixture was subjected to flash column chromatography to give the phenylsulfone C22 (80%) as a white solid. 1H NMR (250 MHz) 1.90-2.30 (m, 4 H), 2.67 (s, 3 H), 3.723.77 (m, 1 H), 3.99-4.04 (m, 2 H), 4.36-4.38 (d, J=5 Hz, 1 H), 4.04-4.34 (m, 1 H) 5.22-5.24 (m, 1 H), 7.19-7.75 (m, 10 H).

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49 NH OH O O N OMe O O C12C24 1)SOCl2,MeOH 2)(Boc)2O,DMAP CH3CN Boc 80% for two steps Formation of Methyl-(2S)-1-(tert-B utoxycarbonyl) Pyroglutamate C24 2.0 eq. of thionyl chloride was added dropwis e to a cooled soluti on of L-2-pyrrolidone-5carboxylic acid in methanol (C=0.3 M). The mixture was allowed to warm to room temperature. After vigorously stirring for 2 h, the solution was evaporated and the residue dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, brine, and dried over anhydrous sodium sulfate. Eva poration of the organic layer gave methyl(S)-pyroglutamate as a crude oil. A solution of this crude ester, 1.2 eq. of di-tert-butyldicarbonate, and 0.1 eq. of DMAP in aceton itrile (C=0.6M) was stirred for 1h, and the residue obtained af ter removal of the solvent wa s subjected by flash column chromatography to give Methyl-(2S)-1 -(tert-Butoxycarbonyl) Pyroglutamate C24 as an oil which solidified under vacuo. 1H NMR (250 MHz) 1.37 (s, 9 H), 1.92-2.52 (m, 4 H), 3.67 (s, 3 H), 4.51 (dd, J1=2.5 Hz, J2=9.1 Hz, 1 H).

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50 N OMe O O NaHCO3 quenching at -10C,1h C24 C25 Boc NaBH4,MeOH N OMe O Boc OH Formation of Methyl-(2S)-1-(tert-B utoxycarbonyl) Amino Alcohol C25 Methyl-(2S)-1-(tert-Buto xycarbonyl) Pyroglutamate C24 was dissolved in methanol (C=0.2 M), and kept at -10C, then 10 eq. of sodium borohydride was added, kept stirring at -10C for 1h. Then the reaction mi xture was quenched by saturated sodium bicarbonate solution, and extracte d with dichloromethane three times. The organic layer was dried over anhydrous sodium sulfate, a nd concentrated under reduced pressure to give the Methyl-(2S)-1-(tert -Butoxycarbonyl) Amino Alcohol C25 as a white oil. Conscientious monitoring and stringent contro l of temperature was crucial in achieving the desired selectively reduced amino alc ohol, otherwise, side products may ensue.

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51 C25 C26 N OMe O Boc OH (CF3CO)2O TEA,CH2Cl2at -5C N OMe O Boc Elimination Product C26 from Methyl-(2S)-1 -(tert-Butoxycarbonyl) Amino Alcohol C25 Methyl-(2S)-1-(tert-Buto xycarbonyl) Amino Alcohol C25 was dissolved in dichloromethane (C=0.5 M), 5.0 eq. of TEA was added and kept stirring at -5C, then 1.2 eq. of trifluoroacetic anhydride was added, kept stirring at -5C for 2h. Then the reaction mixture was quenched by addition of a sma ll amount of water, and extracted with dichloromethane three times. The organi c layer was dried over anhydrous sodium sulfate, and concentrated under reduced pr essure. The crude reaction mixture was subjected flash column chromatogra phy to give the elimination product C26 as a white oil. 1H NMR (250 MHz) 1.39 (s, 6 H), 1.44 (s, 3 H), 2.63 (dd, J1=14.6, J2=20.2, 1 H), 2.94-3.10 (m, 1 H), 3.72 (s, 3 H), 4.51-4.65 (m, 1 H), 4.89 (d, J=10.2, 1 H), 6.54 (d, J=31.7, 1 H).

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52 NaOH,MeOH N OH O Boc C27 at r.t. for 5h 97% C26 N OMe O Boc Formation of Carboxylic Acid C27 by Hydrolysis Methyl ester C26 was dissolved in methanol (C=0.2 M) and then 1.5 eq. of 1.0 N. aqueous NaOH solution was added, kept stirring at room temperature for 5h. Then the reaction mixture was quenched by slow addition of 2.0 N. HCl, as soon as the reaction mixture turned into weakly acidic, ethyl acetate was poured into the reaction mixture, and extr acted with ethyl acetate three times. The organic layer was dried over anhydr ous sodium sulfate, and concentrated under reduced pressure to give carboxylic acid C27 (97%) as a white solid.

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53 H2N OMe O Ph TEA,CH2Cl2at 0C N H N O Boc OMe Ph O N OH O Boc HOBt, EDCI C27 C28 Formation of the Coupled Product C28 via Co upling Reaction of the Carboxylic Acid C27 with (S)-(+)-2-phenylglycine methyl ester hydrochloride The carboxylic acid C27 was dissolved in anhydrous dich loromethane (C=0.4 M) at 0C, then 1.2 eq. of HOBt was added, followed by a ddition of 2.4 eq. of TEA, then addition of 1.2 eq. of EDCI, kept vigorously stirring at 0C for 1h, finally, the solution of (S)-(+)-2phenylglycine methyl ester hydrochloride (d issolved in small amount of anhydrous dichloromethane) was added to the reaction mixture. The reaction mixture was kept vigorously stirring at 0C for 4h. At the end of the reaction, a small amount of water was added, and extracted with ethyl acetate thr ee times, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressu re, then the crude mixture was subjected to flash column ch romatography to give the coupling product C28 as a white solid. 1H NMR (250 MHz) 1.45 (s, 9 H), 2.90 (2 H), 3.71 (s, 3 H), 4.60 (1 H), 5.02 (t, J=1.8, 1 H), 5.56 (d, J=7. 2, 1 H), 6.48 (1 H), 7.32 (m, 5 H).

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54 N H N O Boc OMe Ph O NaBH4:LiCl (1:1) THF:MeOH(1:1) N H N O Boc OH Ph C28 C29 at 0C 90% Formation of the Reduction Product Phenylglycinol C29 Methyl ester C28 was dissolved in THF (C=0.4 M) at 0C, 3.0 eq. of lithium chloride was added, kept stirring at 0C for 5 mins, then 3.0 eq. of sodium borohydride was added portionwise, and equal volume of methanol wa s added dropwise, kept vigorously stirring at 0C for 5 h. At the end of the reaction, all solvents we re evaporated under reduced pressure, into the white reaction mixture, a small amount of water was added, and extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate, and concentrated under re duced pressure to gi ve the reduced product phenylglycinol C29 (90%) as a white solid. 1H NMR (250 MHz) 1.48 (s, 6 H), 1.57 (s, 3H), 2.60 (m, 1 H), 3.00 (m, 2 H), 3.89 (s, 2 H), 4.70 (m, 1 H), 5.10 (t, J=6.3, 1 H), 6.48 (1 H), 7.30 (m, 5 H).

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55 N H N O Boc OH Ph C29 TEA,CH2Cl2at -20C MsCl N H N O Boc OMs Ph C30 Formation of the Methanesulfonate C30 Phenylglycinol C29 was dissolved in dichloromethane (C =0.4 M) at -20C, and 5.0 eq. of TEA was added, then 2.3 eq. of methanesul fonyl chloride was added dropwise, kept vigorously stirring at -20C for 4h. At the end of the reaction, a small amount of water was added to quench the reaction mixture, and extracted with dichloromethane three times. The organic layer was dried over a nhydrous sodium sulfate, and concentrated under reduced pressure to give the product methanesulfonate C30 (90%). 1H NMR (250 MHz) 1.40 (s, 9 H), 2.72 (m, 1 H), 2.96 (m, 1 H), 3.14 (s, 3 H), 4.07-4.23 (m, 2 H), 4.72-5.26 (m, 3 H), 6.47 (1 H), 7.30 (m, 5 H).

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56 References 1) (a) Rinehart, K.L.; Shield, L.S. Topics in Pharmaceutical Sciences ; Breimer, D.D.; Crommelin, D.J.A., Midha, K.K., Eds.; Amst erdam Medicinal Press: Noodwijk, The Netherlands, 1989; p 613. (b) Rinehart, K.L.; Holt, T.G.; Fregeau, N. L.; Keifer, P.A.; Wilson, G.R.; Perun, T.J.; Sakai, R.; Thompson, A.G.; Sthroh, J.G.; Shield L.S.; Seigler, D.S.; Li, L.H.; Martin, D.G.; Grimmelikhuijzen, C.J.P. Gade, G.J. J. Nat. Prod. 1990, 53, 771. (c) Rinehart, K.L.; Sakai, R.; Holt, T.G.; Fregeau, N.L.; Perun, T.J.; Seigler, D.S.; Wilson, G.R.; Shield. Pure Appl. Chem. 1990, 62, 1277. (d) Rinehart, K.L.; Holt, T.G.; Fregeau, N.L.; Stroh, J.G.; Keifer, P.A.; Sun, F.; Li, H.; Martin, D.G. J. Org. Chem. 1990, 55, 4512. (e) Wright, A.E.; Forleo, D.A.; Gunawardana, G.P.; Gunasekera, S.P.; Koehn, F.E.; McConnell, O.J. J. Org. Chem. 1990, 55, 4508. (f) Sakai, R.; Rinehart, K.L.; Guan, Y.; Wang, H. J. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 11456. (g) Sakai, R.; Jares-Erijman, E.; Manzan ares, I.; Elipe, M.; Rinehart, K.L. J. Am. Chem. Soc. 1996, 118, 9017. 2)

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57 (a) Pommmier, Y.; Kohlhagen, G.; Bailly, C.; Waring, M.; Mazumder, A.; Kohn, K.W. Biochemistry 1996, 35, 13303. (b) Moore, R.M.; Seaman, F.C.; Hurley, L.H. J. Am. Chem. Soc. 1997, 119, 5475. c) Moore, R.M.; Seaman, F.C.; Wheelhouse, R.T.; Hurley, L.H. J. Am. Chem. Soc. 1998, 120, 2490. (d) Moore, R.M.; Seaman, F.C.; Hurley, L.H. J. Am. Chem. Soc. 1998, 120, 9973. (e) Seaman, F.C.; Hurley, L.H. J. Am. Chem. Soc. 1998, 120, 13028. (f) Zewail-Foote, M.; Hurley, L.H. J. Med. Chem. 1999, 42, 2493. 3) (a) Jin, S.; Gorfajin, B.; Faircloth. G.; Scotto, K.W. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 6775. (b) Minuzzo, M.; Marchini, S.; Broggini, M.; Faircloth, G.; D’Incalci, M.; Mantovani, R. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 6780. 4) Corey, E.J.; Gin, D.Y.; Kania, R. J. Am. Chem. Soc. 1996, 118, 9202. 5) Cuevas, C.; Perez, M.; Martin, M.J.; Chic harro, J.L.; Fernadez-R ivas, C.; Flores, M.; Francesch, A.; Gallego, P.; Zarzuelo, M.; de la Calle, F.; Garcia, J.; Polanco, C.; Rodriguez, I.; Manzanares, I. Org. Lett. 2000, 2, 2545. 6) Tsuji Naoki, Japanese Patent JP 59225189, 1985.

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58 7) Ikeda, Y.; Idemoto, H.; Hirayama, F.; Yamamoto, K.; Iwao, K.; Asao, T.; Munakata, T. J. Antibiot. 1983, 36, 1279. 8) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552

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59 Appendices

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60 Appendix A Selected 1H and 13C NMR Spectra

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61 Appendix A (Continued)

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Efforts toward the first enantioselective total synthesis of praziquantel and synthetic model studies on ecteinascidin 743 by novel aromatic C-H insertion methodology
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by Chiliu Chen.
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[Tampa, Fla.] :
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Thesis (M.S.)--University of South Florida, 2004.
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ABSTRACT: The thesis is composed of three chapters. The aim of this thesis is to apply the novel dirhodium perfluorobutyrate-catalyzed intramolecular aromatic C-H insertion methodology to the enantioselective total synthesis of praziquantel and synthetic model studies on ecteinascidin 743, which belongs to the important tetrahydroisoquinoline family. The first introductory chapter deals with the biological significance and previous synthetic methodologies. Our novel methodology is based on dirhodium perfluorobutyrate-catalyzed intromolecular aromatic C-H insertion reaction, which is crucial in the pivotal carbon-carbon bond formation when constructing isoquinolone moiety, which is ubiquitous in numerous natural products of significant biological and pharmacological activities. The second chapter takes on the first enantioselective total synthesis of praziquantel, an antihelmintic drug. Praziquantel is used worldwide to treat schistosomiasis, which has tremendous impact on the global fight on this disease affecting 150 million people. We believe this is the first asymmetric total synthesis to date, which is distinct from previous racemic syntheses reported. We also shed light on the mechanistic aspect of this key reaction to rationalize the superb regioselectivity and stereoselectivity achieved. The third chapter explores the synthetic model studies on ecteinascidin 743, a tetrahydroisoquinolone family natural product with significant antitumor and antimicrobial activities. Several different synthetic routes were attempted, including the N-Methyl and the N-Boc routes, and the results achieved contributed significantly to our final synthetic plan of the target molecule.
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