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Total synthesis of streptonigrone Chan, Bryan Ka Ip 2007

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TOTAL SYNTHESIS OF STREPTONIGRONE by BRYAN KA IP CHAN B.Sc, The University of British Columbia, 2005 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA August 2007 © Bryan Ka Ip Chan, 2007 Abstract This thesis describes the total synthesis of streptonigrone. The centerpiece of our route to the target molecule is a facile one-pot construction of 3-alkylpyridones developed in our laboratory. The quinoline segment of the target molecule, prepared through a Conrad-Limpach synthesis, was condensed with 2-benzyloxy-3,4-dimethoxybenzaldehyde to afford a chalcone intermediate suitable for our pyridone-forming reaction. The assembly of the central 3-methylpyridone ring of the natural product was then accomplished through the merger of the chalcone with 2-cyanopropanamide. Functionalization of the pyridone was then completed through an anionic sequence. n Table of Contents Abstract h' Table of Contents hi List of Tables i v List of Figures v List of Schemes V i List of Abbreviations : v n i Acknowledgements x ' 1. INTRODUCTION 1 1.1 Biological activity .....1 1.2 Previous syntheses 3 1.2.1 The Weinreb synthesis of streptonignn J 1.2.2 The Kende synthesis of streptonigrin .6 1.2.3 The Boger formal synthesis of streptonigrin 8 1.2.4 The Kende synthesis of lavendamycin methyl ester 9 1.2.5 The Boger synthesis of streptonigrone 9 1.3 Background on pyridone synthesis 12 1.3.1 Common methods for pyridone synthesis 13 1.3.2 A convenient pyridone synthesis developed in our laboratory ; 19 2. TOTAL SYNTHESIS OF STREPTONIGRONE 25 2.1 Retrosynthetic analysis 25 2.2 Quinoline synthesis 26 2.3 Synthesis of aldehyde 127 30 2.4 Model studies 30 2.5 Synthesis of streptonigrone ;....44 REFERENCES AND NOTES 54 APPENDIX (EXPERIMENTAL SECTION) .61 i n List of Tables Table 1. Reported vs. measured ' H chemical shifts for natural and synthetic List of Figures Figure 1. Streptonigrinoids 1 Figure 2. Pyridone-containing natural products and pharmaceuticals _ .13 Figure 3. H M B C correlations __ ___ 34 Figure 4. Ligands for Buchwald couplings .42 v List of Schemes Scheme 1. Proposed mechanism of topoisomerase II action 2 Scheme 2. Kametani's synthesis of the A B ring segment 4 Scheme 3. L iao ' s synthesis of the A B ring segment 4 Scheme 4. The Weinreb synthesis of streptonigrin 6 Scheme 5. The Kende synthesis of streptonigrin . 7 Scheme 6. The Boger formal synthesis of streptonigrin _____ 8 Scheme 7. The Kende synthesis of lavendamycin __ _ 9 Scheme 8. The Boger synthesis of streptonigrone _; _ 10 Scheme 9. Boger's inverse demand Diels-Alder approach __ .....11 Scheme 10. Boger's synthesis of streptonigrone ......12 Scheme 11. Polonovski rearrangement __ 14' Scheme 12. Synthesis of pyridone via 2-chloropyridine __ 14 Scheme 13. Wil l iams ' synthesis of i l ic icol in 15 Scheme 14. Greene's synthesis of nothapotydine B 15 Scheme 15. Synthesis of pyridones from glutaconic acid. . . ___ 16 Scheme 16. Synthesis of pyridones from 1,5-dicarbonyl ____ _ 16 Scheme 17. Synthesis of vitamin B 6 ____ 17 Scheme 18. [3 + 3] annulation .....18 Scheme 19. Aromatization via expulsion of leaving group on nucleophile 18 Scheme 20. Aromatization via expulsion of leaving group on electrophile 19 Scheme 21. Danishefsky's approach toward camptothecin 19 Scheme 22. A convenient pyridone synthesis developed in our laboratory _ 20 Scheme 23. The pyridone synthesis developed in our laboratory 21 Scheme 24. Attempted formation of 3-alkylpyridones ____ .21 Scheme 25. Radical fragmentation... 22 Scheme 26. The Ciufolini total synthesis of camptothecin. 22 Scheme 27. Retrosynthetic analysis of nothapodytine B 23 Scheme 28. The Ciufolini total synthesis of nothapodytine B 24 Scheme 29. Retrosynthetic analysis .25 Scheme 30. Friedlander quinoline synthesis ...26 Scheme 31. Hypothetical Friedlander reaction _ 27 Scheme 32. Conrad-Limpach synthesis 28 vi Scheme 33. Cyclization mechanism ... .... 28 Scheme 34. Manipulation of chloroquinoline 140 29 Scheme 35. Synthesis of aldehyde 127 30 Scheme 36. Mode l studies .....31 Scheme 37. Preparation of model quinolines _ .31 Scheme 38. Formation of indolizines .... 32 Scheme 39. Aza-Nazarov cyclization ____ 33 Scheme 40. Previously observed aza-Nazarov cyclization 34 Scheme 41. Boger's approach to streptonigrone 35 Scheme 42. Coumarin synthesis 36 Scheme 43. Attempted synthesis of the benzyl protected quinoline _ ...37 Scheme 44. Attempted synthesis of aminoketones 38 Scheme 45. Attempted bromination of the quinoline methyl ketone 38 Scheme 46. Synthesis of aminoketone via diazo intermediate 39 Scheme 47. Pyridone synthesis model studies .40 Scheme 48. Preparation of iodopyridine 40 Scheme 49. S N A r mechanism ...41 Scheme 50. Carboxylation of pyridine .43 Scheme 51. Derivatization of pyridone .43 Scheme 52. Derivatization of pyridone under basic condition ....44 Scheme 53. Synthesis of tetracyclic core _ 45 Scheme 54. Preparation of iodopyridine .45 Scheme 55. Preparation of aminopyridine 46 Scheme 56. Oxidation of quinoline .47 Scheme 57. Functionalization of quinoline quinone .48 Scheme 58. Weinreb's debenzylation of streptonigrin precursor 48 Scheme 59. Boger's deprotection of 54 .49 Scheme 60. Global deprotection with T M S - I . . . . 51 Scheme 61. Preparation of methoxypyridine 226 ...53 v i i List of Abbreviations A c acetyl aq aqueous , A r aryl B n benzyl B O C /er?-butyloxycarbonyl B u butyl ca. circa (Latin) cat catalytic calcd calculated C B Z benzyloxycarbonyl C D I 1,1 '-carbonyldiimidazole cf- confer (Latin) C H F congestive heart failure cone. concentrated d doublet D B U l,8-diazabicyclo[5.4.0]undec-7-ene D C M dichloromethane D D Q 2,3-dichloro-5,6-dicyano-l,4-benzoquinone D I A D diisopropyl azodicarboxylate D M F N, /V-dimethylformamide D M S dimethyl sulfide D M S O dimethyl sulfoxide D N A deoxyribonucleic acid D P P A diphenylphosphoryl azide % Et ethyl E S I electrospray ionization fod 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedione h hour(s) H I V Human Immunodeficiency Virus (AIDS virus) H M B C Heteronuclear Mult iple Bond Correlation H M P A hexamethyl phosphoramide V l l l H M Q C Heteronuclear Mult iple Quantum Coherence H O M O highest occupied molecular orbital H R M S high resolution mass spectrum H z Hertz (s"1) i iso IR infrared L G leaving group L U M O lowest unoccupied molecular orbital m multiplet M e methyl min minute(s) M O M methoxymethyl mp melting point M s methanesulfonyl M S mass spectrometry n normal (as an alkyl group) n - B u L i /t-butyllithium N A D P H reduced nicotinamide adenine dinucleotide phosphate N B S Af-bromosuccinmide NIS /V-iodosuccinmide N M R nuclear magnetic resonance N u nucleophile [O] oxidation o ortho p para P D C pyridinium dichromate Ph phenyl Pht 1,2-phenylenedicarbonyl P P E polyphosphoric ester ppm parts per mil l ion Pr propyl q quartet Qu quinoline R T room temperature ix s singlet S A R structure-activity relationship sat. saturated t tertiary (as an alkyl group) T B D M S /ert-butyldimethylsilyl T f triflate T H F tetrahydrofuran T L C thin layer chromatography T M S trimethylsilyl Tol tolyl x Acknowledgements I wish to express my gratitude to my advisor and mentor, Professor Marco Ciufolini. I have admired his dedication to science, commitment to his students' success and his willingness to share his wisdom. I truly considered myself fortunate to have worked under his direction. I would also like to thank the members of the Ciufolini research group, past and present, for their friendship, insightful discussions, and kind advice. Special thanks must go to David, Dylan and Steven for their help in proofreading this manuscript. Financial support in the form of a Gladys Estella Laird Research Fellowship from the University of British Columbia, and scholarships from the Natural Sciences and Engineering Research Council of Canada are gratefully acknowledged. xi 1. INTRODUCTION Streptonigrone (1), a quinoline-5,8-quinone alkaloid, was first isolated in 1985 from the culture broth of an unidentified Streptomyces species (IA-CAS isolate No. 114).' Along with its congeners, streptonigrin (2)2 and lavendamycin (3),3 streptonigrone belongs to a class of antitumor antibiotics known as the "streptonigrinoids." Due to their diverse biological activities and complex, densely-functionalized structures, streptonigrinoids have generated considerable interest in both the biomedical and the chemical fields.4 o o o Streptonigrone Streptonigrin Lavendamycin Figure 1. Streptonigrinoids 1.1 Biological activity Streptonigrinoids exhibit a number of interesting biological properties. For instance, streptonigrin (2) is a potent cytotoxic agent which is active not only toward common murine cell lines such as L1210 leukemia and. mammary carcinoma, but also against a wide spectrum of human cancers, such as epidermoid and bronchogenic carcinoma.5 Streptonigrin also displays antimicrobial activity against fungal and bacterial organisms, including gram-positive, gram-negative, and acid-fast bacteria.6'7 1 Although the precise mechanism of action of 2 remains unclear, its cytotoxic properties may be attributed at least in part to its potent inhibitory action against DNA o topoisomerase II, an essential enzyme required for DNA replication, and a privileged target for chemotherapeutic intervention.9 DNA topoisomerase II is a nuclear enzyme responsible for the relaxation of torsional strain in supercoiled DNA during replication. The enzyme alters the conformation of DNA through a concerted breaking and rejoining of both DNA strands (Scheme 1). Evidences have suggested that topoisomerase II inhibitors prevent the rejoining of the DNA strands, leading to DNA cleavage and ultimately apoptosis.10 topoisomerase II Scheme 1. Proposed mechanism of topoisomerase II action Furthermore, in vitro studies have shown that streptonigrin promotes the formation of oxygen radicals through an initial single electron reduction of the quinone system by NADPH, followed by the transfer of the single electron to molecular oxygen to generate superoxide radicals." As a consequence of its ability to undergo bioreduction, streptonigrin interferes with oxidative phosphorylation, causing a substantial depletion of cellular ATP.12 In addition, both 1 and 2 are inhibitors of NO-dependent activation of 2 human platelet guanylyl cyclase, an important enzyme involved in intracellular signaling pathways.13 Lastly, streptonigrin is a strong inhibitor of reverse transcriptase, an enzyme found only in retroviruses such as HIV, and an essential component of the replication machinery of such viral species.14 Clinical trials of streptonigrin in humans have revealed severe side effects that limit application in cancer treatment.15 Nevertheless, significant medicinal chemistry research focusing on 1 continues to this date.16 Results from those studies indicated that the quinoline-quinone fragment (A and B rings), which is identical in both streptonigrin and streptonigrone, is an essential pharmacophore of streptonigrinoids.16 This renders streptonigrone an interesting target for both synthetic and pharmacological investigations. 1.2 Previous syntheses Since the determination of the structure of streptonigrin, the namesake of the family, by Woodward and collaborators in 1963, streptonigrinoids have generated intense efforts in the synthetic arena.4 Interest in these molecules is motivated not only by their noteworthy biological properties, but also by their intricate and highly functionalized structures. Initial synthetic studies were mainly focused on the synthesis of the quinoline-5,8-quinone (AB rings) segment as a standalone model system. In 1965, Kametani and coworkers reported a synthesis of the fully functionalized quinoline quinone 8 via a classical Skraup quinoline synthesis, as outlined in Scheme 2.17 Methoxylation and reduction of bromodinitrophenol 4 afforded aniline 5, which was advanced to quinoline 7 upon treatment with glycerol under acidic conditions. 3 Deprotection of the methyl ethers by HBr furnished the complete AB ring system of streptonigrone. OMe 7 o 8 a. aq. N a O H (71%); b. M e 2 S 0 4 , K 2 C 0 3 , P h N 0 2 , 130 °C (68%); c. Fe, aq. HCI, EtOH (76%); d. A s 2 O s , H 2 S 0 4 , 160 °C (9%); e. aq. HBr, 100 °C (87%) Scheme 2. Kametani's synthesis of the A B ring segment In 1967, Liao and collaborators also completed a synthesis of the AB ring fragment using Skraup technology.18'19 This entailed the merger of nitroaniline 9 and acrolein to access the quinoline core of streptonigrin (Scheme 3). However, due to the a. acrolein, H 2 S 0 4 , A s 2 0 5 , H 2 0 (42%); b. H N 0 3 (no details given); c. H 2 , P t 0 2 (no details given); d. N a 2 C r 2 0 7 , H 2 S 0 4 , C H C I 3 (60%); e. B r 2 (no details given); f. N a N 3 , aq. E tOH, RT (100%); g. H 2 , P t 0 2 , M e O H , RT (no yield given) Scheme 3. Liao's synthesis of the A B ring segment 4 lack of a handle for further elaboration, the resultant quinolines from those early works were synthetic dead ends for the total synthesis of streptonigrinoids. It was not until 1980 that the first total synthesis of streptonigrin was achieved by Weinreb and coworkers.20 Since then, the synthesis of streptonigrin also has been accomplished in the research groups of Kende and Boger.21'22 Nevertheless, the work of Weinreb undeniably laid the groundwork for the later syntheses of streptonigrinoids. 1.2.1 The Weinreb synthesis of streptonigrin Weinreb's approach relied on an imino Diels-Alder reaction to construct the CD rings of 2 (Scheme 4). Treatment of diene 13 with methoxyhydantoin 12 in refluxing xylenes furnished 14, which was advanced to pyridine 15 in three steps. Installation of the C-ring amino group was then achieved through an elegant 10-step sequence involving 23 24 a Polonovski oxidation, a Sommelet-Hauser-type [2,3]-sigmatropic rearrangement, and a Yamada-Curtius25 reaction to reach 16. Conversion of 16 to phosphonate 17 then set the stage for the assembly of the quinoline. A modified Friedlander26 quinoline synthesis involving an initial Horner-Wadsworth-Emmons27 coupling of 17 and 19, followed by reductive cyclization and subsequent oxidation of the quinoline then afforded the complete carbon framework of 2. The final functionalization of the quinone was achieved in three steps: iodination by IN3, displacement of iodide with NaN3 and reduction of the azide by sodium dithionite. The Weinreb total synthesis of 2 was completed upon deprotection of the D ring benzyl ether by excess AICI3 and hydrolysis of the C ring ester. 5 a. xylenes, reflux; b. Ba(OH) 2 , aq. dioxane, reflux; c. SOCI 2 , MeOH, reflux; d. Pd-C, PhMe, reflux (33% a-d); e. m-CPBA, DCM, RT (100%); f. A c 2 0 , 120 °C (93%); g. MeOH, K 2 C 0 3 , RT (100%); h. SOCI 2 , PhH, RT (100%); i. (i) /V-(cyanomethyl)pyrrolidine, DMSO, 45 °C, 5 d (ii) f-BuOK, -12 °C, 10 min (iii) oxalic acid, aq. THF, reflux (35%); j . C F 3 C O 3 H , N a 2 H P 0 4 , DCM, RT (100%); k. K M n 0 4 , aq. acetone, RT (100%); I. (i) DPPA, Et 3 N, PhH, reflux (ii) H 2 0 , reflux (83%); m. (i) A c 2 0 , 125 °C (ii) K 2 C 0 3 , MeOH, RT (89%); n. M n 0 2 , CHCI 3 , RT (88%); o. n-BuLi, MePO(OMe) 2 , THF, -78 °C (67%); p. M n 0 2 , CHCI 3 , RT; q. 19, KH, PhH, RT (80% o-p); r. N a 2 S 2 0 4 , aq. MeOH, reflux (60%); s. NaOMe, MeOH, 40 °C (100%); t. Fremy's salt, MeOH, RT (100%); u. IN 3 ,CH 3 CN, RT (91%); v. NaN 3 , aq. THF, RT (58%); w. N a 2 S 2 0 4 , aq. MeOH, reflux (50%); y. AICI 3 , CHCI 3 , RT (80%); z. K 2 C 0 3 , aq. MeOH, RT (79%) Scheme 4 . The Weinreb synthesis of streptonigrin 1.2.2 The Kende synthesis of streptonigrin In parallel to Weinreb's approach, Kende's strategy towards streptonigrin focused on an early construction of the CD ring fragment, followed by a late stage assembly of 21 the quinoline AB ring system through a modified Friedlander synthesis (Scheme 5). The construction of the CD ring system proceeded through a regioselective condensation of the known (3-keto enamine 2128 with methyl acetoacetate (20) to provide the acylpyridone 22. In contrast to Weinreb's Diels-Alder approach, this route led to a pyridone intermediate possessing a methyl ketone functionality, which served as a convenient precursor of the amino group. Elaboration of 22 to pyridine 23 then provided 6 a substrate suitable for a modified Friedlander quinoline synthesis. Condensation of pyridine 23 and imine 24 furnished the complete carbon framework of 2. Advancement to streptonigrin was then accomplished through a route similar to that of Weinreb. O M e a. xylenes, reflux (97%); b. N a B H 4 , THF , / -PrOH, RT (100%); c. P h P O C I 2 , 170 °C (67%); d. C u C N , D M F , reflux (85%); e. MeMgBr, PhH, RT (83%); f. f-BuOK, PhMe, f -BuOH, reflux (90%) g. T F A , 0 °C (85%); h. H N 0 3 , C H 3 N 0 2 , RT; i. M e 2 S 0 4 , K 2 C 0 3 , acetone, reflux (55% g-h); j . O s 0 4 , N M O , aq. acetone, f -BuOH, RT; k. N a l 0 4 , aq. dioxane, 80 °C (75% j-k); I. S e 0 2 , A c O H , reflux (74%); m. N a C I 0 2 , H 2 N S 0 3 H , NaOAc , aq. dioxane, RT (92%); n. AcCI, M e O H , RT (95%); o. D P P A , E t 3 N , P h H , reflux then H 2 0 , reflux (43%); p. N a 2 S 2 0 4 , THF , aq. M e O H , reflux (80%); q. Fremy's salt, aq. acetone, RT (92%) Scheme 5. The Kende synthesis of streptonigrin 7 1.2.3 The Boger formal synthesis of streptonigrin Boger's synthetic approach to 2 was based on the implementation of two consecutive inverse electron demand Diels-Alder reactions to construct the biaryl CD 22 ring system. This innovative sequence began with the [4 + 2] merger of quinoline 29 and tetrazine 34 to give 30 (Scheme 6). Subsequent treatment of this intermediate with enamine 35 then provided a mixture of Diels-Alder adducts 31 and 32 in a 1 : 4 ratio, favoring the desired isomer. Advancement of 32 to the tetracyclic amine 27, an intermediate in Kende's synthesis,21 completed the formal synthesis of 2. OMe a. 34, dioxane, 80 °C (82%); b. 35, DCM, 6.2 kbar, RT (58% of 31 & 32, 1:4); c. NaSePh, THF-HMPA, 70 °C; d. aq. HCI, MeOH, RT; e. DPPA, Et 3N, PhH, reflux (40% c-e); f. Mel, K 2 C 0 3 , THF, 65 °C (94%) Scheme 6. The Boger formal synthesis of streptonigrin 8 1.2.4 The Kende synthesis of lavendamycin methyl ester The total synthesis of lavendamycin, the putative biosynthetic precursor of 1 and 2,29 was first completed by Kende and coworkers in 1984.30 The highlight of their elegant biomimetic approach was the rapid assembly of the pentacyclic framework of 3 via a polyphosphate ester-catalyzed Bischler-Napieralski cyclodehydration of 38, which was readily accessed through the coupling of quinoline 36 with (3-methyltryptophan (Scheme 7). Elaboration of the resultant 39 to lavendamycin methyl ester (40) was then carried out in four steps using conventional transformations. Due to the poor solubility of the natural product in organic solvents, both synthetic and natural 3 were characterized as the methyl esters. a. Me2N(CH2)3N=C=NEt, DCM, RT (90%); b. PPE, 90 °C (31%); c. N a 2 S 2 0 4 , aq. THF-MeOH, reflux (70%); d. K 2 C r 2 0 7 , H 2 S 0 4 , H 2 0, DCM, RT (50%); e. NaN 3 , aq. THF, RT; f. N a 2 S 2 0 4 , aq. THF-MeOH, reflux (30% e-f) Scheme 7. The Kende synthesis of lavendamycin 1.2.5 The Boger synthesis of streptonigrone To this day, the only published total synthesis of streptonigrone was accomplished 31 by Boger and coworkers in 1993. Boger's strategy (Scheme 8) again relied on a 9 Friedlander reaction to assemble the quinoline AB ring system. However, the pyridone ring emerged through an inverse electron demand Diels-Alder reaction of /V-sulfonyl-1-aza-1,3-butadiene 42 with ketene acetal 43. Scheme 8. Boger's retrosynthetic analysis of streptonigrone 32 Thus, 2-amino-3-benzyloxy-4-bromobenzaldehyde (46) was condensed with pyruvic acid to give the quinaldic acid 49, which was then converted to the methyl ester (Scheme 9). This substance underwent cross-Claisen condensation with ethyl acetate, and the emerging 50 participated in a Knoevenagel condensation with the known 2-hydroxylbenzaldehyde 44.33 The resultant was coumarin 51, which was elaborated to N-sulfonyl-l-aza-butadiene 42 through a 3-step sequence. This set the stage for the inverse-demand Diels-Alder reaction with ketene acetal 43 to give the 2-methoxypyridine 41. A 3-step deprotection-reprotection sequence then afforded carboxylic acid 52, which was advanced to the corresponding amine 53 via a Yamada-Curtius25 reaction (Scheme 10). 10 C 0 2 H •CHO h k Br Y NH 2 OBn 46 OH 48 •.f 49 R = OH ' ^ 50 R = C H 2 C 0 2 E t Br OMe OMe .OMe Me OMe a. Br2, AcOH, RT; b. HN0 3 , AcOH, RT; c. HCI, MeOH, RT; d. NaH, BnBr, DMF/(85% a-d); e. LiBH 4, THF, RT (93%); f. PDC, DCM, RT (83%); g. N a 2 S 2 0 4 , aq. THF, reflux (93%); h. pyruvic acid, NaOH, MeOH, RT; i. HCI, MeOH, RT (85% h-i); j. L iCH 2 C0 2 Et, THF, -78°C (86%); k. 44, cat. piperidine, EtOH, 80°C (81%); I. NH2OH.HCI, EtOH, RT (53%); m. MeSOCI, Et 3N, DCM, RT (59%); n. 1,1-dimethoxy-1-propene, PhH, RT; o. f-BuOK, THF, -30°C; p. DDQ, DCM, RT (52% n-p). Scheme 9. Boger's inverse demand Diels-Alder approach Experiment revealed that in situ trapping of the Curtius isocyanate intermediate was ineffective. This was due to partial hydrolysis of the isocyanate to the corresponding amine, leading to a mixture of aminopyridone and carbamate derivative thereof. Our own experience confirmed this undesirable property of the isocyanate in question (vide infra). Accordingly, the isocyanate was hydrolyzed with aqueous LiOH to the corresponding amine, which was left unprotected during the remainder of the synthesis. The endgame involved Fremy's salt (potassium nitrosodisulfonate) oxidation of the quinoline, Lewis acid-catalyzed methoxylation to install the quinone methoxy substituent, and amination of the quinone through an azido intermediate. The final deprotection of the emerging 54 was then achieved by treatment with HBr under reducing condition to give streptonigrone in 23 linear steps from commercially available materials. 11 o OMe a. aq. LiOH, DMSO, 60 °C (89%); b. MOMCI, NaH, DMF, RT (92%); c. aq. LiOH, DMSO, 130 °C (80%); d. DPPA, Et 3N, PhH, reflux then aq. LiOH, THF, RT (84%); e. HBr, DCM, RT (80%); f. Fremy's salt, DCM, Bu 4 NHS0 4 , H 2 0, RT (69%); g. Ti(0/'-Pr)4, NaOMe, THF, 0 °C; , h. NaN 3 , THF-H 2 0, RT (85%); i. NaBH 4 , MeOH, THF, RT (86%); j. HBr, Pd-C, H 2 , C F 3 C H 2 O H , 80 °C (no yield given) Scheme 10. Boger's synthesis of streptonigrone 1.3 Background on pyridone synthesis The foregoing discussion suggests that the assembly of a fully substituted C-ring constitutes the key strategic aspect of any attack on streptonigrinoids. It is also apparent that in the context of streptonigrone, the construction of that pyridone unit is a challenging endeavor that tests the limits of pyridone-forming reactions. Indeed, very few methods for pyridone synthesis have proven capable of addressing that problem. In the next few paragraphs, we shall review some common techniques for the synthesis of pyridones, concluding with a method developed by Ciufolini and coworkers that constitutes the central feature of our own synthesis of 1. 12 1.3.1 Common methods for pyridone synthesis The synthesis of 2-pyridones has generated vast interest from both synthetic and medicinal chemists due to the prominent presence of pyridones in biologically active molecules. 3 4 ' 3 5 Examples of such molecules include natural products such as (+)-camptothecin (55, antitumor agent),36 pyridone L-697,661 (56, HIV reverse transcriptase inhibitor),37 and leporine A (57, insecticide),38 as well as drugs like milrinone (58, cardiotonic drug for CHF)39 and ABT-719 (59, antimicrobial agent).40 (+)-Camptothecin Pyridone L-697661 Leporin A O H 2N Milrinone ABT-719 Figure 2. Pyridone-containing natural products and pharmaceuticals Strategies for the synthesis of 2-pyridones can be generalized into three main categories: (i) modification of preexisting heterocycles, most notably from pyridines, (ii) cyclization of an acyclic system, or (iii) fusion of two or more acyclic fragments 4 1 Manipulation of pyridines has long been recognized as a convenient avenue to 2-pyridones.34'41 For instance, conversion of 2-unsubstituted pyridines to pyridones can be accomplished by a Polonovski-type oxidation via a pyridine ,/V-oxide intermediate 13 (Scheme .11). Similarly, 2-pyridones can be accessed through hydrolysis of 2-halopyridines, which in turn, can be obtained from a pyridine N-oxide. This approach was exemplified in Kametani's synthesis of camptothecin analogues where pyridone 65 served as a central synthetic intermediate (Scheme 12).42 [O] f I Ac 2 Q 1ST ^Ne h e a t " N ' 1 H 0 0 60 61 62 Scheme 11. Polonovski rearrangement a ^ f\\ b t "N© "C0 2 Et Jss, } \ ., _, ' C I ^ N CO,Et N C0 2 H Oe H 63 64 65 a. POCI3, HCI, C H 3 C I , 80 °C (69%); b. aq. HCI, 180 °C (no yield given) Scheme 12. Synthesis of pyridone via 2-chloropyridine Construction of 2-pyridones via cyclization of linear system can be found in many natural product syntheses. For example, in David Williams' work on tenellin43 and ilicicolin H, 4 4 a Dieckmann condensation of 67, followed by oxidation of the resulting dihydropyridone 68 smoothly afforded the protected 2-pyridone core 69 (Scheme 13). Another example of pyridone-forming cyclization can be found in the total synthesis of nothapodytine B (74) by Greene and coworkers.45 In contrast to Williams' approach, Greene's relied on tandem intramolecular Michael reactions to establish the framework of the central pyridone as part of the tetracyclic system of 74 (Scheme 14). Decarboxylative oxidation of the resulting dihydropyridone (73) was then accomplished 14 ilicicolin H (70) a. LiOH, THF-H 2 0, RT (99%); b. CDI, THF; c. NaH, THF, RT (91% b-c); d. chloranil, PhEt, reflux (85%) Scheme 13. Williams' synthesis of ilicicolin by a basic hydrolysis, followed by treatment with palladium on carbon in refluxing p-cymeme to furnish 74. Despite the elegant synthetic planning displayed in both of those examples, it could be argued that accessing pyridones via cyclization of linear systems requires considerable linear operations and lacks the flexibility required for SAR studies. o a. TBDMSOTf, Et 3N, DCM, RT (84%); b. 0 3 , DCM, -78 °C then DMS (60%) c. aq. NaOH, MeOH, DCM, RT.; d. Pd-C, p-cymeme, reflux (60% c-d) Scheme 14. Greene's synthesis of nothapotydine B 15 In contrast to the preceding approaches that involved C-C bond formation, cyclization of linear systems of 1,5-dicarbonyl compounds involving C-N bond construction is also common in the synthesis of simple pyridones (Scheme 15).34'41 For instance, reaction of glutaconic acid (75) with ammonia or derivatives efficiently provided 6-hydroxyl-2-pyridones (76). 4 6 Likewise, condensation between 2 -acetylglutarate derivatives (77) and ammonium acetate provided 3,4-dihydropyridone 78,47 which could be oxidized to the corresponding pyridone 79 (Scheme 16).34 The use of this approach, however, has been mostly limited to the synthesis of simple pyridones, since the construction of the requisite 1,5-dicarbonyl compounds often involves a Michael-type reaction, which, incidentally, corresponds to the initial step of the [3 + 3 ] annulation approach to pyridones (vide infra).41 Thus, unless the required 1,5-dicarbonyl substrate is readily accessible, the [ 3 + 3 ] strategy is often preferred. Me O Me O AAA B M H HO OH heat HO N Bn 75 76 Scheme 15. Synthesis of pyridones from glutaconic acid O O E t 0 2 C ^ ^ [ 0 ] EtO a C M e " C 0 2 E t M e \\ . ° M e ^ N ^ O 77 78 79 Scheme 16. Synthesis of pyridones from 1,5-dicarbonyl The [3 + 3 ] merger of a 1,3-dinucleophile and a 1,3-dielectrophile arguably can be considered as the most popular avenue to 2-pyridones.34 For example, it is long-16 recognized that reactions of 1,3-diketones with cyanoacetamide or malonitrile, in the presence of catalytic base, efficiently afford 3-cyanopyridones. An especially significant application of this process may be found in a 1939 Merck & Co. synthesis of vitamin B 6 , 83, a key step in which was a piperidine-catalyzed condensation of 80 with 81 to provide AQ pyridone 82 as a key intermediate (Scheme 17). CH 2 OEt CH 2 OH O O CONH 2 gPgd,ne r r ^ f C N H O ^ X H 2 O H 80 81 82 Vitamin B 6 (83) Scheme 17. Synthesis of vitamin B 6 Alternatively, 2-pyridones can also be accessed through the merger of an enecarbonyl compound and cyanoacetamide or malonitrile (Scheme 18).41 Mechanistically, such [3 + 3] annulations generally involve an initial Michael addition of the activated methylene compound (85) to give an acyclic adduct (86), which undergoes dehydration to furnish the corresponding 3,4-dihydropyridone 87. Oxidative aromatization of the dihydropyridone then affords the 3-cyanopyridone 88. Unsurprisingly, numerous permutations of this general method involving different oxidants have been developed. For instance, DDQ,49 nitric acid50 and FeC^51 have all been demonstrated to be effective. 17 X </ acid or base CN 84 R 85 X = CONH 2 or CN H R Y N Y ° 87 [O] CN R 2 86 H,0 XL 88 R 2 Scheme 18. [3 + 3] annulation 52 Alternatively, incorporation of a leaving group, such as benzotriazole or pyridine,53 on the nucleophile, allows the final aromatization to occur via an eliminative pathway; that is, in the absence of an oxidant (Scheme 19). Similarly, the presence of a potential leaving group in the [3-position of the enecarbonyl also facilitates aromatization (Scheme 20).54 5 5 ^ acid or base ^ LG " 84 R2 89 X = CONH 2 orCN LG = benzotriazole or pyridine R 1 ^ 0 LG R 2 90 H,0 XL R 2 91 base LG R V ^ N ^ . O R 2 92 Scheme 19. Aromatization via expulsion of leaving group on nucleophile 18 R 1 v ^ O CONH 2 LG base CN 93 R 2 94 C O N H 2 CN base H,0 I e l R 2 LG CN LG R d LG 95 R V ^ N ^ / O R 2 92 96 Scheme 20. Aromatization via expulsion of leaving group on electrophile An example of a pyridone-forming [3 + 3] annulation applied in natural product total synthesis can be found in Danishefsky's work on camptothecin (Scheme 21).55 To access the central pyridone of camptothecin, enamine 97 was treated with chloroglutaconate 98 in the presence of Et3N to give pyridone 99. + Et 3N ? ° 2 M e H \ / C l EtOH ^ ^ J ^ C H g C O a M e ~N C 0 2 M e Me0 2 C C H 2 C 0 2 M e 92% H , 97 98 6 99 Scheme 21. Danishefsky's approach toward camptothecin 1.3.2 A convenient pyridone synthesis developed in our laboratory Building on the classical [3 + 3] annulation protocols, experiments in our laboratory revealed that the merger of an active methylene compound, such as cyanoacetamide, with an enone to yield a pyridone may be accomplished as a one-pot operation.56'57 Depending on precise reaction conditions, the process affords either 3-cyanopyridones, 3-unsubstituted pyridones or 3-alkylpyridones (Scheme 22). 19 H 2 N ^ O R 3 100 2X^  I 101 R 4 " ^ C N f-BuOK DMSO 102 R 4 = 103 R 4 = 104 R 4 = H CN aikyl Scheme 22. A convenient pyridone synthesis developed in our laboratory This "tunable" reaction is believed to proceed (Scheme 23) via an initial r-BuOK-catalyzed Michael addition of the anion of cyanoacetamide to an enone to give an adduct such as 105 as an isolable compound. However, when operating at elevated temperatures (90-100 °C), the Michael adduct undergoes a base-catalyzed dehydration in situ to generate anions 106 (R4 = H) or 110 (R4 = aikyl). When an oc-unsubstituted cyanoacetamide (R4 = H) is used, the strongly basic environment promotes formation of dianion 107. In presence of oxygen, this intermediate is oxidized to a 3-cyanopyridone 103. It was proposed that the oxidation proceeds via a single electron transfer to molecular oxygen and subsequent formal loss of a hydrogen atom. On the other hand, in the absence of oxygen, 3-unsubstituted pyridone 102 emerges as the major product. C O Mechanistically, it was envisioned that the strongly basic reaction conditions facilitate an equilibration between the initially formed dianion 107 with the isomeric 108. Expulsion of cyanide ion then furnishes the anion of unsubstituted pyridone 102, which is ultimately protonated following an acidic aqueous workup. The absence of oxygen is especially critical for the establishment of this equilibrium, since the oxidation of 107 by O2 appears to be quite fast. Likewise, in cases where R4 is aikyl, the corresponding anion 110 undergoes a "decyanidative aromatization" to yield 3-alkylpyridones 104. It should be noted that this reaction embodies one of a very limited number of techniques for the 20 R 3 104 R 3 102 R 3 -,03 Scheme 23. The pyridone synthesis developed in our laboratory direct assembly of 3-alkylpyridones, which are often difficult to access.52' 5 7 ' 5 9 Significantly, variants of the Thesing-Muller reaction53 involving pyridinium ylides 112 or sulfonyl substituted amides 113 (Scheme 24) failed to reach 3-alkyl pyridones.60 H 2 N ^ ° 112 . H 2 N ^ O 1 1 3 R y ° r 4 n(^) R Y ^ Y ° R 4 s ° 2 - R 5 R Y ° r 2 ^ ,-BuOK ' / / | R2V^R4 f-BuOK " R 2 ^ R 3 R 3 R 3 100 / R 5 = Me, 4-Tol i n n 104 R 4 = alkyl 1 0 0 Scheme 24. Attempted formations of 3-alkylpyridones 21 An application of this technology was initially sought in connection with our group's synthesis of (+)-camptothecin (55).60'61 To this end, it was envisioned that construction the pyridone ring of 55 could be achieved through the condensation of enone 114 and oc-cyanoacetamide under aerobic conditions. However, an unexpected radical fragmentation of reactive intermediate 115 (Scheme 25) prevented the implementation of this strategy. Ultimately, this obstacle was circumvented through the oxidation of Michael adduct 117 with SeC>2 (Scheme 26). The resultant pyridone 118 was then advanced to (+)-camptothecin in a straightforward fashion. a. cyanoacetamide,f-BuOK, DMSO, RT (100%); b. 5% S e 0 2 on silica gel, r-BuOOH, AcOH, 110 °C then 10% aq. H 2 S 0 4 (70%); c. NaBH 4 , CeCI 3 .7H 20, EtOH, 45 °C; d. 60% H 2 S 0 4 , EtOH, 115 °C (94%) Scheme 26. The Ciufolini total synthesis of camptothecin 2 2 A more successful application of the direct synthesis of 3-alkylpyridones is apparent in our group's synthesis of nothapodytine B (74).57 Akin to the work on camptothecin, it was envisioned that the central pyridone could be assembled through the condensation of enone 120 and 2-cyanopropionamide (Scheme 27). However, due to the incompatibility of the 1,2-diacylethylene functionality of 120 with an excess of ?-BuOK, the pyridone-forming reaction was performed with a modification to the above procedure. Treatment of 120 with 2-cyanopropionamide and DBU in pyridine furnished the Michael adduct 122 (Scheme 28). Subsequent in situ dehydration and decyanidation were then 74 Scheme 27. Retrosynthesis of nothapodytine B triggered by the addition of acetic anhydride and heating to afford the 0-acetyl derivatives of the pyridone (123 and 124). Treatment of the mixture with HBr in CF3CH2OH smoothly affected the deprotection and N-alkylation of the pyridone to furnish totally synthetic nothapodytine B. 23 a. 2-cyanopropionamide, pyridine, DBU, 80 °C; b. A c 2 0 , 80 °C (50% of 123 and 124 a-b); c. HBr, C F 3 C H 2 O H , RT (91%) Scheme 28. The Ciufolini total synthesis of nothapodytine B 2. TOTAL SYNTHESIS OF STREPTONIGRONE 2.1 Retrosynthetic analysis Encouraged by the successful implementation of our 3-alkylpyridone synthesis in the effort leading to nothapodytine B,57 we envisioned that a similar strategy could be employed to assemble the central pyridone ring of the considerably more challenging natural product, streptonigrone. To that end, enone 126 would be required as a substrate for the pyridone-forming reaction. Substituted X and Z represent precursors of an amino group. Their precise identity would have to be determined through model studies. Regardless, compound 126 is available through the condensation of quinoline ketone 128 with aldehyde 12762 (Scheme 29). Accordingly, the synthesis of quinoline ester 129 embodies the first sub-goal of our venture. o-p MeO MeO. X OMe OMe MeO MeO Z MeO 'N C0 2Me 129 OMe 127 128 Scheme 29. Retrosynthetic analysis 25 2.2 Quinoline Synthesis Despite the existence of numerous methods for the preparation of quinolines,63 all the previous syntheses of streptonigrinoids have employed a Friedlander26 quinoline construction/uzz'J,oz This is no accident: the substitution pattern of the quinoline quinone segment of streptonigrinoids creates requirements and limitations that only a limited number of quinoline-forming techniques are capable of satisfying. The Friedlander reaction is one of these. Even so, the Friedlander reaction can become problematic with substituted aminoaldehydes. In fact, in the work of Weinreb and Kende, "strictly defined" reaction conditions were required for the Friedlander-type cyclization to succeed.20'21 . Furthermore, 2-aminobenzaldehydes carrying substituents at position 6 (cf. R6 in 130, Scheme 30) react poorly.26'32 The substituent in question ultimately becomes the C-5 oxygen functionality of the final quinone of 132. The inability to carry this functionality through the synthesis from the beginning translates into a requirement for a number of late steps to adjust the substitution pattern and oxidation state of the quinoline. Scheme 30. Friedlander quinoline synthesis On the other hand, no syntheses of streptonigrinoids have yet evolved from a quinoline precursor that incorporates the ultimate NEE. group in 132 either in a latent or in an expressed form. Indeed, the NFE; group in question has always been introduced during 26 the final stages of the syntheses.20"22'31 It would seem that it is difficult to devise a suitable protection scheme for intermediates incorporating the amino functionality in question. Also, these intermediates may be too reactive and difficult to advance through the synthesis. The number of operations that would then be necessary to introduce and protect an NH2 group (or equivalent) at an early stage becomes too numerous relative to the sequence necessary to introduce that functionality later on. Scheme 31. Hypothetical Friedlander reaction In light of the foregoing, and in an effort to reach a quinoline carrying the largest possible number of appropriate substituents at an early stage, we avoided the Friedlander construction delineated in Scheme 31, opting instead to employ a Conrad-Limpach reaction64 to gain access to 129 (Scheme 32). Thus, the commercially available 1,2,4-trimethoxybenzene (136) was nitrated regioselectively and then reduced under standard conditions to give aniline 137. Enamino-ester 138 was readily obtained following treatment with dimethyl acetylenedicarboxylate. Thermolysis in diphenyl ether then afforded quinolone 139. The thermal cyclization has been proposed to proceed through a 67t electrocyclic mechanism as depicted in Scheme 33.65 27 139 140 129 a. HN0 3 , AcOH, RT (63%); b. H 2 , Pd-C, MeOH, RT (quant.); c. dimethyl acetylenedicarboxylate, MeOH, 60 °C (58%); d. Ph 2 0, reflux (86%); e. POCI 3, PhH, RT (88%); f. H 2 , Pd-C, Et 3N, EtO Ac, RT (quant.) Scheme 32. Conrad-Limpach synthesis Scheme 33. Cyclization mechanism Treatment of 139 with phosphorous oxychloride, followed by catalytic hydrogenolysis, efficiently afforded the key quinoline ester 129. It is noteworthy that the reduction of chloroquinoline 140 by catalytic hydrogenation was somewhat problematic. Initial experiments involving the customary exposure of 140 to a hydrogen atmosphere in the presence of palladium on activated carbon, either in methanol, ethanol, or ethyl acetate, resulted in overreduction of the pyridine moiety, in spite of close monitoring of the reaction (Scheme 34). It soon transpired that the addition of a base, such as triethylamine, suppressed that undesirable side reaction. We thus presume that 28 overreduction was due to activation of the pyridine segment toward hydrogenation through protonation of the quinoline by the hydrochloric acid liberated during the reaction. The external base reacts preferentially with HCI, avoiding quinoline protonation and thereby preventing overreduction. o 145 Nitration conditions: a. H N 0 3 , DCM, 0 °C; b. HNO3, AcOH, RT; c. HNO3, Hg(OAc)2, A c 2 0 , AcOH, RT; d. N 0 2 B F 4 , CH3CI, 0 °C Scheme 34. Manipulation of chloroquinoline 140 Because 140 was destined to undergo hydrogenolysis to the desired 129, it seemed that introduction of a nitro group at position 7 (quinoline numbering) prior to reduction might ultimately provide a 7-aminoquinoline possessing all the ring-A substituents required for streptonigrone. Nitration of 140 was therefore attempted under various conditions. Unfortunately, all such attempts met with failure. In most cases, only oxidation of the quinoline to the corresponding quinone (145) was observed. 29 2.3 Synthesis of Aldehyde 127 The preparation of the known aldehyde 12762 commenced with a regioselective demethylation of 2,3,4-trimethoxybenzaldehyde (146) by AICI3 in refluxing benzene to give the 2-hydroxylaldehyde 44.33'66 Reprotection of the phenol with benzyl bromide and K2CO3 in DMF efficiently afforded the desired 127 in excellent yields. The regiochemical course of the demethylation reaction has been rationalized on the basis of chelation of the aluminum(III) atom between the carbonyl oxygen and the ortho-methoxy oxygen (cf. 149, Scheme 35).33 CHO 146 (H2Q) © e _ , P " A I C I 3 OMe v OMe OMe 147 © H ^ O ~ A I C I 2 @ f CI ,OMe H ^ ° © A I C ' 2 C l ^ ^ c J - M e ^ OMe OMe 148 OMe OMe 1 4 9 CHO OMe OH OMe 44 CHO ft"" > ^ O M e OMe 127 a. AICI3, PhH, reflux (98%); b. BnBr, K 2 C 0 3 , DMF, RT (98%) Scheme 35. Synthesis of aldehyde 127 2.4 Model studies Again in the interest of minimizing late-stage operations, we wished to convert ester 129 into a suitably functionalized ketone 128, wherein group Z represents a precursor of an amino group. Subsequent condensation of ketone 128 with aldehyde 127 was anticipated to furnish enone 150, which would then participate in our pyridone-forming reaction, leading to a fully functionalized pyridone 151 (Scheme 36). At this 30 juncture, model studies were required to define the nature of Z. Initial experiments focused on intermediates where Z = COOR, CN, or NO2. Quinoline ketones 153-155 were synthesized according to Scheme 37 and subsequently condensed with benzaldehyde or its derivatives. All such attempted Knoevenagel reactions resulted in the formation of indolizines 156-158, instead of the expected benzylidene derivatives 161 (Scheme 38). Similarly, the substituted quinoline ketone 159 provided indolizine 160 when treated with aldehyde 127 under identical conditions. Not unexpectedly, all such indolizines proved to be air-sensitive, turning from a. MeOH, HCI, MeOH, RT (82%) b. EtOAc, f-BuOK, RT (98%); c. CH 3 CN, f-BuOK, RT (54%); d. CDI, THF then C H 3 N 0 2 , f-BuOK, RT (61%) Scheme 37. Preparation of model quinolines 31 bright yellow to dark brown over a period of time upon exposure to the atmosphere. It is worthy to note that the more electron-rich indolizine 160 was much more prone to degradation than its less substituted, electron-poor analogs. Thus, significant darkening occurred after several hours at room temperature, while 156 was stable for days at room temperature. PhCHO piperidine EtOH (Z = COOEt or CN) 153 Z = COOEt 154 Z = CN 155 Z = N 0 2 156 Z = COOEt (88%) 157 Z = CN (71%) aldehyde 127 NH 4OAc PhMe (Z = N0 2) 87% MeO MeO 158 OMe MeO. OMe MeO. COOEt aldehyde 127 piperidine EtOH 49% MeO COOEt OBn OMe 1 6 0 Scheme 38. Formation of indolizines R 5 06 i ^ 161 Ar The formation of the indolizines can be rationalized as being the result of an in situ aza-Nazarov cyclization of the Z-isomer of the initially formed enone 163 (Scheme 39). Upon protonation of the enone carbonyl, the system is poised to undergo a 4n-electron conrotatory electrocyclization. Subsequent deprotonation of presumed intermediate 165 leads to the product. 32 Z = C0 2 Et , CN or N 0 2 The structural assignment of the indolizines was based on the results of several 13 spectroscopic experiments. No carbonyl resonance was observed in the C NMR spectrum of the products. Their 'H NMR spectra exhibited a resonance at ca. 8.5 ppm, accounting for one proton, which was found to be exchangeable with D20. Heteronuclear NMR correlation spectra (lWl3C HMQC experiments) revealed that the exchangeable proton displayed no correlations to C atoms, indicating that the proton was not directly bonded to any carbon atom. These properties suggested that the proton in question belonged to a hydroxyl functionality (Figure 3). Those observations ruled out benzylidene structures 161, which possess no exchangeable protons, and in which all protons are directly attached to a carbon atom. Furthermore, the exchangeable proton displayed three 'H/13C correlations in the 'H713G HMBC spectrum, as expected for the indolizine structure. It is also noteworthy that treatment of the indolizines with 2-cyanopropionamide under our pyridone-forming conditions did not provide any of the 33 corresponding pyridone, signaling that the indolizines do not equilibrate with the corresponding enones under the reaction conditions. Figure 3. H M B C correlations A similar aza-Nazarov cyclization was previously observed in our laboratory during work on camptothecin.60 However, in that case the reaction occurred only in benzyloxy systems 167, and it required the catalytic action of Lewis acids such as lanthanide diketonates. Cyclization was attributed to activation of the carbonyl function through chelation of the lanthanide ion as shown in Scheme 40. Its occurrence in our current system remained surprising not only because of the mildness of the Knoevenagel conditions, but also because of a close precedent described by Boger in connection with o Bn i .0 Yb(fod)3 Yb(fod)3 P r - n n - P r Bn n - P r 170 Scheme 40. Previously observed aza-Nazarov cyclization 34 his synthesis of streptonigrone.31 In their work, ketone 50 and aldehyde 44 condensed uneventfully to give coumarin 51 (Scheme 41). Seemingly, neither 51 nor its presumed forerunner 171 exhibited any propensity to cyclize to indolizines 172-173. Scheme 41. Boger's approach to streptonigrone A possible explanation for the reluctance of 51 and 171 to cyclise may be found in the severe nonbonded interaction that develops as a result of steric compression between the benzyloxy substituent and the aryl residue in indolizines 172-173 (dashed semicircles in Scheme 41). This being the case, we reasoned that methoxy-substituted quinoline 159 may condense successfully with 44 to furnish 175. This coumarin, being a potential Michael acceptor, may well be capable of engaging 2-cyanopropionamide in our pyridone-forming reaction. In our hands, however, the condensation between quinoline ketone 159 and aldehyde 44 produced only a meager 10% yield of coumarin 175 as a component of a largely intractable mixture (Scheme 42). We hypothesized that, akin to the above reactions, the predominant product of this condensation was the sensitive, 35 electron-rich indolizine 174, which decomposed readily in the presence of oxygen. A simple comparison between the results from our experiments and those of Boger evidently suggested that the propensity of the aza-Nazarov cyclization to occur is greatly dependent on sterics: whereas a benzyloxy group (cf. 50) is sufficiently encumbered to block indolizine formation, the steric demand of a methoxy group (cf. 159) is inadequate to suppress cyclization. In addition, coumarin 175 was not a substrate for our pyridone-forming reaction. This may be due possibly to the reduced Michael-type reactivity of the aromatic coumarin system. MeO. CHO C 0 2 E t HO MeO 44 OMe piperidine EtOH [?] (10%) MeO MeO. decomposition MeO MeO. C 0 2 E t OMe 174 MeO Y i Me ^ A MeO T) M e O ^ ^ p OMe 175 CN 121 I MeO. MeO (-BuOK OMe 176 Scheme 42. Coumarin synthesis Continuing efforts to obtain a substrate of the type 161 led us to explore a Conrad-Limpach synthesis of the benzyl-protected quinoline 183, hoping that the increased steric bulk at the C-8 position (quinoline numbering) might suppress indolizine formation. Benzylation of the commercially available 2-methylhydroquinone (177) 36 followed by a standard nitration provided nitrobenzene 178 (Scheme 43). To avoid cleavage of the benzyl ethers, the subsequent reduction of the nitrobenzene was achieved with zinc and aqueous HCI, instead of catalytic hydrogenation. Aniline 179 reacted normally with dimethyl acetylenedicarboxylate to afford 180. Unfortunately, the key thermolytic cyclization step in the Conrad-Limpach quinoline synthesis now furnished only an intractable mixture containing none of the desired 182. This failure was possibly due to an unfavourable steric interaction engendered by the future C-5 (quinoline numbering) OBn substituent (cf. 181). a. NaH, BnBr, DMF, RT (92%); b. HN0 3 , AcOH, RT (82%); c. Zn, HCI, AcOH, RT (93%); d. dimethyl acetylenedicarboxylate, MeOH, reflux (49%); e. Ph 2 0, reflux Scheme 43. Attempted synthesis of the benzyl protected quinoline Although experiment suggested that the propensity of intermediates 163 to undergo aza-Nazarov cyclization was quite sensitive to sterics, we also felt that the presence of an electron withdrawing group, such as an ester or nitrile, at the GX position of enones 163 was biasing the system towards cyclization. In fact, such electron-withdrawing substituents may be anticipated to lower the energy of the LUMO of the 37 enone segment, bringing it closer to the energy of the HOMO of the neighbouring imino linkage (the lone pair on the N atom). This facilitates cyclization. Conversely, the CDI then Scheme 44. Attempted synthesis of aminoketones presence of an electron-releasing functionality, such as a protected amine, might raise the LUMO energy and disfavor indolizine formation. The preparation of such enones required aminoketones 185-186, the synthesis of which, unfortunately, proved to be everything but straightforward. For instance, the Claisen-type condensation of protected glycine 184 with activated quinaldic acid 152 (Scheme 44) was unsuccessful (complex OMe OMe OMe 129 187 188 78% overall * No reaction with: (a) Br2, CHCI 3, RT; (b) NBS, NH 4OAc, CCI 4, 80 °C; (c) CuBr 2, CHCI 3, reflux Overbromination with no desired product with: (a) Br 2, AcOH, RT; (b) Br 2, AcOH, dioxane, RT; (c) Pyridium tribromide, AcOH, RT. Scheme 45. Attempted bromination of the quinoline methyl ketone 38 mixtures, no desired product). Reduction of nitroketone 155 to the corresponding aminoketone was also problematic and poor yielding. Introduction of the amino group via an intermediate bromide was also fruitless, due to complications experienced during the direct bromination of methyl ketone 187 (Scheme 45). Limited success was observed in attempts to access the bromoketone 190 via a diazoketone intermediate 189 (Scheme 46). However, the subsequent displacement by a nitrogen nucleophile, such as azide ion or methanesulfonamide, was unsuccessful (again, complex mixtures). Due to the failure encountered on this front and the encouraging results from the acetylquinoline experiments (vide infra), this route was abandoned in favour of the construction of a pyridone lacking a substituent at position 5. 190 w o 191 Y = MsNH 2 or N 3 a. SOCI 2, 80 °C then C H 2 N 2 , Et 2 0 0 °C (17%); b. HBr, AcOH, RT (35%); c. MsNH 2 , K 2 C 0 3 , DMF, RT or NaN 3, DMF, RT Scheme 46. Synthesis of aminoketone via diazo intermediate Initial model work focused on enone 193. Thus, 2-acetylquinoline68 (192) was uneventfully condensed with benzaldehyde in the presence of aqueous NaOH solution to give enone 193,69 which efficiently combined with 2-cyanopropionamide (?-BuOK, DMSO, 95 °C) to furnish pyridone 194 in essentially quantitative yield (Scheme 47). The 39 Ph Ph a. benzaldehyde, aq. NaOH, EtOH, RT (83%); b. 2-cyanopropionamide, f-BuOK, DMSO, 95 °C (quant.) Scheme 47. Pyridone synthesis model studies latter compound served as a convenient model for the installation of the 5-amino functionality through a novel reaction sequence. Indeed, reaction of 194 with iodine monochloride and K2CO3 in DMF resulted in smooth iodination to give iodopyridone 195 (Scheme 48). We note that 194 was recovered unchanged after exposure to the less reactive I2 or even AModosuccinimide (NIS). Iodopyridone 195 was thermally sensitive, but O-methylation (Ag2CC>3, Mel) yielded the stable methoxypyridine 196. It is noteworthy that the use of Meerwein's salt (trimethyloxonium tetrafluoroborate) as the methylating agent resulted in overmethylation. a. ICI, K 2 C 0 3 , DMF, RT (67%); b. Mel, A g 2 C 0 3 , CHCI 3, RT (85%) Scheme 48. Preparation of iodopyridine In principle, the iodo substituent in 196 is amenable to displacement with appropriate nitrogen nucleophiles. Whereas such a substitution reaction normally requires transition metal catalysts (Cu, Pd, etc.), the carbon atom bearing the iodine in 196 is in 40 direct conjugation with the electron-withdrawing quinoline ring. The halogen is thus poised for substitution via an S^Ar mechanism (Scheme 49). However, attempts to induce direct displacement with nitrogen nucleophiles, such as ammonia, ammonium hydroxide, benzylamine, p-methoxybenzylamine and sodium amide, 7 0 were all unproductive. Traces of 5-aminopyridone (198 where Nu = NH2) were obtained when iodopyridine 196 was treated with ammonium hydroxide in the presence of cupric sulphate at 135 °C in a sealed tube for 24 h,71 but the reaction was not synthetically useful. OMe [?] 196 197 198 Scheme 49. S N A r mechanism Alternatively, installation of the amino group through Pd(0) or Cu(I) promoted Buchwald-type couplings was investigated.72 However, experiments with a number of different ligands and nucleophiles, under various reaction conditions, failed to produce the desired aminopyridine. For example, treatment of 196 with Pd(OAc)2 and BnNH2, a typical amine nucleophile for Buchwald couplings, in the presence of r-BuONa or Cs2C03 as the base and 199, 200 or 201 as the ligands, provided an intractable mixture of products. Similarly, coupling using a catalyst system generated from ethylene glycol and copper(I) iodide73 failed to give the desired product. Due to unfavourable steric interactions, coupling reactions involving simple orr/io-substituted aryl halides are known to proceed in considerably poorer yields than their OTt/io-unsubstituted counterparts.72'74 41 Thus, the difficulties encountered with our system may be attributed to severe steric hindrance around the iodo substituent, which is flanked by two bulky aryl systems. Bulky ligands such as 199-201 may well exacerbate this problem. However, coupling reactions performed with the Fukuyama ligand-free system (Cul, CsOAc, DMSO, 90 °C)74 also failed to provide the desired product. The failure of 196 to participate in nucleophilic substitution reactions led us to investigate the possibility of employing the iodopyridine moiety to engender nucleophilicity at C-5. To that end, an initial metal-halogen exchange would generate a reactive organometallic species, which could be trapped with a suitable electrophile amenable to elaboration into the ultimate amine. This objective was achieved through a two-step sequence. Reaction of 196 with rc-butyllithium and trapping of the intermediate aryllithium species with dry carbon dioxide yielded carboxylic acid 203 (Scheme 50). This substance is a plausible substrate for a Curtius-type rearrangement25 leading to the requisite aminopyridone. Such a reaction was not attempted on substrate 203, but it proved to be quite successful with an actual synthetic intermediate (vide infra). 199 200 201 Figure 4. Ligands for Buchwald couplings 42 The foregoing discussion focuses largely on the successful avenue to a functionalized pyridone. It should be stressed that a number of alternative pathways were investigated, which regrettably turned out to be synthetic dead ends. For instance, drawing on Danishefsky's work on camptothecin,55 the 5-unsubstituted pyridone 194 was treated with formaldehyde under acidic conditions in hope of introducing a hydroxymethyl group as a precursor of a carboxylic acid and ultimately, an amino group (Scheme 51). However, no reaction was observed, possibly due to the hindered nature of the C-5 position in 194. Direct introduction of a nitrogenous functionality through reaction of 194 with azodicarboxylate esters, according to a protocol developed by LeBlanc and collaborators at Merck Frosst Canada, also met with failure. HCHO, aq. HCI, MeOH if-1. DIAD, cat. aq.HCI or H 2 S 0 4 DCM 2. Zn, aq HCI, MeOH 204 X = CH 2 OH or NH 2 Scheme 51. Derivatization of pyridone 43 Attempts to functionalize C-5 in 194 under basic conditions fared no better. It was envisioned that upon N-deprotonation a partial negative charge would arise at the desired 5-position of the pyridone, permitting reaction with appropriate electrophiles. The functionality thus introduced might then be elaborated to an ultimate amino group (Scheme 52). However, deprotonation with NaH or K2CO3 and subsequent trapping with Scheme 52. Derivatization of pyridone under basic condition formaldehyde, azodicarboxylate esters or methyl cyanoformate proved fruitless. These disappointing results induced us to focus a final attack based on the chemistry of Scheme 50. 2.5 Synthesis of streptonigrone Armed with the technology to access the elusive aminopyridone, attention was focused on the total synthesis of streptonigrone. Thus, acetylquinoline 187 was obtained through a Claisen condensation of quinoline ester 129 with ethyl acetate, followed by an acid catalyzed hydrolytic decarboxylation (Scheme 53). In accord with our model studies, 44 Scheme 53. Synthesis of tetracyclic core aldol condensation of ketone 187 with aldehyde 127 furnished chalcone 207. The stage was then set for the pyridone synthesis outlined earlier. Treatment of 207 with 2-cyanopropionamide and potassium teTt-butoxide in DMSO afforded pyridone 208 in 60% yield after chromatography. Iodination using IC1, in the presence of potassium carbonate in D M F yielded iodopyridone 209, a sensitive compound, which was immediately protected as the benzyloxypyridine 210 by treatment with silver carbonate and benzyl bromide (Scheme 54). 209 a. ICI, K 2 C 0 3 , DMF, RT; b. BnBr, A g 2 C 0 3 , PhH, RT (36% overall) Scheme 54. Preparation of iodopyridine 45 The two-step sequence of metal-halogen exchange followed by CO2 trapping performed admirably in the real system, leading to carboxylic acid 211 (Scheme 55). The 25 acid was advanced to the corresponding amine via a Yamada-Curtius rearrangement. In accord with the observations reported by Boger,31 in situ capture of the isocyanate intermediate by either tert-buty] alcohol or benzyl alcohol was less effective (possibly due to severe steric hindrance), providing variable quantities of the free amine in addition to the desired carbamate. Thus, formation of the carbamate was best achieved by LiOH-mediated hydrolysis of the isocyanate to the corresponding amine, followed by N-protection with benzyl chloroformate or di-terr-butyl dicarbonate. a 210 M e O M e O M e O . J \ , I JL N ^ . N L . O B n b-c J N ^ . N . , O B n f Y M e O H 0 2 C ^ 211 N ^ M e J ^ ^ O B h C I ' M e O HN P N ^ M e J ^ ^ O B n C I 212 P = B O C y X ) M e O M e 213 P = C B Z O M e a. n-BuLi, THF , - 78°C then C 0 2 gas; b. ( P h O ) 2 P O N 3 , E t 3 N , P h H , reflux then L iOH, aq. T H F , RT; c. For P = B O C : B O C 2 0 , N a H C 0 3 , T H F , RT (29% overall); For P = C B Z : CBZCI , N a H C 0 3 , THF , RT(37% overall) Scheme 55. Preparation of aminopyridine The next step of the synthesis entailed oxidation of 212-213 to quinolinoquinones 214-215. In the Weinreb, Kende, and Boger ' syntheses of streptonigrinoids, a free OH or NH2 group is present on the quinoline at this stage. Such electron-rich substituents greatly facilitate quinone formation, which in all previous cases was carried out with Fremy's salt. By contrast, our intermediate exhibits only methyl ethers on ring A. We 46 therefore anticipated that a stronger oxidant would be required to effect the desired transformation in the present case. Indeed, treatment of 212 with mild oxidants, such as DDQ, left the compound untouched (Scheme 56). Attempted oxidation with the stronger Ag20 / 70% aqueous HNO3 combination resulted in decomposition of the material. Oxidation of 212 and 213 with CAN (ammonium cerium(IV) nitrate) in aqueous acetonitrile did afford the desired quinoline quinones 214 and 215. However, the success of this oxidation was highly dependent on the protecting group present on the pyridinyl amine. Highest yields (93%) were obtained upon oxidation of an 7V-CBZ substrate, while BOC-protected intermediates reacted poorly. We attribute this to partial release of the N-blocking group during contact with the acidic CAN solution, resulting in the overoxidation of the liberated aminopyridine to a multitude of byproducts. OMe OMe oxidant A g 2 0 / H N 0 3 DDQ H N 0 3 CAN CAN CAN P BOC BOC BOC H BOC CBZ yield no desired product . . . 54% 93% Scheme 56. Oxidation of quinoline The successful oxidation of 213 to quinone 215 set the stage for the introduction 20 of C-7 (quinoline numbering) amino group. In accord to the work of Weinreb, quinone 215 was treated with IN3, prepared in situ from NaN3 and IC1. This provided iodoquinone 47 216 (Scheme 57), a delicate intermediate which was immediately advanced to the light-sensitive azidoquinone 217 by reaction with sodium azide in aqueous THF with protection from light. Reduction of 217 with sodium dithionite in refluxing aqueous methanol afforded the protected streptonigrone 218. By contrast, azide reduction with NaBFL.31 or by catalytic hydrogenation resulted in intractable mixtures. 215 OMe OMe a. IN3, CH 3 CN, RT; b. NaN 3, THF-H 2 0, RT; c. N a 2 S 2 0 4 , MeOH-H 20, reflux (40% a-c) Scheme 57. Functionalization of quinoline quinone The final step in the total synthesis involved a global deprotection of 218. Consistent with the observations of other researchers who have confronted streptonigrinoids in the past, this operation turned out to be nontrivial. To illustrate, Weinreb had to resort to the use of 458 equivalents of A1C13 to effect the debenzylation of 219 to 220 (Scheme 58).20 Scheme 58. Weinreb's debenzylation of streptonigrin precursor 48 The Boger synthesis of streptonigrone required extensive experimentation at this stage, ultimately leading the Scripps chemists to reduce the quinone unit in situ (H2, Pd-C) prior to deprotection with HBr gas in CF3CH2OH (Scheme 59). 3 1 o 54 .OMe N ^ f T H 2 N ^ Me r ¥ .OH "OMe OMe H 2 , Pd-C Air OMe OMe OMe HBr, (9) M e O v H 2 N ' HO H N ^ 1 HO H 2 N ^ Me , O H 222 CJ OMe Scheme 59. Boger's deprotection of 54 OMe We rapidly determined that 218 was intolerant of large excesses of A I C I 3 , undergoing ether cleavage at various sites with this reagent, as well as partial conversion to high molecular weight byproducts. The same was true of BBr3 or aqueous acids (cone. HCI, HBr). The carefully tailored Boger deblocking sequence failed to convert 218 to streptonigrone, resulting instead in loss of material. A modification of that procedure wherein the initial quinone reduction was effected with Na2S204, instead of catalytic hydrogenation, provided a mixture of partially deblocked products. Attempts to achieve 49 complete deprotection by extending the reaction time, raising the reaction temperature, or increasing the amount of the reagents used, only led to complex, intractable mixtures. Ultimately, TMS-I76 emerged as the best deprotecting agent. Initial attempts to deblock 218 relied on close monitoring of the progress of the reaction by electrospray mass spectrometry. This technique indicated that TMS-I cleanly converted 218 to 1 in about 1.5 h at room temperature followed by an additional 2 h at 55 °C. However, only a benzylated derivative of streptonigrone was obtained upon the customary aqueous workup of the reaction mixture. The precise structure of this benzylated derivative of 1 remains undetermined. Considerable troubleshooting revealed that benzyl iodide, a byproduct of the deprotection step, was responsible for the undesired benzylation of the initially produced free streptonigrone. Furthermore, it transpired that such an undesirable event occurred during the concentration phase of the workup, and not during the actual deprotection reaction. Evidently, benzyl iodide was being extracted from the aqueous-organic workup mixture together with free 1. Concentration of the extracts then promoted benzylation. The reason why benzylation did not occur during deprotection, despite the elevated reaction temperature (55 °C) and high reactivity of benzyl iodide, remains unclear. We surmise that temporary "protection" of the nucleophilic sites of 218, especially the amino groups, by the excess TMS-I present in the medium, or protonation of these by HI produced by reaction of TMS-I with adventitious moisture, might have delayed / suppressed the alkylation event (Scheme 60). A simple cure for the above ills was readily devised. Thus, the raw extracts from the biphasic workup were not concentrated, but rather applied directly to a silica gel \ 50 column. Initial elution with CH2CI2 quickly removed unwanted benzyl iodide and other nonpolar contaminants. The desired product was then eluted with 5% MeOH in CH2CI2. MeOH, air oxidation, aq. workup OMe Scheme 60 . Global deprotection with T M S T Fully synthetic 1 was thus obtained in 67% yield from 218. The spectral data measured for synthetic 1 were in perfect accord with those recorded in the literature1 for natural material, as apparent from Table 1. A final comment is in order before closing. The present synthesis of 1 deviates 31 from Boger's, inter alia, for the use of an 0-benzyl protecting group on the pyridine unit in lieu of a methoxy group. The reason is that problems emerged at a late stage of the synthesis with a methoxypyridine analog of 218. Such a compound was synthesized from 208 by a sequence analogous to the one outlined in Scheme 54 (Scheme 61), and it was further elaborated to streptonigrone precursor 226, which is structurally very similar 51 Table 1: Reported vs. measured ' H chemical shifts for natural and synthetic 1. Reported * H Shifts (ppm, natural 1) Measured * H Shifts (ppm, synthetic 1) 8.36 (ABq, 2H) 6.84 (d, IH, 7=9.0) 6.66 (d, 1H, 7=9.0) 6.34 (broad s, IH) 5.05 (broad s, 2H) 4.06 (s, 3H) 3.99 (s, 3H) 3.95 (s, 3H) 2.03 (s, 3H) 8.37 (ABq, 2H) 6.83 (d, 1H,J= 8.6) 6.65 (d, 1H,7= 8.6) 6.31 (broads, IH) 5.04 (broad s, 2H) 4.07 (s,3H) 3.99 (s, 3H) 3.95 (s,3H) 2.03 (s, 3H) to the Boger intermediate 54. Contrary to its close relative, deblocking of 226 under a variety of conditions was unsatisfactory. Deprotection under Boger conditions (preliminary reduction of the quinone with H2, Pd-C, C F 3 C H 2 O H , followed by HBr(g), 80 °C) afforded a mixture of partially deprotected products. Similar results were obtained when deblocking was carried out with aqueous or gaseous HCI or HBr, or with Lewis acids such as BBr3 and AICI3. Modified reaction conditions involving changes in the ratios of reagents, solvent, reaction times, and temperatures failed to give the desired product. More forcing conditions (excess of deprotecting agent and elevated reaction temperatures) only resulted in demethylation of the OMe groups or decomposition of material. Thus, it appears that seemingly trivial differences between 54 and 226 (protection of the ring D phenol as a benzyl ether and of the pyridone amino group as a BOC derivative) actually have a profound influence on the feasibility of the final deblocking sequence. Fortunately, benzyl protected intermediate 218 allowed us to circumvent these unpleasant obstacles. 52 a. ICI, K 2 C 0 3 , DMF, RT; b. Mel, A g 2 C 0 3 , CH 3CI , RT (66% a-b); c. n-BuLi, THF, -78 °C then C 0 2 (66%); d. DPPA, Et 3N, f-BuOH, reflux; e. 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Chem. 2006, 71, 7583. 60 APPENDIX (EXPERIMENTAL SECTION) Experimental Protocols : 63 Preparation of 2,4,5-trimethoxynitrobenzene .65 Preparation of 2,4,5-trimethoxyaniline (137) 68 Preparation of 2-[(2,4,5-Trimethoxyphenyl)amino]-2-butenedioic acid, dimethyl ester (138) _ 71 Preparation of 5,6,8-trimethoxy-(l//)-quinolin-4-one-2-carboxylic acid, methyl ester (139) 74 Preparation of 4-chloro-5,6,8-trimethoxyquinoline-2-carboxylic acid, methyl ester (140) 77 Preparation of 5,6,8-trimethoxyquinoline-2-carboxylic • acid, methyl ester (129) 80 Preparation of ethyl 3-oxo-3-(5,6,8-trimethoxyquinolin-2-yl)propanoate (159) 83 Preparation of l-(5,6,8-trimethoxyquinolin-2-yl)ethanone (187) 86 Preparation of 2-hydroxy-3,4-dimethoxybenzaldehyde (44) ..; 90 Preparation of 2-(benzyloxy)-3,4-dimethoxybenzaldehyde (127) 93 Preparation of (£)-3-(2-(benzyloxy)-3,4-dimethoxyphenyl) -l-(5,6,8-trimethoxyquinolin-2-yl)prop-2-en-l-one (207) ,__ '. __.96 Preparation of 2-cyanopropionamide (121) ___ 99 Preparation of 4-(2-(benzyloxy)-3,4-dimethoxyphenyl)-3-methyl -6-(5,6,8-trimethoxyquinolin-2-yl)pyridin-2(lH)-one (208) ; 102 Preparation of 2-(6-(benzyloxy)-4-(2-(benzyloxy)-3,4-dimethoxyphenyl) -3-iodo-5-methylpyridin-2-yl)-5,6,8-trimethoxyquinoline (210) _ 106 Preparation of benzyl 6-(benzyloxy)-4-(2-(benzyloxy)-3,4-dimethoxyphenyl) -5-methyl-2-(5,6,8-trimethoxyquinolin-2-yl)pyridin-3-ylcarbamate (213) 110 Preparation of benzyl 6-(benzyloxy)-4-(2-(benzyloxy)-3,4-dimethoxyphenyl) -2-(6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl)-5-methylpyridin -3-ylcarbamate (215) 114 Preparation of benzyl 2-(7-amino-6-methoxy-5,8-dioxo -5,8-dihydroquinolin-2-yl)-6-(benzyloxy)-4-(2-(benzyloxy) -3,4-dimethoxyphenyl)-5-methylpyridin-3-ylcarbamate (218). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .117 61 Preparation of totally synthetic streptonigrone ( 1 ) , . , . , , , , „ . . _ , , , , , , , „ . . . . , , , 1 2 1 Preparation of methyl 5,6,8-trimethoxy-l,2,3,4-tetrahydroquinoline -2-carboxylate (144) .' 124 Preparation of methyl quinaldate 126 Preparation of ethyl 3-oxo-3-(quinolin-2-yl)propanoate (153) 129 Preparation of 2-nitro-l-(quinolin-2-yl)ethanone (155) 132 Preparation of ethyl 3-hydroxy-l-phenylpyrrolo[l,2-a]quinoline-2-carboxylate (156) 134 Preparation of l-(2-(benzyloxy)-3,4-dimethoxyphenyl) -2-nitropyrrolo[l,2-a]quinolin-3-ol (158) 137 Preparation of ethyl l-(2-(benzyloxy)-3,4-dimethoxyphenyl)-3-hydroxy-6,7,9-trimethoxypyrrolo[l,2-a]quinoline-2-carboxylate (160)... 139 Preparation of 7,8-dimethoxy-3-(5,6,8-trimethoxyquinoline-2-carbonyl) -2H-chromen-2-one (175) ; 144 Preparation of 2-acetylquinoline (192) 148 Preparation of (£)-3-phenyl- l - (quinol in-2-yl )prop-2-en- l -one (193) 151 Preparation of 3-methyl-4-phenyl-6-(quinolin-2-yl)pyridin-2(lH)-one (194) 154 Preparation of 5-iodo-3-methyl-4-phenyl-6 -(quinolin-2-yl)pyridin-2(lH)-one (195) 157 Preparation of 2-(3-iodo-6-methoxy-5-methyl -4-phenylpyridin-2-yl)quinoline (196) 159 6 2 Experimental Protocols Unless otherwise stated, 'H and 1 3C NMR spectra were recorded on Bruker models AV-300 (300 MHz for 'H and 75.5 MHz for 13C), AV-400dir (400 MHz for ]H and 100.6 MHz for 13C), AV-400inv (400 MHz for 'H and 100.6 MHz for 13C) or AV-600 (600 MHz for *H and 150 MHz for l3C) spectrometers using deuteriochloroform (CDCI3) as the solvent. Chemical shifts are reported in parts per million (ppm) on the 8 scale and coupling constants, /, are in hertz (Hz). Multiplicities are reported as "s" (singlet), "d" (doublet), "t" (triplet), "q" (quartet), "dd" (doublet of doublets), "td" (triplet of doublets), "m" (multiplet), "br" (broad). Infrared (IR) spectra, (cm-1) were recorded on a Perkin-Elmer model 1710 Fourier transform spectrophotometer from films deposited on NaCl plates. Low-resolution mass spectra (m/z) were obtained in the electrospray (ESI) mode on a Waters Micromass ZQ mass spectrometer. High-resolution mass spectra (m/z) were recorded in the electrospray (ESI) mode on a Micromass LCT mass spectrometer by the UBC Mass Spectrometry laboratory. Elemental analyses were performed on a Carlo Erba EA model 1108 elemental analyzer by the UBC Microanalysis Laboratory. Melting points (uncorrected) were measured on a Mel-Temp apparatus. f All reagents and solvents were commercial products and used without further purification except THF (freshly distilled from Na/benzophenone under argon) and CH2CI2 (freshly distilled from CaH2 under argon). Commercial n-BuLi was titrated against Af-benzylbenzamide in THF at -78 °C until persistence of a light blue color. Flash chromatography was performed on Silicycle 230 - 400 mesh silica gel. Analytic and preparative TLC was carried out with Merck silica gel 60 plates with fluorescent indicator. Spots were visualized with UV light. All reactions were performed under dry 63 Ar in flame- or oven-dried flasks equipped with Teflon stirbars. All flasks were fitted with rubber septa for the introduction of substrates, reagents, and solvents via syringe. 64 Preparation of 2,4,5-trimethoxynitrobenzene OMe MeO. OMe A solution of 70% HN03 (5 mL) in AcOH (20 mL) was added dropwise to a solution of 1,2,4-trimethoxybenzene (16.3 g, 96.9 mmol) in AcOH (120 mL). The mixture was stirred at RT for 10 min, resulting in a yellow slurry that was diluted with water (100 mL). The yellow solid was filtered, washed with ice-water (3 x 100 mL), and taken up in DCM (200 mL). The resulting solution was washed with sat. aq. NaHC03 (2 x 50 mL), dried (Na2S04) and concentrated. The residue was recrystallized (MeOH) to afford the title compound (13.0 g, 63%) as a yellow crystalline solid, m.p. 124.0-126.0 °C (lit. 123-124 °C: Downer, N. K.; Jackson, A. J. Org. Biomol. Chem. 2004, 2, 3039). H NMR (CDC13, 400 MHz) 7.56 (s, 1H), 6.55 (s, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.88 (s, 3H) 1 3C NMR (CDCI3, 100 MHz) 155.8, 151.4, 143.4, 131.9, 110.0, 98.6, 58.2, 57.52, 57.45 IR: 2950, 1583,1519,1330, 1261 MS: 236.2 [M + Na]+ HRMS: calcdfor C9HnN05: found: 236.0535 [M + Na] 236.0532 [M + Na] + + 65 1 1 1 1 i 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 i 1 1 1 1 I 1 ' 1 1 I ' 1 ' 1 I 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1) Scheme A l . ' H N M R spectrum of 2,4,5-trimethoxynitrobenzene " " I ' I " 11 170 160 I I | I I I 150 ' | " 1 I | I I I I | I I I I | M M | 140 130 120 110 101 3 90 80 70 60 1 " 1 1 " 1 1 1 1 1 1 1 1 1 " 1 1 1 " 1 1 " 1 50 40 30 20 10 ppm (H) Scheme A2. 1 3 C N M R spectrum of 2,4,5-trimethoxynitrobenzene Scheme A3. IR Spectrum of 2,4,5-trimethoxynitrobenzene Preparation of 2,4,5-trimethoxyaniline (137) OMe M e O ^ L OMe A suspension of the above nitro compound (5.13 g, 24.0 mmol) and 10% Pd-C (300 mg, 280 mmol) in MeOH (225 mL) was stirred under a H 2 atmosphere at RT for 24 h. The suspension was then filtered over Celite® and concentrated. The residue was dissolved in DCM (150 mL), washed with sat. aq. NaHC03 (2 x 50 mL), dried (Na2S04) and concentrated to furnish 137 (4.4 g, quant.) as a purple crystalline solid, m.p. 90.0-91.0 °C (lit.89.5-90.5 °C: Downer, N. K.; Jackson, A. J. Org. Biomol. Chem. 2004, 2, 3039). 'HNMR 6.62 (s, 1H), 6.53 (s, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.75 (s, (MeOH-d4, 300 MHz): 3H) l 3C NMR 145.5, 143.40, 143.37, 131.5, 104.5, 102.1, 58.3, 57.5, 57.1 (MeOH-d4, 100 MHz): IR: 3393, 2940, 1527, 1469, 1234, 1205 MS: 206.3 [M + Na]+ HRMS: calcdforC9H13N03: 206.0793 [M + Na]+ found: 206.0791 [M + Na]+ 68 I 1 1 1 1 I ' 1 1 1 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 Scheme A4. H N M R spectrum of 2,4,5-trimethoxyaniline I •' 1 111 • • • l 1 1 • • I •1 1 1 [ • • • • I • • • • I •1 • • I • • • • I • • • • I •1 1 1 IJ 1 1 1 M 1 1 1 1 1 • • • I'1 1 1 I 1 1 •11'11 • 11 ' 1111' 1 111111111 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm (11} Scheme A 5 . C N M R spectrum of 2,4,5-trimethoxyaniline 69 4(XX).0 3«X> Scheme A6. LR spectrum of 2,4,5-trimethoxyaniline Preparation of 2-r(2,4,5-Trimethoxyphenyl)amino1-2-butenedioic acid, dimethyl ester (138) MeO M e O N R J ^ 1 e 0 2 C / ( C0 2 Me MeO A solution of 137 (5.20 g, 28.4 mmol) and dimethyl acetylenedicarboxylate (3.83 mL, 31.2 mmol) in MeOH (150 mL) was refluxed for 15 h. The mixture was then concentrated in vacuo, and the residue was flash chromatographed (EtOAc:hexanes, 1:3) to give 138 (5.35 g, 58%) as an orange paste. 'HNMR 9.52 (s, 1H), 6.53 (s, 1H), 6.50 (s, 1H), 5.34 (s, 1H), 3.88 (s, (CDCI3, 400 MHz): 3H), 3.79 (s, 6H), 3.74 (s, 3H), 3.71 (s, 3H) 13CNMR 171.1, 165.6, 149.8, 147.3, 146.4, 144.0, 122.8, 108.0, 99.6, (CDCI3, 100 MHz): 91.7, 57.5, 57.4, 53.5, 52.0 IR: 3293, 2954, 1740, 1670, 1617, 1525, 1271, 1217 MS: 326.1 [M + H]+ HRMS: calcd for C 5 H 1 9 N O 7 : 348.1059 [M + Na]+ found: 348.1055 [M + Na]+ 71 ... ft 1 1 1 1 I 1 1 ' 1 I 1 ' 1 1 I ' 1 1 1 I 1 1 1 1 I 1 1 1 1 I 1 1 1 ' I 1 ' 1 1 I 1 1 1 ' I 1 1 1 ' I 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 p p m (11) Scheme A7. ' H N M R spectrum of 138 lift HlJu'iilmnii II J11 wiU'uXwJ- ^iwl^nnifpwmwiwiw | 1 1 1 1 | 1 1 1 1 | I I . , | , | 1 I 1 1 | 1 1 1 1 | 1 1 1 1 | 1 I 1 1 | 1 1 , 1 | I I 1 1 | 1 1 190 180 170 160 150 140 130 120 110 100 Ppm (11) I , I I I I 90 8 1 0 70 1 1 | 1 1 60 1 1 | 1 1 50 1 40 1 1 , 1 1 30 1 1 , 1 1 20 1 1 , 1 1 1 1 10 Scheme A8. U C N M R spectrum of 138 73 Preparation of 5,6,8-trimethoxy-(l/J)-quinolin-4-one-2-carboxylic acid, methyl ester (139} OMeO MeO COzMe OMe A solution of 138 (5.35 g, 16.5 mmol) in phenyl ether (150 mL) was refluxed for 2 h, then it was cooled to RT and poured into petroleum ether (300 mL) to give a yellow precipitate.. The solid was collected by filtration and washed with more petroleum ether (4 x 30 mL) to give 139 (4.15 g, 86%) as a dark yellow solid, m.p. 170.5-171.5 °C. H NMR (MeOH-d4, 400 MHz): 1 3C NMR (MeOH-d4, 150 MHz): IR: MS: HRMS: 7.22 (s, 1H), 6.74 (s, 1H), 4.11 (s, 3H), 4.03 (s, 3H), 3.97 (s, 3H), 3.80 (s, 3H) 179.2, 161.8, 148.9, 144/9, 139.0, 135.1, 125.3, 120.4, 109.7, 101.4, 60.4, 56.0,55.4. 3410, 1737, 1592, 1527, 1267, 1070 294.2 [M + H]+ calcd for Ci4Hi5N06: 294.0978 [M + H]+ found: 294.0977 [M + H]+ 74 1.1 w i i . . ^ 1 1 1 1 I 1 1 1 1 I ' 1 1 1 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I ' • ' 1 1 I 1 1 1 1 I 8.0 7.0 6.0 5.0 4,0 3.0 2 .0 1.0 p p m ( t 1 ) Scheme A10. ' H N M R spectrum of 139 ' I ' ' | I I ' I | I I I I | I I I I | I I I I | I I I I | I I I I | M I I | N I I | I I I I | I I I I | I I I I | I I I I | I I I I | I I I I | M I I | I I I I | I 190 180 170 160 150 140 130 120 110 100 90 . 80 70 6 0 50 40 3 0 p p m ( t 1 ) Scheme A l l . I 3 C N M R spectrum of 139 75 Scheme A12. IR spectrum of 139 Preparation of 4-chloro-5,6,8-trimethoxyquinoline-2-carboxylic acid, methyl ester (140) OMe CI MeO. C0 2 Me OMe A suspension of 139 (4.15 g,. 14.1 mmol) in benzene (120 mL; CAUTION: cancer suspect agent) and POCl3 (60 mL; CAUTION: corrosive, toxic) was stirred at RT for 24 h, then it was then poured over ice (200 mL), neutralized by addition of solid NaHC03 (CAUTION: vigorous foaming) and extracted with EtOAc (5 x 100 mL). The combined extracts were then washed with sat. aq. NaHC03 (2 x 50 mL) and brine (50 mL), dried (Na2S04) and concentrated to afford analytically pure 140 (3.87 g, 88%) as an orange crystalline solid, m.p. 193.5-195.0 °C. H NMR (CDC13, 400 MHz): , 3 C NMR (CDCI3, 100 MHz): IR: MS: HRMS: EA: 8.20 (s, IH), 6.93 (s, IH), 4.08 (s, 3H), 4.06 (s, 3H), 4.02 (s, 3H), 3.87 (s, 3H) 166.0, 154.8, 154.2, 144.7, 141.3, 137.0, 136.7, 125.6, 124.6, 99.7,62.9, 57.9, 57.4, 54.1 2945, 1704, 1606, 1470, 1369, 1250, 1016 334.1 [M(35C1) + Na]+, 336.1 [M(37C1) + Na]+ calcd for Ci4Hi435ClN05: 334.0458 [M + Na]+ found: calcd: found: 334.0459 [M + Na]+ C 53.94%, H 4.53%, N 4.49% C 54.28%, H 4.86%, N 4.57% 77 Scheme A13. ' H N M R spectrum of 140 150 100 50 p p m ( t 1 ) Scheme A14. U C N M R spectrum of 140 4000.0 3600 3200 2300 2400 2000 [ 800 1600 1400 1200 1000 H00 600.0 cni-1 Scheme A15. IR Spectrum of 140 Preparation of 5,6,8-trimethoxyquinoline-2-carboxylic acid, methyl ester (129) OMe MeO C0 2Me OMe A mixture of 140 (636 mg, 2.04 mmol), 10% Pd-C (120 mg, 0.113 mmol), Et3N (1.0 mL, 7.2 mmol) in EtO Ac (50 mL) was stirred under a H2 atmosphere at RT for 45 min, then it was filtered over Celite® and concentrated to afford pure 129 (567 mg, quant.) as an orange crystalline solid, m.p. 164.0-165.5 °C. H NMR (CDCI3, 400 MHz): I 3C NMR (CDCI3, 100 MHz): IR: M S : HRMS: EA: 8.47 (d, IH, J = 8.76), 8.15 (d, IH, J = 8.76), 6.84 (s, IH), 4.04 (s, 3H), 4.01 (s, 3H), 3.99 (s, 3H), 3.89 (s, 3H) 167.0, 154.4, 151.6, 145.5, 135.8, 135.5, 132.0, 126.8, 122.7, 99.2, 62.4, 57.9, 57.2, 53.9 1708,1612,1256,1108 278.1 [M + H]+, 300.1 [M + Na] + calcd for C,4H,5N05: 278.1028 [M + H]+ found: 278.1034 [M + H]+ calcd: found: C 60.64%, H 5.45%, N 5.05% C 60.80%, H 5.66%, N 5.09 % 80 Scheme A16. *H N M R spectrum of 129 T 1 1 1 1 1 1 1 1 1 1 1 190 180 170 160 150 140 130 120 110 100 90 8 ppm(t1) I 0 70 , , | , , 60 I 50 I 40 I 30 I 20 10 Scheme A17. l j C N M R spectrum of 129 Preparation of ethyl 3-oxo-3-(5,6,8-trimethoxyquinolin-2-vl)propanoate (159) OMe MeO OEt OMe O O A suspension of 129 (1.05 g, 3.79 mmol) and NaH (60% dispersion, 0.50 g, 13 mmol) in EtO Ac (20 mL) and toluene (50 mL) was stirred at 110 °C for 15 h (CAUTION: vigorous evolution of highly flammable H 2 gas). The reaction was then cooled to RT and diluted with sat. aq. NH4CI (100 mL; CAUTION). The aqueous phase was acidified to pH 4 with IM HCI and extracted with EtOAc (3 x 50 mL). The combined extracts were washed with brine (50 mL), dried (Na2S04) and concentrated in vacuo. Flash chromatography (Et20 : hexanes, 1:2) of the residue afforded 159 (0.830 g, 66%) as a yellow solid, m.p. 101.0-102.0 °C. H NMR (CDCI3, 400 MHz): 13CNMR (CDCI3, 100 MHz): IR: MS: HRMS: EA: (major keto-tautomer) 8.49 (d, IH, J = 8.78), 8.13 (d, IH, J = 8.78), 6.91 (s, IH), 4.38 (s, 2H), 4.22 (q, 2H, J = 7.14), 4.11 (s, 3H), 4.07 (s, 3H), 3.93 (s, 3H), 1.26 (t, 3H, J.= 7.13) 195.8, 169.6, 154.7, 152.0, 149.9, 136.3, 135.1, 131.7, 127.2, 119.8, 100.1, 62.5, 62.0, 57.9, 57.7, 45.6, 15.1 2984, 1743, 1716, 1688, 1607, 1469, 1360, 1255, 1104 334.1 [M + H]+, 356.1 [M + Na]+ calcd for Ci7Hi9N06: 356.1110 [M + Naf 356.1100 [M + Na]+ found: calcd: found: C 61.25%, H 5.75%, N 4.20% C 61.19%, H 5.75%, N 4.18% 83 ppm (11) Scheme A19. ! H N M R spectrum of 159 rrprr 130 ' | " " I ' r p - r r r p T j n 10 200 190 ppm (11) rrp-r 180 r ryrr 150 120 110 100 Scheme A20. UC N M R spectrum of 159 85 Preparation of l-(5,6,8-trimethoxyquinolin-2-yl)ethanone (187) A suspension of 129 (7.00 g, 25.3 mmol) and NaH (60% in oil, 2.5 g, 63 mmol) in EtO Ac (100 mL) and toluene (350 mL) was stirred at 110 °C for 15 h (CAUTION: vigorous evolution of highly flammable H2 gas). The reaction was then cooled to RT and diluted with sat. aq. NH4CI (100 mL; CAUTION). The aqueous phase was acidified to pH 4 with IM HCI and extracted with EtO Ac (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried (Na2S04) and concentrated in vacuo. The residue was then dissolved in 1,4-dioxane (150 mL; CAUTION: cancer suspect agent). Aqueous IM HCI (100 mL) was added, and the mixture was heated at 70 °C for 15 h. The solution was concentrated, the wet residue was neutralized (sat. aq. NaHCOs), and the mixture was extracted with EtOAc (3 x 100 mL). The combined extracts were washed with sat. aq. NaHC03 (50 mL) and brine (50 mL), dried (Na2S04) and concentrated. Flash chromatography (EtOAc:hexanes:DCM, 1:3:1) of the residue afforded 187 (5.17 g, 78% over 2 steps), yellow solid, m.p. 144.0-145.0 °C. 'HNMR 8.48 (d, 1H, 7=8.82), 8.13 (d, 1H, 7 = 8.78), 6.91 (s, 1H), 4.13 (CDCI3, 400 MHz): (s, 3H), 4.06 (s, 3H), 3.93 (s, 3H), 2.87 (s, 3H) 13CNMR 200.6, 153.8, 150.8, 150.7, 135.7, 134.6, 130.9, 126.3, 119.0, (CDCI3, 100 MHz): 99.3, 61.7, 57.2, 57.0, 25.6 IR: 1690,1608,1357,1254 MS: 284.1 [M + Na]+, 545 [2M + Na]+ HRMS: calcd for Ci 4H 1 5N04: 284.0899 [M + Na]+ 86 •found: . 284.0903 [M + Na]+ calcd: C 64.36%, H 5.79%, N 5.36% found: C 64.52%, H 5.86%, N 5.54 % ) M. i I 8.0 7.0 6.0 5.0 4.0 3.0 2 .0 1.0 p p m ( t 1 ) Scheme A22. ' H N M R spectrum of 187 2 0 0 150 100 50 p p m ( t 1 ) Scheme A23. U C spectrum N M R of 187 88 ( Scheme A24. IR spectrum of 187 Preparation of 2-hydroxy-3,4-dimethoxybenzaIdehyde (44) CHO .OH OMe OMe A mixture of commercial 2,3,4-trimethoxybenzaldehyde (10.0 g, 51.2 mmol) and anhydrous A1C13 (6.90 g, 51.7 mmol) in PhH (130 mL; CAUTION: cancer suspect agent) was stirred at RT for 5 min, then it was heated at 75 °C for 5 h. The mixture was then cooled to RT and quenched with water (50 mL) and cone. aq. HCI (20 mL). The organic layer was separated and the aqueous layer was extracted with E t 2 0 (4 x 50 mL). The combined organic extracts were washed with brine (2 x 50 mL), dried (Jv^ SCu) and concentrated to give 44 (9.14 g, 98.0 %), off-white solid, m.p. 69.5-70.0 °C (lit. 70-72 °C: Reichstein, T.; Oppenauer, R.; Grussner, A.; Rhyner, L.; Glatthaar, C. Helv. Chim. Acta. 1935,18, 816). 'HNMR (CDC13, 300 MHz): 11.20 (s, 1H), 9.75 (s, 1H), 7.29 (d, 2H, 7= 8.72), 6.61 (d, 2H, 7 = 8.72), 3.95 (s, 3H), 3.91 (s, 3H) l 3C NMR (CDCI3, 100 MHz): 195.1, 159.5, 155.9, 136.3, 130.4, 116.7, 104.2, 60.9, 56.4 IR: 2939, 1642, 1505, 1451, 1292, 1265, 1109 MS: 183.3 [M + H]+, 205.2 [M + Na]+ HRMS: calcd for C9H10O4: 205.0477 [M + Na]+ found: 205.0484 [M + Na] + 90 Scheme A25. ' H N M R spectrum of 44 M111111 '1111111 l " l | M M | I M I | M 2 1 0 2 0 0 190 p p m (11) 180 170 160 150 140 130 120 110 100 Scheme A26. C N M R spectrum of 44 91 112.6. no. 70. r.5 60. 54.3 4 , , -—, , , , , , i i , , 4000.0 3600 3200 2800 2400 2000 1S00 1600 1400 1200 1000 HOO 600.0 Scheme A27. IR spectrum of 44 92 Preparation of 2-(benzyloxv)-3,4-dimethoxybenza1dehyde (127) CHO .OBn OMe OMe A mixture of 44 (9.14 g, 50.5 mmol), K2C03 (20.0 g, 151 mmol) and BnBr (6.08 mL, 51.2 mmol) in DMF (150 mL) was stirred at RT for 18 h. The mixture was then quenched with water (200 mL) and extracted with Et20 (5 x 100 mL). The combined organic extracts were washed with brine (3 x 50 mL), dried (Na2SO"4) and concentrated to give 127 (13.4 g, 98%) as a yellow oil. 'H NMR 10.09 (s, IH), 7.55 (d, IH, J = 8.79), 7.25-7.39 (m, 5H), 6.72 (d, (CDC13, 300 MHz): IH, J= 8.77), 5.19 (s, 2H), 3.88 (s, 6H) l3CNMR 188.8, 159.4, 155.6, 142.0, 136.6, 128.73, 128.72, 128.6, 124.1, (CDCI3, 100 MHz): 124.0,107.9,76.8,61.1,56.3 IR: 2942,2841, 1679, 1590, 1495, 1455, 1290, 1262, 1094 MS: 295.1 [M + Na]+ HRMS: calcd for Ci6H,604: 295.0946 [M + Na]+ found: 295.0952 [M + Na]+ 93 p p m ( t 1 ) Scheme A28. lR N M R spectrum of 127 " M i l l M r M i i l l " i M , i r i M i M M i " " i " " r i " i " 190 180 170 160 150 140 130 120 110 100 p p m ( t 1 ) Scheme A29. I j C N M R spectrum 127 115.3, 40,5 J, , , , , , , , , , , , , 4(XX).0 3600 3200 28(X) 24(X) 2(XX) 1S(X) 1600 141X1 1200 1000 S00 600.0 Scheme A30. IR spectrum of 127 95 Preparation of (7iy3-(2-(benzyloxy)-3,4-dim 2-yl)prop-2-en-l-one (207) OMe MeO. OMe To a solution of 187 (156 mg, 0.597 mmol) in EtOH (25 mL) was added dropwise a solution of NaOH (1.0 g, 25 mmol) in water (5 mL). The mixture was then stirred for 5 min at RT. A solution of the 2-benzyloxy-3,4-dimethoxybenzaldehyde (120 mg, 0.657 mmol) in EtOH (2 mL) was then added. After 15 h of stirring at RT, the reaction was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (2 x 50 mL), dried (MgS04) and concentrated. Flash chromatography of the residue (EtOAc : hexanes, 1:2) afforded 207 (256 mg, 83%) as a yellow foam. H NMR (CDC13, 400 MHz): 13 C NMR (CDCI3, 100 MHz): IR: MS: HRMS: 8.53 (d, 1H, J = 8.78), 8.32 (m, 2H, overlapping resonances), 8.28 (d, 1H, J = 8.68), 7.64 (d, 1H, J = 8.82), 7.52 (m, 2H, overlapping resonances), 7.26-7.35 (m, 3H), 6.91 (s, 1H), 6.78 (d, 1H, / = 8.85), 5.14 (s, 2H), 4.11 (s, 3H), 4.08 (s, 3H), 3.96 (s, 3H), 3.95 (s, 3H), 3.90 (s, 3H) 189.6, 155.9, 153.8, 152.9, 151.7, 150.7, 142.8, 139.7, 137.3, 135.7, 134.5, 131.0, 128.9, 128.6, 128.3, 126.1, 123.6, 123.4, 120.5, 120.3, 108.0, 99.0, 76.4, 61.8, 61.3, 57.2, 56.8, 56.3 2935, 1661, 1608, 1584, 1495, 1252, 1095, 1062 516.1 [M + H]+ calcd for C30H29NO7: 538.1842 [M + Na]+ found: 538.1857 [M + Na]+ 96 ppm (tl) Scheme A31. ' H N M R spectrum of 207 Scheme A33. IR spectrum of 207 Preparation of 2-cyanopropionamide (121) CONH, T NC Me Anhydrous NH3 gas (CAUTION: toxic and corrosive) was bubbled through a solution of 2-cyanopropanoic acid ethyl ester (4.00 g, 31.5 mmol) in ethanol (30 mL) for 20 min. The solution was then stirred at RT for 15 h and concentrated to give 121 (3.00 g, 98%) as an off-white solid, m.p. 99.5-101.0 °C. 'H NMR 6.13 (s, br, IH), 5.62 (s, br, IH), 3.96 (q, IH, J = 7.30), 1.52 (d, (MeOH-d4, 400 MHz): 3H, J = 7.30) 13C NMR 170.6, 119.7, 32.8, 16.1 (MeOH-d4, 100 MHz): IR: 3360,3192,1668 HRMS: calcd for C4H6N20: 99.0558 [M + H]+ found: 99.0560 [M + H]+ EA: calcd: C 48.97%, H 6.16%, N 28.56% found: C 49.26%, H 6.22%, N 28.68% 99 p p m ( t 1 ) Scheme A34. ' H N M R spectrum of 121 190 180 170 160 150 140 130 120 110 100 90 80 7 0 6 0 50 p p m ( H ) I I | I I 4 0 I I | I I 3 0 I I | n 2 0 10 Scheme A35.. U C N M R spectrum of 121 ' 101 Preparation of 4-(2-(benzyloxy)-3,4-dimethoxyphenyl)-3-methyl-6-(5,6,8-trimethoxyquinolin-2-vl)pvridin-2(lH)-one (208) OMe OMe A solution of enone 207 (1.54, 2.98 mmol) and 2-cyanopropanamide (300 mg, 3.00 mmol) in DMSO (75 mL) was degassed for 20 min (bubbled through with argon) prior to the addition of potassium fert-butoxide (670 mg, 6.00 mmol). The reaction was then stirred at RT for 5 min and at 100 °C for 5 h. After cooling to RT, IM HCI (100 mL) was then added dropwise (CAUTION: evolution of highly toxic HCN gas) and the resulting mixture was extracted with EtOAc (5 x 50 mL). The combined organic extracts were washed with brine (3 x 30 mL), dried (Na2S04) and concentrated in vacuo. Flash chromatography of the residue (100% EtO Ac then MeOH:DCM, 1:9) afforded 208 (1.02 g, 60%) as a yellow solid, m.p. 92.5-95°C. 10.80 (s, br, IH), 8.38 (d, IH, J = 8.92), 7.70 (d, IH, J = 8.99), 7.05-7.15 (m, 5H), 6.90 (s, IH), 6.89 (d, IH, J = 8.40), 6.78 (d, IH, / = 8.58), 6.69 (s, IH), 4.93 (s, 2H), 4.11 (s, 3H), 4.05 (s, 3H), 3.96 (s, 3H), 3.94 (s, 3H), 3.93 (s, 3H), 2.02 (s, 3H) 163.5, 154.1, 153.2, 149.8, 149.7, 147.5, 145.1, 143.1, 137.6, 137.1, 135.6, 134.6, 131.2, 130.1, 128.6, 128.4, 128.2, 127.1, 124.5, 124.3, 117.6, 108.1, 107.8, 99.4, 75.8, 61.7, 61.4, 57.3, 56.4, 56.3, 14.6 2938,1642, 1610, 1497, 1456, 1354, 1293, 1100 102 'HNMPv (CDC13, 400 MHz): 13CNMR 7 (CDCI3, 100 MHz): IR: 569.1 [M + H]+ calcd for C33H32N2O7: found: calcd: found: 569.2288 [M + H]+ 569.2285 [M + H]+ C 69:70%, H 5.67%, N 4.93% C 69.34%, H 5.85%, N 5.18% I , , , 1 , , 11.0 p p m (11) 10.0 9.0 I 8.0 I 7.0 I 6.0 I 5.0 i I | I I 4.0 3.0 . , | , 2 .0 ' I ' ' ' 1 I 1.0 Scheme A37. *H N M R spectrum of 208 11 • > • i • •111 > • 170 160 p p m (11) T 1 120 Scheme A38. [iC N M R spectrum of 208 105 Preparation of 2-(6-(benzyIoxy)-4-(2-(benzyloxy)-3,4-dimethoxvphenyl)-3-iodo-5-methylpyridin-2-yl)-5,6,8-trimethoxvquinoline (210) OMe OBn Me OBn OMe . OMe A mixture of 208 (1.48 g, 2.61 mmol) and potassium carbonate (2.15 g, 15.6 mmol) in D M F (110 mL) was stirred at RT for 5 min. Iodine monochloride (2.11 g, 13.1 mmol) was then added and the resulting mixture was stirred in the dark at RT for 16 h. The reaction was then diluted with sat. aq. NH4CI (150 mL) and extracted with EtOAc (4 x 75 mL). The combined organic extracts were washed with sat. aq. Na2S2C>3 (75 mL) and brine (75 mL), dried (JN^SOx) and concentrated to give the sensitive iodopyridone. The crude iodopyridone (1.27 g, 1.83 mmol) was immediately dissolved in benzene (55 mL) and treated with Ag 2CC»3 (0.505 g, 1.83 mmol) and benzyl bromide (0.450 mL, 3.66 mmol). The resulting mixture was stirred in the dark for 3 d, then it was filtered through a bed of Celite® and concentrated. Purification by flash chromatography (EtOAc : hexanes, 1:3) afforded 210 (520 mg, 36% over 2 steps) as a pale-yellow foam. ' H N M R 8.46 (d, 1H, J = 8.68), 7.62 (d, 1H, J = 8.63), 7.26-7.46 (m, 5H), (CDCI3, 400 MHz): 7.03-7.22 (m, 5H), 6.90 (s, 1H), 6.77-6.79 (m, 2H, A B system), 5.43 (m, 2H, A B system), 5.06 (m, 2H, A B system), 4.07 (s, 3H), 4.04 (s, 3H), 3.96 (s, 3H), 3.94 (s, 3H), 3.90 (s, 3H), 2.04 (s, 3H) 1 3 C N M R 161.4, 157.3, 154.7, 154.1, 153.9, 153.5, 150.0, 149.0, 142.9, (CDCI3, 100 MHz): 138.3, 138.0, 135.9, 134.8, 130.5, 130.2, 128.6, 128.3, 128.0, 127.8, 127.7, 127.5, 124.5, 124.1, 123.0, 121.9, 107.7, 99.4, 91.6, 77.4, 75.0, 68.1, 61.7, 61.3, 57.5, 56.9, 56.2, 14.6 106 2937, 1601, 1496, 1342, 1099 785.1 [M + H]+ calcd for C40H37N2O7I: 785.1724 [M + H]+ found: 785.1727 [M + Hf calcd: C 61.23%, H 4.75%, N 3.57% found: C 61.47%, H 4.96%, N 3.65% 1 1 11 I 1 1 . 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm(t1) Scheme A40. ' H N M R spectrum of 210 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm (t1) Scheme A41. U C N M R spectrum of 210 108 109 Preparation of benzyl 6-(benzyloxy)-4-(2-(benzyloxy)-3,4-dimethoxyphenyl)-5-methy 2-(5,6,8-trimethoxyquinolin-2-yI)pyridin-3-ylcarbamate (213) MeO MeO. OBn Me .OBn OMe OMe A solution of 210 (222 mg, 0.283 mmol) in THF (2 mL) was added dropwise to a cold (-78 °C) solution of n-butyllithium (0.35 mL of 1.6 M solution in hexanes, 0.57 mmol) in THF (30 mL). Bone dry C02 gas was immediately bubbled through the solution for 10 min at -78 °C and at RT for 20 min. The reaction was then quenched with water (2 x 30 mL) and extracted with EtOAc (30 mL). The aqueous phase was further acidified to pH 2 by addition of IM HCI and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried (Na2S04) and concentrated. The crude residue was filtered through a bed of silica gel (washed with EtOAc:hexanes, 1:1; eluted with MeOH:DCM, 5:95) to afforded a yellow paste (134 mg). A solution of this material plus diphenyl phosphoryl azide (0.26 g, 0.21 mL, 0.96 mmol) and E t 3 N (0.70 mL, 5.0 mmol) in benzene (40 mL) was refluxed for 15 h, then it was cooled to RT and concentrated in vacuo. The residue was taken up in THF (10 mL) and IM LiOH (10 mL). The resulting mixture was stirred at RT for 1 h, then it was diluted with brine (20 mL) and extracted with EtOAc (4 x 10 mL). The combined extracts were washed with brine (10 mL), dried (Na2S04) and concentrated. The crude aminopyridine was then immediately taken up in THF (25 mL) and cooled to 0 °C before the addition of NaHC03 110 (160 mg, 1.90 mmol) and benzyl chloroformate (0.10 mL, 0.70 mmol). The reaction was then allowed to warm up to RT and stirred at RT for 18 h before quenching with water (50 mL). The product was then extracted with EtOAc (4 x 25 mL), washed with brine (25 mL), dried (NaiSCu) and concentrated. Flash chromatography of the residue (EtOAc:hexanes, 1:4) gave 213 (85 mg, 37% over 3 steps) as a yellow paste. H NMR (CDCI3, 400 MHz): 13 C NMR (CDCI3, 100 MHz): IR: MS: HRMS: 10.07 (s, br, IH), 8.44-8.49 (m, 2H, AB system), 6.98-7.57 (m, 16H), 6.81 (s, IH), 6.73 (d, IH, 7= 8.63), 5.54-5.61 (m, 2H, AB system), 5.02-5.12 (m, 2H, AB system), 4.80-4.88 (m, 2H, AB system), 4.05 (s, 3H), 3.97 (s, 3H), 3.93 (s, 3H), 3.89 (s, 3H), 3.84 (s, 3H), 2.01 (s, 3H) 158.5, 154.8, 153.5, 153.0, 150.2, 149.2, 146.8, 142.5, 138.5, 138.4, 137.4, 135.8, 134.0, 130.4, 128.6, 128.3, 128.1, 127.9, 127.77, 127.72, 127.6, 127.5, 127.4, 126.3, 124.2, 123.6, 122.2, 121.8, 107.0, 98.9, 74.8, 67.8, 66.3, 61.8,61.2, 57.5, 56.3, 56.1, 14.0 2941,1733, 1601, 1481, 1354, 1226, 1102 808.3 [M + H]+, 830.3 [M + Na]+ calcd for C48H45N3O9: 808.3234 [M + H]+ found: 808.3244 [M + H]+ 111 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2 .0 1.0 PPm( t1 ) Scheme A43. ' H N M R spectrum of 213 p p m (t1) Scheme A44. U C N M R spectrum of 213 112 Preparation of benzyl 6-(benzyloxy)-4-(2-(benzyloxy)-3,4-dimethoxvphenyl)-2-(6-methoxv-5,8-dioxo-5,8-dihydroquinolin-2-yl)-5-methylpyridin-3-vlcarbamate (215) O M e To a cold (0 °C) solution of 213 (85 mg, 0.11 mmol) in C H 3 C N (20 mL) was added dropwise a solution of eerie ammonium nitrate (175 mg, 0.316 mmol) in water (8 mL). The resulting solution was stirred at 0 °C for 45 min before diluted with water (50 mL) and extracted with EtOAc (4 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried (NaaSCu) and concentrated. The residue was chromatographed (EtOAc:hexanes, 1:1) to give the 215 (75 mg, 93%) as an orange paste. 8.74 (s, br, IH), 8.47 (m, 2H, A B system), 7.04-7.50 (m, 15H), 6.91 (d, IH, J = 8.65), 6.70 (d, IH, J = 8.64), 6.31 (s, IH), 5.47-5.54 (m, 2H, A B system), 4.92-5.05 (m, 2H, A B system), 4.79-4.88.(m, 2H, A B system), 3.96 (s, 3H), 3.92 (s, 3H), 3.86 (s, 3H), 1.95 (s, 3H) 182.6, 179.8, 162.8, 160.3, 159.1, 154.6, 153.9, 149.9, 147.9, 146.1, 142.6, 138.04, 137.99, 137.1, 135.2, 128.7, 128.3, 128.2, 127.93, 127.91, 127.72, 127.66, 127.1, 126.4, 125.9, 124.0, 123.2, 110.7, 107.2, 74.9, 68.1, 66.4, 64.5, 61.2, 56.9, 56.1, 14.1 2937,1734, 1578, 1497, 1244, 1101 778.3 [M + Ff]+, 800.3 [M + Na] + calcd for C46H39N3O9: 778.2765 [M + H ] + found: 778.2779 [M + H ] + 114 ' H N M R (CDCI3, 400 MHz): 1 3 C N M R (CDCI3, 100 MHz): IR: MS: HRMS: 9.0 ppm (t1) 8.0 ' I 1 1 7.0 G.O 5.0 1 1 | 1 1 4.0 1 ' 1 1 3.0 2.0 1.0 Scheme A46. H N M R spectrum of 215 1 1 1 11 1 1 1 11 1 1 1 11 1 1 1 11 1 1 1 11 1 1 1 11 1 1 1 11 1 1 1 11 1 1 1 11 1 1 1 11 1 '" 1 1 1 1 11 1 1 1 11 1 1 1 11 1 1 1 11 1" 11 1 1 1 11 1 1 1 11' 1 ' 11 1 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 Scheme A47. I 3 C N M R spectrum of 215 115 116 Preparation of benzyl 2-(7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl)-6-(benzyloxy)-4-(2-(benzvloxy)-3,4-dimethoxvphenyl)-5-methylpvridin-3-ylcarbamate (218} OMe To a suspension of NaN3 (1.0 g, 15 mmol) in CH3CN (36 mL) in MeOH/ice bath (-10 °C) was added IC1 (0.80 g, 4.93 mmol). The suspension was stirred at -10 °C for 15 min and filtered to give a yellow IN3 solution. To a cold (-10 °C ) solution of 215 (75 mg, 0.097 mmol) in CH3CN (50 mL) was added the above IN3 solution (16 mL) and the resulting solution was stirred at RT for 4 h. The mixture was then diluted with DCM (50 mL) and washed with water (15 mL) and 50% aq. Na2S203 (15 mL), dried (Na2S04) and concentrated in vacuo to give the sensitive 216. This material was dissolved in THF (10 mL). A solution of NaN3 (7.0 mg, 0.11 mmol) in water (2 mL) was added and the resulting mixture was stirred in the dark at RT for 15 h. The reaction was then quenched with water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (10 mL), dried (Na2S04) and concentrated to give the sensitive 217. A mixture of crude 217 and sodium dithionite (220 mg, 1.07 mmol; 85% tech. grade) in MeOH (40 mL) and water (20 mL) was refluxed in the dark for 4 h. The mixture was then cooled to RT, quenched with water (20 mL) and extracted with EtOAc (4 x 25 mL). The combined organic extracts were washed with brine (20 mL), dried 117 (NaaSCU) and concentrated. Purification of the crude residue by preparative T L C (EtOAc : hexanes, 2:1) afforded 218 (30 mg, 40% over 3 steps) as a dark purple wax. H NMR (CDCI3, 400 MHz): 13 C NMR (CDCI3, 100 MHz): IR: MS: HRMS: 8.41 (m, 2H), 7.00-7.50 (m, 15H), 6.92 (d, 1H, J = 8.19), 6.70 (d, 1H, J = 8.60), 5.48-5.55 (m, 2H, AB system), 5.14 (s, br, 2H), 4.91-5.06 (m, 2H, AB system), 4.80-4.89 (m, 2H, AB system), 4.10 (s, 3H), 3.93 (s, 3H), 3.87 (s, 3H), 1.96 (s, 3H) 179.7, 177.5, 160.9, 159.2, 154.7, 153.9, 149.9, 148.0, 144.8, 142.6, 139.6, 138.1, 138.0, 137.4, 137.1, 134.4, 128.7, 128.3, 128.2, 127.92, 127.88, 127.77 (overlapping resonances), 127.68, 127.5, 125.9, 123.3, 107.3, 74.9, 68.0, 66.4, 61.2, 60.7, 56.2, 14.0 3355,2938, 1732, 1614, 1497, 1455, 1351, 1231, 1100 793.4 [M + H] + , 815.3 [M + Na] + calcd for C46H40N4O9: found: 831.2432 [M + K ] + 831.2444 [M + K ] + 118 8.0 7.0 3.0 2.0 Scheme A49. ' H N M R spectrum of 218 • j >11j 1 1 • i • •111 • • • • i 1 • • > i • • •11 • • • • i • • • • i • • • • i • • • • i • >J • i •1 • • i • • • • i 1 •1 • i • 1 1 • i • • • • i 1 1 • • i • • • • i 1 1 ' 1 1 1 1 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm (11) Scheme A 5 0 . 1 3 C N M R spectrum of 218 119 120 Preparation of totally synthetic streptonigrone (1) o o H ,0 N ^ i T H 2 N/ Me r Y .OH 'OMe OMe A solution of 218 (15 mg, 0.019 mmol) and TMS-I (0.50 mL, 3.5 mmol) in CH3CN (2 mL) was stirred at RT for 1.5 h and then heated at 55 °C for 2 h. The mixture was then cooled to RT and quenched with MeOH (5 mL). The resulting solution was stirred at RT for 10 min prior to the addition of water (10 mL) and extraction with DCM (5 x 10 mL). The combined organic extracts were washed with 50% aq. Na2S203 (10 mL) and water (10 mL), dried (Na2S04) and immediately filtered through a bed of silica gel (washed with DCM, followed by elution with 5% MeOH in DCM). The elutant was concentrated and purification by preparative TLC (CH3C1 : acetone : MeOH, 8:1:1) afforded streptonigrone (6 mg, 67%) as a dark solid. H NMR (CDC13, 400 MHz): 13 C NMR (CDC13, 150 MHz): IR: MS: HRMS: 8.31-8.37 (m, 2H, AB system), 6.83 (d, 1H, J = 8.56), 6.65 (d, 1H, / = 8.59), 6.31 (broad s, 1H), 5.04 (broad s, 2H), 4.07 (s, 3H), 3.99 (s, 3H), 3.95 (s, 3H), 2.03 (s, 3H) 180.0, 177.4, 158.4, 156.8, 153.0, 147.0, 145.0, 140.4, 139.1, 137.5, 136.5, 135.9, 134.3, 131.3, 125.2, 124.8, 123.0, 117.9, 114.4, 105.0, 61.4, 60.8, 56.2, 14.7 3355, 2923, 2852, 1734, 1637, 1609, 1458, 1245, 1098 501.0 [M + Na] + calcd for C 2 4H 2 2N40 7 : 501.1386 [M + Na] + found: 501.1392 [M + Na] + 121 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I 8.0 7,0 6.0 5.0 4.0 3.0 2.0 1.0 Scheme A52. ' H N M R spectrum of synthetic streptonigrone Scheme A53. C N M R spectrum of synthetic streptonigrone 122 123 Preparation of methyl 5,6,8-trimethoxy-l,2,3,4-tetrahydroquinoline-2-carboxvlate (144) OMe A mixture of 140 (60 mg, 0.19 mmol), 10% Pd-C (20 mg, 0.019 mmol) in EtOH (7 mL) was stirred under an H 2 atmosphere at RT for 45 min, then it was filtered over Celite® and concentrated to afford pure 144 (50 mg, 96%) as a yellow paste. 'H NMR 6.40 (s, IH), 4.49 (br. s, IH), 4.0 (m, IH), 3.83 (s, 3H), 3.82 (s, (CDC13, 400 MHz): 3H), 3.77 (s, 3H), 3.76 (s, 3H), 2.74-2.84 (m, 2H), 2.24-2.31 (m, IH), 1.98-2.07 (m, IH) MS: 282.1 [M + H]+ 124 1 1 1 I | I I 7.0 I I | I I ! I 6.0 5 I I , I I | I I 0 ' 4.0 . I | I I 3.0 I , | I I I I | 2.0 ppm (t1) 1 Scheme A55. ' H N M R spectrum of 144 125 Preparation of methyl quinaldate N C0 2 Me To a suspension of quinaldic acid (6.58 g, 38.0 mmol) in MeOH (70 mL) was added a 1.25 M HCI in methanol solution (70 mL). The resulting solution was refluxed for 15 h. The mixture was then cooled to RT and concentrated in vacuo. The residue was partitioned between sat. aq. NaHCOs (100 mL) and EtOAc (3 x 75 mL). The combined organic extracts were washed with sat. aq. NaHCOs (25 mL) and water (25 mL), dried (Na2S04), and concentrated in vacuo to give the desired ester (5.85 g, 82%), white solid, m.p. 82.0-83.0 °C (lit. 81-83 °C: Weitgenant, J. A.; Morrison, J. D.; Helquist, P. Org. Lett. 2005, 7, 3609). 'H NMR 8.30 (d, 2H, J = 8.48), 8.19 (d, 1H, J = 8.50), 7.87 (d, 1H, J = (CDC13, 400 MHz): 8.27), 7.78 (t, 1H, /= 7.17), 7.64 (t, 1H, 7= 7.40), 4.08 (s, 3H) 13CNMR 167.0, 148.9, 148.6, 138.3, 131.7, 131.3, 130.4, 129.6, 128.( (CDC13, 100 MHz): 122.0, 54.2 IR: 1714, 1450, 1320, 1144 MS: 210.2 [M + Na]+ HRMS: found: calcdforCnH9N02: 210.0531 [M + Na]+ 210.0536 [M + Na]+ EA: calcd: C 70.58%, H 4.85%, N 7.48% found: C 70.50%, H 4.75%, N 7.52% 126 Scheme A56. *H N M R spectrum of methyl quinaldate " < • i 1 1 *111 1" r 1 1 11" 1 11 1 1 1 11 1 1 •11 • 1 1 • i " 1111 170 160 150 140 130 ' 120 110 100 90 ppm (11) 70 60 50 40 30 20 10 Scheme A57. I 3 C N M R spectrum of methyl quinaldate 4000.0 3600 3200 2800 2400 2000 1S00 ' . 1600 1400 1200 1000 800 600,0 Scheme A58. IR spectrum of methyl quinaldate Preparation of ethyl 3-oxo-3-(quinolin-2-yl)propanoate (153) co2Et Solid r-BuOK (3.00 g, 26.7 mmol) was slowly added to a solution of methyl quinaldate (3.73 g, 19.9 mmol) in EtOAc (75 mL) at RT. The mixture was stirred for 15 min at RT, then it was quenched with water (120 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried (Na2S04) and concentrated. Purification of the crude residue by flash chromatography (EtOAc : hexanes, 1:4) afforded 153 (5.91 g, 98%) as an off-white paste. H NMR (CDC13, 400 MHz): 1 3C NMR (CDCI3, 100 MHz): IR: MS: HRMS: EA: 8.24 (d, IH, / = 8.50), 8.13 (m, 2H, overlapping resonance signals), 7.84 (d, IH, J = 8.17), 7.75 (td, IH, J = 6.92, J = 1.35), 7.62 (td, IH, / = 8.06, J = 1.05), 4.34 (s, 2H), 4.20 (q, 2H, J = 7.13), 1.22 (t, 3H, J = 7.13) 195.9, 169.4, 152.9, 148.0, 138.1, 131.5, 131.1, 130.7, 129.9, 128.7,119.0,62.1,45.7,15.1 2983,1742,1702,1332,1198 266.1 [M + Na]+, 509.1 [2M + Na]+ calcd for C 4 H 1 3 N O 3 : 266.0793 [M + Na]+ found: 266.0798 [M + Na]+ calcd: found: C 69.12%, H 5.39%, N 5.76% C 68.86%, H 5.45%, N 6.02% 129 h\ i fkh 1 1 . J 8.0 7.0 6.0 5.0 — 4.0 3.0 2.0 1.0 PPm (H) Scheme A59. l H N M R spectrum of 153 " " 111111 " 1111 200 190 180 ppm (t1) 170 160 150 r - r r T T 140 130 120 110 100 90 Scheme A60. 1 j C N M R spectrum of 153 105.4 4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 S00 600.0 Scheme A61. IR spectrum of 153 Preparation of 2-nitro-l-(quinolin-2-yl)ethanone (155) 1,1'-Carbonyldiimidazole (7.08 g, 43.7 mmol) was added in portions to a solution of quinaldic acid (6.05 g, 34.9 mmol) in THF (70 mL) and stirred at RT for 30 min before the addition of CH3N02 (11.3 mL, 210 mmol) and f-BuOK (15.7 g, 140 mmol). The mixture was stirred for 2 h at RT, then it was concentrated and partitioned betwen EtOAc (100 mL) and 0.1M HCI (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined extracts were washed with brine (50 mL), dried (Na2S04) and concentrated. Flash chromatrography (EtOAc : hexanes, 1:3) of the residue afforded 155 (4.53 g, 61%) as a yellow solid. 'H NMR 8.37 (d, IH, J = 8.59), 8.17 (d, IH, J = 8.50), 8.16 (d, IH, / = (CDC13, 300 MHz): 8.81), 7.93 (d, IH, J =8.06), 7.81-7.87 (m, IH), 7.69-7.75 (m, IH), 6.62 (s, 2H) \ 132 > 8.50 8.00 - 7.50 7.00 6.50 6.00 PPm (11) Scheme A62. ' H N M R spectrum of 155 133 Preparation of ethyl 3-hvdroxv-l-phenvlpvrrolo[l,2-alquinoline-2-carboxylate (156) Piperidine (1.5 mL, 15.1 mmol) was added dropwise at RT to a solution of 153 (5.91 g, 24.3 mmol) and PhCHO (3.0 mL, 29 mmol) in EtOH (12 mL). The mixture was refluxed for 1 h and concentrated in vacuo. The residue was diluted with EtOAc (100 mL) and water (50 mL). The organic phase was separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (2 x 25 mL), dried (Na2S04) and concentrated. The residue was purified by flash chromatography (EtOAc : hexane, 1:19) to afford 156 (7.05 g, 87.5%) as a yellow solid, m.p. 114.0-116.0 °C. H NMR (CDC13, 400 MHz): 1 3C NMR (CDCI3, 100 MHz):: IR: MS: HRMS: EA: 8.30 (s, IH), 7.41-7.52 (m, 6H), 7.36 (d, IH, 7= 9.31), 7.17 (td, IH, J= 7.07 Hz, 7= 1.02), 7.03 (d, IH,/= 8.52), 6.93 (m, IH), 6.73 (d, IH, J = 9.30), 4.11 (q, 2H, J = 7.21), 0.97 (t, 3H, J = 7.18) 168.4, 140.9, 135.2, 134.9, 131.9, 129.8, 129.5, 128.22, 128.17, 127.5, 125.5, 118.9, 117.8, 117.2, 117.0, 105.7,61.1, 14.7 3338,2982,1674, 1498, 1452, 1377, 1243 354.1 [M + Naf calcd for C 2 1 H 1 7 N O 3 : found: calcd: found: 354.1106 [M + Na]+ 354.1107 [M + Na]+ C 76.12%, H 5.17%', N 4.23% C 75.92%, H 5.26%, N 4.60% 134 ppm{t1) Scheme A63. ' H N M R spectrum of 156 I H » » ) I H M I i » l l M U | I I I H H U | I I I I | M M | I I I I | U 190 180 170 160 150 140 ppm(t1) T I I I I I I , I I I , I , I M 130 120 110 100 Scheme A64. I 3 C N M R spectrum of 156 Scheme A66. IR spectrum of 156 Preparation of l-(2-(benzvloxv)-3,4-dimethoxvphenyl)-2-nitropvrrolo[l,2-alquinolin-3-ol (158} A mixture of 155 (185 mg, 0.856 mmol), aldehyde 127 (256 mg, 0.942 mmol), NH4OAc (75 mg, 0.94 mmol) in toluene (10 mL) was refluxed for 3.5 h. The reaction was then quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (1 x 10 mL), dried (Na2S04) and concentrated. Flash chromatrography (EtOAc : hexanes, 1:5) of the residue afforded 158 (349 mg, 87%) as a dark red paste. 'HNMR 8.11 (s, 1H), 7.47 (d, lH,/= 7.68), 7.33 (d, 1FI,/= 9.46), 7.21 (CDC13, 300 MHz): (d, 1H, J = 7.85), 6.94-7.13 (m, 6H), 6.74-6.88 (m, 4H), 4.88 (s, 2H), 4.01 (s, 3H), 3.92 (s, 3H) 137 ppm (t1) I | i i 8.0 7.0 6.0 5.0 I I | I I 4.0 I I | I I 3.0 Scheme A67. ' H N M R spectrum of 158 Preparation of ethyl l-(2-(benzyloxy)-3,4-dimethoxyphenvl)-3-hydroxy-6,7,9-i trimethoxypyrrolori,2-alquinoline-2-carboxylate (160) OMe Piperidine (0.010 mL, 0.101 mmol) was added dropwise to a solution of 159 (119 mg, 0.357 mmol) and 2-benzyloxy-3,4-dimethoxybenzaldehyde (100 mg, 0.358 mmol) in ethanol (15 mL). The mixture was refluxed for 35 min, then it was diluted with water (30 mL) and EtOAc (30 mL). The organic layer was separated and the aqueous layer was extracted with more EtOAc (3 x 15 mL). The combined extracts were washed with brine (25 mL), dried (Na2S04) and concentrated. Flash chromatography (EtOAc : hexane, 1:4) of the residue afforded the sensitive 160 (103 mg, 49.3%) as a yellow paste. 8.49 (s, IH), 7.34 (d, IH, J= 9.45), 7.08-7.17 (m, 4H), 6.98 (d, IH, J = 9.45), 6.70-6.77 (m, 3H), 6.26 (s, IH), 4.52 (m, 2H, AB system), 4.03-4.23 (m, 2H), 3.92 (s, 3H), 3.84 (s, 3H), 3.795 (s, 3H), 3.790 (s, 3H), 3.09 (s, 3H), 1.12 (t, 3H, J = 7.12) 168.3, 154.0, 151.1, 150.5, 147.4, 143.0, 142.7, 138.3, 130.2, 128.9, 128.6, 128.3, 127.3, 126.0, 124.2, 118.8, 118.6, 118.4, 110.3, 107.3, 104.6, 96.3, 96.2, 75.4, 62.4, 61.9, 61.0, 57.3, 57.2,55.2, 15.0 3254, 2936, 1666, 1597, 1477, 1381, 1260, 1093, 1075 610.1 [M + Na]+ calcd for C33H33NO9: 610.2053 [M + Na]+ found: . 610.2046 [M + Na]+ 139 'HNMR (CDCI3, 400 MHz): TNMR (CDCI3, 100 MHz): IR: MS: HRMS: Scheme A68. ' H N M R spectrum of 160 111111111111111111'111111 " 111111111111111II11II1111 190 180 170 160 150 140 130 120 110 100 ppm (11) I I 70 60 1111" r Scheme A69. liC N M R spectrum of 160 ppm • 9 . 0 i l l ! >f II u ft M 8 . 5 8 . 0 7 . 5 7 . 0 6 . 5 6 . 0 5 . 5 Scheme A70. ' H / I 3 C H M B C spectrum of 160 p p m , ^ : -PULFIWC Wbcgplndqt f- 5 0 MLVMT miO 6 0 IF" "'"pjjj' 7 0 iF 8 0 9 0 ¥ • [ M O O = = 1 1 0 ™ - 1 2 0 § | - 1 3 0 sir 1 4 0 Is 1 5 0 « " 1 6 0 % 1 7 0 ; p p m : 141 143 Preparation of 7,8-dimethoxy-3-(5,6,8-trimetho one (175) MeO. MeO Li N ^ MeO 0 . ril MeO OMe Piperidine (2 drops) was added to a solution of 159 (128 mg, 0.384 mmol) and 2-hydroxy-3,4-dimethoxybenzaldehyde (105 mg, 0.384 mmol) in EtOH (5 mL), and the mixture was refluxed for 1 h. After cooling to RT, the mixture was diluted with water (10 mL) and extracted with EtOAc (4 x 10 mL). The combined extracts were washed with brine (10 mL), dried (Na2S04) and concentrated. Flash chromatography (EtOAc : hexanes, 1:1) of the residue gave 175 (17 mg, 10%) as a yellow solid. H NMR (CDC13, 400 MHz): 13, C NMR (CDCI3, 100 MHz): IR: MS: 8.54 (d, 1H, J = 8.76), 8.45 (s, 1H), 8.13 (d, 1H, J = 8.77), 7.35 (d, 1H, J = 8.71), 6.94 (d, 1H, J = 8.73), 6.88 (s,lH), 4.04 (s, 3H), 4.03 (s, 3H), 4.00 (s, 3H), 3.99 (s, 3H), 3.94 (s, 3H) 191.1, 158.1, 157.1, 153.7, 150.8, 150.3, 149.0, 147.6, 136.1, 135.5, 134.2, 130.9, 126.0, 124.9, 123.2, 120.1, 113.5, 108.9, 99.5, 61.55, 61.50, 57.0 (2 overlapping resonances), 56.5 2944, 2842, 1747, 1610, 1505, 1465, 1362, 1253, 1109,1064 452.1 [M + H]+, 474.1 [M + Na]+, 903.3 [2M + H]+, 925.3 [2M + Na]+ HRMS: calcd for C 24H 2iN0 8: 474.1165 [M + Na]+ found: 474.1181 [M + Na]+ 144 ppm (t1) Scheme A73. ' H N M R spectrum of 175 1 1 1 1 1 1 1 1 1 190 1 PPm (11) " " | " " | " " | " " | " " | • " ' | " " | " " | " ' i | , i 0 170 160 150 140 130 120 110 100 90 I 80 " I " • 70 I 60 I 50 " I " 40 " I " 30 ' 1 I ' 1 20 ' 1 1 1 1 " 1 10 Scheme A74. M C N M R spectrum of 175 l 1 1 l 1 ppm -20 10 9 5 4 3 2 1 - 0 « - 20 r - 40 Ig - 60 nr - 80 F -100 S» -120 °£ -140 -160 lu -180 L" -200 li' ppm -ppm-Scheme A75. ' H / l 3 C H M Q C spectrum of 175 147 Preparation of 2-acetylquinoline (192) A solution of 153 (1.75 g, 7.19 mmol) in 1,4-dioxane (20 mL) containing aq. IM i HCI (20 mL) was stirred at 100 °C for 15 h, then it was concentrated in vacuo. The residual aqueous phase was extracted with EtOAc (3 x 50 mL). The combined extracts were washed with sat. aq. NaHC03 solution (25 mL) and brine (25 mL), dried (Na2S04) and evaporated. The residue was filtered through a bed of silica gel (hexanes : CH2CI2, 1:4) and concentrated to give 2-acetylquinoline (0.74 g, 60%), white solid, m.p. 48.0-50.5 °C (lit. 53 °C: Capuano, L. Chem. Ber. 1959, 92, 2670). 'H NMR (CDCI3, 300 MHz): 13CNMR (CDCI3, 100 MHz): IR: HRMS: EA: 8.24 (d, IH, J = 8.54), 8.19 (d, IH, J = 8.52), 8.11 (d, IH, / = 8.51), 7.85 (d, IH, J = 8.10), 7.77 (td, IH, J = 6.93, J = 1.30), 7.63 (td, IH, J = 7.93, J = 0.92), 2.86 (s, 3H) 201.6, 154.2, 148.2, 137.8, 131.6, 130.9, 130.6, 129.5, 128.6, 118.9,26.5 1697, 1359 calcd for C 1 H 9 N O : found: calcd: found: 194.0582 [M + Na]+ 194.0576 [M + Na]+ C 77.17%, H 5.30%, N 8.18% C 77.09%, H 5.36%, N 8.35% 148 Scheme A77. ' H N M R spectrum of 192 1 •1111' ' ' I'111 11''1111 11111'' I ' ' ' ' 1 •' 111 •' 111' • 11' • • I"1"11"1"" 1111' 1 1 1 1 ' f1" • • I' •1' I" 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 ppm (11) Scheme A78. I 3 C N M R spectrum of 192 Scheme A79. IR spectrum of 192 150 Preparation of (iT)-3-phenyl-l-(quinolin-2-yl)prop-2-en-l-one (193) Water was added dropwise to a solution of 2-acetylquinoline (0.74 g, 4.3 mmol) in EtOH (40 mL) until the solution became slighly cloudy. Aqueous 10% NaOH solution (10 mL) was then added dropwise and the mixture was stirred at RT for 5 min before the dropwise addition of PhCHO (0.30 mL, 4.3 mmol). An orange precipitate started to form. After stirring at RT for 2 h, the solid was filtered and washed with ice-cold water (10 mL) to give 193 (0.93 g, 83%), orange powder, m.p. 128.5-131.0 °C. H NMR (CDCI3, 400 MHz): 13CNMR (CDCI3, 100 MHz): IR: MS: HRMS: EA: 8.55 (d, IH, J= 16.1), 8.18-8.40 (m, 3H), 8.00 (d, IH, J= 16.1), 7.57-7.93 (m, 5H), 7.33-7.54 (m, 3H) 190.6, 154.9, 148.2, 145.6, 138.0, 136.3, 131.6, 131.5, 131.0, 130.5, 129.9 (overlapping resonance signals), 129.6, 128.7, 122.1, 120.1 1669,1605,1576, 1449, 1336 260.2 [M + H]+, 282.1 [M + Na]+ calcd for C,8H,3NO: found: calcd: found: 282.0895 [M + Na]+ 282.0887 [M + Na]+ C 83.37%, H 5.05%, N 5.40% C 83.35%, H 5.14%, N 5.53% 151 r Scheme A80. ' H N M R spectrum of 193 I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I |-l I I I I I I c i I I I 190 180 170 160 150 140 130 120 110 100 90 8 0 70 60 50 4 0 3 0 2 0 10 PPm (11) Scheme A 8 1 . 1 3 C N M R spectrum of 193 152 Scheme A82. IR spectrum of 193 Preparation of 3-methyl-4-phenyl-6-(quinolin-2-yl)pyridin-2(lH)-one (194) To a degassed solution of 193 (100 mg, 0.386 mmol) and 2-cyanopropionamide (42 mg, 0.43 mmol) in.DMSO (2 mL) was added potassium tert-butoxide (90 mg, 0.78 mmol). The mixture was stirred at 95°C for 3.5 h. After cooling to RT, the reaction was then quenched with TM HCI (15 mL) and extracted with EtOAc (4 x 20 mL). The combined organic extracts were washed with water (2 x 20 mL) and brine (2 x 20 mL), dried (Na2S04) and concentrated. Flash chromatrography (EtOAc : hexanes, 1:3) of the residue afforded 194 (120 mg, quant.) as a yellow solid, m.p. 210.0-211.0 °C. 'HNMR 10.91 (s, br, IH), 8.22 (d, IH, J= 8.68), 8.13 (d, IH, J = 8.45), (CDCI3, 400 MHz): 7.82-7.85 (m, 2H), 7.76-7.80 (m, IH), 7.57-7.61 (m, IH), 7.39-7.52 (m, 5H), 6.92 (s, lH), 2.19 (s, 3H) 13CNMR 164.4, 151.3, 148.6, 148.2, 140.6, 138.7, 138.4, 131.5, 130.5, (CDCI3, 100 MHz): 130.0, 129.6, 129.24, 129.20, 129.0, 128.5, 117.4, 108.3, 15.2 IR: 3328,3059,1640,1620,1510 MS: 313.2 [M + Hf HRMS: calcd for C2iH16N20: 313.1341 [M + H]+ found: 313.1336 [M + H]+ 154 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I 1 ' 1 1 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I 1 1 1 I 1 11.0 10.0 9.0 8.0 7.0 6.0 5.0 -4.0 3.0 2.0 1.0 Scheme A83. ' H N M R spectrum of 194 | I I I I | I I I I | I I I I | I I I I | I I I I | I I I I | I M I | I I I I | I I I I | I I I I | I I I I | I I I I | I I I I | I I I I | I I I I | I I I I | I I I I | I 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm (11) Scheme A 8 4 . 1 3 C N M R spectrum of 194 155 156 Preparation of 5-iodo-3-methyl-4-phenyl-6-(quinolin-2-yl)pyridin-2(lH)-one (195) A mixture of 194 (20 mg, 0.064 mmol) and potassium carbonate (60 mg, 0.45 mmol) in D M F (1.5 mL) was stirred at RT for 5 min. Iodine monochloride (20 mg, 0.12 mmol) was then added and the resulting mixture was stirred in the dark at RT for 15 h. The reaction was then diluted with sat. aq. NFLCl (10 mL) and extracted with EtOAc (4 x 10 mL). The combined organic extracts were washed with sat. aq. Na2S203 (10 mL) and brine (2 x 10 mL), dried (Na2S04) and concentrated. Flash chromatrography (EtOAc : hexanes, 1:3) of the residue afforded 195 (20 mg, 67%) as an off-white foamy solid. ! H NMR 8.34 (d, IH, / = 8.63), 8.29 (d, IH, J = 8.66), 8.17 (d, IH, J = (CDCI3, 400 MHz): 8.53), 7.90 (d, IH, J = 8.11), 7.82 (t, IH, J = 8.29), 7.66 (t, IH, 7= 8.06), 7.42-7.53 (m, 3H), 7.14-7.18 (m ,2H), 2.03 (s, 3H) MS: 439.0 [M + H ] + Me Ph 157 Scheme A86. ' H N M R spectrum of 195 Preparation of 2-(3-iodo-6-methoxy-5-methyl-4-phenylpyridin-2-vnquinoli (J96) Ph A suspension of 195 (8.0 mg, 0.018 mmol), Ag2C03 (6.5 mg, 0.024 mmol) and Mel (0.010 mL, 0.16 mmol; CAUTION: cancer suspect agent) was stirred in the dark for 4 d. The resulting mixture was filtered through a bed of Celite® and concentrated to give 196 (7.0 mg, 85%) as a yellow paste. 'HNMR 8.27 (d, lH , / = 8.5), 8.20 (d, 1H, 7=8.5), 7.88 (d, 1H,J = 7.9), (CDC13, 400 MHz): 7.74-7.77 (m, 2H), 7.58 (t, 1H, J = 7.3), 7.39-7.51 (m, 3H), 7.14-7.18 (m, 2H), 4.00 (s, 3H), 2.03 (s, 3H) MS: 453.1 [M + H]+ 159 JJULJAIL I 1 1 1 1 I 2.0 1.0 I 1 1 1 1 I I 1 1 1 1 I 7.0 6.0 4.0 3.0 Scheme A87. ' H N M R spectrum of 196 160 

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