"Science, Faculty of"@en . "Chemistry, Department of"@en . "DSpace"@en . "UBCV"@en . "Tan, Jason Samuel"@en . "2010-01-16T19:07:23Z"@en . "2006"@en . "Master of Science - MSc"@en . "University of British Columbia"@en . "A straightforward synthesis of topopyrones B and D is described. The key reaction involved a convergent avenue to the anthraquinone core utilizing a tandem directed ometalation - metal halogen exchange methodology. The chemistry should be suitable for future SAR studies."@en . "https://circle.library.ubc.ca/rest/handle/2429/18371?expand=metadata"@en . "T O T A L SYNTHESIS OF TOPOPYRONES B A N D D: N O V E L TOPOISOMERASE I INHIBITORS by JASON S A M U E L T A N A THESIS SUBMITTED LN PARTIAL F U L F I L L M E N T OF THE REQUIREMENTS FOR THE D E G R E E OF M A S T E R OF SCIENCE in THE F A C U L T Y OF G R A D U A T E STUDIES (Chemistry) THE UNIVERSITY OF BRITISH C O L U M B I A October 2006 \u00C2\u00A9 Jason Samuel Tan, 2006 A B S T R A C T A straightforward synthesis of topopyrones B and D is described. The key reaction involved a convergent avenue to the anthraquinone core utilizing a tandem directed o-metalation - metal halogen exchange methodology. The chemistry should be suitable for future SAR studies. ii TABLE OF CONTENTS Abstract Table of Contents List of Schemes Table of Abbreviations 1. TOTAL SYNTHESIS OF TOPOPYRONES B AND D 1.1 Introduction 1.2 Background 1.3 Synthesis of Anthraquinones 1.4 Synthesis and Elaboration of 1,3,6,8-tetramethoxynthraquinone 1.5 Synthesis of the o-bromobenzaldehyde Fragment 1.6 Synthesis of Topopyrone D 1.7 Synthesis of Topopyrone B 2. EXPERIMENTAL SECTION i i i LIST OF SCHEMES Scheme 1: Structure and Topo-I Inhibitory Activity of Topopyrones A - D 3 Scheme 2: Retrosynthetic Analysis 5 Scheme 3: Friedel-Crafts Route to Anthraquinones 6 Scheme 4: Hayashi Rearrangement 7 Scheme 5: Synthesis of Ceroalbolinic Acid 8 Scheme 6: Synthesis of Vineomycinone B 2 Methyl Ester 9 Scheme 7: Synthesis of Chrysophanol 10 Scheme 8: Synthesis of Averufin 11 Scheme 9: Directed ortho Metallation 12 Scheme 10: Breakdown of R-Li oligomers 12 Scheme 11: Synthesis of Soranjidiol 13 Scheme 12: Tandem D o M - Metal Halogen Exchange 14 Scheme 13: Improved Synthetic Strategy 15 Scheme 14: Synthesis of Amide 59 and Aldehyde 61 16 Scheme 15: Synthesis of 1,3,6,8-tetramethoxyanthraquinone 17 Scheme 16: Montmorillonite K-10 Catalyzed Chromone Synthesis 18 Scheme 17: Attempted Synthesis of 4 19 Scheme 18: Unsuccessful Fries Rearrangement 20 Scheme 19: Brassard's Synthesis of Averufin 21 Scheme 20: Synthesis of Aldehyde 85 22 Scheme 21: Dianion Formation Using \"Super Base\" 22 Scheme 22: Synthesis of 92 23 Scheme 23: Synthesis of 95 24 Scheme 24: Bromination of 95 24 Scheme 25: Fragmentation of Intermediate 100 25 Scheme 26: Oxidation of Alcohols by NBS 25 Scheme 27: Radical Bromination Route 26 Scheme 28: Synthesis of Fragment 62 26 iv Scheme 29: Synthesis of Anthraquinone 111 28 Scheme 30: Optimization of the Cyclization Step 29 Scheme 31: Synthesis of Topopyrone D 30 Scheme 32: Synthetic Strategy Towards 60 32 Scheme 33: Avenues Towards 60 33 Scheme 34: Chlorination of 127 34 Scheme 35: Synthesis of Amide 60 34 Scheme 36: Deprotonation of 60 35 Scheme 37: Synthesis of 133 36 Scheme 38: Synthesis of Topopyrone B 37 Scheme 39: Synthesis of Trimethyl Ether 138 38 Scheme 40: Deprotection of 136 39 Scheme 41: Acetylation of Topopyrone B 40 Scheme 42: N M R Spectra of 83 46 Scheme 43: IR Spectra of 83 47 Scheme 44: N M R Spectra of 84 49 Scheme 45: IR Spectra of 84 50 Scheme 46: N M R Spectra of 85 52 Scheme 47: IR Spectra of 85 53 Scheme 48: N M R Spectra of 59 55 Scheme 49: IR Spectra of 59 56 Scheme 50: N M R Spectra of 123 58 Scheme 51: IR Spectra of 123 59 Scheme 52: N M R Spectra of 130 61 Scheme 53: IR Spectra of 130 62 Scheme 54: N M R Spectra of 125 64 Scheme 55: IR Spectra of 125 65 Scheme 56: N M R Spectra of 60 67 Scheme 57: IR Spectra of 60 68 Scheme 58: N M R Spectra of 94a 70 Scheme 59: IR Spectra of 94a 71 v Scheme 60: N M R Spectra of 94 73 Scheme 61: IR Spectra of 94 74 Scheme 62: N M R Spectra of 95 76 Scheme 63: IR Spectra of 95 77 Scheme 64: N M R Spectra of 107 79 Scheme 65: IR Spectra of 107 80 Scheme 66: N M R Spectra of 108 82 Scheme 67: IR Spectra of 108 83 Scheme 68: N M R Spectra of 109 85 Scheme 69: IR Spectra of 109 86 Scheme 70: N M R Spectra of 62 88 Scheme 71: IR Spectra of 62 89 Scheme 72: N M R Spectra of 111 92 Scheme 73: IR Spectra of 111 93 Scheme 74: N M R Spectra of 117 95 Scheme 75: IR Spectra of 117 96 Scheme 76: N M R Spectra of 118 98 Scheme 77: IR Spectra of 118 99 Scheme 78: N M R Spectra of 4 101 Scheme 79: N M R Spectra of 119 103 Scheme 80: N M R Spectra of 133 106 Scheme 81: IR Spectra of 133 107 Scheme 82: N M R Spectra of 135 109 Scheme 83: IR Spectra of 135 110 Scheme 84: N M R Spectra of 136 112 Scheme 85: IR Spectra of 136 113 Scheme 86: N M R Spectra of 138 115 Scheme 87: IR Spectra of 138 116 v i T A B L E OF A B B R E V I A T I O N S Ac acetyl Aq. aqueous Bu butyl Calcd. calculated Cone. concentrated D C M dichloromethane D M A P 4-dimethylaminopyridine D M F N, Af-dimethylformamide DMSO dimethylsulfoxide D N A deoxyribonucleic acid Et ethyl H M B C Heteronuclear Multiple Bond Correlation IBX iodoxybenzoic acid L A H lithium aluminum hydride L i T M P lithium 2,2,6,6-Tetramethylpiperidide Me methyl M O M methoxymethyl NBS N-bromosuccinimide NCS /V-chlorosuccinimide N M R nuclear magnetic resonance Py pyridine Sat. saturated T B A F tetrabutylammonium fluoride TBS r-butyldimethylsilyl T F A A trifluoroacetic anhydride THF tetrahydrofuran TIPS triisopropylsilyl T L C thin layer chromatography vii T M E D A N, N, N', /V'-tetramethylethylenedi amine TMS trimethylsilyl Ts tosyl viii TOTAL SYNTHESIS OF TOPOPYRONES B AND D 1 1.1 Introduction Topoisomerases I and II (\"topo I\" and \"topo II\") are essential nuclear enzymes involved in D N A replication, transcription, and repair events.1 They are responsible for the relaxation of supercoiled D N A by reversibly breaking one (topo I) or both (topo II) D N A strands, and by unwinding the severed strand(s), thereby releasing the build up of torsional strain. Inhibition of topoisomerases interferes with the relaxation process, inhibiting cellular growth and reproduction, ultimately proving fatal to the cell. The high replication rate of tumor cells and their tendency to overexpress topoisomerases have made topoisomerase inhibitors an important class of anti-tumor agents.2 A number of anti-tumor drugs target topo-II,3 but selective inhibition of topo-I is also a valid strategy in cancer therapy. Currently, the only topo-I inhibitors approved by the F D A as antineoplastic drugs are derived from camptothecin (CPT): 4 topotecan (Hycamtin, GlaxoSmithKline) and irinotecan (also known as CPT-11, Camptosar, Yakult Honsha K K ) . Topotecan is currently used as a second-line treatment for ovarian cancers and for the treatment of small cell lung cancer, while irinotecan is currently for colon cancers.5 Several other camptothecin derivatives are in clinical trials.6 The success of CPT derivatives as chemotherapy agents has promoted the search of other, non-CPT, topo-I inhibitors.7 An interesting development in this area is the recent discovery of a family of tetracyclic compounds, termed topopyrones (Scheme 1), that are ^ Recent review: Champoux, J.J. Annu. Rev. Biochem. 2001, 70, 369 Cf. Denny, W. A. Expert Opin. Emerging Drugs 2004, 9, 105. (b) Advances in Pharmacology, vol. 29B. Liu, L. F., Ed.; Academic Press: San Diego, CA, 1994. Recent review: Kellner, U.; Sehested, M.; Jensen, P. B.; Gieseler, F.; Rudolph, P. Lancet Oncology 2002, 3, 235 Reviews: (a) Rothenberg, M. L. Ann. Oncol. 1997, 8, 837; (b) Versace, R. W. Expert Opin. Ther. Patents 2003,13, 1. Garcia-Carbonero, R.; Supko, J. G. Clin. Cancer Res. 2002, 8, 641. (a) see ref. 5; (b) Konstadoulakis, M. M.; Antonakis, P. T.; Tsibloulis, B. G.; Stathopoulos, G. P.; Manouras, A. P.; Mylonaki, D. B.; Golematis, B. X. Cancer Chemother. Pharmacol. 2001, 48, 417; (c) Verschraegen, C. F.; Levenback, C ; Vincent, M.; Wolf, J.; Beyers, M.; Loyer, E.; Kudelka, A. P.; Kavanagh, J. J. Ann. N. Y. Acad. Sci. 2000, 922, 349. (a) Meng, L. H.; Liao, Z. Y.; Pommier, Y. Curr. Top. Med. Chem. 2003, 3, 305; (b) Pommier, Y. Biochimie. 1998, 80, 255. 2 potent and selective inhibitors of topo-I. These substances were isolated by Kanai 8 and shown to possess an anthraquinone moiety with an angularly (topopyrone A and C) or linearly (topopyrone B and D) fused 4-pyrone ring. Bioactivity is especially pronounced in topopyrone B (IC50 0.15 ng/mL), which shows activity comparable to that of CPT (IC 5 0 0.10 ng/mL). O O 1 topopyrone A X = CI 3 topopyrone B X = CI 2 topopyrone C X = H 4 topopyrone D X = H Compound I C 5 0 (ng/mL) Topopyrone A 1.22 Topopyrone B 0.15 Topopyrone C 4.88 Topopyrone D 19.63 Camptothecin 0.10 Scheme 1: Structure and Topo-I Inhibitory Activity of Topopyrones A-D (a) Kanai, Y.; Ishiyama, D.; Senda, H.; Iwatani, W.; Takahaski, H.; Konno, H.; Tokumasu, S.; Kanazawa, S. J. Antibiot. 2000, 53, 863; (b) Ishiyama, D.; Kanai, Y.; Senda, H.; Iwatani, W.; Takahashi, H.; Konno, H.; Kanazawa, S. / . Antibiot. 2000, 53, 873. 3 Our laboratory cultivates a long-standing interest in topo-I inhibitors.9 The discovery of 1-4 has thus provided us with an incentive to investigate structure-activity relationship (SAR) aspects of these substances. In order to attain this objective, we required access to topopyrone congeners. Derivatization of the natural products appears to be a poor strategy for analog synthesis, on accounts of anticipated difficulties with the selective functionalization of the tetracyclic nucleus of the natural products, as well as of the poor efficiency of the fermentation process. In the latter respect, the yield of the o especially active topopyrone B is a meager 1.8 mg / 2.5 L of culture broth. Therefore, we have endeavored to devise a concise avenue to fully synthetic topopyrones. Moreover, we have focused on the most potent 3 and its closely related congener 4. 9 (a) Ciufolini, M. A.; Roschangar, F. Angew. Chem. Int. Ed. Engl. 1996, 35, 1692; (b)Ciufolini, M. A.; Roschangar, F. Tetrahedron 1997, 53, 11049; (c) Ciufolini, M. A.; Roschangar, F., in: Targets in Heterocyclic Chemistry; Attanasi, O. A.; Spinelli, D., Eds.; Italian Society of Chemistry: Rome, Italy, 2000, Vol 3. 4 1.2 Background No synthetic work on topopyrones has been recorded in the primary literature as of this writing, although approaches to these molecules have been described in a dissertation10 and in a poster presentation.11 The isolation paper8 indicates that the \"angular\" members of the family transpose to their \"linear\" isomers under basic conditions, signifying that the B and D series of topopyrones is thermodynamic ally favored. This observation allowed us to chart an avenue to the natural products that involves cyclization of an intermediate such as 5 (X = H or CI, Scheme 2) under thermodynamically controlled conditions. Accordingly, the problem of synthesizing topopyrones may be reduced to that of assemblying anthraquinone 6. The acetoacetyl substituent in 5 may be built into the precursors leading to the anthraquinone segment, or it may be introduced on an unsubstituted anthraquinone 6 at an opportune time. The same holds true for the chloro substituent found in 3. OH O OH O O O M e O OMe 3-4 Scheme 2: Retrosynthetic Analysis Implementation of the foregoing strategy requires access to appropriately substituted anthraquinone educts. Methodology for the construction of such motifs will be reviewed in the following section. 1 0 Qi, L. Dissertation, Brown University, Providence, RI, USA, 2003: Diss. Abstr. Int., B 2003, 64, 173 Gattinoni, S. University of Milan, Italy, 2006. 5 1.3 Synthesis of Anthraquinones There are hundreds of naturally occurring anthraquinones that have been discovered and numerous syntheses have been reported in the literature.12 A classical anthraquinone construction involves a double Friedel-Crafts condensation of substituted phthalic acids or anhydrides (cf. 7 in Scheme 3) with appropriate aryl acceptors, initially producing an o-benzoylbenzoic acid 8 which ultimately cyclizes to 9. X = OH, CI or anhydride Scheme 3: Friedel-Crafts Route to Anthraquinones The method, however, is limited to the preparation of certain symmetrical anthraquinones, because of complications posed by the so-called Hayashi rearrangement during the second Friedel-Crafts step (cf. 8 -> 9 Scheme 3).1 3 Such difficulties lead to the formation of mixtures of regioisomeric anthraquinones from homogeneous o-benzoylbenzoic acid. To illustrate (Scheme 4), activation of 10 under protic or Lewis acidic conditions reversibly forms an acylium ion 11, which partitions between two reaction pathways. An ordinary Friedel-Crafts cyclization produces anthraquinone regioisomer 12. However, cyclization of 11 to spirocyclic intermediate 14 may also occur. 12 Thomson, R. H., Naturally Occuring Quinones III: Recent Advances; Chapman and Hall: New York, 1987. Hayashi, M. J. Chem. Soc. 1927, 2516. 6 Agent 14 can now undergo 1,2-acyl shift. Either carbonyl group may migrate (cf. pathways a and b), resulting in formation of a mixture of anthraquinone regioisomers 12 and 15. Alternatively, 14 could fragment back to 11 or to 13, promoting \"scrambling\" of the acyl substituent on ring C, i.e. Hayashi rearrangement. Cyclization of the emerging 13 again leads to the formation of anthraquinone regioisomer 15. This equilibration of o-benzoylbenzoic acid intermediates creates ambiguous mixtures of regioisomers and is understandably impractical in the synthesis of many anthraquinones. a. protic or Lewis acids; b. \"regular\" Friedel-Crafts cyclization. Scheme 4: Hayashi Rearrangement To obviate the above inconveniences, a number of regioselective routes to anthraquinones have been developed. Many such avenues rely on a Diels-Alder reaction between a diene and a quinone. Thus, a regiochemically defined anthraquinone is assembled by the addition of a diene to a naphthoquinone, or by the successive addition 7 of two dienes to a benzoquinone. A representative example is the synthesis of an insect pigment ceroalbolinic acid by Cameron (Scheme 5). 1 4 The adduct 18 of 2,6-dichlorobenzoquinone 16 with diene 17 underwent aromatization upon contact with silica gel to furnish naphthoquinone 19 in 57% yield. A second cycloaddition between naphthoquinone 20 and diene 21 afforded anthraquinone 22 in 55% yield. a. THF; b. S i0 2 (57%, a-b); c. Ac 2 0; d. 80 \u00C2\u00B0C ; e. S i0 2 (55%, d-e); f. AICI3, NaCl (69%). Scheme 5: Synthesis of Ceroalbolinic Acid Cameron, D. W.; Conn, C ; Feutrill, G. I. Aust. J. Chem. 1981, 34, 1945. 8 Danishefsky's total synthesis of Vineomycinone B2 methyl ester is another demonstration of the Diels-Alder approach to anthraquinones (Scheme 6). 15 Cycloaddition of diene 24 to 16 afforded naphthoquinone 26 in 71% yield after methylation. Following isomerization of 26 to the more stable propenyl isomer 27, a subsequent cycloaddition using diene 28 was employed to give anthraquinone 29 (79% yield after methylation). Further elaboration of the side chains at C-2 and C-6 ultimately gave the product 30. a. 16, benzene, reflux; b. 110 \u00C2\u00B0 C (-HCI, -TMSOMe); c. Mel (71% a-c) d. PdCI2(MeCN)2 (95%); e. benzene, reflux; f. Mel (79%). Scheme 6: Synthesis of Vineomycinone B 2 Methyl Ester Danishefsky, S. J.; Uang, B. J.; Quallich, G. J. J. Am. Chem. Soc. 1985, 707, 1285. 9 An alternative anthraquinone synthesis that offers strict regiocontrol relies on Hauser's phthalide annulation reaction. This is illustrated in the synthesis of chrysophanol 35 (Scheme 7).16 Michael addition of phthalide 31 to cyclohexenone 32 gave intermediate 33 which was eventually advanced to 35. O O 3 4 3 5 a. f-BuOLi (80%); b. NBS, Et3N (68%); c. BBr3 Scheme 7: Synthesis of Chrysophanol An interesting variant of the Hauser annulation relies on the addition of the anion of a phthalide to a benzyne. The technique is nicely illustrated in the Townsend synthesis of the mold metabolite, averufin, 42 (Scheme 8).17 Thus, exposure of a mixture of phthalide 36 and aryl bromide 37 to excess L i T M P afforded 41 in 35% yield upon air oxidation. The sequence of events leading to 41 is believed to involve metallation of 37 with consequent elimination of LiBr, resulting in formation of benzyne 39. The M O M protecting group directs the regiochemical sense of addition of the phthalide anion 38 to the 39 and favors formation of product 40. It is unclear whether 40 obtains through a \ 6 Hauser, F. M.; Prasanna, S. / Org. Chem. 1982, 47, 383. Townsend, C. A.; Christensen, S. B.; Davis, S. G. J. C. S. Perkin Trans. I. 1988, 839. 10 stepwise addition of 38 to 39, leading to a MOM-chelated aryllithium intermediate which then adds intramolecularly to the carbonyl group of the phthalide, or through a directed Diels-Alder-type reaction. MOMO MOMO OMOM 0 + 36 37 MOMO OLi OMOM MOMO 40 a. MOMO O L j OMOM MOMO' RO O OR . / 41 R = MOM * 42 R = H a. LiTMP, then air (02) (35%); b. 5% HCI aq., MeOH (80%). Scheme 8: Synthesis of Averufin Another regioselective route to anthraquinones relies on directed ortho metalation (DoM) technology.18 This method permits selective deprotonation of aromatic rings at the ortho position of appropriate substituents termed \"directed metalation groups\" (DMG's). Good DMG's are complexing or chelating substituents, such as OMe, O M O M , and many others, that can coordinate external organolithium agents such as BuLi and direct them toward an ort/io-hydrogen, thereby increasing the kinetic acidity thereof (cf. \" Z \" in 43, Scheme 9). Subsequent treatment of the orr/iolithiated species 45 with an appropriate electrophile provides an OTt/io-substituted product 46 with full regiocontrol. 1 8 Gschwend, H. W.; Rodriguez, H. R. Org. React.. 1979, 26, 1. 1 1 a. R-Li (R = n-Bu, s-Bu, f-Bu), additive = TMEDA, solvent = THF or E t 2 0 Z = C O N R 2 , CONHR, CONH(Cumyl), CSNHR, 2-oxazolino, 2-imidazolino, C F 3 , CH=NR, ( C H 2 ) n N R 2 n = 1, or 2, C H 2 O H , NMe 2 , NHCOR, N H C 0 2 R , OMe, O C H 2 O M e , OCH(Me)OEt, O C O N R 2 ) O S E M , OP (0 )NR 2 , S 0 2 N R 2 , S 0 2 N H R , S 0 2 R . Scheme 9: Directed ortho Metallation The deprotonation step is greatly accelerated by additives such as T M E D A , which break down aggregates of alkyllithiums through ligation.19 This is exemplified in Scheme 10 with a generic R-L i tetramer. The use of Lewis basic solvents such as THF also aid in the separation of alkyllithium aggregates. The resulting dimeric and - especially -monomelic species display substantially enhanced basicity. kinetically kinetically kinetically less basic more basic most basic Scheme 10: Breakdown of R-Li oligomers Slocum, D. W.; Carroll, A.; Dietzel, P.; Eilerman, S.; Culver, J. P.; McClure, B.; Brown, S.; Holman, R. W. Tetrahedron 2006, 47, 865. 12 Especially useful in the context of anthraquinone construction is the Snieckus ortho metalation of yV,iV-dialkylbenzamides, which are among the most powerful D M G ' s . 2 0 The technique is demonstrated in the synthesis of soranjidiol, 52,21 (Scheme 11). Reaction of ort/io-lithiated benzamide 47 with benzaldehyde 48 provided hydroxyamide 49, which upon treatment with acid lactonized to phthalide 50. Friedel-Crafts cyclization afforded anthrone 51 in 71% yield. Oxidation and demethylation provided anthraquinone 52 (70% yield). An analogous approach was used for the synthesis of islandicin, digitopurpone, erythroglaucin, and cynodontin. OMe O 50 51 52 a. s-BuLi, TMEDA, THF; b. TsOH (76%); c. TFAA (71%); d. Cr0 3 , HOAc; e. pyHCI (70%). Scheme 11: Synthesis of Soranjidiol Eventually, Snieckus showed that anthraquinones can be obtained in a one-pot reaction using a tandem D o M - halogen-metal exchange approach (Scheme 12).22 This process involves the merger of an ort/io-lithiated benzamide 53 with an o-Snieckus, V. Chem Rev. 1990, 90, 879. De Silva, S. O.; Watanabe, M.; Snieckus, V. J. Org. Chem. 1979, 44, 4802. Wang, X.; Snieckus, V. Synlett 1990, 313. 13 bromobenzaldehyde 54 to give intermediate 55, which is treated in situ with additional R-L i (usually f-BuLi) to effect a lithium-bromine exchange, thereby triggering cyclization to 57. Oxidation in air finally affords anthraquinone 58. The broad scope of this reaction allows for the rapid construction of complex anthraquinones using readily accessible benzamide and benzaldehyde synthons. Thus, we chose to apply this technology to assemble the anthraquinone core in topopyrones. Our synthetic strategy is illustrated in Scheme 13. We considered both an avenue relying on functionalization of unsubstituted anthraquinone 6, and a more convergent route leading directly to 5 through the merger of fragments 59-60 and 62. Our results are detailed in the next section. 14 OMe O OMe OMe O 59 R = H 61 R = H 60 R = CI OMe T I P S ^ 0 f~\ 62 R= I O v / 0 HO' ^ ^ ^ 0 H O 5 X = HorCI Scheme 13: Improved Synthetic Strategy 15 1.4 Synthesis and Elaboration of 1,3,6,8-tetramethoxyanthraquinone The synthesis of anthraquinone 6 served as a test of the Snieckus tandem D o M methodology. Amide 59 and aldehyde 61 were prepared by the method of Kamila 2 3 and Broering, 2 4 respectively, as shown in Scheme 14. OMe OMe MeO 63 R = COCI OMe 59 R = CONEt2 \" ^ 6 1 X = Br a. Et2NH, toluene, 0 \u00C2\u00B0C(89%); b. Br2, AcOH, r.t. (90%) Scheme 14: Synthesis of Amide 59 and Aldehyde 61 Benzamide 59 was o-lithiated (s-BuLi/TMEDA/THF/-78 \u00C2\u00B0C; Scheme 15) and the resulting organometallic was added to benzaldehyde 61. The presumed intermediate 65 was treated in situ with r-BuLi, resulting in cyclization to a new compound believed to be 66. Air oxidation provided anthraquinone 6 in 60% yield. The balance of the crude product (40%) was 68. Recrystallization from EtOAc afforded pure 6 in 40% yield. Kamila, S.; Mukherjee, C ; Mondal, S.; De, A. Tetrahedron. 2003, 59, 1339. Broering, T. J.; Morrow, Gary W. Synth. Commun. 1999, 29, 1135. 16 Scheme 15: Synthesis of 1,3,6,8-tetramethoxyanthraquinone The formation of byproduct 68 may be explained by invoking protonation of aryllithium species 66. Premature quenching of the reaction was quickly dismissed as a possible cause, since reactions that were allowed to proceed for up to 24 h at room temperature showed no improvement in yields. Thus protonation must have transpired during the reaction. Available evidence suggests that the proton source is the substrate itself, or possibly the solvent (THF). Indeed, intermediate 66 possesses a doubly benzylic hydrogen (marked with an arrow) that may be anticipated to be rather acidic, activated as it is by a pair of aryl groups, one of which permits derealization of negative charge into the amide carbonyl. Formation of 68 may thus reflect a rate of proton transfer that is 17 comparable to that of nucleophilic addition to the amide carbonyl. We note that proton transfer is more likely to occur in a bimolecular mode than in an intramolecular one, because the intramolecular reaction would have to proceed through an unfavorable four-center transition state. Alternatively, kinetic barriers to the addition of the aryllithium unit in 66 to the amide carbonyl may open the door to competitive deprotonation of T H F . 2 5 This event would be accelerated by the presence of T M E D A in the medium. OH HO O a. OH Ph 69 70 OH O OH O O Ph 73 a. montmorillonite K-10, nitrobenzene, 120 \u00C2\u00B0C, (62%). Scheme 16: Montmorillonite K-10 Catalyzed Chromone Synthesis With anthraquinone 6 in hand, we attempted construction of the pyrone subunit by the use of noteworthy reaction that was described in a recent paper dealing with the synthesis of 73 (Scheme 16).26 The authors of this work reported a straightforward route to chromone 73 by coupling of phloroglucinol 69 and acid chloride 70 catalyzed by montmorillonite K-10. The reaction proceeds through esterification of 69 to 71, which f Bates, R. E.; Kroposki, L. M.; Potter, D. E. J. Org. Chem. 1972, 37, 560. Lee, 5. M ; Tseng, T. H.; Lee, Y. J. Synthesis. 2001,15, 2247. 18 then undergoes a Fries rearrangement to give intermediate 72. This substance is transformed to pyrone 73 following an intramolecular 1,4-addition of the phenolic O H group to the unsaturated ester. We hoped that the described method could be applied to the resorcinylic system in anthraquinone 6 (Scheme 17). Thus, 6 was first converted to the hydroxyanthraquinone 74 by refluxing in cone. HBr/AcOH. Treatment of 74 with 2-butynoyl chloride 76 and montmorillonite K-10 in nitrobenzene failed to generate any of the desired pyrone 4, even after heating at 130 \u00C2\u00B0C overnight. Only starting 74 was recovered from these attempts. O X' OR O OR 75 X = OH 76 X = CI OH O OH O c. _ r$ R = Me a ( -74 R = H a. 48% HBr, AcOH, reflux (76%); b. SOCI2, DCM; c. Montmorillonite K-10, nitrobenzene, 76, 130 \u00C2\u00B0C. Scheme 17: Attempted Synthesis of 4 The above results provided no indication as to the nature of the problem that was preventing formation of 4. In particular, it was unclear whether the initial phenol esterification reaction was occurring at all. Accordingly, a monoester of 74 believed to be 77 was prepared in a separate operation, and then subjected to the action of montmorillonite K-10 under the described conditions (Scheme 18). Interestingly, the 19 substrate was converted quantitatively back to 74. This seems to suggest that Montmorillonite K-10 does promote formation of acylium ion 79 at some point in the reaction, but that the subsequent electrophilic acylation of presumed intermediate 78 is thwarted by the deactivating effects of the quinone carbonyls. OH O OH a. d. Et3N, EtOAc, then 76; b. Montmorillonite K-10, nitrobenzene, 130 \u00C2\u00B0C . Scheme 18: Unsuccessful Fries Rearrangement This reluctance of 74 toward electrophilic substitution has also been observed in connection with the synthesis of averufin 42.27 Castonguay and Brassard thoroughly investigated the functionalization of C-2 in systems of type 74 under a variety of Friedel-Crafts acylation, Fries rearrangement, and ort/zo-lithiation conditions. A l l such attempts were uniformly unsuccessful. They eventually achieved conversion of 74 to 42 by treatment with 5-oxohexanal 81 and aqueous sodium bicarbonate, followed by mild acid treatment to trigger internal acetal formation (Scheme 19). The yield was an ungenerous 2 7 Castoguay, A.; Brassard, P. J. Can. Chem. 1977, 55, 1324 20 6.5%. These observations, as well as our own results, induced us to refocus on a route that avoids functionalization of 6 and 74. This means that the anthraquinone must be constructed using fragment 62 (cf. Scheme 13). a. NaHC03, 90 \u00C2\u00B0C (6.5%). Scheme 19: Brassard's Synthesis of Averufin 21 1.5 Synthesis of Fragment 62 We sought to create 62 through hydroxyalkylation of an appropriate arylmetallic reagent with the known 2 8 aldehyde 85. The latter was prepared in 3 steps from ethyl acetoacetate 82 by simple modifications of literature procedures (Scheme 20). 82 83 84 85 a. ethylene glycol, p-TsOH, benzene, reflux dean-stark (90%); b. LAH, THF, 0 \u00C2\u00B0 C (90%); c. (COCI)2, DMSO, DCM, -78 \u00C2\u00B0C, then Et3N, r. t. (91%). Scheme 20: Synthesis of Aldehyde 85 The arylmetallic agent that would add to 85 may be the recently described dianion 86,29 which is prepared by deprotonation of 86 by use of so-called \"super base3 0\" (Scheme 21). Super bases are alkylpotassium species generated in situ through the reaction of alkyllithium species and a tertiary potassium alkoxide such as f-BuOK. 86 87 88 a. ?-BuOK, n-BuLi, THF, -78 \u00C2\u00B0C ; b. 85, THF, -78 \u00C2\u00B0 C - r.t. Scheme 21: Dianion Formation Using \"Super Base\" Cf. Langer, P.; Freifeld, I. Synlett. 2001, 4, 523. Sinha, S.; Mandal, B.; Chandrasekarn, S. Tetrahedron Lett. 2000, 3157. Schlosser, M. J. Organomet. Chem. 1967, 8, 9. 22 The formation of a more ionic organo-potassium complex at the expense of a more covalent organo-lithium one may seem to violate the principles governing transmetallation reactions. In fact, the success of this apparently contrathermodynamic transmetallation process is believed to be due to precipitation of f-BuOLi, which is largely insoluble in solvents such as THF. By a LeChatelier effect, subtraction of t-BuOLi shifts the equilibrium of the reaction toward formation of the organo-potassium species. As anticipated from considerations of metal-C bond polarization, potassium alkyls are exceptionally powerful bases: they are capable of deprotonating even simple alkanes.31 Unfortunately, no reaction was observed upon treatment of 86 with rc-BuLi and t-BuOK, followed by addition of aldehyde 85. An alternative approach involving lithium-bromine exchange of r-butyl ester 90, again followed by addition of 85 was equally unsuccessful. The reaction afforded only traces of 92: the major product (>90% yield) was the dehalogenated form of 90, which arguably arises through protonation of 91 (Scheme 22). OMe OMe a.( O \u00E2\u0080\u00A289 R = H 90 R = f-Bu 91 O 92 a. H 2 S0 4 , MgS0 4, /-BuOH, DCM, r.t. (26%); b. f-BuLi, THF, -78 \u00C2\u00B0C ; c. 85. Scheme 22: Synthesis of 92 31 Finnegan, R. A. Tetrahedron Lett. 1963, 429. 23 After further experimentation, it was found that silyl ether 94 is a competent substrate for this reaction (Scheme 23). Compound 94 was obtained by reduction of 93 with BH3-SMe2 followed by protection with TBSC1. Subjection of 94 to lithium-bromine exchange then reaction with aldehyde 85 afforded 95 in 67% yield. The balance of starting 94 was recovered as the dehalogenated product 96. The moderate yield was perhaps due to competitive deprotonation of the aldehyde by the aryllithium intermediate. HOOC a. BH 3SMe 2 , THF, 40 \u00C2\u00B0C; b. imidazole, DMAP, TBSCI, DCM, r.t. (quantitative a - b); c. f-Bul_i, THF -78 \u00C2\u00B0C, then 85 (67% of 95). The next step in the elaboration of 95 to 62 was the electrophilic bromination of the aromatic ring. Interestingly, reaction of 95 with NBS in C H 3 C N gave an essentially 1 : 1 : 1 mixture of desired 97 and side products 98 and 99 (Scheme 24). Scheme 23: Synthesis of 95 95 OTBS OTBS OTBS 99 97 98 a. NBS, CH 3CN, r.t. Scheme 24: Bromination of 95 24 The formation of 98 is clearly due to an ipso substitution,32 which may be rationalized by assuming an initial electrophilic bromination at the carbon atom situated between the two methoxy groups (Scheme 25). Intermediate 100 may then fragment into a molecule of 98 and one of aldehyde 85. The aromaticity of 98 is a likely driving force for such a fragmentation. 100 Scheme 25: Fragmentation of Intermediate 100 The formation of side-product 99 likely occurs through NBS oxidation of the benzylic alcohol and deketalization of 99 by traces of HBr present in the medium. Oxidations of 1\u00C2\u00B0 and 2\u00C2\u00B0 alcohols to aldehydes or ketones by NBS are not uncommon.33 They are believed to proceed via a hypobromite intermediate 102, which undergoes 1,2-elimination of HBr (Scheme 26). The HBr thus released could be responsible for loss of the ketal. \u00E2\u0080\u0094C-OH \u00E2\u0080\u0094C^OxBr C=0 101 102 103 Scheme 26: Oxidation of Alcohols by NBS Perrin, C. L.; Skinner, G. A. J. Am. Chem. Soc. 1971, 93, 3389. (a) Filler, R. Chem. Rev. 1963, 63, 21; (b) for a recent example see: Lee, J. G ; Lee, J. Y.; Lee, J. M. Synth Commun. 2005, 35, 1911. 25 An alternative interpretation based on radical bromination of the benzylic position leading to 99 (Scheme 27) is less plausible, because the reaction is carried out under conditions that do not promote radical chain processes. - HBr 106 Scheme 27: Radical Bromination Route TIPSs 95 62 o f 107 R = TBS, X = H \u00E2\u0080\u00A21108 R = TBS, X = Br C 'V109 R = H, X = Br a. imidazole, DMAP, TIPSCI, DMF, r.t. (94%); b. NBS, CH 3 CN, r.t.; c. TBAF, THF, r.t. (quantitative b-c); d. (COCI)2, DMSO, DCM, -78 \u00C2\u00B0C, then Et3N (81%). Scheme 28: Synthesis of Fragment 62 It was envisioned that protection of the benzylic alcohol in 95 would suppress - or at least limit - formation of by-products 98 - 99. Therefore, alcohol 95 was protected as a TIPS ether (Scheme 28). The resulting 107 was successfully converted to 108 in 26 quantitative yield. The action of T B A F on 108 induced selective deprotection of the less hindered primary alcohol to give 109. Swern oxidation then provided aldehyde 62. The overall yield of fragment 62 was 76% yield from TBS ether 95. 27 1.6 Synthesis of Topopyrone D The stage was now set for the merger of benzamide 59 and aldehyde 62 in the tandem D o M route to anthraquinone 111 (Scheme 29). To our dismay, this sequence provided the desired 111 in only a meager 17% yield, the major product of the reaction being the uncyclized adduct 112 (mixture of diastereomers). This was a far cry from the 60% crude yield obtained in the synthesis of anthraquinone 6 (see Scheme 15). Interestingly, N M R spectra of compound 111 indicated that the material exists as a 2 : 1 mixture of atropisomers, seemingly due to restricted rotation about the aryl-CHOTIPS bond. This conclusion is supported by the observation that atropisomerism vanished upon release of the TIPS group. 59 MeO OMe O MeO' TIPSv OMe O OMe 0 J ^ TIPS OMe b Qf~}0 b. OMe O TIPS OMeb MeO a. s-BuLi, TMEDA, THF, -78 \u00C2\u00B0C, then 62; b. f-BuLi, -78 \u00C2\u00B0C - r.t., then H 2 0, 0 2 (17% of 111 a-b). Scheme 29: Synthesis of Anthraquinone 111 28 114-115 intractable mixtures containing no desired product a. s-BuLi, TMEDA, THF, -78 \u00C2\u00B0C, then 62 (70%);b. H 2 0; c. IBX, CH 3CN, reflux (83%); d. imidazole, DMAP, TIPSCI, DMF, r.t. (74%); e. HOCH 2CH 2OH, p-TsOH, benzene, reflux dean-stark; f. f-BuLi, THF, -78 \u00C2\u00B0C. Scheme 30: Optimization of the Cyclization Step Investigations directed toward improving the yield of 111 were fruitless. Initially, we reasoned that if proton transfer from the diaryl substituted carbon was in fact the cause of the poor yield, then protection of the OH group in 113 with a bulky silyl group may disfavor approach of a basic agent to the acidic C-H bond (Scheme 30). Thus, the addition product 113 was isolated in good yield (70%), as a mixture of diastereomers, by quenching the reaction after addition of 62 to the anion of the diethylbenzamide 59. Next, 113 was converted to silyl ether 115. Attempts to cyclize 115 by treatment with r-BuLi produced an intractable mixture of products, none of which was the desired one. In a like manner, IBX oxidation of 113 to the corresponding benzophenone 114, followed again 29 by treatment with r-BuLi, gave a complex mixture containing no desired anthraquinone. Attempts to generate a ketal derivative of 114 failed, barring us from examining the possible f-BuLi-promoted cyclization of 116. Despite this discouraging result, we continued the synthesis with T B A F desilylation of 111 to give alcohol 117 cleanly and quantitatively (Scheme 31). Oxidation of 117 with LBX in refluxing C H 3 C N delivered ketone 118 in 88% yield. Finally, treatment of 118 with concentrated aqueous BLBr in refluxing A c O H effected global deblocking and cyclization to fully synthetic topopyrone D. This material was of excellent quality and required no further purification. a. TBAF, THF, r.t., (quantitative); b. IBX, CH 3CN, reflux (88%); c. 48% HBr, AcOH, reflux (quantitative); d. pyridine, AC2O, r.t. Scheme 31: Synthesis of Topopyrone D To our delight, only the thermodynamically favored linear topopyrone was formed in the last step. The linear arrangement of rings was verified by a 2D-FJMBC N M R experiment, which showed AJ correlations of the C-3 carbon with the 30 C-4 proton and with the C-14 protons. Such a correlation has been observed for natural topopyrone D, but obviously not for its angularly fused congener, topopyrone C . 8 Due to the poor solubility of topopyrones in common organic solvents (except DMSO), the isolation paper provided no spectral data of free topopyrones 3 and 4.34 Instead, these were characterized as the respective triacetate 119 and trimethyl ether (cf. 138 in Scheme 39) derivatives. Therefore, 4 was converted to the triacetate 119 by treatment with pyridine and acetic anhydride. As expected, ' H and 1 3 C N M R spectra of 119 were in full accordance with the reported data. We were able to obtain clean 'H and 1 3 C NMR spectra of free topopyrone D in a solution of DMSO - d 6, see experimental. 31 1.7 Synthesis of Topopyrone B Armed with the successful synthesis of topopyrone D, our attention now turned toward topopyrone B, for which we needed to utilize chloroamide 60, in lieu of 59, in the sequence leading to the anthraquinone. Several avenues to 60 may be envisaged. Initially, we considered the union of metallated 2-chlororesorcinol dimethyl ether 120 with an appropriate carboxylating agent (Scheme 32). Methoxy groups are strong DMGs and metallation of anisoles via D o M are well known.35 Furthermore, chloro susbtituents are generally regarded as compatible with metallation reactions, and may themselves behave as D M G ' s . 3 6 Consequently, the presence of a CI atom in 124 was not anticipated to be problematic. CI MeO' OMe O \ NEt, OMe CI o MeO 60 120 c r NEt 2 121 Scheme 32: Synthetic Strategy Towards 60 Contrary to such optimistic expectations, we were unable to deprotonate 124, at least by the use of s-BuLi (Scheme 33). A slightly different approach involved lithium-bromine exchange of 126 followed by addition of the aryllithium intermediate to N,N-diethyl carbamoyl chloride, 121. Compound 126 was prepared from commercial 2-chlororesorcinol by O-methylation and bromination. Reaction with r-BuLi followed by (a) Gilman, H.; Bebb, R.L. J. Am. Chem. Soc. 1939, 61, 109; (b) Wittig, G. Fuhrman, G. Chem. Ber. 1940, 73, 1197. For an example see : Godard, A.; Rocca, P.; Guillier, F.; Duvey, G.; Nivoliers, F.; Marsais, F.;Queguiner, G. Can. J. Chem. 2001, 79, 1754. 32 121 produced amide 60 in a low 20% yield. An alternative route involving formylation of 122 under Vilsmeier-Haack conditions gave 123 in a modest 30% yield. OH OH O 126 a. K 2 C0 3 , Mel, acetone, r.t.; NBS, CH 3CN, r.t. (89%); c. (COCI)2, DMF, 0 \u00C2\u00B0C, then H 2 0, 50 \u00C2\u00B0C (30%); d. s-BuLi, THF, -78 \u00C2\u00B0C, then 121 or C 0 2 ; e. f-BuLi, THF.-78 \u00C2\u00B0C , then 121 (20%). Scheme 33: Avenues Towards 60 Parallel investigations centered on the introduction of chlorine by direct halogenation of substrates such as 127. As shown in Scheme 34, both NCS and S O 2 C I 2 preferentially chlorinated the less hindered C-5 position of 2,4-dimethoxybenzaldehyde 127. 33 a. or b. a. NCS, DCM, r.t.; b. S0 2CI 2, DCM, r.t. Scheme 34: Chlorination of 127 One report demonstrated the regioselective C-3 chlorination of 2,4-dihydroxybenzaldehyde with NaOCl under basic conditions (Scheme 35).37 Application of this method to substrate 129 furnished 123 in quantitative yield. 0-Methylation followed by oxidation of the aldehyde to carboxylic acid 125 (NaC102)38 proceeded efficiently. Transformation of 125 to amide 60 was effected by treatment with S O C I 2 followed by Et 2 NH. Although this less direct approach required more steps, gram scale quantities of 60 was effortlessly prepared in excellent overall yield. OR O a. CN 125 60 1 2 9 b r 1 2 3 R = H M 3 0 R = Me a. NaOCl, KOH, H 2 0, r.t. (quantitative); b. K 2 C0 3 , Mel, acetone, reflux (85%); c. NaCI02, 2-methyl-2-butene, NaH 2 P0 4 buffer (pH = 3.5), f-BuOH, H 2 0 r.t. (90%); d. SOCI2, benzene, reflux, then Et2N, 0 \u00C2\u00B0 C (76%). Scheme 35: Synthesis of Amide 60 3 7 Bui, E.; Bayle, J. P.; Perez, R; Liebert, L.; Courtieu, J. Liq. Cryst. 1990, 8, 513. Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37, 2091. 34 The next step should have been the simple merger of 60 and 62 as outlined in Scheme 29 for the preparation of topopyrone D. Unexpectedly, amide 60 proved to be entirely resistant to deprotonation under standard conditions (s-BuLi/TMEDA, THF, -78 \u00C2\u00B0C). Even an eight-hour exposure to five molar equivalents of 5 -BuLi /TMEDA complex failed to effect orr/io-lithiation, as determined by the failure to incorporate deuterium following CD3OD quenching (Scheme 36). Attempts to force deprotonation by operating at temperatures as high as 0 \u00C2\u00B0C were likewise fruitless. Temperatures higher than 0 \u00C2\u00B0C promoted dechlorination of 60. Furthermore, reaction of THF with the s-BuLi/TMEDA complex becomes rapid at such temperatures, resulting in destruction of active base. This roadblock in our synthetic plans was finally overcome by using the more basic f-BuLi/TMEDA complex, which promoted complete metallation of 60 (as judged by deuterium incorporation following quenching with CD 3 OD) after three hours at -78 \u00C2\u00B0C. OMe O 60 \u00E2\u0080\u0094 Jc -^ ^ ^ p V ^ N E t s 60 M e O ^ ^ D 131 a. 5 eq. s-BuLi, 5 eq. TMEDA, THF, -78 \u00C2\u00B0 C - 0 \u00C2\u00B0C , then CD 3 OD b. 1 eq. f-BuLi, 1 eq. TMEDA, THF, -78 \u00C2\u00B0C, then CD 3OD. Scheme 36: Deprotonation of 60 The reasons for the encountered difficulties remain unclear. The resistance of amide 60 towards deprotonation cannot solely be attributed to the chlorine substituent since a number of chlorinated amides undergo deprotonation without incident. 3 9 3 9 Cf. Langer, P.; Freifeld, I. Synlett. 2001, 4, 523. 35 Furthermore, explanations involving sequestration of the base by chelation/coordination40 effects involving the chlorine atom are implausible, because amide 60 was immune to deprotonation even after addition of excess base, and because 2,3,4-trimethoxybenzamide (an analog of 60 where the chloro substituent is replaced by a methoxy group) undergoes deprotonation in a normal fashion,4' even though the triad of adjacent methoxy groups can undoubtedly chelate/coordinate/sequester the base as effectively as the 2,4-dimethoxy-3-chloro arrangement present in 60. Scheme 37: Synthesis of 133 Reaction of 60 and 62 under the newly modified conditions proceeded through intermediate 132, which upon treatment with f-BuLi followed by air oxidation gave anthraquinone 133 in 20% yield (Scheme 37). As seen earlier for the case of topopyrone 4 0 Cf. Whisler, M. C ; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004, 43, 2206. Sibi, M. P.; Jalil Miah, M. A.; Snieckus, V. / Org. Chem. 1984, 49, 737. 36 D, the desired 133 was accompanied by a significant quantity of debrominated adduct 134 (70 % yield). It should be noted that deprotonation of 60 was conducted in the presence of only one molar equivalent of f-BuLi/TMEDA complex. Use of excess reagent caused formation of dechlorinated products, probably through an unusual lithium-chlorine exchange reaction followed by protonation of the resultant aryllithium species. The synthesis continued according to Scheme 38. Desilylation of 133 with T B A F gave alcohol 135, which was oxidized to ketone 136 by IBX. Deprotection/cyclization of 136 using cone. HBr did not proceed as cleanly as with the dechloro analog (cf. 118 Scheme 31). Instead, this treatment resulted in formation of a mixture of 3 and a mono-methyl ether thereof, the precise structure of which was not determined. 133 O 137 R = H, H, Me a. TBAF, THF, r.t., (91%); b. IBX, CH 3CN, reflux (90%); c. 48% HBr, AcOH, reflux. Scheme 38: Synthesis of Topopyrone B 37 The addition of a phase transfer catalyst42 had no effect on the reaction. The monomethyl ether persisted even after refluxing a solution of 136 in aq. cone. HBr / AcOH for 48 hours. Fortunately, this was not of immediate concern since, as mentioned previously, topopyrone B was characterized as the trimethyl ether 138. Therefore the mixture of the two products was subjected to permethylation by use of Meerwein's salt. The spectra and physical data of compoud 138 thus obtained were in full accordance with the literature data. It should be noted that permethylation of 3 and 137 was not a trivial proposition. Thus, a variety of standard methylation procedures failed to provide 138 in satisfactory yield (Scheme 39). OMe O OMe O 3 + 137 O 138 Procedure (a.) Yield 138 K 2 C0 3 , Mel, acetone, reflux, 48 h none C s 2 C 0 3 , Mel, DMF, 45 \u00C2\u00B0C, 48 h none CH 2 N 2 , Et 20, r.t., 48 h trace Ag 2 0, Mel, DCM, reflux, 48 h 30% Me 30BF 4 , DCM, r.t., 2 h 95% Scheme 39: Synthesis of Trimethyl Ether 138 Landini, D.; Montanari, F.; Rolla, F. Synthesis 1978, 771. 38 In the interest of obtaining a sample of free 3 for biological assays, we now set out to demethylate a portion of 138. Just like many other aspects of topoyrone B chemistry, this transformation was problematic. It is rather ironic that having overcome the troublesome methylation of 3, we were now seeking to optimize the demethylation of 138. Consequently, other more efficient methods for the deprotection of 136 were explored (Scheme 40). Attack of 136 with TMS-I 4 3 engendered extensive decomposition. Use of 12 M BBr3 competently cleaved the methyl ethers, but the product was 139: cyclization to topopyrone B had not occurred under such conditions. The problem was corrected by exposing 139 to the action of cone. HBr in refluxing A c O H to give 3. + 3 136 139 Condition (a.) Result 48% HBr, AcOH, n-C16H33P(C4H9)3Br, reflux 3 and 137 TMS-I, CHCI3, reflux decomposition i) BBr3, DCM, -78 \u00C2\u00B0C - 0 \u00C2\u00B0C; ii) 48% HBr, AcOH, reflux 3 Scheme 40: Deprotection of 136 Jung, M. E.; Lyster, M. A. J. Org. Chem. 1977,42, 3761 39 A new set of difficulties awaited us at this juncture. Topopyrone B was poorly soluble in all common organic solvents, including polar ones such as MeOH, C H 2 C I 2 , EtOAc, M e C N and acetone. Purification of 3 was therefore replete with a host of technical problems. Normal phase column chromatography was impractical. Even preparative T L C was troublesome: for instance, the compound produced a long streak on a T L C plate upon elution with 10% MeOH in CH 2 C1 2 . A promising alternative is to convert 3 to the more soluble triacetate 140, which may be readily purified by standard chromatographic methods as a prelude to release of the acetyl groups (Scheme 41). Deacetylation of 140 by using the standard K2CO3 / MeOH treatment has failed to produce satisfactory results. We are currently exploring techniques for the cleavage of the acetyl groups under neutral conditions in an effort to reach pure topopyrone B. OAc O OAc O 3 a. AcO' CI b. 3 O 140 a. pyridine, A c 2 0 , r.t.; b. K 2 C 0 3 , MeOH. Scheme 41: Acetylation of Topopyrone B 40 In conclusion, and the above difficulties notwithstanding, we feel that the straightforward synthesis of topopyrones B and D developed in the course of this research should prove valuable for the preparation of analogues for SAR studies.44 Various solutions aiming to improve overall yields of 3 - 4 are currently under study in our laboratories. Tan, J. S.; Ciufolini, M. A. Org. Lett. ASAP article, September 15, 2006. 41 E X P E R I M E N T A L S E C T I O N 42 Experimental Index Synthesis ofketal 83 45 Synthesis of alcohol 84 48 Synthesis of aldehyde 85 51 Synthesis of amide 59 54 Synthesis of aldehyde 123 57 Synthesis of aldehyde 130 60 Synthesis of acid 125 63 Synthesis of amide 60 66 Synthesis of alcohol 94a 69 Synthesis of silyl ether 94 72 Synthesis of alcohol 95 75 Synthesis of silyl ether 107 78 Synthesis of silyl ether 108 81 Synthesis of alcohol 109 84 Synthesis of aldehyde 62 87 Synthesis of anthraquinone 111 91 Synthesis of anthraquinone 117 94 Synthesis of anthraquinone 118 97 Synthesis of topopyrone D 4 100 Synthesis of triacetate 119 102 Synthesis of anthraquinone 133 104 Synthesis of anthraquinone 135 108 Synthesis of anthraquinone 136 I l l Synthesis of trimethyl ether 138 114 43 Experimental Protocols. Unless otherwise stated, ' H and 1 3 C N M R spectra were obtained from CDCI3 solutions. 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), \"c\" (complex), \"br\" (broad). FT-IR spectra (cm - 1) were from thin films deposited on NaCl plates. Low- and high-resolution mass spectra (m/z) were obtained in the electrospray (ESI) mode. Melting points are uncorrected. A l l reagents and solvents were commercial products and used without further purification except THF (freshly distilled from Na/benzophenone under Ar) and CH 2 C1 2 (freshly distilled from CaH 2 under Ar). Commercial rc-BuLi was titrated against N-benzylbenzamide in THF at -78 \u00C2\u00B0C until persistence of a light blue color. Flash chromatography was performed on Silicycle 230 -400 mesh silica gel. A l l reactions were performed under dry Ar in flame or over dried flasks equipped with Teflon\u00E2\u0084\u00A2 stirbars. A l l flasks were fitted with rubber septa for the introduction of substrates, reagents, and solvents via syringe. 44 o EtC 83 A solution of ethyl acetoacetate (100.0 g, 0.77 mol), ethylene glycol (143.0 g, 2.30 mol), and /?-TsOH\u00C2\u00BBH 20 (6.5 g, 34.2 mmol) in benzene (1000 mL; C A U T I O N : cancer suspect agent) was refluxed for 5 h with continuous azeotropic H2O separation (Dean-Stark trap). The mixture was then cooled to RT, concentrated to 500 mL in vacuo., washed sequentially with sat. aq. NaHCOs (2 x 100 mL) and brine (100 mL), dried (Na 2S0 4), filtered and concentrated to afford the ketal ester 83 (120.5 g, 90%) as a colorless oil. This material was of excellent purity as judged by N M R and required no further purification. 1 H : 4.06 (q, 2H, J = 6.6), 3.88 (s, 4H), 2.57 (s, 2H), 1.41 (s, 3H), 1.17 (t, 3H, / = 6.6). 1 3 C : 169.2, 107.4, 64.5, 60.2, 44.0, 24.2, 13.9. IR: 1747. H R M S calcd for C 8 H 1 4 0 4 [M + Na] + = 197.0790, found 197. 45 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 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 II 10 9 8 7 6 5 4 3 2 1 0 __J U I , I U I L \u00E2\u0080\u0094 I \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 | \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 j \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 | \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 | \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 | \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 | \u00E2\u0080\u0094 175 150 125 100 75 50 25 Scheme 42 N M R Spectra of 83 46 47 A solution of the above ketal ester 83 (9.0 g, 51.7 mmol) in dry THF (20 mL) was added dropwise to a cold (-5 \u00C2\u00B0C; ice-NaCl bath) suspension of L A H (1.97 g, 51.7 mmol) in dry THF (80 mL). The reaction mixture was stirred at 0 \u00C2\u00B0C for 1.5 h then quenched carefully with aq. sat. Na / K tartrate soln. (100 mL. C A U T I O N : vigorous evolution of highly flammable H 2 gas). The organic layer was separated and the aqueous layer was extracted with E t 2 0 (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried (Na 2S0 4) and concentrated to give alcohol 84 (6.2 g, 91%) as a colorless oil. This material was of excellent purity as judged by N M R and required no further purification. J H : 3.99 (s, 4H), 3.76 (broad s, 2H), 2.76 (broad s, 1H), 1.95 (t, 2H, J = 5.2), 1.36 (s, 3H). 1 3 C : 110.3,64.6, 58.8,40.5,23.9. IR: 3440. H R M S calcd for C 6 H ] 2 0 3 [M + Na] + = 155.0684, found 155.0683. 48 125 100 \"T\" 25 175 150 Scheme 44 N M R Spectra of 84 49 50 H O ^ 85 Dry DMSO (2.79 mL, 39.3 mmol) was added dropwise to a cold (-78 \u00C2\u00B0C) solution of oxalyl chloride (3.38 mL, 39.3 mmol) in dry D C M (130 mL; CAUTION: a vigorous exotherm ensues that produces poisonous CO gas). The mixture was stirred at -78 \u00C2\u00B0C for 15 min, then solution of alcohol 84 (4.0 g, 30.3 mmol) in dry D C M (20 mL) was added dropwise. The resultant solution was stirred at -78 \u00C2\u00B0C for 30 min, then Et3N (16.9 mL, 121 mmol) was added. The mixture was stirred at -78 \u00C2\u00B0C for 5 min then it was allowed to warm to RT over 40 min, with continued stirring. The reaction mixture was washed successively with aq. sat. NH4CI (3 x 50 mL), dried (Na2S04) and concentrated to give 85 (3.6 g, 91%) as a pale yellow oil. This material was of excellent purity as judged by N M R and required no further purification. 1 H : 9.75 (t, 1H, J = 2.8), 4.01 (m, 4H), 2.71 (d, 2H, / = 2.8), 1.43 (s, 3H). 1 3 C : 200.3, 107.6, 64.8, 52.2, 24.9. IR: 1724. HRMS calcd for C 6 H 1 0 O 3 [M + Na] + = 153.0528, found 153.05. 51 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 II 10 9 8 7 ' ' ' ' I ' ' ' ' I | I I I I | I I I ! | 6 5 4 3 2 1 0 l..>\u00E2\u0080\u009EM,l.,.l ,\u00C2\u00BB.,!\u00C2\u00BB < > 1 1 1 1 i 1 200 T\u00E2\u0080\u00941\u00E2\u0080\u0094I\u00E2\u0080\u0094r-n ]\u00E2\u0080\u0094l\u00E2\u0080\u0094l\u00E2\u0080\u0094l\u00E2\u0080\u0094l\u00E2\u0080\u0094|\u00E2\u0080\u0094l\u00E2\u0080\u0094l\u00E2\u0080\u0094l\u00E2\u0080\u0094l\u00E2\u0080\u0094|\u00E2\u0080\u0094l\u00E2\u0080\u0094l\u00E2\u0080\u0094I\u00E2\u0080\u0094I\u00E2\u0080\u0094|\u00E2\u0080\u0094I\u00E2\u0080\u0094I\u00E2\u0080\u0094I\u00E2\u0080\u0094I\u00E2\u0080\u0094|\u00E2\u0080\u0094I\u00E2\u0080\u0094I\u00E2\u0080\u0094l\u00E2\u0080\u0094I\u00E2\u0080\u0094|\u00E2\u0080\u0094I\u00E2\u0080\u0094I\u00E2\u0080\u0094I\u00E2\u0080\u0094r\u00E2\u0080\u0094f 175 150 125 100 75 50 25 Scheme 46 N M R Spectra of 85 52 Scheme 47 IR Spectra of 85 53 OMe O 59 Diethylamine (7.12 mL, 68.5 mmol) was carefully added to a cold (0 \u00C2\u00B0C) solution of 2,4-dimethoxybenzoyl chloride (4.58 g, 22.8 mmol) in dry toluene (70 mL), and the mixture was stirred at 0 \u00C2\u00B0C for 1 h then warmed to RT and stirred for another 5 h. The solution was concentrated and the residue was partitioned between ethyl acetate (50 mL) and aq. sat. N a H C 0 3 (50 mL). The organic layer was washed successively with I M HC1 (50 mL), H 2 0 (50 mL), and brine (50 mL), dried (Na2S04) and concentrated to give pure amide 59 (4.8 g, 89%) as a pale yellow oil. 7.05 (d, 1H, J = 8.4), 6.43 (dd, 1H, J = 8.4, 2.0), 6.39 (d, 1H, J = 2.0), 3.74 (s, 3H), 3.73 (s, 3H), 3.49 (broad q, 2H), 3.09 (q, 2H, J = 7.2), 1.16 (t, 3H, J = 7.6), 0.97 (t, 3H, / = 7.2). 1 3 C : 168.6, 161.0, 156.3, 128.1, 119.6, 104.4, 98.4, 55.3, 55.2, 42.6, 38.7, 13.8, 12.7. IR: intense band with fine structure between 1680 and 1615. H R M S calcd for C 1 3 H 1 8 3 5 C 1 N 0 3 [M + Na] + = 294.0873, found 294.0870. 54 JUL Scheme 48 N M R Spectra of 59 55 56 OH O 123 A suspension of 2,4-dihydroxybenzaldehyde (2.0 g, 14.5 mmol, Fluka) in H 2 O (10 mL) was sequentially treated at RT with a solution of K O H (2.0 g, 35.6 mmol) in H 2 0 (15 mL), followed by commercial bleach.containing 6% NaOCl (21 mL, 16 mmol). The reaction mixture was stirred at RT for 3 h then it was acidified with 6 M HC1 (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried (Na2S04) and concentrated. Purification by flash chromatography (EtOAc:hexanes, 1:1) gave pure aldehyde 123 (2.4 g, quantitative) as a white solid, m.p. 146-148 \u00C2\u00B0C (no m.p. was recorded in the literature). * H (acetone-6f6): 9.80 (s, 1H), 7.60 (d, 1H, / = 8.8), 6.75 (d, 1H, / = 8.8). 1 3 C : 197.1, 162.5, 161.6, 135.5, 117.1, 110.5, 109.1. I R : 1634. H R M S calcd for C 7 H 5 3 5 C 1 0 3 [M + H ] + = 173.0005, found 173.0007. 57 100 50 \u00E2\u0080\u0094r~ 25 Scheme 50 N M R Spectra of 123 58 77.9 c m - 1 Scheme 51 IR Spectra of 123 59 OMe O 130 Neat Me l (7.9 mL, 127 mmol C A U T I O N : toxic, volatile, cancer suspect agent) was added at RT to a solution of the aldehyde 123 (2.2 g, 12.7 mmol) in acetone (50 mL) containing suspended K2CO3 (17.6 g, 127 mmol). The mixture was refluxed for 5 h, then it was filtered and concentrated, and the residue was purified by flash chromatography (EtOAc : hexanes, 1:4) to give 130 (2.2 g, 85%) as a white solid. This material was of excellent purity as judged by N M R and required no further purification. m.p. 105-107 \u00C2\u00B0C (lit. 109-111 \u00C2\u00B0C). 4 5 1 H : 10.19 (s, 1H), 7.75 (d, 1H, / = 9.1), 6.81 (d, 1H, J = 9.1), 3.96 (s, 3H), 3.95 (s, 3H). 1 3 C : 187.9, 161.1, 160.5, 127.8, 123.8, 116.6, 107.7, 62.9, 56.6. IR: 1681. H R M S calcd for C 9 H 9 3 5 C 1 0 3 [M + H ] + = 201.0318, found 201.0317. Plattner, J. J.; Fung, A . K. L.; Parks, J. A . ; Pariza, R. J.; Crowley, S. R.; Pernet, A . G.; Bunnell, P. R.; Dodge, P. W. J. Med. Chem. 1984,27, 1016. 60 62 OMe O 125 A solution of NaC10 2 (80%, 1.4 g, 12.3 mmol) in a N a H 2 P 0 4 buffer (pH 3.5, 50 mL) was carefully added to a solution of aldehyde 130 (2.06 g, 10.3 mmol) in r-butanol (50 mL) containing 2-methyl-2-butene (2.0M in THF, 6.2 mL, 12.4 mmol). The mixture was stirred at RT overnight, then it was basified with I M NaOH(10 mL) and the aqueous layer was washed with EtOAc (2 x 25 mL). The aqueous layer was reacidified with 6M HC1 (5 mL) and extracted with EtOAc (2 x 40 mL). The combined extracts were dried (Na 2S0 4) and concentrated to give pure 125 (2.0 g, 90%) as a white solid. m.p. 168-170 \u00C2\u00B0C. * H : 8.07 (d, 1H, 7=9.1), 6.88 (d, 1H,7 = 9.1), 4.08 (s, 3H), 3.99 (s, 3H). 1 3 C (acetone-t4): 165.8, 160.4, 158.5, 131.9, 119.0, 118.1, 108.2, 62.0, 57.0. I R : 1695. H R M S calcd for C 9 H 9 3 5 C 1 0 4 [M + Na] + = 239.0087, found 239.0089. 63 ' I 1 1 1 ' I 1 2 0 0 1 7 5 \u00E2\u0080\u0094I 1 1 1 - 1 1 1 I 7 5 1 I ' 1 1 1 I ' 5 0 2 5 1 5 0 1 2 5 1 0 0 Scheme 54 N M R Spectra of 125 64 H : 1 1 \u00E2\u0080\u00A2 1 1 1 1 1 . 1 1\u00E2\u0080\u0094 4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 cm-1 Scheme 55 IR Spectra of 125 65 O M e O T h i o n y l c h l o r i d e (1.0 m L , 13.8 m m o l ; CAUTION: c o r r o s i v e , t o x i c ) w a s c a r e f u l l y a d d e d to a s o l u t i o n o f 125 (2.0 g , 9.2 m m o l ) i n d r y b e n z e n e (65 m L ; CAUTION: c a n c e r s u s p e c t agen t ) a n d the m i x t u r e w a s r e f l u x e d f o r 3 h (CAUTION: e v o l u t i o n o f c o r r o s i v e HC1 gas ) . T h e m i x t u r e w a s then c o o l e d to 0 \u00C2\u00B0C p r i o r to d r o p w i s e a d d i t i o n o f a s o l u t i o n o f d i e t h y l a m i n e (7.65 m L , 73.6 m m o l ) i n d r y b e n z e n e (10 m L C A U T I O N : c a n c e r su spec t agent ) . T h e m i x t u r e w a s s t i r r e d o v e r n i g h t at R T , t hen i t w a s w a s h e d w i t h I M a q . NaOH (2 x 50 m L ) , d r i e d ( N a 2 S 0 4 ) a n d c o n c e n t r a t e d . T h e r e s i d u e o f c r u d e a m i d e w a s r e c r y s t a l l i z e d (E tOAc :hexanes, 1:1) to a f f o r d p u r e 60 (1.9 g , 76%) as t a n c r y s t a l s . m.p. 70-72 \u00C2\u00B0C. *H: 7.11 ( d , l H , / = 8.7), 6.73 ( d , 1H,7= 8.7), 3.91 (s, 3H), 3.87 (s, 3H), 3.74, 3.36 ( b r s , 2H), 3.15 ( q , 2H, 7 = 7.3), 1.24 (t, 3H, J= 7.3), 1.02 (t, 3H, J= 7.3). 1 3 C : 167.8, 156.8, 153.4, 125.8, 125.6, 116.8, 107.7, 61.9, 56.6, 43.2, 39.2, 14.1, 12.9. IR: 1634. H R M S c a l c d f o r C i 3 H 1 8 3 5 C l N 0 3 [ M + N a ] + = 294.0873, f o u n d 294.0870. 66 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 1 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 ! 1 1 1 1 I II 10 9 8 7 6 5 4 3 2 1 0 ~ i \u00E2\u0080\u0094 i \u00E2\u0080\u0094 i i 1\u00E2\u0080\u0094i 1 i\u00E2\u0080\u0094 r i 1 1 1 1 i 1 150 125 \u00E2\u0080\u0094 j \u00E2\u0080\u0094 i 1 1\u00E2\u0080\u0094i 1 1\u00E2\u0080\u0094i r-50 25 - i i i i -175 100 75 S c h e m e 56 N M R Spectra of 60 67 68 OMe 94a Commercial BH3\u00C2\u00BBSMe2 solution (36.3 mL, 0.38 mol) was added dropwise to a solution of 3,5-dimethoxy-4-bromobenzoic acid (50.0 g, 0.19 mol) in dry THF (600 mL). The mixture was stirred at 40 \u00C2\u00B0C overnight, then it was quenched with I M aq. HC1 (200 mL. C A U T I O N : evolution of highly flammable H 2 gas) and the volatiles were removed in vacuo. The aqueous residue was extracted with EtOAc (3 x 200 mL), and the combined extracts were dried (Na2S04) and concentrated to give the pure alcohol 94a (47 g, quantitative) as a white solid. m.p. 100 - 102 \u00C2\u00B0C (lit. 100-102 \u00C2\u00B0C).*6 *H: 6.51 (s, 2H), 4.59 (s, 2H), 3.84 (s, 6H), 2.41 (s, 1H). 1 3 C : 156.8, 141.7, 102.8, 99.3, 64.8, 56.3. IR: 3310. H R M S calcd for C 9 H n 7 9 B r 0 3 [M + Na] + = 268.9789, found 268.979. Inoue, I. W O 2003072536 A l 2003. 69 - i 1 1 r 50 200 175 125 100 Scheme 58 N M R Spectra of 94a 70 68.6] , , , , , , , , , I , , , 4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600.0 cm-1 Scheme 59IR Spectra of 94a 71 A solution of the alcohol 94a (47.0 g, 0.19 mol), imidazole (25.9 g, 0.38 mol), 4-D M A P (1.8 g, 15 mmol), and TBSC1 (30.1 g, 0.20 mol) in dry CH 2 C1 2 (400 mL) was stirred at RT overnight, then it was concentrated. The residue was taken up with sat. NH4CI aq. (200 mL) and extracted with EtOAc (3 x 150 mL). The combined extracts were dried (Na2S04) and concentrated, and the residue was purified by flash chromatography (hexanes -> EtOAc:hexanes, 1:1) to afford silyl ether 94 (68 g, quantitative) as a waxy solid. m.p. 34 - 36 \u00C2\u00B0C. . X H : 6.57 (s, 2H), 4.71 (s, 2H), 3.89 (s, 6H), 0.96 (s, 9H), 0.11 (s, 6H). 1 3 C : 157.1, 142.7, 102.3, 64.8, 56.5, 26.1, 18.6, -5.1. IR: 2856, 1589, 1233. H R M S calcd for C i 5 H 2 5 7 9 B r 0 3 S i [M + Na] += 383.0654, found 383.0655. 72 J L J I j . i 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 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 11 10 9 8 7 6 5 4 3 2 1 0 150 125 100 75 50 25 Scheme 60 N M R Spectra of 94 73 1 1 1 1 1 1 1 1 1 1 1 1 1 1 4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600. cin-1 Scheme 61 IR Spectra of 94 74 95 A pentane solution of r-BuLi (1.45M 10.5 mL, 15.2 mmol) was added dropwise to a cold (-78 \u00C2\u00B0C) solution of 94 (2.5 g, 6.9 mmol) in dry THF (25 mL), followed by a solution of aldehyde 85 (0.90 g, 6.9 mmol) in dry THF (5 mL). The mixture was stirred at -78 \u00C2\u00B0C for 1 h then it was allowed to warm to RT overnight. The reaction was quenched with sat. NH4CI aq. (30 mL) and the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined extracts were dried (NaaSCu) and concentrated. Chromatographic purification of the residue (EtOAc:hexanes, 1:1) gave 95 (1.9 g, 67%) as a pale orange oil. 1 H : 6.53 (s, 2H), 5.43 (ddd, 1H, J = 9.6, 9.6, 3.9), 4.70 (s, 2H), 3.97 (m, 4H), 3.82 (s, 6H), 3.54 (d, 1H, J = 9.6), 2.43 (dd, 1H, J = 15.0, 9.6), 1.97 (dd, 1H, J = 15.0, 3.9), 1.45 (s, 3H), 0.95 (s, 9H), 0.10 (s, 6H). 1 3 C : 157.7, 142.4, 118.8, 109.9, 101.9, 65.1, 64.7, 64.3, 63.8, 55.8, 45.2, 26.3, 24.3, 18.5, -4.8. IR: 3565. H R M S calcd for C 2 i H 3 6 0 6 S i [M + Na] + = 435.2179, found 435.2178. 75 II 10 I I 1 0 Scheme 62 N M R Spectra of 95 76 Neat TIPS-OTf (1.85 mL, 6.9 mmol) was carefully added to a solution of 95 (2.7 g, 6.6 mmol), imidazole (0.9 g, 13.2 mmol), and 4-DMAP (64.0 mg, 0.53 mmol) in dry D M F (13 mL), and the mixture was stirred at RT overnight. The reaction was quenched with aq. sat. NaHC03 (50 mL) and extracted with EtOAc (2 x 50 mL). The combined extracts were washed with brine (50 mL), dried (Na2S04) and concentrated. The residue was purified by flash chromatography (hexanes -> EtOAc:hexanes, 1:4) to afford silyl ether 107 (3.5 g, 94%) as colorless oil. X H : 6.50 (br s, 1H), 6.46 (br s, 1H), 5.57 (dd, 1H, J = 9.2, 4.4), 4.70 (br s, 2H), 3.85-3.78 (c, 4H), 3.78 (s, 3H), 3.77 (s, 3H), 2.76 (dd, 1H, J = 14.4, 9.2), 2.23 (dd, 1H, J = 14.4, 4.4), 1.24 (s, 3H), 1.00-0.98 (m, 12H), 0.94 (s, 9H), 0.89-0.85 (m, 9H), 0.08 (s, 6H). 1 3 C : 160.1, 157.0, 142.1, 120.0, 109.5, 102.8, 101.1, 65.3, 64.4, 64.3, 63.1, 55.6, 55.6, 45.1, 26.0, 24.5, 18.2, 18.0, 17.9, 12.5, -5.0. IR: 2865, 1610, 1228. H R M S calcd for .CsoBfoA^ [M+ Na] + = 591.3513, found 591.3518. 78 175 150 125 100 75 50 25 Scheme 64 N M R Spectra of 107 79 ClTl-1 Scheme 65 IR Spectra of 107 80 A solution of 107 (3.5 g, 6.2 mmol) and NBS (1.1 g, 6.2 mmol) in C H 3 C N (20 mL) was stirred at RT for 1.5 h, then it was diluted with aq. sat. NaHC03 aq. (30 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (50 mL), dried (Na2SC>4) and concentrated to give pure 108 (4.0 g, quantitative) as a colorless oil. Proton and 1 3 C N M R spectra indicated that this material exists as a ca. 4:1 mixture of atropisomers. *H (Major atropisomer): 6.94 (s, 1H), 5.57 (dd, 1H, J = 10.5, 3.6), 4.70 (br AB-type system, 2H, J= 15.1), 3.93 (s, 3H), 3.80 (s, 3H), 3.81-3.69 (c, 4H), 3.14 (dd, 1H, J= 14.2, 10.5), 2.12 (dd, 1H,7= 14.2, 3.6), 1.18 (s, 3H), 1.11-0.84 (c, 21H), 0.97 (s, 9H), 0.13 (s, 6H). 1 3 C (Major atropisomer): 157.2, 156.4, 141.1, 126.5, 109.0, 108.2, 105.4, 64.9, 64.5, 64.4, 63.2, 62.1, 55.6, 44.7, 26.1, 24.4, 18.4, 18.2, 12.5, -5.1. IR: 2866. H R M S calcd for C3oH550679BrSi2 [M + Na] + = 669.2618, found 669.2614. 81 175 Scheme 66 N M R Spectra of 108 82 cm-1 Scheme 67 LR Spectra of 108 83 A solution of 108 (4.0 g, 6.2 mmol) and T B A F (1.0M in THF, 5.9 mL, 6.2 mmol) in THF (20 mL) was stirred at RT for 20 min, then it was quenched with aq. sat. NaHCC>3 (30 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (50 mL), dried (Na 2S0 4) and concentrated to give 109 (3.2 g, quantitative) as a colorless oil. Proton and 1 3 C N M R spectra indicated that this material exists as a ca. 4:1 mixture of atropisomers. X H (major atropisomer): 6.84 (s, 1H), 5.58 (dd, 1H, J = 10.5, 3.5), 4.71 (br AB-type system, 2H, J = 14.0), 3.93 (s, 3H), 3.82 (s, 3H), 3.78-3.68 (c, 4H), 3.13 (dd, 1H, 7= 14.0, 10.5), 2.26 (br, 1H, OH), 2.13 (dd, 1H, / = 14.0, 3.5), 1.40-0.80 (m, 21H), 1.17 (s, 3H). 1 3 C (major atropisomer): 157.4, 156.4, 140.9, 127.0, 109.4, 108.9, 106.0, 64.3, 64.2, 63.0, 62.0, 55.7, 53.7, 44.5, 28.5, 24.2, 20.9, 18.2, 18.1, 12.4. IR: 3430. H R M S calcd for C 2 4 H 4 i 7 9 B r 0 6 S i [M + Na] + = 555.1753, found 555.1755. 84 L L J J L J I 175 150 125 100 Scheme 68 N M R Spectra of 109 85 \u00C2\u00BB\u00E2\u0080\u00A2' H 1 . \u00E2\u0080\u00A2 . . 1 1 1 1 1 1 1 1 4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600.0 cm-1 Scheme 69 IR Spectra of 109 86 TIPS Dry DMSO (0.35 mL, 4.8 mmol) was cautiously added to a cold (-78 \u00C2\u00B0C) solution of oxalyl chloride (0.42 mL, 4.8 mmol) in dry D C M (15 mL. C A U T I O N : a vigorous exotherm ensues that produces poisonous CO gas). The mixture was stirred at -78 \u00C2\u00B0C for 15 min, then a solution of 109 (2.0 g, 3.7 mmol) in dry D C M (5 mL) was added and the reaction was stirred at -78 \u00C2\u00B0C for 1 h. Triethylamine (2.1 mL, 14.8 mmol) was injected and the mixture was stirred at -78 \u00C2\u00B0C for 5 min, then it was allowed to warm to RT with continued stirring. The reaction mixture was washed successively with aq. sat. NH4CI aq. (3 x 50 mL), dried (Na2S04) and concentrated. Chromatography of the residue (EtOAc:hexanes, 1:2) gave pure aldehyde 62 (1.6 g, 81%) as a colorless semisolid. 13 Proton and C N M R spectra indicated that this material exists as a ca. 6:1 mixture of atropisomers. J H (major atropisomer): 10.36 (s, 1H), 7.21 (s, 1H), 5.61 (dd, 1H, 7= 10.5, 3.2), 3.99 (s, 3H), 3.90-3.60 (cm, 4H), 3.85 (s, 3H), 3.17 (dd, 1H, J = 14.2, 10.5), 2.17 (dd, 1H, J = 14.2, 3.2), 1.20 (s, 3H), 1.15-0.84 (cm, 21H). 1 3 C (major atropisomer): 191.9, 158.2, 156.6, 135.4, 133.6, 116.3, 108.7, 106.3, 64.4, 64.3, 63.1, 62.5, 56.0, 44.5, 24.3, 18.2, 18.1, 12.4. IR: 1694. H R M S calcd for C 2 4H39 7 9 Br0 6 Si [M + Na] + = 553.1597, found 553.1596. 87 U L J L L I . Scheme 70 N M R Spectra of 62 88 1 1 1 I 1 1 1 \u00E2\u0080\u00A2 1 1 1 1 1 1 4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600.0 cin-1 Scheme 71IR Spectra of 62 89 A solution of benzamide 59 (200 mg, 0.86 mmol) in dry THF (2 mL) was added to a cold (-78 \u00C2\u00B0C) solution of s-BuLi (0.68 mL, 0.90 mmol) and T M E D A (0.14 mL, 0.95 mmol) in dry THF (4 mL), followed, after 3 h, by a solution of 62 (460 mg, 0.86 mmol) in dry THF (2 mL). The mixture was stirred for 1 h, then f-BuLi (1.32 mL of 1.45M pentane solution 1.9 mmol) was added. The reaction was stirred at -78 \u00C2\u00B0C for 2 h and allowed to warm to RT overnight. The mixture was quenched with H 2 O (1 mL) and stirred for 1 h while bubbling air through the solution, then it was diluted with aq. sat. NaHCC>3 (20 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (50 mL), dried (NaiSCu) and concentrated. The yellow residue was purification by flash chromatography (EtOAc:hexanes, 1:1) to give 111 (80 mg, 17% ) as a bright yellow solid. Proton and 1 3 C N M R spectra indicated that this material exists as a ca. 2:1 mixture of atropisomers. *H (major atropisomer): 7.48 (s, 1H), 7.33 (d, 1H, 7= 2.7), 6.78 (d, 1H, 7= 2.7), 5.63 (dd, 1H, 7 = 10.5, 3.2), 4.01 (s, 3H), 3.96 (br s, 6H), 3.95 (s, 3H), 3.90-3.70 (cm, 4H), 3.27 (dd, 1H,7= 14.2, 10.5), 2.15 (dd, 1H,7= 14.2, 3.2), 1.23 (s, 3H), 1.05-0.85 (m, 21 H). 1 3 C (major atropisomer): 184.1, 181,2, 163.8, 162.7, 162.0, 160.2, 136.6, 134.8, 134.5, 122.5, 118.5, 108.8, 105.5, 104.1, 102.3, 64.5, 64.4, 63.7, 63.1, 56.8, 56.1, 44.4, 24.3, 18.3, 18.2, 12.5. 90 IR: 1670. H R M S calcd for C33H46O9S1 [M + Na] + = 637.2809, found 637.2807. 91 A. 0 U * . 175 150 125 100 75 ~1~ 50 Scheme 72 N M R Spectra of 111 92 '\u00E2\u0080\u00A2\u00C2\u00B0H 1 1 1 1 1 1 1 1 \u00E2\u0080\u00A2 1 1 . 1 4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600. cm-1 Scheme 73 TR Spectra of 111 93 OMe O 117 A solution of 111 (45 mg, 0.073 mmol) and T B A F (1.0M in THF, 0.15 mL, 0.15 mmol) in THF (0.5 mL) was stirred at RT overnight, then it was diluted with aq. sat. NaHCC\u00C2\u00BB3 (30 mL) and extracted with EtOAc (2 x 20 mL). The combined extracts were washed with brine (50 mL), dried (Na2S04) and concentrated. Chromatographic purification of the residue (EtOAc ; hexanes, 1:1) gave 117 (30 mg, quantitative) as a yellow solid. Unlike the case of 111, proton and 1 3 C N M R spectra of the present compound indicated the existence of a single species in solution. *H: 7.54 (s, 1H), 7.33 (d, 1H, J = 2.8), 6.78 (d, 1H, / = 2.0), 5.53 (ddd, 1H, J = 8.4, 8.4, 3.2), 4.02-3.96 (m, 4H), 4.02 (s, 3H), 3.99 (s, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.47 (d, 1H, J= 10.0), 2.55 (dd, 1H, J= 14.4, 9.2), 2.02 (dd, 1H, J= 14.4, 3.0), 1.46 (s, 3H). 1 3 C: 183.8, 181.1, 164.1, 162.1, 161.5, 159.6, 136.5, 134.9, 133.3, 122.4, 118.3, 109.9, 105.6, 105.0, 102.5, 64.9, 64.6, 64.3, 63.5, 44.9, 24.5. IR: 3500, 1669. H R M S calcd for C24H26O0 [M + Na] + = 481.1475, found 481.1478. 94 ) L L _ J U U I 175 150 125 100 75 50 25 Scheme 74 N M R Spectra of 117 95 71.8: , , , , , , , , I , , , , 4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600.0 cm-1 Scheme 75 IR Spectra of 117 96 OMe O 118 A mixture of the 117 (7.0 mg, 0.015 mmol) and IBX (13 mg, 0.045 mmol) in C H 3 C N (1 mL) was refluxed for 45 min, then it was cooled to RT, filtered and concentrated. Purification of the residue by preparative T L C (EtOAc) provided 118 (6.0 mg, 88%) as a yellow solid. Proton and 1 3 C N M R spectra of 118 indicated the existence of a single species in solution. *H (7.55 (s, 1H), 7.35 (d, 1H, J = 2.8), 6.80 (d, 1H, / = 2.8), 3.98 (s, 3H), 3.97 (s, 3H), 3.97 (s, 3H), 3.96-3.91 (m, 4H), 3.94 (s, 3H), 3.18 (s, 2H), 1.54 (s, 3H). 1 3C: 199.8, 183.5, 180.4, 164.3, 162.3, 159.5, 158.8, 136.5, 136.3, 132.3, 122.3, 117.9, 107.9, 105.7, 105.2, 102.8, 64.8, 64.2, 56.8, 56.6, 56.2, 52.8, 24.6. IR: 1718, 1670. H R M S calcd for C24H24O9 [M + Na] + = 479.1318, found 479.1320. 97 200 175 150 125 100 75 50 25 Scheme 76 N M R Spectra of 118 98 58 4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 cm-1 Scheme 77 TR Spectra of 118 99 OH O OH O O 4 A solution of 118 (6.0 mg, 0.013 mmol) in A c O H (1.5 mL) and aq. 48% HBr (1.0 mL) was refluxed overnight. The mixture was diluted with H 2 0 (10 mL) and extracted with EtOAc (2 x 40 mL). The combined extracts were washed with brine (50 mL), dried (Na 2S0 4) and concentrated to give fully synthetic topopyrone D (5 mg, quantitative) as an orange solid. *H (DMSO-J 6): 7.55 (s, 1H), 7.07 (d, 1H, J = 2.3), 6.60 (d, 1H, J = 2.3), 6.52 (s, 1H), 2.47 (s, 3H). 1 3 C (DMSO-rf6): 185.4, 182.1, 180.8, 169.9, 164.6, 164.45, 164.41, 164.0, 159.1, 138.1, 134.0, 113.5, 110.4, 110.0, 108.7, 107.6, 106.6, 20.0. 100 \u00E2\u0080\u0094\\u00E2\u0080\u0094 150 I\u00E2\u0080\u0094 125 Scheme 78 N M R Spectra of 4 101 OAc O OAc O Synthetic 4 was acetylated as described in the literature (ref. 8) to afford the corresponding triacetate 119, which was purified by preparative T L C (EtOAc). 1 13 This material produced H and C N M R spectra in complete accord with the literature (values in brackets, ref. 8). 8.19 [8.19] (s, 1H), 7.97 [7.97] (d, 1H, J = 2.1), 7.28 [7.28] (d, 1H, / = 2.1), 6.13 [6.13] (s, 1H), 2.52 [2.52] (s, 3H), 2.45 [2.45] (s, 3H), 2.40 [2.40] (s, 3H), 2.36 [2.36] (s, 3H). 1 3 C: 180.4 [180.2], 178.5 [178.4], 175.9 [175.7], 169.3 (2 overlapping resonances) [169.0], 168.2 [169.0], 165.9 [165.6], 159.7 [159.4], 154.9 (2 overlapping resonances) [154.7], 151.8 [151.6], 136.5 [136.3], 135.5 [135.3], 124.3 [124.1], 124.2 [124.1], 122.4 [122.3], 121.4 [121.2], 118.7 [118.4], 115.6 [115.3], 113.1 [112.8], 21.34 [21.1], 21.27 [21.0], 21.2 [20.9], 20.4 [20.1]. H R M S calcd for C 2 4 H 1 6 O 1 0 [M + Na] + = 487.0641, found 487.0645. 102 I 1 1 1 1 I II 10 I I I I I I I I I I I ' I ' I I I I I I I ' I 1 1 I 1 1 1 ' I 6 5 4 3 2 1 0 175 150 125 100 75 50 25 Scheme 79 N M R Spectra of 119 103 OMe O 1 3 3 A solution of 60 (0.20 g, 0.74 mmol) in dry THF (1 mL) was added to a cold (-78 \u00C2\u00B0C) solution of f-BuLi (1.5M pentane solution, 0.49 mL, 0.74 mmol) and T M E D A (0.11 mL, 0.78 mmol) in dry THF (3 mL). After 3 h, a solution of 62 (0.39 g, 0.74 mmol) in dry THF (1 mL) was added, and after stirring for 1 h, r-BuLi (1.5M pentane solution, 0.97 mL, 1.48 mmol) was injected. The solution was stirred at -78 \u00C2\u00B0C, then it was allowed to warm to RT overnight, and finally it was quenched with H 2 0 (lmL) and stirred under a stream of air for 2 h. The mixture was diluted with aq. sat. NaHCC>3 (30 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (50 mL), dried (Na2SC>4) and concentrated. Chromatographic purification of the 13 residue (EtOAc:hexanes, 1:4) gave 133 (97 mg, 20%) as an orange oil. Proton and C N M R spectra indicated that this material exists as a ca. 2:1 mixture of atropisomers. *H (major atropisomer): 7.57 (s, 1H), 7.50 (s, 1H), 5.63 (dd, 0.5H, J = 10.5, 3.1), 4.06 (s, 3H), 4.04 (s, 3H), 3.98 (s, 3H), 3.96 (s, 3H), 3.90-3.70 (m, 4H), 3.25 (dd, 1H, J = 14.0, 10.5 Hz), 2.19 (dd, 1H, J= 14.4,3.1), 1.23 (s, 3H), 1.10-0.81 (c, 21H). 1 3 C (major atropisomer): 183.0, 180.5, 162.8, 160.6, 159.3, 134.8, 134.7, 133.4, 125.7, 123.3, 122.0, 108.9, 105.1, 104.3, 64.5, 64.4, 63.4, 63.0, 62.2, 57.1, 56.2, 44.7, 24.3, 18.3, 18.2, 12.5. 104 *H (minor atropisomer): 7.57 (s, 1H), 7.51 (s, 3H), 5.76 (dd, 0.5H, J = 7.4, 5.2), 4.06 (s, 3H), 4.04 (s, 3H), 3.98 (s, 3H), 3.92 (s, 3H), 2.58 (dd, 1H, J = 14.4, 7.4), 2.41 (dd, 1H, J = 14.4, 5.2), 1.32 (s, 3H), 1.10-0.81 (c, 21H). 1 3 C (minor atropisomer): 182.96, 180.7, 163.4, 159.2, 157.9, 157.8, 134.8, 134.6, 134.3, 125.6, 123.4, 120.2, 109.1, 105.2, 64.5, 64.3, 63.9, 62.8, 62.2, 56.1, 56.0, 45.2, 24.6, 18.2, 18.1, 12.6. IR: 1672. H R M S calcd for CssFL^ClOoSi [M + Na] + = 671.2419, found 671.2422. 105 1 JfUl^juJLjJll/ i 1 1 1 1 i 1 1 1 11 11 10 9 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I \u00E2\u0080\u00A2 1 1 1 1 I 1 1 ' 1 I 1 1 1 I 7 6 5 4 3 2 1 0 Scheme 80 N M R Spectra of 133 106 107 OMe O 135 A solution of 133 (84 mg, 0.13 mmol) and T B A F (1.0M in THF, 0.26 mL, 0.26 mmol) in THF (1 mL) was stirred at RT overnight, then it was diluted with aq. sat. NaHCC>3 (30 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (50 mL), dried (NaaSCu) and concentrated. Chromatographic purification of the residue (EtOAc : hexanes, 1:1) gave the alcohol 135 (58 mg, 91%) as a yellow solid. Unlike the case of 133, proton and 1 3 C N M R spectra of the present compound indicated the existence of a single species in solution. 1 H : 7.58 (s, 1H), 7.55 (s, 1H), 5.55 (td, 1H, J = 9.2, 3.1 Hz), 4.07 (s, 3H), 4.04 (s, 3H), 4.00 (s, 3H), 4.02-3.98 (m, 4H), 3.97 (s, 3H), 3.48 (c, 1H), 2.56 (dd, 1H, J = 14.8, 9.2), 2.00 (dd, 1H, J= 14.8, 3.5), 1.46 (s, 3H). 1 3 C : 182.7, 180.4, 161.8, 160.1, 159.4, 158.0, 134.9 (2 overlapping resonances), 133.3, 125.9, 123.0, 121.7, 109.9,* 105.2,* 105.1, 64.9, 64.6, 64.1, 63.4, 62.2, 57.1, 56.6, 44.8, 24.5. IR: 3520, 1671. H R M S calcd for C 2 4 H 2 5 3 5 C 1 0 9 [M + Na] + = 515.1085, found 515.1087. 108 175 150 125 100 75 50 25 Scheme 82 N M R Spectra of 135 109 110 OMe O 136 A solution of the 135 alcohol (100 mg, 0.20 mmol) IBX (114 mg, 0.40 mmol) in EtOAc (2 mL) was refluxed for 3 h, then it was cooled to RT, diluted with more EtOAc (30 mL) and washed with I M NaOH (2 x 50 mL). The organic layer was dried (Na 2S0 4) and concentrated. Purification of the residue by preparative T L C afforded 136 (90 mg, 90%) as a yellow solid. 7.59 (s, 1H), 7.55 (s, 1H), 4.08 (s, 3H), 4.02 (s, 3H), 3.98 (s, 3H), 3.94 (c, 4H), 3.91 (s, 3H), 3.18 (s, 2H), 1.54 (s, 3H). 1 3 C : 199.6, 182.5, 179.8, 160.0, 159.6, 159.0, 158.2, 136.2, 133.2, 132.9, 126.2, 122.6, 121.6, 107.9, 105.4 (two overlapping resonances), 64.8, 64.0, 62.1, 57.2, 56.7, 52.9, 29.9. IR: 1718, 1672. H R M S calcd for C24H 23 3 5C10 9 [M + H ] + = 491.1109, found 491.1106. I l l iii , il iii il, L 200 175 150 125 100 75 50 25 Scheme 84 N M R Spectra of 136 112 Scheme 85 IR Spectra of 136 113 OMe O OMe O 138 A solution of ketone 136 (17 mg, 0.035 mmol) in cone. HBr (48%, 1 mL) and acetic acid (1.5 mL) was refluxed overnight., then it was concentrated to give crude topopyrone B (13 mg, quantitative), which without further purification was suspended in dry CH2CI2 (0.8 mL) and treated with solid Meerwein's salt (30 mg, 0.2 mmol) while stirring at RT for 2h. The mixture was partitioned between EtOAc (10 mL) and sat. NaHCOs aq. (10 mL). The organic layer was dried (Na 2S0 4) and concentrated. Purification of the residue by preparative T L C (4% MeOH in D C M containing 0.5% triethylamine) gave pure 138 (3.0 mg, 30%) as a yellow solid. This material produced ' H and 1 3 C N M R spectra in complete accord with the literature (values in brackets, ref. 8). * H : 8.00 [8.00] (s, 1H), 7.59 [7.59] (s, 1H), 6.16 [6.16] (s, 1H), 4.13 [4.13] (s, 3H), 4.08 [4.08] (s, 3H), 4.04 [4.05] (s, 3H), 2.38 [2.38] (s, 3H). 1 3 C : 181.9 [181.7], 179.7 [179.5], 176.4 [176.2], 165.0 [164.8], 162.5 [162.3], 160.2 [160.0], 159.7 [159.5], 158.2 [158.0], 136.9 [136.7], 133.2 [133.0], 126.3 [126.1], 124.8 [124.6], 123.7 [123.5], 122.9 [122.7], 113.2 [113.0], 112.9 [112.6], 105.1 [104.9], 64.1 [63.9], 62.3 [62.1], 57.2 [57.0], 20.2 [20.0]. IR: 1734, 1673. H R M S calcd for C 2 1 H i 5 3 5 C 1 0 7 [M + H ] + = 415.0585, found 415.05. 114 1 1 1 1 1 1 1 1 , , , 1 1 , 10 9 i i | i i 8 i i 1 i i 7 , , , , , , , , i , , , 6 5 1 1 1 1 1 1 ' 4 3 2 . I I I 0 I ' 1 ' ' I ' ' ' 1 I ' 1 ' 1 I 1 ' 150 125 100 75 Scheme 86 N M R Spectra of 138 115 21.74 I , , , , , , , , , , , 4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600.0 cm-1 Scheme 87 IR Spectra of 138 116 "@en . "Thesis/Dissertation"@en . "2006-11"@en . "10.14288/1.0061130"@en . "eng"@en . "Chemistry"@en . "Vancouver : University of British Columbia Library"@en . "University of British Columbia"@en . "For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use."@en . "Graduate"@en . "Total synthesis of topopyrones B and D : novel topoisomerase I inhibitors"@en . "Text"@en . "http://hdl.handle.net/2429/18371"@en .