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Total synthesis of topopyrones B and D : novel topoisomerase I inhibitors Tan, Jason Samuel 2006

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T O T A L SYNTHESIS OF TOPOPYRONES B A N D D: N O V E L TOPOISOMERASE I INHIBITORS  by JASON SAMUEL T A N  A THESIS SUBMITTED LN P A R T I A L F U L F I L L M E N T OF T H E REQUIREMENTS FOR T H E D E G R E E OF  M A S T E R OF SCIENCE  in  T H E F A C U L T Y OF G R A D U A T E STUDIES (Chemistry)  T H E UNIVERSITY OF BRITISH C O L U M B I A  October 2006 © Jason Samuel Tan, 2006  ABSTRACT  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.  ii  T A B L E OF CONTENTS  Abstract Table of Contents List of Schemes Table of Abbreviations  1. T O T A L 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  iii  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 Methyl Ester  9  2  Scheme 7: Synthesis of Chrysophanol  10  Scheme 8: Synthesis of Averufin  11  Scheme 9: Directed ortho Metallation  12  Scheme 10: Breakdown of R - L i 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  vi  T A B L E OF ABBREVIATIONS  Ac  acetyl  Aq.  aqueous  Bu  butyl  Calcd.  calculated  Cone.  concentrated  DCM  dichloromethane  DMAP  4-dimethylaminopyridine  DMF  N, Af-dimethylformamide  DMSO  dimethylsulfoxide  DNA  deoxyribonucleic acid  Et  ethyl  HMBC  Heteronuclear Multiple Bond Correlation  IBX  iodoxybenzoic acid  LAH  lithium aluminum hydride  LiTMP  lithium 2,2,6,6-Tetramethylpiperidide  Me  methyl  MOM  methoxymethyl  NBS  N-bromosuccinimide  NCS  /V-chlorosuccinimide  NMR  nuclear magnetic resonance  Py  pyridine  Sat.  saturated  TBAF  tetrabutylammonium fluoride  TBS  r-butyldimethylsilyl  TFAA  trifluoroacetic anhydride  THF  tetrahydrofuran  TIPS  triisopropylsilyl  TLC  thin layer chromatography  vii  TMEDA  N, N, N', /V'-tetramethylethylenedi amine  TMS  trimethylsilyl  Ts  tosyl  viii  T O T A L 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. They are responsible for 1  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, but selective inhibition of topo-I is 3  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): topotecan 4  (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. Several other camptothecin derivatives are in clinical trials. 5  6  The success of CPT derivatives as chemotherapy agents has promoted the search of other, non-CPT, topo-I inhibitors. An interesting development in this area is the recent 7  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 and 8  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 0.10 ng/mL). 50  O  O  1 topopyrone A X = CI  3 topopyrone B  2 topopyrone C X = H  4 topopyrone D X = H  Compound  I C (ng/mL)  Topopyrone A  1.22  Topopyrone B  0.15  Topopyrone C  4.88  Topopyrone D  19.63  Camptothecin  0.10  X = CI  50  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, 863; (b) Ishiyama, D.; Kanai, Y.; Senda, H.; Iwatani, W.; Takahashi, H.; Konno, H.; Kanazawa, S. /. Antibiot. 2000, 53, 873.  3  53,  Our laboratory cultivates a long-standing interest in topo-I inhibitors. The 9  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 B a c k g r o u n d  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 dissertation and in a poster presentation. The isolation paper indicates that the 10  11  8  "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  OMeO  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. A classical 12  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). Such difficulties lead to the 13  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. A n ordinary Friedel-Crafts cyclization produces anthraquinone regioisomer 12. However, cyclization of 11 to spirocyclic intermediate 14 may also occur. 12Thomson, R. H., Naturally Occuring Quinones III: Recent Advances; Chapman and Hall: New York, Hayashi, M. J. Chem. Soc. 1927, 2516. 6  1987.  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 obenzoylbenzoic 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).  14  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 i 0 (57%, a-b); c. A c 0 ; d. 80 ° C ; e. S i 0 (55%, d-e); f. AICI , NaCl (69%). 2  2  2  3  Scheme 5: Synthesis of Ceroalbolinic A c i d  Cameron, D. W.; Conn, C ; Feutrill, G. I.  Aust. J. Chem. 8  1981,  34,  1945.  Danishefsky's total synthesis of Vineomycinone B2 methyl ester is another demonstration  of the  Diels-Alder  approach  to  (Scheme  anthraquinones  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 ° C (-HCI, -TMSOMe); c. Mel (71% a-c) d. PdCI (MeCN) (95%); 2  e. benzene, reflux; f. Mel (79%).  Scheme 6: Synthesis of Vineomycinone B Methyl Ester 2  Danishefsky, S. J.; Uang, B. J.; Quallich, G. J.  J. Am. Chem. Soc. 9  1985, 707, 1285.  2  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).  Michael addition of phthalide 31 to cyclohexenone 32  16  gave intermediate 33 which was eventually advanced to 35.  O  O  34  35  a. f-BuOLi (80%); b. NBS, Et N (68%); c. BBr 3  3  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). Thus, exposure of a mixture of 17  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 \ 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. 6  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  OMOM  MOMO  O L  j  OMOM  a.  0  MOMO  +  MOMO'  36  37 MOMO  OLi  RO  OMOM  O  OR  MOMO  40  .  / 41 R = MOM * 42 R = H  a. LiTMP, then air (0 ) (35%); b. 5% HCI aq., MeOH (80%). 2  Scheme 8: Synthesis of Averufin  Another regioselective route to anthraquinones relies on directed ortho metalation (DoM) technology. This method permits selective deprotonation of aromatic rings at the 18  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.  11  a. R-Li (R = n-Bu, s-Bu, f-Bu), additive = T M E D A , solvent = T H F or E t 0 Z = C O N R , C O N H R , CONH(Cumyl), C S N H R , 2-oxazolino, 2-imidazolino, C F , CH=NR, ( C H ) N R n = 1, or 2, C H O H , N M e , N H C O R , N H C 0 R , O M e , O C H O M e , OCH(Me)OEt, OCONR OSEM, OP(0)NR , S 0 N R , S0 NHR, S 0 R . 2  2  2  n  3  2  2  2 )  2  2  2  2  2  2  2  2  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. This is exemplified in Scheme 19  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 less basic  kinetically more basic  kinetically most basic  Scheme 10: Breakdown of R - L i 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 DMG's.  20  The technique is demonstrated in the synthesis of soranjidiol, 52, (Scheme 21  11). Reaction of ort/io-lithiated benzamide 47 with benzaldehyde 48 provided hydroxyamide 49, which upon treatment with acid lactonized to phthalide 50. FriedelCrafts cyclization afforded anthrone 51 in 71% yield. Oxidation and demethylation provided anthraquinone 52 (70% yield). A n 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. C r 0 , HOAc; e. pyHCI (70%). 3  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). This 22  process involves the merger of an ort/io-lithiated benzamide 53 with  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  an o-  bromobenzaldehyde 54 to give intermediate 55, which is treated in situ with additional RL 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  OMe  59 R = H  60 R = CI  61 R = H T I P S  62 R =  HO'  ^  ^  O 5 X = HorCI  ^  0  H  Scheme 13: Improved Synthetic Strategy  15  ^  0  I O  f~\ 0 v /  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 and 23  Broering, respectively, as shown in Scheme 14. 24  OMe  OMe  OMe  MeO 63 R = COCI 59 R = CONEt  " ^ 6 1 X = Br  2  a. Et NH, toluene, 0 °C(89%); b. Br , AcOH, r.t. (90%) 2  2  Scheme 14: Synthesis of Amide 59 and Aldehyde 61  Benzamide 59 was o-lithiated (s-BuLi/TMEDA/THF/-78 °C; 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 fourcenter 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 .  25  This event would be accelerated by the presence of T M E D A in the medium.  OH  HO  O  a.  Ph  OH 70  69  OH O  OH O  O  Ph  73 a. montmorillonite K-10, nitrobenzene, 120 ° C , (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). The authors of this work reported a straightforward route 26  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,  Lee, 5. M ; Tseng, T. H.; Lee, Y. J. Synthesis. 2001,15, 2247.  18  37,  560.  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 2butynoyl chloride 76 and montmorillonite K-10 in nitrobenzene failed to generate any of the desired pyrone 4, even after heating at 130 °C overnight. Only starting 74 was recovered from these attempts. O X' OR  O  OR  75 X = OH  OH  O  OH O  76 X = CI  c. _ r$ R = Me -74 R = H  a (  a. 4 8 % HBr, AcOH, reflux (76%); b. SOCI , DCM; c. Montmorillonite K-10, nitrobenzene, 76, 130 2  °C.  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. Et N, EtOAc, then 76; b. Montmorillonite K-10, nitrobenzene, 130 ° C . 3  Scheme 18: Unsuccessful Fries Rearrangement  This reluctance of 74 toward electrophilic substitution has also been observed in connection with the synthesis of averufin 42. Castonguay and Brassard thoroughly 27  investigated the functionalization of C-2 in systems of type 74 under a variety of FriedelCrafts 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. NaHC0 , 90 °C (6.5%). 3  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 aldehyde 85. The latter was prepared in 3 steps from ethyl 28  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 ° C (90%); c. (COCI) , DMSO, DCM, -78 ° C , then Et N, r. t. (91%). 2  3  Scheme 20: Synthesis of Aldehyde 85  The arylmetallic agent that would add to 85 may be the recently described dianion 86, which is prepared by deprotonation of 86 by use of so-called "super base " 29  30  (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  a. ?-BuOK, n-BuLi, THF, -78 ° C ; b. 85, THF, -78 ° 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  88  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 tBuOLi 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 tBuOK, followed by addition of aldehyde 85. A n alternative approach involving lithiumbromine 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  O  a.( •89 R = H 90 R = f-Bu  91  a. H S 0 , M g S 0 , /-BuOH, DCM, r.t. (26%); b. f-BuLi, THF, -78 ° C ; c. 85. 2  4  4  Scheme 22: Synthesis of 92  31Finnegan, R. A. Tetrahedron Lett.  1963, 429.  23  O  92  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. B H S M e , THF, 40 ° C ; b. imidazole, DMAP, TBSCI, DCM, r.t. (quantitative a - b); c. f-Bul_i, THF -78 ° C , then 85 (67% of 95). 3  2  Scheme 23: Synthesis 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).  95 OTBS  97  OTBS  98  a. NBS, C H C N , r.t. 3  Scheme 24: Bromination of 95  24  OTBS  99  The formation of 98 is clearly due to an ipso substitution, which may be 32  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 N B S oxidation of the benzylic alcohol and deketalization of 99 by traces of H B r present in the medium. Oxidations of 1° and 2° alcohols to aldehydes or ketones by NBS are not uncommon.  33  They are believed to proceed via a hypobromite intermediate 102, which undergoes 1,2elimination of HBr (Scheme 26). The HBr thus released could be responsible for loss of the ketal.  —C-OH  101  —C^OxBr  102  C=0  103  Scheme 26: Oxidation of Alcohols by NBS J. Am. Chem. Soc. 1971, 93, 3389. Chem. Rev. 1963, 63, 21; (b) for a recent example see: Lee, J. G ; Lee, J. Y.; Lee, J. M. Synth Commun. 2005, 35,  Perrin, C. L.; Skinner, G. A. 1911.  (a) Filler, R.  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  TIPS  s  95  62  o f 107 R = TBS, X = H •1108 R = TBS, X = Br C  'V109 R = H, X = Br  a. imidazole, DMAP, TIPSCI, DMF, r.t. (94%); b. NBS, C H C N , r.t.; c. TBAF, THF, r.t. 3  (quantitative  b-c); d. (COCI) , DMSO, DCM, -78 ° C , then Et N (81%). 2  3  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.  TIPS OMe b  OMe O  f~}  Q  0  b.  59  MeO'  TIPS OMe 0 J  TIPS OMeb  v  OMe O  MeO  OMe O  ^  MeO  a. s-BuLi, TMEDA, THF, -78 °C, then 62; b. f-BuLi, -78 °C - r.t., then H 0, 0 2  Scheme 29: Synthesis of Anthraquinone 111  28  2  (17% of 111 a-b).  114-115  intractable mixtures containing no desired product  a. s-BuLi, TMEDA, THF, -78 ° C , then 62 (70%);b. H 0 ; c. IBX, C H C N , reflux (83%); d. 2  3  imidazole, DMAP, TIPSCI, DMF, r.t. (74%); e. H O C H C H O H , p-TsOH, benzene, reflux dean2  2  stark; f. f-BuLi, THF, -78 ° C .  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 O H 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, I B X 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 C N delivered ketone 118 in 88% yield. Finally, 3  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, C H C N , reflux (88%); c. 4 8 % HBr, AcOH, reflux (quantitative); d. pyridine, AC2O, r.t. 3  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 NMR  experiment,  which showed J correlations of the C-3 carbon with the A  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 C NMR spectra of free topopyrone D in a solution of DMSO - d , see experimental. 1 3  6  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 D M G s and metallation of anisoles via D o M are well known. Furthermore, chloro susbtituents are 35  generally regarded as compatible with metallation reactions, and may themselves behave as D M G ' s .  36  Consequently, the presence of a CI atom in 124 was not anticipated to be  problematic.  OMe O CI MeO'  \  60  OMe  o  CI  NEt,  MeO  cr  120  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 lithiumbromine exchange of 126 followed by addition of the aryllithium intermediate to N,Ndiethyl carbamoyl chloride, 121. Compound 126 was prepared from commercial 2chlororesorcinol 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 C 0 , Mel, acetone, r.t.; NBS, CH CN, r.t. (89%); c. (COCI) , DMF, 0 ° C , then H 0 , 50 ° C 2  3  3  2  2  (30%); d. s-BuLi, THF, -78 ° C , then 121 or C 0 ; e. f-BuLi, THF.-78 ° C , then 121 (20%). 2  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  SO2CI2  preferentially chlorinated the less hindered C-5 position of 2,4-dimethoxybenzaldehyde 127.  33  a. or b.  a. NCS, DCM, r.t.; b. S 0 C I , DCM, r.t. 2  2  Scheme 34: Chlorination of 127  One  report  demonstrated  the  regioselective  C-3  chlorination of  2,4-  dihydroxybenzaldehyde with NaOCl under basic conditions (Scheme 35). Application 37  of this method to substrate 129 furnished 123 in quantitative yield.  0-Methylation  followed by oxidation of the aldehyde to carboxylic acid 125 (NaC10 ) proceeded 38  2  efficiently. Transformation of 125 to amide 60 was effected by treatment with  SOCI2  followed by E t N H . Although this less direct approach required more steps, gram scale 2  quantities of 60 was effortlessly prepared in excellent overall yield.  OR a.  O  CN  br  1 2 9  1 2 3  M30  125  R  =  60  H  R = Me  a. NaOCl, KOH, H 0 , r.t. (quantitative); b. K C 0 , Mel, acetone, reflux (85%); c. NaCI0 , 22  2  3  2  methyl-2-butene, N a H P 0 buffer (pH = 3.5), f-BuOH, H 0 r.t. (90%); d. SOCI , benzene, reflux, 2  4  2  then Et N, 0 ° C (76%). 2  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  2  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 °C). 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 °C were likewise fruitless. Temperatures higher than 0 °C promoted dechlorination of 60. Furthermore, reaction of T H F 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 C D O D ) after three hours at -78 °C. 3  OMe O —Jc-^  60  ^^pV^NEts  60  M e O ^ ^ D 131 a. 5 eq. s-BuLi, 5 eq. TMEDA, THF, -78 ° C - 0 ° C , then C D O D b. 1 eq. f-BuLi, 1 eq. TMEDA, 3  THF, -78 ° C , then CD OD. 3  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.  39  Cf. Langer, P.; Freifeld, I.  Synlett.  2001, 4, 523.  35  39  Furthermore, explanations involving sequestration of the base by chelation/coordination  40  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, ' even though the triad of adjacent methoxy groups 4  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. Sibi, M. P.; Jalil Miah, M . A.; Snieckus, V. / Org. Chem. 1984, 49, 737.  36  Ed. 2004, 43, 2206.  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 monomethyl 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, C H C N , reflux (90%); c. 48% HBr, AcOH, reflux. 3  Scheme 38: Synthesis of Topopyrone B  37  The addition of a phase transfer catalyst had no effect on the reaction. The 42  monomethyl ether persisted even after refluxing a solution of 136 in aq. cone. HBr / A c O H 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  3  +  OMe O  137 O  138 Procedure (a.)  Yield 138  K C 0 , Mel, acetone, reflux, 48 h  none  C s C 0 , Mel, DMF, 45 ° C , 48 h  none  C H N , Et 0, r.t., 48 h  trace  A g 0 , Mel, DCM, reflux, 48 h  30%  M e 0 B F , DCM, r.t., 2 h  95%  2  3  2  3  2  2  2  2  3  4  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 engendered extensive decomposition. 43  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-C H3 P(C H )3Br, reflux  3 and 137  TMS-I, CHCI , reflux  decomposition  16  3  4  9  3  i) BBr , DCM, -78 ° C - 0 ° C ; 3  ii) 48% HBr, AcOH, reflux  Scheme 40: Deprotection of 136  Jung, M . E.; Lyster, M . A. J. Org. Chem. 1977,42, 3761  39  3  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,  CH2CI2,  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 C1 . 2  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 / M e O H 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  3  O  OAc  CI  a.  O b.  3 AcO' O 140  a. pyridine, A c 0 , r.t.; b. K C 0 , MeOH. 2  2  3  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 S A R 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  EXPERIMENTAL SECTION  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  Ill  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 ) were from thin films -1  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 T H F (freshly distilled from Na/benzophenone under Ar) and C H C 1 (freshly distilled from C a H under 2  2  2  Ar). Commercial rc-BuLi was titrated against N-benzylbenzamide in T H F at -78 °C 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 A r in flame or over dried flasks equipped with Teflon™ 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»H 0 (6.5 g, 34.2 mmol) in benzene (1000 mL; C A U T I O N : 2  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 S0 ), filtered and concentrated to afford the ketal ester 83 (120.5 g, 90%) as a 2  4  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). C : 1 3  169.2, 107.4, 64.5, 60.2, 44.0, 24.2, 13.9. IR: 1747. H R M S calcd for C H 0 [M + Na] = 197.0790, found 197. +  8  1 4  4  45  I  II  1  1  1  1  I  1  1  1  1  10  I  1  9  1  1  1  I  __J  1  1  8  1  1  I  1  1  1  7  1  I  1  1  1  6  1  I  1  I ,  U  1  1  5  '  I  1  1  1  4  I  1  I  1  1  1  1  3  I  1  1  1  2  I  U  1  I  1  1  1  1  L  —I—i—i—i—i—|—i—i—i—i—j—i—i—i—i—|—i—i—i—i—|—i—i—i—i—|—i—i—i—i—|—  175  150  125  100  75  Scheme 42 N M R Spectra of 83  46  50  1  25  I  0  47  A solution of the above ketal ester 83 (9.0 g, 51.7 mmol) in dry T H F (20 mL) was added dropwise to a cold (-5 °C; ice-NaCl bath) suspension of L A H (1.97 g, 51.7 mmol) in dry T H F (80 mL). The reaction mixture was stirred at 0 °C 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 gas). The organic layer was separated and the aqueous layer was 2  extracted with E t 0 (2 x 50 mL). The combined organic layers were washed with brine 2  (100 mL), dried (Na S0 ) and concentrated to give alcohol 84 (6.2 g, 91%) as a colorless 2  4  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 H 0 [M + Na] = 155.0684, found 155.0683. +  6  ] 2  3  48  "T" 175  150  125  100  Scheme 44 N M R Spectra of 84  49  25  50  O H  ^ 85  Dry D M S O (2.79 mL, 39.3 mmol) was added dropwise to a cold (-78 °C) 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 °C 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 °C for 30 min, then Et3N (16.9 mL, 121 mmol) was added. The mixture was stirred at -78 °C for 5 min then it was allowed to warm to R T 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).  13  C : 200.3, 107.6, 64.8, 52.2, 24.9.  IR: 1724. HRMS calcd for C H O [M + Na] = 153.0528, found 153.05. +  6  1 0  3  51  I II  1  1  1  1  I 10 1  1  1  1  I  1  1  1  9  1  I  1  1  1  1  8  7  6  '  '  ' '  I ' ' 5  '  '  I 4  l..>„M,l.,.l  1  1  1  1  i  1  200  n  |  3  2  ,».,!»  I  I  < >  ]—l—l—l—l—|—l—l—l—l—|—l—l—I—I—|—I—I—I—I—|—I—I—l—I—|—I—I—I—r—f T—1—I—r-  175  150  125  100  75  50  Scheme 46 N M R Spectra of 85  52  25  I  I  |  1  I  I  I  !  |  0  Scheme 47 IR Spectra of 85  53  OMe O  59  Diethylamine (7.12 mL, 68.5 mmol) was carefully added to a cold (0 °C) solution of 2,4-dimethoxybenzoyl chloride (4.58 g, 22.8 mmol) in dry toluene (70 mL), and the mixture was stirred at 0 °C 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 (50 mL). The organic layer was washed successively with I M HC1 3  (50 mL), H 0 (50 mL), and brine (50 mL), dried (Na2S0 ) and concentrated to give pure 2  4  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. HRMS  calcd for C H 1 3  3 5 1 8  C 1 N 0 [M + Na] = 294.0873, found 294.0870. +  3  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 0 (15 mL), followed by commercial bleach.containing 6% NaOCl (21 mL, 16 mmol). 2  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 (Na S04) and concentrated. Purification by flash chromatography (EtOAc:hexanes, 1:1) 2  gave pure aldehyde 123 (2.4 g, quantitative) as a white solid, m.p. 146-148 °C (no m.p. was recorded in the literature).  * H (acetone-6f ): 9.80 (s, 1H), 7.60 (d, 1H, / = 6  1 3  8.8), 6.75 (d, 1H, / =  8.8).  C : 197.1, 162.5, 161.6, 135.5, 117.1, 110.5, 109.1.  IR:  1634.  H R M S  calcd for C H 7  35 5  C 1 0 [M + H ] = 173.0005, found 173.0007. +  3  57  100  50  r~  —  25  Scheme 50 N M R Spectra of 123  58  77.9  cm-1  Scheme 51 IR Spectra of 123  59  OMe O  130  Neat M e l (7.9 mL, 127 mmol C A U T I O N : toxic, volatile, cancer suspect agent) was added at R T 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 °C (lit. 109-111 °C). 1  45  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 H 9  35 9  C 1 0 [M + H ] = 201.0318, found 201.0317. +  3  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 (80%, 1.4 g, 12.3 mmol) in a N a H P 0 buffer (pH 3.5, 50 2  2  4  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 6 M HC1 (5 mL) and extracted with EtOAc (2 x 40 mL). The combined extracts were dried (Na S0 ) and concentrated to give pure 125 (2.0 g, 90%) as a white solid. 2  4  m.p. 168-170 °C. * 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.  IR:  1695.  H R M S  calcd for C H 9  35 9  C 1 0 [M + Na] = 239.0087, found 239.0089. +  4  63  '  I  200  1  1  1  '  I  1  175  —I  150  1  1  1  -  125  1  100  1  1  I 75  Scheme 54 N M R Spectra of 125  64  1  I ' 50  1  1  1  I  25  '  H  4000.0  :  1  1  •  1  1  1  1  1  .  1  3600  3200  2800  2400  2000  1800 cm-1  1600  1400  1200  1000  Scheme 55 IR Spectra of 125  65  1—  800  OMe O  Thionyl chloride added to a solution o f  (1.0  13.8  mL,  mmol;  CAUTION: corrosive, toxic) w a s carefully  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 ; C A U T I O N : c a n c e r  suspect agent) a n d the m i x t u r e w a s refluxed 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 g a s ) . T h e m i x t u r e w a s t h e n c o o l e d t o 0 °C p r i o r t o 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 diethylamine  (7.65  mL,  73.6  mmol) in dry benzene  (10  m L  CAUTION: cancer suspect  a g e n t ) . 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 h e n i t w a s w a s h e d w i t h I M a q . (2  x  50  m L ) , dried  (Na2S04)  a n d concentrated.  r e c r y s t a l l i z e d ( E t O A c : h e x a n e s , 1:1)  T h e residue  t o a f f o r d p u r e 60 (1.9  g , 76%)  o f crude  NaOH  amide  was  as t a n c r y s t a l s .  m.p. 70-72 °C. *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 1 3  (q,  2H, 7 = 7.3), 1.24  (t,  3H, J= 7.3), 1.02  (t,  3H, J= 7.3).  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. HRMS calcd for C i H 3  3 5 1 8  ClN0  3  [M +Na]  +  = 294.0873,  66  found  294.0870.  I  1  1  1  II  1  I  1  1  1  10  ~i—i—i  i 175 1—i  1  I  1  1  1  1  I  1  9  1 i—r  1  1  I  1  1  i  150  1  1  1  1  I  1  1  7  8  1  1  1  i  1  1  I  1  6  Scheme 56  1  I  1  1  1  1  5  1  125  1  -i  100  1  I  1  1  4  i  i  1  I  1  3  i-  75  N M R Spectra of 6 0  67  1  1  1  1  !  1  1  1  2  — j — i  50  1  1—i  1  25  1  I 1  1—i  0  r-  68  OMe  94a  Commercial BH3»SMe solution (36.3 mL, 0.38 mol) was added dropwise to a 2  solution of 3,5-dimethoxy-4-bromobenzoic acid (50.0 g, 0.19 mol) in dry T H F (600 mL). The mixture was stirred at 40 °C overnight, then it was quenched with I M aq. HC1 (200 mL. C A U T I O N : evolution of highly flammable H gas) and the volatiles were removed 2  in vacuo. The aqueous residue was extracted with EtOAc (3 x 200 mL), and the combined extracts were dried (Na S04) and concentrated to give the pure alcohol 94a (47 2  g, quantitative) as a white solid.  m.p. 100 - 102 °C (lit. 100-102 °C).*  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 H 9  7 9 n  B r 0 [M + Na] = 268.9789, found 268.979. +  3  Inoue, I. W O 2003072536 A l 2003.  69  -i  200  175  1  1  r  125  100  Scheme 58 N M R Spectra of 94a  70  50  68.6] 4000.0  ,  ,  ,  ,  ,  3600  3200  2800  2400  2000  ,  ,  ,  1800  1600  1400  cm-1  Scheme 59IR Spectra of 94a  71  , I 1200  ,  ,  ,  1000  800  600.0  A solution of the alcohol 94a (47.0 g, 0.19 mol), imidazole (25.9 g, 0.38 mol), 4D M A P (1.8 g, 15 mmol), and TBSC1 (30.1 g, 0.20 mol) in dry C H C 1 (400 mL) was 2  2  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 (Na S04) and concentrated, and the residue was purified by flash 2  chromatography (hexanes -> EtOAc:hexanes, 1:1) to afford silyl ether 94 (68 g, quantitative) as a waxy solid.  m.p. 34 - 36 °C. . 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 H 5  7 9 2 5  B r 0 S i [M + Na] = 383.0654, found 383.0655. +  3  72  JL  j . i  11  1  1  1  1  i  1  10  *  1  1  i  '  9  1  1  1  i  1  1  '  1  8  i  1  7  150  1  1  1  i  6  125  '  1  1  1  i  1  5  100  1  1  1  i  1  1  4  1  1  i  1  1  1  3  75  i  1  1  1  1  2  50  Scheme 60 N M R Spectra of 94  73  1  25  i  1  1  1  1  JI  i  1  0  1  4000.0  1 3600  1  3200  1  2800  1 2400  1  2000  1 1800 cin-1  1  1600  1 1400  Scheme 61 IR Spectra of 94  74  1  1200  1  1 1000  1 800  1 600.  95  A pentane solution of r-BuLi (1.45M 10.5 mL, 15.2 mmol) was added dropwise to a cold (-78 °C) solution of 94 (2.5 g, 6.9 mmol) in dry T H F (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 °C 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 i H 0 S i [M + Na] = 435.2179, found 435.2178. +  2  3 6  6  75  II  10  I  I  Scheme 62 N M R Spectra of 95  76  1  0  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 f o r . C s o B f o A ^ [M+ Na] = 591.3513, found 591.3518. +  78  175  150  125  100  75  Scheme 64 N M R Spectra of 107  79  50  25  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 C N (20 3  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 (Na SC>4) and concentrated to give pure 108 (4.0 g, quantitative) as a colorless 2  oil. Proton and C N M R spectra indicated that this material exists as a ca. 4:1 mixture of 1 3  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, 1 H , 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 C oH550 BrSi [M + Na] = 669.2618, found 669.2614. 79  3  6  +  2  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 S0 ) and concentrated to give 109 (3.2 g, quantitative) as a 2  4  colorless oil. Proton and C N M R spectra indicated that this material exists as a ca. 4:1 1 3  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 4 H 4 i B r 0 S i [M + Na] = 555.1753, found 555.1755. 79  2  +  6  84  LLJJLJI  175  150  125  100  Scheme 68 N M R Spectra of 109  85  »•' H 4000.0  1  3600  .  3200  •  .  2800  .  2400  1  2000  1  1800 cm-1  1  1600  1  1400  Scheme 69 IR Spectra of 109  86  1  1200  1  1000  1  800  1  600.0  TIPS  Dry D M S O (0.35 mL, 4.8 mmol) was cautiously added to a cold (-78 °C) 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 °C 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 °C for 1 h. Triethylamine (2.1 mL, 14.8 mmol) was injected and the mixture was stirred at -78 °C 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 4H39 Br0 Si [M + Na] = 553.1597, found 553.1596. 79  2  +  6  87  ULJLLI.  Scheme 70 N M R Spectra of 62  88  1  4000.0  1  3600  1  3200  I  2800  1  2400  1  2000  1  1800 cin-1  •  1  1  1  1  1  1  1600  1400  1200  1000  800  600.0  Scheme 71IR Spectra of 62  89  A solution of benzamide 59 (200 mg, 0.86 mmol) in dry T H F (2 mL) was added to a cold (-78 °C) solution of s-BuLi (0.68 mL, 0.90 mmol) and T M E D A (0.14 mL, 0.95 mmol) in dry T H F (4 mL), followed, after 3 h, by a solution of 62 (460 mg, 0.86 mmol) in dry T H F (2 mL). The mixture was stirred for 1 h, then f-BuLi (1.32 m L of 1.45M pentane solution 1.9 mmol) was added. The reaction was stirred at -78 °C for 2 h and allowed to warm to R T 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 C N M R spectra indicated that this material exists as a 1 3  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.  0U*. 175  150  125  100  75  Scheme 72 N M R Spectra of 111  92  ~1~ 50  '•°H 4000.0  1 3600  1 3200  1 2800  1 2400  1  1  2000  1800 cm-1  1 1600  1  1400  Scheme 73 TR Spectra of 111  93  •  1 1200  1  .  1  1000  800  600.  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 T H F (0.5 mL) was stirred at RT overnight, then it was diluted with aq. sat. NaHCC»3 (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). 13  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  )LL_JUUI  175  150  125  100  75  Scheme 74 N M R Spectra of 117  95  50  25  71.8: 4000.0  ,  ,  ,  ,  ,  ,  ,  3600  3200  2800  2400  2000  1800 cm-1  1600  , I 1400  Scheme 75 IR Spectra of 117  96  ,  ,  ,  ,  1200  1000  800  600.0  OMe O 118  A mixture of the 117 (7.0 mg, 0.015 mmol) and I B X (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 C N M R spectra of 118 indicated the existence 1 3  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). 13  C: 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  Scheme 76 N M R Spectra of 118  98  50  25  58  4000.0  3600  3200  2800  2400  2000  1800 cm-1  1600  1400  Scheme 77 TR Spectra of 118  99  1200  1000  800  600  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 0 (10 mL) and extracted 2  with EtOAc (2 x 40 mL). The combined extracts were washed with brine (50 mL), dried (Na S0 ) and concentrated to give fully synthetic topopyrone D (5 mg, quantitative) as 2  4  an orange solid.  *H (DMSO-J ): 7.55 (s, 1H), 7.07 (d, 1H, J = 2.3), 6.60 (d, 1H, J = 2.3), 6.52 (s, 1H), 6  2.47 (s, 3H). 1 3  C (DMSO-rf ): 185.4, 182.1, 180.8, 169.9, 164.6, 164.45, 164.41, 164.0, 159.1, 138.1, 6  134.0, 113.5, 110.4, 110.0, 108.7, 107.6, 106.6, 20.0.  100  I—  —\— 150  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). 13  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]. HRMS  calcd  for  C 4H O 2  1 6  1 0  [M  +  102  Na]  +  =  487.0641,  found  487.0645.  I II  1  1  1  1  I 6  I 10  175  150  125  I  I  I  I  100  I 5  I  I  I  I  I '  I  '  I  4  75  Scheme 79 N M R Spectra of 119  103  I 3  I  I  50  I  I  I 2  '  I  1  I 1  1  25  1  1  1  ' I 0  OMe O 133  A solution of 60 (0.20 g, 0.74 mmol) in dry T H F (1 mL) was added to a cold (-78 °C) 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 T H F (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 °C, then it was allowed to warm to RT overnight, and finally it was quenched with H 0 (lmL) and 2  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 (Na SC>4) and concentrated. Chromatographic purification of the 2  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. HRMS  calcd  for  CssFL^ClOoSi  [M + Na]  105  +  = 671.2419,  found  671.2422.  1 i 11  1  1  1  1  i  1  10  1  1  1  I  1 9  7  1  1  1  1  I  1  1  1  JfUl^juJLjJll/ 1  I  6  1  1  5  1  1  I •  1  1  1  1  I  1  4  Scheme 80 N M R Spectra of 133  106  1  3  '  1  I  1  1  I  1  2  1  0  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 T H F (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. HRMS  calcd  for  C H 5 C10 35  24  2  9  [M +  108  Na]  +  =  515.1085,  found  515.1087.  175  150  125  100  75  Scheme 82 N M R Spectra of 135  109  50  25  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 S0 ) 2  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. HRMS  calcd  for  C24H 3 C10 35  2  9  [M +  Ill  H]  +  =  491.1109,  found  491.1106.  iii 200  175  , 150  il  iii  il,  125  100  L 75  Scheme 84 N M R Spectra of 136  112  50  25  Scheme 85 IR Spectra of 136  113  OMe O  OMe O  138  A solution of ketone 136 (17 mg, 0.035 mmol) in cone. H B r (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 R T for 2h. The mixture was partitioned between EtOAc (10 mL) and sat. NaHCOs aq. (10 mL). The organic layer was dried (Na S0 ) and concentrated. 2  4  Purification of the residue by preparative T L C (4% M e O H in D C M containing 0.5% triethylamine) gave pure 138 (3.0 mg, 30%) as a yellow solid. This material produced ' H and C N M R spectra in complete accord with the literature (values in brackets, ref. 8). 1 3  * 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.  HRMS  calcd for C H i 2 1  3 5 5  C 1 0 [M + H ] = 415.0585, found 415.05. +  7  114  1 1 1  1  1  1  1 10  1  ,  ,  ,  1 1 9  ,  i  i  |  i  i  8  I '  150  i  i  1 i 7  1  i  ,  ,  ,  ' ' I' ' ' 125  ,  ,  ,  ,  ,  6  i  , ,  5  1  I'  100  1  '  1  ,  1 4  1  1  1  1  I ' 1  75  Scheme 86 N M R Spectra of 138  115  1  3  2  '  .  I  I  I  0  21.74  4000.0  I  3600  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  3200  2800  2400  2000  1800  1600  1400  1200  1000  800  600.0  cm-1  Scheme 87 IR Spectra of 138  116  

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