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Efforts toward the total synthesis of mitomycins Vialettes, Anne 2009

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EFFORTS TOWARD THE TOTAL SYNTHESIS OF MITOMYCINS  by ANNE VIALETTES Ingénieur de l’École Supérieure de Chimie, Physique Électronique de Lyon, spécialité: Chimie - Chimie des Procédés, 2007   A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENT FOR THE DEGREE OF  MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Chemistry)   THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  May 2009 © Anne Vialettes, 2009 ii  ABSTRACT  This thesis describes our efforts toward the total synthesis of mitomycins. The centerpiece of our route to the target molecule is a homo-Brook mediated aziridine fragmentation, developed in our laboratory. The aziridine moiety of the target molecule was installed through an intramolecular iodoamidification of an olefin. The crystalline triazoline intermediate, available before the homo-Brook rearrangement, was obtained after Reetz allylation on an aldehyde followed by a intramolecular 1,3-diploar cycloaddition of an azido unit onto a terminal olefin. The aldehyde intermediate was synthesized in 9 steps involving a Mitsunobu reaction, a Claisen rearrangement and a Lemieux-Johnson oxidation from readily commercially available products. iii  TABLE OF CONTENTS  ABSTRACT .................................................................................................................................... ii TABLE OF CONTENTS.................................................................................................................. iii LIST OF FIGURES.......................................................................................................................... v LIST OF SCHEMES........................................................................................................................ vi LIST OF ABBREVIATIONS ............................................................................................................ ix ACKNOWLEDGMENTS ................................................................................................................ xv INTRODUCTION............................................................................................................................. 1 1. Isolation and structure determination ................................................................................... 2 2. Biological activity................................................................................................................. 4 3. Previous syntheses .............................................................................................................. 10 3.1 Kishi’s synthesis of MC............................................................................................ 10 3.2 Fukuyama’s synthesis of MC ................................................................................... 14 3.3 Danishefsky’s synthesis of mitomycin K ................................................................. 17 3.4 Jimenez’s synthesis of mitomycin K ........................................................................ 19 3.5 Fukuyama’s synthesis of FR-900482 ....................................................................... 21 3.6 Danishefsky’s synthesis of FR-900482 .................................................................... 24 3.7 Terashima’s synthesis of FR-900482 ....................................................................... 27 3.8 Martin’s formal synthesis of FR-900482.................................................................. 31 3.9 Williams’ synthesis of FR-900482 ........................................................................... 33 3.10 Fukuyama’s synthesis of FR-900482 ..................................................................... 36 3.11 Ciufolini’s synthesis of FR-66979.......................................................................... 39 iv  3.12 Ciufolini’s synthetic studies on mitomycins........................................................... 42 STUDIES TOWARDS THE TOTAL SYNTHESIS OF MITOMYCINS................................................... 47 1. Our retrosynthetic approach ............................................................................................... 47 2. Synthesis of aldehyde 214 .................................................................................................. 49 2.1 Synthesis of phenol 46.............................................................................................. 49 2.2 Preparation of diols 223 and 229 .............................................................................. 50 2.3 Mitsunobu reaction and Claisen rearrangement ....................................................... 51 2.4 Protection of hydroquinones 234 and 235 ................................................................ 52 2.5 Synthesis of aldehydes 201 and 214 ......................................................................... 53 3. Synthesis of benzazocenols 249 and 211............................................................................ 56 3.1 Allylation of aldehydes 201 and 214 ........................................................................ 56 3.2 Synthesis of triazolines 203 and 245 ........................................................................ 57 3.3 Molecular nitrogen extrusion and homo-Brook rearrangement ............................... 59 4. Synthesis of aziridine 209................................................................................................... 62 REFERENCES .............................................................................................................................. 64 APPENDIX (EXPERIMENTAL SECTION) ...................................................................................... 70 v  LIST OF FIGURES  Figure 1: General structures of mitomycinoids ............................................................................ 1 Figure 2: The mitomycinoids family ............................................................................................ 2 Figure 3: Relative stereochemistry of 181.................................................................................. 41 Figure 4: Steric shielding of the free OH in 227 ........................................................................ 51 Figure 5: Cyclization of side products 240 and 241 ................................................................... 55 Figure 6: Diastereoisomeric mixtures of 243 and 244................................................................ 57 Figure 7: ORTEP of triazoline 203............................................................................................. 58 Figure 8: ORTEP of triazoline 245............................................................................................. 59  vi  LIST OF SCHEMES  Scheme 1: Interconversion of mitomycins ................................................................................... 3 Scheme 2: Mitomycin solvolysis in acidic media ........................................................................ 4 Scheme 3: Mechanism of activation of MC ................................................................................. 7 Scheme 4: MC-DNA adducts formed via different alkylation pathways..................................... 8 Scheme 5: Kishi’s retrosynthetic analysis of MC....................................................................... 11 Scheme 6: Synthesis of diols 43 and 49 ..................................................................................... 12 Scheme 7: Synthesis of 8-membered ring compound 41 ........................................................... 13 Scheme 8: Kishi’s synthesis of MC............................................................................................ 13 Scheme 9: Rearrangement of MC............................................................................................... 14 Scheme 10: Fukuyama’s retrosynthetic analysis of MC ............................................................ 14 Scheme 11: Synthesis of chalcone 57......................................................................................... 15 Scheme 12: Synthesis of compound 55 ...................................................................................... 16 Scheme 13: Fukuyama’s synthesis of MC.................................................................................. 17 Scheme 14: Danishefsky’s retrosynthetic analysis of mitomycin K .......................................... 18 Scheme 15: Danishefsky’s synthesis of mitomycin K ............................................................... 19 Scheme 16: Jimenez’s retrosynthetic analysis of mitomycin K ................................................. 20 Scheme 17: Jimenez’s synthesis of mitomycin K ...................................................................... 21 Scheme 18: Fukuyama’s retrosynthetic analysis of FR-900482 ................................................ 22 Scheme 19: Synthesis of 8-membered ring compound 86 ......................................................... 23 Scheme 20: Fukuyama’s synthesis of FR-900482...................................................................... 24 Scheme 21: Danishefsky’s retrosynthetic analysis of FR-900482 ............................................. 25 Scheme 22: Synthesis of intermediate 100 ................................................................................. 25 vii  Scheme 23: Danishefsky’s synthesis of FR-900482 .................................................................. 26 Scheme 24: Terashima’s retrosynthetic analysis of FR-900482 ................................................ 27 Scheme 25: Synthesis of oxazolidine 115 .................................................................................. 28 Scheme 26: Synthesis of aromatic intermediate 114 .................................................................. 29 Scheme 27: Synthesis of 8-membered ring intermediate 112 .................................................... 30 Scheme 28: Terashima’s synthesis of FR-900482...................................................................... 30 Scheme 29: Martin’s retrosynthetic analysis of FR-900482 ...................................................... 31 Scheme 30: Synthesis of diene 141 ............................................................................................ 32 Scheme 31: Synthesis of Fukuyama’s intermediate 97 .............................................................. 32 Scheme 32: Synthesis of enantiopur nitrobenzene 143 .............................................................. 33 Scheme 33: Synthesis of oxazolidinones 145 and 146 ............................................................... 33 Scheme 34: Williams’ retrosynthetic analysis of FR-900482 .................................................... 34 Scheme 35: Synthesis of aziridine 150 ....................................................................................... 34 Scheme 36: Synthesis of 8-membered ring compound 161 ....................................................... 35 Scheme 37: Williams’ synthesis of FR-900482 ......................................................................... 36 Scheme 38: Fukuyama’s retrosynthetic analysis of FR-900482 ................................................ 37 Scheme 39: Synthesis of ketone 172 .......................................................................................... 37 Scheme 40: Synthesis of 8-membered ring intermediate 165 .................................................... 38 Scheme 41: Fukuyama’s synthesis of FR-900482...................................................................... 39 Scheme 42: Ciufolini’s retrosynthetic analysis of FR-66979..................................................... 40 Scheme 43: Synthesis of aldehyde 182 ...................................................................................... 40 Scheme 44: Synthesis of azido alkene 181................................................................................. 40 Scheme 45: Synthesis of benzazocenol 178 ............................................................................... 41 Scheme 46: Ciufolini’s synthesis of FR-66979 .......................................................................... 42 viii  Scheme 47: Retrosynthetic analysis of mitomycin A................................................................. 43 Scheme 48: Formation of mitomycin core 196 .......................................................................... 44 Scheme 49: Synthesis of triazoline 203...................................................................................... 44 Scheme 50: Synthesis of benzazocenol 208 ............................................................................... 45 Scheme 51: Retrosynthetic analysis of MC................................................................................ 48 Scheme 52: Structural analogy between 218 and 219 ................................................................ 48 Scheme 53: Retrosynthetic analysis of 214 ................................................................................ 49 Scheme 54: Synthesis of phenol 46 ............................................................................................ 49 Scheme 55: Monoprotection and reduction of 2-butyne-1,4-diol 226 ....................................... 50 Scheme 56: Monoprotection of cis-2-butene-1,4-diol 230......................................................... 51 Scheme 57: Mitsunobu reaction ................................................................................................. 52 Scheme 58: Claisen rearrangement ............................................................................................ 52 Scheme 59: Protection of hydroquinones 234 and 235 .............................................................. 53 Scheme 60: Synthesis of anilines 237 and 238........................................................................... 54 Scheme 61: Synthesis of azides 200 and 239 ............................................................................. 54 Scheme 62: Synthesis of aldehydes 201 and 214 ....................................................................... 55 Scheme 63: Allylation of 201 and 214 ....................................................................................... 56 Scheme 64: Synthesis of crystalline triazolines 203 and 245..................................................... 58 Scheme 65: Mechanism of cyclization of 202 and 213 .............................................................. 59 Scheme 66: Synthesis of aziridines 204 and 212........................................................................ 60 Scheme 67: Synthesis of benzazocenols 249 and 211................................................................ 61 Scheme 68: Cbz protection of 249 and 211................................................................................ 61 Scheme 69: Synthesis of benzazocenone 209 ............................................................................ 62 Scheme 70: Transformation of 209 into a mitomycin ................................................................ 63 ix  LIST OF ABBREVIATIONS  Å angstrom Ac acetyl AIBN azobisisobutyronitrile Alloc allyloxycarbonyl aq. aqueous br broad Bn benzyl Boc tert-butyloxycarbonyl BOM benzyloxy methyl BOSM based on starting material recovery Bu butyl Bz benzoyl °C degrees Celsius calcd calculated CAN ceric ammonium nitrate cat. catalytic Cbz benzyloxycarbonyl cf. confer (Latin) cm−1 wavenumber(s) conc. concentrated CSA camphorsulfonic acid Cy cyclohexyl x  δ chemical shift in parts per million downfield from tetramethylsilane d doublet DABCO 1,4-diazabicyclo[2.2.2]octane DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC 1,3-dicyclohexylcarbodiimide DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DEAD diethyl azodicarboxylate DEIPS diethylisopropylsilyl DET diethyl tartrate DIAD diisopropyl azodicarboxylate DIB diacetoxyiodobenzene DIBAL diisobutylaluminium hydride DMAP 4-dimethylaminopyridine DMDO dimethyldioxirane DME dimethoxyethane DMF N,N-dimethylformamide DMP Dess-Martin periodinane DMS dimethyl sulfide DMSO dimethyl sulfoxide DNA deoxyribonucleic acid DPPA diphenylphosphoryl azide ee enantiomeric excess ESI electrospray ionisation Et ethyl xi  g gram(s) gem geminal hex hexane HMDS hexamethyldisilazane HMPA hexamethylphosphoramide HRMS high resolution mass spectrum Hz Hertz i iso IBX iodoxybenzoic acid IC50 median inhibitory concentration IR infrared J coupling constant LAH lithium aluminum hydride LDA lithium diisopropylamide m meta m multiplet M molar (moles per litre); mega MC mitomycin C m-CPBA m-chloroperbenzoic acid Me methyl mol mole(s) MOM methoxymethyl mp melting point ms molecular sieves xii  Ms mesyl MS mass spectrometry n normal NBS N-bromosuccinimide NMO N-methylmorpholine-N-oxide NMR nuclear magnetic resonance Nu nucleophile o ortho ORTEP Oak Ridge Thermal Ellipsoid Plot p para PCC pyridinium chlorochromate PDC pyridinium dichromate PG protecting group Ph phenyl PMB p-methoxybenzyl PMP p-methoxyphenyl ppm parts per million PPTS pyridinium p-toluenesulfonate Pr propyl psi pounds per square inch py pyridine q quartet quant. quantitative RCM ring-closing metathesis xiii  RNA ribonucleic acid rRNA ribosomal ribonucleic acid RT room temperature s secondary s singlet sat. saturated t tertiary TASF tris(dimethylamino)sulfonium difluorotrimethylsilicate TBAF tetra-n-butylammonium fluoride TBDPS tert-butyl-diphenylsilyl TBS tert-butyl-dimethylsilyl TES triethylsilane Tf triflate TFA trifluoroacetic acid THF tetrahydrofuran TIPS triisopropylsilyl TLC thin layer chromatography TMEDA N,N,N’,N’-tetramethyl-1,2-ethylenediamine TMS trimethylsilyl tol toluene TPAP tetrapropylammonium perruthenate Troc 2,2,2-trichloroethoxycarbonyl Ts p-toluenesulfonyl UV ultra-violet xiv  μ micro xv  ACKNOWLEDGMENTS  I want to formally express my gratitude towards Pr. Marco A. Ciufolini, my supervisor, for allowing me to join his research group and to thank him for guidance on my research project. I would like to thank the members of the Ciufolini Research Group, past and present, for their friendship and insightful discussions and advice. Specials thanks go to Bryan, David, Dylan, Jean-Christophe, Myriem and Steven. 1  INTRODUCTION  Mitomycins are structurally unique, naturally occurring anticancer antibiotics first isolated in the mid 1950’s.1, 2 These highly functionalised natural products display exceptional potency and retain activity against tumors resistant to other antineoplastic agents.3 The most active member of the family, mitomycin C (hereafter also referred to as MC, 2) is effective against a broad range of solid tumors and it has been used clinically in cancer chemotherapy since the 1970’s.4 The mitomycinoids family was enlarged in the late 1980’s with the discovery of structural related compounds with similar bioactivity, the so-called FR-mitomycinoids (Figure 1).5 Some of the latter compounds have been the subject of pre-clinical studies in Japan.6  Figure 1: General structures of mitomycinoids  The unique biological properties of mitomycinoids as well as their highly functionalised structures have generated considerable interest in both the biomedical and the chemical fields.7 Innovative synthetic methodologies have been developed to solve the chemical challenges associated with the structural fragility of mitomycinoids.8 Our laboratory recently accomplished the total synthesis of FR-66979.9 Those results induced us to explore an extension of the methodology devised for that purpose to the synthesis of the mitomycins.  2  1. Isolation and structure determination  Mitomycins proper may be divided into two structural groups: the A and B series, depending on the relative configuration of the aziridine moiety and the C9 side chain (Figure 2). Mitomycins A, 1, and B, 9, were isolated in 1956 by Hata and co-workers, at the Kitasato Institute in Japan, from fermentation cultures of the microorganism Streptomyces caespitosus.1 Two years later, MC, 2, was obtained from the same culture broth by Wakaki and co-workers at the same institute.2 Porfiromycin, 3, was discovered a few years later as a metabolite of Streptomyces ardus.10 In 1981, Urakawa and co-workers discovered mitomycin H, 7, in Tokyo, Japan.11 In 1987, a scientific team at Fujisawa Pharmaceuticals isolated two compounds structurally related to the mitomycins from Streptomyces sandaensis No. 6897, the mitomycinoids FR-900482, 14, and FR-66979, 15.5 Subsequently, Uchida and co-workers at the same institute synthesized FK-973, 16, a derivative from FR-900482, 14.  Figure 2: The mitomycinoids family  3  More than 20 years after their first discovery, the correct absolute configuration of mitomycins was established in 1983 by Hirayama and co-workers based on the analysis of the X-ray crystallographic data of 2-N-(p-bromobenzoyl) mitomycin C.12 All natural mitomycins have the same C1 and C2 absolute configurations. Therefore, the biosynthetic paths are thought to be the same for all mitomycins, with only the last steps of the synthesis to differentiate them.13 Mitomycin A, and C (1 and 2) differ only by substituent X on the quinone moiety and can undergo facile interconversion:14 basic hydrolysis of MC followed by methylation produces mitomycin A, and treatment of mitomycin A with methanolic ammonia gives back MC (Scheme 1).15 Mitomycins A and C (1 and 2) give, respectively, mitomycin F and porfiromycin (4 and 3) by methylation of the aziridine functionality. Mitomycins G, H and K (6, 7 and 8) are formal derivatives of the mitomycin series A, and arise from the elimination of the carbamate group at C10 in basic media.16 Mitomycins B, and D, (8 and 9) have the opposite configuration at C9 compared to the A series.17 Base-promoted epimerisation at C9 yields 9-epi-mitomycins B and D, which display a higher antimicrobial activity than their parent compounds.18  Scheme 1: Interconversion of mitomycins  4  Mitomycins are fairly stable in basic media but highly reactive under acidic conditions. In dilute aqueous acid (0.05−0.1 N HCl), they undergo facile elimination of methanol to yield unstable aziridinomitosene 18 (Scheme 2).14 This species undergoes facile nucleophilic aziridine opening at C1 with retention of configuration. Thus, aqueous acid hydrolysis furnishes the cis-aminohydrin 19, as the predominant product.19 Such unusual stereochemical outcomes may be due to the hydrogen bound created between the nitrogen of the aziridine and water, thus directing its addition from the top face. Exceptions were found in the methanol / acetic acid or Dowex / methanol solvolysis of MC, the major product being the trans-methoxy amine.20 After longer exposure to mild acidic media, the C7 substituent suffers hydrolysis to give the 7- hydroxyquinone, 20. Carbamate hydrolysis can also happen under stronger acidic conditions.  Scheme 2: Mitomycin solvolysis in acidic media  2. Biological activity  MC has been used as an anticancer agent since 1974.21 It is an important component of combination chemotherapy for breast, lung and prostate cancer. It is also one among the few drugs effective against colorectal cancer. MC is the drug of choice for intravesical administration in superficial bladder cancer4 and is also the single most active agent for treatment of non small-cell lung cancer.22 However, it is no longer used for brain, stomach and 5  pancreatic cancer because of side effects that appear at high concentrations (myelosuppression and hemolytic-uremic syndrome).4 Other mitomycinoids also display cytotoxic properties. Mitomycins B and F (9 and 4) are strongly active against murine tumors, but they are inappropriate for human use because of their significant side effects.23 FR-900482, 14, has shown equal or superior activity to MC on numerous tumor cells.24 It is effective against P388 cancer cells (MC resistant) and shows less toxicity than MC on hematologic studies on mice.25 FR-mitomycinoids seem to be good replacement candidates for MC; however they still display noticeable secondary effects. In addition to antitumor activity, MC exhibits a variety of biological effects in mammalian cells or microorganisms, including inhibition of DNA synthesis, mutagenesis, stimulation of genetic recombination, chromosome breakage, sister chromatid exchange and induction of DNA repair (SOS) response in bacteria.26  In 1963, studies of the molecular pharmacology of MC revealed an extraordinary property of this class of antitumor antibiotic: MC and other members of the mitomycinoid family were found to cross-link complementary strands of the DNA double helix.27 This is so lethal that a single crosslink is sufficient to cause the death of a bacterial cell. Mono-functional alkylation of DNA by mitomycins, i.e. attachment of the drug molecule to only one DNA strand, also accompanied the cross-linking.28 No other natural antibiotic works in this way, with the possible exception of azinomycins29 and bioxalomycin,30 although in both cases the evidence for cross-linking with DNA are still preliminary and the experiments were conducted in vitro with purified or synthetic DNA.  6  Structurally, MC contains three elements that are fundamental for its biological activity: the quinone that can participate in free radical reactions generating superoxide, and the aziridine and carbamate functions that can take part in DNA alkylation. However, neither MC nor its derivatives are reactive towards DNA at pH 7-8.27, 31 The DNA cross-linking and alkylating activities require the reduction of the quinone, which triggers a cascade of chemical events that transform the drug into a highly reactive alkylating agent.32 Quinone reduction in vivo is probably mediated by enzymatic33 and / or metabolic34 processes, but although several enzymes are known to reduce mitomycins, the biological agent responsible for the process in vivo remains unknown. Quinone reduction by electrochemical35 or chemical methods36 also converts mitomycins to potent DNA alkylating agents.  A mechanism for the activation of mitomycins upon reduction of the quinone was proposed in 1964 by Iyer and Szybalski.32 Their proposal envisioned that reduction of MC releases the N4 lone pair of electrons from vinylogous amide resonance with the quinone (Scheme 3, path 1).37 Originally, it was thought that this enables the expulsion of methoxide from C9a, under physiological conditions, to form iminium ion 23, which spontaneously rearranges into leuco-aziridinomitosene 26. Important work by Danishefsky subsequently demonstrated that reduced mitomycins are relatively stable.38 However, they can readily undergo 1-electron oxidation to semiquinone 24, which appear to be the species from which methanol is lost to give the leuco-aziridinomitosene 26 (Scheme 3, path 2).39 The driving force for methanol elimination is believed to be the formation of an aromatic indole system, 25. 7   Scheme 3: Mechanism of activation of MC  Leuco-aziridinomitosene 26 is the active species formed in vivo. Its oxidation can lead to aziridinomitosene 27 (Scheme 4, path 1). Protonation of the latter on its most basic site, the aziridine, induces DNA alkylation, providing monoadduct 29. The extremely electron-rich indole nucleus of 26 can also promote fragmentation of the aziridine ring to produce the unstable vinylogous quinone methide 30, which is highly electrophilic at the C1 position.40 Deprotonation of 30 can yield intermediate 31 (path 2), which equilibrate to 2,7-diaminomitosene, 2,7-DM, 32. Reduction of 2,7-DM to the hydroquinone restored the electron-rich character of the indole nucleus, which now favours expulsion of the carbamate moiety. The resultant 34 is now electrophilic at C10, and it can react with DNA, leading to DNA-monoadduct 35.41 Vinylogous quinone methide 30 can also undergo reaction with a guanine base of DNA at C1 to form adduct 36 (path 3). As for 33, the expulsion of the carbamate moiety is now favoured. The resultant electrophilic carbon C10 of 37 can react with water, leading to decarbamoyl DNA-monoadduct 38 (path 3a). 37 can also react at C10 with another guanine unit from the same DNA strand or from another one, to give the doubly alkylated adducts 39 and 40 (bisalkyation, path 3b). The latter is the most often observed MC-DNA alkylation pathway.40 8   Scheme 4: MC-DNA adducts formed via different alkylation pathways  Early molecular modeling studies indicated that, like most natural antibiotics covalently targeted at DNA, the mitomycin residues are located in the minor groove, both in the 9  monoadduct42 and in the cross-linked adduct43 forms, causing little perturbation in the structure of the duplex DNA. In the case of monoadduct 29, the mitomycin residue is lying inside the slightly widened minor groove, resulting in extensive non-covalent contacts between the drug and the DNA duplex. The indoloquinone ring system is found to be stacked on one side of the duplex along the backbone of the non-bonding strand.44 In the case of intra-strand cross-link adduct 39, the DNA structure exhibits a small bending angle.45 No DNA bending was detected with the monoadducts 29 and 38, nor with the inter-strand cross-link adduct 40.  The reactivity of guanines of double-stranded DNA with MC varies with their sequence context. Guanines in CpG sequence are highly preferred sites of the first mono-alkylation step compared with the other three dinucleotide sequences.46 The selectivity of the first step, though not absolute, is crucial for successful cross-linking and for the biological activity of MC. It requires not only a CpG sequence on the target strand, but also a guanine residue on the opposite strand: the 2-NH group of the opposite-strand guanine activates MC and this non- covalent bond increases the rate of formation of the covalent bond with the target guanine.44 The second alkylation step, i.e. the guanine-to-guanine cross-linking action of MC, is absolutely specific for the duplex DNA sequence CpG-CpG.47 This is due to a specific, unique alignment of the guanine monoadduct in the minor groove, to form the cross-link at CpG-CpG without significant structural reorganisation of the DNA.48 The pre-covalent sequence selectivity described above is thus a mechanism to ensure that MC monoalkylates only those guanines that will allow cross-linking. As a result, MC has only minimal reactivity at the non- cross-linkable guanine sites (ApG, TpG, and GpG), but exhibits maximal reactivity at CpG- guanine sites, where the lethal cross-links are allowed to form subsequently.49 10  3. Previous syntheses  Immediately after the structural elucidation of mitomycins in 1962, these highly- functionalised natural products have generated intense efforts in the synthetic arena. After five decades of extensive research, more than 1000 MC derivatives have been synthesized and efforts towards the total synthesis of mitomycinoids and related compounds are still being conducted.50 Interest in these molecules is motivated not only by their noteworthy biological properties, but also by their intricate and highly functionalised structures. The remarkable concentration of sensitive functionalities display on such a small carbon framework has continuously proven to be a tremendous challenge for the synthetic chemist and has led to the development of innovative new methodologies.8, 14  3.1 Kishi’s synthesis of MC  The first total synthesis of MC, 2, was accomplished by Kishi and co-workers in 1977.51 The tetracyclic mitomycin core was obtained by transannular cyclization of 41 in acidic medium (Scheme 5). Intramolecular Michael addition onto the quinone provided the 8- membered ring 41. The aziridine was introduced from diol 43, which arose from nitrile 44 in 11steps including a selenium oxidation and an osmylation reaction. Nitrile 44 was easily synthesized from 2,6-dimethoxytoluene 45.  11   Scheme 5: Kishi’s retrosynthetic analysis of MC  Commercially available 2,6-dimethoxytoluene 45, gave phenol 46 in 3 steps in very good yield (Scheme 6). Alkylation of phenol 46 followed by Claisen rearrangement52 introduced the alkyl side chain on 47. Oxidation to the p-quinone followed by acetic / zinc reduction and protection gave protected hydroquinone 47. The terminal alkene was oxidized of to the epoxide and acetonitrile was added. Jones oxidation,53 followed by aldol reaction with formaldehyde, introduced the carbamate side chain precursor on 44. Protection of the alcohol allowed the transformation of the ketone into the thioketal (the nitrile group was also transformed into the thioiminoether at that stage). The nitrile group was re-established, a change of protected groups occurred and the dimethyl thioketal group was then converted to the dimethyl ketal, yielding 48. Introduction of a trans-double bond at the α position of the nitrile, conversion of the latter to the acetate, and osmylation of the alkene yielded diols 43 and 49 in a 1:1 ratio.  12   (a) Cl2CHOMe, TiCl4, CH2Cl2, 0°C; (b) m-CPBA, CH2Cl2, 0°C; (c) NaHCO3, MeOH, 0°C (98% over 3 steps); (d) allyl bromide, K2CO3, acetone, reflux; (e) N,N-dimethylaniline, reflux (96% over 2 steps); (f) 70% HNO3, AcOH, RT; (g) Zn, AcOH, 0°C; (h) BnBr, K2C03, DME, DMF, reflux (67% over 3 steps); (i) H2O2, K2CO3, C6H5CN, MeOH, dioxane, RT (77%); (j) LDA, MeCN, −30°C; (k) CrO3,  H2SO4, acetone, H2O, RT (72% over 2 steps); (l) (CH2O)3, MeONa, MeOH, THF, 0°C (69%); (m) Ac2O, py, 0°C; (n) MeSH, BF3 AcOH, −30°C; (o) Et3N, MeOH, RT (70% over 3 steps); (p) MeONa, MeOH, CH2Cl2, RT; (q) BnBr, KH, DMF, RT; (r) HgCl2, Et3N, MeOH, THF, RT (85% over 3 steps); (s) i)LDA, THF, −78°C; ii) PhSeBr, THF, −78°C; iii) H2O2, AcOEt, THF, RT; (t) DIBAL, CH2Cl2, 0°C; (u) NaBH4, MeOH, CH2Cl2, 0°C; (v) Ac2O, py, RT (66% over 4 steps); (w) OsO4, py, THF, RT (37%). Scheme 6: Synthesis of diols 43 and 49  Diol 43 was isolated by chromatography and converted into epoxide 50 in 3 steps in very good yield (Scheme 7). Opening of the epoxide with lithium azide was followed by the mesylation of the two hydroxy groups and selective substitution of the primary mesylate by benzylamine. Further benzylation of the amine gave compound 51. Reduction of the azide precipitated SN2 closure of the aziridine leading to 42. The sensitive aziridine was protected with a 3-acetoxypropyl group introduced by a Michael reaction with acrolein, reduction of the aldehyde to the alcohol, and acetylation. Catalytic hydrogenolysis of the benzyl groups on palladium on carbon furnished a hydroquinone, which was readily oxidized by air to the quinone. The latter underwent a Michael addition with a primary amine to form 8-membered ring intermediate 41. 13  a - c h - j 50 d - g 51 k - o 41 42 43 BnO BnO MeO OAc BnO OH OH OMe OMe BnO BnO MeO NBn2 BnO OMe OMe NH O O MeO OH OMe OMe N(CH2)3OAc N H BnO BnO MeO OH BnO OMe OMe O BnO BnO MeO NBn2 BnO OMs N3 OMe OMe  (a) MsCl, Ph3N, CH2Cl2, 0°C; (b) NaH, DMF, RT; (c) MeONa, MeOH, CH2Cl2, RT (93% over 3 steps); (d) LiN3, DMF, 150°C; (e) Ms2O, py, 0°C to RT; (f) BnNH2, 150°C; (g) BnBr, K2CO3, acetone, reflux (51% over 4 steps); (h) P(OMe)3, THF, reflux; (i) NaH, THF, RT (81% over 2 steps); (j) LiAlH4, Et2O, 0 °C (90%); (k) acrolein, CH2Cl2, RT; (l) B2H6, CH2Cl2, THF, −78°C to RT; (m) Ac2O, py, RT (78% over 3 steps); (n) H2, Pd/C, AcOH, RT; (o) air, MeOH, RT (48% yield over 2 steps). Scheme 7: Synthesis of 8-membered ring compound 41  Tetrafluoroboric acid treatment of 41 in dichloromethane allowed transannular cyclization (Scheme 8). Introduction of the carbamate was followed by aziridine deprotection in 3 steps: the acetyl group was hydrolyzed and the resulting alcohol was oxidized by a Pfitzner-Moffat reaction54 that liberated the acrolein after a retro-Michael reaction. Mitomycin A, 1, thus obtained, was then treated in ammonia to give MC, 2.55  a) HBF4, CH2Cl2, RT (77%); (b) COCl2, N,N-dimethylaniline, CH2Cl2, RT; (c) NH3, CH2Cl2, 0°C (84% over 2 steps); (d) MeONa, MeOH, CH2Cl2, RT; (e) DMSO, DCC, TFA, py, RT; (f) HClO4, N,N-dimethylaniline, CH2Cl2, RT (35% over 3 steps). Scheme 8: Kishi’s synthesis of MC  Kishi and co-workers accomplished the first total synthesis of racemic MC, 2, in 45 steps in 0.06% overall yield. 14  3.2 Fukuyama’s synthesis of MC  Fukuyama’s approach56 was inspired by the so-called mitomycin rearrangement, which comports the equilibration of MC, 2, with isomitomycin C, 53, via albomitomycin C, 52 (Scheme 9). The three compounds transpose through sequential Michael and retro-Michael reactions. MC, 2, is the favoured component of the equilibrium.57  Scheme 9: Rearrangement of MC  Isomitomycin A, 54, was synthesized by the aminolysis of 55 followed by aromatic oxidation to the quinone (Scheme 10). Tetracyclic compound 55 emerged upon intramolecular [3+2] cycloaddition of the azide to the double bond of the lactone in 56, followed by spontaneous molecular nitrogen loss of the intermediate triazoline. A 1,4-Mukaiyama type addition of a siloxyfuran to chalcone 57 gave 56. Chalcone 57 was easily synthesized from 2,6- dimethoxytoluene 45. MeO OMe N3 OTMS Ph O O SEt OBn MeO OMe 54 55 56 45 O MeO O N OCONH2 NH OMe H H OBn MeO OH N OCONHCOCCl3 O SO2Et H H OAc OBn MeO OMe N3 57 Ph O MC O O H2N N NH OMe OCONH2 2  Scheme 10: Fukuyama’s retrosynthetic analysis of MC  15  Chalcone 57 was prepared in 13 steps and in 64% overall yield (Scheme 11).58 Friedel- Crafts type acylation59 of 2,6-dimethoxytoluene 45 followed by Baeyer-Villiger oxidation60 of the resulting aldehyde and methanolysis gave phenol 46. Acetylation of 46 allowed the nitration of the aromatic ring without oxidation of the electron-rich aromatic nucleus to the quinone. Hydrolysis of the acetyl group and catalytic hydrogenolysis of the nitro group gave aminophenol 58. Diazotation of the amine moiety, formation of the azide and aldolisation of the phenol with formaldehyde yielded fully substituted compound 59. Selective protection of the phenol with benzyl bromide and oxidation of the primary alcohol gave aldehyde 60, which underwent an aldol condensation with acetophenone to give highly crystalline chalcone 57.  (a) Cl2CHOMe, TiCl4, CH2Cl2, 0°C; (b) 30% H2O2, SeO2, t-BuOH, 60°C; (c) Et3N, MeOH, RT; (d) Ac2O, py, RT; (e) 90% HNO3 Ac2O, Hg(OAc)2, AcOH, 0°C; (f) 3N NaOH, MeOH, RT; (g) H2, Pd/C, EtOH, RT; (h) NaNO2, HCl, H2O, 0°C; (i) NaN3, H2O, RT; (j) 37% HCHO, KOH, t-BuOH, 80°C; (k) BnBr, K2CO3, DMF, 80°C; (l) PCC, CH2Cl2, RT; (m) PhCOMe, NaOH, MeOH, RT (64% over 13 steps). Scheme 11: Synthesis of chalcone 57  1,4-Mukaiyama type addition of siloxyfuran 61 to chalcone 57 gave intermediate 56 (Scheme 12). Subsequent intramolecular azide-olefin [3+2] cycloaddition, followed by partial reduction of the lactone to the lactol and acetylation furnished acetate 62. Oxidative cleavage of the trimethylsilyl ether on 62 was accomplished with ruthenium tetroxide generated in situ according to the Sharpless method.61 Usually, ruthenium tetroxide causes oxidation of a primary alcohol to the acid, however in the present case the oxidation stopped at the aldehyde. This could be explained by the steric hindrance around the formyl group, which disfavoured the 16  formation of the corresponding gem-diol, known to be an intermediate for the oxidation of aldehyde to acid. However, ruthenium tetroxide induced the oxidation of the ethylsulfanyl group to the corresponding sulfone. The aldehyde was then reduced to the alcohol, which was carbamoylated through reaction with N-(trichloroacetyl)isocyanate to give intermediate 55.  (a) SnCl4, py, CH2Cl2, −78°C (95%); (b) tol, 110°C (86%); (c) DIBAL, THF, −78°C; (d) Ac2O, py, RT (99% over 2 steps); (e) RuO2, NaIO4, AcOEt, H2O, RT (84%); (f) NaBH4, MeOH, RT (97%); (g) CCl3CONCO, CH2Cl2, RT (76%). Scheme 12: Synthesis of compound 55  Aminolysis of the trichloroacetyl group also released the acetyl group to give a hemiacetal, which then suffered loss of ethanesulfinic acid through spontaneous opening to corresponding keto-aldehyde 63 (Scheme 13). This reactive intermediate condensed with the methanolic ammonia present in the medium to provide an unstable 2,5-dihydroxypyrrolidine intermediate 64, which was directly reduced with sodium borohydride to give 65 selectively. Under these conditions, the hemiaminal function present in 65 survived reduction. Evidently, iminium species 66 that is involved in a reduction to 65 is significantly strained and therefore strongly disfavoured. Indeed, the subsequent formation of mixed aminal 67, which presumably arose by addition of methanol to 66, required a fairly harsh treatment of 65 with camphorsulfonic acid in methanol. Isomitomycin A, 54, was synthesized after removal of the benzyl ester and oxidation of the resulting phenol by 2,3-dichloro-5,6-dicyano-1,4- 17  benzoquinone. Treatment with saturated ammonia converted isomitomycin A, 54, into isomitomycin C, 53, which gave MC, 2, through the mitomycin rearrangement. (a) NH3, MeOH then NaBH4, RT (80%); (b) CSA, MeOH, RT (60%); (c) H2, Pd/C, EtOH, RT; (d) DDQ, acetone, H2O, −78°C (77% over 2 steps); (e) NH3, MeOH, RT (85%). Scheme 13: Fukuyama’s synthesis of MC  Ten years after Kishi’s synthesis, Fukuyama and co-workers completed the second racemic total synthesis of MC, 2, in 25 steps with a 10% yield overall.  3.3 Danishefsky’s synthesis of mitomycin K  In 1992, Danishefsky et al. introduced the first total synthesis of mitomycin K, 8.62 The terminal aziridine was introduced by cycloaddition of olefin 69 with (pheny-1-thio)methyl azide and photochemical extrusion of molecular nitrogen from triazoline intermediate 68 (Scheme 14). A Diels-Alder reaction63 between arylnitroso dienophile derived from nitroaromatic 70 and a suitable diene was followed by intramolecular rearrangement yielding tricyclic intermediate 69. Aldehyde 70 was readily available from 2,6-dimethoxytoluene 45. 18  OMe OMe MeO N OMe O N N N SPh OMe OMe MeO N OMe O HO OMe OMe MeO NO2 CHO 6968 70 OMe MeO 45 O O MeO N N OMe mitomycin K Me 8  Scheme 14: Danishefsky’s retrosynthetic analysis of mitomycin K  Reaction of aldehyde 70 with 1-methoxy-1-lithiobutadiene 7164 gave carbinol 72 (Scheme 15). Irradiation of 72 induced a photolytic redox reaction yielding nitroso intermediate 73. An intramolecular Diels-Alder-type reaction63 of the resultant nitroso with the diene generated fused oxazine intermediate 74, which suffered spontaneous photoconversion to pyrroloindoxyl 69. Allylic hemiaminal 69 was oxidized to the lactam, which underwent 1,3- dipolar cycloaddition with (phenylthio)methyl azide to give triazoline 75. The next step was a selective reduction of the lactam (in presence of a ketone) by L-selectride. Reaction of the latter wit 1,1’-thiocarbonydiimidazole in presence of 4-dimathylaminopyridine afforded thiothioxo compound 76. This was followed by a Barton deoxygenation, providing intermediate 68.Ultra- violet irradiation provoked the triazoline decomposition to give the aziridine unit and Raney nickel treatment induced the thiophenyl side chain removal, generating intermediate 77. The exocyclic olefin was introduced by Peterson reaction65 and the aromatic ring was oxidized to quinone with silver II salts, yielding mitomycin K, 8. 19  a OMe OMe MeO N OMe O HO OMe OMe MeO NO2 CHO 70 OMe OMe MeO N OMe O N N N SPh OMe OMe MeO N OMe O c - d h - i j - l 77 7569 b OMe OMe MeO N OMe O 74 O 73 OMe OMe MeO N OMe O N N N SPh 68 O O O MeO N N OMe mitomycin K Me 8 N MeO MeO MeO NO2 OH OMe MeO MeO MeO NO O OMe 72 Me OMe Li+ 71 e - f g OMe OMe MeO N OMe O N N N SPh 76 S S N N  (a) THF, −78°C (80%); (b) hυ 350nm, MeOH, RT (45%); (c) PDC, CH2Cl2, RT (65%); (d) PhSCH2N3, benzene, 80°C (90%); (e) L-selectride, THF, −78°C (77%); (f) 1,1’-(thiocarbonyl)diimidazole, DMAP, CH2Cl2, 35°C (65%); (g) Bu3SnH, AIBN, benzene, 80°C (63%); (h) hυ 254nm, benzene, RT (48%); (i) Raney Ni, H2, acetone, 60°C (70%); (j) TMSCH2Li, THF, −10°C (90%); (k) silver II pinacolate, AcONa, MeCN, H2O, RT (12%); (l) PPTS, CH2Cl2, RT (81%). Scheme 15: Danishefsky’s synthesis of mitomycin K  Danishefsky and co-workers completed the first racemic total synthesis of mitomycin K, 8, in 12 steps with a 0.2% overall yield from aldehyde 70.  3.4 Jimenez’s synthesis of mitomycin K  In 1996, Jimenmez et al. announced the second total synthesis of mitomycin K, 8.66 The construction of the exocyclic olefin from intermediate 78 was closely inspired by Danishefsky’s work (Scheme 16). The aziridine ring arose from Staudinger reduction67 of 79. The tricyclic intermediate 79 was built in 4 in steps from indoloquinone 80, readily available from dimethylanisole 81. 20   Scheme 16: Jimenez’s retrosynthetic analysis of mitomycin K  Nitration of 2,5-dimethylanisole 81 was followed by reaction with dimethyl oxalate and zinc reduction to give compound 82 (Scheme 17). Oxidation with Frémy's salt yielded indoloquinone 80, which was subsequently reduce and protected with tert-butyl-dimethylsilyl groups. Reduction with DIBAL followed by manganese dioxide oxidation transformed the ester functionality into the aldehyde 83. Reaction of 83 with dimethylvinylsulfonium iodide in the presence of sodium hydride and subsequent ring opening of the resultant tetracyclic epoxide with sodium azide and its mesylation gave 79. Oxidation of C9-C9a olefin was done with molybdenum oxide to give a diastereomeric mixture with 46% of the trans isomer, which was isolated and converted to the corresponding aziridine 84. Methylation of aziridine 84 was followed by addition of trimethylsilylmetyllithium on the ketone, same key step as in Danishefsky’s synthesis. Oxidative cleavage of tert-butyl-dimethylsilyl groups led to concomitant Peterson elimination65 and quinone formation yielding mitomycin K, 8.   21   (a) NO2BF4, CH2Cl2, 0°C to RT (75%); (b) (CO2Me)2, t-BuOK, MeOH, Et2O, tol, RT; (c) Zn, HCl, MeOH, Et2O, 0°C (47% over 2 steps); (d) Frémy's salt, Et2O, RT (90%); (e) H2, Pd/C, THF, then TBSOTf, Et3N, CH2Cl2, RT (95%); (f) DIBAL, THF, −78°C; (g) MnO2, CH2Cl2, RT (64% over 2 steps); (h) dimethylvinylsulfonium iodide, NaH, THF, 0°C to RT then NaN3, acetone, H2O (65%); (i) MsCl, Et3N, CH2Cl2, RT (90%); (j) MoO5•HMPA, MeOH, 5°C (46%); (k) PPh3, Et3N, THF, H2O, RT (70%); (l) MeOTf, py, CH2Cl2, 0°C (78%); (m) TMSCH2Li, THF, −10°C (76%); (n) PCC, CH2Cl2, 0°C (63%). Scheme 17: Jimenez’s synthesis of mitomycin K  Jimenez’s total synthesis of mitomycin K, 8, was done in 13 steps with a 1.4% overall yield from commercially available 2,5-dimethylanisole 81.  3.5 Fukuyama’s synthesis of FR-900482  The first total synthesis of (±)-FR-900482, 14 was accomplished by Fukuyama et al. in 1992.68 Their strategy involved the formation of the aziridine ring at the very end of the synthesis (Scheme 18). Tetracyclic compound 85 came from internal hemiacetalization of 86, after introduction of the C7 side chain. Epoxide 86 was derived from the corresponding alkene. Reduction of lactone 87 induced the formation the 8-membered ring structure. Lactone 87 was obtained by addition of furan 89 to aromatic aldehyde 88. 22   Scheme 18: Fukuyama’s retrosynthetic analysis of FR-900482  Aniline 90 was converted to the azide and the phenol was protected as a methoxymethyl ether (Scheme 19). Benzylic bromination followed by displacement of the bromine with p- methoxyphenol furnished ether 91. The phenolic methoxymethyl protecting group was then replaced with a benzyl ether, and the ethyl ester was converted into an aldehyde to give 88. Addition of furan 89 gave a diastereomeric mixture of reactive butenolides, which were protected through Michael addition of thiophenol, yielding intermediate 92. Acetylation and reductive removal of the benzylic acetate provided a single isomer of the azido lactone, which was further reduced to amine 87. Reduction of the lactone provided an intermediate lactol, equilibration of which with the corresponding hydroxyaldehyde set the stage for condensation with the aniline, leading to an 8-membered cyclic imine. This intermediate was further reduced with sodium cyanoborohydride and the amino alcohol was acetylated to afford compound 93. Oxidation of the sulfide and thermolysis of the resultant sulfoxide yielded benzazocine 94. Cleavage of the O-acetyl group was followed by epoxidation of the olefin and Swern oxidation69 yielding epoxy ketone 86. 23   (a) NaNO2, HCl, EtOH, H2O, 0°C then NaN3, 0°C; (b) MOMCl, i-Pr2NEt, CH2Cl2, RT (98% over 2 steps); (c) NBS, Bz2O2, benzene, reflux; (d) PMPOH, K2CO3, DMF, 70°C (47% over 2 steps); (e) TFA, CH2Cl2, RT; (f) BnCl, K2CO3, DMF, 80°C (98% over 2 steps); (g) DIBAL, CH2Cl2, −78°C (100%); (h) PCC, CH2Cl2, RT (98%); (i) 89, SnCl4, CH2Cl2, −78°C then HCl, THF, H2O, RT (96%); (j) PhSH, Et3N, CH2Cl2, RT; (k) Ac2O, py, RT; (l) TESH, BF3, Et2O, CH2Cl2, RT; (m) Zn, AcOH, Et2O, CH2Cl2, RT (47% over 5 steps); (n) DIBAL, CH2Cl2, −78°C; (o) NaBH3CN, TFA, CH2Cl2, MeOH, RT (83% over 2 steps); (p) Ac2O, py, 60°C; (q) m-CPBA, CH2Cl2, 0°C then tol, 170°C (71% over 2 steps); (r) NaOH, MeOH, RT; (s) m-CPBA, CH2Cl2, RT; (t) (COCl)2, DMSO, CH2Cl2, −78 °C then Et3N, −78 °C to RT (92% over 3 steps). Scheme 19: Synthesis of 8-membered ring compound 86  Hydroxymethylation of ketone 86 proceeded with complete diastereoselectivity to furnish 95, an unstable intermediate that was immediately reduced to the diol (Scheme 20). Selective silylation of the primary alcohol and release of the acetamide gave 96. The amine was then oxidized to the hydroxylamine, which was O-acetylated, yielding intermediate 97. Subsequent Swern oxidation69 to the ketone and cleavage of the acetate induced cyclization to hemiacetal 98. Removal of the tert-butyl-dimethylsilyl group was followed by protection of the diol as an acetonide. Opening of the epoxide with sodium azide followed by mesylation of the resultant alcohol gave compound 85. Conversion of the acetonide to the corresponding carbonate was followed by deprotection of the p-methoxyphenyl ether, oxidation of the resultant alcohol to the aldehyde, and protection thereof as a dimethyl acetal, 99. Staudinger reduction67 of the azide triggered aziridine formation. Cleavage of the aldehyde and the phenol protecting groups, followed by regioselective ammonolysis of the cyclic carbonate finally gave FR-900482, 14. 24   (a) HCHO, LiOH, THF, H2O, 0°C; (b) NaBH4, EtOH, −78°C to RT (71% in 2 steps); (c) TBSCl, imidazole, DMAP, CH2Cl2, RT (92%); (d) DIBAL, tol, −78°C (64%); (e) m-CPBA, CH2Cl2, RT; (f) Ac2O, py, RT (83% over 3 steps); (g) (COCl)2, DMSO, CH2Cl2, −78 °C then Et3N, −78 °C to RT (83%); (h) NH2NH2, MeOH, CH2Cl2, RT; (i) n-Bu4NF, THF, RT (96% over 2 steps); (j) Me2C(OMe)2, CSA, CH2Cl2, RT (100%); (k) NaN3, DMF, H2O, 125°C; (l) MsCl, Et3N, CH2Cl2, RT (89% over 2 steps); (m) TFA, CH2Cl2, RT; (n) COCl2, py, CH2Cl2, RT; (o) CAN, MeCN, H2O, RT (74% over 3 steps); (p) PCC, MgSO4, CH2Cl2, RT; (q) CH(OMe)3, CSA, MeOH, RT (76% over 2 steps); (r) PPh3, i-Pr2NEt, THF, H2O, 60°C (71%); (s) H2, Pd/C, EtOH, RT (100%); (t) HClO4, THF, H2O, RT (96%); (u) NH3, CH2Cl2, RT (95%). Scheme 20: Fukuyama’s synthesis of FR-900482  Fukuyama and co-workers accomplished the first racemic total synthesis of FR-900482, 14, in 42 steps with 0.1% overall yield.  3.6 Danishefsky’s synthesis of FR-900482  Danishefsky et al. described the second racemic total synthesis of FR-900482, 14, in 1995.70 It is the only FR-900482 synthesis that does not proceed through an 8-membered ring intermediate. Their approach involved an intramolecular Heck reaction71 to form the final cyclic structure (Scheme 21). The aziridine moiety was introduced from alkene 101. The synthesis started with a hetero Diels-Alder reaction63 between highly functionalised aromatic nitroso 102 and a suitably substituted diene 103. 25   Scheme 21: Danishefsky’s retrosynthetic analysis of FR-900482  Methyl vanillate 104 was modified in 6 steps to give the nitro aromatic system 105 (Scheme 22). Reaction of 105 with sodium iodide in dimethylformamide induced nucleophilic aromatic substitution of the triflate group, and the resultant was converted into nitrosobenzene 102. The next step was a hetero-Diels-Alder reaction63 of 102 with diene 103. This was followed by acteylation of the alcohol to yield 101. The installation of the aziridine began with osmylation of the olefin, mono-triflation of the diol, and nucleophilic substitution of the triflate with azide ion. The emerging trans-azidohydrin 106 was O-triflated as a prelude to Staudinger reduction67 of the azide. The latter triggered the ring closure of the aziridine, which was protected to furnish 100.       (a) HNO3, AcOH, 0°C; (b) LiOH, THF, H2O, RT; (c) BBr3, RT; (d) MeOH, HCl, RT; (e) NaH, BnBr, DMF, 0°C; (f) Tf2O, py, CH2Cl2, 0°C; (g) NaI, DMF, 80°C (no yield given for 7 steps); (h) SmI2, THF, −78°C then oxone, H2O, 0°C (85%); (i) 102, benzene, 80°C (80%); (j) Ac2O, py, CH2Cl2, RT (92%); (k) OsO4, Me3NO•H2O, CH2Cl2, benzene, RT (71%); (l) Tf2O, py, CH2Cl2, 0°C; (m) Bu4NN3, DMF, RT (74% over 2 steps); (n) i) Tf2O, py, CH2Cl2, 0°C; ii) PPh3, THF then NH4OH; iii) methylchloroformate, py, CH2Cl2, 0°C (72%). Scheme 22: Synthesis of intermediate 100  a - f OBn MeO2C NO2 OTf i - j g - h OMe MeO2C OH OBn MeO2C NO I HO OMOM OBn NMeO2C I O OMOM OAc 103 102 106 104 105 n OBn NMeO2C I O OMOM OAc NCO2Me 100 OBn NMeO2C I O OMOM OAc 101 k - m OH N3 26  Cleavage of the acetyl group on 100, oxidation to the aldehyde, and Wittig reaction72 furnished 107, preparing the molecule for the crucial intramolecular Heck arylation (Scheme 23).71 This key step led to intermediate 108 in 93% yield. The exocyclic olefin underwent osmylation reaction and the diol was further transformed into the oxirane, which was opened with samarium iodide to furnish 109. Hydrogenolysis cleaved the benzyl group and the two alcohols were protected as triisopropylsilyl ethers yielding compound 110. Reduction of the aromatic ester with diisobutylaluminium hydride also deprotected the aziridine. Reprotection of the aziridine was followed by oxidation of the previously formed alcohol to the aromatic aldehyde. The triisopropylsilyl ethers were cleaved and replaced with phenyl carbonate residues, leading compound 111. Removal of the methoxymethyl ether, treatment with ammonia, and cleavage of the aziridine protecting group afforded racemic FR-900482, 14. OBn N O NCO2MeMeO2C j - n OMOM O N NCO2Me OMOM OCO2PhPhO2CO OHC TIPSO N O NCO2MeMeO2C OMOMh - i OTIPS o - q 111110 108 OBn NMeO2C I O OMOM OAc NCO2Me a - c 100 OBn NMeO2C I O OMOM NCO2Me d 107 OBn N O NCO2MeMeO2C OMOM e - g OH 109 O N NH OH OCONH2OH OHC FR-900482 14  (a) K2CO3, MeOH, RT (100%); (b) (COCl)2, DMSO, CH2Cl2, −78°C then Et3N, −78 °C to RT; (c) Ph3PCH3Br, NaHMDS, THF, −20°C (75% over 2 steps); (d) Pd(PPh3)4, Et3N, MeCN, 90°C (93%); (e) OsO4, NMO, acetone, H2O, RT (90%); (f) DIAD, PPh3, THF, RT (86%); (g) SmI2, N,N-dimethylethanolamine, THF, −78°C (92%); (h) H2, Pd/C, EtOH (93%); (i) TIPSOTf, i-Pr2NEt, CH2Cl2, 0°C (98%); (j) DIBAL, hexane, CH2Cl2, −78 °C (93%); (k) N-((methoxycarbonyl)oxy)succinimide, py, RT (93%); (l) MnO2, CH2Cl2, RT (85%); (m) TBAF, THF, RT (98%); (n) PhOCOCl, i-Pr2NEt, CH2Cl2, RT (100%); (o) Ph3CBF4, 2,6-di-t-butylpyridine, CH2Cl2, 0°C to RT (75%); (p) NH3, CH2Cl2, i-PrOH, RT (80%); (q) K2CO3, MeOH, H2O, RT (76%). Scheme 23: Danishefsky’s synthesis of FR-900482  27  Three years after Fukuyama’s synthesis, Danishefsky’s racemic total synthesis of FR- 900482, 14, was accomplished in 31 steps from methyl vanillate 104. The overall yield was 3.5%, starting with nitrosobenzene 105.  3.7 Terashima’s synthesis of FR-900482  In 1996, Terashima and co-workers achieved the first enantioselective total synthesis FR-900482, 14.73 The tetracyclic structure was created by internal hemiacetalisation (Scheme 24). The 8-membered ring structure 112 was obtained by an intramolecular aldol reaction of a precursor that was assembled starting with the union of 114 with enantiopure oxazolidine 115, which was derived from L-diethyltartrate 116. The configuration of 115 served to direct the stereochemical outcome of all subsequent transformations.  Scheme 24: Terashima’s retrosynthetic analysis of FR-900482  Conventional transformations advanced L-diethyltartrate, 116, to epoxide 118, which underwent regioselective nucleophilic opening with sodium azide to give a mixture of regioisomers 119 and 120 (Scheme 25). Upon exposure of this mixture to sodium periodate, the desired azide alcohol 119 was isolated. Protection of the primary alcohol, reduction of the azide and protection of the emerging amine gave compound 122. Oxazolidine 115 was obtained after 28  sequential acetonide formation, cleavage of the p-methoxybenzyl ether, and triflation of the alcohol. OTBDPS OPMB OH NHTroc OTBDPS OTf O N Trock - l m - o 115122 CO2Et OHH CO2Et HHO OH O O OBn OH OPMB O a - c d - h i 118117 OH OPMB OH N3 119 OH OPMB N3 OH 120 j CHO OPMB N3 121 OH OPMB OH N3 119 116 L-diethyl tartrate  (a) PhCHO, p-TsOH, tol, reflux (63%); (b) LiAlH4, AlCl3, CH2Cl2, Et2O, 0°C to RT (95%); (c) Me2C(OMe)2, p-TsOH, reflux (98%); (d) NaH, PMBCl, DMF, RT (97%); (e) H2, Raney Ni, EtOH, RT (93%); (f) MsCl, Et3N, CH2Cl2, 0°C (100%); (g) conc. HCl, MeOH, RT (97%, 98% ee); (h) K2CO3, MeOH, RT (88%); (i) NaN3, NH4Cl, EtOH, reflux; (j) NaIO4, THF, H2O, RT (55% over 2 steps); (k) TBDPSCl, Et3N, DMAP, CH2Cl2, RT (91%); (l) PPh3, THF, H2O, RT then TrocCl, aq. NaHCO3, RT (98%); (m) TsOH, Me2C(OMe)2, acetone, RT (97%); (n) DDQ, CH2Cl2, H2O, RT (98%); (o) Tf2O, Et3N, CH2Cl2, −78°C (94%). Scheme 25: Synthesis of oxazolidine 115  The allyl ether of dimethyl isophthalate 123 was subjected to Claisen rearrangement,52 O-benzylation of the phenol, and ester hydrolysis to provide 124 (Scheme 26). Bromolactonisation of this intermediate furnished 125. With the two carbonyl groups thus differentiated, selective reduction of the acid function was achieved via the mixed anhydride. The corresponding primary alcohol was protected as a benzyloxymethyl ether. Reductive cleavage of the bromolactone liberated the other carboxylic acid, which underwent Curtius rearrangement74 and in situ trapping of the transient isocyanate with tert-butanol to furnish intermediate 126. Oxidative cleavage of the olefin using the Lemieux-Johnson procedure,75 gave cyclic aminal 127, which was further elaborated to yield 114. 29   (a) N,N–diethylaniline, reflux (88%); (b) BnBr, K2CO3, acetone, reflux (99%); (c) NaOH, THF, reflux (95%); (d) Br2, aq. NaHCO3, CHCl3, 0°C (72%); (e) ClCO2i-Pr, Et3N, THF then NaBH4, H2O, RT (81%); (f) BOMCl, i-Pr2NEt, CH2Cl2, RT (85%); (g) Zn, NH4Cl, EtOH, H2O, RT (81%), (h) DPPA, Et3N, t-BuOH, RT to reflux (76%); (i) OsO4, NaIO4, dioxane, H2O, RT (92%); (j) NaBH4, EtOH, RT (100%); (k) TBSCl, Et3N, DMAP, CH2Cl2, RT (97%); (l) TBSOTf, py, CH2Cl2, RT then TBAF (92%); (m) AllocCl, aq. NaHCO3, CH2Cl2, RT (98%). Scheme 26: Synthesis of aromatic intermediate 114  The coupling between 114 and 115 occurred by substitution of the triflate by the anion of 114, yielding compound 113 (Scheme 27). Simultaneous cleavage of 2,2,2- trichloroethoxycarbonyl and acetonide groups was followed by N-tosylation and O-mesylation, furnishing intermediate 128. Treatment with sodium hydride induced aziridine cyclization. The two silyl groups were cleaved, liberating the primary alcohols which were oxidized to the aldehydes, furnishing the cyclization precursor 129. The crucial intramolecular aldol reaction proceeded diastereoselectively to afford 130, which possesses the incorrect configuration at C7. Epimerisation of that center ultimately proved to be possible, but it required a fairly lengthy sequence. Indeed, 130 was reduced to a diol, and the primary alcohol was selectively silylated to provide 131. Dess-Martin oxidation76 and desilylation were followed by base-catalyzed epimerisation of the resulting hydroxy ketone, leading to compound 112 after reduction. 30   (a) NaH, THF, −78°C to RT (100%); (b) Zn, AcOH, THF, H2O, RT; (c) TsCl, Et3N, DMF, 0°C to RT (77% over 2 steps); (d) MsCl, Et3N, CH2Cl2, 0°C to RT (94%); (e) NaH, imidazole, THF, reflux (92%); (f) HF, py, 0°C (99%); (g) DMP, CH2Cl2, RT (98%); (h) LiN(TMS)2, THF, −78°C to −5°C (i) NaBH4, H2O, −5°C to 0°C (42%); (j) TBDPSCl, Et3N, DMAP, CH2Cl2, RT (79%); (k) DMP, CH2Cl2, RT (93%); (l) HF, py, 0°C to RT (93%); (m) DBU, THF, RT (64%); (n) NaBH4, THF, H2O, 0°C to RT (87%). Scheme 27: Synthesis of 8-membered ring intermediate 112  The primary alcohol in compound 112 was silylated and the amine was liberated (cleavage of the Alloc group) and oxidized to the hydroxylamine, which was then O-acetylated (Scheme 28). Dess-Martin oxidation76 of the secondary alcohol at C8 gave ketone 132. Removal of the silyl and acetyl groups was followed by internal hemiacetalisation to provide the tetracyclic compound 133. The carbamate side chain was added in two steps and the C8 alcohol was acetylated to allow deprotection of the aziridine, of the phenol, and of the benzylic hydroxyl. Finally, oxidation to the aldehyde and cleavage of the acetyl group yielded (+)-FR- 900482, 14.    (a) TBDPSCl, Et3N, DMAP, CH2Cl2, RT (71%); (b) Pd(PPh3)4, PPh3, THF, RT (83%); (c) m-CPBA, CH2Cl2, −5°C (67%); (d) Ac2O, NaHCO3, RT (69%); (e) DMP, CH2Cl2, RT (88%); (f) HF, py, 0°C to RT (88%); (g) K2CO3, MeOH, 0°C to RT (89%); (h) Cl3COCOCl, py, 0°C to RT (81%); (i) NH3, THF, 0°C to RT (94%); (j) Ac2O, py, DMAP, RT (87%); (k) sodium naphthalenide, DME, −70°C (84%); (l) H2, Pd/C, AcOEt, RT (81%); (m) (COCl)2, DMSO, CH2Cl2, −78°C then Et3N (88%); (n) NH3, MeOH, RT (73%). Scheme 28: Terashima’s synthesis of FR-900482  a - e h - nf - g8 112 N NTs BnO OBOM OH Alloc OH 8 132 N NTs BnO OBOM OTBDPS OAc O O N NH OH OCONH2OH OHC FR-900482 14 O N NTs OH OH OBn 133OBOM 31  Terashima and co-workers achieved the first enantioselective total synthesis of (+)-FR- 900482 , 14. It was done in 57 steps in a 0.1% overall yield, starting from L-diethyltartrate 116.  3.8 Martin’s formal synthesis of FR-900482  In 2000, Martin et al. proposed a formal synthesis of FR-900482, 14, 77 that reached Fukuyama intermediate 9768 by ring-closing metathesis78 (Scheme 29). The work also demonstrated an innovative technique for the construction of the aziridine ring. The starting point of the synthesis was diol 135, which was readily accessed from nitro vanillin 136. 13497 OBn OBn NO2 OH OH 135 OHC OMe OH NO2 136 O N NH OH OCONH2OH OHC FR-900482 14 N O BnO OPMP OTBS OAc OH N BnO OBn OPMB Troc OH  Scheme 29: Martin’s retrosynthetic analysis of FR-900482  5-nitro vanillin 135 was advanced to triflate 136, which underwent nucleophilic aromatic substitution with dimethyl sodiomalonate to furnish 137 (Scheme 30). Reduction of the aldehyde and benzylation of the resultant alcohol yielded 138. Reduction of the malonate gave diol 134. A sequence involving differential protection of the diol, nitro group reduction, protection of the amine as a 2,2,2-trichloroethoxycarbonyl derivative, and N-allylation led to intermediate 140. Cleavage of the silyl ether and Swern oxidation69 gave an aldehyde, which reacted with vinylmagnesium bromide to generate diene 141. 32  OBn OBn NO2 OH OH h - l m - n 140 OBn OBn OPMB OTIPS N Troc135 OHC OMe OH NO2 OBn OBn NO2 CO2Me CO2Mea - c 139136 e - f g OHC OBn NO2 CO2Me CO2Me 138 OHC OBn OTf NO2 d 137 141 N BnO OBn OPMB Troc OH  (a) HBr, AcOH, reflux; (b) NaH, BnBr, DMF, 0°C (82% over 2 steps); (c) Tf2O, py, CH2Cl2, 0°C (95%); (d) NaCH(CO2Me)2, DMF (80%); (e) NaHB4, MeOH, CH2Cl2, RT; (f) NaH, BnBr, DMF, 0°C (90% over 2 steps); (g) DIBAL, CH2Cl2, −78°C (38%); (h) NaH, PMBCl, DMF, 0°C; (i) TIPSOTf, 2,6-lutidine, CH2Cl2, RT (75% over 2 steps); (j) Raney Ni, H2, EtOH, RT (99%); (k) TrocCl, K2CO3, DMF; (l) KH, allylbromide (83% over 2 steps); (m) HF, py, CH2Cl2, 0°C; (n) (COCl)2, DMSO, Et3N then CH2=CHMgBr (65% over 2 steps). Scheme 30: Synthesis of diene 141  The synthesis continued with ring-closing metathesis78 of diene 141, yielding benzazocenol 134. Cleavage of the 2,2,2-trichloroethoxycarbonyl group, N-oxidation of the amine to a hydroxylamine, and subsequent O-acetylation, were followed by epoxidation of the olefin to give compound 142. Finally, a series of deprotection and protection steps yielded Fukuyama intermediate 97. b - e f - h 142 N BnO OBn OPMB OAc OH O 97 N O BnO OPMP OTBS OAc OH a 134 N BnO OBn OPMB Troc OH 141 N BnO OBn Troc OH OPMB  (a) benzene, Cl2(PCy3)2Ru=CHPh, 65°C (78%); (b) Zn, AcOH, THF, H2O, RT (80%); (c) m-CPBA, CH2Cl2, 0°C; (d) Ac2O, py, RT (89% over 2 steps); (e) m-CPBA, CH2Cl2, RT (61%); (f) TFA, CH2Cl2, 0°C; (g) TBSCl, DMAP, imidazole, CH2Cl2, RT (60% over 2 steps); (h) PMPOH, PPh3, DEAD, CH2Cl2, RT (80%). Scheme 31: Synthesis of Fukuyama’s intermediate 97  The Martin formal synthesis of FR-900482 thus reached racemic intermediate 97 in 22 steps in 1% overall yield. However, two interesting aspects of this approach deserve additional comments. First, diol 135 can be desymmetrised through enantioselective acetylation with 33  vinyl acetate catalyzed by PSL (Pseudomonas Species Lipase). This produces highly enantioenriched monoacetate 143 (Scheme 32). Curiously, no information is available in the Martin publication regarding the possible advancement of 143 to enantioenriched 97.  (a) PSL, vinyl acetate, 4Å ms, 35°C (74%, 94% ee). Scheme 32: Synthesis of enantiopur nitrobenzene 143  Secondly, Martin explored a new approach for the introduction of the aziridine ring via an intramolecular iodoamidification of benzazocenol 134 (Scheme 33). Treatment of this material with tosyl isocyanate afforded the N-tosyl carbamate 144, which upon exposure to elemental iodine underwent cyclization to a mixture of diastereomeric oxazolidinones 145 and 146. Unfortunately, the desired product 145 was the minor isomer.  (a) TsNCO, CH2Cl2, 0°C (74%); (b) I2, aq. NaHCO3, CH2Cl2, RT (41%). Scheme 33: Synthesis of oxazolidinones 145 and 146  3.9 Williams’ synthesis of FR-900482  In 2002, Williams et al. detailed a second enantioselective total synthesis of FR- 900482, 14,79 readily available from 147 (Scheme 34). Oxidation of the protected 8-membered ring aniline 148 to the corresponding N-oxide proceeded with simultaneous cleavage of the p- 34  methoxybenzyl group and formation of the hydroxylamine hemiketal 147. The 8-membered ring in 148 was established through an intramolecular reductive amination reaction of an intermediate generated by the union of the trisubstituted nitrobenzene 149 and the optically active aziridine 150. OHC NCO2Me OPMB OMOM NO2MeO2C O N NCO2Me OH OTBS MOMO MeO2C 147 + 150149148 O N NH OH OCONH2OH OHC FR-900482 14 N NCO2Me MOMO MeO2C OH PMB O  Scheme 34: Williams’ retrosynthetic analysis of FR-900482  The preparation of aziridine 150 started with a Sharpless epoxidation80 of alcohol 151 (Scheme 35). Epoxide 152 underwent non-selective opening with sodium azide to give a mixture of isomeric azido alcohols 153 and 154, both of which were advanced to the same ultimate product. Thus, selective protection of the primary hydroxyl and mesylation of the secondary one were followed by reduction of the azide to an amine and consequent formation of the aziridine ring in 155. Protection of the latter as a methyl carbamate, removal of the silyl ether and Dess-Martin oxidation76 provided aldehyde 150. OH NH OPMB OPMB a O OPMB OH c - e 151 155152 OH OPMB OH 153 OH OPMB OH 154 N3 N3 + b OHC NCO2Me OPMB f - h 150 OTBS  (a) Ti(Oi-Pr)4, L-(+)-DET, t-BuOOH, CH2Cl2, −20°C (75%, 87% ee); (b) NaN3, NH4Cl, MeOCH2CH2OH, reflux; (c) TBSCl, Et3N, DMAP, CH2Cl2, 5°C (83% over 2 steps); (d) MsCl, Et3N, CH2Cl2, 0°C to RT; (e) Raney Ni, NH2NH2, EtOH, RT; (f) MeOCOCl, py, RT (68% over 3 steps); (g) TBAF, THF, RT (86%); (h) DMP, CH2Cl2, RT (98%). Scheme 35: Synthesis of aziridine 150  35  The aromatic fragment 149 was synthesized from 3,5-dinitrotoluic acid 156 (Scheme 36). Selective reduction of one of the nitro groups, diazotization, and hydrolysis of the diazonium species furnished phenol 157,81 which was converted into 149 by Fisher esterification and phenol protection.82 Nucleophilic addition of the anion of 149 to 150 afforded an epimeric mixture of alcohols, which, without separation, were protected as the corresponding silyl ethers 158. Oxidative cleavage of the p-methoxybenzyl protecting group, Dess-Martin oxidation76 of the primary hydroxyl, and reduction of the nitro group gave intermediate 159, which cyclized to imine 160. Reduction of the latter provided 8-membered ring aniline 161. OHC NCO2Me OPMB 150 NO2 NO2HO2C N H OMOM MeO2C NCO2Me ODEIPS g - i OH NO2HO2C a - b 161 157156 NH2 CHO OMOM MeO2C NCO2Me ODEIPS OMOM NO2MeO2C 149 c - d e - f NO2 OMOM MeO2C NCO2Me ODEIPS OPMB j N OMOM MeO2C NCO2Me ODEIPS 160 k 159 158  (a) Na2S2O4, py, H2O, RT; (b) aq. H2SO4, NaNO2, 0°C then H2O, RT (49% over 2 steps); (c) H2SO4, MeOH, reflux (93%); (d) MOMCl, K2CO3, acetone, RT (97%); (e) 149, MeONa, MeOH, DMF, 0°C (90%); (f) DEIPSCl, imidazole, CH2Cl2, RT; (g) DDQ, CH2Cl2, RT (72% over 2 steps); (h) DMP, CH2Cl2, RT (90%); (i) H2, Pd/C, MeOH, RT; (j) MgSO4, 4Å ms, CH2Cl2; (k) NaBH3CN, CH2Cl2, MeOH, RT (60% over 3 steps). Scheme 36: Synthesis of 8-membered ring compound 161  The elaboration of 161 to the target molecule continued with protection of the aniline as the p-methoxybenzyl derivative, followed by cleavage of the diethylisopropylsilyl group and Dess-Martin oxidation76 to give ketone 162 (Scheme 37). Treatment with lithium diisopropylamide followed by addition of formaldehyde furnished the diastereomeric aldol adducts 148 and 163 as a 1:1 mixture. The undesired diastereomer 163 was separated and partially epimerized to 148 by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene. Silylation of 36  148 was followed by a one-step protocol allowing the cleavage of the N- p-methoxybenzyl residue and oxidation of the amine to the corresponding hydroxylamine, thus forming the desired hydroxylamine hemiketal 147. Cleavage of silyl ether and reaction of the primary alcohol with trichloroacetyl isocyanate installed the urethane moiety. Removal of the methoxymethyl ether and reduction of both carbomethoxy groups gave intermediate 164. Finally, Swern oxidation69 yielded FR-900482, 14. (a) PMBBr, i-Pr2NEt, CH2Cl2 (86%); (b) TASF, DMF, H2O, RT; (c) DMP, CH2Cl2, RT (75% over 2 steps); (d) LDA, DMF, −45°C then HCHO, THF, −45°C (50%, 50% ee); (e) DBU, tol, RT (70%); (f) TBSOTf, 2,6-lutidine, CH2Cl2, −78°C to 0°C (96%); (g) DMDO, aq. K2CO3, CH2Cl2, 0°C to RT (40%); (h) TBAF, THF, 0°C (92%); (i) Cl3CCONCO, CH2Cl2, 0°C then MeOH, silica gel, RT (86%); (j) TMSBr, CH2Cl2, −45°C (60%); (k) LiBH4, MeOH, THF, RT (78%); (l) (COCl)2, DMSO, THF, −78°C to −40°C then Et3N (33%). Scheme 37: Williams’ synthesis of FR-900482  Williams’ enantioselective total synthesis reached FR-900482, 14, in 29 steps with a 0.1% overall yield.  3.10 Fukuyama’s synthesis of FR-900482  Ten years after their first total synthesis, Fukuyama et al. described an enantioselective avenue to hemicetal 85,83 an advanced key intermediate in their earlier work.68 This new route was further improved in 2004.84 Key steps of the new synthesis were the reductive 37  hydroxylamination of 166 to form the 8-membered ring, and the Sonogashira coupling85 between 105 and 168 (Scheme 38).  Scheme 38: Fukuyama’s retrosynthetic analysis of FR-900482  D-tartaric acid 169 was advanced to 170 in a conventional fashion (Scheme 39). Swern oxidation69 gave the aldehyde, which was readily converted into terminal acetylene 168. Sonogashira coupling85 of 105 and 168 gave acetylene 167, which was transformed into ketone 172 through enamine intermediate 171. d - e D-tartric acid CO2H OH OH HO2C OBn MeO2C NO2 OTf f 105 O O OTBS168 O O OTBS170 HO a - c OBn MeO2C NO2 167 OTBS O O g OBn MeO2C 171 NO2 O O OTBS 169 OBn MeO2C 172 NO2 O O O OTBS N  (a) Me2C(OMe)2, MeOH, p-TsOH, C6H12, RT; (b) LiAlH4, Et2O, RT (55% over 2 steps); (c) NaH, TBSCl, THF, 0°C (76%); (d) (COCl)2, DMSO, CH2Cl2, −78 °C then Et3N, −78 °C to RT; (e) dimethyl 1-diazo-2- oxopropylphosphonate, K2CO3, MeOH, RT (49% over 2 steps); (f) 104, Pd(OAc)2, PPh3, THF, Et3N, 65°C (83%); (g) pyrrolidine, benzene then 50% aq AcOH, RT (90%). Scheme 39: Synthesis of ketone 172  38  Ketone 172 was stereoselectively reduced and the corresponding alcohol was protected (Scheme 40). Cleavage of the acetonide served as the starting point for the creation of epoxide 173. Desilylation of the primary alcohol and Dess-Martin oxidation76 produced nitroaldehyde 166, which upon hydrogenation in the presence of platinum on carbon underwent selective reduction to hydroxylamine 174. This intermediate probably cyclized in situ to nitrone 175, which was further hydrogenated to the ultimate product of the reaction, epoxide 165.  (a) Zn(BH4)2, Et2O, −20°C (96%); (b) TIPSOTf, 2,6-lutidine, CH2Cl2, RT; (c) AcOH, H2O, 100°C (61% over 2 steps); (d) TBSCl, Et3N, DMAP, CH2Cl2, RT; (e) TsCl, DABCO, CH2Cl2, RT; (f) NaH, DMF, 0°C to RT (76% over 3 steps); (g) CSA, MeOH, RT; (h) DMP, CH2Cl2, 0°C to RT; (i) H2, Pt/C, MeOH, RT (89% over 3 steps). Scheme 40: Synthesis of 8-membered ring intermediate 165  Hydroxylamine 165 was protected and the triisopropylsilyl group was cleaved (Scheme 41). Swern oxidation69 and hydroxymethylation followed by acidic work-up gave hemiacetal 176 with good diasteroselectivity (87:13). This material was protected as an acetonide and the aromatic methyl ester was reduced to the alcohol. Protection of the latter as a p–methoxyphenyl ether and regioselective epoxide opening with lithium azide provided an alcohol, which was mesylated to give compound 85. FR-900482, 14, was obtained from 85 by the procedure described in the authors’ 1992 synthesis. 39  j - ra - d e - i N O O OBn O OBn MeO2C 84164 N OH O OTIPS OPMP OMs N3 O N NH OH OCONH2OH OHC FR-900482 14 N OH OH OBn MeO2C O 175 O  (a) 2-methoxypropene, p-TsOH, H2O, CH2Cl2, RT; (b) TBAF, THF, RT (91% over 2 steps); (c) (COCl)2, DMSO, 78 °C then Et3N, −78 °C to RT (82%); (d) 37 % aq. HCHO, LiOH, THF, H2O, 0°C then HCl 1N, 0°C to RT ; (e) PPTS, 2-methoxypropene, Me2C(OMe)2, acetone, RT (65% over 2 steps); (f) DIBAL, CH2Cl2, −78°C (99%); (g) PMPOH, DEAD, PPh3, benzene, RT (96%); (h) LiN3, DMF, H2O, 120°C (83%); (i) MsCl, Et3N, CH2Cl2, RT (80%); (j) TFA, CH2Cl2, RT; (k) (Cl3CO)2CO, py, CH2Cl2, 0°C (92% over 2 steps); (l) CAN, MeCN, H2O, RT (84%); (m) PCC, MgSO4, CH2Cl2, RT; (n) CSA, CH(OMe)3, MeOH, RT (81% over 2 steps); (o) PPh3, i-Pr2NEt, THF, H2O, 60°C (85%); (p) H2, Pd/C, EtOH, RT (97%); (q) HClO4, THF, H2O, RT; (r) NH3 gas, THF, RT (83% over 2 steps). Scheme 41: Fukuyama’s synthesis of FR-900482  Fukuyama’s enantioselective total synthesis of FR-900482, 14, proceeded in 34 steps with 0.8% overall yield, starting from D-tartaric acid 169.  3.11 Ciufolini’s synthesis of FR-66979  The first total synthesis of FR-66979, 15, was achieved by our group,9 based upon methodology developed earlier in our laboratory.86 FR-66979 hemicetal functionality resulted upon transannular cyclisation of ketone 177 (Scheme 42). Benzazocenol 178 was obtained through a ring expansion process that involved fragmentation of aziridine 179. The aziridine, in turn, was prepared by an intramolecular 1,3-dipolar cycloaddition of 181, followed by photochemical extrusion of molecular nitrogen from intermediate triazoline 180. Alkene 181 originated from the nucleophilic addition of an allylmetallic reagent to aldehyde 182, which was prepared from 5-nitrovanillin 136. 40  BnO OBn N O OBn OBn OBn N3 CHO OBn BnO OBn N OBn OH TMS H 177 179 182 OAc OMe OHC OH NO2 136 BnO OBn 181 N3 OH TMS OBn O N NH OH OCONH2OH FR-66979 15OH O BnO OBn HN OBn 178 OH BnO OBn N OBn OH TMS H 180 N N Scheme 42: Ciufolini’s retrosynthetic analysis of FR-66979  The nitro group in Martin diol 135 (cf. Scheme 30)77 permitted the installation of an azido functionality through reduction to an amine, diazotization, and treatment of the diazonium salt with sodium azide (Scheme 43). The emerging azidodiol 183 was monoprotected and oxidized to racemic aldehyde 182.  (a) H2, Raney Ni, MeOH, RT; (b) H2SO4, NaNO2, H2O, 0°C; (c) NaN3, H2O, RT; (d) NaH, BnBr, THF, 0°C; (e) IBX, DMSO (53% over 5 steps). Scheme 43: Synthesis of aldehyde 182  Titanate 185 was prepared in situ by transmetallation of lithiated allyltrimethylsilane 184 with titanium isopropoxide as described by Reetz (Scheme 44).87 Its addition to aldehyde 182 furnished 181 as a diastereomerically homogenous product.  (a) s-BuLi, TMEDA, −40°C then Ti(Oi-Pr)4, −78°C then 182 (84%). Scheme 44: Synthesis of azido alkene 181  41  The relative configuration of intermediate 181 suggests that the addition process occurs with essentially complete Cram-Felkin selectivity88 within the manifold of a Zimmerman- Traxler-type cyclic transition state89 (Figure 3).  Figure 3: Relative stereochemistry of 181  A diastereoselective intramolecular 1,3-dipolar cycloaddition of the azido group to the olefin of 181 yielded crystalline triazoline 180 (Scheme 45). Ultra-violet irradiation of 180 induced the expulsion of molecular nitrogen, giving aziridine 179. Exposure of 179 to base induced a presumed homo-Brook transposition90 of the trimethylsilyl group and consequent anionic fragmentation of the aziridine, providing benzazocenol 178.  (a) tol, 100°C (96%); (b) hυ, THF, RT (77%); (c) n-Bu4NOH, DMF, −20°C (49%). Scheme 45: Synthesis of benzazocenol 178  The synthesis continued along the lines established earlier by Fukuyama.68 Thus, aniline 178 was oxidized to a hydroxylamine, which was O-acetylated (Scheme 46). Epoxidation of the olefin was followed by a Ley oxidation91 of the secondary alcohol, yielding intermediate 177. Cleavage of the acetate induced hemiacetal cyclisation and release of the benzyl protecting 42  group gave compound 186. Selective acetonide formation was followed by azide opening of the epoxide. The primary alcohol and the phenol were selectively acetylated and the last hydroxyl was mesylated, producing intermediate 187. Exchange of the acetonide with a cyclic carbonate gave compound 188. Finally, sequential Staudinger-type aziridine formation67 and aminolysis of both cyclic carbonate and acetate units yielded FR-66979, 15.  (a) m-CPBA, CH2Cl2, 0°C; (b) neat Ac2O, RT (87% over 2 steps); (c) m-CPBA, CH2Cl2, NaHCO3, RT (70%); (d) cat. TPAP, NMO, CH2Cl2, 4Å ms, RT (83%); (e) NH2NH2, H2O, MeOH, CH2Cl2, RT (100%); (f) H2, Pd/C, AcOEt, RT (97%); (g) 2-methoxypropene, PPTS, DMF, RT (83%); (h) LiN3, DMF, 100°C (67%); (i) Ac2O, K2CO3, THF, RT (81%); (j) MsCl, Et3N, CH2Cl2, RT (71%); (k) TFA, CH2Cl2, RT; (l) COCl2, Et3N, CH2Cl2, 0°C (28% over 2 steps); (m) PPh3, i-Pr2NEt, H2O, THF (90%); (n) NH3, MeOH, RT (40%). Scheme 46: Ciufolini’s synthesis of FR-66979  The total synthesis of FR-66979, 15, accomplished by our group was done in 27 steps in 0.1% overall yield.  3.12 Ciufolini’s synthetic studies on mitomycins  A former member of our group, Dr. J. C. Andrez, started the extension of the above methodology to the domain of mitomycins.92 As exemplified by mitomycin A, the mixed aminal subunit can be created by transannular cyclization of 189 (Scheme 47). Furthermore, the aziridine ring can be derived from the olefinic functionality of benzazocenol 190, which is 43  itself the resultant of homo-Brook rearrangement90 / aziridine fragmentation of intermediate 191. As in the FR-66979 synthesis,9 the preparation of aziridine 191 would proceed through nucleophilic addition of titanate 185 to aldehyde 192, followed by intramolecular 1,3-dipolar cycloaddition and photochemical molecular nitrogen extrusion.  Scheme 47: Retrosynthetic analysis of mitomycin A  Dr. Andrez’s work revealed important principles that guided our subsequent efforts. First of all, it became apparent that the aziridine nitrogen in intermediates of the type 189 should be protected as an acetyl derivative. Release of this group can be achieved under mild conditions, either with methanolic potassium carbonate or with methanolic ammonia, even at the stage of highly sensitive late intermediates. Secondly, for the same sensitivity reasons, the hydroquinone should be protected with a group that is labile under neutral conditions. Previous attempts with different protecting groups (methyl, methoxymethyl, p-toluenesulfonyl) failed.92 Moreover, a prerequisite for these protecting groups is that their removal would easily trigger the oxidation of the aromatic ring to the p-quinone. Therefore, the oxygen functionalities in 193 and congeners should all be protected with benzyl-type groups, while the aniline nitrogen should be blocked as a benzyloxycarbonyl derivative. In this manner, all such protecting groups would be cleaved simultaneously during a single hydrogenation step, allowing transannular cyclization to mitomycin core 196 (Scheme 48). 44  HO HO MeO N N OH OH 195 193 MeO N N BnO BnO Cbz Ac O a 194 MeO N N H HO HO Ac O Ac b O O MeO N N OH OH 196 Ac OHOBn  (a) H2, Pd/C, py, RT; (b) air, RT. Scheme 48: Formation of mitomycin core 196  Accordingly, Claisen rearrangement52 of 197 was followed by oxidation of 198 to the quinone, which was readily reduced to the hydroquinone and bis-protected, yielding intermediate 199 (Scheme 49). The azide moiety was introduced in 3 steps and oxidative cleavage of the terminal olefin gave aldehyde 201. Allylation of 201 using Reetz methodology87 afforded cyclization precursor 202. Crystalline triazoline 203 was obtained after intramolecular 1,3-dipolar cycloaddition of the azide onto the olefin of 202.  (a) N,N-dimethylaniline, 220°C (94%); (b) 70% HNO3, CH2Cl2, 0°C; (c) Na2S2O4, Et2O, H2O, RT; (d) NaH, BnBr, DMF, 0°C (86% over 3 steps); (e) 70% HNO3, CH2Cl2, 0°C (84%); (f) Zn, HCl 3N, MeOH, 0°C (67%); (g) H2SO4, NaNO2, H2O, THF, 0°C then NaN3, H2O, 0°C (93%); (h) OsO4, NMO, t-BuOH, H2O, RT (i) NaIO4, t-BuOH, H2O, RT (87%); (i) 184, s-BuLi, TMEDA, THF, −40°C then Ti(Oi-Pr)4, −78°C; (j) tol, 85°C (92% over 2 steps). Scheme 49: Synthesis of triazoline 203  45  Photolysis of triazoline 203 generated molecular nitrogen, yielding aziridine 203 (Scheme 50). Homo-Brook transposition90 followed by aziridine fragmentation was induced by exposure to tetra-n-butylammonium fluoride, providing benzazocenol 205. Following Martin’s methodology (cf. Scheme 33),77 treatment of this material with tosyl isocyanate afforded an N- tosyl carbamate, which upon exposure to elemental iodine underwent cyclization to oxazolidinone 206. Aziridine 207 was obtained by nucleophilic opening of the oxazolidinone ring followed by SN2 displacement of iodide. Sodium naphthalenide treatment allowed the cleavage of the tosyl protecting group. Finally, the aziridine was protected as an acetyl derivative, affording compound 208.  (a) hυ, acetone, RT (68%); (b) TBAF, DMF, −20°C (78%); (c) CbzCl, NaHCO3, THF, RT (99%); (d) TsNCO, THF, RT; (e) I2, NaHCO3, MeCN, RT (88% based on starting material recovery); (f) K2CO3, MeOH, Et2O, RT (83%); (g) sodium naphthalenide, THF, −78°C; (h) Ac2O, py, RT (57% over 2 steps). Scheme 50: Synthesis of benzazocenol 208  Compounds 205 and 206 appeared to be substantially a single diastereomer. However, the stereochemical outcome of the sequence remains uncertain as of this writing. For that reason, the configuration of the aziridine is not indicated. While the chemical properties of 208 were not thoroughly explored, it was discovered that more advanced intermediates arising from the latter resisted hydrogenolytic release of the side chain benzyl group under conditions mild enough to ensure survival of the substrate. We believe that this resistance is due to the folding 46  of the side chain inside the cavity created by the molecule core. This would generate steric hindrance, resulting of non-accessibility of the protecting group to hydrogenolysis agents, thus preventing the further elaboration of 208 into a mitomycin. 47  STUDIES TOWARDS THE TOTAL SYNTHESIS OF MITOMYCINS  Our subsequent approach to the total synthesis of mitomycins envisioned the use of a benzoxy methyl ether at C10. We felt that replacing of the side chain benzyl ether with a benzoxy methyl protecting group would bypass the problems encountered with its removal. Indeed a benzoxy methyl ether at C10 would increase the length of the side chain, making the benzyl functionality more accessible to hydrogenolysis. Thus, our synthetic efforts were focused on the benzoxy methyl ether series. The synthesis was also redone with a benzyl group to confirm the results found by Dr J. C. Andrez.  1. Our retrosynthetic approach  Our retrosynthetic approach is therefore exemplified in Scheme 51 targeting either mitomycin A or C, which, as indicated earlier, are interconvertible. Hydrogenolysis of 209 would induce the liberation of all O-protected functionalities and trigger the transannular cyclization, creating the mixed aminal subunit of these molecules. The aziridine moiety can be introduced by the rearrangement of oxazolidionone 210, which itself originated from benzazocenol 211. The preparation of the latter would proceed through homo-Brook rearrangement90 / aziridine fragmentation of intermediate 212. Aziridine 212, in turn, would arise by intramolecular 1,3-dipolar cycloaddition and photochemical extrusion of molecular nitrogen from an intermediate triazoline. Alkene 213 would derive from the nucleophilic addition of titanate 185 onto aldehyde 214. 48   Scheme 51: Retrosynthetic analysis of MC  While many plausible routes to 214 can be envisioned, the introduction of the formyl group through oxidative cleavage of an alkene would require precursor 219, which is structurally similar to the known compound 218 (Scheme 52).93 Note that a switch of protecting group on the p-quinone will be required on our substrate at the stage of 217. While such an avenue to 214 is somewhat lengthy, our main goal was to extend the chemistry of Scheme 42 to the new substrate. The search for a better synthesis of 214 was thus postponed to a later, more opportune time.  (a) n-Bu3P, DEAD, −25°C (80%); (b) N,N-dimethylaniline, 220°C (quantitative yield); (c) NaH, BnBr, THF, 0°C; (d) 90% HNO3, Ac2O, Hg(OAc)2, CH2Cl2, 0°C (86% over 2 steps). Scheme 52: Structural analogy between 218 and 219  49  In accord with the foregoing, the preparation of 214 was charted as outlined in Scheme 53. The forerunner of 214 would be compound 220, destined to undergo conversion of the nitro group to an azide functionality and subsequent oxidative cleavage of the olefin. Intermediate 220 would be obtained by nitration of 221, which in turn emerges through Claisen rearrangement52 followed by bis-protection of 222. The latter would result upon the union of phenol 44 and alcohol 223 under Mitsunobu conditions94.  Scheme 53: Retrosynthetic analysis of 214  2. Synthesis of aldehyde 214 2.1 Synthesis of phenol 46  Although phenol 46 is commercially available, it is expensive. Fortunately, it can be easily synthesized from 2,6-dimethoxytoluene, 45,51 through a Vilsmeier-Haack reaction95 followed by Baeyer-Villiger oxidation60 of aldehyde 224 with m-chloroperbenzoic acid and methanolysis of the resulting formate ester 224 (Scheme 54). This sequence proceeded in excellent overall yield.   (a) POCl3, DMF, RT (78%); (b) m-CPBA, CH2Cl2, RT (92%); (c) MeOH, K2CO3, RT (99%). Scheme 54: Synthesis of phenol 46  OMe MeO OMe MeO CHO OMe MeO OH a b 45 225224 46 c OMe MeO OCHO 50  2.2 Preparation of diols 223 and 229  Compound 223 is represented in Scheme 53 as the trans-isomer. However, either geometric isomer of the molecule is serviceable, at least in principle, for the conduct of the above sequence, since π bond migration during the Claisen rearrangement52 will cause formation of the same terminal olefin regardless of initial double bond geometry. Past work in this laboratory utilised compound trans-229, which was prepared by mono-benzylation of 2- butyne-1,4-diol 226, followed by triple bond reduction with Vitride™ (Scheme 55).92 The first step proceeded in a moderate 43% yield, while the second one afforded trans-229 in 70% yield. Translation of this chemistry to the benzyloxy methyl series of compound revealed that the mono-protection of 226 was significantly more efficient (76% vs 43%). The beneficial effect of the benzyloxy methyl group was also displayed upon VitrideTM reduction of the alkyne, which now proceeded in 84% yield instead of 70%. OH b OH c trans-223 226 trans-229 OH OBnOBOM OH OH OBn d 227 OH OBOM a 228 (a) NaH, BOMCl, DMF, 0°C (76%); (b) Vitride, THF, 0°C (84%); (c) NaH, BnBr, DMF, 0°C (43%); (d) Vitride, THF, 0°C (70%). Scheme 55: Monoprotection and reduction of 2-butyne-1,4-diol 226  It is imprudent to advance a simplistic explanation for the improved yield of product observed in the benzyloxy methyl series. However, an inspection of molecular models suggests that the benzyloxy methyl protecting group could assume a conformation similar to the one shown on Figure 4. Thus, the free alcohol functionality at the opposite end of the chain would be somewhat sterically protected from the action of additional reagent. An analogous 51  conformation of the benzyl mono-protected compound would deny the molecule the benefit of steric shielding to the free hydroxyl. This might promote a greater extent of bis-protection on 228, accounting for the observed yields. OH O OH OBn 227OH OBOM 228 OH O O vs  Figure 4: Steric shielding of the free OH in 227  The use of commercial cis-2-butene-1,4-diol 230 in an analogous sequence would suppress the need for reduction of an acetylenic intermediate. Accordingly, 230 was subjected to mono-protection as the benzyloxy methyl derivative, whereupon cis-223 was obtained in 67% yield (Scheme 56). Mono-benzylation of 230 proceeded equally well. OBOM OH a OH OH b cis-223 cis-229230 OH OBn  (a) NaH, BOMCl, DMF, 0°C (67%); (b) NaH, BnBr, DMF, 0°C (66%). Scheme 56: Monoprotection of cis-2-butene-1,4-diol 230  2.3 Mitsunobu reaction and Claisen rearrangement  The coupling reaction between phenol 46 and the monoprotected cis or trans diols 223 and 229 was done under Mitsunobu conditions94 in the presence of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (Scheme 57). The products cis or trans-197 and 222 resulted from exclusive SN2 substitution and were easily isolated by flash column chromatography in good yields. 52   (a) DIAD, PPh3, Et2O, 0°C to RT (73% with Bn; 93% with BOM); (b) DIAD, PPh3, Et2O, 0°C to RT (73% with Bn; 71% with BOM). Scheme 57: Mitsunobu reaction  Claisen rearrangement52 of either phenolic ether in refluxing N,N-dimethylaniline96 afforded the expected products in excellent yield (Scheme 58). Indeed, either geometric isomer of the substrate (cis or trans) reacted in a satisfactory manner.  (a) N,N-dimethylaniline, 220°C (97% with Bn; 98% with BOM). Scheme 58: Claisen rearrangement  2.4 Protection of hydroquinones 234 and 235  A key feature of our synthetic planning was that the phenolic functionalities present in late synthetic intermediates must be deblocked simultaneously by a hydrogenolytic technique (Scheme 48). This mandated a change in protecting groups at the stage of 198 and 231. Consequently, oxidation with concentrated nitric acid selectively gave p-quinones 232 and 233 respectively (Scheme 59). Variable amounts of degradation products were formed, but no o- 53  quinone was detected. Moreover, the benzyloxy methyl protecting group survived this step, even though a strong acidic agent was used. Previously, the conversion of the crude quinone into 234 had been achieved by reduction with sodium hydrosulfite and benzylation of the intermediate hydroquinone.97 Reduction in tetrahydrofuran with metallic zinc in the presence of aqueous three molar hydrochloric acid solution proceeded as well. The resulting hydroquinones 234 and 235 were exceedingly sensitive to air oxidation; therefore, they were kept under argon to avoid transformation back to the quinone. Finally, bis-benzylation gave compounds 199 and 221.  (a) 70% HNO3, CH2Cl2, 0°C; (b) Zn, HCl 3N, THF, 0°C; (c) NaH, BnBr, DMF, 0°C (75% with Bn over 3 steps; 45% with BOM over 3 steps). Scheme 59: Protection of hydroquinones 234 and 235  2.5 Synthesis of aldehydes 201 and 214  Intermediates 199 and 221 underwent nitration with concentrated nitric acid in dichloromethane to give 236 and 220 respectively (Scheme 60). As seen previously, this reaction was difficult to control and degradation products began to form soon after the addition of the first quantities of nitric acid (TLC monitoring). Reduction of nitrobenzenes 236 and 220 using zinc / hydrochloric acid in tetrahydrofuran yielded anilines 237 and 238. 54   (a) 70% HNO3, CH2Cl2, 0°C; (b) Zn, HCl 3N, THF, 0°C (25% with Bn over 2 steps; 23% with BOM over 2 steps). Scheme 60: Synthesis of anilines 237 and 238  Anilines 237 and 238 were then transformed to azides 200 and 239 by diazotation and reaction of the diazonium salt with sodium azide (Scheme 61). The reaction is normally performed at −5°C, to avoid deazotation of the diazonium intermediate, in a solvent such as aqueous dioxane. However, these conditions proved to be unsuitable for our substrates. First, the reaction mixture tended to freeze to a thick slush at −5°C. The problem was partially alleviated by switching from dioxane to tetrahydrofuran, although freezing remained an issue as the percentage of water increased during reaction, due to the successive additions of aqueous sodium nitrite and sodium azide solutions. Secondly, the mixture tended to become heterogeneous during the reaction, regardless of whether dioxane or tetrahydrofuran was used as co-solvent.  (a) H2SO4, NaNO2, H2O, THF, 0°C then NaN3, H2O, 0°C then AcONa, H2O. Scheme 61: Synthesis of azides 200 and 239  While the foregoing problems were of a technical nature, a chemical issue became apparent at the stage of azido compounds 200 and 239: the substances readily cyclized to 55  triazolines 240 and 241 upon standing for 2-3 hours, even if kept at low temperature and in the dark (Figure 5).  Figure 5: Cyclization of side products 240 and 241  It was therefore essential to accomplish the oxidative cleavage of the alkene immediately after the introduction of the azide. This was best accomplished by the Lemieux- Johnson procedure (Scheme 62).75 The reaction had previously been carried out in aqueous tert-butanol. The choice of this reaction medium was not optimal, in that the starting material olefin tended to coalesce into oily droplets in this solvent system. This retarded the rate of the Lemieux-Johnson reaction, favouring instead cyclization to undesired triazolines 240 and 241. Solvent systems such as aqueous tetrahydrofuran and, especially, aqueous acetone proved to be better. Still, the desired products 201 and 214 were obtained in only 25-35% overall yield from anilines 237 and 238 respectively, after flash chromatographic purification.   (a) OsO4, NaIO4, acetone, H2O, RT (25% with Bn over 2 steps from 237; 33% with BOM over 2 steps from 238). Scheme 62: Synthesis of aldehydes 201 and 214  56  3. Synthesis of benzazocenols 249 and 211 3.1 Allylation of aldehydes 201 and 214  The organometallic species 185 was prepared in situ by the Reetz method,87 which involves transmetallation of lithiated allyltrimethylsilane 242 with titanium isopropoxide (Scheme 63). In turn, 242 was generated by deprotonation of allyltrimethylsilane 184 with sec- butyllithium / tetramethyl-1,2-ethylenediamine, as described by Fleming.98 Nucleophilic addition of 185 to aldehydes 201 and 214 gave homoallylic alcohols 243 and 244 respectively.  (a) s-BuLi, TMEDA, THF, −40°C; (b) Ti(Oi-Pr)4, −78°C (42% with Bn; 47% with BOM) (BOSM: 65% with Bn; 70% with BOM). Scheme 63: Allylation of 201 and 214  Several difficulties were encountered in the course of this step. First of all, the yields were variable: Yields as high as 65% and 46% were obtained with the benzyl- and the benzyloxy methyl-protected substrates respectively. However, the yield of this step was more commonly in the neighbourhood of 40% with either substrate, and in a few cases the reaction failed altogether. Even with great care given to the reaction conditions (titration of the sec- butyllithium according to the method of Kofron just before the reaction,99 use of freshly distilled tetramethyl-1,2-ethylenediamine and titanium isopropoxide, etc.), this reaction remained problematic. This is contrary to our past experience with the sequences leading to FR-66979 (Scheme 44)9 and to mitomycin intermediate 208 (Scheme 49).97 57  Secondly, the addition of 185 to either susbtrates 201 or 214 afforded a 1:1 mixture of two product diastereoisomers (Figure 6). This was completely unexpected: it will be recalled that the addition of 185 to the aldehydes employed in the synthesis of FR-66979 (cf. compound 181, Scheme 44 and Figure 3)9 and of mitomycin precursor 208 (cf. compound 202, Scheme 49) afforded substantially one (within the limits of 500 MHz 1H NMR spectroscopy) diastereomer of the product. By contrast, the relative configurations of the two isomers obtained in the course of the above reaction remain undetermined.  Figure 6: Diastereoisomeric mixtures of 243 and 244  A final problem of a technical nature was also observed. The workup of the reaction produced significant amounts of a pasty precipitate of titanium dioxide made the filtration step significantly long. In all likelihood, this material entrained a portion of the product, contributing to lowering the yield. Purification of the product was necessary before the next step and was achieved by flash column chromatography. However, the two diastereomers were inseparable. The essentially 1:1 mixture thereof was thus advanced to the following step.  3.2 Synthesis of triazolines 203 and 245  The next step was an intramolecular 1,3-dipolar cycloaddition between the azide and the alkene functionalities of 243 and 244 to give triazolines 203 and 245 respectively (Scheme 64). This requires heating the starting material dissolved in toluene at 90oC for 4 hours. Past 58  experience has shown that atmospheric oxygen dissolved in the medium is deleterious to the reaction, and must be carefully removed. This was best accomplished by bubbling argon through the sonicated solution.  (a) tol, 90°C (55% with Bn; 47% with BOM). Scheme 64: Synthesis of crystalline triazolines 203 and 245  The use of carefully purified starting material and the cautious deoxygenation of the reaction mixture ensured the formation of a triazoline of high purity, which in most cases crystallised upon solvent evaporation, permitting structural elucidation by single-crystal X-ray diffractometry. The ORTEP of compounds 203 and 245 appears in figure 7 and 8 respectively.  Figure 7: ORTEP of triazoline 203  59   Figure 8: ORTEP of triazoline 245  The reaction provided a single diastereomer of the triazoline in 45-50% yield, even though the reaction was started with a 1:1 mixture of unassigned diastereomers. This suggests that only diastereomers 202 and 213 cyclized to products in excellent yield. The cyclization mechanism is shown in Scheme 65.  Scheme 65: Mechanism of cyclization of 202 and 213  3.3 Molecular nitrogen extrusion and homo-Brook rearrangement  Ultra-violet irradiation of triazolines 203 and 245 led to aziridines 204 and 212 (Scheme 66). As in the previous step, it was crucial to deoxygenate the reaction mixture by bubbling 60  argon through the sonicated solution. Contrary to the case of triazoline 180, which required only 20 minutes for photochemical conversion into the corresponding aziridine (Scheme 45),9 photoextrusion of molecular nitrogen from 203 and 245 needed several hours of irradiation to proceed. Therefore the reaction was usually left running overnight. The prolonged irradiation might have promoted the formation of side products, necessitating flash chromatographic purification to isolate the aziridine. It is worth noting that, while the yields of desired products were usually quite high, the reaction was not always reproducible, and in some cases, no product was obtained. a BnO N N N MeO BnO OPG OH TMS H BnO MeO BnO N OPG H TMS OH PG = Bn, 203 PG = BOM, 245 PG = Bn, 204 PG = BOM, 212 (a) THF, hυ, RT (81% with Bn; 82% with BOM). Scheme 66: Synthesis of aziridines 204 and 212  The crucial aziridine fragmentation-ring expansion sequence leading to benzazocenols 249 and 211 requires treatment of aziridines 204 and 212 with a basic agent. The presumed mechanism of this transformation86 involves reversible deprotonation of the OH group and subsequent homo-Brook rearrangement90 of alkoxide 246 to a species which behaves as if it were carbanion 248. Such an agent may partition between two reaction pathways: fragmentation of the aziridine to benzazocenols 249 and 211, or Peterson olefination65 to compound 250 (Scheme 67). In contrast to the case of substrate 179 (Scheme 45),9 for which tetra-n-butylammonium hydroxide was the reagent of choice, tetra-n-butylammonium fluoride is superior for achieving the target transformation on the mitomycin series. The reaction gave exclusively benzazocenols 249 and 211 and no Peterson olefination product 250 was detected. 61  N H OBn OPG MeO OBn a 250 BnO MeO BnO N BnO MeO BnO HN OPG OH OPG H TMS OH BnO MeO BnO N 246 OPG H Si O BnO MeO BnO N 247 OPG H Si O BnO MeO BnO N 248 OPG H OTMS a PG = Bn, 249 PG = BOM, 211 PG = Bn, 204 PG = BOM, 212  (a) TBAF, DMF, −20°C. Scheme 67: Synthesis of benzazocenols 249 and 211  Anilines 249 and 211 are air-sensitive materials on account of the high degree of electron density present in the aromatic nucleus. Therefore, they were immediately protected as benzyl carbamates to give compounds 205 and 251 (Scheme 68), which arose in moderate overall yield from aziridines 204 and 212 respectively. Not unexpectedly, the NMR spectra of 205 and 251 revealed the presence of a 1:1 mixture of two slowly interconverting rotamers of the benzyloxycarbonyl group, as apparent from the fact that all signals in the 1H and 13C spectra were doubled.  (a) CbzCl, NaHCO3, THF, RT (45% with Bn over 2 steps from 204; 40% with BOM over 2 steps from 212). Scheme 68: Cbz protection of 249 and 211   62  4. Synthesis of aziridine 209  The final stage of this research aimed to study the installation of an aziridine functionality onto the olefinic linkage of BOM-protected benzazocenol 251. In accord with principles developed earlier by Dr. J. C. Andrez (Scheme 50),97 carbamate 252 was prepared by reaction of 251 with tosyl isocyanate (Scheme 69). P-toluene sulfonamide, the product of hydrolysis of tosyl isocyanate, proved to be difficult to separate from intermediate 252 even by flash chromatography. Therefore, it was critical to employ equimolar amounts of isocyanate and substrate in this step. Reaction of 252 with elemental iodine77 induced cyclization to oxazolidinone 210 in excellent yield. Whereas the product was clearly obtained as a single diastereomer, it was not possible, at this stage, to determine its relative configuration. The action of methanolic K2CO3 on 210 triggered nucleophilic opening of the activated oxazolidinone ring and SN2 displacement of iodide, resulting in formation of aziridine 253. Again, this material was clearly one diastereomer, but its configuration remains undetermined. Finally, Dess-Martin oxidation76 of the free alcohol gave ketone 209, again as a single diastereomer of unknown relative configuration of the aziridine ring vs. the side chain.100      (a) TsNCO, THF, RT (40%); (b) I2, NaHCO3, MeCN, RT (98%); (c) K2CO3, MeOH, Et2O,  RT (83%); (d) DMP, CH2Cl2, RT (40%). Scheme 69: Synthesis of benzazocenone 209  253 210 a c 209 d 251 MeO OBOM N BnO BnO Cbz OH MeO OBOM N BnO BnO Cbz N O O I Ts MeO OBOM N BnO BnO Cbz OH N Ts MeO OBOM N BnO BnO Cbz O N Ts 252 MeO OBOM N BnO BnO Cbz O NHTs O b 63  An important comment is in order at this juncture. Diastereomerically pure ketone 209 can either be 254 or 256 (Scheme 70). In either case, its conversion to a naturally occurring mitomycin should be possible. Indeed, hydrogenolysis of all benzyl-type protecting groups and subsequent air-oxidation of the liberated hydroquinone would produce the tetracyclic intermediates 255 or 257. The relative configuration of aziridine and side chain in 255 coincides with that of mitomycins A and C; whereas the configuration of 257 correlates with mitomycin B.  (a) H2, Pd/C, py, RT; (b) air, RT. 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Chem. 1976, 41, 1879. 100 Compounds 205, 209, 210, 252 and 253 were only partially characterized.  70  APPENDIX (EXPERIMENTAL SECTION)  Experimental Protocols........................................................................................................... 74 Preparation of 2,4-dimethoxy-3-methylbenzaldehyde 224 .................................................... 76 Preparation of 2,4-dimethoxy-3-methylphenyl formate 225 .................................................. 79 Preparation of 2,4-dimethoxy-3-methylphenol 46 ................................................................. 82 Preparation of 4-(benzyloxy)but-2-yn-1-ol 228 ..................................................................... 85 Preparation of 4-(benzyloxymethoxy)but-2-yn-1-ol 227 ....................................................... 88 Preparation of (E)-4-(benzyloxy)but-2-en-1-ol, trans-229..................................................... 91 Preparation of (E)-4-(benzyloxymethoxy)but-2-en-1-ol, trans-223....................................... 94 Preparation of (Z)-4-(benzyloxy)but-2-en-1-ol, cis-229......................................................... 97 Preparation of (Z)-4-(benzyloxymethoxy)but-2-en-1-ol, cis-223......................................... 100 Preparation of (E)-1-(4-(benzyloxy)but-2-enyloxy)-2,4-dimethoxy-3-methylbenzene, trans-197............................................................................................................................... 103 Preparation of (E)-1-(4-(benzyloxymethoxy)but-2-enyloxy)-2,4-dimethoxy-3- methylbenzene, trans-222..................................................................................................... 106 Preparation of (Z)-1-(4-(benzyloxy)but-2-enyloxy)-2,4-dimethoxy-3-methylbenzene, cis-197................................................................................................................................... 109 Preparation of (Z)-1-(4-(benzyloxymethoxy)but-2-enyloxy)-2,4-dimethoxy-3- methylbenzene, cis-222 ........................................................................................................ 112 Preparation of 6-(1-(benzyloxy)but-3-en-2-yl)-2,4-dimethoxy-3- ....................................... 115 methylphenol 198 ................................................................................................................. 115 Preparation of 6-(1-(benzyloxymethoxy)but-3-en-2-yl)-2,4-dimethoxy-3-methylphenol 231 ........................................................................................................................................ 118 Preparation of 5-(1-(benzyloxy)but-3-en-2-yl)-3-methoxy-2-methylcyclohexa-2,5-diene-1,4- dione 232 .............................................................................................................................. 121 71  Preparation of 5-(1-(benzyloxymethoxy)but-3-en-2-yl)-3-methoxy-2-methylcyclohexa-2,5- diene-1,4-dione 233 .............................................................................................................. 124 Preparation of 5-(1-(benzyloxy)but-3-en-2-yl)-3-methoxy-2-methylbenzene-1,4-diol 234 127 Preparation of 5-(1-(benzyloxymethoxy)but-3-en-2-yl)-3-methoxy-2-methylbenzene-1,4-diol 235 ........................................................................................................................................ 130 Preparation of (5-(1-(benzyloxy)but-3-en-2-yl)-3-methoxy-2-methyl-1,4- phenylene)bis(oxy)bis(methylene)dibenzene 199 ................................................................ 133 Preparation of (5-(1-(benzyloxymethoxy)but-3-en-2-yl)-3-methoxy-2-methyl-1,4- phenylene)bis(oxy)bis(methylene)dibenzene 221 ................................................................ 136 Preparation of (2-(1-(benzyloxy)but-3-en-2-yl)-6-methoxy-5-methyl-3-nitro-1,4- phenylene)bis(oxy)bis(methylene)dibenzene 236 ................................................................ 139 Preparation of (2-(1-(benzyloxymethoxy)but-3-en-2-yl)-6-methoxy-5-methyl-3-nitro-1,4- phenylene)bis(oxy)bis(methylene)dibenzene 220 ................................................................ 142 Preparation of 2,5-bis(benzyloxy)-6-(1-(benzyloxy)but-3-en-2-yl)-4-methoxy-3- methylaniline 237 ................................................................................................................. 145 Preparation of 2,5-bis(benzyloxy)-6-(1-(benzyloxymethoxy)but-3-en-2-yl)-4-methoxy-3- methylaniline 238 ................................................................................................................. 148 Preparation of (2-azido-3-(1-(benzyloxy)but-3-en-2-yl)-5-methoxy-6-methyl-1,4- phenylene)bis(oxy)bis(methylene)dibenzene 200 ................................................................ 151 Preparation of (2-azido-3-(1-(benzyloxymethoxy)but-3-en-2-yl)-5-methoxy-6-methyl-1,4- phenylene)bis(oxy)bis(methylene)dibenzene 239 ................................................................ 154 Preparation of 2-(2-azido-3,6-bis(benzyloxy)-5-methoxy-4-methylphenyl)-3- (benzyloxy)propanal 201 ...................................................................................................... 157 Preparation of 2-(2-azido-3,6-bis(benzyloxy)-5-methoxy-4-methylphenyl)-3- (benzyloxymethoxy)propanal 214 ........................................................................................ 160 Preparation of 2-(2-azido-3,6-bis(benzyloxy)-5-methoxy-4-methylphenyl)-1-(benzyloxy)-4- (trimethylsilyl)hex-5-en-3-ol 243 ......................................................................................... 163 72  Preparation of 2-(2-azido-3,6-bis(benzyloxy)-5-methoxy-4-methylphenyl)-1- (benzyloxymethoxy)-4-(trimethylsilyl)hex-5-en-3-ol 244 ................................................... 166 Preparation of (3aS,4S,5R,6R)-7,10-bis(benzyloxy)-6-(benzyloxymethyl)-8-methoxy-9- methyl-4-(trimethylsilyl)-3a,4,5,6-tetrahydro-3H-benzo[f][1,2,3]triazolo[1,5-a]azepin-5-ol 203 ........................................................................................................................................ 170 Preparation of (3aS,4S,5R,6R)-7,10-bis(benzyloxy)-6-((benzyloxymethoxy)methyl)-8- methoxy-9-methyl-4-(trimethylsilyl)-3a,4,5,6-tetrahydro-3H-benzo[f][1,2,3]triazolo[1,5- a]azepin-5-ol 245 .................................................................................................................. 174 Preparation of (1aS,2S,3R,4R)-5,8-bis(benzyloxy)-4-(benzyloxymethyl)-6-methoxy-7- methyl-2-(trimethylsilyl)-1a,2,3,4-tetrahydro-1H-azirino[1,2-a] benzo[f]azepin-3-ol 204 . 178 Preparation of (1aS,2S,3R,4R)-5,8-bis(benzyloxy)-4-((benzyloxymethoxy)methyl)-6- methoxy-7-methyl-2-(trimethylsilyl)-1a,2,3,4-tetrahydro-1H-azirino[1,2-a]benzo[f]azepin-3- ol 212 .................................................................................................................................... 181 Preparation of ((5R,6S,Z)-7,10-bis(benzyloxy)-6-(benzyloxymethyl)-8-methoxy-9-methyl- 1,2,5,6-tetrahydrobenzo[b]azocin-5-ol 249 .......................................................................... 184 Preparation of (5S,6R,Z)-7,10-bis(benzyloxy)-6-((benzyloxymethoxy)methyl)-8-methoxy-9- methyl-1,2,5,6-tetrahydrobenzo[b]azocin-5-ol 211.............................................................. 187 Preparation of (5R,6S,Z)-benzyl 7,10-bis(benzyloxy)-6-(benzyloxymethyl)-5-hydroxy-8- methoxy-9-methyl-5,6-dihydrobenzo[b]azocine-1(2H)-carboxylate 205 ............................ 190 Preparation of (5S,6R,Z)-benzyl 7,10-bis(benzyloxy)-6-((benzyloxymethoxy)methyl)-5- hydroxy-8-methoxy-9-methyl-5,6-dihydrobenzo[b]azocine-1(2H)-carboxylate 251 .......... 191 Preparation of (5R,6S,Z)-benzyl 7,10-bis(benzyloxy)-6-((benzyloxymethoxy)methyl)-8- methoxy-9-methyl-5-(tosylcarbamoyloxy)-5,6-dihydrobenzo[b]azocine-1(2H)-carboxylate 252 ........................................................................................................................................ 194 Preparation of (3aR,4R,11S,11aS)-benzyl 7,10-bis(benzyloxy)-11- ((benzyloxymethoxy)methyl)-4-iodo-9-methoxy-8-methyl-2-oxo-3-tosyl-3,3a,4,5,11,11a- hexahydrobenzo[b]oxazolo[5,4-e]azocine-6(2H)-carboxylate 210...................................... 195 73  Preparation of (1aS,8S,9S,9aS)-benzyl 4,7-bis(benzyloxy)-8-((benzyloxymethoxy)methyl)-9- hydroxy-6-methoxy-5-methyl-1-tosyl-1a,2,9,9a-tetrahydro-1H-azirino[2,3- f]benzo[b]azocine-3(8H)-carboxylate 253 ........................................................................... 196 Preparation of (1aS,8S,9aS)-benzyl 4,7-bis(benzyloxy)-8-((benzyloxymethoxy)methyl)-6- methoxy-5-methyl-9-oxo-1-tosyl-1a,2,9,9a-tetrahydro-1H-azirino[2,3-f]benzo[b]azocine- 3(8H)-carboxylate 209.......................................................................................................... 198 X-ray Structure Report of (3aS,4S,5R,6R)-7,10-bis(benzyloxy)-6-(benzyloxymethyl)-8- methoxy-9-methyl-4-(trimethylsilyl)-3a,4,5,6-tetrahydro-3H-benzo[f][1,2,3]triazolo[1,5- a]azepin-5-ol 203 .................................................................................................................. 199 X-ray Structure Report of (3aS,4S,5R,6R)-7,10-bis(benzyloxy)-6- ((benzyloxymethoxy)methyl)-8-methoxy-9-methyl-4-(trimethylsilyl)-3a,4,5,6-tetrahydro- 3H-benzo[f][1,2,3]triazolo[1,5-a]azepin-5-ol 245................................................................ 217  74  Experimental Protocols  All reagents and solvents were commercial products used without further purification except THF (freshly distilled from sodium / benzophenone under argon) and CH2Cl2 (freshly distilled from calcium hydride under argon). Commercial s-BuLi was titrated against N- benzylbenzamide in THF at −78 °C until persistence of a light blue color. Flash chromatography columns were performed on Silicycle 230 - 400 mesh silica gel. Analytic and preparative TLC was carried out with Merck silica gel 60 plates with fluorescent indicator. Spots were visualized with UV light. All reactions were performed under dry argon atmosphere in flame- or oven-dried flasks equipped with TeflonTM stirbars. All flasks were fitted with rubber septa for the introduction of substrates, reagents, and solvents via syringes.  All spectra were recorded from batches of purified compounds. 1H and 13C NMR spectra were recorded on Bruker models AV-300 (300 MHz for 1H and 75.5 MHz for 13C), spectrometer using deuteriochloroform (CDCl3) as the solvent. Chemical shifts are reported in parts per million (ppm) on the δ scale and coupling constants, J, are in hertz (Hz). Multiplicities are reported as “s” (singlet), “d” (doublet), “t” (triplet), “q” (quartet), “dd” (doublet of doublets), “ddd” (doublet of doublets of doublets), “dt” (doublet of triplets), “m” (multiplet) and “br” (broad). Infrared (IR) spectra (cm−1) were recorded on a Perkin-Elmer model 1710 Fourier transform spectrophotometer from films deposited on NaCl plates. Low-resolution mass spectra (m/z) were obtained in the electrospray (ESI) mode on a Waters Micromass ZQ mass spectrometer. High-resolution mass spectra (m/z) were recorded in the electrospray (ESI) mode on a Micromass LCT mass spectrometer by the UBC Mass Spectrometry laboratory. Melting points (uncorrected) were measured on a Mel-Temp apparatus. X-ray structures 75  measurments were collected on a Bruker X8 APEX II diffractometer with graphite monochromated Mo-Kα radiation by the UBC Structural Chemistry laboratory. 76  Preparation of 2,4-dimethoxy-3-methylbenzaldehyde 224  POCl3 (120mL, 1.31mol) was added dropwise to DMF (200mL 2.60mol) at 0°C. The reaction mixture was stirred at room temperature for 30 minutes and 2,6-dimethoxytoluene (94.7g, 0.62mol) was added. The reaction mixture was stirred at 120°C for 3 hours, and then cooled down to room temperature. An aqueous solution of AcONa (100g in 600mL) was added. The reaction mixture was stirred at room temperature overnight. The precipitate was filtered and washed with water (200mL). The filtrate was extracted with Et2O (3x250mL). The precipitate was dissolved in Et2O, combined with the organic extracts and washed with water (5x250mL), brine (250mL) dried over MgSO4 and concentrated to afford aldehyde 224 (87.1g, 78%) as a brown solid.  1H NMR:  10.24 (1H, s), 7.75 (1H, d, J = 8.8), 6.75 (1H, d, J = 8.8), 3.91 (3H, s), 3.87 (3H, s), 2.17 (3H, s) 13C NMR: 189.2, 164.0, 162.6, 127.9, 122.8, 120.1, 106.5, 63.2, 55.9, 8.5 IR: 2942, 2842, 1678, 1592, 1461, 1277, 1255, 1107, 1003, 808, 780, 520 MS:  203.2 [M + Na]+ HRMS:  calcd for C10H12O3:   203.0684 [M + Na]+ found:     203.0680 [M + Na]+ mp:   53°C  77  10 9 8 7 6 5 4 3 2 1 ppm  Figure 1: 1H NMR spectrum of 224  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 2: 13C NMR spectrum of 224  78   80  82  84  86  88  90  92  94  96  98  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 3: IR spectrum of 224 79  Preparation of 2,4-dimethoxy-3-methylphenyl formate 225  Aldehyde 224 (87.0g, 482.7mmol) was dissolved in CH2Cl2 (2L) and m-CPBA (125.0g, 724.1mmol) was added portionwise. The reaction mixture was stirred at room temperature overnight and CH2Cl2 was evaporated. The solid obtained was dissolved in AcOEt (800mL) and a saturated aqueous solution of NaHCO3 (600mL) was added. After stirring for 10 minutes, the organic layer was separated, washed with brine (400mL), dried over MgSO4 and concentrated to afford formate 225 (87.4g, 92%) as colorless oil.  1H NMR:  8.27 (1H, s), 6.92 (1H, d, J = 8.9), 6.61 (1H, d, J = 8.9), 3.82 (3H, s), 3.74 (3H, s), 2.17 (3H, s) 13C NMR: 160.1, 156.7, 150.3, 136.8, 121.4, 119.3, 105.7, 60.8, 55.8, 9.2 IR: 2942, 2838, 1763, 1742, 1599, 1485, 1239, 1108, 842, 787 MS:  219.2 [M + Na]+ HRMS:  calcd for C10H12O4:   219.0633 [M + Na]+ found:     219.0631 [M + Na]+ 80  10 9 8 7 6 5 4 3 2 1 ppm  Figure 4: 1H NMR spectrum of 225  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 5: 13C NMR spectrum of 225  81   80  82  84  86  88  90  92  94  96  98  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 6: IR spectrum of 225 82  Preparation of 2,4-dimethoxy-3-methylphenol 46  Formate 225 (87.4g, 445.5mmol) was dissolved in MeOH (300mL) and K2CO3 (75.0g, 542.7mmol) was added. The reaction mixture was stirred at room temperature for 45 minutes. Water (400mL) and AcOEt (300mL) were added. The aqueous layer was separated and washed with AcOEt (2x400mL). The organic layers were combined, washed with brine (250mL), dried over MgSO4 and and concentrated to afford phenol 46 (74.8g, 99%) as a light orange oil.  1H NMR:  6.77 (1H, d, J = 8.8), 6.55 (1H, d, J = 8.8), 5.45 (1H, s br), 3.78 (6H, s), 2.19 (3H, s) 13C NMR: 151.9, 146.0, 142.9, 120.0, 111.7, 106.7, 60.8, 56.0, 9.31 IR: 3416, 2940, 2833, 1488, 1261, 1102, 1016, 731 MS:  191.2 [M + Na]+ HRMS:  calcd for C10H12O3:   191.0684 [M + Na]+ found:     191.0681 [M + Na]+  83  10 9 8 7 6 5 4 3 2 1 ppm  Figure 7: 1H NMR spectrum of 46  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 8: 13C NMR spectrum of 46  84   94.0  94.5  95.0  95.5  96.0  96.5  97.0  97.5  98.0  98.5  99.0  99.5  100.0 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 9: IR spectrum of 46 85  Preparation of 4-(benzyloxy)but-2-yn-1-ol 228  NaH (60%, 14.0g, 350.0mmol) was washed with hexanes and suspended in DMF (450mL) at 0°C. 2-butyne-1,4-diol (226, 60.0g, 696.9mmol) was dissolved in DMF (250mL) and added dropwise onto the NaH suspension over 15 minutes.  The reaction mixture was stirred at 0°C for 1 hour. BnBr (41.5mL, 349.5mmol) was added dropwise over 30 minutes. The reaction mixture was stirred at 0°C for 1 hour, warmed to room temperature and stirred for an extra hour. The reaction mixture was poured on a saturated aqueous solution of NH4Cl (250mL) at 0°C and extracted with Et2O (700mL). The organic phase was washed with water (3x500mL), brine (500mL) and dried over MgSO4. After solvent evaporation, the crude was filtered on silica gel (AcOEt/hexanes 10/90 then AcOEt 100%) to yield mono-protected diol 228 (26.6g, 43%) as a pale yellow oil.  1H NMR:  7.38-7.30 (5H, m), 4.60 (2H, AB q, overlapping inner lines, J = 9.9), 4.31 (2H, t, J = 1.8), 4.22 (2H, t, J = 1.8), 2.08 (1H, s br) 13C NMR: 137.1, 128.5 (2 overlapping resonances), 128.1 (2 overlapping resonances), 127.9, 84.9, 81.7, 71.7, 57.4, 51.0 IR: 3374, 3030, 2858, 1496, 1454, 1353, 1123, 1070, 1015, 742, 698 MS:  199.3 [M + Na]+ HRMS:  calcd for C11H12O2:   199.0735 [M + Na]+ found:     199.0733 [M + Na]+  86  10 9 8 7 6 5 4 3 2 1 ppm  Figure 10: 1H NMR spectrum of 228  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 11: 13C NMR spectrum of 228  87   98.0  98.2  98.4  98.6  98.8  99.0  99.2  99.4  99.6  99.8  100.0 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 12: IR spectrum of 228 88  Preparation of 4-(benzyloxymethoxy)but-2-yn-1-ol 227  NaH (60%, 1.2g, 30.0mmol) was washed with hexanes and suspended in DMF (20mL) at 0°C. 2-butyne-1,4-diol (226, 5.0g, 58.1mmol) was dissolved in DMF (20mL) and added dropwise onto the NaH suspension over 15 minutes. The reaction mixture was stirred at 0°C for 1 hour. BOMCl (5.4mL, 29.2mmol) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour, warmed to room temperature and stirred for an extra hour. The reaction mixture was poured on a saturated aqueous solution of NH4Cl (20mL) at 0°C and extracted with Et2O (70mL). The organic phase was washed with water (3x50mL), brine (50mL) and dried over MgSO4. After solvent evaporation, the crude was filtered on silica gel (AcOEt/hexanes, 10/90 then AcOEt 100%) to yield mono-protected diol 227 (4.54g, 76%) as a pale yellow oil.  1H NMR:  7.40-7.30 (5H, m), 4.85 (2H, s), 4.64 (2H, s), 4.32 (2H, m), 4.29 (2H, m), 2.17 (1H, s br) 13C NMR: 137.5, 128.5 (2 overlapping resonances), 127.9 (2 overlapping resonances), 127.8, 93.0, 84.8, 81.2, 69.7, 54.7, 50.9 IR: 3419, 2890, 1455, 1374, 1167, 1045, 1027, 742, 699, 606 MS:  229.3 [M + Na]+ HRMS:  calcd for C12H14O3:   229.0841 [M + Na]+ found:     229.0836 [M + Na]+  89  10 9 8 7 6 5 4 3 2 1 ppm  Figure 13: 1H NMR spectrum of 227  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 14: 13C NMR spectrum of 227  90   66  68  70  72  74  76  78  80  82  84  86  88  90  92  94  96  98  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 15: IR spectrum of 227 91  Preparation of (E)-4-(benzyloxy)but-2-en-1-ol, trans-229  Alkyne 228 (4.0g, 22.7mmol) was dissolved in THF (45mL). A solution of Vitride™ (65% in toluene, 13.8mL, 45.5mmol) in toluene (1.3mL) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours. A H2SO4 aqueous solution (10%, 70mL) was added dropwise and the reaction mixture was extracted with Et2O (70mL). The organic layer was washed with water (3x50mL), brine (50mL), dried over MgSO4 and concentrated to afford pure alkene trans-229 (2.5g, 70%) as a pale yellow oil.  1H NMR:  7.36-7.27 (5H, m), 5.95-5.78 (2H, m), 4.53 (2H, s), 4.12 (2H, m), 4.03 (2H, m), 2.50 (1H, s br) 13C NMR: 138.1, 132.5, 128.4 (2 overlapping resonances), 127.8 (2 overlapping resonances), 127.7, 127.5, 72.3, 70.1, 62.7 IR: 3418, 3030, 2856, 1956, 1674, 1496, 1454, 1095, 1005, 973, 740, 699 MS:  201.3 [M + Na]+ HRMS:  calcd for C11H14O2:   201.0891 [M + Na]+ found:     201.0897 [M + Na]+  92  10 9 8 7 6 5 4 3 2 1 ppm  Figure 16: 1H NMR spectrum of trans-229  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 17: 13C NMR spectrum of trans-229  93   15  20  25  30  35  40  45  50  55  60  65  70  75  80  85  90  95  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 18: IR spectrum of trans-229 94  Preparation of (E)-4-(benzyloxymethoxy)but-2-en-1-ol, trans-223 OH OBOM  Alkyne 227 (9.0g, 43.6mmol) was dissolved in THF (100mL). A solution of Vitride™ (65% in toluene, 31mL, 108.5mmol) in toluene (3mL) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours. A H2SO4 aqueous solution (10%, 150mL) was added dropwise and the reaction mixture was extracted with Et2O (150mL). The organic layer was washed with water (3x90mL), brine (90mL), dried over MgSO4 and concentrated to afford pure alkene trans-223 (7.6g, 84%) as a pale yellow oil.  1H NMR:  7.40-7.28 (5H, m), 5.97-5.79 (2H, m), 4.79 (2H, s), 4.63 (2H, s), 4.19- 4.14 (4H, m), 1.46 (1H, s br) 13C NMR: 137.8, 132.3, 128.4 (2 overlapping resonances), 127.9 (2 overlapping resonances), 127.7, 127.4, 93.9, 69.4, 67.4, 63.0 IR: 3407, 3031, 2938, 2870, 1455, 1379, 1167, 1104, 1040, 1027, 739, 698 MS:  231.3 [M + Na]+ HRMS:  calcd for C12H16O3:   231.0997 [M + Na]+ found:     231.0995 [M + Na]+  95  10 9 8 7 6 5 4 3 2 1 ppm Figure 19: 1H NMR spectrum of trans-223  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 20: 13C NMR spectrum of trans-223  96   91.0  91.5  92.0  92.5  93.0  93.5  94.0  94.5  95.0  95.5  96.0  96.5  97.0  97.5  98.0  98.5  99.0  99.5  100.0 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 21: IR spectrum of trans-223 97  Preparation of (Z)-4-(benzyloxy)but-2-en-1-ol, cis-229  NaH (60%, 0.24g, 6.1mmol) was washed with hexanes and suspended in DMF (4mL) at 0°C. Cis-2-butene-1,4-diol (230, 1.0mL, 12.2mmol) was dissolved in DMF (2mL) and added dropwise onto the NaH suspension.  The reaction mixture was stirred at 0°C for 1 hour. BnBr (0.72mL, 6.1mmol) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour, warmed to room temperature and stirred for an extra hour. The reaction mixture was poured on a saturated aqueous solution of NH4Cl (5mL) at 0°C and extracted with Et2O (10mL). The organic phase was washed with water (3x8mL), brine (8mL) and dried over MgSO4. After solvent evaporation, the crude was filtered on silica gel (AcOEt/hexanes 10/90 then AcOEt 100%) to yield mono-protected diol cis-229 (836mg, 66%) as a colorless oil.  1H NMR:  7.36-7.28 (5H, m), 5.86-5.70 (2H, m), 4.53 (2H, s), 4.16 (2H, d, J = 5.8) 4.10 (2H, d, J = 6.1), 2.26 (1H, s br) 13C NMR: 137.8, 132.4, 128.4, 128.1 (2 overlapping resonances), 127.9, 127.8 (2 overlapping resonances), 72.5, 65.5, 58.6 IR: 3405, 3029, 2861, 1956, 1647, 1496, 1454, 1071, 1028, 739, 699 MS:  201.3 [M + Na]+ HRMS:  calcd for C11H14O2:   201.0891 [M + Na]+ found:     201.0898 [M + Na]+  98  10 9 8 7 6 5 4 3 2 1 ppm  Figure 22: 1H NMR spectrum of cis-229  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 23: 13C NMR spectrum of cis-229  99   30  35  40  45  50  55  60  65  70  75  80  85  90  95  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 24: IR spectrum of cis-229 100  Preparation of (Z)-4-(benzyloxymethoxy)but-2-en-1-ol, cis-223  NaH (60%, 0.5g, 12.0mmol) was washed with hexanes and suspended in DMF (10mL) at 0°C. cis-2-butene-1,4-diol (230, 2.13g, 24.8mmol) was dissolved in DMF (10mL) and added dropwise onto the NaH suspension. The reaction mixture was stirred at 0°C for 1 hour. BOMCl (2.56g, 12.2mmol) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour, warmed to room temperature and stirred for an extra hour. The reaction mixture was poured on a saturated aqueous solution of NH4Cl (20mL) at 0°C and extracted with Et2O (35mL). The organic phase was washed with water (3x25mL), brine (25mL) and dried over MgSO4. After solvent evaporation, the crude was filtered on silica gel (AcOEt/hexanes 10/90 then AcOEt 100%) to yield mono-protected diol cis-223 (3.2g, 67%) as a colorless oil.  1H NMR:  7.37-7.28 (5H, m), 5.88-5.79 (1H, m), 5.74-5.65 (1H, m), 4.78 (2H, s), 4.63 (2H, s), 4.22-4.17 (4H, m), 2.27 (1H, s br) 13C NMR: 137.6, 132.7, 128.5 (2 overlapping resonances), 127.9 (2 overlapping resonances), 127.8, 127.6, 93.6, 69.5, 62.8, 58.4 IR: 3407, 3031, 2938, 2870, 1455, 1379, 1167, 1104, 1040, 1027, 739, 698 MS:  231.3 [M + Na]+ HRMS:  calcd for C12H16O3:   231.0997 [M + Na]+ found:     231. 0996 [M + Na]+  101  10 9 8 7 6 5 4 3 2 1 ppm Figure 25: 1H NMR spectrum of cis-223  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 26: 13C NMR spectrum of cis-223  102   78  80  82  84  86  88  90  92  94  96  98  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 27: IR spectrum of cis-223 103  Preparation of (E)-1-(4-(benzyloxy)but-2-enyloxy)-2,4-dimethoxy-3- methylbenzene, trans-197  Phenol 46 (7.88g, 46.9mmol) and alkene trans-229 (8.52g, 47.8mmol) were dissolved in Et2O (75mL) at 0°C. DIAD (7.9mL, 37.5mmol) was added dropwise at 0°C. A solution of PPh3 (12.73g, 48.5mmol) in Et2O (60mL) was added dropwise at 0°C over 1 hour. The reaction mixture was stirred at 0°C for 2 hours and at room temperature overnight. The Ph3PO precipitate was filtered through celite and washed with Et2O (30mL). The filtrate was evaporated and purified by flash column chromatography (AcOEt/hexanes 20/80) to give trans-197 (8.97g, 73%) as a pale yellow oil.  1H NMR:  7.37-7.30 (5H, m), 6.73 (1H, d, J = 8.9), 6.52 (1H, d, J = 8.9), 6.07-5.93 (2H, m), 4.56 (2H, m), 4.53 (2H, s), 4.08 (2H, m), 3.83 (3H, s), 3.79 (3H, s), 2.17 (3H, s) 13C NMR: 152.8, 148.8, 146.0, 138.3, 129.6, 128.6, 128.4 (2 overlapping resonances), 127.8 (2 overlapping resonances), 127.7, 121.2, 111.9, 105.2, 72.2, 70.0, 69.5, 60.4, 55.9, 9.0 IR: 2935, 2856, 1593, 1487, 1257, 1114, 737, 698 MS:  351.2 [M + Na]+ HRMS:  calcd for C20H24O4:   351.1572 [M + Na]+ found:     351.1570 [M + Na]+ 104  10 9 8 7 6 5 4 3 2 1 ppm  Figure 28: 1H NMR spectrum of trans-197  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 29: 13C NMR spectrum of trans-197  105   76  78  80  82  84  86  88  90  92  94  96  98  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 30: IR spectrum of trans-197 106  Preparation of (E)-1-(4-(benzyloxymethoxy)but-2-enyloxy)-2,4-dimethoxy-3- methylbenzene, trans-222  Phenol 46 (550mg, 3.3mmol) and alkene trans-223 (440mg, 2.1mmol) were dissolved in Et2O (20mL) at 0°C. DIAD (0.50mL, 2.4mmol) was added dropwise at 0°C. A solution of PPh3 (700mg, 2.7mmol) in Et2O (20mL) was added dropwise at 0°C over 1 hour. The reaction mixture was stirred at 0°C for 2 hours and at room temperature overnight. The Ph3PO precipitate was filtered through celite and washed with Et2O (5mL). The filtrate was evaporated and purified by flash column chromatography (AcOEt/hexanes 20/80) to give trans-222 as a pale yellow oil (700mg, 93%).  1H NMR:  7.37-7.30 (5H, m), 6.72 (1H, d, J = 8.9), 6.52 (1H, d, J = 8.9), 6.00-5.90 (2H, m), 4.80 (2H, s), 4.63 (2H, s), 4.56 (2H, d, J = 4.2), 4.20 (2H, d, J = 4.2), 3.84 (3H, s), 3.79 (3H, s), 2.15 (3H, s) 13C NMR: 152.8, 148.9, 148.0, 137.8, 129.0, 128.6, 128.4 (2 overlapping resonances), 127.9 (2 overlapping resonances), 127.7, 121.2, 111.7, 105.1, 93.9, 69.44 (2 overlapping resonances), 67.4, 60.4, 55.8, 9.0 IR: 2936, 1743, 1593, 1487, 1378, 1257, 1113, 1040, 737 MS:  381.3 [M + Na]+ HRMS:  calcd for C21H26O5:   381.1678 [M + Na]+ found:     381.1665 [M + Na]+ 107  10 9 8 7 6 5 4 3 2 1 ppm  Figure 31: 1H NMR spectrum of trans-222  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 32: 13C NMR spectrum of trans-222  108   50  55  60  65  70  75  80  85  90  95  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 33: IR spectrum of trans-222 109  Preparation of (Z)-1-(4-(benzyloxy)but-2-enyloxy)-2,4-dimethoxy-3- methylbenzene, cis-197  Phenol 46 (511mg, 3.0mmol) and alkene cis-229 (595mg, 2.9mmol) were dissolved in Et2O (5mL) at 0°C. DIAD (0.72mL, 3.42mmol) was added dropwise at 0°C. A solution of PPh3 (980mg, 3.7mmol) in Et2O (5mL) was added dropwise at 0°C over 1 hour. The reaction mixture was stirred at 0°C for 2 hours and at room temperature overnight. The Ph3PO precipitate was filtered through celite and washed with Et2O (5mL). The filtrate was evaporated and purified by flash column chromatography (AcOEt/hexanes 20/80) to give cis-197 (690mg, 73%) as a pale yellow oil.  1H NMR:  7.36-7.29 (5H, m), 6.68 (1H, d, J = 8.9), 6.50 (1H, d, J = 8.9), 5.96-5.79 (2H, m), 4.59 (2H, d, J = 5.9), 4.52 (2H, s), 4.15 (2H, d, J = 5.9), 3.80 (3H, s), 3.78 (3H, s), 2.16 (3H, s) 13C NMR: 153.0, 148.9, 145.9, 138.1, 129.4, 128.9, 128.4, 127.8 (2 overlapping resonances), 127.7 (2 overlapping resonances), 121.2, 112.0, 105.2, 72.3, 65.9, 65.7, 60.3, 55.9, 8.9 IR: 3029, 2935, 2859, 1486, 1257, 114, 1071, 737, 698 MS:  351.3 [M + Na]+ HRMS:  calcd for C20H24O4:   351.1572 [M + Na]+ found:     351.1563 [M + Na]+ 110  10 9 8 7 6 5 4 3 2 1 ppm  Figure 34: 1H NMR spectrum of cis-197  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 35: 13C NMR spectrum of cis-197  111   80  82  84  86  88  90  92  94  96  98  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 36: IR spectrum of cis-197 112  Preparation of (Z)-1-(4-(benzyloxymethoxy)but-2-enyloxy)-2,4-dimethoxy-3- methylbenzene, cis-222  Phenol 46 (3.20g, 19.0mmol) and alkene cis-223 (4.41g, 21.2mmol) were dissolved in Et2O (70mL) at 0°C. DIAD (4.0mL, 19.0mmol) was added dropwise at 0°C. A solution of PPh3 (5.5g, 21.0mmol) in Et2O (60mL) was added dropwise at 0°C over 1 hour. The reaction mixture was stirred at 0°C for 2 hours and at room temperature overnight. The Ph3PO precipitate was filtered through celite and washed with Et2O (10mL). The filtrate was evaporated and purified by flash column chromatography (AcOEt/hexanes 20/80) to give cis-222 (4.84g, 71%) as a pale yellow oil.  1H NMR:  7.38-7.30 (5H, m), 6.72 (1H, d, J = 8.9), 6.51 (1H, d, J = 8.9), 5.99-5.91 (1H, m), 5.85-5.77 (1H, m), 4.81 (2H, s), 4.65 (2H, s), 4.64 (2H, d, J = 6.3), 4.27 (2H, d, J = 6.3), 3.82 (3H, s), 3.79 (3H, s), 2.15 (3H, s) 13C NMR: 152.9, 148.7, 145.8, 137.8, 129.2, 128.8, 128.5 (3 overlapping resonances), 127.9, 127.7, 121.2, 111.8, 105.1, 93.9, 69.5, 65.5, 63.2, 60.3, 55.8, 9.0 IR: 2936, 2885, 1593, 1486, 1257, 1114, 1048, 698 MS:  381.3 [M + Na]+ HRMS:  calcd for C21H26O5:   381.1678 [M + Na]+ found:     381.1679 [M + Na]+ 113  10 9 8 7 6 5 4 3 2 1 ppm  Figure 37: 1H NMR spectrum of cis-222  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 38: 13C NMR spectrum of cis-222  114   30  35  40  45  50  55  60  65  70  75  80  85  90  95  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 39: IR spectrum of cis-222 115  Preparation of 6-(1-(benzyloxy)but-3-en-2-yl)-2,4-dimethoxy-3- methylphenol 198  197 (8.97g, 27.3mmol) was dissolved in of N,N-dimethylaniline (100mL) and refluxed at 230°C for 3 hours. After the reaction mixture was cooled down to room temperature, a HCl aqueous solution (2M, 100mL) and Et2O (100mL) were added. The organic layer was separated, washed with a HCl aqueous solution (2M, 4x100mL), a saturated aqueous solution of NaHCO3 (100mL), dried over MgSO4 and concentrated to afford 198 (8.74g, 97%) as a pale yellow paste. Note: the same procedure is used to convert either cis or trans-197.  1H NMR:  7.38-7.29 (5H, m), 6.45 (1H, s), 6.15 (1H, ddd, J = 6.8, 10.6, 17.3), 6.07 (1H, s), 5.21 (1H, ddd,  J = 1.5, 1.7, 3.6), 5.20 (1H, dt, J = 1.5, 10.2), 4.59 (2H, s), 4.06-4.00 (1H, m), 3.84-3.78 (2H, m), 3.80 (3H, s), 3.76 (3H, s), 2.18 (3H, s) 13C NMR: 151.4, 146.6, 141.3, 138.1, 137.9, 128.4 (2 overlapping resonances), 127.7 (2 overlapping resonances), 127.6, 124.9, 117.4, 116.1, 106.6, 73.2, 73.1, 60.7, 56.1, 44.2, 9.2 IR: 2937, 2858, 1597, 1489, 1460, 1414, 1122, 737, 698 MS:  351.2 [M + Na]+ HRMS:  calcd for C20H24O4:   351.1572 [M + Na]+ found:     351.1562 [M + Na]+ 116  10 9 8 7 6 5 4 3 2 1 ppm  Figure 40: 1H NMR spectrum of 198  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 41: 13C NMR spectrum of 198  117   90  91  92  93  94  95  96  97  98  99  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 42: IR spectrum of 198 118  Preparation of 6-(1-(benzyloxymethoxy)but-3-en-2-yl)-2,4-dimethoxy-3- methylphenol 231  222 (9.14g, 25.5mmol) was dissolved in of N,N-dimethylaniline (100mL) and refluxed at 230°C for 3 hours. After the reaction mixture was cooled down to room temperature, a HCl aqueous solution (2M, 100mL) and Et2O (100mL) were added. The organic layer was separated, washed with a HCl aqueous solution (2M, 4x100mL), a saturated aqueous solution of NaHCO3 (100mL), dried over MgSO4 and concentrated to afford 231 (9.07g, 98%) as a pale yellow paste. Note: the same procedure is used to convert either cis or trans-222.  1H NMR:  7.37-7.29 (5H, m), 6.45 (1H, s), 6.15 (1H, ddd, J = 6.7, 9.8, 16.5), 5.79 (1H, s), 5.21 (1H, m), 5.18-5.15 (1H, dt, J = 1.5, 5.6), 4.79 and 4.78 (2H, AB q, overlapping inner lines, J = 7.5), 4.56 and 4.52 (2H, AB q, overlapping inner lines, J = 10.4), 4.05-3.98 (1H, m), 3.94-3.91 (2H, m), 3.78 (3H, s), 3.77 (3H, s), 2.16 (3H, s) 13C NMR: 151.4, 146.3, 141.0, 137.8 (2 overlapping resonances), 128.4 (2 overlapping resonances), 127.9 (2 overlapping resonances), 127.8, 124.4, 118.2, 116.1, 106.3, 94.6, 70.6, 69.4, 60.8, 56.1, 43.9, 9.2 IR: 3408, 2937, 2835, 1597, 1460, 1414, 1121, 1040, 698 MS:  381.3 [M + Na]+  119  HRMS:  calcd for C21H26O5:   381.1678 [M + Na]+ found:     381.1670 [M + Na]+   10 9 8 7 6 5 4 3 2 1 ppm  Figure 43: 1H NMR spectrum of 231  120  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 44: 13C NMR spectrum of 231   93.0  93.5  94.0  94.5  95.0  95.5  96.0  96.5  97.0  97.5  98.0  98.5  99.0  99.5  100.0 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 45: IR spectrum of 231 121  Preparation of 5-(1-(benzyloxy)but-3-en-2-yl)-3-methoxy-2-methylcyclohexa- 2,5-diene-1,4-dione 232  198 (8.24g, 25.1mmol) was dissolved in CH2Cl2 (100mL) at 0°C. 70% HNO3 (10mL, 225.1mmol) was added dropwise. The reaction mixture was stirred at 0°C for 10 minutes. A saturated aqueous solution of NaHCO3 (50mL) was added. The solution was extracted with CH2Cl2 (3x100mL) and the organic layers were combined, washed with water (100mL), brine (100mL), dried over MgSO4 and concentrated to yield crude quinone 232 as an orange oil.  1H NMR:  7.36-7.25 (5H, m), 6.52 (1H, d, =0.8), 5.92-5.80 (1H, m), 5.20 (1H, m) 5.17-5.14 (1H, dt, J = 1.2, 6.2), 4.50 (2H, s), 3.95 (3H, s), 3.92-3.82(1H, m), 3.64-3.62 (2H, m), 1.94 (3H, s) 13C NMR: 188.3, 182.6, 156.1, 146.4, 137.8, 135.4, 133.0, 128.5, 128.4 (2 overlapping resonances), 127.7 (3 overlapping resonances), 118.0, 73.1, 71.4, 60.8, 41.9, 8.5 IR: 2917, 2849, 1652, 1607, 1454, 1282, 1100, 737, 698 MS:  335.3 [M + Na]+ HRMS:  calcd for C19H20O4:   335.1259 [M + Na]+ found:     335.1256 [M + Na]+ 122  10 9 8 7 6 5 4 3 2 1 ppm  Figure 46: 1H NMR spectrum of 232  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 47: 13C NMR spectrum of 232  123   90  91  92  93  94  95  96  97  98  99  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 48: IR spectrum of 232 124  Preparation of 5-(1-(benzyloxymethoxy)but-3-en-2-yl)-3-methoxy-2- methylcyclohexa-2,5-diene-1,4-dione 233   231 (9.07g, 25.1mmol) was dissolved in CH2Cl2 (100mL) at 0°C. 70% HNO3 (10mL, 225.1mmol) was added dropwise. The reaction mixture was stirred at 0°C for 10 minutes. A saturated aqueous solution of NaHCO3 (50mL) was added. The solution was extracted with CH2Cl2 (3x100mL) and the organic layers were combined, washed with water (100mL), brine (100mL), dried over MgSO4 and concentrated to give crude quinone 233 as an orange oil.  1H NMR:  7.38-7.29 (5H, m), 6.56 (1H, s), 5.92-5.80 (1H, m), 5.22 (1H, m), 5.18 (1H, m), 4.75 and 4.72 (2H, AB q, overlapping inner lines, J = 10.2), 4.58 and 4.54 (2H, AB q, overlapping inner lines, J = 12.6), 3.98 (3H, s), 3.87-3.80 (1H, m), 3.77-3.75 (2H, m), 1.94 (3H, s) 13C NMR: 188.3, 182.6, 156.0, 146.2, 137.6, 165.3, 133.1, 128.6, 128.4 (2 overlapping resonances), 127.8 (3 overlapping resonances), 118.1, 94.7, 69.7, 69.1, 60.8, 41.9, 8.5 IR: 2944, 1653, 1608, 1454, 1283, 1045, 925, 738, 698 MS:  365.3 [M + Na]+ HRMS:  calcd for C20H22O5:   365.1365 [M + Na]+ found:     365.1355 [M + Na]+  125  10 9 8 7 6 5 4 3 2 1 ppm  Figure 49: 1H NMR spectrum of 233  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 50: 13C NMR spectrum of 233  126   70  72  74  76  78  80  82  84  86  88  90  92  94  96  98  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 51: IR spectrum of 233 127  Preparation of 5-(1-(benzyloxy)but-3-en-2-yl)-3-methoxy-2-methylbenzene- 1,4-diol 234  Quinone 232 was dissolved in THF (65mL) at 0°C. A HCl aqueous solution (3N, 65mL, 195.0mmol) was added slowly, then Zn (30g, 458.8mmol) was added portionwise over 30 minutes while the vapours were condensed. The reaction mixture was stirred at 0°C for 30 minutes, filtered through celite and poured on a saturated aqueous solution of NaHCO3 (150mL). The aqueous layer was separated and extracted with AcOEt (3x100mL). The organic layers were combined, washed with brine (150mL), dried over MgSO4 and concentrated to afford crude hydroquinone 234 as a light brown paste.  1H NMR:  7.35-7.27 (5H, m), 6.36 (1H, s), 6.03 (1H, ddd, J = 6.8, 10.5, 17.3), 6.03 (1H, s br), 5.18-5.10 (2H, m), 4.57 (1H, s, br), 4.56 (2H, s) 3.98-3.91 (1H, m), 3.78 (3H, s), 3.76-3.68 (2H, m), 2.17 (3H, s) 13C NMR: 147.1, 146.5, 141.1, 137.9, 137.5, 128.4 (2 overlapping resonances), 127.8 (2 overlapping resonances), 127.7, 125.6, 116.2, 116.1, 110.4, 73.1, 73.0, 60.7, 43.7, 9.1 IR: 3384, 2937, 2863, 1635, 1456, 1421, 1091, 741, 699 MS:  337.0 [M + Na]+ HRMS:  calcd for C19H22O4:   337.1416 [M + Na]+ found:     337.1411 [M + Na]+ 128  10 9 8 7 6 5 4 3 2 1 ppm  Figure 52: 1H NMR spectrum of 234  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 53: 13C NMR spectrum of 234  129   85  86  87  88  89  90  91  92  93  94  95  96  97  98  99  100  101 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 54: IR spectrum of 234 130  Preparation of 5-(1-(benzyloxymethoxy)but-3-en-2-yl)-3-methoxy-2- methylbenzene-1,4-diol 235  Quinone 233 was dissolved in THF (65mL) at 0°C. A HCl aqueous solution (3N, 65mL, 195.0mmol) was added slowly then Zn (30g, 458.8mmol) was added portionwise over 30 minutes while the vapours were condensed. The reaction mixture was stirred at 0°C for 30 minutes, filtered through celite and poured on a saturated aqueous solution of NaHCO3 (150mL). The aqueous layer was separated and extracted with AcOEt (3x100mL). The organic layers were combined, washed with brine (150mL), dried over MgSO4 and concentrated to give crude hydroquinone 235 as a light brown paste.  1H NMR:  7.37-7.28 (5H, m), 6.40 (1H, s), 6.05 (1H, ddd, J = 6.7, 10.8, 17.3), 5.74 (1H, s), 5.19 (1H, m), 5.13 (1H, m), 4.78 (2H, s), 4.56 (1H, s br), 4.53 (2H, s), 3.99-3.93 (1H, m), 3.89-3.88 (2H, m), 3.77 (3H, s), 2.16 (3H, s) 13C NMR: 147.2, 146.2, 140.9, 137.7, 137.6, 128.4 (2 overlapping resonances), 127.9 (2 overlapping resonances), 127.7, 125.3, 116.2, 116.0, 110.3, 94.5, 70.5, 69.4, 60.8, 43.4, 9.1 IR: 3396, 2940, 2881, 1638, 145, 1420, 1096, 1025, 744, 699 MS:  367.1 [M + Na]+ HRMS:  calcd for C20H24O5:   367.1521 [M + Na]+ found:     367.1530 [M + Na]+ 131  10 9 8 7 6 5 4 3 2 1 ppm  Figure 55: 1H NMR spectrum of 235  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 56: 13C NMR spectrum of 235  132   76  78  80  82  84  86  88  90  92  94  96  98  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 57: IR spectrum of 235 133  Preparation of (5-(1-(benzyloxy)but-3-en-2-yl)-3-methoxy-2-methyl-1,4- phenylene)bis(oxy)bis(methylene)dibenzene 199  NaH (60%, 3.5g, 87.5mmol) was washed with hexanes and suspended in DMF (50mL) at 0°C. Hydroquinone 234 was dissolved in DMF (50mL) and added dropwise onto the NaH suspension over 30 minutes. The reaction mixture was stirred at 0°C for 1 hour. BnBr (7.2mL, 60.6mmol) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was poured on a saturated aqueous solution of NH4Cl (50mL) at 0°C and extracted with Et2O (150mL). The organic phase was washed with water (3x100mL), brine (150mL) and dried over MgSO4. After solvent evaporation, the crude was purified by flash column chromatography (AcOEt/hexanes 5/95 to 10/90) to yield 199 (9.8g, 75% yield over 3 steps) as a pale yellow oil.  1H NMR:  7.51-7.28 (15H, m), 6.56 (1H, s), 6.02 (1H, ddd, J = 6.6, 10.4, 17.2), 5.15-5.04 (2H, m), 5.02 (1H, d, A part of AB system, J = 10.9), 5.00 (2H, s), 4.95 (1H, d, B part of AB system, J = 10.9), 4.49 (2H, s), 4.24- 4.17 (1H, m), 3.88 (3H, s), 3.70-3.57 (2H, m), 2.44 (3H, s) 13C NMR: 153.4, 152.2, 144.0, 139.0, 138.5, 138.0, 137.5, 132.4, 128.5 (4 overlapping resonances), 128.3 (2 overlapping resonances), 128.2 (2 overlapping resonances), 127.9, 127.8, 127.6 (2 overlapping resonances), 127.5, 127.3 (2 overlapping resonances), 119.8, 115.9, 106.9, 75.3, 73.3, 72.9, 70.5, 60.5, 42.2, 9.1 134  IR: 3030, 2931, 2857, 1603, 1453, 1119, 1025, 735, 696 MS:  517.3 [M + Na]+ HRMS:  calcd for C33H34O4:   517.2355 [M + Na]+ found:     517.2346 [M + Na]+   10 9 8 7 6 5 4 3 2 1 ppm  Figure 58: 1H NMR spectrum of 199  135  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 59: 13C NMR spectrum of 199   50  55  60  65  70  75  80  85  90  95  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 60: IR spectrum of 199 136  Preparation of (5-(1-(benzyloxymethoxy)but-3-en-2-yl)-3-methoxy-2-methyl- 1,4-phenylene)bis(oxy)bis(methylene)dibenzene 221  NaH (60%, 3.30g, 82.5mmol) was washed with hexanes and suspended in DMF (50mL) at 0°C. Hydroquinone 235 was dissolved in DMF (50mL) and added dropwise onto the NaH suspension. The reaction mixture was stirred at 0°C for 1 hour. BnBr (7.2mL, 60.6mmol) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was poured on a saturated aqueous solution of NH4Cl (50mL) at 0°C and extracted with Et2O (150mL). The organic phase was washed with water (3x100mL), brine (150mL) and dried over MgSO4. After solvent evaporation, the crude was purified by flash column chromatography (AcOEt/hexanes 5/95 to 10/90) to yield 221 (6.1g, 45% yield over 3 steps) as a pale yellow oil.  1H NMR:  7.51-7.29 (15H, m), 6.56 (1H, s), 5.98 (1H, ddd, J = 6.7, 10.4, 17.1), 5.14-5.04 (2H, m), 5.03 (1H, d, A part of AB system, J = 10.9), 5.01 (2H, s), 4.96 (1H, d, B part of AB system, J = 10.9), 4.74 (1H, d, A part of AB system, J = 6.8), 4.69 (1H, d, B part of AB system, J = 6.8), 4.51 and 4.46 (2H, AB q, overlapping inner lines, J = 12.2), 4.20-4.13 (1H, m), 3.87 (3H, s), 3.84-3.71 (2H, m), 2.23 (3H, s) 13C NMR: 153.4, 152.2, 144.1, 138.8, 137.9, 137.8, 137.4, 132.3, 128.5 (4 overlapping resonances), 128.4 (2 overlapping resonances), 128.3 (2 overlapping resonances), 127.9, 127.8 (3 overlapping resonances), 127.6, 137  127.3 (2 overlapping resonances), 119.9, 116.0, 106.7, 94.5, 75.2, 70.9, 70.5, 69.3, 60.5, 42.2, 9.1 IR: 3031, 2933, 2873, 1603, 1453, 1409, 1118, 1043, 1026, 735, 696 MS:  578.3 [M + Na]+ HRMS:  calcd for C34H36O5:   578.2560 [M + Na]+ found:     578.2591 [M + Na]+   10 9 8 7 6 5 4 3 2 1 ppm  Figure 61: 1H NMR spectrum of 221  138  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 62: 13C NMR spectrum of 221   50  55  60  65  70  75  80  85  90  95  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 63: IR spectrum of 221 139  Preparation of (2-(1-(benzyloxy)but-3-en-2-yl)-6-methoxy-5-methyl-3-nitro- 1,4-phenylene)bis(oxy)bis(methylene)dibenzene 236  199 (9.8g, 19.8mmol) was dissolved in CH2Cl2 (50mL) at 0°C. 70% HNO3 (9mL, 142.1mmol) was added dropwise. The reaction mixture was stirred at 0°C for 10 minutes. A saturated aqueous solution of NaHCO3 (50mL) was added. The solution was extracted with CH2Cl2 (3x50mL) and the organic layers were combined, washed with water (100mL), brine (100mL), dried over MgSO4 and concentrated to give crude nitrobenzene 236 as an orange oil.  1H NMR:  7.47-7.28 (15H, m), 6.11 (1H, ddd, J = 3.9, 10.2, 17.6), 5.20 (1H, m), 5.15 (1H, m), 5.09 and 5.05 (2H, AB q, overlapping inner lines, J = 11.3), 4.99 (1H, d, A part of AB system, J = 10.8), 4.94 (1H, d, B part of AB system, J = 10.8), 4.54 (1H, d, A part of AB system, J = 12.7), 4.49 (1H, d, B part of AB system, J = 12.7), 3.98-3.87 (2H, m), 3.84 (3H, s), 3.84-3.79 (1H, m), 2.30 (3H, s) 13C NMR: 153.7, 147.1, 144.7, 143.5, 138.4, 137.1, 136.4, 136.2, 128.6 (4 overlapping resonances), 128.4, 128.3 (2 overlapping resonances), 128.1 (3 overlapping resonances), 127.8 (2 overlapping resonances), 127.6 (2 overlapping resonances), 127.5, 126.7, 125.6, 117.6, 77.1, 74.6, 72.6, 71.5, 60.5, 43.3, 10.0 IR: 3064, 3031, 2937, 2863, 1532, 1367, 1102, 735, 696  140  MS:  562.3 [M + Na]+ HRMS:  calcd for C33H33NO6:   562.2206 [M + Na]+ found:     562.2202 [M + Na]+   10 9 8 7 6 5 4 3 2 1 ppm  Figure 64: 1H NMR spectrum of 236 141  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 65: 13C NMR spectrum of 236   90  91  92  93  94  95  96  97  98  99  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 66: IR spectrum of 236 142  Preparation of (2-(1-(benzyloxymethoxy)but-3-en-2-yl)-6-methoxy-5-methyl- 3-nitro-1,4-phenylene)bis(oxy)bis(methylene)dibenzene 220  221 (6.1g, 11.6mmol) was dissolved in CH2Cl2 (50mL) at 0°C. 70% HNO3 (6mL, 95.2mmol) was added dropwise. The reaction mixture was stirred at 0°C for 10 minutes. A saturated aqueous solution of NaHCO3 (50mL) was added. The solution was extracted with CH2Cl2 (3x50mL) and the organic layers were combined, washed with water (100mL), brine (100mL), dried over MgSO4 and concentrated to give crude nitrobenzene 220 as an orange oil.  1H NMR:  7.52-7.30 (15H, m), 6.12 (1H, ddd, J = 6.7, 10.0, 17.2), 5.22 (1H, m), 5.18 (1H, m), 5.17 (1H, d, A part of AB system, J = 11.4), 5.09 (1H, d, B part of AB system, J = 11.4), 4.99 (1H, d, A part of AB system, J = 10.8), 4.95 (1H, d, B part of AB system, J = 10.8), 4.75 (2H, s), 4.57 (1H, d, A part of AB system, J = 12.6), 4.53 (1H, d, B part of AB system, J = 12.6), 4.07-3.94 (2H, m), 3.88-3.73 (1H, m), 3.85 (3H, s), 2.31 (3H, s) 13C NMR: 153.8, 147.1, 144.7, 143.5, 137.8, 137.1, 136.3, 136.2, 128.6 (4 overlapping resonances), 128.5, 128.4 (2 overlapping resonances), 128.2, 128.1 (2 overlapping resonances), 128.0 (2 overlapping resonances), 127.8 (2 overlapping resonances), 127.7, 126.9, 125.6, 117.8, 94.4, 77.1, 74.6, 69.3, 69.1, 60.5, 43.6, 10.0 IR: 3032, 2939, 2882, 1533, 1455, 1368, 1248, 1114, 1044, 735, 697 143  MS:  592.3 [M + Na]+ HRMS:  calcd for C34H35NO7:   592.2311 [M + Na]+ found:     592.2325 [M + Na]+   10 9 8 7 6 5 4 3 2 1 ppm  Figure 67: 1H NMR spectrum of 220  144  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 68: 13C NMR spectrum of 220   85  86  87  88  89  90  91  92  93  94  95  96  97  98  99  100  101 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 69: IR spectrum of 220 145  Preparation of 2,5-bis(benzyloxy)-6-(1-(benzyloxy)but-3-en-2-yl)-4-methoxy- 3-methylaniline 237  Nitrobenzene 236 was dissolved in THF (65mL) at 0°C. A HCl aqueous solution (3N, 65mL, 195.0mmol) was added slowly then Zn (30g, 458.8mmol) was added portionwise over 30 minutes while the vapours were condensed. The reaction mixture was stirred at 0°C for 30 minutes, filtered through celite and poured on a saturated aqueous solution of NaHCO3 (150mL). The aqueous layer was separated and extracted with AcOEt (3x100mL). The organic layers were combined, washed with brine (150mL) and dried over MgSO4. After solvent evaporation, the crude was purified by flash column chromatography (AcOEt/hexanes 5/95 to 10/90) to yield aniline 237 (2.32g, 25% yield over 2 steps) as a pale orange oil.  1H NMR:  7.50-7.26 (15H, m), 6.17 (1H, ddd, J = 4.5, 10.6, 17.6), 5.16 (1H, ddd, J = 1.7, 2.3, 10.6), 5.10 (1H, ddd, J = 1.7, 2.3, 17.5), 5.01 (1H, d, A part of AB system, J = 10.8), 4.96 (1H, d, B part of AB system, J = 10.8), 4.83 (2H, s), 4.53 (1H, d, A part of AB system, J = 12.3), 4.48 (1H, d, B part of AB system, J = 12.3), 4.44-4.40 (1H, m), 3.98 (2H, s br), 3.96-3.91 (1H, m), 3.84-3.78 (1H, m), 3.81 (3H, s), 2.27 (3H, s) 13C NMR: 147.2, 143.6, 141.2, 138.5, 138.0, 137.6, 137.3, 136.0, 128.5 (2 overlapping resonances), 128.4 (2 overlapping resonances), 128.3 (4 overlapping resonances), 128.0, 127.8 (3 overlapping resonances), 127.6 146  (2 overlapping resonances), 127.4, 123.9, 118.0, 115.3, 75.3, 73.6, 73.0, 71.6, 60.7, 40.4, 9.7 IR: 3432, 3351, 2930, 2862, 1610, 1455, 1067, 1002, 735, 697 MS:  532.4 [M + Na]+ HRMS:  calcd for C32H35NO4:   532.2464 [M + Na]+ found:     532.2456 [M + Na]+   10 9 8 7 6 5 4 3 2 1 ppm  Figure 70: 1H NMR spectrum of 237 147  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 71: 13C NMR spectrum of 237   70  72  74  76  78  80  82  84  86  88  90  92  94  96  98  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 72: IR spectrum of 237 148  Preparation of 2,5-bis(benzyloxy)-6-(1-(benzyloxymethoxy)but-3-en-2-yl)-4- methoxy-3-methylaniline 238  Nitrobenzene 220 was dissolved in THF (25mL) at 0°C. A HCl aqueous solution (3N, 30mL, 90.0mmol) was added slowly then Zn (15g, 229.4mmol) was added portionwise over 30 minutes while the vapours were condensed. The reaction mixture was stirred at 0°C for 30 minutes, filtered through celite and poured on a saturated aqueous solution of NaHCO3 (50mL). The aqueous layer was separated and extracted with AcOEt (3x30mL). The organic layers were combined, washed with brine (50mL) and dried over MgSO4. After solvent evaporation, the crude was purified by flash column chromatography (AcOEt/hexanes 5/95 to 10/90) to yield aniline 238 (1.48g, 23% yield over 2 steps) as a pale orange oil.  1H NMR:  7.51-7.26 (15H, m), 6.11 (1H, ddd, J = 4.4, 10.7, 17.6), 5.18 (1H, ddd, J = 1.6, 2.2, 10.7), 5.10 (1H, ddd, J = 1.6, 2.2, 17.6), 5.01 (2H, s), 4.81 (1H, d, A part of AB system, J = 11.2), 4.77 (1H, d, B part of AB system, J = 11.2), 4.75 (1H, d, A part of AB system, J = 6.8), 4.71 (1H, d, B part of AB system, J = 6.8), 4.51 and 4.47 (2H, AB q, overlapping inner lines, J = 13.0), 4.44-4.37 (1H, m), 4.08-3.97 (2H, m), 3.93 (2H, s br), 3.81 (3H, s), 2.26 (3H, s) 13C NMR: 147.3, 143.6, 141.1, 137.9, 137.8, 137.5, 137.2, 135.8, 128.6 (2 overlapping resonances), 128.5 (2 overlapping resonances), 128.4 (4 overlapping resonances), 128.1, 127.9 (3 overlapping resonances), 127.8 149  (2 overlapping resonances), 127.6, 124.0, 117.7, 115.4, 94.4, 75.2, 73.6, 69.2, 68.6, 60.7, 40.3, 9.7 IR: 3433, 3354, 3064, 3031, 2932, 2875, 1609, 1455, 1420, 1065, 736, 697 MS:  540.3 [M + Na]+ HRMS:  calcd for C34H37NO5:   540.2750 [M + Na]+ found:     540.2740 [M + Na]+   10 9 8 7 6 5 4 3 2 1 ppm  Figure 73: 1H NMR spectrum of 238  150  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 74: 13C NMR spectrum of 238   80  82  84  86  88  90  92  94  96  98  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 75: IR spectrum of 238  151  Preparation of (2-azido-3-(1-(benzyloxy)but-3-en-2-yl)-5-methoxy-6-methyl- 1,4-phenylene)bis(oxy)bis(methylene)dibenzene 200  Aniline 237 (2.15g, 4.2mmol) was dissolved in THF (10mL) at −10°C. A H2SO4 aqueous solution (10%, 13mL, 239.8mmol) was added slowly. A solution of NaNO2 (422mg, 6.1mmol) in water (2mL) was added dropwise. The reaction mixture was stirred at −10°C for 5 minutes. A solution of NaN3 (404mg, 6.2 mmol) in water (2mL) was added dropwise. The reaction mixture was stirred at −10°C for 15 minutes. A solution of AcONa (1.72g, 21.0mmol) in water (10mL) and THF (10mL) was added slowly. The reaction mixture was stirred for 1 hour, warmed up to room temperature and extracted with Et2O (3x60mL). The organic layers were combined, washed with a saturated aqueous solution of NaHCO3 (100mL), brine (100mL), dried over MgSO4 and concentrated to give crude azide 200 as a brown paste.  1H NMR:  7.49-7.30 (15H, m), 6.24 (1H, ddd, J = 7.0, 10.1, 17.1), 5.10-5.0 (2H, m), 4.99 (1H, d, A part of AB system, J = 10.8), 4.95 (1H, d, B part of AB system, J = 10.8), 4.89 (2H, s), 4.55 (1H, d, A part of AB system, J = 12.2), 4.57 (1H, d, B part of AB system, J = 12.2), 4.45-4.37 (1H, m), 3.96-3.88 (1H, m), 3.81 (3H, s), 3.78-3.75 (1H, m), 2.24 (3H, s) 13C NMR: 149.6, 148.1, 147.5, 138.6, 138.3, 137.6, 136.2, 128.5 (6 overlapping resonances), 128.4, 128.3 (2 overlapping resonances), 128.1 (2 152  overlapping resonances), 127.9, 127.7, 127.6 (2 overlapping resonances), 127.4, 126.6, 125.2, 115.8, 75.6, 75.0, 72.7, 72.0, 60.5, 42.2, 9.9 IR: 3031, 2933, 2860, 2111, 1497, 1454, 1107, 735, 697 MS:  530.3 [M + Na-N2]+ HRMS:  calcd for C33H33N3O4:  558.2369 [M + Na]+ found:     558.2361 [M + Na]+   10 9 8 7 6 5 4 3 2 1 ppm  Figure 76: 1H NMR spectrum of 200 153  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 77: 13C NMR spectrum of 200   88  89  90  91  92  93  94  95  96  97  98  99  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 78: IR spectrum of 200 154  Preparation of (2-azido-3-(1-(benzyloxymethoxy)but-3-en-2-yl)-5-methoxy-6- methyl-1,4-phenylene)bis(oxy)bis(methylene)dibenzene 239  Aniline 238 (1.48g, 2.7mmol) was dissolved in THF (7mL) at −10°C. A H2SO4 aqueous solution (10%, 10mL, 188.3mmol) was added slowly. A solution of NaNO2 (280mg, 4.1mmol) in water (1.5mL) was added dropwise. The reaction mixture was stirred at −10°C for 5 minutes. A solution of NaN3 (263mg, 4.1 mmol) in water (1.5mL) was added dropwise. The reaction mixture was stirred at −10°C for 15 minutes. A solution of AcONa (1.08g, 13.2mmol) in water (5mL) and THF (5mL) was added slowly. The reaction mixture was stirred for 1 hour, warmed up to room temperature and extracted with Et2O (3x30mL). The organic layers were combined, washed with a saturated aqueous solution of NaHCO3 (50mL), brine (50mL), dried over MgSO4 and concentrated to give crude azide 239 as a brown paste.  1H NMR:  7.52-7.32 (15H, m), 6.24 (1H, ddd, J = 6.9, 10.3, 17.2), 5.14-5.00 (2H, m), 5.03 (2H, s), 4.92 (1H, d, A part of AB system, J = 11.3), 4.87 (1H, d, B part of AB system, J = 11.3), 4.78 (1H, d, A part of AB system, J = 6.8), 4.74 (1H, d, B part of AB system, J = 6.8), 4.54 (2H, s), 4.43-4.36 (1H, m), 4.08 (1H, dd, overlapping inner lines, J = 9.3), 3.94 (1H, dd, J = 7.2, 9.3), 3.82 (3H, s), 2.23 (3H, s) 13C NMR: 149.7, 148.1, 147.5, 138.2, 137.9, 137.6, 136.2, 128.5 (6 overlapping resonances), 128.4 (3 overlapping resonances), 128.1 (2 overlapping 155  resonances), 128.0, 127.9 (2 overlapping resonances), 127.7, 127.6, 126.5, 125.3, 116.0, 94.4, 75.6, 75.1, 69.6, 69.2, 60.5, 42.2, 9.6 IR: 3064, 2934, 2877, 2112, 1455, 1415, 1111, 1043, 735, 697 MS:  560.3 [M + Na-N2]+ HRMS:  calcd for C34H35N3O5:  588.2474 [M + Na]+ found:     588.2471 [M + Na]+   10 9 8 7 6 5 4 3 2 1 ppm  Figure 79: 1H NMR spectrum of 239  156  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 80: 113C NMR spectrum of 239   70  72  74  76  78  80  82  84  86  88  90  92  94  96  98  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 81: IR spectrum of 239  157  Preparation of 2-(2-azido-3,6-bis(benzyloxy)-5-methoxy-4-methylphenyl)-3- (benzyloxy)propanal 201  Azide 200 was dissolved in acetone (8mL) and water (8mL) at room temperature. OsO4 (0.40mL, 0.002mmol) was added then NaIO4 (7.0g, 32.7mmol) was added portionwise. The reaction mixture was stirred at room temperature overnight, then filtered through celite and extracted with Et2O (3x10mL). The organic layers were combined, washed with a saturated aqueous solution of Na2S2O3 (20mL), brine (20mL) and dried over MgSO4. After solvent evaporation, the crude was purified by flash column chromatography (AcOEt/hexanes 10/90) to yield aldehyde 201 (547mg, 25% yield over 2 steps) as a brown paste.  1H NMR:  9.57 (1H, s), 7.48-7.24 (15H, m), 5.05 (1H, d, A part of AB system, J = 10.7), 4.98 (1H, d, B part of AB system, J = 10.7), 4.93 and 4.89 (2H, AB q, overlapping inner lines, J = 11.4), 4.56 (1H, d, A part of AB system, J = 12.0), 4.48 (1H, d, B part of AB system, J = 12.0), 4.22 (2H, m), 3.83 (3H, s), 3.68 (1H, m), 2.26 (3H, s) 13C NMR: 200.4, 149.3, 147.8, 147.4, 138.1, 137.0, 135.8, 128.6 (5 overlapping resonances), 128.5 (5 overlapping resonances), 128.3 (2 overlapping resonances), 128.2, 127.8, 127.6 (2 overlapping resonances), 126.9, 121.5, 75.9, 75.0, 73.0, 68.5, 60.5, 50.7, 10.0 IR: 3032, 2934, 2868, 2117, 1724, 1455, 1370, 1109, 737, 698  158  MS:  532.3 [M + Na-N2]+ HRMS:  calcd for C32H31N3O5:  560.2161 [M + Na]+ found:     560.2172 [M + Na]+   10 9 8 7 6 5 4 3 2 1 ppm  Figure 82: 1H NMR spectrum of 201 159  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 83: 13C NMR spectrum of 201   50  55  60  65  70  75  80  85  90  95  100 % T  1000   1500   2000   2500   3000   3500 Wavenumbers (cm-1)  Figure 84: IR spectrum of 201 160  Preparation of 2-(2-azido-3,6-bis(benzyloxy)-5-methoxy-4-methylphenyl)-3- (benzyloxymethoxy)propanal 214  Azide 239 was dissolved in acetone (5mL) and water (5mL) at room temperature. OsO4 (0.26mL, 0.001mmol) was added then NaIO4 (4.5g, 21.0mmol) was added portionwise. The reaction mixture was stirred at room temperature overnight, then filtered through celite and extracted with Et2O (3x5mL). The organic layers were combined, washed with a saturated aqueous solution of Na2S2O3 (10mL), brine (10mL) and dried over MgSO4. After solvent evaporation, the crude was purified by flash column chromatography (AcOEt/hexanes 10/90) to yield aldehyde 214 (490mg, 33% yield over 2 steps) as a brown paste.  1H NMR:  9.57 (1H, s), 7.45-7.28 (15H, m), 5.11 (1H, d, A part of AB system, J = 10.7), 5.01 (1H, d, B part of AB system, J = 10.7), 4.91 and 4.86 (2H, AB q, overlapping inner lines, J = 11.4), 4.78 (1H, d, A part of AB system, J = 6.8), 4.73 (1H, d, B part of AB system, J = 6.8), 4.50 (2H, s), 4.31 (1H, dd, J = 6.9, 9.6), 4.20 (1H, dd, overlapping inner lines, J = 6.1), 3.83 (1H, m), 3.83 (3H, s), 2.25 (3H, s) 13C NMR: 200.0, 149.4, 147.8, 147.3, 137.7, 136.9, 135.8, 128.6 (4 overlapping resonances), 128.5 (5 overlapping resonances), 128.4 (2 overlapping resonances), 128.3, 127.9 (2 overlapping resonances), 127.8, 127.7, 127.0, 121.2, 94.4, 75.9, 75.0, 69.3, 65.9, 60.5, 50.7, 10.0 IR: 3032, 2937, 2882, 2117, 1725, 1455, 1370, 1111, 737, 698 161  MS:  562.4 [M + Na-N2]+ HRMS:  calcd for C33H33N3O6:  590.2267 [M + Na]+ found:     590.2261 [M + Na]+   10 9 8 7 6 5 4 3 2 1 ppm  Figure 85: 1H NMR spectrum of 214  162  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 86: 13C NMR spectrum of 214   40  45  50  55  60  65  70  75  80  85  90  95  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 87: IR spectrum of 214  163  Preparation of 2-(2-azido-3,6-bis(benzyloxy)-5-methoxy-4-methylphenyl)-1- (benzyloxy)-4-(trimethylsilyl)hex-5-en-3-ol 243  Allyl trimethylsilane (184, 0.48mL, 3.0mmol) was dissolved in THF (20mL) at −40°C. TMEDA (0.45mL, 3.0mmol) was added slowly then s-BuLi (2.42mL, 3.2mmol) was added dropwise. The solution was stirred at −40°C for 1 hour then cooled down to −78°C. Ti(Oi-Pr)4 (0.98mL, 3.4mmol) was added dropwise and the mixture was stirred for an extra hour. Aldehyde 201 (547mg, 1.0mmol) dissolved in THF (5mL) was added dropwise and the reaction mixture was stirred at −78°C for 3 hours. The reaction mixture was poured on a saturated aqueous solution of NH4Cl (25mL). The TiO2 precipitate was filtered under vacuum and the filtrate was extracted with Et2O (3x15mL). The organic layers were combined, washed with a saturated aqueous solution of NH4Cl (40mL), brine (40mL) and dried over MgSO4. After solvent evaporation, the crude was purified by flash column chromatography (AcOEt/hexanes 10/90) to yield 243 (278mg, 42% yield; 65% yield BOSM) as a yellow oil. Diastereoisomeric mixture (1:1 ratio)  1H NMR:  7.53-7.30 (30H, m), 6.13-5.98 (2H, m), 5.31 (1H, d, J = 11.2), 5.11 (1H, d, J = 11.2), 4.94-4.72 (10H, m), 4.57-4.32 (6H, m), 4.10-3.98 (2H, m), 3.88-3.78 (2H, m), 3.76 (3H, s), 3.72 (3H, s), 3.72-3.62 (2H, m), 3.61- 3.59 (1H, m), 3.38-3.34 (1H, m), 2.26 (3H, s), 2.24 (3H, s), 1.37 (1H, m), 1.34 (1H, m), 0.07 (9H, s), 0.02 (9H, s) 164  13C NMR: 149.5, 149.1, 147.8, 147.6, 137.9, 137.8, 137.7, 137.5, 136.2, 136.0, 135.6, 135.0, 129.1, 128.7 (6 overlapping resonances), 128.6 (4 overlapping resonances), 128.5 (5 overlapping resonances), 128.4 (3 overlapping resonances), 127.9 (3 overlapping resonances), 127.8 (6 overlapping resonances), 127.7 (2 overlapping resonances), 127.6 (3 overlapping resonances), 127.4, 125.5, 125.3, 124.7, 124.1, 113.9, 113.0, 75.7, 75.5, 74.7, 74.5, 73.9, 73.8 (2 overlapping resonances), 73.6, 73.3, 73.1, 60.2, 60.2, 45.8, 43.9, 40.7, 40.3, 9.9, 9.8, -2.2 (6 overlapping resonances) IR: 3496, 2951, 2866, 2113, 1624, 1455, 1106, 734, 696 MS:  674.5 [M + Na]+ HRMS:  calcd for C38H45N3O5Si:  674.3026 [M + Na]+ found:     674.3040 [M + Na]+ 10 9 8 7 6 5 4 3 2 1 ppm  Figure 88: 1H NMR spectrum of 243 165  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 89: 13C NMR spectrum of 243   80  82  84  86  88  90  92  94  96  98  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 90: IR spectrum of 243 166  Preparation of 2-(2-azido-3,6-bis(benzyloxy)-5-methoxy-4-methylphenyl)-1- (benzyloxymethoxy)-4-(trimethylsilyl)hex-5-en-3-ol 244  Allyl trimethylsilane (184, 0.40mL, 2.5mmol) was dissolved in THF (10mL) at −40°C. TMEDA (0.37mL, 2.5mmol) was added slowly then s-BuLi (2.5mL, 2.5mmol) was added dropwise. The solution was stirred at −40°C for 1 hour then cooled down to −78°C. Ti(Oi-Pr)4 (0.74mL, 2.5mmol) was added dropwise and the mixture was stirred for an extra hour. Aldehyde 214 (462mg, 0.81mmol) dissolved in THF (5mL) was added dropwise and the reaction mixture was stirred at −78°C for 3 hours. The reaction mixture was poured on a saturated aqueous solution of NH4Cl (20mL). The TiO2 precipitate was filtered under vacuum and the filtrate was extracted with Et2O (3x10mL). The organic layers were combined, washed with a saturated aqueous solution of NH4Cl (30mL), brine (30mL) and dried over MgSO4. After solvent evaporation, the crude was purified by flash column chromatography (AcOEt/hexanes 10/90) to yield 244 (260mg, 47% yield; 70% yield BOSM) as a yellow oil. Diastereoisomeric mixture (1:1 ratio)  1H NMR:  7.52-7.30 (30H, m), 6.09-5.96 (2H, m), 5.32 (1H, d, J = 11.3), 5.12 (1H, d, J = 11.3), 4.93-4.79 (8H, m), 4.77-4.64 (6H, m),4.57 (2H, d, J = 4.8), 4.52 (2H, d, J = 2.7), 4.37 (2H, dt, J = 17.3, 2.0), 4.16-4.05 (2H, m), 3.85-3.80 (2H, m), 3.78 (3H, s), 3.75 (3H, s), 3.76-3.71 (1H, m), 3.61- 167  3.54 (1H, m), 3.41 (1H, m), 3.33 (1H, m), 2.20 (3H, s), 2.19 (3H, s), 1.39 (1H, m), 1.36 (1H, m), 0.05 (9H, s), 0.03 (9H, s) 13C NMR: 149.5, 149.1, 147.8, 147.7, (2 overlapping resonances), 147.6, 137.9, 137.5 (3 overlapping resonances), 136.2, 135.9, 135.3, 134.7, 129.1, 128.6 (6 overlapping resonances), 128.5 (5 overlapping resonances), 128.4 (3 overlapping resonances), 128.0 (2 overlapping resonances), 127.9 (3 overlapping resonances), 127.8 (3 overlapping resonances), 127.7 (2 overlapping resonances), 127.5 (2 overlapping resonances), 127.3, 125.6, 125.3, 124.6, 124.0, 114.2, 113.2, 94.4, 94.2, 88.3, 77.2, 75.7, 75.4, 74.7, 74.4, 73.7, 73.5, 71.9, 71.1, 70.7, 69.6, 69.4, 60.2, 60.1, 45.9, 43.9, 40.7, 40.2, 30.3, 9.9, 9.8, -2.3 (6 overlapping resonances) IR: 3496, 2951, 2866, 2113, 1624, 1455, 1106, 734, 696 MS:  704.5 [M + Na]+ HRMS:  calcd for C39H47N3O5Si:  704.3132 [M + Na]+ found:     704.3148 [M + Na]+  168  10 9 8 7 6 5 4 3 2 1 ppm  Figure 91: 1H NMR spectrum of 244  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 92: 13C NMR spectrum of 244  169   80  82  84  86  88  90  92  94  96  98  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 93: IR spectrum of 244  170  Preparation of (3aS,4S,5R,6R)-7,10-bis(benzyloxy)-6-(benzyloxymethyl)-8- methoxy-9-methyl-4-(trimethylsilyl)-3a,4,5,6-tetrahydro-3H- benzo[f][1,2,3]triazolo[1,5-a]azepin-5-ol 203  Alkene 243 (250mg, 0.38mmol) was dissolved in toluene (15mL), sonicated under an argon flow for 15 minutes and heated at 90°C for 4 hours. After solvent evaporation, the product was purified by trituration in AcOEt/hexanes to yield triazoline 203 (139mg, 55%) as an off-white solid.  1H NMR:  7.51-7.22 (15H, m), 5.06 (1H, d, A part of AB system, J = 10.8), 5.01 (1H, d, B part of AB system, J = 10.8), 4.92 (1H, d, J = 10.6), 4.62 (1H, d, J = 10.6), 4.47 (1H, d, J = 11.9), 4.33 (1H, dd, J = 16.4; 12.3), 4.30 (1H, d, J = 12.0), 4.21 (2H, m), 3.92-3.84 (1H, m), 3.87 (3H, s), 3.73- 3.65 (1H, m), 3.55-3.41 (2H, m), 2.29 (3H, s), 1.10 (1H, d, J = 11.7), 0.82 (1H, m), 0.08 (9H, s) 13C NMR: 151.0, 149.0, 147.5, 138.1, 137.5, 136.9, 130.6, 128.7 (2 overlapping resonances), 128.6 (2 overlapping resonances), 128.5 (4 overlapping resonances), 128.4 (2 overlapping resonances), 128.2 (2 overlapping resonances), 127.9 (2 overlapping resonances), 127.7, 126.2, 125.6, 75.9, 75.4, 72.9, 71.3, 69.4, 67.1, 60.5, 52.4, 44.2, 35.5, 10.3, -0.6 (3 overlapping resonances) IR: 2936, 2865, 1497, 1458, 1101, 1074, 836, 735, 696 171  MS:  652.5 [M + Na]+ HRMS:  calcd for C38H45N3O5Si:  652.3207 [M + Na]+ found:     652.3213 [M + Na]+ mp:   160°C   10 9 8 7 6 5 4 3 2 1 ppm  Figure 94: 1H NMR spectrum of 203  172  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 95: 13C NMR spectrum of 203   97.0  97.2  97.4  97.6  97.8  98.0  98.2  98.4  98.6  98.8  99.0  99.2  99.4  99.6  99.8  100.0  100.2 % T  1000   1500   2000   2500   3000   3500 Wavenumbers (cm-1)  Figure 96: IR spectrum of 203  173   Figure 97: ORTEP of triazoline 203  174  Preparation of (3aS,4S,5R,6R)-7,10-bis(benzyloxy)-6- ((benzyloxymethoxy)methyl)-8-methoxy-9-methyl-4-(trimethylsilyl)-3a,4,5,6- tetrahydro-3H-benzo[f][1,2,3]triazolo[1,5-a]azepin-5-ol 245  Alkene 244 (250mg, 0.36mmol) was dissolved in toluene (15mL), sonicated under an argon flow for 15 minutes and heated at 90°C for 4 hours. After solvent evaporation, the product was purified by trituration in AcOEt/hexanes to yield triazoline 245 (117mg, 47%) as an off-white solid.  1H NMR:  7.58-7.29 (15H, m), 5.15 (1H, d, A part of AB system, J = 10.6), 5.07 (1H, d, B part of AB system, J = 10.6), 4.98 (1H, d. J = 10.5), 4.71 (1H, m), 4.69 (1H, d, A part of AB system, J = 10.2), 4.64 (1H, d, B part of AB system, J = 10.2), 4.53 (2H, s), 4.43 (1H, dd, J = 16.3, 12.6), 4.26- 4.2 (2H, m), 4.04-3.96 (1H, m), 3.91 (3H, s), 3.85-3.80 (1H, m), 3.74- 3.69 (1H, m), 3.64-3.53 (1H, m), 2.33 (3H, s), 1.24 (1H, d, J = 11.7), 1.06 (1H, m), 0.10 (9H, s) 13C NMR: 150.1, 149.0, 147.7, 137.7, 137.6, 136.9, 130.8, 128.7 (2 overlapping resonances), 128.6 (2 overlapping resonances), 128.5 (6 overlapping resonances), 128.3, 128.2, 127.7 (3 overlapping resonances), 126.2, 125.6, 94.4, 76.0, 75.4, 71.4, 69.3, 67.3, 67.2, 60.5, 52.6, 44.3, 36.0, 10.4, -0.6 (3 overlapping resonances) IR: 2946, 2879, 1497, 1465, 1102, 1080, 838, 739, 698 175  MS:  682.3 [M + H]+ HRMS:  calcd for C39H47N3O6Si:  704.3122 [M + Na]+ found:     704.3146 [M + Na]+ mp:   145°C   10 9 8 7 6 5 4 3 2 1 ppm  Figure 98: 1H NMR spectrum of 245  176  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 99: 13C NMR spectrum of 245   92.0  92.5  93.0  93.5  94.0  94.5  95.0  95.5  96.0  96.5  97.0  97.5  98.0  98.5  99.0  99.5  100.0  100.5 % T  1000   1500   2000   2500   3000   3500 Wavenumbers (cm-1)  Figure 100: IR spectrum of 245  177   Figure 101: ORTEP of triazoline 245 178  Preparation of (1aS,2S,3R,4R)-5,8-bis(benzyloxy)-4-(benzyloxymethyl)-6- methoxy-7-methyl-2-(trimethylsilyl)-1a,2,3,4-tetrahydro-1H-azirino[1,2-a] benzo[f]azepin-3-ol 204  Triazoline 203 (135mg, 0.21mmol) was dissolved in THF (25mL), sonicated under an argon flow for 30 minutes and UV irradiated at room temperature overnight. After solvent evaporation, the crude was purified by flash column chromatography (AcOEt/hexanes 10/90 then 20/80) to yield aziridne 204 (107mg, 81%) as a pale yellow oil.  1H NMR:  7.54-7.28 (15H, m), 5.27 (1H, d, J = 10.7), 4.94 (1H, d, A part of AB system, J = 11.0), 4.86 (1H, d, B part of AB system, J = 11.0), 4.70 (1H, d, J = 10.7), 4.55 (1H, d, A part of AB system, J = 12.0), 4.48 (1H, d, B part of AB system, J = 12.0), 4.46-4.38 (2H, m), 4.10-4.07 (1H, m), 3.91-3.80 (2H, m), 3.74 (3H, s), 2.82 (1H, dt, J = 11.7; 4.7), 2.67 (1H, d, J = 5.1), 2.17 (3H, s), 1.75 (1H, d, J = 4.2), 0.42 (1H, dt, J = 11.6, 2.5), 0.07 (9H, s) 13C NMR: 146.7, 146.2, 146.1, 139.7, 137.8, 137.7, 137.5, 128.5 (4 overlapping resonances), 128.4 (2 overlapping resonances), 128.3 (2 overlapping resonances), 128.2 (2 overlapping resonances), 128.0 (2 overlapping resonances), 127.7 (3 overlapping resonances), 125.4, 121.6, 75.8, 75.6, 74.7, 73.5, 73.2, 60.5, 46.1, 36.5, 33.6, 30.3, 9.5, -1.5 (3 overlapping resonances) 179  IR: 3466, 2949, 2873, 1453, 1245, 1090, 839, 734, 697 MS:  624.3 [M + Na]+ HRMS:  calcd for C38H45NO5Si:  624.3145 [M + Na]+ found:     624.3135 [M + Na]+   10 9 8 7 6 5 4 3 2 1 ppm  Figure 102: 1H NMR spectrum of 204  180  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 103: 13C NMR spectrum of 204   95.0  95.5  96.0  96.5  97.0  97.5  98.0  98.5  99.0  99.5  100.0 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 104: IR spectrum of 204  181  Preparation of (1aS,2S,3R,4R)-5,8-bis(benzyloxy)-4- ((benzyloxymethoxy)methyl)-6-methoxy-7-methyl-2-(trimethylsilyl)-1a,2,3,4- tetrahydro-1H-azirino[1,2-a]benzo[f]azepin-3-ol 212  Triazoline 245 (100mg, 0.15mmol) was dissolved in THF (15mL), sonicated under an argon flow for 30 minutes and UV irradiated at room temperature overnight. After solvent evaporation, the crude was purified by flash column chromatography (AcOEt/hexanes 10/90 then 20/80) to yield aziridne 212 (75mg, 82%) as a pale yellow oil.  1H NMR:  7.57-7.29 (15H, m), 5.30-5.26 (1H, d, J = 10.7), 4.98 (1H, d, A part of AB system, J = 10.7), 4.87 (1H, d, B part of AB system, J = 10.7), 4.79- 4.46 (6H, m), 4.30-4.26 (1H, dd, J = 10.1, 1.9), 4.10 (1H, d, J = 2.0), 3.88-3.78 (1H, m), 3.76 (3H, s), 2.86-2.79 (1H, m), 2.68 (1H, d, J = 5.1), 2.18 (3H, s), 1.76-1.75 (1H, d, J = 4.2), 1.27 (1H, s), 0.45-0.40 (1H, dt, J = 11.6, 2.6), 0.07 (9H, s) 13C NMR: 146.7, 146.3, 146.1, 139.6, 137.8, 137.6, 137.2, 128.5 (5 overlapping resonances), 128.4 (2 overlapping resonances), 128.3 (2 overlapping resonances), 128.1, 127.9, 127.8 (2 overlapping resonances), 127.7, 125.5, 121.5, 94.5, 77.2, 75.8, 74.6, 73.5, 73.2, 69.6, 60.5, 46.1, 36.5, 33.5, 30.3, 9.5, -1.5 (3 overlapping resonances) IR: 3494, 2950, 2887, 1454, 1245, 1090, 839, 734, 697 MS:  676.5 [M + Na]+ 182  HRMS:  calcd for C39H47NO6Si:  676.3070 [M + Na]+ found:     676.3064 [M + Na]+   10 9 8 7 6 5 4 3 2 1 ppm  Figure 105: 1H NMR spectrum of 212  183  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 106: 13C NMR spectrum of 212   80  82  84  86  88  90  92  94  96  98  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 107: IR spectrum of 212 184  Preparation of ((5R,6S,Z)-7,10-bis(benzyloxy)-6-(benzyloxymethyl)-8- methoxy-9-methyl-1,2,5,6-tetrahydrobenzo[b]azocin-5-ol 249  Aziridine 204 (20mg, 0.03mmol) was dissolved in DMF (0.2mL) at −20°C. An aqueous solution of TBAF (40%, 0.1mL, 0.10mmol) was added dropwise. The reaction mixture was stirred for 1 hour at −20°C, warmed up to room temperature and extracted with Et2O (3x2mL). The organic layers were combined, washed with a saturated aqueous solution of NaHCO3 (5mL), brine (5mL), dried over MgSO4 and evaporated to yield benzanocenol 249 as a pale yellow oil.  1H NMR:  7.51-7.29 (15H, m), 5.67-5.62 (1H, m), 5.54-5.467 (1H, m), 5.25-5.19 (1H, m), 4.97 (2H, s), 4.89 (2H, s), 4.50 (2H, s), 3.82 (3H, s), 3.72-3.62 (3H, m), 3.58-3.51 (2H, m), 3.22 (1H, m), 2.26 (3H, s), 1.26 (1H, s) 13C NMR: 149.8, 149.1, 146.1, 137.9, 137.6, 137.5, 136.0, 134.6, 128.6 (2 overlapping resonances), 128.5 (2 overlapping resonances), 128.4 (3 overlapping resonances), 128.2, 128.0, 127.7 (2 overlapping resonances), 127.6, 127.5 (2 overlapping resonances), 125.3, 124.2, 77.2, 75.3, 75.1, 75.0, 73.4, 73.2, 60.4, 49.0, 47.5, 29.7, 10.0 IR: 3471, 2921, 2851, 1454, 1368, 1275, 1081, 735, 697 MS:  552.3 [M + H]+ HRMS:  calcd for C35H38NO5:   552.2750 [M + Na]+ found:     552.2743 [M + Na]+ 185  10 9 8 7 6 5 4 3 2 1 ppm  Figure 108:1H NMR spectrum of 249  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 109: 13C NMR spectrum of 249  186   95.0  95.5  96.0  96.5  97.0  97.5  98.0  98.5  99.0  99.5  100.0 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 110: IR spectrum of 249 187  Preparation of (5S,6R,Z)-7,10-bis(benzyloxy)-6-((benzyloxymethoxy)methyl)- 8-methoxy-9-methyl-1,2,5,6-tetrahydrobenzo[b]azocin-5-ol 211  Aziridine 212 (30mg, 0.05mmol) was dissolved in DMF (0.5mL) at −20°C. An aqueous solution of TBAF (40%, 0.2mL, 0.2mmol) was added dropwise. The reaction mixture was stirred for 1 hour at −20°C, warmed up to room temperature and extracted with Et2O (3x2mL). The organic layers were combined, washed with a saturated aqueous solution of NaHCO3 (5mL), brine (5mL), dried over MgSO4 and evaporated to yield benzanocenol 211 as a pale yellow oil.  1H NMR:  7.50-7.28 (15H, m), 5.62-5.57 (1H, m), 5.52-5.46 (1H, m), 5.26-5.20 (1H, m), 5.03 (1H, d, A part of AB system, J = 10.9), 4.96 (1H, d, B part of AB system, J = 10.9), 4.87 (2H, s), 4.75 (1H, d, A part of AB system, J = 6.8), 4.72 (1H, d, B part of AB system, J = 6.8), 4.52 (2H, AB q, overlapping inner lines, J = 12.8), 3.82 (3H, s), 3.79-3.53 (5H, m), 3.25- 3.24 (1H, d, J = 2.0), 2.25 (3H, s), 1.26 (1H, s) 13C NMR: 149.8, 149.1, 146.1, 137.6 (2 overlapping resonances), 137.5, 136.0, 134.6, 128.6 (2 overlapping resonances), 128.5 (2 overlapping resonances), 128.4 (2 overlapping resonances), 128.3 (2 overlapping resonances), 128.2, 128.0 (2 overlapping resonances), 127.7 (3 overlapping resonances), 125.6, 124.3, 94.3, 77.2, 75.3, 75.1, 73.0, 72.0, 69.4, 60.4, 48.9, 47.5, 30.3, 10.0 188  IR: 3444, 2960, 1634, 1454, 1260, 1027, 800, 698 MS:  604.4 [M + Na]+ HRMS:  calcd for C36H39NO6:   604.2675 [M + Na]+ found:     604.2692 [M + Na]+   10 9 8 7 6 5 4 3 2 1 ppm  Figure 111: 1H NMR spectrum of 211  189  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 112: 13C NMR spectrum of 211   88  89  90  91  92  93  94  95  96  97  98  99  100 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 113: IR spectrum of 211  190  Preparation of (5R,6S,Z)-benzyl 7,10-bis(benzyloxy)-6-(benzyloxymethyl)-5- hydroxy-8-methoxy-9-methyl-5,6-dihydrobenzo[b]azocine-1(2H)- carboxylate 205  Benzanocenol 249 was dissolved in THF (0.2mL) at room temperature. NaHCO3 (5mg, 0.06mmol) was added portionwise, and then CbzCl (3μL, 0.02mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and water (2mL) was added. The layers were separated and the aqueous layer was extracted with Et2O (3x2mL). The organic layers were combined, washed with a HCl aqueous solution (0.05M, 2mL), brine (2mL) and dried over MgSO4. After solvent evaporation, the crude was purified by flash column chromatography (AcOEt/hexanes 20/80) to yield 205 (14.8mg, 45% yield over 2 steps) as a pale yellow oil. Rotameric mixture (1:1 ratio)  1H NMR:  7.50-7.16 (40H, m), 5.47-5.37 (2H, m), 5.28-5.18 (2H, m), 5.07-4.95 (8H, m), 4.89-4.07 (12H, m), 3.86-3.82 (6H, m), 3.74-3.52 (8H, m), 2.28- 2.21 (6H, m), 1.44 (2H, s br) MS:  708.6 [M + Na]+  191  Preparation of (5S,6R,Z)-benzyl 7,10-bis(benzyloxy)-6- ((benzyloxymethoxy)methyl)-5-hydroxy-8-methoxy-9-methyl-5,6- dihydrobenzo[b]azocine-1(2H)-carboxylate 251  Benzanocenol 211 was dissolved in THF (0.5mL) at room temperature. NaHCO3 (13mg, 0.15mmol) was added portionwise, and then CbzCl (8μL, 0.06mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and water (2mL) was added. The layers were separated and the aqueous layer was extracted with Et2O (3x5mL). The organic layers were combined, washed with a HCl aqueous solution (0.05M, 5mL), brine (5mL) and dried over MgSO4. After solvent evaporation, the crude was purified by flash column chromatography (AcOEt/hexanes 20/80) to yield 251 (13mg, 40% yield over 2 steps) as a pale yellow oil. Rotameric mixture (1:1 ratio)  1H NMR:  7.48-7.19 (40H, m), 5.48-5.38 (2H, m), 5.29-5.18 (2H, m), 5.12-4.77 (12H, m), 4.69-4.51(10H, m), 3.96-3.62 (10H, m), 3.89 (3H, s), 3.88 (3H, s), 2.25 (3H, s), 2.21 (3H, s), 1.44 (2H, s br) 13C NMR: 160.0 (2 overlapping resonances), 152.2 (2 overlapping resonances), 151.3, 150.8, 146.3, 146.2, 137.5 (2 overlapping resonances), 137.3 (2 overlapping resonances), 137.2, 136.9, 136.3, 135.9, 135.0, 134.8, 132.2, 131.9, 128.6 (3 overlapping resonances), 128.5 (6 overlapping 192  resonances), 128.4 (10 overlapping resonances), 128.3 (4 overlapping resonances), 128.2 (2 overlapping resonances), 128.1 (4 overlapping resonances), 128.0 (3 overlapping resonances), 127.8 (3 overlapping resonances), 127.6 (3 overlapping resonances), 127.3 (2 overlapping resonances), 125.9, 125.5, 123.9, 123.8, 94.1, 94.0, 77.2, 74.9, 74.7, 74.6, 72.8, 72.1, 71.8, 69.4, 69.2, 64.7, 67.4, 60.4, 60.3, 47.9, 47.6, 47.0, 46.8, 30.3 (2 overlapping resonances), 10.2, 10.1 IR: 3513, 3031, 2930, 2874, 1702, 1455, 1229, 1222, 1043, 736, 698 MS:  738.5 [M + Na]+ HRMS:  calcd for C44H45NO8:   738.3034 [M + Na]+ found:     738.3056 [M + Na]+  10 9 8 7 6 5 4 3 2 1 ppm  Figure 114: 1H NMR spectrum of 251  193  200 180 160 140 120 100 80 60 40 20 0 ppm  Figure 115: 13C NMR spectrum of 251   95.0  95.5  96.0  96.5  97.0  97.5  98.0  98.5  99.0  99.5  100.0 % T  1000   1500   2000   2500   3000   3500   4000 Wavenumbers (cm-1)  Figure 116: IR spectrum of 251 194  Preparation of (5R,6S,Z)-benzyl 7,10-bis(benzyloxy)-6- ((benzyloxymethoxy)methyl)-8-methoxy-9-methyl-5-(tosylcarbamoyloxy)- 5,6-dihydrobenzo[b]azocine-1(2H)-carboxylate 252  Benzanocenol 251 (20mg, 0.03mmol) was dissolved in THF (0.1mL) at room temperature. TsNCO (0.02mL, 0.13mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes and poured on a saturated aqueous solution of NH4Cl (2mL). The layers were separated and the aqueous layer was extracted with Et2O (3x5mL). The organic layers were combined, washed with a saturated aqueous solution of NaHCO3 (3x5mL), brine (5mL) and dried over MgSO4. After solvent evaporation, the crude was purified by flash column chromatography (AcOEt/hexanes 20/80) to yield carbamate 252 (5mg, 20%) as a pale yellow oil. Rotameric mixture (1:1 ratio)  1H NMR:  7.91 (4H, d, J = 8.5), 7.47-7.18 (44H, m), 6.12-6.00 (2H, m), 5.29-4.83 (14H, m), 4.61 (2H, m), 4.35-4.20 (8H, m), 3.84 (6H, s), 3.83-3.58 (10H, m), 2.35 (3H, s), 2.34 (3H, s), 2.25 (3H, s), 2.20 (3H, s), 1.44 (2H, s br) MS:  935.4 [M + Na]+  195  Preparation of (3aR,4R,11S,11aS)-benzyl 7,10-bis(benzyloxy)-11- ((benzyloxymethoxy)methyl)-4-iodo-9-methoxy-8-methyl-2-oxo-3-tosyl- 3,3a,4,5,11,11a-hexahydrobenzo[b]oxazolo[5,4-e]azocine-6(2H)- carboxylate 210  Carbamate 252 (107mg, 0.12mmol) was dissolved in CH2Cl2 (2mL) at room temperature. A saturated aqueous solution of NaHCO3 (2mL) was added and I2 (90mg, 0.35mmol) was added portionwise. The reaction mixture was stirred at room temperature overnight and water (2mL) was added. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3x2mL). The organic layers were combined, washed with a saturated aqueous solution of Na2S2O3 (3x5mL), brine (5mL), dried over MgSO4 and concentrated to afford oxazolidinone 210 (128mg, 98%) as a brown oil. Rotameric mixture (1:1 ratio)  1H NMR:  7.72 (2H, d, J = 8.1), 7.65 (2H, d, J = 8.1), 7.49-7.14 (40H, m), 6.98 (4H, m), 5.27-4.29 (26H, m), 3.94 (6H, s), 3.82-3.65 (8H, m), 3.57-3.43 (2H, m), 2.36 (3H, s), 2.33 (3H, s), 2.18 (3H, s), 2.14 (3H, s) MS:  1061.5 [M + Na]+  196  Preparation of (1aS,8S,9S,9aS)-benzyl 4,7-bis(benzyloxy)-8- ((benzyloxymethoxy)methyl)-9-hydroxy-6-methoxy-5-methyl-1-tosyl- 1a,2,9,9a-tetrahydro-1H-azirino[2,3-f]benzo[b]azocine-3(8H)- carboxylate 253  Oxazolidinone 210 (120mg, 0.12mmol) was dissolved in MeOH (4mL) and Et2O (2 drops) at room temperature. K2CO3 (80mg, 0.58mmol) was added portionwise. The reaction mixture was stirred at room temperature overnight and water (2mL) was added. The layers were separated and the aqueous layer was extracted with Et2O (3x2mL). The organic layers were combined, washed with a HCl aqueous solution (2M, 3x2mL), water (5mL), a saturated aqueous solution of NaHCO3 (3x5mL), brine (5mL), dried over MgSO4 and concentrated to afford aziridine 253 (89mg, 83%) as a brown oil. Rotameric mixture (1:1 ratio)  1H NMR:  7.82 (4H, m), 7.50 (4H, m), 7.42-7.17 (40H, m), 5.19-4.50 (16H, m), 4.49 (4H, m), 4.20-3.94 (4H, m), 3.92 (6H, s), 3.88-3.57 (8H, m), 3.36 (2H, m), 2.67-2.49 (4H, m), 2.42 (6H, s), 2.28 (3H, s), 2.23 (3H, s) 13C NMR:  155.8, 155.4, 152.7 (2 overlapping resonances), 151.5, 151.0, 146.5, 146.4, 144.6, 143.4, 137.6, 137.4, 137.2, 137.0, 136.9, 136.6, 135.9, 135.6, 135.0, 134.9, 130.8, 130.6, 129.7 (4 overlapping resonances), 128.7 (2 overlapping resonances), 128.6 (6 overlapping resonances), 128.5 (8 overlapping resonances), 128.4 (6 overlapping resonances), 197  128.3 (2 overlapping resonances), 128.2 (4 overlapping resonances), 128.1, 128.0 (2 overlapping resonances), 127.9 (4 overlapping resonances), 127.8, 127.7 (5 overlapping resonances), 127.3 (2 overlapping resonances), 127.0, 126.4 (3 overlapping resonances), 126.0, 94.3, 94.2, 77.3, 75.0, 74.8, 74.5, 72.9, 72.8, 71.4, 71.1, 69.5, 69.3, 67.9, 67.5, 60.4, 60.3, 47.9, 47.4 (2 overlapping resonances), 47.1, 44.0, 43.9, 38.3, 38.1, 21.7, 21.5, 10.4, 10.3 MS:  907.6 [M + Na]+  198  Preparation of (1aS,8S,9aS)-benzyl 4,7-bis(benzyloxy)-8- ((benzyloxymethoxy)methyl)-6-methoxy-5-methyl-9-oxo-1-tosyl-1a,2,9,9a- tetrahydro-1H-azirino[2,3-f]benzo[b]azocine-3(8H)-carboxylate 209  Aziridine 253 (23mg, 0.03mmol) was dissolved in CH2Cl2 (2mL) at 0°C. A solution of Dess-Martin periodinane (22mg, 0.05mmol) in CH2Cl2 (0.5mL) was added dropwise. The reaction mixture was stirred at 0°C for 2 hours. The crude was purified by flash column chromatography (AcOEt/hexanes 30/70) to yield ketone 209 (9mg, 40%) as a pale yellow oil. Rotameric mixture (1:1 ratio)  1H NMR:  7.84 (4H, m), 7.40-7.15 (44H, m), 5.33 (2H, m), 5.17-4.92 (6H, m), 4.81-4.40 (12H, m), 4.26-4.01 (4H, m), 3.94 (6H, s), 3.82-3.66 (4H, m), 3.58-3.33 (2H, m), 2.91-2.75 (4H, m), 2.43 (6H, s), 2.30 (3H, s), 2.24 (3H, s) MS:  905.5 [M + Na]+ 199  X-ray Structure Report of (3aS,4S,5R,6R)-7,10-bis(benzyloxy)-6- (benzyloxymethyl)-8-methoxy-9-methyl-4-(trimethylsilyl)-3a,4,5,6- tetrahydro-3H-benzo[f][1,2,3]triazolo[1,5-a]azepin-5-ol 203         for   Prof. Marco Ciufolini    Department of Chemistry  UBC                     December 11, 2008 200                       201      Experimental    Data Collection   A colourless needle crystal of C38H45N3O5Si having approximate dimensions of 0.03 x 0.12 x 0.37 mm was mounted on a glass fiber. All measurements were made on a Bruker X8 APEX II diffractometer with graphite monochromated Mo-Kα radiation.  The data were collected at a temperature of -100.0 + 0.1oC to a maximum 2θ value of 45.5o. Data were collected in a series of φ and ω scans in 0.50o oscillations with 60.0-second exposures. The crystal-to-detector distance was 36.00 mm.   Data Reduction   Of the 16109 reflections that were collected, 4447 were unique (Rint = 0.26); equivalent reflections were merged.  Data were collected and integrated using the Bruker SAINT1 software package. The linear absorption coefficient, μ, for Mo-Kα radiation is 1.17 cm-1. Data were corrected for absorption effects using the multi-scan technique (SADABS2), with minimum and maximum transmission coefficients of 0.658 and 0.996, respectively.  The data were corrected for Lorentz and polarization effects.   Structure Solution and Refinement   The structure was solved by direct methods3.   All non-hydrogen atoms were refined anisotropically.  All hydrogen atoms were placed in calculated positions but were not refined. 202  The final cycle of full-matrix least-squares refinement4 on F2 was based on 4447 reflections and 425 variable parameters and converged (largest parameter shift was 0.00 times its esd) with unweighted and weighted agreement factors of:  R1 = Σ ||Fo| - |Fc|| / Σ |Fo| = 0.300   wR2 = [ Σ ( w (Fo2 - Fc2)2 )/ Σ w(Fo2)2]1/2 = 0.373    The standard deviation of an observation of unit weight5 was 0.95. The weighting scheme was based on counting statistics.  The maximum and minimum peaks on the final difference Fourier map corresponded to 0.50 and –0.34 e-/Å3, respectively.   Neutral atom scattering factors were taken from Cromer and Waber6. Anomalous dispersion effects were included in Fcalc7; the values for Δf' and Δf" were those of Creagh and McAuley8. The values for the mass attenuation coefficients are those of Creagh and Hubbell9. All refinements were performed using the SHELXTL10 crystallographic software package of Bruker-AXS.   References    (1) SAINT. Version 7.46A. Bruker AXS Inc., Madison, Wisconsin, USA. (1997-2007).  (2) SADABS. Bruker Nonius area detector scaling and absorption correction - V2.10, Bruker AXS Inc., Madison, Wisconsin, USA (2003).  (3) SIR97 - Altomare A., Burla M.C., Camalli M., Cascarano G.L., Giacovazzo C. , Guagliardi A., Moliterni A.G.G., Polidori G.,Spagna R. (1999) J. Appl. Cryst. 32, 115-119.  (4) Least Squares function minimized:    Σw(Fo2-Fc2)2  (5) Standard deviation of an observation of unit weight:       [Σw(Fo2-Fc2)2/(No-Nv)]1/2      where: No  = number of observations         Nv  = number of variables  203   (6) Cromer, D. T. & Waber, J. T.; "International Tables for X-ray Crystallography", Vol. IV, The Kynoch Press, Birmingham, England, Table 2.2 A (1974).  (7) Ibers, J. A. & Hamilton, W. C.; Acta Crystallogr., 17, 781 (1964).  (8) Creagh, D. C. & McAuley, W.J .; "International Tables for Crystallography", Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.6.8, pages 219-222 (1992).  (9) Creagh, D. C. & Hubbell, J.H..; "International Tables for Crystallography", Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.4.3, pages 200-206 (1992).  (10) SHELXTL Version 5.1. Bruker AXS Inc., Madison, Wisconsin, USA. (1997).   204                                                 EXPERIMENTAL DETAILS    A. Crystal Data    Empirical Formula C38H45N3O5Si  Formula Weight 651.86  Crystal Color, Habit black, prism  Crystal Dimensions 0.03 X 0.12 X 0.37 mm  Crystal System triclinic  Lattice Type primitive  Lattice Parameters a = 5.912(4) Å  b = 14.615(11) Å  c = 20.083(15) Å  α = 84.34(2) o  β = 88.62(2) o  γ = 80.43(2) o  V = 1703(2) Å3  Space Group P -1 (#2)  Z value 2  Dcalc 1.271 g/cm3  F000 696.00  μ(MoKα) 1.17 cm-1 205  B. Intensity Measurements    Diffractometer Bruker X8 APEX II  Radiation MoKα (λ = 0.71073 Å)  graphite monochromated     Data Images 1115 exposures @ 60.0 seconds  Detector Position 36.00 mm  2θmax 45.5o  No. of Reflections Measured Total: 16109    Unique: 4447 (Rint = 0.26) Corrections Absorption (Tmin = 0.658, Tmax= 0.996)  Lorentz-polarization 206  C. Structure Solution and Refinement    Structure Solution Direct Methods (SIR97)  Refinement Full-matrix least-squares on F2  Function Minimized Σ w (Fo2 - Fc2)2  Least Squares Weights w=1/(σ2(Fo2)+(0.1615P) 20.0000P)  Anomalous Dispersion All non-hydrogen atoms  No. Observations (I>0.00σ(I)) 4447  No. Variables 425  Reflection/Parameter Ratio 10.46  Residuals (refined on F2, all data): R1; wR2 0.300; 0.373  Goodness of Fit Indicator 0.95  No. Observations (I>2.00σ(I)) 1420  Residuals (refined on F): R1; wR2 0.113; 0.262  Max Shift/Error in Final Cycle 0.00  Maximum peak in Final Diff. Map 0.50 e-/Å3  Minimum peak in Final Diff. Map -0.34 e-/Å3 207           Table 2.  Atomic coordinates ( x 10^4) and equivalent isotropic          displacement parameters (A^2 x 10^3) for mc018.          U(eq) is defined as one third of the trace of the orthogonalized          Uij tensor.           ________________________________________________________________                           x             y             z           U(eq)          ________________________________________________________________            C(1)         4250(20)       116(10)      4018(6)       76(4)           C(2)         2180(20)       513(8)       3534(5)       56(4)           C(3)         1850(20)      1569(8)       3400(5)       55(4)           C(4)          240(20)      1933(8)       2788(5)       49(3)           C(5)         1110(20)      1593(8)       2105(5)       53(4)           C(6)          740(20)       609(8)       2022(5)       54(4)           C(7)         -660(20)       452(8)       1500(5)       49(3)           C(8)         -900(20)      -458(9)       1398(6)       55(4)           C(9)           50(20)     -1217(9)       1819(6)       60(4)           C(10)        1370(20)     -1030(9)       2342(5)       57(4)           C(11)        1710(20)      -133(9)       2426(5)       50(3)           C(12)       -1300(30)      3295(8)       3869(6)       81(5)           C(13)        3030(30)      2516(11)      4612(6)      105(6)           C(14)        -910(20)      1420(9)       4700(6)       81(5)           C(15)        3590(30)      1666(9)       1944(6)       70(4)           C(16)        3790(40)      3170(8)       1694(7)      133(9)           C(17)        4990(30)      4066(9)       1871(6)       68(4)           C(18)        6910(40)      4344(17)      1610(9)      124(8)           C(19)        7620(40)      5110(20)      1804(12)     142(12)           C(20)        6210(50)      5622(15)      2240(10)     122(9)           C(21)        4260(40)      5397(11)      2496(7)       89(5)           C(22)        3720(20)      4588(10)      2303(6)       71(4)           C(23)        -610(20)      1260(9)        414(6)       64(4)           C(24)       -1310(20)      2240(10)       119(5)       55(4)           C(25)       -3310(30)      2531(11)      -209(7)       81(5)           C(26)       -3940(40)      3452(16)      -481(7)      104(6)           C(27)       -2370(50)      4059(13)      -459(10)     106(6)           C(28)        -400(40)      3764(13)      -142(9)      108(6)           C(29)         190(30)      2860(12)       133(7)       78(4)           C(30)       -4540(30)      -438(10)       964(6)       85(5)           C(31)        -340(20)     -2186(8)       1727(5)       70(4)           C(32)        1190(30)     -1815(10)      3416(7)       89(5)           C(33)        1270(30)     -2786(10)      3703(6)       66(4)           C(34)        3210(20)     -3218(10)      4051(6)       62(4)           C(35)        3380(30)     -4145(13)      4314(6)       83(5)           C(36)        1570(50)     -4608(12)      4220(9)      108(6)           C(37)        -250(30)     -4203(16)      3877(9)       95(6)           C(38)        -440(30)     -3274(16)      3618(7)       92(5)           N(1)         3090(20)       -14(7)       2962(4)       57(3)           N(2)         5150(20)      -568(10)      3081(7)      102(5)           N(3)         5850(20)      -500(10)      3660(7)      119(5)           O(1)        -1973(15)      1711(5)       2970(3)       60(3)           O(2)         4250(20)      2493(8)       2137(5)      107(4)           O(3)        -1666(13)      1202(5)       1068(4)       52(2)           O(4)        -2164(16)      -582(5)        843(3)       57(3)           O(5)         2260(15)     -1816(5)       2773(4)       63(2)           Si(1)         629(7)       2209(3)       4139(2)       67(1)          ________________________________________________________________  208              Table 3.  Bond lengths [A] and angles [deg] for mc018.            _____________________________________________________________              C(1)-N(3)                     1.424(16)             C(1)-C(2)                     1.578(15)             C(1)-H(1A)                    0.9900             C(1)-H(1B)                    0.9900             C(2)-N(1)                     1.486(13)             C(2)-C(3)                     1.521(14)             C(2)-H(2)                     1.0000             C(3)-C(4)                     1.567(14)             C(3)-Si(1)                    1.898(12)             C(3)-H(3)                     1.0000             C(4)-O(1)                     1.431(12)             C(4)-C(5)                     1.552(14)             C(4)-H(4)                     1.0000             C(5)-C(6)                     1.513(14)             C(5)-C(15)                    1.514(16)             C(5)-H(5)                     1.0000             C(6)-C(11)                    1.343(14)             C(6)-C(7)                     1.412(14)             C(7)-O(3)                     1.390(12)             C(7)-C(8)                     1.395(14)             C(8)-C(9)                     1.374(15)             C(8)-O(4)                     1.401(12)             C(9)-C(10)                    1.402(15)             C(9)-C(31)                    1.502(15)             C(10)-C(11)                   1.383(15)             C(10)-O(5)                    1.403(13)             C(11)-N(1)                    1.409(13)             C(12)-Si(1)                   1.836(13)             C(12)-H(12A)                  0.9800             C(12)-H(12B)                  0.9800             C(12)-H(12C)                  0.9800             C(13)-Si(1)                   1.866(12)             C(13)-H(13A)                  0.9800             C(13)-H(13B)                  0.9800             C(13)-H(13C)                  0.9800             C(14)-Si(1)                   1.864(14)             C(14)-H(14A)                  0.9800             C(14)-H(14B)                  0.9800             C(14)-H(14C)                  0.9800             C(15)-O(2)                    1.421(13)             C(15)-H(15A)                  0.9900             C(15)-H(15B)                  0.9900             C(16)-O(2)                    1.263(14)             C(16)-C(17)                   1.66(2)             C(16)-H(16A)                  0.9900             C(16)-H(16B)                  0.9900             C(17)-C(18)                   1.34(2)             C(17)-C(22)                   1.345(17)             C(18)-C(19)                   1.36(3)             C(18)-H(18)                   0.9500             C(19)-C(20)                   1.38(3)             C(19)-H(19)                   0.9500             C(20)-C(21)                   1.33(2)             C(20)-H(20)                   0.9500             C(21)-C(22)                   1.370(17) 209              C(21)-H(21)                   0.9500             C(22)-H(22)                   0.9500             C(23)-O(3)                    1.441(13)             C(23)-C(24)                   1.490(16)             C(23)-H(23A)                  0.9900             C(23)-H(23B)                  0.9900             C(24)-C(25)                   1.351(17)             C(24)-C(29)                   1.373(17)             C(25)-C(26)                   1.40(2)             C(25)-H(25)                   0.9500             C(26)-C(27)                   1.39(2)             C(26)-H(26)                   0.9500             C(27)-C(28)                   1.32(2)             C(27)-H(27)                   0.9500             C(28)-C(29)                   1.373(19)             C(28)-H(28)                   0.9500             C(29)-H(29)                   0.9500             C(30)-O(4)                    1.405(14)             C(30)-H(30A)                  0.9800             C(30)-H(30B)                  0.9800             C(30)-H(30C)                  0.9800             C(31)-H(31A)                  0.9800             C(31)-H(31B)                  0.9800             C(31)-H(31C)                  0.9800             C(32)-O(5)                    1.424(14)             C(32)-C(33)                   1.471(17)             C(32)-H(32A)                  0.9900             C(32)-H(32B)                  0.9900             C(33)-C(38)                   1.35(2)             C(33)-C(34)                   1.384(16)             C(34)-C(35)                   1.393(17)             C(34)-H(34)                   0.9500             C(35)-C(36)                   1.38(2)             C(35)-H(35)                   0.9500             C(36)-C(37)                   1.31(2)             C(36)-H(36)                   0.9500             C(37)-C(38)                   1.39(2)             C(37)-H(37)                   0.9500             C(38)-H(38)                   0.9500             N(1)-N(2)                     1.360(14)             N(2)-N(3)                     1.263(14)             O(1)-H(1)                     0.8400              N(3)-C(1)-C(2)              107.2(10)             N(3)-C(1)-H(1A)             110.3             C(2)-C(1)-H(1A)             110.3             N(3)-C(1)-H(1B)             110.3             C(2)-C(1)-H(1B)             110.3             H(1A)-C(1)-H(1B)            108.5             N(1)-C(2)-C(3)              115.4(10)             N(1)-C(2)-C(1)               96.1(9)             C(3)-C(2)-C(1)              112.3(9)             N(1)-C(2)-H(2)              110.8             C(3)-C(2)-H(2)              110.8             C(1)-C(2)-H(2)              110.8             C(2)-C(3)-C(4)              111.8(8)             C(2)-C(3)-Si(1)             113.8(8)             C(4)-C(3)-Si(1)             107.5(8)             C(2)-C(3)-H(3)              107.8 210              C(4)-C(3)-H(3)              107.8             Si(1)-C(3)-H(3)             107.8             O(1)-C(4)-C(5)              112.6(9)             O(1)-C(4)-C(3)              106.9(9)             C(5)-C(4)-C(3)              115.9(10)             O(1)-C(4)-H(4)              107.0             C(5)-C(4)-H(4)              107.0             C(3)-C(4)-H(4)              107.0             C(6)-C(5)-C(15)             108.6(10)             C(6)-C(5)-C(4)              113.5(10)             C(15)-C(5)-C(4)             114.6(9)             C(6)-C(5)-H(5)              106.5             C(15)-C(5)-H(5)             106.5             C(4)-C(5)-H(5)              106.5             C(11)-C(6)-C(7)             117.7(10)             C(11)-C(6)-C(5)             122.8(10)             C(7)-C(6)-C(5)              119.5(11)             O(3)-C(7)-C(8)              120.8(9)             O(3)-C(7)-C(6)              119.4(10)             C(8)-C(7)-C(6)              119.7(11)             C(9)-C(8)-C(7)              122.6(10)             C(9)-C(8)-O(4)              119.9(10)             C(7)-C(8)-O(4)              117.5(11)             C(8)-C(9)-C(10)             115.8(11)             C(8)-C(9)-C(31)             122.0(10)             C(10)-C(9)-C(31)            122.2(12)             C(11)-C(10)-C(9)            121.7(12)             C(11)-C(10)-O(5)            123.9(10)             C(9)-C(10)-O(5)             114.4(11)             C(6)-C(11)-C(10)            122.3(10)             C(6)-C(11)-N(1)             120.0(10)             C(10)-C(11)-N(1)            117.6(11)             Si(1)-C(12)-H(12A)          109.5             Si(1)-C(12)-H(12B)          109.5             H(12A)-C(12)-H(12B)         109.5             Si(1)-C(12)-H(12C)          109.5             H(12A)-C(12)-H(12C)         109.5             H(12B)-C(12)-H(12C)         109.5             Si(1)-C(13)-H(13A)          109.5             Si(1)-C(13)-H(13B)          109.5             H(13A)-C(13)-H(13B)         109.5             Si(1)-C(13)-H(13C)          109.5             H(13A)-C(13)-H(13C)         109.5             H(13B)-C(13)-H(13C)         109.5             Si(1)-C(14)-H(14A)          109.5             Si(1)-C(14)-H(14B)          109.5             H(14A)-C(14)-H(14B)         109.5             Si(1)-C(14)-H(14C)          109.5             H(14A)-C(14)-H(14C)         109.5             H(14B)-C(14)-H(14C)         109.5             O(2)-C(15)-C(5)             113.4(11)             O(2)-C(15)-H(15A)           108.9             C(5)-C(15)-H(15A)           108.9             O(2)-C(15)-H(15B)           108.9             C(5)-C(15)-H(15B)           108.9             H(15A)-C(15)-H(15B)         107.7             O(2)-C(16)-C(17)            110.8(11)             O(2)-C(16)-H(16A)           109.5             C(17)-C(16)-H(16A)          109.5 211              O(2)-C(16)-H(16B)           109.5             C(17)-C(16)-H(16B)          109.5             H(16A)-C(16)-H(16B)         108.1             C(18)-C(17)-C(22)           119.0(16)             C(18)-C(17)-C(16)           128.6(18)             C(22)-C(17)-C(16)           112.2(17)             C(17)-C(18)-C(19)           121(2)             C(17)-C(18)-H(18)           119.6             C(19)-C(18)-H(18)           119.7             C(18)-C(19)-C(20)           117(2)             C(18)-C(19)-H(19)           121.5             C(20)-C(19)-H(19)           121.5             C(21)-C(20)-C(19)           125(2)             C(21)-C(20)-H(20)           117.6             C(19)-C(20)-H(20)           117.6             C(20)-C(21)-C(22)           114.8(17)             C(20)-C(21)-H(21)           122.6             C(22)-C(21)-H(21)           122.6             C(17)-C(22)-C(21)           123.6(16)             C(17)-C(22)-H(22)           118.2             C(21)-C(22)-H(22)           118.2             O(3)-C(23)-C(24)            106.1(9)             O(3)-C(23)-H(23A)           110.5             C(24)-C(23)-H(23A)          110.5             O(3)-C(23)-H(23B)           110.5             C(24)-C(23)-H(23B)          110.5             H(23A)-C(23)-H(23B)         108.7             C(25)-C(24)-C(29)           117.8(14)             C(25)-C(24)-C(23)           122.6(13)             C(29)-C(24)-C(23)           119.3(13)             C(24)-C(25)-C(26)           121.8(14)             C(24)-C(25)-H(25)           119.1             C(26)-C(25)-H(25)           119.1             C(27)-C(26)-C(25)           118.4(16)             C(27)-C(26)-H(26)           120.8             C(25)-C(26)-H(26)           120.8             C(28)-C(27)-C(26)           119.2(19)             C(28)-C(27)-H(27)           120.4             C(26)-C(27)-H(27)           120.4             C(27)-C(28)-C(29)           121.9(18)             C(27)-C(28)-H(28)           119.0             C(29)-C(28)-H(28)           119.0             C(28)-C(29)-C(24)           120.5(15)             C(28)-C(29)-H(29)           119.7             C(24)-C(29)-H(29)           119.7             O(4)-C(30)-H(30A)           109.5             O(4)-C(30)-H(30B)           109.5             H(30A)-C(30)-H(30B)         109.5             O(4)-C(30)-H(30C)           109.5             H(30A)-C(30)-H(30C)         109.5             H(30B)-C(30)-H(30C)         109.5             C(9)-C(31)-H(31A)           109.5             C(9)-C(31)-H(31B)           109.5             H(31A)-C(31)-H(31B)         109.5             C(9)-C(31)-H(31C)           109.5             H(31A)-C(31)-H(31C)         109.5             H(31B)-C(31)-H(31C)         109.5             O(5)-C(32)-C(33)            108.8(10)             O(5)-C(32)-H(32A)           109.9 212              C(33)-C(32)-H(32A)          109.9             O(5)-C(32)-H(32B)           109.9             C(33)-C(32)-H(32B)          109.9             H(32A)-C(32)-H(32B)         108.3             C(38)-C(33)-C(34)           119.5(14)             C(38)-C(33)-C(32)           122.3(17)             C(34)-C(33)-C(32)           118.2(15)             C(33)-C(34)-C(35)           119.8(13)             C(33)-C(34)-H(34)           120.1             C(35)-C(34)-H(34)           120.1             C(36)-C(35)-C(34)           118.4(15)             C(36)-C(35)-H(35)           120.8             C(34)-C(35)-H(35)           120.8             C(37)-C(36)-C(35)           121.6(17)             C(37)-C(36)-H(36)           119.2             C(35)-C(36)-H(36)           119.2             C(36)-C(37)-C(38)           120.4(16)             C(36)-C(37)-H(37)           119.8             C(38)-C(37)-H(37)           119.8             C(33)-C(38)-C(37)           120.3(15)             C(33)-C(38)-H(38)           119.8             C(37)-C(38)-H(38)           119.8             N(2)-N(1)-C(11)             121.2(10)             N(2)-N(1)-C(2)              113.9(9)             C(11)-N(1)-C(2)             122.8(10)             N(3)-N(2)-N(1)              110.8(12)             N(2)-N(3)-C(1)              111.9(12)             C(4)-O(1)-H(1)              109.5             C(16)-O(2)-C(15)            112.1(11)             C(7)-O(3)-C(23)             114.3(9)             C(8)-O(4)-C(30)             112.9(9)             C(10)-O(5)-C(32)            112.4(9)             C(12)-Si(1)-C(14)           110.5(7)             C(12)-Si(1)-C(13)           108.0(7)             C(14)-Si(1)-C(13)           108.8(6)             C(12)-Si(1)-C(3)            111.7(5)             C(14)-Si(1)-C(3)            108.7(6)             C(13)-Si(1)-C(3)            109.0(6)            _____________________________________________________________             Symmetry transformations used to generate equivalent atoms:   213       Table 4.  Anisotropic displacement parameters (A^2 x 10^3) for mc018.     The anisotropic displacement factor exponent takes the form:     -2 pi^2 [ h^2 a*^2 U11 + ... + 2 h k a* b* U12 ]      _______________________________________________________________________                U11        U22        U33        U23        U13        U12     _______________________________________________________________________      C(1)     57(10)    117(12)     62(9)     -31(9)     -18(8)     -19(8)     C(2)     66(10)     71(10)     36(7)     -17(7)     -24(6)     -13(7)     C(3)     52(9)      63(9)      54(8)     -17(7)     -21(6)     -14(7)     C(4)     43(9)      72(9)      34(7)      -9(6)       1(6)     -16(7)     C(5)     85(11)     48(8)      33(7)     -17(6)      -1(7)     -24(7)     C(6)     96(11)     54(9)      21(7)     -14(6)     -13(7)     -30(7)     C(7)     62(9)      52(9)      36(7)     -25(7)      -3(6)      -7(7)     C(8)     86(11)     59(9)      32(7)     -28(7)      -2(7)     -29(8)     C(9)     94(11)     54(9)      34(7)      -8(7)      -7(7)     -18(8)     C(10)    90(11)     58(10)     25(7)     -16(7)     -11(7)     -11(8)     C(11)    68(10)     62(9)      26(7)     -19(7)      -9(6)     -20(7)     C(12)   134(14)     74(10)     45(8)     -19(7)     -12(8)     -38(9)     C(13)   117(14)    162(16)     56(9)     -64(10)    -20(9)     -50(11)     C(14)   112(13)     86(11)     51(9)      -4(8)     -20(8)     -27(9)     C(15)   110(14)     73(10)     44(8)     -27(7)       9(8)     -51(9)     C(16)   310(30)     23(9)      56(10)    -13(7)    -106(13)     27(11)     C(17)   112(15)     66(10)     20(7)     -14(7)     -16(8)      10(10)     C(18)    75(18)    200(30)     68(13)     37(15)      3(12)     29(15)     C(19)    88(19)    250(30)    101(19)     50(20)    -22(14)   -100(20)     C(20)   180(30)    140(20)     64(13)     33(13)    -61(14)   -106(19)     C(21)   159(19)     73(12)     48(10)    -21(8)     -11(10)    -48(11)     C(22)    82(12)     87(11)     47(9)      -6(8)      -4(8)     -22(9)     C(23)    70(11)     70(10)     52(9)     -21(8)      23(7)      -9(8)     C(24)    63(10)     78(11)     29(7)     -12(7)     -12(7)     -19(8)     C(25)   102(14)     86(13)     59(9)     -10(9)     -27(9)     -25(10)     C(26)   115(17)    125(17)     56(11)     -5(11)    -36(10)     31(14)     C(27)   130(20)     87(15)     87(14)     10(11)     31(13)      1(14)     C(28)   132(19)     77(15)    114(15)     -4(11)    -17(13)    -17(12)     C(29)    95(13)     84(12)     61(10)    -17(9)     -20(8)     -26(10)     C(30)    63(12)    130(14)     74(10)    -31(9)     -26(8)     -32(9)     C(31)   125(13)     66(9)      32(7)     -21(6)     -11(7)     -40(8)     C(32)   131(15)     75(12)     52(10)    -18(8)      15(9)      12(10)     C(33)   102(14)     60(11)     35(8)     -25(7)      -5(8)       2(10)     C(34)    88(12)     75(11)     27(7)     -12(7)     -18(7)     -19(9)     C(35)   102(14)    100(14)     45(9)     -11(9)     -31(8)       0(11)     C(36)   160(20)     98(15)     76(13)     -5(11)     -3(13)    -37(15)     C(37)    88(16)    134(18)     83(13)    -30(12)     13(11)    -63(13)     C(38)    85(14)    142(17)     49(10)    -34(11)    -17(8)      -4(13)     N(1)     66(9)      66(7)      44(7)     -16(5)     -25(6)     -11(6)     N(2)     67(10)    162(13)     86(10)    -59(9)     -24(8)     -14(9)     N(3)     95(11)    180(14)     85(10)    -76(10)    -33(9)      12(10)     O(1)     82(7)      76(6)      29(4)      -8(4)     -26(4)     -30(5)     O(2)    158(11)     84(8)      90(8)     -22(7)     -15(7)     -43(7)     O(3)     66(6)      55(6)      38(5)     -16(4)      -3(4)      -9(4)     O(4)     88(8)      56(5)      35(5)     -28(4)     -23(5)     -16(5)     O(5)     88(7)      63(6)      37(5)     -22(5)       1(5)      -2(5)     Si(1)    67(3)     102(3)      44(2)     -33(2)     -12(2)     -27(2)     _______________________________________________________________________  214            Table 5.  Hydrogen coordinates ( x 10^4) and isotropic          displacement parameters (A^2 x 10^3) for mc018.           ________________________________________________________________                           x             y             z           U(eq)          ________________________________________________________________            H(1A)        4983           631          4152          91           H(1B)        3711          -223          4426          91           H(2)          735           308          3715          67           H(3)         3390          1747          3289          66           H(4)           84          2628          2739          59           H(5)          166          2009          1753          64           H(12A)       -466          3700          3574         122           H(12B)      -1871          3614          4262         122           H(12C)      -2599          3150          3628         122           H(13A)       4074          1945          4769         157           H(13B)       2414          2843          4997         157           H(13C)       3875          2921          4318         157           H(14A)        141           846          4840         122           H(14B)      -2205          1269          4460         122           H(14C)      -1486          1732          5096         122           H(15A)       4583          1120          2174          84           H(15B)       3844          1644          1456          84           H(16A)       2102          3364          1665         160           H(16B)       4353          2974          1253         160           H(18)        7774          3998          1287         149           H(19)        9020          5295          1646         170           H(20)        6660          6174          2367         147           H(21)        3315          5768          2791         106           H(22)        2366          4383          2484          85           H(23A)      -1149           821           132          77           H(23B)       1078          1106           449          77           H(25)       -4312          2097          -257          97           H(26)       -5404          3660          -676         125           H(27)       -2701          4677          -669         127           H(28)         624          4191          -104         129           H(29)        1648          2663           334          94           H(30A)      -5341          -531           561         128           H(30B)      -5041           199          1082         128           H(30C)      -4899          -882          1334         128           H(31A)        471         -2627          2075         105           H(31B)        233         -2353          1286         105           H(31C)      -1989         -2212          1759         105           H(32A)       -426         -1499          3375         107           H(32B)       1996         -1475          3711         107           H(34)        4428         -2883          4110          74           H(35)        4704         -4451          4552         100           H(36)        1642         -5235          4409         130           H(37)       -1438         -4545          3805         114           H(38)       -1779         -2981          3380         110           H(1)        -2439          1429          2669          90          ________________________________________________________________  215            Table 6.  Torsion angles [deg] for mc018.          ________________________________________________________________            N(3)-C(1)-C(2)-N(1)                                   1.0(14)           N(3)-C(1)-C(2)-C(3)                                -119.7(13)           N(1)-C(2)-C(3)-C(4)                                  56.6(13)           C(1)-C(2)-C(3)-C(4)                                 165.4(10)           N(1)-C(2)-C(3)-Si(1)                                178.7(8)           C(1)-C(2)-C(3)-Si(1)                                -72.5(12)           C(2)-C(3)-C(4)-O(1)                                  64.3(12)           Si(1)-C(3)-C(4)-O(1)                                -61.3(10)           C(2)-C(3)-C(4)-C(5)                                 -62.1(14)           Si(1)-C(3)-C(4)-C(5)                                172.3(8)           O(1)-C(4)-C(5)-C(6)                                 -44.8(14)           C(3)-C(4)-C(5)-C(6)                                  78.7(14)           O(1)-C(4)-C(5)-C(15)                               -170.3(10)           C(3)-C(4)-C(5)-C(15)                                -46.8(15)           C(15)-C(5)-C(6)-C(11)                                67.4(15)           C(4)-C(5)-C(6)-C(11)                                -61.3(17)           C(15)-C(5)-C(6)-C(7)                               -112.3(13)           C(4)-C(5)-C(6)-C(7)                                 119.0(12)           C(11)-C(6)-C(7)-O(3)                               -179.3(11)           C(5)-C(6)-C(7)-O(3)                                   0.4(17)           C(11)-C(6)-C(7)-C(8)                                 -3.4(18)           C(5)-C(6)-C(7)-C(8)                                 176.4(11)           O(3)-C(7)-C(8)-C(9)                                -179.1(11)           C(6)-C(7)-C(8)-C(9)                                   5(2)           O(3)-C(7)-C(8)-O(4)                                   0.5(17)           C(6)-C(7)-C(8)-O(4)                                -175.3(11)           C(7)-C(8)-C(9)-C(10)                                 -3.2(19)           O(4)-C(8)-C(9)-C(10)                                177.2(12)           C(7)-C(8)-C(9)-C(31)                                176.2(11)           O(4)-C(8)-C(9)-C(31)                                 -3.4(19)           C(8)-C(9)-C(10)-C(11)                                 0.0(19)           C(31)-C(9)-C(10)-C(11)                             -179.4(12)           C(8)-C(9)-C(10)-O(5)                                178.4(11)           C(31)-C(9)-C(10)-O(5)                                -1.0(18)           C(7)-C(6)-C(11)-C(10)                                 0.2(19)           C(5)-C(6)-C(11)-C(10)                              -179.5(12)           C(7)-C(6)-C(11)-N(1)                               -178.9(12)           C(5)-C(6)-C(11)-N(1)                                  1.3(19)           C(9)-C(10)-C(11)-C(6)                                 1(2)           O(5)-C(10)-C(11)-C(6)                              -176.7(11)           C(9)-C(10)-C(11)-N(1)                              -179.3(12)           O(5)-C(10)-C(11)-N(1)                                 2.4(19)           C(6)-C(5)-C(15)-O(2)                               -167.6(10)           C(4)-C(5)-C(15)-O(2)                                -39.6(15)           O(2)-C(16)-C(17)-C(18)                              101(2)           O(2)-C(16)-C(17)-C(22)                              -83.4(17)           C(22)-C(17)-C(18)-C(19)                               3(3)           C(16)-C(17)-C(18)-C(19)                             178.3(15)           C(17)-C(18)-C(19)-C(20)                              -4(3)           C(18)-C(19)-C(20)-C(21)                               2(3)           C(19)-C(20)-C(21)-C(22)                               1(3)           C(18)-C(17)-C(22)-C(21)                               0(2)           C(16)-C(17)-C(22)-C(21)                            -175.8(12)           C(20)-C(21)-C(22)-C(17)                              -2(2)           O(3)-C(23)-C(24)-C(25)                              -85.3(14) 216            O(3)-C(23)-C(24)-C(29)                              100.0(13)           C(29)-C(24)-C(25)-C(26)                              -5(2)           C(23)-C(24)-C(25)-C(26)                             179.9(13)           C(24)-C(25)-C(26)-C(27)                               6(2)           C(25)-C(26)-C(27)-C(28)                              -5(3)           C(26)-C(27)-C(28)-C(29)                               4(3)           C(27)-C(28)-C(29)-C(24)                              -4(3)           C(25)-C(24)-C(29)-C(28)                               4(2)           C(23)-C(24)-C(29)-C(28)                             179.2(13)           O(5)-C(32)-C(33)-C(38)                              -91.6(16)           O(5)-C(32)-C(33)-C(34)                               86.0(14)           C(38)-C(33)-C(34)-C(35)                              -0.6(19)           C(32)-C(33)-C(34)-C(35)                            -178.2(12)           C(33)-C(34)-C(35)-C(36)                               0(2)           C(34)-C(35)-C(36)-C(37)                               2(3)           C(35)-C(36)-C(37)-C(38)                              -3(3)           C(34)-C(33)-C(38)-C(37)                               0(2)           C(32)-C(33)-C(38)-C(37)                             177.5(13)           C(36)-C(37)-C(38)-C(33)                               2(2)           C(6)-C(11)-N(1)-N(2)                               -133.7(13)           C(10)-C(11)-N(1)-N(2)                                47.1(18)           C(6)-C(11)-N(1)-C(2)                                 64.0(17)           C(10)-C(11)-N(1)-C(2)                              -115.2(13)           C(3)-C(2)-N(1)-N(2)                                 118.0(11)           C(1)-C(2)-N(1)-N(2)                                  -0.2(14)           C(3)-C(2)-N(1)-C(11)                                -78.5(14)           C(1)-C(2)-N(1)-C(11)                                163.3(11)           C(11)-N(1)-N(2)-N(3)                               -164.5(13)           C(2)-N(1)-N(2)-N(3)                                  -0.7(18)           N(1)-N(2)-N(3)-C(1)                                   1(2)           C(2)-C(1)-N(3)-N(2)                                  -1.5(19)           C(17)-C(16)-O(2)-C(15)                             -169.7(13)           C(5)-C(15)-O(2)-C(16)                               -85.6(16)           C(8)-C(7)-O(3)-C(23)                                -70.5(14)           C(6)-C(7)-O(3)-C(23)                                105.4(12)           C(24)-C(23)-O(3)-C(7)                              -160.4(9)           C(9)-C(8)-O(4)-C(30)                                 97.2(14)           C(7)-C(8)-O(4)-C(30)                                -82.5(13)           C(11)-C(10)-O(5)-C(32)                               68.9(17)           C(9)-C(10)-O(5)-C(32)                              -109.5(13)           C(33)-C(32)-O(5)-C(10)                              151.7(12)           C(2)-C(3)-Si(1)-C(12)                              -144.8(8)           C(4)-C(3)-Si(1)-C(12)                               -20.3(10)           C(2)-C(3)-Si(1)-C(14)                               -22.6(9)           C(4)-C(3)-Si(1)-C(14)                               101.9(9)           C(2)-C(3)-Si(1)-C(13)                                96.0(9)           C(4)-C(3)-Si(1)-C(13)                              -139.6(9)          ________________________________________________________________           Symmetry transformations used to generate equivalent atoms:   217  X-ray Structure Report of (3aS,4S,5R,6R)-7,10-bis(benzyloxy)-6- ((benzyloxymethoxy)methyl)-8-methoxy-9-methyl-4-(trimethylsilyl)-3a,4,5,6- tetrahydro-3H-benzo[f][1,2,3]triazolo[1,5-a]azepin-5-ol 245          for   Prof. Marco Ciufolini    Department of Chemistry  UBC                     February 29, 2008 218                       219      Experimental    Data Collection   A colourless needle crystal of C39H47N3O6Si having approximate dimensions of 0.04 x 0.10 x 0.50 mm was mounted on a glass fiber. All measurements were made on a Bruker X8 APEX II diffractometer with graphite monochromated Mo-Kα radiation.  The data were collected at a temperature of -100.0 + 0.1oC to a maximum 2θ value of 50.0o. Data were collected in a series of φ and ω scans in 0.50o oscillations with 30.0 second exposures. The crystal-to-detector distance was 36.00 mm.   Data Reduction   Of the 15851 reflections that were collected, 6240 were unique (Rint = 0.049); equivalent reflections were merged.  Data were collected and integrated using the Bruker SAINT1 software package. The linear absorption coefficient, μ, for Mo-Kα radiation is 1.17 cm-1. Data were corrected for absorption effects using the multi-scan technique (SADABS2), with minimum and maximum transmission coefficients of 0.879 and 0.995, respectively.  The data were corrected for Lorentz and polarization effects.   Structure Solution and Refinement   The structure was solved by direct methods3.   All non-hydrogen atoms were refined anisotropically.  All hydrogen atoms were placed in calculated positions but were not refined. 220  The material crystallizes with two independent molecules in the asymmetric unit.  The final cycle of full-matrix least-squares refinement4 on F2 was based on 6240 reflections and 475 variable parameters and converged (largest parameter shift was 0.00 times its esd) with unweighted and weighted agreement factors of:  R1 = Σ ||Fo| - |Fc|| / Σ |Fo| = 0.111   wR2 = [ Σ ( w (Fo2 - Fc2)2 )/ Σ w(Fo2)2]1/2 = 0.114    The standard deviation of an observation of unit weight5 was 1.00. The weighting scheme was based on counting statistics.  The maximum and minimum peaks on the final difference Fourier map corresponded to 0.21 and –0.26 e-/Å3, respectively.   Neutral atom scattering factors were taken from Cromer and Waber6. Anomalous dispersion effects were included in Fcalc7; the values for Δf' and Δf" were those of Creagh and McAuley8. The values for the mass attenuation coefficients are those of Creagh and Hubbell9. All refinements were performed using the SHELXTL10 crystallographic software package of Bruker-AXS.   References    (1) SAINT. Version 7.46A. Bruker AXS Inc., Madison, Wisconsin, USA. (1997-2007).  (2) SADABS. Bruker Nonius area detector scaling and absorption correction - V2.10, Bruker AXS Inc., Madison, Wisconsin, USA (2003).  (3) SIR97 - Altomare A., Burla M.C., Camalli M., Cascarano G.L., Giacovazzo C. , Guagliardi A., Moliterni A.G.G., Polidori G.,Spagna R. (1999) J. Appl. Cryst. 32, 115-119.  (4) Least Squares function minimized:    Σw(Fo2-Fc2)2  (5) Standard deviation of an observation of unit weight:       [Σw(Fo2-Fc2)2/(No-Nv)]1/2      where: No  = number of observations 221          Nv  = number of variables   (6) Cromer, D. T. & Waber, J. T.; "International Tables for X-ray Crystallography", Vol. IV, The Kynoch Press, Birmingham, England, Table 2.2 A (1974).  (7) Ibers, J. A. & Hamilton, W. C.; Acta Crystallogr., 17, 781 (1964).  (8) Creagh, D. C. & McAuley, W.J .; "International Tables for Crystallography", Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.6.8, pages 219-222 (1992).  (9) Creagh, D. C. & Hubbell, J.H..; "International Tables for Crystallography", Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.4.3, pages 200-206 (1992).  (10) SHELXTL Version 5.1. Bruker AXS Inc., Madision, Wisconsin, USA. (1997).   222                                                 EXPERIMENTAL DETAILS    A. Crystal Data    Empirical Formula C39H47N3O6Si  Formula Weight 681.89  Crystal Color, Habit colourless, needle  Crystal Dimensions 0.04 X 0.10 X 0.50 mm  Crystal System triclinic  Lattice Type primitive  Lattice Parameters a = 6.2465(12) Å  b = 14.720(3) Å  c = 19.921(4) Å  α = 95.012(8) o  β = 96.054(8) o  γ =  99.423(8) o  V = 1786.6(7) Å3  Space Group P -1 (#2)  Z value 2  Dcalc 1.268 g/cm3  F000 728.00  μ(MoKα) 1.17 cm-1 223  B. Intensity Measurements    Diffractometer Bruker X8 APEX II  Radiation MoKα (λ = 0.71073 Å)  graphite monochromated     Data Images 862 exposures @ 30.0 seconds  Detector Position 36.00 mm  2θmax 50.0o  No. of Reflections Measured Total: 15851    Unique: 6240 (Rint = 0.049) Corrections Absorption (Tmin = 0.879, Tmax= 0.995)  Lorentz-polarization 224  C. Structure Solution and Refinement    Structure Solution Direct Methods (SIR97)  Refinement Full-matrix least-squares on F2  Function Minimized Σ w (Fo2 - Fc2)2  Least Squares Weights w=1/(σ2(Fo2)+(0.0456P) 2+ 0.1388P)  Anomalous Dispersion All non-hydrogen atoms  No. Observations (I>0.00σ(I)) 6240  No. Variables 475  Reflection/Parameter Ratio 13.14  Residuals (refined on F2, all data): R1; wR2 0.111; 0.114  Goodness of Fit Indicator 1.00  No. Observations (I>2.00σ(I)) 3678  Residuals (refined on F): R1; wR2 0.052; 0.094  Max Shift/Error in Final Cycle 0.00  Maximum peak in Final Diff. Map 0.21 e-/Å3  Minimum peak in Final Diff. Map -0.26 e-/Å3 225           Table 2.  Atomic coordinates ( x 10^4) and equivalent isotropic          displacement parameters (A^2 x 10^3) for mc011.          U(eq) is defined as one third of the trace of the orthogonalized          Uij tensor.           ________________________________________________________________                           x             y             z           U(eq)          ________________________________________________________________            C(1)          100(5)       -123(2)       3928(2)       40(1)           C(2)         1789(4)       -485(2)       3522(1)       26(1)           C(3)         1404(4)      -1538(2)       3381(1)       23(1)           C(4)         2713(4)      -1898(2)       2840(1)       22(1)           C(5)         2385(4)      -1590(2)       2127(1)       20(1)           C(6)         3398(4)       -606(2)       2048(1)       20(1)           C(7)         4793(4)       -437(2)       1555(1)       21(1)           C(8)         5712(4)        448(2)       1460(1)       23(1)           C(9)         5380(4)       1203(2)       1872(1)       25(1)           C(10)        4013(4)       1041(2)       2372(1)       24(1)           C(11)        2964(4)        153(2)       2442(1)       21(1)           C(12)        2592(5)      -3275(2)       3993(2)       42(1)           C(13)        -610(5)      -2285(2)       4623(2)       50(1)           C(14)        4125(5)      -1373(2)       4780(1)       42(1)           C(15)          20(4)      -1804(2)       1813(1)       23(1)           C(16)       -2856(4)      -3077(2)       1655(1)       28(1)           C(17)       -3677(4)      -3954(2)       2564(1)       34(1)           C(18)       -5704(4)      -4627(2)       2279(1)       27(1)           C(19)       -7383(4)      -4354(2)       1885(1)       32(1)           C(20)       -9261(4)      -4977(2)       1644(2)       39(1)           C(21)       -9481(5)      -5864(2)       1798(2)       43(1)           C(22)       -7824(5)      -6149(2)       2191(2)       46(1)           C(23)       -5928(5)      -5539(2)       2424(1)       37(1)           C(24)        4053(5)      -1335(2)        489(1)       42(1)           C(25)        4440(30)     -2239(8)        196(13)      27(2)           C(26)        6380(30)     -2081(6)        -92(11)      43(3)           C(27)        7101(18)     -2811(6)       -442(7)       49(4)           C(28)        5877(17)     -3699(6)       -503(6)       47(4)           C(29)        3935(17)     -3856(7)       -214(7)       49(4)           C(30)        3220(20)     -3126(9)        135(10)      35(3)           C(31)        9238(4)        541(2)       1120(2)       55(1)           C(32)        6530(5)       2157(2)       1807(1)       38(1)           C(33)        4742(5)       1843(2)       3477(1)       38(1)           C(34)        5668(4)       2830(2)       3718(1)       27(1)           C(35)        4400(5)       3400(2)       4007(1)       34(1)           C(36)        5228(6)       4312(2)       4216(2)       46(1)           C(37)        7338(6)       4664(2)       4146(2)       54(1)           C(38)        8631(5)       4107(2)       3860(2)       54(1)           C(39)        7788(5)       3195(2)       3649(2)       45(1)           N(1)         1419(3)         -8(1)       2910(1)       25(1)           N(2)           44(4)        621(2)       3000(1)       33(1)           N(3)         -732(4)        586(2)       3553(1)       42(1)           O(1)         4982(3)      -1676(1)       3108(1)       26(1)           O(2)         -602(3)      -2791(1)       1707(1)       27(1)           O(3)        -3595(3)      -3083(1)       2300(1)       33(1)           O(4)         5278(3)      -1178(1)       1156(1)       25(1)           O(5)         6995(3)        583(1)        937(1)       32(1)           O(6)         3737(3)       1803(1)       2787(1)       29(1)           Si(1)        1902(1)      -2113(1)       4188(1)       29(1) 226            C(25B)       4600(30)     -2173(8)        112(13)      27(2)           C(26B)       6470(30)     -2316(6)       -178(10)      42(3)           C(27B)       6682(19)     -3203(7)       -429(7)       56(4)           C(28B)       5030(20)     -3949(6)       -389(7)       67(6)           C(29B)       3172(19)     -3807(8)        -99(9)       75(5)           C(30B)       2960(30)     -2919(10)       152(12)      49(4)          ________________________________________________________________  227              Table 3.  Bond lengths [A] and angles [deg] for mc011.            _____________________________________________________________              C(1)-N(3)                     1.466(3)             C(1)-C(2)                     1.530(3)             C(1)-H(1A)                    0.9900             C(1)-H(1B)                    0.9900             C(2)-N(1)                     1.475(3)             C(2)-C(3)                     1.525(3)             C(2)-H(2)                     1.0000             C(3)-C(4)                     1.528(3)             C(3)-Si(1)                    1.902(3)             C(3)-H(3)                     1.0000             C(4)-O(1)                     1.435(3)             C(4)-C(5)                     1.533(3)             C(4)-H(4)                     1.0000             C(5)-C(6)                     1.511(3)             C(5)-C(15)                    1.514(3)             C(5)-H(5)                     1.0000             C(6)-C(11)                    1.390(3)             C(6)-C(7)                     1.392(3)             C(7)-C(8)                     1.373(3)             C(7)-O(4)                     1.385(3)             C(8)-C(9)                     1.380(3)             C(8)-O(5)                     1.388(3)             C(9)-C(10)                    1.390(3)             C(9)-C(32)                    1.492(3)             C(10)-O(6)                    1.379(3)             C(10)-C(11)                   1.389(3)             C(11)-N(1)                    1.418(3)             C(12)-Si(1)                   1.850(3)             C(12)-H(12A)                  0.9800             C(12)-H(12B)                  0.9800             C(12)-H(12C)                  0.9800             C(13)-Si(1)                   1.863(3)             C(13)-H(13A)                  0.9800             C(13)-H(13B)                  0.9800             C(13)-H(13C)                  0.9800             C(14)-Si(1)                   1.855(3)             C(14)-H(14A)                  0.9800             C(14)-H(14B)                  0.9800             C(14)-H(14C)                  0.9800             C(15)-O(2)                    1.432(3)             C(15)-H(15A)                  0.9900             C(15)-H(15B)                  0.9900             C(16)-O(2)                    1.392(3)             C(16)-O(3)                    1.412(3)             C(16)-H(16A)                  0.9900             C(16)-H(16B)                  0.9900             C(17)-O(3)                    1.424(3)             C(17)-C(18)                   1.499(4)             C(17)-H(17A)                  0.9900             C(17)-H(17B)                  0.9900             C(18)-C(19)                   1.377(3)             C(18)-C(23)                   1.386(4)             C(19)-C(20)                   1.378(4)             C(19)-H(19)                   0.9500             C(20)-C(21)                   1.356(4) 228              C(20)-H(20)                   0.9500             C(21)-C(22)                   1.375(4)             C(21)-H(21)                   0.9500             C(22)-C(23)                   1.373(4)             C(22)-H(22)                   0.9500             C(23)-H(23)                   0.9500             C(24)-O(4)                    1.443(3)             C(24)-C(25)                   1.473(9)             C(24)-C(25B)                  1.495(9)             C(24)-H(24A)                  0.9900             C(24)-H(24B)                  0.9900             C(25)-C(26)                   1.3900             C(25)-C(30)                   1.3900             C(26)-C(27)                   1.3900             C(26)-H(26)                   0.9500             C(27)-C(28)                   1.3900             C(27)-H(27)                   0.9500             C(28)-C(29)                   1.3900             C(28)-H(28)                   0.9500             C(29)-C(30)                   1.3900             C(29)-H(29)                   0.9500             C(30)-H(30)                   0.9500             C(31)-O(5)                    1.423(3)             C(31)-H(31A)                  0.9800             C(31)-H(31B)                  0.9800             C(31)-H(31C)                  0.9800             C(32)-H(32A)                  0.9800             C(32)-H(32B)                  0.9800             C(32)-H(32C)                  0.9800             C(33)-O(6)                    1.441(3)             C(33)-C(34)                   1.490(4)             C(33)-H(33A)                  0.9900             C(33)-H(33B)                  0.9900             C(34)-C(39)                   1.371(4)             C(34)-C(35)                   1.375(4)             C(35)-C(36)                   1.368(4)             C(35)-H(35)                   0.9500             C(36)-C(37)                   1.361(4)             C(36)-H(36)                   0.9500             C(37)-C(38)                   1.371(4)             C(37)-H(37)                   0.9500             C(38)-C(39)                   1.371(4)             C(38)-H(38)                   0.9500             C(39)-H(39)                   0.9500             N(1)-N(2)                     1.375(3)             N(2)-N(3)                     1.252(3)             O(1)-H(1)                     0.81(3)             C(25B)-C(26B)                 1.3900             C(25B)-C(30B)                 1.3900             C(26B)-C(27B)                 1.3900             C(26B)-H(26B)                 0.9500             C(27B)-C(28B)                 1.3900             C(27B)-H(27B)                 0.9500             C(28B)-C(29B)                 1.3900             C(28B)-H(28B)                 0.9500             C(29B)-C(30B)                 1.3900             C(29B)-H(29B)                 0.9500             C(30B)-H(30B)                 0.9500  229              N(3)-C(1)-C(2)              106.8(2)             N(3)-C(1)-H(1A)             110.4             C(2)-C(1)-H(1A)             110.4             N(3)-C(1)-H(1B)             110.4             C(2)-C(1)-H(1B)             110.4             H(1A)-C(1)-H(1B)            108.6             N(1)-C(2)-C(3)              113.7(2)             N(1)-C(2)-C(1)               98.53(19)             C(3)-C(2)-C(1)              113.6(2)             N(1)-C(2)-H(2)              110.2             C(3)-C(2)-H(2)              110.2             C(1)-C(2)-H(2)              110.2             C(2)-C(3)-C(4)              114.1(2)             C(2)-C(3)-Si(1)             111.76(17)             C(4)-C(3)-Si(1)             110.07(16)             C(2)-C(3)-H(3)              106.8             C(4)-C(3)-H(3)              106.8             Si(1)-C(3)-H(3)             106.8             O(1)-C(4)-C(3)              107.5(2)             O(1)-C(4)-C(5)              109.96(19)             C(3)-C(4)-C(5)              118.6(2)             O(1)-C(4)-H(4)              106.7             C(3)-C(4)-H(4)              106.7             C(5)-C(4)-H(4)              106.7             C(6)-C(5)-C(15)             110.94(19)             C(6)-C(5)-C(4)              116.4(2)             C(15)-C(5)-C(4)             112.74(19)             C(6)-C(5)-H(5)              105.2             C(15)-C(5)-H(5)             105.2             C(4)-C(5)-H(5)              105.2             C(11)-C(6)-C(7)             117.7(2)             C(11)-C(6)-C(5)             122.6(2)             C(7)-C(6)-C(5)              119.7(2)             C(8)-C(7)-O(4)              119.4(2)             C(8)-C(7)-C(6)              121.3(2)             O(4)-C(7)-C(6)              119.3(2)             C(7)-C(8)-C(9)              121.3(2)             C(7)-C(8)-O(5)              119.1(2)             C(9)-C(8)-O(5)              119.6(2)             C(8)-C(9)-C(10)             117.7(2)             C(8)-C(9)-C(32)             121.3(2)             C(10)-C(9)-C(32)            120.9(2)             O(6)-C(10)-C(11)            121.9(2)             O(6)-C(10)-C(9)             116.9(2)             C(11)-C(10)-C(9)            121.2(2)             C(10)-C(11)-C(6)            120.4(2)             C(10)-C(11)-N(1)            121.5(2)             C(6)-C(11)-N(1)             118.1(2)             Si(1)-C(12)-H(12A)          109.5             Si(1)-C(12)-H(12B)          109.5             H(12A)-C(12)-H(12B)         109.5             Si(1)-C(12)-H(12C)          109.5             H(12A)-C(12)-H(12C)         109.5             H(12B)-C(12)-H(12C)         109.5             Si(1)-C(13)-H(13A)          109.5             Si(1)-C(13)-H(13B)          109.5             H(13A)-C(13)-H(13B)         109.5             Si(1)-C(13)-H(13C)          109.5             H(13A)-C(13)-H(13C)         109.5 230              H(13B)-C(13)-H(13C)         109.5             Si(1)-C(14)-H(14A)          109.5             Si(1)-C(14)-H(14B)          109.5             H(14A)-C(14)-H(14B)         109.5             Si(1)-C(14)-H(14C)          109.5             H(14A)-C(14)-H(14C)         109.5             H(14B)-C(14)-H(14C)         109.5             O(2)-C(15)-C(5)             107.40(18)             O(2)-C(15)-H(15A)           110.2             C(5)-C(15)-H(15A)           110.2             O(2)-C(15)-H(15B)           110.2             C(5)-C(15)-H(15B)           110.2             H(15A)-C(15)-H(15B)         108.5             O(2)-C(16)-O(3)             111.5(2)             O(2)-C(16)-H(16A)           109.3             O(3)-C(16)-H(16A)           109.3             O(2)-C(16)-H(16B)           109.3             O(3)-C(16)-H(16B)           109.3             H(16A)-C(16)-H(16B)         108.0             O(3)-C(17)-C(18)            112.4(2)             O(3)-C(17)-H(17A)           109.1             C(18)-C(17)-H(17A)          109.1             O(3)-C(17)-H(17B)           109.1             C(18)-C(17)-H(17B)          109.1             H(17A)-C(17)-H(17B)         107.9             C(19)-C(18)-C(23)           118.9(3)             C(19)-C(18)-C(17)           121.3(2)             C(23)-C(18)-C(17)           119.8(3)             C(18)-C(19)-C(20)           120.5(3)             C(18)-C(19)-H(19)           119.8             C(20)-C(19)-H(19)           119.8             C(21)-C(20)-C(19)           120.2(3)             C(21)-C(20)-H(20)           119.9             C(19)-C(20)-H(20)           119.9             C(20)-C(21)-C(22)           120.1(3)             C(20)-C(21)-H(21)           119.9             C(22)-C(21)-H(21)           119.9             C(23)-C(22)-C(21)           120.2(3)             C(23)-C(22)-H(22)           119.9             C(21)-C(22)-H(22)           119.9             C(22)-C(23)-C(18)           120.1(3)             C(22)-C(23)-H(23)           120.0             C(18)-C(23)-H(23)           120.0             O(4)-C(24)-C(25)            105.3(11)             O(4)-C(24)-C(25B)           109.2(11)             C(25)-C(24)-C(25B)            8.7(14)             O(4)-C(24)-H(24A)           110.7             C(25)-C(24)-H(24A)          110.7             C(25B)-C(24)-H(24A)         102.0             O(4)-C(24)-H(24B)           110.7             C(25)-C(24)-H(24B)          110.7             C(25B)-C(24)-H(24B)         115.2             H(24A)-C(24)-H(24B)         108.8             C(26)-C(25)-C(30)           120.0             C(26)-C(25)-C(24)           107.4(8)             C(30)-C(25)-C(24)           132.5(8)             C(25)-C(26)-C(27)           120.0             C(25)-C(26)-H(26)           120.0             C(27)-C(26)-H(26)           120.0 231              C(26)-C(27)-C(28)           120.0             C(26)-C(27)-H(27)           120.0             C(28)-C(27)-H(27)           120.0             C(29)-C(28)-C(27)           120.0             C(29)-C(28)-H(28)           120.0             C(27)-C(28)-H(28)           120.0             C(28)-C(29)-C(30)           120.0             C(28)-C(29)-H(29)           120.0             C(30)-C(29)-H(29)           120.0             C(29)-C(30)-C(25)           120.0             C(29)-C(30)-H(30)           120.0             C(25)-C(30)-H(30)           120.0             O(5)-C(31)-H(31A)           109.5             O(5)-C(31)-H(31B)           109.5             H(31A)-C(31)-H(31B)         109.5             O(5)-C(31)-H(31C)           109.5             H(31A)-C(31)-H(31C)         109.5             H(31B)-C(31)-H(31C)         109.5             C(9)-C(32)-H(32A)           109.5             C(9)-C(32)-H(32B)           109.5             H(32A)-C(32)-H(32B)         109.5             C(9)-C(32)-H(32C)           109.5             H(32A)-C(32)-H(32C)         109.5             H(32B)-C(32)-H(32C)         109.5             O(6)-C(33)-C(34)            108.0(2)             O(6)-C(33)-H(33A)           110.1             C(34)-C(33)-H(33A)          110.1             O(6)-C(33)-H(33B)           110.1             C(34)-C(33)-H(33B)          110.1             H(33A)-C(33)-H(33B)         108.4             C(39)-C(34)-C(35)           118.5(3)             C(39)-C(34)-C(33)           120.9(3)             C(35)-C(34)-C(33)           120.6(3)             C(36)-C(35)-C(34)           120.8(3)             C(36)-C(35)-H(35)           119.6             C(34)-C(35)-H(35)           119.6             C(37)-C(36)-C(35)           120.1(3)             C(37)-C(36)-H(36)           119.9             C(35)-C(36)-H(36)           119.9             C(36)-C(37)-C(38)           120.0(3)             C(36)-C(37)-H(37)           120.0             C(38)-C(37)-H(37)           120.0             C(39)-C(38)-C(37)           119.6(3)             C(39)-C(38)-H(38)           120.2             C(37)-C(38)-H(38)           120.2             C(38)-C(39)-C(34)           121.0(3)             C(38)-C(39)-H(39)           119.5             C(34)-C(39)-H(39)           119.5             N(2)-N(1)-C(11)             118.1(2)             N(2)-N(1)-C(2)              111.59(19)             C(11)-N(1)-C(2)             123.74(19)             N(3)-N(2)-N(1)              112.3(2)             N(2)-N(3)-C(1)              110.0(2)             C(4)-O(1)-H(1)              110(2)             C(16)-O(2)-C(15)            112.46(18)             C(16)-O(3)-C(17)            113.16(19)             C(7)-O(4)-C(24)             113.21(18)             C(8)-O(5)-C(31)             114.08(19)             C(10)-O(6)-C(33)            114.14(19) 232              C(12)-Si(1)-C(14)           110.37(14)             C(12)-Si(1)-C(13)           106.59(14)             C(14)-Si(1)-C(13)           108.30(14)             C(12)-Si(1)-C(3)            110.87(12)             C(14)-Si(1)-C(3)            109.93(13)             C(13)-Si(1)-C(3)            110.71(12)             C(26B)-C(25B)-C(30B)        120.0             C(26B)-C(25B)-C(24)         131.5(9)             C(30B)-C(25B)-C(24)         108.1(8)             C(25B)-C(26B)-C(27B)        120.0             C(25B)-C(26B)-H(26B)        120.0             C(27B)-C(26B)-H(26B)        120.0             C(26B)-C(27B)-C(28B)        120.0             C(26B)-C(27B)-H(27B)        120.0             C(28B)-C(27B)-H(27B)        120.0             C(29B)-C(28B)-C(27B)        120.0             C(29B)-C(28B)-H(28B)        120.0             C(27B)-C(28B)-H(28B)        120.0             C(30B)-C(29B)-C(28B)        120.0             C(30B)-C(29B)-H(29B)        120.0             C(28B)-C(29B)-H(29B)        120.0             C(29B)-C(30B)-C(25B)        120.0             C(29B)-C(30B)-H(30B)        120.0             C(25B)-C(30B)-H(30B)        120.0            _____________________________________________________________             Symmetry transformations used to generate equivalent atoms:   233       Table 4.  Anisotropic displacement parameters (A^2 x 10^3) for mc011.     The anisotropic displacement factor exponent takes the form:     -2 pi^2 [ h^2 a*^2 U11 + ... + 2 h k a* b* U12 ]      _______________________________________________________________________                U11        U22        U33        U23        U13        U12     _______________________________________________________________________      C(1)     53(2)      34(2)      39(2)       7(2)      20(2)      15(2)     C(2)     30(2)      24(2)      23(2)       2(1)       4(1)       4(1)     C(3)     20(1)      23(2)      25(2)       3(1)       1(1)       2(1)     C(4)     22(1)      18(2)      25(2)       4(1)      -1(1)       1(1)     C(5)     23(1)      14(2)      20(1)       1(1)       2(1)       1(1)     C(6)     19(1)      20(2)      19(1)       4(1)      -5(1)       0(1)     C(7)     25(1)      19(2)      18(1)       2(1)      -3(1)       5(1)     C(8)     23(1)      26(2)      18(2)       8(1)       0(1)       0(1)     C(9)     28(2)      19(2)      23(2)       5(1)      -6(1)      -2(1)     C(10)    30(2)      16(2)      21(2)      -1(1)      -7(1)       3(1)     C(11)    20(1)      23(2)      18(1)       3(1)      -2(1)       2(1)     C(12)    52(2)      38(2)      38(2)      15(2)       6(2)      11(2)     C(13)    50(2)      58(2)      48(2)      22(2)      22(2)      11(2)     C(14)    50(2)      46(2)      28(2)       8(2)      -5(1)      10(2)     C(15)    27(2)      13(2)      26(2)       2(1)      -1(1)       0(1)     C(16)    22(2)      25(2)      34(2)       1(1)      -4(1)      -1(1)     C(17)    37(2)      34(2)      31(2)       3(1)       7(1)       5(1)     C(18)    28(2)      22(2)      32(2)       2(1)      11(1)       5(1)     C(19)    28(2)      17(2)      52(2)       5(1)       7(1)       3(1)     C(20)    29(2)      32(2)      58(2)       4(2)       6(2)       6(1)     C(21)    41(2)      26(2)      57(2)       1(2)       8(2)      -7(2)     C(22)    63(2)      22(2)      51(2)      10(2)      13(2)      -1(2)     C(23)    48(2)      30(2)      35(2)      10(2)       7(2)      10(2)     C(24)    55(2)      46(2)      25(2)      -1(2)      -8(2)      20(2)     C(25)    38(3)      33(2)      10(5)       4(2)       1(2)       8(2)     C(26)    56(7)      40(5)      32(6)     -23(6)       8(5)      15(5)     C(27)    67(6)      29(9)      55(6)      -3(7)       5(5)      20(6)     C(28)    83(9)      17(9)      42(6)      -1(6)       6(6)      14(7)     C(29)    54(8)      45(7)      44(7)      -9(5)      -4(6)      12(5)     C(30)    39(6)      27(7)      36(6)      -1(6)      -4(4)       9(5)     C(31)    31(2)      77(3)      61(2)      30(2)      13(2)       9(2)     C(32)    47(2)      27(2)      34(2)       7(1)       4(1)      -8(1)     C(33)    59(2)      26(2)      25(2)      -1(1)      -8(1)       8(2)     C(34)    37(2)      20(2)      22(2)       0(1)      -6(1)       5(1)     C(35)    39(2)      35(2)      28(2)       1(1)       1(1)       5(2)     C(36)    69(2)      36(2)      32(2)      -7(2)       0(2)      18(2)     C(37)    75(3)      27(2)      49(2)      -1(2)     -21(2)      -4(2)     C(38)    38(2)      52(2)      65(2)       9(2)      -8(2)      -9(2)     C(39)    36(2)      48(2)      47(2)      -3(2)      -5(2)      13(2)     N(1)     30(1)      21(1)      27(1)       5(1)       6(1)       8(1)     N(2)     33(1)      29(2)      39(2)       1(1)       2(1)      13(1)     N(3)     47(2)      44(2)      41(2)       6(1)      17(1)      19(1)     O(1)     20(1)      32(1)      27(1)       1(1)       0(1)       5(1)     O(2)     24(1)      16(1)      38(1)      -1(1)      -1(1)      -1(1)     O(3)     35(1)      22(1)      40(1)      -2(1)      10(1)       2(1)     O(4)     31(1)      25(1)      17(1)       3(1)      -1(1)       6(1)     O(5)     31(1)      38(1)      27(1)      14(1)       4(1)       1(1)     O(6)     43(1)      18(1)      24(1)       1(1)      -5(1)       6(1)     Si(1)    30(1)      30(1)      26(1)       8(1)       5(1)       5(1) 234      C(25B)   38(3)      33(2)      10(5)       4(2)       1(2)       8(2)     C(26B)   54(6)      49(7)      29(7)     -10(6)      15(5)      30(6)     C(27B)   92(11)     35(12)     50(6)     -15(8)       9(7)      45(9)     C(28B)  120(16)     33(7)      43(8)      -3(6)     -18(8)      23(10)     C(29B)   87(12)     59(8)      67(10)    -22(6)     -20(8)      14(7)     C(30B)   63(8)      25(7)      57(8)       0(6)     -20(6)      16(6)     _______________________________________________________________________  235            Table 5.  Hydrogen coordinates ( x 10^4) and isotropic          displacement parameters (A^2 x 10^3) for mc011.           ________________________________________________________________                           x             y             z           U(eq)          ________________________________________________________________            H(1A)       -1107          -633          3974          48           H(1B)         787           148          4389          48           H(2)         3298          -253          3759          31           H(3)         -177         -1739          3204          27           H(4)         2312         -2588          2789          27           H(5)         3162         -1989          1839          23           H(12A)       4004         -3212          3814          63           H(12B)       1457         -3642          3654          63           H(12C)       2679         -3585          4408          63           H(13A)      -1854         -2598          4298          75           H(13B)       -901         -1682          4803          75           H(13C)       -397         -2664          4997          75           H(14A)       4619         -1732          5140          63           H(14B)       3581          -837          4982          63           H(14C)       5351         -1158          4531          63           H(15A)       -917         -1537          2121          28           H(15B)       -147         -1535          1376          28           H(16A)      -3252         -3707          1410          34           H(16B)      -3594         -2655          1388          34           H(17A)      -3619         -3860          3064          41           H(17B)      -2379         -4219          2457          41           H(19)       -7246         -3732          1779          39           H(20)      -10405         -4784          1369          47           H(21)      -10783         -6290          1633          51           H(22)       -7991         -6769          2303          55           H(23)       -4768         -5743          2684          44           H(24A)       4571          -841           208          50           H(24B)       2476         -1351           519          50           H(26)        7221         -1475           -51          52           H(27)        8428         -2704          -639          59           H(28)        6367         -4198          -741          57           H(29)        3098         -4463          -256          59           H(30)        1892         -3234           332          41           H(31A)       9885          1053          1467          82           H(31B)      10014           591           718          82           H(31C)       9361           -49          1300          82           H(32A)       7823          2316          2147          56           H(32B)       5541          2600          1880          56           H(32C)       6980          2183          1351          56           H(33A)       5917          1466          3497          45           H(33B)       3643          1596          3768          45           H(35)        2931          3157          4062          41           H(36)        4329          4700          4410          55           H(37)        7915          5296          4296          65           H(38)       10102          4352          3808          65           H(39)        8687          2810          3452          53           H(26B)       7593         -1806          -205          50           H(27B)       7955         -3301          -627          67           H(28B)       5181         -4556          -560          80           H(29B)       2046         -4316           -71          90 236            H(30B)       1684         -2822           350          59           H(1)         5680(50)     -1990(20)      2890(17)      69(13)          ________________________________________________________________  237            Table 6.  Torsion angles [deg] for mc011.          ________________________________________________________________            N(3)-C(1)-C(2)-N(1)                                  -7.9(3)           N(3)-C(1)-C(2)-C(3)                                -128.6(2)           N(1)-C(2)-C(3)-C(4)                                  54.4(3)           C(1)-C(2)-C(3)-C(4)                                 166.1(2)           N(1)-C(2)-C(3)-Si(1)                               -179.89(16)           C(1)-C(2)-C(3)-Si(1)                                -68.2(2)           C(2)-C(3)-C(4)-O(1)                                  66.5(3)           Si(1)-C(3)-C(4)-O(1)                                -60.1(2)           C(2)-C(3)-C(4)-C(5)                                 -59.0(3)           Si(1)-C(3)-C(4)-C(5)                                174.45(17)           O(1)-C(4)-C(5)-C(6)                                 -50.2(3)           C(3)-C(4)-C(5)-C(6)                                  74.1(3)           O(1)-C(4)-C(5)-C(15)                               -179.99(19)           C(3)-C(4)-C(5)-C(15)                                -55.7(3)           C(15)-C(5)-C(6)-C(11)                                75.8(3)           C(4)-C(5)-C(6)-C(11)                                -54.9(3)           C(15)-C(5)-C(6)-C(7)                               -103.0(2)           C(4)-C(5)-C(6)-C(7)                                 126.3(2)           C(11)-C(6)-C(7)-C(8)                                  0.0(3)           C(5)-C(6)-C(7)-C(8)                                 178.8(2)           C(11)-C(6)-C(7)-O(4)                                179.4(2)           C(5)-C(6)-C(7)-O(4)                                  -1.8(3)           O(4)-C(7)-C(8)-C(9)                                -176.0(2)           C(6)-C(7)-C(8)-C(9)                                   3.4(4)           O(4)-C(7)-C(8)-O(5)                                   4.1(3)           C(6)-C(7)-C(8)-O(5)                                -176.5(2)           C(7)-C(8)-C(9)-C(10)                                 -2.5(4)           O(5)-C(8)-C(9)-C(10)                                177.4(2)           C(7)-C(8)-C(9)-C(32)                                174.7(2)           O(5)-C(8)-C(9)-C(32)                                 -5.4(4)           C(8)-C(9)-C(10)-O(6)                                178.7(2)           C(32)-C(9)-C(10)-O(6)                                 1.6(3)           C(8)-C(9)-C(10)-C(11)                                -1.8(4)           C(32)-C(9)-C(10)-C(11)                             -179.0(2)           O(6)-C(10)-C(11)-C(6)                              -175.4(2)           C(9)-C(10)-C(11)-C(6)                                 5.2(4)           O(6)-C(10)-C(11)-N(1)                                 5.1(4)           C(9)-C(10)-C(11)-N(1)                              -174.3(2)           C(7)-C(6)-C(11)-C(10)                                -4.2(3)           C(5)-C(6)-C(11)-C(10)                               177.0(2)           C(7)-C(6)-C(11)-N(1)                                175.4(2)           C(5)-C(6)-C(11)-N(1)                                 -3.4(3)           C(6)-C(5)-C(15)-O(2)                                161.45(19)           C(4)-C(5)-C(15)-O(2)                                -66.0(2)           O(3)-C(17)-C(18)-C(19)                               -8.6(3)           O(3)-C(17)-C(18)-C(23)                              172.8(2)           C(23)-C(18)-C(19)-C(20)                               0.5(4)           C(17)-C(18)-C(19)-C(20)                            -178.1(2)           C(18)-C(19)-C(20)-C(21)                               0.6(4)           C(19)-C(20)-C(21)-C(22)                              -0.5(4)           C(20)-C(21)-C(22)-C(23)                              -0.8(5)           C(21)-C(22)-C(23)-C(18)                               1.9(4)           C(19)-C(18)-C(23)-C(22)                              -1.8(4)           C(17)-C(18)-C(23)-C(22)                             176.8(3)           O(4)-C(24)-C(25)-C(26)                              -84.9(9) 238            C(25B)-C(24)-C(25)-C(26)                             33(13)           O(4)-C(24)-C(25)-C(30)                               99.2(17)           C(25B)-C(24)-C(25)-C(30)                           -143(15)           C(30)-C(25)-C(26)-C(27)                               0.0           C(24)-C(25)-C(26)-C(27)                            -176.4(19)           C(25)-C(26)-C(27)-C(28)                               0.0           C(26)-C(27)-C(28)-C(29)                               0.0           C(27)-C(28)-C(29)-C(30)                               0.0           C(28)-C(29)-C(30)-C(25)                               0.0           C(26)-C(25)-C(30)-C(29)                               0.0           C(24)-C(25)-C(30)-C(29)                             175(2)           O(6)-C(33)-C(34)-C(39)                              -91.6(3)           O(6)-C(33)-C(34)-C(35)                               87.4(3)           C(39)-C(34)-C(35)-C(36)                               0.5(4)           C(33)-C(34)-C(35)-C(36)                            -178.5(3)           C(34)-C(35)-C(36)-C(37)                              -0.7(4)           C(35)-C(36)-C(37)-C(38)                               0.7(5)           C(36)-C(37)-C(38)-C(39)                              -0.4(5)           C(37)-C(38)-C(39)-C(34)                               0.1(5)           C(35)-C(34)-C(39)-C(38)                              -0.2(4)           C(33)-C(34)-C(39)-C(38)                             178.8(3)           C(10)-C(11)-N(1)-N(2)                                37.1(3)           C(6)-C(11)-N(1)-N(2)                               -142.4(2)           C(10)-C(11)-N(1)-C(2)                              -112.0(3)           C(6)-C(11)-N(1)-C(2)                                 68.4(3)           C(3)-C(2)-N(1)-N(2)                                 129.0(2)           C(1)-C(2)-N(1)-N(2)                                   8.5(3)           C(3)-C(2)-N(1)-C(11)                                -80.0(3)           C(1)-C(2)-N(1)-C(11)                                159.4(2)           C(11)-N(1)-N(2)-N(3)                               -158.8(2)           C(2)-N(1)-N(2)-N(3)                                  -6.1(3)           N(1)-N(2)-N(3)-C(1)                                   0.2(3)           C(2)-C(1)-N(3)-N(2)                                   5.4(3)           O(3)-C(16)-O(2)-C(15)                               -81.1(2)           C(5)-C(15)-O(2)-C(16)                               158.4(2)           O(2)-C(16)-O(3)-C(17)                               -91.9(2)           C(18)-C(17)-O(3)-C(16)                              -81.2(2)           C(8)-C(7)-O(4)-C(24)                                -79.5(3)           C(6)-C(7)-O(4)-C(24)                                101.1(3)           C(25)-C(24)-O(4)-C(7)                              -169.0(6)           C(25B)-C(24)-O(4)-C(7)                             -177.1(6)           C(7)-C(8)-O(5)-C(31)                                -87.7(3)           C(9)-C(8)-O(5)-C(31)                                 92.4(3)           C(11)-C(10)-O(6)-C(33)                               70.4(3)           C(9)-C(10)-O(6)-C(33)                              -110.1(3)           C(34)-C(33)-O(6)-C(10)                              142.2(2)           C(2)-C(3)-Si(1)-C(12)                              -155.84(17)           C(4)-C(3)-Si(1)-C(12)                               -27.9(2)           C(2)-C(3)-Si(1)-C(14)                               -33.5(2)           C(4)-C(3)-Si(1)-C(14)                                94.39(19)           C(2)-C(3)-Si(1)-C(13)                                86.1(2)           C(4)-C(3)-Si(1)-C(13)                              -146.01(18)           O(4)-C(24)-C(25B)-C(26B)                            -73.2(16)           C(25)-C(24)-C(25B)-C(26B)                          -138(15)           O(4)-C(24)-C(25B)-C(30B)                             99.3(9)           C(25)-C(24)-C(25B)-C(30B)                            35(13)           C(30B)-C(25B)-C(26B)-C(27B)                           0.0           C(24)-C(25B)-C(26B)-C(27B)                          172(2)           C(25B)-C(26B)-C(27B)-C(28B)                           0.0 239            C(26B)-C(27B)-C(28B)-C(29B)                           0.0           C(27B)-C(28B)-C(29B)-C(30B)                           0.0           C(28B)-C(29B)-C(30B)-C(25B)                           0.0           C(26B)-C(25B)-C(30B)-C(29B)                           0.0           C(24)-C(25B)-C(30B)-C(29B)                         -173.5(19)          ________________________________________________________________     Table 7.  Hydrogen Bonds  Donor --- H....Acceptor [    ARU  ]      D - H      H...A      D...A  D - H...A ---------------------------------------------------------------------------- ---- O(1)  --H(1)   ..O(3)   [  1655.01]    0.82(3)    2.05(3)   2.827(3) 160(3)   Translation of ARU-code to Equivalent Position Code ===================================================    [  1655. ]  = 1+x,y,z  

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