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Development of oxidative methodologies and application toward tetrodotoxin core Mendelsohn, Brian Alan 2010

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DEVELOPMENT OF OXIDATIVE METHODOLOGIES AND APPLICATION TOWARD TETRODOTOXIN CORE by  Brian Alan Mendelsohn B.Sc., University of Washington, 2000  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  DOCTOR OF PHILOSOPHY  in  THE FACULTY OF GRADUATE STUDIES  (Chemistry)  THE UNIVERSITY OF BRITISH COLUMBIA  (Vancouver)  December 2010 © BRIAN ALAN MENDELSOHN, 2010  Abstract  This thesis covers a novel approach to tetrodotoxin that relies on the oxidative amidation of a phenol and intramolecular nitrile oxide cycloaddition to install a -hydroxynitrile unit among the key steps.  These transformations, and others contained herein, effectively set the tetrasubstituted C-8a  stereocenter, as well C-4a formyl equivalent and C-5, C-7 and C-8 hydroxyl groups. Novel reaction types were developed in the course of this work, including a new method for the oxidation of oximes to nitrile oxides using hypervalent iodine reagents.  Additionally, I identified a tandem reaction sequence,  involving the dearomatization of a phenol, followed by [3+2]-dipolarcycloaddition, the first of its kind. This tandem sequence proved a powerful tool for the rapid construction of multicyclic compounds from structurally simpler starting materials. These studies resulted in advanced intermediates which contained much of the structure of the tetrodotoxin core.  ii  Preface  The work presented in this thesis was in part a collaborative effort. However, primarily I, in conjunction with my supervisor Professor Marco A. Ciufolini, developed the ideas and design of the research projects presented herein.  The introductory section (Chapter 1) of this thesis covers a review of previous work by other scientists. Chapter 2 of this thesis covers the work I performed during the course of my Ph.D. studies. I performed the vast majority of the work presented in this thesis, and exceptions are noted in this Preface section. The data described in Tables 2.10, 2.11, 2.12 and 2.13 was generated in conjunction with Mr. Tim Jen, a talented undergraduate student who worked under my direction over two summers. Compounds 2.113 and 2.115 were synthesized by another Ciufolini group member Mr. Florian Tessier.  Dr. Brian Patrick of the Department of Chemistry at UBC performed all crystal structure data collection and analysis. Mr. David Wong and Mr. Marshall Lapawa of the Department of Chemistry at UBC performed all high-resolution mass spectrometry experiments and all elemental analyses.  iii  Table of contents  Abstract ........................................................................................................................................................ ii Preface ......................................................................................................................................................... iii Table of contents ......................................................................................................................................... iv List of tables ................................................................................................................................................ xi List of figures ............................................................................................................................................. xii List of schemes .......................................................................................................................................... xiv List of abbreviations .................................................................................................................................. xvi Acknowledgements ................................................................................................................................... xxi 1  Introduction ..................................................................................................................................1 1.1  Tetrodotoxin ..................................................................................................................................1  1.1.1  Isolation, characterization and natural occurrence ...................................................................2  1.1.2  Tetrodotoxin biosynthesis ........................................................................................................4  1.1.3  Voltage-gated sodium channels................................................................................................5  1.1.4  TTX and naturally occurring voltage-gated sodium channel inhibitors ...................................6  1.2  Synthetic studies ............................................................................................................................7  1.2.1  Kishi’s total synthesis...............................................................................................................7  1.2.2  Isobe’s total synthesis and related studies ..............................................................................11  1.2.3  Du Bois’ total synthesis..........................................................................................................23  1.2.4  Sato’s total syntheses .............................................................................................................27  1.2.5  Funabashi ...............................................................................................................................34  1.2.6  Keana......................................................................................................................................36  1.2.7  Fraser-Reid .............................................................................................................................37  1.2.8  Alonso ....................................................................................................................................40  1.2.9  Taber ......................................................................................................................................41  1.2.10 Fukuyama ...............................................................................................................................43 1.2.11 Ohfune ....................................................................................................................................46 1.2.12 Summary ................................................................................................................................48 2  The oxidative amidation strategy ...............................................................................................50 2.1  General strategy ...........................................................................................................................50  2.2  Oxidative amidation ....................................................................................................................53  2.2.1 2.3  Oxidative amidation in total synthesis ...................................................................................54  Bimolecular oxidative amidation.................................................................................................57 iv  2.3.1  Optimization of scalable bimolecular oxidative amidation conditions ..................................57  2.4  Nitrile oxide [3+2] cycloaddition ................................................................................................61  2.5  Kemp-type keto-isooxazoline fragmentation ..............................................................................73  2.5.1  Access to a suitable dihydroxylation substrate.......................................................................76  2.6  Osmylation of substituted cyclohexene derivative ......................................................................79  2.7  Iodine(III)-mediated oxime oxidation to nitrile oxides ...............................................................82  2.7.1  Oximes as nitrile oxide precusors ..........................................................................................82  2.7.2  Optimization of DIB as a reagent for oxime to nitrile oxide oxidations ................................83  2.7.3  Oxidation of -oxo-ketoximes and ’-dioxo-ketoximes ....................................................89  2.7.4  Intramolecular nitrile oxide cycloaddition .............................................................................93  2.8  Tandem oxidative dearomatization/nitrile oxide [3+2] cycloaddition ........................................95  2.8.1  Sorensen’s use of tandem dearomitization/nitrile oxide [3+2] cycloaddition in Cortistatin core synthesis .........................................................................................................................97  2.9  Diastereoselective tandem oxidative amidation—INOC.............................................................99  2.10  Summary ...................................................................................................................................103  References .................................................................................................................................................104 Appendices ................................................................................................................................................115 A.  Experimental protocols.............................................................................................................116 A.1  Preparation of methyl 2-(1-acetamido-4-oxocyclohexa-2,5-dienyl)acetate (2.32) ...................116  A.2  Preparation of methyl 2-((1r,4r)-1-acetamido-4-(tert-butyldiphenylsilyloxy)cyclohexa-2,5dienyl)acetate (2.37) .................................................................................................................118  A.3  Preparation of 2-((1r,4r)-1-acetamido-4-(tert-butyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetic acid (2.38) .................................................................................................................................119  A.4  Preparation of N-((1r,4r)-4-(tert-butyldiphenylsilyloxy)-1-(3-nitro-2-oxopropyl)cyclohexa-2,5dienyl)acetamide (2.39) ............................................................................................................120  A.5  Preparation of N-((3aS,7aS)-2-oxo-2,3,3a,7a-tetrahydrobenzofuran-3a-yl)acetamide (2.41)...121  A.6  Preparation of N-((2aR,2a1S,3S,5aS)-3-(tert-butyldiphenylsilyloxy)-7-oxo-2a,2a1,3,5a,6,7hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.43).......................................................122  A.7  Preparation of N-((3aS,7aS,E)-2-(nitromethylene)-2,3,3a,7a-tetrahydrobenzofuran-3ayl)acetamide (2.44) ...................................................................................................................123  A.8  Preparation of N-((1r,4r)-1-(2-(tert-butyldimethylsilyloxy)-3-nitropropyl)-4-(tertbutyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetamide (2.46) diastereomers .........................124  A.9  Preparation of compounds 2.49, 2.50, 2.51 and 2.52 ................................................................125  A.9.1  Compound 2.49 ....................................................................................................................126  A.9.2  Compound 2.50 ....................................................................................................................127  A.9.3  Compound 2.51/2.52 ............................................................................................................128 v  A.10  Preparation of trans-9-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-3-nitro-1azaspiro[5.5]undeca-2,7,10-trien-4-one (2.55) .........................................................................129  A.11  Preparation of methyl 2-((1S,4S,5R,6S)-1-acetamido-4-(tert-butyldiphenylsilyloxy)-6-cyano-5hydroxycyclohex-2-enyl)acetate (2.59) ....................................................................................130  A.12  Preparation of N-((2aR,2a1S,3S,5aS)-3-hydroxy-7-oxo-2a,2a1,3,5a,6,7-hexahydroindeno[1,7cd]isoxazol-5a-yl)acetamide (2.60) ..........................................................................................131  A.13  Preparation of methyl 2-((1S,5R,6S)-1-acetamido-6-cyano-5-hydroxy-4-oxocyclohex-2enyl)acetate (2.62) ....................................................................................................................132  A.14  Preparation of N-((2aR,2a1S,3R,5aS)-3-(tert-butyldiphenylsilyloxy)-7-oxo-2a,2a1,3,5a,6,7hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.66).......................................................133  A.15  Preparation of methyl 2-((1S,4R,5R,6S)-1-acetamido-4-(tert-butyldiphenylsilyloxy)-6-cyano-5hydroxycyclohex-2-enyl)acetate (2.67) ....................................................................................135  A.16 Preparation of compounds 2.76-2.88 ............................................................................................136 A.16.1 Preparation of 3-(4-methoxyphenyl)-5-phenyl-4,5-dihydroisoxazole (2.76) .......................136 A.16.2 Preparation of 3,5-diphenyl-4,5-dihydroisoxazole (2.77) ....................................................137 A.16.3 Preparation of 3-(3-nitrophenyl)-5-phenyl-4,5-dihydroisoxazole (2.78) .............................138 A.16.4 Preparation of 3-pentyl-5-phenyl-4,5-dihydroisoxazole (2.79)............................................139 A.16.5 Preparation of 3-phenethyl-5-phenyl-4,5-dihydroisoxazole (2.80) ......................................140 A.16.6 Preparation of 3a,4,5,6,7,7a-hexahydro-3-phenyl-4,7-methano-1,2-benzisoxazole (2.81) ..141 A.16.7 Preparation of 3a,4,5,6,7,7a-hexahydro-3-(3-nitrophenyl)-4,7-methano-1,2-benzisoxazole (2.82) ....................................................................................................................................142 A.16.8 Preparation of 3a,4,5,6,7,7a-hexahydro-3-pentyl-4,7-methano-1,2-benzisoxazole (2.83)...143 A.16.9 Preparation of 3a,4,5,6,7,7a-hexahydro-3-(2-phenylethyl)-4,7-methano-1,2-benzisoxazole (2.84) ....................................................................................................................................144 A.16.10 Preparation of 3-(1,1-dimethylethyl)-3a,4,5,6,7,7a-hexahydro4,7-methano-1,2benzisoxazole (2.85).............................................................................................................145 A.16.11 Preparation of 3a,4,5,6,7,7a-hexahydro-3-(4-methoxyphenyl)-4,7-methano-1,2benzisoxazole (2.86).............................................................................................................146 A.16.12 Preparation of 5-(3-bromopropyl)-4,5-dihydro-3-phenyl-isoxazole (2.87) .......................147 A.16.13 Preparation of 3,5-diphenylisoxazole (2.88) ......................................................................148 A.17  Preparation of 1-(3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benzisoxazol-3-yl)-ethanone (2.90) ..................................................................................................................................................149  A.18  Preparation of 1-(4,5-dihydro-5-phenyl-3-isoxazolyl)-ethanone (2.91) ....................................150  A.19  Preparation of 3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benzisoxazole-3-carboxylic acid ethyl ester (2.93) ................................................................................................................................151  A.20  Preparation of 4,5-dihydro-5-phenyl-3-isoxazolecarboxylic acid ethyl ester (2.94) .................153  A.21  Preparation of 2-isonitrosocyclopentanone (2.100)...................................................................155  A.22  Preparation of compound 2.101 ................................................................................................156 vi  A.23  Preparation of methyl 4-(5-phenyl-4,5-dihydroisoxazol-3-yl)butanoate (2.102) ......................157  A.24  Preparation of 2-isonitrosocyclohexanone (2.103) ....................................................................158  A.25  Preparation of compound 2.104 ................................................................................................159  A.26  Preparation of methyl 5-(5-phenyl-4,5-dihydroisoxazol-3-yl)pentanoate (2.105) ....................160  A.27  Preparation of 3-(hydroxyimino)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (2.106) .............161  A.28  Preparation of compounds 2.107/2.108 .....................................................................................162  A.29  Preparation of (1S,3R)-methyl 1,2,2-trimethyl-3-(5-phenyl-4,5-dihydroisoxazol-3-yl) cyclopentanecarboxylate (2.109/2.110)....................................................................................163  A.30  Preparation of 3,7-dimethyl-6-octenoxime (2.111) ...................................................................164  A.31  Preparation of (6S)-3,3a,4,5,6,7-hexahydro-3,3,6-trimethyl-2,1-benzisoxazole (2.112) ..........165  A.32  Preparation of 4-hydroxy-benzenepropanal oxime (2.123) .......................................................166  A.33  Preparation of N-[(4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-7-oxoindeno[1,7-cd]isoxazol-4a(7H)-yl]acetamide (2.124) .....................................................................................................................167  A.34  Preparation of 4,4a,7a,7b-tetrahydro-4a-methoxy-indeno[1,7-cd]isoxazol-7(3H)-one (2.125) 168  A.35  Preparation of N-benzyl, N-tosyl tyrosine (2.130) ....................................................................169  A.36  Preparation of N-[2-(hydroxyimino)-1-[(4-hydroxyphenyl)methyl]ethyl]-4-methyl-N(phenylmethyl)-benzenesulfonamide (2.132) ...........................................................................171  A.37  Preparation of N-[(3R,4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-3-[[(4-methylphenyl)sulfonyl] (phenylmethyl)amino]-7-oxoindeno[1,7-cd]isoxazol-4a(7H)-yl]-acetamide (2.134) ..............173  B.  Experimental section ................................................................................................................174 B.1  1  H-NMR spectrum and 13C-NMR spectrum for: methyl 2-(1-acetamido-4-oxocyclohexa-2,5dienyl)acetate (2.32) .................................................................................................................174  B.2  1  B.3  1  B.4  1  B.5  1  B.6  1  B.7  1  B.8  1  B.9  1  H-NMR spectrum and 13C-NMR spectrum for: methyl 2-((1r,4r)-1-acetamido-4-(tertbutyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetate (2.37) .....................................................175 H-NMR spectrum and 13C-NMR spectrum for: 2-((1r,4r)-1-acetamido-4-(tertbutyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetic acid (2.38) ...............................................176 H-NMR spectrum and 13C-NMR spectrum for: N-((1r,4r)-4-(tert-butyldiphenylsilyloxy)-1-(3nitro-2-oxopropyl)cyclohexa-2,5-dienyl)acetamide (2.39) ......................................................177 H-NMR spectrum and 13C-NMR spectrum for: N-((3aS,7aS)-2-oxo-2,3,3a,7atetrahydrobenzofuran-3a-yl)acetamide (2.41) ..........................................................................178 H-NMR spectrum and 13C-NMR spectrum for: N-((2aR,2a1S,3S,5aS)-3-(tertbutyldiphenylsilyloxy)-7-oxo-2a,2a1,3,5a,6,7-hexahydroindeno[1,7-cd]isoxazol-5ayl)acetamide (2.43) ...................................................................................................................179 H-NMR spectrum and 13C-NMR spectrum for: N-((3aS,7aS,E)-2-(nitromethylene)-2,3,3a,7atetrahydrobenzofuran-3a-yl)acetamide (2.44) ..........................................................................180 H-NMR spectrum and 13C-NMR spectrum for: N-((1r,4r)-1-(2-(tert-butyldimethylsilyloxy)-3nitropropyl)-4-(tert-butyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetamide (2.46) ................181 H-NMR spectrum for: compound 2.49 ....................................................................................182 vii  B.10  1  H-NMR spectrum and 13C-NMR spectrum for: compound 2.50 .............................................183  B.11  1  B.12  1  B.13  1  B.14  1  B.15  1  B.16  1  B.17  1  B.18  1  B.19  1  B.20  1  B.21  1  B.22  1  B.23  1  B.24  1  B.25  1  B.26  1  B.27  1  B.27  1  B.28  1  B.29  1  H-NMR spectrum for: compound 2.51/2.52 ............................................................................184  H-NMR spectrum and 13C-NMR spectrum for: trans-9-[[(1,1dimethylethyl)diphenylsilyl]oxy]-2-methyl-3-nitro-1-azaspiro[5.5]undeca-2,7,10-trien-4-one (2.55) ........................................................................................................................................185 H-NMR spectrum and 13C-NMR spectrum for: methyl 2-((1S,4S,5R,6S)-1-acetamido-4-(tertbutyldiphenylsilyloxy)-6-cyano-5-hydroxycyclohex-2-enyl)acetate (2.59).............................186 H-NMR spectrum and 13C-NMR spectrum for: N-((2aR,2a1S,3S,5aS)-3-hydroxy-7-oxo2a,2a1,3,5a,6,7-hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.60) .............................187 H-NMR spectrum and 13C-NMR spectrum for: methyl 2-((1S,5R,6S)-1-acetamido-6-cyano-5hydroxy-4-oxocyclohex-2-enyl)acetate (2.62) .........................................................................188 H-NMR spectrum for: N-((2aR,2a1S,3R,5aS)-3-(tert-butyldiphenylsilyloxy)-7-oxo2a,2a1,3,5a,6,7-hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.66) .............................189 H-NMR spectrum and 13C-NMR spectrum for: methyl 2-((1S,4R,5R,6S)-1-acetamido-4-(tertbutyldiphenylsilyloxy)-6-cyano-5-hydroxycyclohex-2-enyl)acetate (2.67).............................190 H-NMR spectrum and 13C-NMR spectrum for: 3-(4-methoxyphenyl)-5-phenyl-4,5dihydroisoxazole (2.76) ............................................................................................................191 H-NMR spectrum and 13C-NMR spectrum for: 3,5-diphenyl-4,5-dihydroisoxazole (2.77) ....192  H-NMR spectrum and 13C-NMR spectrum for: 3-(3-nitrophenyl)-5-phenyl-4,5dihydroisoxazole (2.78) ............................................................................................................193 H-NMR spectrum and 13C-NMR spectrum for: 3-pentyl-5-phenyl-4,5-dihydroisoxazole (2.79) ..................................................................................................................................................194  H-NMR spectrum and 13C-NMR spectrum for: 3-phenethyl-5-phenyl-4,5-dihydroisoxazole (2.80) ........................................................................................................................................195 H-NMR spectrum and 13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-phenyl-4,7methano-1,2-benzisoxazole (2.81) ...........................................................................................196 H-NMR spectrum and 13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-(3-nitrophenyl)-4,7methano-1,2-benzisoxazole (2.82) ...........................................................................................197 H-NMR spectrum and 13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-pentyl-4,7-methano1,2-benzisoxazole (2.83) ..........................................................................................................198 H-NMR spe ctrum and 13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-(2-phenylethyl)-4,7methano-1,2-benzisoxazole (2.84) ...........................................................................................199 H-NMR spectrum and 13C-NMR spectrum for: 3-(1,1-dimethylethyl)-3a,4,5,6,7,7ahexahydro4,7-methano-1,2-benzisoxazole (2.85) ....................................................................200 H-NMR spectrum and 13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-(4-methoxyphenyl)4,7-methano-1,2-benzisoxazole (2.86) .....................................................................................201 H-NMR spectrum and 13C-NMR spectrum for: 5-(3-bromopropyl)-4,5-dihydro-3-phenylisoxazole (2.87) ........................................................................................................................202 H-NMR spectrum and 13C-NMR spectrum for: 3,5-diphenylisoxazole (2.88) ........................203 viii  B.30  1  B.31  1  B.32  1  B.33  1  B.34  1  B.35  1  B.36  1  B.37  1  B.38  1  B.39  1  B.40  1  B.41  1  B.42  1  B.43  1  B.44  1  B.45  1  B.46  1  B.47  1  B.48  1  C.  H-NMR spectrum and 13C-NMR spectrum for: 1-(3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2benzisoxazol-3-yl)-ethanone (2.90) ..........................................................................................204 H-NMR spectrum and 13C-NMR spectrum for: 1-(4,5-dihydro-5-phenyl-3-isoxazolyl)ethanone (2.91) .........................................................................................................................205 H-NMR spectrum and 13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2benzisoxazole-3-carboxylic acid ethyl ester (2.93) ..................................................................206 H-NMR spectrum and 13C-NMR spectrum for: 4,5-dihydro-5-phenyl-3-isoxazolecarboxylic acid ethyl ester (2.94) ...............................................................................................................207 H-NMR spectrum and 13C-NMR spectrum for: 2-isonitrosocyclopentanone (2.100) .............208 H-NMR spectrum and 13C-NMR spectrum for: compound 2.101 ...........................................209  H-NMR spectrum and 13C-NMR spectrum for: methyl 4-(5-phenyl-4,5-dihydroisoxazol-3yl)butanoate (2.102) .................................................................................................................210 H-NMR spectrum and 13C-NMR spectrum for: 2-isonitrosocyclohexanone (2.103)...............211 H-NMR spectrum and 13C-NMR spectrum for: compound 2.104 ...........................................212  H-NMR spectrum and 13C-NMR spectrum for: methyl 5-(5-phenyl-4,5-dihydroisoxazol-3yl)pentanoate (2.105)................................................................................................................213 H-NMR spectrum and 13C-NMR spectrum for: compounds 2.107/2.108................................214  H-NMR spectrum and 13C-NMR spectrum for: (1S,3R)-methyl 1,2,2-trimethyl-3-(5-phenyl4,5-dihydroisoxazol-3-yl) cyclopentanecarboxylate (2.109/2.110)..........................................215 H-NMR spectrum and 13C-NMR spectrum for: diastereomers (6S)-3,3a,4,5,6,7-hexahydro3,3,6-trimethyl-2,1-benzisoxazole (2.112) ...............................................................................216 H-NMR spectrum and 13C-NMR spectrum for: major diastereomer (6S)-3,3a,4,5,6,7hexahydro-3,3,6-trimethyl-2,1-benzisoxazole (2.112) .............................................................217 H-NMR spectrum and 13C-NMR spectrum for: N-[(4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-7oxoindeno[1,7-cd]isoxazol-4a(7H)-yl]-acetamide (2.124).......................................................218 H-NMR spectrum and 13C-NMR spectrum for: 4,4a,7a,7b-tetrahydro-4a-methoxy-indeno[1,7cd]isoxazol-7(3H)-one (2.125) .................................................................................................219 H-NMR spectrum and 13C-NMR spectrum for: N-benzyl, N-tosyl tyrosine (2.130) ...............220  H-NMR spectrum and 13C-NMR spectrum for: N-[2-(hydroxyimino)-1-[(4hydroxyphenyl)methyl]ethyl]-4-methyl-N-(phenylmethyl)-benzenesulfonamide (2.132) ......221 H-NMR spectrum and 13C-NMR spectrum for: N-[(3R,4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-3[[(4-methylphenyl)sulfonyl](phenylmethyl)amino]-7-oxoindeno[1,7-cd]isoxazol-4a(7H)-yl]acetamide (2.134) .....................................................................................................................222 X-ray crystallography data .......................................................................................................223  C.1  X-ray data of methyl 2-(1-acetamido-4-oxocyclohexa-2,5-dienyl)acetate (2.32) .....................223  C.2  X-ray data of N-((3aS,7aS,E)-2-(nitromethylene)-2,3,3a,7a-tetrahydrobenzofuran-3ayl)acetamide (2.44) ...................................................................................................................229  C.3  X-ray data of N-((2aR,2a1S,3S,5aS,7R)-3,7-dihydroxy-2a,2a1,3,5a,6,7-hexahydroindeno[1,7cd]isoxazol-5a-yl)acetamide (2.53) ..........................................................................................235 ix  C.4  X-ray data of trans-9-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-3-nitro-1azaspiro[5.5]undeca-2,7,10-trien-4-one (2.55) .........................................................................243  C.5  X-ray data of methyl 2-((1S,4R,5R,6S)-1-acetamido-4-(tert-butyldiphenylsilyloxy)-6-cyano-5hydroxycyclohex-2-enyl)acetate (2.67) ....................................................................................254  C.6  X-ray data of N-[(4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-7-oxoindeno[1,7-cd]isoxazol-4a(7H)-yl]acetamide (2.124) .....................................................................................................................265  x  List of tables  Table 2.1. Optimization of scalable conditions for bimolecular oxidative amidation. ..............................59 Table 2.2. Larger-scale reproducible conditions for oxidative amidation of phenol 2.31 with acetonitrile. .....................................................................................................................................................................60 Table 2.3. Reduction of dienone 2.32. .......................................................................................................62 Table 2.4. Initial attempts to dehydrate nitroketone 2.39. .........................................................................65 Table 2.5. Nitroketone 2.39 dehydration optimization. .............................................................................69 Table 2.6. Refinements to [3+2] cycloaddition conditions. .......................................................................70 Table 2.7. Optimization of tricycle 2.43 fragmentation.............................................................................74 Table 2.8. DIB-mediated bimolecular [3+2] dipolar cycloaddition: optimization studies. .......................84 Table 2.9. DIB-mediated bimolecular [3+2] dipolar cycloaddition: substrate scope. ...............................86 Table 2.10. DIB-mediated bimolecular [3+2] dipolar cycloaddition: optimization studies. .....................87 Table 2.11. DIB-mediated oxidation of -oxo-aldoximes 2.89 and 2.92. .................................................88 Table 2.13. DIB-mediated oxidation of -oxo-ketoximes. .......................................................................92  xi  List of figures  Figure 1.1. The structure of (−)-tetrodotoxin (TTX). ..................................................................................1 Figure 1.2. Orthoester-lactone equilibrium. ................................................................................................3 Figure 1.3. Method of extracting tetrodotoxin.21 .........................................................................................3 Figure 1.4. Some tetrodotoxin derivatives found in nature36. ......................................................................4 Figure 1.5. Possible TTX biosynthetic pathway. .........................................................................................5 Figure 1.6. Sodium channel inhibitors: tetrodotoxin, saxitoxin and gonyautoxin 3. ...................................6 Figure 1.7. Kishi’s retrosynthetic analysis. .................................................................................................7 Figure 1.7. Isobe’s deoxy tetrodotoxin analogs. ........................................................................................11 Figure 1.8. Isobe’s (−)-tetrodotoxin retrosynthetic rationale from 2-acetoxy-tri-O-acetyl-D-glucal. .......12 Figure 1.9. Isobe’s (−)-tetrodotoxin retrosynthetic rationale from levoglucosenone and isoprene. ..........17 Figure 1.10. Isobe’s updated C-11 hydroxylation and comparison to 1.43. ..............................................22 Figure 1.11. Du Bois’ tetrodotoxin retrosynthetic analysis. ......................................................................23 Figure 1.12. Sato’s retrosynthetic analysis for (±)-tetrodotoxin from myo-inositol. .................................27 Figure 1.13. Sato’s (−)-tetrodotoxin retrosynthetic analysis. ....................................................................30 Figure 1.14. Sato’s updated retrosynthetic analysis for (−)-tetrodotoxin intermediate 1.84. ....................32 Figure 1.15. Funabashi’s retrosynthetic approach to (−)-tetrodotoxin. .....................................................34 Figure 1.16. Fraser-Reid’s retrosynthetic considerations. .........................................................................37 Figure 1.17. Fukuyama’s TTX-core synthon 1.147. .................................................................................43 Figure 1.18. Ohfune’s approach to (−)-tetrodotoxin. ................................................................................46 Figure 1.19. Comparison of retrosynthetic intermediates between completed total syntheses to date......49 Figure 2.1. Retrosynthetic hypothesis for tetrodotoxin. ............................................................................50 Figure 2.2. Generalized strategy for the elaboration of the tetrodotoxin core. ..........................................51 Figure 2.3. Our elaborated tetrodotoxin retrosynthetic analysis. ...............................................................52 Figure 2.4. Oxidative amidation of para-phenols. ....................................................................................53 Figure 2.5. Oxidative amidation of para-phenols. ....................................................................................53 Figure 2.6. Kikugawa-Glover-type reactions. ...........................................................................................54 Figure 2.7. Structures of FR901483 and TAN1251C and Ciufolini’s retrosynthetic logic for the construction of their ring systems................................................................................................................55 Figure 2.8. Sorensen’s144,145 and Honda’s146-148 oxidative cyclization of phenolic secondary amines. .....55 Figure 2.9. Ciufolini modes of oxidative amidation of phenols. ...............................................................56 Figure 2.10. Possible DIB-mediated bimolecular oxidative amidation mechanism. .................................57 Figure 2.11. Effect of phenol concentration on reaction outcome.............................................................58 Figure 2.12. Desymmetrization of dienone 2.8. ........................................................................................61 xii  Figure 2.13. Theoretical dehydration of nitroketone 2.39. ........................................................................64 Figure 2.14. Nitrile oxide [3+2] dipolar cycloaddition..............................................................................64 Figure 2.15. Torssell cyclization: silyl nitronates as 1,3-dipoles...............................................................67 Figure 2.16. Probable enolization of nitroketone 2.39 can inhibit [3+2] cyclization. ...............................72 Figure 2.17. All cis-relationship of compound 2.43. .................................................................................72 Figure 2.18. Comparison of prepared enone 2.62 to proposed tetrodotoxin retron 2.5. ............................75 Figure 2.19. Rationale for expected (but not observed) rate difference between nitroketones 2.39/2.65. 77 Figure 2.20. X-ray image of crystalline 2.67 and rationalization of expected facial selectivity. ..............78 Figure 2.21. Comparison of 1H-NMR: olefin osmylation. ........................................................................80 Figure 2.22. 1H-NMR couplings for 2.68. .................................................................................................81 Figure 2.23. Comparison of advanced intermediate 2.68 with TTX retron 1.170.....................................81 Figure 2.24. Dimerization of nitrile oxides. ..............................................................................................82 Figure 2.25. Conversion of oximes to nitrile oxides and subsequent trapping. .........................................83 Figure 2.26. Predicted course of the DIB oxidation of -oxo-ketoximes. ................................................89 Figure 2.27. Hypothetical tandem oxidative amidation-intramolecular nitrile oxide cycloaddition. ........95 Figure 2.28. Predicted course of the INOC reaction. ................................................................................99 Figure 2.28. NOe NMR spectral expansion of 2.134. .............................................................................102  xiii  List of schemes  Scheme 1.1. Kishi’s Diels-Alder and Beckmann transformations. ..............................................................8 Scheme 1.2. Kishi’s installation of C-11 and C-6 oxygen atoms. ...............................................................8 Scheme 1.3. Installation of C-9 -acetoxy moiety. .....................................................................................9 Scheme 1.4. Baeyer-Villiger oxidation and intramolecular epoxide-opening cyclization...........................9 Scheme 1.5. Kishi’s (±)-tetrodotoxin end game strategy. ............................................................................9 Scheme 1.6. Isobe’s cyclohexane skeleton synthesis: Sonogashira coupling and Claisen rearrangement. .....................................................................................................................................................................13 Scheme 1.7. Isobe’s cyclohexane skeleton synthesis: C-5 and C-11 hydroxyl installation. ......................14 Scheme 1.8. Isobe’s cyclohexane skeleton synthesis: cyclohexanone and exo-olefin installation. ...........14 Scheme 1.9. Isobe’s introduction of nitrogen through intramolecular conjugate addition. .......................15 Scheme 1.10. Isobe’s stereoselective lactone formation. ...........................................................................16 Scheme 1.11. Isobe’s introduction of the guanidine moiety and completion of the total synthesis. .........17 Scheme 1.12. Isobe’s carbocyclic core formation. ....................................................................................18 Scheme 1.13. Isobe’s use of the Overman rearrangement. ........................................................................18 Scheme 1.14. Isobe’s C-8 oxygenation sequence. .....................................................................................18 Scheme 1.15. Isobe’s inversion of C-8 and oxygenation at C-7. ...............................................................19 Scheme 1.16. Isobe’s C-11/C-6 oxygenation sequence and addition of the C-10 acetylide group. ..........19 Scheme 1.17. Isobe’s epoxide-opening cyclization. ..................................................................................20 Scheme 1.18. Isobe’s ortho lactonization and end-game strategy. ............................................................21 Scheme 1.19. Du Bois’ Rh-carbenoid C-H insertion. ................................................................................24 Scheme 1.20. Du Bois’ methylenation.......................................................................................................24 Scheme 1.21. Du Bois’ allylic oxidation and establishment of C-4a and C-5 configurations. ..................25 Scheme 1.22. Du Bois’ Rh-catalyzed nitrene C-H insertion and guanidine formation. ............................26 Scheme 1.23. Sato’s setup for spiro -chloroepoxide formation...............................................................28 Scheme 1.24. Sato’s -chloroepoxide formation and azide ion-mediated ring-opening. ..........................28 Scheme 1.25. Sato’s end game strategy: lactone/orthoester formation, guanidine formation. ..................29 Scheme 1.26. Sato’s synthesis of nitro cyclitol 1.93 employing an intramolecular Henry reaction. .........31 Scheme 1.27. Sato’s McMurry-Nef transformation to common intermediate 1.90. ..................................31 Scheme 1.28. Sato’s Ferrier(II) sequence to common intermediate 1.90. .................................................33 Scheme 1.29. Funabashi’s approach to (−)-tetrodotoxin. ..........................................................................34 Scheme 1.30. Sato’s early independent work on (−)-tetrodotoxin.............................................................35 Scheme 1.31. Keana’s most advanced tetrodotoxin intermediate. .............................................................36 xiv  Scheme 1.32. Fraser-Reid’s synthesis of dioxadamantane core 1.129 via D-mannosan. ..........................38 Scheme 1.33. Fraser-Reid’s synthesis of advanced intermediate 1.134. ...................................................39 Scheme 1.34. Alonso’s radical-cyclization approach. ...............................................................................40 Scheme 1.35. Taber’s C-H insertion strategy. ...........................................................................................42 Scheme 1.36. Fukuyama’s route to diiodo 1.152 enroute to 1.147. ...........................................................43 Scheme 1.37. Fukuyama’s racemic route to TTX core synthon 1.147. .....................................................45 Scheme 1.38. Ohfune’s approach to C-5, 6, 7, 11 tetraol system in (−)-tetrodotoxin. ..............................47 Scheme 2.1. Initial conditions for bimolecular oxidative amidation.153.....................................................57 Scheme 2.2. Synthesis of nitroketone 2.39. ...............................................................................................63 Scheme 2.3. Undesired cyclization reaction of intermediate 2.40/2.38. ....................................................63 Scheme 2.4. An undesired reaction of nitroketone intermediate 2.39. ......................................................65 Scheme 2.5. Reduction/protection sequence of nitroketone 2.39. .............................................................66 Scheme 2.6. [3+2]-dipolar cycloaddition of 2.46. .....................................................................................67 Scheme 2.7. Confirmation of structural geometry: X-ray crystallographic analysis of 2.53. ....................68 Scheme 2.8. Unusual Knoevenagel-type condensation of nitroketone 2.39. .............................................69 Scheme 2.9. Optimized conditions for dehydration of nitroketone 2.39. ..................................................71 Scheme 2.10. Ring-fragmentation and comparison to Kemp-elimination188-190 products..........................73 Scheme 2.11. Kemp-type fragmentation: methanolysis of tricycle 2.43. ..................................................74 Scheme 2.12. Fragmentation sequence: conversion of 2.43 to desymmetrized enone 2.62. .....................75 Scheme 2.13. Synthesis of nitroketones 2.39 and 2.65. .............................................................................76 Scheme 2.14. Synthesis of tricycles 2.43 and 2.66. ...................................................................................77 Scheme 2.15. Methanolysis of tricycle 2.66. .............................................................................................78 Scheme 2.16. Osmylation sequence. ..........................................................................................................79 Scheme 2.17. Dimerization of oxime 2.73.................................................................................................83 Scheme 2.18. The first intramolecular variant. ..........................................................................................93 Scheme 2.19. Other intramolecular variants from Ciufolini group............................................................94 Scheme 2.20. The synthesis of oxime 2.123. .............................................................................................96 Scheme 2.21. Tandem oxidative amidation—INOC. ................................................................................96 Scheme 2.22. Tandem oxidative methoxylation—INOC. .........................................................................97 Scheme 2.23. Sorensen’s use of tandem oxidative dearomatization—INOC towards the cortistatin pentacyclic core. ..........................................................................................................................................98 Scheme 2.24. Synthesis of oxime 2.132. ..................................................................................................100 Scheme 2.25. Diastereoselective tandem oxidative amidation—INOC. .................................................101  xv  List of abbreviations  1D  one-dimensional  2D  two-dimensional  []20D  specific rotation at 20 °C and wavelength of sodium D line  [O]  oxidation  (S)-CBS  (S)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2c][1,3,2]oxazaborole  °C  degrees centigrade  AB  AB system  ABq  AB quartet  Ac  acetyl  acac  acetylacetonate  AcOH  acetic acid  AIBN  azobisisobutyronitrile  Alloc  allyloxycarbonyl  aq  aqueous  B.C.E.  before the common era  Bn  benzyl  BRSM/brsm  based on recovered starting material  Boc  tert-butyloxycarbonyl  Boc2O  di-tert-butyl-pyrocarbonate  BOM  benzyloxymethyl  Bz  benzoyl  c  concentration  calcd  calculated  cat.  catalytic  cf.  confer  CDI  carbonyldiimidazole  cm-1  inverse centimeter/wavenumber  d  deuterio xvi  d / dd / ddd  doublet / doublet of doublets / doublet of doublet of doublets    chemical shift  DBU  1,8-diazabicycloundec-7-ene  dd  doublet of doublets  DIB  diacetoxy iodobenzene (iodobenzene diacetate)  DIBAL  diisobutyl aluminum  DMAP  4-(N,N-dimethylamino)-pyridine  DMF  dimethylformamide  DMSO  dimethyl sulfoxide  CAN  cerium ammonium nitrate  CSA  camphor sulfonic acid  EDC  1-ethyl-3-(3-dimethylaminopropyl) carbodiimide  Et  ethyl  etc.  et cetera  eq  equivalents  g  gram  G  a generic group (see associated text)  GTX  gonyautoxin  h  hour(s)  HFIP  1,1,1,3,3,3-hexafluoroisopropanol  HRMS  high-resolution mass spectrometry  Hz  hertz  IBX  2-iodoxybenzoic acid  IC50  half maximal inhibitory concentration  IDCP  iodonium dicollidine perchlorate  INOC  intramolecular nitrile oxide-olefin cycloaddition  ISOC  intramolecular siloxynitronate-olefin cycloaddition  i  Pr  isopropyl  J  coupling constant  Jaa  axial-axial coupling constant xvii  Jae  axial-equatorial coupling constant  kg  kilogram  L  liter  L  generic sterically demanding group (see text)  LD50  oral median lethal dose  LDA  lithium diisopropylamine  LRMS  low-resolution mass spectrometry  M  molar  m  multiplet  mCPBA  meta-chloroperoxybenzoic acid  Me  methyl  mg  milligram  MHz  megahertz  min  minute  mL  milliliter  MMTr  4-monomethoxytrityl  mol  mole  mmol  millimole  MOM  methoxymethyl  MP  melting point  Ms  mesyl (methane sulfonyl)  n  an integer (0, 1, 2, etc.)  n  normal butyl (linear butyl)  NBS  N-bromosuccinimide  NCS  N-chlorosuccinimide  NIS  N-iodosuccinimide  NMO  N-methyl morpholine oxide  NMR  nuclear magnetic resonance  NOe/nOe  nuclear Overhauser effect  NOESY  nuclear Overhauser effect spectroscopy  Bu  xviii  Nu  generic nucleophile (see text)  o  ortho  ON  overnight (12-16 h)  P  generic protecting group (see text)  p  para  PCC  pyridinium chlorochromate  Ph  phenyl  Pht  phthalate  PIFA  phenyliodine bis(trifluoroacetate)  Piv  pivaloyl  PMB  para-methoxy benzyl  ppm  parts per million  PPTS  pyridinium toluene-4-sulphonate  psi  pounds per square inch  PTSA/p-TsOH  para-toluene sulfonic acid  PyBOP  benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate  q  quartet  R  generic functional group (defined in text)  rt  room temperature  s  singlet  s  seconds  S-H  generic solvent  SM  reaction starting material  SN2’  bimolecular nucleophilic substitution  STX  saxitoxin  t  triplet  TBAF  tetrabutylammonium fluoride  TBHT  di-tert-butyl hyponitrite  TBS  tert-butyldimethylsilyl  TBDPS  tert-butyldiphenylsilyl xix  t  Bu  tert-butyl  TEA  triethylamine  TEMPO  2,2,6,6-tetramethylpiperidine-1-oxyl  TES  triethylsilyl  Tf  triflyl/triflate  TFA  trifluoroacetic acid  TFAA  trifluoroacetic acid anhydride  TFE  trifluoroethanol  THF  tetrahydrofuran  TLC  thin-layer chromatography  TMS  trimethylsilyl  TPAP  tetrapropylammonium perruthenate  Ts  tosyl  TTX  tetrodotoxin  g  microgram  mol  micromole  L  microliter  v/v  volume per volume  w/  with  w/o  without  xx  Acknowledgements  There is no doubt that this dissertation could not have been possible without the guidance of my advisor, Professor Marco A. Ciufolini. I owe him many thanks for allowing me to join his laboratory and giving me a great deal of intellectual freedom on my research endeavors. While many days were difficult, these times taught me patience and I am grateful for his guidance.  I would also like to thank the members of my advisory committee: Professor Jennifer A. Love, Professor Michael D. Fryzuk and most especially my second reader Professor Gregory R. Dake. Thank you for your sagacious advice and discussions over the past five years. I would also like to acknowledge Graduate Advisor Professor Chris Orvig for his support. The UBC Chemistry Department NMR staff also was indispensable due to their help and advice in setting up NMR experiments, and thanks go out to Dr. Nick Burlinson, Dr. Maria B. Ezhova, and Zorana Danilovic.  Many thanks also go to Brian  Ditchburn for the many last-minute glassware repairs and many hours spent introducing me to (the art of) glassblowing.  I have had the pleasure to work in Ciufolini group with some exceptional undergraduate students, graduate students and post-doctoral researchers. I would like to thank especially Tim Jen, Simon J. Kim, Srini Masuna, Bhaskar Reddy, Virender S. Aulakh, Bryan Chan, Dylan Turner, Jaclyn Chau, Kam Ho and Catherine Diering for their friendship and camaraderie. I would also like to acknowledge Dr. Josh Zaifman and Dr. Mathew Smith for their careful proof-reading of my thesis manuscript.  My Ph.D. work was not possible without the love and support of my Mom and Dad. Thank you for always listening to me, even when you had no idea what I was talking about.  Finally, I would like to thank my wife Lynne. You are my best friend and my staunchest supporter. With you, life and all things are much more meaningful.  xxi  1  1.1  Introduction  Tetrodotoxin  Tetrodotoxin (TTX, Figure 1.1) is recognized as one of the most poisonous non-protein molecules known.1,2 With a long history traced back to ancient times, tetrodotoxin has left its mark on Egyptian, Chinese and Haitian civilizations among others. Ancient Egyptian hieroglyphics of several Fifth Dynasty (ca. 2700 B.C.E.) tombs clearly depict the poisonous tetrodotoxin-containing puffer Tetraodon stallatus.3,4 An early Chinese record from the second century B.C.E., the Pen-T’so Chin (The Herbal), lists the eggs of tetraodon (four tooth) fish among its drugs.5  Figure 1.1. The structure of (−)-tetrodotoxin (TTX).  Interestingly, and perhaps horrifyingly, tetrodotoxin poisoning renders the body in a low metabolic state, yet the brain remains unaffected. Near lethal doses can leave a victim of tetrodotoxin poisoning in a near-death state for days, while remaining conscious for the duration.  Victims of  tetrodotoxin poisoning typically undergo feelings of numbness and weakness, followed by paralysis of the limbs and chest muscles which typically leads to death by asphyxiation. Currently, there is no known antidote; however, in vivo studies in mice have indicated possible treatment of tetrodotoxin poisoning with a monoclonal antibody.6  Patients suffering tetrodotoxin poisoning are typically kept alive on  ventilators until they either recover, or do not. The oral median lethal dose (LD50) of tetrodotoxin in mice is 334 g per kg.7 The lethal dose by injection is 8 g per kg, or about 0.5 mg for a 75 kg human assuming the lethal dose is similar for humans and mice.8  1  Ethnobotanist Wade Davis alleged in the 1980s that tetrodotoxin-containing tissue from puffer fish were an ingredient of Haitian voodooism.9 Davis claimed that the partial limb paralysis and other symptoms of lethal and non-lethal doses of tetrodotoxin matched depictions of Haitian voodoo zombies, especially recounts involving the burying of apparently dead victims followed later by exhumation and revivification.  Other scientific studies of modern-day Haitian zombie powders have indicated the  presence of tetrodotoxin.10 More recent analyses generally claim that folklore and stories of zombies created in this manner differ from victims of tetrodotoxin poisoning11 and question the amount of tetrodotoxin that can be administered transdermally in the form of a zombie powder. In modern-day Japan, high-end sushi restaurants still offer carefully prepared puffer fish for adventurous patrons. When prepared properly, consumption of puffer fish sushi results in tingling sensations of the lips and inner mouth surfaces. When prepared incorrectly puffer fish consumption can result in death. A century after its discovery, tetrodotoxin remains an ambitious and worthwhile target that necessarily expands the envelope of current synthetic chemical technology, as evidenced by the large amount of synthetic studies (Chapter 1.2). Efficient syntheses could lead to TTX analogues with varying activities to further the understanding of voltage-gated sodium channels. The unique architecture of tetrodotoxin has provided synthetic chemists with many opportunities to explore new reaction types and procedures to piece together tetrodotoxin and analogues. The work described in this thesis details one such path, as our approach to the tetrodotoxin core yielded new reaction types hitherto unexplored.  1.1.1  Isolation, characterization and natural occurrence  Tetrodotoxin remains a daring target for synthetic chemistry, not only due to its unprecedented highly hydroxylated dioxa-adamantane structure (Figure 1.1), but also due to its extreme toxicity. It is this toxicity that initially drove researchers to attempt isolation studies. In 1910, Japanese scientist Yoshizumi Tahara published and patented complete isolation procedures and characterization analyses.12,13 Though Tahara’s original extracts are now known to contain only trace quantities of tetrodotoxin,4 it is remarkable that he was able to contribute as much knowledge as he did given the crude equipment available during that era. It was not until 1950, well after the isolation of many plant alkaloids (atropine, morphine and strychnine, etc.) and most vitamins (pantothenic acid and biotin, etc.) when tetrodotoxin was isolated in pure form from the ovaries of the puffer fish. 14 The abundantly available pool of tetrodotoxin-containing fish spurred wide interest in its isolation and structure elucidation. Complicating the structure determination of tetrodotoxin is the fact that the compound is zwitterionic, highly polar (only soluble in aqueous acid) and exists in equilibrium between orthoester form 1.1 and lactone form 1.2 (Figure 1.2).15 2  Figure 1.2. Orthoester-lactone equilibrium. The structure of tetrodotoxin was determined through chemical degradations as well as x-ray crystallographic studies of tetrodotoxin derivatives.1,15-17 In 1964, groups led by R. B. Woodward, H. S. Mosher, K. Tsuda and T. Goto all reported the correct structure of tetrodotoxin in Kyoto at the Natural Products Symposium of the International Union of Pure and Applied Chemistry.  The absolute  configuration was elucidated via crystallographic studies a few years later.18 With pure crystalline tetrodotoxin in hand, researchers began to isolate other tetrodotoxin-derivatives from various species of Tetraodon fish.5,19,20 Recently, a United States patent was issued describing a new process for extracting tetrodotoxin from the ovaries of the puffer fish.21 This invention doubles the yield of pure crystalline tetrodotoxin (Figure 1.3).  Figure 1.3. Method of extracting tetrodotoxin.21  3  Tetrodotoxin is found in the tissues of several different animals throughout the world, including species of puffer fish, trigger fish, gobies,22,23 parrotfish, blue-ringed octopodes (Hapalochlaena), moon snails,24 sea stars,25 polyclad flatworms,26 nemerteans, xanthid crabs, frogs,27 western newts (Taricha)1 and other species.28  1.1.2  Tetrodotoxin biosynthesis  Puffer fish species grown in captivity do not contain detectable amounts of tetrodotoxin until they are fed tissues from tetrodotoxin-containing fish.29-31  When tetrodotoxin-containing fish were fed  radiolabeled metabolic precursors (14C-labeled acetate, arginine, citrulline and glucose), the fish failed to produce any labeled tetrodotoxin, yet did produce common metabolites (cholesterol, amines, amino acids, etc.) with  14  C incorporation.32  The elucidation of the biosynthesis of tetrodotoxin is an actively  researched area; current understanding is based upon analogy to other tetrodotoxin derivatives isolated from various organisms (Figure 1.4).33-35 OH  OH 10  HO 4  HO HN  O9 5  11  O  6  4a  7  OH  OH  8 8a  OH NH  HO  O  OH  HO HN  OH NH  O  HO HN  HO  CH3  NH 11-deoxyTTX  NH TTX  HO  CH3  OH NH  NH 5,6,11-trideoxyTTX  HO HN  O  NH  O  O OH  NH 6-epi TTX  O CH3  NH 6,11-dideoxyTTX  HO  OH  NH  O  OH  HO HN  OH O  HO  OH  O  OH  HO HN  O  OH  OH OH NH  NH 5-deoxyTTX  Figure 1.4. Some tetrodotoxin derivatives found in nature36. Since tetrodotoxin is found in such a variety of different organisms, most of which are unrelated phylogenically, and since studies of puffer fish and Taricha newts showed a lack of endogenous tetrodotoxin production in these animals, it has been considered that tetrodotoxin found in these animals comes from an exogenous source, perhaps through the food chain or the environment.37 Various studies38 have determined that tetrodotoxin is actually biosynthesized by various types of bacteria species (Pseudoalteromonas tetraodonis28 certain species of Pseudomonas and Vibrio28 Serratia marcescens39). 4  Little is known about the actual biosynthesis of TTX, but studies have indicated that TTX precursors may come from the amino acid arginine,40 a known precursor for guanidinium functional groups in natural products and a C5 isoprene unit (most probably isopentenyl diphosphate33).41 The currently accepted biosynthetic pathway is shown in Figure 1.5, yet this proposal has not been confirmed conclusively.  H2N  CO2H  OH P OH O O P OH O  CO2H CH3  O  + HN  H2N  CH3  NH2  HN arginine  OH P OH O O P OH O  O HN HN  NH2  TTX  isopentenyl diphosphate  Figure 1.5. Possible TTX biosynthetic pathway.  1.1.3  Voltage-gated sodium channels  The ability for rapid cell-to-cell communication is an important feature of living organisms. Excitable cells communicate rapidly with one another through short-lived electrical potentials, known as action potentials, across their membranes. Every neuron has a separation of charges across its membrane, and at rest this potential is called the resting membrane potential. Electrical signals and transmissions all involve a temporary disruption of this resting potential.42 The resting membrane potential is determined by resting ion channels. Neuronal cells generate action potentials via voltage gated ion channels embedded in the cell’s plasma membrane.43  These ion channel proteins are closed when the voltage potential across the  membrane is near the resting potential of the cell, but they quickly open when the voltage potential is raised above a threshold value. When the ion channels open, a rapid flux of ions across the membrane occurs, resulting in a decrease in the charge separation (voltage) across the membrane (depolarization), and the electrical signal propagates the length of the membrane. During depolarization, a rapid influx of sodium ions causes the polarity of the membrane to reverse relative to the resting state, and this closes the voltage-gated sodium channels.  The lipid bilayer of a cell membrane is nearly impervious to the  movement of sodium ions, and thus the cell actively pumps these ions back across the lipid bilayer to reset the cell for a future action potential. As sodium ions are pumped out of the cell, potassium channels open to allow the influx of potassium ions into the cell, thus returning the cell to its resting potential.  5  1.1.4  TTX and naturally occurring voltage-gated sodium channel inhibitors  Tetrodotoxin, along with saxitoxin (STX), members of the gonyautoxin (GTX) family of compounds (Figure 1.6) and the neurotoxic conotoxin peptides, binds tightly to the extracellular pore opening of the voltage-gated sodium channels.2 Studies suggest that the guanidinium group acts as a bioisostere for sodium ions, and binds like a plug partway into the sodium channel. 44 Studies of TTX derivatives (Figure 1.4) have indicated that important H-bonding interactions between the hydroxyl groups and residues on the outside of the pore opening of the sodium channel exist, and are substantially responsible for the binding to the sodium channel.45  Blockage of the sodium channel effectively  suppresses action potentials by stopping the influx of sodium ions. Sodium channels are transmembrane proteins, and as such are difficult to isolate and characterize.  Tetrodotoxin is an important  pharmacological tool for probing the structure and function of sodium channels.46 By isolating sodium channel proteins, or protein fragments, structural information can be gleaned by checking for TTX binding.47 H2N O OH  O O  OH  H  HO HN HO  OH  H N N HO H OH  tetrodotoxin  NH2  N  H2N NH O NH O NH2  saxitoxin  NH2  HO HN NH HO O O3SO N NH O NH2 NH2 gonyautoxin 3  Figure 1.6. Sodium channel inhibitors: tetrodotoxin, saxitoxin and gonyautoxin 3. In recent years, it has become apparent that small molecules capable of selective, partial blocking of ion channel function may be useful therapeutic resources to combat a number of human diseases,48 such as Parkinson’s disease, and perhaps chronic pain management in terminally ill patients. 49  6  1.2  Synthetic studies  1.2.1  Kishi’s total synthesis  The first total synthesis of racemic tetrodotoxin by Kishi in 1972 remains to this day a historic conquest in synthetic chemistry, especially when considering the technologies available to his group at Kishi’s retrosynthetic analysis (Figure 1.7) features a number of well designed  the time.50-53  transformations, including Baeyer-Villiger oxidation, intramolecular epoxide-opening cyclization, Lewis acid mediated Diels-Alder chemistry and a Beckmann rearrangement. Central to this synthesis is Kishi’s utilization of the bowl-like shape of the cis-decalin system to direct the stereochemistry of the subsequent oxidation/reduction steps to complete the racemic synthesis. HO HO  H H2N  N 8a  H NO H  O guanidine formation  H O 4 OO 4a  O HO AcHN H N AcHN  6 7  OH  OH orthoacid formation  AcO  (±)-tetrodotoxin  4 4a  intramolecular epoxide-opening OAc cyclization  H 6 7  O  OAc O  CH3  4a  HO  Diels-Alder  8a  N 1.8  H 4  O  Beckmann rearrangement  AcHN  4  NH AcO Ac OAc  1.7  OAc  H  4  4a  O O  O  Baeyer-Villiger oxidation  CH3  8a  7  1.4  O  4a  6  O  O  O  OAc  H 4a  O  OAc  1.3  H3C  4  4a  O O NH AcO Ac OAc 1.6  OAc  H O  O  O  NH AcO Ac OAc 1.5  Figure 1.7. Kishi’s retrosynthetic analysis. Kishi’s retrosynthetic disconnections, and those of nearly all of the other synthetic work in the area, begin with the release of the guanidine functionality and formation of the orthoester. Woodward’s pioneering elucidation work15 demonstrated the spontaneous ortholactonization of bridging lactones such as 1.3. Kishi establishes both the trans-relationship between the C-6 and C-7 centers and the cisrelationship between C-8a and C-7 via a trans-lactonization/intramolecular epoxide-opening cyclization operation from 1.4. Seven-membered lactone 1.4 was generated through a Baeyer-Villiger oxidation from the corresponding ketone 1.5 which derives from 1.6. The synthesis begins from cis-decalin 1.7, which was produced from oxime 1.8 by Diels-Alder cycloaddition and Beckmann rearrangement.  7  OH O  H3C O  OH  N  CH3  N 1) MsCl, Et3N 2) H2O, heat  O  8a  H3C  H3C O  O 1.8  O NHAc  4a  4a  SnCl4  NHAc 8a  H3C  H  1.9  H3C  H  O  O  1.7  Scheme 1.1. Kishi’s Diels-Alder and Beckmann transformations. Kishi began his synthesis (Scheme 1.1) from benzoquinone oxime 1.8 as a dienophile for a tinmediated Diels-Alder reaction with butadiene to give the cis-fused decalone 1.9 as the sole isomer. This Diels-Alder reaction appeared to be the first example of a dienophile containing an oxime. Despite the addition of Lewis acid SnCl4 to accelerate the reaction, the regioselectivity of the reaction was controlled by the electron deficient oxime.  Cycloadduct 1.9 was transformed into 1.7 through Beckmann  rearrangement, setting the C-8a carbinol center with the necessary geometry relative to C-4a by nature of the cis-ring fusion.  1) NaBH4  O 5  NHAc  NHAc  8  H3C  2) mCPBA, CSA  O  O  O  8a  4a  O  OH 1) CrO3, pyridine  O  H3C  NHAc  2) ethylene glycol, H3C BF3•OEt2  O  1.7  8  O 1) Al(OiPr)3 2) Ac2O, pyridine  O O 5  4a  NHAc OAc 8  O 1.10  O O  O  1) SeO2 2) NaBH4  O  O  8a  6  AcO  O  1) mCPBA 2) Ac2O 3) TFA; Ac2O  NHAc OAc  6 11  OH  H  11  H3C  8  NHAc OAc  H  Scheme 1.2. Kishi’s installation of C-11 and C-6 oxygen atoms. Bicycle 1.7 was treated with a series of reduction/oxidation and epoxidation operations, utilizing the facial bias of the cis-shaped ring fusion to stereoselectively generate the other stereogenic centers around the cyclohexane skeleton (Scheme 1.2). The C-5 carbinol center, by virtue of the differing steric environments between C-5 and C-8 ketones, was set through NaBH4 reduction and intramolecular epoxide opening. The C-8 stereocenter was generated from a stereoselective Meerwein-Ponndorf-Verley reduction, SeO2-mediated allylic oxidation set the C-11 hydroxyl, and mCPBA epoxidation from the face (convex side) installed the necessary oxygen functionality at C-6.  8  O O  9  NHAc OAc AcO  OEt  1) (EtO)3CH, CSA; Ac2O  O  2) o-Cl2C6H4, heat  O 1) mCPBA, K2CO3  O NHAc OAc AcO  2) AcOH, H2O  O  1.10  O  9  OAc  NHAc OAc AcO  O  1.11  1.5  Scheme 1.3. Installation of C-9 -acetoxy moiety. Kishi then turned his attention to the installation of the -acetoxy moiety at C-9 (Scheme 1.3). Treatment of 1.10 with CSA and triethyl orthoformate gave the corresponding diethyl ketal, which eliminated after heating in dichlorobenzene to give enol ether 1.11. Another -directed stereoselective mCPBA-mediated epoxidation generated the C-9 -acetoxy unit after opening the epoxide with aqueous acetic acid. With 1.5 in hand, Baeyer-Villiger oxidation with mCPBA gave ring-expanded lactone 1.4 (Scheme 1.4). Lactone-ring opening of 1.4 with potassium acetate caused the resulting free-carboxylate at C-10 to undergo an intramolecular epoxide-ring opening at C-7 giving 1.12. Acetylation of the C-6 hydroxyl moiety and thermal elimination gave 1.13 with the dihydrofuran serving as precursor to a C-4 aldehyde.  Scheme 1.4. Baeyer-Villiger oxidation and intramolecular epoxide-opening cyclization.  O AcO O  O  Et3OBF4, Na2CO3 NHAc OAc  AcO  OAc 1.13  AcO  O AcO O  1) EtS  NAc SEt  O  OAc  NH2 OAc 2) AcNH2 3) NH3 AcO  O AcO O  4  O  OAc  1.14  1.15  1) OsO4 2) NaIO4 3) NH4OH H2N  NAc H N NH OAc 2  H  O  HO N 4  H NO H  H O OO OH  OH  (±)-tetrodotoxin  Scheme 1.5. Kishi’s (±)-tetrodotoxin end game strategy. Scheme 1.5 outlines Kishi’s end game strategy.  Treatment of 1.13 with Et3OBF4/Na2CO3  effected removal of the acetamide group afforded 1.14, and the monoacetylguanidine moiety was installed in a three-step operation. Kishi completed the racemic tetrodotoxin synthesis in three additional steps from 1.15. Dihydroxylation of the dihydrofuran with OsO4 followed by sodium periodate cleavage 9  of the resulting 1,2-diol unmasked the C-4 aldehyde. A final aminolysis of the acetyl groups with NH4OH caused the formation of the orthoacid and guanidine and yielded racemic tetrodotoxin. Kishi’s effective work in the construction of the tetrodotoxin core, and full elaboration to the racemic natural product set a standard for three decades.  Kishi’s racemic total synthesis was  accomplished in 32 linear steps and in 0.52% overall yield. Several elegant transformations were employed, including an unusual Diels-Alder reaction with a dienophile containing an oxime.  The  synthesis possesses a high degree of substrate control in the creation of the required stereocenters, all stemming originally from cis-decalin 1.7. Kishi expertly used substrate-controlled hydride reductions, stereospecific substrate-controlled epoxidations, carboxylate attack onto an epoxide and stereospecific substrate-controlled epoxidation of enol ether. Kishi also developed a then-novel procedure for the creation of the guanidine functionality that was used in several later syntheses of tetrodotoxin.  10  1.2.2  Isobe’s total synthesis and related studies  Before Isobe published his two asymmetric tetrodotoxin syntheses,54,55 his group worked on and published the synthesis of several deoxy-analogues of tetrodotoxin (Figure 1.7).56-62 In 2003, Isobe published the first asymmetric total synthesis of (−)-tetrodotoxin. His retrosynthetic analysis is described in Figure 1.8 and differs significantly from not only his previous work on the deoxy-series of TTX analogues, but also from his second asymmetric total synthesis of TTX,55 which was based upon his work in the deoxy-series. OH O HO HO HN  OH  O OH  NH  O HO  CH3  OH  HO HN  NH 11-deoxyTTX  O  O  OH NH NH  8,11-trideoxyTTX  O  HO  CH3  HO HN  CH3  OH NHOH NH  5,11-dideoxyTTX  Figure 1.7. Isobe’s deoxy tetrodotoxin analogs. Isobe’s late stage guanidine formation and closing of the ortho acid closely mirror Kishi’s approach (Chapter 1.2.1). Installation of the C-8 nitrogen functionality was planned to come from a diastereoselective Overman rearrangement and the creation of the carbocycle through aldol chemistry.  11  H H2N  HO  O  O  orthoester formation  H O OO  N H NO H  guanidine OH formation  OH  AcO HO  O  H3C  HN OH  Boc  1.16  1.17  CH3  OTBS  O  O BzO H  O BzO  1.20  OH  H  O  conjugate addition  CH3 O  AcO  H  HN  COCCl3  BzO  O TBDPSO  CH3  CH3  OCH3  BOM  HN OH  BOM  Boc  (-)-tetrodotoxin  OBz O  H3C O  O  H3C O  O  AcO  O  H3C  O H OBz  OBOM  OBOM  O  TBDPSO 1.19  1.18  aldol condensation OTBS OiPr Claisen rearrangement  O HO H  OTBS O  1.21  OAc  OTBS Sonogashira  O  OiPr  O  O  O H3C OH  OiPr  O  CH3  O  I  AcO  OAc OAc  TMS 1.22  1.23  Figure 1.8. Isobe’s (−)-tetrodotoxin retrosynthetic rationale from 2-acetoxy-tri-O-acetyl-D-glucal. Isobe began from 2-acetoxy-tri-O-acetyl-D-glucal derivative 1.23, which was converted to (trimethylsilyl)acetylene 1.22 in six-steps, including Sonogashira coupling with (trimethylsilyl)acetylene (Scheme 1.6). With 1.22 in hand, a Claisen rearrangement effectively transferred the stereochemistry of the allylic isopropenyl ether to the C-4a position in 1.24.  12  4  HO  O  O  i  Pr  4a  OH  1) TBSCl 2) SO3•pyridine, Et3N, DMSO 3) I2 4) NaBH4, CeCl3  1) Pd(OAc)2 TBSO  O  O  Si(CH3)3 i  Pr  TBSO  i  Pr  O H3C  1.23  O  2) PPTS  OH I  O  OCH3  CH3 Si(CH3)3 1.22  4  TBSO  O  O  i  Pr  4a  H3C  K2CO3 o-Cl2C6H4 150 °C  O Si(CH3)3 1.24  Scheme 1.6. Isobe’s cyclohexane skeleton synthesis: Sonogashira coupling and Claisen rearrangement. Isobe next installed the C-5 and C-11 hydroxyl groups through a series of regioselective enolizations (Scheme 1.7). Compound 1.24 was trapped as the terminal silyl enol ether, and then treated with lead tetraacetate before deprotections of the C-11 acetate and the trimethylsilyl group gave 1.25. Enolization of the ketone toward C-5 proved difficult; thus, oxidation of the C-11 hydroxyl allowed for MOM-trapping of the corresponding (and readily enolizable) -keto aldehyde, which was then reduced with NaBH4/CeCl3 to 1.26. Epoxidation of 1.26 and treatment of the resulting products with acidic Amberlyst 15 ion-exchange resin gave dihydroxylacetone 1.21 in a 7:1 ratio of diastereomers at C-5. Oxymercuration and protecting group adjustments gave compound 1.27 as a precursor to intramolecular aldol ring closing.  13  OiPr  O  TBSO  4 4a  1) TBSOTf 2) Pb(OAc)4  5  O  TBSO  OiPr  AcO H3C  O  O AcO TBS  Si(CH3)3  3) TBAF TBSO 4) Et3N, CH3OH, H2O  OiPr  O 4a 5  11  O  OH  Si(CH3)3  1.24  1.25 1) SO3•pyridine, Et3N, DMSO 2) MOM-Cl 3) NaBH4, CeCl3 CH3 O  TBSO BzO O  O 1) TBDPS-Cl 2) BzCl, DMAP  5  OTBS OTBDPS 1.27  O  TBSO  OiPr  HO  3) H2SO4, CH3OH; then HgO 4) TBS-OTf 5) TBS-Cl  1) mCPBA 2) Amberlyst 15  OiPr  O  TBSO  O  O  OH  OH  MOM  1.21  1.26  Scheme 1.7. Isobe’s cyclohexane skeleton synthesis: C-5 and C-11 hydroxyl installation. Isobe next completed the cyclohexane core (Scheme 1.8). A TBAF-mediated annulation reaction followed by dehydration with trichloroacetyl chloride gave carbocycle 1.20. With the carbocycle core in hand, nine-steps modifying the eastern portion of 1.20 gave 1.19.  O  TBSO BzO O  O  CH3  5  1) TBAF 2) Cl3CCOCl, DMAP  TBDPS O  OBz H 5  TBDPS O  O OCH3  OCH3  O  OBOM 1.28  1.20  1.27  OAc  OBz H  O  4a  8  OTBS OTBDPS  1) NaBH4, CeCl3 2) BOM-Cl, DMAP 3) CSA, CH3OH 4) Ac2O, pyridine  OTBS  1) HgO, PPTS 2) Mg(OEt)2  O  CH3  1) NaBH4 2) (CH3)2C(OCH3)2, CSA, acetone  O  CH3  3) PPTS, CH3OH  TBDPS O BzO H 5  4a  8  TBDPS O  OBz H  O  OH  OBOM 1.19  OH  OH OBOM 1.29  Scheme 1.8. Isobe’s cyclohexane skeleton synthesis: cyclohexanone and exo-olefin installation. In previous work on the deoxy-tetrodotoxin series, and later in his 2004 total synthesis, Isobe employed an Overman rearrangement to set the C-8 nitrogen functionality. Attempts to do so with 14  compound 1.19 failed repeatedly. To overcome this, Isobe introduced the nitrogen functionality through an intramolecular conjugate addition reaction (Scheme 1.9). Primary alcohol 1.19 was converted to unsaturated methyl ester 1.30 in four steps.  The C-5 hydroxyl group was then converted to the  corresponding carbamate in two steps with trichloroacetyl isocyanate, and treatment with KOtBu gave bicycle 1.31. The C-5 stereocenter effectively controls the geometry at C-8a when nitrogen is installed. The cyclic carbamate of 1.32 was hydrolyzed to give cyclohexene 1.33.  O TBDPS O  O BzO H 5  4a  8  OBOM  CH3 1) DIBAL-H 2) TEMPO, NCS O CH3 3) NaClO2, NaH2PO4, (CH3)2C=CHCH3 OH 4) (CH3)3Si-CHN2  TBDPS O HO  O H  CH3 CH3  5 8a  O  1) Cl3CCONCO 2) Et3N, CH3OH  O 3) KO Bu CO2CH3 t  H3C  HO  5  CH3  O  CH3  NHBoc  H  OMMTr 1.33  CH3  1) LiBH4 2) MMTr-Cl  5  H  NH 8a  OMMTr  TBDPSO O  BOMO  CO2CH3  O  1) Boc2O, Et3N, DMAP 2) LiOH, CH3OH  8a  8a  1.31  O O  NH  OBOM O  O  1.30  OH H  H  TBDPSO  OBOM  1.19  5  H  H3C  OBOM O CH3 1.32  Scheme 1.9. Isobe’s introduction of nitrogen through intramolecular conjugate addition. Stereoselective lactone formation and inversion at C-5 were then addressed (Scheme 1.10). Seven steps were taken to convert 1.33 to 1.34 in anticipation of the 6-exo-tet epoxide ring-opening. When compound 1.34 was treated with DBU in dichlorobenzene at 130 °C, the cyclic vinyl ether 1.17 was generated under stereoelectronic control, presumably though intermediate Z-enolate 1.35. Successive oxidations with OsO4 and IBX gave -ketolactone 1.37. Reduction of 1.37 with NaBH4 provided 1.16 as the sole diastereomer; the axial C-5 acetoxy group provided severe steric hindrance, forcing hydride reduction from the front face. Bicyclic cyclohexane 1.33 contained the necessary functional features and proper configurations for (−)-tetrodotoxin, and Isobe at this point focused on the introduction of the guanidine and the completion of the total synthesis.  15  1) mCPBA 2) BzCl, Et3N 3) Ac2O 4) NaBH4 5) Ac2O  H3C CH3  O O HO  H 5  NHBoc OMMTr  8a  H3C  H3C  CH3  O O AcO  H  AcO  NHBoc CHO OBOM  O  OH 1.33  H  BzO  OBOM  O  O  1) TFA, CH3OH 2) IBX, DMSO  NHBoc OMMTr  BzO  OBOM  CH3  O  1.18  1.34 DBU o-Cl2C6H4 130 °C  OH H3C  O  H3C O  AcO HO  O  OBz  O BOM  HN OH  OsO4, H3C NMO  O  H3C O  Boc 1.36  O  AcO  H3C  OBz O  HN OH  O  H3C O  BOM  O OBz  AcO  O HN  Boc  Boc  1.17  1.35  O  BOM  IBX, DMSO  O H3C  O  H3C O  AcO O  O O  OBz  O HN OH  BOM  NaBH4  H3C  AcO HO  O  O H OBz O  H3C O  HN OH  Boc  BOM  Boc  1.37  1.16  Scheme 1.10. Isobe’s stereoselective lactone formation. The final stage of the 2003 synthesis (Scheme 1.11) focused on the late-stage introduction of the cyclic guanidine group. A 13-step sequence, mostly involving protection/deprotection transformations, saw the unmasking of the C-7 hydroxyl group, subsequent ortho acid formation and conversion of the C-4 cyclic acetal to the requisite aldehyde for cyclic guanidinylation. The first asymmetric total synthesis of (−)-tetrodotoxin was accomplished in 69 total steps, of which 25 steps involved protecting group manipulations and less than 0.4% overall yield.  Isobe’s 2003 TTX synthesis featured Claisen  rearrangement, epoxidation of an enol ether and configurational inversion, stereospecific, substratecontrolled epoxidation, intramolecular enolate attack on epoxide, stereospecific, substrate-controlled hydride reduction, intramolecular conjugate addition of a carbamate, and stereospecific, substratecontrolled hydride reduction.  16  1) Et3N, CH3OH 2) BzCl, Et3N; Ac2O, DMAP 3) H2, Pd(OH)2/C HO  O H3C  AcO HO  O  H  O  OBz  O  H3C O  HN OH Boc  OAc OAc O AcO  HO BOM 4) Ac2O, DMAP 5) TFA, CH3OH 6) CAN, CH3CN/H2O  H  O OBz  O AcO  BocHN  SCH3  BocHN  HO HN  NBoc 1.39  OAc  O H  OBz  HN OAc  1.38  O HO  O OAc  NBoc  H2N OAc  H  HO  OAc  1.16  HO  HgCl2, Et3N  1) 4 M HCl, THF; 4 M HCl, CH3OH  O  O AcO  OH 2) Ac2O 3) Et3N, CH3OH 4) 2% d-TFA/D2O  OH NHOH  H  O OBz  1) NaIO4 2) TFA, CH3OH  OAc  HO BocN  NHOAc  BocN  H2N ()-tetrodotoxin  1.40  Scheme 1.11. Isobe’s introduction of the guanidine moiety and completion of the total synthesis. In 2004, Isobe published another synthesis of optically active tetrodotoxin55 as the culmination of much work in the deoxy-TTX series.56-62 As an alternative route to TTX, Isobe employed several key transformations, including a Diels-Alder [4+2] between isoprene and levoglucosenone, a readily available carbohydrate-derived chiral building block, for the creation of the carbocycle core (Figure 1.9). Additionally, a highly diastereoselective Overman rearrangement was successfully used to introduce the nitrogen functionality at C-8a. CH3 H H2N  HO N  H NO H  O H O OO  guanidine formation  Cl3C OH orthoacid OH formation (-)-tetrodotoxin  AcO O  O  O O  O O O TES  O  N HO TES  H  CH3  CH3  O O  HN  H  CCl3 OH  OTES  OH OH 1.42  CCl H3C  OH 1.43  CH3  CH3 O H  O  Diels-Alder H  O  HN 3  H3C  1.41  O  CH3 O  CH3 O  OH  Overman rearrangement  CH3 O  H  H  H3C  O  CCl3  H  O  O  HN  H3C  H3C 1.45  1.44  Figure 1.9. Isobe’s (−)-tetrodotoxin retrosynthetic rationale from levoglucosenone and isoprene. 17  O H  O  H  O  O H  O  H3C  H  H BF3•OEt2  O  O  O Br  O O  HO  H 4) LiAlH4 5) CSA, (CH3)2C(OCH3)2  CH3  -bromo levoglucosenone  CH3 H3C  4a  Br levoglucosenone  1) NaBH4 2) TFA, Ac2O 3) Zn-Cu  O  Br2, Et3N  1.47  H CH3 1.45  Scheme 1.12. Isobe’s carbocyclic core formation. Isobe’s Diels-Alder sequence (Scheme 1.12) began from an -bromo levoglucosenone derivative62 with a bromine atom in place as a handle to allow for later-stage oxygenation at C-8. Compound 1.47 was converted to 1.45 in five steps as a prelude to the installation of the C-8a nitrogen functionality via Overman rearrangement (Scheme 1.13). Treatment of 1.45 with trichloroacetonitrile afforded 1.46, which upon heating with K2CO3 in xylenes gave 1.44 as the sole diastereomer with the required C-4a/C-8a configuration. Oxygenation at C-8 was accomplished via an intramolecular SN2’ reaction on dibromo 1.48 with the trichloroacetamide appendage on C-8a, effectively transferring the necessary oxygen atom to C-8 in 1.49, albeit with the incorrect stereochemical configuration for (−)tetrodotoxin (Scheme 1.14).  Scheme 1.13. Isobe’s use of the Overman rearrangement.  O H  O  CH3 O  CH3  CH3  CH3 O  PyHBr3 K2CO3  HN  CH3 O  H  CH3 O O  DBU  CCl3  SN2'  8a  H3C 1.44  p-TsOH  Br  H  CCl3  Br 1.48  O  O  HN CCl3  8a  N  8  H3C  CH3 O  H  8  H3C  CH3 O  HN  CCl3  O  8  H3C  OH  H 1.49  1.43  Scheme 1.14. Isobe’s C-8 oxygenation sequence.  18  O  O  CH3 O  H  H  HN  Ti(OiPr)4  O  HN  7  O H  O  HN  H3C  OH 1.43  CH3 O  H  O  HN CCl3  8a 8  H3C  OH  O  CH3 O  CCl3  8  H3C  CH3  CCl3  CCl3  8a  O  CH3 O  O mCPBA  1) IBX 2) LiAlH(tBuO)3, LiBr 3) NaBH4, CeCl3  CH3  CH3  CH3  OH  7  H3C  OH  1.50  OH  OH  1.51  1.42  Scheme 1.15. Isobe’s inversion of C-8 and oxygenation at C-7. Regio- and stereoselective epoxidation of 1.43, followed by a Ti(OiPr)4-mediated elimination installed the C-7 oxygen moiety to give 1.51 (Scheme 1.15). Configurational inversion of both C-7 and C-8 carbinol centers was accomplished with a sequence of IBX-oxidation to the corresponding -keto cyclohexenone and hydride reductions of the dicarbonyl compound to give 1.42. Isobe’s next sequence (Scheme 1.16) installed the C-11 and C-6 oxygen centers, as well as set the C-9 stereocenter by the addition of the C-10-containing acetylide fragment. TES-protection and allylic oxidation of 1.42 installed the C-11 hydroxyl group, and mCPBA epoxidation installed the C-6 oxygen in the correct configuration and primed the C-5 position for later-stage lactonization sequence (Scheme 1.17). The stereoselective addition of an acetylide as a C-10 carboxylic equivalent gave 1.54 in a 4:1 ratio of diastereomers at C-9 (Scheme 1.16). CH3 O O H  CCl3  8a 7  11  OH  OH  H  1) TESOTf  CH3  CH3 O  O  8 6  O  HN  5  H3C  CH3  CH3  O O  HN CCl3  2) SeO2 3) NaBH4, CeCl3  11  OTES  OH  OTES  1.42  CH3 O  H  1) TESOTf  CCl3 O OTES 9  5  O 2) mCPBA 3) O3 TESO  O  HN  6  OTES  1.52  1.53 (H3C)3Si  CH3 O H O TESO  CH3  CH3 O HN  TESO  COCCl3 OAc 9 10  OTES 1.55  MgBr  O  CH3 O  1) Ac2O 2) TBAF, -10 °C  H O TESO  HN  TESO  COCCl3 OH 9 10  OTES  Si(CH3)3  1.54  Scheme 1.16. Isobe’s C-11/C-6 oxygenation sequence and addition of the C-10 acetylide group.  19  The cleavage of the acetylenic unit was accomplished in a two-step procedure starting with treatment of 1.55 with KMnO4 and sodium periodate (Scheme 1.17). To affect an epoxide-opening cyclization, -keto acid 1.56 was cleaved with alkaline hydrogen peroxide to furnish 1.57, with the required C-5 oxygen moiety in place as part of the lactone bridge. Re-protection of 1.57 lead to 1.41. This epoxide opening sequence was quite reminiscent of Isobe’s 2003 total synthesis54 (Scheme 1.10) in that the C-10 unit attack at C-5 closed the lactone while setting C-5 or C-7. CH3 O O H O TESO  CH3  CH3 HN  COCCl3 OAc  O O  KMnO4, NaIO4  H  COCCl3  HN  OAc  5  TESO  O  H2O2, NaHCO3  H  O OTES  1.55  HN  5 10  TESO  CH3 O  TESO  O  OTES  CH3  CH3  O  COOH  TESO  COCCl3 OAc  TESO 10  O OTES  O  1.56  AcO O Cl3C  HO  O O O O TES  O  N HO TES  1) TESOTf -40 °C 2) Ac2O  O Cl3C  OH 1.41  OTES  O O  O  10  O O TES  N HO TES  5  OH  OH  1.57  Scheme 1.17. Isobe’s epoxide-opening cyclization. Isobe constructed the ortholactone (Scheme 1.18) by TBAF removal of the silyl groups of 1.41 followed by spontaneous ortho acid formation with the newly released C-7 oxygen. Global protection of the hydroxyl groups with acetic anhydride lead to 1.59, and HIO4-mediated cleavage of the acetonide yielded the C-4a aldehyde which was protected as the dimethylacetal 1.60. Mixed acetal 1.61 was generated in a 6:1 ratio of diastereomers at C-8a following selective deprotection of C-9 and C-10 acetate groups and silyl protection of the ortho acid. Reduction of the trichloroacetamide unit allowed for facile introduction of the guanidine moiety in a similar manner to both Kishi’s 1972 racemic synthesis (Scheme 1.5) and Isobe’s 2003 synthesis (Scheme 1.11).  20  AcO O Cl3C  AcO  O O  TBAF  O O TES  O  N HO TES  OH  O Cl3C  OH O  1.41  Ac2O  O O 5  O N HO H  OTES  AcO  10  7  O Cl3C  OH  OH 1.58  OAc O O O  O N HO Ac  OAc  OAc  1.59 1) H5IO6 2) (CH3O)3CH, CSA  O H3CO  1) DIBAL-H -40 °C 2) SCH NHBoc HgCl2 O BocN  H3CO  BocHN  N HO H 1.62  8a  1) NH4OH 2) TBSOTf  O O  Cl3COC N HO Ac  3  BocN  OTBS  OAc  H3C OAc AcO O O 8a H3C O O Cl3COC N HO OAc Ac OAc 1.60  OAc  1.61 OTBS TFA, H2O  O O OH  OH  H2N  H N H NO H  O  O H O O OH  + OH  4,9-anhydrotetrodotoxin  H2N  HO N  H NO H  O H O OO OH  OH  tetrodotoxin  Scheme 1.18. Isobe’s ortho lactonization and end-game strategy. Isobe and co-workers have generated several tetrodotoxin intermediates and derivatives through a number of routes and still appear to be working on synthetic improvements. Recently, Isobe published an update to the 2004 synthesis in which the C-11 oxygen atom is installed early on the isoprene-unit (1.66) during Diels-Alder construction of the carbocyclic core (Figure 1.10).63  21  CH3 O O H  CH3 O  O H  8  OH  7  CH3 O  H  O  HN CCl3  8a  HO  8  8  7  OH  11  1.43  O  CCl3  8a  HO  11  O  C-8 hydroxylation  HN  CCl3  8a  H3C  O  HN 7  CH3  CH3  CH3  11  1.63  1.64 Overman rearrangement CH3 O  CH3 O  O  Diels-Alder  O  H  OH  +  8a  O  OR Br 1.66  HO  7  8  11  -bromo levoglucosenone  1.65  Figure 1.10. Isobe’s updated C-11 hydroxylation and comparison to 1.43.  22  Du Bois’ total synthesis  1.2.3  Justin Du Bois published an impressive stereoselective synthesis of (−)-tetrodotoxin64 shortly after Isobe. This route to (−)-TTX (Figure 1.11) followed a similar late-stage guanidine and orthoacid formation as did Kishi (Figure 1.7) and Isobe (Figures 1.8, 1.9), but ingeniously utilized two C-H activation steps to install the two tetrasubstituted centers C-6 and C-8a. The installation of the nitrogen functionality at C-8a through a nitrene insertion reaction into the C-8a C-H bond is unique.  An  intramolecular rhodium carbenoid C-H insertion reaction at C-6 was used in the construction of the carbocycle, a general strategy also employed by Taber in his work (Chapter 1.2.9) on the tetrodotoxin core. O  O  orthoacid formation  10  O O HO 9 H OH 4a  stereospecific C-H amination  O O  H2N O  6  4  HO HN  HO  OH NHOH  H2N  CH3O CH3 H3C  O  O O  H2N Cl  O  H3C  guanidine formation  O  H  1.67  O  9  O  8a  4a  CH3  HO  O  CH3 CH3  CH3  1.68  ()-tetrodotoxin  stereospecific Rh-catalyzed C-H insertion  OPiv O  O 8a  BnO  10  9  4  aldol  OBn 8  O 1.72  9 8a  10  O  O  6  O  TBSO CH3  CH3 1.71  5  8  O + OHC H TBSO  O  O  6  O H3C  O  H methylenation  8a  4a  H3C  5 6  O  O  CH3  1.70  CH2  9  PivO  N2  H  (H3C)2N  O CH3  O H3C  CH3  1.69  Figure 1.11. Du Bois’ tetrodotoxin retrosynthetic analysis. Du Bois began his synthesis from chiral aldehyde 1.71, which is a readily available derivative of D-isoascorbic acid (Scheme 1.19). A sodium acetate-mediated aldol reaction with dibenzyloxalacetate 1.72 and chiral aldehyde 1.71 provided 1.73, forming the new C-8 to C-8a carbon-carbon bond. Compound 1.73 was converted into diazoketone 1.70 to test the rhodium-catalyzed C-6 carbene C-H insertion. Reaction conditions were screened, and reaction with 1.70 and 1.5 mol % Rh2(NHCOCPh3)4 resulted in the production of cyclic ketone 1.75 as the only detected product. The configuration of the C9 and C-4a stereocenters were set by exploiting the shape of bicyclic 1.75. Reduction of the C-4a carbonyl occurred from the less sterically crowded convex face, as did hydrogenation of the C-8a/C-9 olefin. Acetonide-protection gave compound 1.76, which was oxidatively opened at the lactone, and then methylenated in anticipation of C-5 oxygenation (Scheme 1.20). 23  Scheme 1.19. Du Bois’ Rh-carbenoid C-H insertion.  O O PivO  4a  H  8a  5  O  O H3C  1) (CH3)2NH 2) TPAP, NMO  O CH3  O H3C  CH3  1.76  CH3 N H3C O  Zn, CH2I2, TiCl4 cat. PbCl2  O  PivO  CH3 H3C N O PivO  4a  4a  H  8a  H O  O H3C  5  O CH3  CH3  8a  H3C  1.77  5  O  O  O H3C  CH2  O CH3  O H3C  CH3  1.69  Scheme 1.20. Du Bois’ methylenation. An uncommon allylic oxidation of 1.69 with Ph2Se2 and PhIO2 gave enone 1.78, which was well suited for the establishment of the C-5 and C-4a configurations (Scheme 1.21). Treatment of 1.78 with vinyl cuprate afforded 1,4-addition product which was selectively protonated from the convex face, setting the C-4a configuration. Borane reduction of the resulting ketone gave compound 1.79 as the sole diastereomer, again taking advantage of the convex shape of the molecule, and set the C-5 hydroxyl in the necessary configuration. The C-5 hydroxyl group in 1.79 was made to cleave the stable C-10 amide functionality and pivaloate ester-deprotection afforded -lactone 1.80.  The C-8a tetrasubstituted  carbinolamine was to be set through a rhodium nitrene C-H insertion reaction. A four-step transformation converted 1.80 into intermediate 1.68, the precursor to the planned nitrene insertion.  24  Scheme 1.21. Du Bois’ allylic oxidation and establishment of C-4a and C-5 configurations. Compound 1.68, with the requisite C-9-appended primary carbamate, indeed underwent the desired oxidation at C-8a to give oxazolidinone 1.82 with retention of configuration when reacted with 10 mol % Rh2(NHCOCF3)4 (Scheme 1.22). With the C-8a carbinol in place, Du Bois needed to introduce the cyclic guanidine ring and close the ortho acid. A five-step transformation lead from 1.82 to amino alcohol 1.67. The Boc-protected guanidine was introduced in a manner similar to Isobe (Schemes 1.11, 1.18), and ozonolysis unmasked the C-4 aldehyde. Wholesale acetonide- and Boc-deprotections with wet TFA gave (−)-tetrodotoxin.  25  H2N  O O  9 8a  O  Rh2(NHCOCF3)4 (10 mol%), PhI(OAc)2, MgO  Cl O O  O H3C  O O O H  O CH O 3  1.68  H3C  Cl O O O CH O 3  1.82  CH3  H3C  O3; (CH3)2S then aq. TFA  Boc NHHO BocN  OH OH  ()-tetrodotoxin  H  N O H3C  O O O  CH3O H3C CH3 H3C 1.67  O  O HO H H O O N H2N O H N HO  O HO H2N O  N O H3C  CH3  1) NaSePh 2) mCPBA 3) Boc2O, DMAP 4) K2CO3, CH3OH 5) H2O, 110 °C  NBoc O O  BocHN O  CH3O CH3 H3C 1.83  SCH3  HgCl2, Et3N  Scheme 1.22. Du Bois’ Rh-catalyzed nitrene C-H insertion and guanidine formation. Du Bois completed his synthesis of (−)-tetrodotoxin in 28 linear steps from known aldehyde 1.71 with 0.96% overall yield. This work demonstrated an alternative approach to the Diels-Alder chemistry used to build the six-member carbon framework. Du Bois utilized C-H functionalization as a central feature of his approach, leading to a short and concise synthesis relative to other tetrodotoxin syntheses. The mild conditions for the C-H functionalization reactions, along with other transformations including diastereoselective aldol addition, substrate-controlled hydrogenation, and substrate-controlled hydride reduction, as well as the relative lack of protection/deprotection transformations clearly mark this synthesis as an impressive achievement.  26  Sato’s total syntheses  1.2.4  In 2005, Ken-Ichi Sato published a racemic synthesis of tetrodotoxin starting from myo-inositol.65 His novel and stereocontrolled synthesis involved the typical orthoesterification/guanidine formation as the end-game strategy and the central feature of his route was the formation of a spiro -chloroepoxide and subsequent azide ion-mediated ring-opening (Figure 1.12).  O O OH O OH  H  OH  H N N HO H OH  NH2 guanidine formation  O H3C  (±)-tetrodotoxin  HO HO  HO OH OH OH  OH  -chloroepoxide  H3C  NH2 NHBoc  O H3C  O  O  TBDPS  CH3 1.85  H3C CH3  CH3  O O MOM O O  formation  OH  O MOM O O  1.84  OH OH  OMOM NBoc N H OH  O CH3  spiro  HO  N C  H3C O H3C O O O  orthoacid formation  azide ring opening  O MOM O  Cl  CHO O N3  OH  OH  O H3C  myo-inositol  O CH3 1.87  OTBDPS  O H3C  O  OTBDPS  CH3 1.86  Figure 1.12. Sato’s retrosynthetic analysis for (±)-tetrodotoxin from myo-inositol. To begin, Sato orthogonally protected the secondary hydroxyl groups of myo-inositol in a sevenstep transformation to give compound 1.88 (Scheme 1.23). Another 10-step sequence converted 1.88 to compound 1.89, with the C-4a ketone in place to introduce the C-4 carbon fragment. A Peterson olefination/hydroboration operation and subsequent TBDPS-protection/C-8a oxidation afforded 1.90 with the requisite C-8a ketone in place to introduce the C-9 carbon unit and set up for the key spiro chloroepoxide formation.  An approach to advanced tetrodotoxin intermediates using the spiro -  chloroepoxide as a means of installing the C-8a nitrogen and the C-9 carbon center was worked on by Sato in the early 1990’s66 (Scheme 1.30).  27  1) CH(OEt)3, TsOH 2) NaH, BnBr 3) MOM-Cl, iPr2NEt 4) (COCl)2, DMSO  OH  HO HO HO  O O OH O O MOM  5) LDA, CH2Cl2 6) nBu4NOH, DMSO 7) NaBH4  myo-inositol  11  OH  Cl  H3C  O MOM O  O  TBS O  11 4a  OBn  1.88  H3C  CH3 O OH MOM O O 8a Cl  O  CH3  8a  O H3C  CH3 1.91  1) (CH3)3SiCH2MgCl 2) NaH 3) BH3, NaOH; then H2O2 aq 4) TBAF  CH3  O MOM O O O  LDA, CH2Cl2  OTBDPS  6) (CH3)2C(OCH3)2, PPTS O O O 7) CH2(OCH3)2, P2O5 H3C 8) Pd(OH)2/C, H2 CH3 1.89 9) (CH3)2C(OCH3)2, PPTS 10) (COCl)2, DMSO  6  H3C  O  H3C  6  OH  4a  NaH, BnBr HCl Ac2O TBS-Cl AcOH  8a  OH  6  1) 2) 3) 4) 5)  6  4a  OTBDPS  O CH3  5) TBDPS-Cl 6) Dess-Martin periodinane  1.90  Scheme 1.23. Sato’s setup for spiro -chloroepoxide formation. When treated with sodium azide and 15-crown-5 in DMSO, 1.91 closed to give spiro chloroepoxide 1.87, which was subsequently ring-opened with azide ion to give 1.86 containing the C-8a nitrogen functionality and an aldehyde group at C-9 (Scheme 1.24).  H3C  CH3  O OH MOM O O 8a Cl 9  O H3C  6  4a  O CH3 1.91  H3C  CH3 O O MOM O O  NaN3, 15-crown-5, DMSO  8a  Cl  OTBDPS  O H3C  CH3  9  Cl  N3 OTBDPS  O 1.87  H3C CH3 9 O CHO MOM O O 8a O H3C  OTBDPS  O CH3  1.86  Scheme 1.24. Sato’s -chloroepoxide formation and azide ion-mediated ring-opening. The C-9 aldehyde unit of 1.86 was treated with trimethylsilyl cyanide and protected, giving 1.85 as a 3:2 mixture of C-9 diastereomers; the undesired/minor diastereomer was separated out and recycled back to the desired 1.85 by retreatment with trimethylsilyl cyanide (Scheme 1.25). Sato’s remaining synthetic manipulations, chiefly reduction/oxidation of the C-10 nitrile to the carboxylic acid and lactonering closure, lead to 1.92 which was converted to racemic tetrodotoxin following a sequence with similarity to Kishi (Scheme 1.5), Isobe (Schemes 1.11, 1.18) and Du Bois (Scheme 1.22).  28  N H3C 10 C H3C OMOM 9 O O MOM O 8a N3  H3C  CH3 9 O CHO MOM O O 8a  1) (CH3)3SiCN, Et3N 2) CH2(OCH3)2, P2O5  N3 O H3C  O CH3  O  OTBDPS  H3C  1.86  O 10  O OH O OH  H  OH  9  H N N HO H OH  8a  (±)-tetrodotoxin  NH2  1) 2) 3) 4)  DIBAL-H CrO3, H2SO4 aq H2, Pd/C TBAF  OTBDPS  O  O H3C  CH3 1.85  1) PCC 2) i) 4 M HCl ii) TFA aq iii) AcOH aq  H3C O H3C O O O O  H3C  OMOM NBoc N H OH  O CH3  H3C O H3C 10 OMOM O 9 O O 8a NH2 OH  O CH3  1.92  (BocNH)2C=S, HgCl2  NHBoc  1.84  Scheme 1.25. Sato’s end game strategy: lactone/orthoester formation, guanidine formation. With compound 1.86 in hand, Sato rapidly installed key functionalities on the tetrodotoxin backbone, setting the C-4a nitrogen unit and C-9/C-10 unit, closing the bridging lactone and finally orthoacid and guanidine ring closure. Sato’s synthesis of racemic tetrodotoxin was completed in 36 steps with an overall yield of 0.12% from myo-inisitol. The Sato group achieved a stereoselective synthesis of (−)-tetrodotoxin in 2008, beginning from D-glucose.67 Novel features of this synthesis include an intramolecular Henry reaction followed later by a McMurry-Nef reaction to access 1.90 (Figure 1.13), a common intermediate with Sato’s racemic synthesis of tetrodotoxin from 2005 (Scheme 1.23). This approach by Sato is based significantly on not only the Funabashi approach68 (Chapter 1.2.5), of which Sato participated, but also early independent work by Sato66 himself (Scheme 1.30) from two decades prior.  29  O O OH O  H  H N N HO H  OH  orthoacid formation  OH  OH  H3C O H3C O O O  NH2 guanidine formation  O H3C  ()-tetrodotoxin  OMOM NBoc N H OH  O CH3  N H3C H3C C  N3  NHBoc O H3C  1.84  NO2 BnO  OBn PhS SPh  CH3 1.85  H3C  1.93  H3C CH3  CH3 O MOM O O O O  CH3  spiro O CHO chloroepoxidation MOM O O  OTBDPS ring-opening  O  OTBDPS  O  H3C  Nef reaction  OH OH OH  OMOM  O MOM O O  N3 O H3C  1.90  OTBDPS  O CH3  1.86  Henry reaction NO2  NO2  PhS  O OBn  PhS H BnO  OH 1.94  HO  O OBn  OH H BnO  O  HO HO  O CH3  H3C 1.95  O OH OH  D-Glucose  Figure 1.13. Sato’s (−)-tetrodotoxin retrosynthetic analysis. Sato accessed aldehyde 1.97 in five-steps from known glucose-derivative 1.9669-73 (Scheme 1.26). Henry reaction with the sodium nitronate of nitromethane afforded nitro alcohol 1.98 as an inconsequential 10:1 mixture of diastereomers. Treatment of the 1.98 mixture of diastereomers with methanesulfonyl chloride and triethyl amine afforded nitro-olefin 1.99. Reaction of 1.99 with lithium dithioacetal anion gave 1.100. Acetonide deprotection of 1.100 with refluxing glacial acetic acid gave nitro-hemiacetal 1.94. Nitro cyclitol 1.93 was formed through an intramolecular Henry reaction by treatment of 1.94 with methanolic sodium bicarbonate.  30  H3C HO HO HO  CH3 O  1) mCPBA 2) NaOH aq 3) NaH, BnBr  O  O  3 steps  67-71  O  OH OH  H  D-Glucose  O  O CH3  O  O OBn H  4) AcOH aq 5) NaIO4  O  BnO  1.97  CH3  1.96  O CH3 CH3  CH3-NO2, CH3ONa, CH3OH NO2  PhS  NO2  PhS  O OBn H BnO  CH2(SPh)2, n BuLi  1.100  O OBn H BnO  O O  CH3  O 1.99  CH3  85% AcOH aq reflux  MsCl, Et3N  PhS  NO2  PhS  O OBn H BnO  O CH3  NO2  OH O OBn  H BnO  CH3  O 1.98  NaHCO3, CH3OH, H2O  O CH3 CH3  OH OHOH  OH  NO2 BnO  OH 1.94  OBn PhS SPh 1.93  Scheme 1.26. Sato’s synthesis of nitro cyclitol 1.93 employing an intramolecular Henry reaction. Sato protected the vicinal diol of 1.93 as an acetonide and the C-5 axial hydroxyl group, then converted the dithiane to the TBDPS-protected primary alcohol to give 1.101 (Scheme 1.27). Conditions were screened for the conversion of the C-8a-nitro group to the required C-8a-ketone and found that potassium tert-butoxide and ozone, McMurry’s conditions,74 were effective.  Deprotection and  reprotection of the C-6/C-11 diol gave known tetrodotoxin intermediate 1.90.  Scheme 1.27. Sato’s McMurry-Nef transformation to common intermediate 1.90. With common intermediate 1.90, Sato’s synthesis proceeded to (−)-tetrodotoxin by their established route for racemic tetrodotoxin,65 including the successive spiro -chloroepoxide formation and azide ion-mediated ring-opening sequence (Schemes 1.23, 1.24, 1.25).  31  Sato further optimized the synthesis for the common intermediate 1.90 in 2010, again starting from D-glucose as starting material (Figure 1.14).75 His updated synthesis accessed common tetrodotoxin intermediate 1.90 through an olefination at C-4a to install the C-4 carbon unit, and a Ferrier(II) reaction of enol acetate 1.104 to build the cyclohexane framework.  O O OH O OH  H  H3C O H3C O O O  orthoacid formation  OH NH2  H N N HO H OH  guanidine formation  O H3C  ()-tetrodotoxin  H3C  CH3  O  O  O CH3  NHBoc  O H3C  1.84  CH3 O MOM O O O  OTBS 4a  O H3C  N H OH  4  O  CH2  CH3 1.85  H3C  OMOM  CH3 1.102  CH3  H3C CH3 spiro O CHO chloroepoxidation MOM O O  OTBDPS ring-opening  O  OTBDPS  O  H3C  O  6  N H3C CH3 C O OMOM MOM O O N3  OMOM NBoc  N3 O  H3C  1.90  OTBDPS  O CH3  1.86  olefination  O MOMO H3C O H3C  4a  OAc 8a  6  OH O  OBn 1.103  Ferrier(II) reaction  OAc 8a  MOMO O H3C H3C  4a 6  O 1.104  O O OCH3 Bn  HO HO HO  O OH OH  D-Glucose  Figure 1.14. Sato’s updated retrosynthetic analysis for (−)-tetrodotoxin intermediate 1.84. Sato began this route from commercially available 1.10576 (Scheme 1.28). Peterson olefination of 1.105 installed the C-11 carbon and subsequent epoxidation and base-hydroylsis of the epoxide set the C-11 and C-6 hydroxyl groups. Oxidation of deprotected C-8a hydroxyl to the unstable aldehyde and immediate trapping as the enol acetate afforded 1.104 as the sole isomer. Conditions for the key Ferrier(II) reaction were screened, and it was found that mercury diacetate optimally converted 1.104 into cyclohexanone 1.103 as the major diastereomer, the ratio of the major diastereomer to the sum of the other three diastereomers was found to be 2:1. Sato finished his route to (−)-tetrodotoxin precursor 1.90 in a six-step sequence, borrowing from his 2005 synthesis (Scheme 1.23) the Peterson olefination/hydroboration installation of C-4 and the C-4 oxygen moiety. 32  HO  O  4 steps74  O  HO HO  OH OH  O  Ph  OCH3  6  O  OBn  O  D-Glucose  1.105  H3C  CH3  O MOM O O  O  H3C  O  O TBDPS  CH3 1.90  OAc 8a  MOMO O H3C  4a  H3C  O 11 OCH3 H3C O 5) mCPBA Bn n 6) Bu4NOH 1.104 7) (CH3)2C(OCH3)2, pTsOH 8) TFAA, Et3N Hg(OAc)2, AcOH, 9) K2CO3, Ac2O then NaCl aq  2) TBDPS-Cl 3) Dess-Martin periodinane  TBS  O O  O  H3C  1) Pd(OH)2/C, H2 2) (CH3)2C(OCH3)2, pTsOH  O MOMO H3C O  4a  OAc 8a  6  4a 4  O O  O  6  CH3 1) i) BH3; H2O2, NaOH ii) TBAF  6  O  1) (CH3)3SiCH2MgCl 2) AcOH aq 3) PivCl 4) CH2(OCH3)2, P2O5  OMOM  3) i) (CH3)3SiCH2MgCl H3C ii) TBS-Cl  OH O  OBn  CH3 1.102  1.103  Scheme 1.28. Sato’s Ferrier(II) sequence to common intermediate 1.90.  33  1.2.5  Funabashi  In 1980, the Funabashi laboratory, including Kenichi Sato (Chapter 1.2.4), published a synthetic approach to optically active tetrodotoxin68 based upon then-current work in their group on hexose functionalization. Their strategy employed an intramolecular Henry reaction to create the 6-membered carbocycle 1.106 (Figure 1.15) as a proposed tetrodotoxin precursor.  O O OH O  intramolecular Henry cyclization H  OH NH2  H N N HO H OH  HO  OH (-)-tetrodotoxin  OH  HO  NO2 CHO OH  CHO  H  OH OH OH  H  HO  CH2OH  H  OH  H  CHO CH2NO2  1.106  O  HO HO  OH OH  D-Glucose  Figure 1.15. Funabashi’s retrosynthetic approach to (−)-tetrodotoxin. Funabashi began from D-glucose derivative 1.107.77,78 Aldehyde 1.108 was generated after protection/deprotection steps and sodium periodate cleavage of the resulting 1,2-diol. A Henry reaction with the nitronate of nitromethane on 1.108 and subsequent elimination set the stage for the Michael reaction of 2-lithio-1,3-dithiane to give 1.110. Base-mediated deprotection and intramolecular Henry reaction gave completed carbocycle 1.111.  H O H3C  O  O OH H  CH3 H HOH2C  O  H  1) CH2Br2, NaH 2) AcOH aq 3) NaIO4  O O O  O  H O  CH3  NO2  1) CH3NO2, NaOCH3 2) MsCl, Et3N  H  O  1.107  H  O O  CH3  O  H3C  H3C  H  O O  O CH3  H3C 1.109  1.108 S Li  O2N  OH OH OH O  NO2 S O  S 1.111  S  S S H O O H  NaHCO3  O  O  O  1.110 H C 3  CH3  Scheme 1.29. Funabashi’s approach to (−)-tetrodotoxin. 34  Intermediate 1.111 appeared to be the most advanced TTX-intermediate assembled by Funabashi, but his former student Sato pursued this route independently,66 using the intramolecular Henry cyclization as the key step in assembling the carbocyclic framework as Funabashi. Sato further elaborated the approach by employing an azide-mediated opening of a spiro -chloro-epoxide derivative (Scheme 1.30) to create a more advanced (−)-tetrodotoxin precursor 1.115. This early work set the stage for his eventual conquest of optically active tetrodotoxin65,67 (Chapter 1.2.4) roughly a decade and a half later.  OH OH OH O  O  NO2 S S Ph Ph  1) CH2(OCH3)2, P2O5 2) HgO, HgCl2, BF3•OEt2, (CH3O)3CH  OR OR OR O OCH3  O  O  1.112  R OR O R O O  OPMB NH H N NH2 O H3CO OCH3 1.115  LDA, CH2Cl2  OCH3 1.113  1) NaBH4 2) PMB-Cl, NaH 3) H2, Pd/C; then BrCN 4) NH4OH O  O  Li OR O Cl R O OR Cl OCH3 OCH3 O  R = MOM  NaN3, 15-crown-5, OR CHO DMSO R O OR N3 OCH3 OCH3 O  OR O R O OR O  O  Cl  OCH3 OCH3  1.114  Scheme 1.30. Sato’s early independent work on (−)-tetrodotoxin.  35  1.2.6  Keana  Over nearly two decades, Keana worked on the synthesis of tetrodotoxin and published several papers in the 1970’s and 1980’s reporting their progress.79-81 Generally, Keana approached the synthesis of tetrodotoxin by the construction of the carbocyclic framework via Diels-Alder chemistry (Scheme 1.31) while simultaneously, and uniquely forming the cyclic guanidine at an early stage. Diels-Alder reaction between dienophile pyrimidone 1.116 and 1-acetoxy-3-methyl-butadiene afforded racemic hydroquinazoline 1.117.  Stoichiometric osmium tetraoxide-mediated dihydroxylation of 1.117 gave  compound 1.118 as the major diastereomer. Advanced intermediate 1.118 appeared to be the most advanced proposed tetrodotoxin precursor reported by Keana, containing several key structural components. O  OAc + H3C  H3C  H N  NHAc  H3C O AcO H N  THF 165 °C  N H3C O 1.116  NAc NH  H  O  1.117  OsO4 then H2S  H3C O AcO H HO N HO H3C  NAc NH  H  O  1.118  Scheme 1.31. Keana’s most advanced tetrodotoxin intermediate.  36  1.2.7  Fraser-Reid  In the 1990s, Fraser-Reid’s laboratory, including Ricardo Alonso (Chapter 1.2.8), published several reports on progress toward the formal synthesis of tetrodotoxin.82-84 Fraser-Reid reasoned that then-recent free-radical methods had been shown to be tolerant of a variety of functional groups85,86 whereas previous methods proved incompatible with sugar-derived substrates. Fraser-Reid proposed a possible avenue to a formal synthesis of tetrodotoxin (Figure 1.16) beginning from a carbohydratederived source. R and R' were suitable protection moieties O OH  O O  H  AcO OH  H N N HO H OH  OR H  OR O OHOR H NR'  OAc O  NH2 O  OAc NHAc  OAc Kishi-Goto intermediate 1.12  OH tetrodotoxin  OH O  O  HO  O OH  OH D-Mannosan (1,6-anhydro--D-mannopyranose)  O  O  HO  O 1.119  OH CHO  HO  O O  O  OH  NHR' OH 1.121  OR  OR  NHR' OR 1.120  Figure 1.16. Fraser-Reid’s retrosynthetic considerations. Initially, Fraser-Reid began his sugar-based approach to tetrodotoxin from 1,6-anhydro--Dmannopyranose, exploiting the different reactivity of the sugar’s various hydroxyl groups to achieve suitably functionalized advanced intermediate 1.123 (Scheme 1.32).  Olefination-product 1.124 was  deprotected with HF and reacted with trichloroacetonitrile to give oxazoline 1.125 which was opened with HCl and protected as the triacetate 1.126. Fraser-Reid was able to directly convert 1.126 to 1.127 by reaction with tert-butylhyponitrite (TBHT) in refluxing tert-butyl alcohol.  After protecting group  manipulation, dioxadamantane 1.129 was afforded from reaction of 1.128 with TES-OTf/Ac2O.  37  O OH O  O  O  steps84  SnBu2  O O  OH  OH  O  O  OTBDPS 1.122  D-Mannosan  O  1) Br2 2) Ac2O TBDPSO  (EtO)2P  O  OAc  O  O  CN  TBDPSO  OAc CHCN 1.124  1.123  HF; then Cl3CCN, DBU O O  O  O  OAc  NHAc OAc  1) HCl 2) Ac2O  O  TBHT NC  OAc NHAc  1.127  O O  OAc 1.126  O  O  NC  O  OAc  N  Cl3C  CCl3  O  OAc CHCN  N  1.125 steps84 O O  O  OBn  NHAc OBn  Ac2O, TES-OTf  OAc  O  AcO  OAc TBHT =  O O  OBn  NHAc OBn  1.128  O N N O  O OBn NHAc OBn 1.129  Scheme 1.32. Fraser-Reid’s synthesis of dioxadamantane core 1.129 via D-mannosan. Several years later, Fraser-Reid reported the synthesis of an advanced intermediate of similarity to the Kishi-Goto intermediate 1.12 (Scheme 1.33).  Compound 1.128 was allylated under radical  conditions to afford compound 1.130 as the major diastereomer.  A reduction/iodination sequence,  followed by ozonolysis under Schreiber conditions87 gave the desired methyl ester 1.131. Reductive elimination with Zn in refluxing ethanol, PMB-protection of the hemi-acetal and basic hydrolysis gave compound 1.132 which was ready for an iodolactonization procedure.  Iodolactonization of 1.132,  promoted by iodonium dicollidine perchlorate (I(collidine)2ClO4, IDCP), lead to 1.133. Oxygenation was affected under radical conditions with tributyltin hydride and molecular oxygen to give 1.134, which correlates to the structurally similar Kishi-Goto intermediate 1.12. Conceivably, this approach could be exploited to facilitate a synthesis of tetrodotoxin, but further studies by Fraser-Reid have not appeared in the chemical literature.  38  1) pyridinium bromide perbromide, AcOH 2) allyltributyltin, AIBN O  O O  O  OBn  1) NaBH4 2) I2, PPh3, imidazole 3) O3, CH3OH; Ac2O, Et3N  O H H  O  NHAc OBn  NHAc OBn  1.128  1.130  O OCH3  O  H  OBn I  O  OBn NHAc OBn 1.131 1) Zn 2) PMB-Cl 3) LiOH  AcO O  AcO  OAc O  O  HO  O  OAc NHAc  OAc Kishi-Goto intermediate  OBn  O  OPMB O OBn NHAc  1.134  O2, Bu3SnH, I Et3B  O  OBn  O  OPMB O OBn NHAc 1.133  HO IDCP  OBn  O  OPMB O OBn NHAc 1.132  Scheme 1.33. Fraser-Reid’s synthesis of advanced intermediate 1.134.  39  1.2.8  Alonso  Following his experience with Fraser-Reid, Ricardo Alonso also independently pursued a mannose-based radical cyclization approach to the synthesis of tetrodotoxin. His approach (Scheme 1.34) used a combination of iodoacetal 1.136 as a radical cyclization precursor containing an aldoxime ether as a radical trap.88,89 The cis ring fusion, and thus the C-8a carbinolamine configuration, were set in a radical annulation reaction. Upon treatment with AIBN and Ph3SnH, iodoacetal 1.136 underwent an efficient intramolecular 5-exo-trig cyclization, forcing the approach of the tethered radical chain to the concave face of the bicyclic structure and setting the C-8a tertiary center’s configuration in compound 1.137. After protection as an oxazolidinone, Jones oxidation and installation of the exomethylene, compound 1.140 was created in a stereocontrolled manner.  CH3 O  CH3  O  O  O  1) TBDPS-Cl 2) HOAc aq 3) nBu2SnO; Br2 4) H2NOCH3  OH 1,6-anhydro-2,3isopropylidene--Dmannopyranose  OH NOCH3  O  O  O  TBDPSO  O  1) NIS,  O  2) TBAF OH  1.135  OCH2CH3  O NOCH3  I 1.136 AIBN, Ph3SnH  O O O O  O  triphosgene NOCH3  1.138  O O  O OCH2CH3 O N CH2 OH OCH3  OCH2CH3 1.137 O  O O O O  O  NHOCH3  8a  OH  OCH2CH3  CrO3, H2SO4  O  NaH, (H2CO)n  O NOCH3  O O 8a O  O NOCH3  OH  O O  O  O 1.139  O  OH 1.140  H  OH  H N N HO H OH  8a  NH2  tetrodotoxin  Scheme 1.34. Alonso’s radical-cyclization approach.  40  1.2.9  Taber  In the early 2000s, Taber proposed an approach to optically active tetrodotoxin based on the functionalization of a cyclohexenone created by an intramolecular alkylidene carbene cyclization (Scheme 1.35).90  Taber synthesized an advanced intermediate towards (−)-tetrodotoxin using  91  established carbene-based C-H insertion technology to set the C-6 tertiary alcohol stereocenter. Readily available 1,2;5,6-di-O-isopropylidene-D-mannitol was used to test the feasibility of Taber’s proposed CH insertion strategy. A Sharpless asymmetric epoxidation92 of the corresponding allylic alcohol gave compound 1.141, which was ring-opened with CuBr/isopropenylmagnesium bromide93,94 and the resulting diol protected as the cyclic ketal 1.142. Ozonolysis of the terminal olefin gave 1.143 as a precursor to attempt the intramolecular alkylidene C-H insertion reaction on the C-6 methine. Treatment of 1.143 with trimethylsilyl diazomethane and nbutyl lithium gave compound 1.144 after warming. Taber used the same approach to set the C-6 tertiary stereocenter was employed by Du Bois (Chapter 1.2.3) in his synthesis of optically active tetrodotoxin.64 Ozonolysis, annulation and redox adjustment of 1.144, followed by epimerization of the C-4a center, gave cyclohexenone 1.146, containing stereochemical features substantially contained in the core of (−)-tetrodotoxin.  41  H3C O  CH3 O OH  HO  O (EtO)2P  1) NaIO4; then 2) DIBAL-H 3) D-(-)-diethyl tartrate, Ti(OiPr)4, tBuOOH  H3C  O  O  OEt  H3C  CH3  1) CuBr,  O H2C  O O  2) PTSA,  OH  CH3  H2C H3C  O O  CH3  CH3 O  MgBr  O  CH3  O  O  1.142  1.141  1,2;5,6-di-Oisopropylidene-D-mannitol  O3; then Ac2O  O  H3C  CH3  O  CH3  C H  O H3C 1) O3; DBU; Ac2O 2) DBU 3) NaBH4, CeCl3  n  O  H3C  O  (CH3)3SiCHN2,  O  6  O  H3C  CH3  O  O BuLi  O H3C  O  O  1.144  1.143  CH3 O  CH3  CH3 O  CH3  O  O Dess-Martin periodinane  O  6  O OH 1.145  O  CH3 O  O OH O  O  4a  O  6  OH  O 1.146  H  OH  H N N 4a HO H  OH  NH2  (-)-tetrodotoxin  Scheme 1.35. Taber’s C-H insertion strategy.  42  1.2.10 Fukuyama  Fukuyama’s approach to the core structure of racemic tetrodotoxin was centered on an intramolecular [3+2]-dipolar cycloaddition of a nitrile oxide to set the all cis C-8a, C-4a, C-5 configurations.95 Tricycle 1.147 was envisioned as a possible TTX synthon, containing several of the functional moieties in tetrodotoxin with the correct relative configurations (Figure 1.17).  Figure 1.17. Fukuyama’s TTX-core synthon 1.147. Fukuyama began his synthetic inquiry with imidodicarbonate 1.150, prepared in six-steps from panisaldehyde (Scheme 1.36).  With precursor 1.150 in hand, Fukuyama approached the  iodoaminocyclization reaction according to Taguchi’s protocol96 with LiAl(tBuO)4 and excess I2 to access 1.151 which was converted to diiodo-1.152 straightforwardly.  Compound-1.152 served well as a  precursor to the forthcoming intramolecular nitrile oxide 1,3-dipolar cycloaddition. HO  CHO  OH  1) allyl-MgBr 2) O3; NaBH4  1) Li, NH3 2) PPTS, HOCH3  OCH3  HO  OH  H3CO OCH3  OCH3 1.148  1.149 1) TBSCl 2) triphosgene, benzyl carbamate  I O  OTBS O  O  Cbz N  I  1) TBAF  Cbz N  O I  2) I2, PPh3, imidazole H3CO OCH3 1.152  CbzHN  LiAl(tBuO)4;  O  OTBS  O  I2 H3CO OCH3 1.151  H3CO OCH3 1.150  Scheme 1.36. Fukuyama’s route to diiodo 1.152 enroute to 1.147.  43  Deprotection of the dimethyl ketal and concomitant dehydroiodination of the secondary iodide with hot aqueous acetic acid afforded enone 1.153, which was converted to the silyl enol ether and then the primary iodide was substituted with sodium nitrite to 1.154 (Scheme 1.37). Fukuyama treated 1.154 with di-tert-butyl dicarbonate and DMAP97 to dehydrate the primary nitro group to the corresponding nitrile oxide and induce the subsequent intramolecular 1,3-dipolar cycloaddition with the C-5/C-4a olefin to give tetracycle 1.155 as a single diastereomer. The C-7/C-8 olefin was installed by treatment of silyl enol ether 1.155 with phenylselenium chloride in methanol and mCPBA oxidation to give unsaturated mixed acetal 1.156. A DBU-mediated oxazolidinone-opening gave tricycle 1.157 that was primed for attempts to oxidize the cyclopentene unit. Fukuyama found that dihydroxylation of 1.157 proceeded from the convex face of the bowl-shaped tricycle, and reductive workup with Na2SO3 gave the corresponding oxazolidinone.  Oxazolidinone formation suitably protected the C-9 hydroxyl group, allowing  manipulation of the C-10 hydroxyl group to proceed specifically after reduction of the isooxazoline C=N bond and Alloc protection.  Oxidation at C-10 with Dess-Martin periodinane and Baeyer-Villiger  oxidation afforded ring-expanded lactone 1.159. Methanolysis of lactone 1.160 and palladium-mediated deprotection of the Alloc group afforded isooxazoline 1.147 containing the oxidation level at C-4 found in TTX.  44  I O  I O  O HOAc aq  Cbz N  I  O  1) TBSOTf 2) NaNO2  Cbz N  O  4  O  NO2  Cbz N  100 °C  H3CO OCH3  O  1.152  1.153  OTBS 1.154 Boc2O, DMAP  O Cbz  1) PhSeCl, CH3OH 2) mCPBA; NaHCO3  O N  O Cbz  4a  OTBS  O OTBS  1.156  1.155  DBU 1) OsO4 N O OTBS  H3CO  2) NaBH4 3) Alloc-Cl  5  N O  OTBS  O  O  CbzHN  4 4a  N  5  O  [3+2]  4  N  H3CO  O  Cbz N  N  8 7  O  O  O  HN  OH  O  H  9 10  N Alloc  O H  HN  N Alloc 2) mCPBA  O H3CO OTBS  1.157  1) Dess-Martin periodinane  O  O H3CO OTBS  1.158  1.159 K2CO3, CH3OH  10  HO  10  CO2H 9  H2N HO  4  CHO  8 7  HO HO 11  O  O  CO2CH3  O  9 4  HN  Pd(PPh3)4  O HN  CO2CH3 HO H  8 5 6  OH OH  core skeleton  7  5  N  6  O H3CO OTBS 1.147  N Alloc O H3CO OTBS 1.160  Scheme 1.37. Fukuyama’s racemic route to TTX core synthon 1.147.  45  1.2.11 Ohfune  In early 2003, the Ohfune group communicated work in their laboratory on the stereoselective construction of a tetraol system corresponding to the C-5, 6, 7, 11 hydroxyl groups in (−)-tetrodotoxin.98 The consecutive hydroxyl groups in (−)-tetrodotoxin have proved to be one of the challenges in the construction of the unique core structure. Ohfune approached the tetraol part of tetrodotoxin (Figure 1.18) through a series of repetitive stereoselective epoxidation/base-induced ring-fragmentation reactions beginning from (−)-quinic acid derivative 1.161 which already contained the correct C-6 geometry.  Figure 1.18. Ohfune’s approach to (−)-tetrodotoxin. Ohfune generated allyl sulfone 1.162 as the sole regioisomer via the dehydration of diol 1.161 with (PhS)2/Bu3P, as developed in their laboratory (Scheme 1.38).99 Epoxidation occurring from the lesssterically demanding -face of the allyl sulfone and subsequent base-mediated ring-opening/olefin isomerization gave 1.164 with the correct configuration of the C-5 hydroxy group. The same mCPBA epoxidation/base-mediated ring-opening sequence was repeated on 1.164 to generate 1,3-diaxial diol 1.166. Having set the diaxial C-5, C-7 stereochemistry, Ohfune tackled the installation of the C-6, 11 diol. Protection of 1.166 as the cyclic acetal, removal of the phenyl sulfone group and deprotection of the -OTBS group afforded 1.168.  Inversion of the C-4 stereocenter was accomplished through an  oxidation/reduction sequence, and osmium tetraoxide-based dihydroxylation of the exo olefin lead to 1.169 containing the C-5, 6, 7, 11 tetraol system in (−)-tetrodotoxin. Ohfune’s stereoselective route to the tetraol system by successive epoxidation and allyl sulfone ring-opening operations effectively addressed a method of accessing the 1,2,3-triaxial hydroxyl groups of (−)-tetrodotoxin on a simpler (−)-quinic acid derivative.  46  OCH3 H3C H3C  OCH3  (PhS)2/Bu3P  O O TBSO OCH3  OH  H3C H3C  OH  mCPBA  O O  OCH3 H3C H3C  OCH3 OTBS SPh  1.161  O  O O OCH3 OTBS SO2Ph  1.162  1.163 KOtBu  OCH3 H3C H3C  O O  OH HO  OCH3 KOtBu  5  7  H3C H3C  OCH3 OTBS SO2Ph  OH O  O O  mCPBA  OCH3 H3C H3C  OCH3 OTBS SO2Ph  1.166  O O  OH 5  OCH3 OTBS SO2Ph  1.165  1.164  NaH, CH2Br2  OCH3 H3C H3C  O O OCH3  O  1) nBuMgCl, Pd(acac)2  O OTBS SO2Ph 1.167  2) TBAF  OCH3 H3C H3C  O O  O O OCH3  OH  1.168  1) Dess-Martin periodinane CH2  OCH3 O TBSO O H3C O O H3C  2) NaBH(OCH3)3 3) TBSOTf 4) OsO4  OCH3  11 6  OH  OH 1.169  Scheme 1.38. Ohfune’s approach to C-5, 6, 7, 11 tetraol system in (−)-tetrodotoxin.  47  1.2.12 Summary  Several groups have pursued tetrodotoxin as a synthetic target. The history of the synthesis of tetrodotoxin and of the tetrodotoxin core is marked with various themes which have evolved over time. In comparing the completed tetrodotoxin syntheses to date, it is easy to recognize similar finishing strategies due to tetrodotoxin’s polar guanidine and ortho acid functionalities. Other similarities between synthetic approaches are abundant.  Funabashi created synthetic tetrodotoxin intermediates via  intramolecular Henry addition, a theme used later by Sato in his initial synthesis of optically active (−)tetrodotoxin from D-glucose. The Taber group achieved a synthesis of an advanced intermediate for tetrodotoxin by using an intramolecular carbene insertion to install the C-6 center, a similar method which was used by Du Bois in his remarkable conquest of (−)-tetrodotoxin where he utilized two impressive CH-activation transformations to build (−)-tetrodotoxin, using synthetic methodology published only a couple of years before.  Keana approached the carbocyclic framework synthesis via Diels-Alder  chemistry, as did Kishi and Isobe, but with a twist to simultaneously, and thus far uniquely, install the cyclic guanidine functionality early-stage. Fraser-Reid completed advanced tetrodotoxin intermediates via radical cyclization chemistry, an approach further explored by Alonso. Ohfune used repetitive epoxidation/ring-opening sequences in construction of the tetraol core, similar to work by Isobe. Both Kishi and Isobe approached the hexasubstituted cyclohexane ring through intramolecular epoxide ringopening events, which also set the requisite stereocenters. Fukuyama’s use of a nitrile oxide in an intramolecular 1,3-dipolar cycloaddition to set the all-cis C-8a/C-4a/C-7 configurations lead to work described in Chapter 2 of this thesis as an approach to the core of tetrodotoxin. Despite the major advances in the synthesis of tetrodotoxin and its core, the structural complexity of tetrodotoxin ensures that it will continue to be a synthetic target for years to come. All current total syntheses (summarized in Figure 1.19) to date are long (28-40 linear steps), and the densely functionalized carbocyclic core makes convergent approaches to shorten the synthesis difficult, as evident by the lack of shorter syntheses almost 40 years after the structural elucidation of tetrodotoxin. Tetrodotoxin serves as not only a template upon which to test new reactions and transformations, but also as a source for the very creation and discovery of new reaction types.  48  O OH O  OH  CO2H  HO  O  H  OH  H N N HO H OH  HO  8a  NH2 CHO  NH2  generalized TTX-core synthon  6  HO HO  OH  OH 1.170  tetrodotoxin  CH3 H3C H3C CH3 O MOM O O O  H  O  O 6  8a  O H3C  CH3  PivO  8a  6  AcHN  O  CH3 1.90  OTBS  HO 6  CH3 1.19  O  1.7  1.75 1.45  O HO HO HO  O OH OH  HO HO HO  CH3  OH OH  H3C  OH HO  Sato 2008/2010 asymmetric  Sato 2005 racemic  HO  O  HO  O OH  O  HO  Kishi 1972 racemic  Du Bois 2003 asymmetric  N  R" 8a  CH3  O O  OTBDPS  O  6  8a  O  O O  R R = OBOM, R' R' = OTBDPS, R" = OBz R = R' = R" = H  OAc  O O  O AcO  O  OAc OAc  Isobe 2003 asymmetric  Br Isobe 2004/2010 asymmetric  Figure 1.19. Comparison of retrosynthetic intermediates between completed total syntheses to date.  49  2  2.1  The oxidative amidation strategy  General strategy  It is in the greater context of the afore-mentioned works that we examined tetrodotoxin as a target for total synthesis. The dense and intricate structure of tetrodotoxin provided an opportunity for the exploration of new and unique synthetic strategies. Bearing this in mind, we recognized the possibility described in Figure 2.1. Compound 2.2, which is a generalized product of oxidative amidation of a phenol of type 2.1 where G = an oxygen functionality, or appropriate precursor thereof, may be mapped nicely onto compound 1.170. Compound 1.170 emerges upon release of the guanidine and orthoacid functionalities of tetrodotoxin and is a common retrosynthetic intermediate as per Kishi, Du Bois and Isobe.  O OH  H  O O OH  OH  OH  HO  OH NH2  H N N HO H  HO  OH 6 5  4a  HO  8a  NH2  OH CHO COOH  4  tetrodotoxin  HO  1.170  O 6  G  8a 5 4a  COOR  COOR 2.1  NHAc G  2.2  Figure 2.1. Retrosynthetic hypothesis for tetrodotoxin.  The conversion of compound 2.2 into 1.170 requires, among other things, the stereocontrolled introduction of the C-5 hydroxyl group and C-4 aldehyde (or equivalent moiety). Fukuyama’s work95 (Chapter 1.2.10) indicated that the stereocontrolled introduction of these elements across the C-4a/C-5 olefin could be accomplished via an intramolecular nitrile oxide-olefin cycloaddition (INOC) reaction.100,101 We further envisioned that fragmentation of isooxazoline 2.4 could lead to the revealing of both the C-5 hydroxyl group and also the C-4 formyl unit masked as a cyano group (Figure 2.2). 50  AcHN  H G AcN  G  H AcN  O  [?]  G  COOR  H O  O  N  H O N  O  2.2 2.3  2.4  [?] HO HO  NH2 OH  [?]  H  COOH  HO  CHO OH  H G N  P  H2C  H  OH 1.170  CO Nu  CN O  O  O  P  AcHN  [?]  Nu  G H  O  5  H  2.6  OH  CO Nu  CN 4  2.5  Figure 2.2. Generalized strategy for the elaboration of the tetrodotoxin core.  Our elaborated retrosynthetic analysis is depicted in Figure 2.3 and features a common end-game strategy involving ortholactone and guanidine formation. A sequence involving methylenation to install the C-11 carbon unit, common to the work of Sato (Schemes 1.26, 1.28), as well as osmium tetraoxide dihydroxylations to install the four hydroxyl units across C-6, C-11, C-7 and C-8, elaborates the carbocycle 1.170. Functionalized enone 2.5 is a product of an intramolecular 1,3-dipolar cycloaddition reaction and subsequent isooxazoline fragmentation, with the pendant C-9 arm delivering the dipole to the C-4a/C-5 olefin in a stereocontrolled manner. Dienone 2.2 is rapidly and uniquely assembled from an oxidative amidation reaction of a phenol of type 2.1.  51  O O OH O 6  OH  H  OH  H N N HO H  OH  8a  NH2  orthoacid formation  OH  HO HO  11  6 5  HO guanidine formation  7 4a  8 8a  methylenation  OH COOH  4  OHC  tetrodotoxin  OH NH2  OsO4 dihydroxylations  7 O 8 6 H 5 8a NHAc 4a HO 4 G H 9 OHC COOR 10  1.170  2.5  dienone functionalization  HO  6 8a  G  oxidative amidation  O 6 8a  5 4a  COOR  NHAc G  9  COOR 10  2.1  2.2  Figure 2.3. Our elaborated tetrodotoxin retrosynthetic analysis.  52  2.2  Oxidative amidation  The oxidative amidation of phenols102,103 entails the creation of aza-substituted dienones of type 2.8 from phenolic substrates of type 2.7 (or ortho-substituted derivatives of 2.7). Group N is a suitable nucleophilic nitrogen moiety in 2.7 and is an amide functionality in 2.8 (Figure 2.4). The dashed-curve indicates that the N-group may be either covalently tethered to the phenolic ring (intramolecular) or may be an independent molecule (bimolecular). Hypervalent iodine (III) reagents,104-110 especially PhI(OAc)2 (diacetoxy iodobenzene, DIB) and PhI(OCOCF3)2 (phenyliodine bis(trifluoroacetate), PIFA), are uniquely competent in effecting oxidative amidation reactions of phenols, a special case of oxidative dearomatization of phenols.111 N  N  oxidation  HO  O 2.7  2.8  Figure 2.4. Oxidative amidation of para-phenols.  Oxidative amidation reactions of phenols proceed through an electrophilic intermediate such as 2.9 which is trapped with the nucleophilic N-group (Figure 2.5). The chemical literature is rife with examples of the oxidation of a phenol112 to a transient electrophilic species followed by interception with suitable nucleophiles. Barton113-115 published initial discoveries in this area in the 1950’s as well as others.116,117 As synthetic organic technologies evolved, newer and more effective oxidants were used in phenol oxidation reactions,118 however the development and widespread use of hypervalent iodine reagents permitted easy access to reactions of this type. Contributions to the chemical literature over the past 25 years by Kita,119-121 Pelter,122 Barret,123 and Wipf124,125 testify to the transcendence of oxidative dearomatization of phenols reactions from a novelty-class of reaction to a widely useful paradigm for the creation of synthetically useful products.  Figure 2.5. Oxidative amidation of para-phenols.  53  Oxidative dearomatization reactions, as described in Figures 2.4 and 2.5, are mechanistically distinct from related transformations (Figure 2.6) such as Kikugawa-Glover-type reactions.126-140 These involve the oxidation of an amide unit of type 2.10 to an electrophilic nitrogen-containing intermediate of type 2.11. The nucleophilic electron-rich aromatic ring attacks the electrophilic nitrogen, resulting in products of type 2.12 which formally resemble products of oxidative amidation (2.8) as in Figure 2.5.  O  Z N H  Z N  [O]  2.10 Z = CH3O, PhtN  Z N  O  RO  RO  O  O  2.11  2.12  Kikugawa-Glover-type reactions  Figure 2.6. Kikugawa-Glover-type reactions.  2.2.1  Oxidative amidation in total synthesis  The recognition that oxidative amidation technology could allow the rapid assembly of various nitrogen-containing substances led the development and subsequent refinements of this methodology. Oxidative amidation reactions of the type described in Figure 2.4 were developed in the Ciufolini laboratory to approach synthetic challenges in natural product synthesis programs such as FR901483141 and TAN1251C142 (Figure 2.7). The investigation of different modes of oxidative amidation of phenols can be categorized into three distinct generations (Figure 2.9), all of which evolved to solve specific synthetic challenges in natural product synthesis. All three generations of oxidative amidation reaction are promoted by DIB.143 The first generation of oxidative amidation reaction involved the cyclization of phenolic oxazolines, and was applied to the synthesis of FR901483 and TAN1251C (Figure 2.7). Independently, Sorensen144,145 and Honda146-148 developed oxidative dearomatization-cyclization reactions of phenolic secondary amines 2.13 and 2.15 in their syntheses of FR901483 and TAN1251C (Figure 2.8). The second generation of oxidative amidation involved the intramolecular oxidative cyclization of orthoand para-phenolic sulfonamides and was applied to the synthesis of (−)-cylindricine C149 and towards the himandrine core.150 The third generation oxidative amidation reaction type is the bimolecular reaction of 2- and 4-substituted phenols with nitriles and has been applied towards histrionicotoxins151 and tetrodotoxin.152 The development of the third generation of oxidative amidation as a reliable large-scale (50-100g) reaction was significantly advanced as a result of the synthetic ventures described in Chapter 2.3.1 of this thesis. 54  Figure 2.7.  Structures of FR901483 and TAN1251C and Ciufolini’s retrosynthetic logic for the  construction of their ring systems.  Figure 2.8. Sorensen’s144,145 and Honda’s146-148 oxidative cyclization of phenolic secondary amines.  55  Figure 2.9. Ciufolini modes of oxidative amidation of phenols.  56  2.3  Bimolecular oxidative amidation  The initial conditions (Scheme 2.1) for the bimolecular mode of oxidative amidation in the presence of nitriles153,154 suffered from two main drawbacks: variable yields and costly solvent (1,1,1,3,3,3-hexafluoroisopropanol, HFIP or 2,2,2-trifluoroethanol, TFE). These fluorinated alcohols were initially selected as solvents based on work by Kita,119-121 which indicated that phenol oxidations promoted by DIB proceed best in these solvents, presumably due to their acidic and non-nucleophilic nature. The development of a procedure which reliably allows for efficient large-scale synthesis of compounds of type 2.30 and also avoids costly solvents emerged as an important goal. O R  PhI(OAc)2, CH3CN, HFIP 50-85%  HO 2.29  H  N  R  CH3  O 2.30  Scheme 2.1. Initial conditions for bimolecular oxidative amidation.153  2.3.1  Optimization of scalable bimolecular oxidative amidation conditions  Figure 2.10. Possible DIB-mediated bimolecular oxidative amidation mechanism. 57  Bimolecular oxidative amidation reactions in which the nitrile nucleophile serves as co-solvent suffer when run at higher concentrations of phenol (Figure 2.11). Phenols are better nucleophiles than nitriles such as acetonitrile, and thus tar-like oligomers are obtained from oxidative amidation reactions, which ceteris paribus, are run at higher concentration of phenol starting material. Reactions run at large scale under the initial conditions for oxidative amidation153 yield products contaminated with oligomeric matter which complicates the isolation of the desired dienone products (2.30) by requiring lengthy chromatographic purifications. Fluorinated alcohol solvents such as HFIP and TFE are highly costly, and their avoidance in these oxidative amidation reactions is merited.  Figure 2.11. Effect of phenol concentration on reaction outcome.  Phenol 2.31 was selected as the starting material to begin optimization studies, since the product of its oxidative amidation, compound 2.32, was required for work in assembling the tetrodotoxin core. Our initial optimization studies focused on small-scale optimization (1g of phenol 2.31) based upon the initial 2005 conditions153 (Table 2.1). This reaction worked best when the phenol was added to a solution of DIB in acetonitrile/co-solvent in order to keep the concentration of phenol minimized (see Figure 2.11) and avoid undesired side reaction. A reaction (Table 2.1, entry d) was observed in which PIFA was used without the presence of any fluoro-solvents in the bimolecular oxidative amidation reaction.  This  observation is in accord with work by Wood,155 and suggested that perhaps small amounts of TFA were sufficient replacement for HFIP or TFE in these types of reactions. Entry e in Table 2.1 further indicated that DIB could be used in oxidative amidation reactions of this type, and a more thorough optimization of the bimolecular oxidative amidation reaction was carried out based upon this.154  58  Table 2.1. Optimization of scalable conditions for bimolecular oxidative amidation.  Work to scale this reaction to >10 g indicated that the addition of phenol 2.31 to a solution of acetonitrile/TFA containing DIB was best done with solid, crystalline 2.31. Experiments involving the dissolution of the solid phenol in acetonitrile followed by a slow syringe pump addition gave less efficient yields compared to reactions in which the phenol 2.31 was added as a solid (Table 2.2). Each of the entries in Table 2.2 were carried out at least in triplicate. The sensitivity of this oxidative amidation reaction to the presence of water was also examined. The yield of a reaction solution containing 1% v/v H2O was compared to the corresponding anhydrous solution and found to be nearly equivalent. The color of the reaction mixture for the solution containing 1% H2O was dark brown, compared to the dark blue/purple color of the anhydrous reaction mixture, but no significant difference was observed in the yield or isolation of the product (2.32). Entry f in Table 2.2 showed 70% yield for the reaction when very small amounts of phenol 2.31 were added to the DIB solution over the course of three hours (addition was done manually). These conditions were repeated six times with the same results. In all cases examined in Table 2.2, the workup and isolation remained the same. The crude reaction mixture was concentrated in vacuo by rotorary evaporation (12.7 Torr, 40 °C) and the residue passed through a small plug of silica gel (75 g). Non-polar impurities were eluted with 50:50 ethyl acetate:hexanes, and product eluted with 100% 59  ethyl acetate. The enriched product 2.32 crystallized upon standing, and was recrystallized from a hot solution of acetone:diethyl ether (1:1). Very large crystals of compound 2.32 were obtained from recrystallization (2cm X 2cm X 1cm) which allowed for X-ray crystallographic analysis.156 O  CO2CH3  DIB CH3CN/TFA  HN  additive HO  CH3 CO2CH3  O 10 g 2.31  2.32  entry  a b  addition  additive  yielda (%)  a  syringe pump (3 h)  N/A  25-30  b  solid addition (all at once)  N/A  20-30  c  solid addition (500 mg/30 min)  N/A  40-50  d  solid addition (500 mg/30 min)  H2O 1 % v/v  40-50  e  solid addition (250 mg/15 min)  N/A  45-55  f  solid addition (constant manual addition over 3 h)  N/A  70b+  after flash column chromatography additional product present in supernatant following recrystallization DIB = iodobenzene diacetate  Table 2.2. Larger-scale reproducible conditions for oxidative amidation of phenol 2.31 with acetonitrile.  60  2.4  Nitrile oxide [3+2] cycloaddition  The next objective, once the bimolecular oxidative amidation reaction to create dienone 2.32 was optimized, was to convert 2.32 into a functionalized enone of type 2.5 as Figure 2.3.  The  desymmetrization of dienones of type 2.8 enables stereoselective access to the tetrasubstituted nitrogenbearing carbon in enantiomers 2.33 and 2.34 (Figure 2.12). Structures of type 2.33/2.34 would arise from the selective addition of a generic reagent X-Y across either the pro-(R) or pro-(S) -bond of 2.8. 1,3Dipolar cycloaddition reactions offered a rapid route for the construction of a wide variety of fivemembered heterocycles,157,158 and are well-documented methods for the synthesis of isooxazolines.159-162 Isooxazolines are established precursors to amino ketones, oxo alcohols and other functional groups as well as a variety of natural products from reduction of the N-O bond or other ring-fragmentations.157-162 It was in this mode that we approached the desymmetrization as described generally in Figure 2.2: a nitrile oxide 1,3-dipolar cycloaddition reaction with the C-9 arm delivering the dipole to the dienone to install the functional units at C-4a/C-5.  Figure 2.12. Desymmetrization of dienone 2.8.  In anticipation for the advancement of the ester functionality of 2.32 to an -nitroketone163 as a precursor to reactive nitrile oxide intermediate 2.3 (Figure 2.2), the reduction and protection of dienone 2.32 was desired. Dienone 2.32 proved to be an excellent Michael-acceptor, and the reduction/protection sequence suppressed the possibility of unwanted later-stage intramolecular Michael additions. Various reduction conditions were screened (Table 2.3).  Initial conditions involved NaBH4 and  NaBH4/CeCl3164,165 and resulted in roughly a 1:1 ratio of diastereomers 2.35 and 2.36. A DIBAL-H reduction of 2.32 at –78 °C gave, in good yield, the -diastereomer 2.35. The diastereoselectivity of this 61  reduction can be reversed with a (S)-CBS/BH3 reduction166,167 using 1 mol % of CBS reagent at room temperature.168 Both diastereomers 2.35 and 2.36 have further downstream utility in this approach to the tetrodotoxin core.  The relative configurations of the doubly allylic alcohols 2.35 and 2.36 was  determined on the basis of X-ray crystallographic studies of later intermediates (vide infra).  Table 2.3. Reduction of dienone 2.32.  62  Compound 2.35, the -diastereomer from the DIBAL-H-mediated reduction of dienone 2.32, was protected as the TBDPS-ether using standard conditions, and the methyl ester cleaved with aqueous sodium hydroxide to afford carboxylic acid 2.38 (Scheme 2.2). Acidification of the reaction mixture after saponification of the methyl ester with aqueous sodium hydroxide needed to be done carefully, ensuring that the apparent pH of the solution stayed >2 to avoid lactonization to 2.41 as per Scheme 2.3.169 Activation of acid 2.38 with carbonyldiimidazole (CDI)170,171 and condensation of the resultant acid imidazolide with the nitronate of nitromethane (generated in situ from nitromethane and potassium tertbutoxide) generated nitroketone 2.39 in high yield after flash column chromatography.172  Scheme 2.2. Synthesis of nitroketone 2.39.  O TBDPS  NHAc CO2H  NHAc pH < 2 O quantitative  -OTBDPS = 2.40 -OTBDPS = 2.38  O H 2.41  Scheme 2.3. Undesired cyclization reaction of intermediate 2.40/2.38.  The conversion of nitroketone 2.39 to the reactive intermediate nitrile oxide 2.42 formally entailed a dehydration reaction.  A generic reagent X-Y could be reacted across the nitro group as  indicated in Figure 2.13, affecting the dehydration of nitroketone 2.39 to -keto-nitrile oxide173-175 2.42.  63  TBDPS O H H O N  TBDPS O  NHAc  H  H  NHAc  H H  O O  2.39  TBDPS O  NHAc  O N  Y  O N  O  O  O X  X-Y  2.42  Figure 2.13. Theoretical dehydration of nitroketone 2.39.  The dehydration of nitroketone 2.39 proved quite troublesome (Table 2.4). Initially this was examined using various reagents known for their use in nitro-dehydration reactions. A technique for converting nitroalkanes to their corresponding nitrile oxides was Mukaiyama’s aromatic isocyanate method176 which used such reagents as 4-chlorophenyl isocyanate.177,178 Reactions with nitroketone 2.39 and 4-chlorophenyl isocyanate gave complex mixtures of products. Other known methods for converting alkyl nitro compounds into their nitrile oxide derivatives were attempted as well. Shimizu’s method179 using ethyl chloroformate resulted in the slow conversion of nitroketone 2.39 to adduct 2.43. Hassner’s method,97 used by Fukuyama in his work on the TTX core (Chapter 1.2.10), using 4-(N,Ndimethylamino)-pyridine (DMAP) and di-tert-butyl-pyrocarbonate (Boc2O) was ineffective as well. These methods and reagents, and several others, failed to efficiently produce the desired intramolecular nitrile oxide cycloaddition product 2.43 (Figure 2.14). Common side product 2.44, whose structure was ascertained by X-ray crystallography, arose formally from the intramolecular O-alkylation of the nitroketone enolate via allylic displacement of the OTBDPS unit, and could be generated in high yield by treating the nitroketone 2.39 with triethylamine (Scheme 2.4). The initial data from the studies described in Table 2.4 were tantalizing: trace amount of the desired tricycle 2.43 appeared to be present according to 1H-NMR studies on crude reaction materials. This indicated that the transformation indeed must be possible, but that efficient reaction conditions remained elusive.  TBDPS O  NHAc  TBDPS O  NHAc  O2N 2.39  O  NHAc  TBDPS O  H  H  [3+2] dipolar cycloaddition  O N  O  2.42  O H  O N 2.43  Figure 2.14. Nitrile oxide [3+2] dipolar cycloaddition. 64  Table 2.4. Initial attempts to dehydrate nitroketone 2.39.  O TBDPS  NHAc  NHAc  NO2  Et3N O 2.39 NO2  CH2Cl2 63%  O H 2.44  Scheme 2.4. An undesired reaction of nitroketone intermediate 2.39.  65  Sensing that the -keto-group of nitroketone 2.39 could be responsible for the undesired reactivity seen thus far, we sought to alleviate this potential issue through a reduction/protection sequence (Scheme 2.5). Thus, NaBH4 treatment of nitroketone 2.39 provided unstable nitro alcohol 2.45, a sensitive material that was prone to undergo a retro-Henry fragmentation event, especially upon manipulations or attempted purification. Accordingly, crude nitro alcohol 2.45 was immediately Osilylated with TBSCl/imidazole.  NHAc NO2  NaBH4 (5 eq) CH3OH  NHAc NO2  O  TBDPSO  NHAc NO2 OTBS  OH  TBDPSO 2.39  TBSCl (1.5 eq) imidazole TBDPSO  2.45  2.46  Scheme 2.5. Reduction/protection sequence of nitroketone 2.39.  A careful analysis of 1H-NMR data from the crude reaction mixture to synthesize compound 2.46 indicated the presence of small quantities of tricyclic materials of the type 2.49/2.50/2.51/2.52. The Osilylation event indicated in Scheme 2.6 proceeded with concomitant Torssell-type cyclization162 (Figure 2.15). Thus purified TBS-ether 2.46 was treated with TBSCl (4 eq) and imidazole (4 eq) and resulted in a 1:1 mixture of tricyclic isooxazolines 2.49/2.50 (Scheme 2.6). The lack of diastereoselectivity signaled that the steric demand of the OTBS group was insufficient to exert stereocontrol during the cycloaddition step (see Figure 2.12). Notably, minor amounts of a mixture of diastereomeric nitroso acetals180 2.51 and 2.52 were isolated following flash column chromatography of the desired isooxazolines 2.49/2.50. Upon prolonged standing, both 2.51 and 2.52 spontaneously converted to the desired 2.49 and 2.50. A sample of enriched diastereomer 2.51/2.52 (6% yield) was isolated by flash column chromatography and characterized.  These materials (2.51/2.52) converted to compound 2.49/2.50 upon standing.  The  presence of nitroso acetals 2.51 and 2.52 implicated the intermediacy of siloxy nitronate162,180-184 2.48 en route to desired isooxazolines 2.49 and 2.50. The desired product formed from an intramolecular siloxynitronate-olefin cycloaddition (ISOC) process.  It was unclear if the ISOC pathway occurs  simultaneously with the expected INOC pathway or exclusively.  66  Scheme 2.6. [3+2]-dipolar cycloaddition of 2.46.  Figure 2.15. Torssell cyclization: silyl nitronates as 1,3-dipoles.  Treatment of diastereomers 2.49 and 2.50 with TBAF to release the alcohols afforded a 1:1 mixture of diols 2.53 and 2.54 (Scheme 2.7). Slowly, tiny crystals of 2.53 formed from the reaction mixture and allowed for X-ray structural study185 which elucidated the relative configuration between the C-4a and C-6 (tetrodotoxin numbering) that had been set during a low temperature DIBAL-H reduction of dienone 2.32 (Table 2.3 and Scheme 2.2).  67  NHAc 8a 6  OH  HO O N NHAc  2.53 OTBS  TBDPSO  TBAF +  O N  = 2.49  = 2.50  NHAc OH  HO O N 2.54  Scheme 2.7. Confirmation of structural geometry: X-ray crystallographic analysis of 2.53.  The success with the TBSCl-mediated conversion of 2.46 to cyclized products 2.49/2.50 prompted attempts to try similar conditions for the originally-planned nitroketone dehydration. Treatment of nitroketone 2.39 under various conditions based around TBSCl (Table 2.5) were attempted. This reaction appeared to be quite slow, with conversions to product taking place over approximately a week. Attempts to accelerate the reaction by the addition of 10 equivalents of TBSCl and imidazole each resulted in the unexpected formation of the noteworthy dihydropyridone 2.55 as the major product (65%, Scheme 2.8) with concomitant decrease in the yield of the desired isooxazoline 2.43 (5% yield after flash column chromatography).  The architecturally unique structure of 2.55 was elucidated by X-ray  crystallographic analysis and there appeared to be no other reports of similar molecules in the literature. The compound formally evolved from an unusual Knoevenagel-type186,187 intramolecular condensation of the nitroketone arm of 2.39 with the attached acetamide; it was presumed to proceed through the O-silyl imino ether derivative of the C-8a acetamide unit. Other reactive silylating reagents such as TMS-OTf and TBS-OTf resulted in the rapid and complete degradation of starting nitroketone 2.39.  68  NHAc  NHAc TBDPS O  O  H  TBDPS O  O H  O N  NO2  2.39 entry  conditions  reagent  base  2.43 solvent  temp  time  result  a  TBSCl (2 eq)  -  DMF  65 °C  24 h  2.44  b  TBSCl (2 eq)  -  DMF  RT  24 h  2.44  c  TBSCl (1.2 eq)  DMAP (cat.)  CH2Cl2  RT  3 days  SM + 2.44  d  TBSCl (1.2 eq)  TEA (1.3 eq)  CH2Cl2  RT  3 days  SM + 2.44  e  TBSCl (2.5 eq)  imidazole (3 eq)  DMF  65 °C  24 h  complex mixture  f  TBSCl (2 eq)  imidazole (2 eq)  DMF  65 °C  24 h  trace 2.43a  g  TBSCl (2 eq)  imidazole (2 eq)  DMF  RT  6 days  trace 2.43a  h  TBSCl (10 eq)  imidazole (10 eq)  DMF  RT  3 days  2.55  i  TBSCl (6 eq)  imidazole (8 eq)  CH2Cl2  RT  5 days  trace 2.43a, 2.55  j  TBSCl (2 eq)  imidazole (4 eq)  DMF  RT  4 days  trace 2.43a  k  TBSCl (4 eq)  imidazole (2 eq)  DMF  RT  6 days  16% 2.43b  l  TBSCl (2 eq)  imidazole (2 eq)  DMF, H2O  RT  6 days  SM, trace 2.43a  m  TBSCl (1.1 eq)  imidazole (3 eq)  DMF  RT  6 days  trace 2.43a  n  TBSCl (1 eq)  imidazole (1.1 eq)  CH2Cl2  RT  4 days  mostly SM  a b  based on crude 1H-NMR after flash column chromatography  Table 2.5. Nitroketone 2.39 dehydration optimization.  CH3 NHAc O TBDPS  TBSCl (10 eq), imidazole (10 eq),  NO2 O  DMF  TBDPSO  O 2.39 NO2  HN  65%  2.55  Scheme 2.8. Unusual Knoevenagel-type condensation of nitroketone 2.39.  69  Further attempts to refine conditions for the desired conversion of 2.39 to tricycle 2.43 (Table 2.6) narrowed the search to two-equivalents each of TBSCl and imidazole in dichloromethane at room temperature. These reactions were run at small scale (25-50 mg each). At this time, it was still not possible to resolve the question of whether 2.43 is formed via an INOC or an ISOC mechanism or possibly both. Entry k in Table 2.6 showed that a moderate amount of desired product 2.43 could be obtained after treatment of nitroketone 2.39 with TBSCl/imidazole (2 equivalents each), after a week-long reaction time at room temperature.  Table 2.6. Refinements to [3+2] cycloaddition conditions.  The small scale conditions (Table 2.6, entry k) were transferred to a larger scale (1-5 g) and the same yield was observed (Scheme 2.9). It was noted that the product began to decompose slowly over time in the reaction mixture, so the reaction was typically stopped after a week and the crude material purified by silica gel chromatography. The starting material (2.39) was recovered (35%) in addition to 70  the desired product, thus bringing the yield of 2.43 to a moderate 58% based on recovered starting material (BRSM).  Scheme 2.9. Optimized conditions for dehydration of nitroketone 2.39.  We speculated that the relatively poor reactivity of the -nitro ketone 2.39 could have been due to the facile enolization of 2.39 (Figure 2.16). When enolate 2.57 was exposed to TBSCl/imidazole, we speculated that the formation of both 2.56 and 2.58 were possible. Reaction on the oxygen atom which was formerly the -ketone would lead to synthetic dead-end 2.58 which was unable to undergo either of the desired INOC or ISOC pathways. Conversely, reaction of the silyl halide on an oxygen atom of the nitro group could lead to intermediate 2.56 which we postulate undergoes the desired [3+2] cycloaddition in an ISOC and/or INOC mode. The slow conversion of nitroketone 2.39 to tricycle 2.43 could also have been due to a possible interconversion of silyl intermediates 2.58 and 2.56.  71  NHAc N O  TBDPSO  NHAc  O  N  O  O  TBDPSO  O  O  2.57  2.39  TBSCl imidazole  NHAc N  [?]  OTBS  O  O  TBDPSO  TBSCl imidazole  TBDPSO  NHAc N O TBS  O  O  2.58  2.56  [3+2] not possible [3+2] possible  ISOC/INOC  NHAc O  TBDPSO O N 2.43  Figure 2.16. Probable enolization of nitroketone 2.39 can inhibit [3+2] cyclization.  [3+2] Cycloaddition product 2.43 contains important structural features of the tetrodotoxin core. Chiefly, the all cis-relationship of the C-5, C-4a and C-8a units in the six-membered carbocycle (Figure 2.17) provided a template for which to test our synthetic plans. NHAc 10  8a  TBDPS O  6  H 2.43  4a 5  4  O  O N all cis-relationship  Figure 2.17. All cis-relationship of compound 2.43.  72  2.5  Kemp-type keto-isooxazoline fragmentation  At this juncture, attention turned to focus on the development of a procedure for the fragmentation of keto-isooxazoline 2.43. The base-mediated ring-opening of benzisooxazoles to give cyano phenols is known as the Kemp elimination188-190 (Scheme 2.10). The resulting Kemp-elimination fragment contained the requisite hydroxyl group (for C-5) and a formyl-equivalent nitrile (for C-4a) if this concept were applied towards keto-isooxazolines such as 2.43. The tricyclic ring geometry of compounds like 2.43 suffered from strain, and if a nuclophile such as methoxide were to add to the carbonyl, we hypothesized that a ring fragmentation event would follow, yielding an -cyano alcohol formally resembling Kemp-elimination products. As with the previous section, the implementation of an efficient method to achieve the desired outcome required a good deal of experimentation.  Scheme 2.10. Ring-fragmentation and comparison to Kemp-elimination188-190 products.  Initial attempts to fragment tricyclic isooxazoline structures as per Figure 2.2 were centered on intermediate 2.43 (Table 2.7). Treatment of 2.43 with sodium methoxide in methanol or potassium carbonate in alcohols (methanol, ethanol, benzyl alcohol) failed to induce the desired conversion. Catalytic amounts of lithium carbonate in methanol resulted in some conversion to the desired 2.59, however reaction times were long and complex mixtures of cyclohexene 2.59 were obtained. Imidazole in methanol as well as DMAP did not have any effect on isooxazoline 2.59. Finally, it transpired that efficient recovery (68% isolated yield) of the desired 2.59 was achieved by ring opening with catalytic amounts of lithium carbonate and imidazole in methanol (Table 2.7, entry g).  73  NHAc TBDPS O  TBDPS O  H  H HO  RT, ON  O N  NHAc CO2CH3  O  conditions  2.43  entry  N 2.59  conditions  yield  a  NaOCH3, CH3OH  0%  b  LiOCH3, CH3OH  0%  c  K2CO3, CH3OH  trace 2.59a  d  Li2CO3, CH3OH  10%b  e  imidazole, CH3OH  0%  f  DMAP, CH3OH  0%  g  Li2CO3, imidazole, CH3OH  68%b  a b  based on crude 1H-NMR of reaction mixture after flash column chromatography  Table 2.7. Optimization of tricycle 2.43 fragmentation.  CH3OH, imidazole, Li2CO3  NHAc TBDPS O  O 68% H  O N 2.43  TBDPS  NHAc CO2CH3  O H HO  N  2.59  Scheme 2.11. Kemp-type fragmentation: methanolysis of tricycle 2.43.  Enone 2.62 was ultimately prepared from isooxazoline 2.43 in a short sequence (Scheme 2.12). Desilylation of 2.43 with TBAF or anhydrous HF•pyridine complex resulted in a complex mixture of degradation products. Aqueous 35% HF in acetonitrile effectively liberated the hydroxyl moiety resulting 74  in a 70% recovered yield of compound 2.60. A Dess-Martin191,192 oxidation of enol 2.60 provided diketone 2.61 which degraded upon prolonged chemical manipulations. For this reason, crude diketone 2.61 was treated with catalytic lithium carbonate and imidazole in methanol to afford the target (2.62) in 38% isolated yield over the two chemical transformations. NHAc TBDPS O  NHAc a  O  70% H  NHAc b  O  O  HO H  O N  2.43  O  O N  O N  2.60  2.61 38% over 2-steps  c a) aq HF, THF; b) Dess-Martin periodinane, CH2Cl2; c) CH3OH, imidazole, Li2CO3.  NHAc CO2CH3 O HO  N 2.62  Scheme 2.12. Fragmentation sequence: conversion of 2.43 to desymmetrized enone 2.62.  My work in this thesis described thus far had demonstrated the feasibility of the planned approach to the tetrodotoxin core (Figure 2.3) with the C-8 nitrogen installed through the oxidative amidation of a phenol and the successful introduction of the C-5 hydroxyl and the C-4a formate-equivalent nitrile. Planned TTX retron 2.5 (cf. Figure 2.3) possessed similarity to isolated product 2.62; formally a C-9 oxidation and a partial reduction of the C-4a cyano group were necessary to elaborate our TTX-core intermediate. Other key features of the tetrodotoxin core molecule not yet addressed at this point included the installation of the C-11 hydroxymethyl unit and the cis-dihydroxylation across the C-7/C-8 olefin. oxidation NHAc  8  OP H CO3CH3  O  H  OH 2.5  O  7  CO2CH3  8a 6  O  NHAc  5  H  H  4a  OH  reduction N  2.62  Figure 2.18. Comparison of prepared enone 2.62 to proposed tetrodotoxin retron 2.5.  75  2.5.1  Access to a suitable dihydroxylation substrate  With the synthesis of enone 2.62 accomplished, attention turned to the selective C-7/C-8 dihydroxylation. Advanced intermediates of the type 2.5/2.62 (Figure 2.18) were not suitable substrates for the exploration of the required selective dihydroxylation due to the lack of steric encumbrance on the -face of the carbocycle. Cyclohexene-derivative 2.59 was likewise not a suitable substrate as the bulky -OTBDPS group would likely have directed an osmium tetraoxide-mediated dihydroxylation from the incorrect face of the molecule. However, if the C-6 epimer of compound 2.59 were obtained (see compound 2.67), we envisioned that a large -OTBDPS group could provide enough steric demand as to block the bottom face and appropriately direct the dihydroxylation. With this in mind, we revisited the reduction of dienone 2.32 (cf. Table 2.3). A CBS-reduction of dienone 2.32 provided an inseparable mixture of doubly-allylic alcohols 2.35 and 2.36 in approximately 1:2 ratio.  This mixture of  diastereomers was treated with the same reaction sequence as in Scheme 2.2 to provide a mixture of nitroketones 2.39 and 2.65 (Scheme 2.13). In this sequence, none of the diastereomeric product mixtures were rigorously purified and all compounds were carried forward without purification.  NHAc CO2CH3  HO  2.35  NHAc CO2CH3  HO  1 : 2  NHAc  O TBDPS  +  O + TBDPS  2.39  2.37  NHAc  O  NHAc CO2CH3  +  O TBDPS  1 : 2  2.63  NaOH H2O/THF  1) CDI, THF 2) KOtBu, CH3NO2  NO2 1 : 2  NHAc CO2CH3  O TBDPS  2.36  O NO2  TBDPS-Cl imidazole CH2Cl2  NHAc CO2H  O TBDPS  2.65  2.38  +  NHAc CO2H  O TBDPS  1 : 2  2.64  Scheme 2.13. Synthesis of nitroketones 2.39 and 2.65.  Additionally, it warranted mention that we expected the conversion of nitroketone 2.65 to tricycle 2.66 (Scheme 2.14) to proceed at a faster rate relative to the conversion of nitroketone 2.39 to tricycle 2.43. This expectation was based on the hypothesis that the nitrile oxide-containing arm, as it approached the olefin, could encounter the bulky -OTBDPS unit (Figure 2.19). We expected that this steric clash, which was not possible for nitroketone 2.65 with its -OTBDPS unit orientated away from the emerging 1,3-dipole, would result in a difference in reaction rate and could enhance the efficiency of the dipolar cycloaddition of nitroketone 2.65 relative to nitroketone 2.39. 76  Figure 2.19. Rationale for expected (but not observed) rate difference between nitroketones 2.39/2.65.  It was not possible to efficiently separate nitroketone intermediates 2.39 and 2.65, thus the mixture was treated with the conditions optimized for [3+2] cycloaddition (Chapter 2.4). Similar yields were obtained using the mixture of diasteromers 2.39 and 2.65 as were obtained from the single diasteromer 2.39.  Recovered nitroketones 2.39 and 2.65 were recycled following flash column  chromatography, rendering tricyclic products 2.43 and 2.66 in 20% and 47% yield respectively based on the recovered starting materials. The results indicated in Scheme 2.14 showed that our expectation that nitroketone 2.65 would react faster than nitroketone 2.39 was incorrect.  2.39  + 1 : 2  2.65  TBS-Cl, imidazole, CH2Cl2  O TBDPS  NHAc  NHAc O  O N  +  O +  O TBDPS  NHAc  O + TBDPS  O O N  2.43 12% 20% BRSM  NHAc  O TBDPS  2.66  O  NO2 2.39  NO2 2.65  28% 47% BRSM 40% recovery of starting material  Scheme 2.14. Synthesis of tricycles 2.43 and 2.66.  77  Tricycle 2.66 was ring-fragmented under the same conditions as tricycle 2.43 (cf. Scheme 2.11) using lithium carbonate in methanol with a catalytic amount of imidazole to give substituted cyclohexene 2.67 (Scheme 2.15). Large crystals of intermediate 2.67 were grown for an X-ray diffraction study to examine the ring geometry of this system in anticipation of the planned osmium tetraoxide dihydroxylation. The X-ray crystal structure generated indicated that the OTBDPS unit was blocking the -face in a suitable manner to direct a proposed dihydroxylation event to occur from the less-stericallyencumbered -face (Figure 2.20). Li2CO3 CH3OH imidazole  NHAc  O TBDPS  NHAc CO2CH3  O 90% O N  O TBDPS  C OH  2.66  N  2.67  Scheme 2.15. Methanolysis of tricycle 2.66. top face accessible N  NHAc  C  Ac NH  CO2CH3  H  H3CO2C  O TBDPS  O TBDPS  C OH  N  2.67 bottom face blocked  Figure 2.20. X-ray image of crystalline 2.67 and rationalization of expected facial selectivity.  78  2.6  Osmylation of substituted cyclohexene derivative  Compound 2.67 was treated with N-methyl morpholine oxide and catalytic osmium tetraoxide193 but no reaction was observed after more than a week reaction time (this reaction was monitored periodically for 60 days). Not dissuaded by the failure of the commonly used Upjohn-procedure, we attempted to use stoichiometric osmium tetraoxide to cause the osmylation of the C-7/C-8 olefin. In an NMR-scale experiment (Scheme 2.16), compound 2.67 was dissolved in d5-pyridine and to this solution was added solid crystals of osmium tetraoxide. The reaction was monitored by 1H-NMR and the addition of solid OsO4 continued until the starting material 2.67 was fully consumed.  Scheme 2.16. Osmylation sequence.  Osmate ester 2.68 proved to be too fragile for rigorous purification/isolation sequence. Attempts to isolate pure 2.68 resulted in the decomposition of the product. Additionally, the purported osmate 2.68 appeared to be resistant to (unoptimized) attempts at removing the osmium moiety. The structure of compound 2.68 was proposed to be that indicated in Scheme 2.16 based on enriched samples of 2.68 and careful analysis of 1D and 2D NMR data (cf. Figures 2.21 and 2.22).  79  NHAc CO2CH3 O TBDPS  C OH  N  2.67  O O Os O O TBDPS  O  NHAc CO2CH3 C  OH  N  2.68  Figure 2.21. Comparison of 1H-NMR: olefin osmylation.  The structural assignment of compound 2.68 rested upon an analysis of the vicinal coupling constants gleaned from the 1H-NMR and COSY spectral data. Specifically the C-6 proton showed an 8.2 Hz coupling to the C-7 proton indicative of a trans-diaxial coupling (Figure 2.22). We expected the C6/C-7 axial-axial coupling constant (Jaa) to be about 9.5 Hz as calculated for dihedral angles close to 180°, and the 8.2 Hz coupling indicated a less-than-perfect cyclohexane framework which we understood to be a result of the osmium pinching the backbone. This coupling constant was key to the structural assignment of 2.68, and indicates the osmylation event took place from the top face as anticipated. If the OsO4 had approached the olefin from the bottom face, then we expected the C-6/C-7 coupling constant (Jae) to be closer to 4 Hz.  80  Figure 2.22. 1H-NMR couplings for 2.68.  Compound 2.68 contains key structural features compared to TTX retron 1.170. The lack of C-9 hydroxyl group and the C-11 hydroxymethyl group in compound 2.68 were the major differences between these structures. OsO2  O TBDPS O  6 5  HO  7  8 8a  4a  NHAc  HO  4  CO2CH3 10  2.68  6 5  HO  NC  OH  HO  O  OH  7  8 8a  4a  4  OHC  NH2 OH COOH 10  1.170  Figure 2.23. Comparison of advanced intermediate 2.68 with TTX retron 1.170.  81  2.7  Iodine(III)-mediated oxime oxidation to nitrile oxides  The apparent sluggish reaction times for the conversion of nitroketones 2.39 and 2.65 to their respective tricyclic isooxazoline products (Scheme 2.14) led us to investigate alternative nitrile oxide precursors.  2.7.1  Oximes as nitrile oxide precusors  Oximes are established nitrile oxide precursors.100,101 Oxidation of oximes with various reagents have generated nitrile oxide intermediates which can be trapped in a [3+2]-mode with a variety of dipolarophiles (Figures 2.24 and 2.25). Nitrile oxides (generated from oximes or otherwise) were also known to dimerize194 to give furoxans195,196 of the type 2.71 (Figure 2.24); these products were often used as evidence for the formation of highly reactive nitrile oxide intermediates. Reagents known to oxidize oximes to nitrile oxide species included lead tetraacetate,197 chloramine-T,198 mercuric acetate,199 1chlorobenzotriazole,200 hypohalite  204  manganese  dioxide,201  such as tert-butyl hypochlorite  205  halogens,202,203  and NaClO.  206,207  dimethyldioxirane,194  and  alkali  Ceric ammonium nitrate has been used  to oxidize aromatic aldoximes to nitrile oxides with modest efficiency.208  Potassium ferricyanide-  mediated oxime oxidations were known to proceed only in aqueous solvents.209 Treatment of oximes with N-chlorosuccinimide (NCS) generated the corresponding oximoyl chlorides, and subsequent addition of base can cause the generation of a nitrile oxide as used by Ray and co-workers in their synthesis of pyrimidoazepine-based derivatives.210,211  N  OH  O O H3C  R  H  N O N O  CH3 R C N O  R R  2.69  2.70  2.71  Figure 2.24. Dimerization of nitrile oxides.  Oximes can also be converted to nitrile oxides using iodine(III) reagents such as iodosylbenzene (PhIO)194 and PhICl2212 (Figure 2.25). These iodine(III) reagents were known to require an alkaline workup after the oxidation event, limiting the use of these reagents to base-insensitive substrates.212,213 Hypervalent iodine reagents have also been known to induce oxidative deoximation 214-221 in lieu of nitrile 82  oxide formation. Despite the variety of methods that were available for the oxidation of oximes to nitrile oxides, finding a new oxidizing agent would contribute to the chemistry of nitrile oxides. N  OH  O Ph  R1  R2  I R1 C N O  H  N O  R3  R2  CHCl3 2.69  R3  R1  2.70  2.72  Figure 2.25. Conversion of oximes to nitrile oxides and subsequent trapping.  2.7.2  Optimization of DIB as a reagent for oxime to nitrile oxide oxidations  There was no precedent in the chemical literature for the use of hypervalent iodine reagents commonly employed for oxidative amidation reactions (DIB or PIFA) to oxidize oximes to nitrile oxides. Our initial attempts (not optimized) to use DIB as a reagent to oxidize oximes centered on commercially available oxime 2.73. When treated with DIB in methanol, oxime 2.73 readily formed known furoxan 2.74 which crystallized from the reaction mixture. Furoxan 2.74 was compared to literature data194 and found to be identical, in addition to an unambiguous X-ray crystallographic derived structure (Scheme 2.17). N  OH  PhI(OAc)2 CH3OH  O N O N  H 35-40% unoptimized 2.73  2.74  Scheme 2.17. Dimerization of oxime 2.73.  A test of the feasibility of a DIB-mediated oxime oxidation and subsequent capture of the newly formed nitrile oxide with a dipolarophile began with commercially available oxime 2.75. The test oxidation of 2.75 with DIB in a variety of solvents with varying equivalents of styrene as the dipolarophile trap was summarized in Table 2.8. The typical procedure was dissolving oxime 2.75 in the appropriate solvent followed by the slow addition of the oxime solution to a room temperature solution of DIB and styrene in the same solvent. After the given time, the reaction mixture was concentrated in vacuo and the crude reaction residue was purified by flash column chromatography. Excess of styrene trap had a minor effect on recovered yields. Additionally, methanol was found to be an adequate 83  replacement for the much more costly fluorinated alcohol solvents such as HFIP and TFE. The addition of a small amount of trifluoroacetic acid (TFA) enhanced both the solubility of DIB in methanol and the recovered yield in the test reaction (Table 2.8, entry k). The best results obtained for this reaction involved the room temperature addition of the oxime to a solution of 1.1 equivalents of both DIB and styrene.  N  N O  OH PhI(OAc)2, styrene,  H  solvent H3CO  Ph H3CO 2.76  2.75  entry  DIB (eq)  styrene (eq)  solvent  time (min)  a  1.1  4.0  CHCl3  35  31%  b  1.1  1.1  THF  90  28%  c  1.1  1.1  THF  240  23%  d  1.2  1.4  TFE  15  68%  e  1.3  1.3  HFIP  35  54%  f  1.3  1.1  HFIP  150  54%  g  1.2  4.0  HFIP  45  51%  h  1.2  2.0  HFIP  17  64%  i  1.2  1.3  CH3OH  20  59%  j  1.1  1.1  CH3CN  60  32%  k  1.1  1.1  CH3OH + TFA 60 (1.5 % v/v)  91%  l  1.1  1.1  CH3CN + TFA (1.2 eq)  51%  a  30  yielda  after flash column chromatography  Table 2.8. DIB-mediated bimolecular [3+2] dipolar cycloaddition: optimization studies. 84  The optimized conditions from Table 2.8, entry k were applied to a variety of different oximes and dipolarophiles (Table 2.9). Aromatic oximes with activating and deactivating groups were reacted in good to excellent recovered yields.  The aliphatic oximes tested worked with similar efficiency.  Replacement of the olefin trap with a terminal alkyne resulted in the fully aromatic isoxazole 2.88, but with diminished efficiency (Table 2.9, entry l). Variable amounts of 3,5-diphenyl-1,2,4-oxadiazole 4oxide, the dimer of benzonitrile oxide, were also recovered from the reaction of oxime 2.73 with phenylacetylide (Table 2.9, entry l). The reaction mixtures for these reactions became unusually dark colored, perhaps resulting from a competing in situ formation of alkynyliodonium species.107,221-224 The subsequent reaction of any alkynyliodonium species with methanol (or other nucleophile) could have reduced the amount of dipolarophile available for reaction with a nitrile oxide. Other terminal alkyne traps such as 1-hexyne provided isoxazole products in even lower recovered yields.  Similar to aromatic and aliphatic aldoximes, -oxo-aldoximes were oxidized to -oxo-nitrile oxides in the presence of DIB. The nitrile oxides formed in such a manner were trapped in good to excellent recovered yields (Table 2.10). A screen of reaction conditions using -oximinoacetone 2.89 and norbornylene as the dipolarophile trap was embarked on and summarized in Table 2.10. Similar to before225 (Table 2.8), the best conditions involved room temperature reaction of -oximinoacetone 2.89 and 1.2 equivalents of both DIB and norbornylene in methanol with TFA (0.1 – 1% v/v) (Table 2.10, entries d and e).  In this case, we observed a good recovered yield from the oxidation of -  oximinoacetone 2.89 in methanol with no added trifluoroacetic acid (Table 2.10, entry c), though this appeared to be an exceptional case.  85  Table 2.9. DIB-mediated bimolecular [3+2] dipolar cycloaddition: substrate scope. 86  Table 2.10. DIB-mediated bimolecular [3+2] dipolar cycloaddition: optimization studies.  87  The DIB-mediated oxidation, and subsequent trapping with norbornylene or styrene, of commercially available -oxo-aldoximes 2.89 and 2.92, using conditions from Table 2.10, entry k, proceeded to produce isooxazoline products 2.90/2.91 and 2.93/2.94 with high efficiency (Table 2.11). Good to excellent recovered yields were obtained. Note that entries d and e in Table 2.10 and entry a in Table 2.11 were equivalent. (CEFNO)  174,226-228  This method permitted access to carbethoxy-formonitrile oxide  and related CEFNO cycloadducts 2.93 and 2.94.  Table 2.11. DIB-mediated oxidation of -oxo-aldoximes 2.89 and 2.92.  88  2.7.3  Oxidation of -oxo-ketoximes and ’-dioxo-ketoximes  The DIB-mediated oxidation of oximes to their corresponding nitrile oxides was not only applied to aromatic, aliphatic and -oxo-aldoximes (Chapter 2.7.2), but also to -oxo-ketoximes and ’dioxoketoximes. We predicted that -oxo-ketoximes such as compound 2.95 would react with DIB to give reactive intermediates of the type 2.96, which in turn could react with appropriate nucleophilic solvents leading to the formation of nitrile oxides of the type 2.97 which could be trapped with various dipolarophiles (Figure 2.26). Our hope in this endeavor was to broaden the synthetic utility of the DIBmediated oxime oxidation reactions to allow for wider range of applications and synthetically useful products of the type 2.98 and others.  Figure 2.26. Predicted course of the DIB oxidation of -oxo-ketoximes.  We predicted that nitrile oxides would form from -oxo-ketoximes via the oxidative cleavage of the carbonyl-imino  bond (Figure 2.26). As a test of this hypothesis, we reacted ’dioxo-ketoxime 2.99 with DIB and norbornylene under the conditions which worked well for aromatic, aliphatic, and oxo-aldoximes (Table 2.12, entry a). The isolated yield from the reaction was a moderate 52%, with nearly a third of the unreacted oxime recovered from the reaction mixture. Despite the moderate isolated yields, attempts were made to screen for better conditions by modifying DIB and norbornylene stoichiometry and solvent conditions (Table 2.12). Unfortunately, all other conditions employed only served to decrease the recovered yield for this system, and therefore rigorous optimization studies were left for a future time. The typical procedure for the reactions listed in Table 2.12 was as follows: a solution of ketoxime 2.99 (1.5 mmol) in an appropriate solvent (3 mL) was added very slowly at room temperature to a stirred solution of DIB and norbornylene in the same solvent (2 mL). Appropriate amounts of TFA (or HFIP) were added only to the solution with DIB and norbornylene. Another portion of solvent (0.5 mL) was used to wash any remaining ketoxime 2.99 into the reaction mixture. After the stated time, the mixture was evaporated in vacuo and the residue was purified by flash chromatography. 89  Table 2.12. DIB-mediated oxidation of ’-dioxo-ketoximes: optimization attempts.  Several -oxo-ketoximes were synthesized and tested as substrates in the DIB-mediated oxidation/dipolarophile-trap paradigm. Reactions were run under the same conditions as those in Table 2.11 and the results of the DIB-oxidation of -oxo-ketoximes 2.100, 2.103 and 2.106 are summarized in Table 2.13. Nitrile oxide formation occurred with concomitant solvolytic oxidative C-C bond fission, presumably by the mechanism illustrated in Figure 2.26 where Nu = methanol. The expected adducts of norbornylene were all isolated in good yields. Compounds of the type 2.100 (Table 2.13, entry a) were especially noteworthy as they have been used as building blocks for the synthesis of some prostaglandin 90  analogs.229 The conversion of (D)-camphor-derived -oxo-ketoxime 2.106 into a 1:1 mixture of exocyclic adducts 2.107/2.108 proceeded in high conversion and recovery. For unknown reasons, the conversion of this chiral-ketoxime 2.106 with styrene as the dipolarophile trap consistently proceeded with diminished efficiency relative to the norbornylene adducts (Table 2.13, entry f).  91  Table 2.13. DIB-mediated oxidation of -oxo-ketoximes. 92  2.7.4  Intramolecular nitrile oxide cycloaddition  Several intramolecular versions of the DIB-mediated oxime-oxidation reaction were examined (Schemes 2.18 and 2.19). The first intramolecular variant of this reaction involved the oxime 2.111, a derivative of citronellal, which cyclized in 85% conversion upon exposure to conditions optimized from the bimolecular studies.  The citronellal-derived isooxazoline 2.112 was obtained as a mixture of  diastereomers in a ratio of 3.8:1 as determined from 1H-NMR peak integration. Terpene 2.112 was quite volatile and pleasant smelling, and material was repeatedly lost upon vacuum concentration and during purification. Thus, the reaction yield was calculated by the addition of a 1H-NMR standard to the crude reaction mixture. A known amount of 1,3,5-trimethoxybenzene was added to the crude reaction mixture of 2.112, 1H-NMR data was obtained (the D1 NMR parameter was increased to 20 seconds for quantitative integration) and the reaction conversion was calculated to be 85% based on the comparison of the 2.112 methyl 1H-NMR signals with those of the methoxy 1H-NMR signals from the 1,3,5trimethoxybenzene. A portion of the crude material was purified fully for characterization purposes, and had an []20D = –87.0 (CH2Cl2, c = 0.01). The configuration of this material was not determined due to the nature of the molecule not lending itself to accurate determination of coupling constants: the resonances of the axial hydrogen on the methylene adjacent to the oximino group of 2.112 (about 1.8 ppm) and of the methyl-bearing methine of 2.112 (about 1.50 ppm) overlap with those of other ring hydrogen atoms, precluding the accurate determination of the coupling constants, and thus preventing the determination of the configuration.  Scheme 2.18. The first intramolecular variant.  Two other intramolecular examples were completed in conjunction with another student in the Ciufolini group (Scheme 2.19). Florian Tessier synthesized225 oximes 2.113 and 2.115 and we observed 60-69% recovered yields of the tricyclic isooxazolines 2.114 and 2.116 using the optimized conditions.  93  Scheme 2.19. Other intramolecular variants from Ciufolini group.  Shortly after our initial publication on the DIB-mediated INOC reaction,225 another research group used DIB (and also Koser’s reagent: [hydroxyl(tosyloxy)iodo]benzene) to convert aldoximes to Nacetoxy or N-hydroxy amides through a nitrile oxide intermediate.230  94  2.8  Tandem oxidative dearomatization/nitrile oxide [3+2] cycloaddition  The use of DIB in both phenol dearomatizations and also in oxime oxidations, under similar reaction conditions (polar/acidic solvents, room temperature) seemed a convenient twist of fate; I had wondered if there was some way to tie these two reactions together into one-pot.  Extensive  experimentation with the DIB-mediated INOC reaction, both intermolecularly and intramolecularly, indicated a rate of oxidation of aldoximes to nitrile oxides to be on the order of an hour for complete conversion for the reactions under typical concentrations of 0.5-1.0 M. Comparatively, the rate of reaction for DIB-mediated oxidative dearomatizations at similar reaction concentrations was, practically speaking, instantaneous. This apparent difference in reaction rates boded well for the feasibility of a tandem oxidative dearomatization of phenols/intramolecular nitrile oxide cycloaddition sequence, with both oxidations mediated by DIB sequentially (Figure 2.27). Dienones arising from oxidative amidation, or other oxidative dearomatization type, would be captured by an in situ generated nitrile oxide (2.118) to afford structures of the type 2.119. Dienone products of oxidative dearomatization were already known to be able to participate in tandem reactions, especially 1,4-addition processes, and products of these tandem sequences were densely functionalized, synthetically valuable intermediates. In fact, an oxidative amidation/conjugate addition procedure was a central step in the synthesis of (–)-cylindricine C.149 Other examples include a tandem sequence involving an oxidative hydroxylation/Michael cyclization118,124 of tyrosine derivatives which was used as a key transformation in the synthesis of Stemona alkaloids125 and of hydroxylated amino acids related to parkacine, aeruginosine and castanospermine.231 However, no examples existed in the literature involving a tandem oxidative dearomatization followed by a second oxidation event.  Figure 2.27. Hypothetical tandem oxidative amidation-intramolecular nitrile oxide cycloaddition.  Oxime 2.123 served to explore the feasibility of the hypothesized tandem oxidative amidationINOC sequence. Aldoxime 2.123 was synthesized in a straightforward manner from phenol 2.120 (Scheme 2.20). Conversion of compound 2.120 to the corresponding Weinreb-amide232 2.121 occurred 95  with good efficiency, and lithium aluminum hydride reduction233 on the crude residue gave crude aldehyde 2.122 upon workup. Aldehyde 2.122 was converted to known oxime 2.123234 over three-steps using standard conditions.225 Oxime 2.123 was subjected to the optimized conditions for oxidative amidations, but with an additional equivalent of DIB to account for the second oxidation step, and to our delight tricycle 2.124 was isolated in 71% yield after chromatographic purification (Scheme 2.21). The structural geometry of 2.124 was confirmed by X-ray crystallography: the all-cis C-8a/C-4a/C-5 units are clearly shown in the goblet-shaped image. Remarkable to this tandem transformation was the rapid, stereoselective creation of three new stereogenic carbons from an achiral phenol 2.123 in a single chemical operation. EDCI, TEA HCl•HN(OCH3)CH3 HO  O  OH  HO  O  N O  2.121  2.120  CH3 CH3  LiAlH4 Na2CO3 HCl•H2NOH N  HO  OH 2.123  HO  O  H  2.122  Scheme 2.20. The synthesis of oxime 2.123.  Scheme 2.21. Tandem oxidative amidation—INOC.  96  2.8.1  Sorensen’s use of tandem dearomitization/nitrile oxide [3+2] cycloaddition in Cortistatin  core synthesis  We also subjected oxime 2.123 to similar reaction conditions optimized for the DIB-mediated oxidation of oximes (cf. Table 2.9): chiefly acetonitrile was replaced with methanol which changed the reaction type to a tandem oxidative methoxylation/INOC sequence. Compound 2.125 was isolated in 51% purified yield following reaction of oxime 2.123 with DIB in methanol/TFA. Isooxazoline 2.125 was highly polar and seemed to irreversibly adsorb onto silica gel during purification. Thus, a crude reaction conversion was determined to be 65% using the same technique and 1H-NMR standard as for terpene 2.112. This reaction was the first tandem oxidative alkoxylation/INOC sequence to appear in the chemical literature.  Scheme 2.22. Tandem oxidative methoxylation—INOC.  A few months after this tandem oxidative methoxylation-intramolecular nitrile oxide cycloaddition was published,225 it was adopted by Erik Sorensen and co-workers as the solution to the construction of the pentacyclic core structure of the cortistatins235 (Scheme 2.23). Their approach utilized a phenol as a latent A-ring featuring a tandem intramolecular oxidative cyclodearomatization/dipolar cycloaddition event. The use of our tandem dearomatization/dipolar cycloaddition sequence in this work rendered the rapid construction of the corresponding rings.  97  Scheme 2.23.  Sorensen’s use of tandem oxidative dearomatization—INOC towards the cortistatin  pentacyclic core.  According to Professor Erik Sorensen, the use of our tandem sequence allowed for his completion of the pentacyclic Cortistatin core; without this sequence, alternative routes toward the construction of the pentacytclic core structure would have been less-efficient and contrived.236 The use of this technology by another group shortly after its initial publication stands as a testament of its potential utility for the generation of synthetically useful molecules.  98  2.9  Diastereoselective tandem oxidative amidation—INOC  The second oxidation in the tandem sequence (the INOC step) caused desymmetrization of the dienone intermediate. Specifically, the intramolecular nitrile oxide cycloaddition caused the acetamidebearing carbon (C-8a) to become stereogenic (see Figure 2.12). Selectivity for the pro-(S) double bond could be controlled through utilization of the principle illustrated in Figure 2.28. If the group L were a sterically demanding group, preferably something suitable for later-stage isooxazoline-ring fragmentation, then the INOC step of reactive intermediate 2.127 could proceed through either transition states 2.128 or 2.129. For transition state 2.129, the bulky L group is forced into the developing concavity of the tricyclic framework and would thus suffer from significant steric congestion. In the case of transition state 2.128, the bulky L group would point to the convexity of the emerging bowl-shaped cycloadduct, and since the external orientation of the group L would suffer from less unfavorable steric interactions the reaction is predicted to proceed in this manner.  Figure 2.28. Predicted course of the INOC reaction.  We already had attempted an INOC sequence with compound 2.46, and observed a 1:1 ratio of the possible diastereomeric products (cf. Scheme 2.6). This result indicated that with regard to compound 2.126/2.127, an OTBS group was not of sufficient bulk to have a diastereoselective effect on the INOC step as predicted in Figure 2.28. We then considered other entities which could satisfy the requirements for compounds of the type 2.127. Compound 2.127 could be derived from tyrosine if the L group were a 99  protected nitrogen atom. Oxime 2.132 was synthesized from racemic tyrosine in an eight-step sequence (Scheme 2.24). We hoped that the N-benzyl tosylamido group (–N(Ts)Bn) would be large enough to exert the desired diastereoselectivity. Earlier compounds (derivatives of compound 2.132) which we synthesized that contained a monoprotected nitrogen unit, an N-tosylamido group (–NH-Ts) underwent oxidative amidation followed by conjugate addition instead of the desired INOC; conjugate addition products of this type were published in the chemical literature shortly after our finding by Wipf in related systems.231 Our plan was for the N-benzyl tosylamido group of compound 2.132 to allow for the alleviation of nonbonding interactions (steric avoidance), avoiding transition state 2.129 and favoring 2.128, while also disfavoring any possible Michael addition pathways.  CO2H NH2  HO  1) SOCl2, CH3OH 2) PhCHO 3) NaBH4, CH3OH 4) TsCl 5) NaOH, H2O/THF  CO2H Ts  HO  ()-tyrosine  N  Ph  ()-2.130 64% over five-steps HN(OCH3)CH3, PyBOP, Et3N  N OH  HO  Ts  N  Ph  ()-2.132  1) LiAlH4 2) H2NOH, Na2CO3 Et2O, H2O  O N HO  Ts  N  O  CH3  CH3 Ph  ()-2.131  11% over three-steps (unoptimized)  Scheme 2.24. Synthesis of oxime 2.132.  The exposure of oxime 2.132 to the action of DIB in acetonitrile/TFA resulted in the formation of 2.134 as a single diastereomer (Scheme 2.25). The observed stereochemical outcome was explained by considering that the presumed nitrile oxide (2.133) arising from the DIB-mediated oxidation of oxime 2.132, following the dearomatization of the phenol moiety, indeed observed the principle outlined in Figure 2.28. The transition 2.129 was disfavored due to unfavorable steric compression from the bulky N-benzyl tosylamido group, represented by group L in Figure 2.28, orientated in the concavity of the molecule. Transition state 2.128 conveniently avoided these higher-energy interactions with the bulky Nbenzyl tosylamido group residing on the convex face of the incipient product. Thus tricyclic isooxazoline 2.134 was synthesized diastereoselectively in 44% isolated yield. The majority of the remaining mass 100  from this reaction appeared to be side products related to unintentional oxidations of the N-benzyl tosylamido group.237  HO  Ts  Ts  N  N  Bn  N OH  PhI(OAc)2 2.2 eq, TFA 1% v/v, CH3CN  HO  Bn  N O ()-2.133  ()-2.132  44% NHAc  NHAc Ts  O O N  N Bn  ()-2.135  O O N  Ts N Bn  ()-2.134  not detected  Scheme 2.25. Diastereoselective tandem oxidative amidation—INOC.  The configuration of isooxazoline 2.134 was ascertained on the basis of nuclear Overhauser enhancements (nOe; NOESY spectroscopy) as indicated in Figure 2.28. Specifically, the C-8 olefinic hydrogen atom showed crosspeaks with both the C-4a hydrogen atom and the C-9 hydrogen atom in the NOESY spectra. These crosspeaks indicated a nOe enhancement and therefore spacial proximity. The other diastereomer possible from the reaction in Scheme 2.25 was compound 2.135, and there was no trace of this compound in the crude reaction mixture or in any chromatographic fractions.  101  Figure 2.28. NOe NMR spectral expansion of 2.134.  102  2.10  Summary  The advances accompanying this route towards the tetrodotoxin core fell into two major categories. First, we have further optimized a scalable, less-costly and more-reproducible method for the IIII-mediated oxidative amidation of 4-hydroxyphenyl acetate (2.31). The challenges associated with this primarily included developing a method for the slow addition of the phenol to the reaction mixture, without causing the formation of oligiomeric side products, and also an efficient method for purification of the dienone products. Second, we have explored new methods for the creation of nitrile oxides from oximes. Oximes are established precursors to nitrile oxides, but until now there was not a mild and reliable method for this conversion mediated by hypervalent iodine reagents. Aldoximes and ketoximes of different types have now been shown to undergo DIB-mediated oxidative transformations to nitrile oxides, and these have been used to generate a number of synthetically useful isooxazoline and isooxazole products. The combination of the two main elements contained in this thesis allowed us to create a tandem sequence where the oxidative dearomatization step is immediately, and in the same pot, followed by an oxidative event converting an oxime into the corresponding nitrile oxide and the subsequent intramolecular [3+2] cycloaddition. 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Infared (IR) spectra (cm-1) were recorded on a Perkin-Elmer model 1710 Fourier transform spectrometer from films deposited on NaCl plates or on a Perkin-Elmer Spectrum 100 Fourier transform spectrometer from samples deposited on a Universal ATR Sampling Accessory. Optical rotations were measured on a Jasco P-1010 polarimeter at the sodium D line (589 nm). Unless otherwise stated, low resolution mass spectra (m/z) were obtained in the electrospray (ESI) mode or the atmospheric pressure chemical ionization (APCI) mode on a Waters Micromass ZQ mass spectrometer. High-resolution mass spectra (m/z) were recorded in the ESI or APCI mode on a Micromass LCT mass spectrometer by the David Wong and Marshall Lapawa of the UBC Mass Spectrometry laboratory.  Melting points  (uncorrected) were measured on a Mel-Temp apparatus. All X-ray single crystal measurements were made by Dr. Brian Patrick on a Bruker X8 APEX II diffractometer or a Bruker APEX DUO diffractometer (as indicated) and the refinements were performed using the SHELXTL crystallographic software package of Bruker-AXS. All reagents and solvents were commercial products and used without further purification except for tetrahydrofuran (THF) which was freshly distilled from Na/benzophenone under argon atmosphere and methylene chloride (CH2Cl2) which was freshly distilled from CaH2 under argon atmosphere. Flash column chromatography was performed with Silicycle 230–400 mesh silica gel. All reactions were performed in flame-dried or oven-dried glassware equipped with TeflonTM magnetic stirbars. All flasks were fitted with rubber septa for the introduction of substrates, reagents and solvents via syrings.  115  A. Experimental protocols  A.1  Preparation of methyl 2-(1-acetamido-4-oxocyclohexa-2,5-dienyl)acetate (2.32) NHAc CO2CH3 O Chemical Formula: C11H13NO4 Exact Mass: 223.08 Molecular Weight: 223.23 2.32  Procedure A  To a 1000-mL round-bottomed flask equipped with magnetic stirring bar was added 21.3 g (67.30 mmol) of iodosobenzene diacetate. The flask was fitted with rubber septa through which a large-gauge needle was passed to flush the system with dry argon. After the vessel had been thoroughly purged, 500 mL acetonitrile and 5 mL TFA was added by syringe and stirred at room temperature for 30 min. To this suspension was added portions of crystalline methyl 4-hydroxy-phenylacetate 2.31 (250 mg every 15 minutes) until a total of 10.0 g (60.18 mmol) methyl 4-hydroxy-phenylacetate had been added. The reaction mixture was allowed to stir at room temperature for 16 h. The clear reddish-colored solution was concentrated to a dark-red colored oil in vacuo on a rotary evaporator (12.7 torr, 40 °C) and passed through a short plug of silica gel (75 g), eluting non-polar impurities with 50% ethyl acetate in hexanes and enriched product with 100% ethyl acetate. The enriched product fractions were combined and concentrated to an orange-colored solid (9.5 g – 11.2 g). The enriched product is dissolved in hot acetone (50 mL) and diethyl ether (50 mL) and crystallized at –20 °C overnight. Product crystals were collected by vacuum filtration and washed with minimal amounts of diethyl ether to give 6.95 g – 7.35 g (50 – 55%) of the desired dienone 2.32 as off-white crystals.  116  Procedure B  To a 1000-mL round-bottomed flask equipped with magnetic stirring bar was added 21.3 g (67.30 mmol) of iodosobenzene diacetate. The flask was fitted with rubber septa through which a large-gauge needle was passed to flush the system with dry argon. After the vessel had been thoroughly purged, 500 mL acetonitrile and 5 mL TFA was added by syringe and stirred at room temperature for 30 min. To this suspension was added manually portions of crystalline methyl 4-hydroxy-phenylacetate 2.31 (continuous addition of the solid phenol 2.31 over 3 h) until a total of 10.0 g (60.18 mmol) methyl 4-hydroxyphenylacetate had been added. The reaction mixture was allowed to stir at room temperature for 16 h. The clear reddish-colored solution was concentrated to a dark-red colored oil in vacuo on a rotary evaporator (12.7 torr, 40 °C) and passed through a column of silica gel (~200 g), eluting non-polar impurities with 50% ethyl acetate in hexanes and enriched product with 100% ethyl acetate. The enriched product fractions were combined and concentrated to an orange-colored solid which was recrystallized from hot acetone (~100 mL). Product crystals were collected by vacuum filtration and washed with minimal amounts of diethyl ether to give 9.4 g (42.13 mmol, 70%) of the desired dienone 2.32 as offwhite crystals. Note: repurification/recrystallization of the supernatant could provide additional 2.32.  1  H (d6-acetone): 7.56 (s, 1H), 7.18 (d, 2H, J = 10.23), 6.15 (d, 2H, J = 10.20), 3.61 (s, 3H), 3.02 (s, 2H),  1.88 (s, 3H). 13  C (d6-acetone): 184.14, 169.34, 168.81, 148.56, 127.90, 53.09, 50.93, 41.40, 22.24.  MP: 104–105 °C. IR: 1735, 1675, 1662. ESI-MS: 246.2 [M + Na]+. HRMS: calcd for C11H13NO4 [M + Na]+ = 246.0742, found 246.0736. EA: calcd C 59.19%, H 5.87%, N 6.28%; found C 59.27%, H 5.84%, N 6.24%.  117  A.2 Preparation of methyl 2-((1r,4r)-1-acetamido-4-(tert-butyldiphenylsilyloxy)cyclohexa-2,5dienyl)acetate (2.37) NHAc H  CO2CH3  TBDPSO Chemical Formula: C27H33NO4Si Exact Mass: 463.22 Molecular Weight: 463.64 2.37  Commercial DIBAL-H solution (1M in hexanes, 36.8 mL, 36.8 mmol) was added to a cold (–78 °C), well stirred solution of 2.32 (5.5 g, 24.5 mmol) in THF (250 mL), under argon atmosphere. The mixture was stirred at –78 C for 4 h, and then it was quenched by the sequential addition of water (4 mL), 10% aq NaOH (4 mL), and again water (12 mL). The volatile organics were removed in vacuo, and the crude product was suspended in acetone (200 mL) and filtered through methanol-washed celite. The filtrate was evaporated in vacuo and the residue (5.1 g, 22.6 mmol, 92% yield) was advanced to the next step without further purification. Thus, a portion of this material (3.0 g, 13.3 mmol) in CH2Cl2 (30 mL) was treated with TBDPS-Cl (5.1 mL, 20 mmol) and imidazole (1.4 g, 20 mmol), and the mixture was stirred at rt under an argon atmosphere for 18 h. The mixture was then treated with 0.05M HCl (30 mL) and extracted with ethyl acetate. The combined extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (step gradient of 20-40-100% ethyl acetate/hexanes). Pure fractions were concentrated to give 2.37 (5.3 g, 11.4 mol, 87%) as a clear viscous oil.  1  H (d6-acetone): 7.73 (m, 4H), 7.45 (m, 6H), 6.99 (brs, 1H), 6.14 (d, 2H, J = 10.1), 5.80 (dd, 2H, J2 =  10.3; J1 = 2.8), 4.60 (m, 1H), 3.62 (s, 3H), 2.96 (s, 2H) 1.75 (s, 3H), 1.07 (s, 9H). 13  C (d6-acetone): 170.7, 169.7, 136.5, 134.6, 131.0, 130.7, 130.0, 128.6, 64.5, 52.2, 51.6, 43.3, 27.3,  23.5, 19.7. IR: 1739, 1653. ESI-MS: 486.2 [M + Na]+. HRMS: calcd for C27H33NO4Si•Na+ [M + Na]+ = 486.2077, found 486.2059. EA: calcd C 69.94%, H 7.17%, N 3.02%; found C 69.71%, H 7.45%, N 3.02%. 118  A.3 Preparation of dienyl)acetic acid (2.38)  2-((1r,4r)-1-acetamido-4-(tert-butyldiphenylsilyloxy)cyclohexa-2,5-  NHAc H  CO2H  TBDPSO Chemical Formula: C26H31NO4Si Exact Mass: 449.2 Molecular Weight: 449.61 2.38  A solution of 2.37 (2.2 g, 4.7 mmol) in THF (70 mL) was treated with aqueous 1M NaOH (15 mL) and the mixture was stirred for 18 h at rt. The volatile organics were removed in vacuo, and the residue was partitioned between 50% AcOH/H2O (60 mL) and ethyl acetate (100 mL). The organic layer was dried over MgSO4, filtered and concentrated to give pure 2.38 (2.1 g, 4.7 mmol, 99% yield) as a glassy-solid.  1  H (600 MHz, d6-acetone): 7.73 (m, 4H), 7.46 (m, 6H), 6.96 (brs, 1H), 6.14 (d, 2H, J = 8.7), 5.80 (dd,  2H, J2 = 10.3; J1 = 3.0), 4.62 (m, 1H), 2.88 (s, 2H), 1.74 (s, 3H), 1.06 (s, 9H). 13  C (150 MHz, d6-acetone): 172.0, 170.1, 137.1, 135.2, 131.8, 131.3, 130.6, 130.2, 129.2, 65.3, 52.5,  43.6, 27.8, 24.1, 20.3. ESI-MS: 472.2 [M + Na]+. HRMS: calcd for C26H31NO4Si•Na+ [M + Na]+ = 472.1920, found 472.1912.  119  A.4 Preparation of N-((1r,4r)-4-(tert-butyldiphenylsilyloxy)-1-(3-nitro-2-oxopropyl)cyclohexa2,5-dienyl)acetamide (2.39) NHAc H O  TBDPSO  NO2  Chemical Formula: C27H32N2O5Si Exact Mass: 492.21 Molecular Weight: 492.64 2.39  Carbonyldiimidazole (874 mg, 5.4 mmol) was added to a solution of acid 2.38 (2.0 g, 4.5 mmol) in THF (10 mL) and the mixture was stirred at rt for 1 h. Nitromethane (1.5 mL, 26.9 mmol) followed by KOtBu (2.0 g, 18.0 mmol) were then added and after stirring for an additional 2 h, the volatiles were removed in vacuo. The residue was partitioned between 50% AcOH/H2O (100 mL) and CH2Cl2 (150 mL). The organic layer was dried (MgSO4) filtered and concentrated to give crude nitroketone 2.39, which was purified by flash column chromatography using a step gradient from 30% ethyl acetate/hexanes to 100% ethyl acetate. This afforded 1.8 g (3.7 mmol, 82% yield) of pure 2.39 as a light-yellow colored amorphous solid.  1  H (d6-acetone): 7.74 (m, 4H), 7.47 (m, 6H), 6.18 (dd, 2H, J2 = 10.2; J1 = 1.7), 5.86 (dd, 2H, J2 = 10.3; J1  = 3.2), 5.67 (s, 2H), 4.59 (m, 1H), 3.30 (s, 2H), 1.78 (s, 3H), 1.07 (s, 9H). 13  C (d6-acetone): 195.5, 170.4, 136.6, 134.5, 130.9, 130.8, 130.2, 128.7, 85.2, 64.2, 52.2, 48.7, 27.3,  23.5, 19.7. IR: 1736, 1700, 1656, 1558. ESI-MS: 515.2 [M + Na]+. HRMS: calcd for C27H32N2O5Si•Na+ [M + Na]+ = 515.1978, found 515.1962.  120  A.5  Preparation of N-((3aS,7aS)-2-oxo-2,3,3a,7a-tetrahydrobenzofuran-3a-yl)acetamide (2.41)  NHAc O O H Chemical Formula: C10H11NO3 Exact Mass: 193.07 Molecular Weight: 193.2 2.41  Carboxylic acid 2.38 (also 2.40 and mixtures of the two) readily converts to 2.41 upon treatment with acidic media such as 1M aq HCl. Lactone 2.41 was commonly seen as a side product during the workup and extraction of carboxylic acid 2.38. Lactone 2.41 was intentionally prepared by exposing compound 2.38 to any amount of HCl for a prolonged period of time. 1  H (d6-acetone): 6.12 (m, 1H), 6.00 (m, 2H, 1 olefinic H + NH signals), 5.88 (m, 2H), 5.45 (br d, 1H, J =  3.8), 3.28 (d, 1H, B part of AB, J = 17.5), 2.81 (d, 1H, A part of AB, J = 17.5), 2.01 (s, 3H). 13  C (d6-acetone): 174.2, 170.6, 129.4, 125.9, 123.3, 123.0, 80.8, 57.6, 39.7, 23.9.  ESI-MS: 216.3 [M + Na]+. HRMS: calcd for C10H11NO3 •Na+ [M + Na]+ = 216.0637, found 216.0634.  121  A.6 Preparation of N-((2aR,2a1S,3S,5aS)-3-(tert-butyldiphenylsilyloxy)-7-oxo-2a,2a1,3,5a,6,7hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.43)  NHAc TBDPS O  O H  O N Chemical Formula: C27H30N2O4Si Exact Mass: 474.2 Molecular Weight: 474.62 2.43  A solution of 2.39 (27 mg, 55 mol), TBSCl (17 mg, 110 mol) and imidazole (8 mg, 110 mol) in dry CH2Cl2 (0.5 mL) was stirred at rt for 120 h, then it was concentrated in vacuo. Purification of the crude 2.43 residue by flash column chromatography (50% ethyl acetate/hexanes to 100% ethyl acetate) gave pure 2.43 (10 mg, 38% yield) as a foamy colorless solid.  1  H (d6-acetone): 7.79 (d, 2H, J = 6.8), 7.73 (d, 2H, J = 7.7), 7.64 (brs, 1H), 7.47 (m, 6H), 6.09 (ddd, 1H,  J3 = 10.3; J1 = J2 = 1.6), 5.70 (ddd, 1H, J3 = 10.3; J2 = 3.0; J1 = 1.2), 5.01 (dd, 1H, J3 = 11.1; J2 = 5.0; J1 = 1.4), 4.81 (ddd, 1H, J3 = 4.9; J2 = 2.9; J1 = 1.8), 4.70 (dd, 1H, J2 = 11.1; J1 = 1.0), 3.36 (d, 1H, B part of AB, J = 18.0), 3.04 (d, 1H, A part of AB, J = 18.0), 1.71 (s, 3H), 1.11 (s, 9H). 13  C (d6-acetone): 192.0, 170.3, 163.1, 137.9, 136.6, 136.5, 134.5, 134.3, 130.9, 130.8, 130.4, 128.7,  128.7, 85.4, 67.3, 57.3, 56.0, 52.3, 27.3, 23.0, 19.8. MP: 92–96 °C. IR: 1747, 1660, 1599, 1538. ESI-MS: 497.2 [M + Na]+. HRMS: calcd for C27H30N2O4Si•Na+ [M + Na]+ = 497.1873, found 497.1866.  122  A.7 Preparation yl)acetamide (2.44)  of  N-((3aS,7aS,E)-2-(nitromethylene)-2,3,3a,7a-tetrahydrobenzofuran-3a-  NHAc NO2 O H Chemical Formula: C11H12N2O4 Exact Mass: 236.08 Molecular Weight: 236.22 2.44  A solution of nitroketone 2.39 (33 mg, 67 mol) and triethylamine (50 L) in anhydrous THF (300 L) was stirred for 24 h at rt, then it was concentrated in vacuo. Flash column chromatography of the residue (50% ethyl acetate/hexanes to 75% ethyl acetate) afforded 2.44 (10 mg, 42 mol, 63%) as a crystalline solid (crystallized from ethyl acetate).  1  H (d6-acetone): 7.72 (br s, 1H), 7.19 (s, 1H), 6.17 (dd, 1H, J2 = 9.7; J1 = 5.3), 6.10 (d, 1H, J = 9.5), 5.99  (dd, 1H, J2 = 9.7; J1 = 5.4), 5.88 (dd, 1H, J2 = 9.7; J1 = 3.6), 5.67 (d, 1H, J = 3.6), 4.17 (d, 1H, B part of AB, J = 19.0), 3.40 (d, 1H, A part of AB, J = 19.0), 1.90 (s, 3H). 13  C (d6-acetone): 172.9, 169.7, 131.5, 125.8, 122.6, 121.0, 118.1, 87.0, 58.3, 45.5, 22.3.  MP: 154–156 °C. ESI-MS: 237.2 [M + H]+; 259.1 [M + Na]+. HRMS: calcd for C11H12N2O4•Na+ [M + Na]+ = 259.0695, found 259.0688.  123  A.8 Preparation of N-((1r,4r)-1-(2-(tert-butyldimethylsilyloxy)-3-nitropropyl)-4-(tertbutyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetamide (2.46) diastereomers  NHAc NO2 OTBS  TBDPSO  Chemical Formula: C33H48N2O5Si2 Exact Mass: 608.31 Molecular Weight: 608.92 2.46  Nitro alcohol intermediate: ESI-MS: 517.1 [M + Na]+. HRMS: calcd for C27H34N2O5 [M + Na]+ = 517.2135, found 517.2152.  Product 2.46 diastereomers: Note: NMR data shows overlapping signals which appeared difficult to deconvolute. 1  H (d6-acetone, 400 MHz): 7.74 (m, 4H), 7.46 (m, 6H), 6.91 (br s, 1H), 6.15 (c br m, 1H), 5.94 (c m,  2H), 5.85 (br c m, 1H), 4.81 (c m, 1H), 4.56 (br s, 1H), 4.47 (c m, 1H) 4.40 (c m, 1H), 2.47 (c br m, 1H), 2.29 (c br m, 1H), 1.75 (br s, 3H), 1.07 (br s, 9H), 0.86 (br s, 9H), 0.17 (br s, 3H), 0.08 (br s, 3H). 13  C (d6-acetone, 100 MHz): 169.59, 136.77, 136.75, 136.42, 134.65, 132.11, 131.34, 130.94, 130.79,  130.65, 128.81, 128.80, 136.77, 136.75, 136.42, 134.65, 132.11, 131.34, 130.94, 130.79, 130.65, 128.81, 128.80, 82.37, 68.63, 64.49, 52.94, 43.88, 27.43, 26.43, 26.18, 23.83, 19.78, 18.57, -3.81, -4.79. ESI-MS: 631.3 [M + Na]+. HRMS: calcd for C33H48N2O5 [M + Na]+ = 631.2999, found 631.2994. EA: calcd C 65.09%, H 7.95%, N 4.6%; found C 65.17%, H 8.00%, N 4.82%.  124  A.9  Preparation of compounds 2.49, 2.50, 2.51 and 2.52 NHAc NHAc OTBS  TBDPSO O N  OTBS  TBDPSO H  O N  OTBS  Chemical Formula: C33H46N2O4Si2 Chemical Formula: C39H62N2O5Si3 Exact Mass: 590.3 Exact Mass: 722.4 Molecular Weight: 590.9 Molecular Weight: 723.18  = 2.49  = 2.50   = 2.51  = 2.52  Solid NaBH4 (1.4 g, 36.7 mmol) was added to a cold (0 °C), well stirred solution of nitroketone 2.39 (3.61 g, 7.33 mmol) in methanol (50 mL), and stirring was continued for 2 h. The mixture was carefully poured into 50% AcOH/H2O (100 mL; CAUTION: release of flammable H2 gas) and the acetic acid solution was extracted with ethyl acetate (3 x 150 mL). The combined extracts were dried over MgSO4, filtered and concentrated in vacuo. The alcohol intermediate was found to be extremely sensitive and readily decomposed in a retro-Henry mode. Thus, the crude reaction residue was immediately dissolved in CH2Cl2, and to this solution was added imidazole (2.0 g, 29.4 mmol) and TBSCl (4.4 g, 29.3 mmol). The reaction mixture was stirred for 168 h and then it was concentrated in vacuo. Purification of the residue by flash column chromatography (step gradient 5, 10, 15, 20, 25, 30, 40, 50 and then 100% ethyl acetate/hexanes) yielded the following compounds: ester 2.37 (200 mg, 432 mol, 6% yield), 2.49 (725 mg, 1.2 mmol, 17% yield), 2.50 (775 mg, 1.3 mmol, 18% yield), and a mixture of compounds 2.51 and 2.52 (300 mg, 420 mol, 6% yield, note: the spontaneous conversion of 2.51 and 2.52 to the isooxazolines 2.49 and 2.50 occurred slowly over time).  125  A.9.1  Compound 2.49  NHAc OTBS  TBDPSO O N  Chemical Formula: C33H46N2O4Si2 Exact Mass: 590.3 Molecular Weight: 590.9 2.49  Colorless oil. 1  H (d6-acetone): 7.76 (m, 4H), 7.44 (m, 6H), 5.85 (B-part of AB-type system, app br dt, 1H, J = 10.2),  5.59 (A-part of AB-type system, br d, 1H, J = 10.2), 4.78 (m, 1H), 4.75 (m, 1H), 4.61 (m, 1H), 4.28 (br d, 1H, J = 10.2), 2.90 (B-part of AB-type system, dd, 1H, J2 = 14.0; J1 = 6.9), 2.38 (A-part of AB-type system, dd, 1H, J2 = 14.0; J1 = 4.0), 1.68 (s, 3H), 1.10 (s, 9H), 0.89 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H). ESI-MS: 589.6 [M – H]-; 613.4 [M + Na]+. HRMS: calcd for C33H46N2O4Si2•Na+ [M + Na]+ = 613.2894, found 613.2891.  126  A.9.2  Compound 2.50  NHAc OTBS  TBDPSO O N  Chemical Formula: C33H46N2O4Si2 Exact Mass: 590.3 Molecular Weight: 590.9 2.50  Colorless oil. 1  H (d6-acetone): 7.76 (m, 4H), 7.44 (m, 6H), 7.31 (br s, 1H), 5.88 (B-part of AB-type system, app dt,  1H, J2 = 10.2; J2 = 1.6), 5.69 (A-part of AB-type system, br d, 1H, J = 10.2), 5.11 (dd, 1H, J2 = 9.6; J1 = 4.5 ), 4.66 (m, 1H), 4.63 (m, 1H), 4.28 (br d, 1H, J = 10.2), 2.90 (B-part of AB-type system, dd, 1H, J2 = 13.8; J1 = 9.7), 2.19 (A-part of AB-type system, dd, 1H, J2 = 13.8; J1 = 4.6), 1.67 (s, 3H), 1.08 (s, 9H), 0.90 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H). 13  C (d6-acetone): 169.0, 166.0, 135.8, 135.7, 133.8, 133.6, 132.2, 129.8, 127.7, 127.6, 80.2, 66.8, 65.7,  57.8, 51.9, 51.6, 26.4, 25.2, 22.2, 18.9, 17.9, -5.6, -5.9. ESI-MS: 589.5 [M – H]-; 613.4 [M + Na]+. HRMS: calcd for C33H46N2O4Si2•Na+ [M + Na]+ = 613.2894, found 613.2883.  127  A.9.3  Compound 2.51/2.52  NHAc OTBS  TBDPSO O N  H OTBS  Chemical Formula: C39H62N2O5Si3 Exact Mass: 722.4 Molecular Weight: 723.18  = 2.51  = 2.52  Colorless oil. 1  H (d6-acetone): 7.71 (m, 4H), 7.44 (m, 6H), 7.02 (brs, 1H), 6.01 (d, 1H, J = 10.1), 5.61 (ddd, 1H, J3 =  10.1; J1 = J2 = 4.3), 4.76 (dd, 1H, J2 = 8.4; J1 = 2.2 ), 4.24 (m, 1H), 4.01 (dd, 1H, J2 = 8.4; J1 = 4.8), 3.80 (app q, 1H, J = 6.3), 3.63 (app t, 1H, J = 8.4), 2.91 (dd, 1H, B part of AB-type system, J = 13.9, 6.3), 2.38 (dd, 1H, A part of AB-type system, J = 13.9, 4.2), 1.88 (s, 3H), 1.08 (s, 9H), 0.91 (s, 9H), 0.89 (s, 9H), 0.13 (s, 6H), 0.07 (s, 3H), 0.05 (s, 3H). ESI-MS: 729.6 [M + Na]+. HRMS: calcd for C39H62N2O4Si3•Na+ [M + Na]+ = 729.3908, found 729.3915.  128  A.10 Preparation of trans-9-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-3-nitro-1azaspiro[5.5]undeca-2,7,10-trien-4-one (2.55)  CH3 HN  NO2 O  TBDPSO Chemical Formula: C27H30N2O4Si Exact Mass: 474.2 Molecular Weight: 474.62 2.55  A solution of nitroketone 2.39 (1.7 g, 3.4 mmol) TBSCl (5.1 g, 34.0 mmol) and imidazole (2.3 g, 34.0 mmol) in anhydrous CH2Cl2 (20 mL) was stirred for 48 h at rt, then the reaction was concentrated in vacuo. Silica gel flash column chromatography (50% ethyl acetate/hexanes to 100% ethyl acetate) of the reaction residue afforded 1.1 g (2.2 mmol, 65%) of 2.55 as a crystalline solid, (recrystallized from ethyl acetate), and 83 mg (180 mol) of isoxazoline 2.43.  1  H (d6-acetone): 7.72 (m, 4H), 7.45 (m, 6H), 5.99 (s, 4H), 4.58 (m, 1H), 2.59 (s, 2H), 2.28 (s, 3H), 1.06  (s, 9H). 13  C (d6-DMSO): 178.9, 161.9, 135.3, 133.0, 131.2, 130.1, 128.0, 127.5, 125.2, 63.0, 52.5, 45.6, 26.7,  19.7, 18.7. MP: 212–213 °C ESI-MS: 475.2 [M +H]+; 497.2 [M + Na]+. HRMS: calcd for C27H29N2O4Si [M – H]– = 473.1897, found 473.1913. EA: calcd C 68.33%, H 6.37%, N 5.90%; found C 68.19%, H 6.39%, N 5.89%.  129  A.11 Preparation of methyl 2-((1S,4S,5R,6S)-1-acetamido-4-(tert-butyldiphenylsilyloxy)-6-cyano5-hydroxycyclohex-2-enyl)acetate (2.59) NHAc CO2CH3 O TBDPS  C OH  N  Chemical Formula: C28H34N2O5Si Exact Mass: 506.22 Molecular Weight: 506.67 2.59  Isooxazoline 2.43 (15 mg, 0.0317 mmol) was dissolved in methanol (0.5 mL) at ambient temperature. To this solution was added imidazole (1 mg, 0.0147 mmol) and lithium carbonate (1 mg, 0.0135 mmol). The solution was allowed to stir for 1 h, before the reaction mixture was concentrated in vacuo. The crude residue was passed through a small plug of silica gel (150 mg) using ethyl acetate/hexanes (30-75% ethyl acetate/hexanes). Compound 2.59 was obtained in 68% yield (11 mg, 0.0217 mmol) as a glassy solid. 1  H (d6-acetone): 7.78 (m, 4H), 7.45 (m, 6H), 7.31 (br s, 1H), 5.86 (ddd, 1H, J3 = 10.4; J1 = J2 = 1.8),  5.52 (ddd, 1H, J3 = 10.5; J1 = J2 = 2.9), 4.41 (m, 1H), 4.33 (3, 1H), 4.26 (m, 1H), 3.67 (s, 3H), 3.33 (d, 1H, B part of AB, J = 15.8), 3.17 (d, 1H, A part of AB, J = 15.8), 1.82 (s, 3H), 1.12 (s, 9H). 13  C (d6-acetone): 170.9, 170.3, 136.8, 136.7, 134.4, 133.9, 130.9, 130.9, 130.0, 128.7, 128.6, 119.2, 69.0,  68.9, 68.8, 54.8, 51.9, 41.5, 38.3, 27.3, 23.5, 19.9. IR: 2243, 1737, 1661. ESI-MS: 529.2 [M + Na]+. HRMS: calcd for C28H34N2O5Si•Na+ [M + Na]+ = 529.2135, found 529.2123.  130  A.12 Preparation of N-((2aR,2a1S,3S,5aS)-3-hydroxy-7-oxo-2a,2a1,3,5a,6,7hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.60) NHAc O HO H  O N  Chemical Formula: C11H12N2O4 Exact Mass: 236.08 Molecular Weight: 236.22 2.60  To a solution of isooxazoline 2.43 (40 mg, 0.084 mmol) in dry CD3CN (1 mL) was added drop-wise HF/H2O (35% HF v/v, 3 drops). This reaction was allowed to stir for 96 h, after which volatile organics were removed in vacuo.  The crude product was purified via flash column chromatography (50%  acetone/hexanes, then 75% acetone/hexanes, then 100% acetone) to give pure 2.60 (14 mg, 0.059 mmol, 70% yield) as a glassy solid. Unreacted compound 2.43 was also recovered (3 mg, 0.006 mmol, 7%). 1  H (d6-acetone): 7.73 (brs, 1H), 6.05 (ddd, 1H, J3 = 10.3; J1 = J2 = 1.6 ), 5.70 (ddd, 1H, J = 10.3, 3.0,  1.2), 5.22 (ddd, 1H, J3 = 11.1, 5.2, 1.4), 4.85 (dd, 1H, J = 11.1, 0.9), 4.54 (br m, 1H), 4.22 (br d, 1H, J = 8.2), 3.45 (d, 1H, B part of AB, J = 18.0), 3.04 (d, 1H, A part of AB, J = 18.0), 1.85 (s, 3H). 13  C (d6-acetone): 192.1, 170.5, 163.5, 138.8, 129.9, 85.5, 65.1, 57.7, 56.0, 52.3, 23.2.  ESI-MS: 259.2 [M + Na]+. HRMS: calcd for C11H12N2O4•Na+ [M + Na]+ = 259.0695, found 259.0695.  131  A.13 Preparation of methyl 2-((1S,5R,6S)-1-acetamido-6-cyano-5-hydroxy-4-oxocyclohex-2enyl)acetate (2.62) NHAc CO2CH3 O HO  N  Chemical Formula: C12H14N2O5 Exact Mass: 266.09 Molecular Weight: 266.25 2.62  To a solution of 2.60 (14 mg, 0.0593 mmol) in CD3CN (1.5 mL) was added Dess-Martin periodinane (30 mg, 71 mol). This solution was monitored by 1H-NMR until the reaction had completed (12 h). The crude reaction was filtered through celite and concentrated in vacuo. Crude N-[(4aR,7aS,7bR)-3,4,7a,7btetrahydro-3,7-dioxoindeno[1,7-cd]isoxazol-4a(7H)-yl]-acetamide (2.61) was thus obtained. 1  H (d6-acetone): 8.16 (br s, 1H), 6.55 (dd, 1H, J = 10.4, 2.0), 6.29  NHAc  (dd, 1H, J = 10.4, 0.6), 5.19 (dd, 1H, J = 10.7, 0.7), 4.78 (dd, 1H, J = O  O  O N  Chemical Formula: C11H10N2O4 Exact Mass: 234.06 Molecular Weight: 234.21 2.61  10.7, 1.8), 3.45 (d, 1H, B part of AB, J = 18.0), 3.23 (d, 1H, A part of AB, J = 18.0), 1.89 (s, 3H). ESI-MS: 257.1 [M + Na]+. HRMS: calcd for C11H10N2O4•Na+ [M + Na]+ = 257.0538, found 257.0541.  Diketone 2.61 was not purified nor thoroughly characterized due to significant reactivity. Instead, it was dissolved in dry methanol (700 L) and to this was added Li2CO3 (1 mg, 14 mol), and the mixture was stirred at rt for 8 h. The suspension was filtered through celite and concentrated in vacuo. The reaction residue was purified by flash column chromatography (30% ethyl acetate/hexanes, then 75% ethyl acetate/hexanes, then 100% ethyl acetate) to give pure 2.62 (6 mg, 23 mol, 38% yield) as a glassy solid. 1  H (CD3CN): 7.25 (dd, 1H, J = 10.3, 1.5), 6.10 (d, 1H, J = 10.3), 4.74 (d, 1H, J = 5.0), 4.42 (dd, 1H, J2 =  5.0; J1 = 1.4), 3.68 (s, 3H), 3.18 (app. d, 2H, actually compressed AB system, J = 15.7), 1.87 (s, 3H). 13  C (CD3CN, 100 MHz): 196.46, 171.67, 170.34, 149.24, 127.54, 117.79, 70.16, 56.20, 52.61, 43.74,  41.19, 23.31. IR: 2251, 1732, 1699, 1655. ESI-MS: 289.1 [M + Na]+. HRMS: calcd for C12H14N2O5•Na+ [M + Na]+ = 289.0800, found 289.0794. 132  A.14 Preparation of N-((2aR,2a1S,3R,5aS)-3-(tert-butyldiphenylsilyloxy)-7-oxo-2a,2a1,3,5a,6,7hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.66)  NHAc TBDPS O  O H  O N  Chemical Formula: C27H30N2O4Si Exact Mass: 474.2 Molecular Weight: 474.62 2.66  Dienone 2.32 (15.0 g, 67.3 mmol) was dissolved in THF (200 mL) at room temperature under argon atmosphere. To this solution was added (S)-(–)2-methyl-CBS-oxazaborolidine (1.83 g, 6.73 mmol) followed by the addition of BH3-DMS complex (6.38 mL, 67.3 mmol). This reaction was allowed to stir overnight. The crude reaction residue (mostly 2.35 and 2.36) was thoroughly concentrated in vacuo. The crude reaction residue was dissolved in CH2Cl2 (500 mL) and to this was added imidazole (5.04 g, 74.0 mmol) and TBDPS-Cl (20.3 g, 74.0 mmol). The reaction was allowed to stir overnight at ambient temperature under an argon atmosphere. The crude reaction mixture was poured into a solution of 0.05M aqueous HCl (400 mL) and the aqueous phase was extracted with CH2Cl2 (2 x 400 mL). The combined organic phase was dried over anhydrous MgSO4, filtered through a short plug of silica gel and concentrated in vacuo. The crude mixture of TBDPS-alcohols 2.37/2.63 was dissolved in THF (500 mL) and to this was added a solution of 1M aqueous NaOH (270 mL). The biphasic mixture was vigorously stirred overnight. The volatile organics were removed in vacuo, and the residue was partitioned between 50% AcOH/H2O (500 mL) and ethyl acetate (400 mL). The aqueous layer was extracted a second time with ethyl acetate (250 mL), and the combined organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude mixture of carboxylic acids 2.38/2.64 was dissolved in THF (250 mL) and to this was added carbonyldiimidazole (13.1 g, 80.8 mmol) with stirring at room temperature. The reaction mixture was stirred for 1 h at room temperature, and then nitromethane (100 mL) was added, followed by the addition of solid potassium tert-butoxide (30.2 g, 269.2 mmol). The reaction mixture was stirred at room temperature for 2 h and then the volatiles were removed in vacuo. The residue was partitioned between 50% AcOH/H2O (500 mL) and CH2Cl2 (400 mL). The organic phase was separated and the aqueous phase was washed with additional CH2Cl2 (2 x 400 mL). The combined organic phase was dried over anhydrous MgSO4, filtered through a short silica gel plug and concentrated to give 133  enriched nitroketones 2.39/2.65. The mixture of crude nitroketones was dissolved in CH2Cl2 (300 mL) and to this was added imidazole (9.12 g, 134 mmol) and TBS-Cl (20.20 g, 134 mmol). The reaction mixture was allowed to stir at room temperature under an argon atmosphere for 5 days. The reaction mixture was concentrated in vacuo and purified by flash column chromatography using (50% ethyl acetate/hexanes to 100% ethyl acetate) to give 2.43 (2.7 g, 8% yield over 5 steps) and 2.66 (6.3 g, 20% yield over 5 steps). Significant amount of nitroketones 2.39 and 2.65 were recovered (~28%) and recycled.  1  H (d6-acetone): 7.73 (m, 4H),7.47 (m, 6H), 6.15 (ddd, 1H, J3 = 10.3; J1 = J2 = 1.1 ), 6.01 (ddd, 1H, J =  10.0, 5.3, 0.8), 5.17 (ddd, 1H, J3 = 10.9, 2.0, 0.8), 5.05 (app d, 1H, J = 5.4), 4.16 (dd, 1H, J = 5.4, 2.0), 3.55 (d, 1H, B part of AB, J = 18.3), 3.12 (d, 1H, A part of AB, J = 18.3), 1.93 (s, 3H), 1.09 (s, 9H). ESI-MS: 473.5 [M – H]–, 497.4 [M + H]+, 497.4 [M + Na]+. HRMS: calcd for C27H31N2O4•Na+ [M + Na]+ = 475.2053, found 475.2059.  134  A.15 Preparation of methyl 2-((1S,4R,5R,6S)-1-acetamido-4-(tert-butyldiphenylsilyloxy)-6-cyano5-hydroxycyclohex-2-enyl)acetate (2.67)  NHAc CO2CH3 O TBDPS  C OH  N  Chemical Formula: C28H34N2O5Si Exact Mass: 506.22 Molecular Weight: 506.67 2.67  Isooxazoline 2.66 (900 mg, 1.90 mmol) was dissolved in methanol (10 mL) at ambient temperature. To this solution was added imidazole (10 mg) and lithium carbonate (50 mg). The solution was allowed to stir for 1 h, before the reaction mixture was concentrated in vacuo. The crude residue was passed through a small plug of silica gel (1 g) using ethyl acetate/hexanes (30-75% ethyl acetate/hexanes). Compound 2.67 was obtained in 90% yield (864 mg, 1.71 mmol) as a glassy solid.  1  H (d6-acetone): 7.78 (m, 4H), 7.45 (m, 6H), 7.33 (brs, 1H), 5.92 (ddd, 1H, J3 = 10.3; J2 = 1.3 J1 = 0.4),  5.52 (ddd, 1H, J3 = 10.3, J2 = J1 =2.6), 5.00 (d, 1H, J = 4.7), 4.50 (c m, 1H), 4.34 (dd, 1H, J2 = 4.0 J1 = 1.0), 4.26 (m, 1H), 3.62 (s, 3H), 3.35 (d, 1H, A part of ABq, J = 15.5), 2.88 (d, 1H, B part of ABq, J = 15.5), 1.89 (s, 3H), 1.09 (s, 9H). 13  C (d6-acetone): 169.70, 169.69, 135.91, 135.84, 133.97, 133.30, 131.26, 129.84, 129.83, 128.10,  127.69, 127.64, 117.91, 71.61, 69.50, 55.04, 50.94, 39.98, 39.52, 26.46, 22.67, 19.04. IR: 2247 cm-1, 1719 cm-1, 1639 cm-1. ESI-MS: 529.5 [M + Na]+. HRMS: calcd for C28H34N2O5•Na+ [M + Na]+ = 529.2135, found 529.2122.  135  A.16 Preparation of compounds 2.76-2.88  Representative procedure for the results listed in Tables 2.8 and 2.9: A solution of oxime (1 mmol) in methanol (1 mL) was added slowly (syringe pump, 1 h) at room temperature to a stirred solution of DIB (1.1 eq) and olefin (1.1 eq) in methanol (2 mL) containing TFA (15 L). A white precipitate formed immediately and then slowly redissolved as the reaction progressed. Upon consumption of starting oxime (TLC, about 1 h), the mixture was concentrated in vacuo and the residue was purified by flash column chromatography using a step gradient: 5%-10%-20% ethyl acetate/hexanes.  A.16.1 Preparation of 3-(4-methoxyphenyl)-5-phenyl-4,5-dihydroisoxazole (2.76)  N O  H3CO Chemical Formula: C16H15NO2 Exact Mass: 253.11 Molecular Weight: 253.3 2.76  Representative procedure is located in Appendix section A.16. colorless crystals. 91% yield. 1  H (CDCl3): 7.63 (d, 2H, J = 8.9), 7.39 (m, 5H), 6.93 (d, 2H, J = 8.9), 5.71 (dd, 1H, J = 10.9, 8.2), 3.84  (s, 3H), 3.76 (dd, 1H, J = 16.5, 10.9), 3.32 (dd, 1H, J = 16.5, 8.2). 13  C (CDCl3): 161.24, 155.81, 141.24, 128.88, 128.43, 128.30, 126.03, 122.19, 114.30, 82.44, 55.51,  43.60. MP: 100-101 °C. ESI-MS: 276.3 [M + Na]+. HRMS: calcd for C16H15NO2Na [M + Na]+ = 276.1000, found 276.1001. 136  A.16.2 Preparation of 3,5-diphenyl-4,5-dihydroisoxazole (2.77)  N O  Chemical Formula: C16H15NO2 Exact Mass: 253.11 Molecular Weight: 253.3 2.77  Representative procedure is located in Appendix section A.16. colorless crystals. 71% yield. 1  H (CDCl3): 7.70 (m, 2H), 7.40 (m, 8H), 5.75 (dd, 1H, J = 11.2, 8.4), 3.79 (dd, 1H, J = 16.4, 11.2), 3.35  (dd, 1H, J = 16.4, 8.2). 13  C (CDCl3): 156.23, 141.06, 130.27, 129.61, 128.89, 128.87, 128.35, 126.88, 126.00, 82.70, 43.30.  MP: 72-73 °C. ESI-MS: 224.3 [M + H]+; 246.3 [M + Na]+. HRMS: calcd for C15H13NONa [M + Na]+ = 246.0895, found 246.0894.  137  A.16.3 Preparation of 3-(3-nitrophenyl)-5-phenyl-4,5-dihydroisoxazole (2.78)  N O O2N  Chemical Formula: C16H15NO2 Exact Mass: 253.11 Molecular Weight: 253.3 2.78  Representative procedure is located in Appendix section A.16. yellow oil. 91% yield. 1  H (CDCl3): 8.44 (t, 1H, J = 1.9), 8.27 (ddd, 1H, J = 8.2, 2.4, 1.0), 8.12 (dt, H, J = 7.9, 1.2), 7.61 (t, 1H,  J = 8.0), 7.39 (m, 5H), 5.84 (dd, 1H, J = 8.3, 11.4), 3.84 (dd, 1H, J = 11.4, 16.5), 3.39 (dd, 1H, J = 16.5, 8.3). 13  C (CDCl3): 154.62, 148.62, 140.37, 132.37, 131.49, 130.00, 129.05, 128.67, 125.93, 124.74, 121.72,  83.51. ESI-MS: 269.2 [M + H]+; 291.2 [M + Na]+. HRMS: calcd for C15H12N2O3Na [M + Na]+ = 291.0746, found 291.0736.  138  A.16.4 Preparation of 3-pentyl-5-phenyl-4,5-dihydroisoxazole (2.79)  N O  Chemical Formula: C14H19NO Exact Mass: 217.15 Molecular Weight: 217.31 2.79  Representative procedure is located in Appendix section A.16. colorless oil. 74% yield. 1  H (CDCl3): 7.34 (m, 5H), 5.54 (dd, 1H, J = 10.8, 8.0), 3.36 (dd, 1H, J = 16.7, 10.8), 2.89 (dd, 1H, J =  16.7, 8.0), 2.38, (t, 2H, J = 7.7), 1.59 (m, 2H), 1.32 (m, 4H), 0.89 (m, 3H). 13  C (CDCl3): 158.69, 141.51, 128.75, 128.05, 125.80, 81.28, 45.45, 31.46, 27.73, 26.16, 22.40, 14.03.  ESI-MS: 218.4 [M + H]+. HRMS: calcd for C14H19NONa [M + Na]+ = 240.1364, found 240.1366.  139  A.16.5 Preparation of 3-phenethyl-5-phenyl-4,5-dihydroisoxazole (2.80)  N O  Chemical Formula: C17H17NO Exact Mass: 251.13 Molecular Weight: 251.32 2.80  Representative procedure is located in Appendix section A.16. colorless oil. 63% yield. 1  H (CDCl3): 7.38-7.19 (m, 10H), 5.53 (dd, 1H, J = 1.0, 8.0), 3.31 (dd, 1H, J = 16.8, 11.0), 2.94 (m, 2H),  2.90 (dd, 1H, J = 16.8, 8.0), 2.71 (m, 2H). 13  C (CDCl3): 157.90, 141.37, 140.55, 128.80, 128.73, 128.44, 128.15, 126.52, 125.87, 81.49, 45.72,  32.82, 29.54. ESI-MS: 274.3 [M + Na]+. HRMS: calcd for C17H17NONa [M + Na]+ = 274.1208, found 274.1201.  140  A.16.6 Preparation of 3a,4,5,6,7,7a-hexahydro-3-phenyl-4,7-methano-1,2-benzisoxazole (2.81)  N O  Chemical Formula: C14H15NO Exact Mass: 213.12 Molecular Weight: 213.28 2.81  Representative procedure is located in Appendix section A.16. colorless crystals. 95% yield. 1  H (CDCl3): 7.71 (m, 2H), 7.39 (m, 3H), 4.64 (d, 1H, J = 8.4), 3.50 (d, 1H, J = 8.4), 2.57 (d, 2H, J =  30.4), 1.56 (m, 3H), 1.35 (m, 1H), 1.18 (m, 2H). 13  C (CDCl3): 156.98, 129.78, 129.50, 128.77, 126.92, 87.97, 57.15, 43.09, 39.36, 32.41, 27.52, 22.81.  MP: 98-99 °C. ESI-MS: 214.3 [M + H]+. HRMS: calcd for C14H15NONa [M + Na]+ = 236.1051, found 236.1049.  141  A.16.7 Preparation of 3a,4,5,6,7,7a-hexahydro-3-(3-nitrophenyl)-4,7-methano-1,2-benzisoxazole (2.82)  N O O2N  Chemical Formula: C14H14N2O3 Exact Mass: 258.1 Molecular Weight: 258.27 2.82  Representative procedure is located in Appendix section A.16. colorless crystals. 77% yield. 1  H (CDCl3): 8.47 (t, 1H, J = 1.8), 8.23 (ddd, 1H, J = 8.4, 2.4, 0.9), 8.09 (dt, 1H, J = 7.9, 0.9), 7.58 (t, 1H,  J = 8.0), 4.73 (d, 1H, J = 8.6), 3.52 (d, 1H, J = 8.6), 2.67 (app br s, 1H), 2.52 (app br s, 1H), 1.72-1.32 (m, 4H), 1.23 (m, 2H). 13  C (CDCl3): 155.55, 148.67, 132.55, 131.52, 129.90, 124.32, 121.57, 89.00, 56.61, 43.12, 39.26, 32.52,  27.55, 22.76. MP: 76-77 °C. ESI-MS: 259.3 [M + H]+. HRMS: calcd for C14H14N2O3Na [M + Na]+ = 281.0902, found 281.0906.  142  A.16.8 Preparation of 3a,4,5,6,7,7a-hexahydro-3-pentyl-4,7-methano-1,2-benzisoxazole (2.83)  Representative procedure is located in Appendix section A.16. colorless oil. 91% yield. 1  H (CDCl3): 4.39 (d, 1H, J = 8.2), 2.99 (d, 1H, J = 8.2), 2.51 (brd, 1H, J = 3.2), 2.32 (m, 2H), 2.16 (ddd,  1H, J = 15.3, 8.7, 6.0), 1.57 (m, 4H), 1.43 (m, 1H), 1.33, (m, 4H), 1.14 (m, 3H), 0.89 (m, 3H). 13  C (CDCl3): 158.97, 86.04, 59.47, 42.96, 38.29, 32.24, 31.64, 27.38, 26.72, 26.08, 22.82, 22.45, 14.04.  ESI-MS: 208.4 [M + H]+; 230.4 [M + Na]+. HRMS: calcd for C13H21NONa [M + Na]+ = 230.1521, found 230.1523.  143  A.16.9 Preparation of 3a,4,5,6,7,7a-hexahydro-3-(2-phenylethyl)-4,7-methano-1,2-benzisoxazole (2.84)  Representative procedure is located in Appendix section A.16. colorless oil. 79% yield. 1  H (CDCl3): 7.33-7.18 (m, 5H), 4.41 (d, 1H, J = 8.2), 2.93 (m, 3H), 2.65 (ddd, 1H, J = 15.8, 8.7, 6.5),  2.48 (m, 2H), 2.30 (brs, 1H), 1.51 (m, 2H), 1.40 (m, 1H), 1.12 (m, 3H). 13  C (CDCl3): 158.34, 141.07, 128.63, 128.40, 126.36, 86.26, 59.68, 42.96, 38.32, 32.61, 32.27, 28.70,  27.36, 22.82. ESI-MS: 264.3 [M + Na]+. HRMS: calcd for C16H19NONa [M + Na]+ = 264.1364, found 264.1369.  144  A.16.10 Preparation of 3-(1,1-dimethylethyl)-3a,4,5,6,7,7a-hexahydro4,7-methano-1,2benzisoxazole (2.85)  Representative procedure is located in Appendix section A.16. colorless oil. 75% yield. 1  H (CDCl3): 4.40 (d, 1H, J = 8.3), 3.05 (dd, 1H, J = 8.3, 1.3), 2.53 (brs, 2H), 1.50 (m, 3H), 1.23 (s, 9H),  1.15 (m, 3H). 13  C (CDCl3): 165.27, 87.07, 58.35, 42.79, 39.81, 33.30, 32.18, 29.41, 27.67, 22.85.  ESI-MS: 194.3 [M + H]+; 216.3 [M + Na]+. HRMS: calcd for C12H19NONa [M + Na]+ = 216.1364, found 216.1366.  145  A.16.11 Preparation of 3a,4,5,6,7,7a-hexahydro-3-(4-methoxyphenyl)-4,7-methano-1,2benzisoxazole (2.86)  N O  H3CO Chemical Formula: C15H17NO2 Exact Mass: 243.13 Molecular Weight: 243.3 2.86  Representative procedure is located in Appendix section A.16. colorless crystals. 90% yield. 1  H (CDCl3): 7.65 (d, 2H, J = 8.9), 6.91 (d, 2H, J = 8.9), 4.60 (d, 1H, J = 8.3), 3.83 (s, 3H), 3.46 (d, 1H, J  = 8.3), 2.55 (dd, 2H, J = 30.2, 2.9), 1.57 (m, 3H), 1.35 (m, 1H), 1.17 (m, 2H). 13  C (CDCl3): 160.86, 156.56, 128.46, 122.07, 114.22, 87.68, 57.49, 55.47, 43.11, 39.41, 32.43, 27.56,  22.83. MP: 95-96 °C. ESI-MS: 244.3 [M + H]+; 266.3 [M + Na]+. HRMS: calcd for C15H17NO2Na [M + Na]+ = 266.1157, found 266.1152.  146  A.16.12 Preparation of 5-(3-bromopropyl)-4,5-dihydro-3-phenyl-isoxazole (2.87)  Representative procedure is located in Appendix section A.16. colorless crystals. 83% yield. 1  H (CDCl3): 7.65 (m, 2H), 7.40 (m, 3H), 4.76 (m, 1H), 3.50 (m, 2H), 3.43 (dd, 1H, J = 16.4, 10.4), 3.00  (dd, 1H, J = 16.4, 7.7), 2.06 (m, 2H), 1.84 (m, 2H). 13  C (CDCl3): 156.50, 130.11, 129.64, 128.76, 126.66, 80.39, 40.16, 33.98, 33.52, 28.80.  MP: 53-54 °C. ESI-MS: 268.2 and 270.2 [M + H]+. HRMS: calcd for C12H14NO79BrNa [M + Na]+ = 290.0156, found 290.0163.  147  A.16.13 Preparation of 3,5-diphenylisoxazole (2.88)  Representative procedure is located in Appendix section A.16. colorless crystals. 50% yield. 1  H (CDCl3): 7.87 (m, 2H), 7.47 (m, 8H), 6.84, (s, 1H).  13  C (CDCl3): 170.41, 162.98, 130.22, 130.01, 129.14, 129.01, 128.93, 127.47, 126.82, 125.84, 97.47.  MP: 138-140 °C. ESI-MS: 222.3 [M + H]+; 244.3 [M + Na]+. HRMS: calcd for C15H11NONa [M + Na]+ = 244.0738, found 244.0733.  148  A.17 Preparation of 1-(3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benzisoxazol-3-yl)-ethanone (2.90)  A solution of oxime 2.89 (120 mg, 1.4 mmol) in methanol (3 mL) was added dropwise at room temperature to a solution of norbornylene (158 mg, 1.68 mmol, 1.2 eq), PhI(OAc)2 (541 mg, 1.68 mmol, 1.2 eq), TFA (0.1% v/v, 5 L) and methanol (2 mL) with rapid stirring. The reaction mixture was stirred overnight. The crude product 2.90 was purified by flash column chromatography using a step-gradient: 5%, 10%, 15%, and 20% ethyl acetate/hexanes. Pure fractions of 2.90 were combined and concentrated in vacuo, yielding compound 2.90 as clear viscous oil (0.188 g, 76%).  1  H (CDCl3): 4.65 (d, 1H, J = 8.4), 3.25 (d, 1H, J = 8.4), 2.61 (br s, 1H), 2.51 (br s, 1H), 2.45 (s, 3H),  1.62-1.46 (m, 2H), 1.38-1.02 (m, 4H). 13  C (CDCl3): 193.49, 158.98, 91.01, 54.47, 43.16, 39.20, 32.41, 27.38, 27.16, 22.73.  IR: 1685 cm-1, 1567 cm-1. ESI-MS: 202.3 [M + Na]+. HRMS: calcd for C10H13NO2Na = 202.0844, found 202.0841. Literature characterization is also available in Cecchi, L.; De Sarlo, F.; Machetti, F. Eur. J. Org. Chem. 2006, 21, 4852-4860. Alternative method of synthesis is available in Cecchi, L.; De Sarlo, F.; Machetti, F. Tetrahedron Lett. 2005, 46, 7877-7879.  149  A.18  Preparation of 1-(4,5-dihydro-5-phenyl-3-isoxazolyl)-ethanone (2.91)  A solution of oxime 2.89 (138 mg, 1.6 mmol) in methanol (3 mL) was added dropwise at room temperature to a solution of styrene (200 mg, 1.92 mmol, 1.2 eq), PhI(OAc)2 (618 mg, 1.92 mmol, 1.2 eq), TFA (0.1% v/v, 5 L) and methanol (2 mL) with rapid stirring. The reaction mixture was stirred overnight and then concentrated in vacuo. The pale-yellow crude product 2.91 was purified by flash column chromatography using a step-gradient: 5%, 10%, 15%, and 20% ethyl acetate/hexane. Pure fractions of 2.91 were combined and concentrated in vacuo, yielding 2.91 as clear viscous oil (0.224 g, 75%).  1  H (CDCl3): 7.43-7.27 (m, 5H), 5.77 (dd, 1H, J2 = 11.6, J1 = 8.9), 3.55 (dd, 1H, J2 = 17.9, J1 = 11.6),  3.14 (dd, 1H, J2 = 17.9, J1 = 8.9), 2.55 (s, 3H). 13  C (CDCl3): 193.18, 158.02, 139.68, 129.04, 128.83, 126.01, 85.69, 39.89, 26.90.  IR: 1686 cm-1, 1577 cm-1. ESI-MS: 190.5 [M + H]+; 212.3 [M + Na]+. HRMS: calcd for C11H11NO2Na = 212.0687, found 212.0686. Literature characterization is also available in Cecchi, L.; De Sarlo, F.; Machetti, F. Eur. J. Org. Chem. 2006, 21, 4852-4860. Alternative method of synthesis is available in Cecchi, L.; De Sarlo, F.; Machetti, F. Tetrahedron Lett. 2005, 46, 7877-7879.  150  A.19 Preparation of 3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benzisoxazole-3-carboxylic acid ethyl ester (2.93)  Procedure A  A solution of 2.99 (263 mg, 1.65 mmol) in methanol (3 mL) was added dropwise at room temperature to a solution of norbornylene (186 mg, 1.98 mmol, 1.2 eq), PhI(OAc)2 (638 mg, 1.98 mmol, 1.2 eq), TFA (1% v/v, 55 L) and methanol (2 mL) with rapid stirring. The reaction mixture was stirred overnight and then concentrated in vacuo. The crude product was purified by flash column chromatography using a step-gradient: 5%, 10%, 15%, and 20% ethyl acetate/hexane. Pure fractions of product 2.93 were combined and concentrated in vacuo, yielding 2.93 as clear viscous oil (0.178 g, 52%). Oxime 2.99 (76 mg, 29%, 52% brsm) was also recovered from the purification of the crude 2.93 indicating that the reaction required longer reaction time.  151  Procedure B  A solution of 2.92 (158 mg, 1.04 mmol) in methanol (2 mL) was added dropwise at room temperature to a solution of norbornylene (117 mg, 1.25 mmol, 1.2 eq), PhI(OAc)2 (402 mg, 1.25 mmol, 1.2 eq), TFA (1% v/v, 70 L) and methanol (5 mL) with rapid stirring. The reaction appeared complete in 30 min by TLC. The crude product 2.93 was purified by flash column chromatography using a step-gradient: 5%, 10%, 15%, and 20% ethyl acetate/hexane. Pure fractions of 2.93 were collected and concentrated in vacuo, yielding 2.93 as clear viscous oil (0.194 g, 90%).  1  H (CDCl3): 4.65 (d, 1H, J = 8.5), 4.39-4.22 (m, 2H, J = 3.6), 3.27 (d, 1H, J = 8.5), 2.57 (br d, 2H, J =  10.0), 1.62-1.46 (m, 2H), 1.44-1.37 (m, 1H), 1.34 (t, 3H, J = 7.1), 1.29-1.16 (m, 2H), 1.16-1.06 (m, 1H). 13  C (CDCl3): 160.91, 152.35, 90.31, 61.86, 55.74, 42.98, 39.43, 32.34, 27.23, 22.70, 14.18.  IR: 1715 cm-1, 1580 cm-1. ESI-MS: 232.3 [M + Na]+. HRMS: calcd for C11H15NO3Na = 232.0950, found 232.0948. Literature characterization is also available in Cecchi, L.; De Sarlo, F.; Machetti, F. Eur. J. Org. Chem. 2006, 21, 4852-4860. Alternative method of synthesis is available in Cecchi, L.; De Sarlo, F.; Machetti, F. Tetrahedron Lett. 2005, 46, 7877-7879.  152  A.20  Preparation of 4,5-dihydro-5-phenyl-3-isoxazolecarboxylic acid ethyl ester (2.94)  Procedure A  A solution of 2.99 (251 mg, 1.58 mmol) in methanol (3 mL) was added dropwise at room temperature to a solution of styrene (197 mg, 1.90 mmol, 1.2 eq), PhI(OAc)2 (611 mg, 1.90 mmol, 1.2 eq), TFA (1% v/v, 55 L) and methanol (2 mL) with rapid stirring. The reaction mixture was stirred overnight and then concentrated in vacuo. The crude product was purified by flash column chromatography using a stepgradient: 5%, 10%, 15%, and 20% ethyl acetate/hexane. Pure fractions of product 2.94 were combined and concentrated in vacuo, yielding 2.94 as clear viscous oil (0.205 g, 59%). Oxime 2.99 (98 mg, 39 %) was also recovered from the purification of the crude 2.94 indicating that the reaction required longer reaction time.  153  Procedure B  A solution of 2.92 (152 mg, 1.02 mmol) in methanol (2 mL) was added dropwise at room temperature to a solution of styrene (115 mg, 1.22 mmol, 1.2 eq), PhI(OAc)2 (402 mg, 1.22 mmol, 1.2 eq), TFA (1% v/v, 70 L) and methanol (5 mL) with rapid stirring. The reaction appeared complete in 30 min by TLC. The crude product 2.94 was purified by flash column chromatography using a step-gradient: 5%, 10%, 15%, and 20% ethyl acetate/hexane. Pure fractions of 2.94 were collected and concentrated in vacuo, yielding 2.94 as clear viscous oil (0.183 g, 82%).  1  H (CDCl3): 7.43-7.28 (m, 5H), 5.77 (dd, 1H, J2 = 11.7, J1 = 8.9), 4.36 (q, 2H, J = 7.1), 3.63 (dd, 1H, J2  = 17.9, J1 = 11.7), 3.21 (dd, 1H, J2 = 17.9, J1 = 8.9), 1.37 (t, 3H, J = 7.1). 13  C (CDCl3): 160.67, 151.23, 139.63, 128.97, 128.74, 125.96, 85.04, 62.23, 41.55, 14.21.  IR: 1716 cm-1, 1589 cm-1. ESI-MS: 220.3 [M + H]+; 242.3 [M + Na]+. HRMS: calcd for C12H13NO3Na = 242.0793, found 242.0797. Literature characterization is also available in Cecchi, L.; De Sarlo, F.; Machetti, F. Eur. J. Org. Chem. 2006, 21, 4852-4860. Alternative method of synthesis is available in Cecchi, L.; De Sarlo, F.; Machetti, F. Tetrahedron Lett. 2005, 46, 7877-7879.  154  A.21  Preparation of 2-isonitrosocyclopentanone (2.100)  Oxime 2.100 was synthesized from 3.12 g of α-carbethoxycyclopentanone as detailed by: Cope, A. C.; Estes, L. L. Jr.; Emery, J. R.; Haven, A. C. Jr. J. Amer. Chem. Soc. 1951, 73, 1199.  1  H (CDCl3): 9.92 (br s, 1H), 2.83 (t, 2H, J = 7.6), 2.49 (t, 2H, J = 7.8), 2.07 (quin, 2H, J = 7.7).  13  C (CDCl3): 203.91, 156.32, 38.47, 25.33, 17.57.  IR: 1713 cm-1, 1634 cm-1. ESI-MS: 136.2 [M + Na]+. HRMS: calcd for C5H7NO2Na = 136.0374, found 136.0379.  155  A.22  Preparation of compound 2.101  A solution of 2.100 (50 mg, 0.44 mmol) in methanol (3.5 mL) was added dropwise at room temperature to a solution of norbornylene (50 mg, 0.53 mmol, 1.2 eq), PhI(OAc)2 (170 mg, 0.53 mmol, 1.2 eq), TFA (1% v/v, 55 L) and methanol (2 mL) with rapid stirring. The reaction appeared complete in 30 min by TLC. The crude product 2.101 was purified by flash column chromatography using a step-gradient: 5%, 10%, 15%, and 20% ethyl acetate/hexane. Pure fractions of 2.101 were combined and concentrated in vacuo, yielding compound 2.101 as clear viscous oil (0.074 g, 70%).  1  H (CDCl3): 4.34 (d, 1H, J = 8.2), 3.61 (s, 3H), 2.95 (d, 1H, J = 8.2), 2.44 (br s, 1H), 2.40-2.12 (m, 5H),  2.00-1.76 (m, 2H), 1.56-1.29 (m, 3H), 1.22-0.96 (m, 3H). 13  C (CDCl3): 173.50, 157.88, 86.09, 59.33, 51.54, 42.84, 38.18, 33.25, 32.12, 27.21, 26.01, 22.67, 21.40.  IR: 2953 cm-1, 1732 cm-1. ESI-MS: 260.4 [M + Na]+. HRMS: calcd for C13H19NO3Na = 260.1263, found 260.1265.  156  A.23  Preparation of methyl 4-(5-phenyl-4,5-dihydroisoxazol-3-yl)butanoate (2.102)  A solution of 2.100 (38 mg, 0.34 mmol) in methanol (3.5 mL) was added dropwise at room temperature to a solution of styrene (43 mg, 0.41 mmol, 1.2 eq), PhI(OAc)2 (131 mg, 0.41 mmol, 1.2 eq), TFA (1% v/v, 55 L) and methanol (2 mL) with rapid stirring. The reaction was stirred overnight. The crude product 2.102 was purified by flash column chromatography using a step-gradient: 5%, 10%, 15%, and 20% ethyl acetate/hexane. Pure fractions were combined and concentrated in vacuo, yielding 2.102 as clear viscous oil (0.034 g, 40%).  1  H (CDCl3): 7.47-7.28 (m, 5H), 5.55 (dd, 1H, J2 = 11.4, J1 = 8.2), 3.68 (s, 3H), 3.37 (dd, 1H, J2 = 17.0,  J1 = 10.9), 2.91 (dd, 1H, J2 = 17.0, J1 = 8.2), 2.50-2.36 (m, 4H), 1.94 (quin, 2H, J = 7.3). 13  C (CDCl3): 173.50, 157.65, 141.24, 128.77, 128.12, 125.79, 81.46, 51.72, 45.42, 33.26, 27.22, 21.56.  IR: 2951 cm-1, 1731 cm-1. ESI-MS: 270.4 [M + Na]+. HRMS: calcd for C14H17NO3Na = 270.1106, found 270.1111.  Compound 2.102 was known previously in the literature: Ignatovich, Zh. V.; Chernikhova, T. V.; Skupskaya, R. V.; Bondar', N. F.; Koroleva, E. V.; Lakhvich, F. A. Chem. Heterocycl. Compd. 1999, 35(2), 248-249.  157  A.24  Preparation of 2-isonitrosocyclohexanone (2.103)  A solution of 1,2-cyclohexanedione (0.500 g, 4.459 mmol) in diethyl ether (5 mL) was combined with a solution of NaOH (0.178 g, 1.0 eq, 4.459 mmol) and HCl.H2NOH (0.310 g, 1.0 eq, 4.459 mmol) in 5 mL of water and was stirred vigorously overnight. The biphasic reaction mixture was -extracted with diethyl ether (5 times) and dried over anhydrous MgSO4. The crude product 2.103 was filtered and conventrated and purified by flash column chromatography using a step-gradient: 5%, 10%, 15%, 20%, and 30% ethyl acetate/hexane. Pure fractions of 2.103 were combined and concentrated in vacuo, yielding oxime 2.103 (0.139 g, 25%) as viscous oil.  1  H (CDCl3): 9.56 (s, 1H), 2.79 (t, 2H, J = 6.5), 2.58 (t, 2H, J = 6.5), 1.97-1.74 (m, 4H).  13  C (CDCl3): 196.61, 154.19, 41.03, 25.19, 22.66, 21.78.  IR: 1701 cm-1. ESI-MS: 150.2 [M + Na]+. HRMS: calcd for C6H9NO2Na = 150.0531, found 150.0533.  A similar preparation is known: Wu, S.; Fluxe, A.; Janusz, J. M.; Sheffer, J. B.; Browning, G.; Blass, B.; Cobum, K.; Hedges, R.; Murawsky, M.; Fang, B.; Fadayel, G. M.; Hare, M.; Djandjighian, L. Bioorg. Med. Chem. Lett. 2006, 16, 5859-5863.  158  A.25  Preparation of compound 2.104  A solution of oxime 2.103 (69 mg, 0.54 mmol) in methanol (1.5 mL) was added dropwise at room temperature to a solution of norbornylene (61 mg, 0.65 mmol, 1.2 eq), PhI(OAc)2 (209 mg, 0.65 mmol, 1.2 eq), TFA (1% v/v, 25 L) and methanol (1 mL) with stirring. The reaction mixture was stirred overnight. The crude product 2.104 was purified by flash column chromatography using a step-gradient: 5%, 10%, 15%, and 20% ethyl acetate/hexane. Pure fractions of 2.104 were combined and concentrated in vacuo, yielding 2.104 as clear viscous oil (0.076 g, 56%).  1  H (CDCl3): 4.35 (d, 1H, J = 8.2), 3.61 (s, 3H), 2.94 (d, 1H, J = 8.2), 2.46 (s, 1H), 2.37-2.07 (c m, 5H),  1.73-1.30 (c m, 7H), 1.22-0.97 (c m, 3H). 13  C (CDCl3): 173.78, 158.31, 86.06, 59.33, 51.50, 42.86, 38.21, 33.63, 32.15, 27.26, 26.38, 25.67, 24.56,  22.70. IR: 2952 cm-1, 1733 cm-1. ESI-MS: 252.4 [M + H]+; 274.4 [M + Na]+. HRMS: calcd for C14H22NO3 = 252.1600, found 252.1595.  Compound 2.104 was previously known in the literature: Bondar, N. F.; Isaenya, L. P.; Skupskaya, R. V.; Lakhvich, F. A. Russ. J. Org. Chem. 2003, 39(8), 10891094. 159  A.26  Preparation of methyl 5-(5-phenyl-4,5-dihydroisoxazol-3-yl)pentanoate (2.105)  A solution of 2.103 (75 mg, 0.59 mmol) in methanol (1.5 mL) was added dropwise at room temperature to a solution of styrene (74 mg, 0.71 mmol, 1.2 eq), PhI(OAc)2 (228 mg, 0.71 mmol, 1.2 eq), TFA (0.1% v/v, 3 L) and methanol (1 mL) with rapid stirring. The reaction mixture was stirred overnight. The crude product 2.105 was purified by flash column chromatography using a step-gradient: 5%, 10%, 15%, and 20% ethyl acetate/hexane. Pure fractions of 2.105 were collected and concentrated in vacuo, yielding 2.105 as clear viscous oil (0.036 g, 23%).  1  H (CDCl3): 7.41-7.27 (m, 5H), 5.55 (dd, 1H, J2 = 10.7, J1 = 8.2), 3.67 (s, 3H), 3.36 (dd, 1H, J2 = 16.8,  J1 = 10.7), 2.90 (dd, 1H, J2 = 16.8, J1 = 8.2), 2.46-2.30 (m, 4H), 1.80-1.59 (m, 4H). 13  C (CDCl3): 173.88, 158.11, 141.41, 128.83, 128.16, 125.86, 81.46, 51.69, 45.47, 33.70, 27.59, 25.89,  24.56. IR: 2950 cm-1, 1732 cm-1. ESI-MS: 262.5 [M + H]+; 284.4 [M + Na]+. HRMS: calcd for C15H19NO3Na = 284.1263, found 284.1267.  160  A.27  Preparation of 3-(hydroxyimino)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (2.106)  Compound 2.106 was synthesized as detailed by: Chen, Y. K.; Jeon, S.-J.; Walsh, P. J.; Nugent, W. A. Org. Synth. 2005, 82, 87.  161  A.28  Preparation of compounds 2.107/2.108  A solution of 2.106 (500 mg, 2.76 mmol) in methanol (12.5 mL) was added dropwise at room temperature to a solution of norbornylene (312 mg, 3.31 mmol, 1.2 eq), PhI(OAc)2 (1067 mg, 3.31 mmol, 1.2 eq), TFA (1% v/v, 225 L) and methanol (10 mL) with rapid stirring. The reaction apeared complete in 30 min by TLC. The crude products 2.107/2.108 were purified by flash column chromatography using a step-gradient: 5%, 10%, and 15% ethyl acetate/hexane. Pure fractions were combined and concentrated in vacuo, yielding an inseparatable mixture of 2.107/2.108 (0.609 g, 72%) as clear viscous oil. The diastereoselectivity of the product mixture was determined from 1H-NMR integration to be 1 : 1. Diastereomer 1: 1  H (CDCl3): 4.42 (d, 1H, J = 8.3), 3.67 (s, 3H), 3.05 (d, 1H, J = 8.3), 2.86-2.17 (m, 5H), 1.92-1.74 (m,  1H), 1.61-1.36 (m, 4H), 1.29-1.03 (m, 9H), 0.77 (s, 3H). 13  C (CDCl3): 176.50, 158.91, 86.28, 60.27, 56.46, 51.66, 46.45, 46.16, 43.16, 38.44, 32.28, 27.46, 24.39,  23.48, 22.88, 22.38, 21.15. Diastereomer 2: 1  H (CDCl3): 4.36 (d, 1H, J = 8.3), 3.69 (s, 3H), 2.94 (d, 1H, J = 8.3), 2.86-2.17 (m, 5H), 2.07-1.92 (m,  1H), 1.61-1.36 (m, 4H), 1.29-1.03 (m, 9H), 0.86 (s, 3H). 13  C (CDCl3): 176.68, 158.82, 85.64, 77.36, 60.78, 55.95, 47.20, 45.67, 42.75, 39.43, 32.44, 27.66, 25.81,  22.88, 22.14, 20.48. IR: 2960 cm-1, 1723 cm-1. ESI-MS: 306.4 [M + H]+; 328.4 [M + Na]+. HRMS: calcd for C18H28NO3 = 306.2069, found 306.2062. 162  A.29 Preparation of (1S,3R)-methyl 1,2,2-trimethyl-3-(5-phenyl-4,5-dihydroisoxazol-3-yl) cyclopentanecarboxylate (2.109/2.110)  A solution of oxime 2.106 (500 mg, 2.76 mmol) in methanol (12.5 mL) was added dropwise at room temperature to a solution of styrene (345 mg, 3.31 mmol, 1.2 eq), PhI(OAc)2 (1067 mg, 3.31 mmol, 1.2 eq), TFA (1% v/v, 225 L) and methanol (10 mL) with rapid stirring. The reaction appeared complete in 30 min by TLC. The crude products 2.109/2.110 were purified by flash column chromatography using a step-gradient: 5%, 10%, and 15% ethyl acetate/hexane. Pure fractions were collected and concentrated in vacuo, yielding a mixture of 2.109/2.110 (0.206 g, 24%) as clear viscous oil. The diastereoselectivity of the product mixture was determined from 1H-NMR integration to be 1 : 0.8. Diastereomer 1: 1  H (CDCl3): 7.41-7.27 (m, 5H), 5.62-5.47 (m, 1H), 3.66 (s, 3H), 3.44 (dd, 1H, J2 = 16.5, J1 = 10.6), 3.04-  2.80 (m, 2H), 2.73-2.54 (m, 1H), 2.16-1.82 (m, 2H), 1.62-1.46 (m, 1H), 1.28-1.13 (m, 6H), 0.68 (s, 3H). Diastereomer 2: 1  H (CDCl3): 7.41-7.27 (m, 5H), 5.62-5.47 (m, 1H), 3.68 (s, 3H), 3.29 (dd, 1H, J2 = 16.5, J1 = 10.6), 3.04-  2.80 (m, 2H), 2.73-2.54 (m, 1H), 2.16-1.82 (m, 2H), 1.62-1.46 (m, 1H), 1.28-1.13 (m, 6H), 0.79 (s, 3H). Diastereomers 1 and 2: 13  C (CDCl3): 176.45, 176.43, 159.08, 158.75, 141.46, 141.08, 128.83, 128.80, 128.20, 128.08, 125.91,  125.60, 81.58, 81.16, 77.37, 56.15, 56.11, 51.72, 47.17, 47.04, 46.94, 46.76, 46.46, 46.26, 32.58, 24.16, 24.09, 22.85, 22.81, 22.32, 21.21, 21.14. IR: 2964 cm-1, 1722 cm-1. ESI-MS: 316.4 [M + H]+; 338.4 [M + Na]+. HRMS: calcd for C18H28NO3 = 316.1913, found 316.1909. 163  A.30  Preparation of 3,7-dimethyl-6-octenoxime (2.111)  The first report of the preparation of 2.111 appeared to be: Semmler, Ber., 1893, 26, 2255.  Oxime 2.111 was synthesized according to the procedure outlined in: Caldwell, A. G.; Jones, E. R. H. J. Chem. Soc. 1946, 599-601.  164  A.31  Preparation of (6S)-3,3a,4,5,6,7-hexahydro-3,3,6-trimethyl-2,1-benzisoxazole (2.112)  A solution of the oxime 2.111 (99 mg, 0.44 mmol) in CH3OH (2 mL) was slowly added to a solution of DIB (461 mg, 1.43 mmol) and TFA (15 L) in CH3OH (3 mL) over 15 min. The mixture was stirred at room temperature for 45 min, and then it was concentrated in vacuo. A 1H-NMR spectrum of the crude product thus obtained revealed the presence of two products in a ratio of 3.8:1. These products proved to be quite volatile, especially under reduced pressure. This complicated the calculation of a reaction yield. Accordingly, a crude reaction mixture obtained as detailed above was treated with a known amount (1 mmol) of 1,3,5-trimethoxy benzene as an internal standard, and a 1H-NMR spectrum of the mixture was recorded using a delay of 20 seconds between pulses. Integration of the signals of the internal standard and of the products indicated a chemical yield of 85% for the 3.8:1 mixture of products. Flash column chromatography (33% diethyl ether/pentane) afforded a pure sample of the major diastereomer (30 mg, 18 mmol, 41%) for characterization.  1  H (CDCl3): major: 2.72 (ddd, 1H, J = 13.8, 4.1, 1.4), 2.60 (dd, 1H, J = 12.0, 5.4), 1.87-1.68 (m, 2H),  1.55 (m, 1H), 1.4-1.3 (m, 2H), 1.38 (s, 3H), 1.22 (s, 3H), 1.11 (m, 1H), 1.02 (d, 3H, J = 6.5). 13  C (CDCl3): major: 160.63, 84.24, 56.22, 33.91, 33.35, 33.31, 28.47, 26.61, 22.25, 22.07.  ESI-MS: 168.3 [M + H]+. HRMS: calcd for C10H19NO [M + H]+ = 168.1388, found 168.1384. []D20 = –87.0° (0.01 g/mL, CH2Cl2). 165  A.32  Preparation of 4-hydroxy-benzenepropanal oxime (2.123)  Known compound 2.123 (Kusama, H.; Yamashita, Y.; Uchiyama, K.; Narasaka, K.; Bull. Chem. Soc. Jpn., 70, 1997, 965-975) was synthesized from commercially available 3-(4-hydroxyphenyl)propanal (2.122) according to Oresmaa, L.; Kotikoski, H.; Haukka, M.; Salminen, J.; Oksala, O.; Pohjala, E.; Moilanen, E.; Vapaatalo, H.; Vainiotalo, P.; Aulaskari, P., J. Med. Chem. 2005, 48, 4231-4236.  ESI-MS: 166.1 [M + H]+; 188.4 [M + Na]+. HRMS: calcd for C9H10NO2 [M – H]– = 164.0712, found 164.0708.  166  A.33 Preparation of N-[(4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-7-oxoindeno[1,7-cd]isoxazol-4a(7H)yl]-acetamide (2.124)  A solution of 2.123 (62 mg, 0.375 mmol) in acetonitrile (5 mL) was slowly added to a solution of DIB (226 mg, 0.825 mmol) and TFA (15 L) in acetonitrile (20 mL). This reaction mixture was stirred at room temperature for 1 h, and then the volatile organics were removed in vacuo. The crude product 2.124 was purified by flash column chromatography using a step gradient: 25%-50%-100% ethyl acetate/hexanes, to afford 58 mg of compound 2.124 as colorless crystals (0.266 mmol, 71%).  1  H (d6-acetone): 7.84 (brs, 1H), 6.41 (dd, 1H, J = 10.3, 2.0), 6.15 (dd, 1H, J = 10.3, 0.5), 4.72 (dd, 1H, J  = 9.7, 0.5), 4.28 (ddd, 1H, J = 9.7, 2.0, 1.6), 2.69 (m, 1H), 2.64 (m, 2H), 2.37 (m, 1H), 1.84 (s, 1H). 13  C (d6-acetone): 191.12, 170.45, 169.26, 146.53, 132.66, 79.80, 63.57, 53.49, 42.18, 42.12, 23.07,  19.34. MP: 162.163 °C. ESI-MS: 243.3 [M + Na]+. HRMS: calcd for C11H12N2O3Na [M + Na]+ = 243.0746, found 243.0752.  167  A.34  Preparation of 4,4a,7a,7b-tetrahydro-4a-methoxy-indeno[1,7-cd]isoxazol-7(3H)-one (2.125)  A solution of 2.123 (38 mg, 0.23 mmol) in methanol (1.3 mL) was slowly added to a solution of DIB (162 mg, 0.50 mmol) and TFA (15 L) in methanol (2 mL). This reaction mixture was stirred at room temperature for 1 h, and then the volatile organics were removed in vacuo. The crude product was purified by flash column chromatography (step gradient 50%-100% ethyl acetate/hexanes) to afford 29 mg of compound 2.125 (0.15 mmol, 51%).  1  H (d6-acetone): 6.66 (dd, 1H, J = 10.5, 1.9), 6.36 (dd, 1H, J = 10.5, 0.4), 4.84 (d, 1H, J = 10.1), 4.33  (dd, 1H, J = 10.1, 1.8), 3.20 (s, 3H), 2.69 (m, 2H), 2.49 (m, 2H). 13  C (d6-acetone): 192.28, 169.20, 148.93, 134.26, 77.77, 77.23, 60.57, 53.17, 43.32, 20.46.  ESI-MS: 216.3 [M + Na]+. HRMS: calcd for C10H12NO3 [M + H]+ = 216.0637, found 216.0635.  168  A.35  Preparation of N-benzyl, N-tosyl tyrosine (2.130)  To a solution of SOCl2 (10 mL) in methanol (100 mL) was added tyrosine (10.0 g, 45.9 mmol). This solution was allowed to stir at room temperature over night. Volatile organics were removed in vacuo by rotary evaporation. This crude residue was suspended in methanol (10 mL), and added dropwise to a stirring solution of diethyl ether (300 mL). The white precipitate was collected by filtration and the supernatant discarded.  The methyl ester intermediate was dissolved in acetonitrile (100 mL) and  triethylamine (6.40 mL, 45.9 mmol). Benzaldehyde (5.13 mL, 50.5 mmol) was added via syringe, and the reaction was allowed to stir at room temperature. The reaction finished (by TLC) after 2 h, and was concentrated in vacuo. This crude residue was taken up in methanol (200 mL) and cooled in a 0 °C ice bath for 15 min. To this was added solid NaBH4 (2.08 g, 55.1 mmol), and the reaction mixture was allowed to warm to room temperature overnight. Methanol and volatile organics were removed in vacuo, and the crude residue was suspended in ethyl acetate (250 mL) and extracted successively with saturated aqueous NaHCO3, and saturated aqueous NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Without further purification, the residue was suspended in pyridine (25 mL) followed by the addition of solid tosyl chloride (21.9 g, 115 mmol), and this reaction mixture was stirred over night at room temperature. Pyridine was removed in vacuo, and the crude residue suspended in ethyl acetate (200 mL) and washed with 0.1 M aqueous HCl (200 mL) and H2O (200 mL). The organic phase was dried (MgSO4), filtered through a short silica gel plug (10 g) and concentrated in vacuo. This viscous bis-tosyltyrosine ester residue was dissolved in THF (100 mL), and to this was added a solution of NaOH (7.34 g, 183.6 mmol) in H2O (100 mL). (Upon addition of aqueous NaOH, a white cloudy precipitate formed which slowly disappeared over the course of the reaction.) The reaction was heated to 75 °C and allowed to stir overnight. The reaction was concentrated in vacuo, and re-suspended in ethyl acetate (250 mL). The organic solution was washed successively with 1.0 M aqueous HCl (100 mL) and H 2O (100 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Pure 2.130 (12.5 g, 29.4 mmol, 64%) was obtained as colorless crystals from crystallization in refluxing CH2Cl2.  169  1  H (d6-acetone): 8.20 (brs, 1H), 7.73 (d, 2H, J = 8.3), 7.35 (d, 2H, J = 8.3), 7.35-7.23 (m, 5H), 6.90 (d,  2H, J = 8.5), 6.69 (d, 2H, J = 8.5), 4.65 (d, 1H, J = 16.1), 4.64 (m, 1H), 4.43 (d, 1H, J = 16.1), 3.07 (dd, 1H, J = 13.9, 8.3), 2.72 (dd, 1H, J = 13.9, 6.5), 2.41 (s, 3H). 13  C (d6-acetone): 171.43, 156.93, 144.23, 138.66, 138.46, 131.03, 130.29, 129.21, 128.92, 128.85,  128.46, 128.09, 115.92, 62.36, 50.20, 36.99, 21.40. MP: 154-156 °C. ESI-MS: 426.4 [M + H]+; 448.1 [M + Na]+; 424.3 [M – H]-. HRMS: calcd for C23H23NO5SNa [M + Na]+ = 448.1195, found 448.1209.  170  A.36 Preparation of N-[2-(hydroxyimino)-1-[(4-hydroxyphenyl)methyl]ethyl]-4-methyl-N(phenylmethyl)-benzenesulfonamide (2.132)  Carboxylic acid 2.130 (5.00 g, 11.8 mmol) was dissolved in THF (20 mL) at room temperature. To this solution was added HN(CH3)OCH3•HCl (1.73 g, 17.7 mmol), triethylamine (4.9 mL, 35.4 mmol) and PyBOP (9.21 g, 17.7 mmol). The reaction was stirred for 12 hours, and then the solvent was removed in vacuo. The crude residue was diluted with ethyl acetate (200 mL) and washed successively with 100 mL portions of 0.1 M aqueous HCl and H2O. The organic solution was dried over anhydrous MgSO4, filtered through a silica gel plug (10 g) and concentrated in vacuo. The crude Weinreb amide product was dissolved in THF (100 mL), and this solution was cooled in a 0 °C ice-bath. A suspension of LiAlH4 (0.67 g, 17.7 mmol) in THF (50 mL) was added with vigorous stirring. This heterogeneous reaction mixture was stirred at 0 °C for 4 h. The reaction was quenched at 0 °C by the addition of saturated aqueous NaHSO4 (3 mL) and stirred for 0.5 h, followed by the addition of aqueous 1 M aqueous HCl (5 mL) and then diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous MgSO4, filtered through a silica gel plug (10 g) and concentrated in vacuo. The crude aldehyde was immediately dissolved in diethyl ether (50 mL), and to this was added sequentially a solution of H2NOH•HCl (3.44 g, 35.4 mmol) in H2O (50 mL) and a solution of Na2CO3 (6.25 g, 59 mmol) in H2O (50 mL). This reaction was stirred at room temperature over night and then diluted with diethyl ether (50 mL) and the organic phase was separated, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Pure 2.132 (0.55 g, 1.30 mmol, 11%) was obtained following flash column chromatography with 30% ethyl acetate/hexanes. Note: this reaction sequence was not optimized for higher recovered yield.  171  1  H (d6-acetone): 9.97 (s, 1H), 8.14 (s, 1H), 7.72 (d, 2H, J = 8.3), 7.36 (m, 5H), 7.28 (d, 2H, J = 8.3), 7.15  (d, 2H, J = 6.0), 6.82 (d, 2H, J = 8.7), 6.69 (d, 2H, J = 8.3), 4.61 (ddd, 1H, J1 = 9.1, J2 = J3 = 6.0), 4.46 (ABq, 2H, J = 29.4, 16.0), 3.0 (dd, 1H, J = 13.6, 9.1), 2.87 (s, 3H), 2.71 (dd, 1H, J = 13.6, 6.0), 2.43 (s, 3H). 13  C (d6-acetone): 156.82, 148.49, 144.24, 138.98, 138.93, 131.09, 130.51, 129.28, 129.16, 129.12,  128.26 (two overlapping signals), 115.90, 60.41, 49.67, 37.74, 21.42. ESI-MS: 425.2 [M + H]+, 447.2 [M + Na]+. HRMS: calcd for C23H24N2O5SNa [M + Na]+ = 447.1354, found 447.1362.  172  A.37 Preparation of N-[(3R,4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-3-[[(4-methylphenyl)sulfonyl] (phenylmethyl)amino]-7-oxoindeno[1,7-cd]isoxazol-4a(7H)-yl]-acetamide (2.134)  A solution of oxime 2.132 (20 mg, 0.047 mmol) in acetonitrile (3 mL) was slowly added to a solution of DIB (36 mg, 0.113 mmol) and TFA (15 L) in acetonitrile (3 mL) over 10 min. The mixture was stirred at room temperature for 1 h, and then it was diluted with heptanes (0.4 mL) and concentrated in vacuo by rotary evaporation. The reaction residue was immediately purified by flash column chromatography using a step gradient: 50%-100% ethyl acetate/hexanes, to afford 10 mg of compound 2.134 (0.021 mmol, 44%) as a glassy solid.  1  H (d6-acetone): 7.82 (d, 2H, J = 8.5), 7.76 (brs, 1H), 7.43 (d, 2H, J = 8.5), 7.36 (m, 5H), 6.32 (dd, 1H, J  = 10.2, 2.0), 6.08 (dd, 1H, J = 10.2, 0.4), 4.68 (dd, 1H, J = 9.8, 0.4), 4.64 (m, 1H), 4.58 (d, 1H, J = 15.9), 4.32 (d, 1H, J = 15.9), 3.93 (dt, 1H, J = 9.8, 2.0), 2.87 (dd, 1H, J = 13.6, 8.1), 2.63 (dd, 1H, J = 13.6, 9.2), 2.44 (s, 3H), 1.77 (s, 3H). 13  C (d6-acetone): 189.86, 170.41, 170.33, 166.65, 145.55, 144.85, 137.80, 137.55, 132.59, 130.71,  129.43, 129.31, 128.69, 128.39, 80.95, 62.09, 51.74, 51.66, 51.53, 49.98, 49.92, 22.95, 22.91, 21.44. ESI-MS: 502.2 [M + Na]+; 478.3 [M – H]–. HRMS: calcd for C25H24N3O5S [M - H]- = 478.1437, found 478.1446.  173  B. Experimental section  1 B.1 H-NMR spectrum and 13C-NMR spectrum for: methyl 2-(1-acetamido-4-oxocyclohexa-2,5dienyl)acetate (2.32)  O HN  CH3 CO2CH3  O 2.32  O HN  CH3 CO2CH3  O 2.32  174  1 B.2 H-NMR spectrum and 13C-NMR spectrum for: methyl 2-((1r,4r)-1-acetamido-4-(tertbutyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetate (2.37)  NHAc H  CO2CH3  TBDPSO 2.37  NHAc H  CO2CH3  TBDPSO 2.37  175  1 B.3 H-NMR spectrum and 13C-NMR spectrum butyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetic acid (2.38)  for:  2-((1r,4r)-1-acetamido-4-(tert-  NHAc H  CO2H  TBDPSO 2.38  NHAc H  CO2H  TBDPSO 2.38  176  1 B.4 H-NMR spectrum and 13C-NMR spectrum for: N-((1r,4r)-4-(tert-butyldiphenylsilyloxy)-1(3-nitro-2-oxopropyl)cyclohexa-2,5-dienyl)acetamide (2.39)  NHAc H O  TBDPSO  NO2  2.39  NHAc H O  TBDPSO  NO2  2.39  177  1 B.5 H-NMR spectrum and 13C-NMR tetrahydrobenzofuran-3a-yl)acetamide (2.41)  spectrum  for:  N-((3aS,7aS)-2-oxo-2,3,3a,7a-  NHAc O O H 2.41  NHAc O O H 2.41  178  1 B.6 H-NMR spectrum and 13C-NMR spectrum for: N-((2aR,2a1S,3S,5aS)-3-(tertbutyldiphenylsilyloxy)-7-oxo-2a,2a1,3,5a,6,7-hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.43)  NHAc TBDPS O  O H  O N  2.43  NHAc TBDPS O  O H  O N  2.43  179  1 B.7 H-NMR spectrum and 13C-NMR spectrum for: N-((3aS,7aS,E)-2-(nitromethylene)2,3,3a,7a-tetrahydrobenzofuran-3a-yl)acetamide (2.44)  NHAc NO2 O H 2.44  NHAc NO2 O H 2.44  180  1 B.8 H-NMR spectrum and 13C-NMR spectrum for: N-((1r,4r)-1-(2-(tert-butyldimethylsilyloxy)3-nitropropyl)-4-(tert-butyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetamide (2.46)  NHAc NO2 OTBS  TBDPSO 2.46  NHAc NO2 OTBS  TBDPSO 2.46  181  B.9  1  H-NMR spectrum for: compound 2.49  182  B.10  1  H-NMR spectrum and 13C-NMR spectrum for: compound 2.50  183  B.11  1  H-NMR spectrum for: compound 2.51/2.52  184  13 B.12 1H-NMR spectrum and C-NMR spectrum for: trans-9-[[(1,1dimethylethyl)diphenylsilyl]oxy]-2-methyl-3-nitro-1-azaspiro[5.5]undeca-2,7,10-trien-4-one (2.55)  185  B.13 1H-NMR spectrum and 13C-NMR spectrum for: methyl 2-((1S,4S,5R,6S)-1-acetamido-4(tert-butyldiphenylsilyloxy)-6-cyano-5-hydroxycyclohex-2-enyl)acetate (2.59)  186  B.14 1H-NMR spectrum and 13C-NMR spectrum for: N-((2aR,2a1S,3S,5aS)-3-hydroxy-7-oxo2a,2a1,3,5a,6,7-hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.60)  187  B.15 1H-NMR spectrum and 13C-NMR spectrum for: methyl 2-((1S,5R,6S)-1-acetamido-6-cyano5-hydroxy-4-oxocyclohex-2-enyl)acetate (2.62)  188  B.16 1H-NMR spectrum for: N-((2aR,2a1S,3R,5aS)-3-(tert-butyldiphenylsilyloxy)-7-oxo2a,2a1,3,5a,6,7-hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.66)  NHAc  O TBDPS  O O N 2.66  189  B.17 1H-NMR spectrum and 13C-NMR spectrum for: methyl 2-((1S,4R,5R,6S)-1-acetamido-4(tert-butyldiphenylsilyloxy)-6-cyano-5-hydroxycyclohex-2-enyl)acetate (2.67)  NHAc CO2CH3 O TBDPS  C OH  N  2.67  NHAc CO2CH3 O TBDPS  C OH  N  2.67  190  B.18 1H-NMR spectrum and dihydroisoxazole (2.76)  13  C-NMR spectrum for: 3-(4-methoxyphenyl)-5-phenyl-4,5-  191  B.19  1  H-NMR spectrum and 13C-NMR spectrum for: 3,5-diphenyl-4,5-dihydroisoxazole (2.77)  192  B.20 1H-NMR spectrum dihydroisoxazole (2.78)  and  13  C-NMR  spectrum  for:  3-(3-nitrophenyl)-5-phenyl-4,5-  193  B.21 (2.79)  1  H-NMR spectrum and  13  C-NMR spectrum for: 3-pentyl-5-phenyl-4,5-dihydroisoxazole  N O  2.79  N O  2.79  194  B.22 (2.80)  1  H-NMR spectrum and 13C-NMR spectrum for: 3-phenethyl-5-phenyl-4,5-dihydroisoxazole  195  B.23 1H-NMR spectrum and methano-1,2-benzisoxazole (2.81)  13  C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-phenyl-4,7-  N O H H 2.81  N O H H 2.81  196  B.24 1H-NMR spectrum and 13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-(3-nitrophenyl)4,7-methano-1,2-benzisoxazole (2.82)  N O O2N  2.82  N O O2N  2.82  197  B.25 1H-NMR spectrum and methano-1,2-benzisoxazole (2.83)  13  C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-pentyl-4,7-  198  B.26 1H-NMR spe ctrum and 13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-(2-phenylethyl)4,7-methano-1,2-benzisoxazole (2.84)  N O  H  H 2.84  N O  H  H 2.84  199  B.27 1H-NMR spectrum and 13C-NMR spectrum for: 3-(1,1-dimethylethyl)-3a,4,5,6,7,7ahexahydro4,7-methano-1,2-benzisoxazole (2.85) N O  2.85  N O  2.85  200  B.27 1H-NMR spectrum and 13C-NMR spectrum methoxyphenyl)-4,7-methano-1,2-benzisoxazole (2.86)  for:  3a,4,5,6,7,7a-hexahydro-3-(4-  N O  H3CO  2.86  N O  H3CO  2.86  201  B.28 1H-NMR spectrum and isoxazole (2.87)  13  C-NMR spectrum for: 5-(3-bromopropyl)-4,5-dihydro-3-phenyl-  Br N O  2.87  Br N O  2.87  202  B.29  1  H-NMR spectrum and 13C-NMR spectrum for: 3,5-diphenylisoxazole (2.88)  N O  2.88  N O  2.88  203  B.30 1H-NMR spectrum and 13C-NMR spectrum for: 1-(3a,4,5,6,7,7a-hexahydro-4,7-methano1,2-benzisoxazol-3-yl)-ethanone (2.90)  204  B.31 1H-NMR spectrum and ethanone (2.91)  13  C-NMR spectrum for: 1-(4,5-dihydro-5-phenyl-3-isoxazolyl)-  205  B.32 1H-NMR spectrum and 13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2benzisoxazole-3-carboxylic acid ethyl ester (2.93)  206  B.33 1H-NMR spectrum and 13C-NMR spectrum for: 4,5-dihydro-5-phenyl-3-isoxazolecarboxylic acid ethyl ester (2.94)  207  B.34  1  H-NMR spectrum and 13C-NMR spectrum for: 2-isonitrosocyclopentanone (2.100)  208  B.35  1  H-NMR spectrum and 13C-NMR spectrum for: compound 2.101  209  B.36 1H-NMR spectrum and 13C-NMR spectrum for: methyl 4-(5-phenyl-4,5-dihydroisoxazol-3yl)butanoate (2.102)  210  B.37  1  H-NMR spectrum and 13C-NMR spectrum for: 2-isonitrosocyclohexanone (2.103)  211  B.38  1  H-NMR spectrum and 13C-NMR spectrum for: compound 2.104  212  B.39 1H-NMR spectrum and 13C-NMR spectrum for: methyl 5-(5-phenyl-4,5-dihydroisoxazol-3yl)pentanoate (2.105)  213  B.40  1  H-NMR spectrum and 13C-NMR spectrum for: compounds 2.107/2.108  214  B.41 1H-NMR spectrum and 13C-NMR spectrum for: (1S,3R)-methyl 1,2,2-trimethyl-3-(5-phenyl4,5-dihydroisoxazol-3-yl) cyclopentanecarboxylate (2.109/2.110)  215  B.42 1H-NMR spectrum and 13C-NMR spectrum for: diastereomers (6S)-3,3a,4,5,6,7-hexahydro3,3,6-trimethyl-2,1-benzisoxazole (2.112)  H O N 2.112 crude mixture of diastereomers (3.8:1)  H O N 2.112 crude mixture of diastereomers (3.8:1)  216  B.43 1H-NMR spectrum and 13C-NMR spectrum for: major diastereomer (6S)-3,3a,4,5,6,7hexahydro-3,3,6-trimethyl-2,1-benzisoxazole (2.112)  H O N 2.112 major diastereomer  H O N 2.112 major diastereomer  217  B.44 1H-NMR spectrum and 13C-NMR spectrum for: N-[(4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-7oxoindeno[1,7-cd]isoxazol-4a(7H)-yl]-acetamide (2.124)  NHAc  O O N 2.124  NHAc  O O N 2.124  218  B.45 1H-NMR spectrum and 13C-NMR spectrum for: 4,4a,7a,7b-tetrahydro-4a-methoxyindeno[1,7-cd]isoxazol-7(3H)-one (2.125)  OCH3 O O N 2.125  OCH3 O O N 2.125  219  B.46  1  H-NMR spectrum and 13C-NMR spectrum for: N-benzyl, N-tosyl tyrosine (2.130) HO  COOH N Ts  Ph  2.130  HO  COOH N Ts  Ph  2.130  220  B.47 1H-NMR spectrum and 13C-NMR spectrum for: N-[2-(hydroxyimino)-1-[(4hydroxyphenyl)methyl]ethyl]-4-methyl-N-(phenylmethyl)-benzenesulfonamide (2.132) OH N  HO  N Ts  Ph  2.132  OH N  HO  N Ts  Ph  2.132  221  B.48 1H-NMR spectrum and 13C-NMR spectrum for: N-[(3R,4aR,7aS,7bR)-3,4,7a,7b-tetrahydro3-[[(4-methylphenyl)sulfonyl](phenylmethyl)amino]-7-oxoindeno[1,7-cd]isoxazol-4a(7H)-yl]acetamide (2.134)  O NH O O N  N  Ts  2.134  O NH O O N  N  Ts  2.134  222  C. X-ray crystallography data  C.1  X-ray data of methyl 2-(1-acetamido-4-oxocyclohexa-2,5-dienyl)acetate (2.32) O HN  CH3 CO2CH3  O  2.32  Crystal Data  Empirical Formula  C11H13NO4  Formula Weight  223.22  Crystal Color, Habit  colorless, prism  Crystal Dimensions  0.20 X 0.20 X 0.40 mm  Crystal System  orthorhombic  Lattice Type  primitive  Lattice Parameters  a = 9.1171(15) Å b = 14.639(2) Å c = 16.626(3) Å  = 90°  = 90°  = 90° V = 2219.0(6) Å3  Space Group  P bca (#61)  Z value  8  Dcalc  1.366 g/cm3  F000  944.00  (MoK)  1.02 cm-1  223  Intensity Measurements  Diffractometer  Bruker X8 APEX II  Radiation  MoK ( = 0.71073 Å) graphite monochromated  Data Images  1235 exposures @ 20.0 seconds  Detector Position  36.00 mm  2max  56.0°  No. of Reflections Measured  Total: 24567 Unique: 2658 (Rint = 0.024)  Corrections  Absorption (Tmin = 0.843, Tmax = 0.980) Lorentz-polarization  Structure Solution and Refinement  Structure Solution  Direct Methods (SIR97)  Refinement  Full-matrix least-squares on F2  Function Minimized   w (Fo2 – Fc2)2  Least Squares Weights  w = 1/(2(Fo2) + (0.0545P)2 + 0.7113P)  Anomalous Dispersion  All non-hydrogen atoms  No. Observations (I>0.00(I))  2658  No. Variables  151  Reflection/Parameter Ratio  17.60  Residuals (refined on F2, all data): R1; wR2  0.059; 0.124  Goodness of Fit Indicator  1.05  No. Observations (I>2.00(I))  2035  Residuals (refined on F): R1; wR2  0.042; 0.109  Max Shift/Error in Final Cycle  0.00  Maximum peak in Final Diff. Map  0.26 e-/Å3  Minimum peak in Final Diff. Map  -0.23 e-/Å3  224  Atomic coordinates (x104) and equivalent isotropic displacement parameters (A2 x 103) for mc010. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________ x y z U(eq) ________________________________________________________________ C(1) 8932(2) 4498(1) 8594(1) 43(1) C(2) 9535(2) 3680(1) 8566(1) 45(1) C(3) 8715(2) 2875(1) 8315(1) 43(1) C(4) 7157(2) 3002(1) 8149(1) 44(1) C(5) 6543(2) 3819(1) 8178(1) 40(1) C(6) 7334(2) 4672(1) 8428(1) 37(1) C(7) 6540(2) 5006(1) 9192(1) 44(1) C(8) 7074(2) 5890(1) 9551(1) 48(1) C(9) 6339(3) 7110(1) 10383(1) 69(1) C(10) 7579(2) 5285(1) 7050(1) 43(1) C(11) 7281(2) 6091(1) 6516(1) 58(1) N(1) 7151(1) 5385(1) 7820(1) 41(1) O(1) 9316(1) 2131(1) 8228(1) 60(1) O(2) 8274(2) 6205(1) 9501(1) 78(1) O(3) 5988(1) 6284(1) 9952(1) 57(1) O(4) 8171(1) 4594(1) 6804(1) 59(1) ________________________________________________________________ Bond lengths [A] and angles [deg] for mc010. _____________________________________________________________ C(1)-C(2) C(1)-C(6) C(1)-H(1) C(2)-C(3) C(2)-H(2) C(3)-O(1) C(3)-C(4) C(4)-C(5) C(4)-H(4) C(5)-C(6) C(5)-H(5) C(6)-N(1) C(6)-C(7) C(7)-C(8) C(7)-H(7A) C(7)-H(7B) C(8)-O(2) C(8)-O(3) C(9)-O(3) C(9)-H(9A) C(9)-H(9B) C(9)-H(9C) C(10)-O(4) C(10)-N(1) C(10)-C(11) C(11)-H(11A) C(11)-H(11B) C(11)-H(11C) N(1)-H(1N)  1.319(2) 1.5047(19) 0.9300 1.456(2) 0.9300 1.2275(17) 1.459(2) 1.3213(19) 0.9300 1.5011(18) 0.9300 1.4634(18) 1.541(2) 1.506(2) 0.9700 0.9700 1.190(2) 1.326(2) 1.441(2) 0.9600 0.9600 0.9600 1.2168(18) 1.3457(19) 1.502(2) 0.9600 0.9600 0.9600 0.870(18)  225  C(2)-C(1)-C(6) 123.44(13) C(2)-C(1)-H(1) 118.3 C(6)-C(1)-H(1) 118.3 C(1)-C(2)-C(3) 122.05(13) C(1)-C(2)-H(2) 119.0 C(3)-C(2)-H(2) 119.0 O(1)-C(3)-C(2) 121.47(14) O(1)-C(3)-C(4) 121.68(14) C(2)-C(3)-C(4) 116.83(12) C(5)-C(4)-C(3) 121.37(13) C(5)-C(4)-H(4) 119.3 C(3)-C(4)-H(4) 119.3 C(4)-C(5)-C(6) 124.05(13) C(4)-C(5)-H(5) 118.0 C(6)-C(5)-H(5) 118.0 N(1)-C(6)-C(5) 110.29(12) N(1)-C(6)-C(1) 110.95(11) C(5)-C(6)-C(1) 112.01(11) N(1)-C(6)-C(7) 106.87(11) C(5)-C(6)-C(7) 105.52(11) C(1)-C(6)-C(7) 110.94(12) C(8)-C(7)-C(6) 116.59(12) C(8)-C(7)-H(7A) 108.1 C(6)-C(7)-H(7A) 108.1 C(8)-C(7)-H(7B) 108.1 C(6)-C(7)-H(7B) 108.1 H(7A)-C(7)-H(7B) 107.3 O(2)-C(8)-O(3) 123.58(15) O(2)-C(8)-C(7) 127.05(15) O(3)-C(8)-C(7) 109.36(13) O(3)-C(9)-H(9A) 109.5 O(3)-C(9)-H(9B) 109.5 H(9A)-C(9)-H(9B) 109.5 O(3)-C(9)-H(9C) 109.5 H(9A)-C(9)-H(9C) 109.5 H(9B)-C(9)-H(9C) 109.5 O(4)-C(10)-N(1) 122.54(14) O(4)-C(10)-C(11) 122.37(15) N(1)-C(10)-C(11) 115.08(14) C(10)-C(11)-H(11A) 109.5 C(10)-C(11)-H(11B) 109.5 H(11A)-C(11)-H(11B) 109.5 C(10)-C(11)-H(11C) 109.5 H(11A)-C(11)-H(11C) 109.5 H(11B)-C(11)-H(11C) 109.5 C(10)-N(1)-C(6) 123.18(12) C(10)-N(1)-H(1N) 117.2(11) C(6)-N(1)-H(1N) 119.6(11) C(8)-O(3)-C(9) 116.70(15) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms:  226  Anisotropic displacement parameters (A2 x 103) for mc010. The anisotropic displacement factor exponent takes the form: -2 2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ] _______________________________________________________________________ U11 U22 U33 U23 U13 U12 _______________________________________________________________________ C(1) 36(1) 36(1) 55(1) 0(1) -4(1) -7(1) C(2) 34(1) 43(1) 57(1) 4(1) -8(1) -1(1) C(3) 45(1) 31(1) 51(1) 7(1) -1(1) 2(1) C(4) 42(1) 32(1) 57(1) 0(1) -5(1) -7(1) C(5) 36(1) 35(1) 50(1) 1(1) -7(1) -4(1) C(6) 37(1) 28(1) 44(1) 2(1) -2(1) -2(1) C(7) 43(1) 43(1) 45(1) 0(1) 2(1) -8(1) C(8) 51(1) 48(1) 45(1) -4(1) 0(1) -6(1) C(9) 89(1) 56(1) 62(1) -17(1) 9(1) -3(1) C(10) 38(1) 43(1) 47(1) 3(1) 1(1) -5(1) C(11) 62(1) 57(1) 55(1) 15(1) -2(1) -8(1) N(1) 47(1) 29(1) 47(1) 2(1) 3(1) 4(1) O(1) 54(1) 34(1) 92(1) 1(1) -3(1) 7(1) O(2) 56(1) 72(1) 107(1) -38(1) 9(1) -20(1) O(3) 64(1) 51(1) 56(1) -11(1) 12(1) -5(1) O(4) 61(1) 57(1) 57(1) -5(1) 12(1) 10(1) _______________________________________________________________________  227  Hydrogen coordinates (x104) and isotropic displacement parameters (A2 x 103) for mc010. ________________________________________________________________ x y z U(eq) ________________________________________________________________ H(1) 9525 4993 8723 51 H(2) 10515 3614 8711 53 H(4) 6584 2497 8021 52 H(5) 5561 3868 8034 48 H(7A) 5507 5074 9067 52 H(7B) 6622 4534 9599 52 H(9A) 6773 6956 10891 103 H(9B) 5459 7456 10471 103 H(9C) 7018 7467 10073 103 H(11A) 8174 6425 6431 87 H(11B) 6570 6482 6767 87 H(11C) 6908 5883 6008 87 H(1N) 6730(20) 5898(13) 7949(10) 50(5) ________________________________________________________________ Torsion angles [deg] for mc010. ________________________________________________________________ C(6)-C(1)-C(2)-C(3) 4.4(2) C(1)-C(2)-C(3)-O(1) 174.00(16) C(1)-C(2)-C(3)-C(4) -4.3(2) O(1)-C(3)-C(4)-C(5) -174.20(16) C(2)-C(3)-C(4)-C(5) 4.1(2) C(3)-C(4)-C(5)-C(6) -4.1(2) C(4)-C(5)-C(6)-N(1) 127.64(16) C(4)-C(5)-C(6)-C(1) 3.5(2) C(4)-C(5)-C(6)-C(7) -117.28(16) C(2)-C(1)-C(6)-N(1) -127.42(16) C(2)-C(1)-C(6)-C(5) -3.7(2) C(2)-C(1)-C(6)-C(7) 113.94(17) N(1)-C(6)-C(7)-C(8) -59.72(16) C(5)-C(6)-C(7)-C(8) -177.13(13) C(1)-C(6)-C(7)-C(8) 61.35(16) C(6)-C(7)-C(8)-O(2) -27.0(3) C(6)-C(7)-C(8)-O(3) 153.43(13) O(4)-C(10)-N(1)-C(6) -1.1(2) C(11)-C(10)-N(1)-C(6) 179.36(13) C(5)-C(6)-N(1)-C(10) -58.91(18) C(1)-C(6)-N(1)-C(10) 65.79(17) C(7)-C(6)-N(1)-C(10) -173.14(13) O(2)-C(8)-O(3)-C(9) -3.8(3) C(7)-C(8)-O(3)-C(9) 175.79(14) ________________________________________________________________  228  C.2 X-ray data of N-((3aS,7aS,E)-2-(nitromethylene)-2,3,3a,7a-tetrahydrobenzofuran-3ayl)acetamide (2.44)  NHAc NO2 O H 2.44  Crystal Data  Empirical Formula  C11H12N2O4  Formula Weight  236.23  Crystal Color, Habit  colorless, needle  Crystal Dimensions  0.06 X 0.08 X 0.35 mm  Crystal System  monoclinic  Lattice Type  primitive  Lattice Parameters  a = 8.6012(3) Å b = 9.6959(4) Å c = 13.3029(5) Å  = 90.0°  = 96.914(2)°  = 90.0° V = 1101.35(7) Å3  Space Group  P 21/c (#14)  Z value  4  Dcalc  1.425 g/cm3  F000  496.00  (MoK)  1.10 cm-1  229  Intensity Measurements  Diffractometer  Bruker X8 APEX II  Radiation  MoK ( = 0.71073 Å) graphite monochromated  Data Images  739 exposures @ 30.0 seconds  Detector Position  36.00 mm  2max  50.0°  No. of Reflections Measured  Total: 7510 Unique: 1936 (Rint = 0.033)  Corrections  Absorption (Tmin = 0.916, Tmax = 0.993) Lorentz-polarization  Structure Solution and Refinement  Structure Solution  Direct Methods (SIR97)  Refinement  Full-matrix least-squares on F2  Function Minimized   w (Fo2 – Fc2)2  Least Squares Weights  w = 1/(2(Fo2) + (0.0486P)2 + 0.3430P)  Anomalous Dispersion  All non-hydrogen atoms  No. Observations (I>0.00(I))  1936  No. Variables  159  Reflection/Parameter Ratio  12.18  Residuals (refined on F2, all data): R1; wR2  0.056; 0.101  Goodness of Fit Indicator  1.02  No. Observations (I>2.00(I))  1479  Residuals (refined on F): R1; wR2  0.038; 0.93  Max Shift/Error in Final Cycle  0.00  Maximum peak in Final Diff. Map  0.19 e-/Å3  Minimum peak in Final Diff. Map  -0.15 e-/Å3  230  Atomic coordinates (x104) and equivalent isotropic displacement parameters (A2 x 103) for mc013. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________ x y z U(eq) ________________________________________________________________ C(1) 8669(2) 1754(2) 9456(1) 35(1) C(2) 7705(3) 649(2) 9859(2) 47(1) C(3) 6566(3) 21(2) 9273(2) 54(1) C(4) 6156(2) 394(2) 8226(2) 51(1) C(5) 6837(2) 1449(2) 7816(2) 40(1) C(6) 7981(2) 2369(2) 8440(1) 29(1) C(7) 7095(2) 3656(2) 8768(1) 31(1) C(8) 7871(2) 3970(2) 9800(1) 30(1) C(9) 7764(2) 5075(2) 10401(1) 34(1) C(10) 10253(2) 1914(2) 7539(1) 29(1) C(11) 11505(2) 2509(2) 6980(2) 39(1) N(1) 9248(2) 2811(2) 7876(1) 30(1) N(2) 6732(2) 6166(2) 10131(1) 35(1) O(1) 6758(2) 7153(2) 10727(1) 57(1) O(2) 5814(2) 6126(1) 9346(1) 40(1) O(3) 8813(2) 2941(1) 10157(1) 42(1) O(4) 10154(2) 661(1) 7692(1) 36(1) ________________________________________________________________ Bond lengths [A] and angles [deg] for mc013. _____________________________________________________________ C(1)-O(3) C(1)-C(2) C(1)-C(6) C(1)-H(1) C(2)-C(3) C(2)-H(2) C(3)-C(4) C(3)-H(3) C(4)-C(5) C(4)-H(4) C(5)-C(6) C(5)-H(5) C(6)-N(1) C(6)-C(7) C(7)-C(8) C(7)-H(7A) C(7)-H(7B) C(8)-O(3) C(8)-C(9) C(9)-N(2) C(9)-H(9) C(10)-O(4) C(10)-N(1) C(10)-C(11) C(11)-H(11A) C(11)-H(11B) C(11)-H(11C)  1.478(2) 1.493(3) 1.530(3) 1.0000 1.324(3) 0.9500 1.441(4) 0.9500 1.328(3) 0.9500 1.502(3) 0.9500 1.460(2) 1.551(2) 1.484(3) 0.9900 0.9900 1.336(2) 1.347(3) 1.401(2) 0.9500 1.237(2) 1.341(2) 1.496(3) 0.9800 0.9800 0.9800  231  N(1)-H(1N) N(2)-O(2) N(2)-O(1)  0.80(2) 1.232(2) 1.241(2)  O(3)-C(1)-C(2) 109.90(16) O(3)-C(1)-C(6) 104.35(14) C(2)-C(1)-C(6) 115.07(17) O(3)-C(1)-H(1) 109.1 C(2)-C(1)-H(1) 109.1 C(6)-C(1)-H(1) 109.1 C(3)-C(2)-C(1) 121.5(2) C(3)-C(2)-H(2) 119.2 C(1)-C(2)-H(2) 119.2 C(2)-C(3)-C(4) 122.1(2) C(2)-C(3)-H(3) 119.0 C(4)-C(3)-H(3) 119.0 C(5)-C(4)-C(3) 121.4(2) C(5)-C(4)-H(4) 119.3 C(3)-C(4)-H(4) 119.3 C(4)-C(5)-C(6) 121.5(2) C(4)-C(5)-H(5) 119.3 C(6)-C(5)-H(5) 119.3 N(1)-C(6)-C(5) 111.75(15) N(1)-C(6)-C(1) 109.55(15) C(5)-C(6)-C(1) 114.50(16) N(1)-C(6)-C(7) 109.28(14) C(5)-C(6)-C(7) 108.78(14) C(1)-C(6)-C(7) 102.51(14) C(8)-C(7)-C(6) 104.11(14) C(8)-C(7)-H(7A) 110.9 C(6)-C(7)-H(7A) 110.9 C(8)-C(7)-H(7B) 110.9 C(6)-C(7)-H(7B) 110.9 H(7A)-C(7)-H(7B) 109.0 O(3)-C(8)-C(9) 117.63(17) O(3)-C(8)-C(7) 111.22(15) C(9)-C(8)-C(7) 131.15(17) C(8)-C(9)-N(2) 122.34(18) C(8)-C(9)-H(9) 118.8 N(2)-C(9)-H(9) 118.8 O(4)-C(10)-N(1) 121.50(17) O(4)-C(10)-C(11) 121.89(16) N(1)-C(10)-C(11) 116.61(16) C(10)-C(11)-H(11A) 109.5 C(10)-C(11)-H(11B) 109.5 H(11A)-C(11)-H(11B) 109.5 C(10)-C(11)-H(11C) 109.5 H(11A)-C(11)-H(11C) 109.5 H(11B)-C(11)-H(11C) 109.5 C(10)-N(1)-C(6) 122.18(16) C(10)-N(1)-H(1N) 119.9(15) C(6)-N(1)-H(1) 117.8(15) O(2)-N(2)-O(1) 121.80(17) O(2)-N(2)-C(9) 121.03(16) O(1)-N(2)-C(9) 117.15(17) C(8)-O(3)-C(1) 110.85(14) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms:  232  Anisotropic displacement parameters (A2 x 103) for mc013. The anisotropic displacement factor exponent takes the form: -2 2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ] _______________________________________________________________________ U11 U22 U33 U23 U13 U12 _______________________________________________________________________ C(1) 40(1) 33(1) 34(1) 1(1) 11(1) 8(1) C(2) 63(2) 34(1) 49(1) 12(1) 31(1) 15(1) C(3) 55(2) 30(1) 85(2) 0(1) 42(1) -2(1) C(4) 34(1) 40(1) 80(2) -17(1) 13(1) -8(1) C(5) 32(1) 41(1) 46(1) -10(1) 4(1) 1(1) C(6) 30(1) 26(1) 32(1) -1(1) 9(1) 1(1) C(7) 32(1) 30(1) 32(1) 0(1) 6(1) 1(1) C(8) 30(1) 32(1) 30(1) 5(1) 7(1) 1(1) C(9) 35(1) 38(1) 29(1) 1(1) 4(1) 0(1) C(10) 34(1) 26(1) 28(1) -3(1) 5(1) 0(1) C(11) 44(1) 34(1) 41(1) -2(1) 18(1) -1(1) N(1) 37(1) 21(1) 33(1) 0(1) 12(1) -1(1) N(2) 41(1) 33(1) 35(1) -2(1) 15(1) -2(1) O(1) 79(1) 40(1) 51(1) -15(1) 12(1) 9(1) O(2) 38(1) 42(1) 40(1) 1(1) 7(1) 6(1) O(3) 53(1) 38(1) 33(1) -1(1) -3(1) 12(1) O(4) 45(1) 22(1) 45(1) -2(1) 12(1) 0(1) _______________________________________________________________________  Hydrogen coordinates (x104) and isotropic displacement parameters (A2 x 103) for mc013. ________________________________________________________________ x y z U(eq) ________________________________________________________________ H(1) 9737 1381 9392 42 H(2) 7913 391 10551 56 H(3) 6002 -697 9552 65 H(4) 5382 -127 7821 61 H(5) 6595 1625 7112 48 H(7A) 7198 4439 8302 38 H(7B) 5970 3451 8780 38 H(9) 8413 5115 11031 40 H(11A) 12534 2290 7344 58 H(11B) 11378 3512 6933 58 H(11C) 11422 2114 6298 58 H(1N) 9300(20) 3610(20) 7741(15) 37(6) ________________________________________________________________  233  Torsion angles [deg] for mc013. ________________________________________________________________ O(3)-C(1)-C(2)-C(3) 133.5(2) C(6)-C(1)-C(2)-C(3) 16.1(3) C(1)-C(2)-C(3)-C(4) -2.1(3) C(2)-C(3)-C(4)-C(5) -4.4(3) C(3)-C(4)-C(5)-C(6) -4.5(3) C(4)-C(5)-C(6)-N(1) 143.55(19) C(4)-C(5)-C(6)-C(1) 18.3(3) C(4)-C(5)-C(6)-C(7) -95.7(2) O(3)-C(1)-C(6)-N(1) 90.11(17) C(2)-C(1)-C(6)-N(1) -149.40(16) O(3)-C(1)-C(6)-C(5) -143.46(15) C(2)-C(1)-C(6)-C(5) -23.0(2) O(3)-C(1)-C(6)-C(7) -25.84(17) C(2)-C(1)-C(6)-C(7) 94.66(17) N(1)-C(6)-C(7)-C(8) -93.40(17) C(5)-C(6)-C(7)-C(8) 144.36(16) C(1)-C(6)-C(7)-C(8) 22.75(17) C(6)-C(7)-C(8)-O(3) -11.50(19) C(6)-C(7)-C(8)-C(9) 169.02(19) O(3)-C(8)-C(9)-N(2) -175.46(16) C(7)-C(8)-C(9)-N(2) 4.0(3) O(4)-C(10)-N(1)-C(6) -0.1(3) C(11)-C(10)-N(1)-C(6) -179.44(16) C(5)-C(6)-N(1)-C(10) -62.6(2) C(1)-C(6)-N(1)-C(10) 65.4(2) C(7)-C(6)-N(1)-C(10) 176.99(16) C(8)-C(9)-N(2)-O(2) 3.7(3) C(8)-C(9)-N(2)-O(1) -178.00(18) C(9)-C(8)-O(3)-C(1) 173.94(16) C(7)-C(8)-O(3)-C(1) -5.6(2) C(2)-C(1)-O(3)-C(8) -103.34(18) C(6)-C(1)-O(3)-C(8) 20.56(19) ________________________________________________________________ Symmetry transformations used to generate equivalent atoms:  Hydrogen Bonds Donor --- H....Acceptor [ ARU ] D - H H...A D...A D H...A ----------------------------------------------------------------------------N1 --H1N ..O4 [ 2756.01] 0.807(19) 2.130(19) 2.926(2) 169.5(18) Translation of ARU-code to Equivalent Position Code =================================================== [ 2756. ] = 2-x,1/2+y,3/2-z  234  C.3 X-ray data of N-((2aR,2a1S,3S,5aS,7R)-3,7-dihydroxy-2a,2a1,3,5a,6,7-hexahydroindeno[1,7cd]isoxazol-5a-yl)acetamide (2.53)  NHAc OH  HO O N 2.53  Crystal Data  Empirical Formula  C11H14N2O4  Formula Weight  238.24  Crystal Color, Habit  colorless, prism  Crystal Dimensions  0.10 X 0.10 X 0.25 mm  Crystal System  orthorhombic  Lattice Type  primitive  Lattice Parameters  a = 7.1918(11) Å b = 9.5690(14) Å c = 14.822(2) Å  = 90.0°  = 90.0°  = 90.0° V = 1020.0(3) Å3  Space Group  P 212121 (#19)  Z value  4  Dcalc  1.551 g/cm3  F000  504.00  (MoK)  1.19 cm-1  235  Intensity Measurements  Diffractometer  Bruker X8 APEX II  Radiation  MoK ( = 0.71073 Å) graphite monochromated  Data Images  1107 exposures @ 10.0 seconds  Detector Position  36.00 mm  2max  56.2°  No. of Reflections Measured  Total: 10660 Unique: 2485 (Rint = 0.036)  Corrections  Absorption (Tmin = 0.790, Tmax = 0.988) Lorentz-polarization  Structure Solution and Refinement  Structure Solution  Direct Methods (SIR97)  Refinement  Full-matrix least-squares on F2  Function Minimized   w (Fo2 – Fc2)2  Least Squares Weights  w = 1/(2(Fo2) + (0.0367P)2 + 0.2803P)  Anomalous Dispersion  All non-hydrogen atoms  No. Observations (I>0.00(I))  2485  No. Variables  167  Reflection/Parameter Ratio  14.88  Residuals (refined on F2, all data): R1; wR2  0.049; 0.083  Goodness of Fit Indicator  1.03  No. Observations (I>2.00(I))  2108  Residuals (refined on F): R1; wR2  0.037; 0.078  Max Shift/Error in Final Cycle  0.00  Maximum peak in Final Diff. Map  0.25 e-/Å3  Minimum peak in Final Diff. Map  -0.19 e-/Å3  236  Atomic coordinates (x104) and equivalent isotropic displacement parameters (A2 x 103) for mc009. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________ x y z U(eq) ________________________________________________________________ C(1) 4914(3) 637(2) 6160(1) 20(1) C(2) 4089(3) 298(2) 6920(1) 21(1) C(3) 4957(3) -590(2) 7627(1) 19(1) C(4) 7042(2) -397(2) 7680(1) 18(1) C(5) 8007(2) -70(2) 6791(1) 16(1) C(6) 6865(2) 230(2) 5923(1) 17(1) C(7) 7885(3) 1478(2) 5473(1) 24(1) C(8) 9314(3) 2080(2) 6140(1) 20(1) C(9) 8748(2) 1342(2) 6981(1) 18(1) C(15) 6673(2) -2263(2) 5523(1) 18(1) C(16) 6826(3) -3320(2) 4785(1) 25(1) N(10) 8404(2) 1848(2) 7746(1) 21(1) N(13) 6891(2) -939(2) 5286(1) 19(1) O(11) 7435(2) 821(1) 8249(1) 22(1) O(12) 4112(2) -378(1) 8485(1) 23(1) O(14) 9386(2) 3530(2) 6173(1) 25(1) O(17) 6397(2) -2624(1) 6303(1) 25(1) ________________________________________________________________  237  Bond lengths [A] and angles [deg] for mc009. _____________________________________________________________ C(1)-C(2) C(1)-C(6) C(1)-H(1) C(2)-C(3) C(2)-H(2) C(3)-O(12) C(3)-C(4) C(3)-H(3) C(4)-O(11) C(4)-C(5) C(4)-H(4) C(5)-C(9) C(5)-C(6) C(5)-H(5) C(6)-N(13) C(6)-C(7) C(7)-C(8) C(7)-H(7A) C(7)-H(7B) C(8)-O(14) C(8)-C(9) C(8)-H(8) C(9)-N(10) C(15)-O(17) C(15)-N(13) C(15)-C(16) C(16)-H(16A) C(16)-H(16B) C(16)-H(16C) N(10)-O(11) N(13)-H(13N) O(12)-H(12O) O(14)-H(14O) C(2)-C(1)-C(6) C(2)-C(1)-H(1) C(6)-C(1)-H(1) C(1)-C(2)-C(3) C(1)-C(2)-H(2) C(3)-C(2)-H(2) O(12)-C(3)-C(2) O(12)-C(3)-C(4) C(2)-C(3)-C(4) O(12)-C(3)-H(3) C(2)-C(3)-H(3) C(4)-C(3)-H(3) O(11)-C(4)-C(3) O(11)-C(4)-C(5) C(3)-C(4)-C(5) O(11)-C(4)-H(4) C(3)-C(4)-H(4) C(5)-C(4)-H(4) C(9)-C(5)-C(4) C(9)-C(5)-C(6) C(4)-C(5)-C(6) C(9)-C(5)-H(5)  1.314(3) 1.497(3) 0.9500 1.486(2) 0.9500 1.425(2) 1.513(3) 1.0000 1.465(2) 1.522(2) 1.0000 1.479(2) 1.553(2) 1.0000 1.464(2) 1.553(2) 1.538(2) 0.9900 0.9900 1.389(2) 1.489(2) 1.0000 1.259(2) 1.223(2) 1.324(2) 1.494(2) 0.9800 0.9800 0.9800 1.416(2) 0.84(2) 0.87(3) 0.80(3) 124.04(16) 118.0 118.0 123.73(17) 118.1 118.1 111.63(15) 111.03(14) 112.61(15) 107.1 107.1 107.1 108.54(14) 104.28(14) 115.53(14) 109.4 109.4 109.4 100.79(14) 100.33(13) 120.94(14) 111.1  238  C(4)-C(5)-H(5) 111.1 C(6)-C(5)-H(5) 111.1 N(13)-C(6)-C(1) 111.24(14) N(13)-C(6)-C(5) 112.68(14) C(1)-C(6)-C(5) 110.46(13) N(13)-C(6)-C(7) 107.73(14) C(1)-C(6)-C(7) 110.08(15) C(5)-C(6)-C(7) 104.38(14) C(8)-C(7)-C(6) 109.11(14) C(8)-C(7)-H(7A) 109.9 C(6)-C(7)-H(7A) 109.9 C(8)-C(7)-H(7B) 109.9 C(6)-C(7)-H(7B) 109.9 H(7A)-C(7)-H(7B) 108.3 O(14)-C(8)-C(9) 117.01(15) O(14)-C(8)-C(7) 114.94(16) C(9)-C(8)-C(7) 100.26(14) O(14)-C(8)-H(8) 108.0 C(9)-C(8)-H(8) 108.0 C(7)-C(8)-H(8) 108.0 N(10)-C(9)-C(5) 116.89(16) N(10)-C(9)-C(8) 128.73(17) C(5)-C(9)-C(8) 111.87(14) O(17)-C(15)-N(13) 122.65(16) O(17)-C(15)-C(16) 120.88(17) N(13)-C(15)-C(16) 116.46(16) C(15)-C(16)-H(16A) 109.5 C(15)-C(16)-H(16B) 109.5 H(16A)-C(16)-H(16B) 109.5 C(15)-C(16)-H(16C) 109.5 H(16A)-C(16)-H(16C) 109.5 H(16B)-C(16)-H(16C) 109.5 C(9)-N(10)-O(11) 107.66(14) C(15)-N(13)-C(6) 124.01(15) C(15)-N(13)-H(13N) 121.6(15) C(6)-N(13)-H(13N) 114.4(15) N(10)-O(11)-C(4) 110.17(12) C(3)-O(12)-H(12O) 106.5(16) C(8)-O(14)-H(14O) 106.0(19) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms:  239  Anisotropic displacement parameters (A2 x 103) for mc009. The anisotropic displacement factor exponent takes the form: -2 2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ] _______________________________________________________________________ U11 U22 U33 U23 U13 U12 _______________________________________________________________________ C(1) 24(1) 19(1) 17(1) -1(1) -5(1) 3(1) C(2) 20(1) 24(1) 20(1) -5(1) -1(1) 3(1) C(3) 26(1) 17(1) 14(1) -3(1) 4(1) -1(1) C(4) 25(1) 17(1) 12(1) -1(1) -1(1) 3(1) C(5) 18(1) 17(1) 12(1) 0(1) -1(1) 2(1) C(6) 25(1) 16(1) 10(1) 0(1) -2(1) -1(1) C(7) 34(1) 22(1) 16(1) 3(1) -2(1) -7(1) C(8) 19(1) 21(1) 20(1) 0(1) 2(1) -1(1) C(9) 15(1) 21(1) 18(1) 0(1) -3(1) 1(1) C(15) 19(1) 20(1) 15(1) -2(1) 3(1) -1(1) C(16) 36(1) 22(1) 18(1) -5(1) 7(1) -4(1) N(10) 23(1) 24(1) 17(1) -1(1) -2(1) -1(1) N(13) 28(1) 19(1) 9(1) -2(1) 2(1) -2(1) O(11) 30(1) 24(1) 11(1) -2(1) 0(1) -5(1) O(12) 33(1) 19(1) 16(1) -1(1) 9(1) -1(1) O(14) 26(1) 20(1) 30(1) 0(1) 0(1) -6(1) O(17) 42(1) 17(1) 15(1) 0(1) 6(1) -2(1) _______________________________________________________________________  Hydrogen coordinates (x104) and isotropic displacement parameters (A2 x 103) for mc009. ________________________________________________________________ x y z U(eq) ________________________________________________________________ H(1) 4232 1174 5734 24 H(2) 2867 640 7024 25 H(3) 4727 -1584 7453 23 H(4) 7617 -1247 7956 22 H(5) 9034 -748 6668 19 H(7A) 8523 1160 4918 29 H(7B) 6975 2209 5304 29 H(8) 10572 1730 5962 24 H(16A) 7897 -3928 4899 38 H(16B) 6993 -2841 4206 38 H(16C) 5690 -3884 4765 38 H(13N) 7090(30) -710(20) 4747(15) 27(6) H(14O) 8370(40) 3780(30) 6309(17) 41(8) H(12O) 4080(40) 520(30) 8572(16) 44(7) ________________________________________________________________  240  Torsion angles [deg] for mc009. ________________________________________________________________ C(6)-C(1)-C(2)-C(3) -2.9(3) C(1)-C(2)-C(3)-O(12) 158.39(17) C(1)-C(2)-C(3)-C(4) 32.7(2) O(12)-C(3)-C(4)-O(11) -41.97(19) C(2)-C(3)-C(4)-O(11) 84.04(17) O(12)-C(3)-C(4)-C(5) -158.61(14) C(2)-C(3)-C(4)-C(5) -32.6(2) O(11)-C(4)-C(5)-C(9) -2.36(16) C(3)-C(4)-C(5)-C(9) 116.66(16) O(11)-C(4)-C(5)-C(6) -111.44(16) C(3)-C(4)-C(5)-C(6) 7.6(2) C(2)-C(1)-C(6)-N(13) 102.5(2) C(2)-C(1)-C(6)-C(5) -23.4(2) C(2)-C(1)-C(6)-C(7) -138.15(18) C(9)-C(5)-C(6)-N(13) 145.34(14) C(4)-C(5)-C(6)-N(13) -105.33(18) C(9)-C(5)-C(6)-C(1) -89.55(16) C(4)-C(5)-C(6)-C(1) 19.8(2) C(9)-C(5)-C(6)-C(7) 28.73(16) C(4)-C(5)-C(6)-C(7) 138.06(16) N(13)-C(6)-C(7)-C(8) -131.14(16) C(1)-C(6)-C(7)-C(8) 107.41(17) C(5)-C(6)-C(7)-C(8) -11.14(19) C(6)-C(7)-C(8)-O(14) -137.60(16) C(6)-C(7)-C(8)-C(9) -11.22(19) C(4)-C(5)-C(9)-N(10) -0.6(2) C(6)-C(5)-C(9)-N(10) 123.96(17) C(4)-C(5)-C(9)-C(8) -164.16(14) C(6)-C(5)-C(9)-C(8) -39.64(17) O(14)-C(8)-C(9)-N(10) -3.8(3) C(7)-C(8)-C(9)-N(10) -128.8(2) O(14)-C(8)-C(9)-C(5) 157.36(16) C(7)-C(8)-C(9)-C(5) 32.38(18) C(5)-C(9)-N(10)-O(11) 3.4(2) C(8)-C(9)-N(10)-O(11) 163.74(17) O(17)-C(15)-N(13)-C(6) 1.2(3) C(16)-C(15)-N(13)-C(6) -177.35(16) C(1)-C(6)-N(13)-C(15) -80.6(2) C(5)-C(6)-N(13)-C(15) 44.1(2) C(7)-C(6)-N(13)-C(15) 158.70(18) C(9)-N(10)-O(11)-C(4) -4.89(18) C(3)-C(4)-O(11)-N(10) -119.25(14) C(5)-C(4)-O(11)-N(10) 4.42(17) ________________________________________________________________  241  Hydrogen Bonds Donor --- H....Acceptor [ ARU ] D - H H...A D...A D H...A ----------------------------------------------------------------------------O(12) --H(12O) ..O(17) [ 4656.01] 0.87(3) 1.82(3) 2.6792(19) 170(3) N(13) --H(13N) ..O(11) [ 2654.01] 0.84(2) 2.25(2) 3.061(2) 162.2(18) O(14) --H(14O) ..O(12) [ 4656.01] 0.80(3) 1.98(3) 2.771(2) 172(3) Translation of ARU-code to Equivalent Position Code =================================================== [ 4656. ] = 1-x,1/2+y,3/2-z [ 2654. ] = 3/2-x,-y,-1/2+z  242  C.4 X-ray data of trans-9-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-3-nitro-1azaspiro[5.5]undeca-2,7,10-trien-4-one (2.55)  CH3 HN  NO2 O  TBDPSO 2.55  Crystal Data  Empirical Formula  C27H30N2O4Si  Formula Weight  474.62  Crystal Color, Habit  colorless, prism  Crystal Dimensions  0.24 X 0.30 X 0.50 mm  Crystal System  monoclinic  Lattice Type  primitive  Lattice Parameters  a = 14.9015(14) Å b = 13.8571(13) Å c = 12.6366(14) Å  = 90°  = 106.644(5)°  = 90° V = 2500.0(4) Å3  Space Group  P 21/c (#14)  Z value  4  Dcalc  1.261 g/cm3  F000  1008.00  (MoK)  1.29 cm-1  243  Intensity Measurements  Diffractometer  Bruker X8 APEX II  Radiation  MoK ( = 0.71073 Å) graphite monochromated  Data Images  851 exposures @ 10.0 seconds  Detector Position  36.00 mm  2max  56.6°  No. of Reflections Measured  Total: 24445 Unique: 6127 (Rint = 0.032)  Corrections  Absorption (Tmin = 0.899, Tmax = 0.970) Lorentz-polarization  Structure Solution and Refinement  Structure Solution  Direct Methods (SIR97)  Refinement  Full-matrix least-squares on F2  Function Minimized   w (Fo2 – Fc2)2  Least Squares Weights  w = 1/(2(Fo2) + (0.0528P)2 + 0.6852P)  Anomalous Dispersion  All non-hydrogen atoms  No. Observations (I>0.00(I))  6127  No. Variables  316  Reflection/Parameter Ratio  19.39  Residuals (refined on F2, all data): R1; wR2  0.058; 0.112  Goodness of Fit Indicator  1.03  No. Observations (I>2.00(I))  4713  Residuals (refined on F): R1; wR2  0.042; 0.103  Max Shift/Error in Final Cycle  0.00  Maximum peak in Final Diff. Map  0.38 e-/Å3  Minimum peak in Final Diff. Map  -0.25 e-/Å3  244  Atomic coordinates (x104) and equivalent isotropic displacement parameters (A2 x 103) for mc014. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________ x y z U(eq) ________________________________________________________________ C(1) 9155(1) 3055(1) 5472(1) 24(1) C(2) 9175(1) 2614(1) 4482(1) 25(1) C(3) 8477(1) 1928(1) 3932(1) 26(1) C(4) 7711(1) 1769(1) 4479(1) 28(1) C(5) 8061(1) 1810(1) 5739(1) 22(1) C(6) 7246(1) 1849(1) 6212(1) 29(1) C(7) 7101(1) 1213(1) 6917(1) 32(1) C(8) 7722(1) 375(1) 7338(1) 28(1) C(9) 8535(1) 334(1) 6876(1) 29(1) C(10) 8693(1) 973(1) 6179(1) 24(1) C(11) 9738(1) 3893(1) 5999(1) 34(1) C(12) 5536(1) -1512(1) 6909(1) 35(1) C(13) 5710(2) -2049(2) 5926(2) 59(1) C(14) 4910(1) -645(2) 6449(2) 52(1) C(15) 5032(1) -2178(2) 7519(2) 53(1) C(16) 6697(1) -455(1) 9099(1) 26(1) C(17) 5992(1) 188(1) 9129(1) 38(1) C(18) 5993(1) 683(1) 10081(2) 48(1) C(19) 6711(1) 558(1) 11026(1) 42(1) C(20) 7432(2) -45(1) 11015(1) 50(1) C(21) 7425(1) -549(1) 10070(1) 42(1) C(22) 7467(1) -2234(1) 8291(1) 29(1) C(23) 7356(1) -2810(1) 9152(2) 44(1) C(24) 7891(2) -3627(1) 9492(2) 50(1) C(25) 8553(1) -3890(1) 8981(2) 45(1) C(26) 8682(1) -3337(1) 8131(1) 39(1) C(27) 8144(1) -2521(1) 7789(1) 30(1) N(1) 8600(1) 2710(1) 6027(1) 25(1) N(2) 9876(1) 2888(1) 3966(1) 32(1) O(1) 10181(1) 3717(1) 4066(1) 48(1) O(2) 10140(1) 2277(1) 3420(1) 51(1) O(3) 8411(1) 1534(1) 3044(1) 38(1) O(4) 7188(1) -493(1) 7043(1) 29(1) Si(1) 6723(1) -1148(1) 7838(1) 24(1) ________________________________________________________________  245  Bond lengths [A] and angles [deg] for mc014. _____________________________________________________________ C(1)-N(1) C(1)-C(2) C(1)-C(11) C(2)-N(2) C(2)-C(3) C(3)-O(3) C(3)-C(4) C(4)-C(5) C(4)-H(4A) C(4)-H(4B) C(5)-N(1) C(5)-C(10) C(5)-C(6) C(6)-C(7) C(6)-H(6) C(7)-C(8) C(7)-H(7) C(8)-O(4) C(8)-C(9) C(8)-H(8) C(9)-C(10) C(9)-H(9) C(10)-H(10) C(11)-H(11A) C(11)-H(11B) C(11)-H(11C) C(12)-C(14) C(12)-C(15) C(12)-C(13) C(12)-Si(1) C(13)-H(13A) C(13)-H(13B) C(13)-H(13C) C(14)-H(14A) C(14)-H(14B) C(14)-H(14C) C(15)-H(15A) C(15)-H(15B) C(15)-H(15C) C(16)-C(17) C(16)-C(21) C(16)-Si(1) C(17)-C(18) C(17)-H(17) C(18)-C(19) C(18)-H(18) C(19)-C(20) C(19)-H(19) C(20)-C(21) C(20)-H(20) C(21)-H(21) C(22)-C(27) C(22)-C(23) C(22)-Si(1) C(23)-C(24) C(23)-H(23)  1.3182(17) 1.4001(19) 1.4886(19) 1.4309(18) 1.434(2) 1.2263(16) 1.510(2) 1.5268(18) 0.9900 0.9900 1.4722(17) 1.4980(19) 1.5000(19) 1.315(2) 0.9500 1.485(2) 0.9500 1.4312(17) 1.489(2) 1.0000 1.316(2) 0.9500 0.9500 0.9800 0.9800 0.9800 1.529(3) 1.530(2) 1.532(2) 1.8894(16) 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 1.387(2) 1.391(2) 1.8699(14) 1.384(2) 0.9500 1.367(3) 0.9500 1.364(3) 0.9500 1.381(2) 0.9500 0.9500 1.394(2) 1.397(2) 1.8606(16) 1.380(3) 0.9500  246  C(24)-C(25) C(24)-H(24) C(25)-C(26) C(25)-H(25) C(26)-C(27) C(26)-H(26) C(27)-H(27) N(1)-H(1N) N(2)-O(2) N(2)-O(1) O(4)-Si(1) N(1)-C(1)-C(2) N(1)-C(1)-C(11) C(2)-C(1)-C(11) C(1)-C(2)-N(2) C(1)-C(2)-C(3) N(2)-C(2)-C(3) O(3)-C(3)-C(2) O(3)-C(3)-C(4) C(2)-C(3)-C(4) C(3)-C(4)-C(5) C(3)-C(4)-H(4A) C(5)-C(4)-H(4A) C(3)-C(4)-H(4B) C(5)-C(4)-H(4B) H(4A)-C(4)-H(4B) N(1)-C(5)-C(10) N(1)-C(5)-C(6) C(10)-C(5)-C(6) N(1)-C(5)-C(4) C(10)-C(5)-C(4) C(6)-C(5)-C(4) C(7)-C(6)-C(5) C(7)-C(6)-H(6) C(5)-C(6)-H(6) C(6)-C(7)-C(8) C(6)-C(7)-H(7) C(8)-C(7)-H(7) O(4)-C(8)-C(7) O(4)-C(8)-C(9) C(7)-C(8)-C(9) O(4)-C(8)-H(8) C(7)-C(8)-H(8) C(9)-C(8)-H(8) C(10)-C(9)-C(8) C(10)-C(9)-H(9) C(8)-C(9)-H(9) C(9)-C(10)-C(5) C(9)-C(10)-H(10) C(5)-C(10)-H(10) C(1)-C(11)-H(11A) C(1)-C(11)-H(11B) H(11A)-C(11)-H(11B) C(1)-C(11)-H(11C) H(11A)-C(11)-H(11C) H(11B)-C(11)-H(11C) C(14)-C(12)-C(15) C(14)-C(12)-C(13)  1.375(3) 0.9500 1.376(2) 0.9500 1.382(2) 0.9500 0.9500 0.87(2) 1.2263(17) 1.2294(17) 1.6466(10) 119.64(13) 114.83(12) 125.51(13) 119.75(12) 121.63(12) 118.53(12) 126.56(13) 118.76(13) 114.42(12) 113.26(11) 108.9 108.9 108.9 108.9 107.7 108.85(11) 108.48(11) 112.02(11) 106.81(11) 110.43(12) 110.08(12) 123.71(14) 118.1 118.1 124.08(14) 118.0 118.0 108.79(12) 108.65(12) 112.51(12) 108.9 108.9 108.9 123.93(14) 118.0 118.0 123.72(13) 118.1 118.1 109.5 109.5 109.5 109.5 109.5 109.5 109.31(15) 107.44(16)  247  C(15)-C(12)-C(13) C(14)-C(12)-Si(1) C(15)-C(12)-Si(1) C(13)-C(12)-Si(1) C(12)-C(13)-H(13A) C(12)-C(13)-H(13B) H(13A)-C(13)-H(13B) C(12)-C(13)-H(13C) H(13A)-C(13)-H(13C) H(13B)-C(13)-H(13C) C(12)-C(14)-H(14A) C(12)-C(14)-H(14B) H(14A)-C(14)-H(14B) C(12)-C(14)-H(14C) H(14A)-C(14)-H(14C) H(14B)-C(14)-H(14C) C(12)-C(15)-H(15A) C(12)-C(15)-H(15B) H(15A)-C(15)-H(15B) C(12)-C(15)-H(15C) H(15A)-C(15)-H(15C) H(15B)-C(15)-H(15C) C(17)-C(16)-C(21) C(17)-C(16)-Si(1) C(21)-C(16)-Si(1) C(18)-C(17)-C(16) C(18)-C(17)-H(17) C(16)-C(17)-H(17) C(19)-C(18)-C(17) C(19)-C(18)-H(18) C(17)-C(18)-H(18) C(20)-C(19)-C(18) C(20)-C(19)-H(19) C(18)-C(19)-H(19) C(19)-C(20)-C(21) C(19)-C(20)-H(20) C(21)-C(20)-H(20) C(20)-C(21)-C(16) C(20)-C(21)-H(21) C(16)-C(21)-H(21) C(27)-C(22)-C(23) C(27)-C(22)-Si(1) C(23)-C(22)-Si(1) C(24)-C(23)-C(22) C(24)-C(23)-H(23) C(22)-C(23)-H(23) C(25)-C(24)-C(23) C(25)-C(24)-H(24) C(23)-C(24)-H(24) C(24)-C(25)-C(26) C(24)-C(25)-H(25) C(26)-C(25)-H(25) C(25)-C(26)-C(27) C(25)-C(26)-H(26) C(27)-C(26)-H(26) C(26)-C(27)-C(22) C(26)-C(27)-H(27) C(22)-C(27)-H(27) C(1)-N(1)-C(5)  109.70(16) 112.75(12) 110.76(12) 106.76(12) 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 116.19(14) 123.60(11) 120.19(12) 121.97(16) 119.0 119.0 120.21(17) 119.9 119.9 119.32(16) 120.3 120.3 120.52(17) 119.7 119.7 121.75(16) 119.1 119.1 117.02(14) 122.43(11) 120.55(12) 121.62(16) 119.2 119.2 119.96(16) 120.0 120.0 119.86(16) 120.1 120.1 120.14(16) 119.9 119.9 121.39(14) 119.3 119.3 123.81(12)  248  C(1)-N(1)-H(1N) 118.4(12) C(5)-N(1)-H(1N) 117.1(12) O(2)-N(2)-O(1) 122.22(13) O(2)-N(2)-C(2) 117.89(13) O(1)-N(2)-C(2) 119.88(13) C(8)-O(4)-Si(1) 127.16(9) O(4)-Si(1)-C(22) 108.34(6) O(4)-Si(1)-C(16) 110.63(6) C(22)-Si(1)-C(16) 108.00(7) O(4)-Si(1)-C(12) 104.53(6) C(22)-Si(1)-C(12) 110.14(7) C(16)-Si(1)-C(12) 115.02(7) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms:  249  Anisotropic displacement parameters (A2 x 103) for mc014. The anisotropic displacement factor exponent takes the form: -2 2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ] _______________________________________________________________________ U11 U22 U33 U23 U13 U12 _______________________________________________________________________ C(1) 28(1) 22(1) 20(1) 3(1) 6(1) -3(1) C(2) 29(1) 27(1) 19(1) 2(1) 9(1) -5(1) C(3) 35(1) 25(1) 17(1) 3(1) 6(1) -5(1) C(4) 28(1) 30(1) 22(1) 2(1) 4(1) -8(1) C(5) 26(1) 22(1) 21(1) 1(1) 10(1) -4(1) C(6) 31(1) 24(1) 39(1) 2(1) 18(1) 3(1) C(7) 37(1) 29(1) 39(1) -3(1) 25(1) -4(1) C(8) 38(1) 27(1) 22(1) 2(1) 11(1) -11(1) C(9) 25(1) 27(1) 32(1) 6(1) 4(1) -1(1) C(10) 22(1) 26(1) 26(1) 0(1) 8(1) -3(1) C(11) 46(1) 30(1) 27(1) -4(1) 11(1) -14(1) C(12) 33(1) 43(1) 33(1) -9(1) 14(1) -11(1) C(13) 52(1) 79(2) 50(1) -35(1) 21(1) -19(1) C(14) 40(1) 67(1) 43(1) -2(1) -2(1) -4(1) C(15) 39(1) 62(1) 61(1) 1(1) 19(1) -20(1) C(16) 31(1) 23(1) 26(1) 2(1) 13(1) -4(1) C(17) 35(1) 40(1) 37(1) -9(1) 6(1) 6(1) C(18) 47(1) 44(1) 54(1) -18(1) 18(1) 6(1) C(19) 64(1) 33(1) 33(1) -10(1) 20(1) -9(1) C(20) 66(1) 47(1) 29(1) -4(1) -1(1) 4(1) C(21) 44(1) 42(1) 34(1) -3(1) 3(1) 11(1) C(22) 36(1) 24(1) 32(1) 1(1) 18(1) -3(1) C(23) 62(1) 33(1) 50(1) 11(1) 38(1) 7(1) C(24) 74(1) 36(1) 50(1) 17(1) 33(1) 9(1) C(25) 56(1) 31(1) 49(1) 6(1) 17(1) 11(1) C(26) 40(1) 36(1) 44(1) -3(1) 19(1) 4(1) C(27) 36(1) 29(1) 30(1) 0(1) 16(1) -4(1) N(1) 36(1) 21(1) 20(1) -2(1) 11(1) -7(1) N(2) 35(1) 40(1) 23(1) 1(1) 12(1) -9(1) O(1) 60(1) 46(1) 46(1) -3(1) 29(1) -26(1) O(2) 56(1) 61(1) 49(1) -13(1) 35(1) -10(1) O(3) 57(1) 37(1) 20(1) -6(1) 13(1) -16(1) O(4) 40(1) 26(1) 26(1) 1(1) 14(1) -10(1) Si(1) 28(1) 23(1) 25(1) 0(1) 13(1) -4(1) _______________________________________________________________________  250  Hydrogen coordinates (x104) and isotropic displacement parameters (A2 x 103) for mc014. ________________________________________________________________ x y z U(eq) ________________________________________________________________ H(4A) 7420 1131 4254 33 H(4B) 7221 2266 4215 33 H(6) 6810 2363 5989 35 H(7) 6566 1295 7174 38 H(8) 7959 417 8161 34 H(9) 8965 -184 7097 35 H(10) 9240 899 5943 29 H(11A) 9528 4473 5552 51 H(11B) 10396 3766 6049 51 H(11C) 9674 3993 6741 51 H(13A) 6087 -2626 6190 89 H(13B) 6045 -1625 5547 89 H(13C) 5108 -2238 5411 89 H(14A) 4368 -860 5853 79 H(14B) 5266 -169 6162 79 H(14C) 4695 -353 7039 79 H(15A) 4427 -2371 7018 79 H(15B) 4932 -1835 8154 79 H(15C) 5416 -2752 7777 79 H(17) 5493 293 8476 46 H(18) 5494 1110 10077 57 H(19) 6707 888 11684 51 H(20) 7942 -119 11663 60 H(21) 7931 -970 10083 50 H(23) 6902 -2635 9513 53 H(24) 7802 -4007 10080 60 H(25) 8921 -4453 9213 54 H(26) 9141 -3517 7780 46 H(27) 8237 -2148 7199 36 H(1N) 8618(12) 2974(13) 6656(16) 35(5) ________________________________________________________________  251  Torsion angles [deg] for mc014. ________________________________________________________________ N(1)-C(1)-C(2)-N(2) C(11)-C(1)-C(2)-N(2) N(1)-C(1)-C(2)-C(3) C(11)-C(1)-C(2)-C(3) C(1)-C(2)-C(3)-O(3) N(2)-C(2)-C(3)-O(3) C(1)-C(2)-C(3)-C(4) N(2)-C(2)-C(3)-C(4) O(3)-C(3)-C(4)-C(5) C(2)-C(3)-C(4)-C(5) C(3)-C(4)-C(5)-N(1) C(3)-C(4)-C(5)-C(10) C(3)-C(4)-C(5)-C(6) N(1)-C(5)-C(6)-C(7) C(10)-C(5)-C(6)-C(7) C(4)-C(5)-C(6)-C(7) C(5)-C(6)-C(7)-C(8) C(6)-C(7)-C(8)-O(4) C(6)-C(7)-C(8)-C(9) O(4)-C(8)-C(9)-C(10) C(7)-C(8)-C(9)-C(10) C(8)-C(9)-C(10)-C(5) N(1)-C(5)-C(10)-C(9) C(6)-C(5)-C(10)-C(9) C(4)-C(5)-C(10)-C(9) C(21)-C(16)-C(17)-C(18) Si(1)-C(16)-C(17)-C(18) C(16)-C(17)-C(18)-C(19) C(17)-C(18)-C(19)-C(20) C(18)-C(19)-C(20)-C(21) C(19)-C(20)-C(21)-C(16) C(17)-C(16)-C(21)-C(20) Si(1)-C(16)-C(21)-C(20) C(27)-C(22)-C(23)-C(24) Si(1)-C(22)-C(23)-C(24) C(22)-C(23)-C(24)-C(25) C(23)-C(24)-C(25)-C(26) C(24)-C(25)-C(26)-C(27) C(25)-C(26)-C(27)-C(22) C(23)-C(22)-C(27)-C(26) Si(1)-C(22)-C(27)-C(26) C(2)-C(1)-N(1)-C(5) C(11)-C(1)-N(1)-C(5) C(10)-C(5)-N(1)-C(1) C(6)-C(5)-N(1)-C(1) C(4)-C(5)-N(1)-C(1) C(1)-C(2)-N(2)-O(2) C(3)-C(2)-N(2)-O(2) C(1)-C(2)-N(2)-O(1) C(3)-C(2)-N(2)-O(1) C(7)-C(8)-O(4)-Si(1) C(9)-C(8)-O(4)-Si(1) C(8)-O(4)-Si(1)-C(22) C(8)-O(4)-Si(1)-C(16) C(8)-O(4)-Si(1)-C(12) C(27)-C(22)-Si(1)-O(4)  -170.33(13) 8.0(2) 13.1(2) -168.52(14) 176.88(14) 0.3(2) 2.9(2) -173.73(12) 149.48(13) -36.00(18) 50.88(16) -67.32(15) 168.47(12) -121.14(16) -1.0(2) 122.32(16) 0.0(2) -120.14(16) 0.3(2) 121.07(15) 0.5(2) -1.7(2) 121.77(15) 1.81(19) -121.28(15) -2.3(3) 179.49(14) 1.1(3) 1.1(3) -2.0(3) 0.7(3) 1.5(3) 179.69(15) -0.1(3) 179.08(16) 0.1(3) 0.1(3) -0.3(3) 0.3(3) -0.2(2) -179.27(12) 7.0(2) -171.48(13) 80.84(16) -157.03(13) -38.40(18) 149.99(14) -33.4(2) -31.1(2) 145.53(14) -99.62(13) 137.58(11) -103.19(12) 15.02(14) 139.38(12) -14.59(15)  252  C(23)-C(22)-Si(1)-O(4) 166.32(13) C(27)-C(22)-Si(1)-C(16) -134.45(13) C(23)-C(22)-Si(1)-C(16) 46.46(16) C(27)-C(22)-Si(1)-C(12) 99.18(14) C(23)-C(22)-Si(1)-C(12) -79.91(15) C(17)-C(16)-Si(1)-O(4) 84.30(14) C(21)-C(16)-Si(1)-O(4) -93.80(14) C(17)-C(16)-Si(1)-C(22) -157.30(13) C(21)-C(16)-Si(1)-C(22) 24.61(15) C(17)-C(16)-Si(1)-C(12) -33.84(16) C(21)-C(16)-Si(1)-C(12) 148.06(13) C(14)-C(12)-Si(1)-O(4) -60.25(13) C(15)-C(12)-Si(1)-O(4) 176.89(12) C(13)-C(12)-Si(1)-O(4) 57.50(14) C(14)-C(12)-Si(1)-C(22) -176.44(12) C(15)-C(12)-Si(1)-C(22) 60.71(14) C(13)-C(12)-Si(1)-C(22) -58.68(15) C(14)-C(12)-Si(1)-C(16) 61.25(14) C(15)-C(12)-Si(1)-C(16) -61.60(15) C(13)-C(12)-Si(1)-C(16) 179.01(13) ________________________________________________________________ Symmetry transformations used to generate equivalent atoms: Hydrogen Bonds Donor --- H....Acceptor [ ARU ] D - H H...A D...A D H...A ----------------------------------------------------------------------------N(1) --H(1N) ..O(3) [ 4555.01] 0.868(19) 1.987(19) 2.8434(16) 168.8(18) Translation of ARU-code to Equivalent Position Code =================================================== [ 4555. ] = x,1/2-y,1/2+z  253  C.5 X-ray data of methyl 2-((1S,4R,5R,6S)-1-acetamido-4-(tert-butyldiphenylsilyloxy)-6-cyano5-hydroxycyclohex-2-enyl)acetate (2.67)  NHAc CO2CH3 O TBDPS  C OH  N  2.67  Crystal Data  Empirical Formula  C29H36N2O5SiCl2 (C28H34N2O5Si + CH2Cl2)  Formula Weight  591.59  Crystal Color, Habit  colorless, plate  Crystal Dimensions  0.05 X 0.15 X 0.35 mm  Crystal System  triclinic  Lattice Type  primitive  Lattice Parameters  a = 9.5513(11) Å b = 10.1186(11) Å c = 17.608(2) Å  = 78.541(2)°  = 77.525(2)°  = 69.229(2)° V = 1539.6(3) Å3  Space Group  P -1 (#2)  Z value  2  Dcalc  1.276 g/cm3  F000  624.00  (MoK)  2.89 cm-1  254  Intensity Measurements  Diffractometer  Bruker APEX DUO  Radiation  MoK ( = 0.71073 Å) graphite monochromated  Data Images  2229 exposures @ 10.0 seconds  Detector Position  40.00 mm  2max  61.0°  No. of Reflections Measured  Total: 34341 Unique: 9366 (Rint = 0.028)  Corrections  Absorption (Tmin = 0.872, Tmax = 0.986) Lorentz-polarization  Structure Solution and Refinement  Structure Solution  Direct Methods (SIR97)  Refinement  Full-matrix least-squares on F2  Function Minimized   w (Fo2 – Fc2)2  Least Squares Weights  w = 1/(2(Fo2) + (0.0524P)2 + 0.5909P)  Anomalous Dispersion  All non-hydrogen atoms  No. Observations (I>0.00(I))  9366  No. Variables  393  Reflection/Parameter Ratio  23.83  Residuals (refined on F2, all data): R1; wR2  0.052; 0.106  Goodness of Fit Indicator  1.03  No. Observations (I>2.00(I))  7568  Residuals (refined on F): R1; wR2  0.039; 0.098  Max Shift/Error in Final Cycle  0.00  Maximum peak in Final Diff. Map  0.55 e-/Å3  Minimum peak in Final Diff. Map  -0.49 e-/Å3  255  Atomic coordinates (x104) and equivalent isotropic displacement parameters (A2 x 103) for mc044. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________ x y z U(eq) occ ________________________________________________________________ C(1) 7750(1) 5449(1) 9308(1) 13(1) C(2) 8310(1) 5712(1) 8555(1) 13(1) C(3) 8193(1) 7172(1) 8105(1) 12(1) C(4) 7168(1) 8344(1) 8591(1) 12(1) C(5) 7421(1) 7950(1) 9456(1) 11(1) C(6) 6989(1) 6595(1) 9843(1) 11(1) C(7) 7512(1) 6041(1) 10650(1) 13(1) C(8) 7042(1) 4790(1) 11099(1) 13(1) C(9) 9003(1) 7760(1) 9497(1) 14(1) C(15) 4331(1) 7951(1) 10366(1) 13(1) C(16) 2682(1) 8197(1) 10369(1) 22(1) C(19) 7449(2) 3016(1) 12197(1) 22(1) C(21) 7092(1) 8049(1) 5858(1) 16(1) C(22) 7436(2) 7522(2) 5059(1) 31(1) C(23) 7394(2) 9472(2) 5759(1) 31(1) C(24) 5398(2) 8319(2) 6185(1) 27(1) C(25) 7652(1) 4997(1) 6732(1) 14(1) C(26) 8214(1) 4036(1) 6175(1) 17(1) C(27) 7773(2) 2831(1) 6274(1) 21(1) C(28) 6755(2) 2558(1) 6931(1) 20(1) C(29) 6175(1) 3501(1) 7485(1) 19(1) C(30) 6616(1) 4703(1) 7388(1) 16(1) C(31) 10320(1) 6123(1) 6346(1) 15(1) C(32) 11101(2) 7029(2) 5902(1) 26(1) C(33) 12685(2) 6578(2) 5743(1) 32(1) C(34) 13525(2) 5230(2) 6036(1) 27(1) C(35) 12786(2) 4310(2) 6486(1) 27(1) C(36) 11207(2) 4749(1) 6632(1) 22(1) N(10) 10240(1) 7620(1) 9521(1) 20(1) N(13) 5327(1) 6998(1) 9911(1) 12(1) O(11) 7457(1) 9632(1) 8254(1) 15(1) O(12) 7553(1) 7384(1) 7412(1) 15(1) O(14) 6170(1) 4308(1) 10930(1) 16(1) O(17) 4738(1) 8584(1) 10769(1) 15(1) O(18) 7721(1) 4279(1) 11734(1) 16(1) Si(20) 8194(1) 6654(1) 6593(1) 12(1) C(37) 9750(14) 9010(30) 2305(7) 53(5) 0.70(2) Cl(1) 8649(10) 8810(11) 1685(5) 88(2) 0.70(2) Cl(2) 8626(9) 9554(8) 3186(5) 102(3) 0.70(2) Cl(2B) 8504(2) 9465(2) 3126(1) 38(1) 0.30(2) Cl(1B) 8885(3) 8491(3) 1609(1) 44(1) 0.30(2) C(37B) 9765(4) 8882(9) 2278(2) 25(1) 0.30(2) ________________________________________________________________  256  Bond lengths [A] and angles [deg] for mc044. _____________________________________________________________ C(1)-C(2) C(1)-C(6) C(1)-H(1) C(2)-C(3) C(2)-H(2) C(3)-O(12) C(3)-C(4) C(3)-H(3) C(4)-O(11) C(4)-C(5) C(4)-H(4) C(5)-C(9) C(5)-C(6) C(5)-H(5) C(6)-N(13) C(6)-C(7) C(7)-C(8) C(7)-H(7A) C(7)-H(7B) C(8)-O(14) C(8)-O(18) C(9)-N(10) C(15)-O(17) C(15)-N(13) C(15)-C(16) C(16)-H(16A) C(16)-H(16B) C(16)-H(16C) C(19)-O(18) C(19)-H(19A) C(19)-H(19B) C(19)-H(19C) C(21)-C(22) C(21)-C(23) C(21)-C(24) C(21)-Si(20) C(22)-H(22A) C(22)-H(22B) C(22)-H(22C) C(23)-H(23A) C(23)-H(23B) C(23)-H(23C) C(24)-H(24A) C(24)-H(24B) C(24)-H(24C) C(25)-C(26) C(25)-C(30) C(25)-Si(20) C(26)-C(27) C(26)-H(26) C(27)-C(28) C(27)-H(27) C(28)-C(29) C(28)-H(28) C(29)-C(30) C(29)-H(29)  1.3300(16) 1.5171(15) 0.9500 1.5094(16) 0.9500 1.4267(13) 1.5214(15) 1.0000 1.4153(14) 1.5444(15) 1.0000 1.4708(15) 1.5564(15) 1.0000 1.4761(14) 1.5415(15) 1.5099(16) 0.9900 0.9900 1.2132(14) 1.3354(14) 1.1477(16) 1.2421(14) 1.3433(15) 1.5036(16) 0.9800 0.9800 0.9800 1.4477(15) 0.9800 0.9800 0.9800 1.5306(18) 1.5363(19) 1.5393(18) 1.8941(12) 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 1.4050(16) 1.4072(17) 1.8814(12) 1.3936(17) 0.9500 1.3925(19) 0.9500 1.3895(18) 0.9500 1.3917(17) 0.9500  257  C(30)-H(30) C(31)-C(32) C(31)-C(36) C(31)-Si(20) C(32)-C(33) C(32)-H(32) C(33)-C(34) C(33)-H(33) C(34)-C(35) C(34)-H(34) C(35)-C(36) C(35)-H(35) C(36)-H(36) N(13)-H(13N) O(11)-H(11O) O(12)-Si(20) C(37)-Cl(2) C(37)-Cl(1) C(37)-H(37A) C(37)-H(37B) Cl(2B)-C(37B) Cl(1B)-C(37B) C(37B)-H(37C) C(37B)-H(37D) C(2)-C(1)-C(6) C(2)-C(1)-H(1) C(6)-C(1)-H(1) C(1)-C(2)-C(3) C(1)-C(2)-H(2) C(3)-C(2)-H(2) O(12)-C(3)-C(2) O(12)-C(3)-C(4) C(2)-C(3)-C(4) O(12)-C(3)-H(3) C(2)-C(3)-H(3) C(4)-C(3)-H(3) O(11)-C(4)-C(3) O(11)-C(4)-C(5) C(3)-C(4)-C(5) O(11)-C(4)-H(4) C(3)-C(4)-H(4) C(5)-C(4)-H(4) C(9)-C(5)-C(4) C(9)-C(5)-C(6) C(4)-C(5)-C(6) C(9)-C(5)-H(5) C(4)-C(5)-H(5) C(6)-C(5)-H(5) N(13)-C(6)-C(1) N(13)-C(6)-C(7) C(1)-C(6)-C(7) N(13)-C(6)-C(5) C(1)-C(6)-C(5) C(7)-C(6)-C(5) C(8)-C(7)-C(6) C(8)-C(7)-H(7A) C(6)-C(7)-H(7A) C(8)-C(7)-H(7B)  0.9500 1.3994(18) 1.4048(18) 1.8812(12) 1.397(2) 0.9500 1.376(2) 0.9500 1.387(2) 0.9500 1.3935(18) 0.9500 0.9500 0.842(17) 0.85(2) 1.6485(9) 1.750(7) 1.753(7) 0.9900 0.9900 1.760(3) 1.761(3) 0.9900 0.9900 123.59(10) 118.2 118.2 125.38(10) 117.3 117.3 110.77(9) 106.85(9) 111.34(9) 109.3 109.3 109.3 108.65(9) 111.01(9) 111.12(9) 108.7 108.7 108.7 109.53(9) 111.72(9) 110.88(9) 108.2 108.2 108.2 109.40(9) 111.56(9) 109.42(9) 106.89(8) 108.65(9) 110.84(9) 114.78(9) 108.6 108.6 108.6  258  C(6)-C(7)-H(7B) H(7A)-C(7)-H(7B) O(14)-C(8)-O(18) O(14)-C(8)-C(7) O(18)-C(8)-C(7) N(10)-C(9)-C(5) O(17)-C(15)-N(13) O(17)-C(15)-C(16) N(13)-C(15)-C(16) C(15)-C(16)-H(16A) C(15)-C(16)-H(16B) H(16A)-C(16)-H(16B) C(15)-C(16)-H(16C) H(16A)-C(16)-H(16C) H(16B)-C(16)-H(16C) O(18)-C(19)-H(19A) O(18)-C(19)-H(19B) H(19A)-C(19)-H(19B) O(18)-C(19)-H(19C) H(19A)-C(19)-H(19C) H(19B)-C(19)-H(19C) C(22)-C(21)-C(23) C(22)-C(21)-C(24) C(23)-C(21)-C(24) C(22)-C(21)-Si(20) C(23)-C(21)-Si(20) C(24)-C(21)-Si(20) C(21)-C(22)-H(22A) C(21)-C(22)-H(22B) H(22A)-C(22)-H(22B) C(21)-C(22)-H(22C) H(22A)-C(22)-H(22C) H(22B)-C(22)-H(22C) C(21)-C(23)-H(23A) C(21)-C(23)-H(23B) H(23A)-C(23)-H(23B) C(21)-C(23)-H(23C) H(23A)-C(23)-H(23C) H(23B)-C(23)-H(23C) C(21)-C(24)-H(24A) C(21)-C(24)-H(24B) H(24A)-C(24)-H(24B) C(21)-C(24)-H(24C) H(24A)-C(24)-H(24C) H(24B)-C(24)-H(24C) C(26)-C(25)-C(30) C(26)-C(25)-Si(20) C(30)-C(25)-Si(20) C(27)-C(26)-C(25) C(27)-C(26)-H(26) C(25)-C(26)-H(26) C(28)-C(27)-C(26) C(28)-C(27)-H(27) C(26)-C(27)-H(27) C(29)-C(28)-C(27) C(29)-C(28)-H(28) C(27)-C(28)-H(28) C(28)-C(29)-C(30) C(28)-C(29)-H(29)  108.6 107.5 123.73(11) 126.60(10) 109.66(9) 179.20(14) 122.36(10) 121.59(10) 116.04(10) 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.83(12) 108.71(11) 107.74(11) 111.37(9) 112.24(9) 106.79(8) 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 117.43(11) 121.76(9) 120.77(9) 121.27(12) 119.4 119.4 120.20(12) 119.9 119.9 119.51(12) 120.2 120.2 120.29(12) 119.9  259  C(30)-C(29)-H(29) 119.9 C(29)-C(30)-C(25) 121.29(11) C(29)-C(30)-H(30) 119.4 C(25)-C(30)-H(30) 119.4 C(32)-C(31)-C(36) 116.70(12) C(32)-C(31)-Si(20) 123.98(10) C(36)-C(31)-Si(20) 119.30(9) C(33)-C(32)-C(31) 121.43(13) C(33)-C(32)-H(32) 119.3 C(31)-C(32)-H(32) 119.3 C(34)-C(33)-C(32) 120.62(14) C(34)-C(33)-H(33) 119.7 C(32)-C(33)-H(33) 119.7 C(33)-C(34)-C(35) 119.40(13) C(33)-C(34)-H(34) 120.3 C(35)-C(34)-H(34) 120.3 C(34)-C(35)-C(36) 120.00(14) C(34)-C(35)-H(35) 120.0 C(36)-C(35)-H(35) 120.0 C(35)-C(36)-C(31) 121.83(13) C(35)-C(36)-H(36) 119.1 C(31)-C(36)-H(36) 119.1 C(15)-N(13)-C(6) 123.96(9) C(15)-N(13)-H(13N) 118.8(11) C(6)-N(13)-H(13N) 117.0(11) C(4)-O(11)-H(11O) 107.2(13) C(3)-O(12)-Si(20) 132.22(7) C(8)-O(18)-C(19) 115.81(10) O(12)-Si(20)-C(31) 111.71(5) O(12)-Si(20)-C(25) 108.42(5) C(31)-Si(20)-C(25) 107.94(5) O(12)-Si(20)-C(21) 103.04(5) C(31)-Si(20)-C(21) 116.13(6) C(25)-Si(20)-C(21) 109.34(5) Cl(2)-C(37)-Cl(1) 110.7(7) Cl(2)-C(37)-H(37A) 109.5 Cl(1)-C(37)-H(37A) 109.5 Cl(2)-C(37)-H(37B) 109.5 Cl(1)-C(37)-H(37B) 109.5 H(37A)-C(37)-H(37B) 108.1 Cl(2B)-C(37B)-Cl(1B) 112.94(19) Cl(2B)-C(37B)-H(37C) 109.0 Cl(1B)-C(37B)-H(37C) 109.0 Cl(2B)-C(37B)-H(37D) 109.0 Cl(1B)-C(37B)-H(37D) 109.0 H(37C)-C(37B)-H(37D) 107.8 _____________________________________________________________ Symmetry transformations used to generate equivalent atoms:  260  Anisotropic displacement parameters (A2 x 103) for mc044. The anisotropic displacement factor exponent takes the form: -2 2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ] _______________________________________________________________________ U11 U22 U33 U23 U13 U12 _______________________________________________________________________ C(1) 12(1) 10(1) 16(1) -3(1) -4(1) -2(1) C(2) 12(1) 12(1) 16(1) -5(1) -3(1) -1(1) C(3) 11(1) 13(1) 12(1) -3(1) -2(1) -3(1) C(4) 11(1) 11(1) 12(1) -2(1) -2(1) -3(1) C(5) 10(1) 11(1) 13(1) -2(1) -2(1) -4(1) C(6) 9(1) 11(1) 13(1) -2(1) -3(1) -3(1) C(7) 12(1) 13(1) 14(1) -2(1) -4(1) -4(1) C(8) 11(1) 13(1) 12(1) -3(1) -1(1) -2(1) C(9) 14(1) 13(1) 14(1) -3(1) -2(1) -4(1) C(15) 11(1) 11(1) 16(1) -1(1) -2(1) -4(1) C(16) 11(1) 21(1) 38(1) -13(1) -3(1) -4(1) C(19) 21(1) 22(1) 19(1) 7(1) -4(1) -8(1) C(21) 16(1) 15(1) 15(1) -1(1) -3(1) -4(1) C(22) 38(1) 31(1) 15(1) -4(1) -9(1) 2(1) C(23) 33(1) 17(1) 45(1) 6(1) -17(1) -9(1) C(24) 16(1) 31(1) 26(1) 5(1) -6(1) -3(1) C(25) 12(1) 14(1) 16(1) -2(1) -4(1) -3(1) C(26) 17(1) 16(1) 18(1) -4(1) 0(1) -5(1) C(27) 23(1) 16(1) 24(1) -6(1) -4(1) -6(1) C(28) 22(1) 16(1) 26(1) -1(1) -8(1) -9(1) C(29) 16(1) 20(1) 19(1) 1(1) -3(1) -8(1) C(30) 13(1) 17(1) 16(1) -3(1) -3(1) -3(1) C(31) 14(1) 20(1) 14(1) -4(1) -2(1) -6(1) C(32) 19(1) 32(1) 26(1) 8(1) -8(1) -12(1) C(33) 20(1) 50(1) 26(1) 8(1) -5(1) -19(1) C(34) 14(1) 46(1) 24(1) -12(1) -2(1) -10(1) C(35) 15(1) 26(1) 40(1) -11(1) -7(1) -1(1) C(36) 16(1) 18(1) 32(1) -5(1) -4(1) -5(1) N(10) 15(1) 24(1) 23(1) -5(1) -4(1) -7(1) N(13) 10(1) 12(1) 15(1) -4(1) -3(1) -4(1) O(11) 17(1) 11(1) 16(1) -2(1) 1(1) -4(1) O(12) 15(1) 16(1) 12(1) -4(1) -4(1) -2(1) O(14) 14(1) 16(1) 18(1) -2(1) -4(1) -6(1) O(17) 13(1) 15(1) 18(1) -6(1) -1(1) -5(1) O(18) 18(1) 19(1) 14(1) 2(1) -6(1) -7(1) Si(20) 12(1) 12(1) 11(1) -2(1) -2(1) -4(1) C(37) 46(9) 37(7) 70(10) -6(6) -15(7) -5(6) Cl(1) 64(2) 66(3) 143(5) -23(3) -42(2) -13(2) Cl(2) 63(3) 81(4) 96(4) 20(2) 10(2) 27(2) Cl(2B) 38(1) 27(1) 28(1) 3(1) 14(1) 0(1) Cl(1B) 34(1) 63(1) 42(1) -3(1) -13(1) -23(1) C(37B) 15(2) 28(2) 29(2) -4(2) 5(2) -9(2) _______________________________________________________________________  261  Hydrogen coordinates (x104) and isotropic displacement parameters (A2 x 103) for mc044. ________________________________________________________________ x y z U(eq) ________________________________________________________________ H(1) 7831 4491 9522 15 H(2) 8826 4915 8277 16 H(3) 9228 7267 7957 15 H(4) 6088 8473 8572 14 H(5) 6747 8760 9747 13 H(7A) 8631 5760 10573 15 H(7B) 7097 6832 10973 15 H(16A) 2266 7721 10860 33 H(16B) 2579 7807 9925 33 H(16C) 2126 9223 10323 33 H(19A) 6364 3232 12400 32 H(19B) 8020 2710 12636 32 H(19C) 7779 2251 11868 32 H(22A) 6796 8236 4704 46 H(22B) 7228 6622 5125 46 H(22C) 8506 7372 4838 46 H(23A) 8404 9381 5454 47 H(23B) 7342 9722 6276 47 H(23C) 6627 10222 5483 47 H(24A) 4784 9026 5817 40 H(24B) 5159 8677 6692 40 H(24C) 5174 7425 6256 40 H(26) 8908 4210 5724 21 H(27) 8169 2193 5891 25 H(28) 6458 1734 7000 24 H(29) 5473 3324 7933 22 H(30) 6210 5338 7772 19 H(32) 10543 7972 5704 31 H(33) 13186 7208 5429 38 H(34) 14602 4933 5931 33 H(35) 13357 3381 6696 32 H(36) 10716 4102 6933 26 H(13N) 4997(18) 6547(17) 9677(10) 17(4) H(11O) 6840(20) 10280(20) 8517(12) 36(5) H(37A) 10555 8090 2418 63 H(37B) 10245 9725 2039 63 H(37C) 10599 8018 2434 30 H(37D) 10215 9631 2014 30 ________________________________________________________________  262  Torsion angles [deg] for mc044. ________________________________________________________________ C(6)-C(1)-C(2)-C(3) C(1)-C(2)-C(3)-O(12) C(1)-C(2)-C(3)-C(4) O(12)-C(3)-C(4)-O(11) C(2)-C(3)-C(4)-O(11) O(12)-C(3)-C(4)-C(5) C(2)-C(3)-C(4)-C(5) O(11)-C(4)-C(5)-C(9) C(3)-C(4)-C(5)-C(9) O(11)-C(4)-C(5)-C(6) C(3)-C(4)-C(5)-C(6) C(2)-C(1)-C(6)-N(13) C(2)-C(1)-C(6)-C(7) C(2)-C(1)-C(6)-C(5) C(9)-C(5)-C(6)-N(13) C(4)-C(5)-C(6)-N(13) C(9)-C(5)-C(6)-C(1) C(4)-C(5)-C(6)-C(1) C(9)-C(5)-C(6)-C(7) C(4)-C(5)-C(6)-C(7) N(13)-C(6)-C(7)-C(8) C(1)-C(6)-C(7)-C(8) C(5)-C(6)-C(7)-C(8) C(6)-C(7)-C(8)-O(14) C(6)-C(7)-C(8)-O(18) C(4)-C(5)-C(9)-N(10) C(6)-C(5)-C(9)-N(10) C(30)-C(25)-C(26)-C(27) Si(20)-C(25)-C(26)-C(27) C(25)-C(26)-C(27)-C(28) C(26)-C(27)-C(28)-C(29) C(27)-C(28)-C(29)-C(30) C(28)-C(29)-C(30)-C(25) C(26)-C(25)-C(30)-C(29) Si(20)-C(25)-C(30)-C(29) C(36)-C(31)-C(32)-C(33) Si(20)-C(31)-C(32)-C(33) C(31)-C(32)-C(33)-C(34) C(32)-C(33)-C(34)-C(35) C(33)-C(34)-C(35)-C(36) C(34)-C(35)-C(36)-C(31) C(32)-C(31)-C(36)-C(35) Si(20)-C(31)-C(36)-C(35) O(17)-C(15)-N(13)-C(6) C(16)-C(15)-N(13)-C(6) C(1)-C(6)-N(13)-C(15) C(7)-C(6)-N(13)-C(15) C(5)-C(6)-N(13)-C(15) C(2)-C(3)-O(12)-Si(20) C(4)-C(3)-O(12)-Si(20) O(14)-C(8)-O(18)-C(19) C(7)-C(8)-O(18)-C(19) C(3)-O(12)-Si(20)-C(31) C(3)-O(12)-Si(20)-C(25) C(3)-O(12)-Si(20)-C(21) C(32)-C(31)-Si(20)-O(12)  -4.13(18) -126.21(12) -7.46(16) -76.58(11) 162.34(9) 161.01(9) 39.93(12) -60.39(12) 60.64(12) 175.86(9) -63.11(11) 99.09(13) -138.41(11) -17.27(14) 168.87(9) -68.64(11) -73.16(11) 49.32(11) 47.10(12) 169.58(9) 56.74(12) -64.46(12) 175.74(9) -9.25(16) 171.70(9) 19(10) 142(10) -0.57(18) -178.30(10) 0.15(19) 0.4(2) -0.46(19) 0.03(18) 0.48(17) 178.23(9) 0.9(2) 179.44(12) -1.5(2) 0.7(2) 0.6(2) -1.2(2) 0.4(2) -178.18(11) 0.46(18) -178.84(11) 177.47(10) 56.26(14) -65.06(13) -68.26(13) 170.30(8) 4.61(16) -176.31(10) -30.74(12) 88.08(11) -156.10(10) -88.41(12)  263  C(36)-C(31)-Si(20)-O(12) 90.09(11) C(32)-C(31)-Si(20)-C(25) 152.49(11) C(36)-C(31)-Si(20)-C(25) -29.01(11) C(32)-C(31)-Si(20)-C(21) 29.35(13) C(36)-C(31)-Si(20)-C(21) -152.15(10) C(26)-C(25)-Si(20)-O(12) -171.17(9) C(30)-C(25)-Si(20)-O(12) 11.17(11) C(26)-C(25)-Si(20)-C(31) -50.00(11) C(30)-C(25)-Si(20)-C(31) 132.34(9) C(26)-C(25)-Si(20)-C(21) 77.18(11) C(30)-C(25)-Si(20)-C(21) -100.48(10) C(22)-C(21)-Si(20)-O(12) -175.57(10) C(23)-C(21)-Si(20)-O(12) 60.82(11) C(24)-C(21)-Si(20)-O(12) -57.03(10) C(22)-C(21)-Si(20)-C(31) 61.98(11) C(23)-C(21)-Si(20)-C(31) -61.63(11) C(24)-C(21)-Si(20)-C(31) -179.47(9) C(22)-C(21)-Si(20)-C(25) -60.42(11) C(23)-C(21)-Si(20)-C(25) 175.97(10) C(24)-C(21)-Si(20)-C(25) 58.12(10) ________________________________________________________________  Hydrogen Bonds Donor --- H....Acceptor [ ARU ] D - H H...A D...A D H...A ----------------------------------------------------------------------------O(11) --H(11O) ..O(17) [ 2677.01] 0.85(2) 1.92(2) 2.7578(13) 167(2) N(13) --H(13N) ..O(14) [ 2667.01] 0.842(17) 2.168(18) 3.0024(15) 170.8(16) Translation of ARU-code to Equivalent Position Code =================================================== [ 2677. ] = 1-x,2-y,2-z [ 2667. ] = 1-x,1-y,2-z  264  C.6 X-ray data of N-[(4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-7-oxoindeno[1,7-cd]isoxazol-4a(7H)yl]-acetamide (2.124)  NHAc  O O N 2.124  Crystal Data  Empirical Formula  C11H12N2O3  Formula Weight  220.23  Crystal Color, Habit  colorless, irregular  Crystal Dimensions  0.14 X 0.45 X 0.60 mm  Crystal System  monoclinic  Lattice Type  primitive  Lattice Parameters  a = 7.4372(4) Å b = 7.6194(3) Å c = 18.2141(9) Å  = 90.0°  = 92.696(2)°  = 90.0° V = 1539.6(3) Å3  Space Group  P 21/c (#14)  Z value  4  Dcalc  1.419 g/cm3  F000  464.00  (MoK)  1.05 cm-1  265  Intensity Measurements  Diffractometer  Bruker X8 APEX II  Radiation  MoK ( = 0.71073 Å) graphite monochromated  Data Images  1321 exposures @ 7.0 seconds  Detector Position  36.00 mm  2max  56.0°  No. of Reflections Measured  Total: 12787 Unique: 2466 (Rint = 0.030)  Corrections  Absorption (Tmin = 0.840, Tmax = 0.985) Lorentz-polarization  Structure Solution and Refinement  Structure Solution  Direct Methods (SIR97)  Refinement  Full-matrix least-squares on F2  Function Minimized   w (Fo2 – Fc2)2  Least Squares Weights  w = 1/(2(Fo2) + (0.0455P)2 + 0.3215P)  Anomalous Dispersion  All non-hydrogen atoms  No. Observations (I>0.00(I))  2466  No. Variables  150  Reflection/Parameter Ratio  16.44  Residuals (refined on F2, all data): R1; wR2  0.043; 0.100  Goodness of Fit Indicator  1.04  No. Observations (I>2.00(I))  2132  Residuals (refined on F): R1; wR2  0.037; 0.095  Max Shift/Error in Final Cycle  0.00  Maximum peak in Final Diff. Map  0.26 e-/Å3  Minimum peak in Final Diff. Map  -0.21 e-/Å3  266  Atomic coordinates (x104) and equivalent isotropic displacement parameters (A2 x 103) for mc017. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________ x y z U(eq) ________________________________________________________________ C(1) 4782(2) 8132(2) 1234(1) 25(1) C(2) 4993(2) 9785(2) 1015(1) 27(1) C(3) 3495(2) 11032(2) 942(1) 28(1) C(4) 1663(2) 10528(2) 1217(1) 28(1) C(5) 1555(1) 8679(1) 1519(1) 24(1) C(6) 2985(1) 7286(1) 1359(1) 22(1) C(7) 3042(2) 6165(2) 2071(1) 29(1) C(8) 2813(2) 7472(2) 2711(1) 31(1) C(9) 2006(2) 9041(2) 2321(1) 27(1) C(15) 2077(2) 6802(2) 51(1) 24(1) C(16) 1947(2) 5468(2) -560(1) 33(1) N(10) 1966(1) 10644(2) 2514(1) 34(1) N(13) 2538(1) 6159(1) 727(1) 25(1) O(11) 1393(1) 11644(1) 1867(1) 37(1) O(12) 3726(2) 12512(1) 703(1) 44(1) O(14) 1793(1) 8374(1) -58(1) 30(1) ________________________________________________________________  267  Bond lengths [A] and angles [deg] for mc017. _____________________________________________________________ C(1)-C(2) C(1)-C(6) C(1)-H(1) C(2)-C(3) C(2)-H(2) C(3)-O(12) C(3)-C(4) C(4)-O(11) C(4)-C(5) C(4)-H(4) C(5)-C(9) C(5)-C(6) C(5)-H(5) C(6)-N(13) C(6)-C(7) C(7)-C(8) C(7)-H(7A) C(7)-H(7B) C(8)-C(9) C(8)-H(8A) C(8)-H(8B) C(9)-N(10) C(15)-O(14) C(15)-N(13) C(15)-C(16) C(16)-H(16A) C(16)-H(16B) C(16)-H(16C) N(10)-O(11) N(13)-H(13N) C(2)-C(1)-C(6) C(2)-C(1)-H(1) C(6)-C(1)-H(1) C(1)-C(2)-C(3) C(1)-C(2)-H(2) C(3)-C(2)-H(2) O(12)-C(3)-C(2) O(12)-C(3)-C(4) C(2)-C(3)-C(4) O(11)-C(4)-C(5) O(11)-C(4)-C(3) C(5)-C(4)-C(3) O(11)-C(4)-H(4) C(5)-C(4)-H(4) C(3)-C(4)-H(4) C(9)-C(5)-C(4) C(9)-C(5)-C(6) C(4)-C(5)-C(6) C(9)-C(5)-H(5) C(4)-C(5)-H(5) C(6)-C(5)-H(5) N(13)-C(6)-C(1) N(13)-C(6)-C(5) C(1)-C(6)-C(5) N(13)-C(6)-C(7)  1.3324(16) 1.5105(15) 0.9500 1.4656(16) 0.9500 1.2245(14) 1.5228(17) 1.4787(14) 1.5160(16) 1.0000 1.5079(16) 1.5406(15) 1.0000 1.4629(14) 1.5521(15) 1.5479(17) 0.9900 0.9900 1.5011(17) 0.9900 0.9900 1.2715(16) 1.2308(14) 1.3532(15) 1.5063(16) 0.9800 0.9800 0.9800 1.4509(14) 0.854(17) 124.47(10) 117.8 117.8 122.69(11) 118.7 118.7 120.69(12) 119.49(11) 119.67(10) 103.44(9) 106.01(9) 114.64(9) 110.8 110.8 110.8 99.69(9) 100.66(9) 121.52(9) 111.2 111.2 111.2 107.54(9) 114.86(9) 111.01(9) 109.35(9)  268  C(1)-C(6)-C(7) 111.82(9) C(5)-C(6)-C(7) 102.28(9) C(8)-C(7)-C(6) 105.98(9) C(8)-C(7)-H(7A) 110.5 C(6)-C(7)-H(7A) 110.5 C(8)-C(7)-H(7B) 110.5 C(6)-C(7)-H(7B) 110.5 H(7A)-C(7)-H(7B) 108.7 C(9)-C(8)-C(7) 102.23(9) C(9)-C(8)-H(8A) 111.3 C(7)-C(8)-H(8A) 111.3 C(9)-C(8)-H(8B) 111.3 C(7)-C(8)-H(8B) 111.3 H(8A)-C(8)-H(8B) 109.2 N(10)-C(9)-C(8) 130.38(11) N(10)-C(9)-C(5) 115.88(11) C(8)-C(9)-C(5) 112.23(10) O(14)-C(15)-N(13) 122.25(10) O(14)-C(15)-C(16) 122.18(11) N(13)-C(15)-C(16) 115.57(10) C(15)-C(16)-H(16A) 109.5 C(15)-C(16)-H(16B) 109.5 H(16A)-C(16)-H(16B) 109.5 C(15)-C(16)-H(16C) 109.5 H(16A)-C(16)-H(16C) 109.5 H(16B)-C(16)-H(16C) 109.5 C(9)-N(10)-O(11) 106.84(10) C(15)-N(13)-C(6) 122.79(9) C(15)-N(13)-H(13N) 118.0(11) C(6)-N(13)-H(13N) 118.0(11) N(10)-O(11)-C(4) 107.58(8) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms:  269  Anisotropic displacement parameters (A2 x 103) for mc017. The anisotropic displacement factor exponent takes the form: -2 2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ] _______________________________________________________________________ U11 U22 U33 U23 U13 U12 _______________________________________________________________________ C(1) 22(1) 23(1) 28(1) -2(1) -1(1) 4(1) C(2) 26(1) 24(1) 29(1) -1(1) 2(1) -2(1) C(3) 38(1) 18(1) 27(1) -1(1) -2(1) 1(1) C(4) 30(1) 22(1) 31(1) -4(1) -5(1) 7(1) C(5) 20(1) 24(1) 28(1) -2(1) -1(1) 2(1) C(6) 24(1) 18(1) 24(1) 0(1) -1(1) 2(1) C(7) 35(1) 24(1) 27(1) 4(1) -1(1) 0(1) C(8) 35(1) 33(1) 25(1) 2(1) 1(1) -3(1) C(9) 23(1) 32(1) 27(1) -4(1) 4(1) 0(1) C(15) 22(1) 25(1) 26(1) 0(1) 1(1) -2(1) C(16) 39(1) 32(1) 27(1) -4(1) 2(1) -4(1) N(10) 35(1) 35(1) 32(1) -6(1) 4(1) 4(1) N(13) 32(1) 16(1) 26(1) -1(1) -1(1) 1(1) O(11) 44(1) 28(1) 39(1) -8(1) 2(1) 12(1) O(12) 59(1) 21(1) 52(1) 7(1) 7(1) 3(1) O(14) 34(1) 25(1) 31(1) 4(1) -3(1) 3(1) _______________________________________________________________________  270  Hydrogen coordinates (x104) and isotropic displacement parameters (A2 x 103) for mc017. ________________________________________________________________ x y z U(eq) ________________________________________________________________ H(1) 5833 7437 1316 30 H(2) 6163 10172 903 32 H(4) 691 10736 829 33 H(5) 311 8191 1445 29 H(7A) 2056 5291 2053 34 H(7B) 4204 5538 2134 34 H(8A) 1995 6998 3076 37 H(8B) 3986 7762 2961 37 H(16A) 900 5734 -888 49 H(16B) 1812 4293 -350 49 H(16C) 3042 5511 -838 49 H(13N) 2780(20) 5070(20) 764(9) 40(4) ________________________________________________________________  271  Torsion angles [deg] for mc017. ________________________________________________________________ C(6)-C(1)-C(2)-C(3) 6.23(18) C(1)-C(2)-C(3)-O(12) -176.07(12) C(1)-C(2)-C(3)-C(4) 8.35(17) O(12)-C(3)-C(4)-O(11) -64.99(14) C(2)-C(3)-C(4)-O(11) 110.64(11) O(12)-C(3)-C(4)-C(5) -178.42(11) C(2)-C(3)-C(4)-C(5) -2.79(15) O(11)-C(4)-C(5)-C(9) -22.36(10) C(3)-C(4)-C(5)-C(9) 92.58(11) O(11)-C(4)-C(5)-C(6) -131.31(10) C(3)-C(4)-C(5)-C(6) -16.37(15) C(2)-C(1)-C(6)-N(13) 102.91(12) C(2)-C(1)-C(6)-C(5) -23.50(15) C(2)-C(1)-C(6)-C(7) -137.03(11) C(9)-C(5)-C(6)-N(13) 157.55(9) C(4)-C(5)-C(6)-N(13) -94.01(12) C(9)-C(5)-C(6)-C(1) -80.20(10) C(4)-C(5)-C(6)-C(1) 28.24(14) C(9)-C(5)-C(6)-C(7) 39.22(10) C(4)-C(5)-C(6)-C(7) 147.65(10) N(13)-C(6)-C(7)-C(8) -159.61(9) C(1)-C(6)-C(7)-C(8) 81.40(11) C(5)-C(6)-C(7)-C(8) -37.44(11) C(6)-C(7)-C(8)-C(9) 19.32(12) C(7)-C(8)-C(9)-N(10) -158.72(13) C(7)-C(8)-C(9)-C(5) 6.46(13) C(4)-C(5)-C(9)-N(10) 13.30(13) C(6)-C(5)-C(9)-N(10) 138.18(11) C(4)-C(5)-C(9)-C(8) -154.18(10) C(6)-C(5)-C(9)-C(8) -29.31(12) C(8)-C(9)-N(10)-O(11) 167.17(12) C(5)-C(9)-N(10)-O(11) 2.43(14) O(14)-C(15)-N(13)-C(6) -8.92(17) C(16)-C(15)-N(13)-C(6) 170.69(10) C(1)-C(6)-N(13)-C(15) -70.52(13) C(5)-C(6)-N(13)-C(15) 53.59(14) C(7)-C(6)-N(13)-C(15) 167.86(10) C(9)-N(10)-O(11)-C(4) -18.10(12) C(5)-C(4)-O(11)-N(10) 25.77(11) C(3)-C(4)-O(11)-N(10) -95.20(10) ________________________________________________________________  272  Hydrogen Bonds Donor --- H....Acceptor [ ARU ] D - H H...A D...A D H...A ------------------------------------------------------------------------------N(13) --H(13N) ..O(12) [ 1545.01] 0.851(15) 2.077(15) 2.9166(13) 169.0(15) Translation of ARU-code to Equivalent Position Code =================================================== [ 1545. ] = x,-1+y,z  273  

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