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A synthetic approach to quinocarcin and cyanocycline A : the Ugi reaction of complex aminoacids Turner, Charles Dylan 2012

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   A Synthetic Approach to Quinocarcin and Cyanocycline A: The Ugi Reaction of Complex Aminoacids   by   Charles Dylan Turner    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)    August 2012     © Charles Dylan Turner, 2012     ii  Abstract  This dissertation describes synthetic efforts towards the natural products quinocarcin and cyanocycline A. Our approach capitalizes on the Ugi reaction of a complex pyroglutamol- derived aminoacid. This ambitious strategy first required the synthesis of the aminoacid, which required considerable development; ultimately the route was optimized to become practical and consistently high-yielding. Ugi condensation reactions using this material were successful, providing advanced precursors of the target molecules.   iii  Preface   A portion of the research described in Chapter 2 appeared in Turner, C. D. and Ciufolini, M. A. Useful building blocks for the stereocontrolled assembly of 2,3,5-trisubstituted pyrrolidines. Heterocycles 2012, 85, 85-94.  C.D.T. is responsible for: the performance of each of the experiments reported herein; much of the tactical synthetic planning; and the writing of a complete draft of this dissertation. M.A.C. provided: the overall synthetic strategy; many helpful tactical and technical suggestions; and a thorough editing of this document.  iv   Table of Contents Abstract ........................................................................................................................................... ii Preface............................................................................................................................................ iii Table of Contents ........................................................................................................................... iv List of Tables ............................................................................................................................... viii List of Figures ................................................................................................................................ ix List of Schemes ............................................................................................................................ xiii List of Abbreviations .................................................................................................................. xvii Acknowledgements ..................................................................................................................... xxii 1 Introduction .................................................................................................................................. 1 1.1 Tetrahydroisoquinoline natural products .............................................................................. 1 1.2 Mechanisms of action ........................................................................................................... 5 1.3 Biosynthesis ........................................................................................................................ 10 1.4 Prior syntheses .................................................................................................................... 11 1.4.1 Total syntheses of quinocarcin: Danishefsky .............................................................. 12 1.4.2 Total syntheses of quinocarcin: Fukuyama .................................................................. 13 1.4.3 Total syntheses of quinocarcin: Garner ....................................................................... 15 1.4.4 Total syntheses of quinocarcin: Terashima .................................................................. 17 1.4.5 Total syntheses of quinocarcin: Williams .................................................................... 18 1.4.6 Total syntheses of quinocarcin: Myers ........................................................................ 19 1.4.7 Total syntheses of quinocarcin: Zhu ............................................................................ 21 1.4.8 Total syntheses of quinocarcin: Stoltz ......................................................................... 22 v  1.4.9 Total syntheses of cyanocycline: Evans....................................................................... 24 1.4.10 Total syntheses of cyanocycline: Fukuyama ............................................................. 26 1.4.10 Total syntheses of cyanocycline: Garner ................................................................... 28 1.5 Retrosynthetic considerations ............................................................................................. 30 1.6 The Ugi reaction ................................................................................................................. 31 2 Synthetic Work .......................................................................................................................... 41 2.1 Synthesis of the aminoacid ................................................................................................. 41 2.2 Ugi reactions of complex aminoacids ................................................................................. 65 2.3 Synthetic efforts towards quinocarcin and cyanocycline A ................................................ 74 3 Conclusion ................................................................................................................................. 81 References ..................................................................................................................................... 82 Appendix A: Experimental Protocols ........................................................................................... 89 A.1 Preparation of 218 .......................................................................................................... 90 A.2 Preparation of 220........................................................................................................ 92 A.3 Preparation of 223 .......................................................................................................... 94 A.4 Preparation of 225 .......................................................................................................... 97 A.5 Preparation of 226 .......................................................................................................... 99 A.6 Preparation of 233 ........................................................................................................ 101 A.7 Preparation of 234 ........................................................................................................ 103 A.8 Preparation of 235 ........................................................................................................ 105 A.9 Preparation of 236 ........................................................................................................ 108 A.10 Preparation of 238 ...................................................................................................... 110 A.11 Preparation of 246 ...................................................................................................... 113 vi  A.12 Preparation of 251 ...................................................................................................... 115 A.13 Preparation of 252 ...................................................................................................... 117 A.14 Preparation of 253 ...................................................................................................... 119 A.15 Preparation of 255 ...................................................................................................... 121 A.16 Preparation of 232 from 255 ...................................................................................... 124 A.17 Preparation of 238 from 232 ...................................................................................... 126 A.18 Preparation of 256 ...................................................................................................... 127 A.19 Preparation of 259 ...................................................................................................... 129 A.20 Preparation of 265 ...................................................................................................... 131 A.21 Preparation of 266 ...................................................................................................... 133 A.22 Preparation of 267 ...................................................................................................... 136 A.23 Preparation of 273 ...................................................................................................... 139 A.24 Preparation of 274 ...................................................................................................... 141 A.25 Preparation of 278 ...................................................................................................... 143 A.26 Preparation of 279 ...................................................................................................... 145 A.27 Preparation of 281 ...................................................................................................... 148 A.28 Preparation of 283 ...................................................................................................... 152 A.29 Data for 282 ............................................................................................................... 154 A.30 Procedure for hydrolysis of 274 and Ugi condensation: preparation of 297 ............. 156 A.31 Data for 293 ............................................................................................................... 160 A.32 Data for 300 ............................................................................................................... 162 A.33 Data for 298 ............................................................................................................... 164 A.34 Procedure for hydrolysis of 273 and Ugi condensation: preparation of 294 ............. 166 vii  A.35 Data for 299 ............................................................................................................... 170 A.36 Preparation of 322 ...................................................................................................... 172 A.37 X-ray crystallography data for 293 ............................................................................ 174    viii  List of Tables  Table 1. Minimum Inhibitory Concentrations (MICs) of 1 against selected bacteria .................... 1 Table 2. Optimization of conditions for the selenation / oxidation of 253 ................................... 53 Table 3. Product ratios in the epimerization of 266 to 267 in various solvents ............................ 61    ix  List of Figures  Figure 1. Naphthyridinomycin 1 and its congeners ........................................................................ 2 Figure 2. 1H NMR spectrum of 1 as originally published1 ............................................................. 3 Figure 3. Quinocarcin 7 and its congeners ...................................................................................... 4 Figure 4. A predicted conformational effect in the DNA-cleaving ability of 7 .............................. 9 Figure 5. Rationale for the formation of 226 from 225 ................................................................ 45 Figure 6. Scalar and dipolar couplings observed in the NOE spectra of 266 and 267 ................. 59 Figure 7. Solid-state structure of 293 ............................................................................................ 68 Figure 8. Lactone resonances and Ugi product stereochemistry .................................................. 71 Figure 9. Space-filling model of iminium ion 305 ....................................................................... 73 Figure 10. 1H NMR spectrum of 218 ............................................................................................ 91 Figure 11. 13C NMR spectrum of 218 ........................................................................................... 91 Figure 12. 1H NMR spectrum of 220 ............................................................................................ 93 Figure 13. 13C NMR spectrum of 220 ........................................................................................... 93 Figure 14. 1H NMR spectrum of 223 ............................................................................................ 96 Figure 15. 13C NMR spectrum of 223 ........................................................................................... 96 Figure 16. 1H NMR spectrum of 225 ............................................................................................ 98 Figure 17. 13C NMR spectrum of 225 ........................................................................................... 98 Figure 18. 1H NMR spectrum of 226 .......................................................................................... 100 Figure 19. 13C NMR spectrum of 226 ......................................................................................... 100 Figure 20. 1H NMR spectrum of 233 .......................................................................................... 102 Figure 21. 13C NMR spectrum of 233 ......................................................................................... 102 Figure 22. 1H NMR spectrum of 234 .......................................................................................... 104 x  Figure 23. 13C NMR spectrum of 234 ......................................................................................... 104 Figure 24. 1H NMR spectrum of 235 .......................................................................................... 107 Figure 25. 13C NMR spectrum of 235 ......................................................................................... 107 Figure 26. 1H NMR spectrum of 236 .......................................................................................... 109 Figure 27. 13C NMR spectrum of 236 ......................................................................................... 109 Figure 28. 1H NMR spectrum of 238 .......................................................................................... 112 Figure 29. 13C NMR spectrum of 238 ......................................................................................... 112 Figure 30. 1H NMR spectrum of 246 .......................................................................................... 114 Figure 31. 13C NMR spectrum of 246 ......................................................................................... 114 Figure 32. 1H NMR spectrum of 251 .......................................................................................... 116 Figure 33. 13C NMR spectrum of 251 ......................................................................................... 116 Figure 34. 1H NMR spectrum of 252 .......................................................................................... 118 Figure 35. 13C NMR spectrum of 252 ......................................................................................... 118 Figure 36. 1H NMR spectrum of 253 .......................................................................................... 120 Figure 37. 13C NMR spectrum of 253 ......................................................................................... 120 Figure 38. 1H NMR spectrum of 255 .......................................................................................... 123 Figure 39. 13C NMR spectrum of 255 ......................................................................................... 123 Figure 40. 1H NMR spectrum of 232 .......................................................................................... 125 Figure 41. 13C NMR spectrum of 232 ......................................................................................... 125 Figure 42. 1H NMR spectrum of 256 .......................................................................................... 128 Figure 43. 13C NMR spectrum of 256 ......................................................................................... 128 Figure 44. 1H NMR spectrum of 259 .......................................................................................... 130 Figure 45. 13C NMR spectrum of 259 ......................................................................................... 130 xi  Figure 46. 1H NMR spectrum of 265 .......................................................................................... 132 Figure 47. 13C NMR spectrum of 265 ......................................................................................... 132 Figure 48. 1H NMR spectrum of 266 .......................................................................................... 134 Figure 49. 13C NMR spectrum of 266 ......................................................................................... 134 Figure 50. NOE spectrum of 266, irradiation at 4.47 ppm ......................................................... 135 Figure 51. 1H NMR spectrum of 267 .......................................................................................... 137 Figure 52. 13C NMR spectrum of 267 ......................................................................................... 137 Figure 53. NOE spectrum of 267, irradiation at 3.92 ppm ......................................................... 138 Figure 54. 1H NMR spectrum of 273 .......................................................................................... 140 Figure 55. 13C NMR spectrum of 273 ......................................................................................... 140 Figure 56. 1H NMR spectrum of 274 .......................................................................................... 142 Figure 57. 13C NMR spectrum of 274 ......................................................................................... 142 Figure 58. 1H NMR spectrum of 278 .......................................................................................... 144 Figure 59. 13C NMR spectrum of 278 ......................................................................................... 144 Figure 60. 1H NMR spectrum of 279 at 80 °C in DMSO-d6 ...................................................... 146 Figure 61. 1H NMR spectrum of 279 (CDCl3, rt) ....................................................................... 147 Figure 62. 13C NMR spectrum of 279 ......................................................................................... 147 Figure 63. 1H NMR spectrum of 281 at 80 °C in DMSO-d6 ...................................................... 150 Figure 64. 1H NMR spectrum of 281 (CDCl3, rt) ....................................................................... 151 Figure 65. 13C NMR spectrum of 281 ......................................................................................... 151 Figure 66. 1H NMR spectrum of 283 .......................................................................................... 153 Figure 67. 13C NMR spectrum of 283 ......................................................................................... 153 Figure 68. 1H NMR spectrum of 282 .......................................................................................... 155 xii  Figure 69. 13C NMR spectrum of 282 ......................................................................................... 155 Figure 70. 1H NMR spectrum of 292 (methanol-d4) .................................................................. 158 Figure 71. 1H NMR spectrum of 297 .......................................................................................... 159 Figure 72. 13C NMR spectrum of 297 ......................................................................................... 159 Figure 73. 1H NMR spectrum of 293 .......................................................................................... 161 Figure 74. 13C NMR spectrum of 293 ......................................................................................... 161 Figure 75. 1H NMR spectrum of 300 .......................................................................................... 163 Figure 76. 13C NMR spectrum of 300 ......................................................................................... 163 Figure 77. 1H NMR spectrum of 298 .......................................................................................... 165 Figure 78. 13C NMR spectrum of 298 ......................................................................................... 165 Figure 79. 1H NMR spectrum of 291 (methanol-d4) .................................................................. 168 Figure 80. 1H NMR spectrum of 294 .......................................................................................... 169 Figure 81. 13C NMR spectrum of 294 ......................................................................................... 169 Figure 82. 1H NMR spectrum of 299 .......................................................................................... 171 Figure 83. 13C NMR spectrum of 299 ......................................................................................... 171 Figure 84. 1H NMR spectrum of 322 .......................................................................................... 173 Figure 85. 13C NMR spectrum of 322 ......................................................................................... 173   xiii  List of Schemes Scheme 1. Possible DNA cross-linking mechanism of 2 ............................................................... 6 Scheme 2. Possible disproportionation mechanism of 7 ................................................................ 7 Scheme 3. Possible mechanism for the formation of superoxide ion by 7 ..................................... 8 Scheme 4. Possible DNA alkylation by 7 ....................................................................................... 9 Scheme 5. Proposed biosynthetic origins of 2 .............................................................................. 11 Scheme 6. Danishefsky’s synthesis of racemic 35 ....................................................................... 13 Scheme 7. Fukuyama’s total synthesis of racemic 7 .................................................................... 14 Scheme 8. Chiral auxiliaries in Garner’s total synthesis of 7 ....................................................... 16 Scheme 9. The completion of Garner’s total synthesis of 7 ......................................................... 16 Scheme 10. Terashima’s total synthesis of 7 ................................................................................ 18 Scheme 11. Williams’ synthesis of racemic 10 ............................................................................ 19 Scheme 12. Pseudoephedrine auxiliaries in Myers’ total synthesis of 7 ...................................... 20 Scheme 13. The completion of Myers’ total synthesis of 7 .......................................................... 21 Scheme 14. Zhu’s total synthesis of 7 .......................................................................................... 22 Scheme 15. The early steps of Stoltz’s total synthesis of 7 .......................................................... 23 Scheme 16. The completion of Stoltz’s total synthesis of 7 ......................................................... 24 Scheme 17. Evans’ total synthesis of racemic 2 ........................................................................... 25 Scheme 18. The opening moves of Fukuyama’s total synthesis of 2 ........................................... 27 Scheme 19. The completion of Fukuyama’s total synthesis of 2 ................................................. 28 Scheme 20. Garner’s total synthesis of 2 ...................................................................................... 29 Scheme 21. Retrosynthetic analysis of 7 and 2-6 ......................................................................... 30 Scheme 22. Retrosynthetic analysis of 152 .................................................................................. 31 xiv  Scheme 23. Mechanism of the Ugi four-component condensation .............................................. 32 Scheme 24. Historical application of an MCR by Robinson ........................................................ 33 Scheme 25. The Ugi reaction in Fukuyama’s synthesis of ecteinascidin 743 .............................. 33 Scheme 26. The Ugi reaction in Kawasaki’s synthesis of fructigenine A .................................... 34 Scheme 27. A convertible isocyanide was used in Armstrong’s synthesis of motuporin ............ 34 Scheme 28. Mechanism for the Ugi reaction of amino acids ....................................................... 35 Scheme 29. Examples of the Ugi reaction of alpha amino acids with known product configuration ................................................................................................................................. 36 Scheme 30. Uncatalyzed Ugi reaction of 196 with 197 and 198 .................................................. 37 Scheme 31. Products of the Ugi reaction of amino acids with aromatic aldehydes ..................... 39 Scheme 32. Model for the stereochemical course of the Ugi reaction of amino acids ................. 40 Scheme 33. Initial retrosynthetic analysis of 155 ......................................................................... 42 Scheme 34. Reaction of the enolate of 214 with ethyl formate failed .......................................... 42 Scheme 35. Synthesis of 220 from 214 ........................................................................................ 43 Scheme 36. Claisen-type condensation of 220 ............................................................................. 44 Scheme 37. Synthesis of 225 and its cyclization to undesired isomer 226 ................................... 45 Scheme 38. Alternate retrosynthetic analysis of 155 .................................................................... 46 Scheme 39. Formation of 232 from 224 ....................................................................................... 46 Scheme 40. Hypothesized mechanism of the decomposition of an SEM ether by protic acid..... 47 Scheme 41. Synthesis of 238 using the SEM protecting group .................................................... 49 Scheme 42. Retrosynthesis of lactone 228 by Michael addition .................................................. 50 Scheme 43. The enolate of 214 did not add to 243 or 244 ........................................................... 50 Scheme 44. Attempted Michael-addition route to 228 ................................................................. 51 xv  Scheme 45. Advancement of allylation product 250 to lactone 253 ............................................ 52 Scheme 46. N-methylation of 253 was unsuccessful .................................................................... 52 Scheme 47. Synthesis of 255 from 253 ........................................................................................ 53 Scheme 48. Synthesis of 238 from 255 ........................................................................................ 54 Scheme 49. Synthesis of 256 in 3 steps from 238 ........................................................................ 55 Scheme 50. The enolate of 256 failed to react with sulfonyl azide 51 ......................................... 55 Scheme 51. Initial attempts to react the enolate of 238 with electrophilic nitrogen sources ........ 56 Scheme 53. Attempts to brominate 238 were unsatisfactory ........................................................ 57 Scheme 52. Possible method for the introduction of an amine to lactone 238 ............................. 57 Scheme 54. Synthesis of iodide 265 and its reaction with sodium azide ..................................... 58 Scheme 55. Hypothesized mechanisms for the formation of 266 from 265 ................................. 60 Scheme 56. Direct azidation of the sodium enolate of 238 was unsatisfactory ............................ 62 Scheme 57. Advancement of 266 to amines 273 and 274 ............................................................ 62 Scheme 58. Alternate retrosynthesis via glycinate aldol .............................................................. 63 Scheme 59. Synthesis and glycinate aldol reaction of aldehyde 279 ........................................... 64 Scheme 60. Unexpected rearrangement in the attempted Ugi reaction of 274 ............................. 65 Scheme 61. Possible mechanism for the rearrangement of 274 ................................................... 66 Scheme 62. Hydrolysis of lactones 273 and 274 .......................................................................... 67 Scheme 63. Ugi reaction of 292 .................................................................................................... 68 Scheme 64. Ugi reaction of 291 and presumed configuration of the products ............................. 69 Scheme 65. Ugi products arising from reaction of 291 and 292 .................................................. 70 Scheme 66. Rationale for the stereochemical outcome of the Ugi condensation of 292 .............. 72 Scheme 67. Ugi condensation product ring closure and epimerization ........................................ 74 xvi  Scheme 68. Acid-catalyzed epimerization of 309 ........................................................................ 75 Scheme 69. Attempts to cleave the secondary amide of 297 ........................................................ 75 Scheme 70. Attempts to cleave the secondary amide of 298 ........................................................ 76 Scheme 71. Possible methods for the closure of quinocarcin’s B-ring ........................................ 77 Scheme 72. Method for the Friedel-Crafts closure of quinocarcin’s B-ring ................................ 77 Scheme 73. Friedel-Crafts acylation of 318 was not successful ................................................... 78 Scheme 74. Closure of quinocarcin’s B-ring by the addition of a phenol to an aldehyde ............ 78 Scheme 75. Synthesis and reaction of lactol 322 .......................................................................... 79 Scheme 76. Method for carbanionic closure of quinocarcin’s B-ring .......................................... 80   xvii  List of Abbreviations  [α] specific rotation Ac          acetyl add’n addition Am amyl anh anhydrous aq aqueous Ar aryl Bn        benzyl Boc        tert-butoxycarbonyl br broad BRSM based on recovered starting material BSA          bis(trimethylsilyl)acetamide Bu butyl Bz benzoyl °C degrees Celsius C cytosine (DNA residue) CAN           ceric ammonium nitrate cat. catalytic Cbz benzyloxycarbonyl CC column chromatography CDI          1,1´-carbonyldiimidazole  cf. confer cm−1 wavenumber(s) CSA         camphorsulfonic acid δ chemical shift (ppm downfield from tetramethylsilane) Cyh cyclohexyl d doublet D dextrorotatory DBU         1,8-diazabicyclo[5.4.0]undec-7-ene xviii  DCC         N,N´-dicyclohexylcarbodiimide DCM          dichloromethane DDQ          2,3-dichloro-5,6-dicyano-1,4-benzoquinone de diastereomeric excess DIB (diacetoxyiodo)benzene Dibal diisobutylaluminum hydride DIEA            diisopropylethylamine  DMAP      4-(N,N-dimethylamino)pyridine DMF          N,N-dimethylformamide DMP 2,2-dimethoxypropane DMSO dimethylsulfoxide DMTS dimethylthexylsilyl DNA            deoxyribonucleic acid DOPA 3,4-dihydroxyphenylalanine DPPA       diphenylphosphoryl azide dr diastereomeric ratio E carboxymethyl E entgegen (of an alkene) ee enantiomeric excess ent enantiomeric epi epimeric ESI electrospray ionization Et                ethyl Fmoc fluorenylmethyloxycarbonyl g gram(s) G                guanine (DNA residue) h                hour(s)  [H] reduction HMPA hexamethylphosphoramide HMQC          Heteronuclear Multiple Quantum Coherence HOBt          1-hydroxybenzotriazole  xix  HRMS high resolution mass spectrometry Hz Hertz (s−1) i iso (as an alkyl group) imid            1,3-imidazole i.p. intraperitoneal IR infrared J coupling constant L levorotatory LAH lithium aluminum hydride LDA lithium diisopropylamide HMDS hexamethyldisilizide LN2 liquid nitrogen m meta (as a benzene substituent) m multiplet M molarity Me              methyl MIC minimum inhibitory concentration min minute(s) mol mole(s) MOM methoxymethyl m.p. melting point Ms            methanesulfonyl MS mass spectrometry or molecular sieves n normal (as an alkyl group) NBS          N-bromosuccinimide NIS N-iodosuccinimide NMO N-methylmorpholine-N-oxide NMP N-methylpyrrolidin-2-one NMR         nuclear magnetic resonance NOE nuclear Overhauser effect N-PSP N-phenylselenophthalimide xx  NR            no reaction [O]              oxidation p para (as a benzene substituent) P     unspecified protecting group Ph              phenyl Phth phthalimido PMB          p-methoxybenzyl PMP p-methoxyphenyl ppm parts per million PPTS pyridinium p-toluenesulfonate Pr propyl psi pounds per square inch (lbs in−2) PyBrOP      bromo-tris(pyrrolidino)phosphonium hexafluorophosphate py             pyridine q quartet quant. quantitative R rectus Rf              retention factor rt                  room temperature rxn reaction s singlet S sinister SAM S-adenosyl methionine sat. saturated SEM [2-(trimethylsilyl)ethoxy]methyl SET single electron transfer SN2 bimolecular nucleophilic substitution TBAF tetra-n-butylammonium fluoride TBAT tetra-n-butylammonium difluorotriphenylsilicate TBDPS       tert-butyldiphenylsilyl TBS            tert-butyldimethylsilyl xxi  t         tertiary (as an alkyl group) TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical TES triethylsilyl Tf               trifluoromethanesulfonyl TFA            trifluoroacetic acid TFAA   trifluoroacetic anhydride THF           tetrahydrofuran Thr            threonine TIPS triisopropylsilyl TLC thin layer chromatography TMS           trimethylsilyl TPAP tetra-n-propylammonium Ts p-toluenesulfonyl U-4CR Ugi four-component reaction U-5C-4CR Ugi five center, four-component reaction UV             ultraviolet VT variable temperature xs excess Z zusammen (as an alkene)    xxii  Acknowledgements  I would like to thank those who made financial contributions to this research, including the Department of Chemistry, the University of British Columbia, and others who have provided funding to the research of Prof. Marco Ciufolini. Without their generous support, I would never have completed the program. A special gesture of gratitude is reserved for my mentor and colleague, Prof. Ciufolini, whose innumerable observations involving chemical reactivity and life in general have made my time in graduate school infinitely more insightful. I would also like to thank the members of the Ciufolini group for moral support, and for entertainment in many unexpected forms. Special mention is warranted for the crew in A312: Steven, David, Jaclyn, Jimmy, Josh, Taka, Gloria, Mendelsohn, Patrick, and Leanne. Lastly, thanks to my family. You’re always there when it counts.  1  1 Introduction 1.1 Tetrahydroisoquinoline natural products  In 1975, Canadian researchers at the University of Montreal reported the isolation of a new broad-spectrum antibiotic.1 The material, which was named naphthyridinomycin, 1, was recovered from the culture broth of a bacterium which was identified to be Streptomyces       lusitanus, grown from a soil sample taken on Easter Island in the Polynesian Archipelago. The new alkaloid, a ruby-red, crystalline solid, ultimately yielded to structural assignment by X-ray crystallography. The material, while a potent antibiotic against both Gram-positive and Gram- negative bacteria (Table 1), was also quite toxic. For instance, the intravenous LD50 in mice was equal to 3.1 mg/kg, death occurring 48 hours after injection. The newly discovered compound would become the lead member of a family of tetrahydroisoquinoline-containing antibiotics (Figure 1),2 all of which display an intricate hexa- or heptacyclic structure. The presence of sensitive functionality, such as oxazolidine, quinone, hydroquinone, and hemiaminal motifs, is apparent in all such compounds.  Bacterium MIC (µg/mL) Staphylococcus aureus <0.025 Streptococcus faecalis <0.025 Escherichia coli 0.8 Salmonella pullorum 0.2 Klebsiella pneumoniae 0.05 Proteus  vulgaris 0.4 Table 1. Minimum Inhibitory Concentrations (MICs) of 1 against selected bacteria 2   Figure 1. Naphthyridinomycin 1 and its congeners  Several years after the discovery of 1, a closely related congener called cyanocycline A, 2, was described. This substance, an orange-red crystalline solid, was isolated from a culture broth of Streptomyces actinomycetes, a bacterium found in a soil sample collected in Tama City, Tokyo, Japan.3 X-ray analysis revealed its structure to be nearly identical to that of 1. Indeed, the conversion of the latter into 2 was demonstrated almost simultaneously with the isolation of 2 as a discrete natural product.4 Given the greatly enhanced stability 2 relative to 1, many synthetic and structural studies have utilized the cyano form of the natural product, which may be readily obtained by treatment of culture broths with sodium cyanide. In fact, it has been suggested that 1 may be an artifact of isolation.5 A third group of cytotoxic substances belonging to the same family are the bioxalomycins, 3-6. These natural products were isolated by Bernan and coworkers at the American Cyanamid Company from the bacterium Streptomyces viridostaticus,6 primarily in the form of hydroquinone bioxalomycin α2, 6. In a later paper,5 the authors mention that, in an 3  attempt to isolate naphthyridinomycin 1 from the culture broth of S. lusitanus, the only compound recovered corresponded to bioxalomycin β2, 4. This observation led to the surmise that the actual ―natural products‖ may be the bioxalomycins, which, depending on the precise biochemical conditions and isolation method, may advance to naphthyridinomycin 1 or     cyanocycline 2. The authors speculate that since 1 is more highly crystalline than 5, fortuitous crystallization of 1 occurred in the course of the original X-ray structural work. As seen in Figure 2, the NMR spectrum of the originally isolated material could not have provided definitive evidence of structure. A structurally related tetrahydroisoquinoline natural product, quinocarcin, 7 (Figure 3), was described in 1983 by Tomita et al.7  The new substance, originally termed DC-52, was Figure 2. 1H NMR spectrum of 1 as originally published1 4  isolated from a culture broth of Streptomyces melanovinaceus, an organism first collected from a soil sample taken at Machida-shi, a town near Tokyo, and so dubbed for the mauve color of its colonies growing on an agar medium. An 18-liter culture broth afforded 90 mg of 7 along with 30 mg of DC-52-d, 9, also called quinocarcinol. Though complete structural elucidation using the NMR methods of the time proved impossible, the authors obtained crystals of 9, thus allowing X-ray analysis to prove its structure. Given the similarity between the two molecules, the structure of 7 could be ascertained on the basis of spectral comparison, and confidently assigned when sodium borohydride reduction gave 9.8 Interestingly, the correct absolute configuration of 7 would be predicted by an early computational study based on its binding affinity for DNA.9   The newly discovered material 7 was found to have a minimum inhibitory concentration (MIC) of just under 100 µg/mL against Staphylococcus aureus and a few other bacteria, showing its limited antibacterial capability. However, it was effective against mouse lymphocytic leukemia P388 via intraperitoneal injection, giving a 47% increase of life span at doses of 12.5 mg/kg. More interestingly, it demonstrated growth inhibitory activity comparable to mitomycin C and cisplatin in human tumor cell xenografts in mice.10 A more detailed study using KW2152, the citrate salt of 7, on melanoma xenografts showed significant anti-tumor activity.11 Specifically, with three i.p. dosings of 40 mg/kg, a partial tumor reduction was observed in 6 of Figure 3. Quinocarcin 7 and its congeners 5  10 models, and a complete tumor reduction was observed in 1 of 10 models after 19 days. A nitrile-containing analog of 7, DX-52-1, 8, was entered into Phase I human trials, which were ultimately halted due to safety and toxicity concerns.12 1.2 Mechanisms of action  The mechanism of action of compounds 2-6 has been studied to some extent. Research has shown that cyanocycline A has the ability to cross-link DNA, although the expression of such an activity requires prior reduction of the quinone with dithiothreitol.13 The compound may thus be classified as a bioreductive agent.14 It is likely that the hydroquinone form of the molecule, 11, expels a cyanide ion while opening the B-ring, creating an electrophilic site at C7 (Scheme 1). A second alkylation can then proceed by opening of the E-ring, again assisted by electronic donation from the hydroquinone, to present a second electrophilic site at C13b. Indeed, bioxalomycin α2, 6, which already incorporates a hydroquinone, does not require reductive activation, selectively cross-linking DNA at 5´CG3´ sites. Molecular Mechanics calculations support the assertion that 2 intercalated at the aromatic nucleus might cross-link DNA in the manner suggested.13   6     The mechanism of action of quinocarcin 7 was investigated by the discoverers themselves,15 who determined that it damages DNA through the generation of oxygen radicals, as if it were a quinoid compound. The absence of a quinone moiety in 7 suggested that a novel mechanism might be responsible for the observed effects. Williams carried out extensive investigations in this area.16 A key observation was that pure 7 dissolved in deoxygenated water was slowly converted into an equimolar mixture of two new materials: quinocarcinol 9 and quinocarcinamide 10. This transformation, details of which are outlined in Scheme 2, occurred at Scheme 1. Possible DNA cross-linking mechanism of 2 7  room temperature and it was postulated to involve a Cannizzaro-like disproportionation of iminium ion 16. Available evidence suggests that the process involves single electron transfer from intact 7 to ring-opened isomer 16, leading to radical 19 and radical cation 17. The radical species 19, upon undergoing a further one-electron reduction, is converted to 9. Radical cation 17 will lose a proton, giving electron-rich radical 18, which acts to donate another electron, perhaps to iminium 16, to form oxazolidinium ion 21, which is hydrolyzed to quinocarcinamide 10. When 7 was dissolved in deoxygenated H2 18O, it was noted that recovered 10, when submitted to mass-spectrometric analysis, showed more than 40% label incorporation.      Scheme 2. Possible disproportionation mechanism of 7 8  The generation of such radical species in the presence of oxygen could produce superoxide ion. Specifically, trapping of 21 by a molecule of oxygen may provide 22. Ionization of the latter assisted by the nitrogen atom would release superoxide ion, 23, and ring-opened quinocarcin 16. The superoxide produced by this process might then go on to cause DNA damage through known mechanisms, for example, by dismutation to form hydrogen peroxide and subsequent reduction by adventitious Fe(II) to produce hydroxyl radical (Fenton reaction) (Scheme 3).17 It is conceivable that a parallel mechanism of action may involve DNA alkylation, a possibility which was suggested by Remers and collaborators during a computational study.9 This may occur through addition of a nucleophilic component of DNA—perhaps a guanine C-7 amino group—to iminium ion 16 (Scheme 4).   Scheme 3. Possible mechanism for the formation of superoxide ion by 7 9    Scheme 4. Possible DNA alkylation by 7  However, the aforementioned study revealed that the preferred conformation of 7 was not favorable for oxazolidine ring-opening, meaning that a DNA-alkylation mechanism through an iminium ion at C7 would require the higher-energy conformer 25. However, a stereoelectronic effect of chair-chair conformer 24 (proper alignment of the electronic lone pair overlap of the oxazolidine nitrogen with the antibonding orbital of the C7 hydrogen) would enhance the rate of the disproportionation reaction and facilitate the formation of radical 18.   Figure 4. A predicted conformational effect in the DNA-cleaving ability of 7  On such a basis, Williams endeavored to synthesize two analogs of 7 which differed in configuration at C11a (7 numbering), namely 27 (C11a hydrogen anti to oxazolidine) and 28 10  (C11a hydrogen syn to oxazolidine).16a Anti compound 27 was found to exist as a chair-chair conformer by X-ray crystallography, thus mimicking the stereoelectronic activation of the C7 hydrogen as in 24 (Figure 4). The citrate salts of these two materials were tested for DNA cleavage ability, and it was discovered that 27 was approximately six times more active than its isomer 28, exhibiting superior DNA cleavage yield, based on single strand scissions of covalently closed circular DNA per molecule of 27/28. These observations were taken to support the mechanism of action of Scheme 3.  1.3 Biosynthesis  A few papers have appeared in the literature investigating the biosynthetic origins of naphthyridinomycin, and given the close similarity between its structure and that of cyanocycline, one supposes that the biosynthetic pathways must be closely related. The bacterium S. lusitanus was cultured in the presence of radiolabeled (14C) amino acids and it was discovered that carbon atoms from tyrosine, methionine, glycine, and ornithine were all incorporated into the natural product. An NMR study demonstrated that uniformly labeled 13C tyrosine was incorporated; later, it was found that tyrosine is first modified to 5´-methyl-DOPA before being incorporated.18 The N-, O-, and aromatic methyl groups were shown to derive from the S-methyl group of methionine, presumably after conversion of the latter to S-adenosyl methionine (SAM).19 It has also been reported that glycine is converted to serine before incorporation.20 The origins of C9 and C9´ are still unknown. A pictorial summary of results in this area is found in Scheme 5. 11      1.4 Prior syntheses  An excellent, detailed review of synthetic work targeting both 2 and 7 up to 2002, was published by Williams.2 More recently, developments in the synthesis of 2 have also been reviewed.21 In the interests of providing a new perspective on the great body of work in this area, the current document will focus on the overall synthetic strategies used in each case, along with highlights of key steps and/or difficulties encountered in each synthesis. Only total syntheses of 2, 7, and their direct congeners will be included.  Scheme 5. Proposed biosynthetic origins of 2 12  1.4.1 Total syntheses of quinocarcin: Danishefsky  Danishefsky completed a landmark synthesis of a close congener of quinocarcin in 1985, in the form of quinocarcinol methyl ester 35.22 The synthesis began with allylated phenol 29, the product of a Claisen rearrangement, which was elaborated to 30 through a cyanohydrin intermediate and double-bond isomerization. A key bond-forming sequence furnished tetrahydroisoquinoline 31 through an N-phenylselenophthalimide (N-PSP; the Nicolaou reagent)- mediated cyclization of carbamate 30 in the presence of CSA.23 Further elaboration yielded acetal 33 as a 1:1 mixture of diastereomers. Subsequent release of the Boc and acetal units with BF3•OEt2 triggered formation of an iminium ion, followed by a Mannich cyclization in to give 34. Relative to later syntheses, the formation of the C11-C11a bond (7 numbering) as a key step would prove to be unique. The authors note that the diastereomer of 33 corresponding to the undesired isomer of 34 did not undergo cyclization, which helps explain the moderate yield of this step. The resulting tetracyclic intermediate 34 was carried through deoxygenation of the amide and ketone carbonyl groups, diastereoselective Krapcho decarboxylation, and conversion of the vinyl substituent to a hydroxymethyl group, to give (±)-35. The longest linear sequence in this synthesis was 25 steps starting from m-hydroxybenzaldehyde (Scheme 6). The conciseness of this route is impressive given the synthetic technology available at the time. 13     1.4.2 Total syntheses of quinocarcin: Fukuyama   The first total synthesis of racemic 7 was completed by Fukuyama in 1988.24 The synthesis began with the condensation of piperazinedione 37 with aromatic aldehyde 38 under catalysis by tBuOK (Scheme 7). A subsequent adjustment of protecting groups gave 39. The key formation of the pyrrolidine core was completed by an amidoalkylation reaction wherein a pendant vinylsulfide added to N-acyliminium ion 41. This gave an aldehyde 44 that was immediately reduced to the corresponding alcohol. The C10 configuration is imagined to arise through a Yamamoto-type transition state25 in the attack of the vinyl sulfide (cf. 42). Although  Scheme 6. Danishefsky’s synthesis of racemic 35 14    Scheme 7. Fukuyama’s total synthesis of racemic 7  later syntheses used modified conditions, the formation of the C10-C11 bond by attack of an olefin on an N-acyl iminium ion would be repeated by multiple research groups. The enamide system in 44 underwent diastereoselective hydrogenation under vigorous conditions (100 °C, 2000 psi H2) in the presence of Raney Ni. The resultant was then advanced to 45 through a protection-deprotection sequence, which allowed facile opening of the piperazinone ring. 15  Reaction of 45 with tert-butyl glyoxylate in hot methanol resulted in the diastereoselective formation of tetrahydroisoquinoline 46 through a Pictet-Spengler cyclization. Compound 46 was then advanced to 47, which upon exposure to TMSCN and ZnCl2 was transformed into bridged intermediate 48. Evidently, the intramolecular condensation of the free amine and the aldehyde produced a transient iminium ion, which was trapped by cyanide ion. The use of cyanide as trapping agent was inspired by the work of Hirata, who had previously used it to form the stable quinocarcin derivative DX-52-1.26 Completion of (±)-7 required a relatively high total of 37 steps from commercial diethyl acetamidomalonate, although the methods introduced were often adopted in later syntheses.  1.4.3 Total syntheses of quinocarcin: Garner   Five years after Fukuyama’s effort, Garner completed the first asymmetric synthesis of 7.27 The correct configuration of key stereogenic centers was secured through reactions that employed suitable chiral auxiliaries. Indeed, the opening moves of the synthesis saw the enolate of Evans imide 49 undergoing auxiliary-directed azidation,28 as a prelude to the elaboration of the product 50 into key intermediate 52. It is worthy of note that the latter operation involved the cycloaddition of azidomethane to a maleimide as a means of installing the N-methylaziridine unit. It is also well established that CH3N3 is an exceedingly hazardous material, which may detonate for no apparent reason.29 The above notwithstanding, no safety alerts are present in the paper, contrary to contemporary practice. Upon photochemical irradiation, the aziridine ring   16   Scheme 8. Chiral auxiliaries in Garner’s total synthesis of 7  Scheme 9. The completion of Garner’s total synthesis of 7  in 52 underwent electrocyclic opening to a presumed dipolar species 54, which was intercepted in situ with Oppolzer complex30 53. The product 55 of this noteworthy dipolar cycloaddition reaction was obtained as a stereochemically homogeneous material. The total synthesis of 7 was rapidly completed from 55 as delineated in Scheme 9. A straightforward sequence advanced 55 to phosphonium salt 56. This material, upon deprotonation (t-BuOK) and heating to 120 °C, underwent a highly regioselective Wittig reaction through the intermediacy of strained oxaphosphetane 57 to furnish 58. The latter could be 17  advanced to (−)-7 through six additional steps, for a total of 24 steps from commercially available 2-methoxy-6-methylbenzaldehyde.  1.4.4 Total syntheses of quinocarcin: Terashima   A subsequent asymmetric total synthesis of 7 by Terashima utilized pyroglutamic acid and threose derivatives as the source of chirality.31 In the early stages, protected pyroglutamol 59 was elaborated into 61, while protected D-threose 62 was reacted with 2-methoxy-6-methyl- phenyllithium and the product of such a reaction was re-oxidized to give 63 (Scheme 10). Fragments 61 and 63 were then united through a noteworthy reaction, which entailed the selective deprotonation of 63 at the benzylic methyl group (LDA) and the addition of the corresponding anion to 61. The emerging 64 was oxidized to a diketone, condensation of which with ammonia yielded quinoline 65. This heterocycle was reduced diastereoselectively to the tetrahydroisoquinoline 71 using sodium cyanoborohydride in acidic methanol. The authors report that the reaction proceeded in 93% yield and with ―complete diastereoselectivity.‖ They furthermore indicate that the stereochemical course of the transformation is consistent with a Cram-chelation model32 of nucleophilic attack at C-5, and with an axial attack of hydride at C- 11a on cyclohexenyl-like iminium ion 70.33 Release of the acetonide in 71, oxidative cleavage of the resulting diol using NaIO4 , and reduction of the transient aldehyde afforded 72, setting the stage for closure of the C-ring using Fukuyama’s conditions (ZnCl2, TMSCN, CH2Cl2). Several additional steps provided (−)-7. This synthesis required a total of 37 linear steps beginning with L-glutamic acid.  18   Scheme 10. Terashima’s total synthesis of 7  1.4.5 Total syntheses of quinocarcin: Williams  In 1995, Williams completed his own synthesis of racemic quinocarcinamide 10.34 The key aspect of Williams’ strategy was the execution of a dipolar cycloaddition of substance 76 with methyl acrylate (Scheme 11), in a manner reminiscent of the earlier Garner approach. The assembly of acid chloride 74 proceeded in a conventional fashion, when Friedel-Crafts acylation provided a key bond formation to the aromatic moiety (74 to 75).35 Further elaboration yielded allylic bromide 76. With the addition of triethylamine and methyl acrylate, the cycloaddition of this material proceeded in 62% yield with a 5:1 dr. The authors rationalize the observed stereochemical outcome by the approach of the dipolarophile from the less-hindered β-side of the  19   molecule (cf. 78). Cycloaddition product 79 was converted over a few steps into (±)-10. In total, 25 steps were needed starting from 2-methoxybenzaldehyde 73.  1.4.6 Total syntheses of quinocarcin: Myers  Following a ten-year period of inactivity in this area, Andrew Myers announced an unusually concise enantioselective synthesis of quinocarcin.36 This work showcased the application of aminoacid-derived, masked -aminoaldehydes—the chemistry of which has been extensively studied in the author’s laboratory37—to complex problems in synthesis.  Furthermore, it demonstrated the use of new chiral auxiliaries for the stereocontrolled alkylation of glycine enolates.38  The Myers strategy rested on the merger of fragments 82 and 86, which were prepared as outlined in Scheme 12. In either case, the starting point was glycine amide 80: the resultant of  Scheme 11. Williams’ synthesis of racemic 10 20   Scheme 12. Pseudoephedrine auxiliaries in Myers’ total synthesis of 7  the union of a molecule of glycine with one of pseudoephedrine (the so-called Myers auxiliary). Alkylation product 81 was carried through several steps to provide masked aminoaldehyde 82, while 84 was converted into 86. The latter operation suffered from an annoying (but— unfortunately—predictable39) issue of regioselectivity. Specifically, the Pictet-Spengler reaction of 85 with 2-benzyloxyacetaldehyde furnished primarily the undesired para- type isomer 87 (5:3 ratio with respect to the desired 86). Fortunately, the two isomers were separable. The correct diastereomer 86 was transformed into Fmoc-protected aminoaldehyde 88, which was condensed with 82 in the presence of Na2SO4 to afford an imine (Scheme 13). Release of the Fmoc protection (DBU) and reaction with HCN resulted in formation of the Strecker product 89. A remarkable cascade of reactions ensued upon exposure of the latter to the action of ZnCl2 and TMSCN in 2,2,2-trifluoroethanol. Expulsion of cyanide generated presumed morpholinium ion 90, cyclization and further decyanation gave transient iminium ion 91. This  21   Scheme 13. The completion of Myers’ total synthesis of 7  intermediate then underwent Sakurai-type cyclization to generate 92. The authors conclusively determined that formation of the piperazine preceded Sakurai-type D-ring closure. Finally, compound 92 was elaborated in a straightforward manner to (−)-7. Myers’ convergent synthesis of this challenging molecule proceeded in only 17 steps from glycine methyl ester.  1.4.7 Total syntheses of quinocarcin: Zhu  In 2008, J. Zhu, then at the Institut de la Chimie des Substances Naturelles, at Gif-sur- Yvette, France described yet another synthesis40 that began with a phase-transfer alkylation of glycine imine 94 under conditions developed by Corey (Scheme 14).41 This provided meta- tyrosine derivative 95, which was elaborated to tetrahydroisoquinoline 96 using the well-proven Pictet-Spengler methodology. The resultant 96 was coupled with glutamic acid derivative 97 and carried through several manipulations to give 98. One noteworthy aspect of the synthesis was the use of the unusual Lewis acid Hf(OTf)4 to form the thioamidal 99 by reaction of 98 with ethanethiol. In another reaction that finds close analogy in the work of Fukuyama (Scheme 7),  22   material 99 was treated with AgBF4 to trigger closure of the D-ring of quinocarcin by an amidoalkylation process. The resulting aldehyde 100 was advanced through a few uneventful steps to produce (−)-7. In total, the synthesis comprised 23 steps from m-hydroxybenzaldehyde. 1.4.8 Total syntheses of quinocarcin: Stoltz  Later in the same year, Stoltz published what corresponds to the most recent synthesis of quinocarcin at time of this writing.42 A key strategic principle here was the use of an annulation technique, devised earlier by the authors,43 to secure an advanced intermediate through the reaction of a benzyne with compound 106. As seen in Scheme 15, the preparation of the latter began with the dipolar cycloaddition of 102 to Oppolzer acrylamide 53: a step that is reminiscent of the Garner approach. The bicyclic material 103 that resulted was converted to the N- (benzyloxy)acetyl derivative in preparation for a regioselective methanolysis that gave compound 106. Such a step was carried out in the presence Yb(OTf)3, which presumably   Scheme 14. Zhu’s total synthesis of 7 23   Scheme 15. The early steps of Stoltz’s total synthesis of 7  combined with the substrate to form chelate complex 105. The benzyloxyacetamide unit in 105 possesses enhanced nucleofugal character, resulting in preferential formation of the desired 106. It should be mentioned that the methanolysis reaction was found to be quite problematic in terms of regioselectivity, and that numerous alternatives had to be explored before the above solution materialized. A crucial phase of the synthesis involved the condensation of 106 with a benzyne generated by treatment of arene 107 with tetrabutylammonium triphenyldifluorosilicate (TBAT, Scheme 16), resulting in formation of isoquinoline 111 in 60% isolated yield. A presumed mechanism for this noteworthy transformation envisions an initial regioselective addition of the enamide to the aryne. Subsequently, reactive intermediate 110 undergoes cyclization and ultimate dehydration to 111. The authors provide no rationale for the regioselectivity observed in this key reaction, which afforded a product similar to the Terashima quinocarcin intermediate (Scheme 10). Hydrogenation of 111 gave a 3.3 : 1 mixture of 112 (desired, major) plus the corresponding -diastereomer (undesired, minor). Again, no explanation was provided for the  24   Scheme 16. The completion of Stoltz’s total synthesis of 7  observed selectivity. Further reduction of 112 with NaBH3CN furnished 113, which was readily advanced to (−)-7. The synthesis was finished in an admirably concise manner, needing only 13 steps from commercial entities.  1.4.9 Total syntheses of cyanocycline: Evans  Turning now to a review of published work on 2 and congeners, we note that contrary to the case of 7, only 3 total syntheses of this exceedingly challenging target have been accomplished. The first one of these was completed by Evans in 1986, and it afforded a racemic end product.44 The synthesis began with -lactam 114 (Scheme 17), readily available through the reaction of cyclopentadiene with chlorosulfonyl isocyanate. This material was advanced to epoxide 115, which cyclized regioselectively to alcohol 116 upon treatment with potassium tert- butoxide. The alcohol was converted into 117, setting the stage for the first key step of the 25  synthesis. This entailed the amidoalkylation of phenol 125 with 117 under catalysis by SnCl4. This reaction was found to proceed with good diastereoselectivity, which the authors rationalize based on attack of 125 on the Z-iminium ion, with approach of the nucleophile from the less- hindered α face. The product, 119, was elaborated to hemiaminal 120, dissolution of which in TFA induced a cascade of events leading directly to compound 124. By way of mechanism, one may envision reversible cyclization of 120 to oxazolidine 121 and subsequent dehydration to a presumed iminium ion 122. The latter may engage the nearby aromatic ring in a Pictet-Spengler mode. The overall reaction proceeded in good yield. While the authors do not provide a rationale for the stereoselectivity of this final step, one may surmise that the conformation of the bowl-  Scheme 17. Evans’ total synthesis of racemic 2  26  shaped heterocyclic moiety of 122 only permits cyclization from the Re*-face of the iminium ion. Also of note, the TBS-protected hydroquinone survived the extended acid treatment. The total synthesis of 2 was completed rapidly from 124 and it required 35 steps from commercial materials.  1.4.10 Total syntheses of cyanocycline: Fukuyama  Shortly after Evans’s pioneering report, Fukuyama announced a second total synthesis of racemic 2.45 Strategically, the effort envisioned the union of fragments 126 and 127, followed by appropriate manipulations of the resultant 128 (Scheme 18). It will be seen that the advancement of 131 to 2 proved to be problematic, and it required a highly original solution. In any event, compound 126, readily prepared in 3 steps through the condensation of the tert-butyl ester of N- Boc-dehydroalanine with tert-butyl acetoacetate, was deprotonated (LDA) and the resulting anion was converted into a presumed Zn enolate (addition of ZnCl2). The latter added to aldehyde 127 to yield 128. The next step of the sequence required a diastereoselective reduction of the double bond in 128. Such an operation was best conducted using the free phenol 129 in lieu of 128. Accordingly, hydrogenation of 129 over Rh/C under 1000 psi of H2 provided 130, which was advanced to the key intermediate 131. One unusual element here is the use of the protecting group, N,N-dicyclohexyl-3-carboxypropanamide, rendered in Scheme 18 as substituent Z. This sturdy protecting group, which nonetheless may be released under gently basic conditions (retro-Michael elimination of the carbamate) proved to instrumental for the success of subsequent operations.   27   Scheme 18. The opening moves of Fukuyama’s total synthesis of 2   Innumerable attempts to elaborate 131 into a more advanced precursor of 2, in particular, the introduction of heteroatomic functionality at the starred carbon atom, produced a stream of disappointing results. Success was finally achieved by reaction of the substrate with nitrosyl chloride. The primary product of such a treatment, presumably compound 132 (Scheme 19) was stereoselectively reduced in situ with NaBH3CN, leading to oxime 134. The authors identify the preparation of 134 as ―undoubtedly, the most important step‖ of the synthesis. Raney nickel reduction of the oxime proceeded diastereoselectively to form 135, from which the synthesis was completed in a straightforward manner. Overall, the synthesis required 32 steps.  28   Scheme 19. The completion of Fukuyama’s total synthesis of 2  1.4.10 Total syntheses of cyanocycline: Garner  A formal total synthesis of 2 was described 20 years later by Garner.46 A key early step was the preparation of 1,2-diamino segment 140 through a Merino-type47 addition of aryl Grignard reagent 137 to nitrone 138 (Scheme 20). The addition took place stereoselectively to the Re-face of the nitrone, presumably through chelate complex 139, leading to hydroxylamine 140 as a single diastereomer. This product was advanced to aldehyde 141: the precursor for a crucial dipolar cycloaddition of the type demonstrated earlier in Scheme 8.48 In the event, Oppolzer glycine derivative 142 condensed with 141 to give an imine, which upon deprotonation, generated a 1,3-dipolar entity that underwent cycloaddition to methyl acrylate. Product 144 was thus obtained in a moderately diastereoselective fashion (dr = 4:1). The authors invoke an endo chelation-controlled cycloaddition (cf. 143) to account for the stereochemical outcome of the reaction. In any case, substance 144 was advanced to 145, which resembles Fukuyama’s intermediate 135 (Scheme 19). This material was elaborated to known compound  29   Scheme 20. Garner’s total synthesis of 2  14745 by a sequence similar to that used earlier by Fukuyama, thereby completing the formal synthesis of (−)-2 in a brief 22 steps.  It is clear from the discussion above that, with the exception of the Stoltz synthesis, known routes to the natural products rely on an early introduction of aromatic subunits. It was perceived that a late installation of such segments may lead to improvements in conciseness and overall efficiency, as well as enabling a unified approach to the entire class of molecules, as detailed in the next section.  30  1.5 Retrosynthetic considerations  Our approach imagines the construction of a nitrogenous entity corresponding to the common ―aliphatic‖ core of quinocarcin and the bioxalomycins. Said core would combine with various aromatic fragments to give advanced intermediates suitable for further elaboration into any member of the family or congener thereof. To illustrate (Scheme 21), release of the oxazolidine rings in the natural products furnishes retrons 149 and 151, which are epimeric at the indicated positions.   Scheme 21. Retrosynthetic analysis of 7 and 2-6  Further analysis of 149 and 151 suggests that either could derive from precursor 152, wherein X represents either a pair of H’s, or a carbonyl, or an H and an OH group. Compound 152 could be dissected at the level of bond a to reveal acid 154, which could advance to 152 by an intramolecular aromatic ring acylation process. Prior work in our group had determined that substance 154 should be available through an Ugi-type reaction between amino acid 155, an isonitrile and an aromatic aldehyde (vide infra). Alternatively, retro-Pictet-Spengler dissection of 31  bonds b produces 153, which could emerge upon reaction of a suitably activated form of 155 with an aryl organometallic agent (Scheme 22). Amino acid 155, or an appropriate analog, thus became the primary objective of this investigation.        Before delving into the details of how 155 was prepared, it seems appropriate to review the Ugi reaction, particularly the variant of the process of interest in the present case. A brief summary of key aspects of this chemistry appears in the following section.  1.6 The Ugi reaction  The Ugi reaction involves the condensation of an aldehyde (sometimes, a ketone), an amine, a carboxylic acid, and an isonitrile, to yield α-amido amides. The four components of the Ugi reaction are simply admixed and allowed to combine to furnish the ultimate product. A process so constituted is described as a multicomponent reaction (MCR).  Thus, the Ugi condensation is commonly described as a 4-component reaction (―U-4CR‖ in contemporary parlance), and since its development, it has found wide use, e.g., in divergent (library) synthesis,49 in target-oriented synthesis,50 and in drug discovery.51 Scheme 22. Retrosynthetic analysis of 152  32  A likely mechanism for the U-4CR is shown in Scheme 23. The reaction begins with the reversible condensation of an amine with an aldehyde, or, alternatively, with a pre-formed imine. This species then reacts with the isocyanide to form a putative nitrilium 156, which is trapped by the acid component. A so-called Mumm rearrangement52 follows, irreversibly transferring an acyl group to nitrogen to form product 158. Computational studies on the course of the Ugi reaction have recently been performed, suggesting that the isocyanide addition is an irreversible, rate-limiting step.53   A brief parenthesis is in order at this juncture. It may be argued that Sir Robert Robinson’s celebrated synthesis of tropinone 162 (cf. Scheme 24)54 marked the first use of a multi-component reaction in natural product synthesis. However, the modern era of MCRs began in 1921 with a report by Mario Passerini55 on the reaction of isocyanides with aldehydes and carboxylic acids. These seminal reports languished in the literature for decades, until the work of Ivar Ugi56 brought to the forefront the role of isocyanides in MCRs.57 Isocyanides have remarkable properties, including the incorporation of a stable carbenoid carbon atom that engenders predictable and selective reactivity. These noteworthy agents had been known since  Scheme 23. Mechanism of the Ugi four-component condensation 33    the 1800’s,58 but they had been unjustly neglected for too long, possibly due to their famously noisome odors. The U-4CR has seen some prominent use in total synthesis, for example, in Fukuyama’s synthesis of Ecteinascidin 743 (Scheme 25).59 The key reaction involved the condensation of amine 163 with acetaldehyde, in the presence of protected amino acid 164 and p- methoxyphenylisocyanide 166. In this case, the Ugi reaction acts as a surrogate peptide coupling with concomitant alkylation of the amine component. Further elaboration to was able to yield the natural product.   A clever use of a modification of the Ugi reaction was demonstrated by Kawasaki.60 Ugi precursor imine 168, which was generated by oxidation of the corresponding secondary amine 167 under anhydrous conditions using TPAP/NMO, reacted stereoselectively with p- methoxyphenyl isocyanide 166 and Boc-protected L-phenylalanine 169 to give key intermediate 170. This material was advanced to the alkaloid (−)-fructigenine A (Scheme 26). Scheme 25. The Ugi reaction in Fukuyama’s synthesis of ecteinascidin 743 Scheme 24. Historical application of an MCR by Robinson 34    A recurring theme in the Ugi reaction is the need to cleave the amide resulting from the isocyanide component. One solution, first described by Ugi,61 is to employ a cyclohexenyl isonitrile. The product thus obtained is an enamide, which can be selectively cleaved under gentle acidic conditions. An early step in the total synthesis of motuporin by Armstrong relies upon this chemistry to produce dipeptide 175 as shown in Scheme 27.62     Our particular interest lies in a special form of the Ugi condensation, introduced by Ugi himself,63 in which the carboxylic acid and amine components are part of the same α-amino acid molecule. The reaction is normally carried out in alcohol solvents, leading to products 179 (Scheme 28). Accordingly, it is often referred to as an Ugi five-center, four-component (amino acid, aldehyde, isonitrile, alcohol) reaction, or U-5C-4CR. By way of mechanism, it is likely that Scheme 26. The Ugi reaction in Kawasaki’s synthesis of fructigenine A Scheme 27. A convertible isocyanide was used in Armstrong’s synthesis of motuporin 35  amino acid and aldehyde initially condense to form an imine 176. This is followed by isocyanide attack. The resultant nitrilium 177 is then trapped intramolecularly, followed by ring-opening of imidate 178, often by the alcohol solvent, though trapping by a tethered alcohol to give a lactone is also common.   It is recognized that the foregoing reactions possess inherent potential to proceed diastereoselectively, in that the stereogenic center that is present near the reaction site could direct the attack of the isocyanide to one particular face of the transient iminium ion (cf. 176 => 177). Indeed, chiral auxiliaries have been utilized in ordinary Ugi reactions in order achieve diastereoinduction.64 A (chiral) α-amino acid might well eliminate the need for chiral auxiliaries and elaborate catalysts. The above notwithstanding, the Ugi reaction of α-aminoacids has received only sporadic attention since its initial report. One possible reason is that a key aspect of the chemistry, the question of diastereoselectivity, is poorly understood. Indeed, both the magnitude and the sense of stereochemical induction varies with the precise nature of the amino acid substrate. A sample of reactions for which the configuration of the product has been ascertained by X-ray Scheme 28. Mechanism for the Ugi reaction of amino acids 36  crystallography can be found in Scheme 29. In Ugi’s initial report,63 the reaction of L-proline 180 with tert-butylisocyanide 182 and isobutyraldehyde 181, gave 183, which was found to have the   Scheme 29. Examples of the Ugi reaction of alpha amino acids with known product configuration 37  (S)- configuration at the newly formed center. In Seebach’s parlance, 183 is thus the product of like (l) stereoinduction.65 Later reports by Kim gave conflicting stereochemical results.66,67 For example, the condensation of homoserine 184 with 181 and 182 proceeded with elevated levels of unlike (u) diastereoinduction to furnish 185. On the other hand, the reaction of 186 with 187 and 182 gave 188 with a weak l-induction (dr = 2.4:1), and that of 188 with 182 and 187 occurred with a modest unlike (u) stereoselectivity (dr = 1.7:1). An interesting reaction described by Reissig uses silyloxycyclopropanes as masked aldehydes, and in one case, it also proceeded with u stereoselectivity (dr = 4:1).68 Finally, an example from Sung using L-valine 192 occurred with very high u selectivity.69 As outlined earlier in Scheme 22, our interest lies in the specific variant of the Ugi reaction in which an α-amino acid combines with an isonitrile and an aromatic aldehyde. A survey of the literature prior to 2004 reveals that although examples of efficient Ugi condensation of amino acids with aromatic aldehydes had been recorded, these reactions tend to proceed at slow rates and in variable yields, especially if the aldehyde is electron-rich. Indeed,    preliminary experiments in our lab centering on the condensation of glutamic acid monomethyl ester, 196, with aromatic aldehyde 198, under standard Ugi conditions (MeOH, rt) revealed that the reaction rate was exceedingly slow.70 The reaction proceeded faster at 40 °C, but some starting material (5-10%) remained even after a contact time of 4 days, whereupon the desired 199 was obtained in a modest 30% yield and as a 6:1 mixture of diastereomers (Scheme 30). Scheme 30. Uncatalyzed Ugi reaction of 196 with 197 and 198 38  Suspecting that these difficulties were due to the slow rate of formation of iminium ions such as 176, we sought an artifice that might accelerate the process, such as an appropriate Lewis acid promoter. We thus undertook a study examining the effect of various acid additives.70 Our investigations revealed that a catalytic amount of TiCl4 (5 mol%) in MeOH constituted a superior reaction system. The yield of 199 tripled compared to the uncatalyzed process, and the reaction proceeded much faster. However, the Lewis acid had virtually no effect on the diastereoselectivity, indicating that in all likelihood it was involved only in imine formation. It may be argued that TiCl4 and MeOH are likely to react, giving rise to titanium methoxides and HCl, which could itself promote the reaction. However, it was determined that HCl is not a competent replacement for TiCl4, while Ti(OiPr)4 is essentially as effective. This clearly demonstrated the requirement for a Lewis acid. We presume that Ti(IV) coordinates to the carbonyl group of the aldehyde, thereby accelerating the rate of nucleophilic addition of the amino component. It seems less likely that TiCl4 reacts with water to form TiO2, thus driving the equilibrium toward the imine through a LeChatelier effect. Only 5 mol% Ti(IV) are present, so that this stoichiometric process would make a negligible contribution to the overall reaction. The new conditions proved to effect the Ugi reaction of a broad spectrum of aldehydes and amino acids. For example, phenylalanine, serine, tryptophan, valine, and glutamic acid 5- methyl ester are compatible; as are 3-pyridinylcarbaldehyde, o-anisaldehyde, 2-chloroquinolyl-3- carbaldehyde, 2-chlorobenzaldehyde, and others. Electron-rich aldehydes are quite competent, which is of particular interest due to their low electrophilicity, and for their compatibility with our synthetic goals. Except for 200, all products were recovered with satisfactory levels of diastereoinduction (> 4:1, in several cases > 10:1). Representative examples appear in Scheme 31. The 39  configurations of compounds 199 and 205 were ascertained by X-ray diffractometry, whereupon it was established that the process had occurred with ―like‖ stereoinduction. On such grounds, we extrapolated that all products tabulated in Scheme 31 had the (S) configuration of the newly formed stereogenic carbon, although—rigorously speaking—this hypothesis remains to be confirmed. In particular, the results of Sung (cf. Scheme 29) indicate that caution is warranted in assigning the stereochemistry of valine-derived Ugi products 203 and 207.   Scheme 31. Products of the Ugi reaction of amino acids with aromatic aldehydes 40    A rationale for the stereochemical course of the reaction is offered in Scheme 32. It is presumed that the isocyanide attacks the Re-face of a planar zwitterionic iminium, opposite the adjacent C-C=O bond, which activates the iminium through a stereoelectronic effect. The orientation shown limits A1,3 strain around an iminium with E- geometry. However, in light of the variability of the stereochemical outcomes of products of the Ugi reaction of α-aminoacids, as verified by X-ray analyses, we must stress the uncertainty inherent in such models.   Scheme 32. Model for the stereochemical course of the Ugi reaction of amino acids 41  2 Synthetic Work 2.1 Synthesis of the aminoacid  Having laid out the synthetic plans and provided the necessary background, we will now describe the synthetic endeavors embarked upon in the course of this research. As stated previously, the first goal was the synthesis of a material corresponding to aminoacid 155 (Scheme 22). Our initial retrosynthetic analysis of 155 was imagined to involve diastereoselective amination (this could occur under Evans azidation conditions71 or through a Gennari-Evans-Vederas hydrazination72) of the enolate of 209. It was surmised that the enolate of this material would exist as chelate 208, wherein only the Re face of the nucleophile is readily accessible. Reaction with a suitable electrophilic amination agent should thus produce the desired (D)-aminoacid. The requisite 209 could arise through diastereoselective cyclization of aminoester 210. The selective formation of an all cis pyrrolidine product in a related reaction is documented in the work of Bonjoch.73 In turn, substance 210 appeared to be readily available from pyroglutamol derivative 211, which could be advanced to 210 via nucleophilic addition of a suitable two-carbon segment to the pyrrolidine carbonyl, followed by appropriate manipulations. Finally, substrate 211 could derive from protected pyroglutamol 212 through Claisen- type condensation and facially selective hydrogenation of the resultant. The latter step was anticipated to take place selectively from the face of the molecule anti to the bulky CH2OP side chain.74 Such a stereochemical outcome would produce a material possessing a 3-position configuration that correlates with that at C4 of 2 and cognate natural products, but is opposite that required for the C10 stereocenter of 7. However, it seemed likely that, based on   42    Danishefsky’s synthesis of 35, C10 epi-quinocarcin might be isomerized to the correct diastereomer,22 rendering the above stereochemical issue essentially immaterial. To test the foregoing hypotheses, commercially available pyroglutamol 213 was converted into the N-Boc, O-TBDPS derivative 214 by a literature procedure.75 Deprotonation of 214 with LDA proceeded uneventfully, as apparent from the efficient incorporation of deuterium upon quenching with D2O (cf. 215 – not fully characterized). However, attempts to induce formylation of the enolate with ethyl formate uniformly returned intractable mixtures. In a like vein, attempts to intercept the desired formyl derivative in situ with benzyloxymethyl chloride also failed (Scheme 34).    Scheme 33. Initial retrosynthetic analysis of 155 Scheme 34. Reaction of the enolate of 214 with ethyl formate failed 43  However, a one-carbon unit could be installed at the 3-position of 214 by treating it with Bredereck’s reagent 217,76 a reaction which finds close analogy in the work of Danishefsky,77 Weinreb78 and Terashima.31 In accord with the latter author, the resulting vinylogous urea could be hydrolyzed without loss of the N-tert-butoxycarbonyl by sonication of a suspension of 218 in aqueous H2SO4, and the emerging enol tautomer of the expected aldehyde was protected as a methoxymethyl (MOM) ether. The resulting 219 (not fully characterized) tended to polymerize upon standing. Accordingly, it was immediately subjected to hydrogenation over Pd/C without extensive purification. This reaction proceeded at atmospheric hydrogen pressure (albeit at high catalyst loading) and with good stereoselectivity, giving a 14:1 mixture in which was desired cis- isomer 220 was dominant. This was consonant with our expectations that 219 would be adsorbed onto the catalyst from the face opposite the bulky TBDPS ether.   Our next synthetic goal was the two-carbon homologation of 220 at the 2-position. To this end, a Claisen-type condensation was performed. Addition of a solution of 220 to 1.5 equiv. of the lithium enolate of ethyl acetate was found to produce a mixture of enol and hemiaminal isomers 221 and 222 of the addition product (not characterized) (Scheme 36). Use of additional   Scheme 35. Synthesis of 220 from 214 44   Scheme 36. Claisen-type condensation of 220  base did not improve the yield of the enolate addition, rather leading to material which was more difficult to purify. The crude mixture was reduced with NaBH4 in EtOH, so providing a modest yield of a 1:1 mixture of diastereomers of alcohol 223, which were not separated.  Alcohols 223, after mesylation under standard conditions, underwent elimination (DBU in CH2Cl2) to provide unsaturated ester 225 in excellent yield (the mesylate 224 was not thoroughly characterized). As expected, the Boc-protected nitrogen showed no proclivity to engage the unsaturated lactone in a 1,4-addition. However, release of the Boc group (TFA) occasioned immediate cyclization to 226, which emerged as a single diastereomer. Unfortunately, this material was determined to be the undesired 2,5-trans isomer, in that it failed to lactonize after removal of the MOM protecting group (4M HCl in wet dioxane). Details of these discoveries are presented in Scheme 37. A rationale for the formation of 226 invokes reaction from a conformer in which A1,3 strain is minimized (cf. 227 in Figure 5).  45     The above setback notwithstanding, it appeared that the requisite all cis diastereomer could still be obtained from a variant of 225, in which the carboxylic group and the MOM- protected oxygen are joined to form a lactone (cf. 229, Scheme 38). The Michael-type cyclization of 229 would now take place in a reliably syn mode, giving the desired configuration. Furthermore, a rigid bicyclic system could also provide superior stereocontrol in the subsequent installation of a nitrogen atom adjacent to the lactone carbonyl. Figure 5. Rationale for the formation of 226 from 225 Scheme 37. Synthesis of 225 and its cyclization to undesired isomer 226 46    In the interest of forming an unsaturated lactone such as 229, we attempted the MOM- deprotection of 224, which proved challenging. Under standard aqueous conditions (aq. HCl in THF), loss of the TBDPS protection preceded lactone formation (Scheme 39). It was soon discovered, however, that treatment with wet TFA in the absence of other solvents gave a compound with characteristic lactone peaks in its proton NMR spectrum, and an accompanying loss of the Boc group. This material, 231, which was not fully characterized, emerged as a mixture of diastereomers. The TFA deprotection required overnight at rt; however, it was complete in about 1 hour if heated to 65 °C. Lactone 231 could be advanced to bicyclic compound 232 by treatment of the crude reaction mixture with DBU. Although the desired lactone was produced (as verified by later experiments which produced analytically pure material), the yield was low and the resulting material could not be fully purified, rendering the procedure unsatisfactory (Scheme 39). Clearly, a more acid-labile protecting group was needed.   Scheme 38. Alternate retrosynthetic analysis of 155 Scheme 39. Formation of 232 from 224 47  It rapidly transpired that silyl ethers were inappropriate blocking groups, because analogs of 219 in which an SiR3 unit replaced the MOM segment resisted heterogeneous hydrogenation. We thus opted for a 2-(trimethylsilyl)ethoxymethyl (SEM) protecting group in place of MOM. While the original report by Lipshutz suggests the use of TBAF in hot THF or HMPA to effect deprotection,79 the use of basic conditions with our substrate might lead to problems, given that TBDPS deprotection is expected to proceed very rapidly under the suggested conditions, and that β-elimination of the alcohol derivative (i.e., X in 230) could occur prior to lactonization. However, the literature indicates that such a protecting group may be cleaved easily under acidic conditions, even in the absence of a strong nucleophile (see Scheme 40).80 The TMS cation released during the reaction might be trapped by trifluoroacetate, adventitious water, or the alcohol freed during the course of the deprotection. In the latter case, a standard aqueous workup is expected to reveal the unprotected OH.   The synthesis of an SEM analog of 220, compound 234 (Scheme 41), was achieved by the same route employed earlier to make 220. However, the catalytic hydrogenation of 233 was slow compared to the MOM congener, requiring about 12 hours at 1000 psi. Fortunately, the resulting product 234 was still a 10:1 mixture of separable diastereomers, just as in the case of 220. This correct diasteromer (major product) was reacted with the lithium enolate of ethyl acetate, and the crude product reduced with NaBH4 to give a diastereomeric mixture of alcohols 235 in satisfactory yield. The acetate 236 was formed in high yield using standard conditions. Scheme 40. Hypothesized mechanism of the decomposition of an SEM ether by protic acid 48  The acid lability of SEM ether 236 was then tested by dissolution in neat TFA. It was found that, with no additional water in the reaction mixture, SEM deprotection (and accompanying removal of Boc) occurred within one hour at room temperature. The reaction was performed by simply stirring 236 in TFA at rt before evaporation under reduced pressure, resulting in smooth conversion into lactone 232. Acetate elimination and cyclization also proceeded smoothly in the presence of DBU, and after reductive methylation (HCHO (aq), Pd/C, H2, AcOH), the desired 238 could be obtained in 58% overall yield after chromatography (Scheme 41; 238 is compatible with column chromatography in the free base form). It should be noted that the above procedure, which had performed well on scales up to 100 mg of 236, became problematic upon scale-up. In certain batches, acid treatment of 236 caused formation of byproducts of an unknown nature, and these were inseparable from the desired 232. That these side products were not desilylated forms of 232 is clear from the fact that they could not be converted back to known materials by treatment with TBDPSCl and imidazole. In these cases, all standard purification methods that were examined (alumina or silica gel chromatography with various solvent mixtures, crystallization) failed to surrender pure 232. Attempts to elaborate the crude, impure lactone into 238 was of no avail, in that the impurities coeluted with the target amine as well. Interestingly, it was found that small amounts of pure 232 could be secured by C18 reverse-phase chromatography, but this method was entirely inappropriate for the preparation of significant quantities of lactone. 49    The route to 238 was clearly unsatisfactory: it lacked conciseness; the high-pressure hydrogenation limited material throughput; the use of expensive or cumbersome to prepare Bredereck’s reagent was less than ideal; and, most importantly, TFA deprotection did not provide a reliable procedure upon scale-up, even when SEM protection was used. In search of a more reliable, flexible, concise, and scalable synthesis, we imagined an approach that entails the Michael addition of the enolate of a protected pyroglutamol to an acrylate (Scheme 42). This addition should, in theory, occur preferentially from the less-hindered face of the molecule, giving the desired stereoisomer. Selective reduction of the imide to an alcohol and attack of this alcohol on the ester would give a lactone such as 239. Introduction of unsaturation and cyclization would return the desired 228. An acrylate ester in which group X were, e.g., PhS, would permit an especially direct access to 228 upon the oxidation to the sulfoxide and thermal elimination. Scheme 41. Synthesis of 238 using the SEM protecting group 50    The enolate of 214 appeared to be a rather poor Michael donor toward ethyl or tert-butyl acrylate. Attempted reactions of this sort returned largely starting 214, along with small amounts of what appeared to be a dimer (possibly resulting from the attack of enolate upon an intact molecule of 214), which was a persistent side product whenever we formed the enolate of 214. Similar difficulties have been recorded in the literature.81 Attempted Michael addition of the enolate of 214 to tert-butyl acrylate 243 or ethyl acrylate 244 in the presence of BF3•OEt2 afforded an intractable mixture of numerous products (Scheme 43).   A more electrophilic Michael acceptor, in the form of ethyl 2-(phenylthio)acrylate, 245,82 combined with the enolate of 214 to give a mixture of diastereomeric products in modest yield. It was not clear at this juncture whether such products were epimeric solely (or largely) at the PhS- bearing carbon, or also at the ring carbon; i.e., whether the addition had occurred with acceptable or poor facial selectivity with respect to the enolate. To address the issue of facial selectivity, Scheme 42. Retrosynthesis of lactone 228 by Michael addition Scheme 43. The enolate of 214 did not add to 243 or 244 51  product 246 was subjected to Raney Ni desulfurization in an attempt to reach 247. However, this treatment caused decomposition. Endeavoring then to elaborate 246 to 248 (not fully characterized), the imide was partially reduced using NaBH4/CeCl3 or LiBEt3H. The resultant hemiamidal 248 could be advanced no further: attempted formation of lactone 249 with gentle reductants [NaBH(OAc)3] gave no reaction, while more active reducing agents (LiBH4; NaBH4 alone or in the presence of Et3N) promoted overreduction. Finally, reduction of 246 with Dibal was not regioselective. Details of these finding are found in Scheme 44.   Scheme 44. Attempted Michael-addition route to 228  A surrogate for the Michael addition was available in the reaction of 214 with allyl bromide.83 Contrary to other enolate reactions of pyroglutamols, this process is high-yielding; additionally, it results exclusively in the trans- product. We found that known allylation product 250 could easily be advanced through the several steps necessary to create key lactone 253. To this end, 250 was reduced with LiBH4 to give 251 in quantitative yield. The emerging alcohol was protected as a TBS ether before being subjected to hydroboration with BH3•THF, followed by oxidative cleavage under standard aqueous conditions to give 252. This new primary alcohol  52    was oxidized to the carboxylic acid with RuO4 in biphasic medium, 84 which was superior to oxidation with TEMPO/DIB, provided that the reaction time was carefully controlled. The crude acid was freed of TBS protection using PPTS to provide lactone 253 (Scheme 45). A brief digression is appropriate at this stage. Experiment indicated that the N- methylation of 253, e.g. with NaH/MeI in DMF, was troublesome, affording mixtures of various products (Scheme 46). Given these results, it was decided to postpone N-methylation until after the selenation / selenoxide elimination85 sequence. The latter would thus be carried out with the dianion of 253. Treatment of 253 with two equivalents of LDA at −78 °C in THF, trapping with PhSeBr and oxidation with H2O2, afforded conjugated lactone 255 in only 18-25% yield, signaling that optimization of the reaction conditions would be necessary. After considerable experimentation, it was found that a 54-58% yield of 255 could be realized if a solution of the enolate of 253 was   Scheme 45. Advancement of allylation product 250 to lactone 253 Scheme 46. N-methylation of 253 was unsuccessful 53   cooled to about −110 °C (LN2/EtOH bath) before rapid addition of a pre-cooled (−78 °C) solution of PhSeBr, and prompt quenching (5 minutes) with acetic acid. In particular, a very pure product could be obtained when good stirring was maintained and a slight deficit of PhSeBr was used, as indicated by the disappearance of red-brown color of the reagent immediately following its addition to the enolate. The subsequent oxidation of the selenide was best performed with mCPBA, as oxidation with H2O2 led to small amounts of byproducts. The results of these experiments, giving isolated yields following column chromatography, are presented in Table 2.  Entry Enolate temp. Equiv PhSeBr PhSeBr soln. T Rate of add’n Rxn time (min) Oxidation reagent Scale Yield 1 −78 °C 1.1 rt dropwise 10 H2O2 36 mg 21% 2 −78 °C 2.8 rt dropwise 10 H2O2 74 mg 18% 3 −78 °C 2.0 rt dropwise 10 H2O2 61 mg 25% 4 −78 °C 2.0 rt dropwise 5 mCPBA 54 mg 30% 5 −78 °C 1.3 rt dropwise 5 mCPBA 52 mg 28% 6 −110 °C 1.5 rt dropwise 10 mCPBA 79 mg 33% 7 −110 °C 2.0 rt dropwise 5 mCPBA 55 mg 63% 8 −110 °C 2.0 rt dropwise 10 mCPBA 745 mg 18% 9 −110 °C 2.0 0 °C at once 5 mCPBA 1.5 g 52% 10 −110 °C 2.0 −78 °C at once 5 mCPBA 2.6 g 54% 11 −110 °C 2.0 −78 °C at once 5 mCPBA 4.1 g 58%  Table 2. Optimization of conditions for the selenation / oxidation of 253    Scheme 47. Synthesis of 255 from 253 54  The N-deprotection / cyclization of unsaturated lactone 255 with TFA proved quite sluggish, requiring overnight stirring. When off-the-shelf TFA was used, a significant loss of TBDPS was observed, therefore 1% TFAA (v/v, vs. TFA) was included to remove adventitious water. This made for a much cleaner reaction. Commercial 4N HCl•dioxane proved to be inferior to TFA as a Boc-releasing agent, in that it promoted the formation of numerous byproducts (TLC). Methylation of the amine then occurred under standard reductive amination conditions (HCHO, NaBH3CN, AcOH, MeCN) to give 238 (Scheme 48) in 60-77% overall yield from 255.    Scheme 48. Synthesis of 238 from 255  With a reliable gram-scale route to 238 available, we sought to create a suitable trisubstituted pyrrolidine precursor for nitrogen addition in accordance with Scheme 33. This was accomplished in a straightforward manner. To wit, lactone 238 was hydrolyzed under standard conditions (LiOH, THF/H2O, rt), and the reaction mixture evaporated to give the putative lithium carboxylate. This crude material was then protected at the alcohol by treatment with TBSOTf in CH2Cl2/pyridine. Finally, esterification was performed with TMSCHN2 in CH2Cl2/MeOH, to give 256 in 65% yield over three steps (Scheme 49).  55   Ester 256 resisted deprotonation upon exposure to 1.1 equiv. of LDA at −78 °C for several hours (no deuterium incorporation upon quenching with D2O), but enolate formation was achieved by reaction with 2.5 equivalents of LDA at −15 °C for 3.5 hours. The enolate, however, failed to undergo azidation upon reaction with 51. Even after extended reaction times, such attempts returned largely recovered 256 (Scheme 50). Some decomposition of the substrate was also evident from the 1H NMR spectra of crude reaction mixtures.  Given the difficulties in functionalization of the enolate of 256, we opted to attempt to functionalize lactone 238 directly. Initially, it was thought that reduction of an oxime might give the correct stereochemistry of the emerging aminolactone, but treatment of 238 with isoamyl nitrite and t-BuOK resulted in decomposition (Scheme 51).   Contrary to 256, lactone 238 did undergo enolization upon reaction with 1.1 equiv. of LDA at −78 °C for 2.5 hours. A Gennari-Evans-Vederas71 hydrazination of the enolate produced the expected 259 in about 10% yield. Interestingly, the yield of 259 soared to 72% when the sodium enolate (from 238 and NaHMDS) was employed in the reaction. It also became apparent Scheme 49. Synthesis of 256 in 3 steps from 238 Scheme 50. The enolate of 256 failed to react with sulfonyl azide 51 56  that deprotonation of the lactone with NaHMDS at −78 °C was complete within 1 h (D2O quenching). We suspect that the lack of reactivity of the lithium enolate was due to the formation of kinetically stable Li aggregates. Rather than complicating the experimental protocol by the addition of cosolvents (DMPU; hazardous HMPA,86 etc.) or LiCl,86 we opted to employ the Na enolate of 238 in all subsequent reactions. Not unexpectedly, compound 259 produced broad NMR spectra as a consequence of slow internal rotation of the tertiary Boc segment. No variable-temperature spectra were   obtained, because it became obvious that 259 was a synthetic dead end. Indeed, numerous attempts to deprotect this hydrazine under acidic conditions gave only intractable mixtures (Scheme 51). However, rt 1H NMR indicated it to be essentially diastereomerically pure. In light of subsequent results (vide infra), it may be surmised that the azodicarboxylate reagent had indeed reacted from the convex face to the enolate; i.e., an L--hydrazinoacid had been created, instead of the required D-type material. Given the difficulty of further advancement of 259, no definite stereochemical proof was sought.  Scheme 51. Initial attempts to react the enolate of 238 with electrophilic nitrogen sources 57    An alternate route to introduce the desired amine would involve the SN2 displacement of a suitably situated halide by azide ion (see Scheme 52). Since an electrophile would be expected to approach from the convex face of the molecule, this sequence might produce the desired diastereomer after inversion of configuration during the subsequent SN2 reaction. In pursuit of this plan, the sodium enolate of 238 was quenched with NBS. Though the reaction consistently gave a small amount of the desired bromide (not thoroughly characterized), the yield was too low to be synthetically useful. The enolate failed altogether to react with 2,4,4,6-tetrabromo-2,5-cyclohexadienone or carbon tetrabromide. Alternative -bromination methods proved unsatisfactory, including treatment of 238 with TMSOTf and Et3N followed by NBS, or quenching of the sodium enolate with TMSCl followed by in-situ reaction with NBS (Scheme 53).   Scheme 53. Attempts to brominate 238 were unsatisfactory  Scheme 52. Possible method for the introduction of an amine to lactone 238 58  We were gratified to find that the reaction of the sodium enolate of 238 with I2 proceeded very cleanly, in high yield, and nearly instantaneously. In fact, the enolate solution could be titrated with a THF solution of I2 until the persistence of the brown iodine color, giving a quantitative yield of 265 as a single diastereomer. The incoming electrophile was presumed to have approached from the convex face of the molecule, corresponding to the enolate Si- face, resulting in the configuration depicted in Scheme 54. Iodide 265 darkened upon standing; therefore, it was immediately subjected to an SN2 reaction with azide ion (suspension of NaN3 in DMF). The starting material was consumed rapidly, and the 1H NMR spectra of the crude reaction mixture indicated the presence of predominantly a single isomer of the expected azide. During a larger-scale run of the substitution reaction, a second, more-polar product was observed to form. Mass spectrometry revealed this material to have the same mass as the initial product. We inferred that the new material must  have been an epimer of the original. The two isomeric azides were readily separable by silica gel chromatography, given their widely differing polarities (Rf 0.43 for the original product, and 0.20 for the new one in 25/75 EtOAc/Hexanes). This permitted a thorough stereochemical investigation, which led to the assignment of their relative configurations as indicated in Figure 6 (indicated yields from reaction of 265 with sodium azide) on account of the following observations. Scheme 54. Synthesis of iodide 265 and its reaction with sodium azide 59  An MM+ study revealed that the least energetic conformations of the two diastereomeric azides are as illustrated in Figure 6. The calculated dihedral angle between the protons rendered in blue in the α-isomer 268 ( = 180 oC) and in the -isomer 269 ( = 0 oC) translate into a similar vicinal coupling constant. Indeed, assuming an approximate Karplus relationship87 of the type J = 8.5 cos2 -0.28  (0 <  < 90) J = 9.5 cos2 -0.28  (90 <  < 180)  one may anticipate a difference of ca. 1 Hz between the two coupling constants, rendering a stereochemical assignment on such a basis rather untrustworthy. In fact, the measured J values for the protons in question were 6.3 Hz for 266 and 5.1 Hz for 267 in CDCl3. Fortunately, a 1D NOE study furnished reliable stereochemical evidence in the form of strong dipolar couplings between Hx and the N-methyl H’s, as well as Hx and the bridging lactone H, for the major isomer (see Figure 6). In the minor (desired) isomer, the only notable NOE interaction was between Hy     Figure 6. Scalar and dipolar couplings observed in the NOE spectra of 266 and 267 60   and the bridging lactone H. Thus it was ascertained that the major product of substitution was in fact 266, having the α-configuration at the azide-bearing carbon. These findings demonstrated that the substitution reaction had occurred with retention of configuration, giving the undesired 266. Such an outcome would result from a double inversion of configuration. One possible mechanism for this process envisions the intermediacy of aziridinium ion 27188 (Scheme 55). Selective azide attack at the carbon atom adjacent to the carbonyl system (instead of, e.g., at the Me group) may be rationalized by invoking a lowering of the LUMO at this position as a consequence of mixing of the C-N σ* with the C=O π* orbitals. Elongation of the highlighted C-N bond as a result of strain89 would contribute to LUMO lowering, further promoting regioselectivity in the observed sense. However, it must be stressed that mechanistic studies have not been performed at the present time. Alternate double inversion mechanisms, proceeding, e.g., through intermediate displacement by iodide released in the course of the reaction, cannot be eliminated from possibility.     It was tempting to speculate about the at the origin of the minor, desired, isomer 267. Although a true SN2 reaction could certainly have been competing with the two-step substitution process, it was also possible that epimerization might be occurring in the course of the reaction, through reversible deprotonation of the azido lactone and reprotonation of the enolate from the Scheme 55. Hypothesized mechanisms for the formation of 266 from 265 61  convex face of the molecule. In consideration of this latter possibility, 266 was treated with DBU in CH2Cl2 and the reaction allowed to reach equilibrium. The result was a 1 : 2 mixture of 267 to 266. When the epimerization was attempted in MeCN, it was our pleasure to find that 267 was the major isomer in a ratio of 1.2 : 1 (based on isolated yield). When powerful polar aprotic solvents such as DMF and DMSO were used in the epimerization, a similar product ratio to that observed in MeCN was noted in each case (1H NMR), but partial decomposition was apparent ( Table 3). An attempt to achieve higher conversion of 266 to 267, through complete enolate formation followed by kinetic trapping, also resulted in decomposition. The strong solvent dependence of the equilibration was consistent with the observation that 267 is significantly more polar than 266; therefore, it should accumulate to a greater extent in a more polar solvent.   Entry Solvent Ratio 267 : 266 1 CH2Cl2      1 : 2 2 MeCN   1.2 : 1 3 DMF ~1.2 : 1 4 1:1 MeCN : DMSO ~1.2 : 1  Table 3. Product ratios in the epimerization of 266 to 267 in various solvents  Given the successful isomerization of azide 266, it is clear that a successful direct azidation of lactone 238 would save one or two synthetic steps. Unfortunately, the sodium enolate of 238, when reacted with 2,4,6-triisopropylbenzenesulfonyl azide 51 followed by acetic acid, gave a mixture of products (Scheme 56). Although a small amount of each azide isomer, i.e. 266 and 267, could be identified in the reaction mixture, a third product was also present. Though we suspected this to be the product of diazo transfer (see Evans28) a method for its 62  separation from 267 was not immediately available. Given the difficulty of purification and the fact that the yield of the desired materials seemed quite low, the azidation by nucleophilic displacement of iodide (see Scheme 54) was deemed the method of choice.  Reduction of azides 266 and 267 to their respective amines could be accomplished by hydrogenation (Pd/C) (Scheme 57). Unfortunately, both reactions encountered occasional difficulty; the reduction of azide 266 in particular was capricious. For reasons that remain unclear, some batches of 266 reacted cleanly, while others were rapidly converted into a   multitude of undesired products. Such a variability cannot be attributed to the Pd catalyst, in that in all cases the latter was drawn from the same jar. At this time, one can only speculate about the source of the problem. Reduction of the azide using PPh3 was even less satisfactory. Scheme 57. Advancement of 266 to amines 273 and 274 Scheme 56. Direct azidation of the sodium enolate of 238 was unsatisfactory 63  Throughout the project, we considered alternate synthetic schemes. Interesting possibilities for the synthesis of amino acid 155 arise from hypothetical SN2 closure to form its pyrrolidine ring. Given a fixed configuration of the secondary alcohol (indicated by an arrow in Scheme 58) e.g., in 276, its activation in the presence of the free pyroglutamol-derived amine would lead to stereospecific closure of the five-membered ring, resulting in the necessary stereochemistry. An additional factor which made this route attractive was the possibility of performing a subsequent Ugi reaction on a less-hindered, linear form of the amino acid.  One method to create the desired precursor would be a glycinate aldol proceeding with syn stereochemistry. Evans himself demonstrated that such a process is possible by protection of the gycine nitrogen as an isothiocyanate.90 Such a derivative, functionalized with an appropriate chiral auxiliary, would add to aldehyde 277 to give 276. The necessary glycine derivative is embodied in known imide 280.90 Aldehyde 277, it seemed, could be readily prepared from pyroglutamol derivative 234, a material of which we were in possession. To this end, 234 was reduced with LiBH4, and protected as the TES ether to give protected triol 278. This material was N-methylated by deprotonation using BuLi and subsequent trapping with Me2SO4. The TES ether could be removed in the same pot after PPTS/water Scheme 58. Alternate retrosynthesis via glycinate aldol 64  treatment. The free alcohol was oxidized to the aldehyde under Parikh-Doering conditions91 to give aldehyde 279. Yields were not determined for this sequence. Under catalysis by Sn(OTf)2/N-ethylpiperidine 92 or TiCl4/iPr2NEt/NMP, 93 279 reacted with 280 to give the glycinate aldol product 281 in fair yield as seen in Scheme 59. Upon initial inspection of the 1H NMR, this material appeared to be a 1:1 mixture of diastereomers. A lack of selectivity in this seemingly-reliable variant of the aldol reaction has been observed by Zhu.94 However, it was later discovered by variable temperature (VT) NMR (DMSO-d6, 80 °C) that the alleged diastereomers were in fact rotamers, and that the compound was a single isomer. Time constraints have permitted no further work on this route.     Scheme 59. Synthesis and glycinate aldol reaction of aldehyde 279 65  2.2 Ugi reactions of complex aminoacids  It will be recalled that the Ti(IV)-promoted Ugi reaction devised in our group entailed the use of free aminoacids. This implied that lactones 273 and 274 would have to be hydrolytically cleaved to their corresponding aminoacids. On the other hand, the possibility that a successful Ugi condensation could be achieved with the aminolactones themselves was intriguing. An interesting development unfolded when 274 was submitted to Ugi (U-4CR; acetic acid as the acid component) conditions. Instead of the expected Ugi condensation product, two compounds were isolated. One was the Passerini adduct 282, and the other was a rearranged material with a characteristic 1H NMR signal at 5.90 ppm (Scheme 60). This product displayed     Scheme 60. Unexpected rearrangement in the attempted Ugi reaction of 274  an M/Z of 453, which indicated that a nitrogen atom had been lost relative to the starting aminolactone. Mechanistic considerations and a preliminary COSY NMR study led to the conclusion that the unexpected product must be tetrahydropyridine 290 (Scheme 61; not fully characterized). Some attempts were made to optimize the rearrangement of 274. To our disbelief, changes to the reaction conditions, in particular omission of the aldehyde, inhibited the production of 283. Treatment of 274 with HCl in methanol in the absence of an aldehyde also failed to provoke the rearrangement. On the basis of these observations, we believe that 290 could form through the mechanism depicted in Scheme 61. Preliminary condensation of the 66  aminolactone with the aldehyde would give 284. Previous investigations95 indicate that coordination of the acetic acid additive to Ti(IV) produces a species with enhanced proton acidity, which might catalyze β-elimination of the pyrrolidine nitrogen (i.e., 284 to 285) thanks also to the enhanced mobility of the carbonyl -proton in imine 284. This might explain why the aldehyde is required. Protonation of the enamine functionality in 286 leads to cation 287, wherein the C=O group displays an unusually high degree of electrophilicity. Methanolysis could then occur, and the resultant 288 would cyclize to give 290.   Scheme 61. Possible mechanism for the rearrangement of 274   Our attention thus refocused on the conduct of an Ugi condensation with the free aminoacid form of 273/274, which materials were available by lactone hydrolysis. While the undesired diastereomer 273 could be hydrolyzed cleanly and rapidly to carboxylate 291 (not fully characterized) under basic conditions (LiOH, THF/H2O, rt), a major obstacle was encountered when a similar reaction was attempted using 274. This process resulted in the 67  formation of a 1:1 mixture of the desired 292 plus 291, signaling that epimerization of the substrate had occurred during the reaction. Over time we tested various methods of hydrolysis, and became quite distressed to discover that this epimerization could not be completely avoided. A number of standard conditions were examined (MgBr2•OEt2 in MeOH, K2CO3 in MeOH, LiOOH, MeN(OMe)MgCl), along with some unusual ones (heating in NaOAc (aq), treatment with Yb(OTf)3 (aq), Bu4NOH with and without metal ions). Ultimately, it was found that saponification with KOH in THF/H2O at 0 °C gave carboxylate 292 (not fully characterized) as the dominant component of a 2:1 (1H NMR) mixture of products (Scheme 62). Attempted retrieval of the free acid forms of 291-292 by protonation of the carboxylate (TFA) triggered an immediate re-closure of the lactone. Subsequent Ugi reactions were thus carried out with salts 291 and 292, because we had already determined that lactones are incompetent substrates.   Scheme 62. Hydrolysis of lactones 273 and 274 68     The reaction of the mixture of 292 and its epimer 291 with o-anisaldehyde 73 and tert- butylisocyanide 182 under our documented conditions was quite sluggish. This difficulty could be alleviated by the use of additional TiCl4 (50 mol%; used for all subsequent reactions), which led to the isolation of a mixture of lactones 293 (major) and 294 (minor), obviously arising from 292 and 291, respectively (Scheme 62), and not from the corresponding lactones (cf. Scheme Scheme 63. Ugi reaction of 292 Figure 7. Solid-state structure of 293 69  60). The major product, the more polar of the two, was obtained as a single diastereomer (NMR). Whereas in the free base form the substance was a thick gum, the corresponding hydrochloride eventually crystallized, permitting a structural elucidation by X-ray analysis. An ORTREP representation of 293 is found in Figure 7. It is recognized that while this material arose from reaction of the D-amino acid 292, the stereocenter produced by the Ugi reaction had the L- configuration. This is opposite to what was anticipated based on our previous work. A rationale for this will be presented below (vide infra). The reaction of stereochemically homogeneous 291 with 73 and 182 in the presence of 50 mol% TiCl4 furnished an inseparable 7:1 mixture of stereoisomeric lactones, which on the basis of the foregoing result we assign as diastereomers 294a (major) and 294b (minor; Scheme 64). We stress that a conclusive stereochemical elucidation would require an X-ray crystal structure. Unfortunately, we were unable to obtain crystals of either the free base (thick oil) or the HCl salt of 294.   Scheme 64. Ugi reaction of 291 and presumed configuration of the products  The Ugi reaction, though not high-yielding, appears to be fairly general. Several Ugi products could be isolated from the reactions of 291 and 292 with either 182 or p- methoxyphenylisocyanide 166 and 2-methoxy-5-benzyloxybenzaldehyde 295 or 2-bromo-6-  70   Scheme 65. Ugi products arising from reaction of 291 and 292  methoxybenzaldehyde 296. Interestingly, each Ugi product emerged as the lactone, with the exception of 300, which was recovered as the methyl ester. A rigorous stereochemical assignment of these products (starred centers) is only possible by X-ray crystallography. We do not possess such crystallographic data at the present time. Consequently, the (tentative) configurations shown in Scheme 65 were assigned on the basis— first of all—of the results obtained with D-aminoacid 292 (ul-selectivity). As far as the configuration of the C=O -center of the lactone is concerned, a comparison of the 1H NMR 71  spectra of epimeric pairs 266/267 and 273/274 with those of Ugi products reveals that the resonances of the lactonic methylene protons are crowded together in materials arising from D- aminoacid 292, while they are well separated in those ensuing from L-aminoacid 291 (Figure 8). This aided in the assignment of 297. Finally, lactones possessing the -D-configuration are consistently the more polar (smaller Rf value) isomers. In part because 298 is more polar than 299, it was assigned to the D-aminolactone series.   Figure 8. Lactone resonances and Ugi product stereochemistry 72  A rationale for the reversal of diastereoselectivity observed with aminoacid 292 emerges from an analysis of molecular models of zwitterions 301 and 302 (Scheme 66). Transposition of the reactivity model of Scheme 32 to the (D)-aminoacid series produces structure 301. For R = small alkyl, nucleophilic attack from the Si-face of the imine would be expected on stereoelectronic grounds (cf. Scheme 32 and accompanying discussion). But in the imine derived from 292, access to the Si-face of 302 is blocked by one of the substituents on the pyrrolidine ring. As a result, nucleophilic attack occurs from the Re-face of the imine, leading to the observed 304.   Scheme 66. Rationale for the stereochemical outcome of the Ugi condensation of 292  An MM+ study of simplified iminium ion 305 (Figure 9) provided pictorially appealing support for the foregoing. A computer-generated space-filling model of 305 optimized in the MM+ force field reveals that the Si-face of the imino linkage is blocked by the methyl group at the pyrrolidine C-4 position. This substituent occupies the same general region of space as the hydroxymethyl group in 302. Attack of the isocyanide from the Re-face is therefore favored. 73   Figure 9. Space-filling model of iminium ion 305      74  2.3 Synthetic efforts towards quinocarcin and cyanocycline A  The present section details exploratory work aiming to convert the Ugi lactones described above into more advanced precursors to quinocarcin and cyanocycline. Such an objective requires the formation of the C-C bond indicated in Scheme 67 (double-headed arrow), leading to 306. The nature of substituent Z in the latter would be determined by the precise mode of ring closure (vide infra). In all cases, the configuration of the stereocenter arising from the Ugi reaction of 292 (C10 in Figure 7; starred center in Scheme 68) must be inverted to match the configuration of the corresponding carbon in 7 (C5 in Figure 3) and 2 (C9 in Figure 1). Previous studies96 indicate that isoquinolines such as 307 tend to epimerize to the desired 1,3-cis stereoisomer under equilibrating conditions. Thus, it is likely that the desired isomer is the thermodynamically favorable one, and that epimerization can be readily achieved. Furthermore, equilibration could occur not only through reversible deprotonation of the pendant carbonyl functionality, but also via an acid-catalyzed ring opening according to the mechanism of Scheme 68.   Scheme 67. Ugi condensation product ring closure and epimerization 75   Scheme 68. Acid-catalyzed epimerization of 309  An ancillary issue that was briefly explored at this juncture focused on the removal of the tert-butyl amide in order to suppress possible side reactions. A plausible solution might be to activate the secondary amide with, e.g., a Boc group prior to hydrolysis or alcoholysis, or to release the t-Bu group under acidic conditions (Scheme 69). However, treatment of compound 297 with Boc2O and DMAP in MeCN at 100°C (sealed tube) for 12 h returned only starting material, indicating that neither the amide nor the amine were reactive enough to undergo acylation with Boc anhydride. In a like fashion, heating of 297 in neat TFA at 100°C (sealed tube) returned largely the starting material (some decomposition was evident, though).   Scheme 69. Attempts to cleave the secondary amide of 297  The reluctance of the nitrogen atoms of Ugi products to undergo acylation manifested itself anew when 298, in which a less sterically demanding 4-methoxyphenyl (PMP) replaces the tert-butyl group, was treated with an excess of triphosgene in the presence of Et3N. No reaction 76  occurred (Scheme 70). Attempted oxidative cleavage of the PMP group in the TFA salt of 298 (DDQ in MeCN/H2O) also returned unchanged starting material. Conversely, ceric ammonium nitrate (CAN), under similar conditions, gave an intractable mixture.   Scheme 70. Attempts to cleave the secondary amide of 298  The above observations suggested that the nitrogen functionalities present in the Ugi condensation products are rather sturdy, and that they might well survive unscathed in the course of various reactions aiming to effect the desired cyclization. Accordingly, subsequent studies were carried out with unprotected substrates. Three modes of cyclization of 306 were considered (Scheme 71). Acid treatment of 306 could promote a Friedel-Crafts acylation leading to a ketone form of 307. Second, a suitably positioned phenolic OH might permit the conduct of a phenol-aldehyde condensation, after reduction of the lactone to a lactol. Finally, the same end product would result upon appropriately regioselective metallation of the aromatic unit and nucleophilic attack into the lactone C=O group.   77   Scheme 71. Possible methods for the closure of quinocarcin’s B-ring  One approach to the Friedel-Crafts cyclization of 306 rests on the long-recognized ability of mixed trifluoroacetic anhydrides to acylate aromatic rings.97 In systems containing a free secondary amine such as 306, TFAA provides the unique capability of concurrently protecting the amino group and activating the carboxylic functionality. Scheme 72 illustrates the aforementioned hypothesis, exploration of which requires a free carboxylic acid form of 306.    Scheme 72. Method for the Friedel-Crafts closure of quinocarcin’s B-ring  Basic hydrolysis of 297 under standard conditions (LiOH, THF/H2O, rt) and evaporation of volatiles gave the putative carboxylate salt of 297. This crude material was then dissolved in CH2Cl2/pyridine and treated with TBSOTf (−30 °C to rt). The product thus obtained, carboxylic acid 318 (1H NMR, MS) was not fully characterized, but it was immediately subjected to excess TFAA in cold CH2Cl2. A series of color changes ensued, and when the reaction was finally  78   Scheme 73. Friedel-Crafts acylation of 318 was not successful  worked up, it was found to have occasioned the formation of a complex mixture of products, which could not be identified (Scheme 73). The second approach to the cyclization of Scheme 71 would proceed through the attack of a phenol on a tethered aldehyde (possibly masked as the lactol). A reaction of this sort could proceed under acidic or basic conditions. Such cyclization has been demonstrated in related systems, for example, by Fukuyama,98 and was observed to occur spontaneously in some simpler substrates.99 A suitable precursor for this cyclization is compound 321, which could result upon Dibal reduction of 306 (Scheme 74).   Scheme 74. Closure of quinocarcin’s B-ring by the addition of a phenol to an aldehyde  To test this hypothesis, a mixture of diastereomers of lactol 322 was prepared by hemireduction of the lactone moiety of 297 (excess Dibal, CH2Cl2, −78 to −30 °C) and subsequent debenzylation (Pearlman’s catalyst, 1 atm H2) (Scheme 75). Interestingly, hydrogenolysis of the benzyl group occurred smoothly at the stage of the lactol, but it proceeded 79  in an unsatisfactory manner with lactone 297. With this substrate, the reaction tended to stall, resulting in incomplete deprotection. The reasons for this remain unclear. When lactol 322 was subjected to LiOH at rt, a new material was formed, which was not the desired 323. While the new product remains unidentified, the presence of a single aromatic resonance in its 1H NMR spectrum signifies that no C-C bond formation had occurred at the level of the aromatic nucleus. We speculated that the compound may be hemiamidal 324, and that reaction with a mild base at higher temperatures might promote reversible ring opening and   Scheme 75. Synthesis and reaction of lactol 322  exposure of the free aldehyde, which could then react with the phenol to furnish the requisite 323. To explore this possibility, 322 was treated with NH4OAc in hot THF (ammonium acetate, THF/H2O, 60 °C), and to DMSO at 100 °C. No evidence of the desired cyclization was observed under these conditions. Treatment of 322 with TfOH in cold CH2Cl2 gave a precipitate which did not undergo further reaction. The third mode of cyclization (Scheme 71) envisioned the intramolecular addition of an aryl organometallic agent to, e.g., the ester carbonyl of 300. The exploration of this avenue required a prior optimization of the Ugi reaction of 2-halo-6-methoxybenzaldehydes with 292. It 80  will be recalled (Scheme 65) that this transformation afforded 300 in only 14% yield. Due to time constraints, this optimization has not been performed.   Scheme 76. Method for carbanionic closure of quinocarcin’s B-ring     81   3 Conclusion  In the preceding pages, we have demonstrated a robust synthesis of key lactone 238, and have outlined a number of methods by which it might be advanced to the natural products quinocarcin and cyanocycline A. The elaboration of 238 to 274 allowed examination of a previously-unknown molecular framework with remarkable properties. Furthermore, we have performed the Ugi condensation reaction of an aminoacid in a very challenging context. To our knowledge, this constitutes the first such example in natural product synthesis. We believe the work disclosed herein will prove useful to future research efforts exploring the chemistry of the Ugi reaction, and to chemical synthesis in general. From the efforts described in the preceding pages, it is clear that the Ugi reaction of α- aminoacids has great potential as a key step in the synthesis of highly functionalized molecules. Due to its high diastereoselectivity, mild reaction conditions, and functional-group tolerance, this transformation warrants further investigation in the context of total synthesis. The diastereoselectivity of this process remains unpredictable. Our own work towards the total synthesis of quinocarcin and cyanocycline using the Ugi technology has been hampered by numerous obstacles, which have conspired to render the route untenable, given the limited resources available. Ongoing work according to the Nucleophilic addition route of Scheme 22 is sure to meet with more success.    82  References   1 Kluepfel, D.; Baker, H. A.; Piattoni, G.; Sehgal, S. N.; Sidorowicz, A.; Singh, K.; Vezina, C. J. Antibiot. 1975, 28, 497-502. 2 Scott, J. D.; Williams, R. M. Chem. 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Tetrahedron Lett. 1992, 33, 3919-3922.    89  Appendix A: Experimental Protocols  Melting points were measured on a Mel-Temp apparatus and are uncorrected. Unless otherwise stated, 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded at room temperature on a Bruker Avance II 300 instrument. Chemical shifts are reported in parts per million (ppm) on the δ scale using the solvent residual peak as internal standard, and coupling constants J are in Hz. Multiplicities are reported as “s” (singlet), “d” (doublet), “t” (triplet), “q” (quartet), “dd” (doublet of doublets), “ddd” (doublet of doublet of doublets), “m” (multiplet), “app” (apparent), and “br” (broad). High-resolution mass spectra (m/z) were obtained in the electrospray ionization (ESI) mode on a Micromass LCT instrument by the UBC Mass Spectrometry laboratory. Single crystal X-ray measurement was performed by Dr. Brian Patrick (UBC X-ray service) on a Bruker X8 APEX II diffractometer, with refinements made using the SHELXTL crystallographic software package of Bruker-AXS. Optical rotation was measured on a Jasco P-2000 polarimeter. IR spectroscopy was performed on a Perkin-Elmer Frontier instrument. THF was freshly distilled from Na/benzophenone ketyl under N2, and CH2Cl2 was freshly distilled from CaH2 under N2. Commercial n-BuLi was titrated against diphenylacetic acid until a yellow color persisted. Where indicated, “pH 7 phosphate buffer” refers to Fisher Scientific SB109, which was used as received. Flash chromatography was performed on 230-400 mesh silica gel. Analytical TLC was carried out on aluminum-backed Merck silica gel 60 plates with fluorescent indicator, with spots being visualized by I2 vapor deposition and alkaline aqueous KMnO4. All reactions were performed under dry argon in oven–dried flasks equipped with Teflon™ stirbars. Flasks were fitted with rubber septa for the introduction of substrates, reagents and solvents via syringe.  90  A.1 Preparation of 218   Neat tert-butoxybis(dimethylamino)methane (Bredereck’s reagent; 3.8 mL, 18.0 mmol) was added to a warm (50 °C) solution of 214 (5.5 g, 12.0 mmol) in THF (4 mL) and the mixture was heated to 70 °C. Stirring at this temperature was continued overnight, during which time the solvent had partially evaporated and the reaction mixture had acquired a red color. The mixture was cooled, diluted with THF while still warm and applied directly to a silica gel column. Flash chromatography (elution with a 30/70 to 60/40 EtOAc/hexanes gradient) gave 218 (5.3 g, 10.3 mmol, 86% yield) as a faintly yellow, viscous oil that solidified on long standing to form pale yellow crystals, m.p. 88-89 °C; [α]D 20 –19.2 (c 1.9, EtOH). 1H NMR (300 MHz, CDCl3):  1.05 (s, 9H), 1.44 (s, 9H), 3.01 (s, 6H), 3.06-2.90 (m, 2H), 3.69 (dd, J = 9.8, 6.4, 1H), 3.77 (dd, J = 9.8, 3.3, 1H), 4.13-4.19 (m, 1H), 7.11 (brs, 1H), 7.33-7.46 (m, 6H), 7.57-7.68 (m, 4H); 13C NMR (75 MHz, CDCl3):  19.3, 25.4, 26.8, 28.1, 41.9, 55.5, 64.8, 81.4, 93.8, 127.7, 127.7, 129.7, 133.3, 133.6, 135.5, 135.5, 145.9, 150.9, 170.6; IR (film, cm-1):  1748, 1621; HRMS: calc. for C29H40N2O4Na 28Si [M + Na]+ 531.2655; found 531.2648.   91    Figure 10. 1H NMR spectrum of 218 Figure 11. 13C NMR spectrum of 218 92  A.2 Preparation of 220  A solution of 218 (4.3 g, 8.4 mmol) in THF (17 mL) was added to rapidly stirred H2SO4 (aq) (78 mL of 5% v/v solution) at rt, and the resulting milky suspension was sonicated for 40 min. Solid NaHCO3 was then added in portions (GAS EVOLUTION) until gas evolution ceased. The residue was partitioned between H2O and CH2Cl2, and the organic extract was dried (Na2SO4), filtered, and concentrated under vacuum. To a solution of the residue in CH2Cl2 (20 mL) at rt was added diisopropylethylamine (1.0 mL, 12.6 mmol), followed by the dropwise addition of chloromethyl methyl ether (2.2 mL, 12.6 mmol). The reaction was stirred for 1 hour at rt before being diluted with CH2Cl2 and poured into sat. NH4Cl (aq). The organic layer was separated, dried (Na2SO4), filtered, and evaporated under vacuum. To a solution of the residue in EtOAc (150 mL) was added Pd/C (10%, 2.0 g) and the reaction vessel was flushed with H2. Stirring was continued overnight, when the mixture was filtered through Celite and evaporated to give 220 (3.32 g, 6.31 mmol, 75% yield over three steps) as a colorless oil, which was a 14:1 mixture of cis (220, major) and trans diastereomers. [α]D 20 –18.1 (c 0.5, EtOH); 1H NMR (300 MHz, CDCl3):  1.06 (s, 9H); 1.41 (s, 9H); 2.17-2.40 (m, 2H); 2.77-2.89 (m, 1H); 3.32 (s, 3H); 3.72-3.95 (m, 4H); 4.10-4.21 (m, 1H); 4.54-4.59 (m, 2H); 7.34-7.48 (m, 6H); 7.60-7.68 (m, 4H); 13C NMR (75 MHz, CDCl3):  19.3, 23.5, 26.8, 27.9, 43.2, 55.3, 56.9, 64.2, 67.0, 82.9, 96.5, 127.7, 129.8, 133.1, 133.3, 135.5, 135.6, 149.9, 174.3; IR (film, cm-1):  1784, 1715; HRMS: calc. for C29H41NO6 28Si [M + Na]+ 550.2601; found 550.2598.   93     Figure 12. 1H NMR spectrum of 220 Figure 13. 13C NMR spectrum of 220 94  A.3 Preparation of 223   To a solution of diisopropylamine (82 µL, 0.58 mmol) in THF (3 mL) at –78 °C was added commercial butyllithium (2.5 M in hexanes, 0.25 mL, 0.64 mmol), and the solution was stirred for 15 min. Anhydrous ethyl acetate (57 µL, 0.58 mmol) was then added (syringe), and stirring was continued at the same temperature for 1.5 hours. Dropwise addition of a solution of 220 (252 mg, 0.48 mmol) in THF (1.5 mL) was performed, and the reaction mixture was warmed to –15 °C. Stirring was continued at this temperature until starting material was consumed (TLC, 2 hours). The mixture was poured into sat. NH4Cl (aq), and the aqueous layer was extracted with two portions of CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered, and stripped of volatiles under vacuum to give a colorless oil, which was carried on without purification. To the crude residue as an EtOH (1.5 mL) solution at rt was added NaBH4 (22 mg, 0.58 mmol). The mixture was stirred at rt for 1 hour, when TLC monitoring indicated convergence to a single spot. The mixture was quenched by careful addition of sat. NH4Cl (aq) (GAS EVOLUTION). The mixture was partitioned between water and CH2Cl2, the layers were separated, and the organic extract was dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (30/70 EtOAc/hexanes) to give 223 (135 mg, 0.22 mmol, 46% over two steps), a 1:1 mixture of diastereomers, as a colorless oil. 1H NMR (300 MHz, CDCl3):  1.07 (s, 9H); 1.24-1.33 (m, 3H); 1.43 (s, 9H); 1.55-1.70 (m, 1H); 1.73-1.85 (m, 1H); 2.44-2.62 (m, 2H); 3.24-3.43 (m, 4H); 3.54-3.88 (m, 5H); 4.08-4.27 (m, 3H); 4.55-4.74 (m, 3H); 7.33-7.49 (m, 6H); 7.58-7.68 (m, 4H); 13C NMR (75 MHz, CDCl3):  14.2, 19.3, 26.9, 28.4, 28.5, 30.2, 39.1, 39.5, 39.6, 49.9, 55.5, 60.7, 66.4, 66.6, 67.0, 68.1, 70.1, 79.2, 96.7, 127.7, 95  129.8, 133.2, 133.3, 135.6, 155.7, 172.8; HRMS: calc. for C33H52NO8 28Si [M + H]+ 618.3462; found 618.3467.   96     Figure 14. 1H NMR spectrum of 223 Figure 15. 13C NMR spectrum of 223 97   A.4 Preparation of 225   A CH2Cl2 (2 mL) solution of 223 (215 mg, 0.35 mmol), Et3N (0.07 mL, 0.54 mmol), and MsCl (0.04 mL, 0.53 mmol) was stirred overnight at rt, before being poured into sat. NH4Cl (aq) and extracted with CH2Cl2. The organic extract was dried (Na2SO4), filtered, and evaporated under vacuum to give a colorless oil, which was re-dissolved in CH2Cl2 (3 mL). Addition of DBU (0.06 mL, 0.4 mmol) and stirring at rt for 2 hours caused complete conversion to 225 (TLC). The mixture was diluted with CH2Cl2 and poured into sat. NH4Cl (aq). The organic layer was separated, dried (Na2SO4), filtered, and evaporated under vacuum. Flash column chromatography (25/75 EtOAc/hexanes eluent) gave 225 (192 mg, 0.32 mmol, 90% over two steps) as a colorless oil. [α]D 20 +5.8 (c 0.5, EtOH); 1H NMR (300 MHz, CDCl3):  1.08 (s, 9H); 1.29 (t, J = 7.1, 3H); 1.44 (s, 9H); 1.52-1.67 (m, 2H); 1.76-1.93 (m, 1H); 2.40-2.60 (m, 1H); 3.33 (s, 3H); 3.49-3.63 (m, 3H); 3.63-3.81 (m, 2H); 4.18 (q, J = 7.1, 2H); 4.59 (s, 2H); 4.67 (brd, J = 9.0, 1H); 5.81 (d, J = 15.8, 1H); 6.88 (dd, J = 15.8, 8.5, 1H); 7.34-7.50 (m, 6H); 7.59-7.70 (m, 4H); 13C NMR (75 MHz, CDCl3):  14.2, 19.3, 26.9, 28.4, 32.9, 39.6, 50.0, 55.3, 60.2, 65.6, 69.6, 79.2, 96.5, 122.2, 127.8, 129.9, 133.1, 135.6, 149.7, 155.3, 166.3; IR (film, cm-1):  1713; HRMS: calc. for C33H50NO7 28Si [M + H]+ 600.3357; found 600.3365.   98     Figure 16. 1H NMR spectrum of 225 Figure 17. 13C NMR spectrum of 225 99  A.5 Preparation of 226   To a CH2Cl2 (3 mL) solution of 225 (112 mg, 0.19 mmol) was added TFA (0.15 mL), and the solution was stirred at rt for 6 hours. At this time, TLC monitoring indicated consumption of starting material. The mixture was neutralized by careful addition of sat. NaHCO3 (aq) (GAS EVOLUTION) and dilution with CH2Cl2 and the organic layer was separated, dried (Na2SO4), filtered, and evaporated under vacuum. The residue was dissolved in Et2O, treated with activated charcoal (Norit®), filtered through Celite, and evaporated, giving 226 (80 mg, 0.16 mmol, 86% yield) as a faintly yellow oil. [α]D 20  +15.5 (c 0.5, EtOH); 1H NMR (300 MHz, CDCl3):  1.07 (s, 9H); 1.27 (m, 5H); 1.98-2.16 (m, 2H); 2.46 (dd, J = 15.9, 9.4, 1H); 2.69 (dd, J = 15.9, 3.7, 1H); 3.33 (s, 3H); 3.37-3.46 (m, 2H); 3.48 (d, J = 5.7, 1H); 3.56-3.61 (m, 2H); 4.16 (q, J = 7.1, 2H); 4.58 (s, 2H); 7.33-7.49 (m, 6H); 7.63-7.71 (m, 4H); 13C NMR (75 MHz, CDCl3):  14.2, 19.2, 26.8, 31.2, 40.4, 44.5, 55.2, 57.1, 58.1, 60.4, 66.1, 69.7, 96.5, 127.7, 129.7, 133.4, 135.6, 172.4; IR (film, cm-1):  1729; HRMS: calc. for C28H42NO5 28Si [M + H]+ 500.2832; found 500.2838.   100     Figure 18. 1H NMR spectrum of 226 Figure 19. 13C NMR spectrum of 226 101  A.6 Preparation of 233   A solution of 218 (3.0 g, 5.9 mmol) in THF (12 mL) was added to rapidly stirred H2SO4 (aq) (55 mL of 5% v/v solution) at rt, and the resulting milky suspension was sonicated for 40 min. Solid NaHCO3 was then added in portions (GAS EVOLUTION) until gas evolution ceased. The residue was partitioned between H2O and CH2Cl2, and the organic extract was dried (Na2SO4), filtered, and concentrated under vacuum. To a CH2Cl2 (11 mL) solution of the residue and Hunig’s base (2.1 mL, 12.0 mmol) at 0 °C was added SEMCl (1.6 mL, 9.0 mmol) over several minutes. The reaction was stirred until starting material had been consumed (TLC, about 30 min). Following dilution with CH2Cl2, the mixture was poured into sat. NH4Cl (aq), the layers were separated, and the aqueous layer was extracted with one additional portion of CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered, and the solvent was removed under vacuum. Silica gel chromatography of the residue (20/80 EtOAc/hexanes eluent) gave 233 (3.0 g, 4.8 mmol, 82% yield over two steps), a colorless oil. 1H NMR (300 MHz, CDCl3):  0.01 (s, 9H), 0.95 (t, J = 8.3, 2H), 1.01 (s, 9H), 1.45 (s, 9H), 2,71 (ddd, J = 16.5, 8.9, 2.9, 1H), 2.82 (brd, J = 16.5, 1H), 3.65-3.71 (m, 3H), 3.83 (dd, J = 10.1, 4.6, 1H), 4.21-4.28 (m, 1H), 5.02-5.06 (m, 2H), 7.33-7.48 (m, 7H), 7.57-7.67 (m, 4H); 13C NMR (75 MHz, CDCl3):  −1.4, 17.9, 19.2, 23.5, 26.7, 28.0, 56.1, 64.8, 66.9, 82.3, 96.5, 110.6, 127.7, 127.7, 129.7, 132.9, 133.3, 135.5, 150.3, 150.6, 168.5; HRMS: calc. for C33H49NO6Na 28Si2 [M + Na] + 634.2996; found 634.3007.   102     Figure 20. 1H NMR spectrum of 233 Figure 21. 13C NMR spectrum of 233 103  A.7 Preparation of 234   A solution of 233 (3.0 g, 4.8 mmol) in EtOAc (60 mL) containing suspended Pd/C (10%, 1.3 g) was placed in a Parr reactor, which was pressurized to 1000 psi of H2. After 24 hours of rapid stirring at rt, the catalyst was removed by filtration over a pad of Celite. Evaporation of solvent under vacuum gave the crude hydrogenated product as a 10:1 mixture of cis (234, major) and trans diastereomers. Pure 234 (2.5 g, 4.0 mmol, 83%), [α]D 20 –16.9 (c 1.1, EtOH), was readily isolated by flash chromatography (20/80 EtOAc/hexanes eluent). 1H NMR (300 MHz, CDCl3):  0.01 (s, 9H), 0.92 (t, J = 8.3, 2H), 1.06 (s, 9H), 1.41 (s, 9H), 2.16-2.38 (m, 2H), 2.77- 2.88 (m, 1H), 3.52-3.65 (m, 2H), 3.75-3.85 (m, 3H), 3.91 (dd, J = 9.9, 5.9, 1H), 4.10-4.18 (m, 1H), 4.60-4.65 (m, 2H), 7.34-7.46 (m, 6H), 7.61-7.67 (m, 4H); 13C NMR (75 MHz, CDCl3):  −1.4, 18.0, 19.3, 23.6, 26.8, 27.9, 43.3, 56.9, 64.2, 65.1, 67.21, 82.8, 95.0, 127.7, 129.8, 133.1, 133.3, 135.5, 135.6, 150.0, 174.3; IR (film, cm-1):  1785, 1713; HRMS: calc. for C33H51NO6Na 28Si2 [M + Na] + 636.5153; found 636.3143.   104     Figure 22. 1H NMR spectrum of 234 Figure 23. 13C NMR spectrum of 234 105  A.8 Preparation of 235   Commercial BuLi solution (1.6 M/ hexanes, 13.4 mL, 21.4 mmol) was added to a solution of diisopropylamine (2.9 mL, 20.0 mmol) in THF (43 mL) at –78 °C, and the mixture was stirred for 15 min. Anhydrous EtOAc (2.0 mL, 20.4 mmol) was added (syringe), and stirring was continued for 1.5 hrs at the same temperature. A solution of 234 (6.1 g, 9.9 mmol) in THF (11 mL) was added over several minutes, resulting in a lemon-yellow solution. The mixture was warmed to –25 °C and stirring was continued for 1.5 hrs, at which time TLC indicated that starting material had been consumed. The reaction was quenched with sat. NH4Cl (aq) and stirring was continued as the mixture warmed to rt. The mixture was diluted with CH2Cl2, the layers were separated, and the aqueous phase was extracted with additional CH2Cl2. The combined organic extracts were dried (Na2SO4) and filtered, and the solvent removed under vacuum to give a clear oil that, being a mixture of isomers, was used in the next reaction without further purification. To a solution of the residue in EtOH (62 mL) at 0 °C was added NaBH4 (430 mg, 11.4 mmol). The solution was stirred until TLC monitoring indicated convergence to a single spot, about 40 min. Sat. NH4Cl (aq) was added (GAS EVOLUTION) and stirring continued for 15 min as the mixture was warmed to rt. The mixture was diluted with CH2Cl2, and washed with NH4Cl. The aqueous phase was extracted with more CH2Cl2, and the combined organic extracts were dried (Na2SO4), filtered and the solvent was removed under vacuum. Silica gel chromatography (20/80 to 25/75 EtOAc/hexanes gradient elution) gave 235 (4.8 g, 6.8 mmol, 69% yield over two steps), a colorless oil, as a 1:1 mixture of diastereomers. 1H NMR (300 MHz, CDCl3):  0.08 (s, 9H), 0.93 (brt, 2H), 1.07 (s, 9H), 1.27 (brt, 3H), 1.43 (s, 9H), 1.55-1.71 106  (m, 2H), 1.71-1.84 (m, 1H), 2.43-2.59 (m, 2H), 3.54-3.82 (m, 8H), 4.17 (brq, 3H), 4.63 (m, 3H), 7.34-7.47 (m, 6H), 7.61-7.68 (m, 4H); 13C NMR (75 MHz, CDCl3):  −1.4, 14.2, 18.0, 19.3, 26.9, 28.4, 28.6, 39.0, 39.5, 39.7, 49.9, 60.6, 65.4, 66.3, 66.6, 68.3, 70.2, 79.1, 95.1, 127.7, 129.8, 133.3, 135.6, 135.6, 155.7, 172.8 HRMS: calc. for C37H61NO8Na 28Si2 [M + Na] + 726.3833; found 726.3815.   107     Figure 24. 1H NMR spectrum of 235 Figure 25. 13C NMR spectrum of 235 108  A.9 Preparation of 236   A CH2Cl2 (26 mL) solution of 235 (2.5 g, 3.6 mmol), pyridine (3.3 mL, 42.1 mmol), Ac2O (3.9 mL, 44.0 mmol), and DMAP (53 mg, 0.4 mmol), was stirred overnight at rt, before being evaporated under vacuum. The residue was taken up in CH2Cl2, washed with 0.1 M HCl, dried (Na2SO4), filtered, and evaporated under vacuum. Flash chromatography (20/80 EtOAc/hexanes) of the residue gave 236 (2.60 g, 3.48 mmol, 96% yield), a 1:1 mixture of diastereomers, as a colorless oil. 1H NMR (300 MHz, CDCl3):  0.01 (s, 9H), 0.92 (brt, 2H), 1.07 (s, 9H), 1.24 (brt, 3H), 1.43 (s, 9H), 1.51-1.66 (m, 3H), 2.03 (brs, 3H), 1.93-2.12 (m, 1H), 2.53- 2.74 (m, 2H), 3.49-3.84 (m, 7H), 4.13 (brq, 2H), 4.61 (m, 2H), 5.34-5.44 (m, 1H), 7.35-7.47 (m, 6H), 7.60-7.68 (m, 4H); 13C NMR (75 MHz, CDCl3):  −1.4, 14.2, 18.0, 19.3, 21.0, 26.9, 28.4, 29.2, 36.6, 37.1, 38.2, 38.3, 49.6, 49.8, 60.6, 65.3, 66.2, 66.3, 66.5, 66.6, 71.3, 71.7, 79.2, 95.0, 95.1, 127.7, 129.8, 129.8, 133.2, 133.30, 135.56, 135.6, 155.5, 155.6, 169.9, 170.1, 170.6, 170.7; HRMS: calc. for C39H63NO9Na 28Si2 [M + Na] + 768.3939; found 768.3938.   109     Figure 26. 1H NMR spectrum of 236 Figure 27. 13C NMR spectrum of 236 110  A.10 Preparation of 238   To rapidly stirred TFA (3.9 mL) at rt was added a solution of 236 (166 mg, 0.22 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred at rt for 45 min before being diluted with CH2Cl2 and evaporated at ambient temperature. Periodic addition of CH2Cl2 during evaporation ensured removal of most of the TFA. The residue was taken up in more CH2Cl2 and washed with sat. NaHCO3 (aq). The organic layer was dried (Na2SO4), filtered, and stripped of volatiles under vacuum to leave a yellow-brown oil. The residue was dissolved in CH2Cl2 (5 mL) at rt with stirring and DBU (0.08 mL, 0.49 mmol) was added. The solution was stirred for 30 min before being evaporated under reduced pressure. The residue was loaded on reverse phase (C18) silica gel, washed with water, and eluted with EtOH to give a brownish oil. To a CH3CN (6.5 mL) solution of the residue at 0 °C was added formaldehyde (37% in water, 0.2 mL, 2.7 mmol). After 10 min stirring, NaBH3CN (181 mg, 2.87 mmol) was added, followed by the dropwise addition of AcOH (0.3 mL), and the mixture was stirred for 1 hour at rt. The reaction mixture was poured into sat. NaHCO3 (aq), and the pH was brought to 9 by the addition of sat. Na2CO3 (aq). Extraction with CH2Cl2 and drying (Na2SO4), filtration, concentration under vacuum, and column chromatography (35/65 EtOAc/Hexanes eluent) gave 238 (43 mg, 0.10 mmol, 45% yield over 3 steps) as a colorless oil. [α]D 20  −33.2 (c 0.5, EtOH); 1H NMR (300 MHz, CDCl3): δ 1.05 (s, 9H), 1.40-1.51 (m, 1H), 2.08-2.17 (m, 1H), 2.25 (s, 3H), 2.42-2.65 (m, 4H), 2.81-2.88 (m, 1H), 3.55 (dd, J = 10.2, 5.6, 1H), 3.77 (dd, J = 10.2, 5.0, 1H), 4.07 (dd, J = 11.4, 5.4, 1H), 4.18 (dd, J = 11.4, 4.4, 1H), 7.35-7.47 (m, 6H), 7.62-7.69 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 19.2, 26.8, 31.4, 34.6, 34.7, 39.1, 62.9, 66.5, 67.0, 69.3, 127.7, 129.7, 133.5, 133.6, 135.53, 111  135.6, 172.2; IR (film, cm-1): ν 1748; HRMS: calc. for C25H34NO3 28Si [M + H]+ 424.2308; found 424.2316.   112     Figure 28. 1H NMR spectrum of 238 Figure 29. 13C NMR spectrum of 238 113  A.11 Preparation of 246    To a solution of hexamethyldisilazane (75 µL, 0.35 mmol) in THF (0.8 mL) at −78 °C was added n-BuLi (1.6 M/ hexanes, 0.23 mL, 0.37 mmol) and the solution was stirred for 15 minutes, when 214 (146 mg, 0.32 mmol) was added as a solution in THF (0.5 mL), and stirring was continued for 40 minutes. Finally, ethyl 2-(phenylthio)acrylate 24576 (78 mg, 0.37 mmol) was added as a solution in THF (0.3 mL), and the temperature was maintained for 1.5 hours. The mixture was diluted with CH2Cl2 and poured into sat. NH4Cl (aq). The organic layer was separated, dried (Na2SO4), filtered, and stripped of solvent under vacuum. The residue was purified by column chromatography (25/75 EtOAc/Hexanes eluent) to give 246 (102 mg, 0.15 mmol, 48% yield) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.04 (s, 9H); 1.11-1.19 (m, 3H); 1.45 (s, 9H); 1.73-1.95 (m, 2H); 2.26-2.46 (m, 2H); 3.11-3.29 (m, 1H); 3.63-3.72 (m, 1H); 3.82-4.19 (m, 5H); 7.26-7.33 (m, 3H); 7.35-7.49 (m, 8H); 7.57-7.67 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 13.8, 14.0, 19.1, 26.8, 28.0, 28.9, 29.2, 33.3, 33.5, 39.6, 40.5, 48.5, 48.6, 56.9, 61.2, 61.2, 64.7, 64.8, 82.9, 127.8, 127.9, 128.0, 128.2, 128.9, 128.9, 129.9, 132.5, 132.6, 132.9, 133.2, 133.4, 133.7, 135.5, 135.5, 149.8, 171.8, 171.9, 175.8, 176.0; HRMS: calc. for C37H47NO6S 28SiNa [M + Na]+ 684.2791; found 684.2786.   114     Figure 30. 1H NMR spectrum of 246 Figure 31. 13C NMR spectrum of 246 115  A.12 Preparation of 251   To a solution of 25083 (4.91 g, 9.95 mmol) in THF (48 mL) and EtOH (0.9 mL) at rt was added LiBH4 (325 mg, 14.9 mmol). The mixture was stirred overnight, at which time a careful NH4Cl (aq) quench was performed (GAS EVOLUTION). The mixture was diluted with CH2Cl2 and washed with more NH4Cl (aq), and the organic extract was dried (Na2SO4), filtered, and concentrated under vacuum. The residue was pure 251 (4.85 g, 9.74 mmol, quant.), a colorless oil. [α]D 20   −20.5 (c 1.1, EtOH); 1H NMR (300 MHz, CDCl3): δ 1.08 (s, 9H); 1.43-1.50 (m, 10H); 1.52-1.78 (m, 2H); 1.93-2.07 (m, 1H); 2.07-2.22 (m, 1H); 3.47-3.67 (m, 3H); 3.67-3.77 (m, 1H); 3.90 (brs, 1H); 4.75 (brd, J = 8.5, 1H); 4.99-5.14 (m, 2H); 5.68-5.86 (m, 1H); 7.34-7.50 (m, 6H); 7.60-7.72 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 19.3, 26.9, 28.4, 34.4, 36.8, 50.1, 66.0, 66.5, 79.4, 116.5, 127.7, 129.8, 133.3, 135.6, 136.8, 156.2; IR (film, cm-1): ν 1499, 1693; HRMS: calc. for C29H44NO4 28Si [M + H]+ 498.3040; found 498.3044.   116     Figure 32. 1H NMR spectrum of 251 Figure 33. 13C NMR spectrum of 251 117  A.13 Preparation of 252   To a solution of 251 (6.89 g, 13.8 mmol) in CH2Cl2 (60 mL) at rt was added TBSCl (2.29 g, 15.2 mmol) and imidazole (1.12 g, 16.5 mmol), which generated a white precipitate. The mixture was stirred for 3 hours, at which time it was diluted with CH2Cl2 and washed with 0.1 M HCl (aq). The organic extract was dried (Na2SO4) filtered, and evaporated to give a colorless oil. To a solution of the residue in THF (67 mL) at rt was added BH3•THF (1 M/THF, 15.2 mL, 15.2 mmol). The resulting solution was stirred for 4.5 hours, when water was carefully added (GAS EVOLUTION) until gas evolution had ceased. Then a 1:1 solution of 1 M NaOH and 30% H2O2 (20 mL) was added, and the mixture was rapidly stirred overnight. After quenching with sat. NH4Cl (aq), partial evaporation was performed. The residue was diluted with CH2Cl2, washed with H2O, dried (Na2SO4), filtered, and concentrated. An analytical sample could be obtained by flash column chromatography (25/75 EtOAc/hexanes eluent), giving 252 as a colorless oil. [α]D 20 −22.3 (c 0.5, EtOH); 1H NMR (300 MHz, CDCl3): δ 0.03 (s, 3H); 0.04 (s, 3H); 0.88 (s, 9H); 1.07 (s, 9H); 1.25-1.38 (m, 1H); 1.39-1.51 (m, 11H); 1.50-1.64 (m, 4H); 3.49-3.83 (m, 7H); 4.78 (brd, J = 7.9, 1H); 7.34-7.49 (m, 6H); 7.61-7.72 (m, 4H); 13C NMR (75 MHz, CDCl3): δ −5.4, 18.3, 19.3, 25.9, 26.9, 27.3, 28.4, 29.9, 33.1, 36.8, 49.8, 63.1, 64.7, 66.2, 79.0, 127.7, 129.7, 133.4, 135.6, 155.6; IR (film, cm-1): ν 1698; HRMS: calc. for C35H60NO5 28Si2 [M + H] + 630.4010; found 630.4020.   118     Figure 34. 1H NMR spectrum of 252 Figure 35. 13C NMR spectrum of 252 119  A.14 Preparation of 253   To a solution of the residual 252 (13.8 mmol) in a mixture of CCl4 (28 mL), MeCN (28 mL) and H2O (39 mL) was added NaIO4 (11.7 g, 54.9 mmol) and RuCl3•xH2O (58 mg, ~0.28 mmol). The resultant darkly-colored suspension was subjected to rapid stirring for 1.5 hours, when CH2Cl2 and water were added, and the layers separated. The organic layer was dried (Na2SO4), decanted, and stripped of volatiles under vacuum. The residue was dissolved in Et2O, filtered through celite, and evaporated. Finally, the residue was filtered through a cake of silica gel (elution with 50/50 EtOAc/hexanes) to give a darkly-colored oil. The crude carboxylic acid was dissolved in MeCN (68 mL) and H2O (6.8 mL), to which was added PPTS (1.35 g, 5.37 mmol). The solution was stirred overnight before being partially evaporated, diluted with CH2Cl2 and washed with water. The organic layer was dried (Na2SO4), filtered, and evaporated. Flash column chromatography of the residue (40/60 EtOAc/hexanes eluent) gave 253 (4.30 g, 8.40 mmol, 61% over four steps) as a colorless oil. [α]D 20 −15.3 (c 0.5, EtOH); 1H NMR (300 MHz, CDCl3): δ 1.09 (s, 9H); 1.45 (m, 12H); 1.76-2.01 (m, 2H); 2.35-2.49 (m, 1H); 2.52-2.65 (m, 1H); 3.50-3.63 (m, 1H); 3.64-3.80 (m, 2H); 3.89-4.02 (m, 1H); 4.28-4.29 (m, 1H); 4.74 (brd, J = 8.1, 1H); 7.35-7.50 (m, 6H); 7.60-7.69 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 19.3, 25.6, 26.9, 28.4, 28.9, 29.6, 33.9, 49.4, 65.6, 73.0, 79.6, 127.9, 130.0, 132.9, 135.6, 155.5, 171.3; IR (film, cm-1): ν 1708, 1740; HRMS: calc. for C29H41NO5Na 28Si [M + Na]+ 534.2652; found 534.2646.   120    Figure 36. 1H NMR spectrum of 253 Figure 37. 13C NMR spectrum of 253 121  A.15 Preparation of 255   To a solution of diisopropylamine (2.26 mL, 16.1 mmol) in THF (80 mL) at −78 °C was added butyllithium (1.6 M/ hexanes, 10.6 mL, 16.9 mmol). The solution was stirred for 15 min at this temperature, when 253 (4.12 g, 8.05 mmol) was added as a solution in THF (12 mL), and stirring was continued for 1 hour at the same temperature. The solution was then cooled on an EtOH/LN2 bath (about −110 °C), before a solution of phenylselenyl bromide (3.80 g, 16.1 mmol) in THF (15 mL) pre-cooled to saturation (about −78 °C) was added as rapidly as possible. The resulting solution was stirred for an additional 5 min while the cold bath was maintained, at which time a solution of acetic acid (3.6 mL) in THF (3.6 mL) was added. The mixture was allowed to warm to room temperature with stirring. The resulting yellow mass was dissolved in sat. NH4Cl (aq) and CH2Cl2. After separation, the organic layer was washed successively with sat. NaHCO3 (aq) and sat. Na2S2O3 (aq) before drying (Na2SO4), filtration, and evaporation under vacuum gave a yellow oil. To a suspension of mCPBA (4.20 g, 77% maximum) in CH2Cl2 (68 mL) at −78 °C was added a solution of the residue in CH2Cl2 (21 mL). The mixture was stirred for 1.5 hours at −78 °C, when pyridine (3.5 mL) was added, and the resulting solution was allowed to warm to room temperature. The reaction mixture was poured into sat. NaHCO3 (aq) which had been previously brought to pH 9.5 with 1 M NaOH, and the layers were separated. The organic extract was washed with an additional portion of pH 9.5 NaHCO3 (aq), dried (Na2SO4), filtered through Celite, and evaporated. Flash column chromatography (30/70 EtOAc/hexanes eluent) of the residue gave 255 (2.40 g, 4.71 mmol, 58% yield) as an amorphous white solid, m.p. 121-122 °C. [α]D 20 +10.9 (c 0.5, EtOH); 1H NMR (300 MHz, CDCl3): δ 1.08 (s, 9H); 1.45 (s, 9H); 1.57-1.67 (m, 2H); 2.43-2.56 (m, 1H); 3.54-3.64 (m, 1H); 3.68-3.84 (m, 2H); 122  4.23 (dd, J = 11.3,5.8, 1H); 4.43 (dd, J = 11.3, 4.6, 1H); 4.72 (brd, J = 9.0, 1H); 5.98 (dd, J = 9.8, 1.5, 1H); 6.83 (dd, J = 9.8, 4.3, 1H); 7.35-7.49 (m, 6H); 7.59-7.67 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 19.3, 26.9, 28.4, 31.0, 33.0, 49.5, 66.0, 70.0, 79.7, 120.7, 127.9, 130.0, 132.9, 135.5, 150.2, 155.6, 163.8; IR (cm-1): 1510, 1699, 1720; HRMS: calc. for C29H39NO5Na 28Si [M + Na]+ 532.2495; found 532.2499.   123     Figure 38. 1H NMR spectrum of 255 Figure 39. 13C NMR spectrum of 255 124  A.16 Preparation of 232 from 255   To a solution of 255 (1.16 g, 2.27 mmol) in CH2Cl2 (12 mL) at rt was added TFA (1.2 mL, containing 1% v/v TFAA) and the solution was stirred overnight at rt. Na2CO3 (s) (500 mg, 4.7 mmol) was added followed by the careful dropwise addition of water (5 mL) (GAS EVOLUTION). The mixture was diluted with water and CH2Cl2, and the layers were separated. The organic layer was dried (Na2SO4), filtered, and evaporated to give 232, a faintly-colored oil. [α]D 20  –30.1 (c 1.1, EtOH); 1H NMR (300 MHz, CDCl3):  1.06 (s, 9H), 1.25-1.38 (m, 1H), 1.90- 1.99 (m, 1H), 2.51-2.60 (m, 2H), 2.68 (dd, J = 15.3, 5.4, 1H), 3.19-3.28 (m, 1H), 3.61 (dd, J = 10.1, 6.5, 1H), 3.69-3.77 (m, 2H), 4.08 (dd, J = 11.7, 5.2, 1H), 4.22 (dd, J = 11.6, 4.4, 1H), 7.35- 7.47 (m, 6H), 7.61-7.70 (m, 4H) 13C NMR (75 MHz, CDCl3):  19.2, 26.8, 30.8, 36.4, 36.5, 53.3, 59.9, 67.0, 69.2, 127.7, 129.7, 133.4, 133.5, 135.5, 135.6, 172.2; IR (film, cm-1):  1747; HRMS: calc. for C24H32NO3 28Si [M + H]+ 410.2151; found 410.2148.   125     Figure 40. 1H NMR spectrum of 232 Figure 41. 13C NMR spectrum of 232 126  A.17 Preparation of 238 from 232   To a solution of residual 232 (2.27 mmol) in MeCN (10 mL) was added formaldehyde (37% aq., 1.1 mL, 12.2 mmol) and NaBH3CN (830 mg, 13.2 mmol). After the mixture was cooled to 10 °C, AcOH (2.0 mL) was added dropwise over several minutes. Stirring was continued at rt for forty minutes, when the mixture was diluted with sat. NaHCO3 (aq) and CH2Cl2. The organic layer was separated, and the aqueous layer was extracted with a second portion of CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered, and evaporated. Flash column chromatography (35/65 EtOAc/hexanes eluent) gave 238 (651 mg, 1.54 mmol, 68% yield over two steps) as a colorless oil. Analytical data was identical to the material produced by the procedure reported above.   127  A.18 Preparation of 256   To a solution of 238 (32 mg, 0.076 mmol) in THF (1 mL) at rt was added H2O (0.2 mL) and LiOH•H2O (5 mg, 0.1 mmol). The mixture was stirred for 3 hours before being evaporated under reduced pressure, and co-evaporated once with toluene, to give a white foam. The residue was dissolved in 1:1 CH2Cl2:pyridine (1 mL) at −30 °C, to which was added TBSOTf (0.06 mL, 0.3 mmol). The solution was brought to rt, and stirring continued for 1.5 hours. The reaction mixture was poured into pH 7 phosphate buffer and extracted thrice with CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered, and stripped of solvent under vacuum. The residue, a colorless oil, was dissolved in 1:1 CH2Cl2:MeOH (1 mL) at rt, to which was cautiously added TMSCHN2 (2.0 M/hexanes, 0.15 mL, 0.30 mmol) (GAS EVOLUTION). After the addition was complete the yellow solution was stirred for 25 minutes, before the reaction was stripped of volatiles under reduced pressure. The residue was purified by column chromatography (15/85 EtOAc/hexanes eluent) to give 256 (28 mg, 0.049 mmol, 65% yield over three steps) as a colorless oil. [α]D 20 +5.2 (c 0.7, EtOH); 1H NMR (300 MHz, CDCl3): δ 0.01 (s, 6H); 0.87 (s, 9H); 1.06 (s, 9H); 1.25-1.39 (m, 1H); 1.97-2.10 (m, 1H); 2.27 (s, 3H); 2.29-2.63 (m, 4H); 2.88-2.98 (m, 1H); 3.38 (dd, J = 10.2, 6.6, 1H); 3.48 (dd, J = 10.2, 6.1, 1H); 3.60-3.74 (m, 5H); 7.34-7.46 (m, 6H); 7.66-7.73 (m, 4H); 13C NMR (75 MHz, CDCl3): δ −5.4, −5.4, 18.3, 19.2, 25.9, 26.8, 30.7, 35.0, 41.0, 41.5, 51.4, 63.9, 65.2, 67.1, 67.8, 127.6, 129.5, 133.8, 133.8, 135.6, 135.7, 173.2; IR (film, cm-1): ν 1740; HRMS: calc. for C32H52NO4 28Si2 [M + H] + 570.3435; found 570.3423.   128     Figure 42. 1H NMR spectrum of 256 Figure 43. 13C NMR spectrum of 256 129  A.19 Preparation of 259   To a solution of 238 (39 mg, 0.092 mmol) in THF (1.2 mL) at −78 °C was added NaHMDS (1 M/THF, 0.14 mL, 0.14 mmol), and the solution was stirred for 2 hours at the same temperature. A solution of di-tert-butyl azodicarboxylate (32 mg, 0.14 mmol) in THF (0.3 mL) was then added. Upon consumption of starting material (35 min, TLC), the reaction mixture was poured into sat. NaHCO3 (aq), when extraction proceeded with two portions of CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered, and evaporated. The crude material was purified by column chromatography (15/85 EtOAc/hexanes eluent) to give 259 (43 mg, 0.066 mmol, 72% yield), a colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.05 (s, 9H); 1.21-1.33 (m, 1H); 1.48 (apps, 18H); 2.04-2.21 (m, 1H); 2.33-2.49 (m, 4H); 2.50-2.63 (m, 1H); 2.81-2.96 (m, 1H); 3.54 (dd, J = 11.7, 5.1, 1H); 3.73 (dd, J = 11.7, 4.2, 1H); 4.04 (dd, J = 11.1, 4.5, 1H); 4.16 (appt, J = 11.4, 1H); 5.01 (brs, 1H); 6.67 (brs, 1H); 7.35-7.49 (m, 6H); 7.62-7.75 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 19.3, 26.8, 28.1, 28.2, 36.4, 39.0, 64.9, 65.7, 67.0, 69.7, 77.2, 80.9, 82.5, 127.7, 129.7, 133.5, 133.6, 135.6, 135.7, 155.0, 155.6, 155.7, 171.3; HRMS: calc. for C35H52N3O7 28Si [M + H]+ 654.3575; found 654.3585.   130     Figure 44. 1H NMR spectrum of 259 Figure 45. 13C NMR spectrum of 259 131  A.20 Preparation of 265   To a solution of 238 (628 mg, 1.48 mmol) in THF (12 mL) at −78 °C was added NaHMDS (0.6 M/ toluene, 3.0 mL, 1.8 mmol), and the solution was stirred for one hour at the same temperature. A solution of I2 in THF (100 mg/mL) was then added dropwise until the yellow-brown iodine color persisted (4.0 mL was needed). Stirring continued for 10 minutes, with additional iodine solution added as necessary to maintain the yellow/brown color, when the reaction was quenched by the sequential addition of sat. NH4Cl (aq) (6 mL) and sat. Na2S2O3 (aq) (4 mL). After warming to rt with continued stirring, the resulting white suspension was diluted with pH 7 phosphate buffer and extracted twice with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and stripped of volatiles under vacuum to give a colorless oil which was pure 265 (808 mg, 1.47 mmol, quantitative). [α]D 20 −16.3 (c 0.5, EtOH); 1H NMR (300 MHz, CDCl3): δ 1.05 (s, 9H); 1.61-1.74 (m, 1H); 2.10-2.22 (m, 1H); 2.31 (s, 3H); 2.45-2.56 (m, 1H); 2.56-2.70 (m, 1H); 3.32 (dd, J = 9.9, 1.5, 1H); 3.53 (dd, J = 10.3, 5.5, 1H); 3.72 (dd, J = 10.3, 5.0, 1H); 4.27 (d, J = 11.8, 1H); 4.31 (d, J = 1.4, 1H); 4.84 (dd, J = 11.8, 3.8, 1H); 7.35- 7.49 (m, 6H); 7.62-7.70 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 13.9, 19.2, 26.8, 32.7, 32.9, 39.8, 66.0, 66.4, 69.9, 71.2, 127.7, 129.7, 133.4, 133.5, 135.5, 135.6, 167.8; IR (film, cm-1): ν 1739; HRMS: calc. for C25H32NO3Na 28SiI [M + Na]+ 572.1094; found 572.1083.   132     Figure 46. 1H NMR spectrum of 265 Figure 47. 13C NMR spectrum of 265 133  A.21 Preparation of 266   To 265 (808 mg, 1.47 mmol) and NaN3 (350 mg, 5.4 mmol) was added DMF (8.0 mL), and the resulting suspension was stirred vigorously at rt for 35 minutes. The mixture was diluted with ethyl acetate and half-saturated brine and poured into pH 7 phosphate buffer. The layers were separated, and the aqueous layer was extracted several times with ethyl acetate. The combined organic layers were washed four times with brine, dried (Na2SO4), filtered, and evaporated under vacuum. Flash column chromatography (20/80 to 30/70 EtOAc/hexanes gradient elution) of the residue gave 266 (506 mg, 1.09 mmol, 74% yield) as a colorless oil. In addition, some 267 (33 mg, 0.07 mmol, 5% yield) was isolated. Analytical data for 266: [α]D 20 −29.9 (c 0.5, EtOH); 1H NMR (300 MHz, acetone-d6): δ 1.07 (s, 9H); 1.39-1.51 (m, 1H); 2.13- 2.24 (m, 1H); 2.44 (s, 3H); 2.65-2.81 (m, 3H); 3.63 (dd, J = 10.3, 5.3, 1H); 3.83 (dd, J = 10.3, 4.5, 1H); 4.13-4.22 (m, 1H); 4.34 (dd J = 11.3, 5.5, 1H); 4.48 (d, J = 7.0, 1H); 7.42-7.53 (m, 6H); 7.70-7.78 (m, 4H); 13C NMR (75 MHz, acetone-d6): δ 18.9, 26.4, 29.9, 35.4, 39.8, 63.5, 66.0, 67.6, 68.0, 68.9, 127.8, 129.8, 133.4, 135.5, 169.1; IR (film, cm-1): ν 1754, 2107; HRMS: calc. for C25H32N4O3Na 28Si [M + Na]+ 487.2141; found 487.2136.   134     Figure 48. 1H NMR spectrum of 266 Figure 49. 13C NMR spectrum of 266 135     Figure 50. NOE spectrum of 266, irradiation at 4.47 ppm 136  A.22 Preparation of 267   To a solution of 266 (365 mg, 0.79 mmol) in MeCN (8 mL) at −20 °C was added DBU (12 µL, 0.078 mmol) as a solution in CH2Cl2 (0.12 mL). The mixture was stirred for 2 hours at the same temperature before being diluted with CH2Cl2 and poured into sat. NaHCO3 (aq), the layers were separated, and the aqueous layer was extracted with additional CH2Cl2. After drying (Na2SO4), filtration, and removal of solvent under vacuum, the residue was purified by column chromatography (20/80 to 30/70 EtOAc/Hexanes gradient elution). The desired diastereomer 267 was isolated (178 mg, 0.38 mmol, 49% yield, 81% BRSM), along with some recovered 266 (145 mg, 0.31 mmol). Analytical data for 267: [α]D 20  −54.9 (c 0.5, EtOH); 1H NMR (300 MHz, CDCl3): δ 1.05 (s, 9H); 1.66-1.79 (m, 1H); 2.11-2.22 (m, 1H); 2.51 (s, 3H); 2.57-2.79 (m, 2H); 3.31 (dd, J = 10.3, 5.2, 1H); 3.51 (dd, J = 10.4, 6.0, 1H); 3.74 (dd, J = 10.4, 4.9, 1H); 3.93 (d, J = 5.1, 1H); 4.10-4.25 (m, 2H); 7.35-7.48 (m, 6H); 7.61-7.70 (m 4H); 13C NMR (75 MHz, CDCl3): δ 19.2, 26.8, 32.1, 36.1, 42.7, 61.0, 66.8, 67.3, 67.7, 127.7, 129.6, 129.7, 133.4, 133.6, 135.5, 135.6, 168.6; IR (film, cm-1): ν 1755, 2111; HRMS: calc. for C25H32N4O3Na 28Si [M + Na]+ 487.2141; found 487.2130.   137     Figure 51. 1H NMR spectrum of 267 Figure 52. 13C NMR spectrum of 267 138     Figure 53. NOE spectrum of 267, irradiation at 3.92 ppm 139  A.23 Preparation of 273   A solution of 266 (45 mg, 0.097 mmol) in EtOAc (1 mL) was flushed with argon before Pd/C (10%, 30 mg) was added, and the system was flushed with H2 gas. The mixture was stirred for 5 hours, then filtered through Celite and concentrated under vacuum. The residue was pure 273 (40 mg, 0.091 mmol, 94% yield), a colorless oil. [α]D 20 −31.3 (c 0.3, EtOH); 1H NMR (300 MHz, CDCl3): δ 1.06 (s, 9H); 1.22-1.34 (m, 1H); 1.67 (brs, 2H); 2.07-2.19 (m, 1H); 2.41-2.48 (m, 1H); 2.49 (s, 3H); 2.53-2.67 (m, 2H); 3.52-3.60 (m, 2H); 3.79 (dd, J = 10.5, 4.5, 1H); 4.05 (appt, J = 11.2, 1H); 4.23 (dd, J = 11.2, 5.6, 1H); 7.33-7.48 (m, 6H); 7.61-7.71 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 19.2, 26.8, 30.1, 36.0, 41.1, 56.6, 66.2, 68.3, 69.2, 70.9, 127.7, 129.6, 133.5, 135.6, 176.0; IR (film, cm-1): ν 1749; HRMS: calc. for C25H35N2O3 28Si [M + H]+ 439.2417; found 439.2425.   140     Figure 54. 1H NMR spectrum of 273 Figure 55. 13C NMR spectrum of 273 141  A.24 Preparation of 274   To a solution of 267 (249 mg, 0.54 mmol) in EtOAc (7 mL) was added Pd/C (10%, 80 mg), and the system was flushed with H2 gas. The mixture was stirred for 3.5 hours, filtered through Celite, and concentrated under vacuum. The residue was pure 274 (223 mg, 0.51 mmol, 95% yield), a colorless oil. [α]D 20 −66.1 (c 0.5, EtOH); 1H NMR (300 MHz, CDCl3): δ 1.05 (s, 9H); 1.60-1.74 (m, 1H); 1.89 (brs, 2H); 2.03-2.17 (s, 1H); 2.44 (s, 3H); 2.56-2.79 (m, 2H); 3.30 (dd, J = 10.4, 6.0, 1H); 3.43-3.52 (m, 2H); 3.72 (dd, J = 10.4, 4.9, 1H); 4.14-4.28 (m, 2H); 7.34- 7.48 (m, 6H); 7.61-7.71 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 19.2, 26.8, 31.7, 36.4, 44.1, 55.0, 66.6, 66.8, 67.2, 67.9, 127.7, 129.7, 133.5, 133.7, 135.5, 175.6; IR (film, cm-1): ν 1748; HRMS: calc. for C25H35N2O3 28Si [M + H]+ 439.2417; found 439.2413.   142     Figure 56. 1H NMR spectrum of 274 Figure 57. 13C NMR spectrum of 274 143  A.25 Preparation of 278   To a solution of 234 (1.21 g, 1.97 mmol) in THF (10 mL) and EtOH (0.2 mL) was added LiBH4 (86 mg, 3.94 mmol). The resulting suspension was stirred overnight at rt, when TLC monitoring indicated consumption of starting material. The mixture was quenched with sat. NH4Cl (aq) (GAS EVOLUTION!) and poured into additional sat. NH4Cl (aq). Extraction proceeded with two portions of CH2Cl2 and the combined organic extracts were dried (Na2SO4) and stripped of solvent under vacuum to give a colorless oil, which was carried on without further purification. To a solution of 800 mg of the residue in CH2Cl2 (16 mL) was added TESCl (0.23 mL, 1.4 mmol) and imidazole (95 mg, 1.4 mmol). The solution was stirred for 1 hour at rt before being diluted with CH2Cl2 and washed with 0.05 M HCl (aq). The organic extract was dried (Na2SO4) and stripped of solvent under vacuum to give pure 278 (885 mg, 1.95 mmol), a colorless oil. [α]D 20 −16.0 (c 0.5, CH2Cl2);  1H NMR (300 MHz, CDCl3): δ 0.01 (s, 9H); 0.60 (q, J = 7.8, 6H); 0.91-1.00 (m, 12H); 1.06 (s, 9H); 1.43 (s, 9H); 1.56-1.67 (m, 2H); 1.80-1.91 (m, 1H); 3.50-3.82 (m, 9H); 4.64 (s, 2H); 4.79-4.88 (m, 1H); 7.33-7.48 (m, 6H); 7.61-7.71 (m, 4H); 13C NMR (75 MHz, CDCl3): δ −1.4, 4.3, 6.8, 18.1, 19.3, 26.9, 28.4, 30.4, 38.5, 50.3, 63.7, 65.0, 66.3, 67.9, 78.8, 95.1, 127.7, 127.8, 129.7, 129.8, 133.4, 135.6, 135.6, 155.5; IR (film, cm-1): ν 1715; HRMS: calc. for C33H56NO6 28Si2 [M – SiEt3 + 2H] + 618.3646; found 618.3661.   144     Figure 58. 1H NMR spectrum of 278 Figure 59. 13C NMR spectrum of 278 145  A.26 Preparation of 279   To a solution of 278 (833 mg, 1.14 mmol) in THF (14 mL) at −40 °C was added BuLi (0.78 mL, 1.6 M/ hexanes, 1.25 mmol), and stirring was continued for 30 min as the solution warmed to −10 °C. Dimethyl sulfate (TOXIC) was then added and stirring continued until starting material was consumed (TLC, 1 hour). Water (2 mL) and PPTS (315 mg, 1.25 mmol) were then added and the solution was warmed to rt and left for 3 hours. The mixture was poured into sat. NaHCO3 (aq) and extracted with CH2Cl2. The organic extracts were dried (Na2SO4), filtered, and stripped of solvent under vacuum to give a colorless oil. To a solution of a portion of this material (65 mg, 0.1 mmol) in CH2Cl2 (1.4 mL) and DMSO (0.7 mL) was added triethylamine (0.07 mL, 0.50 mmol) and sulfur trioxide pyridine complex (64 mg, 0.40 mmol). The solution was stirred at rt for 1.5 hours, when TLC monitoring indicated consumption of starting material. The mixture was poured into 0.05 M HCl (aq) and extracted with additional CH2Cl2. The organic extract was dried (Na2SO4) and stripped of solvent under vacuum, and the residue was purified by column chromatography (20/80 EtOAc/Hexanes eluent) to give pure 279 (57 mg, 0.090 mmol), a colorless oil which existed as a rotameric mixture at rt. [α]D 20 −7.7 (c 0.6, CH2Cl2);  1H NMR (300 MHz, CDCl3): δ −0.04-0.05 (m, 9H); 0.87-0.98 (m, 2H), 0.98-1.10 (m, 9H); 1.21-1.54 (m, 10H); 1.82-1.96 (m, 1H); 2.38-2.57 (m, 1H); 2.59-2.81 (m, 3H); 3.49- 3.68 (m, 4H); 3.71-3.81 (m, 1H); 3.84-3.93 (m, 1H); 4.15-4.49 (m, 1H); 4.55-4.72 (m, 2H); 7.32- 7.48 (m, 6H); 7.59-7.70 (m, 4H); 9.69-9.72 (m, 1H); 1H NMR (300 MHz, DMSO-d6, 80 °C): δ 0.00 (s, 9H); 0.84-0.90 (m, 2H); 1.02 (s, 9H); 1.40 (s, 9H); 1.45-1.54 (m, 1H); 1.79-1.89 (m, 1H); 2.38-2.45 (m, 1H); 2.64 (s, 3H); 3.51-3.81 (m, 6H); 4.22 (m, 1H); 4.57 (s, 2H); 7.37-7.49 (m, 146  6H); 7.58-7.66 (m, 4H); 9.61 (s, 1H); 13C NMR (75 MHz, CDCl3): δ −1.4, 18.0, 19.2, 24.2, 26.8, 28.4, 49.0, 49.3, 64.2, 65.2, 65.3, 65.7, 79.4, 79.9, 95.0, 127.7, 128.4, 128.6, 129.7, 132.0, 132.0, 132.2, 133.3, 135.6, 156.0, 156.3, 202.7, 203.4; IR (film, cm-1): ν 1692, 1737; HRMS: calc. for C34H55NO6Na 28Si2 [M + H] + 652.3466; found 652.3464.       Figure 60. 1H NMR spectrum of 279 at 80 °C in DMSO-d6 147    Figure 61. 1H NMR spectrum of 279 (CDCl3, rt) Figure 62. 13C NMR spectrum of 279 148  A.27 Preparation of 281    Sn(OTf)2 method: To a solution of Sn(OTf)2 (260 mg, 0.62 mmol) in THF (2.4 mL) at −78 °C was added 1- ethylpiperidine (0.10 mL, 0.75 mmol) and a solution of 28090 (138 mg, 0.50 mmol) in THF (1 mL). The solution was stirred for 1.5 hours before 279 (313 mg, 0.50 mmol) was added as a solution in THF (0.8 mL). The solution was kept at −78 °C for three hours before being slowly warmed to −30 °C over two more hours. Finally, the mixture was diluted with CH2Cl2 and poured into sat. NH4Cl (aq). The organic layer was separated, dried (Na2SO4) and stripped of solvent under vacuum. The residue was purified by column chromatography (30/70 EtOAc/Hexanes eluent) to give 281 (182 mg, 0.20 mmol, 40% yield), a colorless oil which existed as a rotameric mixture at rt. [α]D 20   −36.8 (c 1.6, CH2Cl2);  1H NMR (300 MHz, DMSO- d6, 80 °C): δ 0.00 (s, 9H); 0.85-0.92 (m, 2H); 1.03 (s, 9H); 1.25-1.35 (m, 1H); 1.39 (s, 9H); 1.62- 1.70 (m, 1H); 2.00-2.09 (m, 1H); 2.67 (s, 3H); 2.94 (dd, J = 10.2, 6.0, 1H); 3.05 (s, 2H); 3.11 (dd, J = 10.2, 2.4, 1H); 3.45-3.54 (m, 1H); 3.54-3.71 (m, 5H); 4.19-4.27 (m, 2H); 4.40 (m, 1H); 4.57 (s, 2H); 4.66-4.73 (m, 1H); 5.14-5.19 (m, 1H); 5.35 (d, J = 3.3, 1H); 7.21-7.36 (m, 5H); 7.39-7.48 (m, 6H); 7.59-7.66 (m, 4H); 9.99 (s, 1H); 13C NMR (75 MHz, CDCl3, rt): δ −1.4, 18.1, 19.2, 25.0, 26.8, 28.4, 28.5, 37.6, 38.8, 38.9, 55.3, 61.2, 64.1, 65.9, 66.1, 67.5, 79.4, 80.0, 84.0, 85.0, 95.3, 127.8, 129.2, 129.4, 129.8, 129.9, 133.1, 133.3, 134.0, 134.1, 135.5, 135.6, 153.7, 149  156.2, 156.4, 165.9, 166.1, 188.3, 188.4; IR (film, cm-1): ν 1689, 1782; HRMS: calc. for C38H60N2O8S 28Si2Na [M + Na] + 783.3507; found 783.3508. NOTE: The molecular ion calculated for this material was the product of methanolysis of the imide according to the following scheme:   TiCl4 method: To a solution of 28090 (27 mg, 0.10 mmol) in CH2Cl2 (0.6 mL) at −78 °C was added TiCl4 (1 M/CH2Cl2, 0.10 mL, 0.1 mmol), followed 15 minutes later by iPr2NEt (19 µL, 0.11 mmol) (a deep purple color appeared) and after an additional 25 minutes, NMP (10 µL, 0.10 mmol). The mixture was stirred for 30 minutes before 279 (61 mg, 0.10 mmol) was added as a solution in CH2Cl2 (0.5 mL). The reaction mixture was warmed to −35 °C, which was maintained for 1.5 hours. The mixture was diluted with CH2Cl2 and poured into water. The organic layer was separated, dried (Na2SO4), filtered, and stripped of solvent under vacuum. The residue was purified by column chromatography (30/70 EtOAc/Hexanes eluent) to give 281 (43 mg, 0.05 mmol, 49% yield), a colorless oil. This material was identical to that obtained using the Sn(OTf)2 method described above. 150      Figure 63. 1H NMR spectrum of 281 at 80 °C in DMSO-d6 151    Figure 64. 1H NMR spectrum of 281 (CDCl3, rt) Figure 65. 13C NMR spectrum of 281 152  A.28 Preparation of 283   To a solution of 274 (49 mg, 0.11 mmol) in MeOH (1 mL) was added o-anisaldehyde (15 µL, 0.12 mmol), acetic acid (13 µL, 0.12 mmol), TiCl4 (1 M/ CH2Cl2, 0.11 mL, 0.11 mmol), and tert-butyl isocyanide (13 µL, 0.12 mmol), and the solution was stirred overnight at rt. After quenching with pH 7 phosphate buffer, the mixture was diluted with EtOAc, poured into water, and the layers separated. The organic extract was dried (Na2SO4), filtered, and evaporated. The residue was purified by column chromatography (25/75 to 30/70 EtOAc/hexanes gradient elution) to give 283 (11 mg), a faintly yellow oil. Compound 282 (7 mg, 0.03 mmol, 27%), a colorless oil, was also recovered. Analytical data for 283: [α]D 20 −15.1 (c 0.4, EtOH); 1H NMR (300 MHz, CDCl3): δ 1.07 (s, 9H); 1.49-1.57 (m, 1H)*; 2.05-2.15 (m, 1H); 2.50-2.55 (m, 4H); 2.93-3.05 (s, 1H); 3.48-3.63 (m, 3H); 3.76 (s, 3H); 3.89 (dd, J = 9.9, 4.9, 1H); 5.90 (d, J = 2.6, 1H); 7.35-7.48 (m, 6H); 7.63-7.72 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 19.2, 26.0, 26.9, 36.1, 39.0, 52.0, 60.7, 65.0, 66.5, 117.6, 127.7, 129.7, 133.5, 135.6, 141.2, 166.0; IR (film, cm-1): ν 1724; HRMS: calc. for C26H35NO4Na 28Si [M + Na]+ 476.2233; found 476.2234. *  Approximate value   153     Figure 66. 1H NMR spectrum of 283 Figure 67. 13C NMR spectrum of 283 154  A.29 Data for 282    Colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.40 (s, 9H); 3.32 (s, 3H); 3.85 (s, 3H); 4.90 (s, 1H); 6.71 (brs, 1H); 6.88-7.00 (m, 2H); 7.20-7.34 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 28.8, 50.8, 55.7, 57.0, 78.9, 111.2, 120.7, 126.0, 128.9, 129.7, 158.0, 170.0; IR (film, cm-1): ν 1678; HRMS: calc. for C14H22NO3 [M + H] + 252.1600; found 252.1601.   155    Figure 68. 1H NMR spectrum of 282 Figure 69. 13C NMR spectrum of 282 156  A.30 Procedure for hydrolysis of 274 and Ugi condensation: preparation of 297    To a solution of 274 (545 mg, 1.24 mmol) in THF (14.5 mL) at −5 °C was added KOH (aq) (0.5 M, 3.0 mL, 1.5 mmol) and water (3.0 mL). The resulting suspension was stirred, keeping the temperature between −5 and 0 °C, for 5 hours, when starting material was consumed (TLC). The mixture was evaporated to dryness under vacuum, giving crude 292 as a foamy, off- white solid. To a solution of the residue in MeOH (7.8 mL) at rt were added 2-methoxy-5- benzyloxybenzaldehyde (330 mg, 1.36 mmol) and TiCl4 (neat, 0.09 mL, 0.8 mmol). The solution was stirred for 5 min, when tert-butylisocyanide (0.17 mL, 1.49 mmol) was added. Stirring was continued for 24 hours, at which time the reaction was quenched by the dropwise addition of a pH 7 phosphate buffer solution (5 mL). The reaction mixture was diluted with EtOAc and water, the layers were separated, and the aqueous layer was extracted with two additional portions of EtOAc. The combined organic extracts were dried (Na2SO4), filtered through celite, and evaporated. Flash column chromatography of the residue (30/70 to 45/55 EtOAc/hexanes gradient elution) gave 297, a faintly yellow foam (247 mg, 0.32 mmol, 26% yield over two steps). [α]D 20 +6.7 (c 0.5, EtOH); 1H NMR (300 MHz, CDCl3): δ 1.06 (s, 9H); 1.31 (s, 9H); 1.39- 1.55 (m, 1H); 2.04-2.17 (m, 1H); 2.24 (s, 3H); 2.50-2.68 (m, 2H); 2.90-3.00 (m, 1H); 3.06-3.22 (m, 2H); 3.49 (dd, J = 10.2, 6.3, 1H); 3.72-3.82 (m, 4H); 4.13 (dd, J = 11.4, 4.2, 1H); 4.25 (dd, J = 11.4, 4.7, 1H); 4.54 (brs, 1H); 5.04 (s, 2H); 6.76-6.83 (m, 2H); 6.83-6.89 (m, 1H); 7.13-7.18 (m, 1H); 7.28-7.49 (m, 10H); 7.63-7.72 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 19.2, 26.8, 28.7, 157  32.3, 35.6, 41.8, 50.6, 55.7, 58.2, 60.2, 66.8, 67.2, 67.9, 68.2, 70.4, 111.9, 114.9, 115.8, 127.4, 127.7, 127.8, 128.5, 128.9, 129.7, 133.5, 135.5, 137.3, 151.3, 153.0, 170.7, 172.8; IR (film, cm- 1): ν 1679, 1748; HRMS: calc. for C45H58N3O6 28Si [M + H]+ 764.4095; found 764.4089.   158      Figure 70. 1H NMR spectrum of 292 (methanol-d4) 159    Figure 71. 1H NMR spectrum of 297 Figure 72. 13C NMR spectrum of 297 160  A.31 Data for 293     Prepared according to the procedure of 297. 30% yield of a colorless oil. [α]D 20 +10.1 (c 0.5, EtOH); 1H NMR (300 MHz, CDCl3): δ 1.05 (s, 9H); 1.31 (s, 9H); 1.35-1.53 (m, 1H); 2.04- 2.18 (m, 4H); 2.51-2.69 (m, 2H); 3.02 (dd, J = 10.5, 5.3, 1H); 3.11-3.19 (m, 1H); 3.21-3.29 (m, 1H); 3.49 (dd, J = 10.2, 6.3, 1H); 3.70-3.78 (m, 4H); 4.19 (dd, J = 11.2, 4.7, 1H); 4.33 (dd, J = 11.2, 6.0, 1H); 4.50 (d, J = 6.2, 1H); 6.76-7.00 (m, 3H); 7.20-7.29 (m, 1H); 7.32-7.48 (m, 7H); 7.59-7.71 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 19.2, 26.8, 28.7, 32.4, 35.3, 41.2, 50.6, 55.1, 58.0, 60.6, 66.6, 67.2, 67.9, 68.6, 110.6, 120.9, 127.6, 128.8, 129.5, 129.7, 133.4, 133.5, 135.5, 156.9, 170.9, 172.7; IR (film, cm-1): ν 1679, 1747; HRMS: calc. for C38H52N3O5 28Si [M + H]+ 658.3676; found 658.3680.   161    Figure 73. 1H NMR spectrum of 293 Figure 74. 13C NMR spectrum of 293 162  A.32 Data for 300   Prepared according to the procedure of 297. 14% yield of a white foam. [α]D 20 +10.5 (c 0.9, EtOH); 1H NMR (300 MHz, CDCl3): δ 1.05 (s, 9H); 1.38 (m, 11H); 1.62-1.73 (m, 2H); 1.95-2.08 (m, 1H); 2.11-2.26 (m, 1H); 2.43-2.55 (m, 1H); 2.79-2.86 (m, 1H); 3.29-3.45 (m, 3H); 3.50-3.64 (m, 5H); 3.74-3.82 (m, 4H); 4.91 (s, 1H); 6.70-6.77 (m, 1H); 6.80-6.89 (m, 1H); 7.03- 7.18 (m, 2H); 7.35-7.49 (m, 6H); 7.62-7.71 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 19.2, 26.8, 28.6, 28.7, 30.6, 39.0, 41.9, 50.8, 52.3, 55.4, 57.5, 62.5, 62.8, 65.8, 67.6, 68.8, 110.4, 124.8, 127.1, 127.7, 127.8, 129.7, 129.8, 133.4, 133.5, 135.5, 135.6, 158.3, 170.1, 173.1; IR (film, cm- 1): ν 1677, 1740; HRMS: calc. for C39H55 79BrN3O6Si [M + H] + 768.3044; found 768.3026.   163     Figure 75. 1H NMR spectrum of 300 Figure 76. 13C NMR spectrum of 300 164  A.33 Data for 298    Prepared according to the procedure of 297. 32% yield of a faintly yellow oil. [α]D 20 −9.8 (c 0.3, EtOH); 1H NMR (300 MHz, CDCl3): δ 1.04 (s, 9H); 1.50-1.66 (m, 1H); 2.05-2.17 (m, 1H); 2.24 (s, 3H); 2.55-2.68 (m, 2H); 3.03 (dd, J = 10.3, 5.2, 1H); 3.15-3.27 (m, 2H); 3.49 (dd, J = 10.1, 6.2, 1H); 3.70-3.83 (m, 8H); 4.17 (dd, J = 11.4, 3.9, 1H); 4.27 (dd, J = 11.4, 4.1, 1H); 4.75 (d, J = 4.7, 1H); 5.03 (brs, 2H); 6.80-6.91 (m, 4H); 7.16-7.21 (m, 1H); 7.29-7.48 (m, 14H); 7.61-7.68 (m, 4H); 8.92 (brs, 1H); 13C NMR (75 MHz, CDCl3): δ 19.2, 26.8, 29.7, 32.1, 35.8, 42.3, 55.5, 56.1, 58.4, 60.3, 66.8, 67.1, 68.0, 70.4, 112.1, 114.0, 115.1, 115.9, 121.0, 127.5, 127.7, 127.8, 128.2, 128.5, 129.7, 131.4, 133.4, 133.6, 135.5, 135.6, 137.1, 151.2, 153.1, 156.0, 169.4, 173.1; IR (film, cm-1): ν 1682, 1745; HRMS: calc. for C48H56N3O7 28Si [M + H]+ 814.3888; found 814.3881.   165     Figure 77. 1H NMR spectrum of 298 Figure 78. 13C NMR spectrum of 298 166  A.34 Procedure for hydrolysis of 273 and Ugi condensation: preparation of 294    To a solution of 273 (57 mg, 0.13 mmol) in THF (1.0 mL) and H2O (0.2 mL) was added LiOH•H2O (7 mg, 0.2 mmol), and the resulting suspension was stirred at rt. Following consumption of starting material (TLC, 4 hours), volatiles were removed under vacuum, and co- evaporation with MeOH was performed, giving crude 291 as a foamy white solid. To a solution of the residue in MeOH (0.8 mL) at rt was added o-anisaldehyde (17 µL, 0.14 mmol), TiCl4 (1 M/CH2Cl2, 0.08 mL, 0.08 mmol), and tert-butylisocyanide (17 µL, 0.15 mmol). The yellow- colored solution was stirred overnight, when dropwise addition of pH 7 phosphate buffer was performed. The mixture was poured into more pH 7 phosphate buffer, and extraction proceeded with three portions of EtOAc. The combined organic extracts were dried (Na2SO4), filtered through celite, and evaporated. Flash column chromatography of the residue (40/60 to 50/50 EtOAc/hexanes gradient elution) gave 294 (33 mg, 0.051 mmol, 39% yield), a colorless oil. [α]D 20 −36.3 (c 0.5, EtOH); 1H NMR (300 MHz, CDCl3): δ 1.02 (s, 9H); 1.30 (s, 9H); 2.03-2.16 (m, 1H); 2.24 (s, 3H); 2.49-2.63 (m, 2H); 3.23-3.29 (d, J = 4.9, 1H); 3.43 (dd, J = 9.5, 5.8, 1H); 3.68 (dd, J = 10.0, 4.6, 1H); 3.83 (s, 3H); 3.98 (dd, J = 11.5, 7.1, 1H); 4.63 (s, 1H); 4.45 (dd, J = 11.1, 4.5, 1H); 6.55 (s, 1H); 6.85-6.97 (m, 2H); 7.21-7.26 (m, 2H); 7.31-7.46 (m, 6H); 7.56-7.69 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 19.2, 26.8, 28.7; 30.9; 31.1, 35.4, 40.7, 50.8, 55.4, 60.1, 60.3, 66.5, 67.9, 68.7, 69.7, 110.9, 121.1, 127.6, 128.8, 129.3, 129.7, 133.5, 135.5, 156.8, 171.0, 167  173.0; IR (film, cm-1): ν 1679, 1748; HRMS: calc. for C38H52N3O5 28Si [M + H]+ 658.3676; found 658.3683.  168      Figure 79. 1H NMR spectrum of 291 (methanol-d4) 169     Figure 80. 1H NMR spectrum of 294 Figure 81. 13C NMR spectrum of 294 170  A.35 Data for 299    Prepared according to the procedure of 294. 26% yield of a faintly yellow oil. [α]D 20 −45.5 (c 0.2, EtOH); 1H NMR (300 MHz, CDCl3): δ 1.03 (s, 9H); 1.23-1.35 (m, 1H); 2.05-2.17 (m, 1H); 2.27 (s, 3H); 2.54-2.65 (m, 3H); 3.36 (brd, J = 4.4, 1H); 3.42 (dd, J = 10.2, 6.1, 1H); 3.69 (dd, J = 10.6, 4.8, 1H); 3.78 (s, 3H); 3.82 (s, 3H); 3.96-4.05 (m, 1H); 4.35 (m, 1H); 4.78 (brs, 1H); 4.93-5.02 (m, 2H); 6.79-6.89 (m, 4H); 7.10 (brd, J = 2.6, 1H); 7.27-7.49 (m, 14H); 7.59-7.68 (m, 4H); 8.88 (brs, 1H); 13C NMR (75 MHz, CDCl3): δ 19.2, 26.8, 30.8, 35.9, 40.9, 55.5, 56.2, 60.5, 61.3, 66.5, 68.1, 68.9, 69.8, 70.5, 112.3, 114.0, 115.0, 116.4, 121.1, 127.5, 127.7, 127.9, 128.1, 128.5, 129.7, 131.4, 133.4, 133.5, 135.5, 137.0, 151.1, 153.2, 156.0, 169.7, 173.7; IR (film, cm-1): ν 1684, 1746; HRMS: calc. for C48H56N3O7 28Si [M + H]+ 814.3888; found 814.3906.   171     Figure 82. 1H NMR spectrum of 299 Figure 83. 13C NMR spectrum of 299 172  A.36 Preparation of 322   To a solution of 297 (17 mg, 0.022 mmol) in CH2Cl2 at −78 °C was added Dibal (1 M/ hexanes, 0.05 mL, 0.05 mmol), and the solution was stirred for 1 hour. Additional Dibal solution (0.02 mL) was added, and the reaction was slowly warmed to −50 °C over 1 hour, when starting material was found to be consumed (TLC). Ethyl acetate (0.05 mL) was added, and after 5 minutes, sat. Rochelle’s salt (aq) was added, whereupon stirring continued as the mixture warmed to rt. The mixture was diluted with CH2Cl2, poured into sat. NaHCO3 (aq), and the layers were separated. The aqueous layer was extracted with additional CH2Cl2, and the combined organic layers were dried (Na2SO4), filtered, and stripped of solvent under vacuum. To a solution of the residue in EtOH (1 mL) was added Pd(OH)2/C (5%, 50-70% H2O, 12 mg), and the reaction vessel was flushed with H2. The suspension was stirred overnight at rt, when it was filtered over a pad of Celite. After volatiles were removed under vacuum, pure 322 (13 mg, 0.019 mmol, 86% yield), was obtained as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.06 (s, 9H); 1.21-1.31 (m, 1H); 1.38 (s, 9H); 1.86-2.02 (m, 2H); 2.25-2.36 (m, 1H); 2.44 (s, 3H); 2.48- 2.59 (m, 1H); 2.73-2.80 (m, 1H); 2.91-2.97 (m, 1H); 3.41-3.81 (m, 6H); 4.26 (brd, J = 5.7, 1H); 5.09 (brs, 1H); 6.50-6.69 (m, 3H); 7.33-7.48 (m, 6H); 7.59-7.70 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 19.2, 26.8, 28.4, 28.6, 37.7, 42.8, 50.9, 56.2, 57.6, 59.8, 61.4, 66.5, 68.0, 69.0, 77.2, 93.9, 112.4, 115.5, 116.8, 127.8, 128.9, 129.8, 133.2, 135.6, 150.5, 172.3; HRMS: calc. for C38H54N3O6 28Si [M + H]+ 676.3782; found 676.3777.   173     Figure 84. 1H NMR spectrum of 322 Figure 85. 13C NMR spectrum of 322 174  A.37 X-ray Crystallography Data for 293  Empirical Formula C38H53N3O5.5SiCl Formula Weight 703.37 Crystal Color, Habit colorless, needle Crystal Dimensions 0.06 X 0.08 X 0.30 mm Crystal System orthorhombic Lattice Type primitive Lattice Parameters a = 11.6026(4) Å  b = 12.6325(4) Å  c = 26.3107(9) Å   = 90o   = 90o   = 90o  V = 3856.4(2) Å3  Space Group P 212121  (#19) Z value 4 Dcalc 1.211 g/cm3 F000 1508.00 (Mo-K) 1.76 cm-1 Data Images 1980 exposures @ 30.0 seconds Detector Position 40.10 mm 2max 52.1o No. of Reflections Measured Total: 134603 Residuals (refined on F2, all data): R1; wR2 0.040; 0.080 Goodness of Fit Indicator 1.08 No. Observations (I>2.00(I)) 7036 Residuals (refined on F): R1; wR2 0.035; 0.079  URL: https://www2.chem.ubc.ca/local/resource/xrdb/member.php; Data set mc048 

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