Studies Toward the Total Synthesis of Subincanadine E

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Graduate College Dissertations and Theses Dissertations and Theses

2015 Studies Toward The otT al Synthesis Of Subincanadine E Corinne Marie Sadlowski University of Vermont, [email protected]

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Recommended Citation Sadlowski, Corinne Marie, "Studies Toward The otT al Synthesis Of Subincanadine E" (2015). Graduate College Dissertations and Theses. Paper 343.

This Dissertation is brought to you for free and open access by the Dissertations and Theses at ScholarWorks @ UVM. It has been accepted for inclusion in Graduate College Dissertations and Theses by an authorized administrator of ScholarWorks @ UVM. For more information, please contact [email protected]. STUDIES TOWARD THE TOTAL SYNTHESIS OF SUBINCANADINE E

A Dissertation Presented

Corinne Marie Sadlowski

The Faculty of the Graduate College

The University of Vermont

In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Specializing in Chemistry

May, 2015

Defense Date: December 3, 2014 Dissertation Examination Committee:

Stephen P. Waters, Ph.D., Advisor Christopher D. Huston, M.D., Chair Matthias Brewer, Ph.D. Rory Waterman, Ph.D. Cynthia J. Forehand, Ph.D., Dean of the Graduate College

Abstract

Progress towards a concise total synthesis of subincanadine E is reported. This natural product was first isolated from the Picralima nitida cell suspension culture line in 1982 under the name pericine and later in 2002 from Aspidosperma subincanum as subincanadine E. It is the most potent compound of its class with in vitro cytotoxicity against both murine lymphoma L1210 and human epidermoid carcinoma KB cells (LD50, 0.3 µg/mL and 4.4 µg/mL, respectively) and was found to be six times more potent than 3 codeine as an opiate agonist in a H-naloxone binding study (IC50, 0.6 µmol/L). The first-generation synthesis produced an undesired internal olefin that, upon attempted isomerization, catalyzed an unusual intermolecular Diels-Alder reaction. A revised second-generation synthesis employed (±)-harmicine and showcased an intramolecular Pd-catalyzed cross-coupling reaction that furnished an unanticipated 5- membered ring instead of the predicted 6-membered ring via methylene linker activation. Further studies utilizing an amide intermediate and organocuprate chemistry produced no desired carbon-carbon bond formation. A third-generation synthesis was carried out from enantiopure (S)-carvone. This route explored regioselective oxime formation and protecting group manipulations for a subsequent Beckmann rearrangement, which provided the first access to 5-amino derivatives of carvone. An intramolecular Pd-catalyzed cross-coupling reaction was performed to construct the aza-bicycle prior to indole installation. Contingent on its success, indole introduction and a double alkylation would provide an akuammicine-like scaffold that can ring-open upon hydride exposure to afford (15S)-subincanadine E in 16 overall steps. This work accomplished 10 steps toward the first total asymmetric synthesis of (15S)-subincanadine E.

Dedication

To my Brother, Evan Sadlowski, for being my motivation to work harder and accomplish more. Any obstacle encountered in my career I endured merely because you have served as an inspiration for persistence through adversity. I admire your strength and aspire to be as dedicated and diligent as you.

ii Table of Contents

Dedication.………………..………....…………………………………………………. .ii

List of Figures………………………………………………………………...…...... vi

List of Schemes………………………………………………………………...... xiii

List of Tables….…...……………………………………...………………………… xviii

Chapter 1: First-Generation Synthesis: Construction of the !-

Carboline…..….………….……………………………………………………………... 1

1.1 Introduction……..……………………...…………………………...... 1

1.2 Previous total syntheses………………...... ……...……………....……...... 6

1.2.1 Synthesis of (±)-subincanadine E……………………………………6

1.2.2 Synthesis of (+)-, (")- and (±)-conolidine…………………………...9

1.2.3 Synthesis of (±)-, and (+)-subincanadine F……………………...... 12

1.2.4 Synthesis of (")-subincanadine A and B………...……….....……. 18

1.2.5 Synthesis of (±)-apparicine...…...………..…………...……...... 20

1.3 Biomimetic extension to other natural products….………...... ……...……... 23

1.4 Retrosynthetic analysis……….…...... ………………….……………....…….28

1.5 Forward route…………...... ……...….……………………………………… 29

1.5.1 Isomerization efforts...…...………..……………...…...……...…… 33

CHAPTER 2: Second-Generation Synthesis: Exploration of an enolate-driven Pd- catalyzed coupling reaction……………………………………………….…….……...37

2.1 Retrosynthetic analysis………………………...……………….…….………37

2.2 Forward route………….…………………….……………………….……… 38

2.2.1 Enolate-mediated Pd-catalyzed cross-coupling precedent.…...... 43

iii 2.3 Coupling results……………………….…….…………………..…….…….. 49

2.3.1 Control experiments….…...……….………………….…….……... 54

2.3.2 Proposal of mechanism……...……….…………………..….…….. 56

2.4 Further Studies……………………….…….………………….…….…...….. 60

2.4.1 Amide synthesis……………………..……………….…….…...... 62

2.4.2 Conjugate addition………………………………..………….……. 64

2.4.3 Intramolecular enolate addition to 2-oxobutanamide..………...... 71

2.4.4 Intramolecular enolate addition to ethyl-2-oxoacetate………...... 76

2.4.5 Intermolecular enolate-driven Pd-catalyzed cross-

coupling…...... 80

2.4.6 Control reactions………………………………………….……...... 82

CHAPTER 3: Third-Generation Synthesis: Enatioselective Synthesis from (S)-Carvone via the Beckmann Rearrangement……...……….………….…....……………………… 85

3.1 Introduction………….………………………….……….…………………... 85

3.2 Retrosynthetic analysis……………………………………………………… 87

3.3 Previous employment of carvone………………...………….………………. 89

3.3.1 Total synthesis of hapalindole Q and (－)-12-epi-fischerindole U

isothiocyanate…….………………………….…………………………...91

3.3.2 Total synthesis of N-methylwelwitindolinone C isocyanate……….93

3.3.3 Chiral [2.2.2] dienes from carvone……..……………..…….…...... 94

3.4 Forward route: oxidation of carvone………………….……………….…….. 95

3.5 Regioselective oxime formation………………….…………………………. 98

3.6 Exploration of protecting group strategies………………….……………….. 99 iv 3.7 Oxime formation via reduction of the enone………………………………. 105

3.8 Beckmann rearrangement………………….……………………….....…… 108

3.9 Alkylation……………….………………………………...……….....……. 113

3.10 Deacetylation……………….………………………………...... ……. 115

3.11 Reduction to ethylamine and reductive amination……………….……….. 119

3.12 Pd-Catalyzed Coupling………………………………………………….... 122

3.13 End-game strategy……………….…………………...... ………………123

3.14 Summary……………….……………………...…………………………...126

CHAPTER 4: Experimental Procedures……………...……….………….…....………. 127

4.1 Methods and materials……………….………………………..………...... 127

4.2 Experimental procedures for the first-generation synthesis……...………… 129

4.3 Experimental procedures for the second-generation synthesis…...………... 136

4.4 Experimental procedures for the third-generation synthesis…...……...... 176

Appendix 1: Spectroscopic Data……………..………...……….………….…...... 196

List of Abbreviations…………………………………...……….………….…...... 329

Bibliography…………………………………..………...……….………….…...... 334

Index…………………………………..………...……….………….……….…....…….353

v List of Figures

Figure 1.1 Structures of subincanadines A-G………………………………………….. 2

Figure 1.2 Indole alkaloids of the pericine type………………………………………... 3

Figure 1.3 (±)-17-nor-subincanadine E.………………………………………………...5

Figure 1.4 Resultant RCM products of compound 61……………………………...... 22

Figure 1.5 1H NMR spectrum of attempted acid-induced isomerization……………... 35

Figure 2.6 Conformation of 113, 119, 142, and their respective enolates……………. 58

Figure 2.7 Predicted intermediates resulting from the hydroboration of

Compound 187……………………………………………………………....…………80

Figure 3.8 Recent natural products synthesized from carvone………………………. 90

1 Figure A.1: H NMR Spectrum of 92 in CDCl3…………………………………….. 196

13 Figure A.2: C NMR Spectrum of 92 in CDCl3………………………………….… 197

1 Figure A.3: H NMR Spectrum of 91 in CDCl3…………………………………….. 198

13 Figure A.4: C NMR Spectrum of 91 in CDCl3……………………………………. 199

1 Figure A.5: H NMR Spectrum of 97b in CDCl3………………………………….... 200

13 Figure A.6: C NMR Spectrum of 97b in CDCl3……………………………….….. 201

1 Figure A.7: H NMR Spectrum of 97a in CDCl3……………………………….…... 202

13 Figure A.8: C NMR Spectrum of 97a in CDCl3…………………………….…….. 203

1 Figure A.9: H NMR Spectrum of 97c in CDCl3…………………………….……... 204

13 Figure A.10: C NMR Spectrum of 97c in CDCl3……………………….………… 205

1 Figure A.11: H NMR Spectrum of 98 in CDCl3……………………….…………... 206

13 Figure A.12: C NMR Spectrum of 98 in CDCl3…………………….…………….. 207

1 Figure A.13: H NMR Spectrum of 103 in CDCl3………………….………………. 208

vi 13 Figure A.14: C NMR Spectrum of 103 in CDCl3……………….………………… 209

1 Figure A.15: H NMR Spectrum of 101 in CDCl3……………….…………………. 210

13 Figure A.16: C NMR Spectrum of 101 in CDCl3………….....…………………… 211

1 Figure A.17: H NMR Spectrum of 101a in CDCl3………….……………………... 212

13 Figure A.18: C NMR Spectrum of 101a in CDCl3……….……………………….. 213

1 Figure A.19: H NMR Spectrum of 100a in CDCl3……….………………………... 214

13 Figure A.20: C NMR Spectrum of 100a in CDCl3…….………………………….. 215

1 Figure A.21: H NMR Spectrum of 106 in CDCl3…….……………………………. 216

13 Figure A.22: C NMR Spectrum of 106 in CDCl3……………………….………… 217

1 Figure A.23: H NMR Spectrum of 109 in CDCl3……………………….…………. 218

13 Figure A.24: C NMR Spectrum of 109 in CDCl3…………………….…………… 219

1 Figure A.25: H NMR Spectrum of 110 in CDCl3…………………….……………. 220

1 Figure A.26: H NMR Spectrum of 111 in CDCl3………………….………………. 221

13 Figure A.27: C NMR Spectrum of 111 in CDCl3……………….………………… 222

1 Figure A.28: H NMR Spectrum of 112 in CDCl3……………….…………………. 223

13 Figure A.29: C NMR Spectrum of 112 in CDCl3…………….…………………… 224

1 Figure A.30: H NMR Spectrum of 112a in CDCl3………….……………………... 225

13 Figure A.31: C NMR Spectrum of 112a in CDCl3……….……………………….. 226

1 Figure A.32: H NMR Spectrum of 99 in CDCl3…………………….……………... 227

13 Figure A.33: C NMR Spectrum of 99 in CDCl3………………….……………….. 228

1 Figure A.34: H NMR Spectrum of 113 in CDCl3……………….…………………. 229

13 Figure A.35: C NMR Spectrum of 113 in CDCl3…………….…………………… 230

1 Figure A.36: H NMR Spectrum of 132 in CDCl3…………….……………………. 231

vii 13 Figure A.37: C NMR Spectrum of 132 in CDCl3…………………….…………… 232

1 Figure A.38: H NMR Spectrum of 133 in CDCl3…………………….……………. 233

1 Figure A.39: H NMR Spectrum of 131 in CDCl3………………….………………. 234

13 Figure A.40: C NMR Spectrum of 131 in CDCl3……………….………………… 235

1 Figure A.41: H NMR Spectrum of 137 in CDCl3……………….…………………. 236

1 Figure A.42: H NMR Spectrum of 138 in CDCl3…………….……………………. 237

13 Figure A.43: C NMR Spectrum of 138 in CDCl3………….……………………… 238

1 Figure A.44: H NMR Spectrum of 138a in CD3OD……….………………………. 239

13 Figure A.45: C NMR Spectrum of 138a in CD3OD………………….…………… 240

1 Figure A.46: H NMR Spectrum of 139a in CDCl3………………….……………... 241

1 Figure A.47: H NMR Spectrum of 139 in CDCl3………………….………………. 242

1 Figure A.48: H NMR Spectrum of 152 in CDCl3……………….…………………. 243

13 Figure A.49: C NMR Spectrum of 152 in CDCl3…………….………………….... 244

1 Figure A.50: H NMR Spectrum of 149 in CDCl3…………….……………………. 245

13 Figure A.51: C NMR Spectrum of 149 in CDCl3………….……………………… 246

1 Figure A.52: H NMR Spectrum of 150 in CDCl3………….………………………. 247

13 Figure A.53: C NMR Spectrum of 150 in CDCl3……….………………………… 248

1 Figure A.54: H NMR Spectrum of 151 in CDCl3……………………….…………. 249

13 Figure A.55: C NMR Spectrum of 151 in CDCl3…………………….…………… 250

1 Figure A.56: H NMR Spectrum of 147 in CDCl3…………………….……………. 251

13 Figure A.57: C NMR Spectrum of 147 in CDCl3………………….……………… 252

1 Figure A.58: H NMR Spectrum of 155 in CDCl3………………….………………. 253

13 Figure A.59: C NMR Spectrum of 155 in CDCl3……………….………………… 254

viii 1 Figure A.60: H NMR Spectrum of 156 in CDCl3……………….…………………. 255

13 Figure A.61: C NMR Spectrum of 156 in CDCl3…………….…………………… 256

1 Figure A.62: H NMR Spectrum of 157 in CDCl3…………….……………………. 257

13 Figure A.63: C NMR Spectrum of 157 in CDCl3………….……………………… 258

1 Figure A.64: H NMR Spectrum of 158 in CDCl3………….………………………. 259

13 Figure A.65: C NMR Spectrum of 158 in CDCl3……….………………………… 260

1 Figure A.66: H NMR Spectrum of 159 in CDCl3………………………….……..... 261

13 Figure A.67: C NMR Spectrum of 159 in CDCl3……………………….………… 262

1 Figure A.68: H NMR Spectrum of 159a in CDCl3…………………….…………... 263

13 Figure A.69: C NMR Spectrum of 159a in CDCl3………………….…………….. 264

1 Figure A.70: H NMR Spectrum of 160 in CDCl3………………….………………. 265

13 Figure A.71: C NMR Spectrum of 160 in CDCl3……………….………………… 266

1 Figure A.72: H NMR Spectrum of 161 in CDCl3……………….…………………. 267

13 Figure A.73: C NMR Spectrum of 161 in CDCl3…………….…………………… 268

1 Figure A.74: H NMR Spectrum of 185 in CDCl3…………….……………………. 269

13 Figure A.75: C NMR Spectrum of 185 in CDCl3………….……………………… 270

1 Figure A.76: H NMR Spectrum of 187 in CDCl3………….………………………. 271

13 Figure A.77: C NMR Spectrum of 187 in CDCl3……….………………………… 272

1 Figure A.78: H NMR Spectrum of 203 in CD3OD…….…………………………... 273

13 Figure A.79: C NMR Spectrum of 203 in CD3OD……………….……………….. 274

1 Figure A.80: H NMR Spectrum of 203a in CDCl3……………….………………... 275

13 Figure A.81: C NMR Spectrum of 203a in CDCl3…………….………………….. 276

1 Figure A.82: H NMR Spectrum of 142 in CDCl3…………….……………………. 277

ix 13 Figure A.83: C NMR Spectrum of 142 in CDCl3………….……………………… 278

1 Figure A.84: H NMR Spectrum of 205 in CDCl3………….………………………. 279

13 Figure A.85: C NMR Spectrum of 205 in CDCl3……….………………………… 280

1 Figure A.86: H NMR Spectrum of 213 in CDCl3……….…………………………. 281

13 Figure A.87: C NMR Spectrum of 213 in CDCl3…….…………………………… 282

1 Figure A.88: H NMR Spectrum of 266 in CDCl3…….……………………………. 283

13 Figure A.89: C NMR Spectrum of 266 in CDCl3….……………………………… 284

1 Figure A.90: H NMR Spectrum of 264 in CDCl3…………………….……………. 285

13 Figure A.91: C NMR Spectrum of 264 in CDCl3………………….……………… 286

1 Figure A.92: H NMR Spectrum of 268 in CDCl3………………….………………. 287

13 Figure A.93: C NMR Spectrum of 268 in CDCl3……………….………………… 288

1 Figure A.94: H NMR Spectrum of 269 in CDCl3……………….…………………. 289

13 Figure A.95: C NMR Spectrum of 269 in CDCl3…………….…………………… 290

1 Figure A.96: H NMR Spectrum of 271 in CDCl3…………….…………………..... 291

13 Figure A.97: C NMR Spectrum of 271 in CDCl3………….……………………… 292

1 Figure A.98: H NMR Spectrum of 273 in CDCl3………….………………………. 293

13 Figure A.99: C NMR Spectrum of 273 in CDCl3……….………………………… 294

1 Figure A.100: H NMR Spectrum of 272 in CDCl3…….…………………………... 295

13 Figure A.101: C NMR Spectrum of 272 in CDCl3………….…………………….. 296

1 Figure A.102: H NMR Spectrum of 277 in CDCl3……………….………………... 297

13 Figure A.103: C NMR Spectrum of 277 in CDCl3…………….………………….. 298

1 Figure A.104: H NMR Spectrum of 279 in d6-DMSO……….…………………….. 299

13 Figure A.105: C NMR Spectrum of 279 in d6-DMSO…….………………………. 300

x 1 Figure A.106: H NMR Spectrum of 282 in CDCl3………………………………….301

13 Figure A.107: C NMR Spectrum of 282 in CDCl3…………………………………302

1 Figure A.108: H NMR Spectrum of 235a in CDCl3………………………………...303

13 Figure A.109: C NMR Spectrum of 235a in CDCl3………………………………. 304

1 Figure A.110: H NMR Spectrum of 234a in CDCl3………………………………...305

13 Figure A.111: C NMR Spectrum of 234a in CDCl3………………………………. 306

1 Figure A.112: H NMR Spectrum of 282a in CDCl3………………………………...307

13 Figure A.113: C NMR Spectrum of 282a in CDCl3………………………………. 308

1 Figure A.114: H NMR Spectrum of 235b in CDCl3………………………………...309

13 Figure A.115: C NMR Spectrum of 235b in CDCl3………………………………. 310

1 Figure A.116: H NMR Spectrum of 234b in CDCl3………………………………...311

13 Figure A.117: C NMR Spectrum of 234b in CDCl3………………………………. 312

1 Figure A.118: H NMR Spectrum of 287 in CDCl3………………………………….313

13 Figure A.119: C NMR Spectrum of 287 in CDCl3………………………………... 314

1 Figure A.120: H NMR Spectrum of 233a in CDCl3………………………………...315

13 Figure A.121: C NMR Spectrum of 233a in CDCl3………………………………. 316

1 Figure A.122: H NMR Spectrum of 304 in CDCl3………………………………… 317

13 Figure A.123: C NMR Spectrum of 304 in CDCl3………………………………... 318

1 Figure A.124: H NMR Spectrum of 305 in CDCl3………………………………….319

13 Figure A.125: C NMR Spectrum of 305 in CDCl3…………………………………320

1 Figure A.126: H NMR Spectrum of 305a in CDCl3………………………………...321

13 Figure A.127: C NMR Spectrum of 305a in CDCl3………………………………. 322

1 Figure A.128: H NMR Spectrum of 311 in CDCl3………………………………….323

xi 13 Figure A.129: C NMR Spectrum of 311 in CDCl3…………………………………324

1 Figure A.130: H NMR Spectrum of 312 in CDCl3………………………………….325

13 Figure A.131: C NMR Spectrum of 312 in CDCl3…………………………………326

1 Figure A.132: H NMR Spectrum of 316 in CDCl3………………………………….327

13 Figure A.133: C NMR Spectrum of 316 in CDCl3…………………………………328

xii List of Schemes

Scheme 1.1 Retrosynthesis of Zhai’s total synthesis of (±)-subincanadine E………….. 7

Scheme 1.2 Proposed biosynthetic conversion of subincanadine C to subincanadine E………………………………………………………………………….9

Scheme 1.3 Micalizio’s total synthesis of conolidine………………………………….10

Scheme 1.4 Asymmetric synthesis of (+) and (－)-conolidine………………………….12

Scheme 1.5 Retrosynthesis of Zhai’s total synthesis of (±)-subincanadine F………….13

Scheme 1.6 Key bond disconnections of Li’s synthesis of (±)-subincanadine F…...… 14

Scheme 1.7 Asymmetric total synthesis of (+)-subincanadine F by the Li group……..16

Scheme 1.8 Retrosynthetic construction of (±)-subincanadine F by the

Waters group………………………………………………………………………...… 17

Scheme 1.9 Takayama’s construction of (－)-subincanadine A and

(－)-subincanadine B………………………………………………………………...… 19

Scheme 1.10 First total synthesis of (±)-apparicine……………………………………21

Scheme 1.11 Alternative route toward intermediate 60………………………………..23

Scheme 1.12 Biosynthesis of apparicine and vallesamine from stemmadenine……….24

Scheme 1.13 Biomimetic conversion of subincanandine E to valpericine and apparicine……………………………………………………………………………… 26

Scheme 1.14 Proposed biomimetic transformation of 17-oxo-subincanadine

E to other natural and unnatural products……………………………………………... 27

Scheme 1.15 Initial retrosynthetic approach toward subincanadine E………………... 29

Scheme 1.16 Formation of tetrahydro-!-carboline 91………………………………....30

Scheme 1.17 Sample of ring cleavage procedures……………………………………. 31 xiii Scheme 1.18 Bonjoch’s ring cleavage conditions applied to 91……………………… 32

Scheme 1.19 Unexpected ring opening product 97a………………………………….. 33

Scheme 1.20 Isomerization strategy…………………………………………………... 34

Scheme 1.21 Proposed dimer resulting from a Diels-Alder reaction…………………. 36

Scheme 2.22 Second-generation retrosynthetic toward subincanadine E……………...38

Scheme 2.23 Synthesis of (±)-harmicine……………………………………………… 39

Scheme 2.24 Ring fragmentation and deprotection of 100a………………………….. 40

Scheme 2.25 Alkylation of the amino-alcohol 106…………………………………… 41

Scheme 2.26 Oxidation of 112………………………………………………………... 42

Scheme 2.27 Protection of 99…………………………………………………………. 42

Scheme 2.28 Pier’s ring annulation using a novel Pd-catalyzed vinyl iodide and enolate coupling of 114……………………………………………………. 43

Scheme 2.29 Bonjoch’s intramolecular coupling of vinyl halides and ketone enolates………………………………………………………………………… 44

Scheme 2.30 Pd-catalyzed cross-coupling reaction applied by Cook………………… 46

Scheme 2.31 Intramolecular enolate-driven Pd-catalyzed coupling mechanism of 119……………………………………………………………………... 47

Scheme 2.32 Proposed intramolecular enolate-driven Pd-catalyzed coupling………...49

Scheme 2.33 Results of the cross-coupling reaction of 113…………………………... 50

Scheme 2.34 Bidentate ligands and their bite angles…………………………………. 52

Scheme 2.35 Wittig reaction established on the 5-membered conjugate of subincanadine E………………………………………………………………………...54

Scheme 2.36 TMS-enol ether formation……………………………………………… 56

xiv Scheme 2.37 Attempted azatricyclic formation toward strychnopivotine……………..57

Scheme 2.38 Proposed mechanism of the 5-membered azabicycle 131……………… 59

Scheme 2.39 Proposed amide precursor 147 that prevents !-hydride elimination…… 61

Scheme 2.40 Forward route toward coupling precursor 147…………………………..62

Scheme 2.41 Synthesis of anhydride 149……………………………………………... 63

Scheme 2.42 Results of the cross-coupling reaction of 147…………………………... 63

Scheme 2.43 Forward route toward conjugate addition precursor 160……………….. 66

Scheme 2.44 Forward route toward conjugate addition amide precursor 164………... 67

Scheme 2.45 Stork’s conversion of diester x to pentacyclic 167……………………... 68

Scheme 2.46 Qin’s attempted synthesis of 169……………………………………….. 69

Scheme 2.47 Proposed synthesis of 170 en route toward 172 via #-allyl coupling…... 70

Scheme 2.48 Proposed synthesis of 174 and 175 en route toward Cu-mediated coupling………………………………………………………………………………... 71

Scheme 2.49 Harley-Mason’s synthesis of 178………………………………………..72

Scheme 2.50 Proposed route to 180 and attempted synthesis of acid chloride 179…... 73

Scheme 2.51 Attempted synthesis of acid chloride 179 or anhydride 182…………….74

Scheme 2.52 Attempted coupling of amino-alcohol 106 and

2-oxobutenoic acid 181……………………………………………………………….. 75

Scheme 2.53 Coupling of benzylamine and acid 181 effort…………………………...75

Scheme 2.54 Nb-alkylation and projected enolate-driven ring closure………………...77

Scheme 2.55 Oxymercuration and hydroboration conditions applied to alkene 187…………………………………………………………………...78

Scheme 2.56 Hydroboration of 194 en route to allocriptopine………………………...79

xv Scheme 2.57 Route toward Pd-catalyzed intermolecular coupling of 142 and 205…... 81

Scheme 2.58 Synthesis of model substrate 212 establishing Pd-catalyzed coupling validity………………………………………………………………………. 83

Scheme 2.59 Intermolecular coupling of Zn enolate 215 and alkenyl halide 216……. 84

Scheme 3.60 Garg’s retrosynthesis of (±)-aspidophylline A…………………………. 86

Scheme 3.61 Stereocontrolled synthesis of (+)-20R-15,20-dihydrocleavamine……… 87

Scheme 3.62 Third-generation retrosynthesis………………………………………… 88

Scheme 3.63 Baran’s retrosynthesis of hapalindole Q 247 and

(－)-12-epi-fischerindole U isothiocyanate 242……………………………………….. 92

Scheme 3.64 Garg’s retrosynthesis of N-methylwelwitindolinone C

isocyanate 251………………………………………………………………………… 94

Scheme 3.65 Carvone-derived diene ligands…………………………………………. 95

Scheme 3.66 Oxidation cleavage of (S)-carvone………………………………………96

Scheme 3.67 2-step oxidation of (S)-carvone…………………………………………. 97

Scheme 3.68 Attempted regioselective oxime formation……………………………... 98

Scheme 3.69 Attempted regioselective protection to provide 270…………………... 100

Scheme 3.70 Attempted regioselective protection to provide 273…………………... 101

Scheme 3.71 Michael adduct formation from the attempted protection of 274……... 102

Scheme 3.72 Acetal protection of (S)-carvone………………………………………. 103

Scheme 3.73 Attempted protection of diol intermediate 279………………………... 104

Scheme 3.74 Oxidation and protection of (S)-carvone……………………………….106

Scheme 3.75 Byproducts of the intramolecular Lewis acid catalyzed cyclization of 281…………………………………………………………………….. 107 xvi Scheme 3.76 Synthesis of oxime 234a from ketone 235a…………………………... 107

Scheme 3.77 Initial Beckmann rearrangement performed on oxime 234b………….. 108

Scheme 3.78 Mechanism for the production of 287…………………………………. 109

Scheme 3.79 Mechanism for the production of N-substituted and un-substituted amides………………………………………………………………… 110

Scheme 3.80 Three literature examples of Chapman-like rearrangements………….. 111

Scheme 3.81 Optimized Beckmann rearrangement on 234a………………………... 112

Scheme 3.82 Conversion of N- alkylated and O-protected byproducts to amide 305……………………………………………………………………………. 113

Scheme 3.83 Acetamide 233a alkylation attempt with mesylated (Z)-olefin 11……. 114

Scheme 3.84 Elimination of the mesylated (Z)-olefin 11 with a strong base………... 115

Scheme 3.85 Deacetylation of 233a and reductive amination with 111……………...116

Scheme 3.86 Deacetylation attempts of sulfonamide 304…………………………… 117

Scheme 3.87 Deacetylation attempts of carbamate 309……………………………... 118

Scheme 3.88 Acetamide reduction to ethylamine 311………………………………. 119

Scheme 3.89 Reductive amination of 108…………………………………………… 121

Scheme 3.90 Alkylation and oxidation to 316………………………………………. 122

Scheme 3.91 Intramolecular Heck coupling of 316…………………………………. 123

Scheme 3.92 Proposed final steps toward subincanadine E…………………………. 125

xvii List of Tables

Table 2.1: Highlighted conditions applied to 113…………………………………….. 50

Table 2.2: Control experiment conditions…………………………………………….. 55

Table 2.3 A sample of cross-coupling conditions applied to 147 and 153…………… 64

Table 2.4 Conditions for the acid chloride or anhydride formation…………………... 74

Table 3.5 Conditions applied to the regioselective oxime formation of 267…………. 99

Table 3.6 Conditions applied to the regioselective protection to provide 273………. 101

Table 3.7 Conditions applied to the protection of diol 279…………...... 104

Table 3.8 Conditions applied to the alkylation of 233a……………………………... 114

Table 3.9 Conditions attempted to deacetylate 233a…………………………………116

Table 3.10 Conditions attempted for the intramolecular Heck coupling of 316…….. 123

xviii Chapter 1: First-Generation Synthesis: Construction of the !-Carboline

1.1 Introduction

The indole alkaloids1 of the stemmadenine type present an interesting scaffold to

the synthetic chemist, featuring impressive pharmacological activity and structural

complexity. Pericine (5a, Figure 1.2) was first isolated from Picralima nitida cell

suspension cultures by Joachim Stöckigt in 19822 and later by Kobayashi and

coworkers from the bark of a Brazilian medicinal plant Aspidosperma subincanum

Mart in 2002,3 under the name subincanadine E. It was obtained as a light yellow oil,

4 with [!]D +45 (c 0.20, CHCl3). This compound, and its N-oxide, was also found in the

stem-bark extract of the Malayan Kopsia arborea along with valpericine 8, the first

1 For reviews of indole alkaloids, see: (a) Kam, T.-S.; Lim, K.-H., Chapter 5 Condylocarpine, Stemmadenine, and Akuammicine Alkaloids. In The Alkaloids, Cordell, G. A., Academic Press: 2008; Vol. 66, pp 12-19. (b) Gul, W.; Hamann, M. T. Life Sciences 2005, 78, 442-453. (c) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S. Natural Product Reports 2013, 30, 694-752. (d) Fischer, J.; Ganellin, C. R., Chapter 8 Monoterpenoid Indole Alkaloids, CNS and Anticancer Drugs. In Analogue-Base Drug Discovery, Nemes, A., Wiley-VCH Verlag GmbH & Co. KGaA: 2010; Vol. 2, pp 189-215. (e) Joule, J. Chapter 4 Indole Alkaloids. In The Alkaloids, Saxton, J. E., The Chemical Society: 1974; Vol. 4, pp. 280-321. (f) Facchini, P. J. Chapter 1 Regulation of Alkaloid Biosynthesis in Plants. In The Alkaloids: Chemistry and Biology, Cordell, G. A., Elsevier: 2006; Vol. 63, pp 1-44. (g) Takayama, H.; Sakai, S.-I., Chapter 11 Monoterpenoid Indole Alkaloid Syntheses Utilizing Biomimetic Reactions. In The Alkaloids, Cordell, G. A., Academic Press: 1998; Vol. 50, pp 415-452. (h). Gribble, G. W. Journal of the Chemical Society, Perkin Transactions, 2000, 1, 1045-1075. (i) Hesse, K.; Schmid, H. Lloydia 1971, 34, 269-291. (j) For indole- containing natural products, see: Nicolaou, K. C. Snyder, S. A. Classics in Total Synthesis II; Wiley-VCH: Weinheim, 2003; Chapters 5, 8, 12, 18, 19, 20, and 22, pp. 169. (k) For an overview of indole synthesis and reactivity, see: Sundberg, R. J. Indoles; Academic Press: San Diego, 1996; pp 175.

2 Arens, H.; Borbe, H. O.; Ulbrich, B.; Stöckigt, J. Planta Medica 1982, 46, 210–214.

3 Kobayashi, J.; Sekiguchi, M.; Shimamoto, S.; Shigemori, H.; Ishiyama, H.; Ohsaki, A. Journal of Organic Chemistry 2002, 67, 6449-6455.

4 Yee, L. Y. (2008). Biomimetic Partial Synthesis of Some Indole Derivatives. Unpublished doctoral dissertation, University of Malaya, Kuala Lumpur, Malaysia.

pentacyclic indole alkaloid of the pericine type.5 Summarized in Figure 1.1 and Figure

1.2 are subincanadines A-G isolated from A. subincanum6 and the pericine type

alkaloids from K. arborea, respectively.

N N N N N N H H H N H OH A HO B HO C D 1 2 3 4

N HO N N

N N N H H H H H O E F G 5 6 7

Figure 1.1 Structures of subincanadines A-G.

These monoterpenoid alkaloids of the pericine type range from possessing either

a one-carbon linker at C6 (apparicine, vallesamine, ervaticine) or a two-carbon

connection at the indolic 3-position to the aliphatic nitrogen (pericine, valpericine,

stemmadenine). The seven novel subincanadines provide interesting architectures,

ranging from an unprecedented 1-azoniatricyclo[4.3.3.0]undecane moiety

5 (a) Lim, K.-H.; Low, Y.-Y.; Kam, T.-S. Tetrahedron Letters 2006, 47, 5037-5039. (b) Lim, K.-H.; Hiraku, O.; Komiyama, K.; Koyano, T.; Hayashi, M.; Ka, T.-S. Journal of Natural Products 2007, 70, 1302-1307.

6 Ishiyama, H.; Matsumoto, M.; Sekiguchi, H.; Ohsaki, A.; Kobayashi, J. Heterocycles 2005, 66, 651-658. 2

(subincanadine A-C and G) to a 1-azabicyclo[5.2.2]undecane (subincanadine D-E) as well as a 1-azabicyclo[4.3.1]decane (subincanadine F) moiety.

5 4 N N N 9 21 N 7 3 O 14 20 CH2OH H 16 13 2 15 N H N 18 H N N H H H H 17 MeO2C CH2OH H 8 5a 9 10 valpericine pericine stemmadenine pericidine N N N

H N N N H CH2OH H H H H O MeO2C 11 12 13 vallesamine ervaticine apparicine

Figure 1.2 Indole alkaloids of the pericine type.

In addition to their structural complexity, preliminary biological studies of the subincanadines suggest a number of potential medicinal benefits. In vitro studies discovered both subincanadine E and F exhibit cytotoxicity against murine lymphoma

L1210 (IC50, 0.3 µg/mL; IC50, 2.4 µg/mL) and human epidermoid carcinoma KB cells

(IC50, 4.4 µg/mL; 4.8µg/mL, respectively). This pronounced pharmacological activity

2 has not been observed in subincanadines A-D (IC50 > 10 µg/mL).

Furthermore, the original isolation paper for subincanadine E in P. nitida cell suspension cultures reported activity against an opioid agonist, demonstrating excellent

analgesic potency. Subincanadine E displayed inhibition of specific 3H-naloxone

binding, (IC50, 0.6 µmol/L) and was more potent compared to a structurally similar

secondary metabolite from the same plant named pericalline, (also known as

apparicine, IC50, 2.3 µmol/L). The weak analgesic codeine possesses activity within

this micromolar range (IC50, 3.6 µmol/L) and comparatively, subincanadine E was six

times more potent. This remarkable activity suggests the likelihood of it being an

opiate agonist in vivo.2

Moreover, the related 17-nor-subincanadine E isolated from Aspidosperma ulei7

was discovered to be a potential treatment for erectile dysfunction (ED) when studied

both in vivo and in vitro (Figure 1.3).8 Studies of its mechanism of action reported

strong relaxant effects on rabbit corpus cavernosum smooth muscle in vitro by a

mechanism that may benefit patients who also suffer from cardiovascular problems

associated with ED, such as hypertension and diabetes.9

7dos Santos Torres, Z. E.; Silveira, E. R.; Rocha e Silva, L. F.; Lima, E. S.; Carvalho de Vasconcellos, M.; Uchoa, D. E. A.; Braz Filho, R.; Pohlit, A. M. Molecules 2013, 18, 6281-6297.

8 (a) Campos, A. R.; Cunha, K. M. A.; Santos, F. A.; Silveira, E. R.; Uchoa, D. E. A.; Nascimento, N. R. F.; Rao, V. S. N. International Journal of Impotence Research 2008, 20, 255–263. (b) Campos, A. R.; Lima Jr., R. C.; Uchoa, D. E. A.; Silveira, E. R.; Santos, F. A.; Rao, V. S. N. Journal of Ethnopharmacology 2006, 104, 240-244.

9 Benvindo, O. D.; Nascimento, N. R. F.; Santos, C. F.; Fonteles, M. C.; Silveira, E. R.; Uchoa, D. E.; Campos, A. R.; Cunha, K. M. A.; Santos, F. A.; Rao, V. S. Asian Journal of Andrology 2011, 13, 747-753.

N H 14

Figure 1.3 (±)-17-nor-subincanadine E.

The challenging framework of subincanadine E in addition to possessing the

greatest potency among its class, prompted us to put forth a synthetic plan toward its

total synthesis. To date, (±)-subincanadine E has been successful constructed once with

no published proceedings on its asymmetric total synthesis.10 In Chapter One and Two,

we wish to provide a detailed account of synthetic studies toward the synthesis of (±)-

subincanadine E. Chapter Three will describe efforts toward the first asymmetric total

synthesis of (")-subincanadine E.

10 Tian, J.; Du, Q.; Guo, R.; Li, Y.; Cheng, B.; Zhai, H. Organic Letters 2014, 16, 3173"3175.

1.2. Previous total syntheses of related indole alkaloids

Though the main architecture of several pericine type varieties had been constructed,11 surprisingly the total synthesis of only (±)-apparicine,12 (")-subincanadine

A-B,13 and (±)-subincanadine F14 had been successfully completed prior to the commencement of this work. This section will highlight the total synthesis of the aforementioned natural products as well as the recently synthesized subincanadine E and the related variant, conolidine.

11 (a) Pentacyclic framework of subincanadine B: Liu, Y.; Luo, S.; Fu, X.; Fang, F.; Zhuang, Z.; Xiong, W.; Jia, X.; Zhai, H. Organic Letters 2006, 8, 115-118. (b) Tetracyclic core of subincandine F: Solé, D.; Bennasar, M.-L.; Jimenez, I. Synthetic Letters 2010, 6, 944-946. (c) Ring skeleton of apparicine: Scopes, D. I. C.; Allen, M. S.; Hignett, G. J.; Wilson, N. D. V.; Harris, M.; Joule, J. A. Journal of the Chemical Society, Perkin Transactions 1977, 2376–2385. (d) Joule, J. A.; Allen, M. S., Bishop, D. I,; Harris, M.; Hignett, G. J.; Scopes, D. I. C.; Wilson, N. D. V. Indole and Biogenetically Related Alkaloids; Phillipson, J. D.; Zenk, M. H., Eds; Academic: London, 1980, pp. 229–247. (e) For biological activity sustaining the pharmacophore of the indole moiety, see: El-Subbagh, H.; Wittig, T.; Decker, M.; Elz, S.; Nieger, M.; Lehmann, J. Archiv der Pharmazie 2002, 9, 443-448.

12 (a) Bennasar, M.-L.; Zulaica, E.; Solé, D.; Alonso, S. Chemical Communications 2009, 23, 3372-3374. (b) Bennasar, M.-L.; Zulaica, E.; Solé, D.; Toca, T.; García-Diaz, D.; Alonso, S. Journal of Organic Chemistry 2009, 74, 8359-8368.

13 Suzuki, K.; Takayama, H. Organic Letters 2006, 8, 4605-4608.

14 Gao, P.; Liu, Y.; Zhang, L.; Xu, P.-F.; Wang, S.; Lu, Y.; He, M.; Zhai, H. Journal of Organic Chemistry 2006, 71, 9495-9498.

1.2.1 (±)-subincanadine E

The synthesis of (±)-subincanadine E was published very recently by Zhai and

10 coworkers and consisted of a Ni(COD)2-mediated intramolecular Michael addition as the key assembly, originally employed in the group’s synthesis of (±)-subincanadine C.15

The retrosynthetic analysis is shown in Scheme 1.1. A final zinc-mediated fragmentation reaction of 15 installed the final 1-azabicyclo[5.2.2]undecane ring system to furnish the natural product. Kobayashi previously suggested intermediate 5a could be biosynthetically derived from 3 and the authors were the first to provide evidence that 3 could be a synthetic precursor to 5a through radical intermediate 20 (Scheme 1.2).2

Scheme 1.1 Retrosynthesis of Zhai’s total synthesis of (±)-subincanadine E.

N Zn-mediated bromination/ fragmentation cyclization N N N N N H H H H OH 5 15 Br 16 (±)-subincanadine E HO Michael addition

Pictet-Spengler O O and HWE NH HCl N I EtO OEt 2 N N O H H CO2Et 19 18a 17 OTBS

15 Yu, F.; Cheng, B.; Zhai, H. Organic Letters 2011, 13, 5782-5783. 7

This sequence was the first to demonstrate a zinc-mediated fragmentation reaction of a quaternary ammonium salt utilized during the total synthesis of an alkaloid.

Pentacyclic 15 was accessed through a double bromination and intramolecular ammonium formation of diol 16, where both diastereomers were taken through the sequence independently in a one-pot, three-step process. Interestingly, utilizing CBr4

/PPh3/NEt3 as brominating reagents instead of LiBr only furnished the desired ammonium salt when using the cis-diastereomer of 16 and did not deliver the pentacylic ammonium when employing the trans-adduct under the same conditions. Intramolecular Michael addition of ester 17 using Ni(COD)2 provided the tetracyclic framework, which can be generated through a Pictet-Spengler condensation of tryptamine salt 18a with 19 prior to alkylation and further manipulation of the two ester functionalities. This synthetic sequence provided (±)-subincanadine E in ten operations from tryptamine hydrochloride in overall high yields. In addition to the use of nearly 5 equivalents of Ni(COD)2, a major drawback of this synthesis is an almost 1:1 dr resulting from the Michael addition that necessitates proceeding through the final series of transformations independently, only to lead to a racemic mixture. The authors are currently investigating an asymmetric route toward (+)-subincanadine E via a desymmetrization step on an analog of 17.16

16 For synthetic details, see scheme in reference 15 in: Tian, J.; Du, Q.; Guo, R.; Li, Y.; Cheng, B.; Zhai, H. Organic Letters 2014, 16, 3173"3175. 8

Scheme 1.2 Proposed biosynthetic conversion of subincanadine C to subincanadine E.

N N N N N H H H H 3 20 5a

1.2.2 Synthesis of (+)-, (")-, and (±)-conolidine

Conolidine was isolated in 200417 from the flowering tropical plant

Tabernaemonta divaricata and has been used extensively in traditional medicine for the treatment of fever and pain.18 Due to its scarcity within the plant, no medicinal evaluations were conducted on conolidine, though more abundant alkaloids common to this species had implicated analgesic activity.19 Micalizio and coworkers were motivated by its drug-like structure and devised a total synthesis that ultimately discovered its efficacy as a non-opioid analgesic in an in vivo model (Scheme 1.3).20

17 Kam, T.-S.; Pand, H.-S.; Choo, Y.-M.; Komiyama, K. Chemistry and Biodiversity 2004, 1, 646–656.

18 Pratchayasakul, W.; Pongchaidecha, A.; Chattipakorn, N.; Chattipakorn, S. Indian Journal of Medical Research 2008, 127, 317–335.

19 Ingkaninan, K.; Ijzerman, A. P.; Taesotikul, T.; Verpoorte, R. Journal of Pharmacy and Pharmacology 1999, 51, 1441.

20 Tarselli, M. A.; Raehal, K. M.; Brasher, A. K.; Streicher, J. M.; Groer, C. E.; Cameron, M. D.; Bohn, L. M.; Micalizio, G. C. Nature Chemistry 2011, 3, 449-453. 9

Scheme 1.3 Micalizio’s total synthesis of conolidine.

N cyclization H N N

N N H H H H R) O O ( 21 22a H 22b Me (±)-conolidine Me

imminium formation PMB deprotection, N oxidation NH N SO Ph 2 OH N H 24 O 23

Li N SO2Ph 25

NPMB PMB N NPMB N

O HO OH 26 27 OH 28 29

This synthesis was based on the reported biosynthetic pathway from stemmadenine to vallesamine put forth by Kutney21 and later realized in vitro by Scott

(see Section 1.3 for biomimetic details).22 In a similar fashion, the imminium ion was generated with paraformaldehyde and underwent cylization of the more stable conformer

22a through minimization of A-1,3 strain. Precursor 23, kinetically stabilized from the stereochemistry of the exo-olefin, was accessed through protecting group removal and

21 Kutney, J. P. Heterocycles 1976, 4, 429-451.

22 Scott, A. I.; Yeh, C. L.; Greenslade, D. Journal of the Chemical Society, Chemical Communications 1978, 947-948. 10 oxidation of 24. This stereoisomeric mixture of alcohols was obtained through oxidation of 27 and addition of organolithium reagent 25. A [2,3]-Wittig rearrangement from the conversion of allylic alcohol 28 to its corresponding stannylmethyl ether with subsequent expose to n-BuLi, favoring formation of the desired (E)-olefin. The sequence originated from pyridine 29 after N-alkylation and hydride reduction, concluding the route after 8 steps with an 18% yield overall.

Following the successful preparation of racemic conolidine, the group sought to complete an asymmetric synthesis from optical enrichment of 28 (Scheme 1.4).

Commercially available lipases furnished the enriched substrates 28a and 28b (both with

>90% ee). Either enantiomer of conolidine was delivered and required only a modification of the original route to a Parikh-Doering oxidation on carbinol 24 to prevent racemization.

Since this compound was determined to possess pharmacological activity and is structurally similar to subincanadine E, we believe a biomimetic relationship could exist between the two. Despite the fact that they were isolated in separate species, Scheme

1.14 in Section 1.3 (page 27) outlines our proposal for the formation of conolidine from subincanadine E that could be obtained through a biogenically derived pathway.

Scheme 1.4 Asymmetric synthesis of (+) and (")-conolidine.

PMB PMB N (±)-8 N

HO Lipase HO

28a 28b

8-steps 8-steps

N N

N N H H H H O 21a 21b (!)-conolidine (+)-conolidine

1.2.3 Synthesis of (±)-, and (+)-subincanadine F

The first reported total synthesis of (±)-subincanadine F was completed by Zhai and coworkers. The route was a six step sequence that involved a SmI2-mediated ring opening to a bridge-containing tetracyclic core followed by an acid-mediated Mannich reaction (Scheme 1.3).11 Full deprotection of 30 to arrive at subincanadine F proved a laborious endeavor. It was anticipated that a Lewis acid, oxidant, or base would remove the PMB group, however the desired product was only obtained in the presence of HCl to simultaneously N-deprotect and decarboxylate in an optimized 28% yield. The (E)- ethenyl appendage was introduced on 31 in hopes that the pendant protecting groups would block the active site and give the desired olefin geometry, resulting in an E/Z ratio 12 of 10:1. Skeletal rearrangement required introduction of a 1-carbon linker to form the tetracycle, which was accessed through SmI2-mediated disconnection of the C/D ring junction. Intermediate 33 was efficiently constructed in a 1-step process via a Pictet-

Spengler cyclization following tryptamine condensation with the requisite ketoester 34.

Scheme 1.5 Retrosynthesis of Zhai’s total synthesis of (±)-subincanadine F.

aldol condensation C N deprotection N with MeCHO, N A dehydration B D N N N H PMB PMB t t 6 O BuO2C O BuO2C O (±)-subincandine F 30 31

O formalin, HCl CO tBu Cl 2 SmI ring- Pictet-Spengler 2 34 opening O HN N

N N PMB NH2 PMB tBuO C O tBuO C O N 2 2 PMB 33 32 18b

Three years later, a protecting-group-free total synthesis was reported by Li and coworkers in 7 steps from commercially available tryptamine in a 33% overall yield

(Scheme 1.6).23 Similar to the previous synthesis, a late-stage (E)-ethenyl addition was promoted by using TiCl4 with i-Pr2NEt as the base which gave none of the (Z)-isomer.

Using two equivalents of t-BuOK, a chemoselective Dieckmann condensation of 36

23 Chen, P.; Cao, L.; Li, C. Journal of Organic Chemistry 2009, 74, 7533-7535. 13 ensued prior to deesterification of 35, taking advantage of steric control since the alternative condensation would demand the generation of a sterically congested quaternary center. Tricyclic compound 37 underwent a Michael addition with methyl acrylate and was readily assembled from the skeletal rearrangement of 38 followed by a subsequent reduction. An initial Pictet-Spengler condensation of tryptamine and bromopyruvate began their synthetic route. This route provided an advantageous incorporation of the 1-carbon linker at C14 without the need to break and reform a ring and avoided the inefficient protecting group removal seen in Zhai’s synthesis.

Scheme 1.6 Key bond disconnections of Li’s synthesis of (±)-subincanadine F.

deesteriﬁcation, aldol condensation, Dieckmann N dehydration N condensation N CO2Me

N N CO Me N H H 2 H O 6 35 O 36 O OMe (±)-subincandine F

CO Me Br 2 39 O rearrangement, Pictet-Spengler reduction NH NH NH2 N Br N N H H H MeO2C O OMe 18 37 38

A more recent asymmetric approach by the Li group assigned absolute stereochemistry of (+)-subincanadine F (Scheme 1.5).24 Comparable to their previous route, an initial double N-conjugate addition on (+)-tryptophan and a Dieckmann condensation afforded 42. Following benzyl ester formation, a number of oxidative conditions were screened, anticipating that the ester group would control stereoselectivity. The uncommon 7-endo-trig ring closure resulted with Cp2FePF6 and t-

BuOK (favored due to the radical-stabilizing effect of the phenyl group)25 without the need of a protecting group on the indole nitrogen and with no evidence of 6-exo-trig cyclization. Cleavage of the two ester groups was achieved in the usual manner, though employment of a methyl group in place of a benzyl group on compound 41 led to decomposition, presumably through enhanced electrophilicity of the ketone due to ring strain. The authors utilized an identical ethylenation as their racemic route to produce the target molecule in 9 steps.

24 Chen, P.; Cao, L.; Tian, W.; Wang, X.; Li, C. Chemical Communications 2010, 46, 8436-8438.

25 (a) Liu, F.; Liu, K.; Yuan, X.; Li, C. Journal of Organic Chemistry 2007, 72, 10231-10234. (b) Chen, P.; Wang, J.; Liu, K.; Li, C. J. Journal of Organic Chemistry 2008, 73, 339-341.

Scheme 1.7 Asymmetric total synthesis of (+)-subincanadine F by the Li group.

CO2Bn aldol condensation, ester N N dehydration N cleavage

N N N H H H H H O 6a O 40 O MeO2C 41 (+)-subincanadine F esteriﬁcation, 7-endo-trig

CO H CO2H double CO2H Dieckmann 2 Michael addition condensation N NH2 N CO2Me N N N H H H O MeO2C MeO2C 44 43 42

Finally, the Waters group published the most current total synthesis of (±)- subincanadine F in 2010 (Scheme 1.6).26 Use of a titanium-mediated intramolecular nucleophilic acyl substitution strategy offered the natural product in 7 steps (Scheme 1.6).

A 6-exo-trig ring closure between the organotitanium moiety and the neighboring ester functionality of intermediate 45 provided the requisite (E)-geometry. The group has described an in situ generation of the titanacyclopropene species from Ti(Oi-Pr)4 and 2 equivalents of i-PrMgCl with alkyne 46 to directly furnish the exo-ethenyl appendage and therefore obviated the need for a late-stage installation (as seen in corresponding syntheses carried out by both Zhai11 and Li13,14). The titanium chemistry originated from

26 Cheng, X.; Duhaime, C. M.; Waters, S. P. Journal of Organic Chemistry 2010, 75, 7026-70028.

Kulinkovich27 and was later applied to the construction of several N-heterocyclic

28 compounds, described by Sato. The Nb-butynyl derivative of indoloazepine 46 was conveniently obtained from a modification of Kuehne’s protocol from tryptamine, methyl chloropyruvate, and butynyl mesylate in 4 steps (See reference 16 and those therein).

Distinct from previous syntheses, this route efficiently closed the bridged-fused ring system with concurrent installment of the olefin moiety. This avoided an E/Z mixture and prevented further functional group manipulation.

Scheme 1.8 Retrosynthetic construction of (±)-subincanadine F by the Waters group.

Ti-mediated nucleophillic N acyl substitution N

N N H Boc Ti (O-Pr-i) 6 O MeO O 2 (±)-subincanadine F 45

NH2 N Pictet-Spengler, H rearrangement, reduction N O 18 MsO N OMe H 48 OMe 46 O Cl O 47

27 For reviews, see: (a) Kulinkovich, O. G. Pure and Applied Chemistry 2000, 72, 1715–1719. (b) Kulinkovich, O. G.; de Meijere, A. Chemical Reviews 2000, 100, 2789–2834.

28 (a) Okamoto, S.; Iwakubo, M.; Kobayashi, K.; Sato, F. Journal of the American Chemical Society 1997, 119, 6984–6990. (b) Okamoto, S.; Kasatkin, A.; Zubaidha, P. K.; Sato, F. Journal of the American Chemical Society 1996, 118, 2208–2216. (c) Sato, F.; Urabe, H.; Okamoto, S. Synthetic Letters 2000, 753– 775. 17

1.2.4 Synthesis of (")-subincanadine A and B

Zhai was the first to construct the main framework of (±)-subincanadine B8a by a route that featured similar methods as Li’s synthesis of (±)-subincanadine F (shown in

Scheme 1.4). Shortly after this, Takayama and coworkers reported the total synthesis of

(")-subincanadine B as well as (")-subincanadine A from (S)-malic acid.10 Although

Zhai achieved the core in only 4 steps, Takayama’s asymmetric synthesis required 16 steps for both A and B with an overall 2.7% and 6.8% yield, respectively. The synthesis hinged upon a concluding intramolecular Nozaki-Hiyama-Kishi coupling of enantiomer

29 51 using NiCl2 and CrCl2 to furnish diastereomers 50 in and 49 in a 2:3 ratio. Each compound was taken on independently through a deprotection and mesylation to close the final ring, affording each respective natural product target as the chloride salt. All spectroscopic and optical properties were identical to the isolated of (")-subincanadine A.

Spectroscopic data was identical for subincanadine B, but optical rotation was opposite and thus provided the enantiomer of natural subincanadine B. This route also featured a diastereoselective Pictet-Spengler reaction using TMSCl as a Lewis acid to form a 9:1 mixture of diastereomers that was recrystallized to isolate 54 as a single diastereomer.

Selectivity was presumed to occur through an intermediate acylimminium intermediate where the indole is presumed to attack the less hindered face (anti to the side chain). The heavy use of protecting-group transformations is one undesirable element throughout this synthesis as well as the excessive number of steps (7) to obtain hydroxyl ketone 56.

29 Daly, E. M.; Taylor, R. E. Chemtracts 2007, 20, 1-8.

Scheme 1.9 Takayama’s construction of (")-subincanadine A and (")-subincanadine B.

N N N N H H 2a HO 49 HO Nozaki-Hiyama- Kishi reaction (-)-subincanadine B MEMO N N H I N N 51 O OMEM N N H H Br 1 50 HO HO MEMO I (-)-subincanadine A 52

O Pictet- HN Spengler N O O O NH N N N H H O H 55 54 53 HO OMEM OPiv PivO OH O

NH PivO TBSO CO2H 2 O HO2C N O OH H 18 56 57 58

1.2.5 Synthesis of (±)-apparicine

Finally, the Alonso group synthesized (±)-apparicine in the most concise route of all the total syntheses described (Scheme 1.10).11a It was first isolated30 from four separate Aspidosperma species (A. olivaceum, A. eburneum, A. multiflorum, and A. gomezianum) and the enantiomeric (+)-apparicine from a fifth (A. Dasycarpon).31 Its core skeleton was constructed in the late 1970s by Joule and coworkers11b-c (void of the ethylidene appendage), but proved unsuitable to generate the complete alkaloid.

Alonso’s 6-step sequence highlighted a final intramolecular Heck reaction which was the first example of an (aza)cylooctene ring construction that generated a strained bridge system. Starting material was recovered during all screened conditions and required the presence of Ag2CO3 in addition to Pd(OAc)2, PPh3, in 1:1 toluene:NEt3 to obtain the desired product, albeit in only a 15% yield. Attempts to improve the yield through indole nitrogen protection were unsuccessful. The 8-membered ring 60 was envisioned to arise from diene 3 through a RCM and subsequent olefin isomerization. Unfortunately, this led to dimeric products as a result of intermolecular metathesis, isomerization of the terminal double bond, or ring-contraction to 67 through coupling of isomerized olefin 66 to liberate propene (Figure 1.4).

30 (a) Part XLVII, Ohashi, M.; Joule, J. A.; Gilbert, B.; Djerassi, C. Experientia 1964, 20, 363-364. (b) Gilbert, B.; Duarte, A. P.; Nakagawa, Y.; Joule, J. A.; Flores, S. E.; Brissolese, J. A.; Campello, J.; Carrazoni, E. P.; Owellon, R. J.; Blossy, E. C.; Brown Jr., K. S.; Djerassi, C. Tetrahedron 1965, 21, 1141- 1166. (c) Van Der Heijden, R.; Lamping, P. J.; Out, P. P.; Wijnsma, R.; Verpoorte, R. Journal of Chromatography 1987, 396, 287-295.

31 Joule, J. A.; Monteiro, H.; Durham, L. J.; Gilbert, B.; Djerassi, C. Journal of the Chemical Society 1965, 4773-4780. 20

Scheme 1.10 First total synthesis of (±)-apparicine.

Boc N N I N

N N N H H H H 13a 59 60 (±)-apparicine Boc Boc N N X

N N N R SO2Ph H 63 62 N MOM R = Boc or Ts CHO 61

N N SO2Ph SO2Ph 64 25a

The problematic terminal alkene was avoided by employing the less crowded diene 63, which was easily obtained from a Friedel-Crafts formylation, reductive amination, and protection of 1-(phenylsulfonyl)indole. Grubbs’ second-generation catalyst cleanly furnished the desired RCM product 62, and upon t-BuOK exposure, isomerization of the double bond and deprotection of the indole nitrogen occurred in one pot (refluxing conditions void of base solely produced the enamide).

R R R N N N

N N N MOM MOM MOM 65 66 67 2

Figure 1.4 Resultant RCM products of compound 61.

Due to complications with protecting group manipulation and coupling conditions, the group published a more thorough discussion of apparicine’s total synthesis several months later.11b They outlined the inflexibility of the protecting group on 60, noting that Boc and Ts would lead to decomposition under most deprotecting conditions, eventually relying on a mild Boc removal using 1.2 M HCl. An alternative route to 60 installed the trisubstituted double bond required for the Heck reaction from a ketone handle (Scheme 1.9). They originally examined dehydration conditions of the tertiary alcohol 71 from MOM-protected substrate 72. Less than a 10% yield of 60 resulted, conceivably from competitive indole deprotection. A more efficient approach was routed through the free indole 70 to arrive at 60 in a 26% yield over four steps.

Completion of the natural product was achieved as shown in Scheme 1.10.

Scheme 1.11 Alternative route toward intermediate 60.

Boc Br MeLi then N phenyl selenation, reductive CHO NBoc amination TsOH ring closure 12 O SePh N N N H OMe H O H O 68 69 70

Boc Boc RCM, acid N MeLi N hydrogenation NBoc 12 X O N N N MOM MOM MOM OH O 71 72 73

1.3 Biomimetic extension to other natural products

Kutney was the first to suggest a biosynthetic relationship between stemmadinine and its 5-nor-indole derivatives, vallesamine and apparicine.19 He provided evidence in feeding studies that tritium-labeled tryptophan was a precursor to apparicine and discovered that C5 of tryptophan was lost while C6 was retained (Scheme

1.3.1).32

32 (a) Kutney, J. P.; Nelson, V. R.; Wigfield, D. C. Journal of the American Chemical Society 1969, 91, 4278-4279. (b) Kutney, J. P.; Nelson, V. R.; Wigfield, D. C. Journal of the American Chemical Society 1969, 91, 4279-4280. 23

Scheme 1.12 Biosynthesis of apparicine and vallesamine from stemmadenine.

H 5 X 6 N N N

N N N H H H CH OH CH2OH CH OH MeO2C 2 MeO2C MeO2C 2 74 75 76

Scott

(±)-apparicine 13a (±)-stemmadenine 9a (±)-vallesamine 11a

Kutney

X N H N N

N N H N H H O CH2OH H2C O OH 77 78 79

A biogenetic pathway from stemmadinine to apparicine was suggested by Potier

and coworkers, featuring a Potier-Polonovski fragmentation of the N-oxide precursor.33

Scott and coworkers provided strong evidence for this proposal through the

transformation of stemmadenine to vallesamine.21 Kutney observed that

decarboxylation or deformylation to the imminium must occur synchronously with

fragmentation, since secodine was converted to apparicine with no loss of the

33 Potier, P. In Indole and Biogenetically Related Alkaloids; Phillipson, J. D., Zenk, M. H., Eds; Academic Press: London, 1980; Chapter 8. 24 methoxycarbonyl group at C16.20 Contrary to this, Scott proved decarboxylation or deformylation participation did not need to occur for the fragmentation to take place.

Furthermore, support for this model was rationalized by the conversion of subincanadine E (isolated from K. arborea and assumed to arise from stemmadenine) to its respective C5 nor-alkaloid apparicine (Scheme 1.3.2).5 Alternative cleavage of the N-oxide to imminium 7 existed in equilibrium with valpericine under protic conditions and could be reverted back to subincanadine E through trapping with

NaBH4. Morever, this imminium could be trapped with a number of nucleophiles, as exemplified by the 3-acetonyl derivative 83 prepared by the authors.

Scheme 1.13 Biomimetic conversion of subincanandine E to valpericine and apparicine.

H2O2 then CF3 N N TFAA N O

N H N N CH OH H MeO2C 2 H 9a 5 80 (±)-stemmadenine (±)-subincanadine E

N N N

N N N SiO2, NH3, H H Me CO 8a 2 82 81 (±)-valpericine (10%) O NaOH N H N N

N H N N H H 83 13a 79 (±)-apparicine (26%)

Based on the biomimetic routes established, it is proposed that 17-oxo- subincanadine E (obtained through a retrosynthesis of this work, see compound 5cin

Scheme 2.2.2) could be a precursor to the related natural products conolobine A and B, as well as 17-oxo-valpericine (Scheme 1.3.3). The imminium (17-oxo-valpericine 8c) could be similarly trapped to generate a number of unnatural and potential biologically active targets worthy of investigation. Not only could a number of unique structures and related natural products be constructed from subincanadine E, but also further skeletal relationships could be deciphered and provide insight to nature’s synthesis of

26 these indole alkaloid compounds. Consequently, the extensive in vivo and in vitro evidence involving subincanadine E throughout these biomimetic transformations proves a sensible pursuit.

Scheme 1.14 Proposed biomimetic transformation of 17-oxo-subincanadine E to other

natural and unnatural products.

CF3 N N O N

N N N H H H O O O 5c 84 85 (±)-17-oxo-subincanadine E

N N

NaOH N N H 8c O 88 O (±)-17-oxo-valpericine H N N N O

N N N H H H H O O O 21 86 (±)-conolobine A 87a (±)-conolidine (±)-conolobine B 87b

1.4 Retrosynthetic Analysis

While previous total syntheses of subincanadine type natural products demonstrated success and presented noteworthy transformations, each route suffered from a combination of low yields, heavy protecting group use, or undesired byproducts.

Particularly, the only previous total synthesis of (±)-subincanadine E required 10 steps and involved a late-stage transformation necessitating the separation of diastereomers, only to lead to a racemic mixture of the natural product. We aimed to provide a more efficient approach that pre-installed the ethylidene appendage in the desired E- geometry while maximizing atom economy through the least number of steps. Our initial investigations explored the utility of an intramolecular Pd-catalyzed coupling reaction as an alternative approach to construct the aza-bicylic ring system. Three such sequences have been investigated to date, each showcasing this chemistry while differing in the structure of their cross-coupling precursor.

Herein we report studies toward the first-generation total synthesis of (±)- subincanadine E. The retrosynthetic plan outlined in Scheme 1.15 would give rise to the natural product in 6 overall steps from tryptamine, providing the shortest total synthesis if accomplished. The major disconnections focused on fragmentation of a 6-5 fused ring system 91 to the larger 9-membered ring 90 and subsequent closure to a

[5.2.2]bicycle. We envisioned a final Pd-catalyzed cross-coupling reaction that would appropriately install the external olefin through #-hydride elimination. We anticipated that the requisite internal olefin would be set in the previous step from a ring

fragmentation reaction of 91. A Pictet-Spengler reaction and lactam reduction would

assemble the cyclic amide 92 from commercially available starting materials.

Scheme 1.15 Initial retrosynthetic approach toward subincanadine E.

N Pd-mediated deprotection, cross-coupling alkylation PG N N I N N N H H H 5 89 90 (±)-subincanadine E ring fragmentation

NH 2 Pictet-Spengler reduction N N O N H 18 O N N H H 92 91 OH O 93

1.5 Forward Route

The first-generation synthesis began with the Pictet-Spengler condensation of

tryptamine and levulinic acid to provide 92 (Scheme 1.16) in a 74% yield after only

four hours under reflux. Subsequent reduction using LiAlH4 provided the tetracyclic

amine framework necessary for an electrophile-induced fragmentation.34 No

34 Wawzonek, S.; Nordstrom, J. D. Journal of Medicinal Chemistry 1965, 8, 265-267 29

purification was required for either step and yields were consistent with literature

precedence.35

Scheme 1.16 Formation of tetrahydro-#-carboline 91.

NH2

N xylenes, reﬂux, LiAlH4, THF, H N O N 18 O 4 h N reﬂux, 4 h N (74%) H (84%) H OH 92 91 O 93

Since the pioneering work done by Dolby and Sakai in the early 1960’s, a

number of reports have been published concerning ring cleavage of tetra- or pentacyclic

indole compounds containing a tetrahydro-#-carboline framework (Scheme 1.17).36

35 (a) Allin, S. M.; Thomas, C. I.; Allard, J. E.; Duncton, M.; Elsegood, M. R. J.; Edgar, M. Tetrahedron Letters 2003, 44, 2335-2337. (b) Ardeo, A.; García, E.; Arrasate, S.; Lete, E.; Sotomayor, N. Tetrahedron Letters 2003, 44, 8445-8448.

36 Dolby, L. J.; Sakai, S. Journal of the American Chemical Society 1964, 86, 5362-5363. (b) Wan, A. S. C.; Yokota, M.; Ogata, K.; Aimi, N.; Sakai, S. Hetereocycles 1987, 26, 1211-1214. 30

Scheme 1.17 Sample of ring cleavage procedures.

ClCO2R, Nu

- ClCO2R, H

BrCN, Nu R N N N (RO)2O, Nu N H X H Nu X 94 RX; Li, NH3 95 X = (CH ) 2 n -x n = 0, 1, 2 RX; CN

Magnus and coworkers conducted a similar ring opening on a carboxy-

substituted system during the total synthesis of vinblastine and strychnine, encouraging

the possibility of fragmentation on our methyl-substituted skeleton.37 According to a

more recent paper published by the Bonjoch group, a similar breakage could be

accomplished through use of a nucleophilic hydroxide (Scheme 1.18).38 It was

recognized that the resultant intermediate 96 could then be subjected to elimination

conditions, providing the desired ring-expanded heterocycle 90a.

37 (a) Magnus, P.; Stamford, A.; Ladlow.; M. Journal of the American Chemical Society 1990, 112, 8210- 8212. (b) Magnus. P.; Giles, M.; Bonnert, R.; Johnson, G.; McQuire, L.; Deluca, M.; Merritt, A.; Kim, C. S.; Vicker, N. Journal of the American Chemical Society 1993, 112, 8116-8129.

38 (a) Bonjoch, J.; Fernandez, J.-C.; Valls, N. Journal of Organic Chemistry 1998, 63, 7338-7347. 31

Scheme 1.18 Bonjoch’s ring cleavage conditions applied to 91.

Na2CO3, CbzCl, Elimination Cbz N Cbz N N N then H O H 2 N N H HO H 91 96 90a

Considering the aforementioned strategies, a detailed procedure adapted from

Bonjoch was conducted. All trials were unsuccessful in developing either intermediate

96 or the desired elimination product 90a. The starting material, however, transformed into something new. Although the more substituted internal olefin was expected to form considering kinetic and thermodynamic arguments, in fact the ring-expanded external olefin was observed (Scheme 1.19). A range of additional conditions and electrophilic species were screened, including acetic anhydride, trifluoroacetic anhydride, and Boc anhydride; all of which produced the undesired external olefin 97a

(as high as 52%) with no detection of the initial olefin. It was decided to move away from the various ring opening procedures and focus on the mechanism by which this product developed.

Scheme 1.19 Unexpected ring opening product 97a.

Cbz N N X H 90a N Na2CO3, CbzCl, THF, o 0 C to rt, 1 h, then H2O, N reﬂux, 6 h H 91

Cbz N N H 97a (52%)

1.5.1 Isomerization efforts

Several references discuss the difficulties encountered on forming the internal olefin, concluding that 9-membered rings often possess elevated ring strain and can cause formation of exocyclic adducts.39 Exocyclic methylene isomers of various ring size were shown to be just as stable as their endocyclic homologues (a thermodynamic argument), but in a few cases, they are slightly more stable.40 It was decided that all means of forcing the molecule open were exhausted and conformational properties of the ring were responsible for its exo-olefin preference.

39 Schriesheim, A.; Muller, R. J.; Rowe Jr., C. A. Journal of the American Chemical Society. 1962, 84, 3164-3168.

40 Mlinari$-Majerski, K.; Vinkovi$, M.; Fry, J. Journal of Organic Chemistry 1994, 59, 664-667.

Because the system exhibited a tendency for promoting the improper olefinated compound, it was decided to take advantage of such a clean conversion and successively expose the system to isomerization conditions.41 Data supplied on alkylidenecycloalkane isomerization specified that maximum %-overlap was required and the isomerization rate was highly dependent on this.42 %-overlap, in turn, was a function of ring size, which was much greater in large rings, making rehybridization less difficult.38 Therefore, it was anticipated that contact with acid might isomerize 97 towards the theoretically more stable internal olefin (Scheme 1.20). Pressing onward, the purified exocyclic isomer

(with either a Cbz, Boc, or Troc protection group) was then subjected to a number of acidic conditions based on comparable literature (p-TsOH, HCl, H2SO4, etc.), but no obvious signs of conversion were detected.43

Scheme 1.20 Isomerization strategy.

PG acid, heat PG N N N N H H 97 90

41 For papers on olefin isomerizations, see: (a) Hubert, A. J.; Reimlinger, H. Synthesis. 1969, 97-112. (b) Marcos-Escribano, A.; Bermejo, F. A.; Bonde-Larsen, A. L.; Retuerto, J. I.; Sierra, I. H. Tetrahedron, 2009, 65, 7587-7590. (c) Lim, H. J.; Smith, C. R.; RajanBabu, T. V. Journal of Organic Chemistry 2009, 74, 4565-4572. (d) Ohta, T.; Ikegami, H.; Miyake, T.; Takaya, H. Journal of Organometallic Chemistry 1995, 502, 169-176.

43 Masters, K. S.; Flynn, B. L. Advanced Synthesis and Catalysis 2009, 351, 530-536.

Despite these results, an interesting product was consistently formed upon each isomerization trial. The resultant 1H NMR spectrum of every isomerization attempt

(varying the N-protecting group on the starting material and the identity of the acid employed) produced the same spectrum after deprotection (Figure 1.5). Further investigation utilizing LC-MS concluded a molecular (M+1) ion that was twice the molecular weight of the desired product.

Figure 1.5 1H NMR spectrum of attempted acid-induced isomerization of 97a.

This result suggested the formation of a dimer species, potentially resulting from an intermolecular cycloaddition (Scheme 1.21). The indole nitrogen could be protonated at C7 to form an S-cis diene 97c primed for intermolecular [4+2] cyclization with the external olefin diene 97a to form spiro-centered dimer 98. The Diels-Alder reaction is a documented means of dimeric natural product formation and has been portrayed as a

35 mechanism of their biosynthesis in various cases.44 Additionally, bisindoles often exhibit more potent biological activity co mpared to their monomeric counterpart.45

Scheme 1.21 Proposed dimer resulting from a Diels-Alder reaction.

Cbz N Cbz N

N p-TsOH, 80 oC H 97c N 18 h (51%) NH Cbz N 97a N NH Cbz

An alternative approach was required, void of an external methyl group in the starting cycloadduct that consistently would form an external olefin, and consequently react to form a dimer complex. Chapter 2 will detail a second-generation synthesis that circumvents this problem through use of harmicine, a tetrahydro-#-carboline that omits the troublesome methyl group.

44 Ichihara, A.; Oikawa, H. Current Organic Chemistry 1998, 2, 365-3954.

45 (a) Wright, C. W.; Allen, D.; Cai, Y.; Phillipson, J. D.; Said, I. M.; Kirby, G. C.; Warhurst, D. C. Phytotherapy Research 1992, 6, 121-124. (b) Keawpradub, N.; Kirby, G. C.; Steele, J. C. P.; Houghton, P. J. Planta Medica 1999, 65, 690-694. For an indole alkaloid dimerization via oxidation, see: (c) Ishikawa, H.; Kitajima, M.; Takayama, H. Heterocycles 2004, 63, 2597-2604. 36

Chapter 2: Second-Generation Synthesis: Exploration of an Enolate-Driven Pd-

Catalyzed Coupling Reaction

2.1 Retrosynthetic analysis

A second-generation synthesis was proposed, avoiding all problematic functionalities through a more reliable means to subincanadine E (Scheme 2.22). A similar disconnect as the previous retrosynthesis was envisioned, in which a variant of the palladium-catalyzed intramolecular coupling would prepare the aza-bicycle through use of a ketone handle (intermediate 99). Utilizing an analogous ring opening strategy as the first-generation sequence, harmicine 101, a known natural product, could be functionalized with the requisite pre-coupling moieties. Such a material could be assembled from a similar condensation of tryptamine with &-butryrolactone. This strategy would install the necessary tetracyclic amine lacking a methyl group from which a new approach could be devised.

Scheme 2.22 Second-generation retrosynthetic toward subincanadine E.

N Wittig N enolate-driven oleﬁnation cross-coupling N I N N N H H H O O 5 99 5c (±)-subincandine deprotection, alkylation, ring oxidation fragmentation

N O PG N N N N H N H H HO 102 101 100 Bischler- Napieralski

O O HN NH2 N N O H H 103 OH 18 104

2.2 Forward route

Formation of the starting tetracyclic amine ((±)-harmacine) is a known process and proceeded without complication.46 Combining tryptamine with lactone 104 provided the amido-alcohol 103 in a 64% yield from which a Bischler-Napieralski reaction was concluded (Scheme 2.23). This step involved a modified exposure of POCl3 as a solvent

46 (a) Bremner, J. B.; Winzenberg, K. N. Australian Journal of Chemistry 1984, 37, 1203-1215. (b) Szawkalo, J.; Czarnocki, S. J.; Zawadzka, A.; Wojtasiewicz, K.; Leniewski, A.; Maurin, J. K.; Czarnocki, Z.; Drabowicz, J. Tetrahedron 2007, 18, 406-413.

38 and a reagent to fuse a 6,5-imminium intermediate. The solvent was carefully removed in vacuo and the crude salts were reduced with NaBH4, resulting in 89% yield over two steps.

Scheme 2.23 Synthesis of (±)-harmicine.

NH 2 p-TsOH, toluene, O HN N H 18 N reﬂux, 9 h H 103 (64%) O OH O 104 POCl3, toluene, reﬂux, 3.5 h

NaBH4, MeOH, N N N 0 oC to rt, 1 h N H H (89%) 101 105 over 2 steps

Given that ring opening procedures are well documented for compounds containing a tetrahydro-#-carboline unit (see Chapter 1, Scheme 1.17), the successive fragmentation step occurred readily. Bonjoch’s method was directly applied, treating harmacine 101 with benzyl chloroformate and base followed by water to yield the protected alcohol 100a (Scheme 2.24). Exposure to Pd/C and hydrogen gas furnished the unprotected amino-alcohol 106. Ethanol or ethyl acetate must be used as the solvent since employing methanol provided a significant amount of the methoxy ether 107

(though this was easily removed in the presence of aqueous acid).47 It was interesting to note than although ammonium formate was used for operational ease during smaller- scale experiments, the substrate did not undergo complete deprotection upon scale-up.

Scheme 2.24 Ring fragmentation and deprotection of 100a.

H N 10% Pd/C, H2, EtOH, rt, 18 h N (75%) HO Na2CO3, CbzCl, H Cbz 106 N N N 0 oC to rt, 1 h, N H H then H2O, reﬂux, 6 h HO H 101 100a 10% Pd/C, H2, N (71%) MeOH, rt, 18 h (55%) N H MeO 107

Analogous to previous reports, the alkylation step was achieved with (Z)-2- iodobut-2-enyl methanesulfonate 111, converting the amino-alcohol 106 to its iodo-olefin counterpart 112 (Scheme 2.25).48 The alkylating species was prepared separately in three steps from crotonaldehyde, whose stereoselectivity was recently improved by Kraft and

47 For examples of similar occurrences in the literature, see: (a) Büchi, G.; Manning, R. E. Journal of the American Chemical Society 1966, 88, 2532-2535. (b) Büchi, G.; Kulsa, P.; Ogasawara, K.; Rosati, R. L. Journal of the American Chemical Society 1970, 92, 999-1005. (c) Gauvin-Hussenet, C.; Séraphin, D.; Cartier, D.; Laronze, J.-Y.; Lévy, J. Tetrahedron, 1993, 34, 465-468.

48 Wanner, M. J.; Boots, R. N. A.; Eradus, B.; de Gelder, R.; Van Maarseveen, J. H.; Hiemstra, H. Organic Letters 2009, 11, 2579-2581.

49 50 coworkers. !-Iodination and NaBH4 reduction followed by mesylation provided the mesylated (Z)-olefin 11 in excellent yields.51

Scheme 2.25 Alkylation of the amino-alcohol 106.

H N N H 1. DMAP, K CO , I , HO 2 3 2 106 H2O, THF, rt, 3 h 109 OHC (45%) MsO

K2CO3, CH3CN, I rt, 20 h 108 2. NaBH4, MeOH, 111 (90%) 0 oC, 3 h 110 (59%)

3. MsCl, NEt3, CH2Cl2, N o I 0 C, 3 h N (94%) H HO 112

Dess-Martin periodinane was initially prepared and used for oxidation of 112,

but the reaction was low yielding and a significant amount of the starting material

remained. Unsatisfied, an alternative means of oxidation was desired. Manganese (II)

dioxide was employed by James Cook to oxidize a similar indole alkaloid scaffold

49 See supporting information in: Krafft, M. E.; Cran, J. W. Synthetic Letters 2005, 8, 1263-1266.

50 Loh, T.-P.; Cao, G.-Q.; Pei, J. Tetrahedron Letters 1998, 39, 1453-1456.

51 Kuehne, M. E.; Wang, T.;Séraphin, D. Journal of Organic Chemistry 1996, 61, 7873-7881.

towards the synthesis of affinine.52 Gratifyingly, employment of this reagent supplied

the target amino-ketone 99 in a respectable yield (Scheme 2.26).

Scheme 2.26 Oxidation of 112.

MnO2, CH2Cl2, N N I I N reﬂux, 36 h N H HO (86%) H O 112 99

The coupling precursor was completed after a Na-protection using Boc

anhydride (Scheme 2.27). Although there was literature precedent for such

transformations to occur without indole N-protection, precautions were taken at this

stage in the synthesis to prevent undesired Pd complexation with the secondary amine.

Scheme 2.27 Protection of 99.

Boc2O, DMAP, N N I I N CH Cl , rt, 1 h N H O 2 2 (64%) Boc O 99 113

52 (a) Yang, J.; Rallapalli, S. K.; Cook, J. M. Tetrahedron Letters 2010, 51, 815-817. (b) Stahl, R.; Galli, R.; Güller, R.; Borschberg, H.-J. Hevetica Chimica Acta 1994, 77, 2125-2132.

2.2.1 Enolate-mediated Pd-catalyzed cross-coupling precedent

Presently, there are only a handful of documented applications of the Pd-

catalyzed intramolecular coupling of vinyl halides and ketone enolates completed; the

most recent concerning indole alkaloid systems.53 The first was performed by Piers,

who transformed an enone functionality into a methylenecyclopentane fragment

(Scheme 2.28).54

Scheme 2.28 Piers’ ring annulation using a novel Pd-catalyzed vinyl iodide and enolate

coupling of 114.

O O 0.2 equiv Pd(PPh3)4,

THF, slow addition of t-BuOK in THF/t-BuOH, H 114 I rt, 1 h 115 (65%)

53 For examples of Pd coupling of vinyl halides and ketones, see: (a) Cao, H.; Yu, J.; Wearing, X. Z.; Zhang, C.; Liu, X.; Deschamps, J.; Cook, J. M. Tetrahedron Letters 2003, 44, 8013-8017. (b) Bonjoch, J.; Diaba, F.; Puigbó, G.; Peidró, E.; Solé, D. Tetrahedron Letters 2003, 44, 8837-8390. (c) Zhao, S.; Liao, X.; Cook, J. M. Organic Letters 2002, 4, 687-690. (d) Zhou, H.; Liao, X.; Yin, W.; Ma, J.; Cook, M. A. Journal of Organic Chemistry 2006, 71, 251-259. (e) Zhang, H.; Boonsombat, J.; Padwa, A. Organic Letters 2007, 9, 279-282. (f) Boonsombat, J.; Zhang, H.; Chughtai, M. J.; Hartung, J. Padwa, A. Journal of Organic Chemistry 2008, 73, 3539-3550. (g) Shen, L.; Zhang, M.; Wu, Y.; Qin, Y. Angewandte Chemie International Edition 2008 47, 3618-3621. (h) Solé, D.; Urbaneja, X.; Bonjoch, J. Organic Letters 2005, 7, 5461-5464.

54 (a) Piers, E.; Marais, P. C. Journal of Organic Chemistry 1990, 55, 3454-3455. (b) Piers, E.; Oballa, R. M. Tetrahedron Letters 1995, 36, 5857-5860.

Slow addition of base to a solution of the enone in THF and a Pd(0) source

initiated formation of the enolate in situ via proton abstraction (see Scheme 1.31 for

mechanistic details). Piers was able to demonstrate this cyclization on a range of other

enone species, including its later application to the total synthesis of (±)-crinipellin B.55

In 2000, a similar coupling was reported on amino-tethered vinyl halides with ketone enolates, creating a bridged framework found in several classes of indole alkaloids

(Scheme 2.29 depicts optimized conditions).56 A survey of different ligands, bases, and solvents was conducted, proving its utility among the formation of nitrogen heterocycles, though with less than respectable yields (see table therein) and dimer 118 as a major byproduct.

Scheme 2.29 Bonjoch’s intramolecular coupling of vinyl halides and ketone enolates.

Bn Bn N Bn N N I 0.2 equiv Pd(PPh3)4, O 1.5 equiv KOt-Bu, THF, reﬂux, 30 min O N O (55-60%) 118 116 117 O Bn

55 Piers, E.; Renaud, J. Journal of Organic Chemistry 1993, 58, 11-13.

56 (a) Solé, D.; Peidró, E.; Bonjoch, J. Organic Letters 2000, 2, 2225-2228. (b) Solé, D.; Diaba, F.; Bonjoch, J. Journal of Organic Chemistry 2003, 68, 5746-5749. (c) Solé, D.; Vallverdú, L.; Solans, X.; Font-Bardía, M.; Bonjoch, J. Journal of the American Chemical Society 2003, 125, 1587-1594.

The same year, Cook showcased this methodology toward the construction of

several natural products. He demonstrated its utility in the first enantioselective total

synthesis of 3-oxegenated sarpagine indole alkaloids affinine, 16-epiaffinine,

vobasinediol, and 16-epivobasinediol through a common intermediate 121.46,57 The

same intermediate was later exploited to generate (+)-vellosimine 123 (Scheme 2.30).58

The yield was later improved by increasing the heat to 80 °C without the use of base.59

57 Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson, J.; Liao, X.; Cook, J. M. Journal of Organic Chemistry 2003, 68, 7565-7581.

58 Wang, T.; Cook, J. M. Organic Letters 2000, 2, 2057-2059.

59 Yin, W.; Kabir, M. S.; Wang, Z.; Rallapalli, S. K.; Ma, J.; Cook, J. M. Journal of Organic Chemistry 2010, 75, 3339-3349. 45

Scheme 2.30 Pd-catalyzed cross-coupling reaction applied by Cook.

R H 1 R2 120a R1 = CH2OH, R2 = H CH3 afﬁnine N 120b R1 = H, R = CH OH 2 2 N O 16-epiafﬁnine H

1. Pd(OAc)2, PPh3, TBAB, K2CO3, 5 mol % DMF-H2O (9:1), H H o Pd (dba) , 6 mol % 70 C, 5 h H 2 3 H O DPEphos, NaOt-Bu, CHO (71%) O N N N N H H N 2. H COCH PPh , H THF, 65-75 oC, 5 h N 3 2 3 H H H KOt-Bu, PhH, rt, 24 h; (75%) I 123 HCl (2N, aq), heat, 6 h 119 121 (+)-vellosimine (73%)

R1 H R2 CH 122a R1 = CH2OH, 3 R2 = H N vobasinediol 122b R1 = H, R = CH OH N HO 2 2 H 16-epivobasinediol

Cook provided a detailed mechanism50 (Scheme 2.31) for the intramolecular

enolate-driven cross-coupling reaction in accordance with the neutral pathway,60

though an anionic pathway would describe the catalytic cycle appropriately.61 As the

!-vinylation of ketones had only been utilized in a handful of reports compared to !-

arylation, there was little mechanistic information known. However, it was believed

that oxidative addition of Pd(0) to the vinyl halide preceded an equilibrium between

60 Heck, R. F. Palladium-catalyzed vinylation of organic halides; Dauben, W. G.; Boswell, G. A.; Danishefsky, S.; Gschwend, H. W.; Heck, R. F.; Hirshmann, R. F.; Kende, A. S., Paquette, L. A.; Posner, G. H., Eds; John Wiley & Sons: New York, 1982, Vol. 27, pp 345-390.

61 Amatore, C.; Jutand, A. Accounts of Chemical Research 2000, 33, 314-321. 46

124 and its enolate to generate Pd(II) species 125.62 Intramolecular coordination of the

Pd to the enolate followed by formation of a palladocycle underwent reductive

elimination to furnish cyclic ketone 121.

Scheme 2.31 Intramolecular enolate-driven Pd-catalyzed coupling mechanism of 119.

H H Pd(OAc)2, PPh3, O O TBAB, K2CO3, N N N N H H H DMF-H2O (9:1), H o 119 I 70 C, 5 h 121 (80%)

Pd(0)L2

H O H O N N N N H H H Pd H L 127 I PdL2 L B: 124 H O H O N

N N PdL N H 2 H H H -I- 126 I PdL2 125

62 This differs from Buchwald’s mechanistic proposal during !-arylation in which the ketone first coordinates to the Pd center prior to deprotonation. This increases the acidity of the proton !- to the ketone, allowing for employment of weaker bases. See Scheme 1 therein: (a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L Journal of the American Chemical Society 2000, 122, 1360-1370. Also, see Scheme 2 in: (b) Palucki, M.; Buchwald, S. L.; Journal of the American Chemical Society 1997, 119, 11108-11109. (c) Kawatsura, M.; Hartwig, J. F. Journal of the American Chemical Society 1999, 121, 1473-1478. 47

Analogous studies conducted on the vinyl bromide equivalent of 119, resulted in

recovered starting material. Cook proposed that oxidative addition was more facile into

the C-I bond and slower addition (as compared to the bromine substrate) would lead to

complexation of Pd(0) with the indole, thus removing it from the catalytic cycle.

However, no protecting groups strategies were employed on the electron-rich indole to

decrease catalyst interaction.63

An improved synthesis toward (+)-macroline and alstonerine published one year

later revealed more details for the same mechanism.64 If the nucleophilic addition of

the iodine by the enolate was relatively slow, this would allow time for E2 elimination

to transpire, providing an alkyne.65 Moreover, (Z)-alkylidenes are oftentimes

incompatible since #-elimination can occur.52a After Cook’s initial studies,66 it was

later revealed that bidentate ligands would provide the highest chance of success due to

their ability to suppress #-elimination and facilitate reductive elimination.67 These

conditions also supress the potential intramolecular attack of the vinyl halide on the

adjacent carbonyl group.

63 Cook utilized a methyl protection on the indole nitrogen when coupling an iodobutenyl unit only; (a) Yu, J.; Wearing, X.; Cook, J. M. Journal of Organic Chemistry 2005, 70, 3963-3979. (b) Zhai, H.; Liao, X.; Cook, J. M. Organic Letters 2004, 6, 249-252.

64 Liao, X.; Zhou, H.; Yu, J.; Cook, J. M. Journal of Organic Chemistry 2006, 71, 8884-8890.

65 This can only occur on the (Z)-ethylidene and is prohibited on the (E)-ethylidene since there is no hydrogen anti to the iodide.

66 See references 61 and 56-58.

67 Van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes, P. Chemical Reviews 2000, 100, 2741-2769.

2.3 Coupling results

Built upon the foundation set by Cook, confidence was placed in the ability of this method to functionally align with the synthesis of subincanadine E (Scheme 2.32).

Considerable effort was spent preparing a literature survey of various combinations to perform. Precautions were taken to avoid known side reactions, preventing possible dealkylation, elimination, isomerization byproducts, or coordination to the free indole nitrogen.

Scheme 2.32 Proposed intramolecular enolate-driven Pd-catalyzed coupling.

N Base, Pd0 N N I I N N N Boc O Boc O Boc O 113 128 129

A variety of both Pd(II) and Pd(0) sources were employed, with and without the use of an external ligand. The enolizing base was explored in both its strength and the identity of the counterion. Solvents were also varied and additives were tested without effectively providing the coupled product. Table 1.1 summarizes a small sample of the many conditions applied.

Scheme 2.33 Results of the cross-coupling reaction of 113.

N I B A N

N N H N I H O O 130 132

N C N D Boc N O 113

N N Boc Boc O O 131 133

Table 2.1: Highlighted conditions applied to 113.

Ligand or Product Entry Base Catalyst Solvent Time Additive & Yield Conditions A 1 KOt-Bu Pd2(dba)3 xantphos THF 4 h 130, 83% 2 NaOt-Bu Pd2(dba)3 BINAP THF 3 h 130, 27% 3 PhOK Pd2(dba)3 - THF 20 h 130, 60% 4 PhOK Pd2(dba)3 xantphos THF 20 h 130, 50% cis-1,2- 5 NaOt-Bu CuI cyclohexane- DMF 12 h 130, 90% diol Conditions B cis-1,2- 6 KOt-Bu CuI cyclohexane- DMF 12 h 132, 43% diol Conditions C 7 NaOt-Bu Pd2(dba)3 xantphos THF 4 h 131, 71% 8 LHMDS Pd2(dba)3 BINAP THF 3 h 131, 54% 9 PhOK Pd(PPh3)4 dppe THF 3 h 131, 26% Conditions D 10 KOt-Bu Pd2(dba)3 xantphos THF 4 h 133, 83% 11 PhOK Pd2(dba)3 - THF 20 h 133, 60% 12 PhOK Pd(PPh3)4 - THF 12 h 133, 50% * All temperatures were at a reflux respective to the solvent.

Scheme 2.33 illustrates the products that resulted. Initially, 113 was subjected to a combination of each palladium source and base listed in Table 2.1 without the use of an external ligand. This resulted in either recovered starting material or its deprotected congener 130. Solvents were briefly explored, since Cook could only promote coupling

52c in a mixture of DMF and H2O. All entries were conducted in this solvent system with no evidence of coupling, thus a typical organic solvent with a moderate boiling point was commissioned.

The addition of a ligand was deemed necessary in most related cases in the literature and therefore attention was next directed at exploring all possible combinations with the ligand and Pd sources in hand. Deprotected starting material 130 (entries 1-5) or dehydrohalogenation (132 or 133, entries 6, and 10-12, respectively) resulted in most cases. However, when xantphos (a large bite angle bidentate ligand) was employed with

Pd2(dba)3, a coupled product was observed. After 2D NMR analysis, it was determined that a 5-membered aza-bicycle 131 was formed rather than the desired 6-membered ring

129 (Scheme 2.33). Additionally, using a smaller bite angle ligand (Scheme 2.34) led to a corresponding decrease in the yield of 131 (entries 7-9). This was true when using either Pd2(dba)3 or Pd(PPh3)4 with a number of different bases.

Scheme 2.34 Bidentate ligands and their bite angles.68

PPh2 PPh2 b O n PPh2 H P PH 2 2 PPh2 P M P

134 135 136 xantphos BINAP dppe b n 108o 93o 86o

Interestingly, the identity of some bases employed was important. Comparing entries 7 and 10, NaOt-Bu provided the coupled product 131 whereas KOt-Bu did not when all other conditions were held constant, suggesting a possible metal cation effect.

Surprisingly, milder bases such as PhOK in combination with Pd2(dba)3 (entries 11-12) were able to produce alkyne 133.

Numerous studies also provided insights regarding the sensitivity of the reaction

to the ratio of Pd to ligand.69 Excess ligand relative to Pd is known to decrease the

amount of active Pd(0)L2 species present, which would inhibit the oxidative addition

step.62 A slower reaction rate would lead to more dehydrohalogenation byproduct and

68 For reviews on bite angles, see: (a) Birkholz (née Gensow), M. N.; Freixab, Z.; van Leeuwen, P. W. N. M. Chemical Society Reviews 2009, 38, 1099–1118. (b) Van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H. Pure and Applied Chemistry 1999, 71, 1443-1452.

69 For reviews on Pd sources and ligands, see: (a) Tsuji, J. Chapter 1 The Basic Chemistry of Organopalladium Compounds in Palladium Reagents and Catalysts: New Prospectives for the 21st Century, Tsuji, J., John Wiley & Sons, Inc.: 2004; Vol.1, pp. 1-26. (b) Choueiry, D.; Negishi, E. Chapter II.2.3 Pd(0) and Pd(II) Complexes Containing Phosphorous and Other Group 15 Atom Ligands in Handbook of Organopalladium Chemistry for Organic Synthesis, Negishi, E., John Wiley & Sons, Inc,: 2002; Vol. 1, pp. 47-66.

a lower yield of the coupled product. Counterintuitive to this, Cook found that a large

excess of phosphine was necessary when using a Pd(II) species and the exact mol %

was substrate dependent.58 The reaction took much longer (3 days) but the amount of

byproducts was significantly decreased.

Experimental exploration of varying Pd(0)/ligand ratios on our substrate did not

affect the yield of 131 to a significant extent (performed on entry 7, Table 2.1). The

optimal catalyst loading was found to be 20 mol % Pd2(dba)3 with 15 mol % xantphos

before the yield began to consistently degrade.

Lastly, a new method70 reported on a copper-mediated preparation of vinyl

sulfides encouraged Cook and coworkers to attempt the coupling conditions on system

119.71 A handful of conditions were attempted, which led to either deprotected starting

material (Table 2.1, entry 5) or deprotected alkyne (Table 2.1, entry 6).

To demonstrate viability of the final steps toward subincanadine E, compound

131 was carried through a deprotection and a concluding Wittig reaction (Scheme 2.35).72

Both steps operated with ease, producing the [5.2.1]-azabicyclo variant of subincanadine

70 Kabir, M. S.; Van Linn, M. L.; Monte, A.; Cook, J. M. Organic Letters 2008, 10, 3363-3366.

71 See reference 58 and the mechanism therein.

72 For an example of a Wittig reaction conducted on a similar scaffold, see Scheme 3 in: Srirama Sarma, P. V. V.; Cook, J. M. Organic Letters, 2006, 8, 1017-1020 and Yu, J.; Wang, T.; Wearing, X. Z.; Ma, J.; Cook, J. M. Journal of Organic Chemistry 2003, 68, 5852-5859. 53

Scheme 2.35 Wittig reaction established on the 5-membered conjugate of

subincanadine E.

N N N TFA, CH2Cl2, CH3PPh3Br, nBuLi,

rt, 1.5 h THF, 0 oC, 1 h, N (95%) N N Boc H then rt, 4.5 h H O O 131 137 (93%) 138

2.3.1 Control experiments

To further probe the nature of the enolate-driven cross-coupling reaction, a number of control reactions were considered (Table 2.2). The reaction was run with only base present, which afforded no 5-membered coupled product 131 (entries 1-3) nor was formation of alkyne 133 detected. Exposure to only a Pd source provided full recovery of the starting material (entries 4-5). Finally, entry 6 and 7 also resulted in starting material exclusively. This indicated no 5-membered ring could be produced without the collective presence of a Pd source, a ligand, and a base.

Table 2.2: Control experiment conditions.

Entry Base Catalyst Ligand Solvent Time Product 1 KOt-Bu - - THF 18 h 113 2 NaOt-Bu - - THF 18 h 113 3 PhOK - - THF 18 h 113 4 - Pd2(dba)3 - THF 18 h 113 5 - Pd(PPh3)4 - THF 18 h 113 6 - Pd2(dba)3 xantphos THF 18 h 113 7 NaOt-Bu Pd2(dba)3 - THF 18 h 113 * All temperatures were at a reflux respective to the solvent.

To ensure the enolate was indeed generated during the course of the catalytic cycle, a silyl enol ether was synthesized and exposed to equivalent conditions listed in

Table 1.1 (Scheme 2.36). The results exactly mirrored its ketone predecessor, differing only in the addition of TBAF.73 The same control experiments were completed on 139 and 139a as well, providing parallel conclusions. This indicated formation of the enolate was prepared as expected and did not interfere with the mechanism leading to 131.

73 See reference 55a for an example of a Pd-catalyzed alkenylation with a silyl enol ether as well as: (a) Kuwajima, I.; Urabe, H. Journal of the American Chemical Society 1982, 104, 6831-6833. (b) Tsukano, C.; Zhao, L.; Takemoto, Y.; Hirama, M. European Journal of Organic Chemistry 2010, 22, 4198-4200. (c) Deiters, A.; Chen, K.; Eary, C. T.; Martin, S. F. Journal of Organic Chemistry 2003, 125, 4541-4550. (d) Hong, X.; France, S.; Padwa, A. Tetrahedron 2007, 63, 5962-5976.

Scheme 2.36 TMS-enol ether formation.

N I N I TESCl, 1M LHMDS,

N NEt , THF, -78 oC, 4 h N Boc 3 Boc O (98%) TESO 113 139

To guarantee all Pd sources were reactive, both Pd2(dba)3 and Pd(PPh3)4 were freshly prepared and employed in entries 1, 7, and 9 of Table 1.1.74 Furthermore, the purchased reagents were tested in the aforementioned entries using a glove box. Each reaction was reproducible in yield and product identity to the previous tested conditions under normal bench top procedures.

2.3.2 Proposal of mechanism

Research of the literature revealed that similar transformations failed to undergo

the desired cyclization. Bonjoch and coworkers were able to promote coupling of a

74 (a) Coulson, D. R. Chapter 4.23 Tetrakis(triphenylphosphine)Palladium(0) in Inorganic Syntheses, Cotton, F. A., McGraw-Hill, Inc,: 1972; Vol. 13, pp. 121-124. (b) Backväll, J.-E.; Nyström, J.-E.; Nordberg, R. E. Journal of the American Chemical Society 1985, 107, 3676-3686. (c) Zalesskiy, S. S.; Ananikov, V. P. Organometallics 2012, 31, 2302-2309.

vinyl iodide and ketone enolate on a model study towards the synthesis of

strychnopivotine, though the required system for completion of the natural product did

not support a parallel coupling (Scheme 2.37).75

Scheme 2.37 Attempted azatricyclic formation toward strychnopivotine.

N H H I N Pd(PPH3)4, t-BuOK X

NO2 NO2 H O O 140 140

Furthermore, intramolecular cyclization of 9-membered rings was documented

to be sluggish and prone to side reactions, such as dehalogenation or dimerization

(neither of which were isolated for this system) and forcing an internalized 6-membered

ring may have a higher degree of strain than its more precedented 8-membered

counterpart.76 Additionally, 9-membered rings possess the highest ring strain (12.6

kcal/mol) of all ring sizes from 5 to 16.77 Since the same iodo-ethylidene appendage

75 (a) Solé, D.; Urbaneja, X.; Cordero-Vargas, A.; Bonjoch, J. Advanced Synthetic Catalysis 2004, 346, 1646-1650. (b) Solé, D.; Urbaneja, X.; Cordero-Vargas, A.; Bonjoch, J. Tetrahedron 2007, 63, 10177- 10184.

76 Ma, S.; Negishi, E. Journal of the American Chemical Society 1995, 117, 6345-6357.

77 Anslyn, E. V.; Dennis A. D. Chapter 2 Strain and Stability in Modern Physical Organic Chemistry, University Science: 2006; Vol. 1, pp. 65-143. 57

has been utilized in analogous transformations, it was believed that the ring size prior to

bicycle formation imparts geometric constraints that are not present in other systems

(Figure 2.6) though calculations would be needed to determine its exact conformation.

our 9-membered ring Cook's 8-membered ring56 Padwa's 6-membered ring52f

H N N I O I

N N H H N H N Boc DMB O 113 119 I O 142

N N I O BocN N O I I O N N 125a 128 H DMB 143

Figure 2.6 Conformation of 113, 119, 142, and their respective enolates.

It was for these reasons that the desired bicycle 129 was regarded as unable to form, allowing for a different reaction pathway to ensue. The undesired bicycle 131 was proposed to materialize according to Scheme 2.38. After standard oxidative addition and base-induced enolate formation, #-hydride elimination could occur to generate an allene.78 Protonation at this site would provide an imminium, equipped to undergo a

Mannich reaction with the pendant enolate to provide the undesired 131 as a racemic

78 Allenes are known intermediates in many Pd-catalyzed reactions. See: (a) Asari, A.; Angelov, P.; Auty, J. M.; Hayes, C. J. Tetrahedron Letters 2007, 48, 2631-2634. (b) Shigehisa, H.; Jikihara, T.; Takizawa, O.; Nagase, H.; Honda, T. Tetrahedron Letters 2008, 49, 3983-3986.

58 mixture.

Scheme 2.38 Proposed mechanism of the 5-membered azabicycle 131.

N N I Pd0, base, ligand,

N N heat Boc Boc O O 113 131

oxidative Mannich addition

N L PdII L N N N Boc I O Boc O 144 146 L I enolization II Pd H+ L !-hydride H elimination N N N N Boc O Boc O 128a 145

This mechanism rationalizes the formation of the 5-membered ring through

which a Pd catalyst and a base was required, supporting the control study results (see

Table 2.2). However, addition of an external ligand was also necessary and this result

opposed the presumption (based on literature precedent) that large bite angle ligands

suppress #-hydride elimination. In fact, our results indicated larger bite angle ligands

(bidentate) increased #-hydride elimination, since more of the Mannich product was

obtained in the presence of a larger bite angle ligand. The control experiments also rule

out the possibility of alkyne isomerization since base alone does not produce any

alkyne. Additionally, the catalytic cycles does not seem to require a strong base for

enolization but a specific salt indicating a cationic metal effect, since NaOt-Bu

provided the coupled product and KOt-Bu did not. This was in accordance with the

literature where KOt-Bu and a Pd source with or without ligand frequently led to

dehydrohalogenation.79

2.4 Further Studies

An alternative cyclization was envisioned to mask the seemingly activated

methylene linker and prevent #-hydride elimination from occurring, allowing a Pd-

catalyzed coupling to transpire. Inserting a carbonyl at this position would be

attainable synthetically and inhibit the undesired cyclized product from forming

(Scheme 2.39).

79 See reference 52 for examples.

Scheme 2.39 Proposed amide precursor 147 that prevents #-hydride elimination.

N N I Pd0, base, ligand, O

N heat N Boc Boc O O 147 148

Rotational restrictions about the amide bond may impart the necessary

geometric conformation such that orbital alignment and therefore coupling would

ensue. Both inter- and intramolecular Pd-catalyzed !-arylation of amides is known,80

though it is mostly limited to lactams or intramolecular couplings of acyclic amides,

with a few exceptions.81 Intermolecular Pd-catalyzed !-vinylation of amide enolates

has only been demonstrated on oxindoles and in only one case to date.82 On the

contrary, intramolecular coupling of a ketone enolate with an amido-vinylhalide has not

been documented.83

80 (a) Deppermann, N.; Thomanek, H.; Prenzel, A. H. G. P.; Maison, W. Journal of Organic Chemistry 2010, 75, 5994-6000. See reference 11 therein. (b) Okita, T.; Osobe, M. Tetrahedron 1994, 50, 11143- 11152. (c) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. Journal of Organic Chemistry 1998, 63, 6546-6553.

81 Hama, T.; Culkin, D. A.; Hartwig, J. F. Journal of the American Chemical Society 2006, 128, 4976-4985.

82 Taylor, A. M.; Altman, R. A.; Buchwald, S. L. Journal of the American Chemical Society 2009, 131, 9900–9901.

83 For an example of an alkene coupled to an amido-vinylbromide, see: Birman, V. B.; Rawal, V. H. Journal of Organic Chemistry 1998, 63, 9146-9147.

2.4.1 Amide synthesis

The proposed amide 147 was formed via ring opening of the common

intermediate 101 with anhydride 149, providing amido-alcohol 150 in a respectable

91% yield (Scheme 2.40). The anhydride was readily synthesized in three steps from

crotonaldehyde using known procedures (Scheme 2.41).84 Indolylic oxidation and

protection afforded the coupling precursor 147.

Scheme 2.40 Forward route toward coupling precursor 147.

O o Na2CO3, THF, 0 C to rt, N N I N 2 h then H O, reﬂux, 18 h N H 2 H HO (91%) 101 150 O O MnO , CH Cl , rt, 36 h O 2 2 2 (91%) I 149 I

O O

Boc2O, CH2Cl2, N N I I N N O DMAP, rt, 3 h O Boc (92%) H 147 151

84 Iodination: (a) see reference 48. Pinnick oxidation; Dalcanale, E. Journal of Organic Chemistry 1986, 51, 567-569. (b) Anhydride formation: (c) Kazemi, F. Synthetic Communications 2007, 37, 3219-3223. 62

Scheme 2.41 Synthesis of anhydride 149.

1. I2, DMAP, K2CO3, SOCl2, Na2CO3, H2O/THF, rt, 3 h O (92%) 1:1 CH2Cl2/dioxane, O O OHC HO O I reﬂux, 18 h 2. NaClO2, NaH2PO4, I I 108 2-methyl-2-butene, 152 (45%) 149 t-BuOH/H2O, rt, 2 h (42%)

All entries listed in Table 2.1 were applied to the amide variant in addition to other combinations described in Table 2.3 (Scheme 2.42). Each attempt resulted in either recovery of starting material (entries 1-4) or dehydrohalogenation product 154

(entry 5).

Scheme 2.42 Results of the cross-coupling reaction of 147.

N I N Boc O O 147 conditions N or O Table 2.1 & Table 2.3 N Boc O N 154 I N Boc TESO 153

Table 2.3 A sample of cross-coupling conditions applied to 147 and 153.

Product Entry Base Catalyst Ligand Additive Solvent & Yield proton 147, 1* K CO Pd (OAc) PPh Toluene 2 3 2 2 3 sponge 99% 154, 2* LHMDS Pd (dba) BINAP - THF 2 3 99% 147, 3* PhOK Pd (dba) - - THF 2 3 70% 147, 4* NaOt-Bu Pd (OAc) P(t-Bu) - THF 2 2 3 97% 154, 5** PhOK Pd(PPh ) Cl - TBACl THF 3 2 2 80% * Using 147 as the starting material. ** Using 153 as the starting material.

Moreover, the TES-enol ether 153 was synthesized and subjected to a number of equivalent conditions, parallel to the amine version 139 in Scheme 2.36 above. Again, the results were consistent with their ketone congener and no evidence of the desired 6- membered bicycle was detected.

2.4.2 Conjugate addition

It was decided to explore other coupling chemistries that could be applied to our substrate and accomplish the identical carbon-carbon bond formation. Switching the original electronics of the coupling precursor would impart nucleophilicity to the iodocarbon instead. An intramolecular Michael reaction could occur between a vinyl 64

organometallic species and a tethered !,#-unsaturated ester. Additionally, such a

substrate would allow for investigations of %-allyl reductive Heck coupling conditions.

Fortunately, the known intermediate 158 could be extended to obtain the desired

functionalities required for a 1,4-conjugate addition to proceed.85 Scheme 2.43 outlines

the forward route, which was subjected to Bonjoch’s ring opening strategy using

TrocCl as the electrophile.37 Protecting group removal, alkylation, and indole nitrogen

protection successfully produced the conjugate addition precursor 160. t-BuLi

mediated iodine-lithium exchange followed by the addition of MnCl2 and CuCl would

convert ester 160 to [5.2.2]-azabicycle 162. All efforts led to decomposition of the

starting material with no obvious signs of conjugate addition.

85 (a) Fokas, D.; Wang, Z. Synthetic Communications 2008, 38, 3816-3822. (b) Magnus, P.; Giles, M.; Tetrahedron Letters 1993, 34, 6355-6358. 65

Scheme 2.43 Forward route toward conjugate addition precursor 160.

AcOH, reﬂux,

NH2 N O N 5.5 h N H 18 (83%) H O O MeO2C 157 O O 9-BBN, THF, 65 oC, 1 h O then diluted in MeOH, 156 2 M HCl in Et2O, 1 h (72%)

Na2CO3, TrocCl, THF, Troc o N 0 C, to rt, 1h N N N H H then H2O, reﬂux, 20 h MeO2C MeO2C (50%) 159 158

1. Zn, AcOH, 2. K2CO3, THF, THF, rt, 5 h rt, 5h (96%) (75%) MsO

I 111

N 20 1. Boc2O, CH2Cl2, DMAP, rt, 3 h (71%) N I 20 N N 15 H 2. t-BuLi, -78 oC, 1 h Boc 15 MeO C MeO2C 2 160 3. MnCl2, CuCl2, 162 THF, -30 oC, 2 h

The conjugate addition was next attempted on amide 164 to determine if the methylene linker was once again problematic (Scheme 2.44). Tetrahydro-#-carboline

158 was modified to undergo ring opening directly with anhydride 160 (see Scheme

2.41 for its synthesis). Exposure to the copper-mediated coupling conditions provided only recovery of starting material and with more equivalents if t-BuLi, a complex mixture of inseparable compounds was produced.

Scheme 2.44 Forward route toward conjugate addition amide precursor 164.

O K2CO3, THF, rt, 5 h (76%) N N I

N O O N H H MeO2C MeO C O 2 158 163 I 160 I

Boc2O, CH2Cl2, DMAP, rt, 3 h (98%)

N O O o 1. t-BuLi, -78 C, 1 h 15 N I N N Boc 2. MnCl2, CuCl2, Boc o 20 MeO2C THF, - 30 C, 2 h MeO2C 165 164

Other researchers have encountered similar difficulties in their attempts to form

the C15-C20 bond. Scheme 2.45 outlines Stork’s system in which closure of the

piperidine ring proceeded in poor yields and was susceptible to a number of side

reactions, including HI elimination, loss of the iodobutenyl side chain, and

deiodination.86 Utilizing greater amounts of lithium not surprisingly provided a

complex mixture of products.

86 (a) Eichberg, M. J.; Dorta, R. L.; Grotjahn, D. B.; Lamottke, K.; Schmidt, M.; Vollhardt, K. P. C. Journal of the American Chemical Society 2001, 123, 9324-9337. (b) Bonjoch, J.; Solé, D. Chemical Reviews 2000, 100, 3455-3482. (c) Martin, D. B. C.; Nguyen, L.; Vanderwal, C. D. Journal of Organic Chemistry 2012, 77, 17-47.

Scheme 2.45 Stork’s conversion of diester 166 to pentacyclic 167.

OTBS

N I N 1. t-BuLi, -78 oC

2. MnCl2, CuCl2, THF, o N OTBS N H -30 C CO2Me H H (35%) MeO C CO2Me 2 CO2Me 166 167

Toward the total synthesis of vincorine, Qin struggled to form a similar bond

(Scheme 2.46).87 The group was able to isolate only the amine starting material with

loss of the side chain by use of either n-BuLi or t-BuLi with CuCN/LiCl88 or TMSCl89

in THF or HMPA at varying temperature. They even attempted a Pd-catalyzed Heck

coupling (with Pd2(OAc)2, PPh3, TBACl, and HCO2Na, NEt3, or piperidine), as well as

90 a radical cyclization (initiated with Bu3SnH, AIBN), and a Ni-catalyzed addition. All

resulted in deiodinated product.

87 Zhang, M.; Huang, H.; Shen. L.; Qin, Y. Journal of the American Chemical Society 2009, 131, 6013- 6020.

88 Dieter, R. K.; Oba, G.; Chandupatla, K. R.; Topping, C. M.; Lu, K.; Watson, R. T. Journal of Organic Chemistry 2004, 69, 3076-3086.

89 Piers, E.; Harrison, C. L.; Zetina-Rocha, C. Organic Letters 2001, 3, 3245-3247.

90 For examples of Ni-catalyzed couplings, see references 56-57 and: Yu, S.; Berner, O. M.; Cook, J. M Journal of the American Chemical Society 2000, 122, 7827-7828. For examples of radical additions, see reference 50.

Scheme 2.46 Qin’s attempted synthesis of 169.

CO2Me

MeO2C Michael addition MeO MeO N or reductive Heck N N I N

168 169

It was originally proposed that %-allyl/Heck coupling could be investigated via the sequence outlined in Scheme 2.47. This was abandoned after a significant portion of the literature revealed that comparable systems failed to produce a cyclization product.85

Scheme 2.47 Proposed synthesis of 170 en route toward 172 via %-allyl coupling.

N I DIBAL-H N I N N Boc reduction Boc MeO2C OH 161 170 Pd0, ligand

N I N N Boc Boc 172 171 Pd OH

Another option was to attempt the coupling on an alkene such that the external olefin at C16 could be directly accessed (Scheme 2.48). Reduction of the !,#- unsaturated ester and acetylation or mesylation would generate an adduct prepped for cuperate-mediated cyclization by the same means as above, with expulsion of the leaving group. Additionally, this route could be explored with the amide version 165, necessitating a selective reductant in the first step. This approach was abandoned as well since generating a nucleophilic carbon at C20 has proved problematic under the necessary reaction conditions.

Scheme 2.48 Proposed synthesis of 174 and 175 en route toward Cu-mediated coupling.

R R

I I N selective 16 N reduction N N H H MeO2C OH R = H2 161 R = H2 170 or O 165 or O 173 O-acetylation

N R R Cu-mediated coupling N I N N Boc H OAc

R = H2 172 R = H2 174 or O 176 or O 175

2.4.3 Intramolecular enolate addition to 2-oxobutanamide

Though a coupling reaction would create a new carbon-carbon bond and furnish

the requisite (E)-ethylidene appendage, addition of an enolate to an electrophilic center

bearing by a leaving group would accomplish the same result. However this alternative

route is less appealing because alkene geometry would not be set. Interested in a final

effort to create the challenging C15-C20 bond, we investigated methods toward such a

system.

Modeled after work done by Harley-Mason (Scheme 2.49), alkene isomers were readily separable after an enolate addition and methoxide elimination of 177.91

Scheme 2.49 Harley-Mason’s synthesis of 178.

MeO O N O Na O E:Z N 3:2 Br THF N N H H O O 177 178

In lieu of repeating his work, we sought a 2-oxobutanoyl group to decorate the

Nb-tryptamine that could furnish a mixture of the (E) and (Z) appendage upon

elimination of water (Scheme 2.50). The desired (E) isomer could readily be

transformed to subincanadine E through an amide reduction and Wittig reaction.

91 (a) Harley-Mason, J. Pure and Applied Chemistry 1975, 41, 167-174. Dadson, B. A.; Harley-Mason, J.; Foster, G. H. Chemical Communications 1968, 1233. (c) Crawley, G. C.; Harley-Mason, J. Chemical Communications 1971, 685. (d) Ban, Y.; Yoshida, K.; Goto J.; Oishi, T.; Takeda, E. Tetrahedron 1983, 39, 3657-3668. 72

Scheme 2.50 Proposed route to 180 and attempted synthesis of acid chloride 179.

O O Cl N O O N O N 179 N N N H H HO H O 101 180 178

Initial efforts toward synthesizing the unassuming acid chloride from !-

ketobutyric acid were unrewarding (Scheme 2.51). Neither thionyl chloride nor oxalyl

chloride were capable of providing the desired 179. Construction of its anhydride also

proved fruitless. Inspection of the literature revealed few claims of its construction,92

though more recent manuscripts disclosed 2-oxobutanoyl chloride was inaccessible

under typical chlorinating conditions.93

92 (a) Chen, J.-H.; Venkatesham, U.; Lee, L.-C.; Chen, K. Tetrahedron 2006, 62, 887-893. (b) Ayitou, A. J.-L.; and Sivaguru, J. Chemical Communications 2001, 47, 2568-2570.

93 !,!-dichloromethyl methyl ether has been used to synthesize 179, though this reagent was not available at the time of this work. See: (a) Pansare, S. V.; Ravi, R. G.; Jain, R. P. Journal of Organic Chemistry 1998, 63, 4120-4124. (b) Ottenheijm, H. C. J.; Tijhuis, M. W. Organic Syntheses 1983, 61, 1-4. (c) Snider, B. B.; Song, F.; Foxman, B. M. Journal of Organic Chemistry 2000, 65, 793-800. (d) Otttenheijm, H. C. J.; De Man, J. H. M. Synthesis 1975, 3, 163-164. Trichloroisocyanuric acid can also accomplish this transformation and was also unavailable at the time of this work. See: (e) Rodrigues, R. C.; Barros, I. M. A.; Lima, E. L. S. Tetrahedron Letters 2005, 46, 5945-5947. This could also be accomplished via N- alkylation with 1-bromo-2-butanone, but this reagent was not accessible at the time. 73

Scheme 2.51 Attempted synthesis of acid chloride 179 or anhydride 182.

O O O O conditions or HO Cl O O Table 2.4 O O O 181 179 182

Table 2.4 Conditions for the acid chloride or anhydride formation.

Entry Conditions Desired Product 1 SOCl2, CH2Cl2, reflux, 18 h 179 2 (COCl)2, CH2Cl2, reflux, 18 h 179 3 SOCl2, reflux, 18 h 179 4 (COCl)2, reflux, 18 h 179 5 (COCl)2, reflux, DMF/ H2Cl2, 18 h 179 SOCl , K CO , CH Cl , dibenzylamine TFA salt, 5 2 2 3 2 2 182 0 oC to reflux, 5 h o 6 P2O5, CH2Cl2, 45 C, 45 min 182 o o 7 DCC, CH2Cl2, 0 C to rt, 18 h then 45 C, 2 h 182

Sensibly, standard peptide coupling conditions were tried next on amino-alcohol

106 (see Scheme 2.24 for its synthesis). No amide bond was formed, even using other coupling agents such as HATU or DCC (Scheme 2.52).94

94 Reference 92e can be used to directly access the desired amide for the in situ generation of the acid chloride from 2-oxobutenoic acid 181. 74

Scheme 2.52 Attempted coupling of amino-alcohol 106 and 2-oxobutenoic acid 181.

O O H EDCI, DIEA, DMAP, N N HO N N O HO O o HO H CH2Cl2, 0 C to rt, 18 h H 106 181 183

As a proof-of-concept, the benzylamine was exposed to the same coupling conditions (Scheme 2.53). This seemingly simple procedure did not afford the desired amide and produced an inseparable mixture of multiple products that was un- interpretable by 1H or 13C NMR.

Scheme 2.53 Coupling of benzylamine and acid 181 effort.

O benzylamine, EDCI, O Bn HO N H O DIEA, DMAP, CH2Cl2, O 0 oC to rt, 18 h 181 184

2.4.4 Intramolecular enolate addition to ethyl-2-oxoacetate

Instead, our attention was directed toward an ethyl 2-oxoacetate moiety as the electrophile (Scheme 2.54).95 This could displace an ethoxide group in which the more electrophilic carbonyl would be attacked for subsequent functional group manipulation.

The three carbonyl groups would need to be differentiated for an amide reduction and two separate Wittig reactions at a later stage. Though less attractive than the original electrophile, the desired aza-bicycle was expected to form with ease. Employing typical ring opening conditions, the di-oxoacetate 186 was constructed and exposed to conditions that orthogonally saponified the ester over the amide. All efforts led to elimination of the ester exclusively, possibly due to its propensity to be conjugated with the indole ring.

95 For synthesis of ethyl-2-chloro-2-oxoacetate 185, see: (a) Zhao, Y.; Wang, G.; Li, Y.; Wang, S.; Li, Z. Chinese Journal of Chemistry 2010, 28, 475-479. The anhydride is also known; (b) Plusquellec, D.; Roulleau, F.; Lefeuvre, M. Tetrahedron Letters 1988, 44, 2471-2476. 76

Scheme 2.54 Nb-alkylation and projected enolate-driven ring closure.

O OEt

N o Na2CO3, 0 C to rt, N O N H N Na CO , H O, 101 1 h, then reﬂux, 14 h H O 2 3 2 O rt, 18 h, (67%) 186 (37%) O O EtO OEt OEt Cl N ester O O saponiﬁcation N 185 H 187 O O OEt OEt [O] N N O O N N H O H HO 189 188

5-exo-trig

N O N

O N H N O H 190 191

The alkenyl intermediate offered an opportunity to undergo selective hydration,

affording the alcohol 188 through either hydroboration or oxymercuration,96 dependent

on the electronic behavior of the double bond. Both were attempted and each failed to

provide the desired alcohol (Scheme 2.55).

96 Beerli, R.; Borschberg, H.-J. Helvetica Chimica Acta, 1991, 74, 110-116. 77

Scheme 2.55 Oxymercuration and hydroboration conditions applied to alkene 187.

O Na2CO3, rt, 1 h, OEt N N N then reﬂux, 22 h O H (90%) N 16 H 101 15 187 O Conditions:

OEt 1 M BH3 THF, Cl rt, 45 min O or 185 Hg(OAc)2, NaBH4, o THF/H2O, 0 C to rt, 24 h

O O OEt OEt

N N O O N N H H R R = BH3 192 193 HO or OH 188

A comparable system was found to undergo hydroboration-oxidation at the

desired C16 position to complete allocriptopine (Scheme 2.56).97 Regioselectivity was

rationalized based on a dative N-B complex, which undergoes intramolecular

hydroboration with one of two possible intermediates; a [5.3.1]bicycle 195 (consisting

of a fused 8 and 6-membered ring) or a [4.4.1]bicycle 196 (two fused 7-membered

rings), the later being more thermodynamically stable.98

97 Valpuesta, M.; Díaz, A.; Suau, R.; Torres, G. European Journal of Organic Chemistry 2006, 4, 964-971.

98 H. C. Brown, Organic Syntheses via Boranes, Wiley-Interscience, New York, 1975. 78

Scheme 2.56 Hydroboration of 194 en route to allocriptopine.

1. 1 M BH3 THF, rt, 30 min O (42%) PCC, CH2Cl2, R R R 16 N N O N 2. H2O2, phosphate HO AcONa, rt, 2 h O (60%) 194 buffer (pH = 8), 197 198 OMe THF, reﬂux, 3 h (74%) R = Bn, PMB, or Me OMe

R H R H N N Thermodynamically B B H more stable H 195 196 [8, 6] [7, 7]

Our system would prepare either a [5.31]-bicycle (a fused 7 and 6-membered ring) or a [5.2.1]-bicycle (a fused 8 and 5-membered ring), in which the former was presumed to be more stable (Figure 2.7). However, the indole nitrogen was also available for dative bonding and could form a 5-membered ring with the undesired regioisomer (the 4-membered ring would be too strained). It’s also possible that the ethyl 2-oxoacetate moiety was complexing with the borane. Since the lone pairs on both Na and Nb are delocalized through conjugation, it was plausible that regiocontrol through dative bonding could not be achieved. Furthermore, prior evidence suggesting conformational flexibility of the 9-membered 187 may have prevented any possible dative bond selectivity from occurring. This could enable orbital alignment of the C15-

C16 olefin such that conjugation with the indole was possible, substantially lowering its

HOMO.

O O OEt OEt H N O N H B O B H H N N H H [7, 6] [8, 5] 199 200 Thermodynamically more stable O OEt H H B N O O O

N OEt N N B [9, 5] H H H 201 202

Figure 2.7 Predicted intermediates resulting from the hydroboration of compound 187.

Experimentally, no boranyl derivative was isolated nor was starting material recovered, suggesting hydration through this method was not probable on our scaffold

(excess borane was used to circumvent exclusive complexation). Failure to promote hydration via oxymercuration also demonstrated low reactivity of the double bond.

2.4.5 Intermolecular enolate-driven Pd-catalyzed cross-coupling

At this stage, all approaches to place an electrophilic fragment on the Nb atom was exhausted and the choice of coupling was revisited through intermolecular

means.99

Scheme 2.57 outlines a pathway by which Pd-catalyazed enolate-driven coupling of 142 would proceed with fragment 205 or 206. Liberation of 207 to the free alcohol followed by mesylation and Nb-deprotection presents an intermediate arranged for SN2 displacement to afford 209. This method ensures the olefin’s geometry as our endeavors originally intended.

Scheme 2.57 Route toward Pd-catalyzed intermolecular coupling of 142 with 205.

Troc N 1. MnO2, CH2Cl2, Pd (dba) , xantphos, Troc N 2 3 Troc N Boc O N N reﬂux, 36 h 142 NaOt-Bu, THF N H (86%) Boc O HO RO 207 203 2. Boc2O, CH2Cl2, DMAP, rt, 3 h I (99%) R = TES 205 RO or TBS 206 O-deprotect, mesylate

N Troc Wittig N-deprotect, N (±)-subincanadine E N N Boc cyclize Boc O 5 O 209 208 MsO

99 For precedent on intermolecular vinylation of ketone enolates, see: (a) Chieffi, A.; Kamikawa, K.; Åhman, J.; Fox, J. M.; Buchwald, S. L. Organic Letters 2001, 3, 1897-1900. (b) Cosner, C. C.; Helquist, P. Organic Letters 2011, 13, 3563-3567. (c) Cosner, C. C.; Bhaskara Reddy Iska, V.a; Chatterjee, A.; Markiewicz, J. T.; Corden, S. J.; Loefstedt, J.; Ankner, T.; Richer, J.; Hulett, T.; Schauer, D. J.; Wiest, O.; Helquist, P. European Journal of Organic Chemistry 2013, 1, 162-172.

The forward direction recycled previously synthesized amino-alcohol 106 as

well as iodo-butenol 110 (Scheme 2.25) which was silyl protected to generate the

requisite intermolecular coupling partner. Exposure to selected coupling conditions

(Table 2.1, entries 7, 2 and Table 2.3, entry 4) with an increased concentration led to Na

deprotection of the Boc group exclusively. The TMS-enol ether of 142 was also

generated and exposed to identical conditions, resulting in starting material once again.

Any new methine peak corresponding to the desired product was not isolated in a

reasonable yield necessary for completion of the synthesis.

2.4.6 Control reactions

To discredit operational complications and demonstrate that the various

conditions employed were sound, a model substrate was studied (Scheme 2.58). Aryl

bromide indeed coupled to tetralone100 substantiating its feasibility, providing both the

mono-coupled product (low catalyst loading) and the di-coupled product (high catalyst

100 For other examples of !-arylation of ketone enolates, see: (a) Marion, N.; Ecarnot, E. C.; Navarro, O.; Amoroso, D.; Bell, A.; Nolan, S. P. Journal of Organic Chemistry 2006, 71, 3816-3821. (b) Lessi, M.; Masini, T.; Nucara, L.; Bellina, F.; Rossi, R. Advanced Synthesis and Catalysis 2011, 353, 501-507. (c) Viciu, M. S.; Germaneau, R. F.; Nolan, S. P. Organic Letters 2002, 4, 4053-4056. (d) Hamanda T.; Chieffi, A.; Åhman, J.; Buchwald, S. L. Journal of Organic Chemistry 2002, 124, 1261-1268. (e) Muratake, H.; Natsume, M. Tetrahedron Letters 1997, 38, 7581-7582. (f) Åhman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. Journal of the American Chemical Society 1998, 120, 1918-1919. (g) Satoh, T.; Kametani, Y.; Terao, Y.; Miura, M.; Nomura, M. Tetrahedron Letters 1999, 40, 5345-5348. (h) Liao, X.; Weng, Z.; Hartwig, J. F. Journal of the American Chemical Society 2008, 130, 195-200.

loading).101 However, utilizing the silyl-protected iodobutene 205 or 206 with tetralone

did not deliver a clean product, even with very low catalyst loading.

Ni(COD)2-mediated vinylation was also attempted in place of Pd (again,

utilizing a bidentate ligand), resulting in only recovered starting material.102 Multiple

new alkene peaks were detected (presumably due to di-coupling, isomerization, or

enolate addition to the carbonyl) and a mono-coupled product was not isolable under

any chromatography conditions applied. As the reaction is known to be ligand-

dependent, comprehensive screening of a number of conditions would be needed to

uncover an optimal system.

Scheme 2.58 Synthesis of model substrate 212 establishing Pd-catalyzed coupling

validity.

O O Ph Br Pd2(dba)3, BINAP, Ph

NaOt-Bu, THF, 70 oC, 210 211 18 h 213 (76%)

O OR O RO Pd2(dba)3, BINAP,

I NaOt-Bu, THF, 70 oC, R = TES 205 210 or TBS 206 18 h 214

101 '-arylation was performed based on ease of operation and possession of materials and a similar !- vinylation was conceded to occur under parallel conditions in accordance with the literature.

102 Ge, S.; Hartwig, J. F. Journal of the American Chemical Society 2011, 133, 16330-16333. 83

Additionally, !-vinylation often required the use of zinc enolates (ZnCl2 and

LiTMP) to decrease basicity and avoid side reactions.93b-c Precedent was established on aryl ketone 215 with an alkenyl bromide, and the authors made no mention of attempts without the use of Zn, suggesting its requirement (Scheme 2.57). Only electron-rich sterically-demanding phosphanes supported coupling (such as t-Bu3P) while the use of arylphosphines failed completely (PPh3 or dppe). Such conditions were not explored and it was decided attention was better directed on a more advantageous route.

Scheme 2.59 Intermolecular coupling of Zn enolate 215 and alkenyl halide 216.

O O O O OMe LiTMP, ZnCl2, Pd2(dba)3, OMe N dtbpf, THF, 22 oC N Br (73%) 215 216 217

At this point, all conditions thought to accomplish formation of the desired C15-

C20 bond were exhausted and efforts were put forth to devise a new route in which this bond was already intact. Focus was directed to install the aza-bicycle prior to introduction of the indole moiety, avoiding potential geometric constraints when fused to a 9-membered ring.

Chapter 3: Third-Generation Synthesis: Enantioselective Synthesis from (S)-

Carvone via the Beckmann Rearrangement

3.1 Introduction

A more elegant route to subincanadine E was inspired by Neil Garg’s total

synthesis of (±)-aspidophylline A (see Scheme 3.57).103 A late stage

rearrangement/cyclization cascade (termed the interrupted Fisher indolization) prepared

the densely substituted cyclohexyl amine skeleton 222, the product of an intramolecular

Heck coupling. This stimulated us to consider assembly of the bicycle prior to

introduction of the planar indole moiety. An alternative disconnect to circumvent C15-

C20 bond formation would avoid former complications and provide an approach

predominantly unexplored in any total synthesis of the pericine type alkaloids (see

Chapter 1, Section 1.2).104

103 Zu, L.; Boal, B. W.; Garg, N. K. Journal of the American Chemical Society 2011, 133, 8877-8879.

104 Conolidine was the only related natural product that was assembled without a tryptamine precursor via introduction of a lithiated indole. See Chapter 1, Section 1.2.2. 85

Scheme 3.60 Garg’s retrosynthesis of (±)-aspidophylline A.

OHC PG PG NH H H H N 2 N N HN O O interrupted Fisher O H indolization H H N CO2Me CO Me H O 2 218 219 220 221

PG H PG N PGN RO N O RO Heck cyclization O X RO RO CO2Me H CO2Me Co2Me CO Me 224 2 223 222

The convergent enantioselective route toward dihydrocleavamine (containing a

tacaman or pseudo-aspidosperma skeleton) served as additional motivation that such a

disconnect of an aza-bicyclic indole alkaloid was achievable.105 Assembly of the

central 9-membered ring played the key role, realized through either: (A) a C2-C16

Pictet-Spengler-like coupling between tryptophol and piperidine 226 followed by N4-

C5 intramolecular alkylation, or (B) N4-C5 formation via indoleacetic acid coupling

with 229 and a subsequent intramolecular Friedel-Crafts acylation (Scheme 3.61).

Introduction of the indole nucleus and a fused aza-bicycle was accomplished during the

final stages, providing evidence that a 9-membered ring as the base of a bridged

105 Danieli, B.; Lesma, G.; Passarella, D.; Silvani, A. Tetrahedron Letters 2000, 41, 3489-3492. 86 framework was accessible without the need to linearly construct the molecule from a tryptamine core.

Scheme 3.61 Stereocontrolled synthesis of (+)-20R-15,20-dihydrocleavamine.

methylation reduction OH OPG 5 4 HO2C N 2nd 1st HN A 20 B HN

14 nd N N 2 N 2 H 1st H 16 H 225 226 227 228 HO2C 229 OMe

3.2 Retrosynthetic analysis

With these bond disconnections in mind, a modern approach was envisioned to expand beyond the aforementioned routes discussed in Chapter 1 and 2 such that a final

C15-C20 bond coupling would be evaded and new bond connectivity would facilitate an enantioselective total synthesis. Scheme 3.62 depicts the retrosynthetic analysis anticipated to furnish (15S)-subincanadine E. Instead of attempting to close a 6- membered ring within a 9-membered framework, the conformationally more robust valpericine 8 could be employed as the final precursor to subincanadine E through an acid-mediated hydride ring opening. This method structurally resembles the 87 biomimetic conversion of subincanadine E to valpericine, suggesting its compatibility with such a transformation (see Scheme 1.13 for biomimetic details). Intermediate 230 would arrive from N-alkylation of 231 after indolization about the ketone handle. The enone intermediate 232 would be generated from a more illustrious intramolecular

Heck coupling process than attempted in retrosynthesis 1 and 2 (see Scheme 1.15, transformation 89 to 5 and Scheme 2.22, 99 to 5c), effectively setting the desired olefin geometry. Synthon 233 was possible by way of a Beckmann rearrangement of oxime

234, stemming from a reduced version of enantiopure carvone.

Scheme 3.62 Third-generation retrosynthesis.

IM N ring- N N opening alkylation

N H H H N N H H H 5a 8 230 indolization, N-deacetylation, alkylation OPG O deprotection, Heck [O] Ac O O coupling N

N N H 233 232 O 231 H

Beckmann I

OPG OPG O oxime [O], formation protection

234 235 236 N O OH 88

Our proposed route is only the third approach using carvone to generate an

indole alkaloid-containing natural product. The first was led by Phil Baran’s entry to

the hapalindole and fischerindole families in 2004106 trailed by Neil Garg’s

construction of N-methylwelwitindolinone C isocyanate in 2011 (see Section 3.3.1 and

3.3.2 for synthetic details, respectively).107

3.3 Previous employment of carvone

Carvone is extremely inexpensive ($23.70/5 mL for (S)-(+)-carvone and $32/5 mL (R)-(")-carvone)108 and each enantiomer is used industrially for different means; (S)- carvone is used for the prevention of potato sprouting and (R)-carvone is used commercially as mosquito repellant.

106 (a) Baran, P. S.; Richter, J. M. Journal of the American Chemical Society 2004, 126, 7450-7451. (b) Entry to only one other nitrogen-containing natural product, nominine, was initiated from carvone to form a common enone intermediate, though the proposed synthesis was never completed. For synthesis of the enone intermediate from carvone, see: de Groot, A.; Jenniskens, L. H. D. Tetrahedron 1998, 54, 5617- 5622. (c) de Groot, A.; Verstegen-Haaksma, A. A.; Swarts, H. J.; Jansen, B. J. M. Tetrahedron 1994, 50, 10073-10082. (d) For the proposed synthesis of nominine, see: Yee Lee Goh, W. (2013) Studies Directed Towards the Natural Product Nominine. Unpublished doctoral dissertation, University of Southhampton, Southhampton, England.

107 Hunter, A. D.; Quasdorf, K. W.; Styduhar, E. D.; Garg, N. K. Journal of the American Chemical Society 2011, 133, 15797–15799.

108 Price according to Sigma-Aldrich in November 2014.

Carvone has a rich history of use among several complex natural products, most recently including the total synthesis of cyperolone,109 kainic acid,110 and cyrneine A111 (Figure

3.8).112 Specifically, Section 3.3.1 and 3.3.2 will focus on the only total syntheses to date utilizing carvone as a starting material toward indole alkaloid natural products. Section

3.3.3 will outline the derivitization of carvone into a series of useful ligands.

Cl HO H H SCN OH CO2H O H NCS O CO H 2 N N N HO CHO H O H 237 238 239 240 241 cyperolone kainic acid cyrneine A N-methylwelwitindolinone Hapalindole Q C isocyanate

Figure 3.8 Recent natural products synthesized from carvone.

109 Klahn, P.; Duschek, A.; Liébert, C.; Kirsch, S. F. Organic Letters 2012, 14, 1250–1253.

110 Takita, S.; Yokoshima, S.; Fukuyama, T. Organic Letters 2011, 13, 2068-2070.

111 Elamparuthi, E.; Fellay, C.; Neuburger, M.; Gademann, K. Angewandte Chemie Internation Edition 2012, 51, 4071-4073.

112 For other natural products initiated from carvone, see: (a) Omphadiol: Liu, G.; Romo, D. Angewandte Chemie Internation Edition 2011, 50, 7537-7550. (b) Platensimycin: Yun, S. Y.; Zheng, J.-C.; Lee, D. Journal of the American Chemical Society 2009, 131, 8413-8415. (c) Peribysin E: Angeles, A. R.; Waters, S. P.; Danishefsky, S. J. Journal of the American Chemical Society 2008, 130, 13765-13770. (d) Guanacastepene E: Shipe, W. D.; Sorensen, E. J. Journal of the American Chemical Society 2006, 128, 7025-7035. (e) Samaderine Y: Shing, T. K. M.; Yeung, Y. Y. Angewandte Chemie Internation Edition 2005, 44, 7981-7984. (f) Briarellins E and F: Corminboeuf, O.; Overman, L. E.; Pennington, L. D. Journal of the American Chemical Society 2003, 125, 6650–6652. (g) Thapsigargins: Oliver, S. F.; Högenauer, K.; Simic, O.; Antonello, A.; Smith, M. D.; Ley, S. V. Angewandte Chemie Internation Edition 2003, 42, 5996-6000. (h) Picrotoxin and corianin: Trost, B.; Krische, M. J. Journal of the American Chemical Society 1999, 121, 6131–6141. (i) Cladantholide: Lee, E.; Lim, J. W.; Yoon, C. H.; Sung, Y.; Kim, Y. K. Journal of the American Chemical Society 1997, 119, 8391-8392. (j) Salsolene oxide: Paquette, L. A.; Sun, L.-Q.; Watson, T. J. N.; Friedrich, D.; Freeman, B. T. Journal of the American Chemical Society 1997, 119, 2767-2768. (k) 7-deacetoxyalcyonin acetate: MacMillan, D. W. C.; Overman, L. E. Journal of the American Chemical Society 1995, 117, 10391–10392. (l) Upial: Taschner, M. J.; Shahripour, A. Journal of the American Chemical Society 1985, 107, 5570-5572.

3.3.1 Total synthesis of hapalindole Q and (")-12-epi-fischerindole U

isothiocyanate

The hapalindoles were originally isolated in 1987113 from the blue-green alga

Hapalosiphon fontinalis whose extracts revealed anti-algal and antimycotic activity,

recently found to be a direct result of RNA-polymerase inhibition.114 The

fischerindoles were isolated in 1992115 and possess similar activity.116 The Baran group

devised a direct coupling of indole with carvone through oxidation of their

corresponding anions to radicals 249 and 250 (Scheme 3.63). After LHMDS

deprotonation, they found that Cu(II)2-ethylhexanoate-mediated coupling when indolic

radical 250 was used in 2-fold excess afforded an optimized yield of 53% (70% based

on recovered starting material). Adduct 248 was carried on to indole 245, which served

as the synthon for divergence to either natural product. Hapalindole Q was obtained

after direct reductive amination and succeeding isocyanate formation of 246. The

fischerindole 242 was derived from identical steps after initial biomimetic ring closure

of 245 using TMSOTf. Diversification of the common intermediate 245 accomplished

113 Moore, R. E.; Cheuk, C.; Yang, X.-Q. G.; Patterson, G. M. L.; Bonjouklian, R.; Smitka, T. A.; Mynderse, J. S.; Foster, R. S.; Jones, N. D.; Swartzendruber, J. K.; Deeter, J. B. Journal of Organic Chemistry 1987, 52, 1036–1043.

114 (a) Doan, N. T.; Rickards, R. W.; Rothschild, J. M.; Smith, G. D. Journal of Applied Phycology 2000, 12, 409-416. (b) Doan, N. T.; Stewart, P. R.; Smith, G. D. Microbiology Letters 2001, 196, 135-139.

115 Park, A.; Moore, R. E.; Patterson, G. M. L. Tetrahedron Letters 1992, 33, 3257–3260.

116 For biological activity of the hapalindoles, fischerindoles, and related natural products, see references therein: Richter, J. M.; Ishihara, Y.; Masuda, T.; Whitefield, B. W.; Llamas, T.; Pohjakallio, A.; Baran, P. S. Journal of the American Chemical Society 2008, 130, 17938–17954. 91

the synthesis of 247 and 242 in 22% and 15% overall yield from (R)-carvone,

respectively.

Scheme 3.63 Baran’s retrosynthesis of hapalindole Q 247 and (")-12-epi-fischerindole U

isothiocyanate 242.

SCN isocyanate H2N reductive O formation amination H H H H H H

NH NH NH 242 243 244

(!)-12-epi-ﬁsherindole acid catalyzed U isothiocyanate ring closure

H H H isocyanate reductive formation amination NCS NH2 O

N N N H H H 247 246 245 hapalindole Q enolization, acetalehyde addition, dehydration

H 240a conjugate [O] 249 addition O O O

N 250a 250 H N N 248

3.3.2 Total synthesis of N-methylwelwitindolinone C isocyanate

The Garg group utilized (S)-carvone in the first enantiospecific 17-step route to

N-methylwelwitindolinone C isocyanate (Scheme 3.64). This compound was found to

reverse P-glycoprotein-mediated multiple drug resistance to a number of anti-cancer

drugs, proving to be a promising lead for drug-resistant tumor formation.117 Highlights

from this synthesis include a nitrene insertion reaction to functionalize the sterically

congested C11 bridgehead carbon as well as an indolyne cyclization that assembled the

[4.3.1]-bicycle (transformation 254 to 253), endorsing this intermediate’s use in total

synthesis. Enone 257 was a known intermediate reported by Natsume118 and resulted

from a 7-step elaboration of (S)-carvone. Though the heaviest number of steps was

required to modify 236 to 253 (13 steps), the greatest synthetic utility was sequestered

from use of indolyne 254 which formed at ambient temperatures and proceeded to 253

in a satisfyingly 46% yield with minimal O-arylated byproduct.

117 (a) Smith, C. D.; Zilfou, J. T.; Stratmann, K.; Patterson, G. M. L.; Moore, R. E. Molecular Pharmacology 1995, 47, 241–247. (b) Zhang, X.; Smith, C. D. Molecular Pharmacology 1996, 49, 288– 294.

118 Sakagami, M.; Muratake, H.; Natsume, M. Chemical and Pharmaceutical Bulletin 1994, 42, 1393– 1398. 93

Scheme 3.64 Garg’s retrosynthesis of N-methylwelwitindolinone C isocyanate 251.

Cl Cl RO

late-stage vinyl chloride & H bridgehead H oxindole H SCN functionalization H formation H 11 O O O H H O O N N N 251 252 253

N-methylwelwitindolinone C indolyne cyclization

Br OR RO

RO dehydro- 7 steps N halogenation 256 H H (S)- carvone Br O O 236 O N 257 255 N 254

3.3.3 Chiral [2.2.2] dienes from carvone

Carvone has also been diversified into several chiral diene ligands for use in

Rh(I)-catalyzed conjugate addition reactions (Scheme 3.65).119 A sequence of seven steps converted either enantiomer of carvone and allowed for diversity-oriented synthesis of the ligand scaffold.

119 (a) Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E. M. Organic Letters 2004, 6, 3873–3876. (b) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. Journal of the American Chemical Society 2004, 126, 1628-1629. (c) Hickmann, V.; Alcarazo, M.; Fürstner, A. Journal of the American Chemical Society 2010, 132, 11042–11044.

Interestingly, saturation between carbon 2 and 3 of ligand 261 provided less than a 10% conversion of 260 to 263.

Scheme 3.65 Carvone-derived diene ligands.

OMe O O 1. NBS, MeOH 1. i-BuLi

2. KOt-Bu 2. PCC O 258 259 236a 1. LDA, allyBr 2. LiNEt2, PhNTf2 3. [Pd], HCO2H

OMe 2 3 O O 261 O O Ecklonialactone A & B Ph 260 O 263 B O Ph 262 [Rh(C2H4)2Cl]2 (80% ee)

3.4 Forward route: oxidation of carvone

The forward route required preliminary efforts to determine if regioselective

oxime formation was possible without needing to first protect the enone carbonyl. This

would diminish the number of overall steps and prevent unnecessary redox changes to

the enone that would be needed for later manipulation.

Prior to these objectives, investigations of the direct oxidation from carvone to

diketone 264 was required (Scheme 3.66). Oxidative cleavage of the double bond

120 under standard literature conditions (OsO4/NaIO4) was sluggish and over-oxidation

products were visible.121 Even with the use of 2,6-lutidine as an additive, suppression

of oxidative degradation products was minimal and starting material was always

122 recovered. Furthermore, powdered K2CO3 and pyridine were separately added to

reduce the formation of 265 to no avail.

Scheme 3.66 Oxidation cleavage of (S)-carvone.

O O O OsO4, NaIO4, OH 2,6-Lutidine, 3:1 THF: H2O 236 (28%) O 264 O 265

120 Pappo, R.; Alen, D. S. Jr.; Lemieux, R. U.; Johnson, W. S. Journal of Organic Chemistry 1956, 21, 478- 479.

121 Aldehydic peaks were also present in the crude NMR, presumably from the cleavage of the internal double bond. Others have reported the presence of over-oxidation and only a few have reported an !- hydroxy ketone side product. See: Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Organic Letters 2004, 19, 3217-3219.

122 Pyridine was tested although it is known to accelerate epimerization via enolization of the resultant aldehyde or ketone. See reference 120.

Although carvone was known to undergo oxidation directly to diketone 264, the

harsh conditions (non-catalytic amounts of nitrous oxide between 50-70 atm for 12

hours at 250 °C) initiated us to pursue other options.123 Using a more consistent two-

step procedure, the diketone was furnished in high yields (Scheme 3.67).124

Epoxidation using mCPBA125 successfully prepared intermediate 264. This reaction

was completely regioselective though not stereoselective, which was adequate for our

purposes. Liberation to the vicinal diol in the presence of periodic acid followed by

further oxidation provided 264 in gram quantities.

Scheme 3.67 2-step oxidation of (S)-carvone.

O O O mCPBA, HIO4 H2O,

o Et O, 0 oC, 1 h CH2Cl2, 0 C, 2.5 h O 2 236 (96%) 266 (68%) O 264

123 Romanenko, E. P.; Starokon, E. V.; Panov, G. I.; Tkachev, A. V. Russian Chemical Bulletin, Internation Edition 2007, 56, 1239-1243. The cyclopropane homo-derivative was reported as a major byproduct of this reaction, resulting from cyclopropanation of the double bond. See Scheme 3 therein.

124 (a) Torosyan, S. A.; Gimalova, F. A.; Valeev, R. F.; Miftakhov, M. S. Russian Journal of Organic Chemistry 2011, 47, 682-686. (b) Baldwin, J. E.; Broline, B. M. Journal of the American Chemical Society 1982, 104, 2857-2865.

125 Employing H2O2 would epoxidize the enone double bond. See: Hatakeyama, S.; Numata, H.; Osanai, K.; Takano, S. Journal of Organic Chemistry 1989, 54, 3515-3517. 97

3.5 Regioselective oxime formation

Regioselective oxime formation was next explored using different bases during exposure of diketone 264 to hydroxylamine hydrochloride in ethanol (Scheme 3.68).

Though oxime formation is a routine transformation, there is no literature on regioselectivity regarding ketone versus enone functionalities. It was hypothesized that the ketone would be more electrophilic and thus prefer 1,2-addition here. To our surprise, all trials led to exclusive 1,2-addition of the enone carbonyl or di-oxime formation (Table 3.5).125

Scheme 3.68 Attempted regioselective oxime formation.

O desired

N 267 OH X OH O conditions N Table 3.4

264 268 O O OH N

269 N OH

Table 3.5 Conditions applied to the regioselective oxime formation of 267.

Entry Base Temperature Time Product 1 - rt 18 h 268, 90% 2 pyridine rt 18 h 268, 81% 3 NaOH rt 18 h 268, 77% 268, 46% + 4 NaOAc!3H O rt 2 d 2 269, 15% 5 NaOH reflux 4 h 269, 92%

3.6 Exploration of protecting group strategies

These results substantiated the need for protection group chemistry of the enone

such that the desired oxime could be acquired. It was anticipated that electronic

differences would enable regioselective protection of one carbonyl over the other,

ideally 1,4-protection over 1,2-protection.126 A cyclic protecting group was chosen to

more clearly understand the di-carbonyl reactivity in this system. Initial attempts with

ethylene glycol protected only the ketone in high yields (Scheme 3.69). Alternative

acids or other conditions did not affect the resultant isomer prepared.

126 This reaction was attempted despite the fact that most ketones have a faster reaction rate than enones. 99

Scheme 3.69 Attempted regioselective protection to provide 270.

O O

O X O 270 1.1 equiv ethylene glycol, p-TsOH, toluene or benzene, reﬂux O O 264

O 271 O 40%

Employment of the softer dithioacetal protecting group was next considered

(Scheme 3.70). Selected conditions are outlined in Table 3.6. A number of different acid catalysts were tested with varying solvents and temperatures.127 Entries 1-4 produced the desired enone-protected product, however this did not go to completion. Increasing the equivalents of dithioethane higher than 1.1 produced a significant amount of the di- protected species. Attempts to optimize the conditions led to substantial starting material recovery, while driving the reaction to completion did not allow for thorough separation

127 See the following references for dithioacetal protecting group conditions employed in Table 3.5. (a) Using iodine: Firouzabadi, H.; Iranpoor, N.; Hazarkhani, H. Journal of Organic Chemistry 2001, 66, 7527- 7529. (b) Using SnCl2!H2O, see Table 1, entry 15: Bez, G.; Gogoi, D. Tetrahedron Letters 2006, 47, 5155- 5157. (c) Using ZnCl2: Lerner, D. B.; Kearns, D. R. Journal of the American Chemical Society 1980, 102, 7612-7613. (d) Using BF3!OEt2: see reference 111c. (e) Using p-TsOH and silica gel: Ali, M. H.; Gomes, M. G. Synthesis 2005, 8, 1326-1332.

100 of di-protected 272 from mono-protected 273.128 It is possible that the steric hindrance of the enone imposed by the neighboring methyl group has decreased selectivity at that position, thus permitting ketone protection as well.

Scheme 3.70 Attempted regioselective protection to provide 273.

S S

S O S 272

conditions Table 3.5

O 264 S S

273 O

Table 3.6 Conditions applied to the regioselective protection to provide 273.

Entry Acid Solvent Temperature Time Product

1 I2 CHCl3 rt 2 d 272 + 273 2 SnCl2!H2O Et2O µW, 100 W 3 min 272 + 273 3 ZnCl2 CH2Cl2 -78 °C to 0 °C 1 h 272 + 273 4 BF3!OEt2 MeOH -78 °C to 0 °C 5 h 272 + 273 silica gel, 5 CH Cl reflux 12 h 272 p-TsOH 2 2

128 Yields for each reaction shown in Table 3.5 were very low. See Chapter 4, Section 4 for highlighted experimental data. 101

Furthermore, it was reported that Michael adduct 276 was the main product on a similar system (piperitone 274) under certain acid-catalyzed conditions (Scheme 3.71).129

The authors mentioned that carvone showed a similar tendency. Supplementary literature disclosed evidence of Michael product formation when attempting to protect a range of enones and the scope was not limited to one acid catalyst in specific.130

Scheme 3.71 Michael adduct formation from the attempted protection of 274.

O Zn(OTf)2, CHCl3, reﬂux S S HS S HS SH 275 274 276 ethane-1,2-dithiol

Lastly, analysis of regioselective protection of a diol intermediate was

investigated. Though simple acetal protection of carvone occurs readily,131 electronic

discrepancies between the two olefins of 277 no longer exist for later oxidation

129 Corey, E. J.; Shimoji, K. Tetrahedron Letters 1983, 24, 169-172.

130 For other examples of selective monothioketalization that exhibit carbonyl differention, see: (a) Evans, D. A.; Truesdale, L. K.; Grimm, K. G.; Nesbitt, S. L. Journal of the American Chemical Society 1977, 99, 5009-5017. (b) Sato, T.; Otera, J.; Nozaki, H. Journal of Organic Chemistry 1993, 58, 4971-4978.

131 However, employment of PPTS as the acid catalyst in a higher boiling solvent leads to p-cymene x exclusively (Scheme 3.72). For comparable protection procedures, see: (a) Greene, T. W. Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, 1981. (b) Nomura, M.; Hisatomi, S.; Fujhiara, Y.; Shibata, M.; Takagi, S.; Sugiura, M. Nihon Yukagakkaishi 1996, 45, 865-870. (c) Use of CdI2 under µW irradiation accelerates the reaction. See: Laskar, D. D.; Prajapati, D.; Sandhu, J. S. Chemistry Letters 1999, 12, 1283-1284. 102

(Scheme 3.72). However, halting the oxidation at the diol would allow for further

manipulation of the enone.

Scheme 3.72 Acetal protection of (S)-carvone.

O O O ethylene glycol, PPTS, ethylene glycol, p-TsOH,

benzene, reﬂux, 22 h toluene, reﬂux, 18 h 277 (85%) 236 (88%) 278

After epoxidation of (S)-carvone, sulfuric acid in water cleanly prepared the ring-opened diol (Scheme 3.73).132 Both ethylene glycol and dithioethane protecting groups were used with various acid catalysts (Table 3.7). Attempted formation of 280 resulted in mostly starting material recovered and in only one case (entry 4) desired product was formed, albeit in a low yield. Efforts to form the sulfur congener resulted in decomposition of the starting material with no identifiable products. It was postulated that protonation of the ketone allowed for intramolecular attack by either pendant alcohol, arranging a 5 or 6-membered ring. This may also occur in the intermolecular fashion, propagating multiple cyclic ether products.

132 Engel, W.; Journal of Agriculture and Food Chemistry 2001, 49, 4069-4075. 103

Scheme 3.73 Attempted protection of diol intermediate 279.

O O O mCPBA, H2SO4, H2O,

o CH2Cl2, 0 C, 2.5 h THF, rt, 2 h (96%) O (90%) 236 266 OH HO 279

HX XH conditions Table 3.6

X X X X X = O 270 HIO4 H2O or S 273

HO O OH 280

Table 3.7 Conditions applied to the protection of diol 279.

Protecting Entry Acid Solvent Temperature Time Group ethylene 1 p-TsOH toluene reflux 22 h glycol 2 dithioethane BF3!OEt2 MeOH 0 °C 1.5 h ethylene 3 p-TsOH benzene reflux 8 h glycol ethylene 4 PPTS benzene reflux 1 d glycol

104

3.7 Oxime formation via reduction of the enone

As direct access to the oxime precursor and regioselective protection were

achievable, a lengthier procedure was adopted. Though other protecting group

strategies exist,133 we directed our attention on the carbonyl reduction of carvone

followed by subsequent silyl protection. This would circumvent the need for

regioselective chemistries and enable succeeding oxidation of the isopropenyl unit to

ensue. The formerly prepared epoxide 266 was subjected to NaBH4 in the presence of

sucrose as a ‘reactant transfer’ agent to prevent formation of the saturated alcohol from

134 135 1,4-addition (Scheme 3.74). The Luche reduction (CeCl3, MeOH) indeed

furnished the desired chemoselective 1,2-addition product according to the literature,

but reportedly was accompanied by intramolecular acid-catalyzed cyclization and

consequently was avoided.136

133 Carvone can be transformed into its TMS-protected cyanohydrin. Cabirol, F. L.; Lim, A. E. C.; Hanefeld, U.; Sheldon, R. A.; Lyapkal, I. M. Journal of Organic Chemistry 2008, 73, 2446-2449.

134 For details on sucrose used as a reactant transfer agent in the chemoselective reduction of !,#- unsaturated aldehydes and ketones, see: Denis, C.; Laignel, B.; Plusquellec, D.; Le Marouille, J.-Y.; Botrel, A. Tetrahedron Letters, 1996, 37, 53-56.

135 Gemal, A. L.; Luche, J.-L. Journal of the American Chemical Society 1981, 103, 5454-5459.

136 Smitt, O.; Högberg, H.-E. Tetrahedron 2002, 58, 7691-7700. Synthetic details toward x can be found in this work. 105

Scheme 3.74 Oxidation and protection of (S)-carvone.

O O OH mCPBA, CH2Cl2 NaBH4, sucrose, 5 >10:1 0 oC to rt, 18 h 0 oC, 1 h syn:anti O O 236 (96%) 266 281

TBDPSCl, DMAP, Imidazole, rt, 18 h (62%) over two steps

OTBDPS OTBDPS

Overall 54 % HIO4 H2O from (S)-carvone

o CH2Cl2, 0 C, 1.5 h O O 235a 282 (79%)

The unstable epoxy allylic alcohol 281 was immediately protected with the more

robust TBDPS group to prevent intramolecular cyclization to previously characterized

bottrospicatols 283 and 284 (Scheme 3.75).137 Use of TBDMS or TMS resulted in a

sizable amount of these products that proved difficult to separate from the desired silyl

ethers (both syn and anti diastereomers of 235a). Oxidative periodic acid cleavage of

epoxide 282 furnished siloxyketone 235a as the dominant diastereomer, though both

were jointly taken on to the next step.

137 (a) Noma, Y.; Nishimura, H.; Hiramoto, S.; Iwami, M.; Tatsumi, C. Agricultural and Biological Chemistry 1983, 46, 2871-2872. (b) Nishimura, H.; Hiramoto, S.; Mizutani, J.; Noma, Y.; Furusaki, A.; Matsumoto, T. Agricultural and Biological Chemistry 1983, 47, 2697-2699. 106

Scheme 3.75 Byproducts of the intramolecular Lewis acid catalyzed cyclization of 281.

OH O O OH Lewis acid

O OH 281 283 284

The oxime was next prepared which efficiently supplied a mixture of (E) and (Z)

isomers (ratio of 5:4, respectively) in a collective 85% yield (Scheme 3.76). Though

the geometric isomers were easily separable by chromatography, thermodynamic

isomerization occurs during the Beckmann rearrangement in the presence of a protic

acid such that only the (E) isomer will rearrange.138 The skeleton was now prepared for

exploration of rearrangement conditions.

Scheme 3.76 Synthesis of oxime 234a from ketone 235a.

OTBDPS OTBDPS

2.5 M NH2OH HCl,

5 M NaOH, reﬂux, 3 h (85%) O 235a N 234a HO

138 Gawley, R. E. Chapter 1 The Beckmann Reactions: Rearrangements, Elimination-Additions, Fragmentation, and Rearrangement-Cyclizations. In Organic Reactions, Kende, A. S., John Wiley & Sons, Inc., 1988; Vol. 35, pp 1-420.

107

3.8 Beckmann rearrangement

Prior to establishing the use of only TBDPS as a protecting group, the more hydrolysable TBS was employed (synthesized in accordance with Scheme 3.74 in comparable yields). Exposure of this oxime derivative to MsCl and AcOH after aqueous workup delightfully underwent rearrangement (Scheme 3.77). However, the

TBS group was readily cleaved in acidic medium. This permitted O-acetylation by means of a stable allylic carbocation intermediate at which all optical activity was lost due to its C2-symmetric nature (Scheme 3.78).

Scheme 3.77 Initial Beckmann rearrangement performed on oxime 234b.

OAc

O OTBS OR N H 287 MsCl, NEt3, AcOH, rt, 33% 2 h CH Cl , 30 min, -30 oC N 234b 2 2 N R= TBS 285 HO MsO or H 286 OAc

N Ms 288 44%

108

Moreover, this was the first entry toward 5-aminocyclohexenol derivatives to be documented. Such a small molecule was surprisingly unknown in the literature and our route readily delivered access to such structures in a succinct manner.

Scheme 3.78 Mechanism for the production of 287.

OTBS OH OH2

H+ O H+ O

N N H H N 234b 289 290 HO

OAc

O AcOH O

N N H H 287 291

Interestingly, a second acetylation product was identified as the N-mesylated adduct 288. Only a few examples in the literature mention the appearance of such a product using typical Beckmann conditions, which occurs from trapping the nitrillium intermediate before introduction of water (Scheme 3.79).

109

Scheme 3.79 Mechanism for the production of N-substituted and un-substituted amides.

OH OH OH OR - MsO H O 2 O

N N N N 286 292 293 H MsO R = H 289 or Ac 287

OMs

OH OR

N N 294 Ms R = H 295 OMs or Ac 288

This mechanism is reminiscent of the Chapman rearrangement, though most N-

substituted amides result under refluxing conditions. Scheme 3.80 provides three

examples noted in the literature. In the last example (reaction 3), benzophenone oxime

301 undergoes esterification, rearrangement to benzoyl imidate 302, and further

rearrangement to produce N-substituted benzanilide 303. The authors of reaction 2 also

postulate an imidate intermediate.139

139 (a) Reaction 1 of Scheme 3.80: Huisgen, H.; Witte, J.; Ugi, I Chemische Berichte 1957, 90, 1844-1849. (b) Reaction 2: Schulenberg, J. W.; Archer, S. Organic Reactions 1965, 14, 1-51. (c) Reaction 3: Bittner, S.; Grinberg, S. Journal of the Chemical Society, Perkin Transactions 1 1976, 1708-1711. 110

Scheme 3.80 Three literature examples of Chapman-like rearrangements.

reaction 1 PicO N O Pic CH2Cl2, N heat (74%) 296 297

reaction 2

SO3H O O SO H O pet. ether, 3 N N N SO3H 65 oC 298 299 300

reaction 3 NO2 NO2

O Ph PPh3, DEAD, N O O N Ph O Ph N Ph heat Ph Ph (87%) NO2 O O 301 302 303

The less labile TBDPS-protected siloxyoxime 234a was instead subjected to the

Beckmann conditions (Scheme 3.81). It was discovered that the secondary addition of acid was not necessary for rearrangement to occur, thus avoiding potential silyl deprotection. The rearrangement proceeded with at an optimal ratio of 1:1.2 of N- mesylated 304 to non-mesylated 233a using a small volume of water added at a rapid stirring speed to the organic solution. A slight excess of MsCl was therefore required and some starting material inevitably persisted. Rearrangement initiated by TsCl

111 instead provided a higher ratio of the mesylated adduct (7:1 of N-mesylated to non- mesylated, not shown).

Scheme 3.81 Optimized Beckmann rearrangement on 234a.

OTBDPS OTBDPS OTBDPS MsCl, NEt3, CH2Cl2, O O

1 drop water, N N H Ms N 234a -30 oC to 0 oC, 30 min 233a 304 HO 34% 41%

N-mesylated or O-acetylated material (Scheme 3.82, either 288 or 287) was easily cleaved under basic conditions forming amido-alcohol 305. Furthermore, any O- silyl protected 304 would lose the protecting group at high temperatures to produce 305 as well, supporting the opportunity for a one-pot process. Since the enone functionality was eventually desired, the alcohol could be oxidized after alkylation. This provided maximal turnover of the starting oxime for consumption in subsequent steps.

112

Scheme 3.82 Conversion of N- alkylated and O-protected byproducts to amide 305.

OAc

N Ms 288

OAc OH NaOH, reﬂux O O

N N H 287 H 305 OTBDPS

N Ms 304

3.9 Alkylation

Acetamide 233a was expected to undergo alkylation using the previously employed mesylate 111 (see Chapter 2, Scheme 2.25 for its synthesis). A strong base was required to deprotonate the amide, which consistently reacted with the alkyl mesylate instead. Adding 15-crown-ether-5 to solvate the sodium cation salt resulting from amide deprotonation (Table 3.8, entry 2) did not change the outcome. Regardless of the base employed, starting material was recovered quantitatively and only some of the mesylate was salvaged.

113

Scheme 3.83 Acetamide 233a alkylation attempt with mesylated (Z)-olefin 111.

MsO OTBDPS OTBDPS I O 111 O

N conditions N H 233a 306

Table 3.8 Conditions applied to the alkylation of 233a.

Entry Base Solvent Temperature Time 1 NaH THF 70 °C 17 h 15-crown-ether- 2 NaH 70 °C 2 h 5, benzene 3 KHMDS THF 70 °C 17 h 4 n-BuLi THF 70 °C 4 h

A control reaction void of the acetamide proved that the base quickly eliminated

the mesylate, rendering it useless for alkylation purposes (Scheme 3.84). Other amide

alkylations did not possess a reagent able to undergo facile E2’ elimination and

140 therefore Sn2 alkylation was not possible for our system.

140 For examples of amide N-alkylation see: (a) Fones, W. S. Journal of Organic Chemistry 1949, 14, 1099- 1102. (b) Park, J. D.; Englert, R. D.; Meek, J. S. Journal of the American Chemical Society 1952, 74, 1010- 1012. (c) Bogdal, D. Molecules 1999, 3, 333-337. (d) Kasuga, J.; Hashimoto, Y.; Miyachi, H. Bioorganic & Medicinal Chemistry Letters 2006, 16, 771–774. (e) Rao, S. N.; Babu, K. S. Organic Communications 2011, 4, 105-111. (f) Zhang, H.; Chen, P.; Liu, G. Synthetic Letters 2012, 23, 2749-2752.

114

Scheme 3.84 Elimination of the mesylated (Z)-olefin 111 with a strong base.

MsO :B

I H I 111 307

3.10 Deacetylation

Since the use of strong base was not possible with our requisite alkylating agent,

it was decided to remove the acetyl group such that a more feasible alkylation of an

amine over an amide could occur. To prevent over-alkylation, reductive amination

between amine 306 and aldehyde 108 (the precursor to mesylate 111) could occur

(Scheme 3.85). Deacetylation of an amide requires more rigorous conditions than its

ester counterpart; nonetheless this transformation is documented in the literature.141

However, all conditions applied resulted in quantitative recovery of starting material or

loss of the silyl protecting group to form amido-alcohol 305. Even removal by way of

methylation with triethyloxyoxonium tetrafluoroborate (Meerwein’s salt, entry 8) that

141 For examples of N-deacetylation conditions, see: (a) Barger, G.; Schlittler, E. Helvetica Chimica Acta 1932, 15, 381-394. (b) Cao, Y.; Du, D.; Yang, X.; Xu, X.; Song, F.; Xu, Y. Agricultural Science and Technology 2012, 13, 1-3. (c) Li, G.-Q.; Gao, H.; Keene, C.; Devonas, M.; Ess, D. E.; Kürti, L. Journal of the American Chemical Society 2012, 135, 7414-7417.

115

was employed for stubborn acetamide removal did not prove fruitful.142

Scheme 3.85 Deacetylation of 233a and reductive amination with 111.

O H OTBDPS OTBDPS OTBDPS conditions 108 O I HN N Table 3.8 H H2N 307 233a 306

OH I

N H 305

Table 3.9 Conditions attempted to deacetylate 233a.

Entry Acid or Base Solvent Temperature Time Product 1 tetramethyl guanidine MeOH rt 18 h 233a 2 HCl EtOH rt 18 h 305 3 SOCl2, pyridine CH2Cl2 rt 2 d 305 4 NaOH EtOH reflux 18 h 305 5 KOH EtOH reflux 18 h 305 6 hydrazine hydrate MeOH rt 2 d 233a 7 NaNH2 THF reflux 18 h 305 + - [OEt3] [BF4] , 8 CH2Cl2 rt 15 h 305 Na2CO3

142 (a) Kozikowski, A. P.; Ishida, H. Journal of the American Chemical Society 1980, 102, 4265-4267. (b) Kishi, Y.; Fukuyama, T.; Nakatsubo, A. F.; Goto, T.; Inoue, S.; Tanino, H.; Suguira, S.; Kakoi, H. Journal of the American Chemical Society 1972, 94, 9219-9221. (c) Hanessian, S. Tetrahedron Letters 1967, 16, 1549-1552. 116

Deacetylation conditions were tested on sulfonimide 304, a byproduct from the

Beckmann rearrangement (Scheme 3.81), since sulfonimides are more susceptible to

cleavage than an N-acetyl group (Scheme 3.86).143 Comparably, a literature example

illustrating the cleavage of the sulfonamide N-methanesulfonylpiperidine proved to be

inert to sodium naphthalene cleavage, suggesting aliphatic amines are inherently

robust.144 It was rationalized that the weaker sulfonimide, through lone pair dual-

delocalization, would be more inclined to cleavage than the sulfonamide example.

Conditions in Table 3.8 were applied (entries 4-5), resulting in N-mesyl and O-silyl

deprotection (product 305).

Scheme 3.86 Deacetylation attempts of sulfonamide 304.

OTBDPS OTBDPS

O conditions

N Table 3.8 HN Ms 304 308 Ms

N H 305

Taking advantage of another intermediate more receptive to deacetylation was

envisioned through Boc protection of acetamide 233a to form an acid-labile carbamate

143 Searles, S.; Nukina, S. Chemical Reviews 1959, 59, 1077-1103.

144 Ji, S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson, W. D. Journal of the American Chemical Society 1967, 89, 5311-5312. 117

(Scheme 3.87). Exhaustive efforts to Boc protect did not proceed to the desired

carbamate 309. Excess DMAP was even used to ensure the acetamide nitrogen was

kept nucleophilic. Literature examples once again indicate that aliphatic and/or

sterically hindered amines are resistant to such a reaction.145 It was plausible that the

secondary nature of the amine as well as steric bulkiness of the neighboring tertiary

carbon on the pseudo-chair would cause interference with nucleophilic attack of the

nitrogen.

Scheme 3.87 Deacetylation attempts of carbamate 309.

OTBDPS OTBDPS OTBDPS Boc O, DMAP, LiOH, THF/H O 1. alkylate with x O 2 O 2 307 N CH2Cl2, rt N HN 2. N-deprotect H Boc 309 310 233a Boc

O Ph

N Si Ph Ph H O NH Si Ph 233b 233c

145 (a) Grehn, L.; Gunnarsson, K.; Ragnarsson, U. Journal of the Chemical Society, Chemical Communications 1985, 1317-1318. (b) Grehn, L.; Gunnarsson, K.; Ragnarsson, U. Acta Chemica Scandinavica 1987, 41b, 18-23. 118

3.11 Reduction to ethylamine and reductive amination

To drive the synthesis forward and focus on condition optimization for the

ensuing intramolecular Heck coupling, it was decided to reduce the acetamide to its

corresponding ethylamine derivative 311 (Scheme 3.88) for utility as a model system.

Original attempts in refluxing THF results in O-deprotected material only, speaking to

its inherent robustness.146 Increasing the energy to refluxing 1,4-dioxane provided the

desired ethylamine 311 in which the silyl protecting group was unavoidably removed

under such forceful conditions. This assisted in step economy since the protecting

group was no longer necessary for the remainder of the synthesis.

Scheme 3.88 Acetamide reduction to ethylamine 311.

OTBDPS OH LiAlH4, 1,4-dioxane, O

reﬂux, 18 h N N (58%) H H 233a 311

146 Reduction using excess Red-Al in THF was also employed but did not provide the desired ethylamine. For precedence, see: Voight, E. A.; Bodenstein, M. S.; Ikemoto, N.; Kress, M. H. Tetrahedron Letters, 2006, 47, 1717-1720.

119

Reductive amination was first performed using iodo-crotonaldehyde 108 with or

147 without Ti(OiPr)4 in the presence of NaCNBH3 (Scheme 3.89). This led to a mixture

of products, ostensibly from Michael addition to 313 followed by a second addition of

the amine to aldehyde 108 and subsequent sodium cyanohydride reduction (since the

pH was kept above 6, reduction of the intermediate aldehyde should not occur). This

diamine formation has been documented in the literature for crotonaldehyde.148

147 (a) For reductive amination of ketones and aldehydes, see: Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. Journal of Organic Chemistry 1996, 61, 3849-3862. (b) Borch, R. F. Organic Syntheses 1972, 52, 124-127. (c) For a review on sodium cyanoborodydride utility, see: Hutchins, R. O.; Natale, N. R. Organic Preparations and Procedures International 1979, 11, 201-246. (c) Lane, C. F. Synthesis 1985, 135-146. (d) For reduction aminations using Ti(OiPr)4 as a Lewis acid catalyst, see: Mattson, R. L.; Pham, K. M.; Leuck , D. J.; Cowen, K. A. Journal of the American Chemical Society 1990, 55, 2552-2554.

148 Andrews, M. G.; Mosbo, J. A. Journal of Organic Chemistry 1977, 42, 650-651.

120

Scheme 3.89 Reductive amination of 108.

O H OH OH OH I Michael 108 addition N N N X 312 313 H 311 NaCNBH3, I DCE, rt, 20 h or I OH NaCNBH3, Ti(OiPr)4, O rt, 3 h

- H O 2 N H 311

I I HO NaCNBH3 HO N N N N OH OH 314 315

Finally, alkylation149 was accomplished with the original mesylate 111 in

reasonable yields and subsequent allylic oxidation occurred with satisfaction (Scheme

3.90).150

149 No O-alkylation was seen under these conditions. For O- versus N-alkylation, see: Mijin, D. Z.; Mi(i$- Vukovi$, M. M.; Petrovi$, S. D. Journal of the Serbian Chemical Society 2004, 69, 711–736.

150 Oxidation also worked with PCC as demonstrated on acetamide x (Scheme 3.86), but was much lower yielding than MnO2. See Chapter 4, Section 4.4 for synthetic details. 121

Scheme 3.90 Alkylation and oxidation to 316.

MsO

I OH 111 OH O MnO2, CH2Cl2, K2CO3, THF,

rt, 5 h N rt, 18 h N N H (33%) 311 (63%) 312 316

I I

3.12 Pd-Catalyzed Coupling

A model substrate was now in hand for optimization of Pd-catalyzed intramolecular coupling (Scheme 3.91). Several catalysts with and without ligands were tested and the base and solvent were also surveyed (Table 3.10). Entries 1-4 provided recovery of starting material. Delightfully, evidence of the coupled product was visible under the conditions outlined in entry 5, albeit in less than a 15% yield after

15 h. Efforts are currently being made to optimize this reaction as well uncovering an appropriate acetamide deprotection for entry to the natural product.

122

Scheme 3.91 Intramolecular Heck coupling of 316.

O Et N conditions

N O H I 316 317

Table 3.10 Conditions attempted for the intramolecular Heck coupling of 316.

Entry Base Catalyst Ligand Solvent Temperature Time

1 K2CO3 Pd(PPh3)4 - THF 70 °C 10 h 2 Ag2CO3 Pd(OAc)2 PPh3 DMF 110 °C 15 h 3 K2CO3 Pd2(dba)3 xantphos THF 70 °C 18 h 4 Na2CO3 Pd2(dba)3 BINAP toluene 110 °C 16 h NEt Pd(OAc) 5 3 2 - CH CN 85 °C 40 h (20 equiv) (40 mol %) 3

3.13 End-game strategy

Following optimization of the Heck coupling, the final natural product can be realized in 5 transformations (Scheme 3.92). The desired secondary amine 318 void of the ethyl group is required for further functionalization of the molecule. After N- deacetylation conditions of 233a (Scheme 3.88) is resolved, it was originally planned the desired amine 318 would undergo aryl coupling between an in situ generated

123

enolate with o-iodonitrobenzene followed by nitro reduction to introduce the indole

ring (simple Fisher indole synthesis is not possible with !,#-unsaturated ketones).

However, this may couple with the external olefin, producing a mixture of coupled

products. Regiocontrol of the indole synthesis was optimized by Rawal and coworkers

using an unsymmetrical nitrophenylating reagent 320 that can be readily prepared in

two steps from o-iodonitrobenzene.151 An alkylative cyclization protocol adopted by

the same group would provide 322 in a two-step manner.152 The final step to open

valpericine 8 can be accomplished with sodium cyanoborohydride in acidic medium to

furnish subincanadine E. This procedure would furnish the natural product in 16 linear

steps overall from (S)-carvone.

151 For precedence of this step, see Scheme 12 in: Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. Journal of the American Chemical Society 2002, 124, 4628-4641.

152 A 1-step procedure is known, but Rawal and coworkers found that cyclization induced by tosylation competed with tosylation of the indole nitrogen. For the one step protocol, see: Rubiralta, M. Diez, A. Bosch, J.; Solans, S. Journal of Organic Chemistry 1989, 54, 5591-5597. For the 2-step protocol, see reference 147. Note that the transformation from x to x after step 1 would probably isolate the chloroamine rather than the O-mesylated amine as reported in this paper. 124

Scheme 3.92 Proposed final steps toward subincanadine E.

1. H H I H N 320 N N TBSCl, LHMDS NO 2 F

DMSO/THF O NEt , THF, -78 oC TBSO H 3 H N H 2. TiCl3, NH4OAc, H THF/H O, 318 319 2 321 excess Br OH Na2CO3, EtOH, reﬂux, 18 h

N N N NaCNBH3, 1. MsCl, NEt3, CH2Cl2

AcOH 2. t-BuOK, THF H N N H N H H H H 5a 8 322

125

3.14 Summary

Efforts toward the second total synthesis of (±)-subincanadine E have been put forth from tryptamine as well as efforts toward the first total asymmetric synthesis of

(15S)-subincanadine Efrom (S)-carvone. Several retrosyntheses have been discussed concerning the asymmetric route, with highlights including undesired intramolecular

Diels-Alder cyclization, formation of 17-oxo-subincanadine E via intramolecular enolate-driven Pd-catalyzed coupling, and copper-mediated 1,4-addition attempts to form the challenging C15-C20 bond. The asymmetric retrosynthesis features a novel route toward a 5-aminocyclohexenol and 5-aminocyclohexenone building blocks unprecedented in the literature by means of a Beckmann rearrangement. An intramolecular Heck reaction proceeded and efforts are currently being made toward its optimization as well as cleavage of a robust N-acetamide. To date, 10 out of 16 total steps have been completed.

126

CHAPTER 4: EXPERIMENTAL PROCEDURES

4.1 Methods and materials

Unless otherwise stated, all non-aqueous reactions were carried out under an

atmosphere of dry nitrogen in either oven-dried or flame-dried glassware.

Tetrahydrofuran, dichloromethane, diethyl ether, benzene, and toluene were dried using

a Glass Contour solvent purification system by SG H2O USA, LLC. All commercially

available starting materials were purchased from Aldrich, Fischer Scientific, or Acros

Organics, and used as received. Analytical TLC was performed on a Whatman Partisil

KF6 0.255 mm silica gel plates with UV indicator. Visualization was accomplished by

irradiation under a 254 nm UV lamp or stained with either an aqueous solution of

CAM, KMnO4, iodine, or vanillin. Flash chromatography was performed using a

forced flow of the indicated solvent system on EM Reagents Silica Gel 60 (230-400

mesh). Removal of solvents was accomplished on a Büchi R-210 rotary evaporator and

compounds were further dried under a Fischer Scientific Maxima C-Plus vacuum line.

All 1H data was conducted at ambient temperatures and recorded on a Varian

UnityInova (500 MHz), Bruker ARX (500 MHz), or Bruker AscendTM (125 MHz)

spectrometer. 13C NMR spectra were recorded on a Bruker ARX (125 MHz) or a

! 127 Bruker AscendTM (500 MHz). Chemical shifts are reported relative to either

chloroform (! 7.24) or methanol (! 3.31) for 1H spectra and either chloroform (! 77.2)

or methanol (! 49.15) for 13C spectra. Data are reported as follows: chemical shift,

multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, br = broad, m =

multiplet), coupling constants (Hz), and number of protons. IR spectra were recorded

on a Thermo Nicolet FT200 FT-IR spectrometer with attenuated total reflectance

(ATR) head. High-resolution mass spectra (HRMS) in CI mode were obtained on a

Waterss GC-TOF mass spectrometer (GCTPremier) employing a direct insertion probe

and methane as the reagent gas. Heptacosa was used as the internal reference. Samples

were dissolved in CH2Cl2 and introduced using a direct insertion probe. Data analysis

was performed in automated fashion using Waters software. For ESI mode, HRMS

were obtained on a Waterss LC-TOF mass spectrometer (LCT-XE Premier) using

electrospray ionization in positive mode. Samples were prepared in 100% CH2Cl2 and

introduced using flow injection through Water Alliance separation module 2695 using a

mobile phase of 100% MeOH (0.1mL/minute). Leucine Enkephaline (Waterss MS kit)

was used as an internal reference (2 ng/ul in acetonitrile/ H2O, 1:1 V/V, was mixed

with 1% acetic acid acetonitrile/ H2O 1% V/V) and introduced by infusion. Standard

settings were used for all other parameters including drying gas, nebulizer flow, and

! 128 cone voltage. The dry gas temperature was default value of 300 °C. Solvents used

were all Optima grade from Fisher.

4.2 Experimental procedures for the first-generation synthesis

N O N H 92

11b-methyl-5,6,11,11b-tetrahydro-1H-indolizino[8,7-b]indol-3(2H)-one (92). To a

stirred solution of tryptamine 18 (0.1674 g, 1.0 mmol, 1 equiv) in xylenes (8 mL) was

added levulinic acid (0.21 mL, 2 mmol, 2 equiv) via syringe. The reaction flask was

equipped with a Dean-Stark trap and condenser, placed under a stream of nitrogen, and

heated to reflux. After 4 h, the solvent was removed and the remaining brown oil was

diluted in chloroform (8 mL), washed with 1 M HCl (1 x 10 mL), 1 M NaOH (1 x 10

mL) and H2O (2 x 10 mL). The combined organic layers were dried over MgSO4 and

concentrated under reduced pressure. The dark brown solid was recrystallized in

1 benzene yielding 0.1770 g (74%) of a light brown solid. Rf = 0.33 (100% EtOAc). H

NMR (500 MHz, CDCl3) ! 7.88 (s, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.32 (d, J = 7.3 Hz,

! 129 1H), 7.17 (td, J = 7.0, 1.2 Hz, 1H), 7.12 (td J = 1.1, 6.9 Hz, 1H), 4.46 (ddd, J = 1.5, 5.8,

13.3 Hz, 1H), 3.08 (td, J = 5.5, 11.0 Hz, 1H), 2.72 – 2.86 (m, 2H), 2.62 – 2.71 (m, 1H)

2.46 (dd, J = 2.3, 9.7 Hz, 1H), 2.27 (ddd, J = 2.2, 8.9, 12.1 Hz, 1H), 2.13 – 2.20 (m,

13 1H), 1.58 (s, 3H). C NMR (125 MHz, CDCl3) ! 172.7, 137.6, 136.1, 126.7, 122.2,

119.8, 118.5, 111.0, 106.9, 35.0, 32.8, 30.7, 25.6, 25.4, 21.2.

N N H 91

11b-methyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole (91). To an oven-

dried round-bottom flask purged with nitrogen was added lactam 92 (0.9604 g, 4 mmol,

1 equiv) in dry THF (68 mL). LiAlH4 (0.3410 g, 14.4 mmol, 3.6 equiv) was slowly

added to the stirred mixture and brought to a reflux for 4 h under nitrogen. Upon

cooling, the solution was quenched with H2O (0.6 mL) via slow pipette addition

followed by 1 M NaOH (0.6 mL) and more H2O (1.8 mL). The resultant solution was

filtered and placed under reduced pressure to provide 0.760 g (84%) of 91 as a light

1 brown solid. Rf = 0.46 (streak in 85:15:1 CH2Cl2:MeOH:NH4OH). H NMR (500

MHz, CDCl3) ! 7.78 (s, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.14

(td, J = 7.1, 1.0 Hz, 1H), 7.08 (td, J = 7.7, 0.9 Hz, 1H), 3.74 (td, J = 6.6, 1.0 Hz, 1H),

! 130 3.22 – 3.31 (m, 2H), 3.08 (ddd, J = 4.0, 9.1, 17.0 Hz, 1H), 2.89 – 2.99 (m, 2H), 2.56

(dd, J = 4.3, 16.9 Hz, 1H), 2.12 – 2.17 (m, 1H), 2.02-2.07 (m, 1H), 1.83 – 1.94 (m, 2H),

13 1.55 (s, 3H). C NMR (125 MHz, CDCl3) ! 138.8, 135.9, 127.1, 121.3, 119.2, 118.1,

110.9, 106.4, 60.1, 53.4 (CH2Cl2), 49.1, 42.2, 37.9, 27.7, 22.2, 16.1.

Boc N N H 97b

tert-butyl 7-methylene-1,2,4,5,6,7-hexahydroazonino[5,4-b]indole-3(8H)-

carboxylate (97b). To a solution of amine 91 (0.1147 g, 0.51 mmol, 1 equiv) in dry

toluene (5 mL) was added Boc anhydride (0.1743 g, 0.75 mmol, 1.5 equiv) and allowed

to stir at rt for 1 h. The reaction mixture was heated to 110 °C in an oil bath for 21 h.

The crude solution was concentrated to yield 0.2245 g of a red oil. Purification was

accomplished by flash chromatography (2:1 hexanes:EtOAc) affording 0.0208 g (12%)

1 of the protected external olefin 97b. Rf = 0.80 (2:1 hexanes:EtOAc). H NMR (500

MHz, CDCl3) ! 7.90 (s, 1H), 7.50 (dd, J = 7.8, 3.2 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H),

7.16 (ddd, J = 8.4, 5.9, 2.1 Hz, 1H), 7.07 (m, 1H), 5.26 – 5.03 (m, 2H), 3.63 – 3.51 (m,

1H), 3.42 (t, J = 5.2 Hz, 1H), 3.23 (t, J = 5.9 Hz, 1H), 3.12 (ddt, J = 20.5, 10.8, 5.7 Hz,

3H), 2.67 (dt, J = 30.1, 5.4 Hz, 2H), 1.97 – 1.75 (m, 2H), 1.52 (H2O), 1.43 (s, 4H), 1.14

! 131 13 (s, 4H). C NMR (125 MHz, CDCl3) ! 156.1, 155.3, 143.1, 143.0, 135.7, 135.6,

135.0, 129.2, 129.2, 122.7, 122.5, 119.5, 119.3, 118.5, 118.3, 112.7, 111.9, 110.6,

110.6, 79.4, 78.8, 49.8, 49.0, 48.4, 47.3, 32.5, 31.8, 28.7, 28.3, 24.7.

Cbz N N H 97a

Benzyl 7-methylene-1,2,4,5,6,7-hexahydroazonino[5,4-b]indole-3(8H)-carboxylate

(97a). To a solution of amine 91 (0.5533 g, 2.4 mmol, 1 equiv) in dry THF (60 mL)

was added NaHCO3 (1.8132 g, 11 mmol, 4.6 equiv). After cooling to 0 °C, benzyl

chloroformate (1.0 mL, 6.7 mmol, 2.8 equiv) was added drop-wise and allowed to

warm to rt over 1 h. H2O was then added (5.4 mL, 293 mmol, 122 equiv) and the

reaction mixture was heated to 50 °C in an oil bath. After 3 h, additional benzyl

chloroformate and H2O was added and continued to stir for 20 h. Once cooled to rt, the

red solution was washed with 2 M NaOH (1 x 30 mL), brine (1 x 30 mL), dried over

Na2SO4, and concentrated to yield 1.6064 g of an orange oil. Purification was

accomplished by flash chromatography (95:5 CH2Cl2:EtOAc) affording 0.46 g (52%)

1 of the protected external olefin 97a. Rf = 0.55 (2:1 hexanes:EtOAc). H NMR (500

MHz, CDCl3) ! 7.89 (d, J = 9.8 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.27 – 7.35 (m, 3H),

! 132 7.15 – 7.21 (m, 3H), 7.09 (td, J = 3.9, 8.0 Hz, 1H), 6.97 (d, J = 7.0 Hz, 1H), 5.28

(CH2Cl2), 5.03 – 5.16 (m, 3H), 4.91 (s, 1H), 4.10 (EtOAc), 3.62 – 3.64 (m, 1H), 3.54 –

3.56 (m, 1H), 3.32 (t, J = 6.3 Hz, 1H), 3.25 (t, J = 6.5 Hz, 1H), 3.10 – 3.16 (m, 2H),

2.62 – 2.67 (m, 2H), 2.03 (EtOAc), 1.93 – 1.97 (m, 1H), 1.78 – 1.83 (m, 1H), 1.24

13 (EtOAc). C NMR (125 MHz, CDCl3) ! 171.4 (EtOAc), 156.5, 155.6, 142.8, 136.8,

135.2, 128.9, 128.4, 28.2, 128.0, 127.5, 122.5, 119.3, 118.0, 112.6, 112.2, 111.5, 110.5,

66.6, 60.5 (EtOAc), 48.4, 47.1, 31.7, 28.5, 24.4, 21.2 (EtOAc), 14.4 (EtOAc).

N N H 97c 1-(7-methylene-1,2,4,5,6,7-hexahydroazonino[5,4-b]indol-3(8H)-yl)ethanone (97c).

1 See procedure for 97a. H NMR (500 MHz, CDCl3) ! 8.02 (s, 1H), 7.52 (d, J = 7.9 Hz,

1H), 7.30 (d, J = 8.1 Hz, 1H), 7.21 – 7.15 (m, 1H), 7.12 – 7.06 (m, 1H), 5.25 (s, 1H),

5.11 (s, 1H), 3.49 – 3.41 (m, 2H), 3.41 – 3.30 (m, 2H), 3.23 – 3.10 (dt, J = 8.5, 3.3 Hz,

13 2H), 2.61 (dd, J = 7.6, 4.2 Hz, 2H), 2.17 – 1.94 (m, 4H), 1.52 (H2O), 1.49 (s, 3H). C

NMR (125 MHz, CDCl3) ! 171.1, 142.7, 135.8, 135.7, 129.0, 122.9, 119.6, 118.0,

113.0, 110.9, 110.0, 48.9, 48.1, 31.3, 28.9, 24.7, 21.9.

! 133 Cbz N

NH N Cbz

98 dibenzyl 4,4',5,5',6,6',7',8,8',14b'-decahydro-1H,1'H-spiro[azonino[5,4-b]indole-

7,9'-azonino[6,5,4-hi]benzo[b]indolizine]-3,3'(2H,2'H)-dicarboxylate (98). To a

solution of the external olefin 97a (0.1123 g, 0.31 mmol, 1 equiv) in dry toluene (14

mL) was added p-TsOH (0.0969 g, 0.51 mmol, 1.6 equiv) and heated to 50 °C in an oil

bath. After 4 h, the reaction solution was washed with saturated Na2CO3 (2 x 15 mL),

brine (1 x 15 mL), dried over Na2SO4, and concentrated to an orange foam.

Purification was accomplished by flash chromatography (2:1 hexanes:EtOAc) affording

1 0.1141 g (51%) of dimer 98. Rf = 0.38 (3:1 hexanes:EtOAc). H NMR (500 MHz,

CDCl3) ! 7.59 – 7.43 (m, 2H), 7.39 – 7.33 (q, J = 4.5, 4.1 Hz, 2H), 7.33 – 7.25 (m, 4H),

7.20 – 6.97 (m, 5H), 5.29 – 4.89 (m, 2H), 4.52 – 4.27 (m, 1H), 4.10 (EtOAc), 3.95 –

3.76 (s, 1H), 3.71 – 3.21 (m, 3H), 3.21 – 2.47 (m, 6H), 2.36 – 2.14 (m, 2H), 2.14 – 1.83

(m, 3H), 1.37 – 1.17 (td, J = 6.8, 3.9 Hz, 2H), 1.17 – 1.03 (d, J = 22.8 Hz, 1H), 1.03 –

13 0.91 (m, 2H), 0.91 – 0.75 (m, 1H). C NMR (125 MHz, CDCl3) ! 157.1, 157.0, 156.8,

156.5, 156.3, 148.0, 147.4, 141.1, 137.4, 137.1, 137.0, 136.9, 136.9, 134.2, 134.2,

! 134 133.9, 133.9, 133.4, 133.1, 133.0, 132.9, 131.7, 131.6, 131.5, 131.4, 129.8, 129.4,

128.7, 128.6, 128.5, 128.1, 128.0, 127.9, 127.7, 127.1, 122.0, 121.8, 121.7, 121.5,

121.4, 121.0, 119.8, 119.7, 118.6, 118.5, 118.1, 118.0, 117.9, 111.9, 111.8, 111.7,

111.2, 111.1, 109.2, 109.0, 104.5, 104.2, 103.6, 67.3, 67.2, 67.0, 66.9, 66.7, 66.3, 66.2,

66.1, 65.4, 49.1, 48.6, 48.3, 47.8, 47.6, 47.5, 46.7, 40.9, 40.8, 40.3, 40.2, 39.1, 38.6,

29.9, 26.4, 26.1, 25.9, 25.8, 25.5, 25.4, 25.1, 24.7, 24.6, 23.4.

! 135 4.3 Experimental procedures for the second-generation synthesis

O HN N H 103

N-(2-(1H-indol-3-yl)ethyl)-4-hydroxybutanamide (103). To a stirred solution of

tryptamine 18 (3.2131 g, 20 mmol, 1 equiv) in dry toluene (30 mL) was added !-

butryrolactone (1.7 mL, 22 mmol, 1.4 equiv) via syringe. After addition of p-TsOH

(catalytic), the reaction mixture was heated at a reflux for 7 h. Once cooled, toluene

was removed by rotary evaporation, the residue was re-dissolved in ethyl acetate (15

mL), and placed in the freezer overnight. Filtration provided 3.3210 g (64%) of a

1 yellow/white solid. Rf = 0.57 (85:15:1 CH2Cl2:MeOH:NH4OH). H NMR (500 MHz,

CDCl3) " 8.19 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.19 (td, J =

1.1, 8.1 Hz, 1H), 7.20 (td, J = 1.0, 7.8 Hz, 1H), 7.01 (d, J = 0.6, 8.0 Hz, 1H), 5.67 (bs,

1H), 3.58 – 3.62 (m, 4H), 2.96 (t, J = 7.7 Hz, 2H), 2.84, (bs, 1H), 2.24 (t, J = 7.4 Hz,

13 2H), 1.80 (p, J = 6.5 Hz, 2H). C NMR (125 MHz, CDCl3) " 195.7, 175.9, 138.2,

128.8, 123.4, 122.3, 119.6, 113.3, 112.2, 62.3, 41.4, 33.71 29.8, 26.3.

! 136 N N H 101

2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole ((±)-harmacine) (101). Under

an atmosphere of nitrogen, amido-alcohol 103 (4.61 g, 17.7 mmol, 1 equiv) was

dissolved in POCl3 (50 mL, 567 mmol, 32 equiv) and heated at reflux for 5 h. Once

cooled to rt, POCl3 was removed in vacuo and the residue was re-dissolved in CH2Cl2

(3 x 40 mL) to ensure complete removal of this reagent. After drying overnight under

vacuum, the lime green foam (crude weight of 4.70 g, 17.4 mmol, 1 equiv) was

exposed to MeOH (350 mL) and cooled to 0 °C. NaBH4 (13.250 g, 350 mmol, 20

equiv) was slowly added over a period of 1 h. The stirred mixture was allowed to

warm to rt. After 2 h, MeOH was removed in vacuo, the resultant crude material was

diluted with diethyl ether (150 mL), washed with H2O (1 x 150 mL), dried over

Na2SO4, and concentrated under reduced pressure to yield 3.35 g (89% over 2 steps) of

1 a yellow solid. Rf = 0.26 (85:15:1 in CH2Cl2:MeOH:NH4OH). H NMR (500 MHz,

CDCl3) ! 8.22 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.07 – 7.14

(m, 2H), 4.23 (td, J = 2.3, 7.3 Hz, 1H), 3.44 (s, MeOH), 3.31 (ddd, J = 2.5, 5.4, 13.0

Hz, 1H), 3.05 – 3.11 (m, 1H), 2.87 – 2.97 (m, 3H), 2.67 (dp, J = 2.1, 15.8 Hz, 1H), 2.22

! 137 13 – 2.31 (m, 1H), 1.78 – 1.94 (m, 3H). C NMR (125 MHz, CDCl3) ! 136.2, 136.6,

127.1, 121.4, 119.3, 118.0, 110.9, 107.3, 57.2, 49.5 (MeOH), 46.0, 29.5, 23.2, 17.8.

N N Boc 101a

tert-butyl 2,3,5,6-tetrahydro-1H-indolizino[8,7-b]indole-11(11bH)-carboxylate

(101a). To a stirred solution of harmacine 101 (0.0508 g, 0.24 mmol, 1 equiv) in dry

CH2Cl2 (4 mL) was added DMAP (0.0291 g, 0.24 mmol, 1 equiv) and Boc anhydride

(0.1001 g, 0.46 mmol, 1.9 equiv). After 3 h, the solution was concentrated to a light

brown foam. Purification was performed by flash chromatography (100% EtOAc to

85:15:1 CH2Cl2:MeOH:NH4OH) yielding 0.0338 g (67%) of a white foam. Rf= 0.79

1 (2:1 hexanes:EtOAc). H NMR (500 MHz, CDCl3) ! 8.01 (d, J = 8.3, 1H), 7.40 (d, J =

7.7, 1H), 7.30 (t, J = 8.3, 1H), 7.23 (t, J = 7.6, 1H), 5.30 (t, J = 7.1, 1H), 3.68 – 3.74 (m,

1H), 3.47 – 3.52 (m, 1H), 3.36 – 3.40 (m, 1H), 3.13 – 3.20 (m, 2H), 2.83 – 2.96 (m,

2H), 2.15 – 2.25 (m, 1H), 1.94 – 2.05 (m, 2H), 1.65 (s, 9H). 13C NMR (125 MHz,

CDCl3) ! 159.6, 136.0, 130.4, 127.6, 125.3, 123.3, 118.4, 115.7, 113.2, 85.2, 59.6,

51.9, 45.4, 30.8, 28.1, 21.9, 17.3.

! 138 Cbz N N H HO 100a

benzyl 7-hydroxy-1,2,4,5,6,7-hexahydroazonino[5,4-b]indole-3(8H)-carboxylate

(100a). To a stirred solution of harmacine 101 (0.6180 g, 2.9 mmol, 1 equiv) in dry

THF (60 mL) was added Na2CO3 (1.4451 g, 13.1 mmol, 4.5 equiv). After cooling to 0

°C under nitrogen, benzyl chloroformate (1.2 mL, 8.1 mmol, 2.8 equiv) was added

drop-wise. The cloudy lime green solution was allowed to stir at rt for 1 h. A reflux

condenser was added and the reaction mixture was brought to 50 °C in an oil bath.

After 25 min, H2O (6.3 mL, 349.2 mmol, 120 equiv) was added and continued to heat

for 3 h, after which the solution turned dark brown. An additional equivalent of the

chloroformate (1.2 mL) and H2O (6.3 mL) was added and allowed to stir at this

temperature for 2 h more. The solvent was removed and the residue was diluted with

chloroform (30 mL), washed with 2 M NaOH (1 x 30 mL), rinsed with brine (1 x 30

mL), dried over Na2SO4, and concentrated under reduced pressure to yield a lime green

oil. Purification was performed by flash chromatography (85:15:1

CH2Cl2:MeOH:NH4OH) yielding 0.748 g (71%) of 100a. A benzyl alcohol impurity

was present, providing 53% of the desired product (Calculated from 1H NMR

1 integrations). Rf = 0.72 (85:15:1 CH2Cl2:MeOH:NH4OH). H NMR (500 MHz,

! 139 CDCl3) ! 8.89 (d, J = 7.4 Hz, 1H), 7.55 (t, J = 6.8 Hz, 1H), 7.38 – 7.42 (m, 6H), 7.21 (t,

J = 7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 5.07 – 5.22 (m, 2H), 4.67 (s, benzyl alcohol)

3.96 – 4.09 (m, 2H), 3.51 – 3.61 (m, 1H), 2.94 – 3.17 (m, 2H), 2.54 – 2.67 (m, 2H),

2.11 – 2.23 (m, 1H), 1.79 – 1.86 (m, 1H), 1.34 (d, J = 14.4 Hz, 1H), 0.78 – 0.86 (m,

13 1H). C NMR (125 MHz, CDCl3) ! 156.2, 136.6, 136.4, 135.5, 135.4, 128.4, 127.9,

126.8, 1216, 118.9, 117.9, 117.7, 111.1, 110.6, 102.0, 67.0, 64.9, 49.3, 48.5, 35.7, 23.3,

21.9.

H N N H HO 106

1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indol-7-ol (106). To the protected amine

100a (0.100 g, 0.27 mmol, 1 equiv) stirred in EtOH (4 mL) was added 10% Pd/C

(0.010 g, cat.) and ammonium formate (0.085 g, 1.35 mmol, 5 equiv) at rt. After

stirring for 18 h the solution was filtered through a plug of Celite and concentrated to

produce 0.0984 g of a bright yellow oil. Purification was performed by flash

chromatography (85:15:1 CH2Cl2:MeOH:NH4OH) yielding 0.0465 g (75%) of a white

1 solid. Rf = 0.25 (85:15:1 CH2Cl2:MeOH:NH4OH). H NMR (500 MHz, CDCl3) ! 8.25

(s, 1H), 7.48, (dd, J = 2.0, 7.1 Hz, 1H), 7.23 (dd, J = 1.5, 7.4 Hz, 1H), 7.08 (pd, J = 1.3,

! 140 7.1 Hz, 2H), 5.08 (dd, J = 2.90 4.7 Hz, 1H), 3.32 (ddd, J = 2.3, 4.6, 14.0 Hz, 1H), 3.05

(ddd, J = 2.2, 11.7, 15.0 Hz, 1H), 2.91 (dd, J = 3.9, 14.7 Hz, 1H), 2.58 – 2.62 (m, 2H),

2.34 – 2.41 (m, 1H), 2.00 – 2.05 (m, 1H), 1.75 – 1.81 (m, 1H), 1.24 – 1.33 (m, 2H),

13 1.06 – 1.15 (m, 1H). C NMR (125 MHz, CDCl3) ! 136.3, 134.5, 128.5, 120.7, 118.4,

117.0, 110.2, 110.2, 68.0, 48.2, 48.1, 37.1, 25.4, 22.8.

OHC

I 109

(Z)-2-iodobut-2-enal (109). To a stirred solution of crotonaldehyde 108 (4.2 mL, 56.7

mmol, 1 equiv) in 1:1 THF/H2O (250 mL) was added K2CO3 (8.3076 g, 68.1 mmol, 1.2

equiv), I2 (19.3347 g, 868 mmol, 15.3 equiv), and DMAP (1.2344 g, 10.1 mmol, cat.)

successively. After 3 h of stirring at rt, the black solution was diluted with EtOAc (200

mL), washed with Na2S2O3 (1 x 100 mL), 0.1 M HCl (1 x 200 mL), dried over MgSO4,

and concentrated yielding 4.500 g (45%) of a black oil. Rf = 0.80 (2:1

1 hexanes:EtOAc). H NMR (500 MHz, CDCl3) 8.67 (s, 1H), 7.28 (q, J = 6.7 Hz, 1H),

4.01 (q, EtOAc), 2.18 (d, J = 6.8 Hz, 3H), 1.98 (s, EtOAc), 1.13 (t, EtOAc). 13C NMR

(125 MHz, CDCl3) ! 187.7, 157.5, 113.4, 60.4 (EtOAc), 22.4, 21.0 (EtOAc), 14.0

(EtOAc).

! 141 HO

I 110

(Z)-2-iodobut-2-en-1-ol (110). To a solution of the aldehyde 109 (4.500 g, 22.96

mmol, 1 equiv) in MeOH (100 mL) cooled to 0 °C was added NaBH4 (1.7391 g, 34.4

mmol, 1.5 equiv) portion-wise and continued to stir for 3 h. Methanol was removed in

vacuo and the residue was dissolved in EtOAc (150 mL), washed with 1 M NaOH (2 x

150 mL), dried over Na2SO4, and concentrated. Further removal of solvent in vacuo

1 for 2 h yielded 2.690 g (59%) of an orange oil. Rf = 0.45 (2:1 hexanes:EtOAc). H

NMR (500 MHz, CDCl3) ! 5.95 (qt, J = 1.2, 6.5 Hz, 1H), 4.23 (s, 2H), 1.78 (dt, J = 1.1,

6.4 Hz, 3H), 1.51 (s, H2O).

MsO

I 111

(Z)-2-iodobut-2-enyl methanesulfonate (111). To a stirred solution of buten-ol 110 in

dry CH2Cl2 (50 mL) wad added NEt3 (2.3 mL, 16 mmol, 1.2 equiv). The reaction

mixture was cooled to 0 °C and MsCl (1.2 mL, 15 mmol, 1.1 equiv) was added drop-

wise and continued to stir for 3 h. The bright yellow solution was washed with water (1

x 50 mL), NaHCO3 (1 x 50 mL), dried over Na2SO4, and concentrated under reduced

1 pressure to yield 3.51 g (94%) of a brown oil. Rf = 0.46 (2:1 hexanes:EtOAc). H

! 142 NMR (500 MHz, CDCl3) ! 6.17 (q, J = 0.9, 6.4 Hz, 1H), 4.87 (q, J =1.0 Hz, 2H), 3.04

13 (s, 3H), 1.81 (dq, J = 0.9, 6.4 Hz, 3H). C NMR (125 MHz, CDCl3) ! 138.5, 77.5,

21.9.

N I N H HO 112

(Z)-3-(2-iodobut-2-enyl)-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indol-7-ol (112).

To a tarred round-bottom flask was added mesylate 111 (0.085 g, 0.31 mmol, 1.4

equiv) in dry THF (2 mL), K2CO3 (0.0655 g, 0.44 mmol, 2.0 equiv), NEt3 (0.048 mL,

0.33 mmol, 1.5 equiv), and amino-alcohol 106 (0.0518 g, 0.22 mmol, 1 equiv). The

reaction mixture was stirred under nitrogen at rt for 21 h. The solvent was removed in

vacuo, the residue was diluted with CH2Cl2 (3 mL), washed with H2O (1 x 3 mL), brine

(1 x 3 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification

was performed by flash chromatography (85:15:1 CH2Cl2:MeOH:NH4OH) yielding

1 0.081 g (90%) of a light brown foam. Rf = 0.70 (85:15:1 CH2Cl2:MeOH:NH4OH). H

NMR (500 MHz, CDCl3) ! 8.04 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 8.0 Hz,

1H), 7.12 (td, J = 1.1, 7.2 Hz, 1H), 7.06 (td, J = 1.0, 8.0 Hz, 1H), 5.85 (q, J = 6.3 Hz,

2H), 3.71-3.74 (m, 2H), 3.61 (d, J = 13.9 Hz, 1H), 3.52 (d, J = 13.6 Hz, 1H), 2.95 –

! 143 2.98 (m, 1H), 2.77 – 2.82 (m, 1H), 2.60 – 2.67 (m, 2H), 2.38 – 2.50 (m, 2H), 1.96 –

2.03 (m, 2H), 1.82 (d, J = 6.5 Hz, 3H), 1.30 – 1.35 (m, 1H), 1.11 – 1.19 (m, 1H). 13C

NMR (125 MHz, CDCl3) ! 137.2, 135.0, 134.0, 128.7, 121.3, 119.0, 118.8, 117.7,

112.3, 110.6, 71.3, 68.1, 55.6, 54.3, 37.4, 24.7, 24.1, 22.1.

N I N H MeO 112a

(Z)-3-(2-iodobut-2-en-1-yl)-7-methoxy-1,2,3,4,5,6,7,8-octahydroazonino[5,4-

b]indole (112a). The alkylation procedure was the same as for compound 112. The

hydrogenation used the same procedure as 106 with the exception of using MeOH as

1 the solvent instead. Rf = 0.65 (95:5:1 CH2Cl2:MeOH:NH4OH). H NMR (500 MHz,

CDCl3) ! 8.66 (bs, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.12 (t, J =

7.1, 15.0 Hz, 1H), 7.14 – 7.06 (t, J = 7.8, 14.9 Hz, 1H), 6.01 (dd, J = 11.0, 5.7 Hz, 1H),

5.83 (q, J = 6.2 Hz, 1H), 3.55 (s, 2H), 3.34 (s, 3H), 2.99 – 2.86 (m, 1H), 2.86 – 2.69 (m,

2H), 2.56 – 2.43 (m, 1H), 2.43 – 2.28 (m, 2H), 2.11 – 1.97 (m, 1H), 1.95 – 1.73 (m,

13 5H), 1.38 – 1.20 (m, 1H), 1.03 – 0.84 (m, 1H). C NMR (125 MHz, CDCl3) ! 135.70,

135.37, 132.92, 128.41, 121.46, 118.85, 117.94, 114.75, 110.88, 110.17, 71.85, 56.86,

55.70, 55.11, 36.04, 25.22, 24.67, 22.11.

! 144 N I N H O 99

(Z)-3-(2-iodobut-2-enyl)-1,2,3,4,5,6-hexahydroazonino[5,4-b]indol-7(8H)-one (99).

Manganese(II) dioxide (0.2332 g, 2.7 mmol, 24 equiv) was added to the alkylated

amino-alcohol 112 (0.0440 g, 0.11 mmol, 1 equiv) and suspended in dry CH2Cl2 (3

mL). The suspension was heated to a reflux and allowed to stir for 21 h. Once cooled,

the solids were filtered through a Celite plug producing a light yellow solution that was

concentrated under reduced pressure to yield 0.0352 g (86%) of the desired amino-

ketone 99. Rf = 0.83 (85:15:1 CH2Cl2:MeOH:NH4OH). No purification was

1 necessary. H NMR (500 MHz, CDCl3) ! 8.86 (s, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.36

(d, J = 8.2 Hz, 1H), 7.29 (t, J = 6.9 Hz, 1H), 7.11 (t, J = 6.7 Hz, 1H), 5.46 (q, J = 6.9

Hz, 1H), 5.24 (s, CH2Cl2) 3.16 (s, 2H), 3.05 (s, 2H), 2.68 – 2.32 (m, 6H), 2.00 (bs, 2H),

13 1.61 (d, J = 6.3 Hz, 3H). C NMR (125 MHz, CDCl3) ! 195.8, 135.7, 135.6, 131.4,

127.6, 125.2, 120.1, 119.8, 111.8, 107.7, 65.8, 55.4 (CH2Cl2), 50.4, 39.3, 29.7, 25.9,

21.6.

! 145 N I N Boc O 113

(Z)-tert-butyl 3-(2-iodobut-2-en-1-yl)-7-oxo-2,3,4,5,6,7-hexahydroazonino[5,4-

b]indole-8(1H)-carboxylate (113). To a stirring solution of ketone 112 (0.0455 g,

0.11 mmol, 1 eqiuv) in CH2Cl2 (1 mL) under nitrogen was added DMAP (0.0039 g,

0.02 mmol, 0.2 equiv) followed by Boc anhydride (0.567 g, 0.17 mmol, 1.7 equiv).

The solution was allowed to stir at rt for 4 h before the solvent was removed in vacuo to

produce 0.0487 g of a dark brown oil. Purification was performed by flash

chromatography (95:5:1 CH2Cl2:MeOH:NH4OH) yielding 0.0292 g (64%) of a light

1 brown foam. Rf = 0.87 (95:5:1 CH2Cl2:MeOH:NH4OH). H NMR (500 MHz, CDCl3)

! 8.08 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 8.4, 16.7 Hz 1H), 7.25

(t, J = 8.8, 16.9 Hz, 1H), 5.61 (q, J = 6.3 Hz, 1H), 3.15 (s, 2H), 2.98 – 2.65 (m, 7H),

2.55 (t, J = 5.8 Hz, 2H), 2.11 – 1.85 (m, 2H), 1.85 – 1.73 (m, 5H), 1.73 – 1.63 (m,

13 12H), 1.47 (s, 18H). C NMR (125 MHz, CDCl3) ! 193.2, 150.2, 137.3, 137.2, 132.2,

128.7, 126.7, 122.7, 120.4, 119.5, 114.6, 106.7, 84.6, 63.4, 54.5, 48.8, 39.8, 28.1, 24.4,

22.4.

! 146 N

N H O 132

3-(prop-1-ynyl)-1,2,3,4,5,6-hexahydroazonino[5,4-b]indol-7(8H)-one (132). To an

oven-dried Schlenk tube was added cis-1,2-cyclohexanediol (0.0028 g, 0.02 mmol, 1

equiv), CuI (0.0059 g, 0.02 mmol, 1 equiv), and dry DMF (0.5 mL). The tube was

purged three times with nitrogen at rt using a vacuum line. After 10 min of stirring, the

Boc-protected amino-ketone 113 (0.0103 g, 0.02 mmol, 1 equiv) was added in dry

DMF (1 mL) followed by KOt-Bu (0.0045 g, 0.04 mmol, 2 equiv). The Schlenk tube

was placed in a pre-heated 80 °C oil bath for 12 h. Once cooled to rt, the black solution

was filtered through a Celite plug and concentrated to 0.0311 g of a yellow foam.

Purification was performed by flash chromatography (2:1 hexanes:EtOAc to 95:5:1

CH2Cl2:MeOH:NH4OH) yielding 0.003 g (43%) of light brown solid. Rf = 0.62 (95:5:1

1 CH2Cl2:MeOH:NH4OH). H NMR (500 MHz, CDCl3) ! 8.90 (s, 1H), 7.66 (d, J = 8.1

Hz, 1H), 7.35, (d, J = 8.2 Hz, 1H), 7.26 (td, J = 1.0, 7.0 Hz, 1H), 7.11 (td, J = 0.9, 7.0

Hz, 1H), 2.65 – 3.07 (m, 7H), 2.59 (m, 2H), 2.45 (bs, 1H), 2.03 (bs, 2H), 1.68 (t, J =

13 2.3 Hz, 3H), 1.56 (s, H2O). C NMR (125 MHz, CDCl3) ! 195.5, 136.2, 135.1, 127.5,

124.7, 119.9, 119.7, 116.7, 111.6, 78.8, 75.1, 68.0, 54.3, 43.7, 39.9, 29.6, 25.6, 24.4.

! 147 N

N Boc O 133 tert-butyl 3-(but-2-yn-1-yl)-7-oxo-2,3,4,5,6,7-hexahydroazonino[5,4-b]indole-

8(1H)-carboxylate (133). To a dry round-bottom flask was added phenol (0.214 g, 2.3

mmol, 23 equiv), KOt-Bu (0.0229 g, 0.2 mmol, 2 equiv) and dry THF (1 mL). After 5

min of stirring, Pd(PPh3) 4 (0.0073 g, 0.006 mmol, 0.06 equiv) and the alkylated ketone

113 (0.0421 g, 0.1 mmol, 1 equiv) was added and the solution was degassed. The

reaction mixture was placed under a stream of nitrogen and added to a 75 °C pre-heated

oil bath. After 12 h of stirring, the brown solution was quenched with ice water (5 mL),

extracted with ethyl acetate (3 x 5 mL), washed with brine (1 x 7 mL), dried over

Na2SO4, concentrated, and placed under reduced pressure yielding 0.0435 g of a brown

oil. Purification was performed by flash chromatography (95:5:1

1 CH2Cl2:MeOH:NH4OH) yielding 0.014 g (50%) of light brown solid. H NMR (500

MHz, CDCl3) ! 8.11 – 8.02 (m, 1H), 7.61 – 7.52 (m, 1H), 7.47 – 7.36 (m, 1H), 7.28

(dd, J = 14.7, 7.3 Hz, 1H), 3.67 – 3.56 (m, 1H), 3.55 – 3.45 (m, 1H), 3.35 (d, J = 5.9

Hz, 3H), 3.23 – 3.07 (m, 2H), 2.89 – 2.68 (m, 3H), 2.56 (s, 1H), 2.29 (p, J = 6.3 Hz,

! 148 2H), 1.94 – 1.81 (m, 1H), 1.66 (s, 2H), 1.56 (s, 11H), 1.29 – 1.13 (m, 3H), 1.03 – 0.75

(m, 13H), 0.61 – 0.41 (m, 7H).

N Boc O 131

(Z)-tert-butyl 7-oxo-13-(prop-1-en-1-yl)-4,5,6,7-tetrahydro-1H-3,6

methanoazonino[5,4-b]indole-8(2H)-carboxylate (131). In a glovebox, Pd2(dba)3

(0.1790 g, 0.18 mmol, 0.2 equiv), NaOt-Bu (0.1439 g, 1.35 mmol, 1.7 equiv), and

xantphos (0.1422 g, 0.18 mmol, 0.2 equiv) was added to a Schlenk reaction vessel. The

Boc-protected ketone 113 (0.4571 g, 0.90 mmol, 1 equiv) in THF (1 mL) was added via

syringe and further diluted with THF (1.5 mL). The reaction vessel was capped,

removed from the glovebox, and purged five times with nitrogen at -78 °C. Once

warmed to rt, the reaction vessel was placed in a pre-heated oil bath set at 70 °C. After

4 h, the solution was concentrated to produce 0.830 g of a brown foam. Purification

was performed by flash chromatography (1:1 hexanes:EtOAc to 95:5:1

1 CH2Cl2:MeOH:NH4OH) yielding 0.180 g (71%) of light brown solid. H NMR (500

MHz, CDCl3) ! 8.12 – 8.06 (m, 1H), 7.53 – 7.47 (m, 2H), 7.39 – 7.32 (m, 3H), 7.28 –

! 149 7.24 (m, 1H), 5.67 – 5.53 (m, 1H), 5.53 – 5.35 (m, 2H), 5.24 (s, CH2Cl2), 4.35 (d, J =

5.9 Hz, 1H), 3.48 – 3.00 (m, 12H), 3.00 – 2.66 (m, 4H), 2.42 – 2.27 (m, 2H), 2.27 –

13 2.09 (m, 2H), 1.71 – 1.62 (m, 6H), 1.61 – 1.46 (m, 6H). C NMR (125 MHz, CDCl3) !

203.0, 149.4, 136.4, 134.1, 132.4, 128.7, 126.2, 125.2, 123.2, 120.7, 119.5, 115.3, 85.1,

66.0, 60.6, 59.7, 56.2 (CH2Cl2), 53.3, 52.3, 28.8, 28.1, 28.1, 21.8, 17.8.

N H O 137

(Z)-13-(prop-1-en-1-yl)-4,5,6,8-tetrahydro-1H-3,6-methanoazonino[5,4-b]indol-

7(2H)-one (137). To a stirring solution of the [5.2.1]bicycle 131 (0.0511 g, 0.13 mmol,

1 equiv) in dry CH2Cl2 (1.5 mL, 23 mmol, 174 equiv) was added TFA (1.5 mL, 20

mmol, 149 equiv) slowly under nitrogen. After 1 h 45 min, the solution was diluted

with CH2Cl2 (15 mL) and quenched with NaHCO3 (15 mL) at 0 °C. The biphasic

solution was separated and the organic layer was washed with 1 M NaOH (1 x 60 mL),

brine (1 x 15 mL), dried over Na2SO4, and concentrated to a brown oil. Purification

was performed by flash chromatography (95:5:1 CH2Cl2:MeOH:NH4OH) yielding

1 0.0358 g (95%) of light brown solid. H NMR (500 MHz, CDCl3) ! 9.17 – 8.98 (s,

! 150 1H), 7.70 – 7.55 (m, 1H), 7.44 – 7.28 (m, 12H), 7.16 – 7.04 (m, 1H), 5.60 – 5.36 (m,

2H), 5.24 (s, CH2Cl2), 4.30 – 4.16 (d, J = 6.5 Hz, 1H), 3.50 – 3.39 (m, 1H), 3.39 – 3.10

(m, 4H), 3.10 – 2.97 (m, 1H), 2.64 – 2.46 (m, 1H), 2.46 – 2.31 (td, J = 13.2, 12.0, 7.7

Hz, 1H), 1.74 – 1.46 (m, 5H).

N H 138

(Z)-7-methylene-13-(prop-1-en-1-yl)-2,4,5,6,7,8-hexahydro-1H-3,6-

methanoazonino[5,4-b]indole (138). Formation of the ylide: To a stirring solution of

CH3PPh3Br (0.5725 g, 1.60 mmol, 7.6 equiv) in dry THF (3 mL) at 0 °C under nitrogen

was added drop-wise 1.3 M n-BuLi (2.1 mL, 0.47 mmol, 2.2 equiv) and continued to

stir at 0 °C for 1 h 20 min. Wittig reaction: The ylide solution (2.1 mL) was added to a

separate flask containing the Boc-deprotected ketone 137 (0.0593 g, 0.21 mmol, 1

equiv) in dry THF (3 mL) at 0 °C. After warming to rt for 4.5 h, the solution was

diluted with CH2Cl2 (24 mL), washed with NH4OH (1 x 24 mL), dried over Na2SO4,

and concentrated. Purification was performed by flash chromatography (1:10

hexanes:EtOAc to 95:5:1 CH2Cl2:MeOH:NH4OH) yielding 0.0550 g (93%) of the

! 151 1 desired product. Rf = 0.67 (95:5:1 CH2Cl2:MeOH:NH4OH). H NMR (500 MHz,

CDCl3) ! 8.35 – 8.18 (s, 1H), 1.57 – 1.41 (m, 1H), 7.55 – 7.44 (dd, J = 13.8, 6.0 Hz,

1H), 7.40 – 7.29 (m, 1H), 7.22 – 7.15 (dd, J = 7.9, 6.4 Hz, 1H), 7.15 – 7.04 (m, 1H),

5.78 – 5.47 (m, 2H), 5.43 – 5.16 (m, 3H), 5.24 (s, CH2Cl2), 4.18 – 3.90 (d, J = 7.6 Hz,

1H), 3.58 – 3.40 (m, 1H), 3.40 – 3.10 (m, 5H), 3.10 – 2.87 (dtd, J = 14.0, 9.5, 5.7 Hz,

2H), 2.58 – 2.36 (dtd, J = 14.0, 9.2, 4.5 Hz, 1H), 2.16 – 1.84 (m, 2H), 1.79 – 1.57 (m,

13 5H), 1.37 – 1.10 (m, 3H). C NMR (125 MHz, CDCl3) ! 144.1, 135.5, 134.6, 134.5,

133.8, 133.4, 130.7, 128.9, 123.1, 120.1, 120.1, 118.5, 115.8, 111.0, 109.7, 76.9, 69.4,

68.1, 54.6 (CH2Cl2), 52.9, 52.8, 33.9, 25.8, 21.2, 17.9.

N I

N Boc TMSO 139a

(E)-tert-butyl 3-((Z)-2-iodobut-2-en-1-yl)-7-((trimethylsilyl)oxy)-2,3,4,5-

tetrahydroazonino[5,4-b]indole-8(1H)-carboxylate (139a). To an oven-dried

Schlenk tube brought to -78 °C was added the Boc-protected ketone 113 (0.0085 g,

0.017 mmol, 1 equiv) in dry THF (1 mL) followed by NEt3 (0.024 mL, 0.17 mmol, 10

! 152 equiv), TMSCl (0.021 mL, 0.17 mmol, 10 equiv), and 1 M LHMDS (0.014 g, 0.085

mmol, 5 equiv). After stirring for 4 h 20 min, the solution was warmed to rt and

diluted with CH2Cl2 (5 mL), added H2O (5 mL), separated, and rinsed with brine (1 x 5

mL), dried over MgSO4, and concentrated to 0.0099 g (99%) of the desired product.

1 The crude material was taken on to the next step. H NMR (500 MHz, CDCl3) ! 8.03 –

7.93 (d, J = 8.3 Hz, 1H), 7.45 – 7.40 (m, 1H), 7.29 – 7.25 (m, 1H), 7.22 – 7.17 (m, 1H),

7.17 – 7.12 (d, J = 7.7 Hz, 1H), 5.91 – 5.74 (q, J = 6.4 Hz, 1H), 5.08 – 4.92 (m, 1H),

3.55 – 3.42 (s, 2H), 3.33 – 3.15 (q, J = 6.9, 5.8 Hz, 1H), 3.12 – 3.01 (q, J = 7.3 Hz, 3H),

3.01 – 2.85 (t, J = 7.4 Hz, 6H), 2.85 – 2.70 (dd, J = 10.0, 3.3 Hz, 2H), 2.65 – 2.43 (m,

2H), 2.13 – 1.96 (t, J = 6.7 Hz, 1H), 1.85 – 1.74 (m, 5H), 1.71 – 1.62 (d, J = 7.0 Hz,

13H), 1.52 (H2O), 1.48 – 1.31 (t, J = 7.2 Hz, 6H), 0.39 – -0.13 (s, 38H).

N I

N Boc TESO 139 (E)-tert-butyl 3-((Z)-2-iodobut-2-en-1-yl)-7-((triethylsilyl)oxy)-2,3,4,5-

tetrahydroazonino[5,4-b]indole-8(1H)-carboxylate (139). To an oven-dried Schlenk

tube brought to -78 °C was added the Boc-protected ketone 113 (0.0111 g, 0.022 mmol,

! 153 1 equiv) in dry THF (1.5 mL) followed by NEt3 (0.061 mL, 0.44 mmol, 20 equiv),

TESCl (0.074 mL, 0.44 mmol, 20 equiv), and 1M LHMDS (0.033 mL, 0.33 mmol, 15

equiv). After stirring for 4 h 20 min, the solution was warmed to rt and diluted with

CH2Cl2 (5 mL), added H2O (5 mL), separated, and rinsed with brine (1 x 5 mL), dried

over MgSO4 and concentrated to 0.011 g (98%) of the desired product. The crude

1 material was taken on to the next step. H NMR (500 MHz, CDCl3) ! 7.99 – 7.94 (d, J

= 8.3 Hz, 1H), 7.45 – 7.39 (d, J = 7.7 Hz, 1H), 7.29 – 7.25 (m, 1H), 7.21 – 7.16 (m,

1H), 5.84 – 5.74 (m, 1H), 5.06 – 4.96 (dd, J = 10.3, 5.9 Hz, 1H), 3.54 – 3.42 (s, 2H),

3.15 – 2.98 (m, 13H), 2.98 – 2.87 (m, 3H), 1.61 – 1.52 (m, 8H), 2.87 – 2.71 (m, 5H),

2.64 – 2.45 (ddd, J = 24.0, 11.9, 5.8 Hz, 2H), 2.08 – 1.92 (dq, J = 14.9, 8.6, 7.5 Hz,

2H), 1.85 – 1.74 (m, 4H), 1.72 – 1.61 (m, 11H), 1.46 – 1.31 (t, J = 7.3 Hz, 14H), 0.96 –

0.78 (pd, J = 10.7, 10.3, 5.3 Hz, 17H), 0.67 – 0.53 (m, 13H).

HO I 152

(Z)-2-iodobut-2-enoic acid (152). To a stirring solution of iodo-crotonaldehyde 108

(7.44 g, 38.0 mmol, 1 equiv) was added H2O (45 mL) and t-BuOH (60 mL). The

solution was brought to 0 °C and NaH2PO4 (18.3334 g, 152 mmol, 4 equiv), NaClO2

! 154 (13.8396 g, 152 mmol, 4 equiv) and 2 M 2-methyl-2-butene 60 mL, 113.9 mmol, 3

equiv) were added. The solution was warmed to rt over 30 min and continued to stir at

rt for an additional 3.5 h. The resultant crude material was acidified with concentrated

HCl, diluted with CH2Cl2 (80 mL), separated, and the aqueous layer was washed with

more CH2Cl2 (6 x 30 mL). The combined organic layers were dried over MgSO4 and

concentrated. The crude material was recrystallized in hexane to produce 3.125 g

1 (42%) of a white crystalline solid. Rf = 0.78 (1:1 hexanes:EtOAc). H NMR (500

13 MHz, CDCl3) ! 7.50 (q, J = 6.7, 13.5 Hz, 1H), 2.03 (d, J = 6.7 Hz, 3H). C NMR (125

MHz, CDCl3) ! 168.3, 151.9, 95.5, 23.2.

O O

O I I 149

(Z)-2-iodobut-2-enoic anhydride (149). To a flame-dried round-bottom flask

containing extra-pure Na2CO3 (1.1906 g, 10.5 mmol, 1 equiv) at 0 °C under nitrogen

and added freshly distilled SOCl2 (0.8 mL, 10.5 mmol, 1 equiv) followed by iodo-

carboxylic acid 152 (1.0471 g, 10.5 mmol, 1 equiv) in 1:1 CH2Cl2:1,4-dioxane (60

mL). The solution was warmed to rt and brought to a reflux for 17 h. Once cooled, the

solids were removed by filtration and the solution was concentrated to 1.93 g (45%) of

! 155 a brown oil. The crude material was taken on to the next step. 1H NMR (500 MHz,

13 CDCl3) ! 7.81 (q, J = 6.7, 13.5 Hz, 1H), 2.16 (d, J = 6.7 Hz, 3H). C NMR (125 MHz,

CDCl3) ! 161.2, 158.7, 99.5, 24.0.

N I N H HO 150

(Z)-1-(7-hydroxy-1,2,4,5,6,7-hexahydroazonino[5,4-b]indol-3(8H)-yl)-2-iodobut-2-

en-1-one (150). To a stirred solution of harmacine 101 (0.0528 g, 0.25 mmol, 1 equiv)

in dry THF (3 mL) was added Na2CO3 (0.1297 g, 1.12 mmol, 4.5 equiv). After cooling

to 0 °C under nitrogen, a solution of anhydride 149 (0.25 mL, 0.63 mmol, 2.5 equiv) in

THF (1.5 mL) was added drop-wise. The dark brown solution was allowed to stir at 0

°C for 1 h and then rt for 2 h. Water (1.7 mL, 30 mmol, 120 equiv) was added along

with additional anhydride 149 (0.25 mL, 0.63 mmol, 2.5 equiv) and the reaction

mixture was brought to 65 °C in an oil bath for 20 h. The solvent was removed in

vacuo, diluted with CHCl3 (10 mL), washed with 2 N NaOH (1 x 10 mL), rinsed with

brine (1 x 10 mL), dried over Na2SO4, and concentrated under reduced pressure to yield

0.1037 g a brown foam. Purification was performed by flash chromatography (1:1

! 156 hexanes:EtOAc to 85:15:1 CH2Cl2:MeOH:NH4OH) yielding 0.0479 g (91%) of a light

1 brown foam. Rf= 0.19 (95:5:1 CH2Cl2:MeOH:NH4OH). H NMR (500 MHz, CDCl3)

! 8.52 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.15 (t, J = 7.1 Hz,

1H), 7.09 (t, J = 7.3 Hz, 1H), 5.94 (q, J = 6.3 Hz, 1H), 5.21 (dd, J = 5.9, 11.4 Hz, 1H),

4.14 (dd, J = 4.0, 13.0 Hz, 1H), 3.72 (td, J = 2.5, 14.0 Hz, 1H), 3.29 (s, MeOH), 3.07

(m, 1H), 2.96 (dd, J = 5.0, 15.9 Hz, 1H), 2.81 (dd, J = 14.2 Hz, 1H), 2.55 (t, J = 12.0

Hz, 1H), 2.05 (m, 1H), 1.81 (d, J = 6.4 Hz, 3H), 1.37 (dd, J = 3.1, 15.7 Hz, 1H), 1.22

13 (m, 1H), 0.91 (m, 1H). C NMR (125 MHz, CDCl3) ! 168.5, 136.1, 135.6, 134.7,

127.7, 121.8, 119.2, 118.0, 111.6, 110.0, 95.6, 66.0, 51.8 (MeOH), 49.8, 36.0, 24.3,

21.7, 21.5.

N I N H O 151

(Z)-3-(2-iodobut-2-enoyl)-1,2,3,4,5,6-hexahydroazonino[5,4-b]indol-7(8H)-one

(151). To a stirring solution of the amido-alcohol 150 (0.44 g, 1.04 mmmol, 1 equiv)

dissolved in CH2Cl2 (10 mL) was added MnO2 (0.7542 g, 8.3 mmol, 8 equiv). The

suspension was allowed to stir at rt for 2 days. The solids were removed by filtration

! 157 and concentrated to produce 0.4114 g of a yellow foam. Purification was performed by

flash chromatography (85:15:1 CH2Cl2:MeOH:NH4OH) yielding 0.4037 g (91%) of a

1 light yellow solid. Rf = 0.3 (95:5:1 CH2Cl2:MeOH:NH4OH). H NMR (500 MHz,

CDCl3) ! 9.65 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.49 (t, J =

7.0 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 5.42 (s, 1H), 5.24 (s, CH2Cl2), 4.20 (bs, 2H), 3.65

(bs, 3H), 3.56 (d, J = 5.2 Hz, 2H), 3.11 (bs, 2.5H), 2.50 (bs, 2H), 1.01 (bs, 2.5H). 13C

NMR (125 MHz, CDCl3) ! 194.7, 168.5, 136.1, 133.7, 127.7, 120.6, 120.2, 118.4,

112.3, 93.2, 52.0 (CH2Cl2), 49.3, 38.9, 26.3, 24.9, 20.1.

N I N Boc O 147

(Z)-tert-butyl 3-(2-iodobut-2-enoyl)-7-oxo-2,3,4,5,6,7-hexahydroazonino[5,4-

b]indole-8(1H)-carboxylate (147). To a stirring solution of amido-ketone 151 (0.0393

g, 0.09 mmol, 1 equiv) in CH2Cl2 (1.5 mL) under nitrogen was added DMAP (0.0069 g,

0.05 mmol, 0.5 equiv) followed by Boc anhydride (0.0372 g, 0.16 mmol, 1.7 equiv) and

continued to stir at rt for 1.5 h. The solution was diluted with CH2Cl2 (4 mL), washed

with Na2CO3 (1 x 5 mL), 1 M NaOH (1 x 5 mL), dried over Na2SO4, and concentrated

! 158 under reduced pressure to yield 0.0596 g of a light brown foam. Purification was

performed by flash chromatography (1:1 hexanes:EtOAc to 95:5:1

CH2Cl2:MeOH:NH4OH) yielding 0.045 g (92%) of a white foam. Rf = 0.46 (95:5:1

1 CH2Cl2:MeOH:NH4OH). H NMR (500 MHz, CDCl3) ! 8.02 (d, J = 8.4 Hz, 1H), 7.49

(d, J = 7.9 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.22 (t, J = 6.2 Hz, 1H), 5.24 (s, CH2Cl2),

4.51 (g, J = 6.2 Hz, 1H), 3.39 (m, 5H), 2.93 (s, 3H), 2.75 (t, J = 5.5 Hz, 2H), 2.33 (bs,

13 2H), 1.51 (s, 11.5H), 0.86 (d, J = 6.3 Hz, 3H). C NMR (125 MHz, CDCl3) ! 195.5,

168.1, 137.2, 137.0, 134.7, 127.7, 127.5, 123.1, 119.4, 114.7, 93.3, 53.4 (CH2Cl2), 51.3,

47.9, 38.6, 27.8, 25.2, 23.5, 20.2.

N N Boc O 154

tert-butyl 3-(but-2-ynoyl)-7-oxo-2,3,4,5,6,7-hexahydroazonino[5,4-b]indole-8(1H)-

carboxylate (154). To an oven-dried Schlenk tube was added amido-ketone 147

followed by 1 M LHMDS, Pd2(dba)2, BINAP, and dry THF. The tube was capped,

brought to -78 °C, and purged 5 times under vacuum refilling with nitrogen. The

Schlenk tube was allowed to warm to rt and then placed in a pre-heated 60 °C oil bath

! 159 for 2 h. Once cooled to rt, the solution was concentrated to 0.0493 g of a brown foam.

Purification was performed by flash chromatography (1:1 hexanes:EtOAc to 95:5:1

CH2Cl2:MeOH:NH4OH) yielding 0.016 g (99%) of light brown foam (some BINAP

present).

N N H O 155

3-(but-2-ynoyl)-1,2,3,4,5,6-hexahydroazonino[5,4-b]indol-7(8H)-one (155). To a

stirring solution of Boc-protected amide 147 (0.0118 g, 0.03 mmol, 1 equiv) in dry

CH2Cl2 (0.288 mL, 4.5 mmol, 150 equiv) was added TFA (0.289 mL, 3.9 mmol, 130

equiv) slowly under nitrogen. After 1.5 h, the solution was diluted with CH2Cl2 (3 mL)

and quenched with NaHCO3 (5 mL) at 0 °C. The biphasic solution was separated and

the organic layer was washed with 1 M NaOH (1 x 5 mL), brine (1 x 5 mL), dried over

Na2SO4, and concentrated to a 0.007 g (59%) of a white solid. Rf = 0.19 (1:1

1 hexanes:EtOAc).!! H NMR (500 MHz, CDCl3) ! 9.12 (s, 1H), 7.67 (d, J = 8.2 Hz, 1H),

7.42 – 7.30 (m, 2H), 7.17 (t, J = 7.3 Hz, 1H), 3.81 – 3.20 (m, 6H), 3.03 – 2.80 (m, 2H),

2.60 – 2.38 (m, 1H), 2.29 (s, 2H), 1.75 – 1.48 (m, 2H), 1.33 – 1.11 (m, 4H), 0.99 – 0.76

! 160 13 (m, 9H), 0.60 – 0.43 (m, 5H). C NMR (125 MHz, CDCl3) ! 194.6, 167.7, 136.3,

136.2, 134.1, 127.0, 120.9, 120.4, 112.4, 99.5, 51.6, 38.5, 30.0, 27.9, 26.3, 25.9, 7.6,

7.0, 6.6, 4.5.

N I N Boc TESO 153

(Z)-tert-butyl 3-((Z)-2-iodobut-2-enoyl)-7-((triethylsilyl)oxy)-2,3,4,5-

tetrahydroazonino[5,4-b]indole-8(1H)-carboxylate (153). To an oven-dried Schlenk

tube brought to -78 °C was added the amido-ketone 147 (0.0216 g, 0.04 mmol, 1 equiv)

dry THF (3 mL) followed by NEt3 (0.112 mL, 0.8 mmol, 20 equiv), TESCl (0.134 mL,

0.8 mmol, 20 equiv), and 1M LHMDS (0.6 mL, 0.62 mmol, 15 equiv). After stirring

for 3 h, the solution was warmed to rt and diluted with CH2Cl2 (3 mL), added H2O (3

mL), separated, and rinsed with brine (1 x 3 mL), dried over MgSO4, and concentrated

to 0.193 g (89%) of the desired product. The crude material was taken on to the next

step.

! 161 O O

O O O 156

dimethyl 2-oxopentanedioate (156). To a stirring solution of !-ketoglutaric acid

(5.0237 g) was added 5% HCl (6.7 mL) in dry MeOH (175 mL) under nitrogen. The

solution was heated to 45 °C for 2 h. The solvent was removed in vacuo and further

purified by vacuum distillation (collected at 162-165 °C) to produce 4.26 g (92%) of

1 the desired 156. H NMR (500 MHz, CDCl3) ! 3.86 (s, 3H), 3.67(s, 3H), 3.14 (t, J =

13 6.5 Hz, 2H), 2.67 (t, J = 6.5 Hz, 2H). ! C NMR (125 MHz, CDCl3) ! 192.4, 172.6,

161.1, 53.2, 52.2, 34.4, 27.6.

N O N H MeO2C 157

methyl 3-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-11b-

carboxylate (157). A stirring solution of tryptamine 18 (3.0207 g, 18.9 mmol, 1 equiv)

and !-ketoglutarate 156 (3.621 g, 20.79 mmol, 1.1 equiv), in acetic acid (57 mL) under

nitrogen was heated at 120 °C for 4 h. The solvent was removed in vacuo and the

crude material was dissolved in CHCl3 (60 mL), washed with H2O (2 x 30 mL), dried

! 162 over Na2SO4, and concentrated to 5.58 g of a blue solid. The crude material was

recrystallized in t-butyl methyl ether yielding 4.442 g (83%) of a pale brown solid. 1H

NMR (500 MHz, CDCl3) ! 8.54 – 8.43 (s, 1H), 7.51 – 7.46 (m, 1H), 7.39 – 7.34 (dt, J =

8.2, 0.9 Hz, 1H), 7.23 – 7.17 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.14 – 7.08 (ddd, J = 7.9,

7.1, 1.0 Hz, 1H), 4.63 – 4.47 (ddd, J = 13.3, 5.4, 1.9 Hz, 1H), 3.85 – 3.72 (s, 3H), 3.27

– 3.14 (dddd, J = 13.3, 10.7, 6.2, 1.3 Hz, 1H), 2.91 – 2.73 (m, 3H), 2.68 – 2.53 (m, 1H),

2.53 – 2.41 (m, 1H), 2.34 – 2.21 (ddd, J = 12.7, 11.5, 9.3 Hz, 1H).! ! 13C NMR (125

MHz, CDCl3) ! 201.4, 173.28, 172.34, 142.3, 136.8, 130.6, 126.4, 123.0, 122.3, 120.1,

118.9, 111.5, 109.8, 65.6, 53.4, 36.8, 32.3, 30.7, 21.0.

N N H MeO2C 158

methyl 2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-11b-carboxylate

(158). A stirring solution of lactam 157 (0.5054 g, 1.78 mmol, 1 equiv) and 0.5 M 9-

BBN in THF (11 mL, 2.8 mmol, 3.2 equiv) was heated at 65 °C under nitrogen for 1 h.

Once cooled to rt, MeOH (3 mL) and 2 M HCl in Et2O (3 mL) was added and

continued to stir at rt for 1 h. The solution was concentrated, diluted with EtOAc (20

! 163 mL) and washed with 3 M HCl (3 x 10 mL). The combined organic layers were

basified with Na2CO3 (7.37 g) and further extracted with EtOAc (2 x 10 mL), dried

over Na2SO4, and concentrated to 0.348 g (72%) of a light brown foam. The crude

1 material was taken on to the next step. H NMR (500 MHz, CDCl3) ! 8.28 – 8.21 (s,

3H), 7.51 – 7.46 (m, 3H), 7.35 – 7.30 (dt, J = 8.1, 0.9 Hz, 3H), 7.19 – 7.14 (ddd, J =

8.2, 7.1, 1.2 Hz, 3H), 7.11 – 7.06 (ddd, J = 7.9, 7.1, 1.0 Hz, 3H), 4.10 (q, EtOAc), 3.81

– 3.68 (s, 9H), 3.38 – 3.28 (m, 6H), 3.21 – 3.09 (ddd, J = 8.9, 7.4, 3.2 Hz, 3H), 3.01 –

2.86 (m, 6H), 2.59 – 2.45 (m, 6H), 2.43 – 2.34 (m, 1H), 2.32 – 2.23 (dt, J = 13.0, 8.1

Hz, 3H), 2.03 (s, EtOAc), 1.98 – 1.76 (m, 8H), 1.76 – 1.56 (m, 7H), 1.56 – 1.32 (m,

13 7H), 1.24 (t, EtOAc).!! C NMR (125 MHz, CDCl3) ! 174.5, 136.4, 132.7, 126.9, 122.4,

119.6, 118.6, 111.2, 109.8, 71.0, 66.7, 60.5 (EtOAc), 52.9, 49.7, 43.9, 42.1, 37.7, 32.0,

27.3, 26.4, 25.8, 24.9, 23.2, 22.2, 21.2 (EtOAc), 16.1, 14.3 (EtOAc).

Troc N N H MeO2C 159 (E)-7-methyl 3-(2,2,2-trichloroethyl) 1,2,4,5-tetrahydroazonino[5,4-b]indole-

3,7(8H)-dicarboxylate (159). To a stirring solution of ester 158 (0.1678 g, 0.62 mmol,

1 equiv) in dry THF (7 mL) at 0 °C was added Na2CO3 (0.3299 g, 2.9 mmol, 4.5 equiv)

! 164 and TrocCl (0.23 mL, 1.6 equiv, 2.5 equiv) under nitrogen. After 1 h, the solution was

warmed to rt and brought to 80 °C for 20 h. Once cooled to rt, the solvent was

removed in vacuo, diluted with CHCl3 (8 mL), washed with 1 M NaOH (1 x 8 mL),

brine (1 x 8 mL), dried with Na2SO4, and concentrated to 0.3441 g of a brown solid.

Purification was performed by flash chromatography (1:1 hexanes:EtOAc) yielding

1 0.1433 g (50%) of white foam. Rf = 0.85 (1:1 hexanes:EtOAc). H NMR (500 MHz,

CDCl3) ! 8.35 (d, J = 14.9 Hz, 1H), 7.54 (t, J = 6.5 Hz, 1H), 7.26 – 7.34 (m, 2H), 7.17

(dt, J = 32.0, 7.3 Hz, 1H), 7.11 (m, 1H), 4.74 (dd, J = 13.9, 2.6 Hz, 3H), 4.01 (q,

EtOAc), 3.64 – 3.76 (dd, J = 5.7, 2.7 Hz, 3H), 3.44 – 3.63 (m, 5H), 3.00 (d, 2H), 2.23

(s, 2H), 2.03 (s, EtOAc), 1.79 – 1.95 (m, 1H), 1.37 – 1.55 (m, 1H), 1.25 (dt, J = 7.0, 3.8

13 Hz, 2H), 1.20 (t, EtOAc). C NMR (125 MHz, CDCl3) ! 171.3 (EtOAc), 166.2, 166.2,

154.9, 154.0, 147.3, 147.2, 136.1, 136.0, 129.1, 129.0, 128.6, 128.4, 128.0, 127.8,

122.4, 122.4, 119.5, 119.5, 118.6, 118.5, 115.0, 114.8, 111.1, 111.0, 95.8, 95.7, 75.1,

75.0, 74.8, 71.7, 70.9, 60.5 (EtOAc), 53.5, 52.3, 52.2, 49.4, 48.7, 46.3, 45.9, 42.0, 32.1,

32.0, 30.8, 30.6, 27.2, 26.5, 26.3, 26.2, 25.7, 24.9, 23.7, 22.1, 22.1, 21.12 (EtOAc), 14.3

(EtOAc).

! 165 H N N H MeO2C 159a (E)-methyl 1,2,3,4,5,8-hexahydroazonino[5,4-b]indole-7-carboxylate (159a). To a

stirring solution of Troc-protected amine 159 (0.9801 g, 2.2 mmol, 1 equiv) in dry THF

(48 mL) under nitrogen was added zinc powder (2.9286 g, 44 mmol, 20 equiv) and

acetic acid (12.6 mL, 220 mmol, 100 equiv). The suspension was allowed to stir at rt

for 18 h. The solvent was removed in vacuo, filtered, brought to 0 °C and taken up in

saturated Na2CO3 (65 mL). The solution was extracted with CH2Cl2 (3 x 50 mL), brine

(1 x 40 mL), dried over Na2SO4, and concentrated to 0.6099 g of a white foam.

Purification was performed by flash chromatography (1:1 hexanes:EtOAc to 85:15:1

1 CH2Cl2:MeOH:NH4OH) yielding 0.444 g (75%) of white foam. H NMR (500 MHz,

CDCl3) ! 8.44 (s, 1H), 7.52 (dt, J = 7.6, 1.1 Hz, 1H), 7.35 (m, 2H), 7.18 (ddd, J = 8.2,

7.0, 1.2 Hz, 1H), 7.08 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 3.75 (s, 3H), 2.92-3.02 (m, 2H),

2.83-2.92 (m, 3H), 2.75-2.83 (m, 2H), 2.19 (ddd, J = 11.7, 5.7, 3.8 Hz, 2H).!!13C NMR

(125 MHz, CDCl3) ! 166.6, 149.1, 136.2, 128.7, 128.5, 128.2, 122.4, 119.4, 118.7,

115.6, 111.0, 52.3, 47.8, 46.6, 32.8, 28.4.

! 166 N I N H MeO2C 160

(E)-methyl 3-((Z)-2-iodobut-2-en-1-yl)-1,2,3,4,5,8-hexahydroazonino[5,4-b]indole-

7-carboxylate (160). To a stirring solution of amine 159a (0.0601 g, 0.22 mmol, 1

equiv) in dry THF (2 mL) was added K2CO3 (0.0974 g, 0.66 mmol, 3 equiv) and

mesylate 111 (0.0888 g, 0.24 mmol, 1.1 equiv). After 45 min of stirring, the solution

was warmed to rt for 6.5 h, diluted with CH2Cl2 (5 mL), washed with saturated

NaHCO3 (1 x 4 mL), brine (1 x 4 mL) and concentrated to 0.1589 g. Purification was

performed by flash chromatography (3:1 hexanes:EtOAc to 85:15:1

CH2Cl2:MeOH:NH4OH) yielding 0.0956 g (96%) with a small mesylate impurity. Rf =

1 0.85 (1:1 hexanes:EtOAc). H NMR (500 MHz, CDCl3) ! 7.97 (s, 1H), 7.50 (d, J = 7.8

Hz, 1H), 7.38 (t, J = 8.5 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.09

(t, J = 7.5 Hz, 1H), 6.18 (q, mesylate) 5.78 (q, J = 6.4 Hz, 1H), 4.88 (s, mesylate), 3.75

(s, 3H), 3.43 (s, 2H), 3.04 (s, mesylate) 2.89 – 2.66 (m, 7H), 2.27 – 2.11 (m, 2H), 1.83

13 (d, mesylate), 1.77 (d, J = 6.4 Hz, 4H), 1.54 (s, H2O).!! C NMR (125 MHz, CDCl3) !

167.0, 152.3, 150.8, 138.5 (mesylate), 136.1, 131.1, 128.5, 128.5, 127.4, 122.21, 119.3,

! 167 118.7, 116.6, 111.3, 110.9 (mesylate), 70.5, 53.8, 52.7, 52.3, 39.0 (mesylate), 32.1,

26.6, 22.8 (mesylate), 21.9, 21.9.

N I N Boc MeO2C 161

(E)-8-tert-butyl 7-methyl 3-((Z)-2-iodobut-2-en-1-yl)-2,3,4,5-

tetrahydroazonino[5,4-b]indole-7,8(1H)-dicarboxylate (161). To a stirred solution

of amine 160 (0.1056 g, 0.23 mmol, 1 equiv) in dry CH2Cl2 (2 mL) was added DMAP

(0.0164 g, 0.12 mmol, 0.5 equiv) and Boc anhydride (0.0981 g, 0.4 mmol, 1.7 equiv).

After 1.5 h, the solution was concentrated to a yellow foam. Purification was

performed by flash chromatography (10:1 hexanes:EtOAc) yielding 0.0889 g (71%) of

1 a yellow foam. H NMR (500 MHz, CDCl3) ! 8.17 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 7.8

Hz, 1H), 7.34 – 7.26 (m, 2H), 7.26 – 7.19 (m, 1H), 5.67 (q, J = 6.3 Hz, 1H), 3.69 (s,

3H), 3.49 – 3.30 (m, 2H), 3.07 – 2.97 (m, 1H), 2.96 – 2.52 (m, 5H), 2.27 (dddd, J =

20.3, 13.6, 9.8, 6.5 Hz, 2H), 1.82 – 1.67 (m, 4H), 1.63 – 1.46 (m, 13H). 13C NMR (125

MHz, CDCl3) ! 166.7, 150.3, 146.8, 136.4, 131.0, 130.1, 130.0, 128.8, 124.5, 122.5,

! 168 122.1, 118.7, 115.9, 111.3, 83.9, 70.5, 52.8, 52.7, 51.9, 34.8, 32.1, 31.8, 28.2, 26.6,

25.5, 22.8, 21.8, 14.3.

O OEt Cl O 185

ethyl 2-chloro-2-oxoacetate (185). To a flame-dried round-bottom flask was added

oxalyl chloride (2.6 mL, 30 mmol, 2 equiv) at 0 °C. Ethanol (0.88 mL, 15 mmol, 1

equiv) was added drop-wise over 15 min. Once the addition was complete, the solution

was allowed to warm to rt over 2 h 20 min. Distillation was performed (reported

boiling point of 132-135 °C) to produce 1.4 g (68%) of the desired acid chloride 185.

1 13 H NMR (500 MHz, CDCl3) ! 4.39 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H). C

NMR (125 MHz, CDCl3) ! 161.1, 155.6, 65.1, 13.8.

! 169 O OEt

N O N H 187

(E)-ethyl 2-oxo-2-(1,2,4,5-tetrahydroazonino[5,4-b]indol-3(8H)-yl)acetate (187).

To a stirring solution of harmicine 101 (0.1175 g, 0.55 mmol, 1 equiv) in dry THF (9

mL) was added extra pure Na2CO3 (0.603 g, 5.55 mmol, 10 equiv) at rt followed by

ethyl oxalyl chloride 185 (0.3 mL, 2.8 mmol, 5 equiv). After 2 h of stirring, additional

185 was added and heated to 60 °C for 13 h. Once cooled to rt, the solution was diluted

with CH2Cl2 (10 mL), washed with 2 M NaOH (1 x 10 mL), brine (1 x 10 mL), dried

over Na2SO4, and concentrated. Purification was performed by flash chromatography

(2:1 hexanes:EtOAc) yielding 0.1547 g (90%) of a yellow foam. Rf = 0.37 and 0.46

1 (3:1 hexanes:EtOAc). H NMR (500 MHz, CDCl3) ! 7.81 (s, 1H), 7.76 (s, 1H), 7.52

(d, J = 7.8 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.29 (t, J = 7.7, 14.0 Hz, 2H), 7.06 – 7.19

(m, 4.5H), 6.64 (d, J = 10.6 Hz, 1H), 6.46 (d, J = 11.3 Hz, 1H), 5.99 – 6.06 (m, 2H),

4.35 (q, J = 7.2, 14.3 Hz, 2.4H), 4.01 (q, J = 7.2, 14.3 Hz, 1.6H), 3.66 – 3.71 (m, 1H),

3.61 – 3.66 (m, 1H), 3.52 – 3.57 (m, 2H), 3.38 – 3.42 (m, 2H), 3.06 – 3.12 (m, 2H),

3.01 – 3.05 (m, 2H), 2.45 – 2.51 (m, 1H), 2.27 – 2.35 (m, 3H), 1.54 (bs, 7H), 1.38 (t, J

= 7.1 Hz, 5H), 1.24 (bs, 4H), 1.05 (t, J = 7.1 Hz, 3H), 0.86 (t, J = 6.8 Hz, 6H). 13C

! 170 NMR (125 MHz, CDCl3) ! 194.97, 168.69, 136.31, 134.89, 133.83, 127.95, 126.96,

120.76, 120.37, 118.60, 112.47, 93.43, 52.19, 49.48, 39.15, 26.53, 25.13, 20.31.

Troc N N H HO 203 2,2,2-trichloroethyl 7-hydroxy-1,2,4,5,6,7-hexahydroazonino[5,4-b]indole-3(8H)-

carboxylate (203). Same procedure as compound 100a. Rf= 0.68 (85:15:1

1 CH2Cl2:MeOH:NH4OH). H NMR (500 MHz, CDCl3) ! 8.42 (s, 1H), 7.51 (dd, J = 7.7,

4.0 Hz, 1H), 7.34 (dd, J = 7.9, 4.3 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.5 Hz,

1H), 5.24 (s, CH2Cl2), 5.12 – 5.23 (ddd, J = 19.4, 10.7, 6.1 Hz, 1H), 4.94 (dd, J = 24.4,

11.8 Hz, 1H), 4.61 (dd, J = 11.9 Hz, 1H), 3.96 – 4.21 (m, 3H), 4.10 (q, EtOAc), 2.92 –

3.23 (m, 3H), 2.53 – 2.34 (m, 2H), 2.01 (s, EtOAc), 1.69 – 1.89 (m, 2H), 1.52 (s, H2O),

1.41 (dd, J = 14.7, 6.3 Hz, 1H), 1.16 – 1.30 (m, 2H), 1.22 (t, EtOAc), 0.75 – 0.94 (ddd,

J = 21.5, 10.4, 4.6 Hz, 1H).!!13C NMR (125 MHz, MeOD) ! 157.0, 156.1, 138.3, 138.2,

137.6, 129.1, 129.0, 122.4, 119.8, 118.7, 112.1, 111.8, 111.6, 97.1, 97.1, 67.4, 67.3,

52.3 (CH2Cl2), 51.3, 50.7, 50.0, 50.0, 49.6, 49.6, 49.5, 49.4, 49.3, 49.3, 49.1, 49.0, 48.8,

48.7, 48.6, 37.5, 36.9, 26.0, 25.9, 24.6, 23.0.

! 171 Troc N N Boc O 203a

2,2,2-trichloroethyl 7-oxo-1,2,4,5,6,7-hexahydroazonino[5,4-b]indole-3(8H)-

carboxylate (203a). To a stirring solution of the amido-alcohol 203 (0.5649 g, 1.39

mmol, 1 equiv) dissolved in CH2Cl2 (15 mL) and added MnO2 (0.9705 g, 11.4 mmol, 8

equiv). The suspension was allowed to stir at rt for 18 h. The solids were removed by

filtration and the solution was concentrated to produce 0.5001 g of a white solid.

Purification was performed by flash chromatography (1:1 hexanes:EtOAc) yielding

1 0.4801 g (86%) of a light yellow solid. Rf = 0.76 (85:15:1 CH2Cl2:MeOH:NH4OH).!! H

NMR (500 MHz, CDCl3) ! 9.15 (d, J = 8.4 Hz, 1H), 7.68 (ddq, J = 8.2, 1.9, 0.9 Hz,

1H), 7.16 – 7.27 (m, 2H), 7.07 (dddd, J = 17.8, 8.0, 6.7, 1.2 Hz, 1H), 4.67 (s, 1H),

4.264 (s, 1H), 3.61 (s, 2H), 3.26-3.52 (m, 4H), 2.91 (s, 2H), 2.33 (s, 2H). 13C NMR

(125 MHz, CDCl3) ! 210.7, 194.9, 194.8, 168.1, 155.1, 153.9, 136.6, 136.5, 133.9,

133.8, 128.1, 128.1, 126.9, 126.8, 120.7, 120.6, 120.4, 119.3, 112.3, 112.2, 95.5, 95.0,

75.4, 745.0, 59.4, 53.6, 50.6, 50.2, 50.12, 48.7, 38.4, 37.9, 28.1, 26.7, 25.6.

! 172 Troc N N Boc O 142

8-tert-butyl 3-(2,2,2-trichloroethyl) 7-oxo-1,2,4,5,6,7-hexahydroazonino[5,4- b]indole-3,8-dicarboxylate (142). To a stirring solution of Troc-protected ketone 203a

(0.4801g, 1.19 mmol, 1 equiv) in dry CH2Cl2 (50 mL) was added DMAP (0.0785 g, 0.60 mmol, 0.5 equiv) and Boc anhydride (0.4649 g, 2.0 mmol, 1.7 equiv). After 3 h, the solution was concentrated to a yellow brown foam. Purification was performed by flash

chromatography (2:1 hexanes:EtOAc) yielding 0.6285 g (99%) of a white foam. Rf=

1 0.56 (1:1 hexanes:EtOAc). H NMR (500 MHz, CDCl3) ! 8.03 (ddt, J = 14.0, 8.4, 0.9 Hz,

1H), 7.54 (ddt, J = 7.9, 4.2, 1.0 Hz, 1H), 7.38 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.28 (dddd,

J = 7.9, 7.0, 5.9, 0.9 Hz, 1H), 4.73 (s, 1H), 4.55 (s, 1H), 4.10 (q, EtOAc), 3.49 (td, J = 7.2,

3.1 Hz, 2H), 3.31 – 3.44 (m, 2H), 3.12 (ddd, J = 19.9, 6.3, 4.3 Hz, 2H), 2.72 – 2.88 (m,

2H), 1.93 – 2.06 (m, 2H), 2.01 (s, EtOAc), 1.54 – 1.62 (m, 9H), 1.47 – 1.53 (m, 1H), 1.44

13 (s, 3H), 1.22 (qt EtOAc). C NMR (125 MHz, CDCl3) ! 198.01, 197.7, 154.9, 154.6,

152.6, 149.7, 149.6, 136.9, 136.7, 135.5, 135.3, 128.7, 128.5, 127.0, 126.9, 123.3, 123.3,

121.7, 121.4, 119.6, 119.5, 115.5, 115.4, 114.5, 111.7, 95.6, 95.1, 85.1, 85.0, 81.2, 75.6,

75.6, 61.5 (EtOAc), 60.5, 58.3, 58.0, 50.6, 50.2, 49.1, 48.3, 40.5, 40.3, 28.1, 28.1, 28.0,

27.6, 26.3, 25.6, 23.2, 22.3, 14.4 (EtOAc).

! 173 TESO

I 205

(Z)-triethyl((2-iodobut-2-en-1-yl)oxy)silane (205). To a stirring solution of iodo-

alcohol 110 (0.9822 g, 4.96 mmol, 1 equiv) in dry DMF (10 mL) was added imidazole

(1.00 g, 14.88 mmol, 3 equiv) under nitrogen. The solution was brought to 0 °C and

TESCl (1.1 mL, 7.4 mmol, 1.5 equiv) was added over 15 min. After stirring at rt for 20

h, the reaction was quenched with H2O (5 mL), diluted with EtOAc (50 mL), separated,

and the organic layer was washed with more H2O (3 x 15 mL), dried over Na2SO4 and

concentrated. Purification was performed by flash chromatography (100% hexanes)

1 yielding 0.805 g (82%) of the desired 205. H NMR (500 MHz, CDl3) ! 5.96 (q, J =

6.4 Hz, 1H), 4.28 (s, 2H), 1.77 (d, J = 6.5 Hz, 3H), 1.52 (H2O), 0.91 (t, J = 8.0 Hz, 9H),

13 0.63 (q, J = 8.0 Hz, 6H). C NMR (125 MHz, CDCl3) ! 129.1, 108.9, 71.5, 21.8, 6.9,

4.7.

O Ph Ph

213 2,2-diphenyl-3,4-dihydronaphthalen-1(2H)-one (213). To an oven-dried Schlenk

tube was added Pd2(dba)3 (0.1085 g, 0.11 mmol, 0.2 equiv), NaOt-Bu (0.1080 g, 1.05

! 174 mmol, 2 equiv), BINAP (0.1026 g, 0.16 mmol, 0.3 equiv), tetralone (0.07 mL, 0.53

mmol, 1 equiv), bromobenzene (0.111 mL, 1.05 mmol, 2 equiv) and THF (2 mL). The

tube was capped, brought to -78 °C, and purged 5 times under vacuum refilling with

nitrogen. The Schlenk tube was allowed to warm to rt and placed in a pre-heated 75 °C

oil bath for 18 h. Once cooled to rt, the solution was poured over ice, diluted with

EtOAc (10 mL), washed with NH4OH (1 x 10 mL), brine (1 x 10 mL), dried over

Na2SO4, and concentrated to 0.3525 g. Purification was performed by flash

chromatography (95:5 hexanes:EtOAc) yielding 0.1202 g (76%) of light yellow foam.

1 H NMR (500 MHz, CDCL3) ! 7.94 (d, J = 8.1 Hz, 1H), 7.35 (hept, J = 7.4 Hz, 3H),

7.18 (t, J = 7.5 Hz, 5H), 7.09 (dq, J = 16.7, 7.9, 7.5 Hz, 3H), 3.81 (dd, J = 13.0, 3.6 Hz,

1H), 2.85 (d, J = 9.9 Hz, 2H), 2.28 (tt, J = 13.9, 7.2 Hz, 1H), 2.16 – 2.05 (m, 1H), 1.52

13 (H2O). C NMR (125 MHz, CDCl3) ! 199.1, 149.0, 144.2, 142.7, 141.6, 140.7, 138.5,

136.8, 136.0, 133.5, 133.4, 133.1, 130.2, 130.0, 129.4, 128.9, 128.7, 128.6, 128.4,

128.2, 127.9, 127.2, 127.2, 126.8, 126.8, 113.6, 51.8, 32.2, 30.3, 29.7, 29.1, 27.4.

! 175 4.4. Experimental procedures for the third-generation synthesis

O 266 (S)-2-methyl-5-(2-methyloxiran-2-yl)cyclohex-2-enone (266). To a stirring solution

of (S)-carvone 236 (15.36 g, 102.3 mmol, 1 equiv) in dry CH2Cl2 (900 mL) was added

mCPBA (26.34 g, 153.4 mmol, 1.5 equiv) and allowed to stir under nitrogen at rt for 24

h. The solution was washed with NaHCO3 (1 x 500 mL), 10% Na2SO3 (1 x 500 mL),

NaHCO3 (1 x 300 mL), H2O (1 x 500 mL), dried over MgSO4, and concentrated.

Purification was accomplished by flash chromatography (8:1 hexanes:EtOAc to 100%

1 EtOAc) affording 13.09 g (77%) of epoxide 266 (Rf = 0.83 in 100% EtOAc). H NMR

(500 MHz, CDCl3) ! 6.71 (tt, J = 6.3, 1.7 Hz, 1H), 2.66 (dd, J = 18.5, 4.6 Hz, 1H), 2.59

– 2.50 (m, 2H), 2.44 – 2.33 (m, 1H), 2.29 – 2.13 (m, 2H), 2.09 – 1.99 (m, 1H), 1.78 –

13 1.71 (h, J = 1.6 Hz, 3H), 1.54 (H2O), 1.34 – 1.26 (d, J = 8.4 Hz, 3H). C NMR (125

MHz, CDCl3) ! 199.0, 198.9, 144.2, 144.0, 135.9, 135.8, 58.1, 58.0, 53.1, 52.6, 41.6,

40.9, 40.6, 40.2, 28.1, 27.9, 19.2, 18.5, 15.9.

! 176 O

O 264 (S)-5-acetyl-2-methylcyclohex-2-enone (264). To a stirring solution of epoxide 266

(0.2676 g, 1.6 mmol, 1 equiv) in dry Et2O (50 mL) at 0 °C was added periodic acid

(0.7144 g, 2.6 mmol, 1.6 equiv) and allowed to stir under nitrogen for 1 h. The solution

was warmed to rt over 3 h, added NaHCO3 (1 x 30 mL), separated, and the aqueous

layer was wash with more Et2O (3 x 15 mL). The organic layers were combined, dried

over MgSO4, and concentrated to 0.2176 g of a bright yellow oil. Purification was

accomplished by flash chromatography (3:10 hexanes:EtOAc) affording 0.1668 g

1 (68%) of diketone 264. H NMR (500 MHz, CDCl3) ! 6.78 – 6.63 (m, 1H), 3.19 – 2.99

(m, 1H), 2.78 – 2.62 (m, 1H), 2.62 – 2.44 (m, 3H), 2.28 – 2.09 (m, 3H), 1.87 – 1.70 (m,

13 2H). C NMR (125 MHz, CDCl3) ! 208.2, 197.3, 142.3, 135.3, 48.0, 39.8, 27.6, 27.2,

15.7.

! 177 OH N

268 O

(S,Z)-1-(5-(hydroxyimino)-4-methylcyclohex-3-en-1-yl)ethanone (268). To a

stirring solution of 2.5 M NH2OH!HCl (0.0311 g, 0.41 mmol, 1.25 equiv) in EtOH (1.6

mL) was added diketone 264 (0.050 g, 0.33 mmol, 1 equiv) and allowed to stir at rt for

18 h. The solution was diluted in CH2Cl2 (5 mL), washed with H2O (1 x 5 mL), dried

over MgSO4, and concentrated. Purification was accomplished by flash

chromatography (1:1 hexanes:EtOAc) affording 0.0494 g (90%) of oxime 268. 1H

NMR (500 MHz, CDCl3) ! 6.04 – 5.89 (m, 1H), 3.23 (dd, J = 16.6, 4.4 Hz, 1H), 2.75

(ddt, J = 11.6, 9.6, 4.7 Hz, 1H), 2.44 – 2.23 (m, 3H), 2.18 (s, 3H), 1.93 – 1.72 (m, 3H).

13 C NMR (125 MHz, CDCl3) ! 209.3, 206.9, 131.0, 130.7, 46.1, 30.9, 28.1, 26.9, 23.9,

17.6.

OH N

N 269 OH

(S,Z)-5-((Z)-1-(hydroxyimino)ethyl)-2-methylcyclohex-2-enone oxime (269). To a

stirring solution of 2.5 M NH2OH!HCl (0.66 mL, 1.66 mmol, 1.25 equiv) and 5 M

! 178 NaOH (0.8 mL, 4.0 mmol, 3 equiv) was added diketone 264 (0.200 g, 1.3 mmol, 1

equiv) in EtOH (6.6 mL) and allowed to stir at rt for 48 h. The solution was diluted in

CH2Cl2 (20 mL), washed with H2O (1 x 20 mL), dried over MgSO4, and concentrated.

Purification was accomplished by flash chromatography (1:1 hexanes:EtOAc) affording

1 0.2021 g (92%) of oxime 269. H NMR (500 MHz, CDCl3) ! 9.62 (bs, 1H), 9.01 (bs,

1H), 5.99 (dd, J = 6.4, 2.0 Hz, 1H), 3.64 (q, J = 7.0 Hz, 1H), 3.28 (dd, J = 16.8, 4.4 Hz,

1H), 2.65 – 2.49 (m, 1H), 2.43 – 2.09 (m, 4H), 1.98 – 1.77 (m, 7H), 1.32 – 1.17 (m,

13 2H), 1.17 – 1.03 (m, 1H). C NMR (125 MHz, CDCl3) ! 204.6, 159.6, 155.9, 132.0,

130.7, 58.6, 39.6, 28.6, 25.8, 18.5, 17.8, 12.3.

O O 271

(S)-2-methyl-5-(2-methyl-1,3-dioxolan-2-yl)cyclohex-2-enone (271). To a stirring

solution of diketone 264 (0.0802 g, 0.53 mmol, 1 equiv) in dry benzene (2 mL) was

added p-TsOH (0.0263 g, .11 mmol, 0.2 equiv) and ethylene glycol (0.0659 g, 1.06

mmol, 2 equiv). The solution was brought to a reflux under nitrogen for 3.5 h. Once

cooled to rt, the solution was diluted in CH2Cl2 15 mL), washed with NaHCO3 (1 x 15

! 179 mL), H2O (1 x 15 mL), dried over Na2SO4, and concentrated. Purification was

accomplished by flash chromatography (4:1 hexanes:EtOAc) affording 0.416 g (40%)

1 of oxime 269. Rf = 0.63 (2:1 hexanes:EtOAc). Major Product: H NMR (500 MHz,

CDCl3) ! 6.76 – 6.59 (m, 1H), 4.03 – 3.81 (m, 6H), 2.63 – 2.35 (m, 3H), 2.35 – 2.14

(m, 5H), 1.78 – 1.67 (m, 3H), 1.31 – 1.17 (s, 3H), 0.91 (d, J = 6.7 Hz, 1H). 13C NMR

(125 MHz, CDCl3) ! 199.8, 144.6, 135.5, 110.1, 65.2, 65.1, 44.0, 39.2, 27.2, 21.7, 15.8.

S S

273 O

(S)-1-(10-methyl-1,4-dithiaspiro[4.5]dec-9-en-7-yl)ethanone (273). To a stirring

solution of diketone 264 (0.3092 g, 2.03 mmol, 1 equiv) in dry MeOH (7 mL) at 0 °C

was added BF3!OEt2 (0.3 mL, 2.44 mmol, 1.2 equiv) and 1,2-dithioethane 275 (0.205

mL, 2.44 mmol, 1.2 equiv) in MeOH (3 mL) via syring pump over 6 h (0.51 mL/hr).

Once warmed to rt, the solution was diluted in EtOAc (30 mL), washed with NaHCO3

(1 x 60 mL), and the aqueous layer was washed with additional EtOAc (3 x 30 mL) and

Et2O (3 x 15 mL). The organic layers were combined and rinsed with brine (1 x 40

mL), dried over Na2SO4, and concentrated to 0.510 g of a salmon-colored oil.

! 180 Purification was accomplished by flash chromatography (15:1 hexanes:EtOAc)

affording 0.042 g (9%) of the mono-protected ketone 273 (Rf =0.46 in 10:1

hexanes:EtOAc) and 0.0115 g (2.5%) of di-protected 272 (Rf =0.5 in 10:1

1 hexanes:EtOAc). H NMR (500 MHz, CDCl3) ! 5.50 (dq, J = 4.1, 1.4 Hz, 1H), 3.45 –

3.27 (MeOH), 3.28 (m, 3H), 3.28 – 3.16 (m, 1H), 2.87 (tdd, J = 11.7, 5.3, 2.5 Hz, 1H),

2.52 (dt, J = 13.4, 2.3 Hz, 1H), 2.17 (s, 3H), 2.15 – 2.07 (m, 2H), 1.95 – 1.92 (m, 3H).

13 C NMR (125 MHz, CDCl3) ! 210.1, 135.7, 124.9, 69.3, 47.8, 45.0, 41.4, 40.3, 28.3,

27.22, 19.8.

S S

S S 272

(S)-6-methyl-9-(2-methyl-1,3-dithiolan-2-yl)-1,4-dithiaspiro[4.5]dec-6-ene (272).

1 See procedure for compound 273. H NMR (500 MHz, CDCl3) ! 5.58 – 5.44 (m, 1H),

3.44 – 3.18 (m, 8H), 3.27 (MeOH), 2.94 – 2.67 (m, 6H), 2.67 – 2.56 (m, 1H), 2.37 –

2.14 (m, 2H), 2.14 – 2.02 (m, 1H), 2.02 – 1.85 (m, 4H), 1.73 (s, 3H), 1.67 – 1.61 (m,

13 1H), 1.37 – 1.11 (m, 8H). C NMR (125 MHz, CDCl3) ! 135.5, 125.9, 70.6, 70.4,

47.1, 46.7, 42.5, 41.2, 40.4, 40.1, 39.8, 30.5, 29.9, 29.5, 24.2, 19.6.

! 181 O O

277 (S)-6-methyl-9-(prop-1-en-2-yl)-1,4-dioxaspiro[4.5]dec-6-ene (277). To a stirring

solution of (S)-carvone 236 (0.3158 g, 2.1 mmol, 1 equiv) in dry benzene (15 mL) was

added ethylene glycol (0.778 g, 4.2 mmol, 2 equiv) and PPTS (0.038 g, 0.15 mmol,

0.07 equiv) and brought to a reflux for 22 h under nitrogen. Once cooled to rt, the

solution was concentrated to 0.3468 g (85%) of 277. Rf = 0.6 in 10:1 hexanes:EtOAc.

1 Major product: H NMR (500 MHz, CDCl3) ! 5.74 – 5.59 (m, 1H), 4.83 – 4.64 (m,

2H), 4.11 – 3.99 (m, 2H), 3.99 – 3.85 (m, 2H), 3.72 (s, 5H), 2.73 – 2.20 (m, 3H), 2.13

(dt, J = 17.4, 5.7 Hz, 1H), 2.08 – 1.81 (m, 4H), 1.81 – 1.53 (m, 8H). 13C NMR (125

MHz, CDCl3) ! 148.9, 134.3, 128.7, 109.3, 66.0, 65.0, 63.9, 40.1, 39.0, 31.1, 20.8,

16.2.

OH HO 279

(5S)-5-(1,2-dihydroxypropan-2-yl)-2-methylcyclohex-2-enone (279). To a stirring

solution of epoxide 266 (4.44 g, 26.7 mmol, 1 equiv) in dry THF (50 mL) was added a

! 182 solution of H2SO4 (1.0653 g, 10.7 mmol, 0.4 equiv) in H2O (50 mL). After stirring at rt

for 2 h, the solution was diluted in H2O (100 mL) followed by NaHCO3 (2.55 g) to a

pH of 6 and H3PO4 (27 drops) to a pH of 3. The solution was extracted with Et2O (2 x

100 mL), rinsed with H2O (1 x 50 mL), dried over Na2SO4, and concentrated. The

remaining salts were removed by dissolution in 1:1 Et2O:EtOH (100 mL), filtration,

and further concentration to 4.49 g (90%) of diol 279 (Rf =0.36 in 100% EtOAc) as a

1 colorless, viscous oil. H NMR (500 MHz, d6-DMSO) ! 6.83 (t, J = 7.9 Hz, 1H), 3.34

– 3.25 (m, 1H), 3.25 – 3.16 (m, 1H), 2.45 – 2.05 (m, 5H), 1.67 (s, 3H), 1.01 (s, 3H).

13 C NMR (125 MHz, d6-DMSO) ! 199.8, 199.6, 146.2, 145.9, 133.7, 133.7, 72.10,

67.2, 56.0, 41.1, 40.8, 38.5, 26.6, 26.2, 21.9, 21.7, 18.5, 15.3.

O 281 (1S,5S)-2-methyl-5-(2-methyloxiran-2-yl)cyclohex-2-enol (281). To a solution of

epoxide 266 (16.41 g, 98.7 mmol, 1 equiv) was added 0.8 M sucrose (1.17 L, 937.9

mmol, 9.5 equiv) followed by the portion-wise addition of NaBH4 (7.1 g, 187.5 mmol,

1.9 equiv) and continued to stir at rt for 1 h. The solution was diluted in CH2Cl2 (1 L),

! 183 separated, dried over Na2SO4, added NEt3 (3 drops), and concentrated. The crude

material was immediately taken on to the next step.

OTBDPS

O 282 tert-butyl(((1S,5S)-2-methyl-5-(2-methyloxiran-2-yl)cyclohex-2-en-1-

yl)oxy)diphenylsilane (282). To a stirring solution of epoxy-alcohol 266 (15.00 g,

101.6 mmol, 1 equiv) containing DMAP (3.2374 g, 26.4 mmol, 0.26 equiv) and

imidazole (14.5216 g, 213.3 mmol, 2.1 equiv) in CH2Cl2 (300 mL) was cannula-

transferred a solution of TBDPSCl (30.674 g, 111.7 mmol, 1.1 equiv) in CH2Cl2 (100

mL) and continued to stir under nitrogen at rt for 24 h. The solution was washed with

H2O (1 x 500 mL), brine (1 x 400 mL), dried over Na2SO4, and concentrated to 43.5 g

of a yellow oil. Purification was accomplished by flash chromatography (40:1

cyclohexane:EtOAc) affording 31.07 g (62% according to 1H NMR integration) of the

(1S)-syn-diastereomers 282 as the major product with minimal contamination of

1 TBDPS-O-TBDPS byproduct. Rf = 0.52 (40:1 cyclohexane:EtOAc). H NMR (500

MHz, CDCl3) ! 7.74 – 7.65 (m, 5H), 7.44 – 7.32 (m, 8H), 5.41 – 5.31 (m, 1H), 4.23 (t,

J = 6.9 Hz, 1H), 2.48 – 2.40 (m, 2H), 2.37 (s, 1H), 1.93 – 1.77 (m, 3H), 1.67 (d, J =

! 184 10.5 Hz, 3H), 1.45 – 1.37 (s, 11H), 1.08 (d, J = 3.4 Hz, 3H), 1.05 (s, 11H). 13C NMR

(125 MHz, CDCl3) ! 137.8, 136.3, 136.2, 135.0, 134.1, 129.8, 129.7, 127.9, 127.7,

127.7, 127.6, 122.7, 122.6, 72.6, 72.5, 58.8, 53.0, 52.9, 39.8, 39.4, 35.5, 27.7, 27.5,

27.3, 27.3, 27.1, 26.8, 20.3, 19.7, 18.4, 18.2.

OTBDPS

O 235a 1-((1S,5S)-5-((tert-butyldiphenylsilyl)oxy)-4-methylcyclohex-3-en-1-yl)ethanone

(235a). To a flame-dried round-bottom flask was added containing HIO4!H2O

(20.9557 g, 91.7 mmol, 1.2 equiv) in dry THF (500 mL) at 0 °C and cannula-

transferred epoxide 282 (31.07 g, 76.41 mmol, 1 equiv) in dry Et2O (150 mL) and

continued to stir under nitrogen for 1 h. Saturated Na2HCO3 (500 mL) was then added

and allowed to warm to rt over 15 min. The solution was filtered through Celite,

separated, washed with 5% Na2S2O3 (1 x 300 mL), brine (1 x 150 mL), dried over

MgSO4, and concentrated to 28.4 g of a colorless oil. Purification was accomplished

by flash chromatography (40:1 hexanes:Et2O) affording 23.56 g (79%) of the (1S)-syn-

diastereomers 235a as the major product with minimal contamination of ring-opened

1 byproducts 283 and 284. Rf = 0.06 (40:1 hexanes:Et2O). H NMR (500 MHz, CDCl3)

! 185 ! 7.79 – 7.71 (m, 6H), 7.48 – 7.34 (m, 9H), 5.44 – 5.39 (m, 1H), 4.37 – 4.28 (m, 1H),

2.75 (s, 0.5H), 2.44 – 2.35 (m, 1H), 2.15 (ddp, J = 13.6, 5.5, 2.7 Hz, 1H), 2.06 – 1.96

(m, 1H), 1.93 (s, 4H), 1.78 – 1.72 (m, 3H), 1.64 – 1.53 (m, 1H), 1.09 (d, J = 9.0 Hz,

13 15H). C NMR (125 MHz, CDCl3) ! 210.3, 137.6, 136.2, 136.2, 135.5, 134.9, 134.6,

133.9, 129.8, 129.8, 129.7, 127.8, 127.7, 127.6, 122.04, 72.0, 47.1, 35.0, 27.7, 27.2,

27.1, 26.7, 20.3, 19.6, 19.1.

OTBDPS

N 234a HO

1-((1S,5S)-5-((tert-butyldiphenylsilyl)oxy)-4-methylcyclohex-3-en-1-yl)ethanone

oxime (234a). To a stirring solution of 2.5 M NH2OH!HCl (17 mL, 42.6 mmol, 1.25

equiv) and 5 M NaOH (20.5 mL, 102.3 mmol, 3 equiv) was added ketone 235a (13.39

g, 34.1 mmol, 1 equiv) in EtOH (170 mL) and brought to a reflux for 3.5 h. The

solution was concentrated to half its volume, diluted in CH2Cl2 (300 mL), washed with

H2O (1 x 150 mL), dried over Na2SO4, and concentrated to 14.67 g. Purification was

accomplished by flash chromatography (40:1 hexanes:EtOAc to 2:1 hexanes:EtOAc)

affording 11.67 g (85%) of the (1S)-syn-diastereomers 234a as the major product with a

! 186 mixture of both (E) and (Z) oxime isomers in a ratio of 7:1, respectively. Rf = 0.24 and

1 0.10 (10:1 hexanes:EtOAc). H NMR (500 MHz, CDCl3) ! 9.48 (s, 1H), 7.85 – 7.71

(m, 6H), 7.53 – 7.32 (m, 9H), 5.44 (d, J = 6.0 Hz, 1H), 4.37 – 4.29 (m, 1H), 2.34 – 2.22

(m, 1H), 2.16 – 2.04 (m, 1H), 2.02 – 1.88 (m, 2H), 1.86 (s, 0.5H), 1.79 (s, 3H), 1.74 (s,

3H), 1.72 – 1.61 (m, 3H), 1.41 – 1.28 (m, 2H), 1.17 (s, 11H), 1.09 (s, 3H). 13C NMR

(125 MHz, CDCl3) ! 160.2, 137.5, 136.2, 136.2, 136.1, 135.4, 135.0, 134.9, 134.7,

133.9, 129.8, 129.7, 129.7, 127.8, 127.7, 127.7, 127.6, 122.5, 72.2, 40.0, 36.4, 35.4,

35.3, 34.8, 34.7, 31.7, 29.1, 27.3, 27.1, 26.7, 25.4, 22.8, 21.7, 20.9, 20.3, 19.6, 19.1,

14.3, 11.6.

OTBS

O 282a

tert-butyldimethyl(((1S,5S)-2-methyl-5-(2-methyloxiran-2-yl)cyclohex-2-en-1-

yl)oxy)silane (282a). To a stirring solution of epoxy-alcohol 266 (4.93g, 29.3 mmol, 1

equiv) containing imidazole (5.0211 g, 73.3 mmol, 2.5 equiv) in DMF (75 mL) was

cannula-transferred a solution of TBSCl (8.8713 g, 58.6 mmol, 2 equiv) in DMF (35

mL) and continued to stir under nitrogen at rt for 16 h. The solution was diluted in

! 187 CH2Cl2 (200 mL), washed with H2O (1 x 175 mL), brine (1 x 100 mL), dried over

Na2SO4, and concentrated to 9.75 g. Purification was accomplished by flash

chromatography (100% cyclohexane) affording 4.58 g (47%) of the (1S)-syn-

diastereomers 282a as the major product with minimal contamination of TBS-O-TBS

1 byproduct. Rf = 0.65 (10:1 hexanes:EtOAc). H NMR (500 MHz, CDCl3) ! 5.48 –

5.35 (m, 1H), 4.19 (td, J = 9.7, 4.7 Hz, 1H), 2.64 – 2.46 (m, 2H), 2.17 – 1.83 (m, 3H),

1.64 (dp, J = 2.6, 1.7 Hz, 3H), 1.33 – 1.15 (m, 4H), 0.96 – 0.80 (m, 10H), 0.13 – 0.00

13 (m, 6H). C NMR (125 MHz, CDCl3) ! 137.6, 122.8, 122.5, 71.3, 71.2, 53.7, 52.8,

40.5, 39.5, 35.7, 35.5, 28.0, 27.9, 26.1, 20.0, 19.9, 18.7, 18.3, 17.8, -3.9, -4.7.

OTBS

O 235b

1-((1S,5S)-5-((tert-butyldimethylsilyl)oxy)-4-methylcyclohex-3-en-1-yl)ethanone

(235b). To a flame-dried round-bottom flask containing HIO4!H2O (4.2805 g, 18.5

mmol, 1.2 equiv) in dry THF (150 mL) at 0 °C was cannula-transferred epoxide 282a

(4.58 g, 15.39 mmol, 1 equiv) in dry Et2O (35 mL) and continued to stir under nitrogen

for 1 h. Saturated Na2HCO3 (60 mL) was then added and allowed to warm to rt over 15

! 188 min. The solution was filter through Celite, separated, washed with 5% Na2S2O3 (1 x

100 mL), brine (1 x 100 mL), dried over MgSO4, and concentrated to 4.35 g of a

colorless oil. Purification was accomplished by flash chromatography (20:1

hexanes:Et2O) affording 2.32 g (59%) of the (1S)-syn-diastereomers 235a as the major

product with minimal contamination of ring-opened byproducts 283 and 284. Rf = 0.39

1 (10:1 hexanes:EtOAc). H NMR (500 MHz, CDCl3) ! 5.47 – 5.31 (m, 1H), 4.22 – 4.08

(m, 1H), 2.66 – 2.51 (m, 1H), 2.20 – 2.02 (m, 6H), 1.72 – 1.48 (m, 4H), 0.96 – 0.76 (m,

13 12H), 0.13 – -0.06 (m, 7H). C NMR (125 MHz, CDCl3) ! 210.1, 137.4, 121.8, 70.29,

47.1, 35.1, 27.9, 27.3, 26.3, 19.9, 18.3, -4.0, -4.8.

OTBS

N 234b HO

1-((1S,5S)-5-((tert-butyldimethylsilyl)oxy)-4-methylcyclohex-3-en-1-yl)ethanone

oxime (234b). To a stirring solution of 2.5 M NH2OH!HCl (10.3 mL, 25.6 mmol, 1.25

equiv) and 5 M NaOH (12.3 mL, 61.5 mmol, 3 equiv) was added ketone 235b (5.51 g,

20.5 mmol, 1 equiv) in EtOH (100 mL) and brought to a reflux for 24 h. The solution

was concentrated to half its volume, diluted in CH2Cl2 (200 mL), washed with H2O (1 x

! 189 200 mL), dried over Na2SO4, and concentrated to 5.08 g. Purification was

accomplished by flash chromatography (20:1 hexanes:EtOAc to 100% EtOAc)

affording 4.47 g (77%) the (1S)-syn-diastereomers 234b as the major product with a

mixture of both (E) and (Z) oxime isomers in a ratio of 7:1, respectively. Rf = 0.36 and

1 0.20 (10:1 hexanes:EtOAc). H NMR (500 MHz, CDCl3) ! 8.78 – 8.60 (m, 1H), 5.26

(dd, J = 4.7, 2.1 Hz, 2H), 4.26 – 4.11 (m, 1H), 4.97 (t, J = 3.4 Hz, 1H), 2.59-2.65 (m,

1H), 2.44-2.51 (m, 1H), 2.10 – 1.98 (m, 3H), 1.98 – 1.76 (m, 7H), 1.76 – 1.62 (m, 6H),

1.62 – 1.48 (m, 2H), 2.68 – 2.55 (m, 18H), 0.95 – 0.79 (m, 12H). 13C NMR (125 MHz,

CDCl3) ! 161.2, 160.7, 137.6, 135.3, 123.5, 122.4, 71.0, 68.5, 40.1, 36.7, 36.0, 35.3,

29.2, 29.2, 26.1, 21.4, 19.9, 18.3, 18.3, 12.8, 11.5, -3.8, -4.0, -4.2, -4.4, -4.7.

OAc

N H 287

(5S)-5-acetamido-2-methylcyclohex-2-en-1-yl acetate (287). To a stirring solution of

oxime 234b (1.26 g, 4.4 mmol, 1 equiv) in dry CH2Cl2 (22 mL) brought to -20 °C was

added MsCl drop-wise (0.375 mL, 4.8 mmol, 1.1 equiv) and continued to stir at this

temperature for 50 min. Once warmed to rt, the solution was diluted with CH2Cl2 (20

mL), washed with cold 1 M HCl (1 x 50 mL), Na2HCO3 (1 x 50 mL), brine (1 x 50

! 190 mL), dried over Na2SO4, and concentrated. The crude material was immediately

dissolved in acetic acid (28 mL) and allowed to stir at rt for 22 h. The solution was

concentrated en vacuo, brought to 0 °C and added 10% NH4OH (60 mL) and CH2Cl2

(60 mL), washed with Na2HCO3 (1 x 60 mL), brine (1 x 60 mL), dried over Na2SO4,

and concentrated to 0.59 g of a dark orange oil. Purification was accomplished by flash

chromatography (4:1 hexanes:EtOAc to 95:5:1 CH2Cl2:MeOH:NH4OH) affording

0.042 g (33%) of acetamide 287 (Rf = 0.54 in 4:1 hexanes:EtOAc) and 0.45 g (44%) of

mesylated acetamide 288 (Rf = 0.74 in 4:1 hexanes:EtOAc). Spectroscopic data for

1 287: H NMR (500 MHz, CDCl3) ! 5.59 – 5.44 (m, 1H), 4.34 (s, 1H), 3.69 (d, J = 3.5

Hz, 1H), 2.32 – 2.20 (m, 2H), 1.96 – 1.88 (m, 1H), 1.84 (s, 3H), 1.75 (s, 3H), 1.72 –

13 1.66 (m, 1H). C NMR (125 MHz, CDCl3) ! 157.1, 133.0, 131.9, 123.6, 70.9, 45.0,

34.1, 27.2, 21.9, 21.7.

OTBDPS

N H 233a N-((1S,5S)-5-((tert-butyldiphenylsilyl)oxy)-4-methylcyclohex-3-en-1-yl)acetamide

(233a). To a stirring solution of oxime 234a (4.2559 g, 8.76 mmol, 1 equiv) in CH2Cl2

(45 mL) and H2O (1 drop) at -35 °C was added MsCl drop-wise (0.814 mL, 10.5 mmol,

! 191 1.2 equiv) and continued to stir at this temperature for 30 min. Once warmed to rt, the

solution was diluted with CH2Cl2 (75 mL), washed with cold 1 M HCl (1 x 150 mL),

Na2HCO3 (1 x 150 mL), brine (1 x 100 mL), dried over Na2SO4, and concentrated to

3.97 g of a white foam. Purification was accomplished by flash chromatography (10:1

hexanes:EtOAc) affording 1.22 g (34%) of acetamide 233a (Rf = 0.81 in 95:5:1

CH2Cl2:MeOH:NH4OH) and 1.73 g (41%) of mesylated acetamide 304 (Rf = 0.36 in

1 4:1 hexanes:EtOAc). H NMR (500 MHz, CDCl3) ! 7.76 – 7.66 (m, 4H), 7.50 – 7.36

(m, 6H), 7.23 (d, J = 7.9 Hz, 1H), 5.40 (t, J = 4.2 Hz, 1H), 4.28 – 4.13 (m, 2H), 2.30 –

2.13 (m, 2H), 2.04 (ddd, J = 14.2, 5.1, 3.7 Hz, 1H), 1.96 – 1.90 (s, 3H), 1.78 – 1.71 (dt,

J = 13.9, 4.0 Hz, 1H), 1.64 (s, 0.5H), 1.54 – 1.47 (m, 2H), 1.16 – 1.06 (m, 9H). 13C

NMR (125 MHz, CDCl3) ! 169.4, 136.2, 136.1, 136.0, 135.9, 135.0, 134.6, 133.4,

133.3, 130.1, 130.0, 129.8, 129.7, 129.6, 127.9, 127.8, 127.7, 127.6, 122.5, 122.3, 70.0,

69.6, 42.3, 35.0, 31.9, 27.3, 27.2, 23.7, 21.6, 19.6.

OTBDPS

N Ms 304 N-((1S,5S)-5-((tert-butyldiphenylsilyl)oxy)-4-methylcyclohex-3-en-1-yl)-N-

(methylsulfonyl)acetamide (304). See experimental procedure for compound 233a.

! 192 1 H NMR (500 MHz, CDCl3) ! 7.76 – 7.67 (m, 5H), 7.41 (dq, J = 14.6, 7.4 Hz, 7H),

5.38 (d, J = 5.8 Hz, 1H), 4.38 – 4.24 (m, 1H), 3.02 (s, 4H), 2.47 – 2.33 (m, 1H), 2.18 –

1.95 (m, 2H), 1.93 – 1.83 (m, 1H), 1.80 (s, 3H), 1.75 (s, 3H), 1.68 – 1.56 (m, 2H), 1.09

13 (s, 11H). C NMR (125 MHz, CDCl3) ! 169.5, 137.8, 136.1, 134.9, 133.8, 129.9,

129.7, 127.7, 127.6, 121.6, 71.7, 39.9, 36.4, 35.8, 31.6, 28.5, 27.2, 25.4, 22.7, 20.1,

19.5, 14.2, 13.6.

N H 311 (1S,5S)-5-(ethylamino)-2-methylcyclohex-2-enol (311). To a flame-dried round-

bottom flask containing acetamide 233a (1.2024 g, 2.95 mmol, 1 equiv) in 1,2-dioxane

(15 mL) was added LiAlH4 (1.1354 g, 29.5 mmol, 10 equiv) portion-wise and brought

to a reflux under nitrogen for 17 h. Once cooled to rt, the solution was brought to 0 °C

and added H2O (1.2 mL), 20 % NaOH (1.2 mL), and more H2O (3.6 mL). This was

filtered, rinsed with EtOH (2 x 20 mL) and CH2Cl2 (2 x 20 mL), and concentrated to

1.3907 g. Purification was accomplished by flash chromatography (100% CH2Cl2 to

85:15:1 CH2Cl2:MeOH:NH4OH) affording 0.260 g (58%) of ethylamine 311 (Rf = 0.16

1 in 85:15:1 CH2Cl2:MeOH:NH4OH). H NMR (500 MHz, CDCl3) ! 5.31 (s, 1H), 3.83

! 193 (t, J = 4.7 Hz, 1H), 3.14 – 3.02 (m, 1H), 2.84 – 2.53 (m, 3H), 2.38 – 2.20 (m, 1H), 2.15

– 1.91 (m, 2H), 1.73 (t, J = 2.1 Hz, 4H), 1.15 – 0.99 (m, 3H). 13C NMR (125 MHz,

CDCl3) ! 137.2, 119.4, 68.6, 51.6, 42.2, 34.3, 33.0, 21.0, 15.4.

N 312

(1S,5S)-5-(ethyl((Z)-2-iodobut-2-en-1-yl)amino)-2-methylcyclohex-2-enol (312).

To a flame-dried round-bottom flask containing ethylamine 311 (0.2807 g, 1.81 mmol,

1 equiv) in dry THF (9 mL) was added K2CO3 (3.8172 g, 27.1 mmol, 15 equiv) and

mesylate 111 (1.0901 g, 3.6 mmol, 2 equiv). After stirring at rt for 2 days, the base was

removed by filtration and the solution was concentrated. Purification was

accomplished by flash chromatography (10:1 hexanes:EtOAc to 100% CH2Cl2 to

95:5:1 CH2Cl2:MeOH:NH4OH) affording 0.3823 g (63%) of amine 312 (Rf = 0.68 in

1 95:5:1 CH2Cl2:MeOH:NH4OH). H NMR (500 MHz, CDCl3) ! 5.84 (q, J = 6.4 Hz,

1H), 5.44 – 5.30 (m, 1H), 4.06 (t, J = 7.2 Hz, 1H), 3.35 – 3.19 (m, 2H), 2.84 (dtd, J =

9.8, 7.5, 2.5 Hz, 1H), 2.55 (h, J = 7.1 Hz, 2H), 2.14 – 1.97 (m, 3H), 1.74 (m, 8H), 0.98

! 194 13 (t, J = 7.1 Hz, 3H). C NMR (125 MHz, CDCl3) ! 136.9, 122.0, 70.5, 61.9, 54.0, 43.5,

35.6, 28.8, 21.9, 19.5, 12.7.

N 316

(S,Z)-5-(ethyl(2-iodobut-2-en-1-yl)amino)-2-methylcyclohex-2-enone (316).

Manganese(II) dioxide (0.1577 g, 1.8 mmol, 16 equiv) was added to amine 312 (0.0376

g, 0.11 mmol, 1 equiv) in dry CH2Cl2 (4 mL) and allowed to stir at rt under nitrogen for

24 h. The solids were filtered through a Celite plug and concentrated. Purification was

accomplished by flash chromatography (10:1 hexanes:EtOAc to 100% EtOAc)

1 affording 0.012 g (33%) of ketone 316 (Rf = 0.88 in 2:1 hexanes:EtOAc). H NMR

(500 MHz, CDCl3) ! 6.74 (d, J = 7.3 Hz, 1H), 5.90 (q, J = 6.4 Hz, 1H), 3.39 – 3.26 (m,

1H), 3.26 – 3.13 (m, 2H), 2.65 – 2.47 (m, 3H), 2.47 – 2.27 (m, 3H), 1.83 – 1.66 (m,

13 5H), 1.03 (t, J = 7.1 Hz, 3H). C NMR (125 MHz, CDCl3) ! 200.2, 144.6, 135.9,

131.1, 111.6, 61.8, 56.1, 43.6, 41.6, 30.5, 21.9, 15.9, 14.0.

! 195

N O N H 92

196

1 Figure A.1: H NMR Spectrum of 92 in CDCl3. !

N O N H 92

197

13 Figure A.2: C NMR Spectrum of 92 in CDCl3. !

N N H 91

198

1 Figure A.3: H NMR Spectrum of 91 in CDCl3. !

N N H 91

199

13 Figure A.4: C NMR Spectrum of 91 in CDCl3. !

Boc N N H 97b !

200

1 Figure A.5: H NMR Spectrum of 97b in CDCl3. !

Boc N N H 97b

201

13 Figure A.6: C NMR Spectrum of 97b in CDCl3. !

Cbz N N H 97a

202

1 Figure A.7: H NMR Spectrum of 97a in CDCl3. !

Cbz N N H 97a

203

13 Figure A.8: C NMR Spectrum of 97a in CDCl3. !

N N H 97c

204

1 Figure A.9: H NMR Spectrum of 97a in CDCl3. !

N N H 97c

205

13 Figure A.10: C NMR Spectrum of 97a in CDCl3. !

Cbz N

NH N Cbz

98 206

1 Figure A.11: H NMR Spectrum of 98 in CDCl3. !

Cbz N

NH N Cbz

207

13 Figure A.12: C NMR Spectrum of 98 in CDCl3. !

O HN N H 103 OH

208

1 Figure A.13: H NMR Spectrum of 103 in CDCl3. !

O HN N H 103 OH

209

13 Figure A.14: C NMR Spectrum of 103 in CDCl3. !

N N H 101

210

1 Figure A.15: H NMR Spectrum of 101 in CDCl3. !

N N H 101

211

13 Figure A.16: C NMR Spectrum of 101 in CDCl3. !

N N Boc 101a

212

1 Figure A.17: H NMR Spectrum of 101a in CDCl3. !

N N Boc 101a

213

13 Figure A.18: C NMR Spectrum of 101a in CDCl3. !

Cbz N N H HO 100a

214

1 Figure A.19: H NMR Spectrum of 100a in CDCl3. !

Cbz N N H HO 100a

215

13 Figure A.20: C NMR Spectrum of 100a in CDCl3. !

H N N H HO 106

216

1 Figure A.21: H NMR Spectrum of 106 in CDCl3. !

H N N H HO 106

217

13 Figure A.22: C NMR Spectrum of 106 in CDCl3. !

OHC

I 109

218

1 Figure A.23: H NMR Spectrum of 109 in CDCl3. !

OHC

I 109

219

13 Figure A.24: C NMR Spectrum of 109 in CDCl3. !

I 110

220

1 Figure A.25: H NMR Spectrum of 110 in CDCl3. !

MsO

I 111

221

1 Figure A.26: H NMR Spectrum of 111 in CDCl3. !

MsO

I 111

222

13 Figure A.27: C NMR Spectrum of 111 in CDCl3. !

N I N H HO 112

223

1 Figure A.28: H NMR Spectrum of 112 in CDCl3. !

N I N H HO 112

224

13 Figure A.29: C NMR Spectrum of 112 in CDCl3. !

N I N H MeO 112a

225

1 Figure A.30: H NMR Spectrum of 112a in CDCl3. !

N I N H MeO 112a

226

13 Figure A.31: C NMR Spectrum of 112a in CDCl3. !

N I N H O 99

227

1 Figure A.32: H NMR Spectrum of 99 in CDCl3. !

N I N H O 99

228

13 Figure A.33: C NMR Spectrum of 99 in CDCl3. !

N I N Boc O 113

229

1 Figure A.34: H NMR Spectrum of 113 in CDCl3. !

N I N Boc O 113

230

13 Figure A.35: C NMR Spectrum of 113 in CDCl3. !

N H O 132

231

1 Figure A.36: H NMR Spectrum of 132 in CDCl3. !

N H O 132

232

13 Figure A.37: C NMR Spectrum of 132 in CDCl3. !

N Boc O 133

233

1 Figure A.38: H NMR Spectrum of 133 in CDCl3. !

N Boc O 131

234

1 Figure A.39: H NMR Spectrum of 131 in CDCl3. !

N Boc O 131

235

13 Figure A.40: C NMR Spectrum of 131 in CDCl3. !

N H O 137

236

1 Figure A.41: H NMR Spectrum of 137 in CDCl3. !

N H 138

237

1 Figure A.42: H NMR Spectrum of 138 in CDCl3. !

N H 138

238

13 Figure A.43: C NMR Spectrum of 138 in CDCl3. !

N TFA

N H 138a

239

1 Figure A.44: H NMR Spectrum of 138a in CD3OD. !

N TFA

N H 138a

240

13 Figure A.45: C NMR Spectrum of 138a in CD3OD. !

N I

N Boc TMSO 139a

2 41

1 Figure A.46: H NMR Spectrum of 139a in CDCl3. !

N I

N Boc TESO 139

242

1 Figure A.47: H NMR Spectrum of 139 in CDCl3. !

HO I 152

243

1 Figure A.48: H NMR Spectrum of 152 in CDCl3. !

HO I 152

244

13 Figure A.49: C NMR Spectrum of 152 in CDCl3. !

O O

O I I 149

245

1 Figure A.50: H NMR Spectrum of 149 in CDCl3.

O O

O I I 149

246

13 Figure A.51: C NMR Spectrum of 149 in CDCl3.

N I N H HO 150

247

1 Figure A.52: H NMR Spectrum of 150 in CDCl3. !

N I N H HO 150

248

13 Figure A.53: C NMR Spectrum of 150 in CDCl3. !

N I N H O 151

249

1 Figure A.54: H NMR Spectrum of 151 in CDCl3. !

N I N H O 151

250

13 Figure A.55: C NMR Spectrum of 151 in CDCl3. !

N I N Boc O 147

251

1 Figure A.56: H NMR Spectrum of 147 in CDCl3. !

N I N Boc O 147

252

13 Figure A.57: C NMR Spectrum of 147 in CDCl3. !

N N H O 155

253

1 Figure A.58: H NMR Spectrum of 155 in CDCl3. !

N N H O 155

254

13 Figure A.59: C NMR Spectrum of 155 in CDCl3. !

O O

O O O 156

255

1 Figure A.60: H NMR Spectrum of 156 in CDCl3.

O O

O O O 156

256

13 Figure A.61: C NMR Spectrum of 156 in CDCl3.

N O N H MeO2C 157

257

1 Figure A.62: H NMR Spectrum of 157 in CDCl3. !

N O N H MeO2C 157

258

13 Figure A.63: C NMR Spectrum of 157 in CDCl3. !

N N H MeO2C 158

259

1 Figure A.64: H NMR Spectrum of 158 in CDCl3. !

N N H MeO2C 158

260

13 Figure A.65: C NMR Spectrum of 158 in CDCl3. !

Troc N N H MeO2C 159

261

1 Figure A.66: H NMR Spectrum of 159 in CDCl3. !

Troc N N H MeO2C 159

262

13 Figure A.67: C NMR Spectrum of 159 in CDCl3. !

H N N H MeO2C 159a

263

1 Figure A.68: H NMR Spectrum of 159a in CDCl3. !

H N N H MeO2C 159a

264

13 Figure A.69: C NMR Spectrum of 159a in CDCl3. !

N I N H MeO2C 160

265

1 Figure A.70: H NMR Spectrum of 160 in CDCl3.

N I N H MeO2C 160

266

13 Figure A.71: C NMR Spectrum of 160 in CDCl3.

N I N Boc MeO2C 161

267

1 Figure A.72: H NMR Spectrum of 161 in CDCl3.

N I N Boc MeO2C 161

268

13 Figure A.73: C NMR Spectrum of 161 in CDCl3.

O OEt Cl O 185

269

1 Figure A.74: H NMR Spectrum of 185 in CDCl3. !

O OEt Cl O 185

270

13 Figure A.75: C NMR Spectrum of 185 in CDCl3. !

O OEt

N O N H 187

271

1 Figure A.76: H NMR Spectrum of 187 in CDCl3. !

O OEt

N O N H 187

272

13 Figure A.77: C NMR Spectrum of 187 in CDCl3. !

Troc N N H HO 203

273

1 Figure A.78: H NMR Spectrum of 203 in CD3OD. !

Troc N N H HO 203

274

13 Figure A.79: C NMR Spectrum of 203 in CD3OD. !

Troc N N H O 203a

275

1 Figure A.80: H NMR Spectrum of 203a in CDCl3. !

Troc N N H O 203a

276

13 Figure A.81: C NMR Spectrum of 203a in CDCl3. !

Troc N N Boc O 142

277

1 Figure A.82: H NMR Spectrum of 142 in CDCl3. !

Troc N N Boc O 142

278

13 Figure A.83: C NMR Spectrum of 142 in CDCl3. !

TESO

I 205

279

1 Figure A.84: H NMR Spectrum of 205 in CDCl3. !

TESO

I 205

280

13 Figure A.85: C NMR Spectrum of 205 in CDCl3. !

O Ph Ph

213

281

1 Figure A.86: H NMR Spectrum of 213 in CDCl3.

O Ph Ph

213

282

13 Figure A.87: C NMR Spectrum of 213 in CDCl3.

O 266

283

1 Figure A.88: H NMR Spectrum of 266 in CDCl3. !

O 266

284

13 Figure A.89: C NMR Spectrum of 266 in CDCl3. !

O 264

285

1 Figure A.90: H NMR Spectrum of 264 in CDCl3. !

O 264

286

13 Figure A.91: C NMR Spectrum of 264 in CDCl3. !

OH N

268 O

287

1 Figure A.92: H NMR Spectrum of 268 in CDCl3. !

OH N

268 O

288

13 Figure A.93: C NMR Spectrum of 268 in CDCl3. !

OH N

N 269 OH

289

1 Figure A.94: H NMR Spectrum of 269 in CDCl3.

OH N

N 269 OH

290

13 Figure A.95: C NMR Spectrum of 269 in CDCl3.

O O 271

291

1 Figure A.96: H NMR Spectrum of 271 in CDCl3. !

O O 271

292

13 Figure A.97: C NMR Spectrum of 271 in CDCl3. !

S S

273 O

293

1 Figure A.98: H NMR Spectrum of 273 in CDCl3. !

S S

273 O

294

13 Figure A.99: C NMR Spectrum of 273 in CDCl3. !

S S

S S 272

295

1 Figure A.100: H NMR Spectrum of 272 in CDCl3. !

S S

S S 272

296

13 Figure A.101: C NMR Spectrum of 272 in CDCl3. !

O O

277

297

1 Figure A.102: H NMR Spectrum of 277 in CDCl3. !

O O

277

298

13 Figure A.103: C NMR Spectrum of 277 in CDCl3. !

OH HO 279

299

1 Figure A.104: H NMR Spectrum of 279 in d6-DMSO.

OH HO 279

300

13 Figure A.105: C NMR Spectrum of 279 in d6-DMSO.

OTBDPS

O 282

301

1 Figure A.106: H NMR Spectrum of 282 in CDCl3. !

OTBDPS

O 282

302

13 Figure A.107: C NMR Spectrum of 282 in CDCl3. !

OTBDPS

O 235a

303

1 Figure A.108: H NMR Spectrum of 235a in CDCl3.

OTBDPS

O 235a

304

13 Figure A.109: C NMR Spectrum of 235a in CDCl3.

OTBDPS

N 234a HO

305

1 Figure A.110: H NMR Spectrum of 234a in CDCl3. !

OTBDPS

N 234a HO

306

13 Figure A.111: C NMR Spectrum of 234a in CDCl3. !

OTBS

O 282a

307

1 Figure A.112: H NMR Spectrum of 282a in CDCl3. !

OTBS

O 282a

30 8

13 Figure A.113: C NMR Spectrum of 282a in CDCl3. !

OTBS

O 235b

309

1 Figure A.114: H NMR Spectrum of 235b in CDCl3. !

OTBS

O 235b

310

13 Figure A.115: C NMR Spectrum of 235b in CDCl3. !

OTBS

N 234b HO

311

1 Figure A.116: H NMR Spectrum of 234b in CDCl3. !

OTBS

N 234b HO

312

13 Figure A.117: C NMR Spectrum of 234b in CDCl3. !

OAc

N H 287

313

1 Figure A.118: H NMR Spectrum of 287 in CDCl3.

OAc

N H 287

314

13 Figure A.119: C NMR Spectrum of 287 in CDCl3.

OTBDPS

N H 233a

315

1 Figure A.120: H NMR Spectrum of 233a in CDCl3.

OTBDPS

N H 233a

316

13 Figure A.121: C NMR Spectrum of 233a in CDCl3.

OTBDPS

N Ms 304

317

1 Figure A.122: H NMR Spectrum of 304 in CDCl3.

OTBDPS

N Ms 304

318

13 Figure A.123: C NMR Spectrum of 304 in CDCl3.

N H 305

319

1 Figure A.124: H NMR Spectrum of 305 in CDCl3. !

N H 305

320

13 Figure A.125: C NMR Spectrum of 305 in CDCl3. !

N H 305a

321

1 Figure A.126: H NMR Spectrum of 305a in CDCl3. !

N H 305a

322

13 Figure A.127: C NMR Spectrum of 305a in CDCl3. !

N H 311

323

1 Figure A.128: H NMR Spectrum of 311 in CDCl3.

N H 311

324

13 Figure A.129: C NMR Spectrum of 311 in CDCl3.

N 312

325

1 Figure A.130: H NMR Spectrum of 312 in CDCl3. !

N 312

326

13 Figure A.131: C NMR Spectrum of 312 in CDCl3. !

N 316

327

1 Figure A.132: H NMR Spectrum of 316 in CDCl3.

N 316

328

13 Figure A.133: C NMR Spectrum of 316 in CDCl3.

! List of Abbreviations

2D NMR……………………………...…..two-dimensional nuclear magnetic resonance

9-BBN…………………………………………………..…..9-borabicyclo[3.3.1]nonane

Ac…………………………………………………………………………………..acetyl

Atm………………………………………………………………………...…atmosphere

BINAP…………………………...……2,2’-bis(diphenylphosphino)-1,1’-binaphthalene

Bn………………………………………………………………………………….benzyl

Boc…………………………………...………………………..……tert-butyl carbamate

Boc2O……………………….………………………………….……tert-butyl anhydride

n-Bu…….………………………………………...……………………….....……n-butyl

t-Bu………………..………………………...………………………….....……tert-butyl

Bz……………………………………………………………………….....………benzyl

c………………………………………………………………………...…..concentration

CAM……………………………………………...………..ceric ammonium molybdate

Cbz…………………………………………………………………..benzyloxy carbonyl

COD……….…………………………..………………………...……1,5-cyclooctadiene

COSY…………………………………………………………...correlation spectroscopy

! 329 Cp…………………………………………………………...……...…..cyclopentadienyl

dba…………………………………………………………………dibenzylideneacetone

DBU………………………………………………...1,8-diazabicyclo[5.4.0]undec-7-ene

DCC…………………………………………….……....!N,N'-dicyclohexylcarbodiimide

DCE……………………………………………………………...…...1,2-dichloroethane

DIEA………………………………………………………...N,N-diisopropylethylamine

DMAP………………………………………..……...…...N,N-4-dimethylaminopyridine

DMF………………………………………..……...... …...dimethylformamide

DMSO……………………………………………………………...... dimethylsulfoxide

DPE..…………………………………………...bis-[2-(diphenylphosphino)phenyl]ether

DPPE..…………………………………….……...1,2-bis-(2-(diphenylphosphino)ethane

dr……………………………………………………………….……diastereomeric ratio

dtbpf……………………………………….…1,1’-Bis(di-tert-butylphosphino)ferrocene

EDCI………………………………...."1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

ee……………………………………………………………….……enantiomeric excess

equiv…………………………………………………………………….……equivalents

Et…………………………………………………………………...... …..ethyl

! 330 HATU……………………………………...... 1-[Bis(dimethylamino)methylene]-

1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

HMPA……….…………………………..……………..….…hexamethylphosphoramide

HOMO…………………………..……………..….…highest occupied molecular orbital

HWE……….…………………………..……………..……Horner-Wadsworth-Emmons

IC50…………………………………………………..……inhibitory concentration, 50%

IR……………………………………………………………...……………….....infrared

KHMDS………………………………...……………...!potassium hexamethyldisilazide

LAH……………………………………………………….….lithium aluminum hydride

LC-MS……………………………………....liquid chromatography-mass spectrometry

LD50……….………………….....………………………………………lethal dose, 50%

LDA………………………………………………...……..…...lithium diisopropylamide

LHMDS…………………………………………………...!lithium hexamethyldisilazide

LiTMP………………………………………………..…...!lithium tetramethylpiperidide

mCPBA……………………………………………………...meta-chloroperbenzoic acid

M……….…………………………..……………...…………………………….....molar

Me……….…………………………..………………………………………….....methyl

MEM……….…………..……………………...…………!-methoxyethoxymethyl ether

! 331 MOM……….…………………………..……………………...... methoxylmethyl ether

Ms……….…………………………..…………………………..………methanesulfonyl

NMR……….…………………………..……………………nuclear magnetic resonance

PCC……………………………………...…………...... ……pyridinium chlorochromate

PG…………………………………………………………………….....protecting group

Ph……….…………………………..…………………………………………...... phenyl

Pet……….…………………………..……………………………….....…..….petroleum

Pic……….…………………………..……………………………………..…..….picrate

PMB……….…………………………..……………………….…para-methoxyl benzyl

PPTS……….…………………………..………...……….pyridinium p-toluenesulfonate

i-Pr……………………………………………………………………...... ……iso-propyl

RCM……………………………………………………..………ring-closing metathesis

rt……………………………………………...………………..………room temperature

TBAF…………………………..…………..……...…...tetra-n-butylammonium fluoride

TBAB…………………………..…………..……..…...tetra-n-butylammonium bromide

TBACl…………………...……..…………..……..…...tetra-n-butylammonium chloride

TBS……………………………………...………………...... ……tert-butyldimethylsilyl

TBDPS……………………………………...…………...... ……tert-butyldiphenylsilyl

! 332 TES……………………………………...……………………...... ……triethylsilyl ether

Tf……………………………………...………………...... ……trifluoromethanesulfonyl

TFA……………………………………...……………………....……trifluoroacetic acid

TFAA……………………………………...……………...……trifluoroacetic anhydride

THF……………………………………...……………...... ……tetrahydrofuran

TLC……………...…………...……………...... ……thin layer chromatography

TMS……………………………………...……………...... …...…trimethylsilyl

Troc……………………...……………...... …!2,2,2-trichloroethyloxycarbonyl

TsOH……………………………………...... …...... …...…para-toluenesulfonic acid

Ts……………………………………...………………...... ……..…para-toluenesulfonyl

µ"……………………………………...………………...... ……..…………...microwave

xantphos…………….…...... ……..…4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

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! 352 Index

17-oxo-subincanadine E………………………………………………….xviii, 26, 27, 126

A-1,3 strain………………………………………………………………………………10 acetamide……………………………………………….114, 116, 118, 119, 121, 122, 126 alkaloid……………………………………………...1, 8, 20, 25, 27, 36, 41, 43, 86, 89, 90 alkaloids…………………………………………………………xi, 1, 2, 3, 6, 9, 44, 45, 85 alkylation…...ii, x, xix, xx, xxi, xxii, xxiii, 8, 11, 40, 41, 65, 73, 77, 86, 88, 112, 113, 114, 115, 121, 122 anhydride……………………………………………xix, xx, 32, 42, 62, 63, 66, 73, 74, 76 apparicine……………………………………..viii, xviii, 2, 4, 6, 20, 21, 22, 23, 24, 25, 26

Aspidosperma subincanum……………………………………………………………..ii, 1

Asymmetric……………………………………………………………………xviii, 12, 16 aza-bicycle…………………………………………………………….ii, 37, 51, 76, 84, 86

Baran………………………………………………………………………...xxi, 89, 91, 92

Beckmann…………………………ii, ix, x, xxi, 85, 88, 107, 108, 109, 111, 112, 117, 126

Biomimetic…………………………………………viii, xviii, 1, 10, 11, 23, 26, 27, 88, 91

Biosynthesis……………..………………………………………………………xviii, 1, 24

Bischler-Napieralski……………………………………………………………………..38 bisindole………………………………………………………………………………….36 bite angle…………………………………………………………………………51, 59, 60

Bonjoch……………………………………….xviii, xix, 31, 32, 39, 43, 44, 56, 57, 65, 67

353 Carvone...ii, ix, xi, xxi, 85, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 102, 103, 105, 106, 124, 126

Chapman……………………………………………………………………...xxi, 110, 111 condensation…………………………………………………………..8, 13, 14, 15, 29, 37 conjugate addition………………………………………………...ix, xx, 64, 65, 66, 67, 94 conolidine……………………………………………………viii, xviii, 6, 9, 10, 11, 12, 85

Cook…………………………………………xix, 41, 42, 43, 44, 45, 46, 48, 49, 51, 53, 68 cross-coupling ……………………..ii, viii, ix, xix, xx, xxiii, 28, 43, 46, 50, 54, 63, 64, 80

Deacetylation…………………………………………………...x, xxii, 115, 116, 117, 118 decarboxylation…………………………………………………………………………..24

Dieckmann…………………………………………………………………………...13, 15

Diels-Alder……………………………………………………………...ii, xix, 35, 36, 126 elimination……..xix, xxii, 28, 31, 32, 47, 48, 49, 58, 59, 60, 61, 67, 72, 76, 107, 114, 115 enantiomer……………………………………………………………………11, 18, 89, 94 enantioselective……………………………………………………………….ix, 45, 86, 87 enol ether………………………………………………………………...xix, 55, 56, 64, 82 enolate….viii, ix, xix, xx, 43, 44, 46, 47, 48, 49, 54, 55, 57, 58, 61, 71, 72, 76, 77, 80, 81, 83, 84, 124, 126 ervaticine…………………………………………………………………………………..2

Fisher indole…………………………………………………………………………….124 fragmentation………………………………………………xix, 7, 8, 24, 28, 30, 31, 39, 40

Friedel-Crafts………………………………………………………………………...21, 86

354 Garg……………………………………………………………..xx, xxi, 85, 86, 89, 93, 94

Grubbs……………………………………………………………………………………21 harmicine…………………………………………………………………ii, xix, 36, 37, 39

Heck………………………………xxii, xxiii, 20, 22, 46, 65, 68, 69, 85, 88, 119, 123, 126

Heck coupling……………………………………...xxii, xxiii, 65, 68, 69, 85, 88, 119, 123 imminium…………………………………………………………….10, 24, 25, 26, 39, 58 indole….ii, xi, 1, 3, 6, 15, 18, 20, 21, 22, 23, 24, 27, 30, 36, 41, 42, 43, 44, 45, 48, 49, 65, 76, 79, 84, 85, 86, 89, 90, 91, 124 intramolecular………ii, ix, xix, xxi, xxii, xxiii, 7, 8, 16, 18, 20, 28, 37, 43, 44, 46, 47, 48, 49, 57, 61, 64, 71, 76, 78, 85, 86, 88, 103, 105, 106, 107, 119, 122, 123, 126 isocyanate……………………………………………………………ix, xxi, 89, 91, 93, 94 isomerization…………………...……...ii, viii, xi, xviii, 20, 21, 33, 34, 35, 49, 60, 83, 107

Kobayashi………………………………………………………………………..1, 2, 7, 17

Kutney ……………………………………………………………………………10, 23, 24

Li…………………………………………………….xviii, 5, 8, 13, 14, 15, 16, 18, 76, 115 ligand…………………………………………………49, 51, 52, 53, 54, 59, 60, 83, 94, 95 ligands……………………………………………..xix, xxi, 44, 48, 52, 59, 90, 94, 95, 122

Luche reduction………………………………………………………………………...105

Mannich………………………………………………………………………….12, 58, 59

Meerwein’s salt…………………………………………………………………………115

Micalizio………………………………………………………………………...xviii, 9, 10

Michael addition…………………………………………………………..7, 8, 14, 15, 120

355 Ni(COD)2…………………………………………………………………………...7, 8, 83 nitrillium………………………………………………………………………………..109 optical rotation…………………………………………………………………………...18 organocuprate……………………………………………………………………………..ii oxidation...ix, xix, xxi, xxii, 11, 36, 41, 42, 62, 78, 91, 95, 96, 97, 102, 105, 106, 121, 122 oxime……………………………..ii, ix, xxi, xxiii, 88, 95, 98, 99, 105, 107, 108, 110, 112

Pd-catalyzed.ii, viii, ix, xix, xx, 28, 43, 46, 47, 49, 55, 58, 60, 61, 68, 80, 81, 83, 122, 126 pericalline………………………………………………………………………………….4 pericine………………………………………………………………….ii, xi, 1, 2, 3, 6, 85

Picralima nitida…………………………………………………………………………ii, 1

Pictet-Spengler………………………………………………………...8, 13, 14, 18, 29, 86

Piers…………………………………………………………………………xix, 43, 44, 68

Piers………………………………………………………………………………43, 44, 68

Potier-Polonovski………………………………………………………………………...24 protecting group………..ii, ix, 10, 14, 15, 22, 28, 35, 65, 99, 100, 105, 108, 112, 115, 119 protecting-group……………………………………………………………………...13, 18

Qin……………………………………………………………………………xx, 43, 68, 69 racemic…………………………………………………………………….8, 11, 15, 28, 58 radical………………………………………………………………………….7, 15, 68, 91

RCM………………………………………………………………………….xi, 20, 21, 22 rearrangement…………….ii, x, xxi, 11, 13, 14, 85, 88, 107, 108, 110, 111, 112, 117, 126

356 reduction……………………………x, xxii, 11, 14, 29, 30, 41, 72, 76, 105, 119, 120, 124 reductive amination…………………………………….x, xxii, 21, 91, 115, 116, 119, 120 regioisomer………………………………………………………………………………79 regioselective……………………………...ii, xxi, xxiii, 95, 97, 98, 99, 100, 101, 102, 105

Regioselectivity…………………………………………………………………………..78

Scott……………………………………………………………………………………...10 stemmadenine………………………………………………………...xviii, 1, 2, 10, 24, 25 subincanadine A……………………………………………………..viii, xviii, 3, 6, 18, 19 subincanadine B……………………………………………………………..xviii, 6, 18, 19 subincanadine C…………………………………………………………………..xviii, 7, 9 subincanadine D…………………………………………………………………………...3 subincanadine E..ii, viii, xi, xviii, xix, xxii, 1, 3, 4, 5, 6, 7, 8, 9, 11, 25, 26, 27, 28, 29, 37, 38, 49, 53, 54, 72, 85, 87, 124, 125, 126 subincanadine F……………………………………...viii, xviii, 3, 6, 12, 13, 14, 16, 17, 18

Takayama……………………………………………………………..xviii, 1, 6, 18, 19, 36 tetrahydro-!-carboline……………………………………………………..xviii, 30, 36, 39 vallesamine……………………………………………………………...xviii, 2, 10, 23, 24 valpericine………………………………………………………xviii, 1, 2, 25, 26, 87, 124

Waters……………………………………………………………...i, iv, v, xviii, 16, 17, 90

Wittig……………………………………………………………..xix, 6, 11, 53, 54, 72, 76

Zhai………………………………………………….xviii, 5, 6, 7, 8, 12, 13, 14, 16, 18, 48

"-vinylation………………………………………………………………………61, 83, 84 357 !-elimination……………………………………………………………………………..48

"-allyl………………………………………………………………………...xx, 65, 69, 70

358