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INDIUM-MEDIATEO ALLYLATIONS OF a-HETEROSUBSTITUTED CYCLOHEXANONES IN AQUEOUS MEDIA

DISSERTATION

Presented in Partial Fulfillment of tfie Requirements for ttie Degree of Doctor of Ptiilosophy in ttie Graduate Scfwol of Ttie Ofiio State University

by

Paul Ctiristoptier Lobtien, B.S., M.S.

The Ohio State University 1998

Dissertation Committee: Professor Leo A. Paquette, Adviser Approved by Professor David J. Hart Professor Matthew S. Platz Adviser Department of Chemistry UMI Number: 9834022

UMI Microform 9834022 Copyright 1998, by UMI Company. All rights reserved.

This microform edition is protected against unauthorized copying under Title 17, United States Code.

UMI 300 North Zeeb Road Ann Arbor, MI 48103 ABSTRACT

With the increasing pressure on the chemical and pharmaceutical industries to reduce

their hazardous waste stream has come the demand to develop environmentally benign

technologies. This goal has t>een espoused by President Clinton’s Green Chemistry Challenge

sponsored by the Environmental Protection Agency. Additionally, the National Research Council

has focused on reducing the detrimental effects of chemicals to improve the environment.

Effective and efficient carbon-cartwn bond forming reactions are the epitome of organic

synthesis. Unfortunately, ttie majority of such transformations are extremely moisture sensitive

requiring anhydrous organic solvents and air-sensitive organometallic reagents in an inert

atmosphere of Ar or N 2 The reduction of such cumt)ersome protocols would be a welcomed addition to the synthetic and industrial chemist’s arsenal. One attractive method is to replace the traditional organic solvent with water. A water-based technology would have inherently explicit advantages. These include;

• reduction of environmental pollution caused by solvent emission and disposal.

• lower process and disposal costs, as compared to hydrocaitwn solvents.

• significant enhancement of operational safety by eliminating toxic and flammable solvents.

• a possOsle increase in stereoselectivity in water.

Recently several research groups have shown that the element indium (In) efficiently promotes allylation reactions in water. The ally! group is widely disseminated in organic chemistry and is often used as a key building block in the synthesis of natural and unnatural products.

Further investigation of this intriguing water-based chemistry is thus warranted with particular attention to stereoselectivity. Stereoselectivity is a key feature of pharmaceutical synthesis as exemplified by the Federal Drug Administration's mandate requiring companies to produce

enantiomerically pure dnjgs.

We undertook a comparative study of the allylindium reagent and some of the more

traditional allylmetal reagents in reaction with a-oxygenated cydohexanones. We focused on the

the diastereoselecthrity obtainable in conjunction with the chelating ability of the neightx)ring

oxygen atom. The aqueous indium protocol was found to be highly superior to the traditional

techniques with respect to the ease of operation of the chemical reaction and diastereoselectivity.

We have further applied this methodoolgy to include a-hydroxycyclohexanones, which otherwise are incompatble with traditional organometallic reagents. We have obtained the highest levels of diastereoselectivity to date with these substrates. The diastereomeric ratio was determined by nuclear magnetic resonance (NMR) techniques and routine chromatographic separation. The experimental procedure simply requires combining in a reaction vessel the a-oxygenated cyclohexanone, allyl bromide, and indium powder in a ratio of 1 ;1.5:1.5, respectively, in water at

0.10 molar concentration.

The implications of this research are expected to be significant because of the inherent advantages. It is anticipated that this novel technology will be adopted by chemical and pharmaceutical industries in the near future and thereby drastically reduce environmental pollution and operational costs as well as irwrease workplace safety. To my wife Anne-Marie,

whose love and support has made this endurable.

To you I owe so very much, for you were too often subjected to my inane episodes.

IV ACKNOWLEDGMENTS

First. I offer my sincere gratitude to Professor Leo A. Paquette. His patience and trust in

me at a turtxjient beginning of my graduate career are gratefully acknowledged. He has senred as

a forceful motivator arxl an understanding advisor. By example, he has induced me to strive for

excellence arxf has done a great deal to bolster my self-confidence. His constant enthusiasm and

meticulous intensity are second to none, and are no doubt contagious.

Second, words are not enough the express my overwhelming appreciation of Donna

Rothe. She unarguably performs her job with the utmost diligence and precision. It was always

my pleasure as Coffee Club President to acknowledge, on behalf of the group, her tremendous contributions. Her insight is unrivaled and greatly appreciated by all.

Sincere thanks are offered to Professors T.V. RaJanBabu, David Hart and Matthew Platz for their encouragement, ttioughtful advice, and constructive criticism during the past several years. I am indetited to Kurt L. Loaning for his expertise in nomenclature.

There are a few select individuals that deserve to be mentioned by name. The friendship of Scott Edmondson in and out of lab made the first years of graduate school extremely rewarding and productive. His enthusiasm and professional demeanor were infectious and he always encouraged me to fulfill my potential. I am extremely thankful for his friendship. I am also thankful to Jeff Johnston for his gracious assistance in all aspects of my graduate career, most notably during my oral proposal and examination. His thoughtful advice arxf encouragement were always insightful and well appreciated. Also duly acknowledged is the entire indium team, including

Roger Rothhaar, Tom Mitzel, and Patrick Bemardelli, who listened as much as they contributed.

Their stimulating conversations were central to the success of my endeavors. Todd Heidebaugh’s often humorous antidotes offered a welcomed respite during the busy day. His fanaticism during the inaugural Crew season was a further source of relief from the mundane. I am grateful to Monty Montgomery for reminding me that there are things outside of lab that one can be as passionate about a s chemistry.

Finally, I must thank ttie many individuals that tested me on the soccer field by providing a fleeting escape from the everyday frustrations of latxxatory wortc, most notably Fatrrice Gailou and

Richard Kryspin. I especially recognize my captains Hans and Mary-Eilen, and express my warm appreciation for their trust in me the keeper of tfieir goal.

VI VITA

Octobers, 1969 Bom • Cincinnati, Otiio

May, 1992 Bachelor of Science, Emory University, Atlanta, Georgia

Septemtrer, 1992-September, 1995 Graduate Teactiing Assistant, The Ohio State University, Columbus, Ohio

October, 1995 Master of Science The Ohio State University, Columbus, Ohio

October, 1995-present Graduate Research Assistant, The Ohio State University, Columbus, Ohio

PUBLICATIONS

Paquette, L. A.; Lobben, P. C. "n-Facial Diastereoselection in the 1,2 Addition of Allylmetal Reagents to 2-Methoxycydohexanone and Tetrahydrofuranspiro-( 2-cyclohexanone)" J. Am. Chem. Soc. 1996, 118, 1917-1930.

Lotiben, P. C.; Paquette, L. A. "Sequenced Reactions with Samarium(ll) Iodide. Tandem Nucleophilic Acyl/Ketyl-Olefin Coupling Reactions* Chemtracts: Organic C/iemsfry 1997, 4, 284.

Paquette, L. A.; Lobben, P. C. "Evaluation of Chelation Effects Operative during Diastereoselective Addition of the Allylindium Reagent to 2- and 3-Hydroxycyclohexanones in Aqueous, Organic, and Mixed Solvent Systems” submitted for publication.

FIELD OF STUDY

Major Field; Chemistry Studies in Organic Chemistry

VN TABLE OF CONTENTS Eaa&

ABSTRACT...... ii

DEDICATION...... iv

ACKNOWLEDGMENTS...... v

VITA...... vil

LIST OF TABLES...... xii

LIST OF FIGURES...... xiii

LIST OF SCHEMES...... xx

LIST OF ABBREVIATIONS AND SYMBOLS...... xxiii

Chapters;

1. INDIUM-MEDIATED ALLYLATIONS AND AQUEOUS CHEMISTRY

1.1. Background...... 1

1.2. Properties of Indium Metal...... 1

1.3. Aqueous Conditions: Advantages ...... 2

1.4. Allyl Group: Utility and Transformations ...... 3

1.5. Organoindium Chemistry ...... 4

1.5.1. Indium-Mediated Allylations ...... 4

1.5.2. Reformatsky-Type Reactions...... 14

1.5.3. Cyclopropanation of Alkenes...... 15

1.5.4. CartX)indation of Alkynes...... 15

viii LIST OF REFERENCES AND NOTES...... 21

2. CONTRIBUTIONS FROM THE PAQUETTE LABORATORY...... 24

LIST O F REFERENCES AND NOTES...... 34

3. a-HETEROSUBSTITUTED CYCLOHEXANONES

3.1. Background...... 35

3.2. Results...... 37

3.2.1. 2-Methoxycyclchexanone ( 6 ) and 1-Oxaspiro[4.5]decan-6-one (9) ...... 37

3.2.2. The Conformâtionally Disparate 2-Methoxy-4-fed-butylcyciohexanones

7 and 8 ...... 41

3.2.3. Evaluation of the Haptophilic Properties of the Tetrahydrofuran Ring in

10 and 11 ...... 48

3.2.4. Competition Experiments ...... 59

3.3. Conclusion...... 62

LIST OF REFERENCES AND NOTES...... 64

4. a-HYDROXYCYCLOHEXANONES

4.1. Background...... 69

4.2. Synthesis ...... 70

4.2.1. c/5-4-fert-Butyl-2-hydroxycyclohexanone (2) and frans-5-fert-Butyl-2-

hydroxycyclohexanone ( 6 )...... 70

4.2.2. frans-4-fert-Butyl-2-hydroxycyclohexanone (3) ...... 75

4.2.3. as- and frans-4-fert-Butyl-2-hydroxy-2-methylcyclohexanone (4 and 5) ...... 78

4.3. Results...... 79

4.4. Competition Experiments ...... 92

ix 4.5. Conclusion...... 95

LIST OF REFERENCES AND NOTES...... 96

5. p-HYDROXYCYCLOHEXANONES AND 4-HYDROXYCYCLOPENTENONES

5.1. Background...... 100

5.2. Synthesis ...... 101

5.2.1. 4-Acetoxy- and 4-Hydroxycyclopentenones (1 and 2)...... 101

5.2.2. trans- and c/s-4-ferf-Butyl-3-hydroxycyclohexanone (3 and 4) ...... 101

5.3. Results...... 103

5.4. Competition Experiments ...... 109

5.5. Conclusion...... 110

LIST OF REFERENCES AND NOTES...... 112

6. 6-SUBSTITUTED 2-HYDR0XY-1-TETRAL0NES

6 .1. Background...... 114

6 .2. Synthesis of 6-Substituted 2-Hydroxy-1-tetralones...... 115

6.2.1. 2-Hydroxy-l tetralone (la ) and 2-Hydroxy-6-methoxy-1-tetralone (1b) ...... 115

6 .2 .2 . 6-Bromo-2-hydroxy-1-tetralone (lc)...... 115

6.2.3. 2-Hydroxy-6-(/V-methyl)acetamido-1-tetralone (Id )...... 117

6.2.4. 6-Cyano-2-hydroxy-1-tetralone (le)...... 119

6.3. Results...... 120

6.4. Competition Experiments ...... 130

6.5. Conclusion...... 133

LIST OF REFERENCES AND NOTES...... 134 7. EXPERIMENTALS...... 136

7.1. Chapter 3 ...... - ...... 137

7.2. Chapter 4 ...... 155

7.3. Chapter 5 ...... 174

7.4. Chapter 6 ...... 181

APPENDICES

A. CHAPTER 3 IR NMR SPECTRA...... 205

B. CHAPTER 4 1R NMR SPECTRA...... 235

C. CHAPTER 5 1R NMR SPECTRA...... 258

D. CHAPTER 8 1R NMR SPECTRA...... 270

E. STRUCTURAL ELUCIDATION AND ADDITIONAL SPECTRA (CHAPTERS 3-8) ...... 304

BIBLIOGRAPHY ...... 329

XI LIST OF TABLES

Table

1.1 Indium-promoted allylations in water ...... 6

1.2 Regio- and stereoselective coupling of aldehydes and y-substituted allyl bromides 9

1.3 Indium-mediated allylation (carboindation) of alkynes ...... 16

2.1 Indium-mediated allylation of a-oxygenated aldehydes ...... 26

2.2 Indium-mediated allylation of p-oxygenated aldehydes ...... 26

2.3 Indium-mediated addition of y^substituted allyl bromides 11c d to a-oxygenated

aldehydes lOa-b ...... 28

3.1 Facial selectivity in nucleophilic additions to 6 and 9 ...... 39

3.2 Facial selectivity in nucleophilic additions to 7 and 8 ...... 45

3.3 Polarities of selected cyclohexanols and spirotetrahydrofuran derivatives (Revalues).55

3.4 Facial selectivity in nucleophilic additions to 10 and 11 ...... 57

3.5 Competitive indium-promoted allylations in water at room temperature ...... 61

4 .1 Competitive indium-promoted allylations in water at room temperature ...... 94

5.1 Competitive indium-promoted allylation of 3 and 4 in water at room temperature 110

6.1 Competitive indium-mediated allylations in water at room temperature ...... 131

6.2 Competitive indium-mediated allylations in 50% THF(aq) at room temperature ...... 132

XII LIST OF FIGURES

Figure BaOR

1.1 The proposed indium/allyl bromide intermediate ...... 4

1.2 Proposed transition states for the indium-mediated allylation of aldehydes

and acyclic ketones...... 10

2.1 Cram-chelate and Felkin-Anh models A and B...... 24

2.2 Chelate-controlled addition of allylindium to 7d selectively producing 9d ...... 27

2.3 Chelation control and Felkin-Ahn transition states for the addition of

Y-substituted allyl bromides 11c-d to a-oxygenated aldehydes lOa-b ...... 29

2.4 Transition states depicting the 1.4 asymmetric induction observed with allyl bromides

19a b ...... 31

2.5 Transition states depicting the 1.4 asymmetric induction observed with allyl bromides

22a b ...... 32

3.1 Chelate-controlled addition to a-oxygenated cydohexanones ...... 36

3.2 Investigation of a-oxygenated cydohexanones 6-11 ...... 37

3.3 Conformational dynamics of 2-methoxycyclohexanone ( 6 )...... 38

3.4 Conformational dynamics of 2-(spirotetrahydrofuranyl)cyclohexanone (9) ...... 40

3.5 Conformational analysis and Newman projedions of 23 and 24 ...... 43

3.6 Conformational analysis of 7 and 8 ...... 46

3.7 Conformational analysis and Newman projedions of 28 and 29 ...... 47

3.8 Conformational analysis of 10 and 11...... 48

3.9 Chelate-controlled addition of the Normant reagent to 34 ...... 51

xiii 3.10 300 MHz ^H.^H COSY 90 spectrum of 10 in CDCI 3 solution...... 52

3.1 1 300 MHz 1H.1H COSY 90 spectrum of 11 in CDCI3 solution...... 53

3.12 NOE difference data for 37 and 38 ...... 54

3.13 NOE difference data for 41 and 42 ...... 58

4.1 a-Hydroxycyclohexanones 1-6 ...... 70

4.2 Proposed tautomerization pattiway via a "enedior intermediate...... 72

4.3 Transition states for allylic oxidation of 19 witti Se 0 2 ...... 77

4.4 Chelate-controlled transition state for the indium-mediated allylation of an a-

hyd roxycycio hexanone ...... 81

4.5 NOE difference data for acetonide 24 ...... 82

4.6 NOE difference data for cis diol 30 ...... 84

4.7 Chelate-controlled transition state for the indium-mediated allylation of 3 (R=H) ...... 86

4.8 NOE difference data for cis diol 33 ...... 88

4.9 NOE difference data for acetonide 34 ...... 88

4.10 NOE difference data for trans diol 35 ...... 90

4.11 NOE difference data for cis diol 36 ...... 90

4.12 Long range semi-selective DEPT for cis diol 36 ...... 91

4.13 NOE difference data for acetonide 37 ...... 92

4.14 Long range semi-selective DEPT for acetonide 37 ...... 92

5.1 p-Oxygenated substrates 1-4 ...... 100

5.2 Proposed transition states for the indium-mediated allylation of 2 and 4 ...... 101

5.3 NOE difference data for cis 12 ...... 104

5.4 NOE difference data for trans 13 ...... 104

5.5 NOE difference data for trans 1,3-diol 15 ...... 107

5.6 NOE difference data for cis 1,3-diol 16 ...... 107

5.7 Long range semi-selective DEPT experiments for cis 1,3-diol 16 ...... 107

xiv 6 .1 NOE difference data for cis cartwnate 18 ...... 122

6.2 NOE difference data for trans cartwnate 43 ...... 122

6.3 NOE difference data for cis cartx>nate 22 ...... 124

6.4 NOE difference data for trans carbonate 23 ...... 124

6.5 NOE difference data for cis cartx>nate 26 ...... 126

6 .6 NOE difference data for trans carbonate 27 ...... 126

6.7 NOE difference data for cis carbonate 30 ...... 128

6.8 NOE difference data for trans carbonate 31 ...... 128

6.9 NOE difference data for cis cartx>nate 34 ...... 130

6.10 NOE difference data for trans carbonate 35 ...... 130

A.1 NMR Spectrum of..10...... 206

A.2 NMR Spectrum of..11...... 207

A 3 NMR Spectrum of..23...... 208

A 4...... 1H NMR Spectrum of 24...... 209

A.5 NMR Spectrum of..25...... 210

A.6 NMR Spectrum of..26...... 211

A.7 NMR Spectrum of 27...... 212

A.8 1H NMR Spectrum of 28 ...... 213

A.9 NMR Spectrum of 29 ...... 214

A.10 1H NMR Spectrum of 30...... 215

A ll NMR Spectrum of 31...... 216

A.12 NMR Spectrum of 33...... 217

A.13 NMR Spectrum of 34...... 218

A.14 ■'H NMR Spectrum of 35...... 219

A.15 NMR Spectrum of 36...... 220

A.16 NMR Spectrum of 37...... 221

XV A.17..... 1H NMR Spectrum of 38 ...... 222

A.18 ..... 1H NMR Spectrum of 39 ...... 223

A.19 ...... NMR Spectrum of 40...... 224

A.20..... 1H NMR Spectrum of 41...... 225

A.21...... ■'H NMR Spectrum of 42...... 226

A.22 1H NMR Spectrum of 43...... 227

A.23 NMR Spectrum of 44...... 228

A.24 1H NMR Spectrum of 45...... 229

A.25 1H NMR Spectrum of 46...... 230

A.26 1H NMR Spectrum of 47...... 231

A.27 1H NMR Spectrum of 48 ...... 232

A.28 NMR Spectrum of 49 ...... 233

A.29 1H NMR Spectrum of 50 ...... 234

B.1...... 1H NMR Spectrum of 4...... 236

B.2 lH NMR Spectrum of 5...... 237

B.3 1H NMR Spectrum of 7...... 238

B.4 NMR Spectrum of 8 ...... 239

B.5 NMR Spectrum of 14...... 240

B.6 NMR Spectrum of 15...... 241

B.7 NMR Spectrum of 17...... 242

B.8 NMR Spectrum of 18 ...... 243

B.9 1H NMR Spectrum of 21 ...... 244

B.10 NMR Spectrum of 22...... 245

B.11 NMR Spectrum of 24...... 246

B.12 NMR Spectrum of 25...... 247

B.13 NMR Spectrum of 26...... 248

XVI B.14

B.15

B.16

B.17

B.18

B.19

B.20

B.21

B.22

C .1

C.2

C.3

C.4

C.5

C .6

C.7

C.8

C.9 1H

C.10

C.11

D.1 1H

D.2

D.3 lH

D.4 1H

D.5

D.6 1H

XVII D.7 1H NMR Spectrum of 7a...... 277

D.8 1H NMR Spectrum of 7b...... 278

D.9 1H NMR Spectrum of 10 ...... 279

D.10 NMR Spectrum of 11...... 280

D.11 1H NMR Spectrum of 13...... 281

0.12..... 1H NMR Spectrum of 14...... 282

D.13 NMR Spectrum of 15...... 283

D.14 NMR Spectrum of 16...... 284

D.15 NMR Spectrum of 17...... 285

D.16 NMR Spectrum of 18 ...... 286

D.17 1H NMR Spectrum of 19 ...... 287

D.18 NMR Spectrum of 20 ...... 288

D.19 NMR Spectrum of 21 ...... 289

D.20 NMR Spectrum of 22...... 290

D.21 NMR Spectrum of 23...... 291

D.22 NMR Spectrum of 24...... 292

D.23 NMR Spectrum of 25...... 293

D.24 NMR Spectrum of 26...... 294

D.25 NMR Spectrum of 27...... 295

D.26 NMR Spectrum of 28 ...... 296

D.27 NMR Spectrum of 29 ...... 297

D.28 NMR Spectrum of 30 ...... 298

D.29 1H NMR Spectrum of 31 ...... 299

D.30 NMR Spectrum of 32...... 300

D.31 NMR Spectrum of 33...... 301

D.32 NMR Spectrum of 34...... 302

xviii D.33 1H NMR Spectrum of 35...... 303

E.1 13c NMR + DEPT Spectrum of 24...... 305

E.2 Long Range Semi-Selective DEPT of 24, Irradiation of H-2 ...... 306

E.3 1 H.1 H COSY 90 Spectmm of 37 ...... 307

E.4 iH.iH COSY 90 Spectrum of 38 ...... 308

E.S 13c NMR + DEPT Spectmm of 38 ...... 309

E.6 Long Range Semi-Selective DEPT of 38, Irradiation of H- 6a ...... 310

E.7 1h ,1h c o s y 90 Spectmm of 42 ...... 311

E.8 13c NMR + DEPT Spectmm of 42 ...... 312

E.9 Long Range Semi-Selective DEPT of 42, Irradiation of H- 6a...... 313

E.10 1h ,1h c o s y 90 Spectmm of 7 ...... 314

E.11 1h,1h COSY 90 Spectmm of 8 ...... 315

E.12 1h ,1h COSY 90 Spectmm of 28 ...... 316

E.13 1h ,1h COSY 90 Spectmm of 30 ...... 317

E.14 1h ,1h c o s y 90 Spectmm of 35 ...... 318

E.15 1h ,1h c o s y 90 Spectmm of 36 ...... 319

E.16 1h ,13c Correlation Spectmm of 36 ...... 320

E.17 Long Range Semi-Selective DEPT of 36, Irradiation of H- 6a...... 321

E.18 1h ,1h COSY 90 Spectmm of 15 ...... 322

E.19 1h ,1h COSY 90 Spectmm of 16 ...... 323

E.20 1h ,13c Correlation Spectmm of 16 ...... 324

E.21 Long Range Semi-Selective DEPT of 16, Irradiation of H- 6a...... 325

E.22 Long Range Semi-Selective DEPT of 16, Irradiation of H-2a ...... 326

E.23 1 H,1 H COSY 90 Spectmm of 18 ...... 327

E.24 1 H,1 H COSY 90 Spectmm of 19 ...... 328

XIX LIST OF SCHEMES

Scheme EaOË.

1.1 Representative transformations of the allyl group ...... 3

1.2 The allylation and aldol methods for p-hydroxy aldehyde production ...... 4

1.3 Indium-mediated allylations ...... 5

1.4 Chan and Li's synthesis of the biologically important glycoside KDN (1) ...... 7

1.5 Indium-mediated allylation of acyloyl-imidazoles and pyrazoles ...... 10

1.6 BZ isomerization prior to the indium-mediated allylation of benzaldehyde ...... 11

1.7 Aqueous indium-mediated dianion chemistry ...... 12

1.8 Li’s Intramolecular annulation of a 5-membered ring...... 12

1.9 Li’s two carton intramolecular ring enlargement strategy ...... 13

1.10 Indium-mediated allylation of heteroatom-containing electrophiles ...... 14

1.11 Indium-mediated coupling of propargyl bromides to aldehydes in water ...... 14

1.12 Cyclopropanation of electron-deficient alkenes mediated by indium metal ...... 15

1.13 Indium-mediated allylation of trifluoroacetaldehyde ethyl hemiacetal ...... 17

1.14 InCla-transmetallation of non-racemic alkoxystannanes; allylation of aldehydes ...... 18

1.15 Approach to L-guiose utilizing InCIg-transmetallation of allylstannane (fl)-24 ...... 19

1.16 Approach to D-(-»-)-altrose utilizing aj-dioxygenated allylstannane (S)-29 ...... 20

2.1 Indium-mediated allylation of a-heterosubstituted aldehydes ...... 25

2.2 Indium-mediated allylation of aldehyde 10b with structurally rigid allyl bromide 16 30

2.3 1,4-Asymmetric addition in the indium-mediated allylation of benzaldehyde ...... 31

2.4 1,4-Asymmetric addition in the indium-mediated allylation of benzaldehyde ...... 32

XX 3.1 Nucleophilic additions to 6...... 38

3.2 Nucleophilic additions to 9 ...... 41

3.3 Synthesis of 2 -methoxy- 4 -fert-l3utylcyclohexanones 7 and 8 ...... 42

3.4 Nucleophilic additions to 7 ...... 44

3.5 Nucleophilic additions to 8 ...... 46

3.6 Synthesis of 2-spiro(tetrahydrofuranyl)cyclohexanones 10 and 11...... 49

3.7 Nucleophilic additions to 10 ...... 56

3.8 Nucleophilic additions to 11 ...... 59

4.1 Synthesis of 7 and 8, precursors to a-hydroxycyclohexanones 2 and ... 6 ...... 71

4.2 Parlter’s synthesis of cis 2,4-dialkoxycyclohexanones 11a-c...... 73

4.3 Parker's modest epimerization of cis 2,4-dialkoxycyclohexanones 11-b-c ...... 73

4.4 Alternative synthesis of 8 , the precursor to substrate 6...... 74

4.5 Stereoselective 1,2-reduction of 16 en route to trans hydroxy ketone 3...... 75

4.6 Futile attempt toward the synthesis of 3 ...... 76

4.7 Synthesis of 22, the precursor to frans-4-fed-txjtyl-2-hydoxycyciohexanone 3) ...... 77

4.8 Synthesis of tertiary alcohols 4 and 5 ...... 79

4.9 Indium-mediated allylation of 4-fe/t-butylcyclohexanone ...... 80

4.10 Indium-mediated allylation of 2-hydroxycyclohexanone (1) ...... 80

4.11 Indium-mediated allylation of a-hydroxycyclohexanone 2 ...... 82

4.12 Selective méthylation of 28 ...... 83

4.13 Indium-mediated allylation of a-hydroxycyclohexanone .6 ...... 84

4.14 Cumbersome deprotection of precursor 22 and indium-mediated allylation of 3 ...... 85

4.15 Selective méthylation of 31 ...... 86

4.16 Indium-mediated allylation of a-hydroxycyclohexanone .4 ...... 87

4.17 Indium-mediated allylation of a-hydroxycyclohexanone .5 ...... 89

4.18 Conversion of cis diol 36 to acetonide 37 ...... 91

xxi 5.1 Synthesis of cyclopentenones 1 and 2 ...... 101

5.2 Synthesis of 3 -hydroxycyclohexanones 3 and 4 ...... 102

5.3 Indium-mediated allylation of cyclopentenone 1 ...... 103

5.4 Indium-mediated allylation of p-hydroxycyclopentenone 2 ...... 104

5.5 Stmcture elucidation via estérification of 14 and hydrolysis of 12 and 13 ...... 105

5.6 Indium-mediated allylation of f/ans-4-fert-butyl-3-hydroxycyclohexanone (3) ...... 106

5.7 Indium-mediated allylation of c/s-4-ferf-butyl-3-hydroxycyclohexanone (4) ...... 108

5.8 Chemical conversion of cis 1,3-diaxial diol 17 to acetonide 18 and cartionate 19 . .109

6.1 Synthesis of 2-hydroxy-1-tetralones la and 1b ...... 115

6.2 Synthesis of the key intermediate 6-acetamidotetralin (4) ...... 116

6.3 Synthesis of 6-bromo-2-hydroxy-l-tetralone (lc)...... 116

6.4 Mechanism of the Moriarty a-hydroxylation protocol involving Phl(OAc )2...... 117

6.5 Second attempt to a-hydroxylate a 6-acetamidotetralone derivative ...... 118

6.6 Third attempt to a-hydroxlylate a 6-amido substituted tetralone...... 118

6.7 Circuitous approach to 2-hydroxy-6(/V-methy)acetamido-1 -tetralone (Id) ...... 119

6.8 Access to the pivotal 6-cyano-2-hydroxy-1-tetralone (le)...... 120

6.9 Indium-mediated allylation of 2-hydroxy-1-tetralone (la)...... 120

6.10 Conversion of cis and trans diols 16 and 17 to their respective cartx>nates...... 121

6.11 Indium-mediated allylation of 2-hydroxy-6-methoxy-1 -tetralone (1b) ...... 123

6.12 Conversion of cis and trans diols 20 and 21 to their respective cartwnates ...... 123

6.13 Indium-mediated allylation of 6-bromo-2-hydroxy-1-tetralone (1c)...... 125

6.14 Conversion of cis and trans diols 24 and 25 to their respective cartsonates ...... 125

6.15 Indium-mediated allylation of ^-methylacetamido substituted tetralone Id ...... 127

6.16 Conversion of cis and trans diols 28 and 29 to their respective cartx)nates ...... 127

6.17 Indium-mediated allylation of 6-cyano-2-hydroxy-i-tetralone (le)...... 129

6.18 Conversion of cis and trans diols 32 and 33 to their respective carbonates ...... 129

xxii LIST OF ABBREVIATIONS AND SYMBOLS

a alpha

[a] specific rotation app apparent (NMR)

Ac acetyl br broad (IR and NMR)

Bn benzyl

Bu butyl n-Bu normaAbutyl t-Bu tert-butyl

°C degrees Celsius

GDI 1,1 '-cartxjnyldiimidazole

COSY correlated spectroscopy calcd calculated c-CgHi 1 cyclohexyl

S chemical shift in parts per million, downfiled from tetramethylsilane d day(s); doublet (spectra)

DBU 1,8-diazabicyclo(5.4.0Iundec-7-ene

DEPT distortionless enhancement by polarization transfer

DIBAL-H diisobutylaluminum hydride

DMAP 4-(A/,/Vdimethylamino)pyridine

DMF A/, AAdimethylformamide

XXIII OMSO dimethylsulfoxide

B electron ionization

Et ethyl

EtOAc ethyl acetate

eq equivalent or equation

FAB fast atom t»mbardment

9 gram(s)

h hour(s)

Hz hertz

IBDA iodot>enzene diacetate

R infrared

imid imidazole

J coupling constant (NMR)

L liter(s)

LAN lithium aluminum hydride

LDA lithium diisopropylamide

M moles per liter

m milli; multiplet (NMR)

micro m-CPBA mefa-chloroperbenzoic acid m medium (IR)

Me methyl

MHz megahertz min minute(s) mol rrx)le(s) mp melting point

XXIV MPLC medium pressure liquid chromatography

Ms methanesulfonyl

MS mass spectrometry; molecular sieves nVz mass to charge ratio (MS)\

NBS ^romosuccinimide

NIS ^iodosuccinimide

NMR nuclear magnetic resonance

NOE nuclear Overhauser effect (NMR) obsd observed p para

PCC pyridinium chlorochormate

PE petroleum ether (30-60 °C)

Ph phenyl pth phthalimide ppm part per million (NMR)

Pr propyl

PPTS pyridinium-para-toluenesutfonate py pyridine q quartet (spectra) rt room temperature s singlet (NMR): strong (IR));second(s) t triplet (NMR)

TBAF tetra-n-butylammonium fluoride

TBAI tetra-n-butylammonium iodide

TBDMS terf-buty Id imethy Isily I

TfOH trifluoromethanesulfonic acid

XXV THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilyi

Ts toluenesulfonyl w weak (IR)

XXVI CHAPTER 1

INDIUM-MEDIATED ALLYLATIONS AND AQUEOUS CHEMISTRY

1.1. Background

Organoindium chemistry has recently become the subject of considerable research by

organic chemists.^ Traditionaliy. the element has been reserved to the inorganic and

organometallic fields.^ The initial report by Rieke in 1975 examined the potential of indium in

Reformatsky-type reactions.^ However, it was not until thirteen years later that the inclusion of

organoindium reagents in organic synthesis began to gain momentum. Butsugan noted indium's

superiority over other allylation protocols "in regard to its generality, high yields and mildness of

reaction conditions."^ Subsequent reports from his laboratory widened the scope of organoindium chemistry to include Barbier allylations of cartx>nyl compounds, Reformatsky-type

reactions, cyclopropanation of alkenes, and cartx)indation of alkynes. Others have also contributed to establishing the organoindium field; most notable are Chan and Li for the application of indium-mediated allylations in aqueous media and subsequently Paquette for probing the stereocontroi elements of such reactions with heterosubstituted aldehydes and cyclic ketones.

1.2. Properties of Indium Metal

Indium (In) (mp. 155 °G, atomic number 49, atomic weight 114.82) has valence states of 1,

2 and 3. The element has a soft white appearance with a slight blue tint. Being ductile and also malleable, the metal produces a high cry' when bent. Although indium is softer than lead, it is relatively non-toxic orally but is highly toxic intravenously. Elemental indium has been reported to

have an LD 50 of lOmg/kg for the hypodermic injection of mice.® It is commonly used as a thin film

in bearings and in dental alloys, and in semiconductor and transistor research. Stable in air, boiling

water, arxl alkali, indium forms mirrors but unlike silver does not readily corrode by forming oxides.

It appears to be effective in electron transfer chemistry, having a first ionization potential (5.79 eV) well below that of zinc (9.39 eV), magnesium (7.74 eV), copper (7.73 eV), tin (7.34 eV) and chromium (6.77 eV). The metal and its salts are commercially available. The metal costs between

$2.00 and $16.00 per gram depending on the quantity, purity and form desired; the salts are comparatHy priced. Although relatively expensive, the metal has the advantage of being readily recycled. Of further importance, elemental indium can be easily rejuvenated from its salts by conventional electrolysis with an aluminum cathode.®^

1.3. Aqueous Conditions: Advantages

With the increasing pressure on the chemical and pharmaceutical industries to reduce its hazardous waste stream has come the demand to develop environmentally benign technologies.^

This has been strengthened by President Clinton’s Green Chemistry Challenge sponsored by the

Environmental Protection Agency. Effective and efficient carbon-cartion bond forming reactions are the epitome of organic synthesis. Unfortunately, the majority of such transformations are extremely moisture sensitive and often employ anhydrous organic solvents (such as THF and DMF), organometallic reagents, and an inert atmosphere of Ar or N 2. Any procedure that would reduce such cumbersome protocols would be a welcomed addition to the synthetic and industrial chemist's arsenal. One attractive method to obtain these goals is to replace the traditional organic solvent with water. A number of reactions have been performed in aqueous environments, including Diels-Aider cycloadditions, Claisen rearrangements, Michael additions, cartxinylations, cartx)n couplings, and alkylations.’’ Where feasible, a water-based technology would have inherently explicit advantages, some of which are not the least bit trivial. These include; "Significant enhancem ent of operational safety in the work place.

•reduction of environmental pollution caused by solvent emission and waste disposal,

•lower process and disposal costs.

• reduced need to use an inert atmosphere and dry reagents and glassware.

•minimization of the need for protecting groups.

•possible attainability of increased stereoselectivity.

1.4. Allyl Group: Utility and Transformations

The allyl group is widely disseminated in organic chemistry and is often used as a key building block in the synthesis of natural and unnatural products.^ This method introduces a hydroxy group and an olefin, both of which are amenable to further chemistry. The resulting homoallylic alcohol can be further elaborated to 1,3- and 1,4-diols, substituted furans, lactones, p- hydroxy ketones, and p,y-epoxy alcohols (Scheme 1.1). The use of crotyl and substituted allyl halides has added complexity and functionalization to these homoallylic alcohols. Allylation followed by ozonolysis has proven to be a valuable alternative to the classical aldol condensation because of the availability of high stereocontroi in the initial coupling (Scheme 1.2). Numerous metals have been shown to mediate this reaction efficiently, metals from almost every group in the periodic table.®® Indium has become the latest metal to join this family and thus has generated much interest in the organic chemistry community.

/ \ X n

r 4 ^ ° Ü — R-O R’ R^R* FT^R'H R

Scheme 1.1: Representative transformations of the allyl group.

3 1 + métal Ri «2 Ra (allylation)

OH G

,K * R 3 ^ h (aldol)

Scheme 1.2: The allylation and aldol methods for p-hydroxy aldehyde production.

1.5. Organoindium Chemistry 1.5.1. indium Mediated Aliyiations

Butsugan established in his seminal report on this subject that allylic iodides and bromides are equally reactive. Allylic chlorides and phosphates are comparatively less reactive.^ Yet, allylic phosphates in the presence of an equimolar quantity of lithium iodide and with prolonged reaction times give moderate yields of the expected homoallylic alcohol. An indium sesquihalide (R 3ln2Xs) has been proposed as an intermediate where only two of the three R groups are said to be utilized in the reaction. Consequently, the reaction requires 1.5 equivalents of the organohalide (RX) because the third R group is not transferred. The stmcture of the air-sensitive sesquihalide intermediate derived from 1.5 equivalent of allylic iodide and 1.0 equivalent of indium metal was deduced through spectroscopic data and experimentation to be that depicted in Figure 1.1. However, it was found by employing the more expensive indium(I) iodide that the allylic halide is quantitatively consumed in the Barbier reaction.^ ° Other differences exist as well;

THF was found to be the choice solvent when employing indium(I) iodide, whereas metallic indium

.... ^CaHg I I ""^CaHs Inals

Figure 1.1: The proposed indium/allyl bromide intermediate. 4 OH 1) PhCHO ^ ^ In. DMF I (94%) 1 (anti/syn 66 : 34) OH 2) PhCHO _ —— ---- 2L_, 1 (anti/syn (77:23) 50:50)

O 3)

In. DMF f-Bu f-Bu (83:17)

4) xM L -C H O In. Lil. DMF, 15h (64%)

Scheme 1.3: Indium-mediated allylations.

was most efficient in DMF. Furthermore, the metal in contrast to its salt afforded greater y- regioselectivity (Scheme 1.3. compare equations 1 and 2). In comparison to eq 1. crotyl phosphate with an equimolar amount of Lil in DMF after 15 h afforded 1 as the sole product in

54% yield and with an anti/syn ratio of 58:42. In comparison to eq 2, crotyl iodide in the presence of indium(I) iodide proceeded at room temperature in 3 h with only minimal difference in yield and diastereoselectivity. However, regioselectivity was greatly compromised in that a 25:31 ratio of 1 and 2 was realized (compare eq. 2 and refer to Figure 1.2 for the requisite transition state diagrams). The major anti product arises from crotyl addition to the re face of the aldehyde; conversely, the syn isomer results from s/face attack as in Figures 8 and 0, respectively. Indium- mediated allylation of 4-ferf-butylcyclohexanone saw essentially the same facial selectivity under three different reaction conditions, allyldiphenylphosphate and Lil in DMF (62%), allyl iodide and Ini in THF (80%), and that depicted in equation 3. These results are in agreement with other

metal-mediated allylations employing the same cyclohexanone J ^ This facial selectivity will be

discussed in more detail in Chapter 4. Equation 4 shows the addition of methyl allyl phosphate to

octanal with Lil as an additive. The resulting homoallylic alcohol 3 was isolated after 15 h in 64%

yield. Comparatively, after 20 h treatment of the same aldehyde with allyl chloride under identical

reaction conditions, but without Lil, 1-undecen-4-ol was produced in only 10% yield.

Butsugan has shown that acid anhydrides can be allylated in DMF at rt. However, unless

the allylic bromide is 3,3 disubstituted (i.e. 4-bromo-2-methyl-2-butene), bisallylation occurs to

produce the ge/TMfiallyl lactone and not the monoallyl hydroxy e s te r.In tric a te studies on the

indium-sesquihalide intermediate were also performed by Butusgan.^^ The results showed that

exclusive y-protonation occurred with dilute HCI(aq), that oxygenation with O 2 gave varied

regioselectivity and moderate yields, and that indium can be replaced by tin v/atransmetallation

with rvBusSnCI, but with varying degrees of £/Z isomerization.

Perhaps the most dramatic contributions have come from Chan and Li. Their 1991 report

established that the indium-mediated allylation could effectively and efficiently be carried out in

aqueous media, a finding that has since caused a fen/or of activity in the chemical oommunity.^^

PA. h ' ^ M, H 2 O entry R metal (M) halide (X) time (h) yield, %

1 H In 1 3 97 2 H In Br 3 95 3 H In Cl 5 60 4 CH3 In Br 5 72 5 CH3 Zn Br 5 18® 6 CH3 Sn Br 3 Qb All reactions were stirred for the time indicated at room temperature and in water with a cartxsnyl/ailyl X/metal ratio of 1:1.5:1 ; * promoted by sonication, ° promoted at 80 "C.

Table 1.1 : Indium-promoted allylations in water.

6 Chan and others had previously illustrated that zinc and tin are particularly effective in aqueous

organometallic c h e m i s t r y in this seminal paper on aqueous indium chemistry the authors

detailed the improved nature of indium over tin and zinc with regard to higher yields, shorter

reaction times, and the needless use of promoters (heat, sonication, and acid catalysts) (Table

1.1). Allyl iodide and allyl bromide were equally reactive, and each afforded very good yields in

their coupling with benzaldehyde (compare entries 1 and 2). In DMF, allyl chloride saw little or no

reactivity, vkJe supra: yet in water the halide was moderately efficient (entry 3). Entries 4-6 clearly

illustrate the superiority of the allylindium reagent over allylstannane and allylzinc in the coupling

with acetophenone. Generally, less side products and a cleaner reaction mixture were obsenred with the indium-mediated reactions. Since then, Chan and Li have further expanded the scope of

aqueous indium chemistry collectively and individually.

Cart)ohydrate chemistry, where solubility can often be a difficult issue, has particularly benefited from this novel aqueous methodology. Chan and Li illustrated in the synthesis of the biologically important glycoside KDN, a member of the sialic acids, that aqueous indium chemistry is particularly effective on unprotected cart)ohydrates, in this case D-(+)-mannose (Scheme

1.4).^® Shortly thereafter, Whitesides et. al. disseminated their results on unprotected cartx)hydrates noting that "[i]ndium-mediated reactions produce fewer byproducts and are more

OH OH OH OMe OMe D-(+)-mannose In, H2O OH OH (62%)

I.O3 . -7 8 °C;Na 2 S0 3 HO#..: 2. HCI(aq), MeOH 3. KOH, MeOH O H ^ CO2H (79% for three steps) 5 (KDN)

Schem e 1.4: Chan and Li's synthesis of the biologically important glycoside KDN ( 1). 7 diastereoselective than the corresponding tin-mediated reactions."^ ^ Their methodology study

culminated in the synthesis of the critically important glycoside NeuSAc. another member of the

sialic acids. The entire reaction sequence paralleled the aforementioned synthesis of KDN by

Chan and Li. The initial step, which involved the coupling of N-acetyl-p-O-mannosamine and ethyl-

a-(bromomethyl)acrylate in a mixture of EtOH and 0.1 N HCI(aq) (6:1 v/v) at 40 °C, afforded a 90%

yield of the expected enoates in a threo/erythro ratio of 4:1 The selectivity results from a

chelate-controlled transition state via chelation with the a-hydroxy group and addition to the si

face of the aldehyde as depicted in A. Schmid (a former student of Whitesides) and coworkers

have also applied this novel methodology to the allylation of unprotected D-pentoses^^ and the

synthesis of 2-deoxy and 2,6 dideoxyhexopyranosides^^. Another important development from the Schmid laix)ratory is that indium can be easily rejuvenated from its salts by conventional electrolysis employing an aluminum cathode.®^

Chan and Isaac performed the first detailed studies on the regio- and stereoselective coupling of aldehydes and y-substituted allyl bromides (Table 1.2).^^ From this study, the authors have t>een able to formulate a working model for the indium-mediated allylation of acyclic carbonyl compounds. The initial indium-couple I is in equilibrium with its regioisomer II, as well as its BZ stereoisomer III, thereby affording the requisite transition states B-E, and eventually the isomeric homoallylic alcohols shown (Figure 1.2). The regioselectivity of the allylation is strongly governed by the size of Ri of the allylic bromide (compare entries 1-4). Whereas anti stereo­ chemistry predominates (via B) in most cases, the initial double bond stereochemistry is irrelevant liecause of thermodynamic equilibration of the allylic indium reagent prior to allylation. In such instances, the major product has the anti stereochemistry (entries 3 and 4). Furthermore, the regiochemistry is not dictated by conjugation with the y-substitutent (entries 3-5). Where y- regioselectivity predominates to afford an anti/syn mixture, the proportion of the anti isomer increases with increasing size (sterics) of the R 2 group of the aldehyde (entries 3,6-7). In the example where Ri=Me and R 2=Ph, a 92% yield was recorded but with an anti/syn ratio of 50/50. entry allylic bromide aldehyde ______product yield, %

1 (CH3)3C ^ " ^ ^ B r APr-CHO (CH3)sC 87 {BZ 80 :20) OH

2 (CH3)3S r Br APr-CHO (CH3)aSr 62 {BZ 75 : 25) OH Ph 3 B r ^ ^ ^ P h APr-CHO 88 (anti/syn 96 :4)

OH Ph T APr-CHO 79 (anti/syn 90 :10) OH MeOzC 88 (anti/syn 72 : 28)

6 B r ^ ^ ''< ^ P h CgHii-CHO 75 (anti/syn 90 :10)

7 B r^ '^ ^ ^ P h n-CsHirCHO n-CsHiy 80 (anti/syn 69 :31)

Table 1.2: Regie- and stereoselective coupling of aldehydes and y-substituted allyl bromides. Ri

Br ^ R i^ In In + In I ^ " III L IL _= ligandK^^r\M ^

R i% 6 ) "in. + R i'ïio -ln . H H R, A, B

OH OH

R2^ V ^ R2^ \ ^ " Ri Ri anti syn

Figure 1.2: Proposed transition states forttie indium-mediated allylation of akjetiydes and acyclic ketones.

In one of Ctian's most recent publications tie describes ttie efficient allylation of acyl-

imidazoles and pyrazoles to form predominately tertiary alcotiols (via bisallylation) and p.y-

unsaturated ketones (via monoallylation), respectively (Sctieme 1.5).''® Forttie pyrazoles (X=N,

Y=CH2), it was proposed ttiat ttie second nitrogen chelates with the allylindium reagent to stabilize intermediate F allowing the reaction to proceed to completion before the homoallylic alcotiol is

O O OH

Ph"^N"^Y HgO. 0 °C ’ Ph^'Y^).

X=CH2.Y=N (95%) (6:94) X=N.Y=CH2 (90%) (75:25)

Scheme 1.5: Indium-mediated allylation of acyloyl-imidazoles and pyrazoles.

10 produced. The reactions were highly regioselective and the yields ranged from good to very

good.

Loh reported that La(OTf )3 increases the rate and diastereoselectivity of the addition of

the allylindium reagent to aldehydes (Scheme 1.6).^°^ He again illustrated that the anti isomer

predominates irrespective of the stereochemistry of the starting allylic bromide, as a result of

double bond isomerization. In this example, the (2)-y-bromocrotonate actually gave a higher

anti/syn ratio. Greater diastereocontrol was also obsen/ed in the indium-mediated allylation of

sugar derivatives in the presence of Yb( 0 Tf)3 in a DMF-H2O solvent system .^^

In, La(0 Tf)3, PhCHO + ‘Br H2O COaEt Ri=H, R2=C0 2 Et, (£) (99%) anti/syn (90 :10) Ri=C02Et, R2=H, (2) (90%) {99 :^)

Scheme 1.6: BZ Isomerization prior to the indium-mediated allylation of benzaldehyde.

Li has exploited this novel methodology in the realm of dianion chemistry (Scheme 1.7). It was found that 2-bromomethyl-3-bromo-1 -propene ( 6) coupled efficiently with two equivalents of benzaldehyde in the presence of indium powder to afford 8 in 75% yield and as a 1:1 mixture of diastereomers (eq 1).^^ However limitations do exist. As illustrated in eq 2, the reaction with the dianion equivalent 1,3-dibromopropene (7) was considerably more complicated.^ A total of four products was obtained, two resulting from dialkylation (9 and 10) and two from reduction of the monoallylated product (1 1 and 12) (eq 2). The 1,3-diol product 9 (54%) along with 8 % of the 1,5- diol product 10 were obtained as a result of dialkylation using two equivalents of benzaldehyde.

Additionally, reduction also occurred before the second alkylation step could occur, resulting in the isolation of 7% of diene 11 and 22% of carbinol 12. The characterization of such reduction products has been previously discussed by the author with reference to aqueous organozinc chemistry. 11 HO II OH jj In. 1) P h ' H MeOH/HCI P ®=©A© (75%) 8 O II in. . OH OH 2)

" ' ' ' ,% A " ' 9 (54%) HO

11 (7%) 12 (22%)

Scheme 1.7: Aqueous indium-mediated dianion chemistry.

ingeniously. Li has utilized this novel methodology for an intramolecular annulation of a 5- cartx)n ring system ^ as well as a ring enlargement strategy to create medium to large ring systems intramoleculariy24. Addition of 2-chloromethyl-3-chloro-1-propene to the sodium enolate of p* ketoester 13 affords intermediate 14 (Scheme 1.8). Treatment of this allyl chloride intermediate with indium powder in 0.1 N HCI(aq) produced the [4.3.0] ring system 15 as a single undefined diastereomer in an overall yield of 64%. Note, this dichloro-dianion equivalent was unreactive intermoleculariy, vide supra (Scheme 1.7). In another report cyclooctanone 16 was reacted with

Indium powder under aqueous conditions to produce 17 as a mixture of diastereomers (Scheme

1.9). Treatment of this mixture with DBU in THF isomerized the double bond into conjugation with

O O OEt I.NaH, DMF HO. Cl In. O.INHCI(aq) 2. c J L c , (98%) (65%) OEt 13 14 15

Schem e 1.8: Li's intramolecular annulation of a 5-membered ring.

12 DBU., COaMe MeOH/HCI THF (50% for COaMe MO steps) COaMe 16 17 18

Schem e 1.9: Li’s two cartx>n intramolecular ring enlargement strategy.

the ketone to afford cyclodecanone 18 in an overall yield of 50%. Similarly 7-, 8 -, 9-, and 14-

memtiered cyclic ketones were efficiently constructed. Application to natural products synthesis

was said to t)e in progress.

Even nitrogen-containing electrophilies are reactive to the allylindium reagent (Scheme

1.10). Umani-Ronchi examined a n u n tero f metals (and metal salts) in the mediated allylation of

imines derived from (S)-valine methyl esters under anhydrous conditions.^ Under a bimetal

redox system consisting of AI (1.5 eq) and InCIs (0.1 eq) in THF, 19 responds to allyl bromide with

the greatest activity in comparison to other metal salts such as PbBr 2, TiCU, BiClg and SnCl 2 (eq

1). The rationale for the high diastereoselectivity arises from a chelate-controlled transition state.

In model G, the isopropyl group blocks the s/face of the imine affording a 87:13 anti/syn ratio, favoring the 1,3-^nti amine 20. Following a study on aldimines,26a Mosset showed that indium

mediates the addition of allyl bromide and ethyl bromoacetate (Reformatsky-type reaction) to enamines and that the alkyl group is introduced a to the nitrogen (eq 2) .26b Classically, electrophilies react at the p position. It was shown that reactivity is mostly governed by the nitrogen substituent and that anhydrous THF at rt is the most suitable solvent. No reaction occurred in CHgCN, CCI 4, or aqueous THF; complex reaction mixtures resulted in CH2CI2 and

CHCI3. The reactions seemed quite precarious overall; the yields fluctuated between quantitative

(as determined by NMR) and 5% (purportedly because of purification problems).

13 P h ^ N, x COaMe (InCIs). THF P h ^ N ^ C O g M e 19 (79%) 20 (87:13)

2) Ov/< - Ov^B I I Br or I R=CH=CH2 (63%) Et'^Et Br^COaMe B ^E t R=COaMe (26%)

Scheme 1.10: Indium-mediated allylation of heteroatom-containing electrophilies.

Although not truly not an allylation reaction, indium also mediates the coupling of

substituted propargyl bromides and aldehydes in water (Scheme 1.11).^^ The product

distribution is highly dependent on the nature of the substituent on the propargyl bromide 21.

Silanes (21b), phenyl, and methyl substituents favor the allene product 22, whereas 21a favors

alkyne 23. The nature of the R group on the aldehyde appears to play a lesser role. The major

product 22b can uniquely be transformed into the minor product 22a via desilylation using KF in

DMF.

O Br. OH

Y

R = 1-napthyl 21a.Y=H (50%) ____ 22a' 3 -*-j ' KF. 23a (10:90) b, Y=SiMeaPh (70%) b —I DMF b (80:20)

Scheme 1.11: Indium-mediated coupling of propargyl bromides to aldehydes in water.

1.5.2. Reformatsky*Type Reactions

A variant of the allylation protocol, yet a reaction in its own right, is the Reformatsky reaction. Remember that Rieke and Chao performed this reaction with indium in 1975.3 Whereas the allylation protocol obviously involves an allylic halide, the Reformatsky-type reaction requires

14 a-halo esters and the resulting products are 0-hydroxy esters (Scheme 1.10, eq 2). Thus, the

indium-mediated Reformatsky reaction has also received considerable attention, as originally

delineated by Butsugan.^SAldehydes and ketones are equally efficient, although sterics and

electronics factors can diminish (or increase) the reaction's efficiency. Similarly, elemental irxfium

and indium(I) iodide can t>oth be employed in this reaction.^ ° The reaction times were shown to

be comparatively longer than analogous allylation procedures. Schick has further shown that the

reaction proceeds quite well under electrochemical conditions using an indium rod as a sacrificial

anode and a nickel net as the cathode.^ Tetrabutylammonum bromide was added as an

electrolyte to a solution of DMF/THF in an undivided cell.

1.5.3. Cyclopropanation of Alkenes

Indium metal also promotes the cyclopropanation of electron-deficient alkenes with active

methylene dibromides in DMF at rt in the presence of Lil (Scheme 1.12).^° No reaction occurs in

THF or Et2 0 and without Lil the yields are considerably diminished. The substituent on the

alkene plays the major role. Whereas methyl vinyl ketone gave high yields, cyclohexene and butyl

vinyl ether were completely unreactive. Still though, the activating groups on the methylene

dibromide can have a small effect on the yield.

E E,E'=CN (94%) CH2=CHC0 Me p ( E.CN, E-COîE! (88 %) MeOC E,E»C0 2 Et (75%)

Scheme 1.12: Cyclopropanation of electron-deficient alkenes mediated by indium metal.

1.5.4. Carboindation of Alkynes

Butsugan also established indium as an effective metal for promoting the cartx)indation of alkynols (Table 1.3).31 The reactions are normally performed at 100-140 °C in DMF. Only terminal alkynes are reactive and a proximal hydroxyl group is necessary. Neither 2-butyn-l-ol, propargyl

15 methyl ether, nor 4-perrtyn-l-ol were reactive toward prenylindium (entries 1-3). Whereas the

indium sesquibromide reacts selectively at the ycarbon, the regioselectivity for the alkyne is less

and highly dependent on the substitution pattern (compare entries 2 and 3). The carboindation is

entry alkyne allylic halide conditions product(s) yield, %

1 HO. DMF, A + 'V s f / k x - Br II n = 1 (65 : 35) 91 n = 2 (73 : 27) 85

2 Ph' ‘Br DMF, A (14:86) 56

Ph' Br DMF, A

(90 :10) 68

80

Br rt p ho 86

6 n-Bu—= Br THF, rt 86

OH 83 ' p-MeOP^ THF,. p-MeOP

OMe OMe THF, rt 90 p-MeOPi p-MeOPI

Table 1.3: Indium-mediated allylation (carboindation) of alkynes.

16 a syn process resulting in E stereochemistry for the non-Markownikov products. However, it was

shown just last year that by simply switching solvents from DMF to THF that coupling between

allylindium and substituted alkynes was successful atroom temperature.^ Although, the alkynols

in this study afforded the expected non-Markownikov products, the respective ethers afforded

the Markownikov products in greater than 95% yield (compare entries 4 and 5, and 7 and 8 ).

Acetylenic ethers and unfuctionalized alkynes in THF were reactive and afforded good yields of

the cartxjindation product (entries 5-6 and 8 ). Analogous reaction were unsuccessful in DMF at

high temperatures

Indium(in) chloride has recently been effectively used in organic chemistry most notably

by Loh, and by Marshall and Hinkle. Loh illustrated that 20 mol% of InClg is effective in promoting the Mukaiyama aldol reaction in water at room temperature.^^ The addition of acetophenone and cycbhexanone silyl enol ether to various aldehydes proceeded in excellent yields. The reaction conditions are very mild, almost neutral. It was even stated that the aqueous phase containing the metal salt could be reused without any deleterious results, most particularly regarding the yield.

The water soluble aldehydes glyoxylic acid and formaldehyde proved especially fruitful. Loh also reported that indium efficiently mediates the allylation of commercially available trifluoroacetaldehyde ethyl hemiacetal in water (Scheme 1 .1 3 ).^ Two methods were compared and contrasted; Sn alone was ineffective in promoting the addition. The advantage of using the

Sn/lnCl3 method is that tin is much less expensive than indium, and only 1.0 equivalent of the allylic halide is required. Premixing of the Sn, metal salt and allylic bromide is essential. This

OH - OH

FaC-^OEt PQÔ " *^30

method diastereoselectivity yield, % In 65 :35 80 SnCIa 6 7 :3 3 72

Scheme 1.13: Indium-mediated allylation of trifluoroacetaldehyde ethyl hemiacetal. 17 methodology has also been applied to the allylation of aldehydes in moderate yields and

cartx)hydrates in very good yields.^ Although the relative stereochemistry was not confirmed, it

is suspected that anti predominates as in Scheme 1.3 and Table 1.2.

Marshall and Hinkle further exploited the versatility of InClg by transmetallating

allylstannanes under anhydrous conditions. It is not the purpose of this chapter to reiterate an

excellent review on this subject that has been published recently by Marshall. This review also

serves as an excellent introduction to Chapter 2. However, a brief description of this

methodology will be discussed.

Transmetallation of the non-racemic a-oxygenated crotylstannanes 24 with InCIs

produced two diastereomeric allylindium species (E,S)-25 and {Z,R^-2S as a result of an Se2’

pathway (Scheme 1.14).^ The major intermediate (E,S)-25 leads to the anti 1,2-diol 26 via a

chairlike transition state. The diastereoselectivity was very good, and either acetonitrile or

acetone was an appropriate solvent. In subsequent work, EtOAc has been used. This method is

in stark contrast to the Lewis acid-promoted allylstannlylation which selectively produces the syn

Sn(n-Bu)s InCIs InCIs OMOM OMOM

(E,S)-25 (fl)-24 (Z,fl)-25

RCHO RCHO

OMOM

R anti/syn yield, % c-CgHi f = 98 :2 88 ® OMOM 96 :4 88 *’ (£)-n-BuCH=CH 84 :16 76® (£)-n-BuCH=CH 83 :17 87^ OMOM ' solvent: acetone; ^ solvent: acetonrtrile OMOM anti-26 syn-26

Scheme 1.14: InCls-transmetallation of non-racemic alkoxystannanes; allylation of aldehydes. 18 adduct through an acyclic transition state. These two methods complement one another and

allow access to anti or syn diols from a common alkoxystannane precursor. Marshall has creatively

applied this methodology in a bi-directional strategy to the Annonaceous acetogenins.^

In his application to the synthesis of rare and unnatural cartx)hydrates, Marshall employed

non-racemic a-oxygenated aldehydes and non-racemic allylic stannanes such as (/7}-24^^ in

Scheme 1.15 and 2936b jp Scheme 1.16. a-Oxygenated aldehyde 27 does not undergo a

chelate-controlled pairing with allylic stannane (A)-24 via (E, S)-25 as illustrated in Scheme 1.14.

Unlike free hydroxy groups (Scheme 1.4, Figure A), it has been shown that OBn and OSiRa

groups are resilient to chelation with the allylindium reagent. This phenomenon will be discussed

in more detail in Chapter 2. Allyl stannanes are incompatible with free hydroxy groups and

demand an anhydrous environment. Although chelate-controlled transition state H accurately

predicts the resulting stereochemistry in the InClg-mediated addition of allylstannane (R)-24 to

aldehyde 27 to afford the anti, syn product 28, the analogous transition state for the coupling of

the enantiomeric reagent (S)-24 and aldehyde 27 incorrectly predicts the syn, syn product.

Since the anti, anti adduct overwhelmingly predominates, a non-chelate chairlike transition state

{i.e. I) is most likely operative in these instances. This further implies that diastereoselection is

reagent-controlled and that the allylindium species is not influenced by the chiral center of the aldehyde, thus reflecting an early transition state. In support of these conclusions, racemic indium

H Æ r c w : - (95 %) MOMÔ ( OBn 27 28 syn

OMOM Me L

L I

Schem e 1.15: Approach to L-gulose utilizing InCla-transmetallation of allylstannane (R)-24. 19 reagent (R/Si-25 was reacted with aldehyde 27 and afforded a mixture of the anti, syn product

28 and the anti, anti diastereomer in a 1:1 ratio resulting from the (A) and (S) absolute

configurations of the reagent. In such reactions, it is proper to expect matched and mismatched

combinations, yet obviously these arguments are mute since diastereocontrol rests mainly with

the reagent and not with both coupling partners. Notably, 28 has the configuration of L-gulose,

requiring ozonolysis of the olefin and deprotection of the hydroxyl groups to complete the

synthesis of the sugar. Scheme 1.16 details the approach to D-(+)-altrose that utilizes a,y- dioxygenated allylstannane 29. Like aldehyde 27 (for L-gulose), reagent (S)-29 incorporates four of the needed six oxygens for the synthesis of D-altrose. Where the olefin of 28 is ultimately ozonolyzed, the olefin of 30 is subject to dihydroxylation.

OMOM ^ J ^ O T B D P S OMOM TBSO> ‘Sn(n-Bu)3 inCIa, EtOAc (S)-29 2) TBSOTf, r OTBS 2 ,6-lutidine (anti/syn 90 :1 0) 30 (82% for two steps)

TBSO OMOM 1) OSO4. NMO TBSO 2) TBSOTf. OTBDPS D-(+)-alt rose 2,6-lutidine TBSO OTBS (97%) 31

Scheme 1.16: Approach to D-(+)-a!trose utilizing a.y-dioxygenated allylstannane (S)-29.

20 LIST OF REFERENCES AND NOTES

(1) (a) Marshall, J. A. Chemtracts-Organic Chemistry 1997, 10,481. (b) Paquette, L. A. In Green

Chemistry: Fontiers in Benign Chemical Synthesis and Processing; Anastas, P.; Williamson, T.,

Eds., Oxford University Press: Oxford 1998, in press, (c) Li, C.-J. Tetrahedron, 1996, 52, 5643.

(d) Cintas, P. Synlett, 1995,1087. (e) Lubineau, A.; Jacques, A.; Queneau, Y. Synthesis 199â,

741. (f) Li, C.-J. Chem. Rev. 1993, 9 3 ,2023. (g) Li, C.-J.; Chan, T.H. Organic Reactions in

Aqueous Media, John Wiley and Sons, Inc.: New York, 1997.

(2) For an introduction to organoindium compounds see, (a) Sullivan, A. C. In Dictionary of

Organometallic Compounds, Chapman and Hall: London, 1995, Vol. 2, p. 1975. (b) Tuck, D. G. In

Comprehensive Organometallic Chemistry, Wilkinson, G.; Stone, F. G. A.; Abel, E. W„ Eds.,

Pergamon: Oxford, 1982, Vol. 1, p. 683. (c) Paver, M. A.; Russel, C. A.; Wright, D. S. In

Comprehensive Organometallic Chemistry II. Abel, E. W.; Stone, F. G. A.; Wilkinson, G., Eds.,

Pergamon: Oxford, 1996, Vol. 1, p. 503.

(3) Chao, L.-C.; Rieke, R. D. J. Org. Chem. 1975, 40, 2253.

(4) Araki, S.; Ito, H.; Butsugan, Y.J. Org. Chem. 1988, 5 3 , 1831.

(5) Horiguchi, S.; Teramoto. K.; Nakaseto, H.; Wakitani, F. Sumitomo Sangyo E/se/1987, 23,

120.

(6) (a) Prenner, R. H.; Binder, W. H.; Schmid, W. Liebigs Ann. Chem. 1994, 73. (b) Binder, W. H.;

Prenner, R. H.; Schmid, W. Tetrahedron 1994, 50, 749.

(7) (a) Anastas, P. T.; Farris, C. T. In Benign by Design: Alternative Synthetic Design for Pollution

Prevention, American Chemical Society: Washington D. C., 1994. (b) Anastas, P.T.; Williamson,

I .e . In Green Chemistry: Design for the Environment, American Chemical Society: Washington

21 D.C., 1996.

(8 ) Breslow, R. Acc. Chem. Res. 1991,24,159.

(9) (a) Yamamoto, V.; Asao, N. Chem. Rev. 1993,93,2207. (b) Roush, W. R. In Comprehensive

Organic Synthesis: Heathcock, C., Ed.; Perganrwn Press: New York, 1991 ; Vol. 2, Ch. 1, pp 1-54.

(10) Araki, S.; Ito, H.; Katsumura, N.; Butsugan, Y.J. Organomet. Chem. 1989, 3 69,291.

(11) (a) Aluminum, maganesium, lithium, potassium and sodium: Gaudemar, M.Tetrahedron.

1976, 3 2 ,1689. (b) Chromium: Hiyama, T.; Okude, Y.; Kimura, K.; Nozaki, H.Bull. Chem Soc.

Jpn. 1982, 55,561. (c) Tin: Naruta, Y.; Ushida, S.; Maruyama, K. Chem. Lett. 1979,919. (d)

Indium: Reetz, M. T.; Haning, H. J. Organomet. Chem. 1997, 5 41, 117. (e) Indium: see

references 4 and 9. (f) Zinc: Wilson, S. R.; Guazzaroni, M. E. J. Org. Chem. 1989, 54, 3087.

(12) Araki. S.; Katsumura, N.; Ito, H.; Butsugan, Y.Tetrahedron Lett. 1989, 3 0 ,1581.

(13) Araki, S.; Shimizu, T.; Johar, P. S.; Jin, S.-J.; Butsugan, Y. J. Org. Chem. 1991, 5 6 , 2538.

(14) Li, C.-J.; Chan, T.-H. Tetrahedron Lett. 1991, 32, 7017.

(15) (a) Chan, T.-H.; Li, C.-J. Organometaiiics 1990, 9, 2649, and references cited therein, (b) Li,

C.-J.; Chan, T.-H. Organometaiiics 1991,10. 2548, and references cited therein.

(16) (a) Chan, T.-H.; Li. C.-J. J. Chem. Soc., Chem. Commun. 1992, 747. (b) Chan, T.-H.; Lee,

M.-C. J. Org. Chem. 1995, 60, 4228.

(17) Kim, E.; Gordon, D. M.; Schmid, W.; Whitsides, G. M. J. Org. Chem. 1993, 58, 5500. (b)

Gordon, D. M.; Whitsides, G. M. J. Org. Chem. 1993, 58, 7937.

(18) Isaac, M. B.; Chan, T.-H. Tetrahedron Lett. 1995, 36, 8957.

(19) Bryan, V. J.; Chan, T.-H. Tetrahedron Lett. 1997, 38, 6493.

(20) (a) Diana, S.-C. H.; Sim, K.-Y.; Loh, T.-P. S/n/eff 1996, 263. (b) Wang, R.; Lim, C.-M.; Tan,

C. H.; Lim, B. K.; Sim, K.-Y.; Loh, T.-P. Tetrahedron Asymmetry 1995, 6 , 1825.

(21) Li, C.-J. Tetrahedron Lett. 1995, 36. 517.

(22) Li, C.-J. Tetrahedron Lett. 1996, 37, 295.

(23) Li, C.-J. Tetrahedron Lett. 1996, 37, 471.

22 (24) U. C.-J. J. Am. Chem. Soc. 1996, 118, 4216.

(25) Basile, T.; Bocoum, A.; Savoia, D.; Umani-Ronchi, A. J. Org. Chem. 1994, 59, 7766.

(26) (a) Beuchet, P.; Le Marrec, N.; Mosset, P. Tetrahedron Lett. 1992, 3 3 ,5959. (b) Bossard,

P.; Oambrin, V.; Lintanf, V.; Beuchet, P.; Mosset, P. Tetrahedron Lett. 1995, 36, 6055.

(27) Isaac, M. B.; Chan, T.-H. J. Chem. Soc., Chem. Commun. 1995, 1003.

(28) Araki, S.; Ito, H.; Butsugan, Y. Synth. Commun. 1988, 18, 453.

(29) Schick, H.; Ludwig, R.; Schwarz, K.-H.; Kleiner, K.; Kunath, A. J. Org. Chem. 1994, 59,

3161.

(30) Araki, S.; Butsugan, Y.J. Chem. Soc., Chem. Commun. 1989,1286.

(31) (a) Araki, S.; Imai, A.; Shimizu, K.; Butsugan, Y.Tetrahedron Lett. 1992, 33, 2581. (b) Araki,

S.: Imai, A.; Shimizu, K.; Yamada, M.; Mori, A.; Butsugan, Y. J. Org. Chem. 1995, 6 0 1841.

(32) Ranu, B. C.; Majee, A. J. Chem. Soc., Chem. Commun. 1997,1225.

(33) (a) Loh, T.-P., Pei, J.; Cao, G.-Q. J. Chem. Soc., Chem. Commun. 1996,1819. Mukiyama has described the use of InCls'CISiMeg in organic solvent to promote the aldol reaction;

Mukaiyama, T.; Ohno, T.; Han, J.-S.; Kobayashi, S. Chem. Lett. 1991, 949. (b) Loh, T.-P.; Li, X.

R. J. Chem. Soc., Chem. Commun. 1996,1929. (c) Loh, T.-P.; Li, X.-R. Tetrahedron Asymmetry

1996, 7, 1535.

(34) Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1995, 60, 1920.

(35) (a) Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1996, 6 1 . 4247. (b) Marshall. J. A.; Hinkle, K.

W. J. Org. Chem. 1997, 62, 5989.

(36) (a) Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1996, 6 1 , 105. (b) Marshall, J. A.; Garofalo, A.

W. J. Org. Chem. 1996, 61, 8732.

23 CHAPTER 2

CONTRIBUTIONS FROM THE PAQUETTE LABORATORY

In Chan’s seminal paper regarding aqueous organoindium chemistry, he demonstrated that free hydroxy groups participate in chelation-control to afford predominately the syn diastereomer, as accurately predicted by the Gram-chelate rrxxfel (A) (Figure 2.1, equation 1).i

Conversely, protected hydroxy groups (i.e. ethers) lead favorably to the anti product as predicted by the Felkin-Ahn model (B) (eq 2). In this model the indium reagent approaches the cartx)nyl at the Bürgi-Dunitz angle (approx. 107°), so as to minimize torsional strain, and opposite the polar non-chelating group which is oriented perpendicular to the carbonyl in order to maximize the overlap of 7t*c-o and o*c-X during the hybridization change from sp2 to sp^. a-Hydroxy aldehyde

1 (R=H) affords the syn diol 2 with a syn/anti ratio of 67:33 (Scheme 2.1). Application of the benzyl ether derivative (R=DCB) reversed the diastereoselectivity in favor of 3 (7624).

YI HI I aiijioiiv/Mallylation reagent DCBO ODCB H ODCB O CHa

Figure 2.1: Cram-chelate and Felkin-Ahn models A and B. 24 R syn/anti yield, % H 6 7 :3 3 85 DCS 2 4 :7 6 75

Scheme 2.1: Indium-mediated allylation of a-heterosubstituted aldehydes.

Paquette and Mitzel have further expanded the subject of acyclic stereocontrol by

examining a number of a- and ^-oxygenated aldehydes (Tables 2.1 and 2.2).^ Whereas aldehyde

4a gave the largest anti ratio irrespective of the employed solvent (entries 1-3).^ The free

hydroxyl derivative 4d exceeded these numisers in water and 50% THF(aq) two and a half times,

but in favor of syn isomer 5d (entries 11 and 12). No reaction occurred in anhydrous THF.

Clearly, the above models are operative as the Cram-chelate model is a good predictor of diastereoselectivity. One equivalent of B^NBr in water had a dramatic effect on the diastereoselectivity, increasing the proportion of syn isomer 5c from 2.1:1 to 8.3:1, LiBr and

MgCl 2 were unresponsive (compare entries 7 and 8 ). The perception is that the salt compresses the chelate-controlled transition state, thereby increasing the reaction rate and the diastereoselectivity. The competition experiment between 4c and 4d produced an average rate difference of 11.1:1 in favor of the hydroxy aldehyde. This fact strongly supports the notion of a favorable chelate-controlled transition state. In this pivotal study, it was clearly established that coordination of the indium reagent and substrate is strong enough to override the detrimental solvation forces that would otherwise discourage chelation in an aqueous environment. The g- oxygenated aldehydes were not so dramatic, and considerable parity was observed in the syn

/anti ratios (Table 2.2).2b The ratios resulting from 7a and 7b were essentially level (entries 1-6).

However, it is quite apparent that the hydroxy group of 7d, and to a lesser degree the methoxy

25 OR OR Br, In. c-CgHi 1 c-CgHii C-CgHi solvent, rt OH OH 4a-d 5a-d 6 a*d

entry R solvent svn/anti ratio view, % 1 a, TBDMS HgO 1 :3.9 90 2 50% THF(aq) 1 :4.2 87 3 THF 1 :4.0 92 4 b. Bn H2O 1 : 1.2 92 5 50% THF(aq) 1 : 2.2 93 6 THF 1 :3.9 87 7 C, MOM H2O 2.1 :1 83 8 H20 /Et4NBr 8 3 :1 — 9 50% THF(aq) 1.7 :1 85 10 THF 1 6 :1 80 11 d,H H2O 9 8 :1 87 12 50% THF(aq) 95:1 87 13 THF no reaction —

Table 2.1 : Indium-mediated allylation of a-oxygenated aldehydes.

RO O Br, In, 7a-d solvent, rt B ad 9a-d

entry R solvent syn/anti ratio yield. % 1 a. TBDMS HgO 1 :1 84 2 50% THF(aq) 1 2 : 1 83 3 THF 1.7:1 77 4 b. Bn H2O 1 :1 80 5 50% THF(aq) 1 :1 84 6 THF 1 :1 72 7 C , CH3 H2O 1 :4 78 8 50% THF(aq) 1 :4 78 9 THF 1 :3.3 69 10 d, H H2O 1 :8.5 77 11 50%THF(aq) 1 : 8.2 74 12 THF no reaction ------

Table 2.2: Indium-mediated allylation of p-oxygenated aldehydes.

26 substitutent of 7c, can effectively support cfieiate-controiied addition of tfie allyl indium reagent,

as evidenced by the emergence of anti isomer 9 (entries 7-11 ). Figure 2.2 illustrates the chelate

model proposed for the allylation of 7d to produce selectively the anti isomer 9b. The level of

anti isomer 9d observed with the p-hydroxy aldehyde almost approaches that observed with the

a-hydroxy counterpart 4d. In Chapter 3, it is demonstrated that substituted a-

methoxycyclohexanones afford a high level of chelate control in all three solvent systems, and

notably are superior to the traditional anhydrous reagents in yield, application, and

diastereoselectivity.

" (anti)

Figure 2.2: Chelate-controlled addition of allylindium to 7d selectively producing 9d.

After this study Paquette and Mitzel compared the diastereoselectivity of crotylindium

(11c) and 3-bromoaliylindium (lid) additions to a-oxygenated aldehydes 10a b (Table 2.3).^

Such coupling partners have the ability to selectively form three contiguous chiral centers via double diastereoselection; four isomers are possible (12-15).'* In the coupling of 10a with 11c the prevalence of syn addition over anti is consistent with a chelate-controlled mode of attack

(Figure 2.3, C and D) thereby favoring the syn diastereomers 12ac and 13ac (where Ri=H and

R2=CH3) in a combined syn/anti ratio of 5.6:1 (entry 1). This is an excellent illustration of allylindium reacting through the lower energy chelate-controlled transition state to afford preferentially the syn diastereomer. The relative stereochemistry of the newly formed carbinol and allyl substitutent (R2) is determined by the propensity of BZisomerization of the allylindium reagent. The transoid form C gives rise to syn stereochemistry whereas the cisoid form D

27 R^O RiO ^2 RiO Rg In^ + HgC + O H2O. rt OH OH 10a Ri=H l i e R2=CH3 12 13 b Ri=TBDMS d R 2*Br {syn, syn) (anti, syn)

R1O Rg

+ H3C OH OH 14 15 (anti, anti) (syn, anti)

12 13 14 15 entry Ri R2 (syn, syn) (anti, syn) (anti, anti) (syn, anti) yield, % 1 H CH3 2.8 2.8 1 — 79 2 TBDMS CH3 0.5 0.5 3 — 91 3 H Br 1 1 0.5 0.5 80 4 TBDMS Br 0.5 0.5 4.5 4.5 88 ^Due to separation problems the yield and diastereoselctivity was determined after hydrogenation (H2 . 5%Pd/C) of the olefin.

Table 2.3: Indium-mediated addition of y-substituted allyl bromides llc-d to a-oxygenated aldehydes lOa-b.

gives rise to an anti relationship. Overall, the parity in the occurrence of 12 and 13 indicates facile

equilibration (entries 1-4). With specific regards to crotylindium (11c), the lack of appearance of

the syn, anti isomer 15c (R 2=CH3) is best explained by the steric repulsion observed in

comparing transition states E (chelate-control with 10a) and F (Felkin-Ahn with 10b). Chelate-

controlled addition of the transoid crotyl reagent to afford syn, anti 15ac is strongly disfavored

because of sterics (F). Instead 10a reacts with 11c via a chelate-controlled transition state with the crotylindium reagent adapting the cisoid form (H) to produce exclusively the anti, anti isomer

14bc. Conversely, 11c would need to adopt the cisoid form in coupling with 10b to form syn, anti isomer 15bc via model E, but it obviousiy reacts solely through its transoid geometry G producing the anti, anti isomer 14bc. In this latter model, the crotyl group attacks anti to the polar

TBDMS substitutent as described above in Figure 2.1, eq 2. Evaluation of 1,3-dibromopropene 28 OH R2

H3C OH 12b (syn, syn)

HO R2

H3C OH 13b (anti, syn)

R1O ÇH3

'^]

CH3-Üï

Figure 2.3: Chelation control and Felkin-Ahn transition states for the addition of y-substituted allyl bromides llc-d to a-oxygenated aldehydes lOa-b.

(lid ) addition to aldehyde 10a resulted in considerable reduction of syn addition (or an increase in anti addition) to a mild syn/anti ratio of 2:1 (compare entries 3 and 1). This diminished selectivity is not necessarily a result of the ineffective chelating ability of the hydroxy group but instead resides in the reagent and the comparatively less sterically demanding bromine atom. Therefore the pathways E and F (where R 2=Br), affording anti, anti 14d and syn, anti 15d are more accessible. Continuing, the reaction of 10b with l i d leads to the highest preponderance of anti addition recorded, with a syn/anti ratio of 13 (compare entry 3, and entry 1 of Table 2 .1). This high diastereoselectivity is based solely on steric arguments and the lack of chelating ability of 29 TBDMS. Note that the diastereoselectivity remained virtually unchanged when the reactions were

performed in 50% THF(aq) and THF. Also included in this study was the benzyl substituted

aldehyde (Ri=Bn); the resulting facial selectivity was halfway between that observed with 10a

and 10b.

In a related article. Paquette and Isaac recorded very impressive ratio in the coupling of allyl bromide 16 with aldehyde 10b (Scheme 2.2) The syn, anti diastereomer 18 was favored over the syn, syn diastereomer 17 by a ratio in excess of 97:3, respectively; the other two diastereomers were not observed. The rationale for this selectivity results from the combination of a very sterically encumbered aldehyde and an allyl txomide that is resistant to E'Z isomerization.

Recall transition state F in Figure 2.3 where steric interaction is minimized by rotating the CH 3 group (of the aldehyde) counterclockwise 120°. Syn/anti 18 would arise from addition to the other face of the aldehyde. So here is a case where polar substitutents alone do not control facial selectivity.

TRHMcjn TBDMSO CH3 TBDMSO

CO2 CH3 Z v /=<"" - V t - c h 3 , ■ o H3C 16 CHgBr, OH " 10b In, HgO, (1 17 ( 3 : 97 ) (75%) (syn. syn) (syn.anti)

Schem e 2.2: Indium-mediated allylation of aldehydelOb with structurally rigid allyl bromide 16.

Paquette et. al. examined the ability of indium to effectively control 1,4 asymmetric induction.^ To this end, the authors examined 11 substituted allyl bromides and 3 aldehydes

(Scheme 2.3). In the end, the authors concluded that indium does not enhance the proportion of the syn isomer through chelation with a proximal hydroxyl group, although there is proposed chelation to the carbonyl via six-membered transition states I and J (Figure 2.4). The reason given is that an internal 5-atom chelate may be disfavored thermodynamically. Through competitive studies it was found that chelation does occur in the formation of the allylindium 30 RO RO RO .Ph PhOHO. ^ ^ P h + In, HgO, rt H ^" V ( DH OH 19a R=TBDMS 20a-b20a-b 2la-b b R=H (syn) (syn) (anti) R syn/anti yield, % TBS 8 9 : 11 64 H 5 4 :4 6 70

Scheme 2.3:1,4-asymmetnc addition in the indium-mediated allylation of benzaldehyde.

20a b , 2la-b (syn) H3&-/ o r T" (an^i) H L

Figure 2.4: Transition states depicting the 1,4 asymmetric induction observed with allyl bromides 19a-b.

reagent with allylic alcohol 19b, but once the aldehyde enters the coordination sphere of the reagent chelation with the resident hydroxyl group is disrupted. The high diastereoselectivity observed with 19a is argued solely on steric considerations where OTBDMS is considerably larger than CH 3 and H. With 19b, diastereoselectivity is minimized as a result of reduced sterics.

In this example, OH is considerably less demanding than OTBDMS and comparable in size to the flanking CH3 (compare I and J). By employing the one-cartxjn ho mo logs of 19a-b it was shown that chelate-control operates more favorably (Scheme 2.4).® Competition studies with equimolar mixtures of 22a and 22b in water with benzaldehyde and indium ( 1.0 eq of each) resulted in the total consumption of 22b. There was no evidence of 23a and/or 24a by ^H NMR analysis of the cmde reaction mixture. Therefore, when free hydroxy groups (i.e. 22b and methoxy groups,

R=CH3) are utilized, then chelation tsetween the indium atom and the hydroxyl group needs to be considered as in transition states K and L (Figure 2.5). The disparity between transition states J and L is not clear and certainly more work needs to be performed to resolve this quandary. 31 RO^ RO^R O ^ R0>

^ _ PhCHO, ^ X ^ .P h H3C _ __ _ In, H2O, rt OH OH 22a R=TBDMS 23a-b 24a-b b R=H (syn) (syn) (anti) R syn/anti yield, % TBS 63 :3 7 63 H 2 5 :7 5 54

Scheme 2.4: 1,4-Asymmetric addition in the indium-mediated allylation of benzaldehyde.

23a-b ____ ^ 24a-b (syn) HaC-yl (="^') " I7 S

Figure 2.5: Transition states depicting the 1,4 asymmetric induction found with allyl bromides 22a b

In related work, Paquette et. al. examined sulfur and nitrogen heterosubstituted acyclic

aldehydes of the type 10 in the indium-mediated coupling with allyl bromide in water.^ It was

shown that an a-methytthio had virtually no diastereoselective capabilities, producing a 1:1

mixture of the syn and anti diastereomers. However the a-phenylthio acted much like the

OTBDMS group affording predominately the anti isomer in a syn/anti ratio of 1:4 when performed

in water. In this latter example, the choice of solvent had only a minor effect on the recorded

diastereoselectivity. It was thus judiciously concluded that the indium reagent is not thiophilic.

Competition studies with equimolar quantities of OTBDMS and OSPh substituted aldehydes

resulted in a relative rate approaching 1:1. With nitrogen as the a-hetero substitutent, considerable chelate control was realized. Whereas the a-dibenzylamino substitutent showed no preference for chelation-control because of sterics (affording the anti isomer with a syn/anti ratio of

1:3.3), dimethylamino showed an amazing propensity for chelation to afford the syn isomer 32 exclusively. Note that none of the anti isomer was detectable by ^ H NMR analysis of the crude reaction mixture. Furthermore the dimethylamino derivative was 2.4 times more reactive than the dibenzylamino derivative in competition studies.

33 LIST OF REFERENCES AND NOTES

(1) Li, C.-J.; Chan. T.-H. Tetrahedron Lett. 1991, 32. 7017.

(2) (a) Paquette, L. A.; Mitzel, T. M. Tetrahedron Lett. 1995, 36, 6863. (b) Paquette, L. A.;

Mitzel, T. M. J. Am. Chem. Soc. 1996, 118,1931.

(4) Paquette, L. A.; Mitzel, T. M. J. Org. Chem. 1996, 61, 8799.

(3) This stereotriad designation (i.e. syn, syn) reflects for the first assignment the addition of the y-

substituted allyl bromide to the cartwnyl and for the second the relationship of the newly formed

carbinol to the resident a-substitutent.

(4) Isaac, M. B.; Paquette, L. A. J. Org. Chem. 1997, 62, 5333.

(5) Paquette, L. A.; Bennett, G. D.; Chhatriwalla, A.; Isaac, M. B. J. Org. Chem. 1997, 6 2 , 3370.

(6) (a) Bennet, G. D. Ph. D. Dissertation, The Ohio State University, 1997. (b) Paquette, L. A.;

Bennett, G. Isaac, M. B.; Chhatriwalla, A. submitted.

(7) Paquette, L. A.; Mitzel, T. M.; Isaac, M. B.; Crasto, C. F.; Schemer, W. W. J. Org. Chem. 1997,

62, 4293.

34 CHAPTER 3I

a*HETEROSUBSTITUTED CYCLOHEXANONES

3.1. Background

The capture by conformâtionally rigid cyclohexanones of sterically unhindered nucleophiles preferentially from the axial direction has been extensively documented.^ The central importance of this phenomenon to our understanding of rc-facial selectivity has resulted in the proposal of several mechanistic models. Dauben's early explanation in terms of product development control and Felkin's original suggestion of torsional strain^ have more recently been joined by theoretically-based treatments. Klein's analysis in terms of the unsymmetrical distribution of ic orbitals,^ Cieplak's concept of Iransition-state stabilization by electron donation into the vacant

orbital associated with the incipient bond,"® and the frontier orbital analyses offered by Houk and Paddon-Row .7 Reetz,® Dannenberg,® Coxon,^® and Boyd^"' attest to the challenging nature of the problem. Ab initio calculations have also appeared.

The impact of a neighboring polar substituent on the control of diastereofacial stereoselection has commanded considerable attention."'®® With a-alkoxy cyclohexanones,

Grignard reagents add with chelation-controlled selectivity (see 1) to give 2 predominantly.^®^

TiCI^-promoted additions proceed via equatorial attack under conditions where the intervention of a chelate complex has been established.^'*® Although RTi(OAPr)g reagents are incapable of chelation, the R group is again delivered preferably to the face opposite to that occupied by the alkoxy group (see 3)."''^^ In fact, bonding from the axial surface can be reliably achieved only by prior formation of a complex between the ketone and the bulky methylaluminum bis(2,6-di-ferf-

35 butyl-4-methylphenoxide) (MAD) reagent.''^ under these circumstances, the MAD so sterically

encumbers the less congested side of the cartwnyl cartxin (see 4) that nucleophllic attack

proceeds as shown to provide 5 (Figure 3.1).

lOH R’ R"

I H H 3

R'-M gBr R'

OH

H

Figure 3.1 : Chelate-controlled addition to a-oxygenated cyclohexanones.

Although an a-chloro substituent can be expected to exhibit diminished chelating ability

relative to alkoxy, stereoselectivity can apparently be achieved under the proper circumstances.

A dramatic example has t>een uncovered in the tetraphenylstibonium bromide-promoted addition

of tin enoiates to six-ring a-chloro ketones. The resulting chlorohydrins are formed exclusively in

that manner in which the 01 and OH groups are cis-disposed.''®

As a consequence of the need to utilize organometaiiics or moisture-sensitive Lewis acids

in the condensations discussed above, all of these many reactions have been routinely

conducted in the strict absence of water. In recent years, the intriguing observation has been

made that indium is capable of promoting addition reactions to cartjonyl compounds in water as the reaction medium.'^*^® Given that essentially no information is available on the stereochemical

response of cyclohexanones in general to metal-based reagents in aqueous environments, we

set out to undertake an indepth study in which C-alkylation and related condensations were

36 accomplished by a variety of methods including aqueous indium protocols. The systems

examined here include 2-methoxycyclohexanone ( 6), its conformationally rigidified 4-fe/t-butyl

homologues 7 and 8 , and the three 2-(spirotetrahydrofuranyl) substituted examples 9-11

(Figure 3.2).

O ,0CH3

6

O

9 10 11

Figure 3.2: Investigation of a-oxygenated cyclohexanones 6-11.

3.2. Results

3.2.1. 2-Methoxycyclohexanone ( 6 ) and 1-Oxasplro[4.5]decan-6-one (9)

The conformational equilibrium defined by 6 was initially reported by Robinson in 1974 to

be heavily dominated by the axial form regardless of solvent (Figure 3.3).^® Subsequent

refinements by NMR showed 6a to be favored (63%) in CCI 4, but appreciably disfavored (20%)

in a more polar solvent.^ This widely disseminated finding,believed to be in conformity with decreased hyperconjugative^ and dipole-dipole interactions^® as well as reduced a (^ 3) strain,24 has recently been further reevaluated at 500 MHz.2® The percent of 6a was found in this setting to range from 57 (in CeDia) to 16 (CD 3CN). The important conclusion that can be drawn from these studies is that the energy barrier between 6a and 6e is sufficiently low that the involvement of 6e in chelation control should not be energetically impeded. 37 ÇH3 PO

I H 6e Sa

Figure 3.3: Conformational dynamics of 2-methoxycyclohexanone ( 6).

Treatment of 6 with allylmagnesium chloride in THF at 0 °C afforded 12 and 13 (Scheme

3.1 ) in a ratio of 2.3:1 (Table 3.1, entry 1 ).^ Equatorial attack was similarly favored when recourse

was made to the organocerate^^ and allylchromium reagents^^ (entries 2 and 3). The proportion

of the less polar axial alcohol was greatest in the CrCl 2-promoted example. This distribution was

closely approximated when recourse was made to the Normant reagent CIMgO(CH 2)3MgCI (entry

4).29 The diols 14 and 15, produced in a 1.5:1 ratio, were altematively available by hydroboration

of 12 and 13^6 and were identified in this manner.

+

13

THF or HgO 1. BHa'MeaS, THF 2 . NaOH, H2O2 6

OH OH .HO., +

15

Scheme 3.1: Nucleophilic additions to 6 .

38 Coupling of 6 to allyl bromide in the presence of indium resulted in a significantly

heightened increase in the level of 12 irrespective of the solvent employed (entries 5-8). The

best selectivity (14.1:1) was obsenred in 1:1 THF-H 2O, and the yields were maximized when the

reaction medium was purely water. Product composition was modestly affected when the

allylirxtium reagent was preformed in refluxing THF (entry 8) prior to addition of the ketone

(compare entry 5).

chelate/non- entry reagent solvent (T. ®C) chelate ratio yield, % For 6: 1 CH2=CHCH2MgCI THF.O 2.3 :1 94 2 CH2=CHCH2MgCI. CeCIa THF.O 4.5 :1 82 3 CH2=CHCH2Br. CrCl2 THF.O 1.2:1 78 4 GIMgO(CH 2)3MgCI THF.O 1.5 ;1 86 5 CH2=CHGH2Br, In THF. 25 9 .0 :1 84 6 GH2=GHGH2Br, In THF-H20(1:1).25 14.1 :1 93 7 GH2=GHGH2Br. In H2O. 25 12.5:1 96 8 GH2=GHGH2Br, In THF. 25* 12.2:1 83

For 9: 9 GH2=GHGH2MgGI THF.O 1.2 :1 88 10 GH2=GHGH2MgGI. GeGla THF.O 1 :2.4 96 11 GH2=GHGH2Br. GrGl2 THF.O 1 :2.6 90 12 GIMgO(GH 2)3MgGI THF.O 1 :8.8 76 13 GH2=GHGH2Br. In THF. 25 5.6:1 82 14 GH2=GHGH2Br, In THF-H2O (1:1). 25 3.9 :1 96 15 GH2=GHGH2Br. In H2O. 25 2.7:1 81 16 GH2=GHGH2Br. In THF, 25* 3.4 :1 72

' All experiments were conducted minimally in duplicate and the reported data represent the average of these experiments. ^ The allyl bromide and indium powder were refluxed in THF for 1 h and cooled to 25 "C before the ketone was added.

Table 3.1 : Facial selectivity in nucleophilic additions to 6 and 9.=

39 A change in the nature of the polar sulistrtuent to a spirocyciic tetrahydrofuran ring

introduces several conformationally countertialandng influences. The geminal disubstitution

requires that the oxygen atom and a methylene carbon be concomitantly projected axially and

equatorially. For 16, the 0-axial isomer has been shown to predominate (ca 68 %) in CSg solution

at 35%) (Figure 3.4).3° This AG“ 3oa of 0.46 kcal/mol favoring 16a has been attributed to the

reduction in syn-axial compression that materializes when the oxygen atom is projected axially.

Although the conformational properties of 9^^ have not been comparably scrutinized, it would

appear logical to assume that the extent to which 9a is populated is significantly greater than 6a.

In light of the fact that the A values for ethyl and methoxyl are 1 .8 and 0.6 kcal/mol, respectively,

simple additivity does not appear to be applicable. This may be because other structural

deformations are also operative. In any event, it should prove more difficult to entice 9 to adopt

the 0 -equatorial conformation relative to 6 , thereby diminishing the attractiveness of metal

chelation.

16e 16a

9e 9a

Figure 3.4: Conformational dynamics of 2-(spirotetrahydrofuranyl)cyclohexanone (9).

The experimental results appear to support this hypothesis. Thus, when the same battery of experiments was applied to 9 (Scheme 3.2), the level of diastereoselection in favor of the cis isomers (17 and 19) was noticeably more normalized (entries 9-16). Although the indium-

40 promoted couplings generally exhibited heightened chelate/rwn-chelate behavior as before, the

more favorable distribution was rx)w encountered in THF (entry 13) and not in aqueous THF (entry

14). Quite unexpected was the discovery that the Normant reagent was notably effective in

eliciting a very respectable (8.8:1) non-chelate-controlled response from 9 (entry 12). Due to the

conformational flexibility of products 17-20, unambiguous assignment of relative

stereochemistry was accomplished by hydroborative interconversion. Diol 19 has previously

been transformed into the Cg symmetric dispiro heterocycle by dehydrative cyclization.^i

HQ

17

9

OH OH HQ, HO.

19 20

Scheme 3.2: Nucleophilic additions to 9

3.2.2. The Conformationally Disparate 2-Methoxy-4-fe/t-butylcyclohexanones 7 and 8

Significant reduction in the conformational mobility of both 6 and 9 was viewed as an invaluable tool for gaining insight into the stereochemical course of the reactions described above. The classical tactic of incorporating a 4-ferf-butyl substituent onto the cyclohexanone ring was adopted. The preparation of 7 and 8 began by conversion of 21 into the silyl enol ether 22

41 OTMS (f-Pr)2NLi. (CeHslO)^. MeaSiCI. BF3-OEÎ2. THF. -78 »C T (2 equiv), MeOH

...OCH3

7

Scheme 3.3: Synthesis of 2-methoxy-4-/eft-butylcyciohexanones 7 and 8 .

(Scheme 3.3). Subsequent oxidation of this intermediate with iodosobenzene in cold (-70 °C)

methanol containing two equivalents of boron trifluoride etherate led directly to 7 and 8 in 60%

yiekJ.32.33 more dominant equatorial isomer 7 (3:1), which was readily separated from 8 by

chromatography on silica gel, provided the highest face selectivity obsenred in this study (entries

17-24, Table 3.2). In all experiments, 23 or 25 proved to be so dominant in the reaction mixtures

(>97:3) that the products of axial attack were not observed upon NMR analysis (Scheme 3.4).

Only in the CeCls-promoted coupiing was 24 formed to a detectable level that permitted its

characterization (Table 3.2).

DEPT experiments^^ were particularly useful in defining the stereochemical features of 23

and 24. This technique takes advantage of heteronuclear three-bond coupling, with the degree

of signal enhancement achieved by pulsing a selected hydrogen frequency and observing a

nucleus being maximized when the dihedral angle relationships are at 0° or 180°. As for carbinol

23, models show the dihedral angle between H-2a and C-7 to be approximately 60° (see A), and the same angle for 24 to be significantly widened to about 180° (see B) (Figure 3.5). Only in the

latter instance was C-7 measurably coupled to H-2a. The methoxyl carbon was seen to exhibit an

enhanced signal in tx>th products, the result of heteronuclear coupling through the oxygen atom. 42 OH B 24

Figure 3.5: Conformational analysis and Newman projections of 23 and 24.

Addition of tfie Normant reagent to 7 proved to be a fiigfily stereocontrolled process as well, giving rise to 25 in 96% yield (entry 20). Since fiydroboration-oxidation of 23 also led to 25. its stereocfiemical assignment was considered secure. Cyclization of 25 by initial regioselective tosylation of its primary fiydroxyl followed by intramolecular Sn 2 displacement^^ provided tfie spirotetrafiydrofuran 27.

Tfie conformational inflexibility of 7 virtually guarantees tfiat tfie metfioxyl oxygen is projected equatorially (Figure 3.6). Tfiis advantageous situation so orients tfie nonbonded electron pairs tfiat a cooperatively matcfied arrangement exists. Tfie stereoisomeric nature of 8 positions tfie metfioxyl substituent axially wfien in tfie cfiair form (Scfi), tfiereby discounting tfie possibility of cfielation control. However, wfiereas 7 is certain to be conformationally rigid, 8 is likely to be only conformationally biased toward 8 c li.^ Tfius, its metfioxyl group need not be confined to an axial disposition by virtue of equilibration with the twist conformer 8 tw. In this geometry, the ethereal oxygen is projected pseudoequatorially and now resides in close proximity to the cartxmyl group. In simple cyclohexanes, tfie twist form is somewhat more than 5 kcal/mol less stable than the chair. For the parent cyclohexanone, the twist form is only 2.7

43 kcal/mol above the c h a i r , a value considerably lower because the ring happens to be flattened

at the cartMnyl cartx>n and the opposite end.^^>^ The difference in AG° between Belt and 8 tw is

very likely of even lesser magnitude because the steric interaction of the axial methoxyl in 8 ch is

relieved when proceeding to the twist geometry.

HQ

THF or H2O 7

OH OH HQ

25 26

TsCI, EtaN, □MAP (cat), CH2CI2

27

Schem e 3.4: Nucleophilic additions to 7

44 chelate/non- entry reagent solvent (T, “C) chelate ratio yield. % For 7: 17 CH2=CHCH2MgCI THF.O >97:3 77 18 CH2=CHCH2MgCI. CeClg THF.O > 97:3 78 19 CH2=CHCH2Br, CrCl2 THF.O 9 :1 72 20 CIMgO(CH 2)3MgCI THF.O > 97:3 98 21 CH2=CHCH2Br, In THF, 25 > 9 7 :3 78 22 CH2=CHCH2Br, In THF-H2O (1:1), 25 >97:3 82 23 CH2=CHCH2Br, In H2O. 25 > 97:3 80 24 CH2=CHCH2Br, In THF. 25'’ > 97:3 80

For 8: 25 CH2=CHCH2MgCI THF.O 1 :1.9 81 26 CH2=CHCH2MgCI, CeClg THF.O 1 :1 90 27 CH2=CHCH2Br, CrCl2 THF.O 13.2 :1 55 26 CIMgO(CH 2)3MgCI THF.O 1.3:1 90 29 CH2=CHCH2Br, In THF. 25 13.1 :1 88 30 CH2=CHCH2Br, In THF-H20(1:1).25 9.5:1 74 31 CH2=CHCH2Br, In H2O. 25 6.3 :1 83 32 CH2=CHCH2Br, In THF. 25'’ 9.4 :1 84

^ All experiments were conducted minimally in duplicate and the reported data represent the average of these experiments. ^ The allyl bromide and indium powder were refluxed in THF for 1 h and cooled to 25 “C before the ketone was a d d ^ .

Table 3.2: Facial selectivity in nucleophilic additions to 7 and 8.®

With the exception of the allylmagnesium chloride and allylcerium examples (entries 25 and

26), the ability of 8 to engage in chelate-controlled metal-mediated allylation reactions is very respectable (entries 27-32). The stereoselectivity of the 1,2-addition process when indium is involved proved to be consistently very good. The change in solvent from THF to H 2O modestly erodes the proportion of 28 formed (Scheme 3.5). This phenomenon has previously been obsen/ed with 9. The emergence of the allylchromium addition as a highly stereocont rolled process merits comment. When a-alkoxy aldehydes are involved,^® crotylchromium reagents have been shown to attack with a high level of anti selectivity. Thus, the chelation-controlled 45 response of 7 and 8 is not entirely unexpected, aittiough the phenomenon is rwt observed in all

of the examples studied in this investigation.

ÇH3

7

H Sch Btw

Figure 3.6: Conformational analysis of 7 and 8 .

HO.

THF or 28 H2O 8 1. BHa'MegS, THF 2. NaOH, H 2 O2

OH OH HO. CH3O.

30 31

Scheme 3.5: Nucleophilic additions to 8

46 We had originally hoped to apply to 28 and 29 the same DEPT analysis that proved so

successful earlier. The Karplus angle between H-2e and C-7 in 28 can reasonably be expected

to be close to 60° (see C), while that in 29 should be significantly smaller because of unfavorable

1,3-diaxlal interactions involving the allyl substituent and likely hydrogen bonding of the hydroxyl

to the metfioxyl oxygen (see D) (Figure 3.7). However, in neither case was heteronuclear

coupling observed between H-2e and C-7. This may simply be a reflection of the fact that

equatorial/equatorial and axial/equatorial couplings are significantly smaller than those of the

axial/axial type, with the result that the associated signals are of much lower intensity.

OH OH

OCH3 CH aa, p 29 H

Figure 3.7: Conformational analysis and Newman projections of 28 and 29.

Alternatively, ^H,‘'H COSY 90 experiments performed on 29 in CgDe solution confirmed H-

6a to reside at 61.69, its downfield location stemming from deshielding contributions arising from

the nearby methoxyl oxygen. Irradiation of H- 6a ^ under DEPT conditions caused C-7 to exhibit a

strong signal in the cartron subspectrum. Further confirmation of the axial orientation of the allyl group was derived from an NOE study in which 10% integral enhancements were seen for H-3a and H-5a when H-7/H-7 were irradiated. In 29, the H-7 protons appear at 5 2.28 as a narrowly split

(Ap = 15.8, Jab = 14.3 Hz) component of an ABX pattern. In contrast, H-7 and H-7 in 28 are

47 much more widely spaced (5 2.40 and 2.16) since the magnetic environment of one of them is significantly perturtsed by the proximal methoxy group.

Reaction of 8 with the Normant reagent provided a 1.3:1 mixture of 30 and 31 in 90% yield

(entry 28). The structural features of these 1,4-diols were established as before by the hydroiMration-oxidation of 28. The resulting 30 proved identical in all respects to the major constituent obtained earlier.

3.2.3. Evaluation of the Haptophlllc Properties of the Tetrahydrofuran Ring in

10 and 11

When chelation operates, nucleophilic attack by the organometallic reagent is skewed toward addition from the equatorial surface of the cartsonyl as a consequence of the haptophilic influence of the neighboring ether oxygen. An interesting relevant question inquires whether the coordinating capability of methoxyl oxygen is superior to or less than that of the tetrahydrofuran ring oxygen. Also, is the trend comparable for different metals? A quick glance at the experimental data for 6 and 9 (Table 3.1 ) might lead one to conclude in favor of methoxyl.

However, the differing conformational dynamics of this pair of a-oxygenated cydohexanones, as pointed out earlier, could bias the experimental observations. For this reason, the selectivities observed for the 7/10 and 8/11 pairs could prove informative. Although subtle differences in

H 7 10

6

llc h lltw

Figure 3.8: Conformational analysis of 10 and 11. 48 the conformational predisposition of these systems are evident, an analysis of the extent of

haptophilic control was considered to be necessary and worthwhile (Figure 3.8).

The route selected for the preparation of 10 and 11 is outlined in Scheme 3.6. The

conversion of 21 to 32 was quickly determined to be problematic because of competitive

formation of the dibenzylidene derivative under conventional aldol condensation conditions.^^^

In order to curtail the formation of this product, the aldol reaction mixture was treated with

methanesulfonyl chloride five seconds after introduction of the benzaldehyde.^^^ The

subsequent addition of tnethylamine was followed either by a reflux period of 1 h or overnight

2. MsCI HC(0 Me)3, 3. EtaN, A T (TsOH)

21 32

n o . o Ph O3. py. 1. CIMgO'''"'-^MgCI, MeOH, CH2CI2: THF, 0 X Me2S 2. TsCI, EtaN. DMAP, CH2CI2 33

O ^ O n MCI, H2O acetone A

36

Scheme 3.6: Synthesis of 2-spiro(tetrahydrofuranyl)cyclohexanones 10 and 11.

49 stirring at room temperature. Product purification was most easily achieved after ketalization.

Once this step had been performed, 33 was obtained in 50% overall yield by direct crystallization

from 95% ethanol. Ozonolysis of 33 resulted in oxidative cleavage of the double bond to give 34

(91%). Implementation of Normant technology at this stage gave rise in 84% yield to a 4.5:1

mixture of diois. The fact that axial attack had predominated was made clear following

monotosylation of the two diols and intramolecular 8 ^ 2 cyclization of these functionalized

intermediates to furnish 35 and 36. For convenience, separation of the diastereomers was

deferred until after deketalization with concentrated HCI in hot aqueous acetone.

With pure samples of cydohexanones 10 and 11 in hand, it was initially assumed that they

might be distinguished on the basis of standard NOE measurements. Analysis was highlighted by

the fact that the major diastereomer displayed four protons between 5 4.2-1. 8 , while the minor

constituent exhibited five protons between 5 3.8 and 2.1 at 300 MHz. For added corroboration,

^H,^H COSY 90 studies were carried out on both compounds. As seen in Figure 3.9, H-9 and H-

9' in 10 appear at appredably lower field than the remaining protons, with H-9 residing well into the deshielding cone of the ketone cartxsnyl. This identification allowed H -8 and

H-8 ', and subsequently H-7 and H-7 to be uncovered. Three of these protons appear as multiplets in the heavily overlapped 5 1.63-1.43 region, while H- 8 ' is centered at 81.38. As expected, H- 6e is characterized by one large geminal and two small vicinal couplings. The proximity of H- 6e and H- 6a to H-5e and H-5a provided key information relative to their location in the spectrum. Clearly indicated was the fact that the signal for H-5e was overlapped with those of

H-7/H-7 and H- 8 . Also, H-5a is sufficiently shielded that it constitutes the ring proton to highest field. The methine proton H-4 could not be traced from H-5a or H-5e. However, because H-5e shows strong W-plan coupling to H-3e and the latter is demonstrably coupled to H-4 and H-3a, the remaining protons were easily located. The principal adoption of a chair-like conformation is supported by the existence of a diagnostic W-coupling between H-3e and H-5e.

50 Full assignment to 11 could be made In an entirely analogous way (Figure 3.10).

Additionally, the significant deshielding experienced by H-4 and H-6a as a consequence of their

1,3-diaxial relationship to the tetrahydrofuranyl oxygen is striking. As seen with 10, the normal

sequencing in rigid six-membered rings is for equatorial protons to appear downfield of their axial

counterparts. This phenomenon is also reflected in the chemical shifts of H-5e/H-5a and H-3e/H-

3a in 11.

With the stereochemistry of 10 and 11 established, the Normant reagent deployed In their

synthesis was seen to exhibit a kinetic preference for equatorial attack (Figure 3.11). A logical

rationalization of this finding would be to involve intramolecular delivery from the equatorial

oxygen of the acetal as in E. The preferred intervention of E is believed to reflect the usual steric

advantages associated with chelation to the less encumbered oxygen atom.

^.....oMgCI

OMgCI

Figure 3.9: Chelate-controlled addition of the Normant reagent to 34.

The two diastereomeric allylation products of 10 proved to be conveniently amenable to chromatographic separation. The less polar diastereomer (Rf 0.35), when subjected to

COSY 90 and NOE experiments, was confirmed to be 37 (see F) (Figure 3.12). Comparable analysis of the more polar homoallylic alcohol (Rf 0.18) was consistent with its fomiulation as 38

(see G). With the unequivocal identification of H-6a, semi-selective long-range DEPT studies established its trans relationship to C-10 {^J).

51 9 O' JlA .

H * m , ,v

JÜ.I III ^ . i S . # -, m ea BH # .4Mli # # Ü1 liai! :R:

U 0 - ^

MA Ml m . ■ 'Y''1 KS? UK ■ iis

I ' I • I • I ' I '— I ' I ■' I— ' I »“ 'r * ? * I * I , —I ", " I » I » T ' I 4.» ) # S.l * 4 >.t }.• I.l l.l l.f l.l M l.l 1.4 1,1 M ,1 .1

Figure 3.10: 300 MHz ’H.^H COSY 90 specirum of 10 In CeDe solution. ■ a i l 5 a 5 en (0 1)88

!Bli

}.I ).7!7 I. t. l.l I. 4 I. I I I

Figure 3.11: 300 MHz COSY 90 spectrum of 11 In CgDg solution. 1.2%

HO

OH 6.4% 0.8%

Ha

Figure 3.12: NOE difference data for 37 and 38.

The polarity distinction defined atx>ve is very pervasive and, in our view, can serve as a very reliable indicator of stereochemistry in this series. We have noted that those cyclohexanols which preferentially adopt an axial hydroxyl are invariably less polar than their equatorial counterparts

(Table 3.3). This is t>elieved to be a reflection of the inability of the sterically more crowded axial

OH to bind as tightly to the adsorbent. Interestingly, a polarity reversal has been noted once the sam e oxygen becomes incorporated into a tetrahydrofuran ring and a second ether functionality resides on an adjacent cartxm. We speculate that this effect may originate from the greater dipole moments present in those molecules that feature at least one axial C-O bond. Beyond that, the stereochemical projection of the second ether oxygen appears to be inconsequential.

As shown in Table 3.4, the substitution of an equatorial methoxyl by a spiro tetrahydrofuran ring has extensive consequences on re-facial stereoselectivity (Scheme 3.7). While the allyl

Grignard reagent attacks from both possible directions with approximately equal facility (entry 33), the cerate and chromium reagents exhibit an almost 2-fold preference for axial attack (entries 34 and 35). The Normant reagent gives rise predominantly to 40, and by a very large margin (14.2:1, entry 36). We are not aware of reports in which an axial preference of this magnitude has been observed previously.

54 OH solvent system

r 1 . r 3 = H, R2 = CH3 0.13 0.10 10% ether in pet. ether r 1 = r3 = H. R2 = CgHs 0.18 0.13 20% ether in pet. ether R U r3 = H, R2 = 0CH3 0.35 0.21 10% ether in pet. ether R^ = WBu. R2 * OCH3. R® = H 0.51 0.46 15% EtOAc in hexanes Ri = f-Bu, R2 = H, r3 = OCH3 0.56 0.47 10% EtOAc in hexanes Ri = H. r 2/r3 = 0(CH2)3* 0.40 0.31 15% ether in pet. ether Ri = WBu. R2/r3 = 0(CH2)3® 0.35 0.18 15% EtOAc in hexanes R^ = f-Bu, r2 /r3 = (CH2)3 0 ® 0.25 0.15 8 % EtOAc in hexanes OH OH OH

Ri = f-Bu, r2 = OCH3, r3 = H 0.23 0.11 50% EtOAc in hexanes r1 = t-Bu, r2 = H. R^ = OCH3 0.25 0.16 40% EtOAc in hexanes Ri = r-Bu, r 2/r 3 = 0(CH2)3^ 0.15 0.09 25% EtOAc in hexanes

\ r > ^ ^ R 2 V p R3 RU r 3 = H. R2 = CH3 0.25 0.13 15% ether in pet. ether r 1 = r 3 = H, R2 = CgHs 0.20 0.13 15% ether in pet. ether

R’ = R3 = H. R2 = OCH3 0.10 0.18 15% ether in pet. ether R’ = H, R2/R3 =0(CH2)3^ 0.14 0.29 20% ether in pet. ether R’ = f-Bu. r 2/r 3 = 0(CH2)3^ 0.22 0.48 15% EtOAc in hexanes R1 = tBu. r 2/r 3 = (CH2)30 ® 0.61 0.76 75% EtOAc in hexanes

‘ The symbolism 0(CH2)3 is meant to indicate that the oxygen atom resides at R^ (> equatorial) while (CH2 ) 3 0 denotes axial attachment at R^.

Table 3.3: Polarities of selected cyclohexanols and spirotetrahydrofuran derivatives (Revalues).

55 HQ PH

THF or H2O 37 38 10 1. BHa-MeoS.THF 2. NaOH. H2O2

OH HO HQ PH

39 40

Scheme 3.7: Nucleophilic additions to 10..

The stereoselectivity of the last reaction may be fostered by projection of the methylene of the heterocyclic ring in the axial direction resulting in steric impedance to bonding from the adjacent equatoriai surface of the cartxjnyl. If this is the case, then the experiments defined in entries 33-35 (Table 3.4) could reflect some overriding of this steric effect by modest chelation to oxygen. The result is the formation of "reduced" amounts of 38. although this diastereomer continues to predominate.

The behavior detailed above clearly does not extend to the allylations promoted by indium

(entries 37-40). In all four condensations studied, the equatorial homoallylic alcohol 37 proved to be the major product. Thus, 10 reacts with the allylindium reagent with much greater chelation control that the other organometallic reagents, irrespective of whether the reaction is conducted in THF or water.

56 chelate/non­ entry reagent solvent (T, ®C) chelate ratio y'Gid, X» For 10: 33 CH2=CHCH2MgCI THF.O 1 :1.1 81 34 CH2=CHCH2MgCI. CeCIa THF.O 1 :1.8 87 35 GH2=CHCH2Br, CrCl2 THF.O 1 :1.7 95 36 CIMgO(CH 2)3MgCI THF.O 1 :14.2 90 37 CH2=CHCH2Br, In THF. 25 11.8:1 86 38 OH2=CHCH2Br. In THF-H20(1:1),25 6.7:1 91 39 GH2=CHCH2Br, In H2O. 25 6.7:1 84 40 GH2=GHGH2Br, In THF. 25" 10.6:1 91

For 11: 41 CH2=GHGH2MgCI THF.O 1 :2.4 80 42 CH2=GHGH2MgGI, GeGla THF.O 1 :2.0 75 43 CH2=GHGH2Br, GrGl2 THF.O 4 .2 :1 72 44 CIMgO(GH 2)3MgCI THF.O 7.6:1 88 45 CH2=GHGH2Br, In THF. 25 14.0:1 88 46 CH2=CHGH2Br, In THF-H20(1:1).25 6.5 :1 74 47 CH2=GHGH2Br, In H2O. 25 6.8 :1 83 48 CH2=GHGH2Br, In THF. 25" 11.0:1 84

^All experiments were conducted minimally in duplicate and the reported data represent the average of these experiments. ^ The allyl bromide and indium powder were reflux^ in THF for 1 h and cooled to 25 "C before the ketone was added. Based on recovered starting material.

Table 3.4: Facial selectivity in nucleophilic additions to 10 and 11.

The studies involving diastereomer 11 were equally revealing. The structural distinction

between 41 and 42 was made by means paralleling those developed earlier for 37 and 38. For

example, the axial alcohol 41 was less polar than 42 (Table 3.3) and exhibited the confirmatory

NOE effects given in H (Figure 3.13). Also, whereas W-coupling between H-€a and H-10 was not evident in 41, it was clearly apparent in the spectmm of 42 (see I). Semi-selective long-range

DEPT experiments again confimied the trans-diaxial relationship of H-6a and C-10.

57 OH

OH 1.3% 1.9%

H

Figure 3.13: NOE difference data for 41 and 42.

Althougfi 43 and 44 proved difficult to separate cfiromatograpfiicaliy, they could be

independently prepared by hydroboration of 41 and of 42. Structural proof, realized in this manner, also permitted configurational assignment to be made with confidence to the dispiro ethers 45 and 46 (Scheme 3.8).

Despite the axial disposition of the ether oxygen in 11, the Grignard and cerium reagents add with a modest preference from the diaxial direction (entries 41 and 42). All of the other organometallics, and particularly the indium reagents exhibit a respectable kinetic preference for the bonding to the equatorial face of the cartwnyl group (entries 43-48). Proper understanding of these facts is dependent on a reasonable knowledge of the extent to which conformations llc h and lltw become involved in the rate-determining transition states. We have earlier discussed how small the free energy difference between these conformera might be. If chelation to lltw operates to a significant degree, heightened levels of equatorial attack should be operational as is seen.

58 +

41 42

11

OH HO PH HO,

43 44

TsCI, EtaN, DMAP, CH2CI2

Scheme 3.8: Nucleophilic additions to 11.

3.2.4. Competition Experiments

Eliel, Frye, and co-wotkers^^ have recently called attention to the fact that in the absence of kinetic studies it becomes impossible to distinguish between chelation as a product-determining event or an unproductive reversible process."^ In their words, "if chelation is the cause of the high stereoselectivity observed in additions to alkoxy ketones, it must also be true that the chelated transition state provides a lower energy pathway to products than the less

59 stereoselective pathway not involving chelation which is available to all ketones.” In order to

probe this important issue in the present context, we have conducted a series of competition

experiments designed to elucidate whether those examples exhibiting increased

stereoselectivity are indeed mediated by more reactive indium chelates. In the interpretation of

these findings, we have assumed that chelation/non-chelation is the only kinetic consideration at

issue. Possible contributions stemming from differing field/inductive effects, orbital overlap

factors, electronegativity effects, and steric contributions are assumed to play a lesser role, but

strictly speaking^ this need not be the case. However, since the order of reactivity does follow

the obsen/ed stereoselection order and since the ketones carry only a single a-oxygen atom, it

can be argued that the correlation is reasonable.

Several revealing pieces of information have emerged from this aspect of the study. Thus, direct competition between 6 and 7 has revealed these two ketones to be almost equally reactive toward the allylindium reagent (entry 49, Table 3.5). Since both of these substrates project their a-methoxyl substituent equatorially for possible complexation to the incoming organometallic reagent and comparable levels of chelation are anticipated, it would be necessary that quite similar rates of addition be observed if complexation to methoxyl oxygen is kinetically relevant. The sensitivity of the allylindium reagent to steric screening is made evident in the direct competition between ketones 7 and 10 (entry 51). Although both of these ketones project their ether oxygens equatorially, only 7 reacts with the organometallic reagent to the point where it is completely consumed. Evidently, therefore, the incorporation of the a-oxygen atom into a tetrahydrofuran ring does not allow for the generation of a kinetically relevant chelate structure as rapidly as that associated with 7. This does not mean that 10 is unable to engage in chelation.

However, it does so much less effectively than 7.

60 first second reaction relative entry ketone ketone time, h rate ratio®

JlyOCHa JL^OCHg 49 I^J 10 1.1 : 1 b

6

50 5 > 99:1• ib.c

7 8

° o-

1 ^ - g : ) 12 >99:1®

52 I T'O 48 2.5:1 ®

10 11

® All experiments were œnducted minim ally in duplicate and the reported data represent the average of these experiments. ® The relative rate ratio was ascertained by quantitative analysis of the alcohol products formed. ®The relative rate ratio was determined by quantitative assessment of the levels of unreacted ketones remaining.

Table 3.5: Competitive indium-promoted allylations in water at room temperature.

Entries 50 and 52 point out the differences in relative rate associated with axial and equatorial projection of the flanking ether oxygen. Since chelation to 10 is sterically impeded, it is not surprising to find that 10 reacts only 2.5 times faster than 11. The extent to which the latter

61 ketone may adopt a twist-boat conformation In order to engage In chelation Is not known.

However, the latter option appears rather unlikely when viewed in the context of the less than

maximal complexing capacity of 10. More revealing In this context is the data associated with entry 50. In this instance, the two possible epimers are substituted by methoxyl and are not sterically disadvantaged. The exclusivity with which 7 reacts In the presence of 8 denotes the substantive kinetic advantage associated with equatorial projection of the methoxyl substituent.

The corresponding highly stereoselective behavior of 7, which gives only the product predicted by Cram's chelate rule. Is In complete accord with the proposal that allylation proceeds via the chelated transition state. A provocative aspect of this finding is that the parallelism between reactivity and stereoselectivity unequivocally operates in water as the reaction medium.

3.3. Conclusion

Allylation reactions performed with indium under aqueous corxJitions have generally been shown to be more stereoselective toward a-alkoxy cydohexanones than related reactions involving other organometallics under anhydrous conditions. In fact, this new reagent system ranks as the most highly selective allylating agent yet reported for aqueous systems, as long as steric effects do not gain heightened importance. In the companion paper,^ neighboring unprotected hydroxyl substituents are shown to be capable of still greater directing effects.

Consequently, this chemistry clearly constitutes a synthetically useful operation well suited for application to more complex problems in organic syntheses.

The fortuitous situation that the rate effects arising from chelation are kinetically dominant has allowed us to probe the orientational consequences of flanking 0 - 0 bond geometry on stereoselective attack at a cyclohexanone carbonyl. It turns out that good agreement with a chelate transition state model is seen, from which heuristic value may be derived. Studies are underway which should ascertain the extent to which other types of effects can possibly contribute to rate enhancement and stereoselection.

62 The present work establishes for the first time that ketones are indeed reactive in indium- promoted allylations conducted in aqueous media. Further, relative reactivities are unquestionably govemed by chelation effects, which in tum are especially sensitive to nonbonded steric congestion. The same correlation is exhibited by aldehydes^ as well as ketones. In effect, an unencumbered a-oxygen which is not deactivated by acylation or silylation is capable of controlling ic-facial diastereoselection in water. The potential synthetic utility of this stereocontrol is made clear by direct comparison with the diastereoselectivities of other allylations performed by different metals in anhydrous organic solvents.

63 LIST OF REFERENCES AND NOTES

(1) (a) The material in Chapter 3 has been slightly modified from our original publication ‘^•Facial

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1528.

65 For a general review of selective reactions involving allylic metal reagents, see Yamamoto, Y.;

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(18) For reviews which focus attention on allylation in aqueous media, consult: (a) Li, C. J. Chem.

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1181. (c) Lubineau, A.; Augé, J.; Queneau, Y.Synthesis 1994, 741.

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(22) Eisenstein, O.; Anh, N. T.; Jean, Y.; Devaquet, A.; Gantacuzene, J.; Salem, L. Tetrahedron

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(23) Corey, E. J.; Burke H. J. J.Am. Chem. Soc. 1955, 77,5418.

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(25) Fraser, R. R.; Faibish, N. C. Can. J. Chem. 1995, 73,88 .

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8835].

(27) Imamoto, T.; Takiyama, N.; Nakamura, K.Tetrahedron Lett. 1985, 26, 4763.

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Vedejs for making the relevant part of this thesis available to us.

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(35) Eliel. E. L.; Wilen. S. H.; Mander. L. N. Stereochemistry of Cartxjn Compounds, John Wiley

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(36) Anet. F. A. L.; Chmumy. G. N.; Krane. J. J. Am. Chem. Soc. 1973. 95, 4423.

(37) Lambert. J. S.; Carhart. R. E.; CorfiekJ. P. W. R. J. Am. Chem. Soc. 1969. 9 1 ,3567.

(38) 2-rerf-Butylcyclohexanone is reported to reside predominantly in the twist conformation:

reference 35. p 733.

(39) (a) Martin. S. F.; Li. W. J. Org. Chem. 1989. 54, 6129. (b) Mulzer. J.; de Lasalle. P.; Freissler.

A. Liebigs Ann. Chem. 1986,1152. (c) Hiyama. T.; Okude, Y.; Kimura. K.; Nozaki. H.Bull. Chem.

Soc. Jpn. 1982. 55. 561. (d) Lewis. M. Kishi. Y. Tetrahedron Lett. 1982. 23, 2343. (e)

Nagaoka. H.; Kishi. Y. Tetrahedron 1981. 37,3873. (f) Hiyama, T.; Kimura. K.; Nozaki, H.

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1685. (h) Okude. Y.; Hirano. S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc. 1977, 99, 3179.

(40) In actuality, the signal for H- 6a is overlapped by those for H-3e and H- 6e. However, these protons cannot exert an effect on C-7 resulting from heteronuclear coupling.

(41) (a) Sanghvi, Y. S.; Rao, A. S. Ind. J. Chem. 1987. 263, 671. (b) Heathcock. C. H.; Buse. C.

T.; Kleschick. W. A.; Pirrung, M. C.; Sohn, J. E.; Lampe, J. J. J. Org. Chem. 1980. 45.1066.

(42) (a) Chen. X.; Horteiano. E. R.; Eliel. E. L.; Frye. S. V. J. Am. Chem. Soc.

1990. 112, 6130. (b) Frye. S. V.; Eliel. E. L.; Cloux. R. J. Am. Chem. Soc. 1987, 109, 1862.

67 (43) Laemmie, J.; Ashby, E. C.; Neumann, H. M. J. Am. Chem. Soc. 1971, 93, 5120.

(44) Das, G.; Thornton, E. R. J. Am. Chem. Soc. 1993, 115, 1302.

(45) Paquette, L. A.; Mttzel, T. M. J. Am. Chem. Soc. 1996, 118, 1931.

(46) (a) Imamoto, T.; Takiyama, N.; Nakumura, K.Tetrahedron Lett. 1985, 2 6 , 4763. (b)

\x\Encydopedia of Reagents for Organic Synthesis, Paquette, L. A., 1995, Volume 2, pp 1031-

1034.

(47) Pray, A. R. Inorg. Synth. 1954, 5,153.

(48) (a) Fumiss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. In Vogel's Textbook of

Practical Organk: Chemistry, Fifth Ed., Longman: Essex, 1989, pp 443-444. (b) Watson, S. C.;

Eastham, J. F. J. Organomet. Chem. 1967, 9 ,165.

(49) Saltzman, H.; Sharefkin, J. S. Org. Synth.-, Wiley: New York, 1973, Coll. Vol. V, p 658.

(50) We thank Mr. Anthony Lombardo for performing this experiment.

68 CHAPTER 4

a-HYDROXYCYCLOHEXANONES

4.1. Background

We sought to further exploit the aqueous conditions available with the indium-mediated

protocol by examining a-substituted hydroxycyclohexanones. Previous reports from our

laboratories illustrated an increased chelating ability of acyclic hydroxy aldehydes/" Therefore, the

combination of the allylindium reagent and hydroxy substitutents in water offers a clear advantage

over the more traditional anhydrous organometallic reagents.^ These commonplace reagents,

although nucleophilic, are rather basic and will deprotonate the hydroxyl function rather than

aliylate the cartxanyl, and thus are completely incompatible with an aqueous medium.

Furthermore, the indium protocol circumvents the protection-deprotection strategy usually

employed with anhydrous nucleophilic additions to hydroxy cartx>nyl substrates and thereby

avoids two cumbersome transformations.^ On the other hand, the allylindium reagent is

completely compatible with free hydroxyl groups in aqueous media. Whereas the traditional allyl

Grignard reagents function via a nucleophilic pathway the allylindium reagent is proposed to react through a single electron transfer (SET) mechanism.^ In the previous chapter, we demonstrated the superiority of the allylindium reagent over some of the more traditional allyl metals and documented increased diastereoselectivity, higher yields, and a more facile experimental procedure.

We aspired to evaluate a-hydroxycyclohexanones 1-5 on these same grounds (Figure

4.1). These substrates can be considered as the a-hydroxy equivalents of the ethers utilized in

69 the preceding chapter.^ In 1-3, the resident a-methoxy group has twen sut)stituted with a free

hydroxyl to arrive at the a-hydroxycydohexanone homologues. a-Hydroxy substrates 4 and 5

were intended to mirror the 2-spiro(tetrahydrofuranyl) substrates. The relative stereochemistry of

the oxygen atom is maintained and the flanking methyl group is introduced to account for the

steric hindrance found with the saturated spirofuran ring. Compound 6 was serendipitous,

resulting from the synthesis of 2 and 3 {vide infra).

Ô'”

OH Ç r ‘ f-Bu

Figure 4.1 : a-Hydroxycyclohexanones 1-6.

4.2. Synthesis

4.2.1. c /5-4-fe/t-Butyl-2-hydroxycyclohexanone ( 2) and frans-S-ferf Butyl-2- hydroxycyclohexanone ( 6 )

The synthesis of 2 and 3 was not as easy as forecasted, especially in light of the fact that there were two successful reports at the time.^"^ We simply envisioned starting from commercially available 4-ferf-butylcyclohexanone and employing one of the most tried and true methods to install an a-hydroxy cartwnyl moiety, the famed Rubottom oxidation (Scheme 4.1, steps 1-3).® From this procedure, a very complex mixture was obtained that decomposed- polymerized in a matter of tiours upon standing at rt or overnight when stored t)elow -10 “0 , 70 1. LDA, THF. -78 °C; 9 ÇTBDMS TMSCI. 0 »C Jk^O TI BDD U M M d S 2. mCPBA, CH2CI2 f T ' r 3. TBAF, THF V ' V f ,i.4 .„ t

Scheme 4.1: Synthesis of 7 and 8, precursors to a-hydroxycyclohexanones 2 and 6.

becoming essentially insoluble in organic solvents and unreactive toward the allylindium reagent.

It should be noted at this point that commercially available 1 exists as a dimer, but is successful in

the indium-mediated allylation {vide supra). The addition of a slight amount of dilute HCI(aq) to this

mixture had no appreciable effect. Next, the crude reaction mixture was reacted with TBDMSCI

and imidazole in DMF (Scheme 4.1, step 4). As anticipated, two products were obtained after

purification by coiumn chromatography. Inspection of the ^H NMR spectra of each isolated

product showed the furthest downfield signal to be a doublet of doublets centered near 4.15

ppm and corresponding to the C-2 methine adjacent to the cartx>nyl. However, unlike the

coupling patterns for the c/s/frans-2-methoxy-4-re/t-butylcyclohexanone systems described in

Chapter 3, both signals showed one large coupling (-12 Hz) and one medium coupling (-6.5 Hz)

indicating axial-axial and axial-equatorial couplings, respectively, to the 0-2 methine. This led to

the conclusion that both methine protons were in an axial orientation. The structures of 7 and 8

were unambiguously determined by ^H.^H, COSY 90 NMR experiments, which established that

there was one methylene (CH 2) between C-2 and C-4 for compound 7 and two methylenes

between C-2 and C-5 for compound 8.^ Once generated, a-hydroxycyciohexanones 2 and 3

had undergone enolization and tautomerization via an "enediol" intermediate to afford 7 and 8

upon silylation with TBDMSCI (Figure 4.2). It is not clear whether the enolization occurred under the installation or during the protection of the hydroxy group. Therefore, the reported yields reflect the extent to which each isomer soleiy engaged in aliylation irrespective of deleterious tautomerization {vide infra).

71 - "enedior

Figure 4.2: Proposed tautomerization pathway via a “enedior intermediate.

Vedejs reported the synthesis of 2 and 3 in communication form. However, no spectral data were available and the experimental details presented as a footnote are vague at best.^

Simpkins et. al. provided experimental details, although spectral data for 2 was given, it was stated that “...3 could not be obtained free from 2“.5c This statement is very precocious and leads to the possibility that 3 had quickly tautomerized and became transposed into a hydroxy ketone 6.

The most compelling evidence for this possibility was gathered more after this study had been completed. Parker et. al. reported in 1992 that mixtures of 2-bromo-4-{fert-butykjimethylsiloxy)- cyclohexanone (cis/trans-9. Scheme 4.2) in varying ratios of 1:2 to 9:1 would isomerize "...on chromatography, stirring with silica gel, or simply on standing, the mixture was converted to isomer

[trans-9], which contained only a trace (<5%) of isomer [cis- 9 ]."Sb At the very least, this statement gives credence to the proposed trans/cis isomerization of 3 to 2 shown in Figure 4.2. The axial preference of halogens and the equatorial preference of hydroxyls in 2 substituted cyclohexanones has been addressed by these autfiors and others.^ In another more recent note f/ans-2-bromo-4-(ferf-butyldimethylsiloxy)cyclohexanone (trans-9) was converted to its

72 NaOH, n-Bu4NHS0 4 . reagent. R3N. _ CH2CI2. H2O [DMAP], CH2CI2 (85%) OTBDMS OTBDMS OTBDMS trans-9 CiS-10 dS-11a, R = TBDMS (92%) d s - llb , R = Ac (85%) d s - llc , R = Ac (80%)

Scheme 4.2: Parker's synthesis of cis 2,4-dialkoxycyclohexanones 11a c

hydroxy derivative cis-10 under phase transfer conditions.^^ Derivatization of cis-10 to cis-lla-c was accomplished using the appropriate reagent (TBDMSOTf, AC 2O and BzCI, respectively) and a tertiary amine base (Scheme 4.2). The object of this exercise was to obtain synthetically useful quantities of the trans-2,4-dialkoxycyclohexanone by eventually epimerizing the a-keto center using DBU (Scheme 4.3). In THF or CH 3CN, the trans isomers of 11b and lie were only favored by roughly 3-4:1, and the reaction with tran s-lla was sluggish. The ambiguity in this study results from the NMR spectra of the cis/trans mixture found in the supporting information of the note. As deduced atx>ve, it is expeded that the (C- 2) a-hydroxy methine in a cis/trans mixture of

11b and 11c would show two downfield signals, a doublet of doublets resulting from the d s isomer having one large axial-axial coupling and one medium axial-equatorial coupling and an apparent triplet belonging to the trans isomer as a result of two small equatorial-equatorial couplings of almost equal value. Instead the spectra of the cis/trans mixtures of 11b and 11c equilibrated in THF revealed two sets of doublets of doublets, both as a consequence of one

DBU. PO OR THF or PC PO OR CH3CN OR P = TBDMS trans-11 b-c 12a-c

Scheme 4.3: Parker's modest epimerization of cis 2.4-dialkoxycyclohexanones 11-b-c.

73 large coupling and one medium coupling. This observation suggests ttiat 12a-c is responsible

for the other doublet of doublet rather than trans 1 ib-c as believed by the autfiors (Scheme 4.3).

Although this cannot unambiguously be determined from the information provided, the possibility of an a-ketol rearrangement during or preceding the derivatization to cis-lla-c sfiould not be discounted. The researchers most likely did not consider the possbility of an a-ketol rearrangement and did not further investigate the compounds or their spectra. They did, however, resort to a different route to obtain the trans-2,4-dialkoxycyciohexanones for reasons simply stated as ’[r]ecogizing the difficulties associated with the dean conversion of substrates

[10] or [11] to the desired [trans isomer]...." Ironically, this route is very similar to our route employed in the synthesis of 3 {vide infra). Furthermore due to the brevity of the publication and the lack of details, as well as the poor quality of the '' H NMR spectra provided with the supporting information, these comments may be inappropriate. By no means though is the a-ketol rearrangement unprecedented.^

Silyl protection of the mixture of 2 and 6 failed to produce useful quantities of 8.

Therefore. 8 was independently synthesized beginning with acetal 13^ (Scheme 4.4).

Deprotection of the acetal followed by stereoselective (axial attack) 1,2-reduction of the resultant

r ~ \ OH 1. HaO^/acetone, Ph reflux TBDMSCI. 2. LiAIH(OMe)a, imid, DM F THF, 0 °C (71%) f-Bu (63%) 13 OTBDMS OTBDMS

O 3 . MeOH- _ O I I CH2CI2, -78 °C I ^hen Me 2S. rt f-Bu (76%) t-Bu 15 P= TBDMS 15 8

Scheme 4.4: Alternative synthesis of 8, the precursor to substrate 6.

74 enone produced allylic alcohol 14 in 63% yieldJ° Subsequent protection of the alcohol as its

TBDMS ether afforded 15 in 71% yield. It was at this point that the equatorial nature of the silyloxy

ether was unambiguously determined through NOE experiments. Finally, ozonolysis of the

benzylidene double bond afforded a 76% yield of a-silyloxycyclohexanone 8 . As the protected

version of 2 and 6 ,7 and 8 are stable to long-term storage at or below room temperature.

4.2.2. frans-4-feit-Butyl-2-hydroxycyclohexanone (3)

Our attention now was focused on the synthesis of the elusive frans-4-rerMxityl-2-

hydroxycyclohexanone (3). After the trials and tribulations associated with the Rubottom

oxidation procedure and the sensitivity of the a-hydroxyketone moiety, it was realized that a

protecting group strategy would have to be implemented. The plan was to protect the ketone

prior to introducing the hydroxy function, as another route to a hydroxy group is the reduction of a

cartx)nyl. Furthermore, with respect to 4-ferf-butylcyclohexanone it is well established that bulky

hydride reagents and in general large nucleophiles prefer equatorial attack (the less hindered

approach) thereby producing axial alcohols.^ ^ Ketone 16^ was initially reduced, following a

similar procedure developed by Evansusing L-Selectride in THF at -78 °C to afford a 1.2:1 ratio of alcohols 17 and 18 in a combined 69% yield (Scheme 4.5). With the observed poor facial

selectivity, it was anticipated that a bulky monodentate chelating hydride reagent in a non-polar solvent would be most efficient. The use of DIBAL-H in hexanes at -78 ®C gave a marked improvement, increasing the ratio to 1.7:1 and improving the yield to 90%, thus making this a

f - \ / - A 0 0 0^0 0^0 ' ' O DIBAL-H, ^.OH > < ^ 0 H hexanes,. i i' . i r -78 “0 (90%)

Scheme 4.5: Stereoselective 1,2-reduction of 16 en route to trans hydroxy ketone 3.

75 more viable process. The improved yield is attributed to a comparatively easier work-up procedure. However, success was short-lived, problems arose upon attempted deprotection of acetal 17. Typical deprotection conditions (conc. HCI(aq) in refluxing acetone/H 2 0 ) produced a mixture of 2 and 3 (Scheme 4.6). The use of Si 0 2 and H 2SO4 in a procedure modified by

Solladié was equally unsuccessful.^^ Additional efforts to effect removal of the acetal moiety under neutral conditions failed. PdCl 2(CH3CN)2^^ in acetone gave a messy reaction as determined by TLC analysis, and FeCl 3-Si0 2 ^^ failed to produce a reaction in acetone or CHCI3.I6

H3O+, acetone, reflux (71%)

Scheme 4.6: Futile attempt toward the synthesis of 3

Finally, it was recognized that success must rest on protecting the ketone and hydroxyl groups in a manner such that their liberation could be performed under neutral conditions. An exocyclic methylene which could be cleanly removed by ozonolysis and a benzyl group which could be cleaved by hydrogenolysis were ultimately selected. Wittig olefination of commercially available 4-tert-butylcyclohexanone provided the protected ketone 19 in 80% yield (Scheme

4.7). 1^ Thie key step to install the axial hydroxy group rested on allylic oxidation using catalytic

Se0 2 -^^ Surprisingly, this reaction was highly diastereoselective, producing axial allylic alcohol

20 as the only diastereomer (>97:3) evident by NMR integration of the crude reaction mixture. 19

76 CHa CHg ...OH PhgPsCHa (SeOa). f-BuOOH. DMSO, 0 »C (HI. CH2CI2 (75%) r-Bu f-Bu f-Bu 19 20 ÇH2 O NaH, BnBr.n-Bu4NI. O3, MeOH, THF, 0 “C -> rt L J -78 ®C; MeaS, rt (51%) I (55%) f-Bu f-Bu 21 22

Schem e 4.7: Synthesis of 22, the precursor to fraAJS-4-ferf-butyl-2-hydroxycyclohexanone (3).

The rationale for this high diastereoseiectivity rests on analysis of the two competing

transition states (Figure 4.3). Reaction of olefin 19 with a catalytic quantity of SeOa initially forms

selenous acid A via a [2,3]-sigmatropic rearrangement.^^ The oxidation step then proceeds

through paiirway a in which the cyclohexene adopts the thermodynamically favorable chair

pH2 (Se02) .OH H (2,3 sigmatropic rearrangement) 19 H

CH2 chair transition H state V o ' O h 20 OH or (Observed) PH2 O ^se-O H boat transition OH state H (not observed)

Figure 4.3: Transition states for allylic oxidation of 1C with SeOa-

77 transition state. The equatorial isomer, which is not observed, would result from the

thermodynamically less favorable boat-like transition state, pathway This facial preference

has been documented in closely related systems.^^ This pathway seems only relevant if the

reaction proceeds through an early transition state. Conversely, if the reaction proceeds through

a late transition state, then the diastereoseiectivity could very well be determined by allylic 1,3

strain, which is minimized with the hydroxyl group axially oriented.^^*^

Benzylation of the allylic alcohol 20 proceeded uneventfully in 51% yield affording 21.

The stereochemistry of the newly formed carbinol center was very apparent at this juncture by the

observed coupling constant of H-2, which appeared as a broad doublet of doublets (S 3.99 (dd, J

= 2.6,2.6 Hz) due to two small equatorial-axial and equatorial-equatorial couplings. Unmasking of

the ketone functionality was accomplished by mild ozonolysis, yielding 55% of 22. Due to the

sensitivity of the a-ketol moiety, the benzyl group was not cleaved until compound 3 was

needed. It was this route that Parker also employed for the synthesis of trans-1 Ib-c (Scheme

4.3).5a

4.2.3. C/5- and frans-4-fe/t-Butyl-2-hydroxy-2-methylcyclohexanone (4 and 5)

Jeffrey Aubé graciously provided detailed synthetic procedures for the synthesis of 4 and 5.23 However, their synthesis suffered from a low overall yield, due in part to over méthylation and poor regioselective enolization. From the outset it was desired to improve the efficiency of these two steps. Our method entailed the initial formation of the dimethylhydrazone of commercially available 4-terf-butylcyclohexanone in essentially quantitative yield (Scheme 4.8).2^

It is known that permethylation is common with unsubstituted, symmetrical ketones. Formation of the dimethylhydrazone circumvents this problem. Monomethylation of the hydrazone using LDA and Mel at 0 °C followed by oxidative hydrolysis using NalO^ and short path distillation provided the diastereomeric a-methyl ketones 23 in 80% overall yield.25 The therrrxjdynamic silyl erwl ether was prepared according to the procedure developed by Krafft and Holton.26 Epoxidation of

78 1. H2N-N(Me3)2. Eton, reflux 2. LDA. THF. 0 °C_ 3. Mel, 0 °C 4. Nal0 4 . MeOH (80% over 4 steps)

0 0 ^ 1. BrMgNfAPrb, 0 °C -> rt; TMSCÎ. EtgO A y 2. mCPBA, CH2CI2, ; V - C H 3 '"OH -78 °C -> rt Y' 3. TBAF, THF 1 + T f-Bu f-Bu (78% over 3 steps) 4 (2.8:1) 5

Scheme 4.8: Synthesis of tertiary alcohols 4 and 5.

the crude silyl enol ether with m-CPBA followed by desilylation with TBAF in THF afforded the tertiary alcohols 4 and 5 in a 2.8:1 ratio and a combined 78% yield from the diastereomeric a- methyl ketones 23. The diastereomers were separated by chromatographic methods and individually purified further by recrystallization. ^ H and NMR comparison of 4 and 5 to the data provided by Aubé proved that the synthesis was successful.

4.3. Results

As a point of reference it was of interest to see how commercially available 4-ferf-butyl- cyclohexanone reacted with the allylindium reagent in the three distinctly different solvent conditions, water, 50% THF(aq), and THF (Scheme 4.9). These results would give us a starting point to evaluate our past and present work. When the reaction solvent was THF a clear two fold increase in stereoselectivity was observed over the water and aqueous THF systems, but all conditions favored the equatorial addition product 24 (compare entries t-3). A notable difference was the reaction time in THF. When commercially available indium powder was used, the reaction was complete in 48 h, but when the indium metal was produced by electrolysis of InCIa with a Pt cathode and electrode the reaction time dramatically decreased to 4 h.27 This rate enhancement

79 has also been observed with zinc.^^ It should be noted that the stereoselectivity observed with

the allylindium reagent is in agreement with the results of other allylmetal reagents.^^

C p H HQ In, + solvent, rt f-Bu 25

reaction entry solvent time (h) 2425 yield, % 1 HgO 3 4.6:1 75 2 50% THF(aq) 4 5.2:1 79 3 THF see text 10.2:1 73

Scheme 4.9: Indium-mediated allylation of 4-ferf-butylcyclohexanone.

Reaction of commercially available 2-hydroxycyclohexanone (1) as a dimer with the allylindium reagent afforded the single diastereomer 26 under all three specified reaction conditions (Scheme 4.10). The diastereoseiectivity was determined by ^H NMR integration of the

O ^ — % JOH OMe ^ Js^OH ^i^Br.In. . (PPTS). solvent, rt DMF, 0 °C 1 26 (88%) 27

reaction Chelate/ entry solvent time (h) non-chelate yield, % 4 H2O 1 >97:3 54 5 50% THF(aq) 1 >97:3 63 6 THF 48 >97:3 51

Scheme 4.10: Indium-mediated allylation of 2-hydroxycyclohexanone (1).

80 unpurified reaction mixture/^ Interestingly, as observed atxjve for 4-ferf-butylcyclofiexanone.

tfie reaction took considerably longer wfien performed in THF (entry 6). This trend persists

throughout this study. The yields were fair to good, with the highest occurring in 50% aqueous

THF (entry 5). The high diastereoseiectivity was quite unexpected because 2-

methoxycyclohexanone only showed an average diastereoseiectivity of 12:1, also favoring the

chelate product.^ The rationale for the high diastereoseiectivity is a chelation-controlled addition

of the allylindium reagent as depicted in A (Figure 4.4; R, R' = H). The indium atom coordinates to

the alcohol, essentially locking the cyclohexanone in to a specific chair conformer. The metal then

activates the cartwnyl, thereby allowing predominant equatorial delivery of the allyl group to form

cis diol 26. The isolated diol in turn was converted in to dimethyl acetonkJe 27 in 88% yield with

HO R

A

Figure 4.4. Chelate-controlled transition state for the indium-mediated allylation of an a- hydroxycyclohexanone.

2-methoxypropene (Scheme 4.10).^° Formation of the acetonide made the allyl product more

conformationally rigid and made possible the application of NOE difference experiments to

support the equatorial nature of the allyl group (Figure 4.5). The strongest evidence for the cis configuration resulted from the irradiation of H-2, with concomitant enhancement of the H-8

(1.9%) and H-7,7 (3.2%) protons.

81 irradiate observe % NOE difference H-2 H-3e 2.4 H -7,7 3.2 H-8 1.9 H-7 H-2 1.2 H-7 H-2 3.2 27 H-8 H-2 1.7

Figure 4.5: NOE difference data for acetonide 24.

Attention was now focused on tfie elusive c/s^-fe/t-butyl-2-fiydroxycyciofiexanone (2).

Witti sufficient quantities of 7 in tiand, tfie removal of tfie TBDMS group (TBAF/THF at ft) afforded

2 in a disappointing 48% yield after a very quick cfiromatograpfiic purification (Si02) (Scfieme

4.11). Unfortunately, 11% of tautomer 6 resulted from tfiis procedure as evidenced by isolation

and cfiaracterization of diol 30. Tfiis isomerization was unavoidable even with rapid techniques.

The yields have been adjusted and reflect the efficency with which 2 underwent allylation, with a-

Ketol 2 was immediately reacted with the allylindium reagent under the trio of reaction conditions.

Single diastereoselection was anticipated as a result of our previous studies with c/s-4-ferf-butyl-2-

OTBDMS ,OH .OH ,0H TBAF. Br, In, solvent, rt f-Bu f-Bu 28

reaction chelate/ entry solvent time (h) non-chelate yield, % 7 HgO 1.5 >97:3 77 8 50% THF(aq) 1.5 >97:3 73 9 THF 25 >97:3 84

Scheme 4.11: Indium-mediated allylation of a-hydroxycyclohexanone 2.

82 methoxycyclohexanone^ and the results above with substrate 1. As expected, single

diastereomer 28 was otAained (entries 7-9). The t-butyl group anctwrs the cyclohexanone,

thereby imposing the cis hydroxy group equatorially and facilitating chelation-controlled delivery

of the allylindum reagent as illustrated in Figure 4.4 (R = f-Bu, R' = H). Again, the reaction in THF

was very sluggish, requiring a reaction time of 1 d versus 90 min when the solvent was water or

50% THF(aq) (compare entries 7-9). The yields were slightly more favorable than found with 1,

ranging from good to very good.

Tfie stereochemistry of the resultant diol was unambiguously determined by chemical

conversion to its monomethyl ether. The reaction of diol 28 with 1.2 eq of NaH in THF at 0 °C in

the presence of excess Mel selectively methylated the secondary, equatorial hydroxyl group in

69% yield affording 29 (Scheme 4.12). The Purdie reagent (Mel and Ag20 in DMF at 60 ®C) was

also effective, but gave a low 30% yield (66% based on recovered starting material). The spectral

data of 28 matched completely those previously reported .2

3 ^ . — THF. 0 «C T f69%l(69%) T f-Bu f-Bu 28 29

Scheme 4.12: Selective méthylation of 28.

Ketone 6 was obtained from 8 in a procedure analogous to that employed with substrate

7 (Scheme 4.13). As would be expected, the results for 6 were very much the same as those descritied for 2. The observed diastereoseiectivity was >97:3 under all three reaction conditions, favoring the chelate isomer cis diol 30 (entries 10-12). The equatorial nature of the transposed a- hydroxy group is again situated for a chelate-controlled transition state similar to that observed with substrates 1 and 2 (Figure 4.4). The reaction mixture in THF again required prolonged 83 OTBDMS OH ÇH

T B ^ THF solvent, rt f-Bu (59%) f-Bu f-Bu 8 6 30

reaction chelate/ entry solvent time (h) non-chelate yield, % 10 H2O 1.25 >97:3 86 11 50%THF(aq) 1.25 >97:3 87 12 THF 16 >97:3 87

Schem e 4.13: indium-mediated allylation of a-hydroxycyclohexanone 6.

mixing. However, the yield in all three trials was consistently 87%. Tautomerization was unavoidable and resulted in the isolation of about 9% of diol 28; the yields have been adjusted accordingly. The stereochemistry of the single diastereomer was unambiguously determined by

NOE difference experiments (Figure 4.6). The most notable result was obtained with the irradiation of H-2 which produced enhancements of allylic protons H-7 (0.8%) and H-7* (1.7%).

The reciprocal irradiations were equally fruitful, H-7 giving a 1.4% enhancement of H-2 where H-7* gave a 2.5% enhancement of the same proton. Furthermore, proton H-5 of 30 (S 1.38 (dddd, J=

12.4,12.4,3.1, 3.1 Hz)) is deshielded by the axial carbinol and found further downfield than proton H-4 (5 0.99 (m)) of regioisomer 28.

irradiate observe % NOE difference H-2 H-4a, 6a 3.9 H-7 0.6 H-7 1.7 H-8 2.2 H-7 H-2 1.4 H-7* H-2 2.5

Figure 4.6: NOE difference data for cis diol 30.

84 With these impressive levels of diastereoseiectivity, interest in ketone 3 was heightened.

With synthetically useful quantities of 22 in hand, débenzylation with H 2 and Pd/C finally gave the elusive trans a-hydroxycyclohexanone 3 in 64% yield. As with substrates 2 arxJ 6 ,3 was not characterized but was rather reacted immediately with the allylindium reagent under the standard conditions (Scheme 4.14). Unsurprisingly, the reactions were complex and the subsequent analyses complicated. The strong propensity of 3 to tautomerize resulted in the isolation of homoallylic alcohol 31, as well as cis diols 28 and 30. When water was employed as solvent, 41% of 31 was isolated along with 23% of isomers 28 and 30 in a ratio of 1:1.7 (entry 13). Aqueous

^ JDH

Hg, Pd/C, Br, in. EtOH solvent, rt f-Bu (64%) f-Bu f-Bu 22 3 31

reaction chelate/ entry solvent time (h) non-chelate yield, % 13 HgO 1.5 >97:3 53 14 50% THF(aq) 1.5 >97:3 48 15 THF (5 days) no reaction ----

Schem e 4.14: Cumbersome deprotection of precursor 22 and indium-mediated allylation of 3.

THF likewise provided 40% of 31 in addition to isomers 28 and 30 (18%) in an increased ratio of

1:2.8 (entry 14). However, no discernible products were observed by TLC analysis when the reaction medium was THF (entry 15). The two fold increase in the isolation of tautomer ic products, in comparison to 2 and 6, is added proof for the strong propensity of 3 to undergo equilibration (Figure 4.2). This clearly illustrates why it was not possible to synthesize and isolate

3 originally via the Rubottom oxidation protocol (Scheme 4.1). Significantly, however, 31 was the only product resulting from substrate 3. The non-chelate cis diol was not evident by ^H NMR 85 B

Figure 4.7. Chelate-controlled transition state for the indium-mediated allylation of 3 (R=H).

analysis of the crude reaction mixture. Comparatively, the analogous methoxy substrate showed

a chelate/non-chelate ratio on average of 8:1 The observance of a single diastereomer further

exemplifies the strong chelating ability of hydroxy groups in aqueous media. A twist-boat chelate-

controlled transition state 8 is proposed to account for the observed high diastereoselection

(Figure 4.7; R = H). The same controls are operating as described above for substrates 1 and 2.

Subsequent to chelation with the axially oriented hydroxyl group, the allylindium reagent causes the cyclohexanone to adopt a twist-boat conformer such that the proximal metal activates the carbonyl towards pseudoequatorial addition. Structural proof for 31 was gained in the same manner as for 28. Selective méthylation afforded 32 in 48% yield (70% based on recovered starting material) (Scheme 4.15). The spectral data matched completely with those previously reported.2

.OH ...OMe NaH, Mel, THF, 0 °C (48%)

Scheme 4.15: Selective méthylation of 31.

86 With the dramatic diastereoselectivities observed thus far, especially with substrates 2

and 3, we were excited about the potential of 4. Surprisingly, the indium-promoted allylation of

afforded solely (>97:3) the chelate-controlled cis diol 33 (Scheme 4.16). This incredible

diastereoseiectivity is in starts comparison to the cis 2-spiro(tetrahydrofuranyl) substrate which on

average favored the chelate-controlled product by a 8:1 ratio.^ It was expected that the hydroxy

group would chelate better than the furan ether oxygen, but could not completely overcome the

sterics associated with the geminal methyl group. No reaction was observed in anhydrous THF

after 5 days (entry 18). Recourse was made to precomplexing the allyl bromide and indium powder

in refluxing THF prior to the addition of the substrate. These conditions were developed in our previous work. Dramatically, the reaction time was decreased from five days to a mere 30 minutes

(entry 19). The reactions in aqueous media were complete in 2.5 h (entries 16 and 17). The yields in all cases were good.

OMe . [PPTSl. ► [^ T 'C H g solvent, rt CH2CI2, reflux (83%) f-Bu f-Bu f-Bu 4 33 34

reaction chelate/ entry solvent time (h) non-chelate yield, % 16 H2O 2.5 >97:3 70 17 50% THF(aq) 2.5 >97:3 69 18 THF® (5 days) no reaction --- 19 THF^ 0.5 >97:3 82

4 and THF was vigorously stirred in a tightly stoppered flask.^ Allyl bromide and indium powder were vigorously refluxed in THF and then cooled to rt before the addition of substrate 4 .

Schem e 4.16: Indium-mediated allylation of a-hydroxycyclohexanone 4.

87 The equatorial orientation of the allyl group was established through NOE difference

experiments; significant enhancements of allyl protons H-8 and H-8* resulted from the irradiation of the axial methyl (C-7) and H-6a (Figure 4.8). The reciprocal enhancements were observed with slightly higher intensities. Conversion of the cis diol 33 to acetonide 34^5 resulted in substantial

NOE differences (Figure 4.9). In some cases the enhancements were several orders of magnitude larger than found with the precursor. Allylic protons H-8 and H- 8' saw a 5% enhancement of the signal due to the methyl group (0-7).

irradiate Observe % NOE difference H-6a H-8* 1.4 H-7 (CHa) H-8 0.9 H-8’ 1.4 H-8 H-7 (CHg) 1.7 H-8” H-7 (CHa) 3.1 H-6a 1.5

Figure 4.8: NOE difference data for cis diol 33.

irradiate observe % NOE difference H-7 (CHa) H- 8 4.7 H-8 * 5.3 H- 8 H-7 (CHa) 3.7 H CHa 34 7 H-8 " H-7 (CHa) 2.2

Figure 4.9: NOE difference data for acetonide 34.

Substrate 5 represents the most dynamic example thus far, fully illustrating the utility and superiority of the aqueous allylindium protocol (Scheme 4.17). After about 2 h in aqueous media, a facial selectivity of >97:3 was recorded favoring the trans diol 35 (entry 20 and 21). The axial nature of the tertiary hydroxy group requires the cyclohexanone to adopt a twist-boat conformer during a chelate-controlled transition state similar to that proposed for 3 (Figure 4.7, R = CHg).

88 > OH PH OH Br. In, r rC H a + solvent, rt f-Bu f-Bu 35 36

reaction Chelate/ entry solvent time (h) non-chelate yield, % 20 H2O 2.5 >97:3 66 21 50% THF(aq) 2.0 >97:3 67 22 THF* 120 2.1:1 90 23 THF* 0.5 1.7:1 96 " The reaction mixture of allyl bromide, indium powder, substrate 4 and THF was vigorously stirred in a tightly stoppered flask. “ Allyl bromide and indium powder were vigorously refluxed in THF and then cooled to rt before the addition of substrate 4.

Schem e 4.17: Indium-mediated allylation of a-tiydroxycyclohexanone 5.

The reactions in THF saw minimal diastereoseiectivity, approximately 2:1 in favor of the chelate- controlled isomer trans diol 35 (entries 22 and 23). The mix and stir method proceeded very slowly and required 5 days for completion. The preformed indium reagent was considerably more reactive but resulted in only a slight decrease in facial selectivity. The propensity for allylindium to effectively engage in chelation via a twist-boat transition state with hydroxy substitutents is overwhelming and cannot tie overstated. This is in stark contrast to the trans-2- spiro(tetrahydrofuranyl) analog which favored the equatorial isomer with an average diastereoseiectivity of 10:1 The resultant stereochemistry of the allyl groups was unambiguously determined by ^H NMR ir%luding NOE difference and long-range semi-selective

DEPT experiments. The axially disposed proton H-6a of trans diol 35 provided significant enhancements of the equatorial allyl group protons (H-8,3.2%) (Figure 4.10). These enhancements would not occur with an axially disposed allyl group. As typically observed, the axial allyl group of cis diol 36 responded very well to NOE difference experiments. Because of

89 the 1.3 diaxial relation between the allyl group. H-3a. and H-5a. notable NOE effects approaching

3-5% were measured (Figure 4.11 ). Furthermore, diastereomer 36 is uniquely well suited to

long-range semi-selective DEPT experiments (Figure 4.12).31 This experiment exploits the rigid

trans-diaxial relationship between a proton (H-6a) and a cartwn atom (C-8 of the allyl group). Thus,

observation of C-8 upon irradiation of H-6a would be proof of an axial allyl group. Because H-6a

overlapped slightly with H-6e a mild enhancement of 0-2 and 0-4 was obsenred in the recorded

DEPT spectrum. The antiperiplanar relationship between H-6e. and C-2 is particularly noteworthy.

The enhancements that resulted from the excitation of H-6a were considerably more intense,

including the structurally defined C-8. The equatorial isomer was unresponsive to this

experiment. Furthermore, diastereomers 35 and 36 were differentiated by chemical means.

irradiate Observe % NOE difference H-6a H-8 3.2 8* 0.9 H-H-9 1.9 H-7 (CHa) H-8 3.3 H-8' 3.2 H-8 H-6a 2.3 H-7 (CHa) 0.8 H-8' H-6a 1.4 H-7 (CHa) 3.9

Figure 4.10: NOE difference data for trans diol 35.

irradiate observe % NOE difference H-3a H-8 2.8 H-8' 1.7 H-5a H-8 3.7 H-3a 4.8 H-8 H-Sa 3.1

Figure 4.11 : NOE difference data for cis diol 36.

90 irradiate observe coupling intensity H-6a 0-8 very 0-1 very 0-5 very mild H OH Hga H-6e 0-2 1.3j 0-4 mild

Figure 4.12: Long range semi-selective DEPT for cis diol 36.

The unique cis diol 36 was converted to its acetonide 37 under standard mild conditions

in 83% yield (Scheme 4.18). Under identical conditions 35 was unreactive due to the rigid trans diaxial 1,2-diol. The same barrage of NMR experiments were performed on 37 as were performed on the diol precursor. However, the results were not as consistent. The observed NOE enhancements paled in comparison, rrwst critically between the axial allyl group, H-5a and H-3a protons (Figure 4.13). The long range semi-selective DEPT experiment failed to give a strong enhancement of C -8 with the irradiation of H- 6a (Figure 4.14). The overlap of H- 6a and H- 6e produced intense responses of 0-2 and 0-4 with only a weak 0-8 signal. The most likely explanation is a flattening of the ring at 0-1 and 0-2 due to acetonide-induced eclipsing of the allyl and methyl groups. This point is brought home in the larege NOE difference observed between

H-8 and the methyl group (4.4%) and the disappearance of sizable NOE differences between the allyl group (H- 8,8 ), and H-3a and H-5a. In any event, the combination of rigorous NMR experiments and chemical transformation unambiguously established the structures of diastereomers trans diol 35 and trans diol 36.

PH OMe

C A . [PPTS], OH3 OH2OI2, reflux (48%)

S chem e 4.18: Conversion of cis diol 36 to acetonide 37. 91 irradiate observe % NOE difference H-3a H-8 1.8 H-5a H-8* 1.7 H-8 4.4 rCHa H-7 (CHa) H-8* H-3a 1.3 H-5a 1.2 37

Figure 4.13: NOE difference data for acetonide 37.

irradiate obsen/e coupling intensity H-6a C-8 mild C-1 very C-5 mild H-€e C-2 1.3j very C-4 very

Figure 4.14. Long range semi-selective DEPT for acetonide 37.

4.4. Competition Experiments

To furtfier support our cfieiate-controi models for indium-mediated allylations, we performed

a number of competition experiments (Table 4.8). Chelation/non-ctielation arguments balance

against steric considerations, field/inductive effects, and orbital overlap factors as an explanation

for high diastereoseiectivityIn this case, the competition experiments parallel the substrate’s

reactivity and stereoselectivity. Chelation-control is marked by an increased reaction rate through

a lowering of the transition state energy, the result being that the more chelate-selective

substrates are also the more reactive. There is a marked effect between an equatorial and axial

hydroxyl group as evidenced by the fourfold increase in the reactivity of cis 4 over trans 5 (entry

19). This difference is about twice that observed for the competition experiment between the cis and trans 2-spiro(tetrahydrofuranyl) congemers (2.5:1, favoring the equatorial diastereomer), but considerably diminished from that obsen/ed with the methoxy pair (>99:1, favoring the equatorial diastereomer).^ This potential discrepancy, however, is due to the increased reactivity of hydroxy 92 substrates 4 and 5 compared to the ether pairs. This conclusion is best illustrated by entry 20 which pits 4 against crs-4-rerf-butyl-2-methoxycyclohexanone (38); the result is a relative rate ratio of 6.1 ;1 favoring the hydroxy moiety. Entries 20-22 clearly establish that a hydroxy group has a tremendous kinetic effect on the reaction rate of the allylindium reagent. Furthermore, the methyl group found in tertiary alcohol 4 negligibly retards chelation with regard to secondary alcohol 2 (compare entries 20 and 22). Entry 23 leads to the conclusion that hemiacetals are kinetically less reactive than a free hydroxyl. This rate however does not appear to be pH dependent. Perhaps 1 is influenced by the increasing concentration of indium salts as the reaction progresses. Loh has reported that the indium-mediated allylation of hemiacetals in water using InClg proceed quite readily.^ Finally, the observed high diastereoseiectivity and relative reactivity in water of a-hydroxy substrates 1*6 are unquestionably the result of chelation control.

The fact that the indium species overrides the solvation forces of the free hydroxyl group in water is very intriguing.

93 entry first ketone second ketone reaction time, h relative rate ratio

19 4.1 :1®

OMe 20 6.1 :1• lb

f-Bu 4

21 8 .5 :1• lb

f-Bu

OH OMe 22 8 6.9 :1• lb

f-Bu f-Bu 35

OH 23 6 1.7:1*’-'= 6 1.5:1*’-''

1 f-Bu (dimer)

“ The relative rate ratio was determined by quantitative assesment of unreacted ketones. " The relative rate ratio was ascertained by quantitative analysis of the alcohol products formed. *= The reaction was run in water with an initial pH of 7.0. " The reaction was run in water with an initial pH of 4.0.

Table 4.1 : Competitive indium-promoted allylations in water at room temperature.

94 4.5. Conclusion

This investigation expands upon ttie acyclic systems probed so successfully earlier by the

Paquette groupé and nicely complements the substituted a-alkoxycyclohexanones used in our previous study found in Chapter 3^. Our experimental results regarding the allylindium reagent clearly demonstrates operation of a viable chelation-controlled addition to 2- hydroxycyclohexanones. Equatorially hydroxyls respond with high stereocontrol to afford a single diastereomeric cis diol. Axially disposed hydroxyl also responded with exceptional diastereoseiectivity, particularly in water and in comparison to an ethereal oxygen. The kinetic effect of an equatorial hydroxy group was clearly evident from competition experiments. In these examples though, the relative rates of reactivity were not as dramatic as found with a- alkoxycyclohexanones. This phenomenon is attributed to the requirement of the axial hydroxyl isomers to secure a twist-boat conformer via chelation with the allylindium reagent prior to nucleophilic addition. The need to cross this energy barrier is reduced with free hydroxyls due to decreased sterics and stronger chelation. Evidently, water does not deter chelation, and may actually facilitate pre-coordination.

95 LIST OF REFERENCES AND NOTES

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M.; Isaac, M. B.; Crasto, 0. F.j Schomer, W. W. J. Org. Chem. 1997, 6 2 , 4293. (c) Paquette, L.

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A.; Mitzei, T. M. J. Org. Chem. 1996, 61, 8799. (d) Paquette, L. A.; Mitzei, T. M. J. Am. Chem.

Soc. 1996, 118, 1931.

(2) For the experimental results exploiting 2-methoxycyclohexanones and its 4-fed-butyl

homologues, and the three a-spirofuran substituted cyclohexanones refer to Chapter 3 or

Paquette, L. A.; Lobben, P. C. J. Am. Chem. Soc. 1996, 118, 1917.

(3) (a) Kocienski, P. J. Protecting Groups, Georg Thieme Veriag: Stuttgart, 1994. (b) Greene, T.

W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, John Wiley & Sons, Inc.: New York,

1991.

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J. Chem. Soc., Chem. Commun. 1990, 505.

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Chem. Soc. 1989, 111, 6861.

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G. M.; Gruber, J. M. J. Org. Chem. 1978, 4 3 ,1599.

(7) See appendices for copies of the ^H, COSY 90 spectra of 7 and 8.

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Related Hydmaromatic Compourxisr, Rabideau. P., Ed.; VCH: Weinheim, 1989; Chapter 2. (b)

DenmarK S. E.; Dappen, M. S.; Sear. N. L; Jacobs. R. T. J. Am. Chem. Soc. 1990. 112,3466.

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Trans. 11990.1239. and references cited therein, (b) Spohn, R. F.; Grieco. P. A.; Nargund. R.

P. Tetrahedron Lett. 1987. 28, 2491.

(10) (a) Brown. H. 0.; Deck. H. R. J. Am. Chem Soc. 1965. 8 7,5620. (b) Brown. H. 0.;

Weissman. D. M. J. Am. Chem. Soc. 1965. 8 75614. .

(11) Dauben. W. G.; Fonken. G. J.; Noyce. D. S.J. Am. Chem. Soc. 1956. 78, 2579.

(12) Evans. D. A.; Chapman. K. T.; Carreira. E. M. J. Am. Chem Soc. 1988. 110,3560.

(13) Carreho. M. C.; Ruano. J. L. G.; Garrido. M.; Ruiz. M. P.; Solladié. G. Tetrahedron Lett. 1990.

31, 6653.

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H.; Hahn. C. S. J. Org. Chem. 1986, 51, 404.

(16) After this route was abandoned a very relevant reference was found that substantiated the epimeriability of axial alkoxy groups to their equatorial counterparts under acidic conditions: Cross,

B.; Whitham, G. H. J. Chem. Soc. 1960,1650.

(17) (a) Wrttig. G.; Schoellkopf, U. Org Synth., Wiley: New York, 1973, Coll. Vol. V, p. 751. (b)

Greenwakj, G.; Chaykovsky,M.; Corey. E. J. J. Org. Chem. 1963, 2 8 ,1128.

(18) (a) Paulmier, C. Selenium Reagents and Intermediates in Organic Synthesis: Pergartron: New

York, 1986; p 353. (b) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526. (c) In

Organoselenium Chemistry, Liotta, D. C. Ed.; Wiley Interscience: New York, 1987.

(19) A diastereoselectivity of >97:3 represents the perceived detection limit of the instrument.

(20) (a) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95,7917. (b) Sharpless. K. B.;

Lauer, R. F. J. Am. Chem. Soc. 1972, 94, 7154.

97 (21) (a) Francis. M. J.; Grant, P. K., Low. K. S.; Weavers. R. T. Tetrahedron 1976, 32 .95. (b)

Trachtenberg. E. N.. Nelson. C. H.. Can/er. J. R. J. Org. Chem. 1970, 3 5 , 1653.

(22) (a) Johnson. F. Chem. Rev. 1968. 68,375. (b) Eliel. E. L ; Wiien, S. H.; Mander. L. N.

Stereochemistry of Organic Compounds, John Wiley & Sons, New York. 1994.

(23) Wang. Y. Ph. D. Thesis. University of Kansas. 1993. We thank Professor J. Aubé for making

this part of the thesis available to us.

(24) Newkome. G. R.; Fishel. D. L. J. Org. Chem. 1966. 31, 677.

(25) Corey. E. J.; Enders. D. Tetrahedron Lett. 1976.3.

(26) Krafft, M. E.; Holton. R. A. Tetrahedron Lett. 1983. 2 4 ,1345.

(27) (a) Tokuda. M.; Satoh, S.; Katoh. Y.; Suginome. H. In Electroorganic Synthesis, Little. R. D.;

Weinberg. N. L. Eds., Dekker New York. 1991; p. 83. (b) Tanaka. H.; Yamashita. S.; Hamatani. T.;

Nakahara. T.; Toni, S. In Recent Advances in Electroorganic Synthesis, Torii. S. Ed.. Elsevier:

New York. 1987; p. 307. (c) Habeeb. J. J.; Tuck. D. G. J. Organomet. Chem. 1977. 134,363. (d)

Habeeb. J. J.; Said. F. F.; Tuck. D. G.J. Organomet. Chem. 1980. 190, 325.

(28) Tokuda. M.; Kurono. N.; Mimura. N.Chem. Lett. 1996.1091.

(29) (a) Review: Yamamoto, Y.; Asao. N. Chem. Rev. 1993, 93,2207. (b) Aluminum, maganesium. lithium, potassium and sodium: Gaudemar, M. Tetrahedron, 1976. 3 2 ,1689. (c)

Chromium: Hiyama, T.; Okude, Y.; Kimura. K.; Nozaki, H.Bull. Chem Soc. Jpn. 1982. 55. 561.

(d) Tin: Namta, Y.; Ushida. S.; Maruyama. K. Chem. Leff.1979,919. (e) Indium: Reetz, M.T.;

Haning, H. J. Organomet. Chem. 1997, 5 41, 117. (f) Indium: Araki, S.; Ito. H.; Butsugan. Y.J.

Org. Chem. 1988, 5 3 , 1831. (g) Zinc: Wilson, S R.; Guazzaroni, M E. J. Org. Chem. 1989, 54.

3087.

(30) (a) Whitaker. K. S.; Whitaker, D. T. In Encyclopedia of Reagents for Organic Synthesis,

Paquette. L. A. Ed. in Chief. John Wiley & Sons. Inc.: Chichester. 1995; Vol. 5. p 3390. (b)

Please see reference 3.

98 (31) (a) Bax, A. J. Magn. Reson. 1983, 52,330:1983, 5 3 . 517. (b) Rutar, V. J. Am. Chem. Soc.

1983, 105, 4095. (c) Rutar, V. J. Magn. Reson. 1984, 5 6 , 87. (d) Wimperis, S.; Freeman, R. J.

Magn. Reson. 1984, 58, 348. (e) Lin, L-J.; Cordell, G. A. J. Chem. Soc., Chem. Commun.

1986, 377.

(32) Das, G.; Thornton, E. R. J. Am. Chem. Soc. 1993, 115, 1302. (b) Frye, S. V.; Eliel, E. L.;

Cloux, R. J. Am. Chem. Soc. 1987, 109,1862. (c) Chen, X.; Hortelano, E. R.; Eliel, E. L.; Frye,

S. V. J. Am. Chem. Soc. 1990, 112, 6130.

(33) Loh, T.-P.; Li, X.-R. J. Chem. Soc., Chem. Commun. 1996,1929.

99 CHAPTER 5

3-HYDROXYCYCLOHEXANONES AND 4-HYDROXYCYCLOPENTENONES

5.1. Background

In the previous chapter, we established the high chelating ability of a-hydroxy groups in water. The possibility of g-hydroxy groups efficiently chelating to the allylindium reagent has only been demonstrated with acyclic aldehydes.^ We desired to probe further the chelating ability of proximal p-hydroxy groups in order to define the limits of this phenomenon. With this objective in mind, we chose to investigate enantiopure 4-hydroxy-2-cyclopentenone (2) and it acetate derivative 1, as well as trans- and c/s-4-ferr-butyl3-hydroxycyclohexanone (3 and 4) (Figure 5.1).

Our anticipation was that substrates 2 and 4 might give rise to heightened levels of trans 1,3 diols

5 and 6 through chelation control (Figure 5.2). X X "OH ^ Y ^ O H 1 r-Bu f-Bu 3 4

Figure 5.1: p-Oxygenated substrates 1-4.

100 Br. In. H20.rt HO ___ >

Br. In. HQ OH

Figure 5.2: Proposed transition states for the indium-mediated allylation of 2 and 4.

5.2. Synthesis

5.2.1. 4-Acetoxy- and 4>Hydroxycyclopentenones (1 and 2)

Cyclopentenones 1 and 2 were synthesized by the known literature procedure, as delineated by Paquette, et. al.^^ PCC oxidation of allylic alcohol 7^= afforded (4fl)-(+)-acetoxy-2- cyclopenten -1 -one (1) in 63% yield (Scheme 5.1). Mild saponification using wheat germ lipase over a nine-day period followed by prolonged continuous extraction afforded (4/7)-(+)-hydroxy-2- cyclopenten-1-one (2) in 44% overall yield.

OAc PCC. NaOAc. , 0%%^^y^QAc wheat germ lipase,^ O OH 4Â MS. CH2CI2, ft \=/ phosphate buffer (63%) 1 (70%)

Scheme 5.1: Synthesis of cyclopentenones 1 and 2.

5.2.2. trans- and c/s-4-rerf-Butyl-3-hydroxycyclohexanones (3 and 4)

Substrates 3 and 4 have been previously synthesized by Evans, Chapman, and Carreira in their much publicized investigation of the reducing ability of Me 4NHB(OAc)3.3-^ Experimental details and references pertinent to the syntheses were given in the full paper. However, we found it necessary to modify a few key steps. Commercially available 4-ferf-butylphenol was 101 OCH3 HO Li. BH3*MeS; ^ NaOH. H2O2 B 2 O/ NH3 (C00H)2 '"OH (36%) (81% over t-Bu f-Bu two steps) 8 PPTS. o '^ o PG C acetone. _ PPTS, acetone. DIBAL-H. H2O. reflux + 9 (65%) ^ H2O. reflux tiexanes (65%) (75%) (78%)

Sctieme 5.2: Synthesis of 3-hydroxycyclohexanones 3 and 4.

methylated on a large scale using NaOH and Me 2S0 4 to afford the anisole 7 (Scheme 5.2)

Birch reduction of this Intermediate followed by acid-catalyzed ketallzatlon of the crude reaction mixture provided olefin 8 in an overall yield of 8 1 % .^ ^ We opted to use oxalic acid rather than the recommended p-toluenesulfonic acid In the ketallzatlon step because of the diminished potential to promote conjugative migration of the double bond.®*^'®-® As suggested, borane methyl sulfide provided regioselective and stereospecific hydroboration of the double bond to afford key intermediate 9. albeit in low yield (36%). The seemingly trivial deprotection of ketal 9 to produce 3 proved rather cumbersome and therefore required considerable experimentation.

Forceful and/or harsh conditions resulted in dehydration and formation of the a.p-unsaturated ketone derivative. The Evan’s procedure made use of 50% HOAc In THF at rt. However. In our hands this reaction proceeded very slowly, and heating of the reaction mixture Induced substantial dehydration. Recourse to the more mild conditions of PPTS in refluxing aqueous acetone cleanly afforded 3 in 65% yield. Access to 4 was achieved by initial oxidation of key intermediate 9 with PDC to afford ketone 10 uneventfully (65%). At this juncture, the use of L-

Selectrlde in THF as reported by Evans resulted In the formation of a >10:1 mixture of 11 and 9. respectively, in an unacceptable yield of 18%. Alternative use of the monodentate chelating 102 reagent DIBAL-H in hexanes {1.5 eq at 0.1 CM) gave a diminished ratio of 3.9:1 still in favor of 11,

but in a much more synthetically useful yield of 78%. The increased yield allowed the efficient

recycling of minor diastereomer 9 through the above route. PPTS-catalyzed hydrolysis of the

dioxolane protecting group afforded 4 in 75% yield. The ^ H and NMR spectra data for 3 and

4 were considerably different from tfwse reported by Evans, Chapman, and Carreira.^ ^

5.3. Results

Indium-mediated ailyiation of 1 efficiently provided homoaliylic alcohols 12 and 13, albeit

with minimal facial selectivity (Scheme 5.3). Although there was a slight preference for trans

addition, the resulting diastereoselective ratios were unaffected by water as gauged by the

highest percentage of 12 (1.8:1) in entry 1. As observed in previous studies, the reaction time in

THF was considerably longer than in aqueous THF or water. The stereochemistry of 12 and 13

was secured through NOE difference experiments. The conformationai flexibility of 12 was most

apparent by a 3.7% enhancement of H-5 when H-4 was irradiated (Figure 5.3). This is likely due to

the competing equatorial occupancies of the allyl and OAc groups as in A and B, respectively.

Regardless of this fact, the enhancement of H-4 and H- 8 ,8 ' clearly supported the trans disposition of these two substitutents. Conversely, the cyclopentene framework of 13 appeared rigid and

NOE difference experiments resulted in sizable through-space interactions between H-4 and H-

5e as well as H-5a and H-8 ,8 ' (Figure 5.4).

o==>r^°A c " V y ° ^ solvent, rt ^ W HO W 12 13

reaction ratio entry solvent time (h) 1 2 :1 3 yield, % 1 HgO 0.5 1.8 :1 77 2 50% THF(aq) 1.5 1.6 :1 83 3 THF 8.0 1.4:1 74

Scheme 5.3: Indium-mediated allylation of cyclopentenone 1. 103 H H O li irradiate Observe % difference NOE H 2 H3C H-4 H-5 3.7 TT H-8 ,8 ’ 0.6 r - ‘ H-8 ,8 ’ H-4 1.2 10 12 H-5 3.5

Figure 5.3: NOE difference data for ois 12.

irradiate obsen/e % difference NOE H-4 H-5e 2.9 H-5e H-4 6.8 2 CH3 7 H-5a H-8 ,8 ’ 1.7 H-8 ,8 ’ H-5a 3.4 13

Figure 5.4: NOE difference data for trans 13.

P-Hydroxycyclopentenone 2 was unstable to long-term storage at or below room temperature. Overtime, a dark brown mixture was produced from tfie pure, pale yellow oil.

However, the short reaction time of the indium-mediated allylation in water and aqueous THF conveniently allowed the diastereoselective ratio to be determined by ^H NMR integration of the crude reaction mixture (Scheme 5.4, entries 4 and 5). Due to the typical long reaction times

in. solvent, rt

reaction ratio entry solvent time (h) 14 :5 yield, % 4 H2O 2.5 5.1 :1 63 5 50% THF(aq) 4.0 3.1 : 1 61 6 THF decomposition

Scheme 5.4: Indium-mediated allylation of p-hydroxycyclopentenone 2 104 required in anhydrous THF the starting material inevitably decomposed (entry 6). The isolated

yields (ca 60%) were slightly compromised in the two other solvent systems in comparison to

acetate derivative 1. The major product from both successful reactions was the cis 1,3-diol 14

and not the desired trans 1,3-diol 5. Evidently, 2 is not subject to chelation-control as anticipated

(Figure 5.2). The minor homoaliylic alcohol 5 was notably more unstable. Elemental analysis

could not confirm the C/H ratio for the molecular formula of C8 H12O2 which was alternatively

established by HRMS. Other spectroscopic data, i.e. IR and NMR provided ample

evidence for the proposed structure. The stereochemistry of homoaliylic alcohols 14 and 5 were

determined via chemical methods. Estérification of alcohol 14 with AC 2O afforded acetate 12 in

54% yield (Scheme 5.5, eq 1). Additionally, independent hydrolysis of esters 12 and 13 with

K2CO3 in MeOH afforded diols 14 and 5, respectively in 86 % and 71% yield (eq 2 and 3). The spectra of the products matched perfectly those obtained via the indium-mediated allylation protocols (Scheme 5.3 and 5.4).

OH AC2O. imid, 1) CH2CI2. 0 °C 14 (54%) 12

H Q ^ ^ . OAc K2CO3. MeOH, 2) 0 °C -> rt (86 %) 14

K2CO3. MeOH, OAc 3) 0 °C -> rt (71%)

Scheme 5.5: Structure elucidation via estérification of 14 and hydrolysis of 12 and 13.

The allylation of 3 occurred without event and produced homoaliylic alcohols 15 and 16

(Scheme 5.6). The ratio between the two resulting carbinols was fairly consistent in all three solvent conditions and expectedly very similar to the ratios reported in Chapter 4 for 4-tert-

105 butylcyclohexanone. Structure elucidation of 16 was accomplished by 1- and 2-D NMR

techniques. NOE difference experiments conclusively establistied ttie equatorial nature of ttie

allyl group via significant enhancements between the allylic protons H-7,7 and vinylic proton H-8,

as well as the equatorial protons H-2e and H-€e (Figure 5.5). As has been continually observed

throughout the entire project, equatorial alcohol 16 was more polar by TLC analysis than axial

alcohol 15. Also, strong enhancements have been consistently ot)sen/ed with the axial allyl

diastereomer. In this specific case a 2.7% interaction with H-7,7 was measured when H-3 of 16

was irradiated. The reciprocal experiment produced a 2.4% enhancement (Figure 5.6). Such

positive results are due to the 1,3-diaxial relationships between the allyl group, and H-3 and H-5a.

The 3.0% NOE difference observed between H-3 and H-2a, trans-diaxial in nature, suggest

conformational flexibility between the chair and boat conformera. Furthermore, two long-range

semi-selective DEPT experiments conclusively established the axial nature of the allyl group of

16 with a strong enhancement of C-7 foilowing independent irradiation of H-2a and H-6a (Figure

5.7)7 The success of this DEPT technique is dependent on the strong heteronuclear three-

bond coupling observed between nuclei with a dihedral angle approaching 180° or 0°. The

experiment occurs by pulsing a selected hydrogen frequency and recording a NMR

spectrum. Oftentimes, ^ couplings are obsen/ed.

OH H Q y ^

1 ^^^Br In. A + . solvent, rt . L^ J.. 1 J T Y OH f-Bu r-Bu f-Bu 3 15 16

reaction ratio entry solvent time (h) 1 5 :1 6 yield. % 7 H2O 2.5 6.6:1.0 73 8 50% THF(aq) 1.5 7 2 :1 .0 76 9 THF 60 5 8 :1 .0 74

Schem e 5.6 Indium-mediated ailyiation of rrans-4-ferf-butyl-3-hydroxycyclohexanone (3). 106 irradiate ot)serve % NOE difference H-2e H-3 4.6 OH H-7,7 1.5 7 __ H-8 1.3 HO 3 H-7,7' H-2e 1.1 15 H-6e 0.8 H-8 H-2e 0.9 H-6e 0.8

Figure 5.5: NOE difference data for trans 1,3 did 15.

irradiate observe % NOE difference H-3 H-2e 1.3 H-2a 3.0 H-5a 1.4 OH H-7,7 2.7 H-7,7 H-2e 1.0 16 H-3 2.4 H-5a 1.2

Figure 5.6: NOE difference data for cis 1,3 did 16.

irradiate observe coupling intensity H-2a C-1 strong C-3 strong OH C-7 medium HO H-6a 0-2 strong 0-4 medium 16

Figure 5.7: Long range semi-selective DEPT experiments for cis 1,3 did 16.

107 A single diastereomer resulted from the allylation of 4 under all three reaction conditions

as determined by NMR analysis of the crude reaction mixtures and subsequent

purification/isolation by silica gel chromatography (Scheme 5.7). We anticipated that axial attack

would predominate as a consequence of chelation with the axial hydroxy group (Figure 5.2). The

reaction in THF required much longer time, as usual, and a much lower yield was realized (entry

12). This low yield is presumed to be a result of decomposition as evidenced by TLC analysis of

the reaction mixture. Long-range semi-selective DEPT experiments showed a strong

enhancement of C-7 following upon the independent irradiation of H-2a and H-6a. This would

only be expected if the allyl group was trans-diaxial to both H-2a and H-6a. However, NOE

difference experiments did not support this possibility. When allylic protons H-7 and H-7" and

vinylic proton H-8 were irradiated, there was not the usual enhancement of H-5a. What was

obsenred was interactions with H-2e, H-2a, and H-€e, H-6a. This is consistent with an equatorially

disposed allyl group and mirrors the results obtained with homoaliylic alcohol 15 (Figure 5.5).

Clear confirmation of the relative stereochemistry of diastereomer 17 was obtained through

chemical conversion to acetonide 18 in 64% yield with 2-methoxypropene and to cartx)nate 19

with /V,/V-cartx>nyldiimidazole in 58% yield (Scheme 5.8). Clearly, if 4 had responded to chelate-

OH Br. In. solvent, rt OH OH r-Bu r-Bu 17

reaction entry solvent time (h) ratio yield, % 10 HgO 2.5 > 9 7 :3 89 11 50% THF(aq) 1.5 > 9 7 :3 89 12 THF 72 > 9 7 :3 39

Schem e 5.7: Indium-mediated allylation of c/s-4-rert-butyl-3-hydroxycyclohexanone (4).

108 J"'" . ^ . ( P P T S ) . CPI, (DMAP), kX ^ i CH2CI2, reflux k X ^ ^ O H 18 17

Scheme 5.8: Chemical conversion of cis 1,3-diaxial diol 17 to acetonide 18 and cart>onate 19.

controlled addition as anticipated in Figure 5.2, the resulting trans 1,3-diol 6 would have been

unreactive to analogous acetonide and cartwnate formation. IR spectroscopy of 19 confirmed

the presence of a cartxjnate cartx>nyl with a strong stretching frequency at 1718 cm*^. Mass

spectroscopy and elemental analysis established the molecular formula C 17H24O2 and the C/H

content, respectively. W-plan coupling, indicative of a rigid chair conformer, was observed from a

^H,^H COSY 90 NMR spectrum between H-2e and H-6e, and H-3e and H-5e: this observation essentially eliminates any possibility of molecular rearrangement.

It is not exactly clear why 4 was resistant to chelation-controlled addition with the allylindium reagent. However, upon examination of our general predictive model developed for such additions, it appears that concomitant coordination of the hydroxyl oxygen and the cartaonyl is important. The premise is that activation of the cartx)nyl is necessary. As can be seen in Figure

5.2, it is not possible for the reagent to activate the cartxinyl oxygen while coordinating to the oxygen lone pair. A simple rational explanation is that coordination of the metal center to the hydroxyl lone pair makes it impossible for the Y^ar1x)n of the allyl group to attack the carbonyl at the needed Bürgi-Dunitz angle of 107°.

5.4. Competition Experiments

As would be expected from the results in Schemes 5.6 and 5.7, there was essentially no kinetic preference exhibited by the allylindium reagent in the competition experiment between 3

109 and 4 (Table 5.1). The slight preference for 4 perhaps can be explained by the accessibility of the

equatorial alcohol of 3 towards unproductive chelation with ttie allylindium reagent. It tias long

been obsenred in this project that diastereomers with equatorially disposed alcohols are more

polar than their axial counterparts as a result of increased interaction with the absortaent. In this

case, the hydroxyl group of 3 may well engage in unproductive chelation, thereby increasing the

opportunity for addition to ketone 4.

reaction first ketone second ketone time (h) relative rate‘

5.5 1 :1.4 OH OH f-Bu f-Bu

' The relative rate ratio was ascertained by quantitative analysis of the alcohol products formed.

Table 5.1 : Competitive indium-promoted allylation of 3 and 4 in water at room temperature.

5.5. Conclusion

No significant degree of chelation was observed with either class of compounds.

However, a study involving only two substrates does not constitute a thorough investigation of

chelation-control by distal hydroxyl groups. Further work must be completed in this area before an

adequate conclusion can be reached. The source of future substrates with proximal hydroxyl groups is in essence limited by the imagination (and availability). Diastereomers 20 and 21 would show the degree by which the allylindium reagent favors endo or exo attack. p-Hydroxy ketones

22 and 23 would provide additional data to the structural requirements for chelate-controlled addition.

110 '1

o OH

23

111 LIST OF REFERENCES AND NOTES

(1) Paquette, L. A.; Mitzel, T. M. J. Am. Chem. Soc. 1996, 118,1931.

(2) (a) Deardorff, D. R.; Windham, C. O.; Craney, 0. L Org. Syn. 1996, 73,25. (b) Paquette, L.

A.; Earie, M. J.; Smith, G. F. Org. Syn. 1996, 73, 36.

(3) We thank Mike Gunzburger for the syntheses of 3 and 4. Do to certain discrepancies with the

published spectral data of 3 and 4 in reference 4, our acquired data are therefore included here:

ForS: white fluffy crystals: mp 118-119 ®C; NMR (300 MHz, CDCI 3) 84.61 (brs, IN),

2.55-2.38 (m, 4M), 2.37-2.24 (m, 1H), 2.07 (dddd, J= 12.8, 12.8,12.8, 4.6 Hz, 1H), 1.97-1.87 (m,

1H), 1.91 (brs, 1H), 1.53 (ddd, J= 12.5,3.4,1.5 Hz, 1H), 1.01 (s, 9H); 1% NMR (75 MHz, CDCI 3) ppm 211.8, 70.2, 50.9, 50.0, 41.5, 32.6, 28.8, 21.4.

For 4: white lustrous flaky crystals; mp 67.5-68.5 °C: ^ H NMR (300 MHz, CDCI3) 5 4.15

(dd, J = 8 .8 , 3.9 Hz, 1H), 2.54 (dd, J= 15.4, 4.0 Hz. 1H), 2.44 (dd, J = 15.5, 5.0 Hz, 1H), 2.38-

2.25 (m, 2H), 1.98-1.90 (m, 2H). 1.55-1.40 (m, 2H), 0.98 (S. 9H); 1% NMR (75 MHz, CDCI 3) ppm

211.9, 68 .6, 52.3, 47.8, 38.5, 32.8, 27.7, 21.6.

(4) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110,3560.

(5) (a) Hiers, G. S.; Hager, F. 0. Org Syn., Coll. Vol. 1 , 1956,58. (b) Wilds, A. L; Nelson, N. A. J.

Am. Chem. Soc. 1953, 75, 5360. (c) Bolon, D. A. J. Org. Chem. 1970, 35, 715. (d) Braude, E.

A.; Webb, A. A.; Sultanbawa, M. U. S. J. Chem. Soc. 1958,3328. (e) Agosta, W. C.; Schreiber,

W. L. J. Am. Chem. Soc. 1971, 93, 3947.

(6) (a) Kocienski, P. J. Protecting Groups, Georg Thieme Veriag: Stuttgart, 1994. (b) Greene, T.

W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, John Wiley & Sons, Inc.: New York,

1991.

112 (7) (a) Bax, A. J. Magn. Reson. 1983, 5 2 , 330:1983, 5 3 , 517. (b) Rutar, V. J. Am. Chem. Soc.

1983, 105, 4095 (c) Rutar, V. J. Magn. Reson. 1984, 56,87. (d) Wimperis, S.: Freeman, R. J.

Magn. Reson. 1984, 5 8 ,348. (e) Lin, L.-J.; Cordell, G. A. J. Chem. Soc., Chem. Commun.

1986, 377.

113 CHAPTER 6

6-SUBSTITUTED 2-HYDR0XY-1-TETRAL0NES

6.1. Background

We have demonstrated that substituted a-hydroxy cyclohexanones effectively participate in chelation-controlied addition with the allylindium reagent. This process is particularly viable in aqueous media, often resulting in higher diastereoselectivity and shorter reaction times in comparison to anhydrous THF. It is intriguing that the reagent can overcome the deleterious effects associated with an aqueous environment that would otherwise discourage chelation. To further expand upon the capabilities of the indium-mediated ailyiation, we desired to probe the stereoelectronic effects that might influence this reaction, primarily focusing on diastereoselectivity and relative reaction rates. With this in mind, we prepared 6-substituted tetralones la e with the express purpose to include the extremely electron-donating methoxy substitutent (1c) and the electron-withdrawing cyano substitutent (1e). The impetus for these selections stems from the classic findings that para substitutents of benzoates have a pronounced effect on the rate of ester hydrolysis under both basic and acidic conditions.^ We expect that competition experiments between these substituted tetralones will reveal this phenomenon in the context of the allylindium reagent.

1a,X = H b, X = OMe c, X = Br d, X = NMeAc e, X =CN

114 6.2. Synthesis of G-Substltuted 2>Hydroxy-l •tetralones

6.2.1. 2-Hydroxy-i-tetraione (la) and 2-Hydroxy-6*methoxy-l-tetralone (lb)

Substrate la was synthesized from commercially available 1-tetralone by the reliable

Rubottom oxidation, with isolation of the intermediate silyl erv)l ether in 92% yield (Scheme 6.1).^

Acyloin 1b was synthesized from 6-methoxy-1 -tetralone in the sam e manner but without isolation of the intermediate silyl enol ether. In this case, the overall yield for the three steps was an unoptimized 36%. Since 6-methoxy-1-tetralone is commercially available and the reaction sequence is straightforward, the low yield was acceptable.

1.LDA, THF, -78 °C; Q TMSCI, rt, HO 2. rrXDPBA, CHgClz: y TBAF, THF la , X = H (83%) b, X = OMe (36%)

Scheme 6.1: Synthesis of 2-hydroxy-1-tetralones la and 1b.

6.2.2. 6-Bromo-2-hydroxy-l-tetralone (lc)

Substrates ic-e originated from a common intermediate, the known 6-acetamidotetralin

(4), which itself was obtainable on large scale via a three-step sequence beginning with commercially available tetralin (Scheme 6.2) Friedel-Crafts acylation of the starting hydrocartxjn with AcCI afforded 6-acetyltetralin (2) in 94% yiekJ.^ Standard formation of the oxime (NHaOH-HCI and NaOAc in MeOH) occurred smoothly to afford 3 in 82% yield. However, purification could be delayed until after the final step with only a modest decrease in overall yiekf.^*^ Optimal conditions for the Beckman rearrangement entailed saturating a solution of oxime 3 in AcOH/Ac20(2:1 v/v) with anhydrous hydrogen chloride . The reaction mixture was then left at rt for 24 h whereby the pivotal acetamkJe 4 precipitated and was easily obtained by filtration in 72% overall yield from tetralin.

115 O j ^ ACC1.AICI3.. NH2OH.HCI. benzene, 0 »C NaOAc. MeOH, (82%) tetralintetr:..rn (94%) 2

II 'I HO AcOH.AczO, CCÇ Hci(g) ’ CHa ^ Ac

Scheme 6.2: Synthesis of the key intermediate 6-acetamidotetralin (4).

6-Bromo-2-hydroxy-1-tetralone was obtained from 4 by an additional trio of reactions and

in an overall yield of 22% (Scheme 6.3). PCC oxidation of 4 afforded the known 6-acetamido-1-

tetralone (5) in 61% yiekJ.^'^ Amide hydrolysis in refluxing HBr(aq) and subsequent Sandmeyer

reaction cleanly afforded the known 6-bromo-1-tetralone (1c), albeit in a modest yield of 52%.4 At

this juncture the Rubottom oxidation failed to install the needed a-hydroxy group, even with

TBDMSCI and other solvent/base combinations^. Recourse to the Moriarty protocol involving

methanolic Phl( 0 Ac)2 worked splendidly.^ Following acidic work-up and purification, the requisite

a-hydroxy tetralone l c was obtained in 70% yield. The mechanism of this interesting reaction is depicted in Scheme 6.4.

PCC. Celite, , benzene, reflux H N (61%) 5 I Ac

HBr(aq), reflux; Phl(OAc)g, piQ NaNOg, H 2O. 0 °C: KOH, MeOH, CuBr, HBr (aq), rt 0 °C -> rt: H3O+ (52%) (70%)

Scheme 6.3: Synthesis of 6-bromo-2-hydroxy-1-tetralone (lc).

116 The initial enolate attacks the iodonium reagent to form an a-iodotetralone intermediate.

A second equivalent of mettwxide anion then pyramidalizes the ketone and the ensuing

oxyanion displaces the ptienyl iodoacetate to afford an intermediate epoxide. Although it is

postulated that a third equivalent of methoxide opens the epoxide, perhaps a more plausible

pathway is an intermediate oxonium ion that precedes this addition. In any event, an acidic work­

up hydrolyzes the stable dimethoxyacetal to afford 6-bromo-2-hydroxy-1 -tetralone (lc). In short,

the cartx>nyl oxygen becomes the hydroxyl oxygen as it is reduced and transposed to the

neighboring cartwn atom.

AcO Q “ OMe -OMe Phl(0Ac)2

■COMe MeO. OMe H3O+ t 5 a 10

Schem e 6.4: Mechanism of the Moriarty a-hydroxylation protocol involving Phl(0Ac)2

6.2.3. 2-Hydroxy-6-(Af-methyl)acetamldo-1-tetralone (Id)

The /V-methyl acetamido derivative Id was considerably more difficult to synthesize.

Originally, we desired the secondary 6-acetamido substrate for our studies. However, the a- hydroxylation of 5 was unsuccessful under several conditions (Scheme 6.3). We hypothesized that this was due to the acidic proton of the amide. Nonetheless, two equivalents of base or prior protection of the amide with a Boc or Bn group proved fmitless. To quell any speculation regarding this acidic hydrogen, it was exchanged with a methyl group. /V-Methylacetamido derivative 7b was obtained from 4 via sequential méthylation and chromic acid benzylic oxidation in an overall yield of 67% (Scheme 6.5). Concem about the general reactivity and stability of the 117 X

1.NaH, Mel g-hydroxylation^. 2. CrOs, AcOH 7aX=H,H Ac bX = 0

Scheme 6.5: Second attempt to a-hydroxylate a 6-acetamidotetralone derivative.

amide caused us to employ a piithalimide group instead (Scheme 6.6). Acid hydrolysis of the

secondary amide 4 afforded the free amine after neutralization of the reaction mixture with 3M

NaOH. Subsequent phthaloylation^ with pth-C02Et (82%) and chromic acid oxidation afforded

tetralone 9 in a modest overall yield of 41%. We expected the phthalimide group with no

enolizable or acidic protons to be robust to an array of a-hydroxylation procedures. Our hopes

were dashed when all attempts towards introducing the needed hydroxy group again failed.

1 .6N HCI(aq), reflux p ------oa, 'p th (82%)

O CrOa, AcOH a-hydroxylation y (50%)

Scheme 6.6: Third attempt to a-hydroxlylate a 6-amido substituted tetralone.

After these trials and tribulations, it was determined that the a-hydroxyl group would have to be installed circuitously. We therefore adopted the successful approach used in Chapter 4 for the synthesis of frans-4-/erf-butyl-2-hydroxycyclohexanone. This approach required the initial synthesis of an olefin from one of our above intermediates prior to the allylic oxidation. With substantial quantities of intermediate tetralone 7 in hand, we performed a typical Wittig olefination

118 (PhaP+CHa r and KHMDS in THF) to obtain olefin 10 in 72% yield (Scheme 6.7). The ensuing

allylic oxidation with catalytic SeOa occurred uneventfully to produce 79% of allylic alcohol 11.^

Ozonolysis of the methylene substitutent unmasked the cartx)nyl in a favorable yield (74%) to furnish the elusive 2-hydroxy-6(AAmethy)acetamido-1-tetralone (Id). For security, we tended to store our material at the allylic alcohol stage until needed. It is duly noted that the existence of amide tautomer in an approximate ratio of 2:1 complicated the and NMR spectra to the point where the spectroscopic data cannot be reliably reported for some intermediates.

Ph3P=CH2, Me THF. 0 »C (72%)

(Se02), f-BuOOH. HO (H+). CH2CI2 (79%)

O3 , MeOH. -78 °C; Me 2S. rt (90%)

Scheme 6.7: Circuitous approach to 2-hydroxy-6(/V-methy)acetamido-1-tetralone (Id).

6.2.4. 6-Cyano-2-hydroxy-1-tetralone (1e)

a-Hydroxy tetralone 1e was obtained in a comparable manner via intermediate olefin 10

(Scheme 6.8). Due to the straightforwardness and overall operational ease of the SeOa approach, other a-hydroxylation procedures involving 6-cyano-1-tetralone (7). most notably the

Rubottom and Moriarty protocols, were not investigated. The required cyano substrate 7 was obtained via a literature procedure from the amine intermediate 12 used in the synthesis of 1c

(Scheme 6.3) 119 1.NaNOz 2. CuCN

12 13 14

CH2 (SeOa), f-BuOOH. HO, 0 3 . MeOH, I r 1 -78 »C; MeaS. r (H+). CHgClg (55%) 15

Scheme 6.8: Access to the pivotal 6-cyano-2-hydroxy-1-tetralone (le).

6.3 Results

a-Hydroxy tetralone la was reacted with the allylindium reagent under the previously established reaction conditions (Scheme 6.9). The most dramatic result occurred when the aqueous medium was replaced with anhydrous THF. A nearly complete reversal in diastereoselectivity was seen (compare entries 1-3). The trans diol 16 predominated in water and aqueous THF, with the latter solvent system (entry 2) producing a maximum ratio of 3.8:1 as measured by ^H NMR integration of the crude reaction mixture. Anhydrous THF on the other hand required a much longer reaction time and culminated in a nearly 2:1 ratio in favor of the syn

HO. HC H O ^ H O ^ In.

solvent, rt ' k 16

reaction entry solvent time (h) 16 17 yield, % 1 H2O 1.5 1 :2.5 82 2 50% THF(aq) 1.5 1 :3.8 95 3 THF 144 1.7:1 72

Schem e 6.9: Indium-mediated ailyiation of 2-hydroxy-1 -tetralone (la).

120 diol 17. The yields varied from good to excellent. As has been continually recorded throughout

this project, the anhydrous THF reactions required longer times than the aqueous reactions to be

completed. However, in this specific investigation the reaction time inexplicably varied from

substrate to substrate{vide infra). The stereochemistry of the product diols was ascertained by

conversion to their cartx>nates under typical conditions (GDI and catalytic DMAP in benzene)

(Scheme 6.10). It was found that simply warming the reaction mixture for a short period of time

(several hours) was often sufficient for complete consumption of starting material, although an

excess of reagent was always typically employed. In some cases, the reaction proceeded at rt.

However, a prolonged reaction time at reflux did not diminish the isolated yield. The resulting cis

and trans carbonates, 18 and 19 respectively, were subjected to extensive NOE difference

experiments. Long range semi-selective DEPT studies were inconclusive due to the dihedral

angles between H-2 and C-9 for the two isomers. For 18 this angle approaches 0°, whereas the

angle is almost 180* for 19. This NMR experiment is selective for three-bond heteronuclear

couplings with a dihedral angle very close to 0° or 180*, which are in general relatively large (-13

Hz) in nature for homonuclear couplings. Therefore, a strong enhancement of C-9 in both

cartx)nates resulted from the selective pulsing of the H-2 frequency. NOE difference

experiments on the other hand unambiguously defined the relative stereochemistry at 0-1 and 0-

2 of the two diastereomers. Strong mutual enhancements were observed between the cis

HO. GDI, (DMAP), HO, benzene, 5 h. rt (90»/o) H

GDI, (DMAP). Vo ' benzene, 24 h, reflux (93%)

Scheme 6.10: Conversion of cis and trans diols 16 and 17 to their respective carbonates. 121 disposed allyi group arxJ H-2 of 18. A 2.7% enhancement of ailyllc protons H-9,9’ occurred when

H-2 was irradiated (Figure 6.1). Application of the sam e NMR technique established the trans

nature of cartwnate 19. Figure 6.2 illustrates that by irradiating the allyl protons the top face

proton H-3' is obsenred (1.5%). The pseudo axial nature of H-3' was deduced from its relative

upfield shift of H-3 as well as its coupling constants. Conversely, irradiation of H-2 enhanced H-4'

to the 1.3% level on the a-surface of the cartxinate. Again, the d s diols (and carbonates) were

always less polar than their trans counterparts by TLC analysis and chromatographic separation.

irradiate observe % NOE difference V q H-2 H - l l ,i r 2.7 H-12 1.9 H-13,13' 1.2 H - ii,ir H-2 2.1 18 H-12 H-2 1.6

Figure 6.1: NOE difference data for cis caitonate 18.

irradiate observe % NOE difference H-2 H-3 2.9 H-4' 1.3 H-3' H-2 1.5 H-4 5.3 H-11 2.5 H-12 3.0 H-11 H-3' 1.5 H-12 H-3' 0.7

Figure 6.2: NOE difference data for trans carbonate 43.

A similar crossover in diastereoselectivity was observed for the methoxy substituted a-

hydroxytetralone 1b (Scheme 6.11). Aqueous THF again gave the maximum ratio of 1:4.4 with

respect to diastereomers 20 and 21 (91%) (entry 5). The reaction time in water and 50% THF(aq) were comparable, approximately 1 h. However, in anhydrous THF the reaction time ranged from 122 HO, HO, HO,HO. Br. In, + solvent, rt OMe OMeOMe 20

reaction entry solvent time (h) 2 0:21 yield, % 4 HgO 1.5 1 :3.0 76 5 50%THF(aq) 1.0 1 :4.4 91 6 THF 18-36 2 .4 :1 63

Schem e 6.11: Indium-mediated allylation of 2-hydroxy-€-methoxy-1-tetralone (1b).

18-36 h and the diastereoselectivity ratio of 2.4:1 favored the cis diol 20 (entry 6). In comparison

to substrate la, the reaction time was dramatically shorter but still consistently longer than

required for aqueous conditions (compare Scheme 6.9, entry 3). From the outset it was expected

that the electron-donating ability of the para-methoxy substituted would retard the indium-

mediated coupling of allyl bromide. In this example however, the substitutent appears to facilitate

addition in anhydrous THF. This apparent anomaly is currently unexplainable and is further complicated by the forthcoming results. The relative stereochemistry of the resultant diols was

secured by extensive NOE difference experiments on the respective carbonate derivatives

CPI, (DMAP), benzene, 12 h, rt (66 %) OMe OMe

CDI,(DMAP), benzene, 8 h, rt* (68 %) OMe OMe

Scheme 6.12: Conversion of cis and trans diols 20 and 21 to their respective carbonates.

123 obtained under the prototypical mild conditions (Scheme 6.12). Cis carbonate 22 reacted

cleanly. Irradiation of H-2 produced strong enhancements of the aliylic protons H-12,12’ (2.5%)

and the vinylic proton H-13 (2.7%). Cartwnate 23 also responded well to similar experiments. In

this instance irradiation of aliylic proton H-12 gave rise to a 1.6% enhancement of H-3'. On the

other face of the cartx)nate derivative, irradiation of H-2 produced a 1.7% enhancement of H-4’

(Figure 6.4).

irradiate observe % NOE difference H-2 H-4’ 1.5 H-12,12’ 2.5 H-13 2.7 H-14,14’ 1.3 7 OMe H-12,12’ H-2 2.7 H-13 H-2 2.4

Figure 6.3: NOE difference data for cis carbonate 22.

irradiate Observe % NOE difference H-2 H-4’ 1.7 H-12 H-3’ 1.6 7 OMe 23 11

Figure 6.4: NOE difference data for trans carix)nate 23.

Bromine-substituted tetralone l c responded positively to the allylindium reagent under

the trio of reaction conditions (Scheme 6.13). Although in all three examples the trans

diastereomer 25 predominated, the ratio in anhydrous THF was considerably diminished from the

maximum ratio of 5.8:1 found in aqueous THF (compare entries 8 and 9). Although a crossover in

the diastereoselectivity was not observed, the magnitude of change from aqueous media to THF was consistent to that found in the previous two substrates la and 1b. The aqueous THF

124 HO. HO. HO. Br, In, + solvent, rt Br Br

reaction entry solvent time (h) 2 4 :2 5 yield, % 7 H2O 1.0 1 :4.5 89 8 50% THF(aq) 0.5 1 :5.8 93 9 THF 10.0 1 :1.5 78

Schem e 6.13: Indium-mediated allylation of 6-bromo-2-hydroxy-1-tetralone (1c).

procedure thus far has consistently afforded the largest percent of the trans diol diastereomer,

typically 20-30% more than the reaction performed in pure water and with a 4-6 fold increase over

the anhydrous THF protocol. The reaction time in THF sharply decreased to 10 h, more than a

one fold decrease in comparison to substrate 1b under identical reaction conditions. The

respective carbonates of the homoallylic alcohols 24 and 25 were efficiently synthesized in

refluxing benzene and as before were subjected to rigorous NOE difference NMR experiments to

establish the relative stereochemistry of the parent diastereomeric diols unambiguously (Scheme

6.14). The cis cartx>nate 26 produced strong enhancements of the allyl protons following the

HO., o CPI, (DMAP). o benzene, reflux, 3 h (87%)

GDI, (DMAP), HO, benzene, reflux, 3 h (79%) Br 27

Scheme 6.14: Conversion of cis and trans diols 24 and 25 to their respective carbonates. 125 irradiation of H-2, the most significant of which were to the aliylic protons H-11,11’ (2.9%) and to

the vinylic proton H-12 (2.2%) (Figure 6.5). The trans cart»nate 56 was equally informative,

giving strong interactions on both faces of the ring system (Figure 6.6). Irradiation of the

downfield H-2 signal resulted in a 1.2% enhancement of the pseudoaxially disposed H-4'.

Irradiation of the aliylic H-11 and the H-3' protons resulted in concurring enhancements of 1.2%

and 4.1%, respectively.

irradiate otsserve % NOE difference H-2 H-11,11' 2.9 V q H-12 2.2 H-13.13' 1.1 H-4 H-2 3.0 7 Br H-12 0.8 26 H-12 H-2 1.8

Figure 6.5: NOE difference data for cis carbonate 26.

irradiate observe % NOE difference H-2 H-3 2.8 V a .-Br H-4' 1.2 H-3' H-11 4.1 7 Br H-12 2.1 H-11 H-3' 1.2

Figure 6.6: NOE difference data for trans carbonate 27.

The indium-mediated allylation of the problematic /V-methylacetamido tetralone Id was telling in water and 50% aqueous THF. However the reaction was demonstrably ineffective in anhydrous THF over a 5 day period (Scheme 6.13). The unreactivity of Id in anhydrous THF is not surprising in light of the developing trend that electron-withdrawing groups or inductive effects increase the reaction rate. In this connection, unsubstituted substrate la had a reaction time of 144 h compared to 10 h for the bromo substrate 1c (Schemes 6.9 and 6.13, entries 3 and 126 HO.

solvent, rt

reaction entry solvent time (h) 28:29 yield, % 10 HgO 2.0 1 :1.5 69 11 50% THF(aq) 3.0 1 :4.0 94 12 THF 120 no reaction 13 THF" >0.5 1 :2.6 81 * Allyl bromide and indium powder were precomplexed under Ng in refluxing THF in 10 minutes, then cooled to rt prior to the addition of the a-hydroxy tetralone.

Scheme 6.15: Indium-mediated allylation of A/-methylacetamido substituted tetralone Id.

9, respectively). The exact cause of this phenomenon remains unclear. Recourse was made to

precomplexing the allyl bromide with the indium powder under N 2 in refluxing THF prior to addition

of the a-hydroxy tetralone. In this instance a moderate diastereoselectivity of 2.6:1 for trans diol

29 was observed (entry 13). This selectivity notably surpassed for the first time the ratio observed

in water by approximately one order of magnitude. The aqueous THF protocol was

uncharacteristically only 1.5 times more selective than the precomplexing reaction and 2.5 times

more selective than the pure water procedure (compare entries 10-13). The trans diol 29 was the

major diastereomer for all three reaction conditions. The yields, although variable, ranged from

good to excellent. The diastereoselectivity of each reaction was determined by ^ H NMR

V o V o , CPI. (DMAP). o. ' " " benzene, reflux, 6h + (87%) .Me 30 Ac Ac

Scheme 6.16: Conversion of cis and trans diols 28 and 29 to their respective cartx)nates.

127 integration of the crude reaction mixtures. Due to the similar polarity of the individual diols, 28 and

29 could only be enriched by tedious and latx>rious chromatographic purification. For structure elucidation purposes, the respective cartwnates were obtained from the diol mixture and isolated by standard chromatographic techniques to afford the pure individual derivatives 30 and 31

(Scheme 6.16). Irradiation of H-2 in d s cartwnate 30 enhanced all the resident allyl protons, most significantly the vinyl proton H-15 (2.1%) (Scheme 6.7). Comparable irradiation of the sam e proton in trans diastereomer 31 gave rise to a 3.0% enhancement for H-4’ (Figure 6.8).

irradiate Observe % NOE difference H-2 H-14,14 1.3 H-15 2.1 H-16 1.3 H-15 H-2 1.9 H-16,16' H-2 0.9

Figure 6.7: NOE difference data for cis carbonate 30

irradiate observe % NOE difference H-2 H-4' 3.0 7 N' 11

Figure 6.8: NOE difference data for trans carbonate 31.

The pivotal 6-cyano-2-hydroxy-l-tetralone (le) reacted with allyl bromide in the presence of indium powder to afforded homoallylic alcohols 32 and 33 (Scheme 6.17). The aqueous THF protocol again afford the greatest ratio in favor of the trans diol (6.3:1). The ratio in water continued to favor diol 33, though at a lower level (3.2:1). As with the N-methylacetamido derivative Id, there was no reaction in anhydrous THF for a period of 5 d. When recourse was made to our precomplex conditions, the diastereomeric carbinols were formed in a 1:1.6 ratio, still

128 solvent, rt le

reaction entry solvent time (h) 32:33 yield, % 14 H2O 2.0 1 :3.2 90 15 50% THF(aq) 1.5 1 :6.3 90 16 THF 120 no reaction 17 THF» 0.5 1 :1.6 88 * Allyl bromide and indium powder were precomplexed under N2 in refluxing THF in 10 minutes, then cooled to rt prior to the addition of the a-hydroxy tetralone.

Scheme 6.17: Indium-mediated allylation of 6-cyano-2-hydroxy-1-tetralone (le).

in favor of trans diol 33, after a brief reaction time of less than 30 min. This disparity between the diastereomeric ratio in aqueous THF and anhydrous THF (roughly a fourfold difference) is in favor consistent to what was observed with unsubstituted tetralone la (Scheme 6.9) and the electron- donating methoxy substituted 1b (Scheme 6.11). Transformation of the individual diols 32 and

33 to the corresponding cart>onates uneventfully furnished cis 34 and trans 35 (Scheme 6.18).

Comprehensive NOE difference measurements unambiguously defined the relative

V o GDI, (DMAP). o ' PhH, 4 h. 65 °C CN (46%)

HO, HO. GDI, (DMAP), PhH, 4 h, 65 °G GN (67%) GN

Scheme 6.18: Conversion of cis and trans diols 32 and 33 to their respective cart 3onates.

129 stereochemistry between the newly formed carfoinol center and C-2. In reference to cis carbonate

34, irradiation of H-2 produced strong enhancements of the allyl protons, with the most notable

interaction involving H-13 (2.6%) (Figure 6.9). Irradiation of the unobstructed upfield aliylic proton

H-12' resulted in a 3.2% enhancement of H-2. Reciprocal treatment of H-2 in diastereomer 35

resulted in the observance of a 1.5% enhancement of H-4’ (Figure 6.10).

irradiate observe % NOE difference H-2 H-4 3.8 H-12' 1.8 H-13 2.6 H-14,14' 1.5 H-12’ H-2 3.2 H-13 H-2 2.1 H-4’ 2.8

Figure 6.9: NOE difference data for cis carbonate 34.

rC N irradiate observe % NOE difference H-2 H-4' 1.5 7 CN

Figure 6.10: NOE difference data for trans caitonate 35.

6.4. Competition Experiments

Competition experiments performed in water and aqueous THF strongly support our

hypothesis that para-substitutents would have a dramatic effect on the rate of the indium-

promoted allylation in aqueous media. Our findings though are somewhat contrary to the

observed reactions rates in THF. Table 6.1 establishes a hierarchy for the relative rate of reactivity for substrates la-d to be H=Br=NMeAo>OMe. We were surprised to see such equality t>etween

substrates la, lc and Id. These observations are yet unexplainable. However, perhaps the

130 reaction relative entry first ketone second ketone time, h rate ratio®

2.8 :1

lb

HO.HO 1.2:1

HO HO 1.1 :1 ,,Me

2.8 :1

OMe

HO. HO. 2 .5 :1 OMe Ac 1b

8 1 :1.4

® The relative rate ratio was determined by quantitative assesment of unreacted ketones.

Table 6.1; Competitive indium-mediated allylations in water at room temperature.

inductive effects® cttaracteristic of 1c and Id are inconsequential to substrate reactivity (i.e. polarization of ttie carbonyl) and that only electron withdrawing and electron-donating effects are of primary concem. Inductive effects are generally marked by polarization of the sigma bond adjacent to the substitutent. Unlike resonance, the associated inductive effects are often diminished at more distant bonds. Not only were these three substrates equally reactive amongst 131 themselves (compare eq 2,3, and 6), the trio was equally competitive against the extremely

electron-donating OMe substrate 1b, roughly by a margin of 2.7:1 (compare eq 1,4, and 5). We

had anticipated that the NMeAc substitutent would be significantly more electron-withdrawing

than that of H and Br.

Upon switching to 50% THF(aq) as the solvent system and employing the 6-CN

substituted tetralone le, we clearly validated the tremendous electron-withdrawing capacity of

the CN group (Table 6.2). Most revealing was the competition experiment between 1b and le in which the cyano substrate reacted with complete predilection over the methoxy substrate

(>97:3), as determined by NMR integration of the crude reaction mixture (eq 8 ). Furthermore parity was observed between cyano tetralone le and substrates la and 1c (entries 7, and 9, respectively). This is incredibly reassuring and in complete agreement to the hierarchy established in water for Table 6.1.

reaction relative entry first ketone second ketone time, h rate ratk)°

2.5:1

> 9 7 :3 OMe

12 1.8 :1

" The relative rate ratio was determined by quantitative assesment of unreacted ketones.

Table 6.2: Competitive indium-mediated allylations in 50% THF(aq) at room temperature.

132 6.5. Conclusion

Clearly, stereoelectronic effects are a decidedly important factor concerning tfie indium-

mediated allylation, most notably in aqueous THF or pure water. The reaction in anhydrous THF is

routinely sluggish and was found to be completely ineffective in conjurxition with the otherwise

most reactive substrate le Because of the unwillingness of le to undergo indium-promoted coupling recourse had to be made to the precomplexing protocol in THF, which expectedly was highly efficient in both yield and rate but not regarding diastereoselectivity. Even so, only a minimal amount of water is needed for an efficient reaction to occur. In some cases as little as 10 equivalents of water are needed in THF for a comparable reaction rate to that observed in 50%

THF(aq). In general, the reaction times are comparable in water and 50% THF(aq), yet the diastereoselectivity was often 15-20% greater in the latter solvent. The aqueous THF protocol are roughly 4-6 times more selective for the trans diol. Conversely, it can be stated that the anhydrous THF conditions are 4-6 times more selective for the cis diol, even though the ratio approaches 1:1. This dilemma obviously warrants further investigation, and perhaps the explanation resides in the dielectric constant of the solvent employed. A number of pure solvents, solvent systems, and aliylic halides have been used in conjunction with indium powder under both aqueous and anhydrous conditions. However to date no pen/asive and systematic study regarding the potential solvent effects on the resulting diastereoselectivity has been reported. Another area of interest with a potential payoff is a similar comprehensive study of the 7- substituted isomers of 36a-e. Particularly appealing would be the head-to-head competition experiments between the equivalent para- and mefa-substituted isomers 1 and 36.

O 36a,X = H

d, X = NMeAc e, X =CN

133 LIST OF REFERENCES AND NOTES

(1) (a) Carey, F. A.; Sundberg, R. J. In Advance Organic Chemistry: Part A. Structure and

Mechanisms. Plenum Press: New York, 1990; p. 197-209. (b) Lowary, T. H.; Richardson, K. S. In

Mechanism and Theory in Organic Chemistry, Harper & Row: New York, 1987; p. 142-151.

(2) (a) Rubottom, G. M.; Gruber, J. M.; Juve, H. D., Jr.Org. Synth. 1985, 6 4 , 118. (b) Rubottom,

G. M.; Gruber, J. M. J. Org. Chem. 1978, 4 3 ,1599.

(3) (a) Allinger, N. L; Jones, E. S. J. Org. Chem. 1962, 2 7 ,70. (b) Biggs, D. F.; Casy, A. F.; Chu,

0 . 1.; Coutts, R. T. J. Med. Chem. 1976, 1 9 ,472. (c) Newman, M. S.; Zahm, H. V. J. Am. Chem.

Sac. 1943, 6 5 , 1097. (d) Grieco, P. A.; Flynn, D. L; Zelle, R. E. J. Am. Chem. Sac. 1984, 106,

6414.

(4) (a) Giardina, G.; Clarke, G. D.; Dondio, G.; Petrone, G.; Sbacchi, M.; Vecchietti, V. J. Med.

Chem. 1994, 3 7 ,3482. (b) Kanao, M.; Watanabe, Y.; Kimura, Y.; Saegusa, J.; Yamamoto, K.;

Kanno, H.; Kanaya, N.; Kubo, H.; Ashida, S.; Ishikawa, F. J. Med. Chem. 1989, 3 2 ,1326. (c)

Itoh, K.; Miyake, A.; Tada, N.; Hirata, M.; Oka, Y. Chem. Pharm. Bull. 1984, 3 2 ,130.

(5) House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. D. J. Org. Chem. 1969, 34, 2324.

(6) (a) Moriarty, R. M.; Prakash, O.; Duncan, M. P.; Vaid, R. K.; Musallam, H. A.J. Org. Chem.

1987, 5 2 , 150; and references cited therein, (b) Moriarty, R. M.; Engerer, S. 0.; Prakash, O.;

Prakash, I.; Gill, U. S.; Freeman, W. A. J. Org. Chem. 1987, 5 2 , 153; and references cited therein, (c) Irie, H.; Matsumoto, R.; Nishimura, M.; Zhang, Y. Chem. Pharm. Bull. 1990, 3 8 ,1852.

(d) Tamura, Y.; Annoura, Yamamoto, H.; Kondo, H.; Kita, Y.; Fujioka, H.Tetrahedron Lett. 1987,

28, 5709.

(7) Nefkens, G. H. L; Tesser, G. I.; Nivard, R. J. F. Reel. Trav. Chim. 1960, 79, 688 .

134 (8 ) (a) Sharpless, K. B.: Lauer, R. F. J. Am. Chem. Sac. 1973, 9 5 ,7917. (b) Sharpless, K. S.;

Lauer, R. F. J. Am. Chem. Soc. 1972, 94, 7154.

(9) March, J. Advanced Organic Chemistry, John Wiley and Sons, Inc.: New York, 1992, p. 17.

135 CHAPTER 7

EXPERIMENTALS

All moisture sensitive reactions were performed under a nitrogen (Ng) atmosphere in

flame-dried glassware. All solvents were pre-dried over 4 A molecular sieves prior to distillation,

and, if necessary, stored over 4 A molecular sieves under N2. Acetonitrile (CH3CN),

chlorotrimethylsilane (TMSCI), dichloromethane (CH 2CI2), diisopropylamine (APr 2NH), NM

dimethylformamide (DMF), dimethysulfoxide (DMSO) and triethylamine (EtgN) were individually

distilled over calcium hydride. Benzene (PhH), tetrahydrofuran (THF) and diethyl ether (Et 2 0 )

were distilled from sodium/benzophenone ketyl. All reagents were purchased as "reagent grade"

and, unless otherwise noted, used without further purification. Indium powder of 99.99% purity

was purchased from Aldrich Chemical Co. in 50 g quantities (27,795-9). Fat extraction Et 2 0 was

used for wort^up extractions, and the combined organic layer extracts were dried over anhydrous

magnesium sulfate (MgSO^) or sodium sulfate (Na2S0 4 ), as noted. Chromatographic

purifications were performed with Scientific Absorbents Incorporated silica gel (230-400 mesh).

The purity of all compounds generally were found to be >95% by TLC and high field ^H and ^^C

NMR.

Melting points were measured on a Thomas Hoover (Uni-melt) capillary melting point

apparatus and are uncorrected. A Perkin-Elmer Model 241 Polarimeter was used to measure all optical rotations. Rotations were measured at 589 nm with a sodium lamp and concentrations are reported in g/100 mL. A Perltin-Elmer 1320 spectrometer was used to record infrared spectra, were are reported in reciporcal centimeters (cm*^). Broad stretching frequency are designated as

136 br. The Ohio State University Campus Chemical instrumentation Center was responsible for

recording high-resolution and fast-atom-bombardment mass spectra using either a Kratos MS-30

or VG 70-25GS mass spectrometer. A Bmker AC 300 FT NMR spectrometer was used to record

proton (^H) and cartx>n (i^C) nuclear magnetic resonance (NMR) spectra and were recorded at

300 MHz and 75 MHz, respectively. Chemical shifts are reported in parts per million (ppm) with the

residual non-deuterated solvent as an internal standard. Splitting patterns are designated as

follows: s, singlet; d, doublet; t, triplet; q, quartet; m. multiplet; br, broad. Coupling constants are

reported in hertz (Hz). Elemental analysis were performed by either the Scandinavian

Microanalytical Laboratory, Heriev, Denmark or Atlantic Microlab Inc., Norcross, GA.

7.1. Chapter 3

Prototypical Allylmagnesium Chloride Allylation.

A. 2-Methoxycyclohexanone.

u r, ur» J Magnesium turnings were washed with 10% HCI, rinsed CH3(Ü ^ CHaOk^ I 1 I I several times with water, slurried in acetone, and dried

.J2 under vacuum before use. A 446 mg (18.3 mmol) sample

of magnesium turnings was flushed with dry nitrogen, covered with dry THF (15 mL), warmed gently, and treated slowly with allyl chloride (0.872 mL,

10.7 mmol) at a rate sufficient to maintain reflux. After1 h, the Grignard solution was cooled to 0

®C. The reaction mixture was stirred at this temperature for 1.5 h, quenched with saturated NH 4CI solution, and extracted with ether. The combined organic layers were washed with brine, dried and evaporated, and the product alcohols were separated by chromatography on silica gel

(elution with 10% ether in petroleum ether). The spectral properties of 12 and 13 are identical to those previously reported .^6

137 B. i>Oxasplro[4.5]decan-6

\ HQ \ Ketone 9 reacted with equal facility to give 17 and 18, the

r I high-field^H and‘'^C spectra of which are identical to those

previously reported.^ ^ 17 18

C. c/s-2-Methoxy-4*fe/t*butylcyclohexanone.

Submission of 7 to the same reaction conditions HQ C H 3 0 < i > ^ afforded alcohols 23 and 24, which were separated by

MPLC on silica gel (elution with 10% ethyl acetate in

23 24 hexanes).

For 23: colorless oil: IR (neat, cm*"') 3472,1639: NMR (300 MHz, CeDe) 5 5.98-5.84

(m, 1 H), 5.10-5.02 (m, 2 H), 3.08 (S, 3 H), 2.75 (dd, J = 11.2, 4.6 Hz, 1 H), 2.45 (ddt, 13.5, 6.5,

1.3 Hz, 1 H), 2.25 (dd, J = 13.6,8.3 Hz, 1 H), 1.98 (d, J= 2.3 Hz, 1 H), 1.87-1.80 (m, 2 H), 1.53

(dq, J = 12.7, 3.6 Hz. 1 H), 1.40-1.32 (m, 2 H), 1.06 (tq, J = 13.6, 2.2 Hz, 1 H), 0.85 (S, 9 H), 0.79

(tt, J = 12.4, 3.1 Hz, 1 H): 13c NMR (75 MHz, CeDe) 6 135.3, 117.3, 83.0, 72.5, 56.2, 46.5, 45.3,

34.4, 32.4, 27.7, 26.9, 22.1: MS nVz (M+-C3H5) calcd 185.1542, Obsd 185.1546.

Anal. Calcd for C u H 2e0 2 : C, 74.29: H, 11.58. Found: C, 74.48: H, 11.60.

For 24: colorless crystals, mp 47-48 °C: IR (film, cm'^) 3484,1639,1467,1393,1366,

1328,1245, 1186: NMR (300 MHz, CeDe) 6 5.99-5.85 (m, 1 H), 5.09-5.03 (m, 2H), 3.07 (s, 3

H), 2.68 (dd, J = 11.2, 4.9 Hz, 1 H), 2.45 (dd, J = 13.6, 6.4 Hz, 1 H), 2.26 (dd, J = 13.6, 8.4 Hz, 1

H), 1.97 (s, 1 H), 1.90 (dt, J = 13.5, 3.1 Hz, 1 H), 1.86-1.48 (m, 4 H), 0.93 (brt, J = 12.9 Hz, 1 H),

0.83 (s, 9 H), 0.87-0.65 (m, 1 H): 13C NMR (75 MHz, CeDe) 6 135.3,117.3, 82.3, 73.3, 56.1, 45.8,

41.7, 35.9, 32.0, 27.6, 25.9, 25.3: MS nVz (M+-C 3H5) calcd 185.1541, obsd 185.1548.

4na/. Calcd for C i 4H2e0 2 : C, 74.29: H, 11.58. Found: C, 74.06; H, 11.56.

138 D. fra n s -2*M ethoxy* 4 -f0 /t>butylcyclohexanone.

Comparable treatment of 8 provided 28 and 29, which CHgOo®' CH3O.. were separated by chromatography on silica gel (elution

with 10% ethyl acetate in hexanes).

For 28: colorless oil; IR (neat, cm'^) 3475,1365,

1100; 1H NMR (300 MHz, CDCI3) S 5.74-5.44 (m, 1 H), 5.18-5.09 (m, 2 H), 3.74 (s, 3 H), 3.04 (brt,

J = 1.6 Hz, 1 H), 2.40 (dd, 13.6, 7.3 Hz, 1 H), 2.16 (dd, 13.6, 7.9 Hz, 1 H), 1.93-1.87 (m, 1

H), 1.64-1.25 (m, 6 H), 0.86 (s, 9 H); 1% NMR (75 MHz, CDCI 3) ppm 133.8,119.1, 81.3, 71.6,

56.1, 43.8, 40.3, 33.6, 32.0, 27.4, 24.2, 21.9; MS ni'z(M+) calcd 226.1933, obsd 226.1924.

4na/. Calcd for C 14H26O2: C, 74.29; H, 11.58. Found: C, 73.68; H, 11.55.

For 29: colorless oil; IR (neat, cm*1) 3566, 1391,1366,1094; ^H NMR (300 MHz, CDCI 3)

6 6.02-5.84 (m, 1 H), 5.12-5.03 (m, 2 H), 3.35 (s, 3 H), 3.19 (brt, J= 1.8 Hz, 1 H), 2.82 (brs, 1 H),

2.28 (ABq of ABX, Ap = 15.8 Hz, JaB = 14.3 Hz, JaX = 6.9 Hz, xJqx * 7.4 Hz, 2 H), 2.00 (br dq, J -

14.1,3.1 Hz, 1 H), 1.69-1.51 (m ,3H), 1.31 (brtt, J = 12.6, 3.1 Hz, 1 H), 1.18-0.97 (m, 2 H), 0.87

(S, 9 H); 13c NMR (75 MHz, CDCI3) ppm 133.7, 117.4, 82.2, 72.4, 56.4, 39.9 (2 C), 34.2, 31.8,

27.5, 25.3, 23.8; MS m /z (M+) calcd 226.1933, obsd 226.1959.

Ana/. Calcd for C l 4H26O2: C, 74.29; H, 11.58. Found: C, 74.22; H, 11.59.

E. (5/7*,9/7*)-9*ferr>Butyi*l*oxasplro[4,5]decan>6>one (10).

Analogous addition of allylmagnesium chloride to 10 gave PH rise to 37 and 38, separation of which by chromatography on

silica gel (elution with 19:1 -* 6:1 hexanes/ethyl acetate)

37 38 provided the pure diastereomers.

For 37: colorless oil; IR (neat, cm'l) 3478,1065; iR

139 NMR (300 MHz. CeDe) 6 6.22-6.08 (m, 1 H), 5.14-5.08 (m, 2 H). 3.60-3.53 (m, 2 H). 2.37 (ddt. J -

13.8.5.4.1.6 Hz. 1 H). 2.27 (brs. 1 H). 2.02-1.87 (m. 3 H). 1.63 (td. J - 12.8. 3.8 Hz. 1 H). 1.57-

1.29 (m. 6 H), 1.064) 74 (m. 2 H). 0.85 (s. 9 H); NMR (75 MHz. CeDe) ppm 135.9.116.7. 88.4.

74.3. 67.6. 46.2. 41.4. 36.0. 33.7. 32.6. 32.3. 27.7. 27.4, 21.9; MS m /z (M+) calcd 252.2089.

obsd 252.2085.

Anal. Calcd for CleH 2s0 2 : C. 76.14; H. 11.18. Found; C. 76.34; H. 11.21.

For 38: colorless oil; IR (neat, cm ^) 3476.1365.1068; ^H NMR (300 MHz. CeDe) S 6.12-

5.98 (m. 1 H). 5.13-5.06 (m. 2 H). 3.76-3.69 (m. 1 H). 3.62 (dd. J = 14.5. 7.8 Hz. 1 H). 2.76 (ddd. J

= 14.6. 6.1.1.4 Hz. 1 H). 2.50 (dd. J = 14.6. 8.5 Hz. 1 H). 2.31 (ddd. J = 12.1.8.7.5.4 Hz. 1 H).

1.86-1.80 (m. 1 H). 1.74-1.53 (m. 3 H). 1.51-1.21 (m. 6 H). 1.05-0.98 (m. 1 H). 0.78 (s. 9 H); I^C

NMR (75 MHz. CeDe) ppm 135.5. 117.6. 88 .6. 75.5. 67.7. 45.8. 38.4. 36.4. 33.8. 32.1.31.9.

27.7. 27.3. 23.3; MS m /z (M+) calcd 252.2089. obsd 252.2079.

/Ina/. Calcd for Cl eH 2802 : C. 76.14; H. 11.18. Found: C. 75.97; H. 11.23.

F. (5/7*,9S*)-9-ferf*Butyl-l*oxaspiro[4,5]decan-6-one (11),

Comparable treatment of 11 produced a mixture of 41 and

42. which were separated chromatographically on silica gel

(elution with 10:1 hexanes/ethyl acetate).

42

For 41 : colorless solid, mp 46-47 °C; IR (film, cm'^)

3498.1467.1437.1064; ^H NMR (300 MHz. CDCI 3) 6 5.96-5.82 (m. 1 H). 5.17-5.07 (m. 1 H).

3.88-3.73 (m. 2 H). 2.32 (dd. J= 13.6. 7.1 Hz. 1 H). 2.26-2.16 (m. 2 H). 1.95-1.72 (series of m. 2

H). 1.65-1.18 (series of m. 10 H). 0.84 (s. 9 H); I^C NMR (75 MHz. CDCI 3) ppm 134.3.118.8.

86.3. 73.7. 68.0. 42.5. 40.3, 35.1. 33.9. 33.2. 31.9. 27.4. 26.3. 21.5; MS m /z (M+) calcd

252.2089, obsd 252.2083.

140 Anal. Calcd for C l 6 H28O2 : C, 76.14; H. 1 1 .1 8. Found: C, 76.24; H. 11.17.

For 42: colorless oil; IR (neat, cm'l) 3563,1365,1055; NMR (300 MHz, CDCI3) 5

6.01-5.87 (m, 1 H), 5.12-5.05 (m, 2 H), 3.92-3.79 (m, 2 H), 2.31 (dd, J - 14.2, 8.4 Hz, 1 H), 2.24-

2.12 (m, 2 H), 1.95-1.81 (m, 3 H), 1.72 (dt, J * 13.7,3.0 Hz, 1 H), 1.64-1.34 (series of m, 5 H),

1.12 (t, J = 13.2 Hz, 1 H), 1.04 (dq, J = 12.9,3.6 Hz, 1 H), 0.84 (s, 9 H); '’^C NMR (75 MHz, CDCI 3)

ppm 134.1, 117.2, 87.8, 74.0, 67.7, 42.1, 37.9, 34.1, 34.0, 31.8, 31.2, 27.5, 25.6, 23.6; MS m /z

(M+) calcd 252.2089, obsd 252.2088.

4na/. Calcd for Cl 6H28 O2: 76.14; H, 11.18. Found: C, 75.79; H, 11.13.

Prototypical CeCIs Mediated Coupling. A 364 mg (0.98 mmol) sample of cerium trichloride heptahydrate was dried according to standard protocol.^^ The cooled salt was slurried with anhydrous THF (3.6 mL) for 3 h under N 2 at rt. A solution of allylmagnesium chloride (1.1 mL of 1 M in THF, 1.1 mmol), prepared in the pre-described manner was added via syringe into this slurry and the reaction mixture was stirred at 0 °C for 20 min. The ketone (0.15 mmol) dissolved in dry THF (1.0 mL) w as next introduced slowly at 0 ®C. Upon completion of the addition (monitored by TLC, most commonly 45 min), aqueous NH4CI solution was added and the usual workup was applied.

Prototypical CrClz-Promoted Coupling. Freshly distilled thionyl chloride (45 mL) was added dropwise during 10 min to finely divided chromium trichloride hexahydrate (17.5 g,

65.7 mmol). The magnetically stirred mixture was slowly wanned to reflux, maintained at this temperature for 2.5 h, and freed of the excess thionyl chloride under reduced pressure to leave a purple-rose colored powder. This solid was stored overnight in a desiccator charged with KOH pellets and free of oxygen.^^

141 A slurry of anhydrous chromium trichloride (4.32 g, 23.7 mmol) in cold (0 “C), dry THF (54

mL) was cautiously treated in five portions with lithium aluminum hydride (517 mg, 13.6 mmol), stirred for 15 min at this temperature, and allowed to warm to 20 °C during another 20 min, at which point the reaction mixture became characteristic dark brown in color. The mixture was recooled to

0 °C, the ketone (3.90 mmol) was introduced via syringe, and stirring was maintained for 15 min before allyl bromide (1.42 g, 11.7 mmol) was added dropwise. After 3 h at 0 °C and 30 min at rt, the reaction mixture was quenched with saturated NaHCOa solution, and diluted with ether. The aqueous phase was extracted with CH 2CI2 (3x) and the combined organic extracts were washed with brine ( 2x), dried, and concentrated.

Prototypical Indium Promoted Couplings.

A. In Dry THF. To a magnetically stirred suspension of indium powder (168 mg, 1.46 mmoi) in dry THF (5 mL) was introduced allyl bromide (0.126 mL, 1.46 mmol) via syringe and the mixture was agitated for 5 min prior to introduction of neat ketone (0.97 mmol). Reaction was allowed to proceed for 3 h at room temperature, 10% hydrochloric acid was then added, and the usual workup conditions applied.

B. In 50% A queous THF. To a reaction vessel containing ailyl bromide (26 mg, 0.21 mmol), indium powder (37 mg, 0.32 mmol), and the ketone (0.19 mmol) was added THF (2.0 mL) and water (2.0 mL). The reaction mixture was stirred at rt until ketone consumption was complete

(TLC analysis), quenched with 10% HCI, and extracted with ether. The combined organic phases were washed once with brine, dried, and concentrated to leave an oily residue that was purified chromatographically.

0. In W ater. A mixture of allyl bromide (30 mg, 0.25 mmol), indium powder (29 mg,

0.25 mmol), ketone (0.15 mmol), and water (2.0 mL) was stirred at rt until ketone consumption was complete (TLC analysis). A workup identical to that in B was employed.

142 0. In THF with Prior Formation of the Allylindium Reagent. A magnetically stirred mixture of allyl bromide (31 mg. 0.26 mmol), indium powder (28 mg. 0.25 mmol), and THF

(0.71 mL) was gently refluxed for 1 h. cooled to rt. and treated with the ketone (0.181 mmol) dissolved in 0.71 mL of THF. The reaction mixture was stirred for 1 h. filtered through a small pad of silica gel (elution with ethyl acetate), and concentrated. Diastereomer separation was accomplished by chromatography on silica gel.

Prototypical Normant Alkylations. A cold (0 °C). magnetically stirred solution of 3- chloro-1-propanol (3.78 g. 40 mmol) in dry THF (40 mL) was treated dropwise with a solution of isopropylmagnesium chloride in ether (20 mL of 2.0 M. 40 mmol) during 20 min and subsequently warmed to room temperature. Flame-dried magnesium turnings (1.46 g. 60 mmol) were quickly added, and the mixture was refluxed for 1 h and left to stand overnight without stirring in order to allow the excess magnesium to settle. The concentration of active Grignard reagent was established by titration of a small portion of the supernatant with menthol and 1,10- phenanthroline according to established procedure.'*^

To a cold (0 “C). magnetically stirred solution of the ketone (1.93 mmol) in dry THF (7.5 mL) was added dropwise the Normant reagent (5.88 mL of 0.365 M, 2.15 mmol). The reaction mixture was stirred at 0 °C for 1 h, quenched with 10% HCI, and diluted with ether. The organic phase was washed with brine ( 2x), dried, and concentrated.

The spectral properties for 14 and 15,2® and of 19 and 20®^ are identical to those previously reported.

143 (1/?*,2/7*,4/?*)-1-(3-Hydroxypropyl)-2-methoxy-4-fff/t- OH HO, txitylcyclohexanol (25): colorless solid, mp 86 °C; IR (film, cm*^)

3734, 1644,1422,1265; ^H NMR (300 MHz, CeDe) 53.51-3.42 (m, 2

H), 3.08 (s, 3 H), 2.67 (dd, J = 11.2,4.6 Hz, 1 H), 1.93 (dt, J = 13.8,3.3 25 Hz, 1 H), 1.87-1.26 (series of m, 10 H), 0.90 (dd, 13.6,4.3 Hz, 1 H),

0.86 (s, 9 H), 0.84-0.74 (m, 1 H); 1^0 NMR (75 MHz, CeDe) 5 84.3, 72.2, 63.5, 56.5, 46.4, 37.2,

34.0, 32.4, 27.7, 27.4, 27.1, 22.1; MS m/'Z(M+) calcd 244.2038, ObSd 244.2038.

Anal. Gated for C l 4H28 O3 : 0,68.81 ; H, 11.55. Found: C, 68.96; H, 11.50.

(1S*,2/î*,4/î*)-l-(3-Hydroxypropyl)-2-methoxy-4-fert-

butylcyclohexanol (26): colorless solid, mp 104 °C; IR (film, cm*^)

3943, 3430,1630; ^H NMR (300 MHz, CeDe) 5 3.47-3.42 (m, 2 H), 3.07

(s. 3 H), 2.59 (dd, J= 11.2, 4.8 Hz, 1 H), 1.98 (dt, J = 13.4, 3.1 Hz, 1 H),

1.81-1.31 (series of m, 10 H), 0.85 (s, 9 H), 0.86-0.64 (m, 2 H); ^^C NMR

(75 MHz. CeDe) 5 82.4, 72.1, 62.5, 55.3, 40.7, 36.6, 34.4, 31.0, 26.7, 26.3, 25.0, 24.2; MS m/z

(M+) calcd 244.2038, Obsd 244.2034.

Anal. Gated for C 14H28 O3: C, 68.81; H. 11.55. Found: C, 68.98; H, 11.38.

(1R*,2S*,4R*)-1-(3-Hydroxypropyl)-2-methoxy-4-fert> C H a o " ^ butylcyclohexanol (30): colorless solid, mp 114-115 °C; IR (CCI 4 ,

cm-1) 3334, 1549, 1252, 1218,1098,1005; ^H NMR (300 MHz, CDCI 3)

30 6 3.73-3.60 (m, 2 H), 3.24 (s, 3 H), 3.19 (s, 1 H), 2.40 (br s. 2 H), 1.92 (br

d. J= 13.5 Hz, 1 H). 1.77-1.25 (seriesof m, 10 H). 0.86 (s, 9 H); 1% (75

MHz, CDCI3) ppm 80.9, 71.8, 63.5, 56.1, 40.3, 36.4, 33.8, 32.0, 27.4, 25.7, 24.0, 21.4 ; MS m /z

(M+) calcd 244.2038, ObSd 244.2041.

Anal. Gated for C 14H28 O3: C, 68.81 ; H, 11.55. Found: C, 68.98; H, 11.40.

144 r'^^OH ('•^*»25*,4f7*)-1-(3-Hydroxypropyl)-2-methoxy-4-/e#t-

butylcyclohexanol (31): colorless oil; IR (neat, cm*^) 3388, 1460,

1393,1365,1097; NMR (300 MHz, CDCI 3) 5 3.67-3.63 (m, 2 H), 3.35 V (S, 3 H), 3.21 (brd, 1.7 Hz, 1 H), 2.68 (brs, 2 H), 2.02 (dq, 14.0, 31 3.1 Hz, 1 H), 1.74-1.51 (series of m, 5 H), 1.31 (tt, J = 12.6,3.1 Hz, 1 H),

1.20 (t, J - 6.9 Hz, 1 H), 1.18-0.87 (series of m, 3 H), 0.85 (s, 9 H); NMR (75 MHz, CDCI 3) ppm

82.5, 72.6, 63.3, 56.4, 40.1,33.7, 32.1,31.8, 27.5, 26.1, 25.5, 23.9; MS m

244.2038, obsd 244.2033.

Anal. Calcd for C 14H28 O3: 0 , 68 .8 1 ; H, 11.55. Found: 0, 68.40; H, 11.42.

OH (5/7*,6/7*,9f7*)-9*ferf6- HQ propanol (39): colorless solid, mp 98.9-99.5 °C; IR (film, cm'^) 3428,1468,

1365, 1065; ^H NMR (300 MHz, CeDe) 5 3.66-3.46 (m, 4 H), 2.05-1.73 (m, 4 H),

39 1.68-1.19 (series of m. 10 H), 0.93-0.76 (m, 2 H), 0.86 (s. 9H); 1% nmR (75 MHz, CeDe) ppm 88.7, 74.4, 67.3, 63.6, 46.0, 36.0, 33.1, 32.8, 32.7, 32.3,

27.7, 27.5, 27.1, 21.9; MS m/z(M+) calcd 270.2195; obsd 270.2197.

Anal. Calcd for CieHaoOe: C, 71.07; H, 11.18. Found: C, 70.98; H. 11.10.

HO pH (5/7*,6S*,9/7*)-9-ferf-Butyl-6-hydroxy-1-oxaspiro[4.5]decane*

6-propanol (40): colorless solid, mp 106-107 °C: IR (film, cm'l) 3404,

1459, 1365, 1067, 1027,1002; ^H NMR (300 MHz. CeDe) 63.77 (td, J-

40 7.6, 5.0 Hz, 1H), 3.65 (td, 7.8, 6.7 Hz, 1 H), 3.56-3.44 (m, 2 H), 2.38-

2.29 (m, 1 H), 2.06 (brs, 2 H), 1.94-1.25 (seriesof m, 12 H), 1.03-0.93 (m, 2

H), 0.80 (s, 9 H); 1% NMR (75 MHz, CeDe) ppm 89.2, 75.5, 67.6. 63.4, 45.8, 36.4,33.2, 32.1,

31.9, 29.9, 27.7, 27.3, 26.6, 23.5; MS m/z(M+) calcd 270.2195, ObSd 270.2192.

/Ana/. Calcd for CleHaoOa: C, 71.07; H, 11.18. Found: C, 71.11; H, 11.12.

145 (5 /7*, 6 S*, 9 S*)- 9 -f0 ft-B u ty l-6 -h y d ro x y - 1-o x a s p ir o [ 4 .5 ] d e c a n e - 6 - OH HO, propanol (43): coloiless solid, mp 109 °C; IR (KBr, cm'l) 3384,1415,

1364,1197,1059,1003, 972: ^H NMR (300 MHz, CeDe) 6 3.73-3.59 (m, 2 H),

3.50-3.43 (m, 1 H), 3.38-3.31 (m, 1 H), 2.18 (qd, J - 8.9, 5.9 Hz, 1 H), 2.04 (br 43 s, 1 H), 1.79-1.28 (series of m, 15 H), 0.92 (s, 9 H); NMR (75 MHz, CeDe)

ppm 86.9, 73.7, 68.0, 63.5, 42.8, 35.3, 33.4, 33.2, 32.6, 32.1, 27.7, 26.7, 26.3, 22.1; MS m /z

(M+) calcd 270.2195, obsd 270.2196.

4na/. Calcd for CleHaoOa: C, 71.07; H, 11.18. Found: C, 71.51; H, 10.97.

(5/7*,6/r*,9S*)-9-fe/t-Butyl-6-fiydroxy-l>cxaspiro[4.5]decane>

6-propanol (44): colorless solid, mp 99.8-100.2 °C; IR (film, cm'^) 3417,

1366,1055; ^H NMR (300 MHz, CeDe) 6 3.70-3.54 (m, 3 H), 3.48 (dd, J =

15.4, 7.6 Hz, 1 H). 2.7-2 2 (br, 2 H), 2.07 (ddd, J = 12.0, 9.3, 9.3 Hz, 1 H),

1.97 (dt, J= 13.0,3.3 Hz, 1 H), 1.90-1.79 (m, 1 H), 1.71-1.35 (series of m,

9 H). 1.16-1.09 (m, 1 H), 1.03-0.89 (m, 2 H), 0.80 (s, 9 H); I^C NMR (75 MHz, CeDe) ppm 88.1.

74.3, 67.6. 63.3, 42.6, 34.4. 33.7. 31.8, 31.3, 30.1, 27.7, 26.8, 25.8, 24.3; MS /n/z(M+) calcd

270.2195, obsd 270.2189.

4na/. Calcd for CieHeoOa: C, 71.07; H. 11.18. Found: C. 70.88; H, 11.13.

O O Jl^^O C H s .0OCH3 (2S*,4S*)-2-Metfioxy-4-fe/t-butylcyclohexanone (7)

and (2/7*,45*)-2-Methoxy-4-fe/t-butylcyclohexanone

* ( 8 ). A nitrogen-blanketed, magnetically stirred suspension of 7 8 iodosobenzene^® (20.5 g, 0.094 mmol) in dry methanol (500 mL) was treated with boron trifluoride etherate (20.39 mL, 0.169 mol) via syringe to give a clear solution which was subsequently cooled to -78 °C. A solution of 22®2 (20.0 g, 0.088 mol) in dry methanol (200 mL) was cooled to -78 ®C and introduced slowly dropwise via cannula. The reaction

146 mixture was stirred for 3 h at -78 X , allowed to stir at rt for 2 h, and freed of methanol under

reduced pressure. The residue was diluted with CH 2CI2 and washed three times with saturated

NaHCOs solution and once with brine prior to drying. Chromatography on silica gel, gradient

elution with 15:1 9:1 hexanes/ethyl acetate, afforded 2.00 g (12%) of 8 and 8.15 g (50%) of 7.

The spectral properties of these ketones are identical to those previously reported.^^

0 ^ 0 6-[(£)-Benzyildene]*8-feft-butyl-l ,4-dioxaspiro[4.5]decane I ^ ^ S ^ P h (33).so A cold (-78 X ), nitrogen-blanketed solution of diisopropylamine (43.2 ¥ mL, 0.311 mmol) in dry THF (650 mL) was treated with n-butyllithium (210.5 mL 33 of 1.6 M in hexanes, 0.337 mol), allowed to warm to rt during 1 h, and retumed to

-78 °C before a solution of 21 (40.0 g, 0.259 mol) in dry THF (400 mL) was slowly introduced via

cannula. After this mixture had stirred in the cold for 1 h, benzaldehyde (26.3 mL, 0.233 mol) was

added, followed 5 s later by methanesulfonyl chloride (40.0 mL, 0.508 mol). The reaction mixture

was warmed to rt during 2 h, treated with triethylamine (300 mL), and refluxed for 1 h or stirred

overnight at rt prior to dilution with water (400 mL) and extraction with ether (4x100 mL). The

combined organic layers were washed with saturated NH 4CI solution and brine, dried, and

evaporated to leave 31.5 g of a yellow oil which was used without further purification.

The above oil was taken up in ethylene glycol (215 mL, 5.73 mol) and trimethyl orthoformate (200 mL, 1.83 mol), treated with p-toluenesulfonic acid (1.24 g, 6.52 mmol), stirred overnight, quenched with one drop of triethylamine, diluted with 50% saturated NaHCOg solution, and extracted with ether. The combined organic phases were dried and evaporated to leave a thick oil which was crystallized from 95% ethanol. There was obtained 37.0 g (50%) of 33 as a fluffy cream-colored solid, mp 87.5 X : IR (film, cm 1) 1479,1366,1188,1098; ^H NMR (300

MHz, CeDe) 5 7.50-7.47 (m, 2 H), 7.41-7.37 (m, 3 H). 7.29-7.23 (m, 1 H), 3.96-3.83 (m, 2 H). 3.81-

3.73 (m, 2 H), 3.27 (brd, 1 H), 2.35-2.24 (m, 2 H), 2.11-1.97 (m, 1 H), 1.94-1.86 (m, 2 H), 1.44-

1.34 (m, 1 H), 0.99 (s, 9 H); 13C NMR (75 MHz, CgDe) ppm 141.6,138.1,129.3, 128.4, 126.7,

147 122.1,109.0, 65.4, 63.6, 49.2, 38.1, 32.7, 28.7, 27.5, 25.1; MS m/z(M+) calcd 286.1933, Obsd

286.1930.

4na/. Calcd C 19 H26O2: C, 79.68; H, 9.15. Found: 0,79.37; H. 9.21.

0 ^ 0 ^ 8-terf*Butyl>1,4-dloxaspiro[4.5]decan*6

g, 17.5 mmol) in a 1:1 mixture of methanol and CH 2CI2 (150 mL) containing 1%

pyridine was ozonolyzed at -78 °C until a faint blue color appeared. The reaction

mixture was purged with oxygen, treated with dimethyl sulfide (8 mL), allowed to warm to rt for 2 h, diluted with 1% NaHCOs solution, and extracted with CH 2CI2 The combined organic layers were dried and concentrated, and the residue was chromatographed on silica gel

(elution with 8:1 hexanes/ethyl acetate) to give 3.37 g (91%) of 34 as a faintly yellow oil; IR (neat, cm'1) 1731,1479,1367,1103,1063,1029; NMR (300 MHz, CeDe) 63.99 (dt, J = 14.1, 7.3

Hz, 1 H), 3.63 (dt, J = 13.1,7.3 Hz, 1 H), 3.47-3.36 (m, 2 H), 2.44-2.31 (m, 2 H), 1.99 (dt, 13.5,

3.2 Hz. 1 H), 1.74-1.63 (m, 1 H), 1.59-1.43 (m, 2 H), 1.15-1.04 (m, 1 H), 0.63 (s, 9 H); 1% NMR (75

MHz, CeDe) ppm 205.1, IO6 .6, 66.1, 64.2, 48.3, 41.4, 35.7, 32.3, 27.1, 24.1 ; MS m /z (M+) calcd

212.1412, obsd 212.1388.

Anal. Calcd for C 12H20O3 : C, 67.89; H, 9.50. Found: C, 67.52; H. 9.51.

r ~ \ (6/?*,8/?*)-8-ferf-Butyl-6-hydroxy-1,4- ,0H OH OH OH dloxasplro[4.5]decane 6 propanol (47)

and (6R',8S*) 8-ferf-Buty 1-6 hydroxy 1,4-

47 48 dloxasplro[4.5]decane 6-propanol (48). A

magnetically stirred solution of 34 (1.21 g, 5.66 mmol) in dry THF (75 mL) was cooled to 0 ®C and treated dropwise via syringe with a solution of the

Normant reagent^^ in THF (14.15 mL, 6.79 mmol). After completion of the addition, the reaction mixture was stirred for 15 min at 0 °C, quenched with saturated NH 4CI solution, and extracted with

148 ether. The combined organic phases were washed with brine, dried, and evaporated.

Chromatography of the residue on silica gel (elution with 90% ethyl acetate in hexanes) afforded

1.33 g (84%) of a 4.4:1 mixture of 47 and 48. A second chromatography under more controlled

conditions afforded pure samples of the two 1,4-diols.

For 47: colorless crystals, mp 62-66 ®C: IR (film, cm*^) 3406,1449,1366,1184; NMR

(300 MHz, CeDe) 8 3.78-3.42 (series of m. 6 H), 2.89 (br s, 1 H). 2.43 (br s, 1 H), 2.09-2.03 (m, 1

H), 1.99 (dt, J= 12.8,3.6 Hz. 1 H), 1.92-1.73 (m. 2 H), 1.69-1.57 (m. 2 H), 1.54-1.44 (m, 1 H), 1.32

(t. 12.3 Hz, 1 H), 1.34-1.22 (m. 1 H), 1.04 (tt, J = 12.5, 3.0 Hz, 1 H), 0.83 (S, 9 H): 1% NMR (75

MHz, CeDe) ppm i l l . 6 , 76.1, 65.9, 65.3, 63.3, 44.2, 36.4, 32.7, 32.2, 30.3, 27.6, 26.8, 24.5;

MS rrVz(M+) calcd 272.1987, obsd 272.2000.

Ana/. Calcd for C l 5H28 O4: C, 66.14; H, 10.36. Found: C. 66.15; H, 10.33.

For 48: colorless crystals, mp 107 °C; IR (film, cm'i) 3398,1365,1189,1151,1088; ^H

NMR (300 MHz, CeDe) 8 3.56-3.42 (m, 6 H), 2.13 (td, J = 13.0,4.0 Hz, 1 H). 2.04 (dt, J = 13.2, 3.0

Hz, 1 H), 1.80-1.53 (m, 7 H), 1.45-1.30 (m, 1 H), 1.33 (t, J = 12.8 Hz, 1 H), 0.90 (s, 9 H); I^C NMR

(75 MHz, CeDe) ppm 111.5 , 75.5, 65.4, 65.1, 63.6, 41.4, 34.4, 32.2, 32.1, 31.3, 27.8. 26.6,

24.3; MS m/z(M+) calcd 272.1987, obsd 272.2010.

Anal. Calcd for C l 5H28 O4: 0. 66.14; H, 10.36. Found: C, 66.11; H, 10.36.

(6/?*,1 2/T)-l 2-fert*Butyl-l ,4,7-trloxadlsplro[4.0.4.4]tetradecane

(35). To a magnetically stirred solution of 47 (2.07 g, 7.60 mmol) in dry CH 2CI2

(35 mL) w as added trimethylamine (2.4 mL, 17.1 mmol), p-toluenesulfonyl chloride

(1.39 g, 9.89 mmol), and DMAP (46 mg, 0.38 mnx)i). The reaction mixture was stirred ovemight at 45 "C, cooled, diluted with ether, and washed with brine prior to drying and concentration. Purification of the residue by chromatography on silica gel (elution with 8:1

149 hexanes/ethyl acetate) afforded 1.54 g (79%) of 35 as a viscous, colorless oil: IR (film, cm'i)

1514,1468,1442,1394,1366; NMR (300 MHz, CDCI 3) 54.21-4.12 (m, 1 H), 4.00-3.88 (m, 3

H), 3.87-3.75 (m, 2 H), 2.11-1.79 (m, 3 H), 1.72-1.45 (m, 6 H), 1.38-1.31 (m, 1 H), 1.14-1.02 (m, 1

H), 0.89 (S, 9 H): 13c NMR (75 MHz, CDCI 3) ppm 111.2, 87.2, 68.2, 65.9, 65.7, 45.7, 37.4, 34.4,

32.7, 32.1, 27.7, 26.7, 23.9; MS m/z{M+) calcd 254.1882, Obsd 254.1890.

Anal. Calcd for C 15H20O3: 0,70.83; H, 10.30. Found: C, 70.75; H, 10.25.

r ~ \ (6/?*,l 2S*)-l2-fert-Butyl-1,4,7-trloxadlsplro[4.0.4.4]tetradecane

j'O (36). Analogous cyclization of 48 (2.69 g, 9.87 mmol) fumistied 1.73 g (69%) of

36 as a faintly yellow oil following chromatograpfiic purification on silica gel (elution

witfi 8:1 hexanes/etfiyl acetate); IR (neat, cm*^) 2951,2871,1478,1435,1366,

1186; 1H NMR (300 MHz, CeDe) 53.98 (dd, J= 14.5, 7.6 Hz, 1 H), 3.81 (ddd, J = 15.0, 7.4, 4.8

Hz, 1 H), 3.60-3.49 (series Of m, 4 H), 2.18-2.04 (m, 2 H), 1.82-1.56 (series Of m, 7 H), 1.44-1.30

(m, 2 H), 0.87 (s, 9 H); ^^C NMR (75 MHz. CeDe) ppm 111.6, 85.8, 68.9, 65.1, 64.5. 42.6, 38.4,

32.6, 32.0, 31.1, 27.8, 26.6, 24.4; MS m/z(M+) calcd 254.1882, obsd 254.1883.

Anal. Calcd for CleH 2e0 3 : C, 70.83; H, 10.30. Found: C, 70.78; H, 10.35.

O (5f7*,9f7*)-9-ferf-Butyl*1-Gxasplro[4.5]decan-6-one (10). A magne­

tically stirred solution of 35 (1.54 g, 6.01 mmol) in acetone (15 mL) and water (15

mL) was treated with concentrated HCI (0.1 mL), refluxed for 12 h, quenched with

a few drops of triethylamine, and extracted with ether. The combined organic phases were dried and concentrated to leave a residue that was chromatographed on silica gel

(elution with 8:1 hexanes/ethyl acetate). There was isolated 1.11 g ( 88 %) of 10 as a colorless solid, mp 65 °C; IR (film, cm'l) 3014, 2694, 2870,1718,1216,1074; ^H NMR (300 MHz, CeDe) 5

4.08 (dd, J= 14.2, 7.1 Hz, 1 H), 3.81 (ddd, J= 13.9, 7.3, 2.2 Hz, 1 H), 2.24 (ddd, J= 14.8, 4.2,

2.6 Hz, 1 H), 1.93 (ddd, J = 14.7,13.5, 6.1 Hz, 1 H), 1.78 (ddd, 12.9, 3.3, 3.3 Hz, 1 H), 1.68

150 (dd, J - 12.4,12.4 Hz, 1 H), 1.63-1.42 (m, 4 H), 1.37-1.28 (m, 1 H), 1.12 (dddd, J « 12.2, 12.2,

3.4, 2.8 Hz,1 H), 1.02 (dddd, J = 12.4,12.4, 4.3,1.1 Hz, 1 H), 0.69 (S, 9 H); 1% NMR (75 MHz,

CDCI3) ppm 211.3, 87.7, 68.4, 45.7, 40.5, 38.8, 35.2, 32.2, 27.5, 27.4, 25.2; MS m /z (M+) calcd

210.1620, obsd 210.1622.

Anal. Calcd for C 13H22O2: 0,74.24; H, 10.54. Found: 0,74.20; H, 10.53.

(5ff*,9S*)‘9*feft*Butyl-1>oxaspiro[4.5]decan*6>one (11). Analogous

treatment of 36 (461 mg, 1.80 mmol) provided 274 mg (74%) of 11 as a clear oil

following chromatographic purification; IR (neat, cm'^) 1721,1480,1428,1366,

1234,1096,1049; ^H NMR (300 MHz, CeDe) 8 3.63-3.56 (m, 1 H), 3.48-3.41 (m, 1

H), 2.83 (ddd, J= 14.1,13.3,5.9 Hz, 1 H), 2.12 (ddd, J= 13.3,8.5,5.1 Hz, 1 H), 2.23 (ddd, J=

13.2, 6.7, 3.7 Hz, 1 H), 1.97-1.85 (m, 2 H), 1.74-1.63 (m, 2 H), 1.56-1.43 (m, 1 H), 1.19 (dd, J =

12.9,12.9 Hz, 1 H), 1.13-0.97 (m, 2 H), 0.73 (S, 9 H); 1% NMR (75 MHz, CeDe) ppm 208.6, 86.4,

68.0, 43.0, 40.5, 38.0, 31.9, 30.9, 28.2, 27.6, 26.1; MS m/z(M+) calcd 210.1620, obsd

210.1608.

Anal. Calcd for C l 3H22O2: C, 74.24; H, 10.54. Found: C, 74.37; H, 10.64.

Hydroboratlon-Oxldatlon of 23. A cold (0 °C), nitrogen-blanketed, magnetically stirred solution of 23 (198 mg, 0.87 mmol) in dry THF (2.0 mL) was treated dropwise with the borane-dimethyl sulfide complex (0.48 mL of 2.0 M in THF, 0.963 mmol) via syringe, and reaction was allowed to proceed at 0 °C for 2 h and at rt for 2 h. With external ice cooling, 3 M NaOH (1 mL) and 30% hydrogen peroxide (1 mL) were introduced and the product was extracted into ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated to leave a residue which was chromatographically purified (silica gel, elution with 2:1 ethyl acetate/ hexanes).

There was isolated 101 mg (47%) of 25 as a fluffy white solid, mp 86 ®C.

151 Hydroboration*Oxldatlon of 28. Analogous treatment of 28 (36 mg, 0.16 mmol) fumistied 22 mg (57%) of 30 as a wliite solid, mp 114-115 °C.

Hydrobcration-Oxldation of 37. Reaction of 37 (292 mg, 1.15 mmol) witti the

Isorane-dimethyl sulfide complex (0.634 mL of 2.0 M in THF, 1.27 mmol) at 0 ®C in the predescnbed manner (1 h 45 min) afforded 188 mg (60%) of 39.

Hydroboration-Oxldation of 38. From 54 mg (0.21 mmol) of 38 and 0.234 mmol of the borane-dimethyl sulfide complex (0 ®C -» 20 ®C ovemight), there was isolated 41 mg (72%) of

40.

Hydroboratlon-Oxldatlon of 41. From 114 mg (0.453 mmol) of 41 and 0.543 mmol of the borane-dimethyl sulfide complex (0 °C -» 20 "C over 2 h), there was obtained 92 mg (75%) of 43.

Hydroboratlon-Oxldatlon of 42. Reaction of 42 (303 mg, 1.20 mmol) in the predescribed manner (0 °C for 5 h) led to the isolation of 44 (292 mg, 90%).

n y (S/7*,6/7*,8/7*)-8-ferf-Butyl-6-methoxy-l-oxasplro[4.5]decane CHsO ^ (27). To a nitrogen-blanketed, magnetically stirred solution of 25 (900 mg,

0.368 mnx)i) in dry CH 2CI2 (2 mL) was added 4-(dimethylamino)pyridine (2 mg). 27 triethylamine (0.154 mL, 1.11 mmol) and p-toluenesulfonyl chloride (105 mg,

0.552 mmol). After 36 h, the reaction mixture was diluted with water and 10% HCI (1.5 mL), and extracted with ether. The combined organic phases were washed with 3% NaOH solution (2 x 1.5 mL) and brine, dried, and concentrated. Chromatography of the residue on silica gel (elution with

6:1 hexanes-ethyl acetate) provided 64 mg (77%) of 27 as a colorless oil; IR (neat, cm"’) 1456,

152 1366,1138,1100,1054; NMR (300 MHz, CeDe) 53.98 (dd, 14.6,7.0 Hz, 1 H), 3.76 (ddd, J

» 7.4, 7.4, 5.5 Hz, 1 H), 3.18 (S, 3 H), 2.78 (dd, J - 11.4, 4.2 Hz, 1 H), 2.11 (ddd, J - 11.7, 8.6, 6.8

Hz, 1 H), 2.00-1.90 (m, 1 H), 1.89-1.82 (m. 1 H), 1.72-1.51 (m, 4 H), 1.48-1.41 (m, 1 H), 1.32 (ddd,

11.7, 8.7, 5.7 Hz, 1 H), 1.17-1.07 (m, 1 H), 0.95 (ddd, J - 12.2.12.2, 3.4 Hz, 1 H), 0.87 (s, 9

H); 13c NMR(75 MHz, CeDe) ppm 85.8, 82.9, 68.9, 56.6, 47.1, 37.8, 34.6, 32.6, 27.6, 26.8,

23.5: MS m /z (M+) calcd 226.1933, obsd 226.1952.

A nai Calcd for Ci4H2e02: C, 74.28; H, 11.58. Found: C, 74.12; H, 11.54.

(5/?*,6S*,12/?*)-12-ferf-Butyl-1,7-dloxadlsplro-

[4.0.4.4]tetradecane (45) and (5/?*,6/7*,12S*)-12-

re/t‘Butyi'1,7*dioxadlspiro[4.0.4.4]tetradecane (46).

Comparable cyclization of a 7.6:1 mixture of 43 and 44 (53 mg,

0.20 mnxjl) during 24 h followed by gradient elution chromatography on silica gel (16:1 -» 5:1

hexanes-ethyl acetate) gave 34 mg (68%) of 45 and 6 mg (12%) of 46.

For 45: colorless oil; IR (neat, cm'1) 1469.1392, 1365,1058; ^H NMR (300 MHz. CeDe) 5

3.73-3.60 (m, 4 H), 1.91-1.77 (m, 3 H), 1.71-1.36 (series of m. 12 H), 0.92 (s, 9 H); I^C NMR (75

MHz. CeDe) ppm 86.4, 85.1, 67.6 (2 C), 43.0, 35.8. 35.0, 33.7, 33.1, 32.1, 27.8, 26.5, 26.4,

23.0; MS m /z (M+) calcd 252.2089, obsd 252.2095.

A n a i Calcd for CleH2e02: C, 76.14; H, 11.18. Found: C, 76.26; H, 11.22.

For 46: colorless solid, mp 53-54 X ; ^H NMR (300 MHz, CeDe) 5 4.03 (ddd, J = 8.7, 7.8,

6.4 Hz, 1 H), 3.87 (td, J = 7.4, 3.7 Hz, 1 H), 3.77-3.61 (m, 2 H), 2.31 (tdd, J = 13.6, 4.1, 1.0 Hz, 1

H), 2.00-1.90 (m, 2 H). 1.84 (tt, J= 12.5,3.6 Hz, 1 H), 1.78-1.43 (series of m, 7 H), 1.28-1.17 (m, 2

H), 1.00 (t, J= 12.9 Hz, 1 H); 1% NMR (75 MHz, CeDe) ppm 87.5, 86.7, 68.8, 67.7, 42.1, 38.7,

33.4, 32.7, 32.2, 31.9, 27.7, 26.6, 26.5, 25.1; MS m /z(U + ) calcd 252.2089, obsd 252.2107.

153 Anal. Calcd for C 16 H28O2 : 0,76.14; H. 11.18. Found: 0,76.16; H. 11.17.

d ^ ^ O —. (5ff*,6/?*,l2/î*)-i2-ferf-Butyl-i,7-dloxadl8plro[4.0.4.4]tetradecane

(49). Analogous processing of 39 (100 mg. 0.370 mmol) during 36 h afforded 75

mg (80%) of 49 as a colorless oil; IR (neat, cm’^) 1440.1365.1060; NMR (300

49 MHz. CeDe) 6 4.05 (dd. 14.9.7.8 Hz. 1 H). 3.89 (td. J = 7.4.3.6 Hz. 1 H). 3.83-

3.68 (m. 2 H), 2.10 (t. 12.5 Hz. 1 H), 2.03-1.93 (m. 1 H), 1.82-1.56 (m. 8 H). 1.50-1.14 (series

of m. 4 H). 1.07 (tt. J= 12.6.3.4 Hz. 1 H). 0.94 (s. 9 H); I^C NMR (75 MHz. CeDe) ppm 88.2. 85.7,

68.4. 67.5, 46.4, 37.2. 34.9. 33.2. 32.4. 32.0. 27.9, 26.8. 26.7, 22.6; MS m /z (M+) calcd

252.2089. Obsd 252.2092.

Anal. Calcd for C l 6H28 O2: C. 76.14; H. 11.18. Found: C, 75.82; H, 11.07.

^.Oq _ j (5f7*,6S*,l2S*)-l2-ferf-ButyM,7-dioxadlspiro[4.0.4.4]tetradecane

(50). Parallel cyclization of 40 (31 mg. 0.12 mmol) delivered 21 mg (73%) of 50

as a colorless oil; IR (neat, cm''') 1448,1394,1366.1060,1034; ^H NMR (300

50 MHz. CeDe) 5 3.81-3.70 (m. 4 H). 2.45-2.34 (m, 2H). 2.01-1.83 (m. 2 H). 1.74-1.37

(series of m, 8 H), 1.34 (t. J= 12.6 Hz. 1 H). 1.06-0.83 (m, 2 H). 0.80 (s. 9 H); NMR (75 MHz.

CeDe) ppm 87.9. 87.6, 68.1, 67.9, 45.9, 39.1, 37.2, 32.1, 32.0,31.0, 27.7, 27.6, 27.4, 25.1; MS

m /z (M+) calcd 252.2089, obsd 252.2089.

Ana/. Calcd for Cl eH2s02: C, 76.14; H, 11.18. Found: C, 76.07; H, 11.13.

Com petition Experim ents. A mixture of 10 (105 mg, 0.50 mmol), 11 (105 mg, 0.50 mmol), allyl bromide (91 mg, 0.75 mmol), indium powder (63 mg, 0.55 mmol), and water (5.5 mL) was stirred at 25 °C in a stoppered flask for 48 h. Following the addition of 10% HCI, the reaction mixture was extracted with ether, and the combined organic phases were washed with brine, dried, and evaporated. The resultant oil was subjected to chromatography on silica gel (gradient

154 elution with 16:1 -* 4:1 hexanes/ ethyl acetate). There was isolated 31 mg of 10 and 77 mg of

11, representing essentially quantitative recovery (viz. 51%) of the unreacted ketones.

In entry 49, the two starting ketones proved difficult to separate cleanly. However, the

pairs of allylated epimers formed from each ketone possess distinctively different Rf values and

analysis was therefore accomplished in this manner. For example, when 0.50 mmol quantities of

6 and 7 were treated with allyl bromide and indium in water as described above and the crude

product mixture was subjected to silica gel chromatography, there was isolated 62 mg of 23/24

and 40 mg of 12/13. The combined total represents an essential quantitative recovery of

possible product alcohols.

7.2. Chapter 4

Prototypical lndlum*Mediated Allylations.

A. In Water. A mixture of allyl bromide (32 ^L, 0.38 mmol), indium powder (43 mg, 0.38

mmol), and 4-ferf-butylcyclohexanone (39 mg, 0.25 mmol) in water (2.5 mL) was tightly stoppered

and magentically stirred at rt for 3 h. The prototypical 10% HCI(aq) quench was avoided. The

reaction mixture was diluted with brine and extracted with Et 2 0 . The combined organic layers were dried over Na 2S04 and concentrated in vacuo. The resultant crude mixture was purified by column chromatography as indicated below.

B. In 50% THF(aq). Indium powder (86 mg, 0.75 mmol) was added to a homogenous solution of 4-fe/t-butylcyclohexanone (77 mg, 0.50 mmol) and allyl bromide (65 pL, 0.75 mmol) in a 1:1 mixture of THF and water (5.0 mL). The usual 10% HCI(aq) querxzh was avoided. The reaction mixture was stirred at rt for 4 h,partitioned with brine and Et 2 0 , and extracted with Et 2 0 .

The organic combine was dried over Na 2S 0 4 and concentrated in vacuo. The cmde mixture was purified as specificed below.

155 c. In Anhydrous THF. A suspension of metallic Indium (86 mg, 0.75 mmol) In an

anhydrous THF solution (5.0 mL) of 4-tert-butylcyclohexanone (77 mg, 0.50 mmol) and allyl bromide (65 pL, 0.75 mmol) was tightly stopperd and stirred at rt for 48 h. The reaction mixture was partioned with brine and Et 2 0 . Tfie separated aqueous layer was extracted with Et 2 0 and tfie combined organic layers were dried over Na 2S0 4 and concentrated in vacuo. The resultant crude products were purified as described.

D. Preformation of the Allyllndlum Reagent In THF. A mixture of Indium powder (0.172 g, 1.50 mmol) and allyl bromide (0.13 mL, 0.15 mmol) In anhydrous THF (5.0 mL) was refluxed under N2 until the metal was no longer visible (ca 45 min). a-Hydroxycyclohexanone

4 (0.184 g, 1.00 mmol) as a solution In THF (5.0 mL) was Introduced to the cooled reaction mixture, which was subsequently stirred at rt for 60 min, diluted with brine, treated with 10%

HCI(aq) solution, and extracted with Et 2 0 . The combined organic layers were dried over MgSO* and concentrated in vacuo. Purification of the crude product was accomplished as dictated.

E. Competition Experiments. A n equimolar mixture of 4 (46 mg, 0.25 mmol) arxJ 5

(46 mg, 0.25 mmol), allyl bromide (32 pL, 0.38 mmol), and indium powder (29 mg, 0.25 mmol) In water (2.5 mL) at rt was stirred in a stoppered flask for 8 h. The reaction mixture was quenched with 10% HCI (aq) and partitioned between brine and ether. The separated aqueous layer was extracted with ether, and the combined organic layers were dried and concentrated.

Coupling invioving 4*ferf-Butylcyciohexanone.

^ ^ c/s-l-Aily!-4-fert-butylcyclohexanol (24) and frans- 1-

Allyl 4-feff butylcycio hexanol (25)^^^: Submission of the

f-Bu parent ketone to the prototypical reaction conditions resulted, after 25 purification (elution with 10% EtOAc in hexanes), in the isolation of

156 carbinols 24 and 25 (Scheme 4.9).

For 24: colorless oil; IR (neat.cm-^) 3385(br), 2941,2868,1365,991, 954, 913: NMR

(300 MHz, CeDe) 5 5.84-5.75 (m, 1H), 5.07-4.97 (m, 2H), 2.04 (ddd, J = 7.4, 1.1,1.1 Hz, 2H),

1.56-1.33 (series of m, 6H), 1.15-1.05 (m, 2H), 0.87 (s, 9H), 0.92-0.75 (m, 2H); NMR (75 MHz,

CeDe) ppm 134.5, 118.0, 69.8, 49.1, 48.2, 37.7, 32.4, 27.8, 22.8 .

For 25 colorless solid, mp 59.5-60.5 “C; IR (KBr, cm 'l) 3312(br), 2945, 2868,1365,

1038, 908; ^H NMR (300 MHz, CeDe) 5 5.98-5.84 (m, 1H), 5.10-5.01 (m, 2H), 2.18 (d, J = 7 .3 Hz,

2H). 1.73-1.67 (m, 2H), 1.52-1.45 (m, 2H), 1.30 (ddd, J = 12.1,12.1,3.5 Hz, 2H), 1.13 (S, 1H),

0.99-0.86 (m. 3H). 0.78 (s. 9H); 13C NMR (75 MHz, CeDe) ppm 134.5,118.0, 71.2, 47.6, 41.4,

38.9, 32.2, 27.7, 24.5.

Coupling Involving 2-Hydroxycyclohexanone (1).

V. JOH (1/r,2fl*)-l-Allyl-1,2-cyclohexanedlol (26). The cyclohexanone C r dimer 1 was subjected to our indium-mediated allyationprotocols with strict 26 accord (Scheme 4.10). The resultant reaction mixture was purified to afford a

single product 26 (gradient elution with 9% EtOAc in hexanes, increasing to

20% and 50%).

For (26): colorless solid, mp 73 -74 °C; IR (KBr, cm 'i) 3405(br), 3269(br), 2939, 2855,

1448, 1408,1145, 1066, 979, 910; ^H NMR (300 MHz, CDCI 3) S 5.94-5.80 (m, 1H), 5.13-5.07

(m, 2H), 3.42 (dd, J= 9.3, 3.9 Hz, 1 H), 2.37 (dd, J= 13.7, 7.5 Hz, 1H), 2.27 (dd, J= 13.7, 7.4 Hz,

1 H), 2.19 (br s, 1H), 1.72 -1.16 (series of m, 8 H); I^C NMR (75 MHz, CDCI3) ppm 133.8,118.5,

73.2, 73.1, 43.5, 34.1, 30.2, 23.2, 21.0; HRMS (El) m /z (M+) calcd for CgHieOa 156.1150, ObSd

156.1160.

Anal. Calcd for CgHieOg: C, 69.19; H, 10.32. Found C, 69.03; H. 10.25.

157 Coupling involving c/g- 4 -fgff-Butyl-2 hydroxycyciohexanone (3).

I /-oj (1 /T,2 /î*, 4 / r ) - 1-Allyl-4 -fert-butyl-1,2-cyclohexanedlol (28). Under V OH the specifics already established, ketone 2 was allylated with indium powder and

allyl bromide (Scheme 4.11). t h NMR anayiisis of the crude reaction mixture f-Bu 28 indicated that tautomerization had occurd and resulted in the fomiation of

approxiamterly 11 % of isomer 30. Purification of the major product 28 was

accomplished with silica gel as the solid phase and 20% EtOAc in hexanes as the eluent.

For (28): colorless solid; mp 99-100 "C; IR (KBr, cm't) 3288(br), 2964, 2907, 2868,

1364, 990, 911 ; tH NMR (300 MHz, CDCI 3) Ô 5.97-5.83 (m, 1H), 5.15-5.10 (m, 2H), 3.42 (dd, J -

11.2, 4.5 Hz, 1H), 2.42 (dd, J = 13.6, 7.7 Hz, 1H), 2.26 (dd, J = 13.6, 7.3 Hz, 1H), 1.93 (br s, 2H),

1.84-1.72 (m, 2H), 1.51-1.44 (m, 1H), 1.37-1.18 (m, 3H), 1.06-0.91 (m, 1H), 0.86 (s, 9H);

NMR (75 MHz, CDCI3) ppm 134.1, 118.6, 73.6, 73.2, 44.9, 41.6, 36.0, 32.0, 30.8, 27.5, 25.1;

HRMS (El) r7^z(M + -C 3H5)calcdforCioHi 902 171.1385, obsd 171.1376.

Ana/. Calcd for C 13H24O2: 0. 73.54; H, 11.39. Found 0, 73.57; H, 11.29.

Coupling Involving frans-S-ferf-Butyl-2-hydroxycyclohexanone ( 6 ). OH (1 /?*,2S*,5S*)-1-Allyl-5-ferf-Butyl-1,2-cyclohexananedlol (30).

^ The indium-promoted allylation of ketone 6 under the trio of reaction conditions

afforded 30 and approxiamterly 9% of isomer 28 as determined by t H NMR

anayiisis of the crude reaction mixture (Scheme 4.13). Isolation of 30 was accomplished by chromatagraphic separation on silica gel (elution with 25% EtOAc in hexanes).

For (30): colorless solid, mp 63-67 °C; IR (KBr, cm 't) 3381 (br), 2951, 2869,1449,1414,

1366,1064, 994, 953, 912; ’H NMR (300 MHz, CDCI 3) 6 5.99-5.84 (m, 1H), 5.16-5.10 (m, 2H),

158 3.37 (dd. J = 11.4,4.8 Hz, 1H), 2.47 (dd. J=13.6. 7.7 Hz. 1H). 2.28 (dd. J-1 3 .6 . 7.4 Hz. 1H).

1.92 (br s. 1H), 1.84-1.89 (series of m. 4H). 1.61-1.47 (m. 1H). 1.38 (dddd. J-12.4.12.4.3.1.3.1

Hz. 1H). 1.09-0.89 (series of m. 2H). 0.84 (s. 9H); 1% NMR (75 MHz. CDCI 3) ppm 134.1.118.6,

74.2. 72.4. 46.4. 44.3. 34.8. 32.2. 31.9, 27.5, 21.6; HRMS (El) m/Z{M+- C3H5) calcd for

C10H19 O2 171.1385, Obsd 171.1385.

Anal. Calcd for C 13H24O2: 0, 73.54; H, 11.39. Found 0, 73.54; H, 11.44.

Coupling invoioving frans 4-ferf-Bufyl 2 hydroxycyclohexanone (4).

^ (1/r,2S*,4fl*)-l-Allyl-4-fe#t-butyi-l,2-cyciohexanedlol (31). % JOH OH Ketone 3, under identical conditions, afforded homoallylic alcohols 31.28 and

30 (Scheme 4.14). Compound 31 was cleanly separated from the mixture by f-Bu 31 column chromatography (elution with 20% EtOAc in hexanes).

For (31): coloriess semi-solid; mp 86-90 X ; IR (KBr, cm"'') 3404(br),

2962, 1394, 1366, 1239, 1174, 1057, 1011, 914; ^H NMR (300 MHz, CDCI 3) 6 5.94-5.80 (m,

1H), 5.06-4.99 (m, 2H), 3.43 (br s, 1H), 2.35 (dd, J = 13.6, 7.4 Hz, 1H), 2.13 (dd, J= 13.6, 7.6 Hz,

1H), 1.73-1.56 (m, 3H), 1.50-1.35 (m, 5H), 1.06 (s, 1H), 0.86 (s, 9H); 1% NMR (75 MHz, CDCI 3)

ppm 134.3, 118.7, 72.3, 71.7, 44.4, 40.5, 33.1, 32.0, 30.5, 27.6, 22.2; HRMS (El) m/z(M+ -

C3H5) calcd for C 10H19 O2 171.1385, obsd 171.1390.

Anal. Calcd for C 13H24O2: C, 73.54; H, 11.39. Found C, 73.72; H, 11.48.

Coupling Involving c/s4-ferf-Butyl-2-hydroxy-2-methylcyclohexanone (4).

^ (1/r,2/?*,4/?*)-1-Allyl-4-ferf-Butyl-2-methyl-l,2- % .OH QLI cyclohexananedlol (33). Ketone 4 was reacted with allyl bromide and I I CH3 indium powder in water, 50% THF(aq), and THF to cleanly afforded a single f-Bu 33 diastereomer (33) after (gradient elution with 17% EtOAc in hexanes,

increasing to 50%) (Scheme 4.16).

159 For (33): colorless oil; IR (neat, cm'i) 3450(br). 2951 : NMR (300 MHz. CDCI 3) 6 6.03-

5.89 (m. 1H). 5.19-5.10 (m. 2H). 2.51 (dd. 13.7.8.3 Hz. 1H). 2.24 (s. 1H). 2.15 (S. 1H). 2.11

(dd. J * 13.7. 6.7 Hz. 1H). 1.77 (ddd. 10.3, 2.8. 2.8 Hz. 1H). 1.59-1.43 (m. 3H). 1.40-1.23 (m.

2H). 1.22 (S. 3H). 1.08 (dddd. J - 12.1,12.1.3.5. 3.5 Hz. 1H). 0.84 (s. 9H); ; NMR (75 MHz.

CDCI3) ppm 134.5. 119.1. 75.0. 74.1. 45.0. 40.7. 38.9, 33.9, 32.1, 27.4, 23.1, 21.7; HRMS (El) m /z (M+) calcd for C 14H26O2 226.1933, obsd 226.1929.

Anal. Calcd for C 14H26O2 : C, 74.29; H, 11.57. Found C, 74.05; H, 11.63.

Coupling involving frans4-rerf-Butyl-2-hydroxy>2-methylcyclohexanone (5).

(1 Aï*,2S*,4/?*)-1-Allyl-4-fert-Butyl-2-methyl-1,2- .OH cyclohexananedlol (35) and (1R*,2R*,45*)-1-Allyl-

4-ferf-Butyl-2-methyl-1,2-cyclohexananedlol (36). f-Bu f-Bu 35 36 Indium-mediated allylation of 5 afforded a single diastereomer in water and aqueous THF (Scheme 4.17). Only anhydrous THF afforded a mixture of homoallylic alcohols 35 and 36. The product(s) were purified by silica gel column chromatography (elution with 11% EtOAc in hexanes).

For (35): colorless oil; IR (neat, cm I) 3490(br), 3075, 2952, 2869, 1468, 1438, 1365,

1240, 1171,1078, 999, 915; ’H NMR (300 MHz. CDCI 3) S 5.98-5.84 (m. 1H). 5.17-5.10 (m. 2H),

2.44 (dd, J= 13.7,7.5 Hz, 1H), 2.35 (dd, J = 13.7, 7.6 Hz. 1H), 1.76-1.19 (series of m. 7H), 1.38

(s, 1H), 1.34 (s. 1H), 1.24 (s, 3H), 0.85 (s, 9H); NMR (75 MHz. CDCI 3) ppm 134.5,119.0,

74.4, 73.6, 42.0, 40.3, 37.4, 32.7, 32.0, 27.5, 24.6, 21.5; HRMS (El) m/z{M+) calcd for

C17H26O2 226.1933, Obsd 226.1936.

Anal. Calcd for C 17H26O2: C, 74.29; H, 11.57. Found C, 74.17; H. 11.60.

160 For (36): colorless oil; IR (neat, cm'"') 3430, 2958, 2869, 1365, 11443, 1065, 996, 943,

909; NMR (300 MHz, CDCI 3) 5 5.95-5.81 (m, 1H), 5.17-5.07 (m. 2H), 2.33 (dd, 14.0, 7.9

Hz, 1H), 2.20 (dd, J - 14.0,6.6 Hz, 1H). 2.19 (s, 1H), 1.94 (s, 1H), 1.76-1.44 (series of m, 5H),

1.24 (dd, J 1 3 .3 ,13.3 Hz, 1H). 1.18 (S. 3H), 1.08-0.95 )m, 1H). 0.85 (s, 9H); 1% NMR (75 MHz,

CDCI3) ppm 133.7, 118.4, 75.2, 74.3, 41.7, 38.1,36.9, 32.0, 31.9, 27.5, 24.5, 23.5; HRMS (El) m /z (M+) calcd for C 17H26O2 226.1933, obsd 226.1956.

Anal. Calcd for C 17H30O2: 0, 74.29; H, 11.57. Found 0 , 74.13; H, 11.52.

^ —. oA * (1/r,2#r)-l-Allyl-1,2-(lsopropyildenedioxy)cyclohexane (27). X l o I I To a magnetically stirred solution of diol 26 (0.156 g, 1.00 mnx)l) in DMF (1.0

27 mL) at O ®C was added 2-methoxypropene (0.19 mL, 2.0 mmol) and PPTS (25

mg, 0.10 mmol). The reaction mixture was stirred at 0 °C for 45 min, diluted with brine, and extracted several times with Et 2 0 . The combined organic layers were dried with anhydrous Na 2S0 4 and concentrated in vacuo. The crude residue was purified by chromatographic separation (elution with 9% EtOAc in hexanes) to afford 0.172 g ( 88 %) of acetonide 27 as a colorless oil; IR (neat, cm*^) 2984, 2935,1378,1368, 1245,1219,1191,

1054,1040,1003; ^H NMR (300 MHz, CDCI3) 5 5.98-5.84 (m. 1H), 5.12-5.02 (m, 2H), 3.90 (d, J =

2.6 Hz, 1 H), 2.37 (dddd. J= 14.4, 6.9,1.2, 1.2 Hz, 1H), 2.28 (dd, J= 14.4, 7.5 Hz, 1 H), 2.12-

2.03 (m, 1H), 1.71-1.44 (series Of m, 6H), 1.49 (S, 3H), 1.33 (S, 3H), 1.18-1.08 (m, 1H); 1 % NMR

(75 MHz, CDCI3) ppm 133.8, 117.7, 106.8, 80.1, 76.2, 40.1, 34.3. 28.5, 27.0, 26.2, 22.7, 19.8;

HRMS (El) m /z (M+) calcd for C 12H20O2 196.1463, obsd 196.1464.

Anal. Calcd for C 12H20O2: C, 73.43; H, 10.27. Found C, 73.51 ; H, 10.20.

(1 /7*,2/7*,4/7*)-l-Allyl-4*ferf-butyl-2-methoxycyclohexanol (26). .OH ,OMe A suspension of NaH (4 mg, 0.17 mmol) and diol 25 (30 mg, 0.14 mmol) in THF

(1.5 mL) at 0 °C was stirred under N2 for 30 min prior to the addition of Mel (0.18 f-Bu 26 mL, 2.8 mmol). The reaction mixture was warmed to rt over a 12 h period,

161 partitioned with brine and extracted with EtaO. The combined organic layers were dried over

anhydrous MgS 0 4 and concentrated in vacuo. Column purification (elution with8 % EtOAc in

hexanes) afforded 22 mg (69%) of the methylated product 26 and 5 mg (17%) of starting material

diol 25. Spectral data for the methyl ether were consistent with those previously reported.^

(1/r,2S*,4/r)-1-Ailyl-4-fe/t-butyl-2-methoxycyclohexanol (32).A .OH mixture of trans diol 31 (31 mg. 0.15 mmol) and NaH (4 mg, 0.18 mmol) in THF

(3.0 mL) was stirred at 0 for 30 min, warmed to rt for 1 h, and recooled to 0 °C f-Bu 32 before the addition of Mel (0.18 mL, 2.9 mmol). The reaction mixture was

subsequently warmed to rt; TLC analysis showed considerable starting material

remaining. An additional 1.2 eq of NaH (4 mg, 0.18 mmol) and additional Mel (0.18 mL, 2.9 mmol) was added. The reaction mixture was stirred at rt under N 2 for 24 h, quenched cautiously with

brine, and extracted with EtaO. The combined organe layers were dried over anhydrous MgSO^ and concentrated in vacuo. Column chromatography (SiOg, elution with 10% EtOAc in hexanes) afforded 15 mg (48%) of methyl ether 32 and 11 mg (36%) of starting diol 31 with an overall yield of 70% based on recovered starting material. Spectral data of methyl ether 32 completely matched those previously reported.^

^ « A''' C W*.2/?*,4fl*)-1-Allyl-4-ferf-butyl-1,2-(lsopropylldenedloxy)-2-

m ethylcyclohexane (34). A solution of diol 33 (86 mg, 0.38 mmol), 2- CH3 methoxypropene (0.14 mL, 1.5 mmol) and PPTS (9 mg, 40 pmol) in CH 2CI2

(3.8 mL) was refluxed for 14 h. The reaction mixture was partioned with brine,

extracted with CH 2CI2 and dried over anhydrous Na 2S0 4 . Purification by column chromatography (elution with 2.5% EtOAc in hexanes) afforded 83 mg (83%) of the desired acetonide 34 as a near coloriess oil; IR (neat, cm*^) 2942, 2868,1639,1467,1376,

1367, 1228,1209, 1162, 1115,1073,1016, 911; ^H NMR (300 MHz, CDCI 3) 5 5.99-5.85 (m,

162 1H). 5.14-5.03 (m. 2H), 2.72 (dd, 14.1.5.4 Hz, 1H). 2.19 (dd, J » 10.8,3.4 Hz, 1H). 1.91 (dd, J

= 14.1, 8.6 Hz. 1H). 1.74-1.61 (m, 3H), 1.53 (S, 3H), 1.47 (s, 3H), 1.24 (S, 3H). 1.21-1.14 (m, 2H).

0.95-0.86 (m, 1H). 0.84 (s, 9H); NMR (75 MHz, CDCI 3) ppm 134.2,117.9,106.6, 83.3, 82.5.

45.4.41.7, 39.4, 32.8, 32.0, 30.3, 30.1, 27.3, 22.2, 21.6; HRMS (El) m/z{M+) calcd for

C17H30O2 266.2246, Obsd 266.2285.

Anal. Calcd for C 17H30O2: G. 76.64; H. 11.35. Found 0, 76.55; H. 11.31.

(1/7*,2/7*,4S*)-1-Allyl-4-ferr-butyl-l,2-(lsopropylldenedloxy)-2<

m ethylcyclohexane (37). A solution of diol 36 (71 mg, 0.31 mmol), 2- CH3 methoxypropene (0.120 mL, 1.26 mmol) and PPTS (8 mg. 30 pmol) in CH 2CI2

(3.0 mL) was refluxed for 10 h, cooled to rt and partioned with brine. The

reaction mixture was extracted with CH 2CI2, and the combined organic layers

were dried with anhydrous Na 2S0 4 and concentrated In vacuo. Purification by column

chromatography (elution with 2.5% EtOAc in hexanes) afforded 40 mg (48%) of the desired

acetonide 37 as a colorless oil; IR (neat, cm ^) 29.43, 2870,1367,1230,1199,1062,1004; ^ H

NMR (300 MHz, CDCI3) 55.96-5.82 (m. 1H), 5.12-5.03 (m, 2H), 2.44 (ddd, J = 14.1,5.6. 1.2 Hz,

1H), 2.19 (dd. J= 14.1,8.7 Hz, 1H), 2.00 (ddd. J= 14.3, 3.4, 2.6 Hz, 1H). 1.83 (ddd, J= 13.8,

5.0, 5.0 Hz, 1H). 1.76 (ddd, J= 14.7,14.7, 4.1 Hz, 1H), 1.66-1.57 (m, 1H), 1.51 (s, 3H), 1.46 (s,

3H), 1.49-1.38 (m, 1H), 1.28 (m, 3H), 1.08 (dd, J= 14.3,12.7, Hz, 1H), 0.93 (dddd, J= 10.9,

10.9, 4.6, 4.6 Hz, 1H), 0.84 (s, 9H); 13C NMR (75 MHz, CDCI 3) ppm 134.7,117.8, 106.7, 83.1,

82.7, 41.3, 39.7, 37.2, 32.8, 32.1, 30.5, 29.8, 27.4, 26.3, 23.4; HRMS (El) m /z (M+ - GH3 calcd for C16H27O2 251.2012, obsd 251.2012.

Anal. Galcd for G 17H30O2: G, 76.64; H, 11.35. Found G, 76.35; H, 11.33.

163 o OTBOMS c/5-4-f0/t-Butyi-2-(feft-butyldimethylsiloxy)- ^ ^ .^ O T B D M S cyclohexanone (7) and trans*5-feft*Butyl-2-(fe/t>

butyidlmethylslioxy)cyclohexanone (8).To a solution f-Bu f-Bu 7 8 of dusopropylamine (3.64 mL, 26.0 mmol) in THF at -78

(100 m L) under N2 was added n-BuU (18.5 mL. 1.3 M/hexanes, 24.0 mmol). The reaction

mixture was warmed to 0 "C over a l h period, and then recooled to -78 °C prior to cannulation of 4-

ferFtxrtylcyclohexanone (3.08 g, 20.0 mmol) as a solution in THF (100 mL) and syringe addition of

TMSCI (3.81 mL, 30.0 mnwl). The reaction mixture was slowly warmed to 0 °C over 4 h, diluted

with EtsN (100 mL), and concentrated in vacuo. The crude reaction mixture was dissolved in

pentane and filtered throught Celite; the filter cake was washed several times with pentane. The

pentane was removed under reduced pressure and the resultant crude oil was distilled (0.55 mm

Hg, 55 °C) to give 3.85 g (85%) of the silyl enol ether as a slightly yellow viscous oil.

Purified m-CPBA (-95%) (2.07 g, 12.0 mmol) was added portionwise to a solution of the

silyl enol ether (2.26 g, 10.0 mmol) in CH 2CI2 (100 mL). The reaction mixture was stirred for 8 h and then partitioned with saturated NaHC 0 3 (aq) solution. The organic layer was separated, washed with saturated NaHC 0 3 (aq) solution, dried over anhydrous Na 2S0 4 , and concentrated in

vacuo \o afford a crude residue. The crude residue was dissolved in THF (90 mL) and treated with

TBAF (10.0 mL, 1.0 M/THF, 10.0 mmol). The reaction mixture was stirred for 8 h, partitioned with saturated NaHCOa (aq) solution, and extracted with EtaO. The combined organic layers were dried over NaaSO^ and concentrated in vacuo to give a complicatcated mixture of a- hydroxycyclohexanones which was used without further purifcation or characterization.

A crude isomeric mixture of a-hydroxy ketones (340 mg, 2.00 mmol), imidazole (233 mg,

3.42 mmol), and TBDMSCI (361 mg, 2.40 mnx)l) in dry DMF (4.0 mL) was stirred at rt for 2 h . The reaction mixture was diluted with brine and extracted multiple times with EtaO. The combined orgainc layers were dried over anhydrous MgSO^ and concentrated in vacuo. Chromatographic

164 purification (elution witti 6% EtOAc in tiexanes) of ttie crude oil afford 0.080 g of less polar isomer

8 (14%) and 0.111 g of more polar isomer 7 (20%). t»tti as neat oils.

For?: IR (neat, cm-1) 2956.2856.1732.1132; 1H NMR (300 MHz. CDCI 3) 64.18 (ddd. J

= 11.6. 6.4.1.0 Hz. 1H), 2.40 (ddd. J - 13.8. 4.3. 2.7 Hz. 1H). 2.27 (ddd. J - 13.8. 5.9, 1.1 Hz.

1H). 2.25-2.19 (m. 1H). 2.02 (dddd. J - 15.7. 3.0. 3.0. 3.0 Hz. 1H). 1.60 (dddd. J = 12.2. 12.2.

2.6. 2.6 Hz. 1H). 1.47 (dd, J - 12.0.12.0 Hz, 1H). 1.37 (dddd. J - 13.4.13.4, 13.4. 4.3 Hz. 1H).

0.91 (S. 9H). 0.89 (s. 9H). 0.12 (S. 3H). 0.01 (S. 3H); 1% NMR (75 MHz. CDCI3) ppm 209.4, 76.7.

46.0. 39.4, 38.5. 32.3. 28.0, 27.6, 25.8, 18.5. -4.6. -5.4; HRMS (El) ffl'z(M+) calcd for

Ci6H3202Si 284.2172, Obsd 284.2145.

Anal. Calcd for Ci6H3202Si: 0.67.55: H. 11.34. Found 0, 67.68; H. 11.43.

For 8 : IR (neat, cnrl) 2955. 2857.1731. 1149. 837; 1H NMR (300 MHz. GDCI 3) 54.14

(ddd. J= 12.0. 6.6 .1.0 Hz. 1H). 2.46 (ddd. J = 12.9. 2.9. 2.9 Hz. 1H). 2.14 (dddd. J= 12.7. 3.3.

3.3. 3.3 Hz. 1H). 2.04 (ddd. J = 13.0,13.0.1.1 Hz. 1H) 1.91 (dddd. J = 12.7.3.0.3.0. 3.0 Hz. 1H).

1.67-1.36 (series of m. 3H). 0.89 (s. 9H). 0.88 (s. 9H). 0.13 (s. 3H). 0.02 (S. 3H); 13c NMR (75

MHz. 00013) ppm 209.6. 77.0. 49.8. 42.2. 35.8. 32.6. 27.3. 25.8. 25.2. 18.5. -4.6. -5.4; HRMS

(El) m /z (M+) calcd for 0i6H3202Si 284.2172. obsd 284.2169.

Ana/. Oalcd for 0i6H3202Si: 0. 67.55; H. 11.34. Found 0. 67.67; H. 11.39.

O OH c/s-4-fe/t-Butyl-2-tiydroxycyclotiexanone (2). To a solution of silyl ettier

7 (1.40 g. 4.95 mmol) in dry THF (5.5 mL) was added TBAF (5.44 mL. 1.0 M/THF.

5.44 mmol). The reaction mixture was stirred at rt for 2 h and then partioned with

brine. The separated aqueous layer was extracted further with Et 2 0 . The combined organic layers were dried over anhydrous Na 2S0 4 and concentrated in vacuo. The resultant caide solid was quickly purified (elution with 10% EtOAc in hexanes) to afford 0.400 g

165 (48%) of 2 as a semi-solid which was immediately used without further characterization. The

ot)servance of 11% of homoallylic alcohol 30 by NMR analysis indicated tautomerization had

occured.

OH , o fran»-5>rerr*Butyl>2*hydroxycyclohexanone ( 6 ). To a solution of silyl ether ÇT- 8 (0.761 g, 2.67 mmol) in dry THF (3.0 mL) was added TBAF (2.94 mL, 1.0 M/THF,

f-Bu 2.94 mmoi). The reaction mixture was stined at rt for 2 h and partitioned with brine. 6 The separated aqueous layer was extracted further with EtaO. The combined organic layers were dried over anhydrous Na 2S0 4 and concentrated in vacuo. The resultant crude solid was quickly purified (elution with 25% EtOAc in hexanes) to afford 0.268 g (59%) of 6 as a semi-solid which was immediately used without further characterization. The observance of homoallylic alcohol 28 ^H NMR indicated that 9% of 6 had tautomerized to 2.

OH fra/is-2-[(E)*Benzylldene]-4-ferf-butylcyclohexanol (14). A 75%

aqueous solution of acetone (20 mL), conc. HCI(aq) (0.1 GmL) and ketal 13^

^'Bu (1.00 g, 3.49 mmol) was refluxed for 2 h, diluted with brine, and extracted with 14 Et2 0 . The combined organic layers were dried over anhydrous MgSO^ and then concentrated in vacuo to afford a crude white solid which was used without further purification

Anhydrous MeOH (1.69 mL, 41.9 mmol) as a solution in THF (11 mL) was slowly added to a solution of LiAIH^ (0.530 g, 14.0 mmol) in dry THF (15 mL) at 0 °C under N2, 5 min later the solid intemriediate enone was added as a THF solution (9.0 mL). After 1 h at 0 °C the reaction mixture was treated siowly with H 2O (0.53 mL),15% NaOH(aq) solution (0.53 mL), and H2O (1.59 ml), stirred at 0 “C for 1 h and extracted several times with Et 2 0 . The combined organic layers were washed with brine, dried with anhydrous Na 2S0 4 , and concentrated in vacuo. The resultant cnjde solid was purified by column chromatography on silica gel (elution with 10% EtOAc in hexanes) to afford 0.537 g of alcohol 14 (63% over two steps) as a white solid, mp 101-102 °C; IR

166 (KBr, cm-1) 3284 , 2949, 2865. 1095,1062, 741, 704; NMR (300 MHz, CDCI 3) 5 7.29*7.12 (m.

5H), 6.50 (s, IN), 4.08-4.04 (m. 1H), 2.98 (dt. J - 13.0, 2.5 Hz, 1H), 2.23-2.17 (m, 1H), 1.87-1.82

(m, lH), 1.70 (brs, 1H), 1.44-1.14 (seriesof m, 4H), 0.82 (s, 9H); NMR (75 MHz, CDCI 3) ppm

144.9, 137.9, 128.8, 128.0, 126.0, 118.1, 73.3, 49.3, 37.6, 32.8, 29.5, 27.4, 25.9: HRMS (El) m /z (M+) calcd for C 17H24O 244.1827, obsd 244.1830.

Anal. Calcd for C 17H2 4 0 :0,83.55; H, 9.90. Found 0,83.39; H, 9.84.

OTBDMS [[rran 5>2-[(E)>Benzylldene]> 4 >re/t>butylcyciohexyl]oxy*ferr*

butyldimethylsilane (15).To a solution of alcohol 14 (0.484 g, 1.98 mmol) in

f-Bu dry DMF (4.0 mL) was added imidazole (0.230 g, 3.38 mmol) and TBDMSCI 15 (0.358 g, 2.37 mmol). The reaction mixture was stirred at rt for 12 h, diluted with brine, and extracted many times with Et 2 0 . The combined organic extracts were dried over anhydrous Na 2S 0 4 and concentrated in vacuo to afford a crude oil. Chromatographic purification of the cmde product (eiution with 5% EtOAc in hexanes) gave 0.506 g (71%) of silyl ether 15 as a slightly yellow oil; IR (neat, cm 'l) 2956, 2858,1130,1108; ^H NMR (300 MHz, CDCI 3) 6 7.34-7.17

(m, 5H), 6.61 (s, 1H), 4.08 (ddd, J = 11.0, 4.9,1.6 Hz, 1H), 3.03 (ddd, J= 13.0, 2.5, 2.5 Hz, 1H),

2.15-2.06 (m, 1H), 1.90-1.86 (m, 1H), 1.55-1.19 (series of m, 4H), 0.98 (s, 9H), 0.89 (s, 9H), 0.16

(s, 3H), 0.14 (s, 3H); 1% NMR (75 MHz, CDCI3) ppm 144.4,138.5, 128.8,127.9, 125.8,119.0,

74.2, 49.3, 37.9, 32.8, 29.6, 27.5, 26.0, 26.0,18.5, -4.8, -4.8; HRMS (El) m /z (M+) calcd for

C23H3 80 SI 358.2692, obsd 358.2707.

Anal. Calcd for C 23H3 8 0 SI: C, 77.03; H, 10.68. Found C, 77.14; H, 10.71.

OTBDMS .0 trans-5-feft-Butyl-2-(fe/t-butyldimethyisMoxy)cyciohexanone ( 8 ). A

-78 “C solution of benzylidene 15 (0.506 g, 1.41 mmol) in CH 2CI2 (7.0 ml) and

f-Bu MeOH (7.0 ml), (with 1% EÎ3N added), was ozonolyzed until a faint blue color 8 appeared. The reaction mixture was purged with oxygen, treated with

167 dimethylsuffîde (0.65 mL) and warmed to rt. The reaction mixture then was diluted with 1%

NaHC0 3 (aq) solution and extracted several times with CH 2CI2. The organic layers were dried over

anhydrous Na 2S0 4 and concentrated in vacuo to afford a crude oil. Purification of the oil by

column chromatography (elution with 6% EtOAc in hexanes) afforded 0.306 g of ketone 8 (76%).

Spectral data were consistent with those previously reported.

0 ^ 0 frana-8-reit-Butyi-l,4-dloxasplro[4.5]decan-6-oi (17) ...OH and cfa-8-ferf-Butyl-l ,4-dloxaspiro[4.5]decan-6>oi

Vt-Bu (18). DIBAL-H (6.82 mL, 1.0 M/hexanes, 6.82 mmol) was added 18 via syringe to a solution of ketal ketone 16^ (1.11 g, 5.25 mmol) in

hexanes (14.2 mL) at -78 °C under N2. The reaction mixture was warmed to rt over a 4 h period before being quenched with a saturated solution of Rochelle salt (Na/K tartrate) and was stirred further ovemight. The aqueous layer was separated and extracted with Et 2Û. The combined organic layers were dried over anhydrous Na 2S0 4 and concentrated in vacuo to afford a crude white solid. Column pu rif cat ion (gradient elution with 17% EtOAc in hexanes, increasing to 33%) of the crude solid afforded 0.662 g of the less polar axial isomer 17 (57%) and 0.370 g of the more polar equatorial isomer 18 (33%).

For 17: mp 57-58 “0; IR (KBr, cm-1) 3510, 2966, 2951,2880, 1179, 1123, 1111, 1058,

1031,1003:1H NMR (300 mHz, CDCI3) 8 3.98-3.90 (m, 4H). 3.63 (s. 1H), 2.20 (s, 1H), 1.96-1.86

(m, 2H), 1.72-1.64 (m, 1H). 1.56 (dddd, J= 13.1,3.4, 3.4, 1.8 Hz, 1H), 1.48-1.35 (m, 2H), 1.22

(dddd, J= 12.9.12.9,12.9. 3.5 Hz, 1H). 0.85 (s. 9H); 13C NMR (75 mHz, CDCI 3) ppm 109.0,

70.0, 65.3, 64.3, 39.3, 31.8, 30.3, 30.2, 27.5, 24.1 ; HRMS (El) nVz (M+) calcd for C 12H22O3

214.1569, Obsd 214.1566.

Anal. Calcd for C 12H22O3 : C, 67.26; H, 10.35. Found C, 67.36: H. 10.43

168 For 18: mp 55-56 “C; IR (KBr. cm"l) 3493. 2963.1088; NMR (300 mHz. CDCI 3) 6 4.12-

3.94 (series of m. 4H). 3.64-3.57 (m. 1H). 2.03-1.92 (series of m. 2H). 1.82 (ddd. J - 13.1.13.1.

3.0 Hz. 1H). 1.67-1.60 (m. 1H). 1.36 (ddd. J * 13.1.13.1.3.7. Hz. 1H). 1.29-1.09 (series of m.

3H). 0.86 (s. 9H): 1% NMR (75 mHz. CDCI 3) ppm 109.5.73.5,65.5. 65.3. 45.9.33.6. 33.5.32.2.

27.6. 24.1 : HRMS (El) m/z(M+) cakxJ for C12H22O3 214.1569. obsd 214.1552.

Anal. Calcd for G 12H22O3: 0.67.26; H. 10.35. Found 0.67.33; H. 10.42

0 OH c/s*4>fe/f>Butyl>2>hydroxycyclohexanone (2) and trans-S- A ^ oh I I II fëfl-Butyl-2 hydroxycyclohexanone(6). Major ketal 17 (0.241

1 I g. 1.00 mmol) was refluxed in 75% aqueous acetone (20 mL) f-Bu f-Bu 2 6 containing concentrated HOI(aq) (10 fxL) for 10 ti. The reaction mixture was cooled to rt. diluted with brine, and partitioned with EtaO. The layers were separated and the aqueous layer was further extracted with Et2 0 . The combined organic layers were dried over anhydrous Na 2S0 4 and concentrated in vacuo to afford 0.120 g (71%) of a cmde mixture of 2 and

6 as determined by ^H NMR. but not the desired axial isomer 3.

CHg 1-ferf Butyl 4-methylenecyclohexane (19). A mixture of NaH (4.80 g. 0.200

mmol) and freshly distilled DMSO (100 mL) was heated to 75-80 °C for 45 min and then

f-Bu cooled to 0 °C. The freshly prepared Wittig salt (Ph 3P CH3l+)^^ (80.85 g. 0.200 mmol). 19 as a solution in warm DMSO (200 mL). was introduced to the chilled (0 ”0) reaction mixture via a pressure equalized addition funnel. The reaction mixture was warmed to rt over a 1 h period and the product was obtained by fractional distillation under reduced pressure.

Chromatographic purification (elution with hexanes) of the higher boiling fractions removed residual DMSO arxl afforded 26.84 g (80%) of olefin 19 IT which was directly oxidized.

169 ÇH2 frans-5-ferf-Butyl-2-methylenecyclohexanol (20). f-BuOOH (32 mL), OH followed by olefin 19 (12.11 g, 79.5 mmol). was added to a solution of SeOa

(0.441 g, 3.98 mmol) and salicylic acid (1.10 g, 7.95 mmol) in CH 2CI2 (40 mL). The f-Bu 20 reaction mixture was stirred at rt under N2 for 40 h, partitioned with brine and

extracted with CH 2CI2 The combined organic layers were washed with 10%

KOH(aq) solution, dried with anhydrous Na 2S0 4 and concentrated in vacuo. Chromatographic

purification (gradient elution with 5% EtOAc, increasing to 10% and 20%, in hexanes) afforded

10.05 g (75%) of ailylic alcohol 20. Neither was the allylic alcohol fully characterized at this stage

nor was the axial disposition of the alcohol firmly established.

CHg ,.OBn Benzyl rrans-5-ferf>Butyl-2*methylenecyclohexyl ether (21). A

solution of allylic alcohol 20 (10.05 g, 59.7 mmol), BnBr (8.48 mL, 71.7 mmol),

NaH (1.94 g, 77.6 mmol), and n-Bu^NI (2.21 g, 5.98 mmol) in THF (300 mL) was

stirred at 0 °C for 2 h and warmed to rt ovemight. The reaction mixture was

cautiously diluted with brine and partioned with Et 2 0 . The aqueous layer was separated and further extracted with Et 2 0 . The combined organic layers were dried over anhydrous Na 2S04

and concentrated in vacuo to afford a yellow oil. This crude reaction material was purified by column chromatography (elution with 2.5 % EtOAc in hexanes) to afford 7.84 g (51% yield) of benzyl ether 21 a slightly yellow oil: IR (neat, cm*^) 2949, 2867,1365,1086,1065, 902, 733,

696: ^H NMR (300 MHz, CDCI 3) 5 7.45-7.26 (m, 5H), 4.96 (dd, J = 2.0, 2.0 Hz, 1H), 4.85 (dd, J =

1.6,1.6 Hz, 1H), 4.58 (d, J = 12.3 Hz, 1H), 4.35 (d, J = 12.3 Hz, 1H), 3.99 (dd, J= 2 .6 , 2.6 Hz, 1H),

2.46-2.35 (m, 1H), 2.30-2.16 (series Of m, 2H), 1.99-1.91 (m, 1H), 1.80 (dddd, J = 12.4,12.4,3.2,

3.2 Hz, 1H), 1.34 (ddd, 13.0, 13.0, 3.0 Hz, 1H), 1.14 (ddd, J= 25.4, 12.4, 4.1 Hz, 1H), 0.94 (S,

9H): 13c NMR (75 MHz, CDCI 3) ppm 147.9,139.2,128.2, 127.4, 127.1, 110.7, 78.8, 68 .8 , 40.9,

34.3, 32.0, 30.7, 28.6, 27.5: HRMS (El) m /z (M+) calcd for CisHgsO 258.1984, obsd 258.1980.

170 o fran 9 -2*(Benzyloxy)< 4 *terr*butyicyclohexanone (22). A -78 °C solution

,..OBn 21 (1.29 g, 5.00 mmol) in MeOH (50 mL) was ozonolyzed until a light blue

color persisted. The reaction mixture was purged with oxygen and warmed, in the f-Bu 22 presence of dimethyl sulfide (5.0 mL), to rt over a 4 h before being concentrated in

vacuo. Purification by column chromatograpfiy (elution with 5% EtOAc in

hexanes) yielded 0.714 g (55%) of ketone 22 as a near coloriess oil; IR (neat, cm*^) 2964,1719,

1455,1367,1091,1062,737, 697; NMR (300 MHz, CDCI 3) 5 7.40-7.27 (m, 5H), 4.51 (d, J *

11.9 Hz, 1H), 4.41 (d, J * 11.9 Hz. 1H). 3.72 (dd, J = 2.7, 2.7 Hz, 1H), 2.82 (ddd, J - 13.6,13.6,

6.0 Hz, 1H), 2.31-2.23 (m, 2H), 2.12-2.03 (m, 1H), 1.96 (dddd, 12.4,12.4, 3.4, 3.4 Hz, 1H),

1.52 (ddd, 14.1,12.6, 3.1 Hz, 1H), 1.42 (dddd, 12.7,12.7, 12.7, 4.0 Hz, 1H), 0.91 (S, 9H);

13c NMR (75 MHz, CDCI3) ppm 212.6,137.5,128.3,127.6 (two 13c signals), 80.9, 71.0, 40.3,

37.7, 34.2, 31.9, 28.1, 27.4; HRMS (El) m'z(M+) calcd forCi 7H2402 260.1776, obsd 260.1780.

Anal. Calcd for C 17H24O2: C, 78.42; H, 9.29. Found C, 78.57; H, 9.32.

0 OH frans>4*feit-Butyl-2-hydroxycyclohexanone (3). An EtOH solution (9.2

mL) of the benzyl alcohol 19 (0.714 g, 2.74 mmol) was stirred under an

atmosphere of H 2 in the presence of 10% Pd/C (0.274g) for 1.5 h. The reaction

mixture was filtered through Celite, concentrated in vacuo and purified by flash chromatography (elution with 20% EtOAc in hexanes) to afford 0.300 g (64%) of 1 as a semi-solid, which was used without further delay. 1H NMR analysis of the resultant crude allylation mixture indicated that 3 had undergone a modest degree of tautomerization to afford homoallylic alcohols

28 and 30.

c/s/frans-4-fe/t-Butyl-2-methylcyclohexanone (23). A solution of

dimethylhydrazine (58.8 mL, 0.733 mol) and 4-ferf-butylcyclohexanone (30.0 g,

0.194 mol) in absolute ethanol (200 mL) was stirred at reflux under a CaCl 2 drying

171 tube for 24 h. The reaction mixture was cooled to rt, and the solvent and excess hydrazine were

removed under reduced pressure. The product was not characterized and was used without

further purification.

To a -78 "C solution of diisopropylamine (32.6 mL, 0.233 mol) in THF (388) was added n-

BuLl (160 mL, 1.6 M/hexanes, 0.256 mol). The reaction mixture was stirred at -78 for 30 min

and warmed to 0 °C for one hour. The crude hydrazone (approx. 0.194 mol) as a 0 °C solution in

THF (200 mL) was introduced by cannula to the cold reaction mixture which was stirred under N 2 for 20 h to eventually afford a cloudy pale yellow color. Syringe addition of Mel (11.5 mL, 0.185 mol) produced a clear yellow solution, which after an additional 10 h of stirring the reaction mixture was partitioned with water and extracted several times with CH 2CI2 The combined organic layers were dried over Na 2S0 4 prior to in vacuo concentration. The oil was dissolved in MeOH (900 mL) and was stirred at room temperature for 12 h in the prescence of phosphate buffer (pH 7) (650 mL, 0.3M), Nal0 4 (91.3 g, 0.427 mol), and water (500 mL). The resultant salts were removed by vacuum filtration where by the filtrate was partitioned with 50% saturated brine and Et 2 0 , and extracted with Et 2 0 . The combined organic layers were washed once with water, dried over

Na2S0 4 , and then concentrated in vacuo. Short path distillation (0.60 mm Hg, 70 °C) afforded

26.12 g (80%) of 4-te/t-butyl-2-methylcyclohexanone (23) as an oily mixture of diastereomers. ^H

NMR analysis confirmed the existence of the installed secondary methyl, and IR and 1% NMR indicated the prescence of a cartx>nyl group.

c/s-4-ferf-Butyl-2-hydroxy-2*methylcyclohexanone (4) '"OH and frans-4-ferf-Butyl 2-hydroxy 2-methyl'

cyclohexanone (5). Dropwise addtion of MeMgBr (0.41 mL, 3.0

M/Et2 0 , 1.2 mmol) was added dropwise to a solution of diisopropylamine (0.17 mL, 1 2 mmol) in dry Et 2 0 (16 mL). After 12 h under N2 a diastereomeric mixture of cis and rrans4-feri-txjtyl-2-methylcyclohexanone (0.160 g, 1.00 mmol), as a solution in

172 dry EtaO (3.0 mL), was added to the white suspension. After 10 min TMSCI (0.38 mL. 3.0 mmol),

EtgN (0.45 mL, 3.2 mmol), and HMPA (87 jiL, 0.50 mmol) were added (in this order ). After an

additional 8 h urxfer N2 the reaction mixture was partitioned between EtaO and saturated

NaHC0 3 (aq) solution. The aqueous layer was seperated and extracted with EtaO. The combined

organic layers were dried over anhydrous Na 2S0 4 and concentrated in vacuo. The resultant

crude silyl enol ether was filtered through a plug of silica gel (elution with 10% EtOAc in hexanes

with 1% EtsN) to remove the residual HMPA. The filtrate was concentrated in vacuo.

The crude silyl enol ether was added to a -78 solution of mCPBA (0.207 g, 1.20 mmol)

and CH 2CI2 (5.0 mL) under N2. The reaction mixture was stirred at -78 "O for 10 min then allowed

to warm to room temperature for 1 h. The reaction mixture was partitioned with cold saturated

NaHC0 3 (aq) solution, and the aqueous portion was separated and extracted further with CH 2CI2.

The combined organic layers were dried over anhydrous MgSO^ and concentrated in vacuo. To

the crude oil was dissolved in THF (3.0 mL) and treated with TBAF (2.0 mL, 1.0 M/THF, 2.0 mmol).

The reaction mixture was stirred for 12 h under N 2, partitioned with brine.a nd extracted with Et 2 0 .

The isolated organic layer was dried over anhydrous Na 2S 0 4 and concentrated in vacuo. The

resultant oil was chromatographically purified (gradient elution with 5% EtOAc in hexanes,

increasing to 13%) to afford 36 mg (27%) of axial alcohol 5 and 98 mg (67%) of equatorial alcohol

4.

For 4: white solid, mp 50-51 °C, IR (KBr, cm-1) 3491 (br), 2968,1716,1451, 1365, 1264,

1180, 1114, 877; 1H NMR (300 MHz, CDCI 3) 6 3.94 (s, IN), 2.55 (ddd, J= 14.2, 14.2, 6.0 Hz,

1H), 2.45 (ddd, J = 14.0, 4.8,2.6 Hz, 1H), 2.15 (ddd, J = 12.6, 3.0,3.0 Hz, 1H), 2.16-2.07 (m,

1H), 1.61 (dddd, J = 12.4, 12.4, 2.7, 2.7 Hz, 1H), 1.47 (dd, J = 12.6, 12.6 Hz, 1H), 1.42 (dddd,

13.0.13.0.13.0, 4.7 Hz, 1H), 1.40 (s, 3H), 0.90 (s, 9H); 13c NMR (75 MHz, CDCI 3) ppm 214.8,

76.0, 44.7, 43.2, 36.9, 32.3, 28.8, 27.6,25.9; HRMS (El) m/z(M+) calcd for C 11H20O2 184.1463, obsd 184.1478.

173 For 5: white solid, mp 73.5-74.5 “C, IR (KBr. cm l) 3473(br). 2952. 2746.1709,1479.

1454. 1422. 1382. 1265. 1236. 1145. 1115. 1096. 1048. 940; iR NMR (300 MHz. CDCI 3) 5 2.82

(ddd. J= 13.8.13.8. 6.3 Hz. 1H). 2.8 (br s. 1H). 2.29 (ddd. J= 13.8.5.0.3.1.1 Hz). 2.05 (ddd. J=

14.2. 3.2. 3.2 Hz. 1H). 2.05-1.97 (m. 1H). 1.80 (dddd. J * 12.5. 12.5. 3.4. 3.4. 1H). 1.41 (dddd. J

= 12.5.12.5.12.5. 4.9 Hz. 1H). 1.39 (dd. J -1 3 .3 .13.3 Hz. 1H). 1.26 (S. 3H). 0.87 (s. 9H); 13c

NMR (75 MHz. CDCI3) ppm 213.6. 74.9. 41.8. 41.4. 36.8. 31.9. 27.6. 27.4. 24.8; HRMS (El) m /z

(M+) calcd for C 11H20O2 184.1463. obsd 184.1462.

7.3. Chapter 5

\ / (4/7)-(-i-)-Acetoxy-2-cyclopenten*1-one (1). Allylic alcohol 7^= (5.75 g,

^ 40.5 mmol) was added to a magnetically stirred suspension of NaOAc (0.38 g.

4.56 mmol) and 4Â molecular sieves (17.5 g) in CH 2CI2 (250 mL) under N2. Finely powdered POO

(12.50 g. 58.00 mmol) was subsequently added in 2-3 g portions over a 5 min period. The reaction mixture was stirred under N2 at rt for 4 h. filtered through Fiorisil, and concentrated /n vacuo to afford an oily yellow residue. The crude product was purified by silica gel chromatography (elution with 20% EtOAc in hexanes) to afford 3.54 g (62%) of enone 1 as a slightly yellow oil. Spectral data of 1 were consistent with those reported in the literature.

\ / (4R)-(+)-hydroxy-2-cyclopenten-1*one (2). A mixture of acetate 1 2 (3.10 g, 22.1 mmol) and wheat gemt lipase (0.66 g) in phosphate buffer (200 mL. pH 5.0.0.05M) was stoppered and magnetically stirred at rt for 9 d. The reaction mixture was continuously extracted with EtOAc for 5 d. The isolated organic layer was concentrated in vacuo and the resulting residue was purified by column chromatography (gradient elution with 30%

EtOAc in PE. increasing to 50%) to afford 0.66 g (21%) of the less polar starting acetate 1 and

174 1.52 g (70 %) of ( 2). The acquired spectral data matched completely with those reported in the

literature.2b

Prototypical Indium Promoted Couplings.

A. In Water. A mixture of enone 1 (28 mg, 0.20 mmol), allyl bromide (26 pL, 0.30

mmol), and indium powder (36 mg, 0.30 mmol) in water (2.0 mL) was stirred at rt for 30 min. The

milky white reaction mixture was diluted with brine and extracted with Et 2 0 . Due to the instabilty of

the products, the prototypical 10% HCI(aq) quench was avoided without any noticable consequences. The combined organic layers were dried and concentrated in vacuo. The

resulting cmde residue was purified as described below.

B. In 50% THF(aq). A solution of enone 1 (28 mg, 0.20 mmol) and allyl bromide (26 pL, 0.30 mmol) in a 1:1 mixture of THF and water (2.0 mL) was vigorously stirred in the presence of indium powder (36 mg, 0.30 mmol) for 1.5 h. The reaction mixture, which developed a milky white consistency, was partitioned between brine and Et 2 0 . The 10% HCI(aq) quench was avoided due to the sensitivity of the homoallylic alcohols. The isolated aqueous layer was extracted with

Et2 0 and the combined organic layers were dried and concentrated in vacuo. As delineated below, the final residue was purified by column chromatography.

C. In Anhydrous THF. A suspension of indium powder (36 mg, 0.30 mmol) was magnetically stirred in a tightly capped THF solution (2.0 mL) of enone 1 (28 mg, 0.20 mmol) and allyl bromide (26 pL, 0.30 mmol) at rt for 8 h. The reaction mixture was partitioned with brine and

Et2 0 , and the two layers were separated. The avoidance of the prototypical 10% HCI(aq) quench seemed inconsequential. The aqueous layer was further extracted with ether. The combined organic extracts were dried and concentrated in vacuo. The resulting residue was chromatographed as specified below.

175 Coupling Involving (4R).(+).Ace*oxy-2-cyclopenten-1-one (l).

(lS,3fl)-l-Allyl-4-cyclopentene-l,3-dlol H O " A = / ^2 13 3-acetate(l2) and (1fl,3/?)-1-Allyl-4-

cyclopentene-1,3-dlol 3-acetate (13).

Indium-mediaited allylation of acetate derivative 1 afforded homoallylic alcohols 12 and 13 which were purified by MPLC (elution with 25% BOAc in hexanes) (Scheme 5.3).

For 12: slightly yellow oil: IR (neat, cm'^) 3448(br), 1735,1242; NMR (300 MHz.

CDCI3) 5 5.98 (dd. J = 5.6.1.1 Hz. 1H). 5.90 (dd. J = 5.6. 2.1 Hz. 1H). 5.85-5.71 (m. 1H). 5.51-

5.46 (m. 1H). 5.18-5.11 (m. 2H). 2.54 (dd. J » 14.5. 7.4 Hz. 1H). 2.38 (ddd. J » 7.3.1.0.1.0 Hz.

2H). 2.04 (S. 3H). 1.82 (dd. 14.5.3.8 Hz. 1H) 1.61 (br S. 1H); 1 % NMR (75 MHz. CDCI3) ppm

170.8.141.4. 133.0. 131.4. 119.3.82.8. 77.4. 44.9. 44.5. 21.2; HRMS (El) - H 2O) calcd for C10H12O2 164.0837. obsd 164.0822; +112.1» (c1.45. CHCI3).

For 13: colorless oil; IR (neat, cm'i) 3440(br). 1735.1435.1373.1242.1098.1044.

917; 1H NMR (300 MHz. CDCI 3) 5 5.98 (dd. J = 5.6. 0.8 Hz. 1H). 5.92 (dd. J = 5.6. 2.1 Hz. 1H).

5.90-5.75 (m. 2H). 5.20-5.13 (m. 2H). 2.46 (d. J = 17.3 Hz. 2H). 2.30 (dd. J = 14.6. 7.2 Hz. 1H).

2.02 (s. 3H). 1.96 (dd. J = 14.6. 3.3 Hz. 1H); NMR (75MHz. CDCI 3) ppm 170.9.141.6. 133.2.

131.8. 119.3. 83.5. 78.5. 46.0. 44.3.21.1 ; HRMS (El) nVz (M+) calcd for C 10H14O3 182.0943.

Obsd 182.0931 ; [a]^^D +118.1» (c 1.23. CHCI3).

Anal. Calcd for C 10H14O3: C. 65.92; H. 7.74. Found 0. 65.76; H. 7.70.

Coupling Involving (4R)-(-f)-hydroxy-2-cyclopenten-1-one (2). HO , VXN^OH (l5,3f7)-1-Allyl-4-cyclopentene-1,3-dlol

14 5 (14) an d (1 R ,3A ) 1 -Allyl-4-cyclopentene-

1,3-dlol (5). Hydroxyl derivative 2 afforded

176 homoallylic alcohols 14 and 5 under our prototypical allylindation procedures. These products

were purified by MPLC (elution with 33% EtOAc in hexanes) (Scheme 5.4).

For 14: faintly yellow oil; IR (neat. cm 'l) 3342(br), 3075, 2930,1640,1430,1352, 1078,

1012,916, 7 8 2 : NMR (300 MHz, CDCI3) 5 5.95 (dd, J = 5.5,2.0 Hz, 1H), 5.89 (d, J - 6.5 Hz,

1H), 5.86-5.72 (m, 1H), 5.18-5.11 (m, 2H), 4.68-4.65 (m, 1H), 4.00-3.50 (brs, 2H), 2.45 (dd, J -

14.2.7.0 Hz, 1H), 2.36 (d, J - 7.3 Hz, 2H), 1.73 (dd, J = 14.2,3.4 Hz, 1H); 1% NMR (75 MHz,

CDCI3) ppm 139.3,135.2,133.4, 118.6,83.1, 75.0,47.2,44.9; HRMS (El) m/z{}A+) calcd for

C8 H12O2 140.0837, obsd 140.0813; [a p o +54.2° (c 1.07, CHCI 3).

Anal. Calcd for C 8 H12O2 : C, 68.55; H, 8.63. Found C, 68.47; H, 8.55.

For 5: yellow oil; IR (neat, cm*’) 3362(br), 3076, 2924,1637,1430,1260,1160, 1086,

914, 838; NMR (300 MHz, CDCI 3) 6 5.95 (dd, J = 5.6, 2.0 Hz, 1H). 5.92-5.79 (m, 1H), 5.87 (dd,

5.6,1.0 Hz, 1H), 5.43-4.99 (series of m, 3H), 2.48 (dd, 7.4, 0.8 Hz, 2H), 2.30 (dd, 14.3,

7.0 Hz, 1H), 2.00-1.70 (brs, 2H) 1.86 (dd, J = 14.3, 3.5 Hz, 1H); 1% NMR (75MHz, CDCI 3) ppm

139.1, 136.3, 133.5, 119.5, 84.0, 76.0, 47.8, 46.2; HRMS (El) m^z(M+) calcd for C 8 H12O2

140.0837, obsd 140.0847.

Estérification of 14. To a nitrogen-blanketed magnetically stirred solution of alcohol

14 (20 mg, 0.14 mmol) in CH 2CI2 (2.9 mL) at 0 °C was added imidazole ( 11 mg, 0.16 mmol) and

AC2O (15 pL, 0.16 mmol). The reaction mixture was slowly warmed to rt over 4 h, at which time

TLC analysis confirmed the continued presence of starting material. To the reaction mixture was added a catalytic quantity of DMAP, which was subsequently stirred for an additional 4 h. The reaction mixture was concentrated in vacuo and filtered through a pipet containing silica gel

(elution with EtOAc). The resulting oil was purified by column chromatography (elution with 25%

EtOAc in hexanes) to afford 14 mg (54%) of acetate 12. The ^H NMR of this product was

177 consistent with the recorded spectmm of the major product resulting from the indium-mediated allylation of 1 (Scheme 5.3).

Hydrolysis of 12. To a magnetically stirred solution of acetate 12 (18 mg, 0.10 mmol) in MeOH (2.0 mL) at 0 “C under Na was added K 2CO3 (28 mg, 0.20 mmol). The reaction mixture was slowly warmed to it over a 3 h period and concentrated in vacuo. The crude residue was dissolved in CH 2CI2 and washed once with water. The organic layer was dried with MgSO^ and concentrated. The cmde residue was filtered through a pipet containing Si 0 2 (elution with

EtOAc) to afford 12 mg ( 86 %) of alcohol 14. The spectral data (^H NMR) of this material and the authentic material resulting from the allylation protocols (Scheme 5.4) were indistinguishable in all respects.

Hydrolysis of 13. Analogous treatment of 13 (40 mg, 0.22 mmol) in MeOH (4.4 mL) with K2CO3 (61 mg, 0.44 mmol) afforded 22 mg (71%) of alcohol 5. The ^H NMR spectmm matched perfectly with that obtained from the indium-mediated allylation of 2 (Scheme 5.4).

Coupling Involving frans-4 tert-Butyl-3-hydroxycyclohexanone (3).

'^.^PH H Q ^ (1ff*,3/?*,4S*)-1-Allyl-4-ferf-butyl-1,3-

cyclohexanediol (15) and (1/?*,3S*,4fl*)-l-Allyl-4- "'OH farf butyl 1,3 cyclohexanediol (16).

The indium-mediated allylation of ketone 3 under the conditions described atwve afforded a mixture of 15 and 16. Column chromatography (gradient elution with 20% EtOAc in hexanes, increasing to 33%) cleanly afforded the individual homoallylic alcohols (Scheme 5.6).

178 For 15: colorless solid; mp 118-119 “C; IR (KBr. cm'^) 3381 (br). 2954.2868.1444.1362.

1107.1065.1019. 985. 919; NMR (300 MHz. CeDe) 5 5.82-5.68 (m. 1H). 5.07-4.96 (m. 2H).

3.85-3.80 (m. 1H). 1.99-1.97 (m. 2H), 1.63 (ddd, J = 12.8. 4.2. 2.9 Hz, 1H). 1.52-1.41 (m. 1H).

1.38-1.28 (m. 2H). 1.11 (S. 9H), 1.08-0.83 (series of m, 3H); 1% NMR (75 MHz. CeDe) ppm 134.0,

118.5. 72.1. 69.7, 53.4. 48.7, 48.2. 37.0, 33.1. 29.6. 22.2; HRMS (El) m /z (M+ - C3H5) calcd for

G10H19 O2 171.1385. Obsd 171.1373.

4na/. Calcd forC i 3H2402 : C. 73.54; H, 11.39. Found C. 73.47; H. 11.27.

For 16: colorless solid, mp 105-106 °C; IR (KBr. cm'i)3296(br). 2951. 2864.1456.1364,

1345.1230.1055. 1010. 999. 909; ^H NMR (300 MHz. CDCI 3) 6 5.95-5.81 (m. 1H). 5.19-5.10

(m. 2H). 3.84-3.78 (m. 1H). 2.23-2.21 (m. 2H). 2.16 (brs. 1H). 1.98 (brs. 1H). 1.88-1.67 (seriesof

m. 2H). 1.60 (dd. J = 13.2.7.9 Hz. 1H), 1.50-1.40 (m. 1H). 1.29-1.11 (series of m. 3H). 0.98 (s.

9H); 13c NMR (75 MHz. CDCI 3) ppm 133.1. 119.2. 71.9. 69.7. 52.4. 45.0. 44.6. 36.6. 32.8. 29.1.

21.1; HRMS (El) m(z(M+ - C3H5) calcd for C 10H19 O2 171.1385. obsd 171.1382.

Anal. Calcd for C 13H24O2; C. 73.54; H. 11.39. Found C. 73.39; H. 11.26.

Coupling Involving c/s-4-tert-Butyl-3-liydroxycyclofiexanone (4).

OH (1/?*,3S*,4S*)-1-Allyl-4-fa/t-butyl-1,3-cyclohexanedlol (15).

Indium-mediated allylation of ketone 4 produced a single diastereomer wfiicfi OH was purified after workup by column chromatography (elution with 20% in f-Bu hexanes) (Scheme 5.7).

For 17: colorless oil; IR (neat, cm 1) 3334(br). 2952. 2868.1444.1394.1364. 1176.

1105, 998.939.914; ^H NMR (300 MHz. CDCI 3) 6 5.92-5.78 (m. 1H). 5.15-5.05 (m. 2H). 4.26 (m,

1H). 2.97 (brs. 2H) 2.17-2.15 (m. 2H). 1.88 (ddd. J = 14.4. 3.2. 3.2 Hz. 1H). 1.81-1.72 (m. 2H),

1.56-1.49 (m. 1H). 1.44 (dd. 14.3. 3.0 Hz. 1H). 1.39 (ddd. J = 13.4.13.4. 3.9 Hz. 1H). 1.00-

179 0.92 (m. 1H). 0.96 (s. 9 H); NMR (75 MHz, CDCI3) ppm 133.3,118.9, 72.5, 69.1, 50.8, 48.1.

42.8. 37.8, 32.6, 28.6, 16.9; HRMS (El) nVz(M*) calCd for C13H24O2 212.1776. Obsd 212.1777.

Anal. Calcd for C13H24O2: C, 73.54; H, 11.39. Found C, 73.44; H. 11.34.

(1/î*,5S*,6S*)-1-Allyl-6-fe/t-butyl-3,3-dlmethyl-2,4-

dloxablcyclo[3.3.1]nonane (18). A solution of diol 17 (0.101 g, 0.478

^ mmol), 2-mettioxypropene (0.183 mL, 1.91 mmol), and PPTS (12 mg, 48 f-Bu Kunol) in CH2CI2 (4.8 mL) was refluxed under N 2 for 12 h, cooled to rt and partitioned with brine. The aqueous layer was isolated and further extracted with CH 2CI2. The combined organic layers were dried with anhydrous Na 2S0 4 and concentrated in vacuo. The crude oil was purified by silica gel chromatography (elution with 2.5% EtOAc in hexanes) to afford

77 mg (64%) of the desired acetonide 39 as a clear oil; IR (neat, cm'"') 2958,1377,1364,1243,

1187,1146,1002; ^H NMR (300 MHz, GDCI3) 6 5.90-5.76 (m, 1H), 5.09-5.00 (m, 2H), 4.50 (dd, J

= 4.4, 0.9 Hz, 1H). 2.51 (ddd, J = 14.1,5.3, 3.1 Hz. 1H). 2.29-2.12 (m, 2H). 1.86 (dddd. J = 12.9.

12.9. 12.9. 4.5 Hz, 1H). 1.71-1.64 (m, 1H), 1.59-1.53 (m, 1H), 1.57 (s, 3H), 1.36 (S. 3H). 1.25

(ddd. J = 13.1. 13.1. 4.7 Hz. 1H). 1.25-1.20 (m. 1H). 0.94 (s, 9H). 0.87 (ddd. J = 12.6. 3.7. 1.0 Hz.

1H); 13c NMR (75 MHz. CDCI3) ppm 134.1. 117.7, 96.8, 72.4. 68.2. 52.7. 47.5. 38.3. 33.3. 32.6.

31.9. 31.5. 28.7. 19.2; HRMS (El) m/z(M+) calcd forCi 6H28 C>2 252.2089. obsd 252.2089.

(1/?*,5S*,6S*)-1-Allyl-6-ferf-butyl-2,4-dloxa-2,4-

dloxablcycio[3.3.1]nonan>3-one (19). A solution of diol 17 (30 mg.

^ 0.14 mmol), CDI (20 mg. 0.14 mmol), and catalytic amount of DMAP in f-Bu benzene (1.4 mL) was heated at reflux under N 2 for 12 h. TLC analysis showed the presence of starting material. A second equivalent of CDI (20 mg. 0.14 mmol) was added to the reaction mixture and reflux was continued under N 2 for an additional 12 h. The reaction mixture was concentrated in vacuo to leave a crude residue, which was purifed by column

180 chromatography on silica gei(elution with 20% EtOAc in hexanes) to afford 20 mg (58%) of

carbonate 38 as a white solid, mp 90-91 “C; IR (KBr. cm 'i) 1718.1398,1217,1123,1081:

NMR (300 MHz, CDCI3) 8 5.86-5.72 (m. 1H), 5.19-5.09 (m, 2H), 4.91-4.90 (m, IN), 2.46-2.31 (m,

2H), 2.16-2.00 (m, 2H), 1.86-1.76 (m, 1H), 1.72-1.51 (series of m, 3H), 1.28-1.23 (m, 1H), 0.98 (S,

9H): 13c NMR (75 MHz, CDCI 3) ppm 150.0,131.1,119.9, 81.9, 75.6, 50.8, 44.9, 35.4, 34.0,

32.5, 28.2,17.9; HRMS (El) m /z (M+ + H) calcd for C 14H23O3 239.1647, obsd 239.1666.

Anal. Calcd for C 14H22O3: C, 70.56: H, 9.30. Found C, 70.40; H, 9.36.

Competition Experiment. An equimolar mixture of 3 (43 mg, 0.25 mmol) and 4 (43

mg, 0.25 mmol), allyl bromide (32 pL, 0.38 mmol), and indium powder (29 mg, 0.25 mmol) in water

(2.5 mL) was stirred at rt in a tightly stoppered flask for 5.5 h. The reaction mixture was quenched

with 10% HCI(aq) and partitioned between ether and brine. The separated aqueous layer was

extracted with ether, and the combined organic layers were dried and concentrated.

7.4. Chapter 6

3,4-Olhydro-2-hydroxy-l(2H)-naphthalenone (la). n-BuLi (15.2

mL, 1.6 M/hexanes, 24.3 mmol) was added to a -78 °C solution of N,N- n diisopropylamine (2.84 mL, 20.3 mmol) in THF (78 mL) under N 2. The

reaction mixture was slowly warmed to 0 ®C over 3 h and recooled to -78 °C prior to the addition of

1-tetralone (2.28 g, 15.6 mmol) and TMSCI (2.57 mL, 20.3 mmol) as a solution in THF (78 mL).

The reaction mixture was subsequently warmed to rt over 12 h, diluted with Et 3N (78 mL), and concentrated in vacuo. The residual solid was diluted with pentane and the lot was filtered through Celite. Concentration of the organic layer under reduced pressure and subsequent distillation (bp 83 “C/0.4 mmHg) of the resulting crude oil afforded 3.13 g (92%) of the silyl enol ether intermediate as a slightly yellow oil.

181 mOPBA (2.96.17.2 mmol) was cautiously added to a solution of the silyl enol ether (3.13

g, 14.3 mmol) in CH 2CI2 (72 mL) under N2. The reaction mixture was stirred at rt for 14 h. washed

with saturated NaHC 0 3 (aq) solution, dried over MgSO^.and concentrated in vacuo. TBAF (14.3

mL, 1 .OM/THF, 14.4 mmol) was added to a solution of the resulting crude oil in THF (57 mL). The

reaction mixture was stirred at rt for 12 h, diluted with saturated NaHCOsfaq) solution, and

partitioned with Et 2 0 . The isolated organic layer was washed two times with 2N HCI(aq) solution,

one time with brine, dried over anhydrous MgS 0 4 , and concentrated in vacuo. The crude residue

w as purified by flash chromatography (elution with 33% EtOAc in hexanes) to afford 2.09 g (83%)

of la as a flight tan solid, mp 39-40 “C: IR (neat, cm*'') 3474(br), 3067,3027, 2946, 2870,2838,

1682, 1603, 1458, 1390, 1281, 1228,1145, 1090, 993, 935, 749: NMR (300 MHz, CDCI 3) 6

8.01 (d, J - 7.8 Hz, 1H), 7.50 (ddd, J - 7.5, 7.5, 1.2 Hz, 1H), 7.34-7.23 (m, 2H), 4.37 (dd, J = 13.5,

5.4 Hz, 1H). 3.55 (br s, 1H). 3.13 (ddd, J = 17.1,12.7, 4.4 Hz, 1H), 3.01 (ddd, J = 17.1,4.8, 2.6

Hz, 1H), 2.55-2.47 (m, 1H), 2.02 (dddd, J = 12.8,12.8,12.8, 4.9 Hz, 1H); 1^0 NMR (75 MHz,

CDCI3) ppm 199.6, 144.3, 134.1, 130.4, 128.9, 127.5, 126.9, 73.8, 31.8, 27.7; HRMS (El) m /z

(M+) calcd for C 10H10O2 162.0681, obsd 162.0680.

3,4-Dlhydro>2-hydroxy-6-methoxy*l(2H)-naphthalenone

(1b). To a N2 blanketed solution of diisopropylamine (3.64 mL. 26.0 OMe mmol) in THF (100 mL) at -78 °C was added n-BuLi (19.5 mL, 1.6

M/hexanes, 31.2 mmol). The reaction mixture was warmed to 0 ®C over a 1 h period and recooled to -78 °C. A solution of 6-methoxy -1 -tetralone (3.52 g, 20.0 mmol) in THF (100 mL) was added via a pressure equalized addition funnel followed by TMSCI (32.9 mL, 26.0 mmol) via syringe. The reaction mixture was slowly warmed to rt over 12 h, diluted with Et 3N, and concentrated in vacuo.

The crude residue was diluted with pentane, filtered through Celite and concentrated in vacuo.

The resulting oil was used without further purification.

182 To a rt solution of the crude silyl enol ether (approx. 20.0 mmol) in CH 2CI2 (100 mL) under

N2 was added purified 95% mOPBA (3.79 g, 22.0 mmol) in several portions. The reaction mixture

was stirred for 14 h and partitioned with saturated NaHCOafaq) solution. The separated aqueous

layer was further extracted with CH 2CI2 and the combined organic layers were concentrated in

vacuo. The crude residue was dissolved in THF (80 mL) and treated with TBAF (20.0 mL, 1.0

M/THF, 20.0 mmol). The reaction mixture was stirred at rt under N2 for 8 h, diluted with saturated

NaHC0 3 (aq) solution, and extracted with Et 2 0 . The combined organic layers were washed twice with 2N HCI(aq) solution, once with brine, dried over anhydrous MgS 0 4 and concentrated in vacuo. The cmde solid was purified by bulb-to-bulb distillation and recrystallization

(hexanes/EtOAc) to afford 1.27 g (32%) of a-hydroxytetralone 1b as a light brown solid, mp 85.0-

86.5 °C; IR (KBr, cm 1) 3477(br), 1664, 1599, 1493, 1456, 1386, 1334, 1250, 1209, 1148, 1092,

1044,1026, 996, 933, 845, 790, 606; ^H NMR (300 MHz, CDCI3 ) 8 8.00 (d, 8.7 Hz, 1H), 6.85

(dd, 8.7, 2.5 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 4.31 (dd, 13.3, 5.4 Hz, 1H), 3.85 (s, 3H),

3.10 (dd, J = 12.8, 4.4 Hz, 1H), 2.97 (ddd, J = 17.0, 4.7, 2.6 Hz, 1H), 2.49 (dddd, J= 10.4, 5.3,

4.5, 2.6 Hz, 1H), 2.00 (dddd, 12.9,12.9,12.9, 4.8 Hz, 1H); 1% NMR (75 MHz, CDCI3) ppm

198.1, 164.2, 146.9, 130.0, 123.8, 113.6, 112.7, 73.4, 55.5, 31.8, 28.0; HRMS (El) m/z(M+) calcd for Ci 1H12O3 192.0787, obsd 192.0785.

Anal. Calcd for Gi 1H12O3: 0, 68.74; H, 6.29. Found 0, 68 .66; H. 6.32.

5',6',7',8-Tetrahydro-2" acetonaphthone (2). According to the 0 5 -,'Ac 2 procedure of Newman and Zahm,3c AICI 3 (146.67 g, 1.10 mol) was cautiously added to a mechanically stirred solution of tetralin (135 mL, 1.00 mol) and AcCI ( 72.5 mL, 1.02 mol) in benzene (500 mL) at 0 ®C. The reaction mixture was slowly warmed to rt over 12 h, poured onto ice (1 kg) and extracted with EtOAc. The isolated organic layer was washed with brine, dried over anhydrous MgS 0 4 and concentrated in vacuo to afford a cmde oil. Distillation, bp 102-104 ®C

183 (0.09 mmHg) [lit-^^bp 132.5-134.5 "C (3.5-4 mmHg)]. produced 162.83 g (94%) of 6-

acetyRetralin (2) as a slightly yellow oil.

oa #/-(5.6,7,8

hydroxylamine*HCI ( 86.86 g, 1.25 mol) and NaOAc (205.08 g. 2.50 mol) in

MeOH (1.0 L) was stirred at rt under a drying tube of CaCIa for 48 h . The reaction mixture was diluted with water (500 mL) and extracted with EtaO. The combined organic layers were subsequently washed with brine, dried over MgS 0 4 , and concentrated in vacuo to afford a crude white solid. The bulk solid was used without further purification. A small sample was recrystallized from MeOH to afford oxime 3 as a fine white crystalline solid, mp 104.5-106 °C [lit.^ 104-105 "C].

A solution of the crude oxime (approx. 0.50 mol) in AC 2O (75 mL) and AcOH (150 mL) was saturated with HCI(g), tightly stoppered and left to stand at rt for three days. The resulting precipitate was collected by vacuum filtration, washed with cold water and allowed to dry under vacuum overnight affording 49.22 g (52%) of 6-acetamidotetrafin (4) as a fluffy white solid, mp103-105 “C. [Iit.3a mp 106-106.5 °C].

Af-(5,6,7,8*Tetrahydro*5-oxo-2-naphthyl)acetamlde (5). A 3-

l^,H necked, 500 mL flask was equipped with a stopper, a reflux condenser

Àc topped with a CaCl 2 drying tube, and an overhead mechanical stirrer and charged with 6-acetamidotetralin (4) (3.79 g, 20.0 mmol), Celite (50 g), POO (21.56 g, 100 mmol), and benzene (200 mL). The reaction mixture was refluxed for 12 h, cooled to rt, diluted with

Et2 0 , and filtered through Celite. The filter cake was washed several times with Et 2 0 . The organic layer was dried over anhydrous MgSO^ and concentrated in vacuo. The resulting crude oil was purified by flash chromatography on silica gel (elution with 66% EtOAc in hexanes) to give

184 2.47 g (61%) of 6-acetamido-l-tetralone (5) as a white fluffy solid, mp 126-127 °C [iit.^® mp 124.5-

125 °C]. Large scalepurificatlon was effected by recrystallization from aqueous alcohol.

6*Bromo*3,4>dlhydro-1-(2H)’naphthalenone (6). Following the

specific procedure by Giardina et. a /.^ , a solution of 6-acetamido-l -tetralone ôaBr (5) (5.08 g, 25.0 mmol) and 25% HBr(aq) (12.5 mL) was refluxed for 2 h under

a CaCl2 drying tube and cooled to 0 ®C. A solution of NaN 0 2 (1.81 g. 27.0 mmol) in H 2O (6.7 mL)

was slowly added dropwise to the reaction mixture, followed 15 min later by a solution of CuBr

(3.87 g, 27.0 mmol) in 48% HBr(aq) (18.8 mL). The reaction mixture was warmed to rt over 4 h,

diluted with water, and extracted with a 4:1 mixture of B 2O and EtOAc. The combined organic

layers were washed with brine, dried over anhydrous Na 2S0 4 , and concentrated in vacuo.

Recrystallization (PE/EtOAc) afforded 2.92 g (52%) of 6-bromo-1-tetralone (6) as a white

crystalline solid, n p 24-26 »C; IR (KBr, cm 'l) 1684,1586, 818; NMR (300 MHz, CDCI3 ) 5 7.77-

7.74 (m, 1H), 7.33-7.30 (m, 2H), 2.83 (t, J = 6.1 Hz, 2H), 2.56-2.52 (m, 2H). 2.07-1.99 (m, 2H);

13c NMR (75 MHz, CDCI3) ppm 196.9, 145.9, 131.3, 131.1, 129.7, 128.5, 128.2, 38.6, 29.1,

22.8.

O 6-Bromo-3,4-dlhydro-2-hydroxy-1-(2H)-naphthalenone ( 1c).

To a N2 blanketed solution of 6-bromo-1-tetralone 6( ) (0.638 g, 2.84 Br mmol) in MeOH (10.0 mL) at 0 °C was added a methanolic solution of KOH

(2.387 g, 42.5 mmol, 18.0 mL) followed by iodobenzene diacetate (1.096 g, 3.40 mmol). As the color changed from green to orange, the reaction mixture was warmed to rt over 4h. The reaction

mixture was diluted with brine and extracted with Et 2 0 . The combined organic layers were washed twice with 10% HCI(aq) solution, once with brine, dried over anhydrous MgSO^ and concentrated in vacuo. The crude solid was purified chromatographically (elution with 10% EtOAc in hexanes) to afford 0.476 g (70%) of 6-bromo-2-hydroxy-1-tetralone (1c), mp 89-90 °C; IR (KBr

185 cm-1) 3490,1679,1590,1272,1184,1101,1077, 992, 935, 895; NMR (300 MHz, CDCI 3) S

7.89 (d, J = 8.3 Hz, 1H), 7.50-7.46 (m, 2H), 4.36 (ddd, J = 13.5, 5.4, 2.0 Hz, 1H), 3.83 (d, J = 2.0

Hz, 1H), 3.14 (ddd, J = 17.3,12.8, 4.5 Hz, 1H), 3.00 (ddd, 17.3, 4.7, 2.6 Hz, 1H), 2.57-2.48

(m, 1H). 2.03 (ddd, J - 26.2,12.9,4.8 Hz, 1H); 1% NMR (75 MHz, CDCI3) ppm 198.7,145.9,

131.8,130.4,129.5,129.1,73.7,31.5, 27.4 (one quaternary signal not obsen/ed); HRMS

(El) m /i (M+) calcd for CioHg®^ BrOa 241.9766, obsd 241.9771 and calcd for CioHg^SSrOa

239.9786, Obsd 239.9785.

oa M-Methyl-M-(5,6,7,8-tetrahydro-2-naphthyl)acetamide (7a). 7a ^ NaH (0.72 g, 30 mmol) was added portionwise to a solution of 6-

acetamidotetralin (4) (4.73 g, 25.0 mmol) in dry benzene (50.0 mol) under

N2. After 10 min, Mel (3.1 mL, 50 mmol) was added to the reaction mixture was subsequently stirred at 60 °C under N2 for 12 h before t)eing slowly quenched with brine and concentrated in vacuo. The crude residue was partitioned between Et 2 0 and brine. The isolated aqueous layer was extracted further with Et 2 0 , whereby the combined organic layers were dried over anhydrous

MgS 0 4 and concentrated in vacuo. The crude soiid was either sublimed or purified by chromatography (elution with 50% EtOAc in hexanes) to afford 4.87 g (96%) of 6-(N- methyl)acetamidotetralin (7a) as an off-white fluffy solid, mp 58-59 °C; IR (KBr, cm'^) 2934,1662,

1612,1502, 1419, 1384, 1354,1141; ^H NMR (300 MHz, CDCI 3) 5 7.04 (d, J = 8.7 Hz, 1H), 6.85-

6.83 (m, 2H), 3.19 (S, 3H), 2.73 (brs, 4H), 1.83 (S, 3H), 1.79-1.75 (m, 4H); 1% NMR (75 MHz,

CDCI3) ppm 170.5, 141.8, 138.5, 136.6, 130.1, 127.1, 123.8, 37.0, 29.2, 28.8, 22.8 , 22.7,

22.2; HRMS (El) m /z (M+) calcd for C 13H17NO 203.1310, obsd 203.1312.

A/>Methyl>Af-(5,6,7,8-tetrahydro*5-oxo-2-naphthyl)acetamide

Me (7b). A solution of CrOg (9.99 g, 0.100 mmol) dissolved in AcOH (25 mL)

and H 2O (5.0 mL) was added dropwise to a chilled (~10 °C) solution of 6-

186 (AAnethyl)acetamidotelralin (7a) (5.08 g, 25.0 mmol) in AcOH (20 mL). The reaction mixture was warmed to ft over 8 h, cautiously quenched with 50% NaHC 0 3 (aq) solution, aixt extracted with

EizO. The combined organic layers were dried over anhydrous MgS 0 4 and concentrated in vacuo. The resulting cmde solid was purified by either sublimation or column chromatography

(elution with 50% EtOAc in hexanes) to afford 3.71 g (70%) of 6-(A/-methyl)acetamido-1-tetralone

(7b) as a white solid, mp 104-105 ®C: IR (KBr, cm ^) 3490,2491,1735,1664,1602,1493,1420,

1376,1351,1278, 1224,1186, 1136,1089, 1026, 981, 904, 837; NMR (300 MHz, CDCI 3) 5

8.03 (d, J » 8.2 Hz. 2/3H), 7.80 (S. 1/3H), 7.27-7.25 (m, 2/3 H), 7.10 (d 2.1 Hz. 1/3H), 7.07 (d. J

= 2.2 Hz. 1 H), 3.24 (s. 66% Of 3H). 3.20 (S. 33% of H). 2.97-2.93 (m. 2H), 2.65-2.61 (m, 2H) 2.17-

2.09 (m. 2H). 1.91 (s. 66% of 3H). 1.82 (s. 33% of 3H); 1% NMR (75 MHz, CDCI 3) ppm (major rotamer signals) 197.0, 170.0, 148.5, 146.0, 131.8, 131.4, 128.8, 126.7, 38.8, 37.0, 29.6, 23.0,

22.4, (minor rotamer signals) 197.4.170.4.130.3,125.4,125.0, 38.7, 29.1, 22.9; HRMS (El) m /z

(M+) calcd for C 13H15NO2 217.1103, obsd 217.1104.

A nal Calcd for C 13H15NO2: 0, 71.87; H, 6.96. Found 0, 72.04; H, 7.07.

N-Methyl-A/-(5,6,7,8-tetrahydro-5-methylene-2-

. ,Me naphthyl)acetamlde (7b). To a suspension of CH 3 PPh 3 l (2.53 g, 6.27 10 Ac mmol) in THF (3.1 mL) at 0 °C under N2 was added KHMDS (12.5 mL, 0.5

M/toluene, 6.27 mmol) followed 10 min later by the solid tetralone 7b (1.24 g, 5.69 mmol), at which time the reaction mixture changed from a deep yellow color to a ruby red. The reaction mixture was warmed to rt over a 4 h period, diluted with saturated NH^CKaq) solution, and extracted with Et 2 0 . The combined organic layers were washed with brine, dried over anhydrous

MgS 0 4 , and concentrated In vacuo. The resulting cmde solid was purified by flash chromatography on silica gel (gradient elution with 50% EtOAc in hexanes, increasing to 66%) to afford 0.235 g (19 %) of unreacted tetralone 7b and 0.880 g (72%) of olefin 10 as a white solid, mp 49-51 “0; IR (KBr, cm'"') 2938,1655,1602,1561,1496,1425, 1378,1349; ^H NMR (300

187 MHz. CDCb) 6 7.64 (d. J * 8.3 Hz, 2/3H), 7.41 (d, J = 2.1 Hz. 1/3H). 7.13 (d. J = 8.0 Hz. 1/3H),

6.96-6.90 (m. 5/3H). 5.46 (s. 2/3H). 5.43 (S. 1/3H). 4.98 (S. 1H). 3.22 (S. 33% Of 3H). 3.22 (S, 66%

Of 3H). 2.84-2.80 (m. 2H). 2.55-2.51 (m. 2H). 1.91-1.82 (m. 2H). 1.87 (s. 33% of 3H). 1.86 (S. 66%

Of 3H); ■'3c NMR (75 MHz. CDCI3) ppm (complicated by rotamers) 170.6,170.5,143.6,142.5,

142.4, 142.3, 138.7, 136.8, 136.1. 134.1. 130.5. 127.2. 125.9, 125.5, 124.4, 122.5, 108.9,

108.8, 37.1. 37.0. 32.9. 32.8. 32.7, 30.3. 30.0, 23.4, 22.3; HRMS (El) m/z{M+) calCd for

C14H17NO 215.1310, Obsd 215.1313.

Anal. Calcd for C 14H17NO: C. 78.10; H, 7.96. Found C. 77.54; H. 7.94.

CHz Af-Methyl-N-(5,6,7,8-tetrahydro-6-hydroxy-5-methylene-

L%Ls_JL._„Me 2-naphthyl)acetamlde ( 11). f-BuGaH (0.411 mL, 4.0 M/CH2CI2,

11 * Ac 1.64 mmol) was added to a mixture of Se 0 2 (3.0 mg, 23 pmol) and

salicylic acid ( 6.0 mg, 46 nmol) followed by olefin 10 (96 mg, 0.46 mmol) as a solution in CH 2CI2

(0.46 mL). The reaction mixture was stirred at rt for 4 h, diluted with 10% KOH(aq) solution and extracted with CH 2CI2 The combined organic layers were washed with 50% K 2C0 3 (aq) solution, dried over anhydrous MgS 0 4 and concentrated in vacuo. The crude solid was chromatographically purified on silica gel (elution with 66% EtOAc in hexanes) to afford 82 mg

(79%) of allylic alcohol 11 as a white solid, mp 146-147 ®C; IR (neat, cm*') 34l7(br), 2968, 2957,

2928, 1652, 1617, 1605, 1496, 1435, 1384, 1051; 'H NMR (300 MHz, de-DMSG, T=363 K) 5

7.66 (d, J = 8.2 Hz, 2/3H), 7.53 (d, J= 2.1 Hz, 1/3H), 7.16 (d, J = 8.4 Hz, 1/3H), 7.09-7.04 (m,

5/3H), 5.58 (d, 14.3 Hz, 1H), 5.32-5.30 (m, 1H), 4.32 (ddd, J = 8.7, 1.7, 1.7 Hz, 1H), 3.73 (br s,

1H), 3.16 (S, 33% of 3H), 3.15 (S, 66% Of 3H), 2.96 (ddd, J= 17.0, 6.0, 6.0 Hz, 1H), 2.81 (ddd, J =

16.8, 5.8, 5.8 Hz, 1H), 2.01-1.91 (m, 1H), 1.83 (S, 66% Of 3H), 1.82 (s, 33% Of 3H), 1.83-1.74 (m,

1H); NMR (75 MHz, de-DMSG, T=363 K) ppm (complicated by rotamers) 168.7,167.8,145.9,

143.4, 142.4, 137.2, 132.3, 129.5, 126.3, 125.6, 124.5, 124.2, 122.7, 108.4, 107.8, 68 .6 ,

188 68.5, 36.5,36.4, 31.3, 31.3, 26.2, 25.9, 21.8 , 21.7; HRMS (El) calcd for C14H17NO2

231.1259, Obsd 231.1253.

Anal. Calcd for C 14H17NO2: 0,72.70; H, 7.41. Found 0,72.54; H, 7.39.

A/-Methyi-Af-(5,6,7,8-tetrahydro-6-hydroxy-5-oxo-2-

naphthyOacetamlde (id). A -78 ®C solution of allylic alcotiol 11 Id 1 Ac (0.502 g, 2.17 mmol) in a 1:1 mixture of CH2CI2 and MeOH (21 .8 mL) containing 1% pyridine (0.22 mL) was ozonolyzed until a faint blue color persisted (-20 min) and was quencfied with dimethyl sulfide (0.32 mL). The reaction mixture was warmed to rt over 4 h, diluted with CH 2CI2, partitioned with brine, and extracted with EtOAc. The combined organic layers were dried over anhydrous MgS 0 4 and concentrated in vacuo. The crude oil was purified by column chromatography on Fiorisil (elution with 75% EtOAc in hexanes) to afford 0.376 g

(74%) of 6-(AAmethyl)acetamido-2-hydroxy-1-tetralone (Id) as a colorless oil; IR (neat, cm'i)

3422(br), 1688,1656,1603,1378; ^H NMR (300 MHz, de-DMSO, T=363 K) 5 7.91 (d, J = 8.9 Hz,

2/3H), 7.73 (d, J = 2.3 Hz, 1/3H), 7.48 (dd, J= 8.2, 2.3 Hz, 1/3H), 7.39 (d, J = 8.2 Hz, 1/3H), 7.29-

7.27 (m, 4/3H), 4.31 (ddd, J = 12.0, 4.8, 4.8 Hz, 1H), 4.24 (br s. 1H), 3.21 (s, 66% of 3H), 3.18 (s,

33% Of 3H), 3.09-3.03 (m, 2H), 2.33-2.24 (m, 1H), 2.05-1.93 (m. 1H). 1.91 (s. 66% of 3H), 1.84 (s.

33% of 3H); NMR (75 MHz, de-DMSO, T=363 K) ppm (complicated by rotamers) 197.4,

168.8, 148.4, 145.2, 142.8, 142.6, 132.1, 131.6, 129.8, 129.4, 127.7, 126.1. 124.5. 124.1,

72.5, 36.6, 36.4, 31.6, 26.7, 26.4, 22.0, 21.7; HRMS (El) nVz(M+) calcd for C 1 3 H1 5 NO3

233.1052, obsd 233.1055.

6-Amino-3,4-dlhydro-1(2H)-naphthalenone ( 12). As prescribed by

Allinger and Jones^a a mixture of acetamide 5 (5.58 g, 27.4 mmol) and 6N

HCI(aq) (37.5 mL) was refluxed for 2 h. The reaction mixture was cooled to rt

189 and basified. The resulting product was collected by filtration and recrystallized from aqueous

alcohol to afford 3.46 g (78%) of amine 12 as a white solid, mp 130-131 °C [iit.^^ mp 133-134 °C].

5,6,7,8*Tetrahydro*5*oxo-2-naphthonltrlle (13). Precisely

according to the procedure by Allinger and Jones,6-am ino-1-tetralone (12)

(4.15 g, 25.7 mmol) was successively treated with NaN 0 2 and CuCN

(generated in situ). Following the prescribed wort(-up, the crude tetralone was purified by column

chromatography on silica gel(elutk>n with 20% EtOAc in hexanes) and recrystallization

(EtOAc/hexanes) to afford 1.77 g (40%) of 6-cyano-1-tetralone (13) as a fluffy reddish-orange

solid ; mp 134-135 “C (lit.3« mp 133-134 ®C]: IR (KBr, cm’"') 2942, 2230,1685,1431,1410,1327,

1282,1188,1132, 832; NMR (300 MHz, CDCI 3) 58.08 (d, J= 8.7 Hz, 1H), 7.57 (s, 1H). 7.55

(d, 8.7 Hz, 1H), 3.00 (t, J = 6.1, Hz, 2H), 2.69 (t, J = 6.2 Hz, 2H). 2.16 (q. J= 5.4 Hz, 2H); 1^0

NMR (75 MHz, CDCI3) ppm 196.6, 144.9, 135.2, 132.7, 129.9, 127.8, 118.0, 116.4, 38.8, 29.2,

22 . 6 .

2 5,6,7,8-Tetrahydro-5-methylene-2-naphthonltrlle (14). KHMDS

'CN mL, O.SM/toluene, 3.07 mmol) was added via syringe to a suspension of

Ph 3PCH3Br (1.19 g, 3.33 mmol) in THF (2.5 mL) at 0 °C under N 2. The reaction mixture was allowed to warm to rt over a 1 h period and recooled to 0 °C prior to the addition of the solid 6-cyano-1-tetralone (7) (0.438 g, 2.56 mmol). The reaction mixture, which turned from an intense yellow to a very deep purple, was warmed to rt over a 4 h period, quenched with saturated NH^CIfaq) solution, and extracted with Et 2 0 . The combined organic layers were dried over MgSO^ and concentrated in vacuo. The cmde solid was purified by silica gel chromatography (elution with 17% EtOAc in hexanes) to afford 0.365 g (84%) of olefin 14 as carmine crystals, mp 52-53 °C: IR (KBr, cm'l) 2928,2220,1624,1489,1406, 909,881, 831; ^H

NMR (300 MHz, CDCI3) 5 7.68 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H). 7.38 (s, 1H), 5.58 (s.

190 1H), 5.12 (S. 1H). 2.84 (t. J - 6.3 Hz. 2H), 2.55 (t, J = 5.9 Hz, 2H), 1.88 (q. J = 6.2 Hz. 2H):

NMR (75 MHz. CDCI3) ppm 141.9. 139.3. 138.1. 132.9. 129.2. 124.9. 119.0, 111.6, 32.5, 30.1,

23.0; HRMS (El) m/z(M+) calcd for C i 2H11N 169.0891, obsd 169.0898.

CHg HO^ JL 5,6,7,8-Tetrahydro-6-hydroxy-5-methylene-2-

‘CN t"*®)- f-BuOaH (1.62 mL, 4 .OM/CH2CI2, 6.48 mmol) 15 was added to a mixture of salicylic acid (30 mg. 0.22 mmol) and Se 0 2 (12 mg, 0.11 mmol) followed by a solution of olefin 14 (0.365 g. 2.16 mmol) in GH 2CI2 (2.7 mL). The reaction mixture was stirred at rt for 12 h. diluted with CH2CI2. and washed successively with solutions of 10% KOH(aq) and 50% K2C0 3 (aq). The separated aqueous layers were individually extracted with CH2CI2, and the collected organic layers were combined and dried over MgSO^, and concentrated in vacuo. The resulting crude solid was purified by column chromatography on silica gel (elution with 33% EtOAc in hexanes) and recrystallization (EtOAc/hexanes) to afford

0.218 g (55%) of allylic alcohol 15 as an off-white solid; mp 82-84 ®C; IR (KBr, cm'^) 3323(br),

2934, 2228,1479, 1148, 1092, 1049, 897, 828; ^H NMR (300 MHz, CDCI3) 5 7.68 (d, J = 8.8 Hz,

1H), 7.43 (d, J= 8.8 Hz, 1H), 7.41 (s, 1H), 5.70 (s, 1H). 5.47 (s, 1H), 4.54 (dd, J=7.2, 3.7 Hz, 1H),

3.08 (ddd, J= 17.2, 6.8 , 6.8 Hz, 1H), 2.85 (ddd, J = 17.2, 6.3, 6.3 Hz, 1H), 2.11-1.94 (m, 3H); ’^0

NMR (75 MHz, CDCI3) ppm 144.8, 137.6, 137.2, 132.7, 129.5, 125.7, 118.9, 112.3, 111.1,

70.1, 30.7, 25.9; HRMS (El) m

Anal. Gated for G 12H11NO: G, 77.80; H. 5.99. Found G, 77.56; H, 5.94.

5,6,7,8-Tetrahydro-6-hydroxy-5-oxo-2-naphthonitrlle (1 e).

A -78 °G solution of allylic alcohol 11 (0.254 g, 1.37 mmol) in a 1:1

mixture of MeOH and GH2GI2 (13.8 mL) with 10% pyridine (1.4 mL) was ozorx)lyzed (- 20 min) until the faint yellow solution gave way to a clear reaction mixture. TLG analysis indicated that no starting material remained. The reaction mixture was quenched with

191 MeaS (0.20 mL, 2.7 mmol), warmed to rt over a 2 h period, partitioned with brine, and extracted

with CH 2CI2 The combined organic layers were dried over Na 2S 0 4 and concentrated in vacuo.

The crude solid w as purified by column chromatography on Fiorisil (elution with 33% EtOAc in

hexanes) to afford 0.969 g (71%) of a-hydroxy-1-tetralone le as a light yellow solid, mp 133-135

»C; IR (KBr, cm-1) 3492 , 2233,1692,1280,1254,1231,1100,1001; NMR (300 MHz, CDCI 3)

6 8.12 (d, J = 7.9 Hz, 1H), 7.62 (d, 7.9 Hz, 1H), 7.60 (s. 1H), 4.43 (dd, J = 13.6,5.5 Hz, 1H),

3.77 (brs, 1H), 3.19 (ddd, J* 17.4, 5.1,2.7 Hz, 1H), 3.08 (ddd, 17.4, 5.1, 2.7 Hz, 1H), 2.61-

2.53 (m, 1H), 2.07 (dddd, J= 12.8,12.8,12.8,5.2 Hz, 1H); 1^0 NMR (75 MHz, CDCI3) ppm

198.4, 144.7, 133.4, 132.8, 130.2, 128.2, 117.7, 117.3, 73.9, 31.3, 27.4; HRMS (El) m/z(M+)

calcd for C 11H9 NO2 187.0633, obsd 187.0637.

Anal. Calcd for Gi 1H9 NO2: 0, 70.56; H, 4.85. Found 0, 70.51 : H, 4.90.

Prototypical Indium-Promoted Couplings.

A. In Water. A mixture of 2-hydroxy-l-tetralone (la) (41 mg, 0.25 mmol), allyl bromide

(32 pL, 0.38 mmol), and indium powder (43 mg, 0.38 mmol) in water (2.5 mL) was tightly

stoppered and stirred at rt for 1.5 h producing a milky white solution. The reaction mixture was

diluted with brine, quenched with 10% HCI(aq) solution, and extracted with Et 2 0 . In several

instances, the 10% HCI(aq) quench was deemed detrimental to the product(s) and its use was

therefore avoided without any adverse effects. The combined organic layers were dried and

concentrated in vacuo. The resulting crude product(s) were purified as described below

B. In 50% THF(aq). Indium powder (43 mg, 0.38 mmol) was added to a magnetically

stirred solution of allyl bromide (32 pL, 0.38 mmol) and 2-hydroxy-1-tetralone (la) (41 mg, 0.25

mmol) in a 1:1 mixture of THF and H2O (2.5 mL). The reaction mixture was stirred at rt for 1.5 h, diluted with brine, quenched with 10% HCI(aq) solution, and extracted with EtgO. In several instances, the 10% HCI(aq) was deemed detrimental to the product(s) and therefore was avoided

192 without any adverse effects. The combined organic extracts were dried and concentrated in

vacuo to afford a crude mixture. The resulting impure product(s) were purified as stated, vide

infra..

C. In Anhydrous THF. A THF (2.5 mL) solution of allyl bromide (32 pL, 0.38 mmol)

and 2-hydroxy-1-tetralone (la) (41 mg, 0.25 mmol) with added indium powder (43 mg, 0.38 mmol)

was tightly stoppered and was vigorously stirred at rt for 6 d. The reaction mixture was diluted with

ether, partitioned with brine, quenched with 10% HCI(aq) solution, and extracted with Et 2 0 . An

equally effective procedure that avoided the 10% HCi(aq) quench entailed filtration of the reaction

mixture through a pipet containing silica (elution with EtOAc). The combined organic layers were

dried and concentrated in vacuo. Chromatographic purification as described afforded the pure

individuals diois {vide infra).

D. Precomplex In THF. A suspension of indium powder (17 mg, 0.15 mmol) in a solution of THF (1.0 mL) and allyl bromide (13 pL, 0.15 mmol) was vigorously stirred at reflux for 15

min under N2, ultimately producing a slightly cloudy homogenous solution. The reaction mixture was cooled to rt prior to the addition of the 6-(/V-methyl)acetamido tetralone substrate id, and was stirred at rt for 30 min, quenched with brine, and extracted with Et 2 0 . The combined organic extracts were dried and concentrated in vacuo. The residue was purified as detailed below.

E. Competition Experiments. A mixture of equimolar amounts of hydroxytetralones la (20.2 mg, 0.125 mmol) and 1b (24.0 mg, 0.125 mmol), indium powder (14.3 mg, 0.125 mmol), allyl bromide (13 pL, 0.15 mmol), and water (1.25 mL) was stirred in a tightly stoppered flask at rt for

8 h. The reaction mixture was diluted with brine and partioned with ether. The aqueous layer was extracted with Et 2 0 and the combined organic layers were dried over Na 2S 0 4 and concentrated

193 in vacuo. ^H NMR analysis of the the cmde reaction mixture afforded unfettered integration of the

the most downfield signals corresponding to H -8 of the unreacted starting hydroxytetralones.

Coupling involving i,2,3,4-Tetrahydro-2-hydroxynapthalenone (la). c/s>1-Allyl*1.2,3,4-tetrahydro-1,2- HO, HO. naphthalenedlol (16) and frans 'H 16 17 1,2,3,4-telrahydro-1 ,2 naphthalenedlol

(17). a-Ketol la was reacted according to the above protocols to afford a mixture of diols 16 and

17 (Scheme 6.9). The individual homoallylic alcohols were isolated via chromatographic purification on silica gel (elution with 20% EtOAc in hexanes).

For 16: colorless oil; IR (neat, cm 1) 3406(br). 3073, 3019, 2934, 1639,1469, 1453,

1278, 1208, 1053, 998, 961,916, 766: ^H NMR (300 MHz, CDCI 3) 8 7.58-7.55 (m, 1H), 7.26-

7.07 (series of m, 3H), 5.79-5.65 (m, 1H), 5.14-5.07 (m, 2H), 3.94 (dd, J = 6.7, 3.2 Hz, 1H), 2.96

(dd, J = 17.1, 7.2 Hz, 1H), 2.77-2.50 (series of m, 5H), 2.08-1.90 (m, 2H); NMR (75 MHz,

CDCI3) ppm 139.6, 135.8, 133.4, 128.5, 127.4, 127.4, 126.4, 118.8, 73.6, 70.7, 45.0, 26.2,

25.2; HRMS (El) m /z (M+) calcd for C 13H16O2 204.1150, obsd 204.1167.

Anal. Calcd for C 13H16O2: C, 76.44; H, 7.89. Found 0, 76.29; H, 7.97.

For 17: colorless white solid; mp 91-92 °C; IR (KBr, cm*^) 3360(br), 3074, 3008, 2959,

2894, 2842, 1639, 1488, 1438, 1355,1289, 1182, 1128, 1073; NMR (300 MHz, CDCI 3) 5

7.44-7.39 (m, 1H), 7.23-7.15 (m, 2H), 7.10-7.07 (m, 1H), 5.94-5.80 (m, 1H), 5.18-5.11 (m, 2H),

3.97 (dd, J = 11.4, 4.4 Hz, 1H), 3.00-2.87 (m, 2H), 2.74 (dd, J = 13.9, 8.2 Hz, 1H), 2.57, (br s, 2H),

2.47 (dd, 13.9, 6.7 Hz, 1H), 2.11 (dddd, J = 13.3, 6.6, 4.3, 4.3 Hz, 1H), 2.04-1.90 (m, 1H); 1^0

NMR (75 MHz, GDCI3) ppm 140.4, 134.8, 133.8, 128.5, 127.3, 126.3, 125.7, 119.3, 75.1, 74.4,

40.6,26.8,26.1 ; HRMS (El) m /z (M+) calcd for C 13H16O2 204.1150, obsd 204.1148.

Anal. Calcd for C 13H16O2: C, 76.44; H, 7.89. Found C, 76.33; H, 7.89.

194 Coupling Involving 1,2,3,4>Tetrahydro>2-hydroxy-6>methoxynaphthalenone (1b). HQ^ y—^ H Q,^^ c/s-1-AllyM,2,3,4-tetrahydro*6- I II I methoxy-1,2-naphthalenedlol (20) OMe ^^^^^OMe 20 21 and frans>1-Allyl>l,2,3,4-tetrahydro-

6-me*hoxy-1,2 naphthalenedlol (21). The indium-mediated allylation of lb afforded, after column chromatography on silica gel (elution with 25% EtOAc in hexanes), homoallylic alcohols

20 and 21 (Scheme 6.11).

For 20: colorless oil: IR (neat, cm'i) 34021 (br), 2937,1608,1500,1252,1049; ’H NMR

(300 MHz, CDCI3) 8 7.49 (d, 8.7 Hz, 1H), 6.81 (dd, J = 8.7, 2.7 Hz, 1H), 6.60 (d, J = 2.7 Hz,

1H), 5.77-5.63 (m, 1H), 5.15-5.06 (m, 2H), 3.95 (brs, 1H), 3.78 (s, 3H), 2.94 (ddd, J = 17.1, 6.9,

6.9 Hz, 1H), 2.77-2.66 (m, 2H), 2.60-2.53 (m, 2H), 2.33 (br s, 1H), 2.04-1.94 (m. 2H); 1% NMR

(75 MHz, CDCI3) ppm 158.7, 137.5, 133.6, 131.7, 128.8, 118.7, 112.9, 112.7, 73.4, 70.7, 55.2,

44.7, 26.4, 25.9: HRMS (El) m/2 (M+) calcd for C 14H18 O3 234.1256, obsd 234.1260.

Anal. Calcd for C 14H18 O3: 0, 71.77: H, 7.74. Found 0, 71.49: H. 7.74.

For 21: colorless solid: mp 107-108 °C: IR (KBr. cm*'') 3356(br), 1608,1501,1262, 1238,

1076, 1034, 1004, 932, 847: 'H NMR (300 MHz, CDCI 3) 8 7.34 (d, J = 8.7 Hz, 1H), 6.76 (dddd, J

= 8 .6, 2.7, 0.7, 0.7 Hz, 1H), 6.60 (d, J = 2.7 Hz, 1H), 5.96-5.82 (m. 1H), 5.19-5.11 (m, 2H). 3.96

(dd, J = 11.0, 4.2 Hz, 1H), 3.77 (s, 3H), 2.96-2.90 (m, 2H), 2.72 (dddd, 13.9, 8.1,1.1, 1.1 Hz,

1H), 2.48 (dddd, J= 13.9, 6.7,1.2, 1.2 Hz, 1H), 2.11 (dddd, 13.4, 6 .6 , 4.4, 4.4 Hz, 1H), 1.97

(dddd, J= 13.4,11.0, 9.0, 7.9 Hz, 1H): 1% NMR (75 MHz, CDCI3) ppm 158.7,

136.4, 134.0, 132.8, 127.6, 119.2, 112.9, 112.1, 74.7, 74.6, 55.2, 40.8, 27.0, 26.1 : HRMS (El) m/z{M+) calcd for G 14H18 O3 234.1256, obsd 234.1238.

Anal. Calcd for C 14H18O3: C, 71.77: H, 7.74. Found C, 71.72: H, 7.68.

195 Coupling involving 6-Bromo-l,2,3,4-tetrahydro-2-hydroxynaphthalenone (ic).

HCL y— ^ HQ, y — ^ c/5-1*Allyl-6-bromo-1,2,3,4-tetrahydro- HO^ HO, ' I L Â JL 1,2 naphthalenedlol (24) and trans-1- 24 25 Allyl-6-bromo-l ,2,3,4-tetrahydro-1,2-

naphthalenedlol (25). Following the prototypical reaction conditions established above, 1C

produced a mixture of diols 24 and 25, which were isolated by silica gel chromatography (elution

with 20% EtOAc in hexanes) (Scheme 6.13).

For 24: colorless oil; IR (neat cm'l) 3401 (br), 2931, 1590,1473, 1047, 989, 952, 822; ^H

NMR (300 MHz, CDCI3) 5 7.44 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (dd, J = 3.8,

3.0 Hz, 1H), 5.81-5.67 (m, 1H), 5.14-5.07 (m, 2H), 3.98 (br s, 1H), 2.97 (ddd, J = 15.4, 7.7, 7.7

Hz, 1H), 2.74 (brs, 1H), 2.71 (ddd, J= 17.3, 5.8, 5.8 Hz, 1H), 2.61 (dd. J = 14.3, 7.4 Hz, 1H), 2.49

(dd J= 14.3, 7.2 Hz, 1H), 2.30 (brs, 1H), 2.06-1.99 (m, 2H); 1^0 NMR (75 MHz, CDCI3) ppm

138.8, 138.0, 133.0, 131.1, 129.5, 129.3, 121.3, 119.2, 73.4, 70.5, 45.2, 25.9, 24.7; HRMS (El)

- H2O) calcd for C 13H138 IB1O 266.0129, obsd 266.0137 and calcd for C i 3H i3^9 BrO

264.0149, obsd 264.0194.

AnaL Calcd for C i 3HisBr0 2 : C, 55.14; H, 5.34. Found 0, 55.18; H, 5.40.

For 25: colorless solid; mp 120-121 =C; IR (KBrcm'l) 3364(br), 1477,1074, 920; ^H NMR

(300 MHz, GDCI3) 8 7.32-7.23 (m, 3H), 5.91-5.76 (m, 1H), 5.20-5.10 (m, 2H), 3.93 (dd, J = 11.4,

4.4 Hz, 1H), 3.00-2.83 (m, 2H), 2.71 (dd. J = 13.9, 8.1 Hz, 1H), 2.62 (br s, 1H), 2.58 (br s, 1H),

2.41 (dd, J= 13.9, 6.8 Hz, 1H), 2.15-2.06 (m, 1H), 2.02-1.88 (m, 1H); 1% NMR (75 MHz, CDCI 3) ppm 139.5, 137.1, 133.3, 131.2, 128.8, 128.2, 121.3, 119.8, 74.8, 74.0, 40.4, 26.6, 25.9;

HRMS (El) m /z (M+ - H2O) calcd for Gi3Hi38 iBrO 266.0129, obsd 266.0096 and calcd for

C l3H i3^®BrO 264.0149, Obsd 264.0163.

Anal. Galcd for Gi 3HigBr 0 2 : C, 55.14; H, 5.34. Found G, 54.90; H, 5.32.

196 Coupling involving A/-iMethyi-M>(5,6,7,8-tetrahydro-6-hydroxy-2-naphthyi-5- oxo)acetamide (1d). ^ HC. N-(c/»-5-Aiiyi-5,6,7,8-tetrahydro- HO,

Ac methyiacetamide (28) and N-itrans- 5-Aiiyi-5,6,7,8-tetrahydro-5,6.*

dihydroxy-2-naphthyi)-Af-methyiacetamide (29). The indium-mediated allylation of Id,

in accordance to our prototypical reaction conditions, afforded a mixture of diols 28 and 29

(Scheme 6.15). Because of the polar nature and similar polarity, the individual diols could only be

enriched in composition through tedious and latx)rious chromatography (elution 85% EtOAc in

hexanes).

For 28: Slightly yellow oil; IR (neat, cm'"') 3420(br), 2931,1737,1636, 1608,1499,1425,

1381,1061 ; NMR (300 MHz, CDCI 3) 6 7.62 (d, J= 8.3 Hz, 1H), 7.04 (dd, J = 8.4, 2.0 Hz, 1H),

6.91 (s, 1H), 5.85-5.71 (m, 1H), 5.24-5.06 (m, 2H), 4.03 (brd, J= 4.2 Hz, 1H), 3.23 (s, 3H), 3.04-

2.94 (m, 1H), 2.81-2.45 (series of m, 3H), 2.10-2.04 (m, 2H), 1.87 (d, J = 3.7 Hz, 3H); 1% NMR

(75 MHz, CDCI3) ppm (complicated by rotamers and slight impurity of diastereomer 29); HRMS (El) m/z(M+) calcd for C 16H21NO3 275.1522, obsd 275.1500.

For 29: faint yellow oil; IR (neat, cm*1) 3404(br), 2934, 1735, 1654, 1637, 1605, 1498,

1388,1074; ^H NMR (300 MHz, CDCI 3) 5 7.48 (d, J = 3.8 Hz, 2/3H), 7.12-6.89 (series of m, 7/3H),

5.95-5.72 (m, 1H), 5.22-5.02 (m, 2H), 4.03-3.98 (m, 1H), 3.21 (s, 3H), 3.03-2.92 (m, 1H), 2.82-

2.35 (series of m, 3H), 2.20-1.95 (series of m, 2H), 1.84 (s, 3H); NMR (75 MHz, CDCI 3) ppm

(complicated by rotamers and a slight impurity of diastereomer 28); HRMS (El) m/z(M+) calcd for

C16H21NO3 275.1522, obsd 275.1520.

197 Coupling Involving i,2,3,4-tetrahydro-2-hydroxynaphthalenone-6-carbonltrlle (le). HQ. ^ c/s-5-Allyl-5,6,7,8-tetrahydro-5,6- HO, I dlhydroxy-2-naphthonltrile (32) and ON ON 33 frans-5-Allyl-5,6,7,8-tetrahydro-5,6-

dlhydroxy-2-naphthonltrlle (33). Under the afore mentioned reaction conditions 6-cyano-

2-hydroxy-l-tetralone (la) afforded diols 32 and 33 after silica gel purification (elution with 50%

EtOac in hexanes) (Scheme 6.17).

For 32: clear oil; IR (neat, cm*"') 3432(br), 2934, 2229,1056; NMR (300 MHz, CDCI 3) 5

7.69 (d, J = 8.1 Hz, 1H), 7.49 (dd, J = 8.2, 0.8 Hz, 1H), 7.39 (s, 1H), 5.85-5.71 (m, 1H), 5.18-5.08

(m, 2H), 4.05 (dd, J = 4.0,4.0 Hz, 1H), 3.04 (ddd, J = 17.4,8.6,8.6 Hz, 1H), 2.92 (brs, 1H), 2.76

(ddd, J = 17.4, 5.4, 5.4 Hz, 1H), 2.56 (dd, J = 14.4, 7.2 Hz, 1H), 2.46 (dd, J = 14.3, 7.5 Hz, 1H),

2.32 (br s, 1H), 2.12-2.05 (m, 2H); 1% NMR (75 MHz, CDCI3) ppm 145.6, 136.9, 132.4, 132.1,

129.6,128.5,119.7, 118.9, 111.0, 73.5, 70.4, 45.4, 25.6, 24.1; HRMS (El) m/z(M*) calcd for

C1 4 H1 5 NO2 229.1103, Obsd 229.1093.

For 33: slight yellow solid; mp 97-98 "C; IR (KBr, cm'^) 3446(br), 2225,1281, 1116,

1076,1034, 996,928: ^H NMR (300 MHz, CDCI 3) 5 7.54 (d, J = 8.1 Hz, 1H). 7.45 (d, J = 8.2 Hz,

1H), 7.38 (s, 1H), 5.87-5.73 (m, 1H), 5.22-5.10 (m, 2H), 3.97 (dd, J = 11.5, 4.5 Hz, 1H), 3.05-2.89

(m, 2H), 2.79-2.72 (m, 2H), 2.54 (brs, 1H), 2.39 (dd, J = 13.9, 6.9 Hz, 1H), 2.21-2.12 (m, 1H),

2.06-1.92 (m, 1H): 13c NMR (75 MHz, CDCI3) ppm 145.8, 136.1,132.7, 132.2.129.1, 127.4,

120.3, 118.8, 111.1, 74.8, 73.6,40.2, 26.4, 25.7; HRMS (El) m/z(M+) calcd for C14H15NO2

229.1103. Obsd 229.1093.

198 c /s -1 -Allyl-1,2 ,3 ,4 -tetrahydro- 1 ,2-naphthalenedlol, Cyclic

C arbonate (18). A mixture of cis diol 16 (60 mg, 0.29 mmol), GDI (95

' H mg, 0.59 mmol) and a catalytic quantity of OMAP in benzene (2.9 mL) was

stirred under N2 for 5 h and concentrated in vacuo to afford a cnjde oily residue. Chromatograpfiic purification (elution witfi 14% EtOAc in fiexanes) gave 61 mg (90%) of cis caitwnate 18 as a dear oil: IR (neat, cm*'') 2949,1794,1193,1054; 'H NMR (300 MHz, CDCI 3)

5 7.53 (dd, J = 9.1, 2.1 Hz, 1H), 7.51-7.26 (m, 2H), 7.15 (dd, J = 6.4, 2.1 Hz, 1H), 5.55-5.41 (m,

1H), 5.25-5.17 (m, 2H), 4.85 (dd, 7.8, 4.6 Hz, 1H), 2.93-2.83 (m,3H), 2.60 (ddd, J = 16.1,8.7,

4.2 Hz, 1H), 2.25-2.15 (m, 1H), 2.05-1.93 (m, 1H); 1% NMR (75 MHz, CDCI3) ppm 153.8.136.8,

133.3, 130.0, 128.9, 128.3, 127.6, 127.4, 121.3, 82.5, 79.1, 44.8, 26.5, 24.4; HRMS (El) m /z

(M+) calcd for C 14H14O3 230.0943, obsd 230.0941.

Anal. Calcd for C 14H14O3:0, 73.03; H, 6.13. Found 0,73.02; H, 6.13.

fra n s -1 Allyl 1,2,3,4-tetrafiydro 1,2-napfithalenedlol, Cyclic

C arbonate (19). A benzene solution (4.0 mL) of trans diol 17 (41 mg, H 19 0.20 mmol), GDI (36 mg, 0.22 mrrwl) and a catalytic quantity of DMAP was refluxed under N2 for 12 h. TLG analysis indicated the presence of starting material. The readion mixture was charged with an additional 1.2 eq of GDI (36 mg, 0.22 mnwl), refluxed under N 2 for 24 h, and concentrated reduced pressure. The resulting dark oil was purified by flash column chromatography on silica gel(elution with 20% EtOAc in hexanes) to yield 43 mg (93%) of trans cartDonate 19 as a clear oil; IR (neat, cm*') 1806,1190,1125,1106,1067,993, 767; NMR

(300 MHz, GDGI3) 5 7.29-7.15 (m, 4H), 5.85-5.71 (m, 1H), 5.17 (ddd, J= 10.1,0.7, 0.7 Hz, 1H),

5.07 (ddd, J= 17.0, 2.8,1.3 Hz, 1H), 4.55 (dd, 13.6, 5.6 Hz, 1H), 3.26-3.05 (m, 2H), 2.69 (dd,

14.2, 6.6, Hz, 1H), 2.50-2.37 (m, 2H), 2.25 (dddd, J = 13.6, 12.5, 9.4, 7.4 Hz. 1H); '^G NMR

(75 MHz, GDGI3) ppm 155.0, 136.6, 132.6, 129.4, 129.2, 128.4, 126.0, 123.3, 120.8, 85.5,

82.7, 39.1, 25.6,18.9; HRMS (El) m /z (M+) calcd for G 14H14O3 230.0943, obsd 230.0941.

199 Anal. Calcd for C 14H14O3: 0 .7 3 .0 3 : H. 6.13. Found 0 .73.13; H, 6.14.

c/s-1-Ally 1-1,2,3,4-tetrahydro-6-methoxy-l ,2-

naphthalenedlol, Cyclic Carbonate (22). A mixture of cis diol

20 (26 mg, 0.11 mmol), GDI (53 mg, 0.33 mmol) and a catalytic quantity of DMAP in benzene (1.1 mL) was stirred at rt for 12 h under N 2 - The solvent was removed under reduced pressure to leave an oily residue which was purified by flash chromatography on silica gel(ekJtion with 14% EtOAc in hexanes) to afford 19 mg ( 66%) of cis carbonate 22 as a clear oil; IR

(neat, cm*1) 2940, 1792, 1611, 1578, 1505, 1445, 1361, 1336, 1277, 1251, 1195, 1139, 1053,

1013; NMR (300 MHz, CDCI3) 5 7.45 (d, J = 8.7 Hz, 1H), 6.87 (dd, J = 8.7, 2.7 Hz, IN), 6.66 (d,

J= 2.6 Hz, 1H) 5.53-5.39 (m, 1H), 5.24-5.16 (m, 2H), 4.83 (dd, J = 7.2, 4.4 Hz, IN), 3.81 (s, 3H),

2.91-2.80 (m, 3H), 2.58 (ddd, J= 16.3, 7.8,4.4 Hz, 1H), 2.19-1.99 (m, 2H); ^^0 NMR (75 MHz,

CDCI3) ppm 159.7, 154.1, 138.5, 130.2, 129.1, 125.2, 121.2 , 113.7, 112.9, 82.7, 79.1, 55.3,

44.6, 26.4, 24.7; HRMS (El) m/z (M+) calcd for C 15H16O4 260.1049, obsd 260.1057.

Anal. Calcd forC isH i 6 0 4 : C, 69.22; H, 6.20. Found C, 69.33; H, 6.19.

trans-^ -Allyl-1,2,3,4-tetrahydro-6-methoxy-l ,2-

naphthaienedlol, Cyclic Carbonate (23). A benzene solution OMe 23 (2.7 mL) of trans diol 21 (63 mg, 0.27 mmol), GDI (86 mg, 0.53 mmol) and a catalytic quantity of DMAP was stirred at rt under N 2 for 8 h. TLG analysis indicated remaining starting material. An additional equivalent of GDI (43 mg, 0.26 mmol) was added to the reaction mixture, which was subsequently stirred at rt for 8 h under N2 and concentrated in vacuo.

The residual oil was purified by flash chromatography on silica gel (elution with 14% EtOAc in hexanes) to produce 47 mg ( 68 %) of trans cartxinate 23 as a clear oil; IR (neat, cm*^) 2914(br),

1801, 1611, 1576, 1501, 1466, 1440, 1339, 1310, 1273, 1253, 1186, 1127, 1100, 1065, 994,

962, 944; ^H NMR (300 MHz, GDCI 3) 6 7.15 (d, J = 8.4 Hz, 1H), 6.76-6.68 (m, 2H), 5.84-5.70 (m,

200 1H). 5.18-5.02 (m. 2H). 4.53 (dd. J » 13.7,5.5 Hz, 1H), 3.77 (s, 3H), 3.22-3.01 (m, 2H), 2.66 (dd,

14.1, 6.6 Hz, 1H), 2.47-2.33 (m, 2H), 2.22 (dddd, J = 13.6,12.4, 9.7, 7.6 Hz, 1H); 1% NMR

(75 MHz, CDCI3) ppm 159.5, 155.1, 134.1. 129.5, 128.9, 124.5,120.7, 114.7, 111.3, 85.4,

82.9,55.2,39.3,25.7,18.9; HRMS (El) m'z(M+) calcd for C 15H16O4 260.1049, obsd 260.1057.

Anal. Calcd for G 15H16O4: 0, 69.22: H, 6.20. Found 0, 69.32; H, 6.18.

c/s*l*Aliyl-6>broino*l,2,3,4>tetrahydro>l,2*naphthalenedlol,

Cyclic Carbonate (26). A benzene solution (2.0 mL) of diol 24 (27 26 ^ mg, 94 pmol), GDI (30 mg, 0.19 mmol), and a catalytic quantity of DMAP was heated at reflux under N2 for 3 h. The reaction mixture was cooled to rt and concentrated in vacuo. The resulting cmde residue was chromatographed on silica gel (elution with 14% EtOAc in hexanes) to afford 25 mg (87%) of cis carbonate 26 as white crystals, mp 81-82 °G; IR (KBr, cm'^)

1803, 1364, 1237, 1057, 1026; ^H NMR (300 MHz, GDGI 3) 5 7.46 (dd, J = 8.4, 1.9 Hz, 1H), 7.40

(d, J= 8.4 Hz, 1H), 7.33 (d, J= 1.7 Hz, 1H). 5.52-5.38 (m, 1H), 5.25-5.19 (m, 2H), 4.84 (dd, J =

7.7,4.5 Hz, 1H), 2.86 (ddd, J= 16.5,8.0, 4.3 Hz, 1H), 2.83 (d, J = 7.2 Hz. 1H), 2.58 (ddd, J =

16.4, 8.4. 4.2 Hz, 1H), 2.24-2.13 (m, 1H), 2.06-1.94 (m, 1H); 1% NMR (75 MHz, GDGI 3) ppm

153.6, 138.9, 132.4, 131.2, 130.7, 129.5, 129.3, 123.2, 121.8, 82.0, 78.8, 44.6, 26.2, 24.2;

HRMS (El) m/z{M+) calcd forG i 4Hi38 iBr0 3 310.0028, obsd 310.0057 and calcd for

C i4H i3^®Br0 3 308.0048, obsd 308.0082.

Anal. Gated for Gi 4Hi3Br0 3 : G, 54.39; H. 4.24. Found G, 54.47; H, 4.27.

rrans-1-Allyl-6-bromo-1,2,3,4-tetrahydro-1,2-

naphthalenedlol, Cyclic Carbonate (27). A N2 blanketed solution Br of trans diol 25 (67 mg, 0.24 mmol), GDI (0.115 g, 0.712 mmol) and a catalytic quantity of DMAP in benzene (4.8 mL) was heated at reflux for 3 h. The cooled reaction mixture was concentrated In vacuo and the remaining residue was purified by flash

201 chromatography on silica gel (elution with 22% EtOAc in hexanes) to afford 58 mg (79%) of trans

carbonate 27 as a nearly colorless oil; IR (neat, cm*'') 1806,1599,1479,1336,1198,1128,

1064,990,821,783: 'H NMR (300 MHz, CDCI 3) 57.36-7.33 (m, 2H), 7.11 (d, J = 7.9 Hz, 1H),

5.81-5.67 (m, 1H), 5.18 (dd, J - 10.1, 0.6 Hz, 1H), 5.05 (dd, J ~ 17.0,1.2 Hz, 1H), 4.51 (dd,

13.7, 5.6 Hz, 1H), 3.23-3.02 (m, 2H), 2.67 (dd, J - 14.1,6.4 Hz, 1H), 2.50-2.40 (m, 1H), 2.34 (dd,

14.0, 7.8 Hz, 1H), 2.28-2.16 (m, 1H); NMR (75 MHz, CDCI 3) ppm 154.6,135.5,134.9,

132.1, 129.2, 128.9,125.0, 122.3, 121.2, 85.0, 82.2, 38.8, 25.3, 18.7; HRMS (El) m/z(M+)

calcd for Ci 4H i3®''Br0 3 310.0028, obsd 309.9989 and calcd for C i 4H i3^®Br0 3 308.0048, obsd

308.0078.

Anal. Calcd for C i 4H i3Br0 3 : 0,54.39; H, 4.24. Found 0,54.64; H, 4.40.

A/>(c/s-5*Allyl-5,6,7,8-tetrahydro<

Me -I Me 5,6-dlhydroxy-2naphthyl)-A/-

Ac 31 Ac methyiacetamide, Cyclic Carbonate

(30) and Af-(frans-5>Allyl-5,6,7,8-tetrahydro«5,6*dihydroxy-2naphthyl)-N-

methyiacetamide, Cyclic Carbonate (31). A solution of diols 28 and 29 (57 mg, 0.21

mmol), CDI (67 mg, 0.41 mmol), and a catalytic quantity of DMAP in benzene (10.0 mL) was

refluxed under N2 for 6 h. The reaction mixture was cooled to rt and concentrated in vacuo. The

resulting residue was dissolved with EtOAc, filtered through a pipet containing silica gel (elution

with EtOAc) and concentrated in vacuo. MPLC purification of the crude residue (elution with 80%

EtOAc in hexanes) afforded 20 mg (33%) of cis cartronate 30 and 34 mg (54%) of trans carbonate

31, both as clear oils.

For 30: IR (neat, cm*'') 2936, 1801, 1656, 1609, 1501, 1438, 1422. 1378, 1353, 1195,

1055,1013; 'H NMR (300 MHz, CDCI3) 6 7.58 (d, J = 8.3 Hz, 1H), 7.16 (dd. J = 8.3, 2.1 Hz, 1H),

7.00 (brs, 1H), 5.56-5.42 (m, 1H), 5.27-5.21 (m, 2H), 4.88 (dd, J= 7.4, 4.4 Hz, 1H), 3.26 (brs,

202 3H). 2.95-2.83 (m. 1H), 2.89-2.85 (m, 2H), 2.62 (ddd. J = 16.4,8.0, 4.3 Hz, 1H), 2.21 (ddd,

18.0.8.5, 4.3 Hz, 1H), 2.11-2.00 (m, 1H), 1.90 (br s, 3H); 1% NMR (75 MHz, CDCI 3) ppm 170.2,

153.6, 144.9, 138.5, 129.6, 129.2, 129.0, 126.6, 126.1, 121.8, 82.0, 78.9, 44.5, 37.1, 26.1,

24.3, 22.5: HRMS (El) m

Anal. Calcd for CiyHigNO^'O OHgO: C, 65.79; H, 6.49. Found 0, 65.88: H, 6.40.

For 31: IR (neat, cm'1) 2980, 2934, 1805, 1738, 1659, 1611, 1495, 1435, 1378, 1178,

1063: ^ H NMR (300 MHz, CDCI3) 6 7.30 (d, J = 8.0 Hz, 1H), 7.05 (d, J - 8.0 Hz, 1H), 7.01 (br s,

1H), 5.84-5.71 (m, 1H), 5.20 (d, 9.7 Hz, 1H), 5.07 (dd, J= 17.0,1.2 Hz, 1H). 4.56 (dd, J =

13.6, 5.6 Hz, 1H), 3.23 (S, 3H), 3.27-3.06 (m, 2H), 2.71 (dd, J = 14.2, 6.6 Hz, 1H), 2.53-2.45 (m,

1H), 2.39 (dd, J = 14.2, 7.8 Hz, 1H), 2.34-2.20 (m, 1H). 1.85 (brs, 3H): 1% NMR (75 MHz, CDCI 3) ppm 170.2, 154.8, 144.8, 136.1, 134.8, 129.0, 127.8, 127.8, 124.8, 121.2, 85.0, 82.3, 38.9,

37.1, 25.5, 22.4, 18.7; HRMS (El) rra'z(M+) calcd for Ci 7H19 NO4 301.1314, obsd 301.1309.

Anal. Calcd for C i 7H i9 NO4*0.5H2O: C, 65.79: H, 6.49. Found C, 66.28: H, 6.43.

V o . c/s-5-Allyl 5,6,7,8 -tefrahydro 5,6 dlhydroxy-2-

naphthonitrile. Cyclic Carbonate (34). A benzene solution (3.2 CN mL) of cis diol 32 (15 mg, 65 pmol), CDI (21 mg, 0.13 mmol), and a catalytic quantity of DMAP was stirred at 65 "C under N2 for 4 h. The reaction mixture was concentrated in vacuo and the residual yellow oil was chromatographed (elution with 25% EtOAc in hexanes) to give 8 mg (46%) of cis cartjonate 34 as a slightly yellow oil; IR (neat, cm'^) 2956,

2231, 1798, 1734, 1444, 1415, 1362, 1337, 1316, 1238, 1194, 1141, 1058, 1013, 933, 837,

769: : ’H NMR (300 MHz, CDCI 3) 57.66 (d, J = 8.2 Hz, 1H), 7.62 (dd, J = 8 .2 ,1.4 Hz, 1H), 7.49 (s,

1H), 5.52-5.38 (m, 1H), 5.26-5.20 (m, 2H), 4.89 (dd, J= 7.9, 4.7 Hz, 1H), 2.92 (ddd, J= 16.4, 7.7,

4.2 Hz, 1H), 2.85-2.76 (m, 2H), 2.64 (ddd, J = 16.4, 8.9, 4.2 Hz, 1H), 2.27 (dddd, J= 13.8, 7.8,

4.4, 4.4 Hz, 1H), 2.00 (dddd, J= 13.8, 8.7, 4.4, 4.4 Hz, 1H); NMR (75 MHz, CDCI3) 8 153.2,

203 138.5, 138.0, 132.0, 130.9, 128.9, 128.8, 122.4, 118.0, 112.9, 81.6, 78.6, 44.6, 26.1, 24.2;

HRMS (El) m /z (M+ - C3H5 - CO2) calcd for CnH gN 0170.0606, obsd 170.0618.

Anal. Calcd for C 15H13NO3:0.70.58: H, 5.13. Found 0,70.41 ; H. 5.24.

fra n 5>5 *Allyl> 5 ,6 ,7 ,8 >tetrahydro- 5 ,6 >dlhydroxy- 2-

naphthonltrlie. Cyclic Carbonate (35). A solution of GDI (71 mg,

35 0.44 mmol), a catalytic quantity of DMAP, arxf trans diol 33 (50 mg, 0.22 mmol) in benzene (4.4 mL) was magnetically stirred at 65 °C under N 2 for 4 h. The reaction mixture was cooled to rt and concentrated in vacuo. The resulting crude oil was purified by column chromatography on silica gel (elution with 25% EtOAc in hexanes) to afford 38 mg (67%) of trans cartx>nate 35 as a slightly yellow oil; IR (neat, cm'^) 2978, 2920, 2230,1811,1734,1475,1436,

1321,1248,1186,1113,1067, 1003: NMR (300 MHz, CDCI 3) 5 7.53 (d, J= 7.9 Hz, 1H), 7.48

(S, 1H), 7.36 (d, J = 7.9 Hz, 1H), 5.81-5.67 (m, 1H), 5.20 (d, J = 10.1 Hz, 1H), 5.04 (dd, J= 17.0,

1.1 Hz, 1H), 4.51 (dd, J = 13.6, 5.7 Hz, 1H), 3.25 (dd, J = 17.2,10.1 Hz, 1H), 3.18-3.09 (m, 1H),

2.72 (dd, J= 14.2, 6.3 Hz, 1H), 2.55-2.45 (m, 1H), 2.35 (dd, J = 14.2, 8.1 Hz, 1H), 2.33-2.21 (m,

1H): 13c NMR (75 MHz, CDCI3) ppm 154.2, 141.3, 134.3, 132.9, 129.9, 128.4, 124.4, 121.7,

118.1,112.6, 84.7, 81.7, 38.5, 25.3,18.5; HRMS (El) rrKz (M+- C 3H5 - CO2) calcdforCnHgNO

170.0606, obsd 170.0583.

Anal. Calcd for C 15H13NO3: C, 70.58: H, 5.13. Found C, 70.30; H, 5.21.

204 APPENDIX A

CHAPTER 3 1H NMR SPECTRA

205 D

10

ro o o> il

r— — I " r E l.eo #.00 #.00 7.00 7.00 1.00 i.oo O.OO 0.00 4.00 4.00 0 00 1.00 1.00 t.O O 1 .0 0

Figure A.1: NMR Spectrum ol 10. " I " " I ' '— j — r ' ~ •P 8.00 7,30 7.00 6.30 6.00 3 .no 9.00 4.90 4.00 3.90 ?.90 3.00 1.90 1.00 .90 0.0 i'MM

Figure A.2: NMR S pectrum of 11. HO, r CH3 O,

00

.so s . 00 7.so 7.00 S. SO 6.00 S.50 S.00 ^SO 4.00 S.50 3.00 ,’.50 0.00 (.50 (.00 IT

Figure A 3: NMR Spectrum of 23. HO. CH3O,

ro <0

8.00 7.907.00 6.90 6.00 9.90 9.00 4.90 4.00 3.003.90 2.00 t.SO 1.00 .90 PPM

Figure A.4: NMR Spectrum of 24. OH HO,

\J\

i.90 6.00 7.90 7.00 6.00 9.90 9.004.90 4.00 2.60 t.OO PPM

Figure A.5: NMR S pectrum of 25. OH

26

ro

a.!to a.00 7.00 7.oo a.oo e.oo o.oo e.oo 4.00 4,00 9.00 9.00 2.00 2.00 1.00 1.00 .00 0.0 PPM

Figure A.6 : NMR Spectrum of 26. ro ro

6.so 0.00

Figure A.7: NMR Spectrum ol 27. to w

.90 a.oo 7.50 7.00 0.50 0.00 9.90 9.00 4.90 4.00 3.90 PPM

Figure A.8: NMR Spectrum of 28. I l I ’ I ■ I ...... W 6 00 7.60 7.00 .60 6.00 6.60 5.00 4.60 4.00 3.50 3.00 2,00 2.00

Figure A.9: NMR S pectrum of 29. OH

ro O l

.90 8 .0 0 7.00 6.90 6.00 9.00 4.00 3.50 3.00 2.50 2.00 1.90 ).00 .90 0.0

Figure A.10: NMR S pectrum of 30. OH HO,

ro

90 00 90 9.00 4.00 a.oo 2.00 PPM 1.00 .90

Figure A.11: '•h NMR Spectrum of 31. r ~ \

1.90 6.00 7.90 7.00 6.90 6.00 9.90 9.00 4.00 3.90 3.00 2.90 2.00 1.90 1.00 .90

Figure A.12: NMR S pectrum of 33. /—\

ro 00

T-- .90 e.oo 7.90 7.00 6.90 6.00 9.90

Figure A.13: NMR Spectrum of 34. r ~ \ 0

35

K)

CO

.50 6.00 7.90 7.00 6.90 6.00 9.90 9.00 4.90 4.0 0 3 .9 0 3.00 1.90 1.00 PPM

Figure A.14: NMR Spectrum of 35. ro

I • I 6.50 6.00 7.50 7.CO 6.50 6.00 5.50 5.00 4.50 4.00 9.50 9,00 2.50 .50 0.0 PPM

Figure A.15: NMR Spectrum of 36. ro ro

.90 8.00 7.90 7.00 6.90 8 .0 0 9.90 9.00 4.90 4.00 9.90 9.00 2.90 2.00 1.90 1.00 PPM .90

Figure A.16: NMR Spectrum of 37. U i

Figure A.17: NMR Spectrum of 38. OH HO.

ro ro

—1— t ' I a. 50 a. 00 7.5 0 T joT" 6.50 6.00 5.50 5.00 4 50 3.&0 2.50 2.00 1.50 1.00 .50 0.0 PPM

Figure A.18: NMR Spectrum of 39. HO

ro K>

\}J

■ I ' ■ ' ' T ~ ' I I ' ■ I I $.50 a.00 7.so 7.00 6.90 6.00 9.90 9.00 4.90 4.00 3.90 3.00 2.90 PPM

Figure A.19: NMR Spectrum of 40. HO.

41

ro ro ui

"I"' "I" ^ I ■ I ------• I I I.SO 0.00 7.so 7.00 6 . so 6 .0 0 S.SO 4.80 4.00 3.SO 3.00 2.SO PPM

Figure A.20: NMR S pectrum of 41. IV} o>IV)

B.SO 6.00 7.60 7.00 6.90 6.00

Figure A.21: NMR Spectrum of 42. OH HO,

ro

"I ' ' 1---- r ' "I"' ^ i • I r 6.90 6.00 7.90 7.00 6.90 6.00 5.90 9.00 4.90 4.00 3.90 3.00 2.90 2.00 .00 0.0 PPM

Figure A.22: NMR Spectrum of 43. HO PH

ro ro 00

6.00 7.50 7.00 6.506.00 5.50 5.00 4.50 4.00 3.50 3.00 2.00 l.SO 1.00 .50 0.0 PPM

Figure A.23: NMR S pectrum of 44. n

ro ro (O

I...... I " '— n I—...... I...... r " 90 a . 00 7.00 6.90 6.00 9.90 9.00 4.90 4.00 9 .9 0 9 .0 0 9 .6 0 PPM

Figure A.24: NMR Spectrum of 45. ■•w ^

I — — r - ■ ...... "T 1 " so 0 .0 0 7.80 7.00 8.80 "Too" 8.80 8.00 4.80 4,00 a.so 3,00 1.00 .80 0,0 PPM

Figure A.25: NMR S p ectru m of 46. f ~ \ .OH OH

ro CO

9.00 7.50 7,00 6.00 9.90 9.00 4.00 3.90 9.00 2.90 2.00 1.90 1.00 .90 0.0

Figure A.26: NMR S pectrum of 47. OH OH

ro ro

8.00 7.90 7.00 6.906.00 9.90 9.00 4.00 3.90 3.00 2.00 1.90 1.00 .80 0.0

Figure A.27: NMR Spectrum of 48. n

W

6.00 7.90 7.00 6.90 €.009.90 9.00 4.50 4.00 9.90 3.002 .0 0 1.90 1.00 .90 0.0 PPM

Figure A.28: NMR Spectrum of 49. ro w

"T I.so B.OO 7.50 7.00 6.50 6.00 5.50 5.00 4.50 4.00 3.50 3.00 2.50 1.00 .50 0 .0 PPM

Figure A.29: NMR Spectrum of 50. APPENDIX B

CHAPTER 4 1H NMR SPECTRA

235 OH

f-Bu

ro CO

4 5 0 00 f 'I 'N

Figure 8.1: NMR S pectrum of 4, /■Bu

8 00 ) 50 ’00 6 50 6 00 3 90 4 30 4 00 J.90 3 00 2 90 2 00 | 90 0 0 PPM

Figure B.2: NMR S pectrum of 5. .OTBDMS

f-Bu

00

e 00 7 9 0 7 0 0 6 9 0 6 00 4 9 0 4 0 0 3 9 0 3 00 ? 9 0 PPM ? 00

Figure 8.3: NMR Spectrum of 7. q t b d m s .0

s (O

A

5 50 ■n— 5 0

Figure B.4: NMR Spectrum of 8. OH

/-Bu

ro o

50 e 00 > "0 7 00 6 50 6 00 5 50 5 00 4 50 4 00 3 50 3 00 ? 50 2 00 I 50 1 00 50 0 0

Figure B.5: NMR Spectrum of 14. OTBDMS

f-Bu

SO SO 00 so 00 4 . 0 0 3 .so 3.00 2.50 2.00 l.SO 1.00 PPK .SO 0.0

Figure B.6 : NMR Spectrum of 15. f-Bu

lO ro

— I— ''I' 1 so 7 0 0 6 SO s so 4 so PPM

Figure B.7: NMR Spectrum of 17. ,0H

f-Bu

ro A CO

—"T—' 7 . 0 0 4 5 0 PPM

Figure 8.8: NMR Spectrum of 18. yOBn

f-Bu

5 0 8 00 6 5 0 6 00 5 5 0 5 0 0 4 0 0 3 5 0 3 00 ? 5 0 2 no

Figure B.9; NMR Spectrum of 21. ..•OBn

/-Bu

ro

DU ï B.OO 7 5 0 6 5 0 6 00 5 5 0 5 0 0 4 50 4 0 0 3 5 0 3 00 2 5 0 2 00 5 0 PPM

Figure 8.10: NMR Spectrum of 22. PH

f-Bu

O)

>00 0,00 VA" 4 . 0 0 1 . 00 t.o o t.to 00

Figure B.11: NMR Spectrum of 24. .IA à u AL

. -1 I .. J . JI. . .. .1 J ' r , ...... 1------1 I ' » r ■ y * 00 8 30 e 00 P 5 0 # SO 1.00 3 30 3.00 4.30 4.00 3 30 1 00 * 30 * 00 1.30 1.00 .30 0 0

Figure B.12; NMR Spectrum of 25. 26

ro 00

I J _____

t 00

Figure B.13: NMR Spectrum of 26. K..-V'

ro ■u (O

7 50 7 00 6 00 4 5 0

Figure B.14: NMR Spectrum of 27. .OH ,0 H

/-Bu

7.50 7.00 6.50 6.00 5 .5 0 5 .0 0 4.50 4.0 0 3 .5 0 3.0 0 2 .5 0 2.00 *.80 1.00 .50 PPM 0.0

Figure B.15: NMR Spectrum of 20. OH pH

/-Bu

ro Ol

Figure 8.16: NMR Spectrum of 30. . OH X . _,0 H

ro ui ro

I

—1— 50 e 00 » 5 0 7 0 0 5 5 0 4 5 0

Figure B.17: NMR Spectrum of 31. PH PH "CHa

f-Bu 33

to Ü1 CO

J t I

1------r* — 50 6 GO ? 50 ? 00 6 50 6 00 5 50 5 00 4 5 0 4 00 3 50 3 00 PPM

Figure B.18: NMR Spectrum of 33. "CH:

1 so 7 00 6 50 6 00 5 50 5 00 4 00 3 50 3 00 PPM ? 50 ? 00 I 50

Figure B.19: NMR Spectrum of 34. p H ..OH

CH3

f-Bu 35

cn 01

jL ______

a 508 00 7 50 6 50 6 00 5.50 5 00 4 50 4 003 50 3 00 2 50 2 00 .50 PPM

Figure 8.20: NMR Spectrum of 35. /-Bu 36

ro cn o>

/ I jdLJLJ uV*JV_

-TT-. ^ .1 . y J ■...... , J - ' I ...... 1— r ~ r^ 0 6 00 ? 50 7 00 6 50 6 00 5 50 0 00 4 0 0 3 50 3 00 2 so 2 00 so 0 0 PPM

Figure 8.21: NMR Spectrum of 36. ro ui •sj

6 5 0

Figure 8.22: NMR Spectrum ot 37. APPENDIX C

CHAPTER 5 NMR SPECTRA

258 OH f-Bu

ro cn

— r — " T " " ”T^ ~T" 0 CO 0 30 1.00 ;)o I 00 1.30 1.00 0 .0 0 4.00 3 .0 0 3 00 1 .3 0 3 00 1.30 1.00 .30 0.0

Figure C.1: NMR Spectrum of 3. f-Bu

O

— ■•"1 "I" • OQ 1.00 4 . 0 0

Figure C.2: NMR Spectrum of 4, HO, 'v / V ^ O A c

12

ÉlÀ __

% CD • 00 TOO t 00 9 . 9 0 9 00 t 00 J . 9 0 ) 00 t.oo 1.00 9 0

Figure C.3; NMR s|>ectrum of 12. OAc a 13

I

9 00 • 00 I so I 00 ) so }.eo f.OO

Figure C.4; NMR Spectrum of 13. ro o> w

u u V ~ ~ r ~ " I >10 oo

Figure C.5: NMR Spectrum of 14. to 2

A J L ^ U L

V Ï -T^ — ; s 9 I.OQ to 0 0

Figure C.6: NMR bpectrum of 5. OH

OH f-Bu

ro cn cn

0 9 0 0 00 1.0 0 9 .so 4 . 0 0 2 .so 2.00 I.SO 1.00

Figure C.7: NMR Spectrum of 15. HQ

'"OH f-Bu

— P - 9 00 0 &0 0 00 >00 700 $ tO 0.00 0 00 0.00 ) 00 1 09 > 0 0 1.00 1.90 1.00 0 0

Figure C.8; NMR Spectrulm of 16. OH /-Bu

* 6 0 0 .0 0 0 00 f .e o 9 .0 0 4 . M 4 . 0 0 t o e i . s e 1.00

Figure C.9: NMR Spectrum of 17. /-Bu

f 1.00 I 50 6.00 9 9 0 9 . 0 0 4.00 9 90 9 00 9.90 9.00 1.90 % .00 90 0 0

Figure C.10: NMR Spectrum of 18. f-Bu

« 00 f 00 ft 00 9 . 9 04 SO 1 9 0 ?.oo 1 . 9 0 t.oo

Figure C.11; NMR Spectrum ol 19. APPENDIX D

CHAPTER 6 '■ h NMR SPECTRA

270 9 0 0 e 90 • 00 7 . 9 0 1.0 0 6.00 9 . 0 0 4 . 0 0 9 00 }.eo I 0 0

Figure D.1: NMR Spectrum of la. HO

OMe 1b

IV>-si ro

■ L _

t Q9 • 9 9 1.09 I.M ? . 9 0 I.M I.QO ? 00 . 9 0

Figure D.2: NMR Spedtrum of 1b. ro CO

A----

9 0 0 e 00 6.00 6 .0 0 4 . 6 0 4 . 0 0 9 . 6 0 *00 1.00

Figure D.3: NMR Spectrum of 1c. H i

Me

|N«-UM'J| ( • m ja

K .. i

IM:.. iiitiii

Figure D.4: NMR S pectrum ol Id . HO

CN le

e w 6 .0 0 ) CO 4 . 0 0 1 .00

Figure D.5: NMR Spectrum of 1e. ro O)

.00 8 80 9 00 4 4 00 ) 50 9 9 0 9 00

Figure D.6: NMR Spectrum of 6 c Me 7a Ac

ro 'O

\ L. ..I

9 to • to « CO ? 50 1.09 5 50 6.00 5 50 5.00 4 00 5 .5 0 3 00 1 .5 0 1 .0 0

Figure D.7: NMR Spectrum of 7a. Me

ro 's i 00

»«« I'w ' «.«» 1,#»j.'m *.w •.» ».'«» ».'*» »« *.'» >.'»»

Figure D.8: NMR Spectrum of 7b. Me 10

(O

.00 .00 9 00 >.00 > 00 00

Figure D.9: NMR Spectrum of 10. HO

Me 11 r Ac INi IMMI I • M« l«

K O

0 00 0 .0 0 *50 Figure D.10: NMR Spectrum of 11. s

Figure D.11: NMR S pectrum of 13. CN

S ro

UL

9 00 0 50 ? 00 0 50 Too 5 00 1 ..W ) 00 I 00

Figure D.12: NMR Spectrum of 14. ro 00 w

lU L

9 CO 0 9 0 0 00 00 00 4 . 0 0 } 00 i 00

Figure D.13: NMR Spectrum of 15. HO

H 16

9 0 0 0 00 ) 00 t 00

Figure D.14: NMR Spectrum of 16. HQ HO

H 17

00ro ui

9 CD 0 5 0 ) 00 ? 00

Figure D.15: NMR Spectrum of 17, °Vo.

8 0>

0 .0 0 0 5 00 00 5 . 0 0 ] 9 0 ) 00 t 00 1 .00

Figure D.16: NMR Spectrum ol 10. lO 00 ■vj

y 00 a 00 0 00 «00 3 00 ] 00

Figure D.17; NMR Spectrum of 19. HO. y HO

OMe 20

s 00

Figure D.18; NMR Spectrum of 20. OMe

N> CO to

!..

— I— « 0 0 3 00 3 00 ; .) o ? 00 i to i oo 0 9 0 I QO } 40 I 04 0 00 0 00 U 0 0 0 00

Figure D.19: NMR Spectrum of 21 V o ,

OMe

/

ro to o

4 _ i i L ___

9 0 3 0 5 0 6 . 0 9 5 00 3 00 2 00

Figure D.20: NMR Spectrum of 22. OMe 23

JüV ___ , -A,._ ..>v

— I— —r" — I.M 6.00 ) 60 0 0

Figure D.21: NMR Spectrum of 23. H O , y

ro

0 OC 0 00 6 00 3 50 00 ? 00) 1 .5 0 .5 0

Figure D.22; NMR Spectrum of 24. HO, HO

Br 25

8 00

7 . 0 0 » 50 6 00 3 9 0 ? 9 0 7 00

Figure D.23: NMR Spectrum of 25. o V o . , - /

Br 26

% A

VIL I 9 00 Q ao • 00 I 00 ).00 & 50 6.00 0 50 9.00 4.00 3 50 3 00 > 90 9 00 I 90 I 00 50 0 0

Figure D.24: NMR Spectrum of 26. en

A f%

"'T'" I " '•-I'" 9 0 0 0 ) 0 0 00 y 00 r 00 o oo o oo o oo o.oo 4 00 I 00 I 00 00 0 0

Figure D.25: NMR S pectrum of 27. HO,

,Mé

(major)

I 00 4 00 ) 50 ? 50 } 00 0PM ) 00

Figure D.26: NMR Spectrum of 28. HQ HO,

Me 29 (major)

9 00 # SO • 00 1 00 S 00 ) so ) 00 » 00 I'I'M

Figure D.27: ^ H NMR Spectrum of 29. ,.Me

00

■ ’ I - - . • ,T- ' -1 .r% - - ■ - ,1 . - J t ■ , - t I - , - * 00 » 59 t.OP 7.50 7.00 5.50 6.00 5.50 5.00 4.50 4.00 3.50 3 00 f 50 f.OO I 50 I 00 50 0 0 PPM

Figure D.28: NMR Spectrum of 30. .Mé 31 Ac

ë (O

9 00 0 00 I 00 > 00 7.00 0.00 0 00 0.00 0.00 ^ 0 }.Q0 I >P ^ "7 Vo 'w 0 0

Figure D.29: NMR Spectrum of 31. HO. > HO

ON 32

0» o o

a.JO «.00 ) 00

Figure D.30: NMR Spectrum ol 32. HO

CN 33

w o •A

00 90 0 0 .00 00 8 00 0 .9 0 0.00 6.00

Figure D.31: NMR Spectrum of 33. V o .

W o ro

Jll------

•"'r* I" > 00 0 0 0 0 0 0.00 1.00 *00 0 00 0 .0 0 Figure D.32: NMR Spectrum of 34. CN 35

u

fU J

i CO t.0 9 9 00 • 0 0 6 SO 6.00

Figure D.33: NMR S pectrum of 35. APPENDIX E

STRUCTURAL ELUCIDATION

AND

ADDITIONAL SPECTRA

(CHAPTER 3-6)

304 24

m##i w o tn

###ft t I # # i # # #

MO >10 >00 190 190 170 190 190 HO 1:0 l>9 110 100 90 90 70 90 90 40 90 >0 10 0

Figure E.1: NMR + DEPT Spectrum of 24. HO

24

w o 0)

...... — ' I "...... y . . . - > T > . . . | q . , . . , . . . . , f . . . 2K )»: \l« t)l tu tu 140 1)9 129 M9 199 90 10 29 99 90 9 99 20 19 (

Figure E.2; Long Range Seml-Selectlve DEPT of 24, Irradiation ol H-2. HO, %

J

CO o ■vl

• .0 0 .8 Y1.0 4.',0 1.0 1.1 TÎT Figure E.3: COSY 90 Spectrum of 37 (CDCI 3 ). J l j J ü i 1 . 1 . • ■ • @ (MQB G#- ill. •! “ .. ©• S W ® '

a 0B9KD w o @ o 00 ■B (B o # ni m

m a * ' T

a D m a a

•1 II m. ffi 9 ■

Figure E.4: JH COSY 90 Spectrum of 38. OH

s t 111 38

1 n r r sw

nÉ 'W i ■»» » i » r V *rWe*#wn**rr«##eK

too w W 10 00 «0 «0 >0 10

Figure E.5: NMR + DEPT Spectrum of 38. 11

w o

270 210 300 ttO 100 110 160 160 MO 1)0 130 110 100 00 10 00 40 M 30 10 0

Figure E.6 : Long Range Seml-Selectlve DEPT of 38, Irradiation of H- 6 a. CO

L t.O

Figure E.7: COSY 90 Spectrum of 42. I

TPT

CO ro

#L

*20 210 200 100 100 170 100 100 140 170 120 110 100 00 00 70 00 50 40 20 20 10 0 PPM

Figure E.8 : NMR + DEPT Spectrum of 42. G)

CO

ISO Jto 1 7 0 1 0 9 1 4 0 1 9 0 120 100

Figure E.9; Long Range Semi Selective DEPT of 42, Irradiation of H 6a. f-Bu

Ail__

00 A,

OB.e

"I, ' ' ' * I ' * » * I * » • "’ 'I * » * » J * ' • • I

Figure E.1 0 : COSY 90 Spectrum of 7. OTBDMS .0

f-Bu

-_JL A j \ à a fUL.. J i ^

■ h . —... : X

• 0 « ) ' I • Û • • ' h - * » o' '

CO - en i • f « ! 0 ' 1 W m ' 0 t|ln> S ' S « « ' # : 0 • # *10 mati ' 1 S3 . am . a

; ■

1.»

ea • CD 111 m

40 3 t 3 0 >0 }0 1.5 10 5 00

Figure E.11: JH COSY 90 Spectrum of 8. PH PH

/-Bu 28 J l J

1.9 M m» u mm i.i 05

1.9

4.9

9.9

9.9

■pr I 'I I »'■» I I ' 1 iTo’ 1.9 1.9 Figure E.12: COSY 90 Spectrum of 28. • ^ m : • 1 • • " @>l

f B W • mSm w / # w 8 g m 'si

0 m m . /

.. .

o p OB ■ . «

B 0 B8 #-

' ' * * ' ' ' I ' ' ' ' I ' ' ' ' I ' ' » *'\ ' I » 1111 » » 111111 » 11 i 111111 »» 1.0 O.e 9.0 4.9 4.0 1.9 1 0 1.9 1.0 1.9

Figure E.13: ^HjH COSY 90 Spectrum of 30. PH

,PH.

I If* / •• ' /

*. I It r.y rt • t w Up iti **r Ww 00

f Tfl u

'1 —r- 9 * 99 I Q Figure E.14: COSY 90 Spectrum of 35. PH

f-Bu

V— i CO a>a CO

/ 9 r h 4#

I I ' I ■ 1 ' '* I ' » I ■■f I ■- — I— '' f f f 0 II 16 pfn ] \ 77 1.0 Figure E.15; COSY 90 Spectrum of 36. pH

COro o

130 ilO "« '«0 10 ,, ,« w Figure E.16: Correlation Spectrum of 36. COfO

ilO it9 200 190 190 170 160 160 140 190 |2Q 110 100 90 00 70 60 00 40 90 20 PPM

Figure E.17: Long Range Semi Selective DEPT of 36, Irradiation of H 6 a. OH

OH f-Bu A j

] o CD u ro M

9 9 9 0 3 9 4 0 ) 0 }.9 I 9 I 0 Figure E.18: COSY 90 Spectrum of 15. HQ

OH f-Bu 16

w M U

p

9 9 0 4 9 4 0 ) 9 9 0 ? 9 I 0 t 9 I 0

Figure E.19: IrJ h COSY 90 Spectrum of 16. roCO A

120 110 too

Figure E.2 0 : Correlation Spectrum of 16. "OH

w ro in

"I”” l?0 no 90 BO ?0 50 40 )0 70

Figure E.21; Long Range Semi-Selective DEPT of 16, Irradiation of H-6a. 51 3

w fO o>

■'-r' 210 200 190 190 |?0 160 1)0 |«Q |30 120 HO iOO 90 0

Figure E.22: Long Range Semi Selective DEPT of 16, Irradiation of H-2a. I., il I i À k /

0 0 □ □ □ :P EB Bia w C3) a fO O G3 □ □ -g

• B o @5 ft 0 e *> 'A ^ o o

e a p " o '

T-I-T- ft 5 & 0 « 3 40 ’’•I 3 0 ft ft ft 0 I ft

Figure E.23: COSY 90 Spectrum of 18. , Il Ml H 19

w ro 0 3

...... ' ' I » ■ t ■ I I I I » I I t » f I I 8.9 8.0 4,8 ^0 8 8 1.0 2.8 Figure E.24: ^H.^H COSY 90 Spectrum of 19. BIBLIOGRAPHY

Paquette, L. A. In Green Chemistry: Fontiers in Benign Chemical Synthesis and Processing; Anastas, P; Williamson, T., Eds.; Oxford University Press: Oxford 1998.

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Paulmier, C. Selenium Reagents and Intermediates in Organic Synthesis, Pergamon: New York, 1986; p 353.

Organoselenium Chemistry, Liotta, D. C. Ed.; Wiley-lnterscience: New York, 1987.

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Tanaka, H.; Yamashita, S.; Hamatani, T.; Nakahara, T.; Torii, S. In Recent Advances in Electroorganic Synthesis, Torii, S. Ed.; Elsevier: New York, 1987; p 307.

Whitaker, K. S.; Whitaker, D. T. In Encyclopedia of Reagents for Organic Synthesis, Paquette, L. A. Ed.-in-Chief; John Wiley & Sons, Inc.: Chichester, 1995; Vol. 5, p 3390.

330 Carey, F. A.; Sundberg, R. J. Advance Organic Chemistry: Part A, Structure and Mechanisms, Plenum Press: New York, 1990; p 197-209.

Lowary, T. H.; Richardson, K. S. Mechanism and Theory in Organic Chemistry, Harper & Row: New York, 1987; p 142-151.

March, J. Advanced Organic Chemistry, John Wiley and Sons, Inc.: New York, 1992, p 17.

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