β-Acryloyloxysulfonyl Tethers for Intramolecular Diels-Alder

Cycloaddition Reactions

A dissertation submitted

to Kent State University in partial

fulfillment of the requirements for the

degree of Doctor of Philosophy

by

Natasha Chumachenko

November 2005

Dissertation written by

Natasha Chumachenko

M.S., Lviv Polytechnic Institute, Ukraine, 1984

Ph.D., Kent State University, 2005

Approved by

Dr. Paul Sampson, Chair, Doctoral Dissertation Committee

Dr. Roger Gregory, Members, Doctoral Dissertation Committee

Dr. Alexander Seed

Dr. Brett Ellman

Dr. Laura Leff

Accepted by

Dr. Roger Gregory, Chair, Department of Chemistry

Dr. John Stalvey, Dean, College of Arts and Sciences

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TABLE OF CONTENTS

LIST OF SCHEMES...... VI

LIST OF FIGURES ...... XI

LIST OF TABLES ...... XII

ACKNOWLEDGMENTS ...... XIII

LIST OF ABBREVIATIONS AND DEFINITIONS ...... XV

1. INTRODUCTION...... 1

1.1. GENERAL ...... 1

1.2. CYCLOADDITION REACTIONS OF SULFONYL DIENES...... 9

1.2.1. CYCLOADDITION OF 1-SULFONYL-1,3-DIENES...... 9

1.2.2. CYCLOADDITION OF 2-SULFONYL-1,3-DIENES...... 15

1.2.2.1. Synthesis and Diels-Alder dimerization of 2-sulfonyl-1,3-dienes...... 15

1.2.2.2. Diels-Alder cycloaddition reactions of 2-sulfonyl-1,3-dienes...... 21

1.2.2.3. Diels-Alder cycloaddition reactions of heteroatom-substituted 2-sulfonyl-

1,3-dienes ...... 36

1.2.3. CYCLOADDITION OF DISULFONYLATED 1,3-DIENES ...... 41

1.3. DIELS-ALDER REACTIONS EMPLOYING DISPOSABLE TETHERS...... 54

2. SYNTHESIS OF Β-HYDROXY SULFONE-BASED TETHERS FOR

INTRAMOLECULAR DIELS-ALDER CYCLOADDITION REACTIONS ...... 60

2.1. SYNTHESIS OF β-HYDROXY SULFONES via EPOXIDE OPENING WITH

ZINC SULFINATES IN AQUEOUS MEDIA...... 60

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2.1.1. GENERAL ...... 60

2.1.2. SYNTHESIS OF SIMPLE ZINC SULFINATES AND THEIR REACTIONS

WITH EPOXIDES ...... 67

2.1.3. EPOXIDE OPENING WITH ZINC (Z)-1,3-BUTADIENYL SULFINATE

(195) ...... 72

2.2. SYNTHESIS OF β-HYDROXY SULFONES via COUPLING OF ...... 88

SULFINATE ANIONS WITH -BROMO KETONES FOLLOWED BY

REDUCTION...... 88

2.3. ESTERIFICATION OF β-HYDROXY SULFONES...... 91

3. DIELS-ALDER CYCLOADDITION REACTIONS OF Β-

ACRYLOYLOXYALKYL BUTADIENYL SULFONES...... 100

4. SOME SYNTHETIC TRANSFORMATIONS OF THE OBTAINED DIELS-

ALDER CYCLOADDUCT 223D...... 115

5. CONCLUSIONS ...... 122

6. EXPERIMENTAL SECTION ...... 125

6.1. GENERAL ...... 125

6.2. SYNTHESIS OF β-HYDROXY SULFONES via EPOXIDE OPENING WITH

ZINC SULFINATES IN AQUEOUS MEDIA...... 128

6.2.1. SYNTHESIS OF SIMPLE ZINC SULFINATES AND THEIR REACTIONS

WITH EPOXIDES ...... 128

6.2.2. EPOXIDE OPENING WITH ZINC (Z)-1,3-BUTADIENYL SULFINATE

(195) ...... 139

iv

6.2.3. SYNTHESIS OF β-HYDROXY SULFONES via CONDENSATION OF

SULFINATE ANION WITH -BROMO KETONES FOLLOWED BY

REDUCTION...... 153

6.2.4. ESTERIFICATION OF β-HYDROXY SULFONES ...... 159

6.3. INTRAMOLECULAR DIELS-ADER CYCLOADDITION OF -ACYLOXY

SULFONES 215a-d, 216a-d AND 217b,c...... 168

6.4. SOME SYNTHETIC TRANSFORMATIONS OF THE OBTAINED DIELS-

ALDER CYCLOADDUCT 223d...... 184

7. REFERENCES...... 194

v

LIST OF SCHEMES

Scheme 1. Synthesis and DA dimerization of 1-sulfonyl cyclopentadienes from sulfenyl

chlorides...... 10

Scheme 2. Synthesis and DA dimerization of 1-sulfonyl cyclopentadienes from sulfonyl

bromides ...... 11

Scheme 3. Synthesis of 1-sulfonyl-5,5-dimethyl-cyclopentadienes 25a-c ...... 12

Scheme 4. Diels-Alder reactions of 1-sulfonyl-5,5-dimethyl-cyclopentadiene 25c ...... 13

Scheme 5. Diels-Alder reactions of 3-p-tolylsulfonyl-2-pyrone 31...... 13

Scheme 6. Diels-Alder reaction of 3-p-tolylsulfonyl-2-pyrone 31 in the presence of

Yamamoto's "MAD" Lewis acid...... 14

Scheme 7. Diels-Alder reactions of 3-p-tolylsulfonyl-2-pyridones 35...... 14

Scheme 8. Dimerization pathways of 2-sulfonyl-1,3-dienes ...... 16

Scheme 9. Synthesis and dimerization of 2-p-tolylsulfonyl-1,3-diene 38...... 17

Scheme 10. Synthesis and dimerization of 2-phenylsulfonyl-1,3-diene 43...... 17

Scheme 11. Synthesis and dimerization of 3-methyl-2-phenylsulfonyl-1,3-diene 48 ...... 18

Scheme 12. Synthesis of 2-sulfonyl-1,3-dienes by Julia coupling...... 19

Scheme 13. Backvall synthesis of 2-sulfonyl-1,3-dienes by sulfonylmercuration-

elimination sequence ...... 19

Scheme 14. Backvall synthesis of 2-sulfonyl-1,3-dienes by selenosulfonation-oxidation

sequence ...... 19

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Scheme 15. Synthesis and dimerization of 4-alkyl-2-sulfonyl-1,3-diene 52 by Hoffmann

method...... 20

Scheme 16. Dimerization of 2-acyl-4-alkyl-1,3-dienes 56 ...... 21

Scheme 17. Diels-Alder reactions of 2-p-tolylsulfonyl-1,3-diene 38 with electron

deficient dienophiles ...... 23

Scheme 18. Diels-Alder reactions of 2-phenylsulfonyl-1,3-diene 43...... 24

Scheme 19. Diels-Alder reactions of 2-phenylsulfonyl-1,3-diene 52a ...... 25

Scheme 20. Diels-Alder cycloaddition of 2-phenylsulfonyl 1,3-dienes with 1-indolyl

magnesium iodide ...... 28

Scheme 21. Two possible mechanisms of DA cycloaddition of 2-phenylsulfonyl 1,3-

dienes with 1-indolyl magnesium iodide ...... 28

Scheme 22. Diels-Alder cycloaddition of 2-phenylsulfonyl 1,3-dienes with 1-indolyl

magnesium iodide, substituted at C-2 or/and C3 ...... 29

Scheme 23. Diels-Alder cycloaddition of 2-phenylsulfonyl 1,3-diene with chiral enol

ethers ...... 30

Scheme 24. Diels-Alder cycloaddition of 2-phenylsulfonyl 1,3-dienes with chiral

enamine ...... 30

Scheme 25. Diels-Alder cycloaddition of chiral 2-phenylsulfonyl-1,3-dienes with N-

phenylmaleimide and phenyltriazolinedione ...... 31

Scheme 26. Cross Diels-Alder reactions of 2-phenylsulfonyl-1,3-dienes and Danishefsky

diene ...... 32

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Scheme 27. Cross Diels-Alder reactions of 2-phenylsulfonyl-1,3-dienes and

cyclopentadiene...... 32

Scheme 28. Cross Diels-Alder reactions of 2-phenylsulfonyl-1,3-dienes and 2,3-

dimethylbutadiene (81) ...... 33

Scheme 29. Cross Diels-Alder reactions of 2-phenylsulfonyl-1,3-dienes and 1,3-

cyclohexadiene (84) ...... 34

Scheme 30. Cross Diels-Alder reactions of 2-phenylsulfonyl-1,3-dienes and 6,6-

dimethylfulvene (88) ...... 35

Scheme 31. Cross Diels-Alder reactions of 2-phenylsulfonyl-1,3-dienes and

nonbornalidene (91) ...... 35

Scheme 32. Synthesis of 2,3-dihetero-substituted 1,3-dienes 94-96...... 37

Scheme 33. Synthesis of 2-(phenylseleno)-2-sulfonyl-1,3-diene ...... 39

Scheme 34. Diels-Alder reactions of 2-(phenylseleno)-2-sulfonyl-1,3-diene 106 ...... 39

Scheme 35. Synthesis and Diels-alder cycloaddition of (Z)-2-phenylsulfonyl-1-

trimethylsilyl-1,3-butadiene (110)...... 41

Scheme 36. Synthesis of 1,3-bis(phenylsulfonyl)-1,3-butadienes 114a-e ...... 42

Scheme 37. Condensation of 1,3-bis(phenylsulfonyl)-1,3-butadienes 114a-e with

enamines...... 43

Scheme 38. Synthesis of 1,3-bis(phenylsulfonyl)-1,3-butadiene (123)...... 44

Scheme 39. In situ synthesis of 1,3-bis(phenylsulfonyl)-1,3-butadiene (123)...... 44

Scheme 40. Synthesis of 2,3-bis(arylsulfonyl)-1,3-butadienes 131...... 45

Scheme 41. Condensations of 1,3-bis-sulfonylated diene 123 with enamines ...... 46

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Scheme 42. Condensations of 1,3-bis-sulfonylated diene 131a with enamines...... 47

Scheme 43. Condensations of 2,3-bis-sulfonylated diene 131a with imines...... 48

Scheme 44. Condensations of 1,3-bis-sulfonylated diene 123 with imines...... 48

Scheme 45. Condensations of 2,3-bis-sulfonylated diene 131b with imines...... 49

Scheme 46. Mechanism of the condensations of 2,3-bis-sulfonylated diene 131a with

imines ...... 50

Scheme 47. Condensations of 1,3-bis-sulfonylated dienes 114a,b with imines ...... 50

Scheme 48. [2 + 4] Cycloaddition of diene 123a with 1-diethylamino-1-propyne...... 52

Scheme 49. Intramolecular Diels-Alder reactions of vinylsulfonic acid derivatives with

carbocyclic 1,3-dienes...... 56

Scheme 50. Intramolecular Diels-Alder reactions of vinylsulfonic acid derivatives with

acyclic 1,3-dienes ...... 57

Scheme 51. Diels-Alder reactions employing a sulfonamide based tether...... 58

Scheme 52. Synthesis of 1-butadienyl β-hydroxyalkyl sulfones by condensation of (Z)-

butadienyl sulfinate anion with epoxides...... 61

Scheme 53. Synthesis of β-hydroxy sulfones from commercially available sulfonyl

chlorides ...... 68

Scheme 54. Condensation of epoxides with Zn (Z)-butadienyl sulfinate (195) obtained in

situ ...... 73

Scheme 55. Michael-type cyclization of (E)-β-hydroxypropyl dienyl sulfone 186b in the

presence of K2CO3 ...... 78

ix

Scheme 56. Condensation of epoxides with previously separated Zn (Z)-butadienyl

sulfinate (195) ...... 80

Scheme 57. Condensation of propylene oxide with previously separated Zn (Z)-

butadienyl sulfinate (195) in the presence of K2CO3 ...... 82

Scheme 58. Condensation of Michael adduct 201 with propylene oxide in the presence of

K2CO3...... 84

Scheme 59. (Z)/(E) isomerization of butadienyl sulfones...... 86

Scheme 60. Synthesis of β-hydroxyalkyl butadienyl sulfones from α-bromo ketones .... 89

Scheme 61. Esterification of β-hydroxy sulfones 186a-d ...... 93

Scheme 62. Proposed mechanisms for the reaction of dicyclohexyl carbodiimide with

acids...... 95

Scheme 63. Reaction of carbodiimides with alcohols catalyzed by CuCl and followed by

esterification...... 97

Scheme 64. Reaction of diisopropyl carbodiimide with (E)-b-(dienylsulfonyl) alcohol

186b in the presence of CuCl ...... 98

Scheme 65. Diels-Alder cycloaddition reactions of tethers 215a-d, 216a-d and 217b,c 101

Scheme 66. Base-mediated opening of DA cycloadduct 223d followed by methylation

...... 116

Scheme 67. Attempted iodolactonization of 227 and 228 ...... 117

Scheme 68. Epoxidation of 223d ...... 119

Scheme 69. Epoxidation of 228 ...... 120

Scheme 70. Chemical transformations of 233 ...... 120

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LIST OF FIGURES

Figure 1. "Normal" and "Inverse" modes of the Diels-Alder cycloaddition reaction...... 1

Figure 2. DA reaction of butadienyl sulfone and acrylate ester connected by a tether...... 2

Figure 3. Regioselectivity and endo-/exo-stereoselectivity issues in DA reactions...... 4

Figure 4. π-Facial selectivity and endo-/exo-stereoselectivity issues in DA reactions...... 6

Figure 5. Combined data for Diels-Alder reactions of methyl acrylate with 2-

sulfonyldienes 43, 96 and 106...... 40

Figure 6. Diels-Alder reactions of 2,3-ethylenedisulphonyl-1,3-butadiene 164...... 53

Figure 7. Examples of silicon- and boron-based tethers for Diels-Alder reactions ...... 55

Figure 8. Suggested preferred conformation of β-hydroxy sulfones 185b and 186b ...... 76

Figure 9. Four possible Diels-Alder products from the substrate 215b ...... 106

Figure 10. Transition states energies and geometries of the four possible Diels-Alder

products from the substrate 215b ...... 110

Figure 11. Calculated bond lengths in the major endo-1 transition state (A) and in 1-

methylsulfonyl butadiene (B)...... 111

Figure 12. Calculated charges in the major endo-1 transition state ...... 112

Figure 13. Calculated charges in 1-methylsulfonyl butadiene...... 113

Figure 14. Crystal structure of lactone 230...... 118

Figure 15. Suggested preferred conformation of b-hydroxy sulfones 185b-d, 186b-d,

189a-d, 190b,d, 201 and 202 and b-acyloxy sulfone products (215-218)...... 126

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LIST OF TABLES

Table 1. Diels-Alder reactions of 2,3-dihetero-substituted 1,3-dienes 94, 95, 96 ...... 38

Table 2. Intramolecular Diels-Alder reactions of vinylsulfonic acid derivatives with

acyclic 1,3-dienes ...... 57

Table 3. Regioselective Opening of Propylene Oxide Using Zn Sulfinates 188a-d ...... 69

Table 4. Preparation of Butadienyl sulfones 185a,b and 186a,b...... 75

Table 5. Esterification of (E)-β-(dienylsulfonyl) alcohols 186a-d to afford acrylate esters

...... 94

Table 6. Diels-Alder cycloaddition reactions of β-acryloyloxyalkyl butadienyl sulfones

215a-d, 216a-d and 217b,c ...... 103

Table 7. Base-mediated opening of DA cycloadduct 223d...... 116

Table 8. ∆ν/ JAB values for β-hydroxy sulfones 189a-d, and 190b,d...... 127

Table 9. ∆ν/ JAB values for β-hydroxy sulfones 185b-d, 186b-d, 201 and 202 ...... 127

Table 10. ∆ν/ JAB values for β-acyloxy sulfones 215b-d, 216b-d, 217b,c and 218d ...... 127

Table 11.Chemical shifts of H4a proton in cycloadducts 223-225 ...... 169

Table 12. ∆ν/ JAB values for cycloadducts 223-225 and decomposition product 226h .. 169

xii

ACKNOWLEDGMENTS

The author wishes to thank to Dr. Paul Sampson for being the most brilliant and hard working teacher I ever met, for his two outstanding organic chemistry courses and for his advise and useful suggestions which made the presented research possible.

The author acknowledges Kent State University for a University Fellowship and financial support.

The author thanks the members of the Organic Chemistry division at KSU, especially to Dr. Alex Seed for his help and his pleasant disposition and Alexander Semiyonov for always being there for me.

The author thanks Matthias Zeller and Allen D Hunter for the crystal structure determinations, Larry Mauer for making glassware, and Dr. Mahinda Gangoda for his assistance with nOe experiments and general NMR techniques.

The author wish to thank Diana Skok for her exceptional efficiency as a business manager, whish made all the problems on business part of my life in Kent unnoticeable.

I feel deeply thankful to Carol Haven for her efficiency as a graduate secretary and her heart of gold. I wish to thank Arla Dee McPherson for being a marvelous secretary and a most kind, tolerating and beautiful woman.

Last, but not least, the author wishes to thank her husband, Yehor Novikov, for the help in quantum chemical calculations, useful discussions, great chemical ideas, and most of all for his care, acceptance and psychological support. The author is deeply thankful to

xiii

her son, Serga Chumachenko, for his beautiful loving attitude, for taking an equal share in the housework, for his help in the preparation of this manuscript and for his cheer and the rare ability to understand.

xiv

LIST OF ABBREVIATIONS AND DEFINITIONS

Å angstrom (s)

Ac acetyl

Aq aqueous bp boiling point br broad (spectral)

BHT 2.5-di-tert-buthyl-4-methyl phenol-

Bn benzyl

Bu butyl t-Bu tert-butyl

ºC degree Celsius calcd calculated cm centimeter

δ chemical shift d day(s), doublet

DCC N,N’-dicyclohexylcarbodiimide

DEAD diethyl azodicarboxylate

DMAP 4-dimethylaminopyridine

DMF dimethylformamide

DMSO dimethyl sulfoxide

Et ethyl

GC gas chromatography

xv

h hour(s)

Hz hertz

IR infrared

J coupling constant

L liter(s)

LDA lithium diisopropylamide m multiplet, meter(s), milli

M moles per liter m-CPBA m-chloroperbenzoic acid

Me methyl

MHz megahertz min minute(s) mol mole(s) mp melting point

NMR nuclear magnetic resonance

Ph phenyl ppm parts per million

Pr propyl i-Pr isopropyl

Py pyridine q quartet quint quintet

xvi

Rf retention factor rt room temperature s singlet, second(s) sext sextet

SN1 substitution nucleophilic unimolecular

SN2 substitution nucleophilic bimolecular stereogenic center a tetrahedral atom bearing 4 different groups t triplet

THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilyl; tetramethylsilane

xvii

1. INTRODUCTION

1.1. GENERAL

The Diels-Alder (DA) reaction, i.e. the [4+2] cycloaddition of diene 1a,b and dienophile 2a,b, is one of the most powerful carbon-carbon bond forming processes

(Figure 1).1,2

Diels –Alder cycloaddition reactions fall into two major categories:

• “Normal” electron demand DA reactions - an electron-poor dienophile reacts with

an electron-rich diene. In this case the rate of the cycloaddition is increased by the

introduction of electron-withdrawing substituents on the dienophile and electron-

donating substituents on the diene.

• “Inverse” electron demand DA reactions – an electron-poor diene reacts with an

electron-rich dienophile. In this case the rate of the cycloaddition is increased by

the introduction of electron-donating substituents on the dienophile and electron-

withdrawing substituents on the diene.

Figure 1. "Normal" and "Inverse" modes of the Diels-Alder cycloaddition reaction

"Normal" electron demand cycloaddition "Inverse" electron demand cycloaddition

EDG EDG EWG EWG EWG EWG EDG EDG + +

Electron-rich Electron-poor Electron-poor Electron-rich diene (1a) dienophile (2a) diene (1b) dienophile (2b)

EWG - electron withdrawing group; EDG - electron donating group.

1 2

The simplest non-substituted diene (butadiene) is considered to be an electron-rich diene. If there are no substituents present in the dienophile (ethylene or acetylene), it is neither electron-poor nor electron-rich. As a result, the cycloadditions employing such dienophiles are usually very slow and are accompanied by polymerization processes.3

As one might expect, if both diene and dienophile are electron-poor (or if both of them are electron-rich), the DA cycloaddition reaction should be very slow or simply not occur at all. Indeed, this is often the case, however, the topic of this dissertation concerns the successful cycloaddition reactions of butadienyl sulfones (electron-poor dienes) and acrylate esters (electron-poor dienophiles) (Figure 2).

Figure 2. DA reaction of butadienyl sulfone and acrylate ester connected by a tether

O SO2 SO2 O O O +

Electron-poor Electron-poor diene dienophile

The fact that butadienyl sulfones do react with acrylate esters, albeit at rather high temperatures (100-130oC), has been known before. The detailed literature data about these transformations is presented in Part 1.2 of this Introduction. Regretably, organic chemistry theory at the moment cannot provide a rationalization for the observed reactivity. Our goal was not to provide such a rationalization, which would be the subject of a theoretical/computational investigation, but to develop a regio- and stereoselective variant of the DA cycloaddition of butadienyl sulfones and acrylate esters. Why?

Because, if the resulting cycloadducts could be obtained in a regio- and stereoselective

3

manner, they would represent useful intermediates for a variety of further transformations leading to other potentially useful products.

As will be shown in a moment, DA cycloaddition reactions can potentially result in a number of products, which differ in their regiochemistry (have different positions of substituents relative to each other) and their stereochemistry (have different orientations of substituents in space). In practice, this means that complex and often inseparable mixtures of different cycloadducts are frequently formed, which renders the process to be of little practical use. This was the case for the cycloaddition of butadienyl sulfones and acrylate esters before our work.

To achieve our goal, we connected the diene and dienophile with a potentially disposable sulfone-based tether. Using functional group-based disposable tethers is one of the known methods to improve the selectivity of DA cycloadditions. An overview of the different kinds of tethers developed to date is presented in Part 1.3 of this

Introduction. However, we are the first to employ a sulfone-based tether.

4

Figure 3. Regioselectivity and endo-/exo-stereoselectivity issues in DA reactions

1 1 R 1 R is a trans-substituent R2 R on the diene + 3 R R1 is 1c 2c a cis-substituent on the diene Different Regioselectivity Different endo-/exo- Different endo-/exo- Stereoselectivity Stereoselectivity R1 R1

R2 endo R2 endo 1 1 R2 R R2 R exo exo R3 R3 endo R3 endo R3 Diastereomers Diastereomers exo exo

R1 R1 R2 exo R2 endo 2 2 R exo R endo 3 3 R endo R exo 3 R3 endo R exo R1 R1 34 56

Let us examine the regio- and stereoselectivity of DA cycloaddition reactions. As can be seen from Figure 3, there are two possible regiochemical orientations of the diene 1c and the dienophile 2c. Furthermore, for each regioisomer, two stereo-isomers can be formed. These stereoisomers differ in the orientation in space of substituents R2 and R3 from the dienophile relative to the substituent R1 from the diene. If a dienophile substituent is syn- to the trans-substituent R1 on the diene, it is considered to be endo- oriented, while if a dienophile substituent is anti- to the trans-substituent R1 on the diene, it is considered to be exo-oriented.

5

When depicting the example given in Figure 3, we have arbitrarily chosen for the dienophile to approach from the bottom face of the diene. In reality, the probabilities that the dienophile would approach from the bottom or top face of the diene are the same; so another four compounds enantiomeric to 3-6 (mirror images of 3-6) will form in reality.

This means that each of compounds 3-6 will be formed as a racemic mixture (the mixture of two enantiomers). Because most chemical and physico-chemical properties of enantiomers are the same, for many purposes a racemic mixture is considered to be a

“clean compound”. However, in drug synthesis, the biological activity of the two enantiomers is usually different, so it is of utmost importance to be able to synthesize enantiomerically pure compounds (just one enantiomer). One of the ways to do this is to connect the diene and dienophile with an enantiomerically pure tether. Let’s discuss this possibility.

6

Figure 4. π-Facial selectivity and endo-/exo-stereoselectivity issues in DA reactions

R

1 * R R2 A + R3

Different π-Facial Selectivity

Different endo-/exo- Different endo-/exo- Stereoselectivity Stereoselectivity 2 1 1 R R R R 2 R R R R

R1 R1 R2 R2

exo-TS endo-TS exo-TS endo-TS

R R R R

1 1 1 1 R DiastereomersR Diastereomers R Diastereomers R R2 R2 R2 R2

7a 8a 9a 10a

R R R R

R1 R1 R1 R1 DiastereomersDiastereomers Diastereomers R2 R2 R2 R2

7b 8b 9b 10b

R

1 * R R2 ent-A + R3

7

If the diene and dienophile are connected by a tether, and if the tether is short enough

(3-5 carbon atoms), which is usually the case, only one of the two possible regioisomers can be formed. This decreases the number of possible cycloadducts by half - this regioisomeric outcome is depicted in Figure 4. If the tether is bearing a stereogenic center

(Figure 4), this stereogenic center will serve as “a reference” to distinguish between the bottom-face and the top-face of the dienophile’s approach, because the resulting bottom- face attack cycloadducts 7a and 8a will no longer be enantiomeric to the corresponding top-face attack cycloadducts 9a and 10a (now they are diastereomeric). In addition, the chirality of the tether can influence the stereochemical outcome of the reaction. Because all four compounds 7a-10a are diastereomeric and are formed through transition states of different energy, the rates of their formation would be different and, in principle, one of the compounds can often be formed predominantly and be separated as a clean product.

One enantiomer of the tethered DA substrate (A) affords cycloadducts 7a-10a, while its enantiomer (ent-A) will give the corresponding enantiomeric cycloadducts 7b-10b. As will be seen later, the DA cycloaddition chemistry described in this dissertation afforded clean endo-major products 8a/b. Because we were using a less expensive racemic tether, we obtained our products as racemic mixtures of 8a and 8b. However, the significance of the work is, that if enantiopure tethers are used (which would be straightforward – see later), the resulting DA cycloadducts would be produced in an enantiopure manner.

8

This dissertation will describe:

• how we prepared the DA cycloaddition substrates, with the diene and dienophile

tethered using a sulfonyl moiety - Chapter 2. While trying to prepare these

tethered DA precursors, we found a new way to synthesize β-hydroxy sulfones in

neutral aqueous media. The details of this work will also be given in Chapter 2;

• the details of the DA cycloaddition reactions of the tethered DA precursors -

Chapter 3;

• some further transformations of the obtained DA cycloadducts, which, indeed,

turned out to be very interesting synthetic intermediates - Chapter 4.

Before presenting details of this chemistry, however, it is necessary to describe the literature background for these areas of chemistry.

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1.2. CYCLOADDITION REACTIONS OF SULFONYL DIENES

Only very limited examples exist of cycloaddition reactions of 1-sulfonyl-1,3-dienes, while a rather more extensive literature exists for the analogous 2-sulfonyl-1,3-dienes. No review literature exists in this area. Therefore, a detailed review of the preparation and cycloaddition reactions of various sulfonyl-substituted dienes is presented.

1.2.1. CYCLOADDITION OF 1-SULFONYL-1,3-DIENES

Short overview: The available data about cycloaddition reactions of 1-sulfonyl-1,3- dienes are restricted to cyclic dienes and are too scarce to establish any reactivity trends.

Sulfonylcyclopentadienes 15a-d are extremely prone to DA dimerization – they prefer this dimerization pathway over Diels-Alder cycloaddition with electron-rich or electron- poor dienophiles. More sterically crowded sulfonylcyclopentadiene 25c reacts with some electron-deficient dienophiles at 120-130oC to form endo-cycloadducts. Interestingly, the reaction times increase with decreasing electron-deficiency of the dienophile. The reaction with methyl acrylate proceeds with 59/19 regioselectivity. No reaction was observed with methyl crotonate. DA cycloadditions of electron-rich dienophiles to sulfonyl-substituted 2-pyrone 31 and 2-pyridone 35 have also been reported, however, in these cases it is probable that the conjugated lactone/amide group rather than the sulfone group determines the diene’s reactivity.

Hartke and Gleim4 prepared sulfonylcyclopentadiene dimers 17a-c (Scheme 1).

Reaction of cyclopentadiene (11) with sulfenylchlorides 12a-c gave trans-β-chloro-

10

thiocyclopentenes 13a-c, which were oxidized with mCPBA to the corresponding chlorosulfones 14a-c. Alkylsulfonylcyclopentenes 14a,b spontaneously lost hydrogen chloride to give dicyclopentadienes 17a,b, presumably via 1-alkylsulfonyl-1,3-dienes

15a,b. Phenylsulfonylcyclopentene 14c was dehydrohalogenated with DBU to give dicyclopentadiene 17c, presumably via 1-alkylsulfonyl-1,3-diene 15c. Treatment of 14c with sodium hydride resulted in cyclopentadienide anion 16c, which was characterized by

1H NMR spectroscopy and gave 17c on acidification.

Scheme 1. Synthesis and DA dimerization of 1-sulfonyl cyclopentadienes from sulfenyl chlorides.

SO2R SO2R mCPBA o 17a (41%); R = Alk Et2O, -15 C, -HCl Cl 17b (43%) 2 h 14a,b 15a,b RSCl SR SO2R (12a-c) SO Ph CH Cl , 2 2 2 Cl NaH H+ CaCO3, 11-25 oC 13a, R = Me - (no yield given); 17a-c SO R 13b, R = Et (85%); 16c 2 13c, R = Ph (87%)

R = Ph SO2Ph SO2Ph mCPBA DBU o 51% Et2O, -15 C, Cl 2 h 14c (68%) 15c

Hartke et al also reported5 that addition of sulfonyl bromides 18a-d to cyclopentadiene

(11) yielded corresponding mixtures of cis- and trans-4-bromo-3-sulfonylcyclopentenes

19a-d and 20a-d (Scheme 2). On treatment with sodium hydride, 19a-d and 20a-d were converted into the sodium sulfonylcyclopentadienides 16a-d. By cation exchange, more stable salts 21 were obtained. Protonation of 16a-d and 21 was intended to result in sulfonylcyclopentadienes 15a-d, however, dienes 15a-d are unstable and tend to form

11

Diels-Alder dimers 17a-d immediately. Only 1-(phenylsulfonyl)cyclopentadiene 15c could be intercepted in a low yield and characterized by analysis and spectroscopy.

Scheme 2. Synthesis and DA dimerization of 1-sulfonyl cyclopentadienes from sulfonyl bromides

+ RSO2Br SO2R SO2R SO2R Na (18a-d) NaH + - CCl4, Br Br 80 oC 11 19a, R = Me (traces); 20a, R = Me (94%); 16a-d 19b, R = Et 43% (19b+20b); 20b, R = Et; MX, 19c, R = Ph (74%); 20c, R = Ph (ca 4%); -NaX 19d, R = p-Tol (56%) 20d, R = p-Tol (24%)

SO2R + SO2R SO2R M + H - 17a-d 15a-d 21 SO2R + + + + M = (AsPh4) for R = Me (61%); M = (NEt4) for R = o-Tol (100%); + + + + M = (NEt4) for R = Ph (100%); M = (PPh4) for R = o-Tol (93%) + + M = (PPh4) for R = Ph (88%);

Bridges and Fischer6 separated diene 15c in 85% yield by dissolving chlorosulfone

14c in 2.5M sodium hydroxide followed by acidification with HCl and extraction with ether. The diene 15c is a crystalline solid, which fully dimerizes in the solid phase after

16 h at -20 oC. Bridges and Fisher attempted to achieve Diels-Alder cycloaddition of diene 15c with N-phenylmaleimide, N-phenyldihydrotriazoledione and ethoxyethylene, however, only dimer 17c was obtained in all cases.

In 1988 Miller and Ullah described7 the synthesis of 1-sulfonyl-5,5-dimethyl- cyclopentenes 24a-c via ZnCl2 catalyzed [2+3] cycloaddition of allyl chloride 22 and 1- alkynyl sulfides 23a-c, followed by oxidation. Base-catalyzed dehydrochlorination of

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24a-c gave 1-sulfonyl-5,5-dimethyl-cyclopentadienes 25a-c, which turned out to be quite stable and not prone to immediate dimerization (Scheme 3).

Scheme 3. Synthesis of 1-sulfonyl-5,5-dimethyl-cyclopentadienes 25a-c

1 2 Cl 1. ZnCl2,R S R Me Me 23a-c t-BuOK, THF Me Me Cl 2. H O , AcOH, rt, 12h 2 o2 80 C, 3 h 1 2 1 2 22 R O2SR R O2SR 24a R1 = Ph, R2 = H (90%); 25a-c 24b R1 = Ph, R2 = Ph (98%); 1 2 24c R = Me, R = H (98%)

The authors did a brief examination of Diels-Alder cycloaddition reactions of diene

25c (Scheme 4). In all reactions involving C=C dienophiles, endo-cycloadducts (26-29) were formed; a decrease in the electron-deficient character of the dienophile (from maleic anhydride to methyl acrylate and phenyl vinyl sulfone) led to longer reaction times (from

24 h to 2 days and 7 days, respectively). It is noticeable that, while phenyl vinyl sulfone gave a single endo-cyclaodduct 29, the reaction with methyl acrylate produced a mixture of two endo-regioisomers 27 and 28, the major product (27) having the same regiochemistry as 29.

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Scheme 4. Diels-Alder reactions of 1-sulfonyl-5,5-dimethyl-cyclopentadiene 25c

Me Me Me Me Me H 24 h 2 days Me H O 98% 1 Ph Ph E O MeO2SPh MeO2S MeO2S E2 O 1 2 26 25c 27, E = H, E = COOMe (59%); 7 days 28, E1 = COOMe, E2 = H (19%) 85% 4 days 90% Me Me Me Me All reaction conditions: COOMe Xylene, reflux H Ph Ph No reaction with SO Ph COOMe MeO2S 2 FURAN and MeO2S 29 30 COOMe

In 1986 Posner et al demonstrated8 that 3-p-tolylsulfonyl-2-pyrone (31), prepared from 3-bromo-2-pyrone, reacted with several equivalents of various alkyl vinyl ethers 32 to produce endo-Diels-Alder adducts 33 via an inverse electron-demand cycloaddition mechanism in excellent chemical yields. (Representative examples employing 32a-c are given in Scheme 5; endo/exo ratios were >12/1). Introducing different chiral substituents

R allowed formation of the bridged bicyclic lactone adducts 33 in up to 90% de.

Scheme 5. Diels-Alder reactions of 3-p-tolylsulfonyl-2-pyrone 31

SO2 p-Tol RO Tos O 32a-c OOR o CH2Cl2, 25-68 C O O 31 endo-33a-c 32a and 33a, R = Et, 90% yield; 32b and 33b, R = Ph(i-Pr)CH, 94% yield, 84% de; 32c and 33c, R = Ph(t-Bu)CH, 90% yield, 90% de

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In 1990 Posner reported9 that, in the presence of 0.5 equiv of Yamamoto’s “MAD”

Lewis acid 34, the reaction of 3-p-tolylsulfonyl-2-pyrone (31) with 2 equiv enantiomerically pure vinyl ether (S)-32b proceeded at much lower temperature (-45 oC,

4/1 toluene/dichloromethane) and, after 12 h, resulted in an improved 96% de for the endo-diastereomer 33b (Scheme 6).

Scheme 6. Diels-Alder reaction of 3-p-tolylsulfonyl-2-pyrone 31 in the presence of Yamamoto's

"MAD" Lewis acid

Ph Ph SO p-Tol H O Ph 2 H H O Tos O (S)-32b OO O t-Bu Tos O 31 Me OAlMe endo-33b O O t-Bu 34 2

We believe that the strong influence of the Lewis acid catalyst suggests that the lactone rather than the sulfone group plays the determining role in the reaction outcome.

Scheme 7. Diels-Alder reactions of 3-p-tolylsulfonyl-2-pyridones 35

SO p-Tol Tos 2 RO O OOR 32a, R = Et; 32d, R = Bu O N o 1 CH2Cl2, 25-68 C R O2S 35 36a,b 1 o 36a, R = Et, R = C6F5, 25 C, 6 h, 7 kbar, 90% yield, 5.4/1 endo/exo; 1 o 36b, R = Bu, R = p-Tol, 50 C, 56 h, 5 kbar, 78% yield, 6.8/1 endo/exo

Posner et al also investigated10 DA cycloaddition of alkyl vinyl ethers 32a,d with 2- pyridones 35, which have more aromatic character than 2-pyrone 31. It was found that to

15

achieve reproducible formation of bicyclic products 36a,b, high pressure is necessary

(Scheme 7). The results were not improved in the presence of Lewis acid catalysts.

From the above discussion, it can be seen that very little is known about the DA cycloaddition reactions of 1-sulfonyl-1,3-dienes. These examples are restricted to cyclic dienes, and data are too scarce to establish any general reactivity trends.

1.2.2. CYCLOADDITION OF 2-SULFONYL-1,3-DIENES

In contrast to 1-sulfonyl-1,3-dienes, a much more extensive literature is available describing the DA reactions of 2-sulfonyl-1,3-dienes, probably because a broader range of methods to access these dienes have been developed.

1.2.2.1. Synthesis and Diels-Alder dimerization of 2-sulfonyl-1,3-dienes

Short overview: 2-Sulfonyl-1,3-dienes are available by thermolysis of 3-sulfonyl- substituted sulfolenes (five-membered ring); Julia coupling/elimination of allylic sulfones with aldehydes; base-induced coupling/elimination of vinyl sulfones with aldehydes; and, most important, by two efficient Backvall methods, transforming 1,3-dienes into 2- phenylsulfonyl-1,3-dienes by one-pot sulfonylmercuration-elimination or selenosulfonation-oxidation sequences.

As is summarized in Scheme 8, the dimerization pathways of 2-sulfonyl-1,3-dienes depend on the substitution patterns. The dimerization of non-substituted 2-sulfonyl-1,3- dienes (R1 = R2 = H, Path A) is spontaneous at room temperature and regio-random. The dimerization of 4-substituted 2-sulfonyl-1,3-dienes (R1 = H, Path B) is also spontaneous at room temperature but regio- and stereo-selective. Probably because the s-cis-

16

conformation is not favorable for 3-substituted 2-sulfonyl-1,3-dienes (R2 = H, Path C), their DA dimerization requires high temperatures and prolonged reaction times to result in two regio-isomers. It is worth noticing that, in all cases, the sulfone-substituted double bond acts as a preferable dienophile.

Scheme 8. Dimerization pathways of 2-sulfonyl-1,3-dienes

R2

RO S 1 2 R = H SO2R 2 Path B R = Alk Only R2 rt product

RO2S RO S 2 Path C RO S + RO S 1 2 2 2 1 R R = Me, R = H SO2R H o R2 110 C, 3 days MeMajor Me product R1 = H 2 Path A R = H RO2S rt

PhO2S + RO2S SO2R H SO2R Major RO2S product

In 1978 a group of Japanese scientists reported11 that heating 3-(p-tolylsulfonyl)-3- sulfolene (37) led to almost quantitative formation of 1,4-bis-(p-tolylsulfonyl)-4- vinylcyclohexene (39), presumably through 2-p-tolylsulfonyl-1,3-diene intermediate 38

(Scheme 9).

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Scheme 9. Synthesis and dimerization of 2-p-tolylsulfonyl-1,3-diene 38.

Br Br Ts o Ts p-TolSO2Na xylene, 140-150 C NaOH, MeOH 2 h (97%) S S Ts O2 O2 Ts 37 38 39

Along the same lines, in 1987 Ta-shue Chou reported12 that 4-bromo-2-sulfolene (40), available from 3-sulfolene by a reaction sequence of bromine addition and partial dehydrobromination, reacted with sodium phenyl sulfinate to afford intermediate direct- substitution product 41 which, under the reaction conditions, rapidly isomerized to give

3-(phenylsulfonyl)-3-sulfolene (42) (Scheme 10). Thermolysis of 42 gave a mixture of

44a-c.

Scheme 10. Synthesis and dimerization of 2-phenylsulfonyl-1,3-diene 43

Br SO2Ph SO2Ph o PhSO2Na xylene, 140-150 C S DMF, rt, 24 h S S 2 h (100%) O2 O2 O2 40 41 42

SO2Ph SO2Ph PhO2S SO2Ph ++

SO2Ph PhO2S 43 PhO2S H 44a 44b 44c Ratio 44a / 44b / 44c = 6/2/1, ref.12; Ratio 44a / 44b / 44c = 6/traces/1, ref.18, pyrolysis of 42 in xylene; 17 Ratio 44a / 44b / 44c = 57/19/24, ref. , dimerization of neat 43 proceeded at rt.

A year later Chou reported13 that thermolysis of 42 as a dilute solution in toluene under reflux for 7 h followed by flash column chromatography afforded clean (free from dimers) diene 43 in 35% yield. A dilute solution of 43 in toluene (4 mg/mL) was found to

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be stable for at least 1 week at –10 oC with <5% of dimerization, but it dimerized completely in about 3 h after it was concentrated.

Chou also described13 the preparation of 3-methyl-2-phenylsulfonyl diene 48 from readily available sulfone 45 (Scheme 11). Treatment of 45 with sodium phenylsulfinate produced a mixture of two isomeric sulfolenes 46 and 47 (ca 1/2), which underwent thermolysis in toluene to give a good yield of 3-methyl-2-phenylsulfonyl diene 48.

Interestingly, diene 48 turned out to be much more thermally stable than 43. A neat sample of 48 dimerizes <60% after being heated to 130 oC for 3 days to give a mixture of two regioisomers 49a and 49b (Scheme 11).

Scheme 11. Synthesis and dimerization of 3-methyl-2-phenylsulfonyl-1,3-diene 48

Me Br Br Me SO2Ph Me SO2Ph

PhSO2Na, NaOH Py, toluene, reflux, 51 h + S MeOH, reflux, 7 h S S (86%) O2 O2 O2 45 46 47

Me PhO2S PhO2S Toluene, reflux SO Ph 2 + 3 days SO2Ph SO2Ph 48 49a (53%) 49b (4%)

In 1986 Julia reported14 the synthesis of 1,4-disubstituted-2-phenylsulfonyl dienes 51 starting from readily available (E)-1-phenylsulfonyl-2-pentene (50) by condensation with an aldehyde and subsequent acetylation/elimination (Scheme 12). The initially obtained mixture of stereoisomers (E,E)-51 and (E,Z)-51 was separated by flash chromatography to give >99% pure (E,E)-51. No DA dimerization was described.

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Scheme 12. Synthesis of 2-sulfonyl-1,3-dienes by Julia coupling

2 equiv NaOH, SO Ph 1. BuLi, THF SO Ph SO Ph 2 2. RCHO, -30 oC 2 ether, 3 h, rt 2 R 3. NH Cl/H O (E,E) / (E,Z) = 4 2 94/6 (75%) 50 4.Ac2O, DMAP OAc R 63% (E,E)-51 Threo/erythro = 6/4 R = Et or n-Hex

Backvall developed two efficient methods to transform 1,3-dienes into 2- phenylsulfonyl-1,3-dienes. The first method15 relies upon a one-pot sulfonylmercuration- elimination sequence (Scheme 13).

Scheme 13. Backvall synthesis of 2-sulfonyl-1,3-dienes by sulfonylmercuration-elimination sequence

PhSO2Na, HgCl2 2M NaOH (aq) HgCl DMSO/H2O, 1/5, rt Et2O or CH2Cl2, rt SO2Ph SO Ph 43 2

The second method16 relies upon a one-pot selenosulfonation-oxidation sequence

(Scheme 14).

Scheme 14. Backvall synthesis of 2-sulfonyl-1,3-dienes by selenosulfonation-oxidation sequence

R PhSeSO2Ph R mCPBA R SePh o CH2Cl2, 0 C or rt, 15 min, rt SO2Ph SO Ph 17-22.5 h 52 2

Backvall confirmed17 that the dimerization of 2-phenylsulfonyl-1,3-butadiene (43) on concentration is fast and regio-random. According to him, 43 gives a 57/19/24 mixture of isomeric products 44a-c, as is shown in Scheme 10. 2-Phenylsulfonyl-1,3-pentadiene

(52a) (Equation 1) also dimerized readily and had to be handled as a dilute solution in ether or dichloromethane, however, it gave a single regioisomer 53a on dimerization.

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PhO S Me 2 (eq 1)

SO2Ph Me SO2Ph 52a 53a Me

In 1990 Hoffmann et al18 synthesized a series of 1,3-alkadienes 52a-e starting from phenyl vinyl sulfone 54 (Scheme 15), which was coupled with different aldehydes in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) to give 2-phenylsulfonyl-substituted allylic alcohols 55. (E)-Selective dehydration of 55 produced mixtures of the corresponding dienes 52a-e and their dimers 53a-e in 70-86% yield, which could be chromatographically separated.

Hoffmann confirmed that the dimerization of 4-alkyl-substituted dienes 52 is regioselective, and also established it to be completely stereoselective. Only one diastereomer (exo-52) formed (shown in Scheme 15; the structure was confirmed by X- ray crystallography).

Scheme 15. Synthesis and dimerization of 4-alkyl-2-sulfonyl-1,3-diene 52 by Hoffmann method

OH MsCl. DABCO, RCH2CHO (1-5 equiv) R DMAP, rt SO Ph DABCO (cat) 2 SO Ph 54 rt, 3-12 h (46-81%) 55 2

R R R R R SO2Ph

SO2Ph PhO2S PhO2S PhO2S 52a-e exo-TS exo-53a-e "exo" refers to the position OAc of SO2Ph group Me (a-e): R = Me, Et, Me2CH, PhCH2, CH Me

21

Hoffmann18 compared the dimerization of sulfone-substituted dienes 52 and carbonyl- substituted dienes 56 (Scheme 16).

Scheme 16. Dimerization of 2-acyl-4-alkyl-1,3-dienes 56

R R R R R

O O + O O O R1 R1 R1 R1 R1 56 exo-57 endo-57 R1 = OMe, exo/endo = 5/1 to 10/1; 1 R = Me, exo/endo = 2/1 to 4/1

According to Hoffmann, carbonyl-activated dienes 56 are more reactive than sulfonyl activated dienes 52, however the dimerization of 56 is less stereoselective and results in the formation of two diastereomers exo-57 and endo-57 (Scheme 16).

1.2.2.2. Diels-Alder cycloaddition reactions of 2-sulfonyl-1,3-dienes.

Short overview: 2-Sulfonyl-1,3-dienes showed an interesting duality in their DA cycloaddition reactions with olefins by reacting with both electron-deficient and electron- rich dienophiles. Reactions with electron-deficient dienophiles proceed through several different DA mechanisms and usually give several stereo- and regioisomers. The reaction selectivity strongly depends on the presence and position of alkyl substituents in the diene’s backbone, and it is changed, but not necessarily improved, in the presence of

Lewis acids. Only one case of an enantioselective cycloaddition reaction of enantiopure sulfonyl dienes with N-phenylmaleimide and phenyltriazolinedione has been reported

(Scheme 25).

22

Cycloadducts with electron-rich dienophiles are formed in a regioselective manner. It is conceivable that the major reaction pathway is a two step process including initial

Michael addition followed by cyclization (Path A in Scheme 21) although a concerted inverse electron demand DA pathway cannot be completely excluded (Path B in Scheme

21). Chiral enol ethers and enamines were employed as dienophiles, however, the diastereoselectivity of the resulting cycloadducts was low.

Cross DA reactions of 2-sulfonyl-1,3-dienes have been investigated. With extremely electron-rich diene partners, the sulfone-bearing double bond of 2-sulfonyl-1,3-dienes acts as an electron-deficient dienophile in a normal electron demand DA reaction. With less electron-rich diene partners, the cycloadducts resulting from inverse electron demand

DA reactions of 2-sulfonyl-1,3-dienes with one of the double bonds of the diene partner are formed in a competitive manner.

In 1978 a group of Japanese scientists reported11 that the diene 38, while being produced on thermal decomposition of sulfolene 37, can be intercepted with a series of electron-deficient dienophiles in high yields and with complete regio- and stereoselectivity (Scheme 17). A ten-fold excess of dienophile was employed during these studies.

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Scheme 17. Diels-Alder reactions of 2-p-tolylsulfonyl-1,3-diene 38 with electron deficient dienophiles

COOMe O O O Ts xylene, reflux, 3h; Ts COOMe Ts COOMe MeOOC then CH2N2 (99%) xylene, reflux, 3h S or COOMe COOMe (98%) O2 MeOOC COOMe 37 xylene, reflux, 3h (50%) 1 2 R = H; R = CO2Me (100%) xylene, R1 = H; R2 = COMe (100%) 140-150 oC, 1 2 Molar ratio R1 = H; R2 = CHO (84%) R R Pyridine diene/dienophile R1 = H; R2 = CN (89%) 1/10 1 2 Ts R = H; R = Ph (64%) 1 1 2 R R = Me; R = CO2Me (93%) 2 58 R

Backvall further demonstrated17 that 2-phenylsulfonyl-1,3-dienes showed an interesting duality in their [4 + 2] cycloaddition with olefins by reacting with both electron-deficient and electron-rich dienophiles. In all cases, a large excess of dienophile was used to prevent dimerization of the dienes. Reactions of 2-phenylsulfonyl-1,3- butadiene 43 are shown in Scheme 18. Neat diene 43 reacted with methyl acrylate in refluxing dichloromethane to afford, after 40 hours, a mixture of two regioisomers 59 and

60 in 2/1 ratio and 74% overall yield (Scheme 18). In contrast, as was shown previously11

(Scheme 17), when the analogous 2-p-tolylsulfonyl-1,3-butadiene (38) is generated in situ at 140-150 oC, only one regioisomer (58) was produced in quantitative yield. This might suggest that Diels-Alder cycloaddition of 38 is reversible at 140-150 oC. The regioselectivity of the reaction of 43 with methyl acrylate was lowered (to 1/1) in the presence of aluminum chloride.

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Scheme 18. Diels-Alder reactions of 2-phenylsulfonyl-1,3-diene 43

PhO2SPhO2S CO2Me CO2Me + CH Cl , 40 oC, 45 h 2 2 CO Me PhO2S (74%) 2 59 60 59 / 60 = 2 / 1; PhO2S 43 OEt in the presence of AlCl3: CH Cl , 40 oC, 45 h 59 / 60 = 1 / 1 2 2 OEt (54%) 61

ON PhO2S

CH2Cl2, rt, 2 h (70%) NR2 62

The analogous 4-methyl-substituted diene 2-phenylsulfonyl-1,3-pentadiene 52a (R =

Me) also showed the same duality of reactivity in DA cycloaddition with olefins17

(Scheme 19). The reaction with methyl vinyl ketone was investigated only in the absence of a Lewis acid catalyst and resulted in a predominant formation of two diastereomeric products endo-64 and exo-64 in a 65:29 ratio. The reaction with methyl acrylate was slow in the absence of Lewis acid, and in this case DA dimerization of 52a competed.

However, in the presence of AlCl3 the cycloaddition reaction with methyl acrylate occurred smoothly and a dramatic predominance of the endo-stereoisomer 66 was observed (Scheme 19).

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Scheme 19. Diels-Alder reactions of 2-phenylsulfonyl-1,3-diene 52a

ON PhO2S

CH2Cl2, rt, 60 h (50%) NR2 63

PhO2S PhO2S PhO2S PhO2S COR COR + + rt, CH Cl 2 2 COR COR

52a endo-64,66 exo-64,66 65,67

R = Me, large exess of alkene, no AlCl3, 72 h, Ratio endo-64 / exo-64 / 65 (two isomers) = 65 / 29 / (3 + 3), (68%). R = OMe, 5 equiv of alkene, 5 equiv AlCl3, 3 h, Ratio endo-66 / exo-66 / 67 = 93 / 4 / 3, (95%).

Julia reported14 that reaction of the 1,4-dialkyl-substituted 2-phenylsulfonyl-1,3-diene

(E,E)-51 with methyl vinyl ketone yielded a mixture of three isomers, the major being endo-cycloadduct 68a (Equation 2).

O H Et Et n-Hex COMe 10 mol equiv. O H + (eq 2) o Xylene, 135 C, PhO S PhO S SO2Ph 72 h (48%) 2 2 (E,E)-51 H n-Hex n-Hex 68a (34%) 68b,c (14% of 4/6 mixture)

The preferable formation of “para”-cycloadducts 58 (Scheme 17), 59 (Scheme 18), 64,

66 (Scheme 19) and 68a (Equation 2) along with the preferable formation of “para”- dimer 44a from diene 43 (Scheme 10) and the exclusive formation of “para”-dimers exo-53a-e from 4-alkyl-substituted dienes 52a-e (Scheme 15) suggest that “para”- regiopreferences are “intrinsically favorable” in the reactions of 2-sulfonylated 1,3-dienes with electron-poor dienophiles in the absence of Lewis acids. We propose that this

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“para”-cycloaddition proceeds through an exo-TS, analogous to the transition state reported18 for the dimerization of dienes 52a-e (Scheme 15). Because both reaction participants are electron-deficient, this “para”-cycloaddition can be viewed neither as a

“normal” nor as an “inverse” electron demand Diels-Alder cycloaddition. However, the introduction of the sulfone group into the electron-rich butadiene backbone, while lowering the diene’s HOMO, still allows for a slow “normal” electron demand DA reaction leading to “meta”-byproducts formed in low quantities: cycloadducts 60

(Scheme 18), 65, 67 (Scheme 19) and 68b/c (Equation 2) along with the formation of

“meta”-dimer 44c from diene 43 (Scheme 10). This assumption explains the increase in the amount of “meta”-cycloadducts 60 (Scheme 18) in the presence of Lewis acid, which lowers the LUMO of the dienophile and decreases the HOMO/LUMO gap.

We suggest that the influence of the electron-donating methyl group in position 4 of diene 52a competes with the influence of the electron-withdrawing sulfonyl group in position 2. The cycloadducts endo-64,66 (Scheme 19) are formed as a result of a

“normal” electron demand DA reaction, where the regio- and stereochemistry is determined by the presence of the methyl group. The cycloadducts exo-64, 66 (Scheme

19) are formed as a result of the “intrinsically favorable” “para”- reaction, where the regio- and stereochemistry is determined by the presence of the sulfonyl group. Endo- cycloaddition determined by the methyl group proceeds faster than exo-cycloaddition determined by sulfone group. In the presence of aluminum chloride, the LUMO of the methyl acrylate dienophile was lowered, and the reaction rate of the “normal” electron- demand DA reaction was further increased, affording mainly one stereo- and regioisomer

27

endo-66. Logically, the reaction of 52a with methyl vinyl ketone, which was done in the absence of Lewis acid, resulted in a 65/29 mixture of endo-64 (“normal” electron demand) and exo-64 (“intrinsically favorable” by sulfone group in position 2).

In the case of 1,4-dialkyl-substituted diene 51 (Equation 2) the ethyl and hexyl groups favor opposite regiochemistries of the cycloadduct.

For both dienes 43 and 52a, the inverse electron-demand DA reactions with electron- rich dienophiles were completely regioselective (Scheme 18 and 19). The regioselectivity was obviously determined by the presence of the sulfonyl group in position 2.

Backvall also studied DA cycloaddition of 2-phenylsulfonyl-1,3-dienes with 1-indolyl magnesium iodide (Scheme 20).19 More than two equivalents of 1-indolyl magnesium iodide were used. In good agreement with the results observed above for other electron- rich dienophiles (see the formation of 61, 62 and 63), the reactions were completely regioselective, but, perhaps surprisingly, they were not stereoselective considering the relative position of the substituents in the C-1 and C-4 positions of the diene backbone, and mixtures of two diastereomers 69a and 69b were obtained.

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Scheme 20. Diels-Alder cycloaddition of 2-phenylsulfonyl 1,3-dienes with 1-indolyl magnesium iodide

o SO2Ph 1. Benzene/ether (1/1), 24 h, 20 C, Me 2. H O+ + 3 N 65%, Ratio 69a /69b = 1/7 MgI Me

R1 1 1 R R SO Ph R SO Ph R H 2 R H 2 SO2Ph 1. Benzene/ + ether (1/1) + N + 2. H3O N N H 2 H 2 MgI R2 H R H R 69a 69b R = H, R1 = H, R2 = H, 5 min, 0oC, 65% R = H, R1 = H, R2 = Me, 5 min, 0oC, 62% R = H, R1 = Me, R2 = Me, 3 h, 20oC, 64%, Ratio 69a /69b = 1/3 1 2 o R = OMe, R = H, R = H, 10 min, 0 C, 42%

Non-stereospecific formation of 69a and 69b suggests that the major pathway is a two step process (Path A in Scheme 21) although, according to the authors,19 a concerted pathway cannot be completely excluded (Path B in Scheme 21).

Scheme 21. Two possible mechanisms of DA cycloaddition of 2-phenylsulfonyl 1,3-dienes with 1- indolyl magnesium iodide

1 R 1 R SO Ph SO2Ph H 2 - + Path A [MgI] N 2 N 2 MgI R R

R1 1 1 R SO Ph R H 2 SO2Ph SO2Ph H + Path B H3O N N H 2 N 2 MgI R2 R H H R MgI

29

In 1994 Barnwell et al20 applied the reaction above to synthesize cycloaddition products 70, employing 2-phenylsulfonyl-1,3-butadienes 43 or 52a and the Grignard derivatives of 2-methylindole, 3-methylindole and 2,3-dimethylindole (Scheme 22). The authors also found that neither the Grignard derivative of 2-phenylindole, nor its lithio or potassio derivatives, would participate in the cycloaddition.

Scheme 22. Diels-Alder cycloaddition of 2-phenylsulfonyl 1,3-dienes with 1-indolyl magnesium iodide, substituted at C-2 or/and C3

SO Ph R R 2 SO2Ph 1 + N R N 1 R 2 MgI R2 H R 43, 52a 70 R = H, R1 = H, R2 = H, 35% (65% reported by Backvall16) R = H, R1 = Me, R2 = H, 65% R = H, R1 = Ph, R2 = H, NO reaction R = H, R1 = Me, R2 = Me, (23% reported by Backvall16) R = Me, R1 = H, R2 = H, 30% 1 2 R = Me, R = Me, R = H, 50%

Backvall investigated the possibility of an asymmetric variant of the [4 + 2] cycloaddition of 2-phenylsulfonyl-1,3-butadiene (43) with chiral electron-rich dienophiles.21 In his earlier report17 of the reaction applying achiral enol ethers, a large excess of the enol ether was utilized to depress the competing Diels-Alder dimerization of the sulfonyl diene. With chiral dienophiles this approach was obviously unattractive.

To overcome the problem with its dimerization, the sulfonyl diene 43 was added slowly as a dilute solution in dichloromethane to a solution of an equimolar amount of the chiral enol ether in toluene at 70 oC (Scheme 23). The dichloromethane was removed continuously by distillation. Two chiral enol ethers 71a and 71b were produced.

30

Dimerization of the diene still competed, the yields of the products 71a,b were moderate and their diastereomeric excesses were low (Scheme 23).

Scheme 23. Diels-Alder cycloaddition of 2-phenylsulfonyl 1,3-diene with chiral enol ethers

OR* PhO2S 32b,e * K CO , OR* PhO2S 2 3 o 43 toluene, 70 C 71a 40% (50% de) 71b 25% (15% de) 32b R* = (α)-isopropenyl)benzyl 32e R* = (-)-menthyl

Because of the low reactivity of enol ethers, Backvall et al focused their attention on reactions of 43 and 52a with chiral enamines derived from (S)-2-methoxymethyl- pyrrolidine (Scheme 24). As was proposed by Barnwell for indolyl magnesium iodide

(Scheme 21),20 Backvall also suggested the possibility of the formation of 72 occurring in two steps, the first step being Michael addition followed by cyclization.

Scheme 24. Diels-Alder cycloaddition of 2-phenylsulfonyl 1,3-dienes with chiral enamine

Me PhO S PhO S 2 Me Me OMe 2 Me OMe K CO , 2 3 o * toluene, 70 C N N R R 43, 52a 72 R = H, 53% (72% de); R = Me, 92%, cis/trans = 1.9/1, * Cis/trans refers to relative positions of R and N (cis 71% de, trans 71% de)*

In 1998 Pradilla et al described22 the cycloaddition reactions of enantiopure sulfonyl dienes 73a,b with N-phenylmaleimide (Scheme 25). The reactions proceeded with complete facial selectivity to afford very unstable cycloadducts 74a,b as single endo stereoisomers which lactonized spontaneously in the reaction medium to give 75a,b in

31

high yields. It was also shown that 73a reacts with phenyltriazolinedione in just 1 hour at temperatures as low as –78 oC in high yield and with complete stereoselectivity (Scheme

25).

Scheme 25. Diels-Alder cycloaddition of chiral 2-phenylsulfonyl-1,3-dienes with N-phenylmaleimide and phenyltriazolinedione

O

1 R1 OH N Ph HO R1 R O O H p-TolO S H H 2 O SO2p-Tol O SO2p-Tol 1-1.5 eq Ph N H Toluene, rt PhHN 2 2-5 days O H 2 2 R R O R 73a,b 74a,b O 75a R1 = Bu, R2 = Pr (86%) 1 2 N 75b R = Bn, R = Me (82%) R1 = Bu; N Ph HO Bu 2 N O R = Pr H O N SO2p-Tol 1.5-2 eq Ph N N CH Cl , 2o 2 -78 C to rt, O Pr 1h 76 (79%)

Ta-shue Chou investigated13 cross Diels-Alder (CDA) reactions of 2-(phenylsulfonyl)-

1,3-dienes 43 and 48. For the cycloaddition reactions below that were performed at

130 oC, the protected 3-sulfolene form of the diene 43 was used directly, since the extrusion of SO2 proceeds rapidly at this temperature and diene 43 was generated in situ in the presence of other dienes. In all the other cases, free dienes 43 or 48 were used.

Electron-rich Danishefsky diene reacted with the more electron-deficient double bond of 43 or 48 at 30 oC to result in chemoselective and regioselective formation of the mixtures 77/78 (Scheme 26).

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Scheme 26. Cross Diels-Alder reactions of 2-phenylsulfonyl-1,3-dienes and Danishefsky diene

H+ O O OTMS SO2Ph Toluene, 30 oC OMe + + R OMe 4 equiv 43, R = H; SO2Ph SO2Ph 48, R = Me R R 1 equiv 77a,b 78a,b R = H, 16 h, 13% of 77a and 82% of 78a; R = Me, 24 h, 8% of 77b and 76% of 78b;

Surprisingly, cross DA reactions of cyclopentadiene (a much less electron-rich diene) with 2-(phenylsulfonyl)-1,3-dienes 43 and 48 at 130 oC proceeded in a totally different manner and selectively furnished cycloadducts 79 resulting from the apparent regioselective cycloaddition reaction of 43/48 as dienes with cyclopentadiene as a dienophile (Scheme 27)!

Scheme 27. Cross Diels-Alder reactions of 2-phenylsulfonyl-1,3-dienes and cyclopentadiene

7 SO2Ph Toluene, 1 o PhO2S 6 8 130 C PhO2S + 9 2 4 R = H, 4 equiv R R 5 3 R = Me, 20 equiv R 43, R = H; 79a R = H, 29 h, 90%; Does NOT 48, R = Me 79b R = Me, 24 h, 89% form 1 equiv Cope 130 oC 1 SO2Ph 9 8 Toluene, 7 25 oC + 79a,b + 6 + Dimers of 3 2 SO2Ph 43 (24%) R = H, 100 equiv R 5 R = Me, 100 equiv 43, R = H; 4 R 48, R = Me 80a,b 1 equiv R = H, 29 h, 79a (16%), 80a (55%); R = Me, 42 h, 79b (29%), 80b (58%)

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In order to examine this problem in more detail, the authors performed a room temperature CDA reaction between 43/48 and cyclopentadiene (Scheme 27). The formation of much smaller amounts of 79 was observed, while the major products were bicyclic compounds 80, the expected cycloadducts from a consideration of the electronic nature of the reactants. Compounds 80 were fully converted into 79 at 130 oC, presumably by sigmatropic Cope rearrangement. A reversible Diels-Alder reaction mechanism was ruled out because no traces of 79b could be detected when 80a was heated to 130 oC in the presence of 2 equiv of 48, nor were any traces of 79a detected when 80b was heated to 130 oC in the presence of 2 equiv of 43. Importantly, no conversion into 79a,b was observed when 80a,b were stirred at rt for 3 days, which means that, at rt, the compounds 79 and 80 formed independently.

Scheme 28. Cross Diels-Alder reactions of 2-phenylsulfonyl-1,3-dienes and 2,3-dimethylbutadiene

(81)

SO Ph 2 PhO S MeMe R Me Me 130 oC 2 + + Toluene R R Me Me SO Ph 81 43, R = H; 82a,b 83a,b 2 48, R = Me R = H, 55 equiv R = H, 18 h, 82a (13%), 83a (40%), dimers of 43 (47%); R = Me, 30 equiv 1 equiv R = Me, 6 days, 82b (15%), 83b (68%)

The independent formation of two types of cross products 82a,b and 83a,b (in addition to the dimers of the two starting materials) was also observed on reaction of 43 or 48 with 2,3-dimethyl-1,3-butadiene (81) (Scheme 28). As above, the cycloadducts 82 and 83 were found not to be interconvertible at the reaction temperature (in this case

34

130 oC). The major product being 83a,b suggests that, in two competing modes, CDA reactions favor the more electron-rich diene 81 reacting as the diene moiety.

Scheme 29. Cross Diels-Alder reactions of 2-phenylsulfonyl-1,3-dienes and 1,3-cyclohexadiene (84)

No transformation 130 oC SO Ph 2 PhO S 130 oC 2 + + R

R R SO2Ph 84 43, R = H; 85a,b 86a,b SO2Ph R R = H, 55 equiv 48, R = Me R = H, 24 h, 85a (75%), 86a (<1%); 87a,b R = Me, 30 equiv R = Me, 4 days, 85b (44%), 86b (<1%) 1 equiv Not observed 84 + 43 25 oC 85a (28%) + 86a (<1%) + dimers of 43 (67%) 70 equiv 1 equiv 9 days 84 + 48 25 oC 85b (3%) + 48 (85%) 20 equiv 1 equiv Toluene, 4 days

On moving to 1,3-cyclohexadiene (84) the situation changed (Scheme 29).

Cycloaddition with 43/48 at 130 oC furnished predominantly 85a,b along with some traces of one other cycloadduct. The structure of this cycloadduct was assigned to be

86a,b because no Cope rearrangement of this minor product was observed at 130 oC. All efforts toward the identification of the formation of 87a,b during room temperature CDA reactions of 1,3-cyclohexadiene (84) with 43 or 48 were in vain (Scheme 29). This might lead to the conclusion, that 85a,b were formed directly by a Diels-Alder cycloaddition mechanism; however, there is still a possibility that 87a,b did form during the reaction process, but that they rearranged into 85a,b too rapidly to be detected.

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Scheme 30. Cross Diels-Alder reactions of 2-phenylsulfonyl-1,3-dienes and 6,6-dimethylfulvene (88)

SO Ph 2 PhO S 130 oC 2 + + Toluene SO2Ph R R 88 43, R = H; R = H, 48 h, 89a (88%); R R = H, 55 equiv 48, R = Me R = Me, 18 h, 89b (90%) 90a,b(0%) R = Me, 30 equiv 1 equiv

88 + 43 25 oC 89a (63%) + 90a (<3%) 20 equiv 1 equiv Toluene, 48 h

88 + 48 25 oC 89b (36%) + 90b (<1%) + 48 (53%) 10 equiv 1 equiv Toluene, 24 h

CDA reactions of 43 and 48 with 6,6-dimethylfulvene (88) proceeded in a similar way

(Scheme 30). The observation of cycloadducts 90a,b (albeit in very small quantities) in reactions performed at ambient temperature makes it impossible to rule out the possibility that the formation of 89a,b resulted from a tandem Diels-Alder cycloaddition/Cope rearrangement. No attempts were made to independently transform 90a,b into 89a,b.

Scheme 31. Cross Diels-Alder reactions of 2-phenylsulfonyl-1,3-dienes and nonbornalidene (91)

SO Ph 2 PhO S 130 oC 2 + R R 91 43, R = H; R = H, 3 days, 92a (82%); R = Me, 24 h, 92b (84%) R = H, 55 equiv 48, R = Me R = Me, 30 equiv 1 equiv

91 + 43 25 oC 92a (57%) + dimers of 43 (12%) 100 equiv 1 equiv 6 days

o 91 + 48 25 C 92b (5%) + 48 (75%) 80 equiv 1 equiv 3 days

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CDA reactions of 43 and 48 with norbornalidene (91) proceeded chemoselectively to give only one type of products 92a,b (Scheme 31). Lowering the temperature led only to the same products (92a,b), recovering of starting material and dimer formation.

O O H Me R Me R + (eq 3) O S R R 2 O2S H O O 93

A group of Russian authors investigated Diels-Alder cycloadditions of diene 93 with p- quinones (Equation 3).23 The reactions proceeded in high yields and were accelerated in the presence of Lewis acid (BF3*Et2O), suggesting that a normal Diels-Alder mechanism involving the HOMO of 93 is operating here.

1.2.2.3. Diels-Alder cycloaddition reactions of heteroatom-substituted 2-sulfonyl-1,3-

dienes

Short overview: Introduction of an electron-donating heteroatom substituent in the C-3 position of the diene backbone increases the tendency for the normal electron-demand

DA reaction of 2-sulfonyl-1,3-dienes with electron-deficient dienophiles to occur, leading to the formation of regioisomers having “para”-orientation of the activating electron- donor group on the diene and electron-withdrawing group (EWG) on the dienophile. In this case, the SO2Ph group on the diene ends up “meta” to the EWG on the dienophile.

As might be expected, this tendency is further enhanced in the presence of Lewis acids.

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Diels-Alder reaction of 2-sulfonyl-1,3-dienes bearing a trimethylsilyl substituent in the

C-1 position of the diene backbone has also been reported.

Ta-shue Chou described the synthesis of 2,3-dihetero-substituted 1,3-dienes 94 and 96

(Scheme 32).24

Scheme 32. Synthesis of 2,3-dihetero-substituted 1,3-dienes 94-96

SPh BrSPh Br SPh NBS, MeCN, + S reflux, 2h S S O2 O2 O2 (76%) (19%)

PhSNa, MeOH, PhSO2Na, DMF, reflux, 5 h rt, 1 h

PhS SOPh PhS SPh PhO2SPhOSPh 2S SPh mCPBA + S S S S O2 O2 O2 O2 (quant) (66%) (33%) 130 oC 130 oC, quant 130 oC, 75%

SPh SPh SPh Diene 94 decomposes SOPh SPh on standing SO Ph 95 94 96 2 Peter Chou described the synthesis of 2,3-dihetero-substituted 1,3-diene 95 (Scheme

32) and investigated Diels-Alder reactions of dienes 94-95 (Table 1).25 The data indicated that both diene reactivity and reaction regioselectivity increase in the order PhS > PhSO

> PhSO2. Lewis acid catalysis greatly increased regioselectivity and exclusively gave

“meta”-products 100 and 102 (“meta”-orientation of COMe/CO2Me and PhSO2). These

38

results are entirely consistent with a normal electron demand DA reaction with the SPh group activating the diene toward cycloaddition. The impact of the SOPh and SO2Ph groups seems to be outweighed by the strongly electron-donating nature of the SPh group.

Table 1. Diels-Alder reactions of 2,3-dihetero-substituted 1,3-dienes 94, 95, 96

O O R R SO Ph SO Ph MeO2C 2 MeO2C 2 Ph N Me SPh SPh SPh SPh O 97a-c 98b,c 100 102

R SO Ph SO Ph a, R = SPh; 2 2 b, R = SOPh; O MeO C MeO C c, R = SO2Ph; 2 SPh SPh 2 SPh 99b,c Me 101 103

Entry Reactant Dienophile Conditions Product (Ratio) Yield (%) 1 94 N-phenylmaleimide 135 oC, 2.5 h 97a 98

2 95 N-phenylmaleimide 160 oC, 2 h 97b 62

3 96 N-phenylmaleimide 200 oC, 3 h 97c 90

4 95 HC≡CCOOMe 170 oC, 6 h 98b/99b, 6/4 72

5 96 HC≡CCOOMe 200 oC, 6.5 h 98c/99c, 7/3 50

o 6 96 H2C=CHCO–Me 190 C, 7 h 100/101, 75/25 81

o 7 96 H2C=CHCOOMe 200 C, 8 h 102/103, 75/25 98

8 96 H2C=CHCO–Me ZnCl2, rt, 24 h 100 90

9 96 H2C=CHCOOMe ZnCl2, rt, 72 h 102 85

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Back et al reported26 the synthesis of 2-(phenylseleno)-3-(p-toluenesulfonyl)-1,3- butadiene (106) by free radical selenosulfonation of 1,4-dichloro-2-butyne (104) followed by reductive elimination of chlorine from intermediate 105 (Scheme 33).

Scheme 33. Synthesis of 2-(phenylseleno)-2-sulfonyl-1,3-diene

p-TolSO SePh, 2 SO2 p-Tol SO2 p-Tol Cl C H , AIBN NaI (20 eq), acetone 6 6 Cl reflux, 30 h (76%)Cl reflux, 24 h (95%) Cl SePh SePh 104 105 106

Back et al26 performed several experiments to determine whether the novel diene 106 would undergo Diels-Alder cycloaddition. The results are summarized in Scheme 34. The thermal cycloaddition of 106 with methyl acrylate afforded a 1.6/1 mixture of the two regioisomers 107 (“meta”-orientation of CO2Me and p-TolSO2) and 108 (“para”- orientation of CO2Me and p-TolSO2). It was found that the yield and regioselectivity found during the formation of 107 was enhanced if performing the reaction at rt in the presence of boron trifluoride etherate (Scheme 34).

Scheme 34. Diels-Alder reactions of 2-(phenylseleno)-2-sulfonyl-1,3-diene 106

p-TolO2SCO2Me p-TolO2S CO2Me + 200 oC, p-xylene, PhSe PhSe CO2Me p-TolO2S 9 h (60%) 107 108 Ratio 107/108 = 1.6/1 PhSe 106 CO2Me 107 + 108 rt, BF3*Et2O, 3 days (72%) Ratio 107/108 = 9.1/1

p-TolO2S CO2Me O rt, BF3*Et2O, PhSe 3 days (63%) 109

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The combined data for cycloadditions of methyl acrylate with 2-sulfonyldienes 43, 96 and 106 are presented in Figure 5.

Figure 5. Combined data for Diels-Alder reactions of methyl acrylate with 2-sulfonyldienes 43, 96 and 106

"meta" "para" Diene acts as a donor, "Intrinsically favored" normal electron-demand; by SO2Ph group

CO2Me

PhO2SCO2Me PhO2S 60 59 o No LA: CH2Cl2, 40 C, 45 h (74%) - 1/2 LA Present: AlCl3 - 1/1

PhSe PhSe CO2Me p-Tol O2SCO2Me p-Tol O2S 107 108 No LA: p-xylene, 200 oC, 9 h (60%) - 1.6/1 LA Present: BF3*Et2O, rt, 3 days (72%) - 9.1/1

PhS PhS CO2Me

Ph O2SCO2Me PhO2S 102 103 No LA: p-xylene, 200 oC, 8 h (98%) - 3/1 LA Present: ZnCl2, rt, 3 days (85%) - only 102 formed

The formation of “meta”-regioisomers is enhanced with an increase in the electron- donating ability of the substituent in the C-3 position of the diene (H < PhSe < PhS), which increases the electron density in the C-4 position of the dienes (the coefficient at

C-4 in the HOMO of the diene is enhanced). The formation of “meta”-regioisomers is also strongly enhanced in the presence of Lewis acid, and the enhancement is proportional to the electron-donating ability of the substituent in the C-3 position of the diene. These observations are in full agreement with “meta”-products being formed as a

41

result of normal electron-demand Diels-Alder cycloaddition, where the effect of the arylsulfonyl substituent on diene reactivity and regioselectivity is overwhelmed by the electron-donating C-3 substituent.

Scheme 35. Synthesis and Diels-alder cycloaddition of (Z)-2-phenylsulfonyl-1-trimethylsilyl-1,3- butadiene (110)

1. BuLi (1 eq), THF, -78 oC; SPh SPh SPh 2. Me3SiCl (5 eq), 1. BuLi (1 eq), o o Recovered -78 to -30 C; THF, -105 C; starting TMS TMS + S 3. aq NH4Cl (84%) S 2. Salicylic acid, S material o O2 O2 THF, -120 C; O2 (51%) (38%)

Ph Kugelrohr distillation, Ph 145-150 oC, 0.1 torr N O O N O O mCPBA H H 1.3 (eq) (2.5 eq) TMS TMS TMS Toluene, SO Ph CH2Cl2, SPh sealed tube, 2 0 oC, 3 h o PhO2S 80 C, 10 h 111(84%) 110(78%) (81%)

Peter Chou also described27 the synthesis of (Z)-2-phenylsulfonyl-1-trimethylsilyl-1,3- butadiene (110) (Scheme 35). Heating of 110 with N-phenylmaleimide gave endo- cycloadduct 111 in good yield. However, no insight into the impact of the phenylsulfonyl group in controlling the DA reactivity of the diene is available from this study.

1.2.3. CYCLOADDITION OF DISULFONYLATED 1,3-DIENES

Short overview: The main bulk of the data about disulfonylated 1,3-dienes include their condensations with electron-rich carbon dienophiles (enamines, 1-diethylamino-1- propyne) and hetero-dienophiles (imines). It has not been clearly established if these

42

condensations proceed via a Diels-Alder reaction mechanism, or via a Michael-type addition-cyclization sequence. However, in one case, it was demonstrated that 2,3- ethylenedisulphonyl-1,3-butadiene readily reacted with both electron-rich and electron- poor dienophiles, suggesting a DA mechanism.

In 1985 Masuyama et al described28 the synthesis of 1,3-bis(phenylsulfonyl)-1,3- butadienes 114a-e by Knoevenagel-type condensation of 1,3-bis(phenylsulfonyl)propene

(112) with aldehydes 113a-e (Scheme 36). The condensation is affected by steric hindrance and does not work for ketones.

Scheme 36. Synthesis of 1,3-bis(phenylsulfonyl)-1,3-butadienes 114a-e

PhO SSOPh R1CHO (113a-e) 2 2 PhO2SSO2Ph Py (cat), AcOH (cat), HR1 112 benzene, reflux, 2 h 114a, R1 = Ph (83%), single stereoisomer; 114b, R1 = trans-PhCH=CH- (87%); 1 114c, R = Me2CH, pentane, reflux (90%), single stereoisomer 1 O 114d, R = (88%) single stereoisomer O 114e (55%) CHO

Masuyama investigated condensations of one of these dienes (114d) with enamines

117a-c, produced in situ from the corresponding ketones 115a-c and morpholine 116

(Scheme 37). The condensations resulted in the formation of Diels-Alder-like cyclic products 118a-d and 119e, however, the authors suggested the reaction mechanism to be a Michael-type addition-cyclization sequence (Scheme 37). Initially formed product 118e

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spontaneously lost a molecule of sulfinic acid to give 1,2,3,4-tetrasubstituted benzene

119e. The products 118a,b did not lose sulfinic acid in refluxing toluene; instead they were transformed into tetrasubstituted benzenes 120a,b, probably as a result of oxidation with air (see an analogous formation of 141 in Scheme 41).

Scheme 37. Condensation of 1,3-bis(phenylsulfonyl)-1,3-butadienes 114a-e with enamines

2 PhO SSOPh R2 TsOH (cat) R 2 2 R + HN O N O + 3 Benzene, R3 1 O reflux HR 115a-e 116 117a-e 114d R1 R1 PhO SPhOR3 S 2 DBU, Toluene 2 (CH2)n 2 reflux - HN O R SO2Ph SO2Ph 118a-e 120a,b

118a, R2 R3 = -(CH ) -, 5 h, (74%); Toluene, 2 3 reflux 2 3 118b, R R = -(CH2)4-, 7 h, (87%); R1 PhO S R3 2 3 2 118c, R R = -(CH2)5-, 9 h, (81%);

R2 118d, R2 R3 = -(CH ) CH(t-Bu)CH -, 9 h, (47%); 119e 2 2 2 2 3 118e, R = Et, R = Me, 30 h, toluene, (55%).

Padwa et al29,30 synthesized the nonsubstituted 1,3-bis(phenylsulfonyl)-1,3-butadiene

(123) from 1,3-bis(phenylsulfonyl)propene (112) in a very similar manner to that employed by Masuyama28 (Scheme 38). Treatment of 112 with n-BuLi, followed by condensation with formaldehyde, resulted in the formation of the expected primary alcohol 121 (76%) along with diol 122 (20%) formed by the further reaction of 121 with formaldehyde under the basic conditions used. The alcohol 121 was separated by column chromatography and dehydrated to furnish the desired diene 123.

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Scheme 38. Synthesis of 1,3-bis(phenylsulfonyl)-1,3-butadiene (123)

o 1. n-BuLi, DME, -78 C; PhO SSOPh PhO SSOPh PhO2S o 2 2 2 2 2. CH2O, -78 C, 1 h + 112 SO2Ph OH HO OH 121(76%) 122(20%) o BBr3, 80 C, 20 min, Silica then Et3N gel

PhO2SSO2Ph PhO2SSO2Ph

123(71%) O 124

Padwa et al31 found that diene 123 was prone to self-dimerization. To avoid this problem, while studying the cycloaddition reactions of 123, the authors opted to generate

123 in situ from sulfone 126 which was, in turn, obtained by the oxidation of 1,4- bis(phenylsulfonyl)-2-(phenylthio)-2-butene (125) (Scheme 39).

Scheme 39. In situ synthesis of 1,3-bis(phenylsulfonyl)-1,3-butadiene (123)

PhS PhO2S PhO2S 30% H2O2 Et3N, benzene, rt PhO S SO Ph PhO S SO Ph SO Ph 2 125 2 2 126 2 123 2

Padwa also prepared29,30 isomeric 2,3-bis(arylsulfonyl)-1,3-butadienes 131a,b from 2- butyne-1,4-diol (127) by a modification of the procedure reported by Okamyra and

Jeganathan32 (Scheme 40). On treatment with arylsulfenyl chlorides, diol 127 was transformed into disulfenate esters 128a,b, which rapidly underwent a series of [2,3]- sigmatropic rearrangements to give disulfoxides 130a,b. Oxidation of 130a,b with mCPBA produced the desired dienes 131a,b in high yield.

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Scheme 40. Synthesis of 2,3-bis(arylsulfonyl)-1,3-butadienes 131

SAr O HO O S Ar ArSCl [2,3] H CC Et N 2 OH 3 O 127 ArS ArS O 128a, R = Ph; 129a, R = Ph; 128b, R = o-NO2Ph 129b, R = o-NO2Ph [2,3]

SO2Ar SOAr mCPBA

SO2Ar SOAr 131a, R = Ph; 130a, R = Ph; 131b, R = o-NO2Ph 130b, R = o-NO2Ph

Padwa et al studied31 the condensations of 1,3-bis-sulfonylated diene 123 with a series of enamines (Scheme 41). Unlike Masuyama, Padwa believed the reactions to proceed by a Diels-Alder cycloaddition mechanism, rather than by a Michael-type addition- cyclization sequence. The authors did not provide a rationale for this belief. The reaction of diene 123 with 1-morpholinocyclohexene (117b) initially produced an intermediate

132, which spontaneously lost morpholine to furnish another unstable intermediate 133 that was capable of either undergoing a [1,5]-hydrogen shift to give 134 or losing a molecule of sulfinic acid to give 135. Padwa’s results are in good agreement with

Masuyama’s report about condensation of diene 114d with 1-morpholinocyclohexene

(117) (see Scheme 37). Heating a sample of 134 in benzene in the presence of base resulted in quantitative elimination of phenylsulfinic acid to give 135.

The reaction of diene 123 with pyrrolidinyl enamine 136 was done under somewhat milder conditions (room temperature vs reflux in benzene). The suggested intermediate

46

137 still spontaneously lost a molecule of pyrrolidine to furnish 138, however, no [1,5]- hydrogen shift occurred and the product 138 was separated in 74% yield. Room temperature reaction of diene 123 with N-methyl-1,2,3,4-tetrahydropyridine (139) resulted in an 84% yield of the cyclic product 140, which did not spontaneously lose amine functionality from the newly formed six-membered ring, however, compound 140 is air sensitive and, upon standing, was converted into 1,3,5-trisubstituted phenyl amine

141.

Scheme 41. Condensations of 1,3-bis-sulfonylated diene 123 with enamines

Me Me PhO2S PhO2S Me Me Et3N (1 equiv),

CH2Cl2, rt, 6 h N Me Me PhO2S SO2Ph 137 138 (74%) NH 136

NOPhO2S PhO2S SO Ph 2 117b Et N (1 equiv), PhO S 3 2 benzene, reflux, 20 h N 123 PhO2S SO2Ph 132 133 O Et3N (2 equiv), Me N CH2Cl2, rt, 8 h (84%) PhO S PhO S 139 2 2 + PhO S PhO S 2 air 2 SO2Ph N NHMe 134 (9%) 135 (89%) Et3N, benzene, PhO2S Me SO2Ph reflux (quant.) 140 141 (68%)

Padwa et al reported31 that 2,3-bis-sulfonylated diene 131a reacted with enamines

117b and 139 similarly to the 1,3-bis-sulfonylated diene 123 and produced Diels-Alder cycloadducts 142 and 143 (Scheme 42). Without any support, the authors suggested the

47

reactions mechanism to be true a Diels-Alder cycloaddition, however, we think it more probable that the formation of 142 and 143 occurred as a result of a Michael-type addition-cyclization sequence as proposed by Masuyama. Our suggestion is supported by two facts. Firstly, according to molecular mechanic calculations reported by Padwa,29

2,3-phenylsulfonyl-1,3-butadiene (131a) exists exclusively in the transoid conformation and possesses an enormous barrier (>50 kcal/mol) for rotation about the 2,3-bond.

Secondly, as will be shown below, all the reported attempts to react 131a with various electron-rich dienophiles did not result in the formation of “true” Diels-Alder cycloadducts.

Scheme 42. Condensations of 1,3-bis-sulfonylated diene 131a with enamines

NOPhO2S PhO S 2 117b CH Cl , rt, PhO2S SO Ph 2 2 N 2 24 h (61%) 131a 142 O Me N CH2Cl2, rt, 8 h (81%) 139

PhO2S o PhO2S CHCl3, 80 C oxidation with air, PhO S N PhO S NHMe 2 3 h (92%) 2 143Me 144

As was reported by Padwa et al,29 2,3-bis-sulfonylated diene 131a reacted with N- benzylidenemethylamine and other simple imines to produce, after 24 h at 25oC, novel rearranged piperidines 145-148 (Scheme 43).

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Scheme 43. Condensations of 2,3-bis-sulfonylated diene 131a with imines

PhO S PhO S 2 R2CR=NR1 2 NR1 2 CH2Cl2, rt, 24 h R SO2Ph 131a R PhO2S 145, R = H, R1 = Me, R2 = Ph (81%); 1 2 146, R = H, R = CH2Ph, R = Ph (90%); 1 2 147, R = D, R = CH2Ph, R = Ph (81%); 1 2 α 148, R = H, R = CH2Ph, R = -Naphthyl (75%)

The same rearranged piperidines 145-148 were obtained after 2 h at 25oC in the reaction of 1,3-bis-sulfonylated diene 123 with the same set of imines (Scheme 44). In addition, the reaction of diene 123 with an aliphatic imine (e.g. N- propylidenebenzylamine) gave cycloadduct 150.29 The reaction of 2,3-diene 131a with the same aliphatic amine resulted in a complex mixture of unidentified products.

Scheme 44. Condensations of 1,3-bis-sulfonylated diene 123 with imines

PhO2S PhO2S 1 PhO2S 1 R2CR=NR1 NR NR CH Cl , rt R 2 2 R2 R2 SO2Ph SO2Ph PhO2S 123 149 145-148, 150

145, R = H, R1 = Me, R2 = Ph, 2 h, (88%); 1 2 146, R = H, R = CH2Ph, R = Ph, 2 h, (yield is not given); 1 2 147, R = D, R = CH2Ph, R = Ph, 2h, (yield is not given); 1 2 148, R = H, R = CH2Ph, R = α-Naphthyl, 2h, (yield is not given); 1 2 150, R = H, R = CH2Ph, R = C2H5, 12 h, (68%)

The authors investigated whether placement of a more potent electron-withdrawing substituent in the C-2 and C-3 positions of the diene backbone might enable it to participate in an inverse electron demand Diels-Alder reaction. However, the reaction of

2,3-bis[(o-nitrophenyl)sulfonyl)]-1,3-diene 131b with two different aryl amines

49

exclusively gave rearranged products 151 and 152 (Scheme 45) in somewhat lowered yields comparing with less electron-deficient diene 131a (compare with Scheme 43).29

Scheme 45. Condensations of 2,3-bis-sulfonylated diene 131b with imines

ArO S ArO S 2 PhCH=NR1 2 NR1 CH2Cl2, rt, 24 h SO2Ar Ph 131b, SO2Ar Ar = o-NO2Ph 151, R1 = Me, (73%); 1 152, R = CH2Ph, (62%)

To explain the observed rearrangement, the authors suggested that small amounts of aryl sulfinate are present in the reaction mixture, which catalyze the rearrangement of

2,3-bis-sulfonylated diene 131a into the corresponding 1,3-sulfonylated diene 123

(Scheme 46). The rearrangement begins with Michael addition of aryl sulfinate to 131a, resulting in the formation of carbanion 153, which undergoes a proton shift to give carbanion 154 followed by ejecting of aryl sulfinate to produce diene 123. This more reactive diene 123 undergoes a rapid [4+2] cycloaddition, followed by a subsequent

[1,3]- hydrogen shift to form piperidines 145-148 (Scheme 46). The same mechanism works for diene 131b.29

50

Scheme 46. Mechanism of the condensations of 2,3-bis-sulfonylated diene 131a with imines

HH H proton PhO S - PhO S SO Ph PhO S - SO Ph 2 PhSO2 2 2 shift 2 2 - H SO2Ph SO2Ph SO2Ph 131a 153 154

- PhSO2- [1,3]- PhO2S 1 PhO2S 1 1 NR H shift NR ArCH(D)=NR PhO2S SO2Ph H(D) H(D) fast Ar Ar 123 SO2Ph SO2Ph 145-148 149

Padwa demonstrated that the 1,3-bis-phenylsulfonyl dienes 114a,c possessing a substituent in the C-4 position of the diene backbone gave condensation products 155 and

156 on reaction with benzylidenemethylamine (Scheme 47). Diene 114a was also reacted with dihydroisoquinoline to give cycloadduct 157. It was noted that the incorporation of a substituent onto the C-4 position of the diene required higher temperatures relative to the unsubstituted diene 123.29

Scheme 47. Condensations of 1,3-bis-sulfonylated dienes 114a,b with imines

RR

PhO2S PhO2S PhCH=NMe NMe o CH2Cl2, 50 C, 24 h Ph

SO2Ph SO2Ph 114a, R = Ph; 155, R = Ph (82%); 114c, R = i-Propyl 156, R = i-Propyl (80%)

Ph PhO S N 2 N o CH2Cl2, 50 C, 24 h

PhO2S 157 (93%)

51

Padwa et al also investigated reaction of 1,3-disubstituted diene 123 and 2,3- disubstituted diene 131a with amidine,31 reaction of 1,3-disubstituted dienes 114a,c and

123 with the sulfur-bearing heterodienophile N,N-dimethylthioformamide,29,31 and reaction of 1,3-disubstituted diene 123 and 2,3-disubstituted diene 131a with indole.31

Barnwell et al20 and Padwa et al31 independently reported the condensation of diene 131a with indolylmagnesium iodide. Barnwell et al20 also reported condensations of 131a with

2-methyl- and 2-phenylindolylmagnesium iodide, while Padwa also investigated condensations of 131a with 3-methylindolylmagnesium iodide.31

Padwa et al31 made an attempt to achieve a Diels-Alder cycloaddition of diene 131a with 1-diethylamino-1-propyne (158), however, the reaction resulted in the smooth formation of [2 + 2] cycloaddition product 159.33 No rearrangement of 131a into 123 was observed in this case, probably because of the low reaction temperature (-5 oC) (Equation

3).

PhO2S PhO2S o CH2Cl2, -5 C, 1 h Me Me NEt2 (eq 3) SO Ph 81% 2 NEt2 131a 158PhO2S 159

1,3-Bis(phenylsulfonyl)butadiene 123, when generated in situ from trisulfone 126, reacted with 1-diethylamino-1-propyne (158) at rt to give a mixture of two [2 + 4] cycloaddition products 161 and 162 (Scheme 48). The authors suggested that initially formed cycloadduct 160 undergoes loss of phenylsulfinic acid to produce o-toluidine 161 or a competitive [1,3]-hydrogen shift resulting in 162. When the reaction was performed in benzene at 80 oC for 3 h, only one product, o-toluidine 161, was obtained in 85% yield.31

52

Scheme 48. [2 + 4] Cycloaddition of diene 123a with 1-diethylamino-1-propyne

PhO2S SO2Ph SO2Ph + Me NMe2 PhO2S PhO2S 126 123 158, 2.6 equiv CH2Cl2, rt, 81%

PhO2S MePhO2S Me PhO2S Me 21% 67% - PhSO H [1,3]- NMe 2 NMe NMe 2 2 shift 2 SO2Ph SO2Ph 161 160 162

As an extension to their work, Padwa et al31 studied the reaction of ynamine 158 with

4-substituted 1,3-bis(phenylsulfonyl)-1,3-butadienes 114a,c (Equation 4).

R SO Ph PhO2S Me 2 CH2Cl2, rt, 8 h + Me NMe (eq 4) 2 [1,3]-hydrogen PhO S R NMe 2 158 shift 2 114a R = Ph; SO2Ph 114c R = i-Pr 163a (89%); 163c (85%)

Lee et al demonstrated34,35 that 2,3-ethylenedisulphonyl-1,3-butadiene 164 is a very reactive diene. Although electron-deficient, this diene readily reacted with both electron- rich and electron-poor dienophiles (Figure 6).

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Figure 6. Diels-Alder reactions of 2,3-ethylenedisulphonyl-1,3-butadiene 164

o CH Cl , rt, Benzene, 150 C, 2 2 O N 2 h (80%) 46 h (16%)

o CH2Cl2, 60 C, OEt CH Cl , 60 oC, O 2 2 45 h (45%) 2 87 h (85%) S Benzene, 160 oC, OCOMe o 48 h (66%) COOMe CH2Cl2, 60 C, S 45 h (84%) O Benzene, 160 oC, 2 SPh 164 o 48 h (85%) COMe CH2Cl2, 60 C, 45 h (77%) Benzene, 140 oC, O TMS 69 h (97%) Benzene, 130 oC, N Ph o 116 h (49%) CH2Cl2, 70 C, 180 h (26%) Ph O

It was also reported35 that diene 164 participated in hetero a Diels-Alder cycloaddition with N-benzylidenemethylamine to form bicyclic product 165 (Equation 5).

O2 O2 S MeN S Ph NMe (eq 5) CH Cl , 11 oC, S 2 2 S Ph 10 h (84%) O2 O2 164 165

As has just been shown in Section 1.2, Diels-Alder reactions of sulfonyl dienes are not completely understood to date, and no examples of intramolecular DA cycloaddition reactions of sulfonyl dienes had been reported prior to our studies. Therefore much was to be gained through our study of the intramolecular DA cycloaddition reactions of butadienyl sulfones tethered to acrylate ester dienophiles. Before discussing our investigations of such intramolecular DA reactions involving 1-sulfonyl-1,3-dienes, it is important to understand the literature background concerning Diels-Alder reactions employing disposable tethers.

54

1.3. DIELS-ALDER REACTIONS EMPLOYING DISPOSABLE TETHERS

Short overview: To the best of our knowledge, only three publications exist that describe just two types of tethers for intramolecular DA reactions based on sulfur-containing functional groups, involving the use of sulfonate esters and sulfonamides. In all cases, this sulfur-containing group is connected to the dienophile.

It has been known that temporary tethers can be used to control the regio- and stereoselectivity of Diels-Alder cycloaddition reactions.36 Most commonly used to date are silicon- and boron-based tethers, some examples of which are presented in Figure 7.

However, to the best of our knowledge, only two types of tethers based on sulfur- containing functional groups have been reported and, in both cases, this sulfur-containing group is connected to the dienophile.

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Figure 7. Examples of silicon- and boron-based tethers for Diels-Alder reactions

O COOEt O O O O SiR2 Si Si O R2 SiR2 R2 H H COOMe COOEt COOMe

O O O R2Si O O Me2Si O R Si O Si 2 O Me O O 2 R R Ph Ph

R R B B O O O O

COOMe COOMe

Metz and coworkers reported37 sulfonate ester- and amide-based tethers. Esterification of a mixture of cyclopentadienyl alcohols 166 with vinylsulfonyl chloride gave, ultimately, exo sultone 167 with high diastereoselectivity (Scheme 49). Interestingly, reaction of cyclohexadienyl alcohol 168a with vinylsulfonyl chloride gave vinylsulfonate ester 169a, which in refluxing toluene underwent diastereoselective endo-cycloaddition resulting in sultones 170a and 171a. Analogous endo-cycloaddition was observed in refluxing toluene for vinylsulfonamide 169b, which resulted in sultams 170b and 171b

(Scheme 49). Intramolecular Diels-Alder reactions in refluxing toluene of acyclic trienes

173 resulted in mixtures of exo-products 174 and endo-products 175, with the ratio of

174 to 175 increasing with the increased bulk of the R1 substituent on the tether (Scheme

50).

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Scheme 49. Intramolecular Diels-Alder reactions of vinylsulfonic acid derivatives with carbocyclic

1,3-dienes

O SO2Cl OH O2S S O o Et3N, THF, 0 C, O O Me 64% Me 166 Me exo-167

SO2Cl + o O2S H H Et3N, THF, 0 C, XH 95% 169a X O O S O S O 85% 169b Me Me X X Me Me 168a,b 169a,b endo-170a,b endo-171a,b a: X = O, Toluene, BHT, reflux: 170a/171a = 10.2 : 1 (58%) a: X = O, 13 kbar, CH2Cl2, rt: 170a/171a = 54.6 : 1 (92%) b: X = NBn, Toluene, BHT, reflux: 170b/171b = 9.3 : 1 (77%) b: X = NBn, 13 kbar, CH2Cl2, rt: 170b/171b = 30.3 : 1 (93%)

Metz and coworkers observed37 the acceleration of the intramolecular DA reaction of vinylic esters 169a, 173a-c and amides 169b, 173d,e by application of high pressure which led to excellent yields of sultones 170a/171a (Scheme 49), 174a-c/175a-c (Scheme

50, Table 2) and sultams 170b/171b (Scheme 49), 174d,e/175d,e (Scheme 50, Table 2) at ambient temperature. While the addition of a radical scavenger (BHT) was necessary to suppress side reactions at elevated temperature, it was not needed under these high- pressure conditions. Interestingly, attempts to trigger the cyclization at lower temperature using different Lewis acids were not effective.

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Scheme 50. Intramolecular Diels-Alder reactions of vinylsulfonic acid derivatives with acyclic 1,3- dienes

R3 R3 R3 R3 SO2Cl + Et N, THF, H H o3 R2 0 C, 76% R2 SO R2 SO R2 SO 2 H 2 H 2 XH X X X

R1 R1 R1 R1 172 a-e 173a-e exo-174a-e endo-175a-e

Table 2. Intramolecular Diels-Alder reactions of vinylsulfonic acid derivatives with acyclic 1,3-dienes

1 2 3 172- X R R R 13 kbar, CH2Cl2, rt Toluene, BHT, reflux 175 174 : 175 Yield (%) 174 : 175 Yield (%) a O H H H 1.0 : 2.3 88 1.0 : 1.0 76 b O Me H Me 1.0 : 2.0 78 1.4 : 1.0 64 c O t-Bu Me H 3.6 : 1.0 79 4.7 : 1.0 76 d N H H H 1.0 : 1.6 79 1.0 : 1.0 76 e N Me H Me 1.0 : 1.9 81 1.6 : 1.0 61

Overman et al reported38 an example of Diels-Alder cycloaddition employing a sulfonamide-based tether (178) (Scheme 51). Their two-step sequence generated three cycloadducts 179-181. The structures of 180 and 181 were not established. The major products, 179 and 180 were formed in approximately a 3.4/1 ratio, as determined by 1H

NMR analysis of the crude reaction mixture at 100 oC. The third minor cycloadduct 181 was detected only during chromatographic purification.

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Scheme 51. Diels-Alder reactions employing a sulfonamide based tether

ClP(O)(OEt)2, LHMDS (2.1 equiv) OCHCO2Et N THF, -78 to 0 oC N -78 to 0 oC O S O S + 2 Me N 2 - Li N

CBZ O P(OEt)2 CBZ 176 177

H 77% H N + 180 + 181 (<5%) N O2S S N N O H H O CBZ CBZ CO Et CO Et 2 2 Ratio 179/180 = 3.4/1 178 179

The above examples all involve intramolecular DA cycloaddition reactions where the sulfur-based tether is directly attached to the dienophile. In contrast, no examples have been reported of intramolecular DA cycloaddition reactions involving a sulfur-based tether where the sulfur substituent is directly attached to the diene. This is surprising, because the literature contains many examples of intermolecular DA reactions where the diene is substituted with sulfur-containing functional groups, including sulfonyl- substituted dienes, as discussed earlier (Section 1.2).

We aimed our study at the development of such new sulfone-based tethers for intramolecular Diels-Alder cycloaddition reactions, where the sulfonyl group is attached to the C-1 position of the diene. We were interested in this type of tethers because (i) as has been shown in Section 1.2.1, DA cycloaddition reactions of 1-sulfonyl-1,3-dienes have been less widely investigated than DA reactions of 2-sulfonyl-1,3-dienes, (ii) DA reactions of both 1-sulfonyl-1,3-dienes and 2-sulfonyl-1,3-dienes with electron-poor dienophiles are often not regioselective, so a connection of the diene and dienophile by a

59

tether is called for as a means to improve the regioselectivity, and (iii) DA cycloadducts obtained from 1-sulfonyl-1,3-dienes (allylic sulfones) are very promising synthetic intermediates that might find application in the synthesis of other more complex targets.

In contrast, 2-sulfonyl-1,3-dienes offer somewhat less synthetic potential. The precursors of the 1-sulfonyl-1,3-diene-based tethers targeted in our studies would be β-hydroxyalkyl butadienyl sulfones. Thus, before actually beginning our DA studies, we needed to develop a reliable way to synthesize these compounds. Our results about the synthesis of

β-hydroxyalkyl butadienyl sulfones are presented in the next chapter.

2. SYNTHESIS OF β-HYDROXY SULFONE-BASED TETHERS FOR

INTRAMOLECULAR DIELS-ALDER CYCLOADDITION REACTIONS

2.1. SYNTHESIS OF β-HYDROXY SULFONES via EPOXIDE OPENING WITH

ZINC SULFINATES IN AQUEOUS MEDIA

Short overview: A new straightforward route to various β-hydroxy sulfones was developed, proceeding via opening of ethylene oxide or propylene oxide with readily accessible zinc sulfinates under essentially neutral aqueous conditions. Reactions of zinc methyl, butyl, p-tolyl and benzyl sulfinates with propylene oxide proceeded regioselectively in 63-67% yield. 2-(Methylsulfonyl)ethanol, a common reagent for the protection of various functional groups, was obtained by this methodology from ethylene oxide in 78% yield. The corresponding opening of epoxides with zinc 1,3-butadienyl sulfinate afforded β-hydroxyalkyl butadienyl sulfones in 30% yield. Detailed mechanistic studies revealed that the yields of these products were limited by their consumption in competing intra- and intermolecular Michael addition processes.

2.1.1. GENERAL

At the beginning of our study aimed at the development of new sulfonyl tethers for intramolecular Diels-Alder cycloaddition reactions, we attempted the synthesis of the β- hydroxy sulfones 186 by condensation of (Z)-butadienyl sulfinate anion 183 with epoxides 184a,b (R = H, Me) (Scheme 52). (Z)-Butadienyl sulfinate anion 183 is readily available from commercially available and inexpensive butadiene sulfone (182) on

60 61

treatment with n-BuLi in THF,39 EtMgBr in ether,40 or NaH in DMSO.41 Synthesis of 2- methyl-(Z)-butadienyl sulfinate anion from the corresponding 3-methylbutadiene sulfone has also been reported. This transformation was achieved on treatment with n-BuLi in

THF,39 ethylmagnesium bromide in ether,40 phenyl- and 2,6-dimethylphenylmagnesium

40 42 iodide in ether/toluene, potassium tert-butoxide in isopropanol or LiN(SiMe3)2 in

THF.43 Seeing the accessibility of (Z)-butadienyl sulfinate anions, we considered that the nucleophilic opening of ethylene oxide (184a) or propylene oxide 184b using (Z)-183 might provide an attractive entry to 1-(Z)-butadienyl-β-hydroxyalkyl sulfones 185.

Double bond isomerization44,45 would then give the corresponding (E)-β-hydroxy sulfone 186 (Scheme 52).

Scheme 52. Synthesis of 1-butadienyl β-hydroxyalkyl sulfones by condensation of (Z)-butadienyl sulfinate anion with epoxides

R1 O- Met + Isomeri- Base O OH zation OH S S S 1 S 184a-d O2 O 1 O R 2 R O2 182 (Z)-183 185a (R1 = H) 186a (R1 = H) 185b (R1 = Me) 186b (R1 = Me) 1 1 1 1 184a R = H; 184b R = Me; 184c R = CH2OH; 184d R = CH2Cl

S-Alkylation of sulfinate anions with alkyl halides is an established method for the synthesis of aliphatic sulfones.39,40,46,47 S-Alkylation of both (Z)-1,3-butadienyl sulfinate

183 and (Z)-2-methyl-1,3-butadienyl sulfinate has also been reported. (Z)-1,3-Butadienyl sulfinate 183 was S-alkylated with benzyl bromide and methyl iodide in refluxing methanol in 10-25% yield,39 with benzyl chloride in refluxing ethanol in 13% yield40 and with allyl bromide in DMSO (no yield given).45 In the patent literature, Julia42 prepared

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four allyl dienyl sulfones by reaction of potassium 2-methyl-1,3-butadienyl sulfinate with

β-vinyl-ionol in AcOH (71%), geranyl bromide in DMSO/MeOH (50%), 1-chloro-3- methyl-2-butene in DMSO (85%), 1-bromo-3-methyl-2-butene in THF (70%) and 1,4- dibromo-2-methyl-2-butene in DMSO/MeOH (56%). Burger44 employed the same potassium salt in reaction with five more allylic halides (38-97% yield), benzyl halide

(81% yield) and methyl halide (29% yield) in DMSO at rt.

However, the preparation of β-hydroxy sulfones by opening of epoxides with sulfinate anions has been much less thoroughly investigated. Sodium or potassium sulfinates have been exclusively used. The main challenge of this transformation is that, as it proceeds, the pH of the reaction medium constantly increases and, very soon, the reaction medium becomes extremely basic (pH 14) (Equation 6).

- + 1 R O Na R H2O R OH S + S + NaOH (eq 6) O 1 O O 2 R

In Culvenor’s early studies in this area, simple symmetrical epoxides (ethylene oxide

(184a, R1 = H), cyclohexene oxide) were opened in 50-55% yield using sodium p-tolyl sulfinate in aq alcohol.48 Opening of a simple unsymmetrical epoxide 184b (R1 = Me) was also performed – however, even with careful neutralization of base generated during the reaction, the β-hydroxy sulfone adduct was obtained in only 40% yield.49 Similar chemistry, requiring careful titration of the ongoing reaction with aq acid to neutralize the base generated during the reaction, was employed in opening epoxides 184c,d (R1 =

49 CH2OH (no yield reported), CH2Cl (25% yield)). In the absence of this neutralization protocol, side reactions ensued. It has also been reported50 that sodium aryl sulfinates (Ar

63

= C6H5, 4-MeC6H4, and 4-MeOC6H4), under Lewis acid catalysis with magnesium nitrate

(Mg(NO3)2*6H2O), open propylene oxide in 64-83% yield if the epoxide is used as the solvent. Lower yields (23-42%) were noted when stoichiometric amounts of longer chain

1-epoxyalkanes were employed, and these reactions failed completely when using other epoxides or aryl sulfinates. More recently, the use of two-phase reaction systems has been exploited to avoid potential problems associated with the base generated during these reactions. Crandall and Pradat demonstrated that sodium p-tolyl sulfinate (1.5 equiv) opens cyclohexene oxide in high yield when using a two-phase system (4:3:3 mixture of water, benzene and acetone) on refluxing under phase transfer catalysis with tetra-n-butylammonium chloride or bromide.47 Bhattacharyya and coworkers reported that montmorillonite clay facilitates nucleophilic opening of various epoxides by sodium p-tolyl sulfinate (1.5 equiv) at rt in 52-80% yield using a very similar two-phase system

51 (2:1:1 mixture of water, benzene and acetone). Regioselective SN2 opening at the less crowded end of unsymmetrical epoxides was observed. The authors proposed that montmorillonite clay acts as a Lewis acid catalyst, coordinating with the epoxide oxygen.

Later, Bhattacharyya reported that the use of polyethylene glycol (PEG) 4000 as a phase transfer catalyst in refluxing water:benzene (1:1) achieved similar results (70-90% yield).52 The authors suggested that PEG 4000 allows the transport of the sulfinate ion into the organic layer.

To the best of our knowledge, besides sodium aryl sulfinates, only perfluorinated sulfinate anions have been employed to date in epoxide ring opening reactions.53 Sodium

2-(perfluorooctyl)ethylsulfinate (RFCH2CH2SO2Na, 1 equiv) reacts with cyclohexene

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oxide (1 equiv) in ethanol/water (1/1) to give the corresponding β-hydroxy sulfone product, albeit with low (27%) conversion.

It remained unclear whether the existing methods described above would be amenable to the use of other more water-soluble sulfinate nucleophiles. Moreover, in all the reported two-phase reactions between sulfinate anions and epoxides, the pH of the aqueous layer increases to 14 as the transformation proceeds. Therefore, we presumed that high yields might be expected only if, a) the epoxide resides primarily in the organic layer, and b) the β-hydroxy sulfone product is relatively stable under strongly basic conditions and/or also preferentially resides in the organic layer.

To examine the utility of these two-phase reaction systems with more water-soluble sulfinate salts, we investigated the reaction of sodium methyl sulfinate with propylene oxide (1.37 equiv). Both Crandall47 and Bhattacharyya51 used a 1.5/1 ratio of p- toluenesulfinate/ epoxide in their studies, presumably to avoid problems associated with the rapid hydrolysis of the epoxide during the latter stages of their reactions (pH 14).

Since we needed to employ valuable sulfinate salts and inexpensive epoxides in future studies, we employed a 1/1.37 ratio of sulfinate/epoxide. This also allowed direct comparison with our studies using Zn sulfinates (see Part 2.1.2).

First the reaction of sodium methyl sulfinate with propylene oxide (1.37 equiv) was attempted in the presence of Bu4NBr (5 mol%) under the conditions described by

Crandall and Pradat47 (Equation 7, conditions a). Removal of the organic solvents in vacuo afforded a strongly basic aqueous solution (pH 14). Neutralization of the solution

(as indicated using phenolphthalein) required 0.45 equiv of aq HCl, indicating a

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maximum 45% conversion into the desired β−hydroxy sulfone product. The 1H NMR spectrum of the crude reaction product, obtained after water removal in vacuo, showed a complex mixture of products in which the ratio of desired β−hydroxy sulfone : propylene glycol : (Bu)4NBr was approximately 4 : 7 : 1. This established the maximum possible yield of the desired sulfone at around 20% and suggested that around 25% of the product decomposed under the strongly basic conditions. Attempted purification of the organic product by vacuum distillation afforded complex mixtures containing less than 50% of the desired product.

O 1.37 equiv H3C O H3C OH S Na o S (eq 7) a. Bu4NBr (0.05 equiv), 20 h, 80-85 C, O O 2 H2O/benzene/acetone 4/3/3; b. Montmorillonite clay, 20 h, rt a. 20% of <50% pure product b. 31% of 80-90% pure product H2O/benzene/acetone 2/1/1

Slightly better results were obtained under the Bhattacharyyra conditions51 when we treated sodium methyl sulfinate with 1.37 equiv of propylene oxide in the presence of montmorillonite clay (Equation 7, conditions b). Neutralization of the strongly basic (pH

14) solution at the end of the reaction required only 0.2 equiv of aq HCl. Workup gave

31% of crude β−hydroxy sulfone, which was approximately 80-90% pure by 1H NMR analysis. The larger amount of the formed product (approximately 0.25-0.28 equiv) comparing with the amount of acid (0.2 equiv) required for the neutralization suggested that approx 0.05-0.08 equiv of base was absorbed by the acidic sites present in the montmorillonite clay.

Given the disappointing results obtained for the more water-soluble methyl sulfinate anion in the above studies, it was recognized that an alternative approach was needed for

66

ring opening of water-soluble epoxides with base-sensitive sulfinate anions. If a reaction could be developed that proceeded under essentially neutral aqueous conditions, the need for the organic phase should be obviated. We anticipated that such approach would also be amenable to the preparation of base-sensitive β-hydroxy sulfones such as 185 and 186

(See Scheme 52).

We considered that epoxide opening with sulfinate ion 183 might be achieved in aqueous medium if we used metal sulfinates (RSO2)nMet for which the corresponding metal hydroxides Met(OH)n are insoluble in water and would thus precipitate from the reaction medium, effectively maintaining neutral reaction conditions. Ideally, the metal sulfinates should be readily available and inexpensive. To make large scale synthesis possible, the corresponding metal hydroxides should precipitate in a form that can be removed by simple filtration. Zinc sulfinates fulfill all the above requirements. Initially formed Zn(OH)2 should undergo facile dehydration to give ZnO, which would immediately precipitate from aqueous medium. It has long been known that a wide range of readily available sulfonyl chlorides (a wide range of sulfonyl chlorides are commercially available) can be efficiently reduced with zinc to the corresponding zinc sulfinates. The reduction is usually performed in water,54,55,56 sometimes in moist ether,57,58 methanol58 or, rarely, in moist toluene.58 In most cases, after the reduction is finished, the reaction mixture has been either acidified to obtain the corresponding

55,57 sulfinic acids or treated with excess aq NaOH/Na2CO3 solution to produce the corresponding sodium sulfinates.54,56 However, in two cases, zinc aryl sulphinates

67

58 59 Zn(O2SAr).nH2O and Zn(O2SCH2NHC6H5).nH2O have been isolated, albeit in low to moderate yields.

As is shown below, we found that zinc sulfinates are, indeed, effective nucleophiles for the ring opening of simple symmetrical and unsymmetrical epoxides under essentially neutral conditions in a simple one-phase aqueous reaction, providing an attractive new entry to the synthesis of base-sensitive β-hydroxy sulfones and β-hydroxy sulfones derived from water-soluble sulfinate anions.

2.1.2. SYNTHESIS OF SIMPLE ZINC SULFINATES AND THEIR REACTIONS

WITH EPOXIDES

Short overview: A series of β-hydroxy sulfones 189a-d were synthesized in good yields under neutral aqueous conditions by the nucleophilic opening of ethylene oxide or propylene oxide with zinc methyl, butyl, p-tolyl and benzyl sulfinates 188a-d. These Zn sulfinate salts were readily accessible by reduction of the corresponding sulfonyl chlorides 187a-d or from the corresponding sodium or lithium salts. These reactions favored S-attack of the sulfinate anion over O-attack and, in the case of propylene oxide, proceeded with high regioselectivity. This method represents a significant improvement over previously available epoxide ring opening reactions with sulfinate nucleophiles.

As expected, Zn reduction of commercially available sulfonyl chlorides 187a-d afforded the respective Zn sulfinates 188a-d (Scheme 53, Table 3) in yields (78-92%)

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that were far higher than those reported previously for the isolation of zinc sulfinate salts.58 Interestingly, Zn methyl and butyl sulfinates did not precipitate from the reaction mixture unless water was added. They were isolated as the corresponding dihydrates

188a and 188b. On the contrary, Zn benzyl and p-tolyl sulfinates precipitated directly from the ethanol solution. The precipitates contained some solvating ethanol, which was substituted by water on drying in air to produce the corresponding dihydrates 188c and

188d. If kept under high vacuo at 80 oC (compound 188a) or 60 oC (compounds

188b,c,d) for 4 hours, the zinc sulfinate dihydrate salts fully lose water to afford the corresponding anhydrous salts. While the anhydrous salts produced from 188a,c,d remain crystalline, salt 188b is transformed into an oil.

Scheme 53. Synthesis of β-hydroxy sulfones from commercially available sulfonyl chlorides

R Cl 1) Zn, EtOH R O O S S Zn * 2H O 2 H O O2 2) H2O O 2 2 187a (R = Me) 188a-d 187b (R = n-Bu) 187c (R = CH2Ph) 187d (R = p-Tol)

R OH R OH R O HO S ++S + O S OH OH 2 O2 O 189a-d 190a-d 191a-d 192

The reaction of Zn sulfinates 188a-c with propylene oxide provided 63-67% yields of the desired β-hydroxy sulfones 189a-c (Table 3, entries 1-4) after a straightforward workup, which did not require column chromatography. However, only 41% yield was obtained in the case of Zn p-tolyl sulfinate 188d (Table 3, entry 5). For less water-soluble sulfinate salts 188b-d we considered that it might be possible to facilitate reaction in the

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heterogeneous mixture using ultrasonication. However, this had little impact on the reaction of 188b (Table 3, compare entries 2 and 3), and so was not investigated further.

The reaction of Zn methyl sulfinate 188a, which is very soluble in water, was essentially completed in 2 h, while less water-soluble Zn sulfinates 188b,c required longer reaction times. Reaction of p-tolyl sulfinate 188d was far from complete even after 16 h.

The synthesis of 189a-c was accompanied by the formation of two major byproducts: sulfones 190a-c, formed as a result of epoxide opening at the more substituted end, and sulfinate esters 191a-c, resulting from O-attack of the sulfinate anion on the epoxide. The sulfinates 191a-c were formed as 1:1 mixtures of diastereomers. Out of all observed byproducts, only 2-methanesulfonylpropan-1-ol (190a) has been previously described in the literature.60 The structures of the compounds 190a-c and 191a-c were tentatively assigned from their mixtures with 189a-c using NMR analysis. In the case of p-tolyl sulfone 189d we did not observe the formation of the corresponding sulfinate ester 191d.

1H and 13C NMR analysis of the crude reaction mixture showed the desired sulfone 189d along with only the sulfone byproduct 190d. However, if the reaction of Zn sulfinate

188d was interrupted after 1h 30 min, small pairs of resonances were observed in the 13C

NMR spectrum of the reaction mixture at 66.0/66.2 and 70.40/70.46 ppm. By comparison with the sulfinate esters 191a-c obtained earlier, we tentatively attribute these signals to the C1 and C2 carbons of the 2-hydroxypropyl fragments in the two diastereomers of

191d.

Table 3. Regioselective Opening of Propylene Oxide Using Zn Sulfinates 188a-d

Entry Zn- Yield of Equiv of Reaction Approx molar ratio Isolated

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salt 188a-d propylene conditions 189 : 190 : 191 : 192a yield of from oxide (time, temp.) in crude productb 189c 187a-d employed 1 188a 92% 1.36 2h, 75 oC 86/8/6/21 65%

2 188b 92% 1.55 12h, 70 oC 85/8/7/34 67%

3 188b 92% 1.55 4h, 80 oC, 85/8/7/42 64% ultrasound 4 188c 91% 2.01 7h, 70oC 85/8/7/85 63%

5 188d 78% 1.68 16h, 70oC 93/7/0/93 41%

6 188dd n/a 1.68 4h, 75oC 93/7/0/20 64%

a. Generated via hydrolysis of excess propylene oxide in situ.

b. Determined through NMR analysis of the crude reaction product.

c. After purification by distillation followed by crystallization (189a,b) or by crystallization from the crude

reaction mixture (189c,d).

d. Obtained in situ from commercially available sodium p-tolyl sulfinate and zinc chloride (0.5 equiv).

β-Hydroxy sulfones 189a,b are too highly soluble in water to permit effective recrystallization, while crystallization from organic solvents does not allow complete separation from the propylene glycol byproduct. As a result, crude mixtures of β-hydroxy sulfones 189a,b were distilled in high vacuo (0.1 mm Hg), which allowed the removal of the more volatile propylene glycol and most of the sulfinate esters 191a,b.

Recrystallization of the distilled products from toluene (189a) or a toluene/hexanes mixture (189b) was sufficient to completely remove the corresponding byproducts

190a,c. In the case of the less water-soluble β-hydroxy sulfones 189c,d, simple recrystallization of the crude reaction mixtures from water was sufficient to obtain pure

β-hydroxy sulfone products 189c,d.

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As outlined in the next section (Section 2.1.3), we learned through subsequent studies that β-hydroxyalkyl butadienyl sulfones 185 were most effectively prepared via reaction of simple epoxides with samples of Zn 1,3-butadienyl sulfinate that were freshly prepared and used in situ; these reactions proceeded much faster than when using samples of Zn

1,3-butadienyl sulfinate that were previously separated and dried. Therefore, we returned to the low yielding synthesis of p-tolyl sulfone 189d, and treated the commercially available Na p-tolyl sulfinate with ZnCl2 (0.5 equiv). The Zn p-tolyl sulfinate precipitate was not filtered, but was immediately treated with propylene oxide. To our delight, the reaction was completed in 4 h to give 64% isolated yield of the desired sulfone 189d (see

Table 3, entry 6).

O Me OH Me O HO 188a S + + (eq 8) H O S OH OH 2 O2 O 193, 78% 194

2-(Methylsulfonyl)ethanol (193) has seen widespread use in protecting various functional groups. For example, it is used in the synthesis of urethane-protected amines and amino acids,61 protected phosphate esters62 and protected phenols.63 Given this widespread use, we decided to examine the feasibility of preparing 193 through reaction of the Zn methyl sulfinate 188a with ethylene oxide (Equation 8). This transformation was complete in 2 hours at 70 oC; the ratio of sulfone 193/sulfinate ester 194/ethylene glycol, observed by 1H NMR analysis of the crude reaction mixture, was 93/7/11. To our delight, straightforward vacuum distillation (0.1 mm Hg) of the crude reaction mixture afforded 78% yield of essentially clean β-hydroxy sulfone 193. (Depending on the run, this material might contain up to 1.5% of sulfinate ester 194.) Given the readily

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accessibility of zinc sulfinate 188a and the straightforward nature of the chemistry, this approach constitutes an attractive entry to 2-(methylsulfonyl)ethanol (193). We presume that this methodology will prove equally useful in the synthesis of other β-sulfonyl ethanol derivatives.

2.1.3. EPOXIDE OPENING WITH ZINC (Z)-1,3-BUTADIENYL SULFINATE

(195)

Short overview: Opening of epoxides with zinc (Z)-1,3-butadienyl sulfinate 195, followed by DMAP-mediated alkene isomerization, afforded β-hydroxyalkyl (E)- butadienyl sulfones 186a,b in 30% yield. Detailed mechanistic studies revealed that the yields of these products were limited by their consumption in competing intra- and intermolecular Michael addition processes. Nevertheless, in spite of these competing side reactions, this method provides a convenient one-pot approach for the preparation of sensitive β-hydroxyalkyl (E)-butadienyl sulfones 186a,b from commercially available butadiene sulfone (182).

Given that we had successfully developed a practical approach for the synthesis of β- hydroxy sulfones 189a-d and 193 using simple Zn sulfinate salts 188a-d, we were now in a position to explore the preparation of the more challenging butadienyl sulfones 185 and

186. The presence of a potent Michael acceptor motif within 185 and 186 was recognized as a significant challenge to the successful execution of these studies. This work required

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the use of Zn (Z)-1,3-butadienyl sulfinate (195), which we anticipated would be accessible from commercially available butadiene sulfone (182).

Scheme 54. Condensation of epoxides with Zn (Z)-butadienyl sulfinate (195) obtained in situ

1. 1 equiv n-BuLi, THF, -78 oC, 15 min O S Zn * 2H2O S 2. add H2O; THF removed; O O2 add 0.50-0.55 equiv ZnCl2 2 182 195 R 10 mol % DMAP, CH2Cl2, rt, 36 h o O (3 equiv), 70-75 C, Time

2β 2α β α H H H2 H2 3 6a 5 1 OH H 1 OH 4 S 3 S 4 1 Intermolecular 6b O 1 6b O 1 OR H 5 2 R + H 2 R Michael + addition H6a 185a,b 186a,b + S products O2 3' 3 5 H6a 198, cis-199, trans-199 4' S 4 S O2 + O2 5' H6b 6' 196 197 1 1 R = H (185a, 186a, 198); R = CH3 (185b, 186b, cis-199, trans-199)

Treatment of butadiene sulfone (182) with 1 equiv of n-BuLi in THF at –78 oC, followed by addition of water with warming to rt and then removal of the THF in vacuo, afforded a clear solution of Li (Z)-butadienyl sulfinate (183, Met = Li). This solution was transferred into a glass pressure vessel and treated with 0.50-0.52 equiv ZnCl2, affording

Zn (Z)-butadienyl sulfinate (195) as a white precipitate. Propylene oxide (3 equiv) was added, and the vessel was closed and kept at 70-75 oC for 3h. At the end of the reaction, the pH of the solution was 8.3-8.6. NMR analysis of the crude product, obtained after extraction with dichloromethane, showed the presence of a mixture of (Z)-butadienyl sulfone 185b, (E)-butadienyl sulfone 186b, (E, Z)-bis-butadienyl sulfone (196) and

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(E,E)-bis-butadienyl sulfone (197) (see Scheme 54; Table 4, entry 1). The desired products 185b and 186b, which were not separable by column chromatography, were obtained as a 1/3.5 mixture in 30% overall yield. Bis-butadienyl sulfones 196 and 197, which also do not separate by column chromatography, were obtained as a 1/3.5 mixture in 43% overall yield. Similar results were obtained on reaction with ethylene oxide (see

Scheme 54; Table 4, entry 2), however, a small amount of cyclization product 198 was also observed; the combined yield of 185a and 186a was again 30%.

To our delight, when chromatographed mixtures of products 185a/186a, or

185b/186b, were treated with 10 mol % DMAP in dichloromethane for 36 h at ambient temperature, quantitative (Z)- to (E)-isomerization occurred to cleanly afford the desired

(E)-β-hydroxy sulfones 186a,b. In the preparation of 186a,b we found it more practical to add 10 mol% DMAP to the concentrated dichloromethane extracts of the crude reaction mixtures. After reaction for 36 h, column chromatography cleanly afforded the

(E)-isomeric products 186a,b (30% yield) and 197 (43% yield).

It should be noted that, in the absence of solvent, compounds 185a,b and 186a,b are prone to rapid polymerization. The yields of compounds 185a,b, 186a,b, 196 and 197 were calculated by 1H NMR analysis using 2,6-di-tert-butyl-4-methylphenol as an internal standard. To evaluate the reliability of these calculations, in several cases the solvent was removed in high vacuo and the isolated yield was compared with that established by use of an internal standard. These yields were always in good agreement

(no more than 1% deviation). Compounds 185a,b and 186a,b could be stored for up to

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two weeks at –5 oC in dichloromethane solution in the presence of 2,6-di-tert-butyl-4- methylphenol without noticeable decomposition.

Table 4. Preparation of Butadienyl sulfones 185a,b and 186a,b

1 a b,c d Entry R ZnCl2 Time pH Approximate product ratio Yield, % 185 186 cis-- trans- (equiv) (h) 199 (or 199 (185+186) 198) 1 CH3 0.52-0.50 3 8.3-8.6 1 3.5 Traces 0 30

2 H 0.52-0.50 3 8.3-8.6 1 3.3 0.4 n/a 30

e 3 CH3 0.52-0.50 1.66 8.3-8.6 1 1 0 0 25

f 4 CH3 0.52-0.50 5 8.3-8.6 1 7 0.2 0.1 23

5 CH3 0.50-0.49 3 10.2 1 3.5 0.6 0.3 30

6 CH3 0.50-0.49 5 10.2 1 7 4.4 1.2 -

7 CH3 0.35 3 14 0 <0.2 4.8 1 -

a – Measured at the end of the reaction prior to workup. b – Bis-butadienyl sulfones 196 and 197 are not included; the ratio of 196/197 closely paralleled the ratio of 185/186. c – Measured by 1H NMR analysis of the crude product. d – After purification by column chromatography. e – Large amounts of intermolecular Michael addition products were seen in the 1H NMR spectrum. f – Trace amounts of intermolecular Michael addition products were seen in the 1H NMR spectrum. A comparison of the 1H NMR spectra of (Z)-butadienyl sulfones 196 and 186a,b, and the corresponding (E)-isomers 197 and 186a,b, demonstrated the expected differences in coupling patterns and chemical shifts. The (Z)-isomers showed the expected downfield field (7.44 ppm) γ-vinylic proton resonances. In his study of the 1H NMR spectra of (E)- and (Z)-2-methyl-1,3-butadienyl sulfones, Burger44 established by nOe experiments that

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those sulfones showing a downfield γ-H absorption (7.80-7.27 ppm) possess the (Z)- configuration. For the corresponding (E)-isomers, the β-vinylic protons were furthest

α β downfield (7.16-7.22 ppm). The assignment of protons H2 and H2 were made based on the assumption that, in CDCl3 solution, A (Figure 8, R = C4H5) is the preferred conformation. Acludia reported64 that the preferred conformation for the corresponding methyl sulfone is A (R = Me) due to both steric and electronic interactions. The

65 preferred axial orientation of the SO2Me group in 5-methylsulfonyl-1,3-dioxolanes also supports an attractive electrostatic interaction between the β-sulfonyl and oxygen substituents.

Figure 8. Suggested preferred conformation of β-hydroxy sulfones 185b and 186b

CH3 β α H2 H2

HO H SO2R A Decreasing the reaction time from 3 h to 1 h 40 min (see Scheme 54; Table 4, compare entries 1 and 3) led to: a) a decrease in the combined isolated yield of (Z)- and

(E)-β-hydroxypropyl dienyl sulfones 185b and 186b from 30% to 25%; b) a decrease in the ratio of (E)/(Z)-products 186b and 185b from approximately 3.5/1 to 1/1; c) the observation of a significant amount of a complex mixture of intermolecular Michael addition products (see below). Interestingly, the amount of ZnO precipitate formed did not change with this shorter reaction time – in both cases, a quantitative recovery of Zn based on initially added ZnCl2 was achieved. Extending the reaction time from 3 h to 5 h

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(Table 4, entry 4) led to: a) a decrease in the combined yield of (Z)- and (E)-β- hydroxypropyl dienyl sulfones 185b and 186b from 30 to 23%; b) a decrease in the combined yield of bis-sulfones 196 and 197 from 43 to 28%; c) an increase in the ratio of

(E)/(Z)-products 186b and 185b from approximately 3.5/1 to 7/1. The amounts of intermolecular Michael addition products formed in this run were negligible.

From the data above we feel it safe to conclude that (Z)- to (E)-isomerization occurs for both (Z)-butadienyl sulfone 185b and (E, Z)-bis-butadienyl sulfone (196) under the reaction conditions and that prolonged reaction times lead to product decomposition.

Very small amounts of cyclization products 198, cis-199 and trans-199 were observed at longer reaction times (Table 4, entries 2 and 4). Such products were not seen at shorter reaction times (see entry 3). It should be noted that the pH of the reaction mixture remained essentially neutral until all Zn ions precipitated in the form of ZnO and then, at the end of the reaction, it increased to 8.3-8.6 (Table 4, entries 1-4). We postulated that these cyclization side reactions begin after this increase in pH and proceed relatively slowly under these slightly basic conditions. To examine this hypothesis, we repeated two of the above experiments using slightly less ZnCl2 (0.50-0.49 equiv). As expected, this change afforded a slightly more basic medium (pH 10.2) at the end of the reaction. This change did indeed increase the amount of cyclization byproduct formation. Some cyclization products cis-199 and trans-199 were now observed after 3 hours (compare entries 1 and 5), and their formation increased further when the reaction time was extended to 5 hours (compare entries 4 and 6). When the amount of ZnCl2 was further decreased (0.35 equiv, entry 7) the reaction medium at the end of the transformation was

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now very basic (pH 14). Under these conditions, the desired β-hydroxypropyl dienyl sulfone products 185b and 186b were no longer present in the crude reaction mixture even after 3 hours. Only cyclization products cis-199 and trans-199 were separated from the reaction mixture in 31% and 5% isolated yield, respectively, along with a 1/4.5 mixture of bis-butadienyl sulfones 196 and 197 in 14% isolated yield.

Scheme 55. Michael-type cyclization of (E)-β-hydroxypropyl dienyl sulfone 186b in the presence of

K2CO3

0.21 equiv H5b 3b H5b 3b O H O H - K2CO3, 5a 5a O CH H H 3a - 3 H2O S 3a S H 186b OH H C H + H C 3 O 3 O H2 H2O O O S 6 6 H H2 H O2 A cis-199 trans-199 0.21 equiv K CO , H O 2 3 2

Based on the experimental observations above, we assumed that cyclized byproducts

199 were formed via base-mediated Michael-type cyclization from initially produced butadienyl β-hydroxyalkyl sulfones 185b and/or 186b. Indeed, on heating an aqueous solution of clean (E)-β-hydroxypropyl dienyl sulfone 186b in the presence of 0.21 equiv of K2CO3, a 4/1/0.6 mixture of cis-199/trans-199/unreacted 186b was formed after 5 h at

75 oC. After 9 h, a 6/1/0.3 mixture of these products was obtained (Scheme 55). The stereochemistry of the cis- and trans-diastereomers of 199 was assigned based on a careful analysis of their 1H NMR spectra. The 1H NMR spectrum of cis-199 shows strong support for a predominant conformation having both the vinyl and methyl substituents equatorial. The assignment of the axial protons H3b and H6 was based on the large

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coupling constants observed for the pairs H2/H3b and H5b/H6 (11.2-11.0 Hz); consequently, small coupling constants were observed for the pairs H2/H3a and

H5a/H6 (1.9-2.0 Hz). Equatorial protons H3a and H5a demonstrate strong W coupling (3.5

Hz). Similar patterns were observed for the 1H NMR spectrum of 198. The 1H NMR spectrum of trans-199 shows that, as might be expected, two major conformations are

6 5 present in CDCl3 solution. The coupling constants of H with the two protons H became closer (7.1 and 2.9 Hz), while the coupling between H2 and the two H3 protons are now very similar (5.7 and 4.4 Hz). W-Coupling is now observed for both pairs of cis-protons

H3 and H5 (2.3 Hz and 1.7 Hz).

The increase in the cis-199/trans-199 ratio after time suggests that isomerization favoring the more thermodynamically stable cis-199 product occurs under these basic conditions, presumably via a retro-Michael/Michael mechanism. This supposition was supported by a control experiment. When a 1/1 mixture of cis-199/trans-199 was heated

o to 80 C in water in the presence of 0.21 equiv of K2CO3 for 10 h, the formation of cis-

199/trans-199/186b in a 15/0.3/1 ratio was observed by 1H NMR analysis of the crude reaction product.

In an attempt to improve the modest yields obtained for the desired products 185a,b and 186a,b in the above experiments, we decided to first separate the Zn (Z)-butadienyl sulfinate 195. The reaction was conducted as described above, however, the Zn (Z)- butadienyl sulfinate precipitate 195, formed after addition of ZnCl2 to the corresponding

Li butadienyl sulfinate (183, Met = Li), was isolated by filtration. It was carefully washed with water and then dichloromethane to remove traces of LiCl and any organic

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impurities that might be present. After drying in vacuo, we obtained clean Zn (Z)- butadienyl sulfinate dihydrate 195 in 72% isolated yield from butadiene sulfone (182).

Scheme 56. Condensation of epoxides with previously separated Zn (Z)-butadienyl sulfinate (195)

R H2b H2a R 3 3 1 OH O O O 4 S 4 S 1 OH S Zn * 2H O + 2 2 6a O O O H2O H 5 2 R 5 2 6 195 185a,b 200a,b H6b 195

O CH3 O 3 10 8 2 3 14 12 2 9 7 2 S 195 S 1 OH 4 S 1 OH 4 S S 9 7 2 13 11 10 8 O2 O2 O2 5 5 CH3 6 2016 202

Approximate product ratio by 1H NMR analysis of the crude reaction mixture:a

R = CH3 - 185b : 200b : 2(201) : 3(202) = 18 : 18 : 30 : 34; R = H - 185a : 200a = 3 : 1

1β 1α O H H 3 10 8 2 S 2 4 S OH 9 7 O2 5 CH3 6 203 a. The concentration of 201 was doubled and the concentration of 203 was tripled in the ratio expression to reflect the presence of two and three butadienyl moieties, respectively, in these compounds.

To our surprise, when the isolated salt 195 was treated with 3 equiv of propylene oxide at 75 oC for 8 hours in aq solution, the conversion of the salt to organic products (as established by 1H NMR analysis of the crude reaction mixture) was only around 40%.

None of the bis-dienyl sulfone byproducts 196 and 197 were detected by either TLC or

NMR analysis of the crude reaction product, and no (E)-β-hydroxypropyl dienyl sulfone

186b was observed. (Z)-β-Hydroxypropyl dienyl sulfone 185b was formed in low yield, along with product 200b (derived from O-attack of the sulfinate anion on propylene oxide) and intermolecular Michael addition products 201 and 202 (see Scheme 56).

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Column chromatography gave an inseparable mixture of 185b and 200b (13% combined yield), clean Michael addition products 201 (11%) and 202 (13%), and less than 1% of

203, which results from regioisomeric ring opening of propylene oxide. Similar results were observed for the reaction of 195 with ethylene oxide. The reaction was interrupted after 2 h at 75oC, when column chromatography gave an inseparable 3/1 mixture of S- alkylated product 185a and O-alkylated product 200a (20% combined yield). Significant amounts of the corresponding intermolecular Michael addition products were also formed, however, in this case we did not separate and fully characterize them.

1H NMR signals due to the β-hydroxypropyl dienyl sulfones 185a and 185b did not overlap with signals due to the corresponding O-alkylated products 200a and 200b, which allowed for their ready characterization from the isolated mixtures of 185a/200a and 185b/200b. To obtain clean 185a and 185b, the mixtures of 185a/200a and

185b/200b were (separately) treated with saturated aq NaHCO3 at rt. After 4 h, this resulted in complete hydrolysis of the O-alkylated products 200a and 200b, and clean sulfones 185a and 185b were separated by dichloromethane extraction of the aqueous reaction mixtures. In the case of 200b, both 1H and 13C NMR analysis were consistent with the presence of a 1:1 mixture of two diastereomers.

The fact that the above reaction using purified Zn salt 195 proceeded so much more slowly than when this salt was generated and used in situ (Scheme 54) suggested a possible role for lithium butadienyl sulfinate, which may be in equilibrium with Zn butadienyl sulfinate 195 when the salt is used in situ. To further probe this hypothesis, we treated an aq solution of the isolated Zn salt 195 with 0.1 equiv of LiOH, which

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presumably would lead to the formation of some Li butadienyl sulfinate and ZnO.

Propylene oxide (3 equiv) was added and the reaction was allowed to proceed for 9 h at

75 oC. The pH of the final reaction mixture was around 6, indicating that the Zn salt 195 had not been completely consumed. The 1H NMR spectrum of the crude reaction product was almost identical to that seen when the reaction was performed in the absence of added LiOH. Thus, these reactions proceed fastest when using freshly prepared (in situ)

Zn salt rather than when using preisolated Zn salt, whether in the presence or absence of added Li+ ion.

Scheme 57. Condensation of propylene oxide with previously separated Zn (Z)-butadienyl sulfinate

(195) in the presence of K2CO3

OH S OR O O O 3 equiv 2 R S Zn * 2H2O 186b + O 0.2 equiv K2CO3, S o 2 H O, 75 C, 10 h O 195 2 2 S cis-199, trans-199 O2 197 Approximate product ratio by crude 1H NMR analysis: 186b : 2(197) : cis-199 : trans-199 = 28 : 15 : 46 : 11

In the light of above results we decided to examine the more “naked” K butadienyl sulphinate in equilibrium with Zn butadienyl sulphinate. We treated clean Zn salt 195 with 3 equiv of propylene oxide in the presence of 0.2 equiv of K2CO3. The reaction mixture was heated to 75 oC for 9 hours (Scheme 57). The pH at the end of the reaction was 9.2, indicating that the Zn sulfinate salt was fully consumed; however, the total conversion into products 186b, 197 and 199 was only around 40%. At present, we have no definitive explanation for this observation.

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From the above experiments, we concluded that, in aqueous medium: a) the formation of bis-sulfones 196 and 197, the isomerization of (Z)-β-hydroxypropyl dienyl sulfones

185a,b into (E)-β-hydroxypropyl dienyl sulfones 186a,b, and the formation of cyclic products 198 and 199, all seem to require slightly basic conditions; b) under slightly basic conditions the amount of intermolecular Michael addition products (such as 201, 202 and

203) decreases with time (see Table 4, compare entries 3 and 4) and the O-alkylated products 200a and 200b, if formed, are hydrolyzed under the reaction conditions.

We hypothesized that the above data could be rationalized if we assumed that, under basic catalysis, Michael addition of dienyl sulfinate anions to (Z)- or (E)-β- hydroxypropyl dienyl sulfones 185a,b and 186a,b is reversible. To support this hypothesis, we treated purified Michael adduct 201 with 3.3 equiv of propylene oxide in the presence of 0.11 equiv of K2CO3 (Scheme 58). The reaction mixture was heated at 75 oC for 3 h. By 1H NMR analysis of the crude reaction mixture, we observed that: a) 7% and 40% of the butadienyl fragments derived from 201 became incorporated as part of the (Z)- and (E)-β-hydroxyethyl dienyl sulfones 185b and 186b, respectively; b) 14% and

18% of these butadienyl fragments formed (E,Z)-bis-dienyl sulfone 196 and (E,E)-bis- dienyl sulfone 197, respectively; c) 8% of the butadienyl material remained incorporated within the starting Michael adduct 201; d) 13% of this butadienyl material was incorporated within a new Michael adduct 204, which is stereoisomeric with the starting material (201).

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Scheme 58. Condensation of Michael adduct 201 with propylene oxide in the presence of K2CO3

O2 S S OH O2 201 OH-

O O - 2 2 S + S S OH S - OH O2 (B) O2 (C)

- SO2; CH2=CHMe - OH - 185b or 186b - O O S 2 S S O + OH O2 196 (Z)-183 186b OH-

- 196 O (Z)-183 or OH or 197 (E)-183 O2 OH S S S O2 O2 (D) 185b O - - (Z)-183 or OH OH 196 or (E)-183 197 O- S S + O O2 197 (E)-183 185b or 186b OH-

O2 S S OH O2 204

Product ratio by crude 1H NMR analysis: 185b : 186b : 2(196) : 2(197) : 2(201) : 2(204) = 7 : 40 : 14 : 18 : 8 : 13

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To rationalize the observed results we propose that, under basic catalysis, two deprotonation paths lead from 201 to the formation of two putative intermediates B and C

(see Scheme 58). Decomposition of B via the elimination pathway shown leads to (E, Z)- bis-dienyl sulfone 196, while decomposition of C leads to the reversible formation of the

(E)-product 186b and butadienyl sulfinate anion (Z)-183. This (Z)-anion 183 can irreversibly react with propylene oxide to form the (Z)-product 185b or reversibly react with any Michael acceptor present in the reaction mixture (for example, (E,Z)-bis-dienyl sulfone 196, (Z)- and (E)-β-hydroxypropyl dienyl sulfones 185b and 186b). Michael reaction with 196 leads to intermediate D which, after base-mediated elimination, can afford both bis-dienyl sulfones (E, Z)-196 and (E, E)-197 along with both butadienyl sulfinate anions (Z)-183 and (E)-183.

As a result of all the possible interconversions shown in Scheme 58, in the presence of catalytic amounts of base, the concentrations of (E)-products 186b (as well as 197) should increase with time in the reaction mixture – this was observed (Table 4, compare entries 1, 3 and 4). Also, as expected, shorter reaction times lead to higher residual concentrations of (Z)-intermediates 185b (as well as 196), along with intermolecular

Michael addition products such as 201 and 204 (Table 4, entry 3). As was observed for the reaction of previously separated Zn sulfinate 195 (shown in Scheme 56), in the absence of base, no (E)-product 186b and no bis-dienyl sulfones 196 or 197 can be formed. The intermolecular Michael addition products such as 201 and 202 should then be present in significant amounts. These adducts can only have the (Z)-configuration within the butadienyl group.

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Interestingly, the mechanism proposed above helps to explain some literature data.

Burger44 established that pregenerated anhydrous potassium 2-methyl-1,3-butadienyl sulfinate, prepared by Julia’s method,42 has the (Z)-configuration, which is retained on reaction of this anion with primary halides (allylic, benzylic and methyl) in anhydrous

DMSO to exclusively afford (Z)-sulfones. In line with Burger’s report, Naf 45 expected that the treatment of butadiene sulfone (182) with potassium tert-butoxide in DMSO, followed by addition of allyl bromide, would also give (Z)-sulfone; however, he observed rapid (Z)- to (E)-isomerization under these reaction conditions. Naf attributed this isomerization to a radical process, because no (E)-sulfone formation occurred when (Z)- sulfone was treated with different bases (LDA, potassium tert-butoxide, sodium methoxide) in various solvents (THF, DMF, DMSO) at temperatures ranging from –78 oC to +50 oC.45 In contrast, complete conversion of (Z)- to (E)-sulfone occurred on

o treatment with I2 (2 h/90 C).

Scheme 59. (Z)/(E) isomerization of butadienyl sulfones

RRH - - + R R1 Nu Nu H H Nu S 1 H SO2R 1 O2 H Base H SO2R H (E) H (F)

Rotate

R R H R - - 1 + O2 Nu Nu SO2R H Nu S SO R1 R1 H 2 H Base H H H (G) H (Frot)

We propose that the absence of (Z)/(E)-isomerization in Burger’s alkylation experiments can be attributed to the strictly aprotic nature of the reaction medium (see

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Scheme 59). Reversible Michael addition of the nucleophile (Nu- = 2-methyl-1,3- butadienyl sulfinate anion) to a (Z)-sulfone product would give allylic anion E (R =

CH3). Partial double bond character at the C1-C2 bond presumably inhibits bond rotation; thus elimination of Nu- would cleanly regenerate the (Z)-sulfone. In contrast, one equivalent of tert-butanol was present in the sulfinate alkylation study reported by

Naf, generated during the in situ formation of the sulfinate anion. This would allow for protonation of the initially formed anion (E, R = H) to form intermediate F (R = H). We propose that allylic 1,3-strain will disfavor conformation F relative to Frot.66 Free rotation around the C1-C2 single bond followed by deprotonation of the more stable conformation

(Frot) would lead to anion G (R = H), which would decompose to produce (E)-sulfone and regenerate the nucleophile. In our case of DMAP-induced isomerization of (Z)- sulfones 185a,b into (E)-sulfones 186a,b, the β-hydroxy group provides the means for intramolecular protonation of the intermediate (E, R = H), and the resulting alkoxide can subsequently achieve intramolecular deprotonation of the rotamer (Frot, R = H).

Consistent with this assertion, as will be shown later, acylation of the β-hydroxy group of

(Z)-sulfones 185a,b completely suppresses DMAP-induced (Z)/(E)-isomerization.

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2.2. SYNTHESIS OF β-HYDROXY SULFONES via COUPLING OF

SULFINATE ANIONS WITH α-BROMO KETONES FOLLOWED BY

REDUCTION

Short overview: (E)-Butadienyl β-hydroxyalkyl sulfones bearing β-phenyl and β-tert- butyl substituents were successfully synthesized in high yields from butadiene sulfone via a three-step sequence: (i) coupling of (Z)-butadienyl silyl sulfinate 205 with α-bromo acetophenone or bromomethyl tert-butyl ketone; (ii) reduction of the resulting ketones into the corresponding secondary alcohols using sodium borohydride/methanol; (iii)

DMAP-induced (Z)/(E)-isomerization.

As an alternative approach to the β-hydroxy sulfone-based tethers required for our intramolecular Diels-Alder cycloaddition reactions, we attempted to employ α-halo ketones as electrophiles to trap the (Z)-butadienyl sulfinate anion. Because opening of ethylene oxide and propylene oxide with zinc sulfinate 195 (Section 2.1) provided us enough of β-hydroxy sulfones 186a and 186b (R1 = H and Me) for use in further transformations (see Section 2.3), we concentrated our attention on commercially available α-bromo acetophenone and bromomethyl tert-butyl ketone, which, after coupling with the (Z)-butadienyl sulfinate anion followed by reduction and (Z)-/(E)- isomerization, would provide β-hydroxy sulfones 186c and 186d (R1 = Ph and tert-Bu).

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Scheme 60. Synthesis of β-hydroxyalkyl butadienyl sulfones from α-bromo ketones

o 1 1. n-BuLi, THF, -78 C, 5 min; R -CO-CH2Br, TBAF, 2. Me SiCl, -78 oC, 1.5 h O -78 oC to rt overnight 3 S S OTMS O2 182 205

NaBH4 (1.05 equiv), O MeOH/H O OH S 2 S O 1 o O 1 2 R -35 C to rt 2 R over 1h 15 min 1 206 R = Ph (70%) 185c R1 = Ph 1 207 R = t-Bu (54%) 185d R1 = t-Bu

NaBH4 (1.4 equiv), 20 mol% DMAP, MeOH/H2O, o -35 C to rt CH2Cl2, rt, 2 days over 1h 15 min

OH OH OH S + S S O2 1 O 1 O 1 R 2 R 2 R 185c R1 = Ph 208c R1 = Ph 186c R1 = Ph (92%, two steps) 1 1 185d R = t-Bu 208d R = t-Bu 186d R1 = t-Bu (85%, two steps) 185/208 = ca 1/0.35

In our initial attempts, Zn, Li and K butadienyl sulfinates, each freshly prepared from

182 in THF, failed to react with α-bromo ketones, which were recovered unreacted.

Therefore, we turned our attention to a report by Bouchez and Vogel,67 which described that allyl or α-carboxyalkyl sulfinate anions, produced in situ from the corresponding silyl sulfinates, reacted with α-bromo esters to generate the corresponding sulfones. To our delight, this approach worked well for the reaction of (Z)-butadienyl silyl sulfinate

205 with α-bromo acetophenone and bromomethyl tert-butyl ketone to furnish (Z)-β-oxo sulfones 206 and 207, in 70% and 54% yields respectively (Scheme 60). In our first attempts, a somewhat lower yield (40%) was observed for tert-butyl ketone 207. The yield was improved when a radical scavenger (2,6-di-tert-butyl-4-methyl phenol) was

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added to the reaction mixture immediately following the ketone addition (prior to the warm up, see Experimental Section).

Oxo sulfones 206 and 207 were reduced in high yield to produce the corresponding

(Z)-β-hydroxyalkyl butadienyl sulfones 185c and 185d; however, optimization of this step required some experimentation. In our first attempt, we treated ketone 206 with 1.15 equiv of sodium borohydride at 0 oC. The reduction proceeded in high yield; however, the product was contaminated with 8-9% of a byproduct, which was inseparable by column chromatography. When the reaction was repeated at -35 oC employing 1.4 equiv of sodium borohydride, the amount of this byproduct increased to 20-23%. By NMR analysis of the crude reaction mixture, we were able to identify the byproduct as the over- reduced allylic sulfone 208c (Scheme 60). The ratio of (Z)-β-hydroxyalkyl butadienyl sulfone 185c / (E)-β-hydroxyalkyl 2-butenyl sulfone 208c closely correlated with the amount of sodium borohydride employed (185c/208c = 100/35 for 1.4 equiv of NaBH4 and 185c/208c = 100/10 for 1.15 equiv of NaBH4). When the reaction was performed at

-35 oC employing 1.05 equiv of sodium borohydride, only clean desired product 185c was observed by 1H and 13C NMR analysis of the crude reaction mixture. The same reaction conditions, when employed to reduce tert-butyl-substituted oxo sulfone 207, resulted in the clean formation of tert-butyl-substituted (Z)-β-hydroxyalkyl butadienyl sulfone 185d.

Column chromatography of 185c and 185d resulted in their isolation in 92% and 85% yields, respectively. However for practical use, this column chromatography is not necessary. Our next step was the isomerization of (Z)-butadienyl sulfones 185c,d into

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(E)-butadienyl sulfones 186c,d, which occurred in the presence of 20 mol % of DMAP in anhydrous dichloromethane. When crude products 185c,d were subjected to the DMAP- mediated isomerization, their (E)-isomers 186c,d were separated by column chromatography with the same high yields (92% and 85% respectively) for two steps from 206 and 207.

In our first attempts, the isomerization of 185d required 4 days to go to completion.

Later, we found out that increasing the concentration of the dichloromethane solution of

185c and 185d from 0.07 M to 0.14 M led to their complete isomerization into 186c and

186d after 36 hours.

Interestingly, when clean oxo sulfones 206 and 207 (0.14 M solutions in anhydrous dichloromethane) were treated with 25 mol % of DMAP, no traces of (Z)-/(E)- isomerization were observed by NMR after 4 days. As has been discussed in Section

2.1.3, the presence of a proton source was necessary to accomplish this isomerization.

As a result of the above studies, we now had an efficient entry to (E)-butadienyl β- hydroxyalkyl sulfones 186a-d on a multigram scale. We were thus in a position to assemble the corresponding β-acryloyloxyalkyl butadienyl sulfones needed for our intramolecular Diels-Alder cycloaddition chemistry.

2.3. ESTERIFICATION OF β-HYDROXY SULFONES

Short overview: A series of β-acryloyloxy sulfones – substrates to be investigated in subsequent intramolecular Diels-Alder cycloaddition reactions – were successfully

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synthesized. The prepared β-acyloxy sulfones differed in the bulk of the substituent on sulfone tether (H, Me, Ph and tert-Bu) and also by the substitution on the acrylate ester residue (methacrylate, acrylate, α-bromoacrylate and crotonate esters), thus providing a variety of possibilities for Diels-Alder studies. The esterification was accomplished employing DCC/DMAP-based methods, as well as via the preliminary formation of mixed anhydrides of α-bromoacrylic and 2,4,6-trichlorobenzoic acids followed by reaction with the requisite butadienyl sulfonyl-substituted alcohol in the presence of LiCl and triethylamine.

The esterification of (E)-β-(dienylsulfonyl) alcohols 186a-c with methacrylic acid

(209) to afford the corresponding methacrylate esters 215a-c, as well as the esterification of alcohols 186a,b with acrylic acid (210) to afford the corresponding acrylate esters

216a,b, proceeded in good yield (81-93%) using conventional DCC/DMAP methods

(Scheme 61, Table 5, entries 1-3, 6, 7, method A). No alcohol decomposition was observed under the reaction conditions. The yields of all the reactions above were strongly dependent on the molar ratio of acid/DCC. The high yields were achieved only if a slight excess of the acid was used (acid/DCC = 1.06-1.07/1). In contrast, if the same molar amounts of acids and DCC were used, or if an excess of DCC was employed, large amounts of N-acylureas 220 (Scheme 62) accumulated in the reaction mixture. The amounts of the formed N-acylureas 220 were proportional to the bulk of the R1 substituents (i.e. the steric crowding of the reaction center). For phenyl-bearing alcohol

186c, less than 50% of the corresponding ester 216c was formed even when an excess of

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acid was used (Table 5, entry 8, method A). For the most crowded tert-butyl-bearing alcohol 186d no formation of esters 215d or 216d occurred on reaction with either methacrylic or acrylic acids; in each case, only the formation of the corresponding 1,3- dicyclohexyl-2-methacryloyl urea68 and 2-acryloyl-1,3-dicyclohexyl urea (220) was observed.

Scheme 61. Esterification of β-hydroxy sulfones 186a-d

2 1 2 R O R R A, B or C 2 + O S S OH HO2C O 1 2 R O 1 1 2 2 186a R = H; 186b R = CH3; 209 R = CH3; 215a-d R = CH3; 186c R1 = Ph; 186d R1 = t-Bu 210 R2 = H; 216a-c R2 = H; 211 R2 = Br 217b,c R2 = Br

1 2 1 2 215a R = H, R = CH3; 216a R = H, R = H; 1 2 1 2 1 2 215b R = CH3, R = CH3; 216b R = CH3, R = H; 217b R = CH3, R = Br; 1 2 1 2 1 2 215c R = Ph, R = CH3; 216c R = Ph, R = H; 217c R = Ph, R = Br 1 2 1 2 215d R = t-Bu, R = CH3 216d R = t-Bu, R = H

Reagents: A - DCC, DMAP, CH2Cl2, rt, 2 days, (acid/DCC = 1.06-1.07/1); B - DCC, DMAP, CH2Cl2, rt, 2 days, (acid/DCC = 1.95/1, preliminary ahydride formation); C - 2,4,6-trichlorobenzoyl chloride, Et3N, LiCl, THF, rt, 24h. R2 R2 R2 O t-Bu 3 3 D 3 2 + R O R O R S S OH O OO 2 t-Bu O 186d 2 3 2 3 212 R = CH3, R = H; 215d R = CH3, R = H; 213 R2 = H, R3 = H; 216d R2 = H, R3 = H; 2 3 2 3 214 R = H, R = CH3 218d R = H, R = CH3

Reagents: D - DMAP (1.1 equiv), CH2Cl2, rt, 30h.

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Table 5. Esterification of (E)-β-(dienylsulfonyl) alcohols 186a-d to afford acrylate esters

Entry Product R1 R2 (R3 = H) Methoda Yield (%)b

1 215a H CH3 A 85

2 215b CH3 CH3 A 93

3 215c Ph CH3 A 81

c 4 215d t-Bu CH3 B 50

5 215d t-Bu CH3 D 76

6 216a H H A 85

7 216b CH3 H A 83

8 216c Ph H A 45-48

9 216c Ph H B 81

10 216d t-Bu H D 74

c 11 217b CH3 Br A 28

12 217c Ph Br C 47c (59d)

2 3 13 218d t-Bu R = H; R = CH3 D 75

a See Scheme 61.

b Isolated yields after purification by silica chromatography.

c Non-optimized yields.

d Based on consumed β-hydroxy sulfone.

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Scheme 62. Proposed mechanisms for the reaction of dicyclohexyl carbodiimide with acids

O R2 HO HO CO R2 Base- CyNCNCy CyNCNCy (A) O H+ H+ - O O H R2 H H Cy NCNCy CyN C NCy Cy N C NCy + O O H O R2 Cy NCNCy 2 + R 219 220 O

- O R2

O O O O H H ROH Cy NCNCy + + - O DMAP RO O 2 2 O R2 R2 R R

In an attempt to improve this situation, we turned our attention to the mechanism of this esterification reaction. Two mechanisms have been proposed for the reaction of carbodiimides with acids. Khorana69 suggested that initial protonation of carbodiimide is followed by the addition of the carboxylate anion to produce O-acylisourea 219 (Scheme

62), It has been reported that the unstable O-acylisourea 219 is prone to rapidly rearrange into an N-acylurea (220) via a four-center transition state;70 however, in the presence of an excess of the carboxylate anion it can also form the anhydride of the acid and urea.

When the resulting anhydride reacts with an alcohol, carboxylate anion is regenerated during ester formation. If the formation of O-acylisourea 219 and regeneration of the carboxylate anion occur at comparable rates, most of the O-acylisourea 219 is

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transformed into urea and the acid anhydride, while the formation of N-acylurea 220 is negligible. However, if the esterification is slow and the carboxylate anion is not regenerated fast enough, most of the O-acylisourea 219 would be transformed into N- acylurea 220, which was indeed observed in our case for more sterically crowded alcohols 186c,d.

Kolodziejczyk71 proposed that O-acylisourea 219 and N-acylurea 220 are formed independently via four-membered transition state (A) (Scheme 62) by proton or base attack, respectively. In our case, this might partially account for the high yields of ester requiring large amounts of acid, however, the fact that, in the absence of excess carboxylate anion, O-acylisourea 219 would rapidly rearrange into an N-acylurea 220 remains true.

The considerations above suggested that, if the acid anhydride was preformed and then treated with alcohol and base, the reaction yields should improve. Indeed, when we reacted 1.30 equiv of DCC with 2.54 equiv of acrylic acid (210) for 4 hours, filtered the reaction mixture under argon to remove urea and then treated crude acrylic anhydride with 1 equiv of 186c in the presence of 20 mol % of DMAP, the yield of separated ester

216c was 81% (Table 5, entry 9, method B). However, under the same reaction conditions, the tert-butyl-substituted alcohol 186d and methacrylic acid (209) gave only

50% yield of the corresponding methacrylate ester 215d (Table 5, entry 4, method B). As will be shown in Section 3, the tert-butyl-substituted tethers 215d and 216d resulted in the highest yield and diastereoselectivity during Diels-Alder cycloaddition. As a result, we thought it rewarding to look for a better yielding way to obtain these compounds. To

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our delight, the reactions of 186d with commercially available methacrylic (212), acrylic

(213) and crotonic (214) anhydrides in the presence of 1.1 equiv of DMAP proceeded cleanly, albeit slowly (30 hours), to give 74-76 % isolated yields of the desired esters

215d, 216d and 218d (Scheme 61, Table 5, entries 5, 10, 13, method D).

Not surprisingly, esterification using α-bromoacrylic acid (211) was problematic. To the best of our knowledge, no examples of esterification of α-bromoacrylic acid (211) using an alcohol have been reported. Esterification to afford a phenyl ester (10% yield) was reported in one case.72 Three esters of 211 have been prepared via carboxylate alkylation using (i) benzyl bromide,73 (ii) allyl bromide74 and (iii) epichlorohydrin.75 The best yield to date was achieved by us when alcohol 186c was treated with the mixed anhydride derived from α-bromoacrylic acid (211) and 2,4,6-trichlorobenzoyl chloride in the presence of LiCl and triethylamine (Scheme 61, Table 5, entry 12, method C). α-

Bromoacrylate ester 217c was obtained in 47% isolated yield (59% based on recovered unreacted β-hydroxy sulfone 186c).

Scheme 63. Reaction of carbodiimides with alcohols catalyzed by CuCl and followed by esterification.

OH R H H+ H + H i-PrNCN i-Pr i-Pr N C N i-Pr i-Pr N C N i-Pr CuCl O O O - 1 R 221 R :O R

H H O i-Pr NCN i-Pr + ROR1 O

Another carbodiimide-based approach to the synthesis of esters76 proceeds via CuCl catalyzed formation of O-alkylisoureas 221, which react with acids to produce urea and

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the corresponding ester (Scheme 63). The usual starting material to form O-alkylisoureas

221 is diisopropyl carbodiimide (a liquid at rt) rather than dicyclohexyl carbodiimide (a solid at rt), because the first step of the reaction is, usually, done without solvent by simply mixing the carbodiimide, alcohol and catalyst at ambient temperature. We examined this method to achieve esterification of the (E)-β-(dienylsulfonyl) alcohols

186a-c with acrylic acids. However, the treatment of alcohol 186b with diisopropylcarbodiimide in the presence of CuCl resulted in a close to quantitative formation of (E)-butadienyl propen-1-yl sulfone (222) (Scheme 64). We believe that the formation of sulfone 222 is facilitated by the acidic nature of the protons α- to the sulfone group in 186b, allowing a [1,5] hydrogen shift via the six-membered transition state shown. As a result, it became clear that this approach would not be amenable to the synthesis of esters derived from β-hydroxy sulfones.

Scheme 64. Reaction of diisopropyl carbodiimide with (E)-b-(dienylsulfonyl) alcohol 186b in the presence of CuCl

i-Pr HN OH i-PrNCN i-Pr S i-Pr O2 CuCl N O 186b CH3 H CH3 SO2

H H i-Pr NCN i-Pr + S O O2 222

At this point in our study we had successfully synthesized a series of β-acyloxy sulfones that differed in the bulk of the substituent on the sulfone tether (H, Me, Ph and t-

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Bu) and also in the substitution on the acrylic acid residue (methacrylate, acrylate, α- bromoacrylate and crotonate esters). Therefore, we were in a position to begin an investigation of intramolecular Diels-Alder cycloaddition reactions of these substrates.

3. DIELS-ALDER CYCLOADDITION REACTIONS OF β-

ACRYLOYLOXYALKYL BUTADIENYL SULFONES.

Short overview: β-Hydroxy sulfone-based tethers were employed for the first time to achieve thermally-mediated intramolecular Diels-Alder cycloaddition. The reactions proceeded with complete regioselectivity, high (10/1) to complete endo/exo-selectivity, and resulted in the preferential formation of one of the two possible endo-cycloadducts.

The yields and stereoselectivities were proportional to the bulk of the R1 substituent on the β-acyloxysulfonyl tether.

At the very beginning of the discussion we would like to emphasize that, while the formation of three diastereomeric products 223-225 was observed in thermally-mediated

IMDA reactions of 215a-d, 216b-d and 217b,c (Scheme 65, Table 6),77 in all cases the major diastereomer (223) could be easily separated as a pure material after conventional column chromatography or by simple crystallization from the crude reaction mixture.

The yields of this pure material varied depending on the substituent R1 on the tether: 47-

58% for R1 = Me; 49-63% for R1 = Ph and 71-72% for R1 = tert-Bu.

100 101

Scheme 65. Diels-Alder cycloaddition reactions of tethers 215a-d, 216a-d and 217b,c

2 R Heat, T oC O Toluene, 0.01-0.04 M S O 1 2 R O (see Table 6) 2 215a-d R = CH3; 2 1 1 216a-d R = H; a R = H; b R = CH3; 217b,c R2 = Br c R1 = Ph; d R1 = tert-Bu;

R1 R1 R1 R1

O2S H4a O O2S H4a O O2S H4a O O2S O OO Oif R2 = Br 2 ++2 2 O R R R - HBr 223a-i 224b-i 225a-i 226h,i endo-Major endo-Minor exo-Product

1 2 a R = H, R = CH3; 1 2 1 2 1 2 b R = CH3, R = CH3; e R = CH3, R = H; h R = CH3, R = Br; 1 2 1 2 1 2 c R = Ph, R = CH3; f R = Ph, R = H; i R = Ph, R = Br 1 2 1 2 d R = tert-Bu, R = CH3; g R = tert-Bu, R = H;

As had been expected, thermally-mediated IMDA reactions of 215a-d, 216b-d and

217b,c (Scheme 65, Table 6) occurred with complete regioselectivity. Complete endo- diastereoselectivity was observed for the acrylate derivatives 216b-d, while for the methacrylate and α-bromoacrylate derivatives (215b-d and 217b,c) the endo/exo- diastereoselectivity was 10/1, The one reaction that proceeded with low endo diastereoselectivity was when R1=H (215a), which reacted to afford a 3/1 mixture of endo/exo adducts. The absence of the formation of exo-products 225e-g in the Diels-

Alder cycloaddition of acrylate substrates 216b-d might have been expected, while the high endo/exo-selectivity observed for methacrylate substrates 215b-d, as well as bromoacrylate substrates 217b,c, was a pleasant surprise. It is well-documented that dienophiles derived from methacrylic acid (209) usually show poor diastereoselectivity in

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Diels-Alder reactions and often show a proclivity to undergo exo-cycloaddition.78,79

Interestingly, while the endo/exo-diastereoselectivity was significantly increased (from

3/1 to 10/1) on introducing a substituent R1 (Me) in place of a hydrogen atom on the tether’s backbone (Table 6, compare entries 1 and 2), it remained relatively unchanged

(~9/1 to ~14/1) on changing the R1 group from a relatively small Me group to the larger

Ph and t-Bu substituents (see Table 6, entries 2-7 and 12,13).

All reactions resulted in the preferential formation of one of the two possible endo- cycloadducts. The endo-Major (223)/endo-Minor (224) diastereoselectivity in IMDA reactions involving Me- (215b, 216b, 217b) and Ph-substituted (215c, 216c) substrates was comparable (~4/1) while, for t-Bu-substituted substrates 215d and 216d, the diastereoselectivity was improved to ~20/1.

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Table 6. Diels-Alder cycloaddition reactions of β-acryloyloxyalkyl butadienyl sulfones 215a-d, 216a-d and 217b,c

Entry SM Major R1 R2 T oC Time, Ratio of Isolated yeld of product h 223 / 224/ 225 / 223 SMa 1 215a 223a H CH3 130 29.5 100 / --- / 33 / 20 42% (223a + 225a) 2 215b 223b CH3 CH3 128 32.5 100 / 25 / 12 / 22 47% (223b + 224b 3 215b 223b CH3 CH3 140 41 100 / 25 / 12 / --- 36%

4 215c 223c Ph CH3 138 28 100 / 25 / 10 / 20 49%

5 215c 223c Ph CH3 145 50 100 / 25 / 10 / --- 49%

6 215d 223d t-Bu CH3 138 47 100 / 4 / 12 / --- 65%

7 215d 223d t-Bu CH3 125 40 100 / 4 / 12 / --- 72%

8 216a n/a H H 145 50 Decomposition n/a

9 216b 223e CH3 H 130 43 100 / 30 / --- / --- 54% of 223e + 18% of 224e 10 216c 223f Ph H 127 43 100 / 25 / --- / 23 57% of 223f + 16% of 224f 11 216d 223g t-Bu H 125 40 100 / 6 / --- / --- 71% of 223g + 2-3% of 224g b 12 217b 223h CH3 Br 115 21 100 / 27 / 9 / --- 58%

13 217c 223i Ph Br 127 21 100 / 12 / 8 / ---b 63%

14 218d n/a R1 = t-Bu, 145 50 Decomposition n/a R2 = H, 3 R = CH3

a Determined from 1H NMR analysis of the crude reaction mixtures. b The ratio cannot be reliably determined because 224 and 225 are unstable.

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For the substrates 215a-d, derived from methacrylic acid (209), the major endo- cycloadducts 223a-d were separated as single diastereomers after crystallization. The relative stereochemistry of the major endo-cycloadducts 223a,b,d was confirmed by their

X-ray crystal structures.80b,a,81 The relative stereochemistry of the remaining major endo- cycloadduct 223c was established by NOE experiments and 1H NMR analysis.

The minor endo-cycloadducts 224b-d and exo-cycloadduct 225a were characterized by

1H and 13C NMR analysis of the residual mother liquors, obtained after the crystallization of 215a-d. The presence and relative amounts of exo-cycloadducts 225a-c were tentatively determined based on the integration of H4a in the 1H NMR spectra of the crude reaction mixtures. The exo-cycloadduct 225d was separated as a pure material for analysis, and its crystal structure has been determined.81 To achieve the separation, column chromatography was performed on the mother liquor obtained after the crystallization of 223d, which resulted in a mixture of endo-Major 223d / endo-Minor

224d / exo-225d in a 30/23/100 ratio. Recrystallization of this mixture from a minimum amount of EtOAc gave a pure sample of exo-225d.

For cycloadditions involving the substrates 216b-d, derived from acrylic acid (210), both the major endo-cycloadducts 223e-g and the minor endo-cycloadducts 224e-g were cleanly separated as single diastereomers by column chromatography. Relative stereochemistry of major endo-product 223g was established by X-ray analysis.81 For the rest of the products, their relative stereochemistry was established by NOE experiments.

For cycloadditions involving substrates 217b,c, derived from α-bromoacrylic acid

(211), the major endo-cycloadducts 223h,i were purified by silica chromatography. The

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relative stereochemistry of the major endo-cycloadduct 223h was confirmed through X- ray crystal structure determination,80c while the relative stereochemistry of the major endo-cycloadduct 223i was confirmed by 1H NMR analysis. Unfortunately, the minor endo-cycloadducts 224h,i underwent partial dehydrobromination on exposure to silica to afford the corresponding dienes 226h,i. In the case of 224h, we were able to obtain a sample of diastereomerically pure material from the silica column and confirmed its relative stereochemistry by X-ray crystal structure determination,80d however, the dehydrobromination of 224i was too fast to permit its isolation. The presence and relative amounts of minor endo-product 224i and exo-products 225h,i were tentatively determined based on the integration of H4a in the 1H NMR spectra of the crude reaction mixtures.

We observed that increasing the bulk of the substituent R1 on the tether backbone is beneficial for avoiding side reactions during these IMDA reactions. The nonsubstituted substrate 216a, derived from acrylic acid (210), failed to give any intramolecular cycloaddition product and was completely polymerized on heating (120 oC) in toluene.

Large amounts of polymerization products were produced in IMDA reactions of the other non-substituted (215a) and Me-substituted (215b-217b) substrates, while for Ph (215c-

217c) and t-Bu-substituted (215d, 216d) substrates, much less tar formation was observed.

Interestingly, the cycloaddition of α-bromoacrylate substrates 217b,c proceeded faster than for the analogous methacrylate (215b,c) and acrylate substrates (216b,c) and required ~10 oC lower reaction temperatures. Furthermore, the fact that the acrylate

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substrate 216a failed to give any IMDA reaction products, while the corresponding methacrylate derivative 215a was converted into IMDA products in 42% yield, contradicts the conventional wisdom that normal-electron demand Diels-Alder reactions of methacrylate dienophiles are usually more difficult than for the corresponding acrylate substrates.78,79

We also established that, while α-substitution in the acrylate ester moiety seems to be beneficial for these IMDA reactions, β-substitution in the acrylate ester slows the reaction down to the extent of being impractical. Heating crotonate ester substrate 218d to 145 oC in toluene for 40 hours resulted in the formation of only trace amounts of inseparable mixtures of DA products along with some tar formation. Most of the starting material was recovered unreacted. Increasing the temperature (xylenes, 180 oC, 15h) led to extensive tar formation.

To gain an insight into the reaction mechanism we conducted a search for the minimum energy transition states (TS) corresponding to the four possible Diels-Alder products (Figure 9) that could be potentially obtained from the substrate 215b.

Figure 9. Four possible Diels-Alder products from the substrate 215b

CH3 CH3 CH3 CH3

O2S O O2S O O2S O O2S O b b b b OOOO a CH3 a CH3 a CH3 a CH3 endo-1 endo-2 exo-1 exo-2

A major difficulty with such transition state calculations is that the “initial guess” geometry should closely resemble that of the actual TS. If the geometry of the initial

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guess is far from the actual TS geometry, the transition state search most likely would locate some other stationary point (usually corresponding to the reactant or the product).

The presence of a conformationally flexible seven-membered ring in the DA products under consideration made coming up with a good initial geometry a particularly challenging task. We approached the problem as follows.

First, the four possible Diels-Alder products (Figure 9) were subjected to molecular mechanics global minimization by using the Tinker package82,83 (Scan module). The opposite regioisomers were not considered because of excessive strain arising in the transition state. After the search was completed, the conformers found were sorted by their energies. For each compound, the 100 lowest energy conformers were selected.

In a second step, semi-empirical geometry optimization (using the AM1 method available within the AMSOL package84,85) was performed and the conformers were resorted again. During this process, about 10 to 20% of initial guess geometries merged together, resulting in 80 to 90 geometries for each product.

In the third stage, semi-empirical geometry optimization of each conformer was repeated again, but now bond lengths for the bonds a and b (Figure 9) were increased by

0.1Å from their initial values. These new unnatural bond lengths were not allowed to change while the geometry of rest of the molecule was optimized at a semi-empirical level. After this optimization, the bonds a and b were again increased by 0.1Å and the process was repeated until a and b reached the lengths expected in the transition state leading to that compound (ca 2Å). During this process the number of conformers for each compound decreased by 40 to 50% due to the merging of conformers. At this point, an

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attempt to locate a true transition state was performed for the four lowest energy conformers obtained for each endo-1, endo-2, exo-1 and exo-2 compounds, working at the ab-inito HF6-31G* level (available within GAMESS package86,87). However, in each case, no true saddle point was located. Instead, if the a and b bond lengths were around

2Å or longer, the calculations converged to the Diels-Alder precursor, while, if the a and b bonds lengths were shorter than 2Å, the calculations converged to the final Diels-Alder product. To explain these disappointing results, we considered that the a and b bond lengths might be significantly different from each other in the actual transition state. To find these actual transition state bond lengths, we fixed a at 1.8 Å, while b was increased by 0.1 Å increments in a series of successive optimizations of the rest of the molecule at the semi-empirical level. Then, in turn, bond b was fixed at 1.8 Å, while a was increased by 0.1Å increments in a similar series of successive optimizations. As a result of these series of calculations, we found out that the lowest energy conformers corresponded to a being around 1.9 Å, and b being around 2.5 Å. We repeated the third stage of our calculations - semi-empirical geometry optimization of each conformer - but now bond lengths for the bonds a and b were increased by slightly different amounts (around 0.1 Å) from their initial values until a reached 1.9 Å, and b reached 2.5 Å.

In the fourth stage, geometry optimization at the ab initio HF6-31G* level (available within the GAMESS package86,87) was performed with a and b still fixed at 1.90Å and

2.50Å, respectively, for the ten lowest energy conformers for each compound. An extensive conformer merging was observed at this stage, leading only to one geometry

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for endo-1, exo-1, and exo-2 compounds (see Figure 9) while, for the endo-2 compound, four different geometries remained.

In the fifth stage, the bond length restriction was removed and true saddle points were located starting from all 6 initial guesses. The results are presented in Figure 10.

To our delight, the calculation results fully coincided with the experimental observations! The lowest energy transition state geometry was determined to be endo-1, which would lead to the formation of endo-product 223b. The preferential formation of endo-product 223b has been, indeed, observed in practice. The second lowest energy transition state geometry was determined to be endo-2, which would lead to the experimentally observed formation of endo-product 224b. The energy difference between endo-1 and endo-2 is not large (0.62 kcal/mol), which corresponds to a 4.6/1 ratio of reaction rates at 130 oC and is in a good agreement with the experimentally observed 4/1 ratio for 223b/224b.

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Figure 10. Transition states energies and geometries of the four possible Diels-Alder products from the substrate 215b

O O

S O S O

O O O O

endo-1 0 kcal/mol endo-2 +0.62 kcal/mol

O O O S O S O O

O

O

Exo-1 +1.88 kcal/mol Exo-2 +2.48 kcal/mol

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The third lowest energy transition state geometry was determined to be exo-1, which would lead to the observed formation of a minor exo-product 225b. The energy difference between endo-1 and exo-1 is large (1.88 kcal/mol), corresponding to a 10.3/1 ratio of reaction rates at 130 oC. Again, this closely coincides with the experimentally observed 10/1 ratio of 223b/225b. The energy difference between endo-1 and the lowest energy exo-2 transition state is quite large (2.48 kcal/mol), corresponding to a 22/1 ratio of reaction rates at 130 oC, which means that the minor exo-product should be formed in very small amounts that could not be reliably detected by NMR spectroscopy. In practice, no evidence for this minor exo-cycloadduct was seen in the NMR spectrum of the crude reaction product.

Figure 11. Calculated bond lengths in the major endo-1 transition state (A) and in 1-methylsulfonyl butadiene (B)

1.52 1.54 O 1.44 O 1.44 1.80 1.42 1.77 S O S O O 1.77 1.33 1.76 2.53 1.47 1.38 4a 1.20 1 O 1.32 4 9a 1.51 2 1.39 1.40 1.48 31 3 1.402 1.95 1.32 4 A B

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The transition states geometries (Figure 10) suggest that (i) the stereoelectronically preferred s-trans ester conformation,78 and (ii) steric interactions between R1 and the carbonyl group, and are responsible for the observed diastereoselectivity.

Figure 12. Calculated charges in the major endo-1 transition state

.161 .196 .162 .201 H .155 H H H H .181 -.446 0.051 -.695 -.459 .041 H O -0.062 0.203 S 1.432 -.692 -.258 O O 0.045 .206 S O -0.258 H .184 .264 -.354 -0.180 H -.386 O -0.090 H.186 0.061 -.123 -.025 -0.025 -.438 H.164 0.065 -.167 -.286 .174 H.153 0.007 0.087 H -.250 H.192 0.098 .174 .174 H.181 H H

Interestingly, the calculation results not only coincided with the observed diastereoselectivity, but also allowed us to have some insight in the reaction mechanism.

The bond lengths in the endo-1 TS are depicted in Figure 11. The data suggested that the

Diels-Alder reaction proceeds as an asynchronous concerted process, where the formation of bond a is more advanced than the formation of bond b at the transition state.

This would correspond to the developing of partial radical character of the carbon atoms

C-4a and C-9a. The partial radical at C-9 would be stabilized by a methyl group88 and even more by a bromine atom,88 which explains why the proclivity toward DA reaction

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increases in the order: acrylates (216) < methacrylates (215) < α-bromoacrylates (217).

Comparing the bond lengths in the endo-1 TS to those in 1-methylsulfonyl butadiene

(Figure 11) demonstrates that while, in the latter compound, the length of the single and double bonds are as expected (1.48 Å vs 1.32 Å), in the endo-1 TS these bonds all have the same length (ca 1.39 Å).

The charge distribution in the major endo-1 TS is depicted in Figure 12.

Figure 13. Calculated charges in 1-methylsulfonyl butadiene

.201 H -.697 .191 Charge distribution in the O H sulfonyl butadienyl fragment of TS endo-1 -.691 .188 O -.602 H S -0.022 -0.062 1.440 0.052 S 0.045 S .199 1 H .197 1 -.390 -0.193 -0.180 H 2 0.114 0.061 -.085 3

.167 4 3 -.165 0.009 0.007 H 2 -.300 H 0.039 0.098 4 .174 0.114+0.009+0.039 = 0.162 0.061+0.007+0.098 = 0.166

.172 H

It is rewarding to compare the distribution of charges in the major endo-1 TS with those in 1-methylsulfonyl butadiene (Figure 13). The comparison shows that, in the endo-

1 transition state, the charges on the oxygen and sulfur atoms, as well as on the C1 and

C3 atoms of the butadienyl fragment, remained practically unchanged when compared to those in 1-methylsulfonyl butadiene, while some redistribution of the electron density has occurred from C4 to C2 in heading to the endo-1 TS. Overall, no net loss of electron

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density from the butadienyl fragment to the acrylate dienophile is observed in the TS.

This, along with the absence of δ+ charge development at C-1 and C-3 in the diene supports the generation of partial radical character at the transition state.

In conclusion, the linkage of a 1-sulfonyl-1,3-butadiene and various acrylate dienophiles by a two carbon tether bearing a large Ph or t-Bu substituent allowed efficient diastereoselective formation of the corresponding endo-IMDA cycloadducts. The most interesting compounds for the further synthetic transformations seems to be cycloadducts

223b-d, possessing a newly formed quaternary carbon which is generated in a diastereoselective manner. Among the cycloadducts 223b-d, the product 223d was obtained in the highest yield after simple crystallization of the crude reaction mixture.

Therefore, we undertook some preliminary investigations of potentially useful synthetic transformations that 223d can undergo. The results are presented in the following chapter

(Chapter 4).

Is should also be noted that the reduction of ketones 206 and 207 could be accomplished in an enantioselective manner89 producing, after DMAP-induced isomerization, single enantiomers of the corresponding alcohols 186c and 186d. The esterification of 186c and 186d proceeds without disturbing the newly formed stereogenic center, therefore, the corresponding major cycloadducts 223 could be available in enantiopure form (on a multigram scale) after exact repetition of the chemistry described above. We believe this potential for asymmetric induction in the

IMDA reactions developed by us greatly increases the value the work.

4. SOME SYNTHETIC TRANSFORMATIONS OF THE OBTAINED DIELS-

ALDER CYCLOADDUCT 223d.

As has been described in Chapter 3, the cycloadduct 223d was available in good yield as a single diastereomer. It possessed allyl sulfone functionality, which is quite useful in organic synthesis,90 and a quaternary carbon, preparation of which in a stereoselective manner can often be a quite challenging task.89 Hence, we considered exploiting the utility of the cycloadduct 223d as a synthetic building block.

We found that treatment of cycloadduct 223d with LDA leads to the formation of two diastereomeric products: 227, where the stereochemistry of the sulfur-bearing carbon atom is retained and 228, where the stereochemistry of the sulfur-bearing carbon atom is inverted (Scheme 66). The ratio 227/228 depends on the amount of base used and on the reaction conditions (Table 7). We propose that the results can be explained by considering that, in 223d, the tertiary hydrogen atom α- to sulfur on the cyclohexane ring

(H4a) is sterically crowded and not prone to facile kinetic deprotonation. The secondary hydrogen atoms α- to sulfur on the tether (H6) are more accessible and can be kinetically deprotonated, albeit slowly because crowding by the adjacent t-Bu group is still large.

This leads to an initial E1cb reaction, cleaving the lactone ring to afford the carboxylate anion A. In contrast to 223d, the H4a position in carboxylate intermediate A is much more assessible for removal by the base and, as a result, the newly formed carboxylate anion A can be further deprotonated to produce bis-anion B. The protonation of any remaining A

115 116

during the workup occurs with retention of the stereochemistry at C-4a leading to 227, while the protonation of B favors the formation of the more thermodynamically stable product 228. That initial deprotonation of 223d to form both anions A and C occurs simultaneously is feasible but seems highly unlikely because no scrambling of stereochemistry of 223d was observed under any of the explored conditions (Table 7).

Scheme 66. Base-mediated opening of DA cycloadduct 223d followed by methylation

t-Bu t-Bu t-Bu 6 O S O S - O S - 2 H4a O 2 H O 2 O - - - O Base O Base O

223d AB H+ H+ t-Bu t-Bu t-Bu t-Bu

O2S O O2S OH O2S OH O2S OMe - CH N O O O 2 2 O

C 227 228 229

Table 7. Base-mediated opening of DA cycloadduct 223d

Entry LDA (equiv); Conditions Conversion Ratio addition time 227/228 1 1.0; 15 min THF, -78 oC to rt over 15 min 65 % 2/0.9

2 1.0; 45 min THF, -78 oC 2 h, then AcOH at -78 oC 55% 5/1

3 2.2; 10 min THF, -30 oC to rt over 15 min 77% 0.9/10

4 2.2; 10 min THF, -30 oC to rt over 1.5 h 100% only 228

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On treatment with excess base we obtained the clean acid 228 in 87% yield (Table 7, entry 4), which was quantitatively methylated with diazomethane to form the ester 229.

The acid 227 was characterized from the 5/1 mixture with 228 obtained in the experiment corresponding to entry 2 (Table 7).

The obtained highly substituted cyclohexene could serve as a useful building block for many potential transformations (see below). As an attractive approach for further elaboration we attempted an iodolactonization reaction on 228, which would result in the stereoselective introduction of an oxygen atom in the ring. However, when we attempted the iodolactonization reaction on the acid 228, only starting material was recovered after

3 days under standard iodolactonization conditions (Scheme 67). Interestingly, when a

5/1 mixture of 227/228 (obtained in the experiment corresponding to entry 2, Table 7) was subjected to the same conditions, acid 227 completely reacted in 24 hours to give a single product in 90% yield, while acid 228 was recovered unreacted (Scheme 67). The structure of 230 was confirmed by X-ray analysis (Figure 14).

Scheme 67. Attempted iodolactonization of 227 and 228

t-Bu t-Bu O2 H S t-Bu O2S OH O2S OH Me O

I2, KI, NaHCO3 I O + O O CH2Cl2/H2O 24 h H 227 228 230 227/228 = 5/1 Single product t-Bu 90% from 227

O2S OH I2, KI, NaHCO3 O No reaction CH2Cl2/H2O 3 days 228

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We believe that iodolactonization of 228 was prevented by an extensive crowding and steric strain in the potential product resulting from the large iodine atom and sulfone group being in the close proximity to each other. However, we achieved close to quantitative separation of 227 from 228 and synthesized a potentially useful lactone 230, in which the iodine atom could be reductively removed and the ester group hydrolyzed, leading to the diastereoselective formation of a highly substituted cyclohexanol.

Regrettably, time did not permit an investigation of this chemistry.

Figure 14. Crystal structure of lactone 230

Epoxidation of the C=C bond in 223d seemed like another useful reaction that would open up access to its more highly oxidized derivatives. Reaction of 223d with mCPBA proceeded slowly, probably because of the presence of the allylic electron-withdrawing sulfone group. Regardless of the reaction temperature (20 oC vs 45 oC), the epoxidation resulted in quantitative formation of a 1/1 mixture of diastereomeric epoxides 231 and

232 (Scheme 68). Both products are crystalline materials and have a sufficient difference in their Rf values (0.65 for 231 and 0.32 for 232 in EtOAc/Hexanes 2/1) to be easily

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separated by column chromatography. Unfortunately, NOE experiments did not allow for a definitive assignment of the relative stereochemistry of the epoxide ring. The crystal structure determinations of these compounds are underway.

Scheme 68. Epoxidation of 223d

t-Bu t-Bu t-Bu

O2S O O2S O O2S O mCPBA, CH2Cl2 + O rt, 5 days rt O O O O or 2 days, reflux 223d 231 (49%) 232 (49%) Product ratio by crude NMR: 231/232 = 1/1

The cleavage of the seven-membered ring in 223d was highly beneficial for the diastereoselectivity of the epoxidation. Reaction with mCPBA of both acid 228 and the corresponding methyl ester 229 resulted in quantitative transformation into a 10/1 mixture of the corresponding diastereomeric epoxides. In the case of the acid (228), the diastereomeric ratio was established by 1H NMR analysis of the crude reaction mixture, which was then treated with diazomethane to produce 233 and 234 in a 10/1 ratio

(Scheme 69). In the case of the ester (229), the products 233 and 234 were formed in the same 10/1 ratio right away (Scheme 69). The same observed diastereoselectivity suggests that the approach of mCPBA away from the large sulfone group is much more important in the determination of stereochemical outcome, than the possibility of the precoordination of mCPBA with the carboxyl group that is often observed in chelation- controlled epoxidation reactions.91

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Scheme 69. Epoxidation of 228

t-Bu t-Bu

t-Bu Order of events I: O2S OMe O2S OMe (ii CH2N2 O S OH (ii) mCPBA, rt, 4 days 2 OOO + O OR O Order of events II: 233 234 (i) mCPBA, rt, 4 days 77-79%* 7-9%* 228 (ii) CH2N2 Product ratio by crude NMR: 233/234 = 100/12 to 100/10 * isolated yield for 3 steps from 223d

One great value of γ-sulfonyl epoxides is their propensity to undergo deprotonation/ epoxide fragmentation resulting in allylic alcohols.92 In general, allylic alcohols undergo a variety of very useful transformations (e.g. Sharpless epoxidation, Pd-catalyzed allylic alkylation, Claisen rearrangement, etc). In our case, we considered that further oxidation of the OH group leading to enone 236 would provide a potential dienophile for normal- electron demand DA reactions with a variety of dienes.

Scheme 70. Chemical transformations of 233

O t-Bu t-Bu O O2S OMe O2S OMe I OAc LDA, THF AcO OAc O O O o -30 C CH2Cl2, rt HO 233 235 t-Bu t-Bu O2S OMe O2S OMe O Me2AlCl (1 equiv) O O CH2Cl2, rt, 2 days O 55% (preliminary) 236 237 77% (2 steps)

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As was expected, the major epoxide 233 was opened with LDA and then oxidized with Dess-Martin periodinane93 to cleanly produce the α,β-unsaturated ketone 236 in

77% yield for two steps. Surprisingly, on reaction with isoprene, 236 did not undergo the anticipated DA reaction, but rather underwent a hetero-Diels-Alder reaction at the ketone

C=O group to afford spiro-compound 237 as a single diastereomer (the exact stereochemistry has yet to be established). The transformation required a very strong

Lewis acid (Me2AlCl). No reaction was observed and the starting ketone was recovered if the reaction was attempted in the presence of ZnCl2 or BF3*Et2O. No reaction was observed in a protonated solvent (isopropanol). While hetero-DA reactions involving aldehydes are a well-established synthetic method, the corresponding reactions involving ketones are much more difficult.94 Such reactions usually involve highly activated ketones, and very few reports exist about hetero-DA reactions of unactivated ketones.95

Huang and Rawal95 recently reported that hydrogen bonding was sufficient to promote the hetero-DA reaction of unactivated ketones with the highly reactive diene, 1-amino-3- siloxybutadiene, however, to the best of our knowledge, our reaction represents the first example of a hetero-DA reaction when both the ketone and diene are unactivated.

Regrettably, time did not permit further investigation of this exciting chemistry.

5. CONCLUSIONS

1. A new straightforward route to various β-hydroxy sulfones was developed,

proceeding via opening of ethylene oxide or propylene oxide with readily

accessible zinc sulfinates under essentially neutral aqueous conditions. Reactions

of zinc methyl, butyl, p-tolyl and benzyl sulfinates with propylene oxide

proceeded regioselectively in 63-67% yield. 2-(Methylsulfonyl)ethanol, a

common reagent for the protection of various functional groups, was obtained by

this methodology from ethylene oxide in 78% yield.

2. Opening of epoxides with zinc 1,3-butadienyl sulfinate afforded (E)-butadienyl β-

hydroxyalkyl sulfones bearing β-H and β-methyl substituents in 30% yield.

Detailed mechanistic studies revealed that the yields of these products were

limited by their consumption in competing intra- and intermolecular Michael

addition processes.

3. (E)-Butadienyl β-hydroxyalkyl sulfones bearing β-phenyl and β-tert-butyl

substituents were successfully synthesized in high yields from butadiene sulfone

via a three-step sequence: (i) coupling of (Z)-butadienyl silyl sulfinate 205 with

α-bromo acetophenone or bromomethyl tert-butyl ketone; (ii) reduction of the

resulting ketones into the corresponding secondary alcohols using sodium

borohydride/methanol; (iii) DMAP-induced (Z)/(E)-isomerization.

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4. The esterification of synthesized (E)-butadienyl β-hydroxyalkyl sulfones was

accomplished employing DCC/DMAP-based methods, as well as via the

preliminary formation of mixed anhydrides of α-bromoacrylic and 2,4,6-

trichlorobenzoic acids followed by the esterification reaction in the presence of

LiCl and triethylamine. The esterification provided a series of β-acryloyloxy

sulfones that differed in the bulk of the substituent on the sulfone tether (H, Me,

Ph and tert-Bu) and also by the substitution on the acrylate ester residue

(methacrylate, acrylate, α-bromoacrylate and crotonate esters), thus providing a

variety of possibilities for Diels-Alder studies.

5. Τhermally-mediated intramolecular Diels-Alder cycloaddition reactions of newly

synthesized β-acryloyloxy sulfones proceeded with complete regioselectivity,

high (10/1) to complete endo/exo-selectivity, and resulted in the preferential

formation of one of the two possible endo-cycloadducts. The yields and

stereoselectivities were proportional to the bulk of the R1 substituent on the β-

acyloxysulfonyl tether. The proclivity toward DA reaction increased in the order:

acrylates < methacrylates < α-bromoacrylates. In case of R1 = tert-butyl, the

major endo-cycloadducts were separated in 71-72% yield.

6. The search for the minimum energy transition states (TS) for one of these IMDA

reactions was accomplished at the ab initio HF6-31G* level for each of the

possible diastereomers: endo-1, endo-2, exo-1 and exo-2. The energy differences

in the four calculated transition states were in complete agreement with the

experimentally observed diastereoselectivity preferences.

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7. The calculation results suggested that the Diels-Alder reaction proceeds as an

asynchronous concerted process, no net loss of electron density from the

butadienyl fragment to the acrylate dienophile is observed in the TS, no δ+ charge

development occurs at C-1 and C-3 in the diene. The results suggests the

generation of partial diradical character at the transition state.

8. The synthetic utility of the cycloadduct 223d, which was available in good yield

as a single diastereomer, was partially exploited. Derived from 223d, α,β-

unsaturated ketone 236 on reaction with isoprene underwent a hetero-Diels-Alder

reaction at the ketone C=O group to afford a single spiro-diastereomer. This, to

the best of our knowledge, is the first example of a hetero-DA reaction when both

the ketone and diene are unactivated.

6. EXPERIMENTAL SECTION

6.1. GENERAL

1H NMR spectra were recorded on a Bruker AMX 300 NMR spectrometer at 300

MHz or on a Bruker AVANCE 400 NMR spectrometer at 400 MHz, using TMS as an internal reference. 13C NMR spectra were recorded on the same spectrometers at 75 MHz or 100 MHz with CDCl3 or DMSO-d6 as an internal reference. Unless otherwise indicated, NOE spectra were recorded on a Bruker AVANCE 400 NMR spectrometer at

400 MHz. Indicated NOE spectra were recorded on a Varian 500 NMR spectrometer at

500 MHz.

TLC analysis was performed using silica coated plates (Sorbent Technologies). Flash column chromatography was conducted on silica gel Premium Rf Grade (40-75 µm

(200x400 mesh), Sorbent Technologies).

The glass pressure vessel (150 mL) was purchased from Chemglass and used with magnetic stirring. Commercial reagents and solvents (Acros) (including anhydrous EtOH and CH2Cl2) were used as received. THF was freshly distilled from Na/benzophenone.

Deionized water was used for aqueous reactions. All non-aqueous reactions were carried out under an atmosphere of argon using vacuo- or oven-dried glassware, employing syringe techniques. Commercially available 2.5 M n-BuLi solution in hexane (Aldrich) was used. Melting points were determined using a Thomas-Hoover apparatus and are

125 126

uncorrected. Combustion analyses were conducted by Chemisar Laboratories Inc.,

Ontario, Canada or Atlantic Microlaboratories, USA.

Attention: In the absence of solvent, compounds 185, 186, 196, 197, 200-204, 206,

207 and 215-218 were prone to facile polymerization. They could be stored without noticeable decomposition for up to a week as dichloromethane solutions at –5 oC. When preparing these compounds, the removal of solvents after column chromatography was always performed in vacuo at 0-5 oC; the oily residue was immediately diluted with dichloromethane and stored in the presence of 2,6-di-tert-butyl-4-methylphenol at –5 oC.

As a result, it was impractical to obtain combustion analysis data for these compounds.

The yields of compounds 185, 186, 196, 197, 200-204, 206, 207 and 215-218 were calculated by 1H NMR analysis using 2,6-di-tert-butyl-4-methylphenol as an internal standard. To evaluate the reliability of these calculations, in several cases the solvent was removed in high vacuo and the isolated yield was compared with that established by use of an internal standard. These yields were always in good agreement (no more than 1% deviation).

Figure 15. Suggested preferred conformation of β-hydroxy sulfones 185b-d, 186b-d, 189a-d, 190b,d,

201 and 202 and β-acyloxy sulfone products (215-218)

R1 β α H2 H2

HO H1 SO2R A

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α β The assignment of protons H2 and H2 in the various β-hydroxy sulfone (185b-d,

186b-d, 189a-d, 190b,d, 201 and 202) and β-acyloxy sulfone products (215-218) were made assuming that, in CDCl3 solution, A (Figure 15, R = C4H5) is the preferred

2α 2β 1 conformation. The protons H , H and H compose a first-order AMX system if ∆ν/ JAB

> 6, or a non-first-order ABX system if ∆ν/ JAB < 6. For the ABX system, only JAB values below can be considered as an accurate measure of the coupling constant; apparent values

96 of JAX and JBX, presented in the text below, are dependent on spectrometer frequency.

The ∆ν/ JAB values for each compound are presented in Tables 8-10.

Table 8. ∆ν/ JAB values for β-hydroxy sulfones 189a-d, and 190b,d

Compound 189a 189b 190b 189c 189d 190d

∆ν/ JAB 3.1 3.7 2.0 4.9 2.7 6.2

Table 9. ∆ν/ JAB values for β-hydroxy sulfones 185b-d, 186b-d, 201 and 202

Comp. 185b 186b 185c 186c 185d 186d 201 202

∆ν/ JAB 1.9 1.7 4.3 4.1 2.7 2.3 5.9 5.3

Table 10. ∆ν/ JAB values for β-acyloxy sulfones 215b-d, 216b-d, 217b,c and 218d

Comp. 215b 215c 215d 216b 216c 216d 217b 217c 218d

∆ν/ JAB 5.3 7.2 <1 5.1 7.2 <1 5.2 8.2 <1

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6.2. SYNTHESIS OF β-HYDROXY SULFONES via EPOXIDE OPENING WITH

ZINC SULFINATES IN AQUEOUS MEDIA

6.2.1. SYNTHESIS OF SIMPLE ZINC SULFINATES AND THEIR REACTIONS

WITH EPOXIDES

6.2.1.1. General Procedure for Preparation of Zinc Sulfinate salts: Zinc methyl sulfinate dihydrate (188a).

R Cl R O S S Zn * 2H2O O2 O 2 187a-d 188a-d a (R = Me); b (R = n-Bu); c (R = CH2Ph); d (R = p-Tol)

Anhydrous ethanol (80 mL) containing zinc powder (9.35 g, 143 mmol, 1.11 equiv) was heated to reflux with stirring. Mesyl chloride (187a) (10.0 mL, 129 mmol, 1.00 equiv) was added dropwise over 10 min through the condenser, so as to maintain even boiling.

The first mL should be added very carefully, making sure that the reaction initiates, otherwise the reaction mixture effervesces vigorously. Additional anhydrous ethanol (10 mL) was used to wash the condenser. No precipitate formed, and the zinc almost totally dissolved. The reaction mixture was further refluxed for 15 min. It was then allowed to cool over 30 min with stirring and, finally, it was filtered. The residual zinc powder (0.44 g, 6.7 mmol, 0.05 equiv) recovered on the filter was washed with ethanol (10 mL). Upon the addition of water (10 mL) with stirring to the combined filtrates (ca 100 mL), a white precipitate slowly formed. Crystallization was continued for 30 min at rt, then for 1 h at

0 oC. The resulting white crystalline solid was filtered, washed with ice-cold ethanol (2 x

10 mL) and was allowed to air-dry at rt overnight. The title compound 188a was obtained

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as a white solid (15.5 g, 59.5 mmol, 92%), which was used without further purification.

1 13 H NMR (300 MHz, DMSO-d6) δ 2.26 (s, 6H, CH3), 3.42 (s, 4H, H2O); C NMR (75

MHz, DMSO-d6) δ 48.8. Anal. Calcd. for C2H10O6S2Zn: C, 9.25; H, 3.88; S, 24.70; Zn,

25.19. Found: C, 9.01; H, 3.85; S, 24.97; Zn, 25.03.

When heated in a capillary, the dihydrate salt 188a released water vapor at 117-118 oC to afford a glass-like residue, which we presumed to be the anhydrous salt. If the solid hydrate was kept in high vacuo (0.1 mm Hg) at 80 oC for 4 h, the water was fully removed to afford the corresponding anhydrous zinc sulfinate, mp 133 oC. The only change in the 1H NMR spectrum relative to the dihydrate 188a was the disappearance of the water signal at δ 3.42.

6.2.1.2. Zinc n-butyl sulfinate dihydrate (188b).

The reaction was performed according to the general procedure 6.2.1.1 using zinc powder

(2.20 g, 33.7 mmol, 1.10 equiv), anhydrous ethanol (20 mL) and n-butanesulfonyl chloride (187b) (4.00 mL, 30.65 mmol, 1.00 equiv). Additional ethanol was used to wash the condenser (5 mL) and to wash the filtered residual zinc powder (5 mL). Upon the addition of water (30 mL) with stirring to the combined filtrates (ca 30 mL), a white precipitate slowly formed. Crystallization was continued for 30 min at rt, then for 30 min at 0 oC. The title compound 188b was obtained as a white solid (4.85 g, 14.1 mmol,

1 92%), which was used without further purification. H NMR (300 MHz, DMSO-d6) δ

0.87 (t, J=7.2 Hz, 6H, CH3), 1.34 (sextet, J=7.3 Hz, 4H, CH3CH2), 1.42-1.55 (m, 4H,

13 CH3CH2CH2), 2.33 (t, J=7.7 Hz, 4H, CH2SO2), 3.40 (s, 4H, H2O); C NMR (75 MHz,

130

DMSO-d6) δ 13.9, 21.8, 24.0, 60.6. Anal. Calcd. for C8H22O6S2Zn: C, 27.95; H, 6.45; S,

18.66; Zn, 19.02. Found: C, 27.36; H, 6.98; S, 19.52; Zn, 18.47.

When heated in a capillary, the dihydrate salt 188b released water vapor at 119-120 oC.

An attempt to dry the solid product 188b in high vacuo (0.1 mm Hg) at 60 oC led to apparent melting and partial removal of water from the hydrated crystals, as evidenced by a decrease in intensity for the water signal in the 1H NMR spectrum at δ 3.40.

6.2.1.3. Zinc benzyl sulfinate dihydrate (188c).

The reaction was performed according to the general procedure 6.2.1.1 using zinc powder

(2.18 g, 33.4 mmol, 1.09 equiv), anhydrous ethanol (40 mL) and benzylsulfonyl chloride

(187c) (5.85 g, 30.7 mmol, 1.00 equiv). A white precipitate formed during the addition of the benzylsulfonyl chloride. Additional ethanol (10 mL) was used to wash the condenser.

The reaction mixture was further refluxed for 45 min, and was then allowed to cool to rt with stirring over 45 min. Crystallization was continued for 15 min at 0 oC. The title compound 188c was obtained as a light grayish solid (5.25 g, 14.0 mmol, 91%), which was used without further purification. An analytical sample was recrystallized from

o 1 water, mp (dec) 208-209 C. H NMR (300 MHz, DMSO-d6) δ 3.40 (s, 4H, H2O), 3.61

13 (s, 4H, CH2), 7.16-7.32 (m, 10H, Ph) C NMR (75 MHz, DMSO-d6) δ 68.9, 126.5,

128.1, 130.0, 133.2. Anal. Calcd. for C14H18O6S2Zn: C, 40.83; H, 4.41; S, 15.57; Zn,

15.88. Found: C, 40.54; H, 4.48; S, 16.01; Zn, 15.71.

131

If the solid was kept in high vacuo (0.1 mm Hg) at 60 oC for 4 h, the water was fully removed, which was shown by the disappearance of the water signal in the 1H NMR spectrum at δ 3.40.

6.2.1.4. Zinc 4-methylphenyl sulfinate dihydrate (188d).

The reaction was performed according to the general procedure 6.2.1.1 using zinc powder

(3.14 g, 48.0 mmol, 1.10 equiv) in anhydrous ethanol (80 mL) and 4- methylphenylsulfonyl chloride (187d) (8.32 g, 43.7 mmol, 1.00 equiv) in anhydrous ethanol (50 mL). A white precipitate formed during the addition of the 4- methylphenylsulfonyl chloride solution. Additional ethanol (10 mL) was used to wash the condenser. The reaction mixture was further refluxed for 2 hours and was then allowed to cool to rt with stirring over 45 min. Crystallization was continued for 15 min at 0 oC. The title compound 188d was obtained as a light grayish solid (7.00 g, 17.0 mmol, 78%), which was used without further purification. An analytical sample was recrystallized

o 1 from water, mp (dec) 251 C. H NMR (300 MHz, DMSO-d6) δ 2.32 (s, 6H, CH3), 3.40

13 (s, 4H, H2O), 7.21 (d, J=7.8 Hz, 4H, Ar), 7.47 (d, J=7.9 Hz, 4H, Ar); C NMR (75 MHz,

DMSO-d6) δ 20.9, 124.4, 128.7, 139.0, 152.2. Anal. Calcd. for C14H18O6S2Zn: C, 40.83;

H, 4.41; S, 15.57; Zn, 15.88. Found: C, 40.99; H, 4.64; S, 15.42; Zn, 15.92.

If the solid was kept in high vacuo (0.1 mm Hg) at 60 oC for 4 h, the water was fully removed, mp (dec) 152oC. The only change in the 1H NMR spectrum relative to the dihydrate 188d was the disappearance of the water signal in the 1H NMR spectrum at δ

3.40.

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6.2.1.5. General Procedure for Preparation of β-Hydroxy Sulfones 189: 1-

Methanesulfonylpropan-2-ol (189a).64

R OH 188a-d S ++R OH R O O S S OH 2 O 2 O 189a-d 190a-d 191a-d

A suspension of zinc sulfinate 188a (8.31g, 32.0 mmol, 1.00 equiv) and propylene oxide

(6.10 mL, 87.2 mmol, 2.73 equiv) in water (80 mL) was heated in a 150 mL glass pressure vessel at 75 oC with magnetic stirring for 2h 30 min. The reaction mixture was filtered while still hot. The filtered ZnO precipitate was washed with water (2 x 10 mL).

On drying in air the weight of the precipitate was 2.79 g (32.0 mmol of ZnO would correspond to 2.61 g). The combined filtrates were concentrated in vacuo to remove most of the water. Sequential addition of toluene followed by concentration in vacuo afforded a colorless oil. 1H NMR analysis of the crude reaction product showed the presence of

189a, 190a, 191a and propylene glycol in a 86/8/6/21 ratio. The crude product was distilled (bp 117-121 oC at 0.1 mm Hg) to give 7.30 g (52.9 mmol, 83%) of 189a contaminated with approx 6-7% of 190a. Crystallization of the distillate from toluene

(270 mL) gave clean 189a (5.20 g, 37.6 mmol, 59%), mp 67-69 oC. Concentration of the mother liquor in vacuo to ca 100 mL gave an additional crop of clean 189a (0.53 g, 3.84

1 mmol, 6%). Total yield of 189a was 65%. H NMR (300 MHz, CDCl3) δ 1.33 (d, J=6.4

2α 2β Hz, 3H, O-CHCH3), 3.00-3.12 (m, 1H, SO2CH H CH), 3.05 (s, 3H, CH3SO2), 3.21 (dd,

2α 2β 13 J=14.5, 9.9 Hz, 1H, SO2CH H CH), 4.36-4.47 (m, 1H, O-CHCH3); C NMR (75 MHz,

CDCl3) δ 23.4, 42.7, 62.1, 63.0.

133

Removal of toluene from the mother liquor in vacuo gave 1.34 g (approx. 9.70 mmol,

15%) of a mixture of 189a, 190a and 191a in a 7/7/0.7 ratio.

2-Methanesulfonylpropan-1-ol (190a)61 (assigned from the mixture with 189a and

191a):

1 H NMR (300 MHz, CDCl3) δ 1.39 (d, J=7.2 Hz, 3H, SO2-CHCH3), 2.99 (d, J=0.4 Hz,

3H, CH3SO2), 3.14-3.24 (masked) (m, 1H, SO2-CHCH3), 3.94-3.96 (m, 2H,

13 CHCHAHBOH); C NMR (75 MHz, CDCl3) δ 10.4, 40.4, 60.8, 61.7.

2-Hydroxypropyl methanesulfinate (191a) (obtained as a 1:1 mixture of diastereomers; assigned from the mixture with 189a and 190a):

1 H NMR (300 MHz, CDCl3) δ 1.20 (d, J=6.4 Hz) / 1.21 (d, J=6.4 Hz) (3H total, O-

CHCH3), 2.71 (s)/2.71(s), separated by 1 Hz (3H total, CH3SO), 3.90-4.12 (m, 3H, SO-

13 O-CHAHBCH); C NMR (75 MHz, CDCl3) δ 18.7/19.0, 44.2, 66.3/66.4, 74.2/74.5.

6.2.1.6. 1-(Butane-1-sulfonyl)propan-2-ol (189b).97

The reaction was performed according to the general procedure 6.2.1.5 using zinc sulfinate 188b (4.28 g, 12.5 mmol, 1.00 equiv) and propylene oxide (2.70 mL, 38.6 mmol, 3.09 equiv) in water (55 mL). The reaction was heated at 65-70 oC for 12 hours 30 min. The filtered precipitate was washed with dichloromethane (3 x 20 mL) and air-dried

(1.17 g; 12.5 mmol of ZnO would correspond to 1.01 g). 1H NMR analysis of the crude reaction product showed the presence of 189b, 190b, 191b and propylene glycol in a

85/8/7/34 ratio. The crude product was distilled (bp 116-118 oC at 0.1 mm Hg) to give

4.00 g (12.2 mmol, 89%) of 189b contaminated with approx 6-7% of 190b and 4-5% of

134

191b. Crystallization of the distillate from toluene (8 mL) / hexane (2 mL) at –25 oC gave clean 189b (3.01 g, 16.6 mmol, 67%) as a colorless solid, which was partially melted at

1 rt. H NMR (300MHz, CDCl3) δ 0.97 (t, J= 7.3 Hz, 3H, CH3CH2), 1.32 (d, J=6.4 Hz, 3H,

O-CHCH3), 1.48 (sextet, J=7.5 Hz, 2H, CH3CH2), 1.75-1.88 (m, 2H, CH3CH2CH2), 3.00

2α 2β (dd, J=14.5, 2.3 Hz, 1H, SO2CH H CH), 3.05-3.16 (m, 2H, CH2CH2SO2), 3.18 (dd,

2α 2β 13 J=14.5, 9.3 Hz, 1H, SO2CH H CH), 4.43 (dqd, J=9.4, 6.4, 2.4 Hz, 1H, O-CHCH3); C

NMR (75 MHz, CDCl3) δ 13.7, 21.8, 23.3, 23.8, 54.3, 60.1, 62.7.

2-(Butane-1-sulfonyl)propan-1-ol (190b) (assigned from the mixture with 189b and

191b; the protons of the butyl group overlap with those of 189b and 191b):

1 H NMR (300 MHz, CDCl3) (partial spectrum) δ 1.37 (d, J=7.2 Hz, 3H, SO2-CHCH3),

3.16-3.26 (m, 1H, SO2-CHCH3), 3.90 (dd, J=12.1, 4.0 Hz, 1H, CHCHAHBOH), 3.98 (dd,

13 J=12.1, 7.1 Hz, 1H, CHCHAHBOH); C NMR (75 MHz, CDCl3) δ 10.3, 13.7*, 21.8*,

23.8*, 52.0, 59.2, 61.8 (* coincides with signals due to 189b).

2-Hydroxypropyl butane-1-sulfinate (191b) (obtained as a 1:1 mixture of diastereomers; assigned from the mixture with 189b and 190b; the protons of the butyl group overlap with those of 189b and 190b):

1 H NMR (300 MHz, CDCl3) (partial spectrum) δ 1.21 (d, J=6.1 Hz) / 1.19 (d, J=6.1 Hz)

(3H, O-CHCH3), 3.80-4.12 (m, 3H, SO-O-CH2CH).

6.2.1.7. 1-(Phenylmethanesulfonyl)propan-2-ol (189c).98

The reaction was performed according to the general procedure 6.2.1.5 using Zn sulfinate

188c (2.19 g, 5.32 mmol, 1.00 equiv) and propylene oxide (1.50 mL, 21.4 mmol, 4.02

135

equiv) in water (30 mL). The reaction was heated at 70 oC for 7 h. The filtered precipitate was washed with dichloromethane (3 x 20 mL) and air-dried (0.545 g; 5.32 mmol of ZnO would correspond to 0.433 g). 1H NMR analysis of the crude reaction product showed the presence of 189c, 190c, 191c and propylene glycol in ratio 85/8/7/85. No distillation was performed. Crystallization of the crude product from water (50 mL) clearly gave the title compound 189c as a white solid (1.16 g, 5.41 mmol, 51%). Concentration of the mother liquor to 10 mL gave an additional crop of clean 189c (0.280 g, 1.31 mmol, 12%), mp 98-

o 1 99 C. Total yield of 189c is 63%. H NMR (300 MHz, CDCl3) δ 1.24 (d, J=6.4 Hz, 3H,

2α 2β O-CHCH3), 2.84 (dd, J=14.6, 1.8 Hz, 1H, SO2CH H CH), 3.08 (dd, J=14.6, 9.6 Hz, 1H,

2α 2β SO2CH H CH), 4.29 (d, J=13.9 Hz, 1H, PhCHAHB), 4.41 (d, J=13.9 Hz, 1H,

13 PhCCHAHB), 4.35-4.48 (m, 1H, O-CHCH3), 7.35-7.46 (m, 5H, Ph); C NMR (75 MHz,

CDCl3) δ 23.3, 58.3, 60.8, 62.9, 128.0, 129.1, 129.2, 131.2.

2-(Phenylmethanesulfonyl)propan-1-ol (190c) (assigned from the mixture with 189c and 191c; several resonances overlap with those of 189c and 191c):

1 H NMR (300 MHz, CDCl3) δ 1.27 (d, J=7.2 Hz, 3H, SO2-CHCH3), 3.10-3.22 (m, 1H,

SO2-CHCH3), 3.80-4.13 (m, 2H, CHCHAHBOH, overlaps with 191c), 4.31 (d, J=13.8 Hz,

1H, PhCHAHB), 4.41 (d, J=13.9 Hz, 1H, PhCHAHB, coincides with 189c), 7.28-7.46 (m,

13 5H, Ph, overlaps with 189c); C NMR (75 MHz, CDCl3) δ 10.2, 57.7, 59.3, 62.0; aromatic carbons cannot be reliably assigned.

2-Hydroxypropyl phenylmethanesulfinate (191c) (obtained as a 1:1 mixture of diastereomers; assigned from the mixture with 189c and 190c; several resonances overlap with those of 189c and 190c):

136

1 H NMR (300 MHz, CDCl3) (partial spectrum) δ 1.11 (d, J=6.2 Hz, 3H, SO2-CHCH3),

3.80-4.13 (m, 5H, CH2-SO-O-CH2CH-O, overlaps with 190c, aromatic proton resonances

13 overlap with those of 189c and 190c); C NMR (75 MHz, CDCl3) δ 18.6/18.9, 66.5/66.6,

64.3, 75.0/75.4; aromatic carbons cannot be reliably assigned.

6.2.1.8. 1-(4-Methylphenylsulfonyl)propan-2-ol (189d).50,99

6.2.1.8.1. The reaction was performed according to the general procedure 6.2.1.5 using zinc sulfinate 188d (3.30 g, 8.01 mmol, 1.00 equiv) and propylene oxide (1.90 mL, 27.2 mmol, 3.40 equiv) in water (60 mL). The reaction was heated at 70 oC for 16 h. The filtered precipitate (1.51 g) was washed with dichloromethane, air-dried, extracted with

DMSO-d6, filtered and the residual solid was dried in vacuo. The mass of the residual

1 solid was 0.41 g (reduced by approx. 1.1 g). H NMR analysis of the DMSO-d6 extract showed mostly zinc sulfinate 188d. If it is assumed that the original filtered precipitate contained approx 1.1 g (2.67 mmol) of zinc salt 188d, then the residual solid should contain 8.01-2.67=5.34 mmol of ZnO (0.43 g). No distillation was performed. The combined aqueous and dichloromethane filtrates obtained after the removal of the precipitate were concentrated in vacuo to remove most of the water. Sequential addition of toluene followed by concentration in vacuo afforded a colorless oil. Crystallization from water (50 mL) gave the title compound 189d as a white crystalline solid (1.41 g,

6.58 mmol, 41%), mp 78 oC. [Based on consumed Zn sulfinate the yield was 70%.] 1H

NMR (300 MHz, CDCl3) δ 1.24 (d, J=6.4 Hz, 3H, O-CHCH3), 2.45 (s, 3H, CH3-Ar), 3.14

2α 2β (dd, J=14.3, 2.8 Hz, 1H, SO2CH H CH), 3.27 (dd, J=14.3, 8.6 Hz, 1H,

137

2α 2β SO2CH H CH), 4.30 (dqd, 9.0, 6.4, 2.8 Hz, 1H, O-CHCH3), 7.39 (app. d, J=8.5 Hz, 2H,

13 Ar), 7.80 (app. d, J=8.4 Hz, 2H, Ar); C NMR (75 MHz, CDCl3) 21.8, 22.7, 62.5, 63.5,

128.1, 130.3, 136.3, 145.4.

5.2.1.8.2. A solution of commercially available sodium 4-methylphenyl sulfinate hydrate

(0.9% water) (2.92 g, 16.2 mmol, 1.00 equiv) in water (40 mL) was placed in a 150 mL glass pressure vessel and was treated with aq ZnCl2 (20 mL of an aq solution containing

1.10 g (8.1 mmol, 0.50 equiv) of ZnCl2) with magnetic stirring. A white precipitate formed, which was presumed to be zinc sulfinate 188d. Propylene oxide (1.90 mL, 27.2 mmol, 1.68 equiv) was added and the reaction mixture was heated at 75 oC with magnetic stirring for 4h, and was then filtered while still hot. The pH of the aqueous filtrate was

7.1. The filtered ZnO precipitate was washed with water (2 x 20 mL). On drying in air, the mass of the precipitate was 0.72 g (8.1 mmol of ZnO would correspond to 0.66 g).

The combined filtrates (ca 100 mL) were allowed to crystallize for 3 h to cleanly afford the title compound 189d as a white crystalline solid (1.66 g, 7.75 mmol, 48%). The mother liquor was concentrated in vacuo to remove most of the water. Sequential addition of toluene followed by concentration in vacuo afforded a colorless oil, which was treated with dichloromethane (40 mL). The insoluble solid residue (0.84 g) was filtered out. The filtrate was concentrated in vacuo to afford a colorless oil (1.65 g). 1H

NMR analysis of this oil showed the presence of 189d, 190d, and propylene glycol in a

81/19/95 ratio. Crystallization from water (40 mL) gave an additional crop of clean title compound 189d (0.560 g, 2.61 mmol, 16%). Total yield of 189d was 64%. The mother

138

liquor was concentrated in vacuo to give a colorless oil (0.96 g). 1H NMR analysis of this oil showed the presence of 189d, 190d, and propylene glycol in a 62/48/132 ratio.

2-(4-Methylphenylsulfonyl)propan-1-ol (190d) (assigned from the mixture with 189d):

1 H NMR (300 MHz, CDCl3) δ 1.24 (d, J=6.4 Hz, 3H, O-CHCH3, coincides with 189d),

2.45 (s, 3H, CH3-Ar, coincides with 189d), 3.21-3.37 (masked by 189d) (m, 1H, SO2-

CHCH3), 3.73 (dd, J=12.1, 5.0 Hz, 1H, CHCHAHBOH), 3.98 (dd, J=12.1, 6.2 Hz, 1H,

CHCHAHBOH), 7.39 (app. d, J=8.5 Hz, 2H, Ar, coincides with 189d), 7.76 (app. d, J=8.3

13 Hz, 2H, Ar); C NMR (75 MHz, CDCl3) δ 11.44, 18.9, 61.3, 61.8, 128.9, 130.0, 134.1,

139.7.

Me OH Me O 188a S + S OH O2 O 193 194

6.2.1.9. 2-Methanesulfonylethanol (193).100

The reaction was performed according to the general procedure 6.2.1.5 using zinc sulfinate 188a (15.2 g, 58.7 mmol, 1.00 equiv) and ethylene oxide (7.80 mL, 156 mmol,

2.66 equiv) in water (152 mL). The reaction was heated at 70 oC for 2 h. The filtered precipitate was dried in air (4.57 g; 58.7 mmol of ZnO would correspond to 4.77g). 1H

NMR analysis of the crude reaction product showed the presence of 193, 194 and ethylene glycol in a 93/7/11 ratio. The crude product was distilled (bp 135-145 oC at 0.1 mm Hg) to give the title compound 193 as a colorless oil (11.4 g, 92.1 mmol, 78%)

1 contaminated with 0.5-1.5% of 194. H NMR (300 MHz, CDCl3) δ 3.05 (s, 1H, CH3),

13 3.28 (t, J=5.4 Hz, 2H, SO2CH2) 4.07 (t, J=5.4 Hz, 2H, O-CH2); C NMR (75 MHz,

CDCl3) δ 42.8, 56.4, 56.9.

139

2-Hydroxyethyl methanesulfinate (194) (assigned from the mixture with 193):

1 H NMR (300 MHz, CDCl3) δ 2.72 (s, 1H, CH3), 3.77-3.83 (m, 2H, O-CH2) 4.1-4.25 (m,

13 2H, SO-O-CH2); C NMR (75 MHz, CDCl3) δ 44.2, 61.6, 71.3.

6.2.2. EPOXIDE OPENING WITH ZINC (Z)-1,3-BUTADIENYL SULFINATE

(195)

O S Zn * 2H2O S O O2 2 182 195

2β 2α β α H H H2 H2 R 3 6a 5 3 1 1 OH H OH 4 O 4 S 3 S S 1 OH 4 2 6b O 1 + 6b O2 1 + O H 5 2 R H R 5 185a,b 186a,b 6 200a,b H6a OR1 3' 3 5 H6a 4' S S 4 S O2 6b + O2 + 5' H O2 6' 196 197 198, syn-199, anti-199

O CH3 O 3 10 8 2 3 14 12 2 9 7 2 S S 1 OH 4 S 1 OH + 4 S S 9 7 2 13 11 10 8 O2 O2 O2 5 5 CH3 6 (Z)-config: 201 6 202 (E)-config: 204 1β 1α O H H 3 10 8 2 R1 = H (185a, 186a, 200a, 198); S 2 4 S OH 1 9 7 R = CH3 (185b, 186b, ,200b syn-199, anti-199) O2 5 CH3 6 203

140

6.2.2.1. Zinc (Z)-1,3-butadienyl sulfinate dihydrate (195).

Butadiene sulfone (182) (4.73 g, 40.0 mmol, 1.00 equiv) was dissolved in anhydrous

THF (120 mL) under argon, and cooled in a dry ice/acetone bath. n-BuLi (2.5M in hexanes, 16.00 mL, 40.0 mmol, 1.00 equiv) was added dropwise over 25 min, maintaining the reaction temperature below –68 oC. Initially a yellow solution was observed and then a cream precipitate formed. The addition of n-BuLi was stopped after a bright red coloration had developed in the reaction mixture. The reaction mixture was allowed to warm up to –50 oC, and then water (30 mL) and hydroquinone (ca 0.05g) were added. The precipitate immediately dissolved, and the red coloration disappeared. The organic solvents were removed in vacuo, resulting in a light yellow aqueous solution (ca

30 mL) of lithium (Z)-1,3-butadienyl sulfinate. The solution was cooled in ice, and aq

ZnCl2 (5 mL of an aq solution containing 2.705 g (19.85 mmol) of ZnCl2) was added dropwise with stirring. The reaction mixture was left in an ice bath for 20 min, then the resulting white precipitate was filtered, washed with ice-cold water (20 mL) followed by dichloromethane and dried in vacuo. The title compound 195 was obtained as a cream solid (4.80 g, 14.3 mmol, 72%), mp 128-130 oC.

1 6b 6a 101 H NMR (400 MHz, DMSO-d6) δ 5.26 (br d, J=10.0 Hz, 2H, H H C=CH), 5.34 (br d,

6b 6a 101 J=16.8 Hz, 2H, H H C=CH), 6.02 (br d, J=10.0 Hz, 2H, =CH-SO2), 6.26 (dd, J=11.2,

13 10.4 Hz, 2H, CH=CH-SO2), 6.94 (dddd, J=16.8, 11.2, 10.1, 1.0 Hz, 2H, CH2=CH); C

NMR (100 MHz, DMSO-d6) δ 121.8, 131.2, 131.6, 146.6. Anal. Calcd. for C8H14O6S2Zn:

C, 28.62; H, 4.20; S, 19.10; Zn, 19.48. Found: C, 28.04; H, 4.33; S, 18.61; Zn, 19.01.

141

6.2.2.2. General procedure for the reaction of in situ prepared Zn (Z)-1,3-butadienyl sulfinate 195 with epoxides.

The light yellow aqueous solution (ca 30 mL) of Li (Z)-1,3-butadienyl sulfinate (40.0 mmol) obtained in experiment 6.2.2.1 was added dropwise with stirring and cooling in ice to the glass pressure vessel containing ZnCl2 (19.6-20.8 mmol, 0.49-0.52 equiv) in water (20 mL). A white precipitate of zinc (Z)-1,3-butadienyl sulfinate was formed. An additional aliquot of water (40 mL) was used to complete the transfer of Li sulfinate.

Epoxide (120 mmol, 3 equiv) was added, the vessel was closed, and the solution was heated at 70-75 oC with stirring for the time indicated in Table 4. The resulting reaction mixture was cooled to rt and filtered. The precipitate was washed with water (3x20 mL), then with dichloromethane (100 mL) (dichloromethane washings were collected into a separate flask) and dried in air overnight. The mass of the precipitate was 1.58-1.68 g, which corresponds to 19.4-20.6 mmol of ZnO.

The separately collected dichloromethane washings were treated with 2,5-di-tert-butyl-4- methylphenol (0.100 g, 0.454 mmol), dried over MgSO4 and filtered. A sample of this product was concentrated in vacuo and immediately subjected to 1H NMR analysis, which demonstrated that this product contained mostly a mixture of bis-butadienyl sulfones 196 and 197.

The combined aqueous washings were extracted with dichloromethane (4x100 mL). The combined dichloromethane extracts (ca 400 mL) were treated with 2,5-di-tert-butyl-4- methylphenol (0.200 g, 0.908 mmol), dried over MgSO4, filtered, concentrated in vacuo

142

at 0-5 0C and immediately subjected to column chromatography or 1H NMR analysis.

(See section 6.1 for discussion of the stability and handling of the products.)

To separate the mixture of 185a,b and 186a,b, column chromatography was performed using either (i) EtOAc/Hexanes (1.5/1): Rf (196 and 197) = 0.62, overlaps with Rf (syn-

199 and anti-199) = 0.58, Rf (185a and 186a) = 0.24, Rf (185b and 186b) = 0.30, Rf (201,

203, 204) = 0.09, Rf (21) = 0.04; or (ii) Et2O/CH2Cl2 (1/3): Rf (196 and 197) = 0.73, Rf

(185b and 186b) = 0.22.

To separate 198, syn-199 and anti-199, column chromatography was performed in

EtOAc/petroleum ether (1/2), Rf (196 and 197) = 0.36; Rf (198) = 0.19; Rf (syn-199) =

0.25; Rf (anti-199) = 0.19.

6.2.2.3. Reaction of previously isolated Zn (Z)-1,3-butadienyl sulfinate dihydrate 195 with propylene oxide.

Zinc (Z)-1,3-butadienyl sulfinate dihydrate 195 (4.00 g, 11.9 mmol, 1.00 equiv) was transferred into a glass pressure vessel and hydroquinone (ca 0.03 g) was added, followed by water (75 mL) and propylene oxide (5.10 mL, 4.23 g, 72.9 mmol, 3.05 equiv). The vessel was closed and heated at 75 oC with stirring for 8 h. The reaction mixture was cooled to rt and filtered. The precipitate was washed with water (3x20 mL), then with dichloromethane (3x50 mL). The aqueous layer was separated and extracted with dichloromethane (4x80 mL). The combined dichloromethane fractions (ca 470 mL) were treated with 2,5-di-tert-butyl-4-methylphenol (0.100 g, 0.456 mmol, 0.038 equiv), dried

0 with MgSO4, filtered, concentrated in vacuo at 0-5 C and immediately subjected to column chromatography or 1H NMR analysis.

143

Column chromatography was performed with gradient elution: elution with

EtOAc/Hexanes (1.5/1) gave a 1/1 mixture of 185b and 200b (0.553 g, 3.12 mmol, total yield 13%); elution with EtOAc/Hexanes (2/1) gave 201 (0.391 g, 1.31 mmol, 11%) and

203 (ca 0.03 g); elution with EtOAc/Hexanes (2.5/1) gave 202 (0.320 g, 0.776 mmol,

13%).

6.2.2.4. Reaction of previously isolated Zn (Z)-1,3-butadienyl sulfinate dihydrate 195 with ethylene oxide.

The transformation was carried out according to general procedure 6.2.2.3 using zinc (Z)-

1,3-butadienyl sulfinate dihydrate 195 (4.00 g, 11.9 mmol, 1.00 equiv), hydroquinone (ca

0.03 g) and ethylene oxide (3.60 mL, 3.17 g, 72.1 mmol, 3.03 equiv) in water (75 mL).

The reaction mixture was heated at 75 oC with stirring for 2 h. Column chromatography using EtOAc/Hexanes (2/1) gave a 2/1 mixture of 185a and 200a (0.772 g, 4.75 mmol, total yield 20%).

2-((Z)-Buta-1,3-diene-1-sulfonyl)ethanol (185a). a. Prepared as a 1/3.3 mixture with 186a in 30% overall yield according to the general procedure 6.2.2.2 (3 h, 0.52-0.50 equiv of ZnCl2). b. 6.2.2.5. To obtain a sample of clean title compound 185a to be used for NMR analysis, the 2/1 mixture of 185a and 200a (0.77 g, 4.8 mmol), synthesized according to procedure

6.2.2.4, was treated with saturated aqueous NaHCO3 (50 mL) containing hydroquinone

(ca 0.03 g). The reaction mixture was stirred at rt for 4 h, and then extracted with

144

dichloromethane (4x40 mL). The combined dichloromethane extracts were treated with

2,5-di-tert-butyl-4-methylphenol (ca 0.05 g), dried with MgSO4, filtered, concentrated in vacuo at 0-5 0C and immediately used for the 1H NMR analysis.

1 Compound 185a: H NMR (300 MHz, CDCl3) δ 3.02 (t, J=6.0 Hz, 1H, OH), 3.26-3.30

(m, 2H, H2), 4.02-4.09 (m, 2H, H1), 5.67 (br d, J=16.6 Hz, 1H, H6b),101 5.69 (br d, J=10.0

Hz, 1H, H6a),101 6.17 (br d, J=11.1 Hz, 1H, H3), 6.73 (app t, J=11.3 Hz, 1H, H4), 7.34-

5 13 7.48 (m, 1H, H ); C NMR (75 MHz CDCl3) δ 56.4, 58.2, 126.5, 129.6, 129.9, 143.8.

1-((Z)-Buta-1,3-diene-1-sulfonyl)propan-2-ol (185b). a. Prepared as a 1/3.5 mixture with 186b in 30% overall yield according to the general procedure 5.2.2.2 (3 h, 0.52-0.50 equiv of ZnCl2). b. To obtain a sample of clean title compound to be used for NMR analysis, the 1/1 mixture of 185b and 200b (0.55 g, 3.12 mmol), synthesized according to procedure

6.2.2.3, was treated with saturated aqueous NaHCO3 (40 mL) and isolated as described in procedure 6.2.2.5.

1 Compound 185b: H NMR (300 MHz, CDCl3) δ 1.31 (d, J=6.4 Hz, 3H, CH3), 3.11 (dd,

α β J=14.4, 2.7 Hz, 1H, H2 ), 3.20 (dd, J=14.4, 8.7 Hz, 1H, H2 ), 3.30 (d, J=2.7 Hz, 1H, OH),

4.43 (app dqt J=9.1, 6.4, 2.7 Hz, 1H, H1), 5.68 (br d, J=17.2 Hz, 1H, H6b),101 5.69 (br d,

J=9.5 Hz, 1H, H6a),101 6.18 (br d, J=11.1 Hz, 1H, H3), 6.75 (app t, J=11.3 Hz, 1H, H4),

5 13 7.44 (dddd, J=16.4, 11.5, 10.3, 1.0 Hz, 1H, H ); C NMR (75 MHz, CDCl3) δ 23.0, 62.6,

63.2, 126.5, 129.7, 129.9, 143.7.

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2-((E)-Buta-1,3-diene-1-sulfonyl)ethanol (186a).

Prepared according to the general procedure 6.2.2.2 (ethylene oxide, 3 h, 0.52-0.50 equiv of ZnCl2). After drying over MgSO4, the combined dichloromethane extracts (ca 400 mL) were filtered, concentrated to a volume of ca 150 mL and treated with DMAP (0.500 g, 4.09 mmol). The resulting solution was kept at rt for 36 h, and was then subjected to column chromatography to afford the title compound 186a as a colorless oil (1.95 g, 12.0 mmol, 30%).

1 2 H NMR (300 MHz, CDCl3) δ 3.00 (t, J=6.0 Hz, 1H, OH), 3.26-3.31 (m, 2H, H ), 4.02-

4.10 (m, 2H, H1), 5.68 (br d, J=10.0 Hz, 1H, H6a), 5.77 (br d, J=16.9 Hz, 1H, H6b), 6.47

(dd, J=14.9, 0.6 Hz, 1H, H3), 6.48 (dddd, J=16.9, 10.9, 10.0, 0.6 Hz, 1H, H5), 7.21 (br dd,

4 13 J=15.0, 10.8 Hz, 1H, H ); C NMR (75 MHz, CDCl3) δ 56.4, 57.4, 129.0 (two signals coincide), 132.5, 144.3.

1-((E)-Buta-1,3-diene-1-sulfonyl)propan-2-ol (186b).

Prepared according to the procedure described above for 186a (except propylene oxide was employed as epoxide) as a colorless oil (2.14 g, 12.1 mmol, 30%).

1 H NMR (300 MHz, CDCl3) δ 1.31 (d, J=6.4 Hz, 3H, CH3), 3.09 (dd, J=14.4, 2.8 Hz, 1H,

α β H2 ), 3.17 (dd, J=14.5, 8.7 Hz, 1H, H2 ), 3.21 (d, J=2.8 Hz, 1H, OH), 4.39 (app. dqt

J=9.0, 6.3, 2.8 Hz, 1H, H1), 5.69 (br d, J=10.0 Hz, 1H, H6a), 5.77 (br d, J=16.7 Hz, 1H,

H6b), 6.43 (br d, J=15.0 Hz, 1H, H3), 6.47 (dddd, J=16.9, 10.8, 10.0, 0.5 Hz, 1H, H5), 7.22

4 13 (br dd, J=15.0, 10.9 Hz, 1H, H ); C NMR (75 MHz, CDCl3) δ 22.9, 62.4, 62.7, 128.7,

129.4, 132.4, 144.8.

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(E,Z)-bis-Buta-1,3-dienyl sulfone (196).

Prepared according to the general procedure 6.2.2.2 (propylene oxide, 3 h, 0.52-0.50 equiv of ZnCl2) as a 1/1.36 mixture with 197. The dichloromethane washings of the ZnO precipitate (ca 100 mL) were combined with the dichloromethane extracts (ca 400 mL) obtained from extraction of the aqueous layer, treated with 2,5-di-tert-butyl-4- methylphenol (0.200 g, 0.908 mmol), dried with MgSO4, filtered, concentrated in vacuo at 0-5 oC and immediately subjected to column chromatography to give a 1/1.36 mixture of 196/197 in 43% overall yield.

1 6a H NMR (300 MHz, CDCl3) δ (E)-butadienyl moiety: 5.64 (br d, J=10.0 Hz, 1H, H ),

5.74 (br d, J=16.9 Hz, 1H, H6b), 6.42 (br d, J=14.9 Hz, 1H, H3), 6.46 (dddd, J=16.9, 10.9,

10.0, 0.6 Hz, 1H, H5); 7.19 (ddt, J=14.9, 10.9, 0.7 Hz, 1H, H4); (Z)-butadienyl moiety:

5.63 (br d, J=16.9 Hz, 1H, H6b’),101 5.64 (br d, J=10.0 Hz, 1H, H6a’),101 6.10 (dq, J=11.0,

0.7 Hz, 1H, H3’), 6.66 (app t, J=11.3 Hz, 1H, H4’), 7.44 (dddd, J=16.6, 11.5, 10.3, 1.1 Hz,

5’ 13 1H, H ); C NMR (75 MHz, CDCl3) δ 127.5, 128.6, 129.0, 130.2, 130.6, 132.7, 142.7,

142.8.

(E,E)-bis-Buta-1,3-dienyl sulfone (197).

Prepared in 43% yield according to the general procedure 6.2.2.2 (propylene oxide, 3 h,

0.52-0.50 equiv of ZnCl2). The dichloromethane washings of the ZnO precipitate (ca 100 mL) were combined with the dichloromethane extracts (ca 320 mL) obtained from extraction of the aqueous layer, treated with 2,5-di-tert-butyl-4-methylphenol (0.200 g,

o 0.908 mmol), dried with MgSO4, filtered and concentrated in vacuo at 0-5 C to a volume

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of ca 75 mL. The resulting solution was treated with DMAP (0.500 g, 4.09 mmol), kept at rt for 36 h, concentrated in vacuo at 0-5 oC and immediately subjected to column chromatography.

1 6a H NMR (300 MHz, CDCl3) δ 5.64 (br d, J=10.0 Hz, 1H, H ), 5.74 (br d, J=16.9 Hz, 1H,

H6b), 6.39 (dd, J=14.9, 0.6 Hz, 1H, H3), 6.46 (dddd, J=16.9, 10.9, 10.0, 0.6 Hz, 1H, H5);

4 13 7.16 (ddt, J=14.9, 10.9, 0.7 Hz, 1H, H ); C NMR (75 MHz, CDCl3) δ 128.5, 129.9,

132.7, 143.4.

5β β 5β β 5β β H 3 H H3 H 3 O H O O H 5α 5α α H 3α H 5 3α S H S 3α H S H 6β H C O H H C H O 3 3 O H2 O O O 6α 6 6 H H2 H H2 H 198 cis-199 trans-199

[1,4]Oxathiane-2-ethenyl-4,4-dioxide (198).

A sample for analysis was prepared according to the general procedure 6.2.2.2 (ethylene oxide, 3 h, 0.52-0.50 equiv of ZnCl2). The title compound 198 was isolated as a white crystalline solid after column chromatography (EtOAc/petroleum ether, 1/2).

1 3β H NMR (300 MHz, CDCl3) δ 2.98 (dd, J=13.8, 11.0 Hz, 1H, H ), 3.01 (app ddt, J=13.9,

α α 3.7, 2.1 Hz, 1H, H5 ), 3.11 (ddd, J=13.8, 3.7, 2.3 Hz, 1H, H3 ), 3.20 (br ddd, J=13.9,

β α 12.2, 4.6 Hz, 1H, H5 ), 4.07 (app td, J=12.5, 2.1 Hz, 1H, H6 ), 4.36 (ddd, J=12.7, 4.6, 2.2

β Hz, 1H, H6 ), 4.43 (app dddt, J=10.9, 5.5, 2.2, 1.1 Hz, 1H, H2), 5.28 (app dt, 10.6, 1.1 Hz,

1H, HcisHtransC=CH), 5.39 (app dt, 17.3, 1.2 Hz, 1H, HcisHtransC=CH), 5.83 (ddd, 17.3,

13 10.6, 5.5 Hz, 1H, CH2=CH-); C NMR (75 MHz, CDCl3) δ 52.0, 56.9, 65.2, 76.8, 117.8,

134.9.

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Cis-[1,4]oxathiane-2-ethenyl-6-methyl-4,4-dioxide (syn-199). a. Prepared according to the general procedure 6.2.2.2 using 0.35 equiv of ZnCl2

(propylene oxide, 3 h). The title compound syn-199 was isolated as a white crystalline solid (2.19 g, 12.4 mmol, 31%) after column chromatography (EtOAc/petroleum ether,

1/2). b. 6.2.2.6. A solution of K2CO3 (0.079 g, 0.57 mmol, 0.21 equiv) in water (5 mL) was added to a solution of 2-((E)-buta-1,3-diene-1-sulfonyl)ethanol (186b) (0.48 g, 2.7 mmol,

1.00 equiv) in water (26 mL). The reaction mixture was heated at 75 oC with stirring for 5 h. After cooling to rt, it was extracted with dichloromethane (4x30 mL), and the

1 dichloromethane extracts were dried over MgSO4, filtered and concentrated in vacuo. H

NMR analysis showed the presence of a 4/1/0.6 mixture of syn-199/anti-199/unreacted

186b. Column chromatography (EtOAc/hexanes, 1/3) followed by crystallization from toluene/hexanes (1/4, 20 mL) afforded the title compound syn-199 (0.24 g, 1.4 mmol,

50%), mp 50 oC. (After heating for 9 h at 75oC, a 6/1/0.3 mixture syn-199/anti-

199/unreacted 186b was observed to be present in the crude reaction product by 1H NMR analysis.)

1 H NMR (300 MHz, CDCl3) δ 1.38 (d, J=6.3 Hz, 3H, CH3), 2.86 (dd, J=13.8, 10.9 Hz,

β β α 1H, H5 ), 2.89 (dd, J=13.5, 11.1 Hz, 1H, H3 ), 3.04 (ddd, J=13.4, 3.5, 2.0 Hz, 1H, H5 ),

α 3.07 (ddd, J=13.5, 3.6, 2.1 Hz, 1H, H3 ), 4.14 (dqd, J=11.0, 6.3, 1.9 Hz, 1H, H6), 4.47

(app dddt, J=11.3, 5.5, 1.9, 1.4 Hz, 1H, H2), 5.27 (app dt, 10.6, 1.1 Hz, 1H,

HcisHtransC=CH), 5.38 (app dt, 17.3, 1.1 Hz, 1H, HcisHtransC=CH), 5.83 (ddd, 17.3, 10.6,

2 3α 2 3β 6 5α 5.5 Hz, 1H, CH2=CH-); COSY cross peaks observed between H / H , H / H , H / H

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6 5β 13 and H / H ; C NMR (75 MHz, CDCl3) δ 21.4, 55.5, 57.5, 71.9, 75.8, 117.7, 135.0.

Anal. Calcd. for C7H12O3S: C, 47.71; H, 6.86; S, 18.20. Found: C, 48.02; H, 7.33; S,

18.17.

Trans-[1,4]oxathiane-2-ethenyl-6-methyl-4,4-dioxide (anti-199). a. Prepared according to the general procedure 6.2.2.2 using 0.35 equiv of ZnCl2

(propylene oxide, 3 h). The title compound anti-199 was isolated as a white crystalline solid (0.36 g, 2.04 mmol, 5%) after column chromatography (EtOAc/petroleum ether,

1/2). b. The title compound anti-199 (0.048g, 0.27 mmol, 10%), mp 80 oC, was prepared according to procedure 6.2.2.6.

1 H NMR (400 MHz, CDCl3) δ 1.44 (d, J=6.64 Hz, 3H, CH3), 2.95 (ddd, J=13.9, 7.1, 1.7

Hz, 1H, H5). 3.07 (ddd, J=14.0, 5.7, 2.3 Hz, 1H, H3), 3.14 (app dt, J=13.9, 2.9 Hz, 1H,

H5), 3.23 (ddd, J=14.1, 4.4, 1.8 Hz, 1H, H3), 4.55 (app dquint, J=3.6, 6.8 Hz, 1H, H6),

2 4.80-4.87 (m, 1H, H ), 5.36 (app dt, 10.6, 1.3 Hz, 1H, HcisHtransC=CH), 5.40 (app dt, 17.3,

1.3 Hz, 1H, HcisHtransC=CH), 5.83 (ddd, 17.3, 10.6, 5.8 Hz, 1H, CH2=CH-); COSY cross

α β α β peaks observed between the pairs H2 / H3 , H2 / H3 , H6 / H5 and H6 / H5 ; the strong

COSY cross peaks observed between the pairs of protons at 2.95 / 3.23 and 3.07 / 3.14 ppm are due to W-coupling (J=1.7 Hz and J=2.9 Hz, respectively), and suggest that these

13 protons are cis- to each other. C NMR (100 MHz, CDCl3) δ 19.5, 54.6, 56.5, 67.2, 71.6,

119.2, 134.1. Anal. Calcd. for C7H12O3S: C, 47.71; H, 6.86; S, 18.20. Found: C, 47.69; H,

7.20; S, 18.54.

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2-Hydroxyethyl (Z)-buta-1,3-dienyl sulfinate (200a) (assigned from the mixture with

185a obtained in procedure 6.2.2.4).

1 1 H NMR (300 MHz, CDCl3) δ 2.93 (t, J=6.0 Hz, 1H, OH), 3.72-3.88 (m, 2H, H ), 4.12-

4.18 (m, 1H, H2), 4.27-4.34 (m, 1H, H2), 5.54 (br d, J=9.5 Hz, 1H, H6a),101 5.56 (br d,

J=16.4 Hz, 1H, H6b),101 6.21 (br d, J=10.3 Hz, 1H, H3), 6.66 (app t, J=10.9 Hz, 1H, H4),

5 13 6.95 (dddd, J=16.4, 11.4, 10.1, 1.0 Hz, 1H, H ); C NMR (75 MHz, CDCl3) δ 61.8, 70.2,

126.5, 130.2, 136.0, 139.7.

2-Hydroxypropyl (Z)-buta-1,3-dienyl sulfinate (200b) (obtained as a 1:1 mixture of diastereomers, assigned from the 1/1 mixture with 185b synthesized in procedure

6.2.2.3).

1 H NMR (300 MHz, CDCl3) δ 1.19 (d, J=6.4 Hz, 3H, CH3), 3.02 (d, J=3.9 Hz) / 3.07 (d,

J=4.0 Hz) (1H, OH), 3.86 (dd, J=10.7, 7.2 Hz) / 4.14 (dd, J=10.7, 2.8 Hz) (1H), 3.95-4.07

(m, 2H), 5.54 (br d, J=10.0 Hz, 1H, H6a),101 5.55 (br d, J=16.6 Hz, 1H, H6b),101 6.22 (br d,

J=9.5 Hz, 1H, H3), 6.66 (app t, J=10.9 Hz, 1H, H4), 6.95 (dddd, J=16.5, 11.4, 10.0, 1.0

5 13 Hz, 1H, H ); C NMR (CDCl3) δ 18.7/19.0, 66.4, 72.7/73.0, 126.5, 130.2, 136.0,

139.59/139.63.

1-[4-((Z)-Buta-1,3-diene-1-sulfonyl)-(E)-but-2-ene-1-sulfonyl]propan-2-ol (201).

Prepared according to the general procedure 6.2.2.3. The title compound 201 was isolated as a colorless oil (0.391 g, 1.31 mmol, 11%) after column chromatography

(EtOAc/Hexanes, 2/1).

151

1 H NMR (300 MHz, CDCl3) δ 1.39 (d, J=6.4 Hz, 3H, CH3), 2.95 (d, J=3.7 Hz, 1H, OH),

α β 2.97 (br d, J=14.3 Hz, 1H, H2 ), 3.25 (dd, J=14.3, 9.6 Hz, 1H, H2 ), 3.76-3.90 (m, 3H) and 3.95-4.04 (m, 1H) (2H7 and 2H10), 4.37-4.50 (m, 1H, H1), 5.68 (br d, J=17.6 Hz, 1H,

H6b),101 5.70 (br d, J=8.9 Hz, 1H, H6a),101 5.89-6.03 (m, 2H, H8,9), 6.13 (br d, J=11.0 Hz,

1H, H3), 6.80 (app t, J=11.3 Hz, 1H, H4), 7.40 (dddd, J=16.5, 11.4, 10.4, 0.8 Hz, 1H, H5);

13 C NMR (75 MHz, CDCl3) δ 23.4, 58.1, 59.1, 59.3, 63.2, 125.4, 126.4, 127.4, 129.9,

130.1, 144.8.

1-{4-[4-((Z)-Buta-1,3-diene-1-sulfonyl)-(E)-but-2-ene-1-sulfonyl]-(E)-but-2-ene-1- sulfonyl}propan-2-ol (202).

Prepared according to the general procedure 6.2.2.3. The title compound 202 was isolated as a colorless oil (0.320 g, 0.776 mmol, 13%) after column chromatography

(EtOAc/Hexanes, 2.5/1).

1 H NMR (300 MHz, CDCl3) δ 1.34 (d, J=6.4 Hz, 3H, CH3), 2.95 (d, J=4.1 Hz, 1H, OH),

α β 3.02 (dd, J=14.7, 1.1 Hz, 1H, H2 ), 3.28 (dd, J=14.7, 9.7 Hz, 1H, H2 ), 3.75-4.04 (m, 8H,

2H7,10,11,14), 4.39-4.53 (m, 1H, H1), 5.70 (br d, J=17.4 Hz, 1H, H6a),101 5.71 (br d, J=8.7

Hz, 1H, H6b),101 5.88-6.18 (m, 4H, H8,9,12,13), 6.16 (br d, J=11.0 Hz, 1H, H3), 6.81 (app t,

J=11.3 Hz, 1H, H4), 7.40 (dddd, J=16.6, 11.3, 10.4, 0.9 Hz, 1H, H5); 13C NMR (75 MHz,

CDCl3) δ 23.4, 55.1, 55.4, 58.2, 59.2, 60.0, 63.2, 125.5, 125.8, 127.0, 127.1, 127.9, 129.8,

130.3, 144.9.

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2-[4-((Z)-Buta-1,3-diene-1-sulfonyl)-(E)-but-2-ene-1-sulfonyl]propan-1-ol (203).

An analytical sample (ca 0.03 g) was isolated by procedure 6.2.2.3.

1 H NMR (300 MHz, CDCl3) δ 1.36 (d, J=7.2 Hz, 3H, CH3), 2.56 (t, J=5.1 Hz, 1H, OH),

3.32 (app dquint, J=3.6, 7.3 Hz, 1H, H2), 3.79-4.06 (m, 2H, H1 and 4H, H7,10), 5.66 (br d,

J=17.3 Hz, 1H, H6b),101 5.68 (br d, J=9.8 Hz, 1H, H6a),101 5.87-6.04 (m, 2H, H8,9), 6.11 (br d, J=11.0 Hz, 1H, H3), 6.79 (app t, J=11.3 Hz, 1H, H4), 7.40 (dddd, J=16.6, 11.5, 10.2,

5 13 1.0 Hz, 1H, H ); C NMR (75 MHz, CDCl3) δ 10.0, 56.7, 58.4, 59.4, 62.3, 125.3, 126.2,

127.1, 130.0 (two signals coincide), 144.8.

6.2.2.7. Reaction of 201 with propylene oxide in the presence of K2CO3.

Compound 201 (0.39 g, 1.3 mmol, 1.0 equiv) was treated with propylene oxide (0.30 mL,

0.25 g, 4.3 mmol, 3.3 equiv) in the presence of K2CO3 (0.020 g, 0.14 mmol, 0.11 equiv) in water (10 mL) in the presence of hydroquinone (ca 0.01 g). The reaction mixture was heated at 75 oC with stirring for 3 h, cooled to rt and extracted with dichloromethane

(4x10 mL). The combined dichloromethane extracts were treated with 2,5-di-tert-butyl-4-

o methylphenol (ca 0.03 g,), dried over MgSO4, filtered, concentrated in vacuo at 0-5 C and immediately subjected to 1H NMR analysis, which showed a 7/40/7/9/4/7 mixture of

185b/186b/196/197/201/204 (see Scheme 58).

1-[4-((E)-Buta-1,3-diene-1-sulfonyl)-(E)-but-2-ene-1-sulfonyl]propan-2-ol (204).

A sample of the title compound 204 for NMR analysis was obtained by procedure 6.2.2.7 followed by column chromatography using EtOAc/hexanes (2/1). The fraction with Rf =

153

0.18 consisted of a 1/1.6 mixture of 201/204. The NMR assignments of the title compound were made from the NMR spectra of this mixture.

1 H NMR (300 MHz, CDCl3), partial assignment for those signals which do not coincide with those due to 201: δ 5.79 (br d, J=16.8 Hz, 1H, H6a),101 6.43 (d, J=14.9 Hz, 1H, H3),

6.48 (app dt, J=16.9, 10.7 Hz, 1H, H5); 7.19 (dd, J=14.9, 10.9 Hz, 1H, H4); 13C NMR

(CDCl3) δ 23.4 (coincides with 201), 58.1, 58.6, 59.2, 63.2 (coincides with 201), 126.6,

127.1, 127.7, 129.6, 132.4, 145.8.

6.2.3. SYNTHESIS OF β-HYDROXY SULFONES via CONDENSATION OF

SULFINATE ANION WITH α-BROMO KETONES FOLLOWED BY

REDUCTION

O OH OH S S + S O2 1 O2 1 O 1 S R R 2 R O 2 206 R1 = Ph 185c R1 = Ph 208c R1 = Ph 182 207 R1 = t-Bu 185d R1 = t-Bu OH S O 1 2 R 186c R1 = Ph 186d R1 = t-Bu

6.2.3.1. 2-[(Z)-Butadienesulfonyl]-1-phenylethanone (206).

Butadiene sulfone (182) (3.55 g, 30.0 mmol, 1.00 equiv) was dissolved in anhydrous

THF (60 mL) under argon and cooled in a dry ice/acetone bath. n-BuLi (2.5M in hexanes,

12.0 mL, 30.0 mmol, 1.00 equiv) was added dropwise over 15 min, maintaining the reaction temperature below –68 oC. Initially, a yellow solution was observed, and then a

154

cream precipitate formed. The addition of n-BuLi was stopped immediately after a bright red coloration had developed in the reaction mixture liquid phase. After just 2-3 min of stirring at –78 oC, trimethylchlorosilane (4.10 mL, 3.49g, 32.1 mmol, 1.07 equiv) was added dropwise. Little or no rise in the reaction temperature was observed. After the first drops of TMSCl had been added, the reaction mixture liquid phase became light yellowish, while the precipitate did not change in color (cream). After stirring the resulting mixture at –78 oC for 25 min, the precipitate disappeared. The mixture was stirred for a further 1 h at –78oC. A solution of α-bromoacetophenone (15.7 g, 78.9 mmol, 2.63 equiv) in THF (40 mL) was then added dropwise over 15 min, followed by

Bu4NF (32 mL, 1 M solution in THF, 32 mmol, 1.07 equiv), then 2,6-di-tert-butyl-4- methyl phenol was added (ca 0.05 g). It is important to add the ketone slowly because it partially precipitates out of the cold reaction mixture. Both additions proceeded without noticeable increases in the reaction temperature. The reaction mixture was left in the dry ice/acetone bath to warm up to rt overnight.

The reaction mixture was concentrated in vacuo. The oily residue was twice co- evaporated with EtOAc (150 mL) in vacuo. A third addition of EtOAc (150 mL) resulted in the formation of a white precipitate of Bu4NBr. After 15 min of stirring at rt, the precipitate was filtered out and the filtrate was concentrated in vacuo. Column chromatography was performed with gradient elution: the first elution (EtOAc/Hexane,

1/10) gave recovered α-bromoacetophenone; the second elution (EtOAc/Hexane, 1/3; Rf of 206 = 0.20, Rf of α-bromoacetophenone = 0.55) gave the title compound 206 as a colorless oil (4.98 g, 21.1 mmol, 70%).

155

1 6a 101 H NMR (300 MHz, CDCl3) δ 4.68 (s, 2H, CH2), 5.64 (br d, J~11 Hz, 1H, H ), 5.65

(br d, J~16 Hz, 1H, H6b),101 6.29 (br d, J=11.1 Hz, 1H, H3), 6.76 (app t, J=11.3 Hz, 1H,

H4); 7.38 (dddd, J=17.2, 11.5, 9.6, 1.0 Hz, 1H, H5), 7.48-7.55 (m, 2H, Ph), 7.61-7.68 (m,

13 1H, Ph), 7.97-8.02 (m, 2H, Ph); C NMR (75 MHz, CDCl3) δ 63.2, 125.7, 129.1, 129.5,

129.9, 130.0, 134.7, 135.9, 144.3, 188.7.

6.2.3.2. 1-[(Z)-Butadienesulfonyl]-3,3-dimethyl-2-butanone (207).

The title compound 207 (1.174 g, 5.43 mmol, 54%) was obtained as colorless oil by procedure 6.2.3.1 from butadiene sulfone (182) (1.18 g, 10.0 mmol, 1.00 equiv) in anhydrous THF (20 mL) using trimethylchlorosilane (1.35 mL, 1.15 g, 10.6 mmol, 1.06 equiv) and 1-bromo-3,3-dimethyl-2-butanone (3.60 mL, 4.47 g. 25.0 mmol, 2.50 equiv) in anhydrous THF (5 mL) and Bu4NF (10.6 mL, 1 M solution in THF, 10.6 mmol, 1.06 equiv). The title compound 207 was obtained in lower yield (0.867 g, 4.01 mmol, 40%) if

2,6-di-tert-butyl-4-methyl phenol was added the next morning (just before the workup).

1 H NMR (300 MHz, CDCl3) δ 1.19 (s, 9H, t-Bu), 4.25 (s, 2H, CH2), 5.65 (br d, J~10 Hz,

1H, H6a),101 5.64 (br d, J~17 Hz, 1H, H6b),101 6.35 (br d, J=11.1 Hz, 1H, H3), 6.72 (app t,

4 5 13 J=11.3 Hz, 1H, H ), 7.35-7.49 (m, 1H, H ); C NMR (75 MHz, CDCl3) δ 25.8, 45.4,

61.2, 126.6, 129.5, 130.2, 143.3, 204.2.

6.2.3.3. 2-[(Z)-Butadienesulfonyl]-1-phenylethanol (185c).

α-Sulfonyl ketone 206 (4.61g, 19.5 mmol, 1.00 equiv) was dissolved in methanol (240 mL) and cooled to –35 oC. Sodium borohydride (0.775 g, 20.5 mmol, 1.05 equiv) was

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dissolved in water (10 mL) at 0 oC and was added dropwise to the solution of α-sulfonyl ketone 206 with stirring, so that the temperature never rose above –30 oC. The resulting reaction mixture was warmed up to 0 oC over 1 h 30 min, and was then treated with

EtOAc (240 mL) and water (200 mL). The solvents (ca 200 mL) were removed in vacuo.

Additional ethyl acetate (200 mL) was added and, again, the solvents (ca 250 mL) were removed in vacuo. The residue was treated with EtOAc (200 mL), which resulted in its separation into two layers. The organic layer was washed with water (50 mL). The combined aqueous layers were extracted with dichloromethane (3x50 mL). The combined organic layers were then dried with MgSO4, filtered and concentrated in vacuo to afford a crude oil, which was used directly in the next step without purification. The title compound was pure by 1H and 13C NMR analysis. It could be further purified by column chromatography (EtOAc/Hexane, 1/3, Rf = 0.24), which afforded 185c as a colorless oil (4.29 g, 18.0 mmol, 92%).

1 2α H NMR (300 MHz, CDCl3) δ 3.23 (dd, J=14.6, 2.1 Hz, 1H, H ), 3.44 (dd, J=14.6, 10.6

β Hz, 1H, H2 ), 3.54 (d, J=2.7 Hz, 1H, OH), 5.31 (app dt, J=10.1, 2.4 Hz, 1H, H1), 5.65 (br d, J~17 Hz, 1H, H6b),101 5.67 (br d, J~10 Hz, 1H, H6a),101 6.19 (br d, J=11.1 Hz, 1H, H3),

6.71 (app t, J=11.3 Hz, 1H, H4), 7.37-7.51 (m, 1H, H5), 7.26-7.37 (m, 5H, Ph); 13C NMR

(75 MHz, CDCl3) δ 63.8, 68.9, 125.9, 126.6, 128.6, 129.0, 129.7, 130.0, 141.1, 143.7.

6.2.3.4. 2-[(E)-But-2-enesulfonyl]-1-phenylethanol (208c).

The title compound 208c was obtained as a 25/100 mixture with 185c when the reduction was conducted by procedure 6.2.3.3 at 0 oC, employing larger amounts of sodium

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borohydride (0.960 g, 25.4 mmol, 1.30 equiv). The title compound 208c was characterized from the mixture.

1 H NMR (300 MHz, CDCl3) δ 1.78 (br.d, J=6.6 Hz, 3H, CH3), 2.99 (br.d, J=14.7 Hz, 1H,

α β H2 ), 3.40 (dd, J=14.7, 10.3 Hz, 1H, H2 ), 3.47 (d, J=2.6 Hz, 1H, OH), 3.67 (br dd,

J=14.0, 7.1 Hz, 1H, CHAHBSO2), 3.85 (dd, J=14.0, 7.8 Hz, 1H, CHAHBSO2), 5.29 (app dt, J=10.3, 2.5 Hz, 1H, H1), 5.88 (app dtq, J=15.1, 7.5, 1.7 Hz, 1H, H4), 5.88 (dq, J=15.3,

5 13 6.6 Hz, 1H, H ), 7.26-7.40 (m, 5H, Ph); C NMR (75 MHz, CDCl3) δ 18.5, 58.7 (two signals coincide), 69.1, 117.3, 125.9 (two signals coincide), 128.6, 129.0 (two signals coincide), 137.1, 141.5.

6.2.3.5. 2-[(E)-Butadienesulfonyl]-1-phenylethanol (186c).

Crude β-hydroxy sulfone 185c, obtained by procedure 6.2.3.3 after concentration in vacuo, was diluted with dichloromethane (100 mL), treated with DMAP (0.464 g, 3.80 mmol, 0.20 equiv) and left for two days at rt. The reaction mixture was concentrated in vacuo and immediately subjected to column chromatography (EtOAc/Hexane, 1/3, Rf =

0.24) to afford the title compound 186c as a colorless oil (4.29 g, 18.0 mmol, 92% for two steps from 206).

1 2α H NMR (300 MHz, CDCl3) δ 3.18 (dd, J=14.7, 2.4 Hz, 1H, H ), 3.38 (dd, J=14.6, 10.0

β Hz, 1H, H2 ), 3.71 (d, J=3.0 Hz, 1H, OH), 5.23 (app dt J=10.0, 2.6 Hz, 1H, H1), 5.63 (br d, J=10.0 Hz, 1H, H6a), 5.71 (br d, J=16.9 Hz, 1H, H6b), 6.41 (app dt, J=16.9, 10.4 Hz,

1H, H5), 6.44 (d, J=15.3 Hz, 1H, H3), 7.15 (dd, J=14.9, 11.0 Hz, 1H, H4), 7.23-7.38 (m,

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13 5H, Ph); C NMR (75 MHz, CDCl3)

δ 62.9, 69.0, 126.0, 128.5, 128.97, 129.02, 129.4, 132.6, 141.3, 144.2.

6.2.3.6. 1-[(Z)-Butadienesulfonyl]-3,3-dimethyl-2-butanol (185d).

The title compound 185d (0.732 g, 3.35 mmol, 85%) was obtained as a colorless oil by procedure 6.2.3.3 from α-sulfonyl ketone 207 (0.852 g, 3.94 mmol, 1.00 equiv) in methanol (125 mL) and sodium borohydride (0.157 g, 4.15 mmol, 1.05 equiv) in water (4 mL).

1 2β H NMR (300 MHz, CDCl3) δ 0.93 (s, 9H, t-Bu), 3.08 (dd, J=14.3, 9.9 Hz, 1H, H ), 3.09

α (d, J=3.2 Hz, 1H, OH), 3.21 (dd, J=14.3, 1.5 Hz, 1H, H2 ), 3.88 (ddd, J=9.9, 3.0, 1.5 Hz,

1H, H1), 5.67 (br d, J~17 Hz, 1H, H6b),101 5.68 (br d, J~9 Hz, 1H, H6a),101 6.20 (br d,

J=11.1 Hz, 1H, H3), 6.74 (app t, J=11.3 Hz, 1H, H4), 7.45 (dddd, J=16.5, 11.5, 10.3, 1.1

5 13 Hz, 1H, H ); C NMR (75 MHz, CDCl3) δ 25.5, 35.1, 58.6, 73.6, 126.5, 129.6, 129.9,

143.6.

6.5.3.7. 1-[(E)-Butadienesulfonyl]-3,3-dimethyl-2-butanol (186d).

The title compound 186d (0.732 g, 3.35 mmol, 85%) was obtained as a colorless oil by procedure 6.2.3.5 from the crude β-hydroxy sulfone 185d, using DMAP (0.092 g, 0.75 mmol, 0.22 equiv) in CH2Cl2 (25 mL) for 2 days at rt. If 50 mL of CH2Cl2 was used, it took 4 days for the reaction to proceed to completion.

1 2β H NMR (300 MHz, CDCl3) δ 0.93 (s, 9H, t-Bu), 3.08 (dd, J=14.4, 9.9 Hz, 1H, H ), 3.19

α (dd, J=14.4, 1.7 Hz, 1H, H2 ), 3.86 (dd, J=9.9, 1.7 Hz, 1H, H1), 5.66 (br d, J=10.4 Hz,

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1H, H6a), 5.75 (br d, J=16.9 Hz, 1H, H6b), 6.40-6.54 (m, 1H, H5), 6.52 (d, J=15.1 Hz, 1H,

3 4 13 H ), 7.15 (br dd, J=15.0, 10.9 Hz, 1H, H ); C NMR (75 MHz, CDCl3) δ 25.6, 35.2,

57.9, 73.6, 128.9, 129.3, 132.5, 144.0.

6.2.4. ESTERIFICATION OF β-HYDROXY SULFONES

2β α 2 1 2 H H2 R O R R 6a 5 8a 2 + H 1 O H S 3 S 7 4 OH HO2C 6b O 1 8b H 2 R O H 1 1 2 2 186a R = H; 186b R = CH3; 209 R = CH3; 215a-d R = CH3; 186c R1 = Ph; 186d R1 = t-Bu 210 R2 = H; 216a-d R2 = H; 211 R2 = Br 217b,c R2 = Br

5 3 2 O H6a S S 4 1 O 6b O 2 t-Bu O H 2 218d 221

6.2.4.1. 2-[(E)-Butadienesulfonyl]ethyl methacrylate (215a) – Method A.

A solution of DCC (1.74 g, 8.43 mmol, 1.41 equiv) in anhydrous dichloromethane (3 mL) was added dropwise over 25 min at rt to a stirred solution of β-hydroxy sulfone 186a

(0.973 g, 6.00 mmol, 1.00 equiv), methacrylic acid (209) (0.77 mL, 0.78 g, 9.1 mmol. 1.5 equiv) and DMAP (0.147 g, 1.20 mmol, 0.20 equiv) in anhydrous dichloromethane (8 mL). A white precipitate formed. The reaction mixture was stirred for 24 h at rt and was then filtered. The filtered precipitate was washed with dichloromethane and dried in air to afford the recovered dicyclohexyl urea (DCU) byproduct (1.50 g, 6.69 mmol). The combined dichloromethane filtrate was concentrated in vacuo and immediately subjected

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to column chromatography (EtOAc/Hexane, 1/2, Rf = 0.27) to give the title compound

215a as a colorless oil (1.18 g, 5.12 mmol, 85%).

1 H NMR (300 MHz, CDCl3) δ 1.90 (app t, J=1.3 Hz, 3H, CH3), 3.38 (t, J=5.9 Hz, 2H,

H2), 4.52 (t, J=5.9 Hz, 2H, H1), 5.59 (quintet, J=1.5 Hz, 1H, H8a), 5.64 (br d, J=10.1 Hz,

1H, H6a), 5.73 (br d, J=16.9 Hz, 1H, H6b), 6.08 (br s, 1H, H8b), 6.39 (dd, J=15.0, 0.5 Hz,

1H, H3), 6.41 (dddd, J=16.9, 10.9, 10.0, 0.6 Hz, 1H, H5), 7.17 (dd, J=15.0, 10.9 Hz, 1H,

4 13 H ); C NMR (75 MHz, CDCl3) δ 18.3, 54.3, 58.2, 126.8, 128.9, 129.3, 132.3, 135.6,

144.8, 166.7.

6.2.4.2. 1-[(E)-Butadienesulfonyl]prop-2-yl methacrylate (215b).

The title compound 215b (1.50 g, 6.15 mmol, 93%) was obtained by procedure 6.2.4.1

(Method A) from β-hydroxy sulfone 186b (1.17 g, 6.64 mmol) after column chromatography (EtOAc/Hexane, 1/2.5, Rf = 0.29).

1 H NMR (300 MHz, CDCl3) δ 1.43 (d, J=6.4 Hz, 3H, CH3), 1.92 (app t, J=1.3 Hz, 3H,

2α 2β CH3), 3.20 (dd, J=14.8, 4.2 Hz, 1H, H ), 3.46 (dd, J=14.8, 7.8 Hz, 1H, H ), 5.41 (ddq,

J=7.8, 4.2, 6.4 Hz, 1H, H1), 5.60 (quintet, J=1.6 Hz, 1H, H8a), 5.65 (br d, J=9.8 Hz, 1H,

H6a), 5.74 (br d, J=16.8 Hz, 1H, H6b), 6.10 (br s, 1H, H8b), 6.38 (d, J=15.1 Hz, 1H, H3),

6.42 (app dt, J=16.9, 10.4 Hz, 1H, H5), 7.15 (dd, J=14.9, 11.0 Hz, 1H, H4); 13C NMR (75

MHz, CDCl3) δ 18.3, 20.3, 60.0, 65.8, 126.5, 128.8, 129.1, 132.3, 136.0, 144.6, 166.1.

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6.2.4.3. 2-[(E)-Butadienesulfonyl]-1-phenylethyl methacrylate (215c).

The title compound 215c (1.12 g, 3.66 mmol, 81%) was obtained by procedure 6.2.4.1

(Method A) from β-hydroxy sulfone 186c (1.07 g, 4.50 mmol) after column chromatography (CH2Cl2/Hexane, 3/1, Rf = 0.13).

1 2α H NMR (300 MHz, CDCl3) δ 1.92 (br s, 3H, CH3), 3.39 (dd, J=15.0, 3.3 Hz, 1H, H ),

β 3.75 (dd, J=15.0, 9.6 Hz, 1H, H2 ), 5.60-5.66 (m, 2H, H8a, H6a), 5.72 (br d, J=16.9 Hz,

1H, H6b), 6.17 (br s, 1H, H8b), 6.26 (br d, J=14.9 Hz, 1H, H3), 6.30 (dd, J=9.6, 3.3 Hz,

1H, H1), 6.36 (app dt, J=16.9, 10.6 Hz, 1H, H5), 7.14 (dd, J=14.9, 10.9 Hz, 1H, H4), 7.27-

1 7.43 (m, 5H, Ph); H NMR (CD3OD) δ 1.92 (dd, J=1.6, 1.0 Hz, 3H, CH3), 3.52 (dd,

α β J=15.0, 3.0 Hz, 1H, H2 ), 3.96 (dd, J=15.0, 9.9 Hz, 1H, H2 ), 5.63 (br d, J=10.1 Hz, 1H,

H6a), 5.67 (m, 1H, H8a), 5.75 (br d, J=16.9 Hz, 1H, H6b), 6.18 (br s, 1H, H8b), 6.26 (dd,

J=9.9, 3.0 Hz, 1H, H1), 6.49 (dddd, J=16.9, 10.8, 10.0, 0.4 Hz, 1H, H5), 6.57 (dd, J=14.9,

0.6 Hz, 1H, H3), 7.14 (br dd, J=14.9, 10.9 Hz, 1H, H4), 7.29-7.45 (m, 5H, Ph); 13C NMR

(75 MHz, CDCl3) δ 18.4, 60.8, 70.7, 126.6, 126.8, 128.8, 129.2, 129.2, 132.3, 135.9,

137.9, 144.8, 165.6.

6.2.4.4. 1-[(E)-Butadienesulfonyl]-3,3-dimethylbut-2-yl methacrylate (215d).

(a) Method B. A solution of DCC (1.06g, 5.14 mmol, 1.30 equiv) in anhydrous dichloromethane (3 mL) was added dropwise using a syringe pump over 1 h with stirring to a solution of methacrylic acid (209) (0.85 mL, 0.86 g, 10 mmol, 2.54 equiv) in anhydrous dichloromethane (3 mL). After stirring for an additional 3 h, the reaction mixture was filtered under argon and the filtrate was added dropwise over 25 min to a

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solution of β-hydroxy sulfone 186d (0.852 g, 3.94 mmol, 1 equiv) and DMAP (0.635 g,

5.20 mmol, 1.32 equiv) in anhydrous dichloromethane (5 mL). The reaction mixture was stirred at rt for 15 h, filtered, and the filtrate was concentrated in vacuo and immediately subjected to column chromatography to give the title compound 215d as a colorless oil

(0.567 g, 1.98 mmol, 50%).

(b) Method D. A solution of β-hydroxy sulfone 186d (3.62 g, 16.6 mmol, 1 equiv) methacrylic anhydride (212) (3.00 mL, 94%, d=1.042, 2.88 g, ca 18 mmol, ca 1.1 equiv) and DMAP (2.10 g, 17.2 mmol, 1.04 equiv) in anhydrous dichloromethane (70 mL) was stirred at rt for 30 h. The reaction mixture was diluted with dichloromethane (80 mL), washed with water (2x50 mL), dried and filtered. The filtrate was concentrated in vacuo and immediately subjected to column chromatography (EtOAc/Hexanes, 1/3, Rf = 0.24) to give the title compound 215d as a colorless oil (3.61 g, 12.6 mmol, 76%).

1 H NMR (300 MHz, CDCl3) δ 0.94 (s, 9H, t-Bu), 1.93 (app t, J=1.2 Hz, 3H, CH3), 3.27

α, β (m, 2H, H2 2 ), 5.32 (m, 1H, H1), 5.59 (app quintet, J=1.5 Hz, 1H, H8a), 5.63 (br d,

J=10.0 Hz, 1H, H6a), 5.74 (br d, J=16.8 Hz, 1H, H6b), 6.11 (br s, 1H, H8b), 6.34 (br d,

J=14.9 Hz, 1H, H3), 6.39 (app dt, J=16.9, 10.5 Hz, 1H, H5), 7.13 (dd, J=14.9, 10.9 Hz,

4 13 1H, H ); C NMR (75 MHz, CDCl3, one signal masked) δ 18.5, 25.7, 35.6, 56.2, 74.1,

126.3, 128.1, 129.0, 132.4, 136.0, 145.1, 166.3.

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6.2.4.5. 2-[(E)-Butadienesulfonyl]ethyl acrylate (216a).

The title compound 216a (1.07 g, 4.95 mmol, 85%) was obtained by procedure 6.2.4.1

(Method A) from β-hydroxy sulfone 186a (0.941 g, 5.80 mmol) and acrylic acid (210) after column chromatography (EtOAc/Hexane, 1/2.5).

1 2 H NMR (300 MHz, CDCl3) δ 3.41 (app t, J=6.0 Hz, 2H, H ), 4.56 (app t, J=6.0 Hz, 2H,

H1), 5.68 (br d, J=9.9 Hz, 1H, H6a), 5.77 (br d, J=16.9 Hz, 1H, H6b), 5.89 (dd, J=10.4, 1.4

Hz, 1H, H8a), 6.09 (dd, J=17.3, 10.4 Hz, 1H, H7), 6.41 (br d, J=14.9 Hz, 1H, H3), 6.43

(dd, J=17.3, 1.4 Hz, 1H, H8b), 6.45 (app dt, J=16.9, 10.5 Hz, 1H, H5), 7.20 (dd, J=14.9,

10.9 Hz, 1H, H4).

6.2.4.6. 1-[(E)-Butadienesulfonyl]prop-2-yl acrylate (216b).

The title compound 216b (1.19 g, 5.17 mmol, 83%) was obtained by procedure 6.2.4.1

(Method A) from β-hydroxy sulfone 186b (1.10 g, 6.24 mmol) and acrylic acid (210) after column chromatography (EtOAc/Hexane, 1/2.5, Rf = 0.24).

1 H NMR (300 MHz, CDCl3) δ 1.44 (d, J=6.4 Hz, 3H, CH3), 3.19 (dd, J=14.8, 4.4 Hz, 1H,

α β H2 ), 3.44 (dd, J=14.8, 7.6 Hz, 1H, H2 ), 5.42 (ddq, J=7.6, 4.4, 6.4 Hz, 1H, H1), 5.66 (br d, J=9.9 Hz, 1H, H6a), 5.74 (br d, J=16.9 Hz, 1H, H6b), 5.87 (dd, J=10.4, 1.5 Hz, 1H, H8a),

6.06 (dd, J=17.2, 10.4 Hz, 1H, H7), 6.37 (dd, J=14.9, 0.6 Hz, 1H, H3), 6.41 (dd, J=17.2,

1.5 Hz, 1H, H8b), 6.42 (dddd, J=16.9, 10.9, 10.0, 0.6 Hz, 1H, H5), 7.16 (ddt, J=14.9, 10.9,

4 13 0.7 Hz, 1H, H ); C NMR (75 MHz, CDCl3) δ 20.3, 60.0, 65.7, 128.1, 128.8, 129.2,

131.9, 132.4, 144.7, 164.9.

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6.2.4.7. 2-[(E)-Butadienesulfonyl]-1-phenylethyl acrylate (216c).

The title compound 216c (0.877g, 3.00 mmol, 81%) was obtained by procedure 6.2.4.4a

(Method B) from β-hydroxy sulfone 186c (0.882 g, 3.70 mmol) and acrylic acid (219) after column chromatography (CH2Cl2/Hexane, 3/1, Rf = 0.11).

1 2α H NMR (300 MHz, CDCl3) δ 3.39 (dd, J=15.0, 3.5 Hz, 1H, H ), 3.75 (dd, J=15.0, 9.5

β Hz, 1H, H2 ), 5.64 (br d, J=10.0 Hz, 1H, H6a), 5.71 (br d, J=16.9 Hz, 1H, H6b), 5.87 (dd,

J=10.4, 1.4 Hz, 1H, H8a), 6.10 (dd, J=17.3, 10.4 Hz, 1H, H7), 6.26 (br d, J=14.9 Hz, 1H,

H3), 6.32 (dd, J=9.5, 3.4 Hz, 1H, H1), 6.36 (app dt, J=16.9, 10.4 Hz, 1H, H5), 6.43 (dd,

J=17.3, 1.4 Hz, 1H, H8b), 7.13 (dd, J=14.9, 10.9 Hz, 1H, H4), 7.27-7.43 (m, 5H, Ph); 13C

NMR (75 MHz, CDCl3, one signal masked) δ 60.5, 70.6, 126.7, 127.9, 128.8, 129.16,

129.24, 132.3, 132.4, 137.7, 144.8, 164.4.

6.2.4.8. 1-[(E)-Butadienesulfonyl]-3,3-dimethylbut-2-yl acrylate (216d).

The title compound 216d (0.967 g, 3.55 mmol, 74%) was obtained by procedure 6.2.4.4b

(Method D) from β-hydroxy sulfone 186d (1.05 g, 4.80 mmol) and acrylic anhydride

(213) after column chromatography (EtOAc/Dichloromethane, 1/30, Rf = 0.37).

1 2α 2β H NMR (400 MHz, CDCl3) δ 0.94 (s, 9H, t-Bu); 3.22-3.30 (m, 2H, H and H ); 5.28-

5.37 (m, 1H, H1); 5.64 (d, J = 10.0 Hz, 1H, H6a); 5.74 (d, J = 16.9 Hz, 1H, H6b); 5.87 (dd,

J = 10.4, 1.4 Hz, 1H, H8a); 6.11 (dd, J = 17.3, 10.4 Hz, 1H, H7); 6.34 (dd, J = 14.9, 0.5

Hz, 1H, H3); 6.39 (dddd, J = 16.9, 10.9 10.1, 0.6 Hz, 1H, H5); 6.42 (dd, J = 17.3, 1.4 Hz,

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8a 4 13 1H, H ); 7.15 (dd, J = 15.0, 10.9 Hz, 1H, H ); C NMR (CDCl3, 75 MHz) δ 25.7, 35.6,

56.0, 74.0, 127.9, 128.1, 129.1, 131.8, 132.5, 145.4, 165.2.

6.2.4.9. 2-[(E)-Butadienesulfonyl]-3,3-dimethylbut-2-yl crotonate (218d).

The title compound 218d (1.045 g, 3.65 mmol, 75%) was obtained by procedure 6.2.4.4b

(Method D) from β-hydroxy sulfone 186d (1.06g, 4.87 mmol) and crotonic anhydride

(214) after column chromatography (EtOAc/Hexane, 1/3).

1 H NMR (400 MHz, CDCl3) δ 0.93 (s, 9H, t-Bu), 1.88 (dd, J = 6.9, 1.7 Hz, 3H, CH3),

3.22-3.25 (m, 2H, H2), 5.26-5.34 (m, 1H, H1), 5.63 (br d, J = 10.0 Hz, 1H, H6a), 5.72 (dd,

J = 16.9 Hz, H6b), 5.83 (dq, J = 15.5, 1.7 Hz, 1H, H7), 6.34 (br d, J = 14.9 Hz, 1H, H3),

6.38 (br dt, J = 16.9, 10.3, 1H, H5), 6.99 (dq, J = 15.5, 6.9, 1H, H8), 7.14 (dd, J = 15.0,

4 10.9 Hz, 1H, H ); APT (100 MHz, CDCl3) δ 25.5 (CH3), 30.3 (CH3), 35.4 (C), 56.1

(CH2), 73.3 (CH), 122.2 (CH), 127.9 (CH), 128.7 (=CH2), 132.4 (CH), 145.0 (CH), 145.9

(CH), 165.3 (C).

6.2.4.10. 1-[(E)-Butadienesulfonyl]prop-2-yl 2-bromoacrylate (217b).

The title compound 217b (0.764 g, 2.47 mmol, 28%) was obtained by procedure 6.2.4.1

(Method A) from β-hydroxy sulfone 186b (1.54 g, 8.74 mmol) and 2-bromoacrylic acid

(211) after column chromatography (EtOAc/Hexane, 1/2, Rf = 0.20).

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1 H NMR (300 MHz, CDCl3) δ 1.47 (d, J=6.4 Hz, 3H, CH3), 3.21 (dd, J=14.9, 4.0 Hz, 1H,

α β H2 ), 3.47 (dd, J=14.9, 8.0 Hz, 1H, H2 ), 5.43 (ddq, J=8.0, 4.0, 6.5 Hz, 1H, H1), 5.66 (br d, J=9.9 Hz, 1H, H6a), 5.75 (br d, J=16.8 Hz, 1H, H6b), 6.30 (d, J=1.8 Hz, 1H, H8a), 6.40

(br d, J=14.9 Hz, 1H, H3), 6.44 (dddd, J=16.9, 10.9, 10.0, 0.6 Hz, 1H, H5), 6.98 (d, J=1.8

8b 4 13 Hz, 1H, H ), 7.17 (br dd, J=14.9, 10.9 Hz, 1H, H ); C NMR (75 MHz, CDCl3) δ 20.2,

59.8, 68.2, 120.8, 128.7, 129.4, 131.9, 132.3, 144.9, 160.8.

6.2.4.11. 2-[(E)-Butadienesulfonyl]-1-phenylethyl 2-bromoacrylate (217c) -

Method C.

2-Bromoacrylic acid (211) (0.780 g, 5.17 mmol, 1.88 equiv) was dissolved in anhydrous

THF (12 mL) and cooled to 0 oC. Triethylamine (1.52 mL, 1.09 g, 10.8 mmol, 3.92 equiv) was added dropwise with stirring. The reaction mixture was stirred at 0 oC for 10 min, then 2,4,6-trichlorobenzoyl chloride (0.78 mL, 1.22 g, 4.99 mmol, 1.81 equiv) was added. The reaction mixture was stirred at 0 oC for 1h 20 min, when it became dark brown. Solid LiCl (0.293 g, 6.91 mmol, 2.51 equiv) was added, followed by a solution of

β-hydroxy sulfone 186c (0.656 g, 2.75 mmol, 1 equiv) in anhydrous THF (12 mL). The reaction mixture was stirred for 15 h at rt and was then diluted with ether (75 mL) and filtered. The filtrate was diluted with EtOAc (50 mL) and refiltered. The filtrate was concentrated in vacuo and immediately subjected to column chromatography

(EtOAc/Hexane, 1/3) to give the title compound 217c as a colorless oil (0.484 g, 1.30 mmol, 47%) and recovered β-hydroxy sulfone 186c (0.132 g, 0.55 mmol, 20%).

1 2α 217c: H NMR (300 MHz, CDCl3) δ 3.39 (dd, J=15.1, 3.1 Hz, 1H, H ), 3.80 (dd, J=15.1,

167

β 9.8 Hz, 1H, H2 ), 5.66 (br d, J=10.0 Hz, 1H, H6a), 5.74 (br d, J=16.9 Hz, 1H, H6b), 6.29

(d, J=1.8 Hz, 1H, H8a), 6.30 (dd, J=9.9, 3.1 Hz, 1H, H1), 6.34 (br d, J=14.9 Hz, 1H, H3),

6.40 (app dt, J=16.9, 10.4 Hz, 1H, H5), 7.02 (d, J=1.8 Hz, 1H, H8b), 7.16 (dd, J=14.9, 10.9

4 13 Hz, 1H, H ), 7.27-7.45 (m, 5H, Ph); C NMR (75 MHz, CDCl3) δ 60.4, 72.9, 120.4,

126.7, 128.8, 129.3, 129.4, 129.5, 132.28, 132.31, 137.0, 144.9, 160.4.

6.2.4.12. (E)-Butadienyl-propen-1-yl sulfone (222).

Compound 186b (0.52 g, 2.95 mmol, 1 equiv), diisopropylcarbodiimide (0.45 g, 3.57 mmol, 1.2 equiv) and a few mg of CuCl were mixed at rt and left to stir overnight. The reaction mixture was diluted with dichloromethane (10 mL), filtered and the filtrate was concentrated in vacuo. The title compound 222 (0.39 g, 2.47 mmol, 84%) was separated by column chromatography (dichloromethane) as a colorless oil.

1 H NMR (300 MHz, CDCl3) δ 1.96 (dd, J=6.9, 1.7 Hz, 3H, CH3), 5.62 (br d, J=10.0 Hz,

1H, H6a), 5.71 (br d, J=16.9 Hz, 1H, H6b), 6.29 (dq, J=15.0, 1.7 Hz, 1H, H2), 6.32 (dd,

J=14.9, 0.5 Hz, 1H, H3), 6.44 (dddd, J=16.9, 10.9, 10.0, 0.5 Hz, 1H, H5), 6.92 (dq,

1 4 13 J=15.0, 6.9 Hz, 1H, H ), 7.15 (dd, J=14.9, 10.9 Hz, 1H, H ); C NMR (75 MHz, CDCl3)

δ 17.6, 128.3, 130.0, 130.9, 132.7, 143.0, 143.9.

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6.3. INTRAMOLECULAR DIELS-ALDER CYCLOADDITION OF β-ACYLOXY

SULFONES 215a-d, 216a-d AND 217b,c.

2 R Heat, T oC O Toluene, 0.01-0.04 M S O 1 2 R O (see Table 6) 2 215a-d R = CH3; 2 1 1 216a-d R = H; a R = H; b R = CH3; 217b,c R2 = Br c R1 = Ph; d R1 = tert-Bu;

6α 7 6α 1 7 H H H R H 1 β 1 β 7 1 R H6 R H6 H R O2S 4a O O2S 4a O O2S 4a O H H H O2S O 2 4 9a OOOif R = Br 2 ++2 2 O 2 R R R 3 1 - HBr 223a-i 224b-i 225a-i 226h,i endo-Major endo-Minor exo-Product

1 2 a R = H, R = CH3; 1 2 1 2 1 2 b R = CH3, R = CH3; e R = CH3, R = H; h R = CH3, R = Br; 1 2 1 2 1 2 c R = Ph, R = CH3; f R = Ph, R = H; i R = Ph, R = Br 1 2 1 2 d R = tert-Bu, R = CH3; g R = tert-Bu, R = H;

6.3. General procedure for intramolecular Diels-Alder Cycloaddition of β-acyloxy sulfones 215a-d, 216a-d and 217b,c.

A solution of β-acyloxy sulfone 215a-d, 216a-d or 217b,c and 2,5-di-tert-butyl-4- methylphenol (5-7 mol %) in toluene or xylenes (bp 136-140 oC) was heated in a 150 mL glass pressure vessel (time and temperature indicated in Table 6). After cooling to rt, the reaction mixture was filtered and the filtered solid was washed with toluene. The combined filtrates were concentrated in vacuo and the residue was purified by either crystallization or column chromatography.

169

The presence and amounts of exo-products 225b,c,h,i were determined by the presence and integration of H4a in the 1H NMR spectrum of the crude reaction mixtures (Table 11).

Exo-product 225d was separated and characterized as a pure material.

Table 11. Chemical shifts of H4a proton in cycloadducts 223-225

Compound δ H4a, ppm

a b c d e f g h i

223 3.67 3.70 3.85 3.71 4.12 4.26 4.12 4.32 4.47

224 N/A 3.56 3.71 3.63 3.89 3.98 3.89 4.44 4.74

225 3.92 3.94 4.15 4.25 ------4.51 4.80

α β As above, the protons H6 , H6 and H7 in the cycloadducts compose AMX or ABX coupling systems. For those exhibiting ABX systems, apparent values of JAX and JBX, presented in the text below, are dependent on the spectrometer frequency. The ∆ν/ JAB values are given in Table E5.

Table 12. ∆ν/ JAB values for cycloadducts 223-225 and decomposition product 226h

Compound 223b 224b 223c 224c 223d 224d 225d 223e 224e

∆ν/ JAB 3.1 7.0 5.3 17 7.4 14.7 2.1 2.9 5.0

Table 12 (continues)

Compound 223f 224f 223g 224g 223h 224h 226h 224i

∆ν/ JAB 5.8 11 7.4 6.5 2.7 3.1 0.85 4.6

170

6.3.1. (4aSR,9aSR)-9a-Methyl-5,5-dioxo-1,2,4a,9a-tetrahydro-8-oxa-5λ6-thiabenzo- cycloheptan-9-one (223a).

β-Acyloxy sulfone 215a (0.85 g, 3.69 mmol) was heated in toluene (90 mL, 0.041 M) at

130 oC for 29.5 h. Column chromatography (EtOAc/Hexanes, 1/1), gave a 100/33 mixture of cycloadducts 223a and 225a (0.36 g, 1.56 mmol, 42%). A clean sample of the title compound 223a was obtained as a white crystalline solid by crystallization of the mixture from EtOH, mp 139-141 oC.

1 1 2 H NMR (CDCl3) δ 1.34 (s, 3H, CH3), 1.79-1.89 (m, 1H, H /H ), 2.04-2.43 (m, 3H,

H1/H2), 3.29 (ddd, J=14.5, 3.2, 2.4 Hz, 1H, H6), 3.55 (ddd, J=14.5, 11.0, 5.5 Hz, 1H, H6),

3.67 (br s, 1H, H4a), 4.47 (ddd, J=12.3, 5.5, 2.3 Hz, 1H, H7), 4.64 (ddd, J=12.3, 11.0, 3.4

7 4 3 13 Hz, 1H, H ), 5.83-5.91 (m, 1H, H ), 6.24-6.32 (m, 1H, H ); C NMR (CDCl3, one signal masked) δ 22.2, 26.1, 43.9, 57.2, 64.1, 67.3, 114.7, 135.9, 179.2; X-ray crystal structure is reported in ref. 80b. Anal. Calcd. for C10H14O4S: C, 52.16; H, 6.13. Found: C, 52.16;

H, 6.13.

(4aSR,9aRS)-9a-Methyl-5,5-dioxo-1,2,4a,9a-tetrahydro-8-oxa-5λ6- thiabenzocycloheptan-9-one (225a).

The mother liquor remaining after the crystallization of compound 223a (Experiment

6.3.1) was concentrated in vacuo to obtain a 100/75 mixture of 223a and 225a as a white solid. Spectral data of the title compound 225a were assigned from this mixture:

1 1 2 H NMR (CDCl3) δ 1.54 (s, 3H, CH3), 1.80-2.38 (m, 4H, H /H ), 3.41 (br dd, J=15.6, 5.1

Hz, 1H, H6), 3.55 (ddd, J=15.7, 10.5, 2.4 Hz, 1H, H6), 3.92 (br s, 1H, H4a), 4.59 (ddd,

J=14.4, 5.4, 2.3 Hz, 1H, H7), 5.03 (br dd, J=14.5, 10.6 Hz, 1H, H7), 5.99-6.07 (m, 1H,

171

4 3 13 H ), 6.16-6.23 (m, 1H, H ); C NMR (CDCl3) δ 15.2, 21.9, 33.9, 43.1, 54.8, 61.5, 64.3,

113.8, 133.4, 174.9.

6.3.2. (4aSR,7RS,9aSR)-7,9a-Dimethyl-5,5-dioxo-1,2,4a,9a-tetrahydro-8-oxa-5λ6- thiabenzocycloheptan-9-one (223b).

β-Acyloxy sulfone 215b (1.25 g, 5.12 mmol) was heated in xylenes (500 mL, 0.010 M) at

140 oC for 41 h. Column chromatography (EtOAc/Hexanes, 1/1.5), gave a 100/25 mixture of cycloadducts 223b and 224b (0.70 g, 2.87 mmol, 56%) as a white solid.

Crystallization of the mixture from EtOAc/Hexanes (1/2, 12 mL) gave the title compound

223b as a white crystalline solid (0.45 g, 1.84 mmol, 36%), mp 149 oC.

1 H NMR (400 MHz, CDCl3) δ 1.31 (s, 3H, CH3), 1.52 (d, J=6.4 Hz, 3H, CH3), 1.82-1.90

β (m, 1H, H1/H2), 2.05-3.36 (m, 3H, H1/H2), 3.25 (dd, J=14.3, 2.9 Hz, 1H, H6 ), 3.36 (dd,

α J=14.3, 11.1 Hz, 1H, H6 ), 3.70 (br s, 1H, H4a), 4.99 (ddq, J=11.1, 2.9, 6.4 Hz, 1H, H7),

4 3 13 5.83-5.89 (m, 1H, H ), 6.24-6.31 (m, 1H, H ); C NMR (CDCl3) δ 20.2, 21.7, 22.1, 25.1,

43.9, 64.5, 66.5, 73.1, 114.3, 135.9, 179.0; X-ray crystal structure is reported in ref. 80a.

Anal. Calcd. for C11H16O4S: C, 54.08; H, 6.60. Found: C, 54.12; H, 6.63.

(4aSR,7SR,9aSR)-7,9a-Dimethyl-5,5-dioxo-1,2,4a,9a-tetrahydro-8-oxa-5λ6- thiabenzocycloheptan-9-one (224b).

White solid, spectral data assigned from the 1/1 mixture of 223b/225b obtained as a second fraction after column chromatography by procedure 6.3.2.

172

1 ≈ 1 2 H NMR (CDCl3) δ 1.49 (s, 3H, CH3), 1.48 (d , 3H, CH3), 1.62-1.76 (m, 1H, H /H ),

α 2.01-2.38 (m, 3H, H1/H2), 3.09 (ddd, J=14.5, 3.4, 1.1 Hz, 1H, H6 ), 3.43 (dd, J=14.5, 9.0

β Hz, 1H, H6 ), 3.56 (br s, 1H, H4a), (H7 is hidden by H7 of 225b), 5.80-5.93 (m, 1H, H4),

3 13 6.23-6.32 (m, 1H, H ); C NMR (CDCl3) δ 20.1, 22.4, 25.3, 31.7, 45.0, 58.5, 70.1, 72.1,

118.0, 135.3 (C=O was not observed).

6.3.3. (4aSR,7SR,9aSR)-9a-Methyl-5,5-dioxo-7-phenyl-1,2,4a,9a-tetrahydro-8-oxa-

5λ6-thiabenzocycloheptan-9-one (223c).

β-Acyloxy sulfone 215c (0.84 g, 2.74 mmol) was heated in toluene (250 mL, 0.011 M).

After 15 h at 118 oC, conversion to cycloadduct was less than 25% (1H NMR analysis).

Heating was continued for an additional 24 h at 138 oC – conversion to cycloadduct was

87% (1H NMR analysis). Removal of the solvent in vacuo afforded a 100/25/10/20 mixture of cycloadducts 223c, 224c, 225c and β-acyloxy sulfone 215c. Crystallization of the crude reaction mixture from EtOAc/Hexanes (1/3) gave the clean title compound

223c as a white solid, mp 208-209 oC (0.41 g, 1.34 mmol, 49%). Identical results were obtained if the reaction was performed for 28 h straight at 138 oC (Table 6, entry 4).

If the reaction was performed for 50 h at 145 oC (0.017M in toluene) (Table 6, entry 5), the conversion of 215c to cycloadducts was complete (1H NMR analysis), however, the yield of 223c remained 49%, while the crystallization was more difficult.

1 1 H NMR (400 MHz, CDCl3) δ 1.39 (s, 3H, CH3), 1.89-1.97 (m, 1H, H ), 2.07-2.20 (m,

β 1H, H1), 2.24-2.40 (m, 2H, H2), 3.52 (br dd, J=14.3, 2.9 Hz, 1H, H6 ), 3.71 (dd, J=14.3,

≈ The value of the coupling constant was not calculated because of overlapping signals.

173

α 11.6 Hz, 1H, H6 ), 3.85 (br s, 1H, H4a), 5.87 (dd, J=11.5, 2.8 Hz, 1H, H7), 5.88-5.93 (m,

4 3 13 1H, H ), 6.28-6.34 (m, 1H, H ), 7.36-7.46 (m, 5H, Ph); C NMR (CDCl3, one signal masked) δ 21.8, 22.1, 25.3, 44.1, 64.1, 67.0, 77.2, 114.2, 126.0, 129.2, 129.3, 136.1,

136.2, 178.4. Anal. Calcd. for C16H18O4S: C, 62.72; H, 5.92. Found: C, 62.25; H, 5.87.

1 NOE (400 MHz): irradiation of the CH3 group resulted in enhancement of the two H protons and strong enhancement of H4a; irradiation of H4a resulted in strong enhancement

α of H4 and a weak negative NOE of H3; irradiation of H6 resulted in enhancement of H4a

β β α and H6 ; irradiation of H6 resulted in strong enhancement of H7 and H6 and a weak negative NOE of H4a.

(4aSR,7RS,9aSR)-9a-Methyl-5,5-dioxo-7-phenyl-1,2,4a,9a-tetrahydro-8-oxa-5λ6- thiabenzocycloheptan-9-one (224c).

Spectral data was partially assigned from the white solid mixture of 223c/224c obtained from further crystallization of the mother liquor in procedure 6.3.3: 1H NMR (400 MHz,

1 2 CDCl3) (partial listing) δ 1.60 (s, 3H, CH3), 1.78 (ddd, J=14.0, 11.9, 5.2 Hz, 1H, H /H ),

α 2.06-2.47 (m, 3H, H1/H2), 3.19 (ddd, J=14.4, 2.9, 1.4 Hz, 1H, H6 ), 3.71 (br s, 1H, H4a),

β 3.79 (dd, J=14.5, 11.1 Hz, 1H, H6 ), 5.79 (dd, J=11.0, 2.9, 1H, H7), 5.92-5.98 (m, 1H,

4 3 13 H ), 6.32-6.39 (m, 1H, H ), 7.28-7.33 (m, 2H, Ph); C NMR (CDCl3, one signal around

77 ppm and one signal of Ph are masked) δ 22.9, 26.8, 33.5, 45.2, 58.6, 71.5, 119.5,

129.2, 129.3, 135.0, 136.4, 177.3.

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6.3.4. (4aSR,7SR,9aSR)-7-t-Butyl-9a-methyl-5,5-dioxo-1,2,4a,9a-tetrahydro-8-oxa-

5λ6-thiabenzocycloheptan-9-one (223d).

β-Acyloxy sulfone 215d (1.434 g, 5.01 mmol) was heated in toluene (450 mL, 0.011 M) at 125 oC for 40 h. Crystallization of the crude reaction mixture from EtOAc/Hexanes

(1/3, 70 mL) gave the title compound 223d as a white crystalline solid (0.876 g, 3.06 mmol, 61%), mp 216-217 oC, turns light yellow on melting. Recrystallization of the concentrated mother liquor from EtOAc/Hexanes (1/3, 18 mL) gave a second crop of clean 223d (0.156 g, 0.54 mmol, 11%), mp 216-217 oC, turns light yellow. Total yield of the title compound 223d was 1.032 g, 3.60 mmol, 72%.

If the transformation was conducted at 138 oC for 47 h, the yield was slightly lowered to

65%.

1 H NMR (400 MHz, CDCl3) δ 1.04 (s, 9H, t-Bu), 1.32 (s, 3H, CH3), 1.84-1.91 (m, 1H,

β H1), 2.05-2.36 (m, 3H, H1/H2), 3.21 (dd, J=14.1, 2.6 Hz, 1H, H6 ), 3.47 (dd, J=14.1, 11.8

α Hz, 1H, H6 ), 3.71 (br s, 1H, H4a), 4.50 (dd, J=11.8, 2.6 Hz, 1H, H7), 5.84-5.90 (m, 1H,

4 3 13 H ), 6.24-6.30 (m, 1H, H ); C NMR (CDCl3) δ 22.0, 22.1, 25.2, 25.8, 34.2, 44.1, 59.6,

67.0, 83.6, 114.4, 135.9, 179.0. Anal. Calcd. for C14H22O4S: C, 58.71; H, 7.74. Found: C,

58.87; H, 7.72.

NOE (400 MHz): irradiation of Me resulted in strong enhancement of H4a and enhancement of H1 at 1.84-1.91 ppm; irradiation of H4a resulted in strong enhancement of

α α H4 and weak enhancement of H6 ; irradiation of H6 resulted in enhancement of H4a and

β β α H6 ; irradiation of H6 resulted in enhancement of H7 and H6 ; irradiation of H7 resulted

β in weak enhancement of H6 .

175

(4aSR,7RS,9aSR)-7-t-Butyl-9a-methyl-5,5-dioxo-1,2,4a,9a-tetrahydro-8-oxa-5λ6- thiabenzocycloheptan-9-one (224d).

The residue obtained by concentration of the mother liquor after the second crystallization in procedure 6.3.4 was subjected to column chromatography

(dichloromethane). The first fraction gave 0.09 g (0.30 mmol, 6%) of almost clean product 223d; the second fraction (shaving) gave 0.14 g of a mixture of endo-Major 223d

/ endo-Minor 224d / exo-225d in a 30/23/100 ratio. The spectral data of the title compound 224d were assigned from this mixture.

1 1 2 H NMR (CDCl3) δ 0.97 (s, 9H, t-Bu), 1.54 (s, 3H, CH3), 1.65-1.85 (m, 1H, H /H ), 1.85-

α 2.40 (m, 3H, H1/H2), 2.89 (ddd, J=14.1, 2.4, 1.3 Hz, 1H, H6 ), 3.58 (dd, J=14.1, 11.7 Hz,

β 1H, H6 ), 3.63 (br s, 1H, H4a), 4.43 (dd, J=11.7, 2.4 Hz, 1H, H7), 5.83-5.93 (m, 1H, H4),

3 13 6.22-6.32 (m, 1H, H ); C NMR (CDCl3) δ 22.9, 25.7, 26.9, 33.9, 36.1, 45.2, 53.6, 71.9,

83.7, 119.6, 134.6, 177.9.

(4aSR,7RS,9aRS)-7-t-Butyl-9a-methyl-5,5-dioxo-1,2,4a,9a-tetrahydro-8-oxa-5λ6- thiabenzocycloheptan-9-one (225d).

The title compound 225d was obtained as a crystalline white solid by crystallization of the mixture of endo-Major 223d / endo-Minor 224d / exo-225d (30/23/100 ratio) obtained in the procedure described above for 224d, from a minimum amount of EtOAc.

1 H NMR (400 MHz, CDCl3) δ 1.05 (s, 9H, t-Bu), 1.48 (s, 3H, CH3), 1.86-1.96 (m, 1H,

α β β H1 ), 2.06-2.13 (m, 1H, H1 ), 2.20-2.35 (m, 2H, H2), 3.38 (dd, J = 15.6, 8.2 Hz, 1H, H6 ),

α 3.48 (dd, J = 15.6, 3.2 Hz, 1H, H6 ), 4.25 (br s, 1H, H4a), 4.56 (dd, J = 8.2, 3.1 Hz, 1H,

7 4 3 13 H ), 5.91-5.96 (m, 1H, H ), 6.09-6.16 (m, 1H, H ); C NMR (CDCl3) δ 16.5, 22.1, 25.3,

176

33.4, 36.0, 44.8, 55.6, 62.9, 81.6, 114.3, 132.3, 177.4. Anal. Calcd. for C14H22O4S: C,

58.71; H, 7.74. Found: C, 58.66; H, 7.74.

NOE (400 MHz): irradiation of H7 resulted in strong enhancement of H4a and weak

α α enhancement of H6 ; irradiation of H4a resulted in strong enhancement of H7, H4 and H1 ;

α β irradiation of H6 did not resulted in any strong enhancement; irradiation of H6 resulted

α in weak enhancement of H6 and weak enhancement of Me; irradiation of Me resulted in

β β weak enhancement of H6 , H1 and H2.

6.3.5. (4aSR,7RS,9aSR)-7-Methyl-5,5-dioxo-1,2,4a,9a-tetrahydro-8-oxa-5λ6- thiabenzocycloheptan-9-one (223e).

β-Acyloxy sulfone 216b (0.79 g, 3.43 mmol) was heated in toluene (150 mL, 0.019 M) at

130 oC for 43 h. Column chromatography (EtOAc/Hexane, 1/1) gave the title compound

o 223e as a white solid (0.43 g, 1.87 mmol, 54%, Rf = 0.34), mp 183-184 C, and the minor endo-product 224e as a white solid (0.14 g, 0.61 mmol, 18%, Rf = 0.21), mp 174-

175 oC, as separate fractions. Total yield of cycloadducts was 72%.

1 223e: H NMR (300 MHz, CDCl3) δ 1.52 (d, J=6.4 Hz, 3H, CH3), 2.02-2.21 (m, 3H,

H1/H2), 2.28-2.41 (m, 1H, H1/H2), 3.00-3.09 (m, 1H, H9a), 3.27 (dd, J=14.4, 2.8 Hz, 1H,

β α H6 ), 3.41 (dd, J=14.4, 10.8 Hz, 1H, H6 ), 4.12 (br s, 1H, H4a), 5.00 (ddq, J=10.8, 2.8, 6.4

7 4 3 13 Hz, 1H, H ), 5.89-5.99 (m, 1H, H ), 6.28-6.39 (m, 1H, H ); C NMR (75 MHz, CDCl3) δ

19.9, 20.4, 24.8, 41.9, 60.3, 64.4, 73.2, 115.4, 137.1, 175.9. Anal. Calcd. for C10H14O4S:

C, 52.16; H, 6.13. Found: C, 52.12; H, 6.08.

177

α NOE (500 MHz): irradiation of H4a resulted in strong enhancement of H4, H6 and H9a;

7 6β irradiation of H resulted in enhancement of CH3 and H .

(4aSR,7SR,9aSR)-7-Methyl-5,5-dioxo-1,2,4a,9a-tetrahydro-8-oxa-5λ6- thiabenzocycloheptan-9-one (224e).

The title compound 224e was obtained as a white solid in 18% yield by procedure 6.3.5.

1 H NMR (300 MHz, CDCl3) δ 1.51 (d, J=6.5 Hz, 3H, CH3), 1.89 (dddd, J= 13.7, 9.7, 7.4,

4.1 Hz, 1H, H1), 2.10-2.23 (m, 1H, H1/H2), 2.33-2.43 (m, 1H, H1/H2), 2.49-2.65 (m, 1H,

α β H1/H2), 3.13 (ddd, J=15.1, 2.6, 1.5 Hz, 1H, H6 ), 3.38 (dd, J=15.2, 9.1 Hz, 1H, H6 ), 3.50

(app q, J=4.0 Hz, 1H, H9a), 3.89 (br s, 1H, H4a), 4.95 (ddq, J=9.0, 1.4, 6.5 Hz, 1H, H7),

4 3 13 5.86-5.93 (m, 1H, H ), 6.06-6.14 (m, 1H, H ); C NMR (75 MHz, CDCl3) δ 21.4, 22.6,

25.9, 39.2, 58.1, 63.1, 70.0, 117.2, 135.1, 171.9. Anal. Calcd. for C10H14O4S: C, 52.16; H,

6.13. Found: C, 52.19; H, 5.95.

NOE (500 MHz): irradiation of H4a resulted in strong enhancement of H4, H9a and H1

(1.89 ppm) and in enhancement of H7; irradiation of H7 resulted in strong enhancement of

9a 6α 4a CH3 and H , and enhancement of H and H .

6.3.6. (4aSR,7SR,9aSR)-5,5-Dioxo-7-phenyl-1,2,4a,9a-tetrahydro-8-oxa-5λ6- thiabenzocycloheptan-9-one (223f).

β-Acyloxy sulfone 216c (0.733 g, 2.51 mmol) was heated in toluene (250 mL, 0.010 M) at 127 oC for 43 h. Column chromatography (dichloromethane) gave the clean title

o compound 223f as a white solid (0.420 g, 1.44 mmol, 57%, Rf = 0.27), mp 165-166 C.

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A second fraction contained a ca 1/1 mixture of minor endo-product 224f (Rf = 0.19) and unreacted 216c (Rf = 0.16).

1 1 2 1 2 223f: H NMR (400 MHz, CDCl3) δ 2.08-2.27 (m, 3H, H /H ), 2.32-2.44 (m, 1H, H /H ),

β 3.10-3.18 (m, 1H, H9a), 3.52 (dd, J=14.5, 2.8 Hz, 1H, H6 ), 3.73 (dd, J=14.4, 11.5 Hz, 1H,

α H6 ), 4.26 (br s, 1H, H4a), 5.87 (dd, J=11.5, 2.8 Hz, 1H, H7), 5.96-6.02 (m, 1H, H4), 6.34-

3 13 6.40 (m, 1H, H ), 7.35-7.46 (m, 5H, Ph); C NMR (100 MHz, CDCl3) δ 20.0, 24.8, 41.9,

60.8, 64.4, 77.6, 115.3, 126.0, 129.2, 129.4, 136.2, 137.3, 175.5. Anal. Calcd. for

C15H16O4S: C, 61.62; H, 5.52. Found: C, 61.36; H, 5.44.

NOE (400 MHz): irradiation of H9a resulted in strong enhancement of H4a and enhancement of H1 around 2.2 ppm; irradiation of H4a resulted in strong enhancement of

α α H4 and H9a, and weak enhancement of H6 ; irradiation of H6 resulted in enhancement of

β β α H4a and H6 ; irradiation of H6 resulted in enhancement of H7 and H6 and a weak

β negative NOE of H4a; irradiation of H7 resulted in enhancement of H6 and Ph.

(4aSR,7RS,9aSR)-5,5-Dioxo-7-phenyl-1,2,4a,9a-tetrahydro-8-oxa-5λ6- thiabenzocycloheptan-9-one (224f).

The title compound 224f was obtained as a white solid (0.12 g, 0.41 mmol, 16%), mp 184 oC, by crystallization of the mixture of 224f and 216c, obtained by procedure 6.3.6, from

EtOAc/Hexane (1/2).

1 1 1 2 H NMR (400 MHz, CDCl3) δ 1.90-2.00 (m, 1H, H ), 2.16-2.26 (m, 1H, H /H ), 2.34-

α 2.42 (m, 1H, H1/H2), 2.45-2.58 (m, 1H, H1/H2), 3.31 (app dt, J=15.0, 2.1 Hz, 1H, H6 ),

β 3.58-3.64 (m, 1H, H9a), 3.72 (dd, J=15.0, 10.2 Hz, 1H, H6 ), 3.98 (br s, 1H, H4a), 5.78

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(dd, J=10.2, 1.6 Hz, 1H, H7), 5.92-5.98 (m, 1H, H4), 6.17-6.24 (m, 1H, H3); 13C NMR

(100 MHz, CDCl3) δ 22.3, 25.6, 40.0, 58.9, 63.6, 75.6, 117.6, 126.0, 129.3, 129.4, 135.1,

136.6, 172.6. Anal. Calcd. for C15H16O4S: C, 61.62; H, 5.52. Found: C, 61.76; H, 5.49.

NOE (400 MHz): irradiation of H9a resulted in strong enhancement of H4a and H7;

α irradiation of H4a resulted in strong enhancement of H4 and H9a; irradiation of H6

β resulted in enhancement of H7 and H6 ; irradiation of H7 resulted in enhancement of H9a.

6.3.7. (4aSR,7SR,9aSR)-7-t-Butyl-5,5-dioxo-1,2,4a,9a-tetrahydro-8-oxa-5λ6- thiabenzocycloheptan-9-one (223g).

β-Acyloxy sulfone 216d (1.36 g, 5.00 mmol) was heated in toluene (450 mL, 0.011 M) at

125 oC for 40 h. Crystallization of the crude reaction mixture from a minimum amount of

EtOAc gave the title compound 223g as a white crystalline solid (0.83 g, 3.05 mmol,

61%), mp 189 oC. Column chromatography (dichloromethane) of the concentrated mother liquor gave the clean title compound 223g as a white solid (0.13 g, 0.48 mmol,

10%), mp 189 oC. Total yield of the title compound 223g is 0.96 g, 3.53 mmol, 71%. The second chromatography fraction contained minor endo-product 224g, contaminated with

223g.

1 1,2 223g: H NMR (400 MHz, CDCl3) δ 1.03 (s, 9H, t-Bu), 2.00-2.21 (m, 3H, H ), 2.29-

α β 2.40 (m, 1H, H1 ), 3.00-3.10 (m, 1H, H9a), 3.23 (dd, J = 14.1, 2.5 Hz, 1H, H6 ), 3.49 (dd,

α J = 14.1, 11.7 Hz, 1H, H6 ), 4.09-4.15 (m, 1H, H4a), 4.50 (dd, J = 11.7, 2.5 Hz, 1H, H7),

4 3 13 5.92-5.98 (m, 1H, H ), 6.30-6.37 (m, 1H, H ); C NMR (75 MHz, CDCl3) 20.0, 24.8,

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25.8, 34.2, 42.0, 59.7, 60.9, 84.0, 115.6, 137.1, 176.1. Anal. Calcd. for C13H20O4S: C,

57.33; H, 7.40. Found: C, 57.46; H, 7.38.

β NOE (400 MHz): irradiation of H7 resulted only in a weak enhancement of H6 ;

α irradiation of H4a resulted in strong enhancement of H9a, H4, H6 and also in a weak

β α β negative enhancement of H6 ; irradiation of H6 resulted in strong enhancement of H6

β α and H4a; irradiation of H6 resulted in strong enhancement of H6 , weak enhancement of

H7 and weak negative enhancement of H9a, irradiation of H9a resulted in strong

α enhancement of H4a and H1 .

(4aSR,7RS,9aSR)-7-t-Butyl-5,5-dioxo-1,2,4a,9a-tetrahydro-8-oxa-5λ6- thiabenzocycloheptan-9-one (224g).

The title compound 224g was obtained as a white solid (0.02-0.03 g, ca 0.09 mmol, 2%), mp 131 oC, by two crystallizations of the crude product 224g, obtained as the second chromatography fraction by procedure 6.3.7, from EtOAc/Hexane (1/1).

1 1 H NMR (400 MHz, CDCl3) H NMR (400 MHz, CDCl3) δ 1.01 (s, 9H, t-Bu), 1.83-1.93

α β (m, 1H, H1 ), 2.11-2.21 (m, 1H, H2), 2.30-2.37 (m, 1H, H1 ), 2.39-2.51 (m, 1H, H2), 3.11

α β (ddd, J = 14.8, 2.4, 1.6 Hz, 1H, H6 ), 3.35 (dd, J = 14.8, 10.0 Hz, 1H, H6 ), 3.49-3.53 (m,

1H, H9a), 3.86-3.91 (m, 1H, H4a), 4.37 (dd, J = 10.0, 1.6 Hz, 1H, H7), 5.86-5.91 (m, 1H,

4 3 13 H ), 6.08-6.15 (m, 1H, H ); C NMR (CDCl3) δ 22.2, 25.5, 25.6, 34.7, 39.7, 53.4, 63.8,

81.5, 117.7, 134.6, 173.0. Anal. Calcd. for C13H20O4S: C, 57.33; H, 7.40. Found: C,

57.19; H, 7.41.

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NOE (400 MHz): irradiation of H7 resulted in enhancement of H9a and weak

α α enhancement of H6 ; irradiation of H4a resulted in enhancement of H9a, H4 and H1 ; irradiation of H9a resulted in strong enhancement of H4a, H7 and weak enhancement of

α β β α H1 and H1 ; irradiation of H6 resulted in strong enhancement of H6 and weak

α β enhancement of H4; irradiation of H6 resulted only in strong enhancement of H6 and a

α very weak enhancement of H7. W coupling is present between H6 and H4a.

6.3.8. (4aSR,7RS,9aRS)-9a-Bromo-7-methyl-5,5-dioxo-1,2,4a,9a-tetrahydro-8-oxa-

5λ6-thiabenzocycloheptan-9-one (223h).

β-Acyloxy sulfone 217b (0.31 g, 1.0 mmol) was heated in toluene (100 mL, 0.010 M) at

115 oC for 21 h. Column chromatography (dichloromethane/ether, 40/1) gave the title compound 223h as a yellowish solid, which was clean by 1H and 13C NMR analysis (0.18 g, 0.58 mmol, 58%, Rf = 0.37). A second fraction contained a ca 100/15 mixture of minor endo-product 224h (Rf = 0.22) and 223h. The first fraction containing 223h was treated with decolorizing charcoal and crystallized from EtOAc/Hexane (1/1) to give the title compound 223h as a white solid (0.15 g, 0.49 mmol, 48%), mp 198-200 oC.

1 1 2 H NMR (CDCl3) δ 1.59 (d, J=6.4 Hz, 3H, CH3), 2.30-2.48 (m, 4H, H /H ), 3.34 (dd,

β α J=14.4, 2.8 Hz, 1H, H6 ), 3.47 (dd, J=14.4, 11.1 Hz, 1H, H6 ), 4.32 (br s, 1H, H4a), 5.00

(ddq, J=11.1, 2.8, 6.4 Hz, 1H, H7), 5.83-5.91 (m, 1H, H4), 6.33-6.42 (m, 1H, H3); 13C

NMR (CDCl3) δ 20.2, 23.2, 28.5, 54.4, 64.3, 68.0, 74.9, 112.9, 136.1, 172.1; X-ray crystal structure is reported in ref. 80c. Anal. Calcd. for C10H13BrO4S: C, 38.85; H, 4.24.

Found: C, 38.83; H, 4.22.

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α NOE (500 MHz): irradiation of H4a resulted in strong enhancement of H4 and H6 ;

7 6β irradiation of H resulted in enhancement of CH3 and H .

The minor product 224h partially decomposed on the silica column to produce dehydrobromination product 226h (Rf = 0.16).

(4aSR,7SR,9aRS)-9a-Bromo-7-methyl-5,5-dioxo-1,2,4a,9a-tetrahydro-8-oxa-5λ6- thiabenzocycloheptan-9-one (224h).

A very small analytical sample of the title compound 224h for X-ray diffraction analysis, elemental analysis and melting point determination was obtained as a white crystalline

o solid (mp 198-200 C, decomposes) by slow evaporation of CDCl3 from an NMR tube containing the ca 100/15 mixture of 224h and 223h, obtained by procedure 6.3.8. The 1H and 13C NMR data of the title compound 224h was assigned from this mixture.

1 1 2 H NMR (CDCl3) δ 1.59 (d, J=6.4 Hz, 3H, CH3), 2.26-2.48 (m, 3H, H /H ), 2.53-2.63 (m,

β α 1H, H1/H2), 3.43 (dd, J=14.5, 8.5 Hz, 1H, H6 ), 3.58 (dd, J=14.5, 3.8 Hz, 1H, H6 ), 4.44

(br s, 1H, H4a), 5.41 (ddq, J=8.6, 3.8, 6.3 Hz, 1H, H7), 5.78-5.87 (m, 1H, H4), 6.35-6.45

3 13 (m, 1H, H ); C NMR (CDCl3) δ 20.3, 22.7, 31.4, 57.5, 60.9, 66.5, 69.9, 112.6, 135.8,

167.7; X-ray crystal structure is reported in ref. 80d. Anal. Calcd. for C10H13BrO4S: C,

38.85; H, 4.24. Found: C, 38.63; H, 4.14.

NOE (500 MHz): irradiation of H4a resulted in strong enhancement of H4, H7 and in

α enhancement of H6 ; irradiation of H7 resulted in strong enhancement of H4a and

6α enhancement of H and CH3.

7-Methyl-5,5-dioxo-1,2-dihydro-8-oxa-5λ6-thiabenzocycloheptan-9-one (226h).

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A small sample of the title compound 226h was collected after the column chromatography in procedure 6.3.8.

1 1 2 H NMR (CDCl3) δ 1.44 (d, J=6.3 Hz, 1H, CH3), 2.26-2.65 (m, 3H, H /H ), 2.81-2.98 (m,

α β 1H, H1/H2), 3.62 (dd, J=14.1, 10.7 Hz, 1H, H6 ), 3.58 (dd, J=14.1, 3.5 Hz, 1H, H6 ), 5.41

(ddq, J=10.6, 3.7, 6.3 Hz, 1H, H7), 5.37 (ddd, J=9.8, 5.1, 4.3 Hz, 1H, H4), 6.49 (dt, J=9.8,

1.8 Hz, 1H, H3).

6.3.9. (4aSR,7SR,9aRS)-9a-Bromo-7-phenyl-5,5-dioxo-1,2,4a,9a-tetrahydro-8-oxa-

5λ6-thiabenzocycloheptan-9-one (223i).

β-Acyloxy sulfone 217c (0.35 g, 0.94 mmol) was heated in toluene (94 mL, 0.010 M) at

127 oC for 21 h. Column chromatography (EtOAc/Hexanes, 1/5) gave the title compound

o 223i as a white solid (0.22 g, 0.59 mmol, 63%, Rf = 0.28), mp 212-214 C. The minor endo-product 224i decomposed on the silica column.

1 1 2 6β H NMR (CDCl3) δ 2.36-2.51 (m, 4H, H /H ), 3.58 (dd, J=14.5, 2.8 Hz, 1H, H ), 3.80

α (dd, J=14.5, 11.5 Hz, 1H, H6 ), 4.47 (br s, 1H, H4a), 5.87 (dd, J=11.5, 2.8 Hz, 1H, H7),

4 3 13 5.87-5.96 (m, 1H, H ), 6.36-6.45 (m, 1H, H ), 7.37-7.47 (m, 5H, Ph); C NMR (CDCl3)

δ 23.2, 28.6, 55.2, 64.0, 68.4, 78.8, 112.8, 126.1, 129.3, 129.6, 135.3, 136.3, 171.8. Anal.

Calcd. for C15H15BrO4S: C, 48.53; H, 4.07. Found: C, 48.25; H, 3.94.

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6.4. SOME SYNTHETIC TRANSFORMATIONS OF THE OBTAINED DIELS-

ALDER CYCLOADDUCT 223d.

8 O2 t-Bu t-Bu t-Bu H 2' 1' 2β S H Me t-Bu 2' O 1' O2S OH O2S OH O2S OCH3 α 1 H2 3 2 I O 6 1 O O β O 3 4 5 4 5 6 H H H 3α 227 228 229 H 230 7α 6 H H t-Bu t-Bu 7β t-Bu H t-Bu 1' 2' O S 8a O S O S O S 2 H O 5 2 O 2 H2 2 8b 1 COOMe COOMe 3a O 1 O Me O O 7 O 3 Me O Me 2 5 4 1a 3 6 231 232 233 234 t-Bu t-Bu t-Bu 1' 1' 1' 2' 2' 2' O2S OMe O2S OMe O2S OMe 2 2 8 3 3 1 7 1 O 1 O O 9 O 2 5 6 5 6 6 10 HO 4 O 4 3 11 235 236 5 4 237

6.4.1. (1RS,2SR)-2-((E)-3’,3’-Dimethyl-but-1’-ene-1’-sulfonyl)-1-methyl-cyclohex-3- enecarboxylic acid (228).

A solution of cycloadduct 223d (0.573 g, 2.00 mmol, 1 equiv) in THF (25 mL) was

o cooled to –30 C and treated with LDA (4.4 mmol, 2.2 equiv; obtained from i-Pr2NH

(0.35 mL, 0.49 g, 4.8 mmol) and n-BuLi (1.76 mL, 2.5 M in hexanes, 4.4 mmol) in 15 mL of THF) over 10 min. The reaction mixture was warmed up to rt over 1.5 h, then treated with saturated aq NaHCO3 (50 mL) and the organic solvents were removed in vacuo. The remaining aqueous solution was extracted with dichloromethane (2x15 mL) and the dichloromethane extracts were discarded or evaporated in vacuo to recover any

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unreacter starting material. The aqueous solution was acidified with aq concentrated HCl to pH 1 and was then extracted with dichloromethane (4x20 mL). The combined dichloromethane extracts were dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to produce the title compound 228 (0.500 g, 1.75 mmol, 87%) as a

1 colorless oil: H NMR (300 MHz, CDCl3) δ 1.11 (s, 9H, t-Bu), 1.46 (s, 3H, CH3), 1.85-

2.00 (m, 2H, H5,6), 2.14-2.26 (m, 2H, H5,6), 4.43 (app qint, J= 2.6 Hz, 1H, H2), 5.62-5.76

(m, 1H, H4), 6.00-6.16 (m, 1H, H3), 6.15 (d, J=15.3 Hz, 1H, H1’), 6.88 (d, J=15.3 Hz, 1H,

2’ 13 H ); C NMR (75 MHz, CDCl3) δ 18.1, 21.9, 28.5, 32.5, 34.5, 43.2, 65.3, 118.6, 124.4,

132.0, 160.0, 182.3.

6.4.2. (1RS,2RS)-2-((E)-3’,3’-Dimethyl-but-1’-ene-1’-sulfonyl)-1-methyl-cyclohex-3- enecarboxylic acid (227).

The title compound 227 was obtained by procedure 6.4.1, employing 1.0 equiv of LDA and reaction conditions presented in Table 7, entry 2, except that AcOH (1.6 equiv) was added to the reaction mixture at –78 oC prior to the warm up. The title compound 227 was obtained as a colorless oil, as a 5/1 mixture with 228 in 50 % combined yield (0.289 g, 1.00 mmol), and was characterized from the mixture. Unreacted starting material

(44%) was also recovered in this experiment. Compound 227: 1H NMR (300 MHz,

5,6 CDCl3) δ 1.10 (s, 9H, t-Bu), 1.36 (s, 3H, CH3), 1.70-1.80 (m, 1H, H ), 2.05-2.35 (m,

3H, H5,6), 3.87 (br d, J= 5.1 Hz, 1H, H2), 5.60-5.81 (overlaps with 228, m, 1H, H4), 5.96-

6.11 (overlaps with 228, m, 1H, H3), 6.22 (d, J=15.4 Hz, 1H, H1’), 6.80 (d, J=15.4 Hz,

1H, H2’).

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6.4.3. (1RS,2SR)-2-((E)-3’,3’-Dimethyl-but-1’-ene-1’-sulfonyl)-1-methyl-cyclohex-3- enecarboxylic acid methyl ester (229).

The combined dichloromethane extracts (ca 80 mL) obtained in 6.4.1 were treated with

≠ stirring with an excess of freshly prepared diazomethane solution at rt. Etherial diazomethane was added until the very light yellow coloration of the diazomethane persisted in the reaction mixture. The reaction mixture was stirred until the excess diazomethane decomposed and the yellow coloration disappeared (ca 30 min), dried with

MgSO4 and filtered. The filtrate was concentrated in vacuo to produce the title

1 compound 229 (0.526 g, 1.75 mmol, 87%) as a colorless oil: H NMR (400 MHz, CDCl3)

5,6 5,6 δ 1.11 (s, 9H, t-Bu), 1.45 (s, 3H, CH3), 1.83-1.95 (m, 2H, H ), 2.08-2.24 (m, 2H, H ),

2 4 3.75 (s, 3H, OCH3), 4.45 (app. quint, J= 2.8 Hz, 1H, H ), 5.65-5.71 (m, 1H, H ), 5.99-

6.06 (m, 1H, H3), 6.22 (d, J=15.4 Hz, 1H, H1’), 6.80 (d, J=15.4 Hz, 1H, H2’); 13C NMR

(100 MHz, CDCl3) δ 18.0, 21.9, 28.3, 32.4, 34.4, 43.2, 52.6, 65.6, 118.7, 124.3, 131.7,

159.6, 176.4.

6.4.4. (1RS,4SR,5SR,8SR)-8-((E)-3’,3’-Dimethyl-but-1’-ene-1’-sulfonyl)-4-iodo-1- methyl-6-oxa-bicyclo[3.2.1]octan-7-one (230).

The 5/1 mixture of 227/228 (0.289 g, 1.00 mmol, 1.0 equiv) obtained by procedure 6.4.2 was dissolved in dichloromethane (24 mL) and treated with a solution of NaHCO3 (0.76 g, 9.05 mmol, 9.0 equiv) and KI (0.16 g, 0.96 mmol, 9.6 equiv) in water (18 mL). Iodine

(0.18 g, 7.1 mmol, 7.1 equiv) was added, and the reaction mixture was stirred for 24 h.

≠ Prepared from Diazald® according to Technical Bulletin Al-180 at www.sigma-aldrich.com/tech_library

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The resulting solution was diluted with dichloromethane (24 mL) and treated with saturated aq Na2SO3 until the iodine color disappeared. The layers were separated, and the organic layer was washed with aq saturated NaHCO3 (2x10 mL) and with water (20 mL), dried over MgSO4 and concentrated in vacuo. The residue was crystallized from a minimum amount of EtOAc/Hexanes (3/1) to produce the title compound 230 (0.310 g,

o 1 0.75 mmol, 90% from 227) as a white solid: mp 160 C; H NMR (400 MHz, CDCl3) δ

2α 1.14 (s, 9H, t-Bu), 1.50 (s, 3H, CH3), 1.74 (br dd, J=13.8, 6.2 Hz,1H, H ), 1.97 (app td,

β β J=13.4, 5.6 Hz,1H, H2 ), 2.08 (br dd, J=16.6, 5.5 Hz,1H, H3 ), 2.41 (app ddt, J=16.6,

α 13.0, 6.1 Hz,1H, H3 ), 4.19 (s, 1H, H8), 4.59 (dd, J=5.4, 4.5 Hz, 1H, H4), 5.05 (br d, J=

4.4 Hz, 1H, H5), 6.13 (d, J=15.3 Hz, 1H, H1’), 6.99 (d, J=15.3 Hz, 1H, H2’); 13C NMR (75

MHz, CDCl3) δ 17.7, 22.3, 28.3, 29.4, 33.8, 35.0, 45.5, 71.9, 78.0, 122.6, 162.8, 175.9;

NOE (400 MHz): irradiation of H5 resulted in enhancement of H4; irradiation of H4

α resulted in enhancement of H5 and H3 ; irradiation of H8 resulted in enhancement of H5

β α β and H2 ; irradiation of H3 resulted in strong enhancement of H3 and enhancement of H4

2α 8 and H ; irradiation of CH3 resulted weak enhancement of H and a very weak

2α 2β enhancement of H and H . Anal. Calcd for C14H21IO4S: C, 40.78; H, 5.13. Found: C,

40.92; H, 5.23.

6.4.5. (1aSR, 3aRS, 6SR, 8aSR, 8bSR)-6-t-Butyl-3a-methyl-8,8-dioxo-hexahydro-1,5- dioxa-8λ6-thia-cyclopropa[3,4]benzo[1,2]cycloheptan-4-one (231).

A solution of cycloadduct 223b (0.573 g, 2.00 mmol, 1 equiv) and mCPBA (65%, 1.32 g, ca 5 mmol, 2.5 equiv) in dichloromethane (20 mL) was stirred for two days at rt, diluted

188

with dichloromethane (30 mL) and treated with saturated aq Na2SO3 (7 mL).The layers were separated, and the organic layer was washed with water (2x20 mL), dried over

MgSO4, and concentrated in vacuo. The title compound 231 (0.28 g, 0.93 mmol, 47 %) was separated by column chromatography (Rf (EtOAc/Hexanes, 1/3) = 0.29; Rf

(EtOAc/Hexanes, 2/1) = 0.65) as a white solid, mp 198-199 oC; 1H NMR (400 MHz,

2,3 CDCl3) δ 1.04 (s, 9H, t-Bu), 1.47 (s, 3H, CH3), 1.66-1.74 (m, 1H, H ), 1.97-2.09 (m,

β 1H, H2,3), 2.11-2.23 (m, 2H, H2,3), 3.24 (ddd, J = 14.2, 2.6, 0.6 Hz, 1H, H7 ), 3.38 (app.

α br t, J = 4.3 Hz, 1H, H1a), 3.55 (dd, J = 14.2, 11.8 Hz, 1H, H7 ), 3.78 (br s, 1H, H8a), 4.06

(ddd, J = 3.7, 1.5, 0.7 Hz, 1H, H8b), 4.52 (dd, J = 11.8, 2.6 Hz, 1H, H6); 13C ATP NMR

(100 MHz, CDCl3) δ 19.4 (CH2), 23.7 (CH3), 24.5 (CH2), 25.6 (CH3, t-Bu), 33.9 (C),

44.4 (C), 50.3 (CH), 52.6 (CH), 60.9 (CH2), 65.2 (CH), 83.0 (CH), 178.2 (C); NOE (400

β MHz): irradiation of H6 resulted in weak enhancement of H7 ; irradiation of H8b resulted in enhancement of H8a and H1a; irradiation of H8a resulted in enhancement of H8b and

7α 7β H , weak enhancement of CH3 and weak negative enhancement of H ; irradiation of

H1a resulted in enhancement of H8b and weak enhancement of aliphatic protons in δ 1.97-

8a 2.23 region; irradiation of CH3 resulted in enhancement of H . Anal. Calcd for

C14H22O5S: C, 55.61; H, 7.33. Found: C, 55.41; H, 7.35.

(1aRS, 3aRS, 6SR, 8aSR, 8bRS)-6-t-Butyl-3a-methyl-8,8-dioxo-hexahydro-1,5- dioxa-8λ6-thia-cyclopropa[3,4]benzo[1,2]cycloheptan-4-on (232).

The title compound 232 (0.28 g, 0.93 mmol, 47 %) was separated by column chromatography from the reaction described in procedure 6.4.5. Rf (EtOAc/Hexanes, 1/3)

o 1 = 0.03; Rf (EtOAc/Hexanes, 2/1) = 0.32, as a white solid: mp 185 C; H NMR (400

189

3β MHz, CDCl3) δ 1.03 (s, 9H, t-Bu), 1.35 (s, 3H, CH3), 1.58-1.65 (m, 1H, H ), 1.85-1.95

α β (m, 1H, H3 ), 2.13-2.27 (m, 2H, H2), 3.24 (dd, J = 14.1, 2.6 Hz, 1H, H7 ), 3.33-3.37 (m,

α 1H, H1a), 3.47 (dd, J = 14.1, 11.7 Hz, 1H, H7 ), 3.53 (dd, J = 5.0, 1.4 Hz, 1H, H8a), 3.59

(dd, J = 5.0, 3.5 Hz, 1H, H8b), 4.54 (dd, J = 11.7, 2.6 Hz, 1H, H6); 13C APT NMR (100

MHz, CDCl3) δ 19.8 (CH2), 21.8 (CH2), 23.1 (CH3), 25.6 (CH3, tBu), 34.0 (C), 42.6 (C),

46.9 (CH), 50.8 (CH), 60.4 (CH2), 65.6 (CH), 83.7 (CH), 177.4 (C); NOE (400 MHz):

β irradiation of H6 resulted in weak enhancement of H7 ; irradiation of H1a resulted in

α enhancement of H8b, the two H2 protons and H3 ; irradiation of H8a resulted in weak

8a 3α enhancement of CH3; irradiation of CH3 resulted in enhancement of H and H . Anal.

Calcd for C14H22O5S: C, 55.61; H, 7.33. Found: C, 55.65; H, 7.30.

6.4.6. (1RS, 2RS, 3RS, 6RS)-2-((E)-3’,3’-Dimethyl-but-1’-ene-1’-sulfonyl)-3-methyl-

7-oxa-bicyclo[4.1.0]heptane-3-carboxylic acid methyl ester (233).

(a) The acid 228 (0.500 g, 1.75 mmol) obtained by procedure 6.4.1 was treated with mCPBA as described in procedure 6.4.5, except that, after drying with MgSO4, the dichloromethane solution was treated with ethereal diazomethane as described in procedure 6.4.3, dried with MgSO4 and filtered. The filtrate was concentrated in vacuo and subjected to column chromatography (EtOAc/Hexanes, 1/3, Rf = 0.20) to produce the title compound 233 (0.490 g, 1.55 mmol, 89% from 228; 78% from 223d) as a white solid, mp 110-111 oC.

(b) The ester 229 (0.526 g, 1.75 mmol) obtained by procedure 6.4.3 was treated with mCPBA as described in procedure 6.4.5. The title compound 233 (0.492 g, 1.55 mmol,

190

89% from 229; 78% from 223d) was separated by column chromatography (as described

o 1 above) as a white solid: mp 110-111 C; H NMR (400 MHz, CDCl3) δ 1.14 (s, 9H, t-

4α Bu), 1.43 (s, 3H, CH3), 1.44 (ddd, J=13.3, 5.7, 2.2 Hz, 1H, H ), 1.44 (app td, J=13.0, 5.3

β α Hz,1H, H4 ), 1.96 (app tdd, J=14.0, 5.7, 2.1 Hz, 1H, H5 ), 2.12 (app ddt, J=15.6, 5.2, 1.9

β Hz, 1H, H5 ), 3.41-3.44 (m, 1H, H6), 3.4 (br d, J=3.8 Hz, 1H, H1), 4.4 (br s, 1H, H2), 6.21

1’ 2’ 13 (d, J=15.3 Hz, 1H, H ), 6.94 (d, J=15.3 Hz, 1H, H ). C NMR (100 MHz, CDCl3) δ

16.6, 19.5, 28.3, 29.1, 34.5, 41.4, 48.8, 51.1, 52.7, 63.4, 124.2, 160.4, 176.1; NOE (400

β MHz): irradiation of H2 resulted in enhancement of H1, H4 and H1’; irradiation of H1 resulted in enhancement of H2 and H6 and weak enhancement of H1’ and H2’; irradiation

6 5α 5β 4α of H resulted in enhancement of H and H ; irradiation of CH3 and H resulted in

4β 1 5α strong enhancement of H and enhancement of H and H . Anal. Calcd for C14H22O5S:

C, 56.94; H, 7.65. Found: C, 56.75; H, 7.65.

(1SR,2RS,3RS,6SR)-2-((E)-3’,3’-Dimethyl-but-1’-ene-1-sulfonyl)-3-methyl-7-oxa- bicyclo[4.1.0]heptane-3-carboxylic acid methyl ester (234).

The title compound 234 (0.044 g, 0.14 mmol, 7% from 223d) was obtained by column chromatography (EtOAc/Hexanes, 1/3, Rf = 0.13) of the reaction mixture obtained by

1 either procedure 6.4.6 a or b, as a colorless oil: H NMR (400 MHz, CDCl3) δ 1.13 (s,

4β 4α/5 9H, t-Bu), 1.49 (s, 3H, CH3), 1.63-1.72 (m, 1H, H ), 1.75-1.87 (m, 2H, H ), 2.01-2.12

5 6 1 (m, 1H, H ), 3.30-3.35 (m, 1H, H ), 3.48 (app t, J=3.8 Hz, 1H, H ), 3.75 (s, 3H, OCH3),

4.22 (dd, J=3.7, 0.5 Hz, 1H, H2), 6.39 (d, J=15.4 Hz, 1H, H1’), 6.93 (d, J=15.4 Hz, 1H,

2’ 13 H ); C NMR (100 MHz, CDCl3) δ 19.9, 20.9, 28.3, 29.9, 34.3, 44.0, 50.3, 52.5, 52.8,

191

64.3, 125.6, 159.1, 175.9; NOE (400 MHz): irradiation of H1’ resulted in enhancement of

β H2 and H1; irradiation of H2 resulted in enhancement of H1, H4 and H1’ and a weak enhancement of H2’; irradiation of H1 resulted in enhancement of H2 and H6 and weak enhancement of H1’; irradiation of H6 resulted in enhancement of the two H5 protons;

2 1’ 2’ irradiation of CH3 resulted in enhancement of H , H and H . Anal. Calcd for

C14H22O5S: C, 56.94; H, 7.65. Found: C, 56.79; H, 7.69.

6.4.7. (1RS,4RS)-2-((E)-3’,3’-Dimethyl-but-1’-ene-1’-sulfonyl)-4-hydroxy-1-methyl- cyclohex-2-enecarboxylic acid methyl ester (235).

A solution of epoxide 233 (0.700 g, 2.21 mmol, 1 equiv) in THF (15 mL) was cooled to

o –78 C and treated with LDA (2.75 mmol, 1.24 equiv; obtained from i-Pr2NH (0.49 mL,

0.35 g, 3.5 mmol) and n-BuLi (1.1 mL, 2.5 M, 2.75 mmol) in 10 mL of THF) over 10 min. The reaction mixture was warmed up to –30 oC, stirred for 2 h, and then treated with

AcOH (3.3 mmol) and warmed up to rt. The reaction mixture was diluted with water (10 mL) and dichloromethane (40 mL). The layers were separated, the aqueous layer was extracted with dichloromethane (2x20 mL). The combined organic fractions were dried with MgSO4, filtered and concentrated in vacuo. The title compound 235 (0.609 g, 1.92 mmol, 87%) was separated by column chromatography (EtOAc/Hexanes, 3/2) as a

1 colorless oil: H NMR (400 MHz, CDCl3) δ 1.10 (s, 9H, t-Bu), 1.48 (s, 3H, CH3), 1.64-

1.80 (m, 2H, H5/6), 1.95-2.03 (m, 1H, H5/6), 2.07-2.15 (m, 1H, H5/6), 2.48 (br d, J=7.2 Hz,

1H, OH), 4.33-4.42 (m, 1H, H4), 6.11 (d, J=15.3 Hz, 1H, H1’), 6.87 (d, J=15.3 Hz, 1H,

192

2’ 3 13 H ), 6.93 (d, J=2.4 Hz, 1H, H ); C NMR (100 MHz, CDCl3) δ 23.5, 27.7, 28.3, 34.2,

34.6, 44.3, 52.8, 66.1, 126.5, 143.2, 145.4, 157.2, 174.7.

6.4.8. 2-((E)-3’,3’-Dimethyl-but-1’-ene-1’-sulfonyl)-1-methyl-4-oxo-cyclohex-2- enecarboxylic acid methyl ester (236).

A solution of crude alcohol 235 (0.609 g, 1.92 mmol, 1 equiv) obtained by procedure

6.4.7 (before column chromatography) in dichloromethane (15 mL) was cooled to 0 oC and treated with Dess-Martin periodinane (7.80 mL, 10.6 g, 15% wt solution in CH2Cl2,

3.74 mmol, 2 equiv). The reaction mixture was stirred at 0 oC for 1 h, warmed to rt, filtered and concentrated in vacuo. The title compound 236 was separated by column chromatography in EtOAc/Hexanes 2/3 (0.53 g, 1.70 mmol, 77% from 233) as a colorless

1 oil: H NMR (400 MHz, CDCl3) δ 1.13 (s, 9H, t-Bu), 1.68 (s, 3H, CH3), 2.10-2.19 (m,

1H, H5/6), 2.37-2.46 (m, 1H, H5/6), 2.48-2.62 (m, 2H, H5/6), 6.18 (d, J=15.3 Hz, 1H, H1’),

3 2’ 13 6.67 (s, 1H, H ), 6.98 (d, J=15.3 Hz, 1H, H ); C NMR (100 MHz, CDCl3) δ 22.2, 28.2,

33.9, 34.6, 35.5, 45.5, 53.1, 125.3, 133.4, 159.9, 161.4, 173.0, 196.9.

6.4.9. 8-((E)-3’,3’-Dimethyl-but-1’-ene-1’-sulfonyl)-4,9-dimethyl-1-oxa- spiro[5.5]undeca-3,7-diene-9-carboxylic acid methyl ester (237).

A solution of 236 (0.44 g, 1.40 mmol, 1 equiv) and isoprene (0.60 mL, 0.41 g, 6.0 mmol,

o 4.3 equiv) in dichloromethane (10 mL) was cooled to – 78 C and treated with Me2AlCl

(1.40 mL, 1M solution in hexane, 1.40 mmol, 1 equiv) with stirring over 15 min. The reaction mixture was left to warm up overnight and then stirred at rt for 24 h. The

193

reaction mixture was treated with aq. sat NH4Cl (10 mL) and was filtered. The layers of the filtrate were separated, and the aqueous layer was extracted with dichloromethane (10 mL). The combined organic fractions were dried over MgSO4, filtered and concentrated in vacuo. The title compound 237 was separated by column chromatography

1 (dichloromethane) as a colorless oil: H NMR (400 MHz, CDCl3) δ 1.09 (s, 9H, t-Bu),

1.52 (s, 3H, CH3), 1.73 (br s, 3H, CH3) 1.73-1.78 (m, 2H), 1.91-2.06 (m, 3H), 2.14 (br d,

5 2 3 J=18.2 Hz, 1H, H ), 3.73 (s, 3H, OCH3), 4.05-4.18 (m, 2H, H ), 5.5 (br s, 1H, H ), 6.08

(d, J=15.3 Hz, 1H, H1’), 6.98 (d, J=15.3 Hz, 1H, H2’), 6.95 (s, 1H, H7); 13C NMR (APT,

100 MHz, CDCl3) δ 23.2 (CH3), 23.5 (CH3), 28.3 (CH3), 30.5 (CH2), 33.5 (CH2), 34.1

(C), 38.6 (CH2), 44.9 (C), 52.6 (CH3), 61.8 (CH2), 69.3 (C), 119.1 (CH), 127.0 (CH),

129.5 (C), 141.9 (CH), 146.7 (C), 156.9 (CH), 174.5 (C); NOE (400 MHz): irradiation of

H1’ and H2’ resulted in no enhancement; irradiation of H3 resulted in enhancement of both

2 3 5 H protons and =CCH3; irradiation of =CCH3 resulted in enhancement of H and one H

9 1’ 2’ proton (δ 2.14 ppm); irradiation of C CH3 resulted in enhancement of H and H and protons at δ 1.73-1.78 and 1.91-2.06 ppm. Anal. Calcd for C20H30O5S: C, 62.80; H, 7.91.

Found: C, 62.19; H, 8.08.

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91 See for example: (a) Fan, C.-A.; Hu, X.-D.; Tu, Y.-Q.; Wang, B.-M.; Song, Z.-L.

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93 Dess, D B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.

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202

95 Huang, Y.; Rawal, V. H. J. Am. Chem. Soc., 2002, 124, 9662 – 9663 and references

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101 The exact value of this coupling constant was difficult to measure because of the

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