PROGRESS TOWARD THE TOTAL SYNTHESIS OF THE HIGHLY

PROGRESS TOWARD THE TOTAL SYNTHESIS OF THE HIGHLY

SELECTIVE CYTOTOXIC NATURAL PRODUCT, MAOECRYSTAL V

by

Tsuhen Michelle Chang

_________________________ Copyright © Tsuhen Michelle Chang

A Dissertation Submitted to the Faculty of

DEPARTMENT OF CHEMISTRY AND BIOCHEMISTRY

In Partial Fulfillment of the Requirements for the Degree of

DOCTOR OF PHILOSOPHY

WITH A MAJOR IN CHEMISTRY

In the Graduate College

THE UNIVERSITY OF ARIZONA

2012

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THE UNIVERSITY OF ARIZONA

GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Tsuhen Michelle Chang entitled Progress Toward the Total Synthesis of the Highly Selective Cytotoxic Natural Product, Maoecrystal V and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy ___________________________________________________ Date: 04/11/12 Dr. Hamish Christie ___________________________________________________ Date: 04/11/12 Dr. Ann Walker ___________________________________________________ Date: 04/11/12 Dr. John Jewett ___________________________________________________ Date: 04/11/12 Dr. Dennis Lichtenberger Final approval and acceptance of this dissertation is contingent upon the candidate's submission of the final copies of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement. ____________________________________________________Date: 04/11/12 Dissertation Director: Dr. Hamish Christie

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STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at the University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the copyright holder. SIGNED: Tsuhen Michelle Chang

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TABLE OF CONTENTS

LIST OF FIGURES ............................................................................................... 8

LIST OF TABLES .................................................................................................. 9

LIST OF SCHEMES ............................................................................................ 10

ABSTRACT ......................................................................................................... 18

CHAPTER 1 – THE BACKGROUND .................................................................. 19

1.1 Total synthesis .......................................................................................... 19

1.2 Maoecrystal V – A natural product ............................................................ 21

1.2.1 Kauranes and ent-kauranes – a general class of molecules ........... 21

1.2.2 Isolation and structure determination of maoecrystal V ................... 24

1.2.3 Biological activity of maoecrystal V ................................................. 26

1.2.4 Proposed biosynthesis of maoecrystal V ......................................... 26

1.3 Reported synthetic strategies towards maoecrystal V .............................. 28

1.3.1 The Baran strategy .......................................................................... 29

1.3.2 The Yang strategy ........................................................................... 32

1.3.3 The Nicolaou strategy ..................................................................... 36

1.3.4 The Singh strategy .......................................................................... 40

1.3.5 The Thomson strategy .................................................................... 42

1.3.6 The Trauner strategy ....................................................................... 47

1.3.7 The Danishefsky strategy ................................................................ 51

1.3.8 The Zakarian strategy ..................................................................... 56

1.3.9 The Chen strategy ........................................................................... 60

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TABLE OF CONTENTS – Continued

1.3.10 The Sorensen strategy .................................................................. 63

1.4 Summary and overview of the synthetic approaches to maoecrystal V .... 68

CHAPTER 2 – THE PLAN .................................................................................. 69

2.1 Planning a synthetic route to maoecrystal V ............................................. 69

2.1.1 Key transformations – The details ................................................... 71

2.1.2 The orthoester strategy ................................................................... 72

2.2 The proposed tandem Michael-Aldol ........................................................ 73

2.2.1 Control of diastereoselectivity ......................................................... 73

CHAPTER 3 – FORMATION OF THE CYCLOHEXENONE INTERMEDIATE ... 75

3.1 Initial attempts to form the orthoester intermediate 3.1 ............................. 75

3.2 Formation of the -unsaturated cyclohexenone ..................................... 78

3.3 Initial steps to form the nitrile intermediate ................................................ 79

3.4 Attempts to functionalize the nitrile ........................................................... 82

3.5 Completion of the cyclohexenone ............................................................. 85

3.6 Use of the Horner-Wadsworth-Emmons (HWE) reaction as alternative

strategy .................................................................................................... 88

CHAPTER 4 – EXPORING THE MICHAEL-ALDOL REACTION........................ 94

4.1 Attempts to achieve 1,4-addition ............................................................... 94

4.2 Initial studies using the pyruvate fragment ............................................... 95

4.2.1 Organolithium reagents ................................................................... 95

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4.2.2 Silyl enol ether reagents .................................................................. 96

4.2.3 Attempts using iminium and enamine chemistry ............................. 98

4.2.4 Organozinc, organocopper and organocuprate investigations ...... 100

4.2.5 The use of vinyl rather than allylic substrates ................................ 111

4.3 Testing the aldol reaction to form the bicyclo[2.2.2]octane ..................... 116

4.4 Model compound studies – Replacement of the ketoester ..................... 117

4.5 Exploring the aldol reaction using the modified substrate ....................... 124

4.6 Obtaining the bicyclo[2.2.2]octane intermediate ..................................... 130

CHAPTER 5 – A MODIFIED STRATEGY ......................................................... 133

5.1 A modified strategy toward maoecrystal V .............................................. 133

5.1.1 Modifications of the original synthetic route ................................... 138

5.1.2 Modified intramolecular tandem Michael-aldol reaction – the new key

transformation ................................................................................................... 143

5.2 Further functionalization – Addition to the ketone ................................... 147

5.3 Investigations into an appropriate protecting group ................................ 148

5.4 Investigations into an appropriate nucleophile ........................................ 149

5.5 Investigation of the oxidative cleavage of the alkynyl substitutent and

subsequent lactone formation ................................................................ 153

5.6 Concurrent investigation of the furanoid ring formation and reverse

prenylation .............................................................................................. 155

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5.7 Further elaboration of the advanced intermediates ............................. 167

CHAPTER 6 – FUTURE WORK ....................................................................... 173

6.1 Outline of route for completion of maoecrystal V .................................... 173

6.2 An Enantioselective Synthesis ................................................................ 175

6.2.1 Trials with an enantioselective Michael-aldol reaction ................... 175

6.2.2 Desymmetrization.......................................................................... 176

APPENDIX A .................................................................................................... 180

A.1 Experimental – Reactions in Chapter 3 .................................................. 181

A.1.1 Spectra of Compounds from Chapter 3 ........................................ 210

B.1 Experimental – Reactions in Chapter 4 .................................................. 247

B.1.1 Spectra of Compounds from Chapter 4 ........................................ 288

C.1 Experimental – Reactions in Chapter 5 .................................................. 336

C.1.1 Spectra of Compounds from Chapter 5 ........................................ 371

REFERENCES ................................................................................................. 412

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LIST OF FIGURES

Figure 1.1 – The Core Structure of Kaurane/ent-Kaurane .................................. 21

Figure 1.2 – A Sampling of Compounds in the Kaurane Family ......................... 22

Figure 1.3 – Standard Numbering for ent-Kaurene Type Structures .................. 23

Figure 1.4 – Maoecrystal V with -Unsaturation Highlighted and Standard

Numbering of Carbon Framework ....................................................................... 23

Figure 1.5 – X-ray Crystal Structure of Maoecrystal V ....................................... 25

Figure 2.1 – The Bicyclo[2.2.2]octane Intermediate ............................................ 70

Figure 3.1 – The -Unsaturated Cyclohexenone, a Key Intermediate ............. 76

Figure 4.1 – Maoecrystal V and the Aldol Product ............................................ 118

Figure 4.2 – Model System Compared to Actual Orthoester Containing

System .............................................................................................................. 118

Figure 4.3 – Further Evidence of Configuration Assignment ............................. 122

Figure 5.1 – Stereochemical Outcome of the Michael-aldol Reaction Confirmed

by X-ray Crystal Structure ................................................................................. 146

Figure 5.2 – The Last Congested Carbon-Carbon Bond Formation Needed .... 156

Figure 5.3 – X-ray Crystal Structure of Furanoid Ring Intermediate 5.49 ......... 158

Figure 5.4 – X-ray Crystal Structure of Lactone Ring Intermediate 5.64 ........... 166

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LIST OF TABLES

Table 1.1 – IC50 of Maoecrystal V and cis-Platin ................................................. 26

Table 4.1 – Investigation into Organocopper Reaction Conditions ................... 106

Table 4.2 – Investigations of Substrates for the Aldol Ring Closure Reaction .. 131

Table 5.1 – Investigation of Optimal Conditions for Double Cyclization ............ 145

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LIST OF SCHEMES

Scheme 1.1 - Sun et al. Proposed Bio-synthetic Conversion of epi-Eriocalyxin A

to Maoecrystal V ................................................................................................. 27

Scheme 1.2 - Sun et al. Proposed Bio-synthetic Conversion of 7,20-epoxy-ent-

kaurane to the Maoecrystal V Carbon Framework .............................................. 28

Scheme 1.3 – Baran’s Model Study .................................................................... 29

Scheme 1.4 – Synthesis of the IMDA Intermediate ............................................. 30

Scheme 1.5 – Baran’s IMDA Reaction ................................................................ 31

Scheme 1.6 – Synthesis of Phenol Intermediate 1.33 ........................................ 33

Scheme 1.7 – The Key IMDA Reaction .............................................................. 34

Scheme 1.8 – Completion of the Total Synthesis of Maoecrystal V .................... 35

Scheme 1.9 – Nicolaou’s Syntheis of an IMDA Intermediate .............................. 37

Scheme 1.10 – Nicolaou’s IMDA Reaction ......................................................... 37

Scheme 1.11 – The Intramolecular Cyclopropanation/Fragmentation ................ 38

Scheme 1.12 – Construction of the Pentacyclic Lactone .................................... 39

Scheme 1.13 – Synthesis of the Aromatic Precursor .......................................... 41

Scheme 1.14 – Oxidative Dearomatization and IMDA ........................................ 41

Scheme 1.15 – Synthesis of Singh’s Tricyclic Intermediate ................................ 42

Scheme 1.16 – Synthesis of Thomson’s Tetracyclic Intermediate ...................... 43

Scheme 1.17 – An Attempt to Form the Furanoid Ring ...................................... 44

Scheme 1.18 – An Attempt to Form the Lactone Ring ........................................ 45

Scheme 1.19 – An Attempt to Form the Lactone Ring ........................................ 46

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LIST OF SCHEMES – Continued

Scheme 1.20 – Trauner’s First-Generation Approach to Maoecrystal V ............. 48

Scheme 1.21 – Overcoming the Undesired Stereoselectivity ............................. 49

Scheme 1.22 – Stepwise Approach to Aldol Addition ......................................... 50

Scheme 1.23 – Trauner’s Investigation of the Reverse Prenylation ................... 51

Scheme 1.24 – Danishefsky’s Original IMDA Route ........................................... 52

Scheme 1.25 – Danishefsky’s Synthesis of a Precursor for IMDA ...................... 52

Scheme 1.26 – Danishefsky’s Modified IMDA .................................................... 53

Scheme 1.27 – Attempts toward Stereoselective Furanoid Ring Formation ....... 54

Scheme 1.28 – Methodology for Epimerization at C-5 ........................................ 55

Scheme 1.29 – Zakarian’s Formation of the Furanoid Ring ................................ 57

Scheme 1.30 – Formation of the IMDA Substrate (Zakarian) ............................. 58

Scheme 1.31 – The IMDA Reaction - Forming Zakarian’s Advanced Inter-

mediate ............................................................................................................... 59

Scheme 1.32 – Installation of the gem-Dimethyl Groups and Lactone Ring ....... 60

Scheme 1.33 – Lactone Ring Formation ............................................................. 61

Scheme 1.34 – Reversal of C-5 Stereochemistry ............................................... 62

Scheme 1.35 – Proposed Cascade Reaction ..................................................... 64

Scheme 1.36 – Proposed 1,5-Hydride Shift ........................................................ 65

Scheme 1.37 – Diels-Alder Reaction – Sorensen’s Version ............................... 65

Scheme 1.38 – Formation of the Allenone Intermediate ..................................... 67

Scheme 2.1 – The Proposed Synthetic Plan ...................................................... 69

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Scheme 2.2 – The Proposed Tandem Michael-aldol Reaction ........................... 71

Scheme 2.3 – The Key Transformation .............................................................. 71

Scheme 2.4 – Proposed Result of Opening the Orthoester ................................ 72

Scheme 2.5 – Chelation Control Model in the Tandem Michael-aldol Reaction . 73

Scheme 3.1 – Key Transformation Under Investigation ...................................... 75

Scheme 3.2 – First Attempt at Cyclohexenone Intermediate Synthesis .............. 76

Scheme 3.3 – Investigation of the Tollens Reaction for Triol Formation ............. 77

Scheme 3.4 – Formation of Pentaerythritol via a Tollens Condensation

Reaction .............................................................................................................. 77

Scheme 3.5 – Envisioned Routes to Intermediate 3.10 ..................................... 79

Scheme 3.6 – Formation of the Orthoester Alcohol ............................................ 80

Scheme 3.7 – Further Functionalization of the Orthoester Intermediate ............. 81

Scheme 3.8 – Plan for Organometallic Addition to the Nitrile ............................. 83

Scheme 3.9 – Orthoester Hydrolysis Investigations ............................................ 84

Scheme 3.10 – Incomplete Basic Hydrolysis ..................................................... 85

Scheme 3.11 – Completion of the Orthoester Cyclohexenone Intermediate ...... 86

Scheme 3.12 – Details of Vinyl Magnesium Bromide Addition ........................... 87

Scheme 3.13 – Allylmagnesium bromide Avoids Side-product Formation .......... 87

Scheme 3.14 – The HWE Approach to Cyclohexenone 3.10 ............................. 88

Scheme 3.15 – Initial Attempt to Synthesize the Substrate for the HWE

Reaction .............................................................................................................. 89

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Scheme 3.16 – Methylation of Ester 3.28 Allowed for Nucleophilic Addition ...... 89

Scheme 3.17 – Initial HWE Reaction did not Yield the Desired Cyclo-

hexenone ............................................................................................................ 90

Scheme 3.18 – Use of the HWE Reaction in Exploring the Effect of the

Enolizable Proton ................................................................................................ 91

Scheme 3.19 – Completion of Orthoester Cyclohexenone by the HWE

Reaction .............................................................................................................. 92

Scheme 4.1 – Proposed Michael-Aldol Reaction ................................................ 94

Scheme 4.2 – Key Transformation Tested with a Lithium Enolate ...................... 96

Scheme 4.3 – Mukaiyama Aldol Trials ................................................................ 97

Scheme 4.4 – Results of Mukaiyama Aldol Reaction .......................................... 98

Scheme 4.5 – Envisioned Proline Promoted Condensation ................................ 99

Scheme 4.6 – Investigating an Enamine Nucleophile ....................................... 100

Scheme 4.7 – Modified Route Using an Organometallic Addition ..................... 101

Scheme 4.8 – Formation of Ethyl 2-(bromomethyl)acrylate .............................. 102

Scheme 4.9 – Model Studies of Organometallic Addition ................................. 102

Scheme 4.10 – An Example of Allylic Cuprate Addition .................................... 103

Scheme 4.11 – Use of TMSCl Facilitates Michael Addition .............................. 104

Scheme 4.12 – Studies of the Organocopper Addition on Cyclohexenone ....... 105

Scheme 4.13 – Product Obtained from Organocopper Conditions ................... 107

Scheme 4.14 – Further Investigations with the Model Compound .................... 108

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Scheme 4.15 – Testing the 2,6-lutidine Modified Conditions ............................ 109

Scheme 4.16 – Organozinc Results .................................................................. 110

Scheme 4.17 – Organocuprate Results ............................................................ 110

Scheme 4.18 – Proposed Aldol Reaction ......................................................... 111

Scheme 4.19 – Modified Route to the Ketoester .............................................. 112

Scheme 4.20 – Investigating the Oxidative Cleavage ....................................... 113

Scheme 4.21 – Suggested Intermediate in Modified Ozonolysis ...................... 113

Scheme 4.22 – Route to the Ketoester ............................................................. 114

Scheme 4.23 – Synthesis of Phosphonate 4.47 ............................................... 115

Scheme 4.24 – Chelation Control in the Proposed Transition State of the Aldol

Reaction ............................................................................................................ 116

Scheme 4.25 – Test of Ring Closure with the Ketoester ................................... 117

Scheme 4.26 – Synthesis of the Ketoester Test Compound ............................. 119

Scheme 4.27 – Synthesis of the Aldehyde and Ketone Test Compounds ........ 119

Scheme 4.28 – Results of the Base Promoted Ring Closure on the Test

Compounds ...................................................................................................... 120

Scheme 4.29 – Oxidation to the Diketone Intermediate .................................... 121

Scheme 4.30 – Diastereoselectivity of the Ring Closure on the Model System 122

Scheme 4.31 – Chelation Control in the Proposed Transition of the Aldol

Reaction ............................................................................................................ 123

Scheme 4.32 – Synthesis Diketone 4.67 ......................................................... 124

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Scheme 4.33 – Comparison of 1,2-addition Products ....................................... 125

Scheme 4.34 – Results of Ring Closure Investigations of Modified Orthoester

Intermediates .................................................................................................... 126

Scheme 4.35 – Synthesis of the MOM-protected Alcohol ................................. 127

Scheme 4.36 – Synthesis of the Benzyl Protected Alcohol ............................... 127

Scheme 4.37 – Reactivity of Differently Protected Alcohol Substrates ............. 128

Scheme 4.38 – Synthesis of Simple Diketone Substrate .................................. 129

Scheme 4.39 – Results of Ring Closure Investigations of Ketone 4.81 ........... 129

Scheme 4.40 – Results of Ring Closure Investigations of Aldehyde 4.83 ........ 130

Scheme 5.1 – Modified Strategy to Bicyclo[2.2.2]octane Substrate – the New

Strategy / Key Transformation .......................................................................... 133

Scheme 5.2 – Results of Ring Closure Investigations of Aldehyde 5.2 ............ 134

Scheme 5.3 – The Modified Synthetic Plan ...................................................... 135

Scheme 5.4 – The Model System for the Aldol Ring Closure Reaction ............ 136

Scheme 5.5 – Formation of 6-endo and 6-exo-hydroxybicyclo[2.2.2]-

octan-2-one ....................................................................................................... 137

Scheme 5.6 – Substituent on C-15 – a Useful Handle ...................................... 138

Scheme 5.7 – The Original Route to Aldehyde 5.2 ........................................... 138

Scheme 5.8 – Previous Functionalization Obstacle .......................................... 139

Scheme 5.9 – Shortened Synthetic Sequence Using a Methylcerium

Reagent ............................................................................................................ 140

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Scheme 5.10 – Synthesis of Cyclohexene 5.31 from Methyl Ketone 5.10 ........ 141

Scheme 5.11 – Current Approach to the Bicyclo[2.2.2]octane Intermediate ..... 142

Scheme 5.12 – Exploring the Modified Tandem Michael-Aldol Reaction .......... 143

Scheme 5.13 – Optimized Double Cyclization Conditions ................................ 146

Scheme 5.14 – Potential Synthetic Route via Cyanide Addition ....................... 148

Scheme 5.15 – Protection of Alcohol 5.4 .......................................................... 149

Scheme 5.16 – Trying to Trap the Cyanohydrin (Boc-Version) ......................... 150

Scheme 5.17 – Trying to Trap the Cyanohydrin (CDI-Version) ......................... 150

Scheme 5.18 – Investigation of Nucleophilic Addition to Ketone 5.29

and 5.30 ............................................................................................................ 152

Scheme 5.19 – Investigations of Alkyne Functionalization ............................... 153

Scheme 5.20 – Further Functionalization of Alkyne 5.37 .................................. 154

Scheme 5.21 – Investigations into Lactone Ring Formation ............................. 155

Scheme 5.22 – Formation of the Furanoid Ring Containing Intermediate ........ 157

Scheme 5.23 – Plan for the Prenyl Fragment Addition ..................................... 159

Scheme 5.24 – Synthesis of Intermediate 5.54 ................................................ 159

Scheme 5.25 – Exploring the Reverse Prenylation ........................................... 160

Scheme 5.26 – Suggested Mechanism of Formation of Side Product 5.57 ...... 161

Scheme 5.27 – Synthesis of Benzyl Protected Substrate ................................. 162

Scheme 5.28 – Successful Reverse Prenylation .............................................. 163

Scheme 5.29 – Attempts to Elaborate the Furanoid Intermediate .................... 164

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Scheme 5.30 – The Diol Substrate was Used in Studies for Both the Furanoid

and Lactone Ring Formation ............................................................................. 165

Scheme 5.31 – Successful Lactone Ring Formation ........................................ 165

Scheme 5.32 – Shortening the Route to the Lactone Ring Intermediate .......... 167

Scheme 5.33 – Oxidation of Diol 5.64 ............................................................... 167

Scheme 5.34 – Potential Routes for Cyclohexenone Formation ....................... 168

Scheme 5.35 – Attempts to Functionalize Intermediate 5.68 ............................ 169

Scheme 5.36 – Selective TBS-protection of the Diol Problematic .................... 170

Scheme 5.37 – TES-protection of the Diol 5.64 ............................................... 171

Scheme 5.38 – Silyl Migration Observed .......................................................... 171

Scheme 5.39 – Oxidation of TES-protected Substrates .................................... 172

Scheme 6.1 – Potential Route for Elaboration of Aldehyde 6.1 ........................ 173

Scheme 6.2 – Potential Route for Elaboration of Lactol 6.7 .............................. 174

Scheme 6.3 – Jørgensen’s Diastereoselective Michael-aldol Reaction ............ 175

Scheme 6.4 – Potential Pathway to an Enantioselective Michael-aldol

Reaction ............................................................................................................ 176

Scheme 6.5 – An Example of Asymmetric Acylation, Wirz et al. ...................... 177

Scheme 6.6 – An Example of Asymmetric Yeast Reduction ............................. 177

Scheme 6.7 – Potential Entry Point into an Enantioselective Synthesis ........... 178

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ABSTRACT

Strategies to synthesize the natural product maoecrystal V have been

investigated. The initial strategy involved a tandem Michael-aldol reaction to

form the [2.2.2] bicyclic core of maoecrystal V. This proposed route was not

successful. A modified route to maoecrystal V, inspired by studies on the aldol

ring closure reactions, enabled the synthesis of a complex intermediate that

allowed for the formation of the core structure. Further elaboration of this key

intermediate afforded the methodology to form four of the five rings in

maoecrystal V. Additionally, this key intermediate allowed for further

modifications that can potentially be an entry point toward an enantioselective

synthesis of maoecrystal V that intersects with the initial synthesis of the racemic

compound.

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CHAPTER 1 – THE BACKGROUND

“The synthetic chemist is more than a logician and strategist; he is an explorer

strongly influenced to speculate, to imagine, and even to create. These added

elements provide the touch of artistry which can hardly be included in a

cataloguing of the basic principles of synthesis, but they are very real and

extremely important…”

- E.J. Corey1

“Chemists make molecules. They do other things as well, to be sure – they study

the properties of these molecules; they analyze, they form theories as to what

makes molecules stable, why they have the shapes or colors that they do; they

study mechanisms, trying to find out how molecules react. But at the heart of

their science is the molecule that is made, either by a natural process or by a

human being.

- R. Hoffmann2

1.1 Total synthesis

Complex molecules often inspire the work of synthetic chemists. Whether the

target molecule is a natural product, medicinally important active ingredient, or an

organic compound of theoretical interest in chemistry or biology – exploration of

new synthetic routes has inspired new methodology and educated the minds of

20

generations of chemists. Total synthesis is the science and art of designing a

method and route to a molecule from relatively simple molecular fragments.

One of the goals of natural product total synthesis is to prepare a compound in

greater quantity than available from natural sources. However, total synthesis

has also resulted in an ability to confirm the structure of a novel natural product.

A recent example of this is Scheidt’s synthesis of marine macrolide

Neopeltolide.3 In addition, total synthesis tests the limitations of our current

chemical methods. In his introduction the article, “The Art and Science of Total

Synthesis at the Dawn of the Twenty-First Century,” Nicolaou states that “Being

both a precise science and a fine art, this discipline has been driven by the

constant flow of beautiful molecular architectures from nature and serves as the

engine that drives the more general field of organic synthesis forward.”4 Lastly,

an additional, and often overlooked, purpose of total synthesis is to train the next

generation of synthetic chemists.

In 1828 Friedrich Wöhler synthesized urea and in doing so, demonstrated that

organic compounds could be made from inorganic precursors.4 The field has

obviously progressed from urea to many complex and beautiful molecular

architectures, some of which include cubane, brevetoxin B, and ginkolide B. In

particular, complex, polycyclic structures intrigue and inspire chemists to attempt

to design a total synthesis in a simple and efficient manner.

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1.2 Maoecrystal V – A natural product

1.2.1 Kauranes and ent-kauranes – a general class of molecules

Kauranes and ent-kauranes are a subgroup of the tetracyclophytane diterpenes.

This sub-group contains C-20-non-oxygenated and C-20-oxygenated ent-

kauranes, where the latter group is further classified depending upon their

oxidation pattern. The nomenclature for these compounds is ambiguous as the

terms ent-kaurane and kaurane are often used interchangeably. Indeed, the term

kaurane and ent-kaurane often refer to the same tricyclic fused structure (see

Fig. 1.1).5

H

H

1.1

Figure 1.1 – The Core Structure of Kaurane/ent-Kaurane

Based upon the ent-kaurane carbon skeleton, a growing family of compounds

have been isolated (see Figure 1.2), some of which have been studied and

tested for biological activity.6

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Figure 1.2 – A Sampling of Compounds in the Kaurane Family 7-9

Different target activity is related to the different functionality present in the

molecule.10 Many of these compounds exhibit interesting and useful biological

activities. Some include antitumor and antibacterial activity. Antibacterial activity

is thought to be related to the C-15, C-16, C-17 α-methylene cyclopentanone

(standard numbering of the kaurane family is used here), presumably as it

functions as a conjugate addition acceptor to a thiol containing enzyme (see

Figure 1.3).6,10,11 Hydrogen-bonding interactions between a C-6 hydroxyl and the

C-15 carbonyl has been proposed to enhance the antibiotic activity.

23

Figure 1.3 - Standard Numbering for ent-Kaurene Type Structures 6

The antitumor activity has also been attributed to the same α-methylene

cyclopentanone and the same hydrogen bonding sites as described above. In

addition, the hydroxyl groups at C-7 and C-14 were found to augment the

antitumor activity.10,11 These compounds have also been used as insect growth

inhibitors; likewise, this activity has been attributed to the α-methylene

cyclopentanone.6,10,11

O

OO

O

O

1.9

O

OO

O

O

1

2

3 4

5

7

89

1011

1213 14

1516

17

18 19

20

Figure 1.4 – Maoecrystal V with -Unsaturation Highlighted and Standard

Numbering of Carbon Framework

The ent-kaurane, maoecrystal V, is a highly congested molecule whose carbon

structure has been modified greatly from the basic ent-kaurane skeleton. Indeed,

24

the α-methylene functionality that was in the cyclopentanone is now seen as a

cyclohexenone (see Figure 1.4). Maoecrystal V exhibits biological activity.

However, the congestion due to the adjacent carbon C-4 containing geminal

methyl groups makes conjugate addition via a thiol-containing enzyme a

questionable route for biological activity. Additional intramolecular hydrogen-

bonding interactions are also not possible.

1.2.2 Isolation and structure determination of maoecrystal V

Maoecrystal V is a member of the ent-kaurane family of terpenes and is one of

over 600 novel diterpenoids isolated from the Isodon genus (formally Rabdisia)

found primarily in tropical and sub-tropical Asia.10,12 The crude plants or extracts

from various Isodon species are often used in traditional Chinese folk medicine to

treat respiratory and gastrointestinal bacterial infections, inflammation and

cancer. This has led numerous groups to focus on the isolation and identification

of the organic components present in the members of this genus. As of 2006,

over 50 diterpenes have been isolated and identified from this plant.12,13

Maoecrystal V was first isolated from Isodon eriocalyx in the 1990s by Sun and

co-workers.14 This effort identified 50 other ent-kauranoids, including 30 novel

compounds.14,15 The structure of maoecrystal V was preliminarily established

based on 1- and 2- dimensional nuclear magnetic resonance spectroscopy, mass

spectrometry and infrared spectroscopy. However, the proposed structure was

refined over several iterations and ultimately unequivocally established in 2004

25

by single crystal X-ray crystallography (see Figure 1.5 - Reprinted with

permission from Org. Lett., Vol. 6, No. 23, 2004. Copyright (2004) American

Chemical Society).12

Figure 1.5 – X-ray Crystal Structure of Maoecrystal V12

Maoecrystal V itself contains a unique bicyclo[2.2.2]octane system. It is of

particular interest because a [3.2.1]-bicycle is more characteristic of ent-

kauranoids as seen in previously mentioned examples (see Figure 1.2). The

structure has five highly congested rings. In addition to the bicyclo[2.2.2]octane

system, there is also a furanoid ring and a spirocyclic lactone in relation to a

cyclohexenone ring. Additionally, it contains six chiral centers, including three

contiguous quaternary chiral centers of which two are contiguous, fully carbon-

substituted centers. It has been said that this compound is “by far the most

modified naturally occurring ent-kauranoid known to date.”14,15 These structural

characteristics make maoecrystal V a unique and challenging target for studies in

synthesis.

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1.2.3 Biological activity of maoecrystal V

Maoecrystal V was evaluated for its cytotoxicity towards five human tumor cell

lines.14 It displayed highly selective cytotoxicity towards the HeLa cell line. This

activity profile is intriguing because, as mentioned above, maoecrystal V lacks

the α-methylidene cyclopentanone (which is generally credited as the key

functionality to ent-kaurane cytotoxicity) but instead includes a highly congested

cyclohexenone ring system.16

Table 1.1 – IC50 of Maoecrystal V and cis-Platin14

IC50 (μg/mL)

Test substance K566 A549 BGC-823 CNE HeLa

Maoecrystal V 6.43 x 104 2.63 x 104 1.47 x 104 not

determined 0.02

cis-platin 0.38 1.61 0.25 2.31 0.99

1.2.4 Proposed biosynthesis of maoecrystal V

Two partial biosynthetic routes to the maoecrystal V framework have been

proposed by Sun et al.12,14 The conclusions drawn concerning the biosynthesis

are based on interconversions of other known ent-kauranoids to the maoecrystal

V framework. The first route proposed suggests that maoecrystal V is obtained

from epi-eriocalyxin A (see Scheme 1.1).

27

O O

O

O

HH

H

O

O

OO

O

OA complexset of biosynthetictransformations

15

15

16

16 99

13 13

8

8

epi-eriocalyxin A maoecrystal V1.91.10

Scheme 1.1 - Sun et al. Proposed Bio-synthetic Conversion of epi-Eriocalyxin A

to Maoecrystal V 17

The rearrangement of the carbon “bridge” of C-15 and C-16 on maoecrystal V

from being attached on C-8 to C-9 is similar to an acid-catalyzed rearrangement

on another compound in the kaurane family. However, this previously observed

acid-catalyzed rearrangement required key oxy-substituents that epi-eriocalyxin

A lacks. This observation thus leads to the conclusion that the transformation to

maoecrystal V “might be biochemically generated and enzyme-catalyzed.”15

The second route proposed starts from 7,20-epoxy-ent-kaurane 1.11 (see

Scheme 1.2). In studying another compound (isolated from the same medicinal

herb), namely maoecrystal Z, Sun et al. propose that both compounds could

originate from the same kaurane 1.11. The pathway proceeds through a

proposed series of transformations that are suggested to “be biochemically

generated and enzymatically catalyzed.”18

28

Scheme 1.2 - Sun et al. Proposed Bio-synthetic Conversion of 7,20-epoxy-ent-

kaurane to the Maoecrystal V Carbon Framework 17,18

It is important to note that these proposed biosyntheses are working hypotheses

and further investigation would be required to confirm their validity.

1.3 Reported synthetic strategies towards maoecrystal V

With such medicinal interest and synthetic challenges, numerous “progress

towards the total synthesis” papers have been published. Groups reporting

progress toward the total synthesis studies include Baran, Danishefsky,

Nicolaou, Sorensen, Trauner, Yang, Singh, Thomson, Zakarian and Chen.4,17,19-

22 Each of the known approaches will be discussed. Since the structure was

fully elucidated in 2004, only one group, Yang et al., has published a total

synthesis.

29

1.3.1 The Baran strategy19

In 2009 Baran et al. published the beginning of their approach to the synthesis of

the carbon skeleton of maoecrystal V. They began their work by doing some

model compound studies (see Scheme 1.3).

Scheme 1.3 – Baran’s Model Study

In exploring the coupling of a -keto aldehyde to a silyl enol ether, they realized

that the desilylation of a key ketone intermediate 1.17 gave the undesired

regioisomeric dienol ether which was problematic in the subsequent

intramolecular Diels-Alder reaction (IMDA).

30

Thus, they devised a route in which the diene was further dehydrogenated giving

the aromatic ring. Then the desired regioisomer was obtained by the Wessely

oxidation and this resulting diene 1.18 was useful in an IMDA reaction. The

major product 1.19 was the undesired diastereomer.

With the information gained from the model studies, work on the synthesis of the

actual carbon skeleton commenced. Knowing that the silylation of the ketone

would ultimately give the wrong regioisomer of the diene, a direct route to the

aromatic intermediate was used (see Scheme 1.4). This route began with the

coupling of the -unsaturated ketone intermediate 1.20 (prepared in three

steps from a commercially available diketone) with an aryl bismuth fragment.

Ar

O

OH

TBSO OMOM

Ar3BiCl2DBU

Ar=

1. Li(t-BuO)3AlH2. acryloyl chloride

OTBSO

Ar

OTBSO

O

1. TFA2. Pb(OAc)4

AcOH O

OTBSO

OAc

major isomer

1.20 1.21

1.22 1.23

O

O

O

O

Scheme 1.4 – Synthesis of the IMDA Intermediate

At this point, following the previously studied steps of reduction, esterification,

deprotection and Wessely dearomatization, the intermediate required for the

31

IMDA was obtained. This intermediate was subjected to IMDA conditions of

heating in a microwave reactor in o-DCB in the presence of BHT to obtain the

product in 79% yield (see Scheme 1.5).

At this juncture, the product of the IMDA reaction (1.25) was hydrogenated and

the acetate group was removed using SmI2 (see Scheme 1.5). The samarium

intermediate was protonated by methanol to give the methyl ketone as a mixture

of diastereomers (17:3) with the desired diastereomer as the major product.

Scheme 1.5 – Baran’s IMDA Reaction

Baran’s approach is elegant in that in the IMDA step, both the bicyclo[2.2.2]-

octane system as well as the lactone ring is formed. The use of the Wessely

oxidation is a creative solution to the diene being formed as the undesired

32

regioisomer. To finish the synthesis a functional handle to incorporate the

furanoid ring is needed. Additionally the TBS-protected alcohol needs to be

converted into the -unsaturated ketone required in the cyclohexenone ring

1.3.2 The Yang strategy23,24

After publishing a partial synthesis in 2009, very similar to Baran’s approach,

Yang et al. continued work on this compound. Their efforts and revisions to the

initial synthetic approach have resulted in the only total synthesis of maoecrystal

V. It is an efficient 16 step synthesis starting with 2,2-dimethylcyclohex-3-enone

and dimethyl carbonate (see Scheme 1.6).

The resulting -ketoester was subjected to oxidative arylation and the result of

this coupling is the formation of the first quaternary chiral center. This oxidative

coupling reaction and its use of the aryl-lead intermediate is reminiscent of

Baran’s use of the aryl-bismuth intermediate in the Barton arylation to form the

same type of intermediate in preparation for the upcoming Wessely oxidation and

subsequent intramolecular Diels-Alder (IMDA) reaction.

33

O O

CO2MeOMOM

Pb(OAc)3

O

MeO2C

OMOM

O

O

O , NaHpyr, CHCl3,

60 C

1. (Bu4N)BH4MeOH, 40 C

2. LAH, THF

OMOM

OH

HO

1. DMAP, EDCI, CH2Cl22-(diethoxyphosphoryl)-acetic acid

2. TsN3, DBU, 0 C

ROOH

O

O PO

OEt

OEt

N2

1. Rh2(OAc)4, PhH2. t-BuOK, (HCHO)n

THF, 0 C3. TFA, DCM

O

OOH

O

1.32 R = MOM

1.27 1.28 1.29

1.30 1.31

1.33

Scheme 1.6 – Synthesis of Phenol Intermediate 1.33

After some investigation, the two step treatment of the resulting aryl -ketoester

with (Bu4N)BH4 followed by LiAlH gave the diol with the desired configuration.

The observed diastereoselectivity was attributed to the “directing and

accelerating effect of the cationic-π interaction between the ammonium salt and

the phenyl ring in the substrate, which delivers the hydride to the ketone from the

top face.” The diol was then coupled with the diethyl phosphonate fragment

followed by treatment with TsN3 to give the diazo ester. With this phosphonate

intermediate, they are able to execute a Rh-catalyzed O-H bond insertion and

34

consecutive Horner-Wadworth-Emmons (HWE) reaction with paraformaldehyde

leading to the phenol 1.33 (after alcohol deprotection).

Phenol 1.33 was subjected to Wessely oxidative acetoxylation. This differs from

Baran’s synthesis and use of the “simpler” vinyl ester intermediate as the

dienophile in the IMDA. The result of the Wessely oxidative acetoxylation did

result in the diene required, but as a mixture of diastereomers 1.34. This

oxidation reaction oxidizes the phenol, giving an acetoxy ketone. The resulting

diene is set up for a Diels-Alder cycloaddition with the exocyclic methylene

group, and is similar to the strategy used by Baran. The mixture of

diastereomers (1.34) was subjected to IMDA conditions to give three products

(see Scheme 1.7).

Scheme 1.7 – The Key IMDA Reaction

35

Unfortunately, the stereoselectivity of this key step is not high, which results in

three isomers (totaling 76%). The team's desired compound was isolated in 36%

yield. Six more steps were required to complete the total synthesis (see Scheme

1.8).

Scheme 1.8 – Completion of the Total Synthesis of Maoecrystal V

Treatment of the IMDA product with NBS resulted in a bromide intermediate

which, upon reaction with Bu3SnH, gave an allylic radical, which was trapped with

TEMPO to give the hydroxyl amine. Reductive cleavage of the

tetramethylpiperidine and acetoxy groups followed by regioselective

hydrogenation and Dess-Martin periodinane (DMP) oxidation gave the C-16

epimer of maoecrystal V. Epimerization of the methyl bearing chiral center was

required and thus achieved under basic conditions using DBU to give a 1:1

mixture of the C-16 epimer and maoecrystal V.

36

Overall, this route published by Yang et al. is efficient in that only 16 steps are

required. The main drawback is that the IMDA reaction, while efficient in forming

the bicyclo[2.2.2]octane system as well as the lactone and hydrofuran ring,

resulted in a mixture of three isomers and the product that was desired was only

obtained in 36%. However, it is the only total synthesis to date and an elegant

synthetic route. In particular, the total synthesis is concise due to the use of a

bond insertion to form the seven-membered ring as well as the use of the

Wessely oxidation to form the substrate for the IMDA reaction.

1.3.3 The Nicolaou strategy25

In October of 2009, the Nicolaou group published their approach toward the

functionalized maoecrystal V core structure. Their approach was two-fold and

gave two advanced intermediates.

For the first approach, the beginning of their synthesis was the decarboxylative

Heck reaction with 2,6-dimethoxy benzoic acid and cyclohexenone (see Scheme

1.9). The resulting dimethyl intermediate was mono-demethylated with BBr3.

The desired alkenyl methyl ester was obtained through an O-alkylation with the

pyrrolidine fragment followed by elimination of its nitrogen moiety, thus

incorporating the dienophile. Formation of the silyl enol ether gave the requisite

diene for the IMDA.

37

OMe

CO2H

OMe

O1. Pd(TFA)2

Ag2CO32. BBr3

O

OH

OH

1. NaH

NCO2Me

Br

2. Na2CO3, MeI

O

OMe

O

MeO2C

TBSOTfNEt3

OTBS

OMe

O

MeO2C

OTBS

O

RMeO

1.39 1.40 1.41

1.42 1.43R = CO2Me

Scheme 1.9 – Nicolaou’s Syntheis of an IMDA Intermediate

At this point, the intramolecular [4 + 2] cycloadditon was performed without any

purification of the TBS enol ether to give the exo diastereomer as the major

product (see Scheme 1.10).

OTBSOMe

OMeO2C CO2Me

OTBS O

O

O

RMeO

MeO

1.43 R = CO2Me

K2CO3hydroquinonethen 1N HCl

1.43 1.44 .

Scheme 1.10 – Nicolaou’s IMDA Reaction

38

In this step, bicyclo[2.2.2]octane system is formed and thus, one of the all

carbon-substituted chiral centers is formed. The next hurdle was to form the

second of the contiguous all-carbon quaternary centers, and this was done

through an “intramolecular carbene-mediated cyclopropanation/fragmentation

process” (see Scheme 1.11).

CO2Me

O

O

MeO

1. NaOH2. (COCl)23. TMSCHN2

O

O

MeO O

N2

Rh2(OAc)4

O

O

MeO O

silicagel

O

O

O O

H2Pd/C

O

OO

O

H

5

1.44 1.45

1.46 1.47 1.48

Scheme 1.11 – The Intramolecular Cyclopropanation/Fragmentation

To this end, the methyl ester was saponified, functionalized to the acid chloride

and reacted with TMSCHN2 to give a diazo ketone. Treatment of this ketone with

a rhodium catalyst resulted in formation of the cyclopropane, which was then

fragmented to give the diene. The final step hydrogenation resulted in their first

39

advanced intermediate (1.48). It is important to note that the hydrogenation does

not give the desired epimer needed for maoecrystal V.

Their second approach gives a much more advanced intermediate, in that it also

incorporates the six-membered lactone ring. The beginning of the scheme is

very similar to the previous synthesis, in that it starts with the intramolecular Heck

reaction. The only difference being that, the demethylation step is complete and

both methyl groups are removed. This allows for incorporation of the MOM

protecting group prior to the incorporation of the methyl ester. As a result, the

product of the IMDA reaction contains a MOM protected phenol (see Scheme

1.12).

O

CO2MeH HCO2Me

O

O

MOMO CO2Me

O

O

O

OMeOMe

1. aq HCl2. PIFA, KHCO3

MeOHH2

Pd/C O

MeO

OMe

O

O

NaOH

CO2HH H

O

MeO

OMe

O

O

ClCH2IKOtBu

18-crown-6 O

MeO

OMe

O

O

O

O

O

O O

O

maoecrystal Vfor comparison

C15C16

5

1.49 1.50 1.51

1.52 1.53 1.9

Scheme 1.12 – Construction of the Pentacyclic Lactone

40

The dearomatization was done by first deprotecting the MOM-protected alcohol

and treatment with phenyliodine bis(trifluoroacetate) (PIFA) to give the dienone.

Subsequent hydrogenation gave the diketone compound containing the furanoid

ring, although it is again epimeric to maoecrystal V at C-5 (Scheme 1.12).

Saponification with NaOH gave carboxylic acid 1.52, which was followed by

alkylation with ClCH2I. Unfortunately, triple instead of double alkylation occurred.

Importantly, this second approach provided a creative method for incorporation of

the lactone ring. Although this is an advanced intermediate, further work is

needed in that the ketone on the [2.2.2] bicyclic system is on C-16 instead of C-

15. Additionally, they obtained the undesired diastereomer (in relation to C-5) in

the hydrogenation of the diketone. The cyclohexenone ring is not complete, and

the alkylation to form the lactone, although intriguing, gave an over-alkylated

product.

1.3.4 The Singh strategy26

The Singh group has also been studying a simple entrance to the main tricyclic

core of maeocrystal V. Their approach, similar to the previously mentioned

approaches, also uses a dearomatization followed by an IMDA reaction. To

begin, they synthesize an aromatic precursor from a readily available diol (see

Scheme 1.13).

41

Scheme 1.13 – Synthesis of the Aromatic Precursor

Protection of the diol followed by stepwise oxidative cleavage of the terminal

alkene followed by reduction of the aldehyde with NaBH4 gave alcohol 1.55.

Subsequent esterification and deprotection gave diol precursor 1.56. The

aromatic compound (1.56) underwent an oxidative dearomatization to give diene

1.57, required for entry into the IMDA reaction (see Scheme 1.14).

Scheme 1.14 – Oxidative Dearomatization and IMDA

42

The IMDA reaction to give tricyclic intermediate 1.58, occurs stereoselectively in

75% yield. At this point, their focus turned to converting the -keto-epoxide (see

Scheme 1.15).

Scheme 1.15 – Synthesis of Singh’s Tricyclic Intermediate

Epoxide opening followed by Jones oxidation gave the carboxylic acid

intermediate, which upon heating underwent decarboxylation. Finally,

hydrogenation gave Singh’s advanced tricyclic intermediate. Their approach is

simple and efficient in forming the bicyclo[2.2.2]octane system as well as the six-

membered ring lactone. However, their intermediate lacks functional handles for

further elaboration.

1.3.5 The Thomson strategy 27

In 2010, the Thomson group also published their approach to the carbocyclic

core of maoecrystal V. This approach is unique in that the bicyclo[2.2.2]octane

system is formed via a Diels-Alder reaction with nitroethylene. Their approach,

43

while fascinating, encountered unexpected, interesting chemistry which has thus

far prevented them from completing the total synthesis. Their synthesis began

with a regioselective Rubottom oxidation of 3,3-dimethycyclohexanone and

protection of the newly formed alcohol (see Scheme 1.16).

Scheme 1.16 – Synthesis of Thomson’s Tetracyclic Intermediate

The resulting ketone 1.62 underwent a HWE reaction with the Weinreb amide

phosphonate shown, which then reacted with an organolithium reagent to afford

the TBS protected dienone 1.63. Treatment with ferrous chloride effected the

Nazarov reaction, the transformation giving a spirocyclic ketone as a single

stereoisomer. Reduction of the ketone set up the diene to undergo a Diels-Alder

44

reaction with the reactive nitroethylene as the dienophile. The stereoselectivity

was predicted due to the TBS group controlling the facial selectivity of both the

Nazarov and Diels-Alder reactions. At this juncture, the synthetic plan was to

use the Nef reaction to convert the nitroalkane to the corresponding ketone, but

all attempts were met with minimal success.

They then turned their attention to forming the furanoid ring. Treatment of the

tetracyclic intermediate 1.65 with KOH resulted in complete epimerization of the

nitro group, which was an unexpected result (see Scheme 1.17).

Scheme 1.17 – An Attempt to Form the Furanoid Ring

Hydrogenation followed by Jones oxidation resulted in the ketone which

underwent a stereoselective Rubottom oxidation of the thermodynamically more

45

stable enol silane. Unfortunately, conditions to bring about the desired furanoid

ring formation to make the carbon-oxygen bond with C-5 could not be found.

Similar conditions used by Suárez and co-workers did not bring about the desired

ether formation, but rather a Grob fragmentation, which was hypothesized to be

due to “favorable alignment of the broken σC-C with σ*C-N of the leaving [nitro]

group.”

At this point, they turned their attention to formation of the lactone ring first,

before trying to form the bridging cyclic ether. However, attempts toward the

functionalization of the ketone via a Baeyer-Villiger reaction did not afford the

desired lactone. Instead, another lactone resulted from insertion at the other side

of the ketone. The undesired insertion, in conjunction with the TBS group being

removed in the acidic conditions, resulted in ketalization (see Scheme 1.18).

Scheme 1.18 – An Attempt to Form the Lactone Ring

To avoid the problems mentioned above, the epimerized Diels-Alder product was

subjected to a Rubottom oxidation (see Scheme 1.19).

46

Scheme 1.19 – An Attempt to Form the Lactone Ring

However attempts to oxidatively cleave the -hydroxy ketone led to complex

reaction mixtures. Another approach was to use an unsaturated ketone

intermediate 1.69 for the oxidative cleavage reaction. However, under various

hydrogenation conditions, a major product that was isolated was an unexpected

cyclopropane intermediate 1.70. The authors speculate that “the close proximity

and alignment of σ*C-N of the nitro group allows for an intramolecular alkylation of

the presumed palladium enolate intermediate.” The last transformation gave the

desired lactone ring. This was accomplished by treatment with periodic acid to

give the aldehyde intermediate, which was then reduced, and thus allowed

lactonization to occur.

Thomson’s approach was highly problematic as they encountered many

setbacks while trying to install both the lactone ring as well as the tetrahydrofuran

ring. The advanced tetracyclic intermediate contains an unwanted cyclopropane

ring, which one could foresee as being problematic, in particular to installation of

47

the cyclic ether. Additionally, due to the failure of the Nef reaction, the

conversion of the nitro functionality to a ketone has not been achieved. Lastly, a

total synthesis would still require the functionalization to the cyclohexenone ring.

1.3.6 The Trauner strategy 22

The Trauner group has also been working towards an efficient route to

maoecrystal V. Their approach is unique in that it does not approach forming the

bicyclo[2.2.2]octane system via a Diels-Alder type of reaction. Rather, the

incorporation is done through an aldol reaction. The synthesis of the

bicyclo[2.2.2]octane system starts with cyclohexenone 1.72 that is obtained by

alkylation with ethyl bromoacetate followed by Sakurai allylation. Ozonolysis

affords an aldehyde. The aldol reaction, under acidic conditions gave the desired

bicyclo[2.2.2]octane system as a 7:1 mixture of endo and exo isomers, which

could be separated after TBS protection to obtain the major diastereomer 1.73

(see Scheme 1.20). The authors mention that this synthetic approach via the

aldol reaction provides an intermediate that has the potential to be elaborated in

a symmetric fashion, as this has been developed by Kitahara et al. With the

successful aldol reaction complete, formation of the tertiary alcohol was explored,

in particular, reaction with Nagata’s reagent. Unfortunately, the cyanohydrin

formation gave the undesired diastereomer and transesterification to give a five-

48

membered ring lactone also occurred.

O

EtO

O

1. O3 then DMS2. HCl3. TBSCl, imid.

O

OTBS

EtOO

1. Et2AlCN2. LDA, CH2O

-40 C3. Me2CO, p-TsOH

OTBS

O

CN

OOO

1. DIBALH2. NaOH

OTBS

OO

OO

[M]

OTBS

OO

OOH

1.72 1.73 1.74

1.75 1.76

Scheme 1.20 – Trauner’s First-Generation Approach to Maoecrystal V

However, with this intermediate 1.74, the planned installation for the second all

carbon-substituted center via the addition of formaldehyde was explored. Under

LDA conditions, this was alkylation was successful as was the second Fráter-

Seeback alkylation. Protection of the diol, reduction of the lactone and treatment

with base led to the fragmentation of the lactol with the loss of cyanide. The keto

aldehyde 1.75 was used to explore a reverse prenylation reaction. However,

conditions to effect this transformation were not found.

Due to the addition of the cyanide giving the undesired diastereomer, other small

nucleophiles were studied in order to overcome the previously-observed

49

stereoselectivity. Ultimately, the anion of the TMS-acetylene (TMSA) added to

bicyclic ketone to give the desired stereoisomer (see Scheme 1.21).

O

OTBS

EtOO

1. TMSA, BuLi2. NaH, 40 C

OTBS

O

1. Pd/CaCO3H2, pyr

2. LDA, CH2O-40 C to rt

OTBS

O

O

OHO

HO

OTBS

O

OHO H

12% 54%

1.73 1.77

1.78 1.79

Scheme 1.21 – Overcoming the Undesired Stereoselectivity

NaH conditions resulted in both the formation of the five-membered ring lactone,

as well as the removal of the TMS group, to give the terminal alkyne, which was

reduced to give the alkene using Lindlar reduction. The double aldol addition

with formaldehyde with lactone 1.77 proved to be challenging, which was

presumed to be due to the more crowded steric environment. They reasoned

that the second alkylation was difficult “due to the considerable steric hindrance

that would be encountered in the formation of the requisite dianion through

double deprotonation” of intermediate 1.77. Ultimately, a route to successful

dialkylation was found. The alkylation was carefully controlled to give only mono-

alkyation (see Scheme 1.22). Oxidation with DMP and reduction of the enol

50

gave the hydroxymethyl lactone. With the -proton now more accessible, the

second aldol reaction proceeded give the diol in satisfactory yield. Ozonolysis

gave the lactone/lactol product 1.84.

OTBS

O

LDA, CH2O-40 C

O

OTBS

O

O

H

1. DMP2. NaBH4

OTBS

O

OH

LDACH2O-40 C

OTBS

O

OHO

HO

O3then DMS

OTBS

O

OHHOOO

1.80 1.81 1.82

1.83 1.84

HO

HO

O

O

O O

O


1.9

Scheme 1.22 – Stepwise Approach to Aldol Addition

Trauner’s approach was creative, in that the unexpected stereoselectivity of the

cyanide addition was reversed using an acetylene fragment. This ultimately

resulted in the formation of the six-membered ring hemiacetal intermediate 1.84.

The “undesired” diastereomer was used to explore future steps required for

futher elaboration to maoecrystal V. In particular, aldehyde intermediate 1.75

(see Scheme 1.23), albeit the undesired diastereomer, was used to explore the

reverse prenylation reaction to form the sterically crowded center and access the

-unsaturated six-membered ring.

51

Scheme 1.23 – Trauner’s Investigation of the Reverse Prenylation

Their paper ends with commentary that they plan to streamline their synthesis

and have expectations that an intramolecular approach may be required.

1.3.7 The Danishefsky strategy20,21

In 2009, Danishefsky’s group published a synthetic strategy for accessing the

bicyclo [2.2.2]-octane core of maoecrystal V, utilizing an IMDA reaction. Toward

this end, they designed a highly functionalized precursor and it did indeed

undergo an IMDA reaction but with the undesired facial selectivity (see Scheme

1.24).

52

O

O

OTBSMeO2C

R

OO

O

MeO2C

R

O

O

O O

O


1.9

180 Csealedtube

PhMe

1.78 1.79

Scheme 1.24 – Danishefsky’s Original IMDA Route

Due to this result, a modified sequence was designed in which the precursor was

less densely functionalized and symmetrical. The modified approach starts with

the Birch-type vinylogous acylation followed by a two step reduction re-oxidation

to give intermediate 1.82 (see Scheme 1.25).

CO2Me

Cl

O LDA, THF-78 C

O

CO2Me1. DIBALH

-78 C2. MnO2, CH2Cl2

O

OH Cl

O

SO2Ph

1. py, CH2Cl2, 0 C

2. TBSOTf, NEt3CH2Cl2, -78 C

OTBS

O

O

SO2Ph

1.80 1.81 1.82

1.83 1.84

Scheme 1.25 – Danishefsky’s Synthesis of a Precursor for an IMDA Reaction

53

This first step forms one of the two quaternary all-carbon chiral centers. This is

followed by esterification, which put into place the dienophile fragment.

Subsequent TBS enol ether formation forms the diene required for the IMDA

reaction.

IMDA cyclization gave the cycloadduct product, and upon in situ treatment with

TBAF, removed the TBS group and resulted in the spontaneous elimination of

the sulfone moiety, the bicyclo[2.2.2]octane intermediate 1.85 was obtained (see

Scheme 1.26).

Scheme 1.26 – Danishefsky’s Modified IMDA

Like the previous IMDA cycloaddition in the Danishefsky’s more complex system

(see Scheme 1.24), this reaction forms the second of the two quaternary carbon

centers required in maoecrystal V (see Scheme 1.26). With this simpler Diels-

Alder substrate, the correct facial selectivity was achieved. Attention turned

toward forming the tertiary alcohol on C-8, which is required for the formation of

the furanoid ring (see Scheme 1.27).

54

OO

O

HO

OO

O

1. H2O2, NaOHMeOH, 0 C

2. MgI2, DCM45 C

3. Bu3SnH, AIBNPhMe, reflux

OO

O

OH

1. m-CPBA, CH2Cl22. p-TsOH, H2O

CH2Cl2

1. Pd/C, H2EtOH

2. DMPNaOMe, O2

MeOH, 40 C

OO

O

O

OH

undesiredaldol

OO

O

O

undesiredisomer

H

O

H

5

88

1.85 1.86

1.87 1.88 1.89

OH

5 5

Scheme 1.27 – Attempts toward Stereoselective Furanoid Ring Formation

It was found that epoxide formation was stereoselective. Ring opening to form

the iodohydrin, followed by reduction, gave the desired tertiary alcohol

intermediate 1.86. In trying to form the furanoid ring, the alkene intermediate

was treated with m-CPBA to obtain a stereoselective epoxidation. Acidic

conditions resulted in epoxide opening by the tertiary alcohol and the formation of

the furanoid ring. Unfortunately, X-ray analysis of 1.87 showed the undesired

isomer at C-5 (see Scheme 1.27). In trying to reverse the stereocenter at C-5 to

obtain the desired epimer, the adjacent alcohol was oxidized to the ketone. This

diketone intermediate 1.88 was exposed to basic conditions. The result was an

unexpected intramolecular aldol reaction.

55

To avoid the unexpected intramolecular aldol pathway, the ketone at C-16 was

removed by dithioketal formation, followed by reduction with Raney-Ni (see

Scheme 1.28).

OO

O

O

incorrectisomer

1. CH3CH2SHBF3•OEt2, CH2Cl2

2. Raney-NiEtOH, 75 C

3. DMP, CH2Cl2

OH

1. NaBH4, MeOHCH2Cl2, -78 to -50 C

2. MsCl, DMAPCH2Cl2, 50 C

3. DBU, PhMe, 128 C

OO

O

DMDO, CH2Cl20 C then

Et2O, BF3•OEt2

O O

O

O LA

HO O

O

O

H

OO

O

HO

H

1616

1.87 1.90

1.91 1.92 1.93

15

5

Scheme 1.28 – Methodology for Epimerization at C-5

Oxidation of the alcohol at C-5 gave the ketone functionality. Further treatment

of the ketone intermediate 1.90 (which, unlike the diketone, could not undergo

the competing aldol pathway) surprisingly did not result in epimerization. They

hypothesize that the “intermolecular delivery of a proton to the ring junction

position” is too congested. Therefore, a pathway to allow for an intramolecular

transfer of a “strategically placed hydrogen atom” was used. To this end, ketone

intermediate 1.90 was reduced with NaBH4 followed by formation of the

56

methanesulfonate and elimination. This resulted in alkene intermediate 1.91.

This allowed for the epoxide formation, and rearrangement under Lewis acidic

conditions, an intramolecular hydride delivery gave the desired epimer at C-5.

This furanoid intermediate 1.93 showcases the success of using an IMDA

reaction to form the bicyclo[2.2.2]octane ring system. Additionally, creative

methodology was explored to enable the epimerization of C-5 of the furanoid ring

juncture. Similar to Nicolaou’s synthetic work on maoecrystal V, further work is

needed in that the C-16 ketone on the [2.2.2] bicyclic system needs to be

installed. Additionally, the geminal dimethyl substituents as well as the

cyclohexenone functionality need to be completed.

1.3.8 The Zakarian strategy28

As can be seen by the previously discussed work (especially that of Thomson

and Danishefsky) the installation of the furanoid ring is difficult because of the

ring strain as well as the congestion, due to its being flanked by the

bicyclo[2.2.2]octane system on one side and the cyclohexenone ring on the

other. With this analysis in mind, Zakarian’s group approached the synthetic

design by early installation of the furanoid ring followed by an IMDA reaction.

57

The synthesis starts with alkylation of sesamol under Mitsunobu conditions,

followed by coupling with methyl chloroxoacetate to give the ketoester

intermediate (see Scheme 1.29).

Scheme 1.29 – Zakarian’s Formation of the Furanoid Ring

Functional group transformation of the ketoester to the diazoester gave the

substrate that was used for formation of the benzofuran ring, creative in that it is

used an intramolecular C-H functionalization process with a rhodium catalyst.

At this point in their investigations, the C-10 carbon of the maoecrystal V model

was methylated to mimic the quaternary center in the natural product.

Methylation gave a 3:1 mixture of diastereomers, which upon reduction of the

ester, could be separated (see Scheme 1.30). In investigating the removal of the

58

methylidene group, it was found that treatment with MeMgBr at reflux afforded

the desired monoprotected ethyl ether. Upon oxidative dearomatization in

ethanol, the o-quinone intermediate, with a diethyl ketal functionality, was

obtained. Finally, reaction with acryloyl chloride gave the acrylate intermediate,

which was the substrate for the IMDA reaction.

O

OO

CO2MeH

H

1. LiN(SiMe3)2ZnEt2, MeIDMPU, THF

2. LAH, THF

O

OO

H

OH

1. MeMgBrPhH, 80 °C

2. PhI(OCOCF3)2NaHCO3, EtOH

O

O

H

OH

OEtEtO Cl

O

DIPEADMAP

O

O

H

O

OEtEtO

O

dr = 3:11.97 1.98

1.99 1.100

Scheme 1.30 – Formation of the IMDA Substrate (Zakarian)

With the IMDA substrate prepared, conditions were investigated and it was

observed that heating the acrylate in o-DCB in the presence of BHT resulted in

cycloaddition which gave the lactone/enol ether product (see Scheme 1.31), their

advanced intermediate, which they feel is suitable for eventual elaboration to

maoecrystal V.

59

Scheme 1.31 – The IMDA Reaction - Forming Zakarian’s Advanced Intermediate

Zakarian’s strategy of forming the furanoid ring prior to the formation of the

bicyclo[2.2.2]octane ring system avoids the problem encountered by previous

groups. Additionally, the advanced intermediate already incorporates the prenyl

fragment. Synthetic work still needs to be done to form both the cyclohexenone

the lactone rings (see Scheme 1.31), in particular, forming another carbon-

carbon bond at the C-8 position which is sterically congested and neopentyl.

Additionally, the extra carbon-carbon bond at C-11 needs to be cleaved in order

to form the lactone ring in maoecrystal V.

1.3.9 The Chen strategy29,30

Chen and coworkers have continued the work of Nicolaou in a second paper

published in 2011 in which methodology is developed to further the effort toward

completion of the total synthesis. They begin directly with the diene intermediate

60

1.50 described in their 2009 paper. The installation of the gem-dimethyl

substitutents was the first task that was investigated (see Scheme 1.32).

CO2Me

O

O

O

OMeOMe

1. NiCl2, NaBH4MeOH, 0 °C

2. Pd/C, H2EtOH

3. NaBH4, MeOH4. NaH, Ag2O

BnBr, DMF, 0 °C

CO2Me

OBn

OBnO

OMeOMe

1. TFA, CH2Cl2, 0 °C2. Tebbe reagent

PhMe/pyr (5:1)., 0 °C3. Et2Zn, CH2I2,

PhMe, 40 °C

1. Pd(OH)2H2, MeOH2. DMP, CH2Cl23. PtO2, H2AcOH, 40 °C

1.50 1.103

1.104 1.105

O

CO2Me

O

O

O

CO2Me

BnO

OBn

Scheme 1.32 – Installation of the gem-Dimethyl Groups and Lactone Ring

Starting with diene 1.50, a two step reduction of the diene gave an inseparable

mixture of four diastereomers, which was functionalized to the benzyl ether

derivatives 1.103 (see Scheme 1.32). The removal of the dimethyl ketal

functionality was done under acidic conditions to give the ketone.

Transformation of the ketone to the spirocyclic cyclopropane 1.104 was done via

a Tebbe reaction followed by Simmons-Smith reaction. Debenzylation of the

cyclopropane intermediate and oxidation of the resulting diol provided the

diketone intermediate. The cyclopropane was opened, to give the gem-dimethyl

61

groups at C-4 under acidic hydrogenolysis conditions, affording intermediate

1.105.

In the previously published work, use of the chloroiodomethane fragment to form

the lactone ring was effective but there was a problem of the undesired

installation of the exocyclic methylene moiety at C-2 (see Scheme 1.33).

Scheme 1.33 – Lactone Ring Formation

To avoid this extra alkylation, the olefin, in what would be the cyclohexenone ring

in maoecrystal V, was first introduced by the Saegusa oxidation. With the C-2

position safely “protected”, the saponificaition of the ester and subsequent

lactonization was successful.

62

At this juncture, there was a need for to establish methodology to obtain the

desired configuration at the C-5 position. To investigate this reversal, the diene

intermediate 1.108 (previous intermediate, see Scheme 1.32) was the starting

point (see Scheme 1.34). 1,2-reduction of the enone was stereoselective. Acidic

conditions transformed the dimethyl ketal to a ketone.

CO2Me

OH

O

O

OMeOMe

1. PPTSacetone/H2O (20:1)40 C

2. Pd/CH2, EtOH

CO2Me

OH

OHO

OH

H H

correctisomer

Ph3PMeBrLHMDS

THF, 0 C

CO2Me

OH

OHO

H

H H

1. Et2Zn, CH2I2PhMe, 40 C

2. DMP, CH2Cl23. PtO2, H2,

AcOH, 40 C

CO2Me

O

OH H

O

1 5

4

1.108 1.109

1.110 1.111

Scheme 1.34 – Reversal of C-5 Stereochemistry

This allowed for hydrogenation under normal Pd/C and H2 conditions to give the

desired isomer 1.109. The authors hypothesize that the “directing effect of a

stereochemically defined hydroxyl group”, formed at C-1 in the NaBH4 reduction

step, would “counter the intrinsic facial bias exhibited by the substrate.” A four-

step sequential procedure involving a Wittig olefination, a Simmons-Smith

63

cyclopropanation, a DMP oxidation and PtO2-mediated hydrogenolysis converted

the dihydroxy ketone at C-4 into the diketone (1.111).

This further work, a continuation of Nicolaou’s efforts, has provided methodology

for solving some of the challenges encountered by their approach with the IMDA

reaction. Methodology was developed to convert the dimethyl ketal at C-4 into

the gem-dimethyl groups. Additionally, a hydroxyl-directed hydrogenation was

employed to obtain the desired configuration at C-5.

1.3.10 The Sorensen strategy17

In 2010, McLeod’s thesis published the work done under Sorensen on the total

synthesis of maoecrystal V. Much of the work showed that many different

potential routes were explored. The bicyclo[2.2.2]octane system was formed by

a Diels-Alder reaction. Initially, they explored model systems to try to induce a

carbonyl-dependent cascade to form the lactone ring, cyclohexenone ring, and

the furanoid ring all in one step (see Scheme 1.35).

64

Scheme 1.35 – Proposed Cascade Reaction

However, when the model system was tested under conditions to initiate the

proposed cascade, it did not give the desired product and this route was

abandoned.

The new route that was explored would hinge on a 1,5-hydride shift as the key

step to forming the crowded carbon bond between C-4 and C-5 (see Scheme

1.36). Toward this end, they needed the allenone intermediate to test the 1,5-

hydride shift.

65

Scheme 1.36 – Proposed 1,5-Hydride Shift

Thus, the synthesis began with the preparation of this key intermediate (1.115).

To begin, dimethyl-2,2-bis(hydroxymethyl)malonate was protected to form the t-

butyl acetal (see Scheme 1.37), followed by Krapcho decarboxylation, which

gave cyclic mono-ester 1.117.

Scheme 1.37 – Diels-Alder Reaction – Sorensen’s Version

66

Aldol reaction with a commercially available vinylogous ester followed by

hydrolysis gave the -unsaturated ketone 1.118 as a single diastereomer.

Subsequent silyl enol ether formation and reduction of the ester gave the alcohol

intermediate1.119, which reacted with dimethylacetylene dicarboxylate (DMAD)

in a Diels-Alder reaction. The result of the Diels-Alder reaction was a mixture of

the hydroxyl ester as well as the lactone product. This mixture was taken directly

into the next step and subjected to mildly acidic fluoride conditions. Thus, the

TBS enol ether was deprotected to give the ketone as well as the cyclization of

the hydroxyl ester to the lactone ring.

With the successful Diels-Alder reaction, attention was turned to put in place the

allenone fragment. The ketone was first functionalized to trisubstituted olefin

1.121 by formation of the triflate followed by Negishi conditions (see Scheme

1.38). This was followed by deprotection of the acetal. Subsequently basic

conditions afforded a hetero-1,4-conjugate addition to give the required furanoid

ring. The unreacted primary alcohol was oxidized by DMP to give the

corresponding aldehyde intermediate 1.122. Finally, addition of the lithiated

allene fragment to the aldehyde and oxidation gave allenone 1.123, which was

used to test the 1,5-hydride shift. Many conditions were tested to afford this type

of 1,5-hydride shift. Various Lewis acids, solvents, temperatures were tried

unsuccessfully. Stronger Lewis acids and Brønsted acids were also investigated

as well as radical conditions all without success.

67

OO

OO

O

t-Bu

1. KHMDSTf2O, -78 C

2. Pd(PPh3)4THF, Et2Zn

OO

OO

t-Bu

CO2MeCO2Me

1. CSA, MeOH2. NaOMe

MeOH, 60 C3. DMP, Na2CO3

CH2Cl2, 0 C

OO

O

OCO2Me

•Li

1.

Et2O, -78 C2. DMP, Na2CO3

CH2Cl2O

OO

O

CO2Me

•

1,5-hydrideshift

1.120 1.121

1.122 1.123

Scheme 1.38 – Formation of the Allenone Intermediate

At this point in the synthesis, it was realized that if the 1,5-hydride shift could not

be utilized to form the cyclohexenone intermediate 1.114 , “activation” of the C-5

in the furanoid ring to form the C-4 to C-5 bond would be required.

Intermolecular approaches to install functionality at the C-5 of the furanoid ring,

such as radical chemistry, catalytic oxidations, dioxirane chemistry, and hydride

abstraction chemistry, all were not successful. Ultimately, it was concluded that

although the route that was attempted yielded interesting chemistry, the strategy

they investigated may be flawed.

68

1.4 Summary and overview of the synthetic approaches to maeocrystal V

In examining all the approaches of various groups, it becomes clear that the

dense, congested polycyclic structure has been a synthetic challenge. A majority

of groups have used various IMDA approaches. In fact, the one total synthesis

uses this approach. All groups have obtained a mixture of endo and exo

products. Some have been fortunate in having the desired diastereomer be the

major product. Thomson’s, Trauner’s and Sorensen’s group have approaches

that are vastly different from the IMDA routes. In all three cases, difficulties in

forming the cyclic ether and/or the lactone ring have been encountered.

Trauner’s aldol approach utilizes the well-used aldol reaction that has the

potential to be selective in that asymmetric studies of the aldol reaction have

been previously explored. Their approach has been very useful, in particular,

because our synthetic route has some similar functional handles, and their

studies have become useful to our studies and will be mentioned in this writing.

69

CHAPTER 2 – THE PLAN

2.1 Planning a synthetic route to maoecrystal V

The logic of our approach toward maoecrystal V (2.9) is outlined in Scheme 2.1.

Scheme 2.1 – The Proposed Synthetic Plan

70

The overall plan starts with the construction of orthoester cyclohexenone

intermediate 2.2 from commercially-available pentaerythritol (see Scheme 2.1).

Cyclohexenone intermediate 2.2 would be involved in the key step, a proposed

tandem Michael-aldol reaction. The tandem Michael-aldol reaction would result

in the formation of the the bicyclo[2.2.2]octane ring system in maoecrystal V.

From the orthoester intermediate 2.3, hydrolysis of the orthoester functional

group would result in lactone ring formation. Subsequent oxidation of the 1,3-diol

in intermediate 2.4 would give dialdehyde 2.5. An in situ ring closure to form the

furanoid ring is expected to give lactol intermediate 2.6. Reaction of aldehyde

2.6 with the organolithium nucleophile would give alkene 2.7. The formation of

the congested C-4 to C-5 bond is potentially possible via an intramolecular

reaction between the alkene and an in situ-formed oxocarbenium intermediate on

the furanoid ring. This ring closure, followed by an oxidation, would complete the

formation of the last ring, the cyclohexenone, to give maoecrystal V (2.9). Thus,

bicyclo[2.2.2]octane compound 2.3 was identified as a key intermediate.

Figure 2.1 – The Bicyclo[2.2.2]octane Intermediate

71

This key bicyclo[2.2.2]octane intermediate was expected to result from a tandem

Michael-aldol reaction between cyclohexenone 2.2 and a methyl pyruvate

fragment (see Scheme 2.2).

Scheme 2.2 – The Proposed Tandem Michael-aldol Reaction

2.1.1 Key transformations – The details

Therefore, the tandem Michael-aldol reaction to functionalize cyclohexenone 2.2

to bicyclo[2.2.2]octane 2.3 is key to the overall synthesis of maoecrystal V (see

Scheme 2.3). The initial synthetic efforts would be focused on the synthesis of

intermediate 2.2 in order to fully explore the key transformation.

Scheme 2.3 – The Key Transformation

72

2.1.2 The orthoester strategy

The orthoester functional group is also key in the strategy and design of the

synthesis. The orthoester has been used as a carboxylic acid protecting group.

Corey employs this methodology in various syntheses such as the total

syntheses of hybridalactone, (±)-retigeranic acid, and prostaglandin D2.31-33 A

key to approaching the congested polycyclic ring system of maoecrystal V was to

use this functional group in a two-fold manner.

First, the orthoester was expected to provide a good method to overcome the

steric demands of the two all-carbon-substituted chiral centers (C-9 and C-10)

embedded within the molecule (see Scheme 2.3). In “tying back” the three

carbons, neopentyl C-9 of intermediate 2.11 (see Scheme 2.2) would be made

accessible to alkylation. Secondly, serving simultaneously as a protecting group,

the orthoester upon hydrolysis, reveals three alcohol groups needed for further

functionalization (see Scheme 2.4).

OMe

CO2R

OH hydrolysis

OMe

OH

OO

HOHOOO

O

OMe

OH

OHHOHO CO2H

2.3 2.12 2.4

Scheme 2.4 – Proposed Result of Opening the Orthoester

73

Upon acid treatment, the revealed triol would be desymmetrized upon lactone

ring formation. Additionally, the functional handles required for further

elaboration are already incorporated into the molecule.

2.2 The Proposed tandem Michael-aldol

2.2.1 Control of diastereoselecivity

The tandem Michael/Aldol reaction could potentially provide diastereoselectivity

via a chelation controlled mechanism.

Scheme 2.5 – Chelation Control Model in the Tandem Michael-aldol Reaction

As demonstrated in Scheme 2.5, after the 1,4-addition, subsequent aldol reaction

was expected to proceed via a six-membered ring transition state due to a

chelation controlled transition state. In the bicyclo[2.2.2]octane intermediate 2.3,

the chiral center at C-8 would be formed diastereoselectively. A tandem

intramolecular Michael/aldol reaction would be key in developing a route in which

74

the diastereoselectivity at C-8 would be controlled by chelation in the ring closure

reaction by a metal ion. As a result, this would provide selectivity in the newly

formed quaternary chiral center at C-8 rather than a diastereomeric mixture.

75

CHAPTER 3 – FORMATION OF THE CYCLOHEXENONE INTERMEDIATE

3.1 Initial attempts to form the orthoester intermediate 3.1

The initial approach toward the synthesis of maoecrystal V required synthesizing

the Michael-aldol substrate, which under basic conditions would potentially result

in the formation of the desired bicyclo[2.2.2]octane intermediate 3.2 (see Scheme

3.1).

Scheme 3.1 – Key Transformation Under Investigation

Therefore, the first step in our synthesis was to explore how to synthesize the

-unsaturated cyclohexenone with the orthoester functional group (see

compound 3.1). This was identified as one of the key intermediates necessary in

the synthesis. With this intermediate in hand, the tandem Michael/Aldol reaction

could be fully explored (see Figure 3.1).

76

Figure 3.1 – The -Unsaturated Cyclohexenone, a Key Intermediate

Initially, the synthetic plan was to start with the methyl cyclohexenone and build

on the orthoester group via a Tollens reaction34 (see Scheme 3.2). 2-Methyl

cyclohexenone was alkylated with allyl bromide using LDA conditions.

Scheme 3.2 – First Attempt at Cyclohexenone Intermediate Synthesis

At this point, selective oxidative cleavage of the terminal alkene was desired.

Various oxidative cleavage methods were investigated and found to be

unsuccessful in revealing the aldehyde necessary for the Tollens condensation

reaction. Selectivity between the terminal alkene over the deactivated -

unsaturated alkene was expected but not observed. This led to a revised

approach, involving alkylation with methyl 2-bromoacetate followed by LiAlH4

reduction to produce the diol. Subsequent Swern oxidation35 gave the desired

dicarbonyl compound 3.4 (see Scheme 3.3).

77

Scheme 3.3 – Investigation of the Tollens Reaction for Triol Formation

This aldehyde intermediate was then used to explore various basic conditions for

the Tollens reaction. It was envisioned that the triol (from a Tollens condensation

with aldehyde 3.4) could be reacted with triethyl orthoacetate to give the

orthoester intermediate 3.1. The Tollens condensation reaction is usually done

under basic conditions and can be used to convert the aldehyde to the

corresponding triol. An example of this is the synthesis of pentaerythritol from

acetaldehyde (see Scheme 3.4).36

Scheme 3.4 – Formation of Pentaerythritol via a Tollens Condensation

Reaction36

78

However, reaction of aldehyde 3.4 under various basic conditions such as

Ba(OH)2, Ca(OH)2, and LiOH in the presence of formaldehyde did not result in

any of the triol but rather repeatedly gave a mixture of products, none of which

were isolable for structural determination.

The presence of multiple reactive sites in cyclohexenone substrate 3.4 may have

contributed to the mixture of products observed. This synthetic route was

attempted because it would have been quite straightforward to obtain the

cyclohexenone substrate required to investigate the Michael-aldol reaction.

However, this result led us to discard this methodology as a possible route to the

desired cyclohexenone intermediate.

3.2 Formation of the -unsaturated cyclohexenone

At this juncture, it was envisioned that a better route to the cyclohexenone

orthoester intermediate would be to first form the orthoester and then build the

cyclohexenone ring. With this in mind, two routes were investigated (see

Scheme 3.5). One approach was to form dialkene intermediate 3.12 after the

orthoester formation. Olefin methathesis37 of the dialkene would give the desired

cyclohexenone ring.

79

O

OO O

HO

HOHO O

O

OO O

O

POMe

OOMe

O

OO O

orthoesterformation

OR

HornerWadsworthEmmons

OlefinMetathesis

3.10

3.11

3.12

3.13

Scheme 3.5 – Envisioned Routes to Intermediate 3.10

The second approach was to make the orthoester and then form phosphonate

aldehyde intermediate 3.13 that would allow for a Horner-Wadsworth-Emmons38-

42 (HWE) type of reaction to give the cyclohexenone ring.

3.3 Initial steps to form the nitrile intermediate

The formation of the orthoester from pentaerythriol and triethyl orthoformate (see

Scheme 3.6) has been previously reported. The procedures by Hall et al.43

required the use of a high boiling solvent, dioctyl phthalate. This reaction has

also been done in toluene.44,45 Not having dioctyl phthalate readily available, the

80

reaction was initially tried with toluene. The result was an intractable reaction

mixture which appeared to be a thick, unmanageable oligomer with no products

identifiable by 1H NMR. Heating the reaction mixture under vacuum did not

sublime off any substantial amount of the orthoester alcohol product 3.15. Hall et

al. employed the use of dioctyl phthalate as the solvent in this type of reaction in

which they had to heat the reaction mixture to 195 ºC.43 They report that “Yields

were variable and the extreme conditions made these experiments somewhat

difficult.” In this study, it was found that the solvent was not necessary for this

reaction (see Scheme 3.6).

Scheme 3.6 – Formation of the Orthoester Alcohol

After distilling off most of the ethanol formed in the reaction, a thick, white slurry

was obtained. The orthoester alcohol 3.15 was sublimed (140 ºC, under 0.1 torr)

and collected as a white solid. This reaction was very reliable and could be

repeated on large scale to obtain hundreds of grams and whose product could be

recrystallized but can also be used directly in the next step after the sublimation.

81

With orthester alcohol 3.15 in hand, further functionalization to the

cyclohexenone was explored. Formation of the methanesulfonate of the alcohol

under normal conditions using triethylamine and methanesulfonyl chloride in

CH2Cl2 was high yielding (see Scheme 3.7) although the product is not stable to

column chromatography.

O

OO

OH

MsCl, NEt3CH2Cl2, 0 °C O

OO

OMsQuantitative

NaCN, DMSO110 C

O

OO

CN

72%

I

n-BuLi, THF-78 °C

O

OO

CN

67%

O

OO

CN

major minor

9 9

3.15 3.16

3.17

3.18

3.19 3.20

Scheme 3.7 – Further Functionalization of the Orthoester Intermediate

This is not a problem as the crude mesylate 3.16 can be reacted with NaCN in

DMSO to give nitrile 3.17 in good yield. Both these steps are very reliable and

the crude nitrile can be purified by recrystallization from ethanol. These first

three steps of the synthesis can reproducibly be done on hundreds of grams with

high yields and no purification is necessary until the nitrile is isolated and

recrystallized.

82

At this point, the nitrile was alkylated with homoallyl iodide using n-BuLi (see

Scheme 3.7). Alkene 3.19 was obtained although it was observed that there was

some side product, which turned out to be the dialkylated product 3.20. The ratio

of alkylated to dialkylated product was initially 7:1. This was surprising since the

neopentyl carbon is sterically hindered. Adding the nitrile anion mixture to a

cooled, stirring solution of homoallyl iodide resulted in obtaining a favorable ratio

of 20:1. Trials with HMPA did not improve the ratio significantly. Various bases

such as NaHMDS, KHMDS, n-BuLi, and LDA were tested. The best results

(conversion and product ratio) are obtained using 0.95 eq. of n-BuLi as the base

and adding the alkylating agent to the nitrile anion solution. Although the

dialkylation was unexpected, it demonstrated that this second alkylation was

possible as this is the C-9 carbon which would be involved with the aldol reaction

to form one of the quaternary all-carbon-substituted stereocenters in the

bicyclo[2.2.2]octane system. The C-9 carbon was accessible to alkylation,

despite being neopentyl at the carbon being alkylated and the orthoester strategy

of “tying back” the three carbons had excellent potential.

3.4 Attempts to functionalize the nitrile

On the outset, the most straightforward method to functionalize nitrile 3.19 was

expected to involve an organometallic addition,46-49 followed by hydrolysis of the

ketimine intermediate 3.21 to yield desired ketone 3.22 (see Scheme 3.8).

83

Scheme 3.8 – Plan for Organometallic Addition to the Nitrile

With this in mind, various organometallic agents were tested against nitrile 3.19

in anticipation of addition to the nitrile. This included vinyl lithium as well as vinyl

Grignard, which would have yielded the dialkene intermediate for the olefin

metathesis. However, none of these organometallic nucleophiles seemed to add

to the nitrile. In fact, any organometallic reagent, even the simple methyl

Grignard did not add. It was not clear at the outset the reason for the lack of

reactivity of the nitrile, as it is not particularly sterically hindered. Further

investigation, of this compound and more advanced compounds, revealed that

the protons are particularly acidic and the result was that rather than

organometallic addition, deprotonation was the major mechanistic trap. This

problem was solved at a later time but for the time being, it is noted here that

other methods for functionalization were utilized, as it was necessary to obtain

the cyclohexenone necessary to test our key transformation.

An alternative pathway was to hydrolyze the nitrile to the corresponding

carboxylic acid. As the orthoester functionality is very acid-sensitive, any acid-

promoted hydrolysis conditions are not amenable. In considering an alternative

84

route in the early stages of the investigation, the nitrile easily hydrolyzed under

acidic conditions (see Scheme 3.9), and as expected, the orthoester hydrolyzed

as well. Intramolecular ring closure gave lactone 3.23. Subsequent protection of

the diol resulted in benzylidene acetal 3.24. However, addition to the lactone to

form ketone 3.25, with various organometallic nucleophiles, was unsuccessful.

The route was not pursued further.

O

OO

CN

3.19

12 M HCl3:1 Dioxane:H2O

reflux O

O

HO

HO

cat. p-TsOHTHF

43%over two steps

Ph

OMe

OMe

O

O

OOPh

[M] R R

O

OOPh

OH

3.23

3.24 3.25

Scheme 3.9 – Orthoester Hydrolysis Investigations

Due to the incompatibility of the orthoester with acid hydrolysis conditions, base

hydrolysis was explored to give the carboxylic acid product. Investigations of

basic conditions showed that, in all cases, the hydrolysis was partial, leading only

to isolation of the amide rather than the carboxylic acid. Even heating with

sodium peroxide50,51 only yielded amide 3.26 (see Scheme 3.10).

85

Scheme 3.10 – Incomplete Basic Hydrolysis

3.5 Completion of the cyclohexenone

Due to the unsuccessful conversion of amide 3.26 to acid 3.27, amide 3.26 was

converted to methyl ester 3.28. Using the conditions reported by Visigalli et al.,52

the amide was functionalized to the methyl ester upon heating in sealed tube at

110 ºC in the presence of dimethylformamide dimethylacetal (DMF-DMA) in

methanol (see Scheme 3.11). The methyl ester was converted to Weinreb amide

3.2953,54 which was then reacted with vinylmagnesium bromide to give dialkene

3.12.

86

, THFO

OO O

NO

OO O

90%O

cat Grubbs2nd Gen.

DCMOO

O

O

80%

O

OO O

NH2O

OO O

OMe

HN(Me)(OMe)•HClMeMgCl, THF, -20 °C

95%88%

Me2N OMe

OMe

MgBr0 °C rt

3.26

MeOH, 110 °C

3.28

3.29 3.12 3.10

Scheme 3.11 – Completion of the Orthoester Cyclohexenone Intermediate

With the dialkene 3.12 in hand, a straightforward metathesis with Grubbs second

generation catalyst37 yielded cyclohexenone 3.10 in useful yields for a total of

nine steps from commercially available pentaeryritol. This route requires an

additional four steps in comparison to a direct organometallic addition (see

Scheme 3.8).

The reaction of the vinyl Grignard with the Weinreb amide, although initially

successful, became problematic on larger reaction scale. The workup required

slow addition of the reaction mixture to a large volume of NaHCO3. Otherwise, a

side-product (the result of the N,O-dimethylhydroxylamine adding to the formed

-unsaturated ketone in a 1,4-addition) would form in appreciable amounts

(see Scheme 3.12).

87

Scheme 3.12 – Details of Vinyl Magnesium Bromide Addition

However, with careful quenching, the by-product could be minimized and the

dialkene isolated in useful yields.

The N,O-dimethylhydroxylamine side-product 3.30 could be avoided by using

allyl allylmagnesium bromide instead of the vinylmagnesium bromide as the

nucleophile (see Scheme 3.13).

Scheme 3.13 – Allylmagnesium bromide Avoids Side-product Formation

88

However, this route required an extra step to isomerize the terminal alkene to

give the -unsaturated ketone 3.31 as a mixture of E/Z isomers. Dialkene 3.32

was also useful in the synthesis and gave cyclohexenone 3.10.

3.6 Use of the Horner-Wadsworth-Emmons (HWE) reaction as alternative

strategy

Athough it was gratifying that the orthoester cyclohexenone was made, the

previously mentioned problem encountered in the addition of the vinyl

magnesium bromide to the Weinreb amide prompted examination of the HWE

pathway toward the cyclohexenone (see Scheme 3.14).

Scheme 3.14 – The HWE Approach to Cyclohexenone 3.10

Dimethyl methylphosphonate was deprotonated with n-BuLi and, in the presence

of HMPA, was treated with the methyl ester (see Scheme 3.15)

.

89

POMe

O OMe

n-BuLi, THFHMPAO

O

OMe

OO

O

OO

O

POMe

OOMe

3.28 3.33

Scheme 3.15 – Initial Attempt to Synthesize the Substrate for the HWE Reaction

However, even upon warming, the methyl ester was unreactive toward the

phosphonate addition. Seeing this result and also considering the unreactive

nitrile that was previously observed, it was hypothesized that the problem here

was the acidic proton. Due to the ready enolization of the ester, the

dimethyoxyphosphoryl methyl lithium was behaving as a base and deprotonating

methyl ester 3.28 rather than nucleophilically adding. This was also

hypothesized to be the problem with the organometallic addition to the nitrile. To

test this hypothesis, the enolization pathway was blocked by installation of a

methyl group (see Scheme 3.16).

POMe

O OMe

n-BuLi, THFHMPA

O

O

OMe

OO

O

OO

O

POMe

OOMe

3.28 3.35

O

O

OMe

O OLDA, MeI

THF-78 °C to rt

98%

3.34

Me Me71%

Scheme 3.16 – Methylation of Ester 3.28 Allowed for Nucleophilic Addition

90

Thus, methyl ester 3.28 was deprotonated with LDA and MeI was added as the

methylating agent. With the methyl group in place, the reaction of the methyl

ester with the phosphonate anion took place, as deprotonation could no longer

occur at the neopentyl carbon, thus favoring nucleophilic addition (see Scheme

3.16).

Phosphonate 3.35 was subjected to oxidative cleavage conditions in order to

obtain aldehyde 3.36. However, ozonolysis conditions did not provide the

aldehyde. Oxidative cleavage conditions using OsO4 and NMO·H2O as the

reoxidant also did not provide the aldehyde. In both cases, cyclohexene 3.38

was obtained (see Scheme 3.17).

O3, NMO•H2OCH2Cl2, 0 C

orOsO4, NMO•H2O

then NaIO43:1 Me2CO/H2O

O

OO

O

O

POMe

OOMe

MeO

OO

O

POMe

OOMe

3.35

Me

not isolated

O

OO

O

OH

POMe

OOMe

MeO

OO

O

POMe

OOMe

Me

3.36

3.37 3.38

Scheme 3.17 – Initial HWE Reaction did not Yield the Desired Cyclohexenone

91

This result indicated that the oxidative cleavage reaction in both cases did

provide aldehyde 3.36. The resulting phosphonate anion reacted with the

proximal aldehyde. This is expected as the first step in the HWE reaction. But

rather than forming the oxaphosphetane intermediate, elimination occurred,

giving the undesired cyclohexenone 3.38.

Seeing this result, dimethyl methylphosphonate was replaced with diethyl

ethylphosphonate. With yet another extra methyl group installed, the undesired

elimination reaction could not occur. Thus, phosphonate 3.39 provided the

product of the HWE reaction, cyclohexenone 3.40 (see Scheme 3.18).

POEt

O OEt

O

OO

O

OMe

POEt

OOEt

DBU, LiClMeCN O

OO

O

Me

O

O

OMe

O O

Me

1. n-BuLiHMPA, THF

2. NMO H2OOsO4, NaIO4

36% over3 steps

LDA, MeITHF

-78 °C to rt

98%

O

O

OMe

OO

H

3.28 3.34

3.39 3.40

Scheme 3.18 – Use of the HWE Reaction in Exploring the Effect of the

Enolizable Proton

92

With the methyl group in place, the reaction of the methyl ester with the

phosphonate anion took place. The HWE reaction with DBU as the base gave

the cyclcohexenone orthoester, albeit with an “extra” methyl group. However,

this result provided insight into the previously mentioned failed attempts at

organometallic addition to the nitrile and would become useful in shortening the

synthesis.

Methyl ester 3.28 was also chlorinated in the position of the ketone

phosphonate. The plan to use this route by replacing the “blocking” methyl with

chloride was successful (see Scheme 3.19).

POMe

O OMe

1. OsO4, NMO•H2Othen NaIO4

2. DBU, LiClMeCN, 0 C

O

OO

O

Cl

O

O

OMe

O O

Cl

1. n-BuLi, THF2. K2CO3, MeI

acetone

40%

LDA, CCl4THF

-78 °C

62%

O

O

OMe

OO

H 50%

O

OO

O

Cl

POMe

OOMe

3.34 3.41

3.42 3.43

Scheme 3.19 – Completion of Orthoester Cyclohexenone by the HWE Reaction

The methyl ester was chlorinated with CCl4 and that product reacted with the

dimethyl methyl phosphonate anion. Surprisingly, the ethyl phosphonate did not

93

react with the ester and the dechlorinated methyl ester was recovered.

Therefore, an extra step of methylating the ketone phosphonate was required.

Oxidative cleavage followed by the intramolecular HWE reaction gave the

cyclohexenone product. Ultimately, this route was not used. Direct

organometallic addition to the nitrile 3.19 was found to be possible (see Scheme

3.8). Knowing that the neopentylic proton to the orthoester was particularly

acidic proved to be invaluable later in the synthetic studies.

After investigating the three routes to the cyclohexenone intermediate, it was

clear that the synthetic scheme of forming the orthoester first, followed by a ring

closure to form the cyclohexenone, would be the most straightforward.

Additionally, the olefin metathesis route was chosen as the shortest and most

efficient to make the desired cyclohexenone ring. With the cyclohexenone in

hand, the next step was the investigation of the intramolecular Michael-aldol

reaction.

94

CHAPTER 4 – EXPLORING THE MICHAEL-ALDOL REACTION

4.1 Attempts to achieve 1,4-addition

With the completion of cyclohexenone orthoester 4.1, focus shifted to exploring

the addition of the pyruvate fragment (1,4-addition) followed by a planned aldol

ring closure (see Scheme 4.1). This key transformation had been proposed for

forming the bicyclo[2.2.2]octane ring. It was initially envisioned that enolate 4.2,

formed from methyl pyruvate, could be the nucleophile in a Michael addition to

cyclohexenone 4.1, to give ketoester intermediate 4.3. Under the basic

conditions required for the Michael reaction, the ketoester could potentially

undergo an intramolecular aldol reaction to form alcohol 4.4.

OOO

OO

O

O

OH

O

OOO

O

O

O

O

Michael Aldol

4.1 4.2

4.3

4.4

OO

O

CO2Me

8

8

Scheme 4.1 – Proposed Michael-Aldol Reaction

95

The ketoester functional group was part of the synthetic design because the

congested C-8 chiral center would be set as a result of the aldol reaction.

Additionally, the ketone group of the ketoester is highly reactive and the ester on

C-8 would be useful to further elaborate to the lactone ring in maoecrystal V.

Conjugate addition to a cyclohexenone can be commonly acheived with the use

of an organocopper or organocuprate reagent but the goal was to examine the

optimal conditions for a tandem Michael-Aldol reaction. If indeed, optimal base

conditions could be found for the Michael addition with a methyl pyruvate

derivative, then the in situ aldol reaction could be expected. Many different

pyruvate derivatives and pyruvate equivalents as nucleophiles were investigated.

In the following section, various methods will be discussed. In many cases,

regioselectivity in the addition to the cyclohexenone was problematic.

4.2 Initial studies using the pyruvate fragment

4.2.1 Organolithium reagents

Investigation began with the simplest of the pyruvate nucleophiles.

Deprotonating methyl pyruvate with LDA resulted in the formation of the lithium

enolate (see Scheme 4.2). Normally, the lithium enolate would be expected to

add to the cyclohexenone in a 1,2-rather than a 1,4-sense.55,56 However, the

lithium enolate reagent was tested because the neighboring substituent, the

96

bulky orthoester group, could potentially hinder 1,2-addition and thus favor 1,4-

additon. The enolate, formed from methyl pyruvate, was reacted with

cyclohexenone intermediate 4.1. The 1,2-addition product did indeed result from

this reaction. This aldol addition product was not isolated. Rather, the resulting

oxyanion reacted with the ester in an intramolecular reaction forming the

spirocyclic dihydrofuran dione as a diastereomeric mixture. This intermediate,

4.6, could not be further elaborated toward maoecrystal V.

Scheme 4.2 – Key Transformation Tested with a Lithium Enolate

4.2.2 Silyl enol ether reagents

Another alternative was to use the silyl enol ether via a Mukaiyama-Michael

reaction.57 The Mukaiyama-Michael reaction is the condensation between a silyl

97

enol ether and an aldehyde or ketone. Thus, the silyl enol ether of methyl

pyruvate was formed (see Scheme 4.3).

OTMS

O

O

O

O

O

NEt3TMSClTHF

77%

TiCl4 or BF3•OEt2O

OO

O

O

O

O

O

OO

O

4.7 4.8

4.1

4.3

Scheme 4.3 – Mukaiyama Aldol Trials

These types of condensation reactions usually require a Lewis acid in either

stoichiometric or catalytic amounts (such as TiCl4 in Mukaiyama’s archetypical

example in 1973)57 to activate the ketone as an electrophile toward the addition

of the silyl enol ether. In this case, a strong Lewis acid is problematic in

conjunction with the presence of the orthoester functionality. Addition of Lewis

acids such as TiCl4 or BF3·OEt2, even in catalytic amounts, resulted in immediate

opening of the orthoester (see Scheme 4.4).

98

TiCl4 or BF3•OEt2CH2Cl2

OH

O

OOO

O

OTMS

O

O

Not isolated4.1

CO2MeOO

O

4.4

Scheme 4.4 – Results of Mukaiyama Aldol Reaction

Other Lewis acids as well as known activating reagents (such as SnCl4, DBU,

TBAF) were tested, but were found to be either too mild (and only the

cylcohexenone starting material was isolated) or too harsh and proved not

compatible to the orthoester functionality. For these reasons, this method was

abandoned.

4.2.3 Attempts using iminium and enamine chemistry

Another common method for 1,4-addition is the use of an in situ formed enamine

species as an active nucleophile (see Scheme 4.5). The enamine undergoes

condensation with aldehydes and ketones to give iminium intermediate 4.10

which upon hydrolysis gives the desired ketoester 4.3.58

99

Scheme 4.5 – Envisioned Proline Promoted Condensation

There are many examples using proline or proline derivatives as promoter

molecules to catalytically mediate aldol reactions.59,60 Efforts to effect

condensation between cyclohexenone 4.1 and methyl pyruvate, with proline and

known promoters such as tetra-butylammonium bromide (TBAB), were

unsuccessful. Recovery of the cyclohexenone starting material was often the

result and heating led to decomposition rather than nucleophilic addition.

To further investigate the possibility of an enamine type of addition, the reaction

was separated into two steps, the formation of the enamine and the addition to

cyclohexenone (see Scheme 4.6).

100

Scheme 4.6 – Investigating an Enamine Nucleophile

Thus, the enamine of the pyruvate fragment (4.11) was formed first (see Scheme

4.6) and then reacted with cyclohexenone 4.1. Various solvents such as toluene

and acetonitrile were tested, and even upon heating to reflux overnight, only

starting material was obtained. Mild Lewis acids can often be used in the

enamine reactions. Thus the reaction was also screened with these activating

reagents such as CuBr2 and SbCl3. The enamine was completely unreactive and

the starting material cyclohexenone was the re-isolated from these types of

reactions.

4.2.4 Organozinc, organocopper and organocuprate investigations

At this juncture, having no success with employing an enolate-type nucleophile,

attention turned to using the organocopper and organocuprate pyruvate

derivatives as nucleophiles for the Michael reaction. Conjugate additions are

often successful with “soft” nucleophiles.61 Thus, an appropriate organocuprate

101

reagent 4.12 would be chosen to investigate this route to the Michael product

(see Scheme 4.7).

Scheme 4.7 – Modified Route Using an Organometallic Addition

The 1,4-addition product 4.13 could potentially undergo subsequent oxidative

cleavage to give the substrate 4.15 (see Scheme 4.7). The -ketoester

intermediate 4.14 is the substrate necessary to investigate the intramolecular

aldol reaction to form the bicyclo[2.2.2]octane.

To gain access to the chosen organocopper reagent, an appropriate

bromoalkene was synthesized according to known procedures (see Scheme

4.8).62

102

Scheme 4.8 – Formation of Ethyl 2-(bromomethyl)acrylate62

A model compound, cyclohexenone, was used to test conditions that might yield

the addition product, which upon cleavage would afford ketoester 4.20 (see

Scheme 4.9). Thus, the design of an appropriate nucleophile had to incorporate

an unsaturated ester as the olefin would reveal the desired ketoester functionality

(following ozonolysis), which was crucial to the subsequent aldol reaction.

O

OEt[M]

O O

O

OEt

O

1.

2. Ozonolysis

4.19 4.20

Scheme 4.9 – Model Studies of Organometallic Addition

Lipshutz et al. reported on the temperamental behavior of allylic organocuprates

in the presence of -unsaturated ketones.63 As such, it is known that allylic

cuprates are ill-behaved and regioselectivity is often not observed. Lipshutz et

al. report that “they are overly reactive and in need of attenuation if discrimination

103

between the 1,4- and 1,2-modes of addition is to be achieved.”63 An example of

this is the addition of the allyl cuprate to the unsaturated ketone intermediate

4.21 (see Scheme 4.10).64 The result was a mixture of starting material, 1,2 and

1,4 products with no selectivity observed.

Scheme 4.10 – An Example of Allylic Cuprate Addition64

However, this type of addition has been studied and it has been shown that a

“neutral organocopper complex… together with TMSCl, provide an effective

means of delivering allylic ligands in a Michael sense.”65-67 Therefore, under

conditions of using TMSCl as an additive and a CuCN·LiCl complex to form the

organocopper reagent (RCuL vs. R2CuLi), a “deactivated” organocopper reagent

is formed. This “deactivated” organocopper reagent that would add exclusively in

the 1,4-sense to cyclohexenone (see Scheme 4.11).68 An example of this is the

addition of the allylic reagent 4.26 to cyclopentanone 4.25 which gave exclusively

the 1,4-addition product.

104

Scheme 4.11 – Use of TMSCl Facilitates Michael Addition68

Organocopper reagents have been synthesized from the reaction of copper salts

with various organometallic reagents. Organolithium reagents and Grignard

reagents are often used for this type of transmetallation to give the desired

organocopper reagent. However, because of the need to incorporate the

adjacent “ester” functionality as part of the nucleophilic fragment, an organozinc

reagent was more suitable. In constrast to organomagnesium and organolithium

reagents, the carbon-zinc bond in an organozinc nucleophile has been shown to

be highly covalent in nature and hence less reactive, allowing for preparation of

derivatives with a wider range of functionalities.69 In particular, it would allow for

direct incorporation of the ester group (part of the pyruvate fragment) which

would have been incompatible with either the organolithium or Grignard

reagents.

Thus, the synthetic plan was to react bromoalkene 4.18 with zinc powder to

obtain the organozinc species 4.29.70 In situ reaction of the organozinc with an

appropriate copper reagent leads to the organocopper reagent 4.30. After initial

screening of organocopper and organocurate reaction conditions with

105

cyclohexenone as the Michael acceptor, it was observed that a ratio of three

different products could be isolated (see Scheme 4.12).

Scheme 4.12 – Studies of the Organocopper Addition on Cyclohexenone

In addition to the formation of the desired 1,4-addition product, the two side

products that were isolated showed two competing reactions – the Wurtz

coupling of the organozinc reagent and 1,2-addition (see Scheme 4.12). Despite

using Lipshutz’s reported method of forming the deactivated organocopper

reagent,63 the regioselectivity was problematic.

Screening of various conditions to form the organocopper reagent was

investigated using cyclohexenone as the Michael acceptor. It was found that the

106

CuBr•Me2S reagent rather than the CuCN•2LiCl complex afforded a useful

organocopper reagent. Optimization of conditions thus led to acceptable yields

of the Michael product (See Table 4.1).

Table 4.1 – Investigation into Organocopper Reaction Conditions

O

EtO

O

OEt

O

Wurtz Product

O

O

1,2-addition product

OR OROEt

O

1,4-addition product

4.31 4.32 4.33

Entry Conditions Result

1 cat CuCN•2LiCl (-10 ºC) Cyclohexenone (-25 ºC)

4.32

2 cat CuCN•2LiCl (-78 ºC)

Cyclohexenone (78 ºC → RT) 4.32

3 cat CuCN•2LiCl (-20 ºC) Cyclohexenone (-78 ºC) 4.33

4 1.1 eq CuCN•2LiCl (-78 ºC → -20 ºC)

Cyclohexenone (-78 ºC) 4.33

5 2.1 eq CuCN•2LiCl (-78 ºC → -20 ºC)

Cyclohexenone added as ATPH71 complex (-78 ºC)

4.33

6 2.1 eq CuCN•2LiCl and TMSCl

(-10 ºC → 0 ºC) Cyclohexenone (-78 ºC)

No major product isolated

7 2.1 eq CuBr•Me2S (-78 ºC)

Cyclohexenone (-78 ºC) 4.33

8 2.1 eq CuBr•Me2S and TMSCl

(-78 ºC → -25 ºC) Cyclohexenone added at -78 ºC

4.31 48% yield

107

With satisfactory conditions found with the model compound, the same

conditions were used to react with orthoester cyclohexenone 4.1. The

application of the organocopper reaction with TMSCl as an additive did indeed

give the 1,4-addition product (see Scheme 4.13).

BrZn OEt

O

O b) CuBr•SMe2, thenTMSClc) Cyclohexenone

a)

O

OO

O OHO

O

OHOAcO

HOOEt

O

O

OEt

4.1 4.34

4.35

4.29

HO

H H

H

Scheme 4.13 – Product Obtained from Organocopper Conditions

Unfortunately, the TMSCl additive was not compatible with the orthoester

functionality. It was deduced that the orthoester had cleaved. Upon orthoester

cleavage, one of the resulting alcohol groups reacted with the ketone to give

hemiacetal product 4.35 (tentatively assigned). Interestingly, the 1,4-addition

was diastereoselective as only one isomer was isolated.

108

Because of this result, base “buffered” conditions were tested using the model

compound. Thus, the presence of a hindered base, such as 2,6-lutidine might

prevent the orthoester from being cleaved. The reaction conditions mentioned

above were again tested on the model compound with the addition of 2,6-lutidine.

Interestingly, the compound isolated was exclusively the 1,2-addition product

(see Scheme 4.14).

Scheme 4.14 – Further Investigations with the Model Compound

However, the 1,2-addition product 4.36, unlike the spirocyclic dihydrofuran 4.6

from the organolithium reaction, was seen as potentially useful in the synthetic

scheme because the resulting tertiary alchol was TMS-protected and did not

react with the existing ester to form a 5-membered ring. Upon reaction with tetra-

n-butylammonium fluoride (TBAF) to remove the TMS protecting group, an in situ

anionic oxy-Cope rearrangement occurred to give the same product as would

result from 1,4-addition (see Scheme 4.14). Again, the conditions that were

found effective for the model compound were tested against the orthoester

109

substituted cyclohexenone 4.1. However, it did not react and only the starting

material was recovered (see Scheme 4.15).

Scheme 4.15 – Testing the 2,6-lutidine Modified Conditions

The results of the organocopper trials revealed that the organocopper reagents

were not reactive enough and did not add to the cyclohexenone intermediate 4.1.

It was observed that the 1,2-addition product could be trapped and undergo a

oxy-Cope reaction to give the 1,4-addition product. In the previous reactions, the

organocopper reagents had their reactivity “tamed” due to the allylic cuprates

being ill-behaved toward -unsaturated ketones.63,65,66 However, if 1,2-addition

is useful via anionic oxy-Cope rearrangement, the allylic organocopper reagent

does not have the constraints that 1,4-addition requires and as a result, more

reactive nucleophiles could be used.

The more reactive organozinc reagent was investigated (see Scheme 4.16). The

organozinc reagent was not reactive at -78 ºC but upon warming, the organozinc

reacted to give the Wurtz product exclusively.

110

OO

OO

BrZn OEt

O

TMSCl, 2,6-lutidineTHF, -78 C

CyclohexenoneIntermediate 4.1

and WurtzCoupling Product 4.32

4.1

4.29

Scheme 4.16 – Organozinc Results

The organocuprate reagent did add to the cyclohexenone intermediate, albeit in

a 1,2-addition, as expected (see Scheme 4.17).

Scheme 4.17 – Organocuprate Results

However, without the addition of TMSCl, the resulting tertiary alcohol reacted

with the ester to give the spirocyclic dihydrofuran dione product 4.6. Addition of

111

the TMSCl (as an additive and to trap the tertiary alcohol and avoid the synthetic

trap of ring closure) gave no reaction.

4.2.5 The use of vinyl rather than allylic substrates

Due to the inability to add the pyruvate fragment or its allyl equivalent, a modified

synthetic route was devised to obtain ketoester 4.3 to test the second ring

closure (aldol reaction), of the key transformation, before more effort was

expended to make the 1,4-addition of the allyl fragment successful (see Scheme

4.18). The aim was to be able to move forward to test the synthetic plan to form

the bicyclo[2.2.2]octane.

Scheme 4.18 – Proposed Aldol Reaction

Rather than using the allylic nucleophile, vinyl cuprate was prepared via vinyl

magnesium bromide. The vinyl cuprate was reacted with cyclohexenone 4.1

(see Scheme 4.19). The vinyl cuprate, unlike the problematic and promiscuous

112

allylic nucleophile was successfully added and the resulting alkene was isolated

(5:1 dr).

Scheme 4.19 – Modified Route to the Ketoester

The mixture of diastereomers obtained from the vinyl cuprate addition was

subjected to ozonolysis conditions. Initially, the ozonolysis reaction was carried

out using addition of dimethyl sulfide (DMS) to decompose the ozonide.

However, even with the ozonolysis progress being monitored to avoid side

reactions, very low yields of around 15% were obtained. Due to this result other

oxidative cleavage conditions were investigated. One alternative was the

stepwise dihydroxylation and subsequent diol cleavage reaction sequence (see

Scheme 4.20). Using NMO/OsO4 conditions, the diol was obtained, however, in

low yields. Attempts to convert the diol to the aldehyde (via oxidative cleavage)

were unsuccessful. Subjecting the diol to NaIO4 conditions resulted in a product

in which the orthoester was hydrolyzed (confirmed by 1H NMR).

113

Scheme 4.20 – Investigating the Oxidative Cleavage

Ultimately, it was found that the alkene could be oxidized to the aldehyde using a

modified ozonolysis method utilizing addition of NMO●H2O (see Scheme 4.21).72

R3NO

R

OO

ONR3

RO

OO

R

primaryozonide

R

OO

O

CH2

carbonyloxide

O

O

O

R

1,2,4-trioxolane

DMS

amineoxide

O R

O R

4.41 4.42 4.43 4.44 4.45

4.46

4.47 4.45

O3NR3 orNMO

Scheme 4.21 – Suggested Intermediate in Modified Ozonolysis72,73

This method of ozonolysis avoids the formation of the 1,2,4-trioxolanes 4.44 by

intercepting the carbonyl oxide 4.43 with the nucleophilic amine oxide 4.46 (see

Scheme 4.21). The addition of the amine oxide to the carbonyl oxide generates

114

an unstable zwitterionic peroxyacetal 4.47. The peroxyacetal intermediate

undergoes decomposition to generate aldehyde 4.45.73

As stated by Dussault et al., “This reaction, which appears to involve an

unprecedented trapping and fragmentation of the short-lived carbonyl oxide

intermediates, avoids the hazards associated with generation and isolation of

ozonides or other peroxide products.”72 Additionally we found that Dussault’s

strategy was highly useful in our synthesis as these conditions do not require the

tradition DMS reduction step and the reaction mixture can then be worked up

with a Na2S2O3/NaHCO3 solution to remove the excess NMO. The product is

used directly in the next step without any purification, as the aldehyde was not

stable to chromotography (see Scheme 4.22).

O

OO O

H

H

OOO

O

O

NMO•H2O,O3, CH2Cl2

-78 C

P

O

OO

O

O

OTES

O

OO O

OTES

O

O

48%over 2 steps

LiNTMS2

NEt3, MeOHO

OO O

O

O

O

83%

4.37 4.40

4.48 4.3

4.47

Scheme 4.22 – Route to the Ketoester

115

After investigating the HWE reactions with a variety of known basic conditions

(such as Ba(OH)2 and DBU), it was found that the crude aldehyde could be

reacted with TES-protected phosphonate 4.47, with LiNTMS2 as the base, in

good yields.

The silyl enol ether type of phosphonates required for the HWE could be made in

a four step sequence from tartaric acid (see Scheme 4.23). Tartaric acid 4.49

was converted to the methyl ester under boric acid conditions74 followed by

oxidative cleavage with periodic acid.75 This resulted in the methyl glyoxylate

4.51 which was reacted with dimethyl phosphite in the presence of catalytic p-

TsOH to give methyl phosphonate 4.52.76 The methyl phosphonate could be

protected with TBSCl or TESCl.

Scheme 4.23 – Synthesis of Phosphonate 4.47

116

The TBS-protected version of the phosphonate intermediate was originally made

following a known procedure.76 However, it was found that deprotection of the

HWE product (the TBS-protected silyl enol ether) with TBAF and other fluoride

based reagents (as the orthoester is not compatible with the usual acidic

conditions) gave yields of about 15%. The TES-protected intermediate 4.48 was

thus synthesized and subsequent deprotection under mildly basic conditions

gave the desired ketoester (see Scheme 4.22) in much higher yields (83%).

4.3 Testing the aldol reaction to form the bicyclo[2.2.2]octane

With the desired ketoester synthesized, the key aldol reaction to form bicyclo

[2.2.2]-octane was investigated. It was initially envisioned that a lithium base

would be used to effect this key transformation (see Scheme 4.24).

Scheme 4.24 – Chelation Control in the Proposed Transition State of the Aldol

Reaction

117

However, testing of various lithium basic such as LDA and LHMDS all resulted in

decomposition. After further examination, it was concluded that the common

enolate forming base conditions (NaOMe, NaHMDS, KOtBu, NaOH) did not give

the ring closure product. Additionally, decomposition was a problem (see

Scheme 4.25).

Scheme 4.25 – Test of Ring Closure with the Ketoester 4.3

4.4 Model compound studies – replacement of the ketoester

The ketoester had been chosen initially for two main reasons. First, upon the

desired aldol ring closure, the sterically congested C-8 chiral center of

maoecrystal V (see Figure 4.1) would be made. Secondly, the ketoester would

provide a more reactive electrophilic carbonyl in the planned aldol ring closure

than many other carbonyl containing functional groups. However, due to

decomposition under the aldol conditions, further investigation into its suitability

was needed. Therefore model studies were used to determine possible

replacements for the ketoester functionality.

118

O

OO

O

O

8

O

CO2Me

OH8

maoecrystal V4.54 4.4

OO

O

Figure 4.1 – Maoecrystal V and the Aldol Product

Because all the base conditions tested for the aldol reaction had resulted in total

compound decomposition, three model systems were designed and tested for

determining if the ketoester functionality was not base compatible and if so, what

fragment would be suitable (see Figure 4.2).

Figure 4.2 – Model System Compared to Actual Orthoester Containing System

Three derivatives were made. First, cyclohexenone 4.56 was reacted with the

previously-used allylic organocuprate and the resulting alkene was subjected to

ozonolysis to give ketoester test compound 4.55 (see Scheme 4.26).

119

[Cu] OEt

O

O

O

OEt

O

1.

2. O3, CH2Cl2DMS

33%

O

4.56 4.55

Scheme 4.26 – Synthesis of the Ketoester Test Compound

Cyclohexenone 4.56 was also reacted with allyltrimethylsilane in the presence of

TiCl4 as the Lewis acid to give the Michael product with the terminal olefin 4.5777

(see Scheme 4.27).

Scheme 4.27 – Synthesis of the Aldehyde and Ketone Test Compounds

120

Alkene 4.57 was further functionalized with two separate routes. An oxidative

cleavage with OsO4/NaIO4 gave aldehyde 4.58. The same alkene starting

material could be dihydroxylated, mono-protected with TBSCl and oxidized

(using a final Ley oxidation)78,79 to give the protected keto-alcohol 4.60.

With these three model compounds synthesized, all were subjected to various

enolate forming basic conditions. Similar to the results of attempting base

promoted ring closure on the elaborated orthoester (containing the ketoester

4.3), decomposition was observed with the model ketoester compound 4.55 (see

Scheme 4.28).

O

O

OTBS

K2CO3MeOH

OH

OTBS

O

56%

O

O

O

O

O

O

OH

O

ProductDecomposition

87%

VariousConditions

K2CO3MeOH

4.55

4.58

4.60

4.62 a, 4.62b

4.61

Scheme 4.28 – Results of the Base Promoted Ring Closure on Test Compounds

121

This led to the conclusion that the ketoester functionality was unsuitable for the

aldol ring closure step. Aldehyde 4.58 as well as the TBS-protected ketoalcohol

compound cyclized under basic conditions, giving the bicyclo[2.2.2]octane

products in both cases.

Additional support for the bicyclic assignment was obtained by oxidation to

diketone 4.63 and confirmed by observed symmetry in 1H NMR (see Scheme

4.29)

OH

O

TPAPNMO H2O

CH2Cl24Å MS

97%

O

O4.87 4.63

Scheme 4.29 – Oxidation to the Diketone Intermediate

Ring closure of the TBS-protected alcohol 4.60 also gave two diastereomeric

products. Due to anisotropic shielding caused by the carbonyl group the

structures of both diastereomers could be assigned by 1H NMR (see Scheme

4.30). In particular, the protons residing in the shielded region of the carbonyl

group were shifted upfield at 1.3 ppm and 3.2-3.3 ppm in comparison to their

deshielded counterpart at 2.7 ppm and 3.4-3.7 ppm respectively.

122

Scheme 4.30 – Diastereoselectivity of the Ring Closure on the Model System

Further NMR studies were also done. HMBC provided further evidence for this

assignment of configuration (see Figure 4.3).

Figure 4.3 – Further Evidence of Configuration Assignment

In the undesired ring closure product, the 3-bond C-H coupling of the protons on

C-14 was highly informative. The carbon to which the TBS-protected alcohol is

attached is approximately eclipsed with the “top” proton (as drawn on C-14) and

123

thus has a small coupling constant of 3.3 Hz. However the geminal proton on C-

14 is not eclipsed and has a dihedral angle of approximately 109º (CVFF). This

gives a larger coupling constant of 10.9 Hz, confirming our previous structural

assignment.

It was also confirmed that the diastereoselectivity of the ring closure could be

controlled by using a lithium base. The diastereoselectivity was predicted to be

controlled by a chelating metal counter ion with a suggested six-membered ring

transition state (see Scheme 4.31).

Scheme 4.31 – Chelation Control in the Proposed Transition of the Aldol

Reaction

This selectivity was demonstrated in the model system. Under K2CO3/MeOH

conditions, with no chelating metal present, the undesired product 4.64 was

obtained as a major product (11:1). Switching to LDA/THF conditions, the

product obtained was predominantly the desired diastereomer 4.62a (35:1) (see

Scheme 4.30). This result may reflect a kinetic versus thermodynamic product

distribution.

124

4.5 Exploring the aldol reaction using a modified substrate

After obtaining these encouraging results, the orthoester starting material for the

aldol reaction was modified to have the protected alcohol motif rather than the

ketoester. This was done using a combination of methods that had been

established, from previous experience, to be compatible with the orthoester

functionality (see Scheme 4.32).

1. NMO•H2OOsO4

2.imid., TBSCl3. NMO•H2O

TPAP, 4Å MS

O

OO O

O

OTBS

O

OO O BrMg

O

OO O

O

OO HO

THF, -78 °C

H

H

H

H

H

KH, 18-crown-6THF, 0 °C rt

97% 66%

41%

4.1 4.65

4.66 4.67

Scheme 4.32 – Synthesis Diketone 4.67

Starting with cyclohexenone 4.1, Grignard addition to the ketone gave alcohol

4.65. Reaction of the alcohol with KH/18-crown-6 promoted the Cope

rearrangement and gave ketone 4.66. The Grignard addition resulted in 1,2-

addition but was remedied by the anionic oxy-Cope rearrangement to give

125

diketone 4.66 (see Scheme 4.33). Elaboration to the protected alcohol motif was

straightforward – dihydroxylation, mono-protection, and oxidation.

This route was possible since the allylmagnesium bromide nucleophile has no

ester component (as compared to the previous allyllic nucleophiles 4.12, 4.29),

the subsequent lactone formation cannot occur and thus the 1,2-addition is not a

dead-end (see Scheme 4.33). The TBS-protected alcohol 4.67 was subjected to

ring closure conditions (see Scheme 4.34).

Scheme 4.33 – Comparison of 1,2-addition Products

The TBS-protected alcohol 4.67 was subjected to ring-closure conditions (see

Scheme 4.34). Ring-closure investigation with the TBS-protected alcohol, using

LDA as the base, did not result in obtaining the desired bicyclo[2.2.2]octane

product 4.68. Unlike the previous ketoester trials, the starting matereial was

recovered and no decomposition was observed. Refluxing K2CO3/MeOH was

tried. Yet again, the starting material was the major product although 5% of the

ring closure product 4.69 (without the TBS group) was also isolated. This led to

the hypothesis that perhaps the TBS protecting group was too large and thus

126

prevented the desired ring closure. The TBS group was removed with TBAF and

the substrate resubjected to basic conditions. Aldol ring-closure product 4.69

obtained.

O

OO O

O

OTBS

OH

O

H

H

OTBS

K2CO3MeOHreflux

5%

OH

O

LDA, THF-78 °C to rt

StartingMaterial

1. TBAF, THF-78 C

2. K2CO3, MeOH

OH

O

4.67 4.68

4.69

4.69

OO

O

OO

O

OO

O

OH

OH

Scheme 4.34 – Results of Ring Closure Investigations of Modified Orthoester

Intermediates

This led to investigations into making the protected alcohol with other protecting

groups that would have differing steric effects. Thus another series of this type of

orthoester intermediate was synthesized (see Scheme 4.35 - 4.36).

127

Scheme 4.35 – Synthesis of the MOM-protected Alcohol

The MOM-protected alcohol was synthesized in the same manner as the TBS-

protected substrate. Starting with diol 4.70, the mono-protection with MOMCl

followed by Ley oxidation80 afforded the MOM-protected substrate (see Scheme

4.35).

O

OO O

ClMg OBn

THF, -78 C

87%

O

OO HO

BnO

KOtBu18-crown-6THF, 0 C

NMO•H2OOsO4 then

NaIO4

O

OO O

BnO

O

OO O

O

BnO

39%

23%

4.1

4.72

4.73

4.74 4.75

Scheme 4.36 – Synthesis of the Benzyl Protected Alcohol

128

The benzyl protected alcohol was synthesized via a route that incorporated the

Cope rearrangement methodology. Instead of using the simpler allylmagnesium

Grignard, the allylic nucleophile was functionalized to contain a benzyl protected

alcohol. After 1,2-addition and Cope rearrangement, oxidative cleavage afforded

the protected benzyl alcohol 4.75.

Both substrates (4.71 and 4.75) were treated with the previously established

basic conditions of K2CO3/MeOH as well LDA/THF (see Scheme 4.37).

Scheme 4.37 – Reactivity of Differently Protected Alcohol Substrates

Despite the smaller protecting group, neither of these substrates afforded the

desired ring closure/aldol product. Rather, in all cases, the starting material was

isolated from the reaction mixture.

Also synthesized was the diketone 4.81 which lacked the required alcohol

functionality for further elaboration to maoecrystal V (see Scheme 4.38). This

was envisioned as a “smaller” substituent (in comparison to -OTBS, -OMOM, -

129

OBn). The diketone 4.81 was synthesized from previously prepared Weinreb

amide 4.78. Addition of methylmagnesium chloride followed by Grubbs

metathesis afforded -unsaturated ketone 4.80. An intramolecular Michael

addition gave the desired diketone 4.81.

N

O

OO O

OMe

MeMgClTHF

0 C rt

89%

O

OO O

O

cat Grubbs2nd Gen.

O

OO O

O

K2CO3MeOH

O

OO O

O

57%

52%

4.78 4.79

4.80 4.81

Scheme 4.38 – Synthesis of Simple Diketone Substrate

Reacting the diketone under LDA or LHMDS conditions proved unsuccessful in

effecting ring closure (see Scheme 4.39).

Scheme 4.39 – Results of Ring Closure Investigations of Ketone 4.81

130

Prolonged heating under K2CO3/MeOH also proved unsuccessful (see Scheme

4.39). Failed cyclization via the aldol reaction was hypothesized to be a steric

issue (substituent size next to the C-8) and/or the reactivity issue of the carbonyl

at C-8. Varying the substituent size did not affect the desired ring closure.

4.6 Obtaining the bicyclo[2.2.2]octane intermediate

The route to ketone 4.81 could be modified to synthesize aldehyde 4.83 (see

Scheme 4.40). This was envisioned as the “smallest” carbonyl group possible (in

comparison to -OTBS, -OMOM, -OBn, -Me). Additionally, carbonyl (C-8) of the

aldehyde is more reactive than the previously investigated ketones.

Scheme 4.40 – Results of Ring Closure Investigations of Aldehyde 4.83

131

Aldehyde 4.83 successfully underwent the intramolecular Michael reaction to

give aldehyde 4.84. In the same reaction mixture, the double ring closure

product 4.85 was also isolated (see Scheme 4.40). Aldehyde 4.84 did produce

the bicyclo[2.2.2]octane product 4.85 (see Table 4.2)

Table 4.2 – Investigations of Substrates for the Aldol Ring Closure Reaction

Entry R Group Result

1 Decomposition

2

No Reaction

3

Aldol Product

4

No Reaction

5

No Reaction

6

No Reaction

7 H

O

Aldol Product

132

The ketoester did not give the aldol ring closure as it resulted in substrate

decomposition. The majority of ketone substituents were unreactive (see entries

2-6 in Table 4.2). The aldehyde substituent was the only successful substrate in

the aldol ring closure reaction. These results led to modification of the synthesic

route, to use aldol product 4.83 for further elaboration toward maoecrystal V.

133

CHAPTER 5 – A MODIFIED STRATEGY

5.1 A modified strategy toward maoecrystal V

Based on the results of the previous studies, the strategy was modified to use

aldehyde 5.2 to form the bicyclo[2.2.2]octane ring system (see Scheme 5.1).

O

OO O

O

O

OH

OO

O

O

Me

OO

O

O

O

OO

O

O

O

crossmetathesis

MichaelReaction

O

OO

H H

Nu

OH

OO

O

CO2R

OHAldol 8 8

5.1 5.2

5.3 5.4

5.5 5.6

Scheme 5.1 – Modified Strategy to Bicyclo[2.2.2]octane Substrate – the New

Strategy / Key Transformation

The aldehyde reacts in an intramolecular Michael reaction to give enolate 5.3.

Tautomerization to enolate 5.4 and subsequent aldol reaction provides the

desired bicyclo[2.2.2]octane product.

134

Thus, alkene 5.1 was reacted with crotonaldehyde to give aldehyde 5.2 and

subsequent aldol reaction under basic conditions provided the

bicyclo[2.2.2]octane product 5.4. The modified Michael-aldol reaction was

somewhat successful, although it did result in a mixture of single and double

cyclization products (see Scheme 5.2).

K2CO3MeOH

5.427%

O

OO O

O

OO O

H

O

5.1 5.2

OH

cat Grubbs2nd Gen.

65%

O

OO O

H

O

5.3

8

8

O

OH

OO

O

17%

Scheme 5.2 – Results of Ring Closure Investigations of Aldehyde 5.2

With aldehyde 5.1 chosen as the substrate in the modified strategy to obtain a

bicyclo[2.2.2]octane intermediate, the synthetic plan now needed to include a

nucleophilic addition to the ketone on C-8 (see Scheme 5.3).

135

OR

OO

O

OH

CNO

OR

OO

O

H+

OR

HO

HO

HO

OH

CN

OR

HO

HO

HO

OH

CO2H

OR

OHHO

HOO

O

CN8

8

OH

OO

R3Si

Me

Me

Li

Maoecrystal V

[O]

O

O

O O

O

O

O O

HO

OO

OR

O

OOO

OR

OR

O

OO

OR

OH

MO

R3Si

OR

5.7 5.8 5.9 5.10

5.11 5.12 5.13

5.14

5.15 5.16 5.17

Scheme 5.3 – The Modified Synthetic Plan

Cyanide addition to the ketone would provide nitrile 5.8. Simultaneous hydrolysis

of the orthoester group as well as the nitrile would give tetraol intermediate 5.10.

In situ ring closure would provide lactone intermediate 5.11. Oxidation of diol

5.11 would give dialdehyde 5.12. An intramolecular ring closure would give

furanoid intermediate 5.13. Reaction of aldehyde 5.13 with organolithium

nucleophile 5.14 would give alkene 5.15. An intramolecular reaction between the

alkene and an in situ-formed oxocarbenium ion intermediate on the furanoid ring,

followed by oxidation would result in the formation of the required cyclohexene

136

ring. Deprotection, oxidation, and methylation would result in a total synthesis of

maoecrystal V (5.17).

To use aldehyde 5.2 as the substrate for the modified synthetic plan, optimization

of the aldol ring closure reaction was required. An aldol reaction using aldehyde

5.18 was the method that provided a useful entry into the bicyclo[2.2.2]octane

ring system (see Scheme 5.4).

Scheme 5.4 – The Model System for the Aldol Ring Closure Reaction

This type of simplified ring closure had been studied in the synthesis of various

other natural products (see Scheme 5.5).81,82 In 1963, Ireland et al. studied this

type of intramolecular aldol reaction in synthetic studies toward the alkaloid

atisine.81 This is an important intramolecular process. It is useful for the

construction of bridged steroid derivatives since it leads to a bicyclo[2.2.2]octane

system. In 1966, Ireland et al. employed this type of intramolecular aldol in the

synthesis of kaurene.83

137

An important consideration in this type of ring closure is diastereoselectivity. In

the simplified case of compound 5.20, ring closure gives an epimeric mixture of

6-endo- and 6-exo-hydroxybicyclo[2.2.2]octan-2-ones which are in equilibrium

through the parent ketoaldehyde (Scheme 5.2).82

Scheme 5.5 – Formation of 6-endo and 6-exo-hydroxybicyclo[2.2.2]octan-2-one82

It has been shown that in this system, the endo product is the thermodynamic

and kinetic product. The endo epimer has 0.6 kcal/mol less strain energy than

the exo epimer.82,84,85

These results were encouraging for this synthesis in that there would potentially

be the necessary diastereoselectivity in the ring closure reaction. In particular,

the hydroxyl group on C-15 is potentially useful as a handle to control the

diastereoselective addition to the ketone on C-8 as well as the addition to the

proposed oxocarbenium intermediate 5.13 (see Scheme 5.6).

138

Scheme 5.6 – Substituent on C-15 – a Useful Handle

5.1.1 Modifications of the Original Synthetic Route

Initially, synthesis of enal 5.2 required a lengthy nine steps from penterythritol

(see Scheme 5.7). The synthesis of aldehyde 5.2 from pentaerythritol is

discussed in chapter four.

Scheme 5.7 – The Original Route to Aldehyde 5.2

However, a shorter sequence of steps is now employed for the large scale

synthesis of -unsaturated aldehyde 5.2, required for the tandem Michael-

aldol. Since the early stages of the synthetic work toward maoecrystal V, an

139

ongoing investigation into a shorter route to functionalize nitrile 5.25 (see

Scheme 5.8) had been continually on going.

Scheme 5.8 – Previous Functionalization Obstacle

Indeed, the lengthy route was primarily due to the inability to add nucleophiles

directly to nitrile 5.25. The original route required a lengthy procedure to

functionalize the nitrile to the diene 5.26. As previously discussed, the evidence

pointed toward the acidity of the neopentyl proton as being problematic. In

looking for a solution, organocerium reagents were considered.86 Imamoto et al.

has shown organocerium reagents to be less basic than Grignards and

organolithium reagents.87 Additionally, they react cleanly and are reliable

nucleophiles.88

Attempts to functionalize nitrile 5.25 were investigated using the organocerium

reagent. The nitrile could quickly be functionalized to the desired ketone 5.1 with

the use of a methylcerium reagent (see Scheme 5.9).

140

O

OO

CN

O

OO

O

I

n-BuLi, -78 °Cthen MeMgCl

CeCl3, THF0 °C

75%from the nitrile

AcOH, H2OTHF, rt

O

OO

CN

O

OO

NH

5.28 5.25

5.28 5.1

Scheme 5.9 – Shortened Synthetic Sequence using a Methylcerium Reagent

Therefore, starting from nitrile 5.28, addition of n-BuLi followed by addition of the

homoallyl iodide gave the alkylated nitrile 5.25 (the dialkylated species previously

discussed could be avoided with careful addition of less than one equivalent of n-

BuLi). In situ addition of the organocerium reagent (made from

methylmagnesium chloride) resulted in methyl addition to nitrile 5.25. Workup of

this reaction with non-acidic conditions to avoid hydrolysis of the orthoester

resulted in the isolation of imine 5.28, which could be hydrolyzed to the desired

ketone 5.1 using acetic acid. Thus, the methylcerium reagent allowed for direct

alkylation of the nitrile and this route avoids the lengthy hydrolysis sequence that

had been used previously.

141

The organocerium route was employed in making cyclohexenone 5.31 which was

used in investigating the previously proposed key transformation (see Scheme

5.10).

Scheme 5.10 – Synthesis of Cyclohexene 5.31 from Methyl Ketone 5.1

Application of the new strategy outlined in Scheme 5.4 required -unsaturated

aldehyde 5.2 as it was the substrate necessary for the modified tandem Michael-

aldol reaction. Using the organocerium reagent, synthesis of the -unsaturated

aldehyde 5.2 was a short six step sequence from commercially available

pentaerythritol 5.24 (see Scheme 5.11).

142

O

OO

O

O

OO

CNHO OH

OHHO

1. p-TsOH, MeC(OEt)3neat, 130 °C

2. MsCl, Et3NCH2Cl2, 0 °C

3. NaCN, DMSO95 °C, 12 h

1. i) n-BuLi, -78 °Cthen

I

Grubbs (II) catCH2Cl2, rt

75%

80%

71%

ii) MeMgClCeCl3, THF

0 °C2. AcOH, H2O

THF, rt

O

O

OO

O

O

5.24 5.28

5.1 5.2

Scheme 5.11 – Current Approach to the Bicyclo[2.2.2]octane Intermediate

From pentaerythritol 5.24, the steps of orthoester formation with

triethylorthoacetate, formation of the methanesulfonate and reaction with sodium

cyanide gives nitrile 5.28 with 71% yield over three steps. Then the modified

step of alkylating with homoallyl iodide and in situ addition of the methylcerium

reagent gave the imine product which can be hydrolyzed to ketone 5.1 in 75%

yield over two steps. Finally, olefin metathesis with crotonaldehyde gives the

-unsaturated aldehyde 5.2 in 80% yield. The synthesis to this new key

intermediate, aldehyde 5.2, is shortened from what would originally have been

nine steps to six high yielding steps, each of which can be carried out on

multigram scale.

143

5.1.2 Modified Intramolecular Tandem Michael Aldol Reaction – the New

Key Transformation

Aldehyde 5.2 was synthesized to be used as the substrate in testing our modified

strategy, which was a tandem intramolecular Michael-aldol reaction. The

conditions that were previously successful in the aldol reaction (K2CO3/MeOH)

were found to promote the desired ring closure to some extent (see Scheme

5.12).

O

OO O

O

HO

OO O

H

O

K2CO3MeOH

O

OH

OO

O

K2CO3MeOH

O

OH

OO

O

5.3 5.45.2

5.4

5 : 817% : 27%

O

OO O

H

O O

OH

OO

O5.3 5.4

5 : 8

Scheme 5.12 – Exploring the Modified Tandem Michael-Aldol Reaction

For an unoptimized reaction, the results were promising. Two products were

isolated in a ratio of 5:8. One product was the result of the first ring closure – the

Michael reaction giving aldehyde 5.3. The major product was the desired

144

product whereby the subsequent aldol reaction had occurred to give the

bicyclo[2.2.2]octane intermediate 5.4. Interestingly, the observed ratio of singly

versus doubly cyclized products represents the equilibrium ratio between these

two compounds under the K2CO3/MeOH conditions. If the doubly cyclized

product is isolated by chromatography and resubjected to the same

K2CO3/MeOH conditions, after a several hours, the equilibrium between the two

aforementioned products is reached. The same two products can be isolated in

the same ratio of 5:8.

The product ratio from the K2CO3/MeOH reaction conditions was not satisfactory.

Under the original conditions, 17% of Michael product 5.3 was isolated and only

27% of the desired bicyclo[2.2.2]octane product 5.4 was obtained from the

reaction. Thus, optimization was required.

Under some basic conditions, only product A (5.3), the result of the Michael

cyclization, was isolated. In other conditions, both product A and B (5.3 and 5.4)

were isolated as a mixture, much like the initial K2CO3/MeOH reaction conditions

used. Other reactions conditions gave primarily the desired product B (5.4) but

in low yields. After investigations into varying the base identity, reaction

temperature, and solvent systems, optimal reaction conditions were chosen (see

Table 5.1).

145

Table 5.1 – Investigation of Optimal Conditions for Double Cyclization

Base Conditions Result

1 LDA (0.9 eq) THF, -78 °C to RT A, major decomposed

2 KOtBu 1% THF, RT Mixture A and B and SM

3 KOtBu (0.8 eq) THF, -25 °C B with unknown impurity

4 KOtBu (0.1 eq) THF, -25 °C Product unknown impurity

5 K2CO3 CH2Cl2, RT No reaction

6 K2CO3 MeOH, reflux 2hrs Total decomposition

7 K2CO3 Acetone w/cat MeOH Mixture A and B and SM

8 K2CO3 DMF, RT No reaction

9 K2CO3 MeCN w/cat MeOH No reaction

10 K2CO3 DMF w/cat MeOH B – 52%

11 K2CO3 DMF/MeOH

cat BHT B – 45%

12 K2CO3 DMF w/cat MeOH

(no workup) B – 60%

13 Na2CO3 3:1 Dioxane/H2O B – 45%

14 Na2CO3 3:1 Dioxane/H2O

(no workup) B – 63%

15 DBU MeCN, RT(no workup) B - 12%

16 DBU MeCN (slow addition of SM,

no workup) B - 28%

17 DBU DMF, RT B - 40% (some product lost

in aqueous workup)

18 DBU DMF, 0 °C SM and B

19 DBU MeCN (dilute SM and DBU

soln – slow addition B – 22%

146

Using the 3:1 Dioxane/H2O solvent system as well as Na2CO3 as the base, the

desired bicyclo[2.2.2]octane intermediate can be obtained in 63% yield (see

Scheme 5.13). This reaction behaved well under scale up conditions and can

also be carried out on a multigram scale with slightly lower yields

Scheme 5.13 – Optimized Double Cyclization Conditions

The diastereoselectivity of the aldol cyclization was also of particular interest. As

previously discussed, the desired endo product was expected to be the major

diastereomer.

O

OH

OO

O 5.4

Figure 5.1 – Stereochemical Outcome of the Michael-aldol Reaction Confirmed

by X-ray Crystal Structure

147

The secondary ring closure is diastereoselective. Only one isomer of the

bicyclo[2.2.2]octane product was isolated. The crystal structure of the bicyclic

compound confirms the configuration of the alcohol chiral center (see Figure 5.1).

The exo product was not isolated from the reaction mixture.

The observed diastereoselectivity would play an important part in the further

functionalization toward maoecrystal V. The alcohol group allowed for

diastereoselective control of subsequent reactions in the elaboration of

bicyclo[2.2.2]octane 5.4.

5.2 Further functionalization – addition to the ketone

With the bicyclic framework completed, the next step was to investigate the

nucleophilic addition to ketone 5.7 (see Scheme 5.14). Thus, diastereoselective

addition to ketone 5.7 was crucial to the further functionalization toward

maoecrystal V.

Cyanide addition to ketone 5.7 would be ideal as it would potentially allow for

both the incorporation of one carbon as well as the formation of the lactone ring

upon hydrolysis (see Scheme 5.14).

148

OR

OO

O

OH

CNO

OR

OO

O

H+

OR

HO

HO

HO

OH

CN

OR

HO

HO

HO

OH

CO2H

OR

OHHO

HOO

O

CN

5.7 5.8 5.9

5.10 5.11

Scheme 5.14 – Potential Synthetic Route via Cyanide Addition

Another key aspect of this addition was that it was expected to be

diastereoselective. The alcohol becomes useful to control the formation of

subsequent chiral centers. In the nucleophilic addition to ketone 5.7, it was

expected that addition would favor approach from the bottom face (as drawn),

away from the alcohol group.

5.3 Investigations into an appropriate protecting group

The next step was to protect the alcohol group of ketone 5.4 which would allow

for nucleophilic addition to the ketone. At this stage, it was found that the alcohol

could be easily protected with either the –TES (triethylsilyl) or –Boc (tert-

butyloxycarbonyl) protecting groups (see Scheme 5.15). The alcohol on the

149

intermediate 5.4 was too hindered for (tert-butyldimethyl chloride) TBSCl to be

used.

Scheme 5.15 – Protection of Alcohol 5.4

Different protecting groups were necessary at a later stage, due to the

constraints of later reaction conditions. These will be discussed as they were

encountered. At this point, for the purposes of investigating the appropriate

nucleophile for addition to the ketone, the –TES and –Boc protected substrates

were used.

5.4 Investigations into an appropriate nucleophile

The usual nucleophilic cyanide reagents were investigated. NaCN, KCN,

TMSCN, and Nagata’s reagent (Et2AlCN)89 were tested as potential nucleophilic

reagents but in all cases, only starting material was recovered and cyanide

addition was not effected. Investigations were made into intramolecular trapping

of the cyanohydrin, one reason for the use of the Boc-protecting group (see

150

Scheme 5.16). However, despite testing the Boc-protected substrate against a

battery of hydrocyanation conditions, none yielded the desired transformation.

Scheme 5.16 – Trying to Trap the Cyanohydrin (Boc-Version)

Use of a more reactive trapping group was explored. Thus, the imidazole

carbamate intermediate 5.32 was made (see Scheme 5.17).

Scheme 5.17 – Trying to Trap the Cyanide Addition Product (CDI-Version)

151

Intermediate 5.32 was made with the consideration that the carbonyl group of

this derivative would be a more reactive electrophilic target than that of the Boc-

protecting group (the imidazole being a good leaving group). However, upon

reacting the imidazole intermediate 5.32 with various cyanide addition reagents,

the desired transformation did not occur. In fact, under some reaction conditions

(e.g. as in the KCN, 18-crown-6, ACN reaction), the product that was isolated

was the result of the imidazole carbamate fragment reacting with the cyanide

nucleophile to give the carbonocyanidate product 5.33. Heating this product at

reflux overnight under the same cyanide addition conditions still did not afford the

desired product of the cyanide addition to the ketone.

Unable to add cyanide to the ketone, even using trapping methods, other

nucleophiles were considered (see Scheme 5.18). In broadening the scope of

the search for a useful nucleophile, many “acyl” equivalents were examined. The

organolithium derivative (resulting from reaction of vinyl ethyl ether and t-BuLi) as

well as its organocerium derivative was unreactive toward the ketone group (see

Scheme 5.18). The “smaller” vinylmagnesium bromide and its organocerium

derivative were both examined as well, with no success. Only the TMS-

acetylide, termed a “slender” anion by Trauner,22 resulted in addition to the

ketone. It is hypothesized that the challenge here is a combination of 1) the

crowded environment around the neopentyl ketone as well as 2) an undesired

deprotonation reaction.

152

OPG

OO

O

OH

CNO

OPG

OO

O

CN

R

[M]

M= Mg or Li or CeR = H or OEt

OPG

OO

O

OH

R

OBoc

OO

O

OH

Me3Si [Ce]

-78 C -30 °C

TMS

73%PG = Boc

5.29, PG = TES5.30, PG = Boc

5.34 5.35

5.36

Scheme 5.18 – Investigation of Nucleophilic Addition to Ketone 5.29 and 5.30

As evidence of the undesired deprotonation, even the organomagnesium and

organolithium version of the “slender” TMS-acetylene did not add and only the

corresponding organocerium reagent was successful as a nucleophile. All other

reactions resulted in unreacted starting material.

The TMS-acetylene reaction was highly diastereoselective, the anion adding to

only one face of the ketone. This expected outcome was confirmed by X-ray

diffraction analysis.

153

5.5 Investigation of the oxidative cleavage of the alkynyl substitutent and

subsequent lactone formation

With the addition of the alkynyl nucleophile, further functionalization required

cleavage of the TMS group followed by oxidative cleavage of the terminal alkyne

to give either the carboxylic acid or ester intermediate (see Scheme 5.19).

Scheme 5.19 – Investigations of Alkyne Functionalization

The trimethysilyl (TMS) group can be cleaved using TBAF. However, oxidative

cleavage of the resulting terminal alkyne using RuO4 conditions90-92 gave

unsatisfactory results. Additionally, ozonolysis did not oxidatively cleave the

alkyne. Thus, the usual cleavage conditions of a terminal alkyne proved to be

ineffective, perhaps due to the crowded environment existing around the alkyne.

To further elaborate this intermediate, the alkyne was hydrogentated under

Lindlar conditions to give the alkene in good yield (see Scheme 5.20). The

154

alkene was also subjected to various oxidative cleavage conditions and it was

found that ozonolysis with added NMO·H2O resulted in effecting alkene cleavage,

forming aldehyde 5.41.

OBoc

OO

O

OH

OBoc

OO

O

OH

O

Pd on BaSO4pyr, PhMe

78%

OBoc

OO

O

OHO3, NMO•H2OCH2Cl2, 0 C

67%

OBoc

OO

O

OH

CO2H

[O]

5.37 5.40

5.41 5.38

Scheme 5.20 – Further Functionalization of Alkyne 5.37

However, further oxidation to the carboxylic acid could not be achieved.

Therefore, the aldehyde intermediate 5.41 was subjected to acidic conditions to

affect the hydrolysis of the orthoester (see Scheme 5.21). In situ hemiacetal

formation was expected and the mixture of four possible diastereomers was

further reacted, without purification, under basic conditions to cleave the acetate

group. Potentially, this series of steps would result in triol 5.43 as a mixture of

two diastereomers. However, these steps gave a crude material the identity of

which was inconclusive by 1H NMR. However, it could be determined that the

mixture of products was the result of the migration of the Boc protecting group

155

under the basic conditions due to the close proximity of numerous alcohol groups

on the molecule. Thus, it was concluded that a different protecting group was

needed.

OBoc

OO

O

OH

O

PPTS4:1

THF/H2O

K2CO3MeOH0 C

OBoc

HOAcO

OH

OHO

OBoc

AcOHO

OH

OHO

OBoc

HOHO

OH

OHO

Oxidation

OBoc

HOHO

OH

OO

1H NMR

inconclusive

5.41 5.42a 5.42b

5.43 5.44

Scheme 5.21 – Investigations into Lactone Ring Formation

5.6 Concurrent investigation of the furanoid ring formation and reverse

prenylation reaction

While work was on-going in the direction of the lactone ring formation, concurrent

investigations into the furanoid ring formation were also carried out. Of particular

interest was the methodology to form the congested carbon-carbon bond

between C-4 and C-5 on maoecrystal V (see Figure 5.2).

156

O

OO

O

O

4

5

Figure 5.2 – The Last Congested Carbon-Carbon Bond Formation Needed

Starting with the previously synthesized alcohol 5.4, it was found that addition of

the alkynyl cerium regeant could be effective without protection of the alcohol

functionality. Thus, TMS-acetylene addition was done on alcohol 5.4 to give diol

5.45 (see Scheme 5.22). Cleavage of the TMS group (to give the terminal

alkyne) was done using K2CO3/MeOH rather than TBAF as it gave much better

yields. Previously, with the synthetic route of first installing the Boc-protecting

group, basic TMS cleavage conditions would not have been suitable, especially

with the aforementioned evidence that the proximal hydroxyl group participates in

Boc migration. However, because the organocerium acetylene addition could be

done in the presence of the unprotected alcohol, this afforded us the opportunity

to remove the TMS group with high yields under the K2CO3/MeOH conditions.93

Due to the concurrent nature of the investigation into the lactone ring formation

and the furanoid ring formation, initially, the protecting group that was installed

was the Boc group. However, upon discovering evidence of the unsuitable

nature of the Boc group (in the lactone ring formation sequence), the p-

methoxybenzyl (PMB) protecting group was used instead.

157

OH

OO

O

OH

SiMe3

K2CO3, MeOH

91%

OH

OO

O

OH

1. cat PPTS, THF/H2O2. (MeO)2CMe2, PPTS3. K2CO3, MeOH

Bu2SnOPhMe

then PMBBr

81% (4 steps)

OPMB

OH

OO HO

OPMB

OO

O

OH

DMP, CH2Cl2

98%

OPMB

O

OO

HO

OH

OO

O

O

Li TMS

-78 Cthen CeCl3

76%

5.4 5.45

5.46 5.47

5.48 5.49

Scheme 5.22 – Formation of the Furanoid Ring Containing Intermediate

Therefore, diol 5.46 was mono-protected as a PMB derivative via an in situ tin

acetal formation94,95 (see Scheme 5.22). Hydrolysis of the orthoester,

subsequent protection of the resulting diol with 2,2-dimethoxypropane, and

acetate cleavage afforded diol 5.48 – all high yielding steps. Carefully monitored

Dess-Martin periodinane (DMP)96 oxidation gave lactol 5.49. The structure of the

compound was analyzed by X-ray diffraction and was confirmed to be that shown

(see Figure 5.3).

158

Figure 5.3 – X-ray Crystal Structure of Furanoid Ring Intermediate 5.49

The X-ray crystal structure that was obtained was informative in that it confirmed

the formation of the furanoid ring. Additionally, it also demonstrated the

stereoselective addition of the alkynyl group.

With successful furanoid ring formation, the next step in the synthesis was to

explore the reverse prenylation reaction to form the congested bond between C-4

and C-5 (see Scheme 5.23). The furanoid ring was the result of an

intramolecular ring closure, giving a hemiacetal. The hemiacetal presented an

opportunity to take advantage of oxocarbenium chemistry to form the congested

C-4 to C-5 bond. Trauner et al.22 found that on a related system, the reverse

prenylation to a neopentyl aldehyde was not successful. Because this necessary

carbon-carbon bond is so congested, the advantage of using an oxocarbenium

intermediate as a more reactive electrophile seemed a possible solution. This

next step – a nucleophilic additon of a prenyl fragment to an oxocarbenium ion –

would form the last crowded chiral center at C-5.

159

OPMB

O

OO

OPMB

O

OO

RO

LewisAcid

[M]OPMB

O

OO

OPMB

O

OO

HO

4

5

5

5.49 5.50

5.51

5.52

5.53

Scheme 5.23 – Plan for the Prenyl Fragment Addition

Lactol intermediate 5.49 was functionalized to acetate 5.54, a substrate suitable

for testing the viability of the planned reverse prenylation (see Scheme 5.24).

Scheme 5.24 – Synthesis of Intermediate 5.54

160

BF3·OEt2, TiCl4, MgBr2·OEt2, ZnCl2, and SnCl4 were tested as Lewis acids to

promote oxocarbenium ion formation and tributyl(3-methyl-2-butenyl)tin was

tested as the nucleophile. The reverse prenylation product was not one of the

products isolated in any of these reactions (see Scheme 5.25).

Scheme 5.25 – Exploring the Reverse Prenylation

A less bulky nucleophile, allyl trimethylsilane, was also tested with both BF3·OEt2

and SnCl4 as Lewis acids. No allyl addition was observed. The TMS ether of

isobutyraldehyde was made97 and also tested as a prenyl substitute. No addition

to the lactol was observed. However an interesting aldehyde side product was

isolated. This side product is the result of the silyl enol ether adding to the p-

methoxybenzyl cation (5.59). This provided evidence that the PMB protecting

group was too labile, perhaps due to its close proximity to the formed

oxocarbenium ion (see Scheme 5.25). It was hypothesized that the benzylic

161

oxygen of the –OPMB group could add to the proximal oxocarbenium ion forming

a 5-membered ring intermediate. This would allow for a subsequent

fragmentation of the PMB group (see Scheme 5.26). This p-methoxybenzyl

cation could then react with the silyl enol ether of isobutyraldehyde to give the

isolated side product.

O

O

OO

O

O

O

OO

O

oxocarbenium ion

O

H

OSiMe3

O

O

5.57 5.57

5.57 5.57 5.57

Scheme 5.26 – Suggested Mechanism of Formation of Side Product 5.57

Due to this result, the less labile benzyl (Bn) group was used. Thus the synthesis

from diol 5.46 consisted of six steps to the prenylation substrate 5.59 (see

Scheme 5.27).

162

1. cat. PPTS, THF/H2Othen NaOMe

2. (MeO)2CMe2, PPTS3. DMP, CH2Cl24. Ac2O, DMAP

CH2Cl2

BnBrNaH, THF

82%

64%

OH

OO

O

OH

OBn

OO

O

OH

OBn

O

OO

AcO

OH

OO

O

OH

Pd on BaSO4pyr., MeOH

98%

5.46 5.57

5.58 5.59

Scheme 5.27 – Synthesis of Benzyl Protected Substrate

The diol 5.46 was mono-protected with benzyl bromide. Hydrolysis of the

orthoester was simplified by adding base directly to the reaction mixture after

completion of the ring opening to effect an in situ acetate removal. Protection to

form the acetonide was followed by oxidation to the lactol with DMP. The lactol

alcohol was then functionalized as an acetate group, which was the substrate

necessary to test the reverse prenylation – in this case, with the less labile benzyl

group on the proximal alcohol (see Scheme 5.28).

Acetate 5.59 was then tested in the reverse prenylation conditions using SnCl4 as

the Lewis acid. Both allyltrimethylsilane and tributyl(3-methyl-2-butenyl)tin were

tested as potential nucleophiles (see Scheme 5.28).

163

Scheme 5.28 – Successful Reverse Prenylation

Isolation of the reverse prenylation product using the reaction conditions was

successful in the presence of the less labile benzyl protecting group. One of the

previously tested Lewis acids, SnCl4 served as a useful acid. This advanced

intermediate is of importance as it demonstrates the feasibility of our synthetic

plan to 1) use the orthoester to quickly functionalize both the furanoid ring as well

as 2) the use of reverse prenylation to form the congested C-4 to C-5 bond in

maoecrystal V. Only one diastereomer from this alkylation at C-5 was obtained

but diastereoselectivity of the addition needs to be confirmed.

Although the methodology used to form the furanoid ring and test the reverse

prenylation is highly informative, this advanced intermediate did not become

useful on the route to maoecrystal V. Investigations into further elaboration of

this furanoid intermediate were not successful (see Scheme 5.29).

164

OBn

O

OO

p-TsOHor

PPTS

OBn

O

HOHO

OBn

O

OO

O

O

Ozonolysis

5.62 5.61 5.63

Scheme 5.29 – Attempts to Elaborate the Furanoid Intermediate

Initially, attempts were made to cleave the acetonide but the usual mild acid

conditions only resulted in decomposition of the substrate. Additionally, attempts

to cleave either alkene (or both) were not successful. Reaction of meta-

chloroperoxybenzoic acid (m-CPBA) did not result in obtaining epoxide

formation. Rather, the starting material was obtained. Ozonolysis conditions

resulted in decomposition.

While work on the formation of the furanoid ring was being completed (to obtain

intermediate 5.61), simultaneously, the previously discussed diol alkyne

intermediate 5.45 was also being used to further explore lactone ring formation

(see Scheme 5.30). In particular, the use of the less labile benzyl protecting

group was also expected to address the previously encountered problem of

undesired Boc migration.

165

Scheme 5.30 – The Diol Substrate was Used in Studies for Both the Furanoid

and Lactone Ring Formation

Diol 5.45 was converted to the acetonide intermediate 5.65 in 5 steps as

described for the furanoid studies sequence. Ozonolysis of the alkene to the

aldehyde results in an in situ ring closure, forming a lactol. The lactol was

oxidized to the desired lactone under Swern conditions35 (see Scheme 5.31).

Scheme 5.31 – Successful Lactone Ring Formation

166

Synthesis of this advanced intermediate proves that the formation of the lactone

ring is possible. Additionally, the alkyne nucleophile is useful for installing a one

carbon unit necessary for formation of the lactone ring. The structure of the

lactone ring intermediate was also confirmed by X-ray crystal analysis (see

Figure 5.4).

Figure 5.4 – X-ray Crystal Structure of Lactone Ring Intermediate 5.64

On-going work to shorten the synthesis became useful and the route to the

lactone ring intermediate can be accomplished in three steps from alkene

intermediate 5.58. Hydrolysis of the orthoester group afforded tetraol 5.67.

Tetraol 5.67 was found to be a better substrate for ozonolysis so a shorter route

to lactone intermediate 5.64 was possible (see Scheme 5.32). Additionally, by

employing the mild oxidation conditions of iodine and calcium carbonate,98 the

lactol could be oxidized to the lactone, leaving the primarily alcohols unoxidized.

Thus, use of the acetonide could be avoided. Thus, the shortest route from the

alkene 5.58 to diol 5.64 became a three step procedure of hydrolysis, ozonolysis,

and oxidation (see Scheme 5.32)

167

Scheme 5.32 – Shortening the Route to the Lactone Ring Intermediate

5.7 Further elaboration of the advanced intermediates

With routes that establish the synthetic methodology to make the furanoid ring as

well as the lactone ring, focus turned toward merging the two routes toward the

synthesis of maoecrystal V. This effort began with further elaboration of

advanced lactone intermediate 5.64.

The diol substrate 5.64 was subjected to oxidizing conditions to try to

simultaneously effect formation of both the C-1 aldehyde and lactol ring (see

Scheme 5.33).

Scheme 5.33 – Oxidation of Diol 5.64

168

With the formation of the furanoid and lactone ring complete, attention turned

toward setting up to complete the cyclohexenone ring. Two potential routes to

effect the formation of the cyclohexenone ring were envisioned (see Scheme

5.34). From hemiacetal intermediate 5.68, the alcohol could potentially be

functionalized to the isobutyraldehyde fragment. Additonally, the aldehyde in

intermediate 5.68 could be functionalized to a methyl ketone. This would set up

for an intramolecular aldol reaction to give the cyclohexenone.

Scheme 5.34 – Potential Routes for Cyclohexenone Formation

The other route, also from intermediate 5.68, would form the cyclohexenone ring

via an olefin metathesis reaction (see Scheme 5.34). The alcohol in intermediate

5.68 could potentially be functionalized adding the prenyl fragment. Additonally,

169

the aldehyde in intermediate 5.68 could be functionalized to the -unsaturated

ketone. This would set up for the metathesis reaction to give the cyclohexenone.

With the purpose of forming the -unsaturated ketone (for the metathesis

route), vinylmagnesium bromide was reacted with intermediate 5.68 (see

Scheme 5.35). However, none of the alkene product was isolated from this

reaction. Other organometallic reagents such as methylmagnesium chloride

were also unsuccessful as nucleophiles to the aldehyde. Decomposition of the

substrate was often the result when trying to add to the aldehyde via an

organometaliic substrate.

Scheme 5.35 – Attempts to Functionalize Intermediate 5.68

170

Thus attempts were made to functionalize the lactol alcohol first. To prepare the

substrate for either a reverse prenylation or addition of the isobutyraldehyde

fragment via the silyl enol ether, acetate formation was attempted. Using the

previously established conditions of DMAP and acetic anhydride, surprisingly the

acetate was not formed. Rather, even under such mild conditions, it was

determined that substantial decomposition was occurring.

Because direct methods to functionalize the lactol aldehyde intermediate were

not successful, it was deemed that for further elaboration, triol 5.64 requires

mono-protection. This would allow for functionalization of the lactol alcohol on C-

5 and the alcohol on C-1 separately (see Scheme 5.36).

Scheme 5.36 – Selective TBS-protection of the Diol is Problematic

Mono-protection of diol 5.64 was challenging. Experimental results gave

evidence that selectivity between the two alcohols was not high. Use of the TBS

protecting group gave a mixture of three products – the two mono-protected

diastereomers as well as the doubly protected TBS product (see Scheme 5.36).

171

The TES protecting group fared better and some selectivity was observed at low

temperatures (see Scheme 5.37).

Scheme 5.37 – TES-protection of the Diol 5.64

However, migration of the silyl protecting groups was noticeable (see Scheme

5.38).

Scheme 5.38 – Silyl Migration Observed

Each of the mono-protected TES compounds could be isolated with good purity

by chromatography. If left overnight, silyl migration was evident. Thus

immediate oxidation of both products was necessary to maintain product purity.

172

The other synthetic option was to oxidize the mixture of TES-protected

diastereomers as separation of the two products could be affected to give both

aldehyde 5.79 and lactol 5.80 (see Scheme 5.39).

Scheme 5.39 – Oxidation of TES-protected Substrates

The synthesis of maoecrystal V is currently at this point. With the two TES-

protected substrates, it is now possible to explore the formation of the last ring,

the cyclohexenone ring.

173

CHAPTER 6 – FUTURE WORK

6.1 Outline of route for completion of maoecrystal V

The synthesis of the TES-protected compounds will allow for further elaboration

to maoecrystal V. With the two oxidation products that are TES-protected, both

have potential to be utilized toward the total synthesis.

OBn

OHO

OTESO

O

OBn

OHO

OTESO

O

OBn

OO

OO

OBn

OHO

OTESO

O

OBn

OO

OO

O

O

OO

O

O

Aldol

Metathesis

6.1 6.2 6.3

6.4 6.5 6.6maoecrystal V

Scheme 6.1 – Potential Route for Elaboration of Aldehyde 6.1

The planned routes from the protected intermediates are similar to the route

described in the previous chapter. Having one of the two alcohols protected

174

allows for independent elaboration. Both the planned aldol route, as well as the

metathesis route, is still viable. From the aldehyde, addition of the vinyl fragment

and eventual reverse prenylation prepares for the metathesis route to form the

cyclohexenone ring (see Scheme 6.1). On the other hand, elaboration of the

aldehyde to the methyl ketone and eventual addition of isobutyraldehyde sets up

for the aldol reaction to form the cyclohexenone.

From the hemiacetal intermediate 6.7, formation of the cyclohexenone ring would

require a reverse prenylation (see Scheme 6.2).

Scheme 6.2 – Potential Route for Elaboration of Lactol 6.7

175

The TES-protected alcohol would then be functionalized to the -unsaturated

ketone. Subsequent metathesis would give the cyclohexenone. On the other

hand, addition of the isobutyraldehyde fragment followed by functionalization of

the TES-protected alcohol to the methyl ketone would set up for an aldol reaction

to give the cyclohexenone ring.

6.2 An Enantioselective synthesis

6.2.1 Trials with an enantioselective Michael-aldol reaction

The key transformation, the intramolecular Michael-aldol reaction is a potential

entry point into an enantioselective synthesis of maoecrystal V. Jørgensen et al.

reported a strategy for enantioselective and diastereoselective Michael-aldol

reactions (see Scheme 6.3)99. Reactions of -ketoesters with -unsaturated

ketones were catalyzed with Jørgensen’s imiazolininone catalyst 6.12.

.

Ar1

O

R1

Ar2

O

CO2R

NH

N

CO2H

Ph(10 mol%)EtOH, rt

Ar2R1

O OAr1

CO2R

O

Ar1Ar2 CO2R

R1

HO

6.14

6.10

6.11

6.12

6.13

20-85% yielddr>97 : 3

ee 83-99%

Scheme 6.3 – Jørgensen’s Diastereoselective Michael-aldol Reaction99

176

In comparison, the key transformation in this synthesis is also a Michael-aldol

reaction. Reaction of a racemic mixture of -unsaturated aldehyde 6.10 and

use of a chiral catalyst (such as proline), the intramolecular Michael reaction

could potentially provide cyclohexanone intermediate 6.11 as a mixture of two

diastereomers. Upon, equilibration of the enolate to intermediate 6.12 and

subsequent aldol ring closure, this reaction could afford the ketone alcohol as

one enantiomer (see Scheme 6.4)

O

OO O

O

O

OH

OO

O

OO

O

O

O

OO

O

O

O

MichaelReaction

H

HAldol 8

6.10racemic 6.11

6.12 6.14aone enantiomer

H

H

H

NH

O

OHH

Scheme 6.4 – Potential Pathway to an Enantioselective Michael-aldol Reaction

6.2.2 Desymmetrization

Additionally, the racemic product of the tandem Michael-aldol reaction itself could

potentially be an entry point for an enantioselective synthesis. Asymmetric

acylation of meso-diol has been extensively studied by Wirz et al. involving

177

commercially available enzymes.100 An example of this is the use of Lipase QL

to furnish alcohol intermediate 6.16 as one enantiomer (see Scheme 6.5).

Scheme 6.5 – An Example of Asymmetric Acylation, Wirz et al.100

Oxidation to the diketone is another potential strategy to the enantioselective

total synthesis. Cyclohexane-1,3-diones can be asymmetrically reduced to

obtain one enantiomer. A common procedure is to use Baker’s yeast to reduce

cyclohexanone-1,3-diones.101 An example is bicylco[2.2.2]octane 6.17 (similar to

the product of the intramolecular Michael-aldol reaction), which is reduced to

ketone alcohol 6.18 (see Scheme 6.6).101-103

Scheme 6.6 – An Example of Asymmetric Yeast Reduction101-103

178

The racemic product of the ketone alcohol intermediate 6.14a and 6.14b could

potentially either be reduced to the meso diol product or oxidized to the achiral

compound (see Scheme 6.7). With either the meso-diol product 6.19 or the

achiral diketone product 6.20, desymmetrization of the substrates would result in

obtaining one enantiomer of the ketone alcohol. This one enantiomer would be

the entry point to the remainder of the synthesis and would therefore give

maoecrystal V as one enantiomer at the end of the synthesis.

Scheme 6.7 – Potential Entry Point into an Enantioselective Synthesis

Initial work has been done to both reduce and oxidize the racemic ketone

alcohol. Various conditions were not effective in obtaining the diketone

179

compound. However, in exploring the reduction of the ketone alcohol, sodium

borohydride (NaBH4) has been found to give the meso product 6.15 in good

yields. Thus, the product of the tandem Michael-aldol could potentially be an

entry point for an enantioselective synthesis.

180

APPENDIX A

General Procedures. All reactions were carried out under an argon atmosphere

with dry solvents using anhydrous conditions unless otherwise noted. RBF refers

to a round-bottom flask. Dry tetrahydrofuran (THF), diethyl ether (Et2O),

dichloromethane (CH2Cl2), and toluene were obtained by passing these solvents

through activated alumina columns. Dry triethylamine (Et3N), diisopropylamine,

pyridine, dimethyl sulfoxide (DMSO) and acetonitrile (MeCN) were obtained by

distilling over CaH2. Evaporation refers to removing solvents under reduced

pressure using a rotary evaporator. Reactions were monitored by thin layer

chromatography (TLC) carried out on silica gel plates and visualized using UV

light or stained with anisaldehyde, ceric ammonium molybdate (CAN), or basic

aqueous potassium permanganate (KMnO4).

1H NMR and 13C NMR spectra were recorded on Bruker DRX-600, Bruker DRX-

500, Bruker DRX-400, or Bruker DRX-250 and calibrated using residual

undeuterated solvent as an internal reference (CHCl3 @ 7.26 ppm 1H NMR, C6H6

@ 7.15 ppm 1H NMR, H2O @ 4.79 ppm 1H NMR, CHCl3 @ 77.0 ppm 13C NMR).

The following abbreviations (or combinations thereof) were used to explain the

multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, os =

overlapping signals, b = broad singlet. Intermediates that have not been

assigned numbers in the text are numbered sequentially in the experimental

section by chapter beginning with A1.

181

A.1 Experimental – Reactions in Chapter 3

Synthesis of Compound 3.3

Diisopropylamine (7.0 mL, 53 mmol) and THF (20 mL) were added to a RBF and

the mixture cooled with an ice-water bath followed by dropwise addition of n-BuLi

(2.30 M in hexanes, 17 mL, 59 mmol) using a syringe pump. The reaction

mixture was stirred at 0 °C for 10 min and then cooled with a dry ice/acetone

bath. 2-Methylcyclohex-2-enone (5.0 g, 53 mmol) as a THF solution (10 mL) was

added dropwise to the freshly prepared LDA solution at -78 °C and the resulting

mixture was allowed to stir for 30 min. Allyl bromide (19 mL, 0.26 mol) was

added dropwise and then the reaction mixture was warmed to rt. Reaction

progress was monitored by TLC. The reaction mixture was quenched by a

saturated NH4Cl solution. The mixture was extracted with EtOAc (3 x 50 mL) and

the combined extract washed with brine (50 mL) and dried with MgSO4 and

evaporated. The crude material was purified using flash chromatography

(hexanes/EtOAc = 95/5) to obtain alkene 3.3, 2.76 g (35%).

1H NMR (600 MHz, CDCl3) δ 6.68 (bs, 1H), 5.83 – 5.72 (m, 1H), 5.09 – 4.97

(os, 2H), 2.66 – 2.56 (m, 1H), 2.41 – 2.27 (os, 3H), 2.15 – 2.09 (m,

1H), 2.06 (dq, J = 13.4, 4.5 Hz, 1H), 1.76 (s, 3H), 1.74 – 1.67 (m,

1H).

182

TLC Rf = 0.25 (hexanes/EtOAc = 95/5) [Anisaldehyde]


Diisopropylamine (1.4 mL, 10 mmol) and THF (4.0 mL) were added to a RBF and


(2.30 M in hexanes, 3.5 mL, 9.1 mmol). The reaction mixture was stirred at 0 °C

for 10 min and then cooled with a dry ice/acetone bath. 2-methylcyclohex-2-

enone (1.0 g, 9.1 mmol) as a THF solution (1.0 mL) was added dropwise to the

freshly prepared LDA solution at -78 °C and the resulting mixture was allowed to

stir for 30 min. Methyl 2-bromoacetate (6.9 mL, 46 mmol) was added dropwise

and then the reaction was warmed to rt. Reaction progress was monitored by

TLC. The reaction was quenched by a saturated NH4Cl solution. The mixture

was extracted with CH2Cl2 (3 x 20 mL) and the combined extract washed with

brine (20 mL) and dried with Na2SO4 and evaporated. The crude material was

purified using flash chromatography (hexanes/EtOAc = 4/1) to obtain ester 3.5,

0.586 g (36%).

1H NMR (600 MHz, CDCl3) δ 6.69 (s, 1H), 3.68 (s, 3H), 2.89 – 2.79 (os, 2H),

2.48 – 2.38 (m, 1H), 2.33 (d, J = 18.8 Hz, 1H), 2.25 (dd, J = 8.5, 2.4

Hz, 1H), 2.10 – 2.02 (m, 1H), 1.83 – 1.76 (m, 1H), 1.75 (s, 3H).


183


O

90%

LiAlH4THF/

dioxaneMeO2C

OH

OH

3.5 3.6

LiAlH4 (63 mg, 1.7 mmol) was weighed into a RBF and Et2O (1.5 mL) was added.

The reaction flask was cooled with a dry ice/acetone bath followed by dropwise

addition ester 3.5 (0.10 g, 0.55 mmol) as a THF solution (1.5 mL). The reaction

mixture was stirred at -78 °C for 1 h and then warmed to rt. Reaction progress

was monitored by TLC. After 2 h, the reaction was complete and quenched by

sequential addition of water (0.15 mL), 15% NaOH (0.15 mL), and water (0.45

mL). The reaction mixture was filtered through Celite®. The Celite® pad was

washed with Et2O (6 x 3.0 mL). The crude material was purified using flash

chromatography (hexanes/EtOAc = 5/95) to obtain diol 3.6 as a mixture of

diastereomers, 0.078 g (90%).

1H NMR (600 MHz, CDCl3) δ 5.51 (s, 1H), 3.83 – 3.77 (os, 2H), 3.72 – 3.66

(m, 1H), 3.03 (bs, 2H), 2.05 – 2.00 (m, 1H), 1.98 – 1.93 (m, 1H),

1.75 (s, 3H), 1.70 – 1.58 (os, 4H), 1.45 – 1.35 (m, 1H).


184


OH

OH

DMSO, (COCl)2CH2Cl2, Et3N-78 0 ºC

O

O74%

3.6 3.4

CH2Cl2 (2.0 mL) was added to a RBF followed by DMSO (49 µL, 0.69 mmol).


addition of oxalyl chloride (51 µL, 0.59 mmol). The reaction mixture was stirred

at -78 °C for 30 min. A solution of diol 3.6 (35 mg, 0.22 mmol) in CH2Cl2 (2.0 mL)

was added dropwise and the reaction mixture was stirred for 1 h at -78 °C. NEt3

was added and the reaction mixture was stirred for an additional 5 min and then

gradually warmed to rt. Reaction progress was monitored by TLC. After 15 min

at rt, the reaction was complete. The reaction was quenched by water (5.0 mL).

The mixture was extracted with CH2Cl2 (3 x 5.0 mL) and the combined extract

washed with brine (10 mL) and dried with Na2SO4 and evaporated. The crude

material was purified using flash chromatography (hexanes/EtOAc = 70/30) to

obtain aldehyde 3.4, 0.021 g (74%).

1H NMR (250 MHz, CDCl3) δ 9.85 (s, 1H), 6.75 (m, 1H), 2.9 – 3.1 (os, 2H),

2.3 – 2.6 (os, 3H), 2.07 (m, 1H), 1.7 – 1.9 (m, 1H), 1.8 (s, 3H)


185


Pentaerthritol (40 g, 0.29 mol) and triethylorthoacetate (54 mL, 0.29 mol) and p-

TsOH (0.15 g, 7.9 mmol) was placed in a RBF set up with a distillation apparatus

and heated to 140 °C gradually in 20 degree increments. Ethanol was collected

(54 mL) until no more distilled off. The reaction flask was cooled to rt and

transferred to a Kugelrohr apparatus. The orthoester alcohol 3.15 was sublimed

and deposited into an ice-cooled collecting flask as a white solid (47 g, 86%). No

purification was necessary and the compound was carried onto the mesylated

alcohol directly. An analytical sample was prepared by recrystallizing from

toluene. All data matched previously published literature data.

MP 118-120 °C

IR (Polyethylene Card) 3448, 1401, 1367, 1294, 1132, 1044 cm-1

1H NMR (600 MHz, CDCl3) δ 4.02 (s, 6H), 3.46 (d, J = 4.6 Hz, 2H), 1.50 (t, J

= 4.7 Hz, 1H), 1.46 (s, 3H)

13C NMR (125 MHz, CDCl3) δ 108.5, 69.3, 61.4, 35.6, 23.4


186

Alcohol 3.15 (41 g, 0.25 mol) and CH2Cl2 (830 mL) were added to a RBF and the

flask cooled with an ice-water bath followed by addition of NEt3 (39 mL, 0.28

mol), added in one portion to the reaction flask. MsCl (30 mL, 0.38 mol) was

added dropwise using a syringe pump. Upon completion of addition of MsCl, the

reaction mixture was gradually warmed to rt and allowed to stir for 1 h at rt.

Reaction progress was monitored by TLC. The reaction was quenched with a

0.1 M solution of K2CO3 (1.0 L). The mixture was extracted with CH2Cl2 (3 x 200

mL) and the extract washed with brine (100 mL) and dried with Na2SO4 and

evaporated. Methanesulfonate 3.16 was isolated as a yellow solid (60 g,

quantitative yield) and was again carried forward with no further purification.

TLC Rf = 0.15 (hexanes/EtOAc = 7/3) [KMnO4]

IR (Polyethylene Card) 3105, 2933, 2894, 1737, 1472, 1403, 1351,

1297, 1173, 1132, 1039 cm-1

1H NMR (500 MHz, CDCl3) δ 4.03 (s, 6H), 3.99 (s, 2H), 3.03 (s, 3H), 1.46 (s,

3H)

13C NMR (125 MHz, CDCl3) δ 108.9, 68.3, 66.1, 37.5, 34.3, 23.2


Methanesulfonate 3.16 (60 g, 0.25 mol) was dissolved in DMSO (500 mL) and

NaCN (25 g, 0.50 mol) was added in one portion. The reaction flask was fitted

with an air condenser and heated with an oil bath (at 110 °C) for ~4 h. The

187

reaction progress was monitored TLC. The reaction mixture was poured into a

5% Na2CO3 solution and extracted with CH2Cl2 (3 x 250 mL). The combined

extract was washed successively with 5% Na2CO3 (1 x 100 mL) and brine (1 x

100 mL) and dried with Na2SO4 and evaporated. The brown solid was purified by

recyrstallization from EtOH (9 mL/g) to obtain nitrile 3.16 as light brown crystals

(30 g, 72% after two crops).

MP 174-178 °C



1125, 1054, 1024 cm-1

1H NMR (500 MHz, CDCl3) δ 4.05 (s, 6H), 2.27 (s, 2H), 1.47 (s, 3H)

13C NMR (125 MHz, CDCl3) δ 114.3, 108.7, 70.0, 31.6, 23.1, 18.7


Into a RBF, commercially available 3-Buten-1-ol A1 (45 g, 0.52 mol) was

dissolved in CH2Cl2 (1.3 L) and cooled with an ice-water bath and NEt3 (146 mL,

0.42 mol) was added in one portion to the reaction flask. MsCl (45 mL, 0.21 mol)

was added dropwise with a syringe pump. Upon completion of the addition, the

reaction mixture was gradually warmed to rt and allowed to stir for 30 min at rt.

The reaction mixture was poured into water (1.0 L) and extracted with CH2Cl2 (3

x 500 mL). The combined extract were washed successively with 1 N HCl (500

188

mL) and brine (1 x 500 mL) and dried with Na2SO4 and evaporated. Crude

methanesulfonate A2 (78 g, quantitative yield) was carried forward with no

further purification.

1H NMR (600 MHz, CDCl3) δ 5.71 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.12 –

5.03 (m, 2H), 4.16 (t, J = 6.7 Hz, 2H), 2.91 (s, 3H), 2.41 (q, J = 6.6

Hz, 2H)

Into a RBF was added NaHCO3 (33 g, 0.39 mol) followed by sequential addition

of HPLC-grade acetone (1.3 L), methanesulfonate A2 (78 g, .52 mol), and NaI

(118 g, 0.78 mol). The reaction flask was fitted with a condenser, stirred

vigorously with a mechanical stirrer, and allowed to reflux overnight (the reaction

mixture turning from bright yellow to white). The reaction was cooled to rt and

quenched by water (1.5 L) and extracted with Et2O (3 x 500 mL). The combined

extract was washed with brine (500 mL), dried with MgSO4, and evaporated

using a 120 Torr pump (as the product is volatile) and to obtain crude homoallyl

iodide 3.18. Distillation of the crude product (85 °C, 120 Torr) gave homoallyl

iodide 3.18 (62 g, 66%) as a colorless liquid.

1H NMR (500 MHz, CDCl3) δ 1H NMR (500 MHz, CDCl3) δ 5.76 (ddt, J =

17.3, 10.9, 6.7 Hz, 1H), 5.16 – 5.09 (m, 2H), 3.18 (t, J = 7.2 Hz,

2H), 2.62 (q, J = 7.1 Hz, 2H)

13C NMR (125 MHz, CDCl3) δ 136.9, 117.0, 37.7, 4.7

189

Synthesis of Compound 3.19 (and side-product 3.20)

Nitrile 3.17 (12 g, 0.07 mol) and THF (200 mL) were added to a RBF and the

mixture cooled with a dry ice/acetone bath followed by dropwise addition of n-

BuLi (1.82 M in hexanes, 41 mL, 0.07 mol). The reaction mixture was stirred at -

78 °C for 30 min. Homoallyl iodide (17 g, 0.090 mol) as a THF solution (30 mL)

was added dropwise using a syringe pump and the resulting mixture was allowed

to stir for an additional 1 h at -78 °C. The reaction mixture was then warmed to

rt. Reaction progress was monitored by TLC. After 1h, the reaction was

quenched by a saturated NaHCO3 solution. The mixture was extracted with

CH2Cl2 (3 x 250 mL) and the combined extractwashed with brine (100 mL) and

dried with Na2SO4 and evaporated. The crude material was purified using flash

chromatography (hexanes/EtOAc = 75/25) to obtain alkene 3.19 as a yellow

liquid, 10.5 g (67%). The dialkylated product 3.20 was collected in earlier

fractions in to give 1.59 g (12 %).

Data corresponding to alkene 3.19



1129, 1057 cm-1

190

1H NMR (600 MHz, CDCl3) δ 5.76 – 5.64 (m, 1H), 5.18 – 5.05 (os, 2H), 4.04

(s, 6H), 2.42 (ddd, J = 12.5, 4.3 Hz, 2H), 2.20 – 2.10 (m, 1H), 1.60

(tdd, J = 12.6, 7.8, 4.8 Hz, 1H), 1.50 (tdd, J = 10.5, 7.3, 3.1 Hz, 1H)

13C NMR (125 MHz, C6D6) δ 135.7, 117.2, 116.8, 109.2, 68.6, 34.1, 31.9,

31.5, 25.17, 23.6

Data corresponding to dialkene 3.20


1H NMR (600 MHz, CDCl3) δ 5.75 (ddt, J = 16.8, 10.2, 6.5 Hz, 2H), 5.07 (dd,

J = 21.5, 13.7 Hz, 4H), 4.11 (s, 6H), 2.27 – 2.16 (os, 4H), 1.71 (ddd,

J = 13.8, 11.8, 5.4 Hz, 2H), 1.53 (ddd, J = 14.0, 11.8, 5.5 Hz, 2H),

1.44 (s, 3H)


Nitrile 3.19 (0.10 g, 0.45 mmol) and 3:1 dioxane:water (10 mL) were added to a

RBF. 1 M HCl (0.19 mL, 2.2 mmol) was added. The reaction mixture was stirred

and allowed to reflux overnight. Reaction completion was confirmed by TLC.

The mixture was evaporated to obtain diol 3.23 as a white solid. Diol 3.23 (0.72

g, 80%) was carried forward with no further purification.

191

TLC Rf = 0.52 (MeOH/EtOAc = 10/90) [KMnO4]

1H NMR (600 MHz, CDCl3) δ 5.91 (td, J = 17.0, 6.7 Hz, 1H), 5.11 (dd, J =

32.8, 13.8 Hz, 2H), 4.37 (d, J = 9.4 Hz, 1H), 4.29 (d, J = 9.4 Hz,

1H), 3.68 (dq, J = 24.8, 11.7 Hz, 5H), 2.77 – 2.73 (m, 1H), 2.36 (dt,

J = 14.2, 7.0 Hz, 1H), 2.26 (td, J = 14.8, 7.4 Hz, 1H), 1.81 (td, J =

14.4, 8.2 Hz, 1H), 1.70 (td, J = 14.3, 6.7 Hz, 1H).


Diol 3.23 (0.19 g, 0.89 mmol), p-TsOH (0.011 g, 0.050 mmol), and THF (10 mL)

were added to a RBF. The reaction mixture was stirred overnight. Reaction

completion was confirmed by TLC. The reaction was quenched by a saturated

NaHCO3 solution. The mixture was extracted with EtOAc (3 x 20 mL) and the

combined extractwashed with brine (10 mL) and dried with MgSO4 and

evaporated. The crude material was purified using flash chromatography

(hexanes/EtOAc = 75/25) to obtain acetonide 3.24, 0.17 g (65%).

TLC Rf = 0.50 (hexane/EtOAc = 75/25) [KMnO4]

1H NMR (600 MHz, CDCl3) δ 7.51 – 7.35 (m, 5H), 5.78 (ddt, J = 17.0, 10.3,

6.7 Hz, 1H), 5.48 (s, 1H), 5.10 (dd, J = 18.1, 13.7 Hz, 2H), 4.70 (d,

192

J = 9.5 Hz, 1H), 4.28 (d, J = 9.4 Hz, 1H), 4.09 – 4.01 (m, 3H), 3.97

(d, J = 11.6 Hz, 1H), 2.42 (td, J = 14.2, 7.0 Hz, 1H), 2.31 (td, J =

14.9, 7.2 Hz, 1H), 2.22 (dd, J = 8.7, 6.0 Hz, 1H), 1.79 (td, J = 14.5,

8.7 Hz, 1H), 1.53 (dt, J = 14.2, 6.7 Hz, 1H).


O

OO O

NH2Quantitative

Na2O2, H2O

O

OO

CN

3.19 3.26

Nitrile 3.19 (14 g, 0.060 mol) was brought up in water (500 mL) and stirred

vigorously (the nitrile does not dissolve but forms oily droplets in the water).

Sodium peroxide (9.6 g, 0.12 mol) was added, all in one portion. The reaction

mixture was heated with a water bath (at 50 °C) with vigorous stirring. After 2 h,

more sodium peroxide was added (4.8 g, 0.06 mol). Reaction progress was

monitored by TLC. A white precipitate had formed in the reaction vessel which

dissolved upon addition of EtOAc (200 mL). Na2SO3 (27 g, 0.21mol) was added

and the reaction mixture was vigorously stirred until all the solid had dissolved.

The mixture was extracted with EtOAc (4 x 100 mL) and the combined

extractdried with MgSO4 and evaporated. Amide 3.26 was obtained as a white

powder, 15 g (quantitative yield). The amide 3.26 can be carried forward without

further purification or can be recrystallized from EtOAc (10 mL/g).


193

1H NMR (600 MHz, CDCl3) δ 5.71 (tdd, J = 15.1, 8.0, 5.7 Hz, 1H), 5.40 (bd,

J = 44.0 Hz, 2H), 5.08 – 4.98 (os, 2H), 4.10 (dd, J = 8.3, 3.3 Hz,

3H), 3.97 (dd, J = 8.3, 3.3 Hz, 3H), 2.23 – 2.14 (m, 1H), 1.96 – 1.86

(os, 2H), 1.78 (tdd, J = 12.7, 7.7, 4.9 Hz, 1H), 1.44 (s, 3H), 1.46 –

1.38 (os, 1H)

1H NMR (600 MHz, D2O) δ 5.81 (td, J = 16.9, 7.2 Hz, 1H), 5.06 (dd, J = 19.3,

13.8 Hz, 2H), 4.16 (dd, J = 8.6, 3.2 Hz, 3H), 4.06 (dd, J = 8.6, 3.2

Hz, 3H), 2.33 (dd, J = 12.3, 2.8 Hz, 1H), 2.14 – 2.07 (m, 1H), 1.92

(td, J = 15.5, 7.5 Hz, 1H), 1.63 (tdd, J = 12.9, 7.4, 5.4 Hz, 1H), 1.57

– 1.50 (m, 1H), 1.46 (s, 3H)


Amide 3.26 (9.8 g, 0.040 mol) was dissolved in HPLC grade MeOH (160 mL) and

the solution was transferred into a thick-walled glass reaction flask (pressure

vessel). DMF-DMA (26 mL, 0.20 mol) was added and the pressure vessel was

sealed and heated with an oil bath (at 110 °C) for 48 h. The resulting dark brown

solution was cooled to rt and evaporated. The dark brown oily residue (which

contained the product as well as DMF-DMA) was purified by flash

194

chromatography (hexanes/EtOAc = 75/25) giving methyl ester 3.28 as a white

solid (9.2 g, 88%).

MP 34-36 °C


1H NMR (600 MHz, CDCl3) δ 5.70 (ddd, J = 16.8, 13.7, 6.9 Hz, 1H), 5.04 –

4.95 (os, 2H), 4.04 (dd, J = 8.4, 3.3 Hz, 3H), 3.89 (dd, J = 8.4, 3.3

Hz, 3H), 3.70 (s, 3H), 2.25 (dd, J = 12.4, 2.6 Hz, 1H), 2.07 – 1.99

(m, 1H), 1.88 (dq, J = 14.6, 7.4 Hz, 1H), 1.76 – 1.67 (m, 1H), 1.43

(s, 3H), 1.46 – 1.37 (os, 1H).

13C NMR (150 MHz, CDCl3) δ 172.3, 136.5, 116.2, 108.4, 77.2, 77.0, 76.8,

69.2, 51.8, 45.8, 34.5, 31.8, 25.6, 23.2


Methyl ester 3.28 (9.1 g, 36 mmol) and dry THF (90 mL) were added to a RBF

and the mixture was stirred until all the methyl ester had dissolved. N,O-

Dimethylhydroxylamine hydrochloride (5.22 g, 0.053 mol) was added all in one

portion and the reaction flask was placed in a dry ice bath maintained at -20 °C

by adding dry ice chips. Methylmagnesium chloride (3.0 M in THF) was added

dropwise using a syringe pump, maintaining the dry ice bath at approximately -20

195

°C. The bath was allowed to warm to -10 °C and reaction progress was

monitored by TLC until complete. The reaction mixture was poured into a

vigorously stirring solution of saturated NaHCO3 (100 mL), extracted with CH2Cl2

(3 x 100 mL), dried with Na2SO4, and evaporated. Weinreb amide 3.29 was

obtained as a yellow oil and purified flash chromatography (hexanes/EtOAc =

3/2) to obtain Weinreb amide 3.29 (9.64 g, 95%) as a yellow solid.

MP 81-84 °C


1H NMR (600 MHz, CDCl3) δ 5.78 – 5.68 (m, 1H), 5.05 – 4.96 (os, 2H), 4.09

(dd, J = 8.4, 3.2 Hz, 3H), 3.92 (dd, J = 8.4, 3.2 Hz, 3H), 3.66 (s,

3H), 3.18 (s, 3H), 2.81 (d, J = 11.5 Hz, 1H), 2.05 – 1.95 (m, 1H),

1.90 – 1.76 (os, 2H), 1.42 (s, 3H), 1.46 – 1.37 (os, 1H).

13C NMR (125 MHz, C6D6) δ 173.1, 137.8, 115.4, 109.2, 69.7, 60.7, 40.5,

35.8, 3.18, 31.6, 26.2, 24.0

Synthesis of Compound 3.12 (and side-product 3.30)

Weinreb amide 3.29 (1.6 g, 5.4 mmol) in THF (5.5 mL) were added to a RBF and

cooled with an ice-water bath and vinylmagnesium bromide (0.97 M, 28 mL, 27

196

mmol) was added dropwise using a syringe pump. The reaction mixture was

maintained at 0 °C. Reaction progress was monitored by TLC until reaction was

complete. The reaction mixture was transferred into a flame-dried addition funnel

and added slowly (~5 mL/min) into saturated NaHCO3 (750 mL). The aqueous

layer was extracted with EtOAc (3 x 200 mL) and the combined extractions dried

with MgSO4 and evaporated. The dialkene 3.12 was purified by flash

chromatography (hexanes/EtOAc = 70/30) to obtain 1.27 g (90%).

Data corresponding to dialkene 3.12


1H NMR (600 MHz, C6D6) δ 6.30 – 6.22 (m, 1H), 6.12 (d, J = 17.4 Hz, 1H),

5.78 (d, J = 10.5 Hz, 1H), 5.55 (td, J = 16.8, 6.5 Hz, 1H), 4.87 (dd, J

= 20.0, 13.8 Hz, 2H), 4.02 (dd, J = 8.4, 3.4 Hz, 3H), 3.90 (dd, J =

8.4, 3.4 Hz, 3H), 2.69 (d, J = 11.8 Hz, 1H), 1.91 – 1.83 (m, 1H),

1.76 – 1.63 (os, 2H), 1.34 (d, J = 11.7 Hz, 1H), 1.30 (s, 3H)

Data corresponding to methoxyamine side product 3.30


1H NMR (600 MHz, CDCl3) δ 5.68 (dt, J = 17.5, 6.6 Hz, 1H), 5.05 – 4.97 (os,

2H), 4.06 (dd, J = 8.2, 3.3 Hz, 3H), 3.92 (dd, J = 8.2, 3.3 Hz, 3H),

3.48 (s, 3H), 2.91 – 2.78 (os, 2H), 2.66 (t, J = 6.5 Hz, 2H), 2.57 (s,

3H), 2.48 (dd, J = 11.6, 2.6 Hz, 1H), 2.05 – 1.95 (m, 1H), 1.86 (td, J

= 15.0, 7.6 Hz, 1H), 1.78 – 1.66 (m, 1H), 1.42 (s, 3H), 1.47-1.34

(os, 1H).

197


Dialkene 3.12 (1.2 g, 4.8 mmol) and CH2Cl2 (15 mL) were added to a RBF.

Grubbs 2nd Generation catalyst (0.21 g, 0.24 mmol) was added in one portion

and the reaction mixture stirred for 2 h. Reaction progress was monitored by

TLC until the reaction was complete. Most of the CH2Cl2 was evaporated and the

crude material, a brown oil, was purified by flash chromatography.

Cyclohexenone 3.10 was obtained, 0.87 g (80%) as a tan solid.


1H NMR (600 MHz, CDCl3) δ 6.94 – 6.89 (m, 1H), 5.97 (d, J = 10.0 Hz, 1H),

4.20 (dd, J = 8.1, 3.2 Hz, 3H), 4.08 (dd, J = 8.1, 3.2 Hz, 3H), 2.44

(ddd, J = 19.2, 8.8, 4.3 Hz, 1H), 2.41 – 2.33 (m, 1H), 2.23 (dd, J =

12.4, 4.4 Hz, 1H), 2.00 (dq, J = 13.1, 4.3 Hz, 1H), 1.79 (ddd, J =

17.9, 13.3, 5.1 Hz, 1H), 1.45 (s, 3H)

13C NMR (125 MHz, C6D6) δ 196.8, 148.0, 130.5, 109.1, 69.0, 46.2, 35.3,

25.5, 24.1, 23.4

198

Synthesis of Compound 3.10 (via allylmagnesium bromide)

Weinreb amide 3.29 (0.25 g, 0.88 mmol) in THF (5.0 mL) were added to a RBF

and cooled with an ice-water bath and titrated allylmagnesium bromide (0.56 M,

5.5 mL, 3.1 mmol) was added dropwise using a syringe pump. The reaction

mixture was gradually warmed to rt. Reaction progress was monitored by TLC

until reaction was complete (3 h at rt). The reaction was quenched by a

saturated NaHCO3 solution. The mixture was extracted with EtOAc (3 x 10 mL)

and the combined extractwashed with brine (10 mL) and dried with MgSO4 and

evaporated. The crude material was purified using flash chromatography to

obtain a mixture of product 3.31 and 3.32. This mixture of products was not

separated and used as a mixture in the next step.


O

OO O NEt3

THF

3.32

O

OO O

3.31major

O

OO O

3.32minor

The mixture of isomers 3.31 and 3.32 (0.23 g, 0.86 mmol), THF (5.0 mL), and

NEt3 (0.12 mL, 0.87 mmol) were added to a RBF. The reaction mixture was

stirred for 2 h. Most of the THF and NEt3 was evaporated and the crude material,

199

a mixture of E/Z isomers 3.32, was not further purified and compound was

carried onto the next step.

Dialkene 3.32 (0.23 g, 0.86 mmol) and CH2Cl2 (5.0 mL) were added to a RBF.

Grubbs 2nd Generation catalyst (37 mg, 0.04 mmol) was added in one portion

and the reaction mixture stirred for 3 h. Reaction progress was monitored by

TLC until the reaction was complete. Most of the CH2Cl2 was evaporated and the

crude material, a brown oil, was purified by flash chromatography.

Cyclohexenone 3.10 was obtained, 0.20 g (53% over three steps) as a tan solid.

1H NMR matched cyclohexenone 3.10 from previous olefin metathesis reaction.



Diisopropylamine (0.37 mL, 2.6 mmol) and THF (10 mL) were added to a RBF

and the mixture cooled with an ice-water bath followed by dropwise addition of n-

BuLi (1.38 M in hexanes, 1.8 mL, 2.5 mmol). The reaction mixture was stirred at

0 °C for 10 min and then cooled with a dry ice/acetone bath. Methyl ester 3.28

200

(0.20 g, 0.78 mmol) as a THF solution (1.0 mL) was added dropwise to the

freshly prepared LDA solution at -78 °C and the resulting mixture was allowed to

stir for 30 min. Methyl iodide (97 µL, 1.6m mol) was added dropwise and then

the reaction was warmed to rt and allowed to stir overnight. The reaction was

quenched by a saturated NaHCO3 solution. The mixture was extracted with

CH2Cl2 (3 x 10 mL) and the combined extractwashed with brine (10 mL) and

dried with Na2SO4 and evaporated. The crude material was purified using flash

chromatography to obtain methyl ester 3.34, 2.1 g (98%).

TLC Rf = 0.25 (acetone/CH2Cl2 = 1/99) [KMnO4]


J = 19.6, 13.6 Hz, 2H), 4.06 (dd, J = 8.5, 3.2 Hz, 3H), 3.93 (dd, J =

8.5, 3.2 Hz, 3H), 3.70 (s, 3H), 2.07 – 1.98 (m, 1H), 1.86 (td, J =

12.2, 4.5 Hz, 1H), 1.79 – 1.70 (m, 1H), 1.42 (s, 3H), 1.34 – 1.28 (td,

J = 12.2, 4.5 Hz, 1H), 1.10 (s, 3H).


Dimethylmethyl phosphonate (67 µg, 0.62 mmol) and THF (1.0 mL) were added

to a scintillation vial and the mixture cooled with a dry ice/acetone bath followed

by dropwise addition of n-BuLi (1.82 M in hexanes, 0.32 mL, 0.59 mmol). The

201

reaction mixture was stirred at -78 °C for 30 min. Methyl ester 3.34 (42 mg, 0.16

mmol) as a THF solution (0.25 mL) was added dropwise followed by addition of

HMPA (0.20 mL) the resulting mixture was gradually warmed to rt and stirred for

4 h. Reaction progress was monitored by TLC. The reaction was quenched by a

saturated NaHCO3 solution. The mixture was extracted with CH2Cl2 (3 x 1.0 mL)

and the combined extractwashed with brine (1.0 mL) and dried with Na2SO4 and


obtain phosphonate 3.35, 0.40 g (71%).

TLC Rf = 0.21 (CH2Cl2/EtOAc = 10/90) [KMnO4]


J = 20.6, 13.7 Hz, 2H), 4.05 (dd, J = 8.4, 3.1 Hz, 3H), 3.94 (dd, J =

8.4, 3.1 Hz, 3H), 3.80 (d, J = 11.1 Hz, 6H), 3.17 (dd, J = 21.3, 15.2

Hz, 1H), 2.94 (dd, J = 22.8, 15.2 Hz, 1H), 2.01 – 1.88 (m, 2H), 1.76

(dd, J = 20.0, 12.2 Hz, 1H), 1.40 (s, 3H), 1.27 (s, 3H), 1.32 – 1.22

(m, 1H).


202

Ozonolysis Procedure

Phosphonate 3.35 (20 mg, 0.055 mmol), NMO·H2O (22 mg, 0.16 mmol), and

CH2Cl2 (2.0 mL) were added to a RBF and the mixture cooled with an ice-water

bath (at 0 °C). The reaction was sparged with ozone containing oxygen and

monitored by TLC until the starting material (phosphonate 3.35) was consumed.

The reaction was quenched by a solution of 1:1 saturated NaHCO3/Na2S2O3.

The mixture was extracted with CH2Cl2 (3 x 0.5 mL) and the combined

extractwashed with brine (0.5 mL), dried with Na2SO4, and evaporated. The

crude material was purified using flash chromatography to obtain cyclohexenone

3.38, 0.14 mg (73%).

OsO4 Procedure

Phosphonate 3.35 (25 mg, 0.07 mmol) and 3:1 acetone/water mixture (2.3 mL)

were added to a scintillation vial. Once the phosphonate dissolved, OsO4 (1 g/25

mL in water) (21 µL, 0.0034 mmol) and NMO·H2O (28 mg, 0.21 mmol) were

added and the reaction mixture was stirred overnight. TLC confirmed the alkene

starting material had been consumed. NaIO4 (74 mg, 0.35 mmol) was added to

the vigorously stirring reaction mixture. Reaction progress was monitored by

TLC and when the diol intermediate was consumed, the reaction was filtered

through a cotton plug. The filtrate extracted with CH2Cl2 (3 x 0.5 mL) and the

combined extractwashed with brine (0.5 mL), dried with Na2SO4, and evaporated.

The crude material was purified using flash chromatography to obtain

cyclohexenone 3.38.

TLC Rf = 0.18 (MeOH/EtOAc = 2.5/97.5) [KMnO4]

203


Diethylmethyl phosphonate (0.49 g, 3.0 mmol) and THF (5.0 mL) were added to

a RBF and the mixture cooled with a dry ice/acetone bath followed by dropwise

addition of n-BuLi (1.38 M in hexanes, 2.0 mL, 2.8 mmol). The reaction mixture

was stirred at -78 °C for 30 min. Methyl ester 3.34 (0.42 g, 1.5 mmol), as a THF

solution (0.25 mL), was added dropwise. HMPA (1.0 mL) was added to the

reaction mixture. The resulting reaction mixture was gradually warmed to rt and

then stirred for 1 h. Reaction progress was monitored by TLC . The reaction

was quenched by a saturated NaHCO3 solution. The mixture was extracted with

CH2Cl2 (3 x 5.0 mL) and the combined extractwashed with brine (1.0 mL), dried

with Na2SO4, and evaporated. The crude material was purified using flash

chromatography (CH2Cl2/EtOAc = 5/95) to obtain phosphonate A3, 0.152 g

(51%).

Data corresponding to phosphonate 3.39



J = 22.6, 13.6 Hz, 2H), 4.13 – 4.06 (os, 4H), 3.98 (dd, J = 8.4, 3.1

Hz, 3H), 3.89 (dd, J = 8.4, 3.1 Hz, 3H), 3.41 (dq, J = 21.0, 6.9 Hz,

1H), 2.00 – 1.92 (os, 2H), 1.87 – 1.81 (m, 1H), 1.43 (s, 3H), 1.38 (s,

204

3H), 1.37 (q, J = 6.7 Hz, 3H), 1.31 (dd, J = 15.5, 7.1 Hz, 6H), 1.17

(dd, J = 12.1, 8.5 Hz, 1H).

Phosphonate A3 (62 mg, 0.16 mmol) and an 3:1 acetone/water mixture (5 mL)

were added to a RBF. Once the phosphonate dissolved, OsO4 (1 g/25 mL in

water) (48 µL, 0.0076 mmol) and NMO·H2O (62 mg, 0.46 mmol) were added and

the reaction mixture was stirred overnight. TLC confirmed the alkene starting

material had been consumed. NaIO4 (0.16 g, 0.76 mmol) was added to the

vigorously stirring reaction mixture. Reaction progress was monitored by TLC

and when the diol intermediate was consumed, the reaction was filtered through

a cotton plug. The filtrate extracted with CH2Cl2 (3 x 5.0 mL) and the combined


crude aldehyde was used in the next step without purification.


The crude aldehyde (4.1 mg, 10 µmol) from the previous reaction, acetonitrile

(0.5 mL), DBU (1.6 µL, 0.01 mmol), and LiCl (0.8 mg, 0.2 mmol) were added

successively and stirred vigorously. The reaction progress was monitored by

TLC. After 30 min, the reaction was complete. The reaction was quenched by a

saturated NaHCO3 solution. The mixture was extracted with CH2Cl2 (3 x 0.5 mL)

205

and the combined extractwashed with brine (0.25 mL), dried with Na2SO4, and

evaporated. The crude phosphonate 3.40 was purified by flash chromatography,

0.9 mg (36%).


1H NMR (600 MHz, CDCl3) δ 6.65 (s, 1H), 4.24 (dd, J = 8.3, 3.1 Hz, 3H),

4.03 (dd, J = 8.3, 3.2 Hz, 3H), 2.40 – 2.26 (os, 2H), 2.02 – 1.95 (m,

1H), 1.74 (s, 3H), 1.64 (dt, J = 13.4, 4.6 Hz, 1H), 1.43 (s, 3H), 1.08

(s, 3H).


Diisopropylamine (0.37 mL, 2.6 mmol) and THF (5 mL) were added to a RBF and


(1.37 M in hexanes, 1.8 mL, 2.5 mmol). The reaction mixture was stirred at 0 °C

for 10 min and then cooled with a dry ice/acetone bath. Methyl ester 3.28 (0.20

g, 0.78 mmol) as a THF solution (0.25 mL) was added dropwise to the freshly

prepared LDA solution at -78 °C and the resulting mixture was allowed to stir for

1 h. CCl4 (27 mL, 2.3 mmol) was added dropwise. Reaction progress was

monitored by TLC. The reaction was quenched by a saturated NaHCO3 solution.


extractwashed with brine (0.25 mL) and dried with Na2SO4 and evaporated. The

206

crude material was purified using flash chromatography to obtain methyl ester

3.41, 0.17 g (80%).



4.99 (os, 2H), 4.15 (dd, J = 8.5, 3.2 Hz, 3H), 4.06 (dd, J = 8.5, 3.2

Hz, 3H), 3.81 (s, 3H), 2.39 – 2.31 (m, 1H), 2.17 (ddd, J = 13.8,

10.8, 4.8 Hz, 1H), 1.95 – 1.86 (m, 1H), 1.75 (ddd, J = 13.7, 11.3,

4.4 Hz, 1H), 1.44 (s, 3H).


Dimethylmethyl phosphonate (0.65 mL, 6.0 mmol) and THF (5.0 mL) were added

to a scintillation vial and the mixture cooled with a dry ice/acetone bath followed

by dropwise addition of n-BuLi (2.27 M in hexanes, 2.5 mL, 5.7 mmol). The

reaction mixture was stirred at -78 °C for 30 min. Methyl ester 3.41 (0.42 g, 1.5

mmol), as a THF solution (0.25 mL), was added dropwise. The resulting reaction

mixture was stirred for 1 h. Reaction progress was monitored by TLC. The

reaction was quenched by a saturated NaHCO3 solution. The mixture was

extracted with CH2Cl2 (3 x 2.0 mL) and the combined extractwashed with brine

207

(1.0 mL), dried with Na2SO4, and evaporated. The crude material was purified

using flash chromatography to obtain phosphonate A4, 0.45 g (77%).

Data corresponding to phosphonate A4



4.94 (os, 2H), 4.13 (dd, J = 8.3, 2.8 Hz, 3H), 4.05 (dd, J = 8.3, 2.9

Hz, 3H), 4.13 (dd, J = 8.3, 2.8 Hz, 3H), 4.05 (dd, J = 8.3, 2.9 Hz,

3H), 3.51 (dd, J = 20.2, 16.7 Hz, 1H), 3.34 (dd, J = 20.2, 16.7 Hz,

1H), 2.30 – 2.16 (os, 2H), 1.90 – 1.80 (m, 1H), 1.69 (t, J = 10.7 Hz,

1H), 1.41 (s, 1H).

Phosphonate A4 (0.10 g, 0.26 mmol) was dissolved in acetone (0.5 mL). To the

vigorously stirring mixture was added K2CO3 (46 mg, 0.33 mmol) and the

reaction mixture was cooled with an ice-water bath and allowed to stir for 5 min.

MeI was added dropwise and the reaction mixture was allowed to warm to rt and

stirred overnight. The reaction was quenched by a saturated NaHCO3 solution.



crude phosphonate 3.42 (35 mg, 34%) was used without further purification.

TLC Rf = 0.14 and 0.20 (CH2Cl2/EtOAc = 40/60) [Anisaldehyde]

208


Phosphonate 3.42 (34 mg, 0.09 mmol) and a 3:1 acetone/water mixture (2.0 mL)

were added to a scintillation vial. Once the phosphonate dissolved, OsO4 (1 g/25

mL in water) (27 µL, 0.0043 mmol) and NMO·H2O (35 mg, 0.26 mmol) were

added and the reaction mixture was stirred for 4 h. TLC confirmed the alkene

starting material had been consumed (CH2Cl2/hexanes = 70/30). NaIO4 (92 mg,

0.43 mmol) was added to the vigorously stirring reaction mixture. Reaction

progress was monitored by TLC (MeOH/EtOAc = 15/85) and when the diol

intermediate was consumed, the reaction mixture was filtered through a cotton

plug. The filtrate extracted with CH2Cl2 (3 x 0.5 mL) and the combined


crude phosphonate A5 (29 mg, 80%) was used without further purification.


Phosphonate A5 (29 mg, 0.07 mmol), acetonitrile (0.5 mL), DBU (12 µL, 0.08

mmol), and LiCl (6.3 mg, 0.15 mmol) were added successively and stirred

vigorously. The reaction progress was monitored by TLC. After 5 min, the

reaction was complete. The reaction mixture was quenched by a saturated

NaHCO3 solution. The mixture was extracted with CH2Cl2 (3 x 0.5 mL) and the

209

combined extractwashed with brine (0.25 mL), dried with Na2SO4, and

evaporated. The crude phosphonate 3.43 was purified by flash chromatography,

yielding 8 mg (40%).


1H NMR (600 MHz, CDCl3) δ 6.69 (d, J = 4.8 Hz, 1H), 4.37 (dd, J = 8.2, 2.8

Hz, 3H), 4.18 (dd, J = 8.2, 2.9 Hz, 3H), 2.72 – 2.63 (m, 1H), 2.33 (d,

J = 19.5 Hz, 1H), 2.20 – 2.14 (os, 2H), 1.80 (s, 3H), 1.46 (d, J = 6.4

Hz, 3H).

210

Spectra of Compounds from Chapter 3

Figure 3.1 – 1H NMR of Compound 3.3 (600 MHz, CDCl3)

211


212


213


214


215

Figure 3.6 – 13C NMR of Compound 3.15 (125 MHz, CDCl3)

216


217


218


219


220

Figure 3.11 – 1H NMR of Compound A2 (600 MHz, CDCl3)

221


222


223


224

Figure 3.15 – 13C NMR of Compound 3.19 (125 MHz, C6D6)

225


226


227


228


229

Figure 3.20 – 1H NMR of Compound 3.26 (600 MHz, D2O)

230


231


232


233


234

Figure 3.25 – 1H NMR of Compound 3.12 (600 MHz, C6D6)

235


236


237


238

Figure 3.29 – 1H NMR of Compound 3.31 and 3.32 (mixture) (600 MHz, CDCl3)

239


240


241


242


243


244


245

Figure 3.37 – 1H NMR of Compound A4 (500 MHz, CDCl3)

246


247

B.1 Experimental – Reactions in Chapter 4


• Using the organolithium

O

OO

O

O

O

O

LDA, THF-78 C

O

OO O

O O

4.1 4.6

Diisopropylamine (25 µL, 0.18 mmol) and THF (3.5 mL) were cooled with an ice-

water bath followed by dropwise addition of n-BuLi (1.94 M in hexanes, 0.10 mL,

0.19 mmol). The reaction mixture was stirred for 10 min and then cooled with a

dry ice/acetone bath. Methyl pyruvate (12 µL, 0.13 mmol) as a THF solution (0.5

mL) was added dropwise to the freshly prepared LDA solution at -78 °C and the

resulting mixture was allowed to stir for 30 min. Cyclohexenone 4.1 (20 mg,

0.089 mmol) as a THF solution (0.5 mL) was added dropwise and the reaction

mixture and was allowed to stir for 1 h. Reaction progress was monitored by

TLC. The reaction mixture was quenched with a saturated NaHCO3 solution.

The reaction mixture was extracted with EtOAc (3 x 5.0 mL) and the combined

extract washed with brine (5.0 mL), dried with MgSO4, and evaporated. The

crude material was purified using flash chromatography (hexanes/EtOAc = 25/75

until methyl pyruvate eluted, then hexanes/EtOAC = 1/1) to obtain compound 4.6,

14 mg (53%).


248

1H NMR (500 MHz, CDCl3) δ 5.85 – 5.78 (m, 1H), 5.75 – 5.68 (m, 1H), 4.12

4.14 (dd, J = 8.1, 3.0 Hz, 3H), 4.09 (dd, J = 8.1, 3.0 Hz, 3H), 3.02

(dd, J = 20.8, 2.2 Hz, 1H), 2.79 (d, J = 20.9 Hz, 1H), 2.57 – 2.42

(os, 2H), 2.35 – 2.22 (m, 1H), 1.45 (s, 3H), 1.39 – 1.29 (os, 2H)


To a RBF was added THF (6.5 mL) followed by sequential addition of NEt3 (0.96

mL, 6.9 mmol), methyl pyruvate (0.50 g, 4.7 mmol), and TMSCl (0.70 mL, 5.5

mmol). The reaction mixture was stirred at rt for 3.5 h. Reaction progress was

monitored by TLC. Once the reaction was complete, pentane (7.5 mL) was

added and the reaction mixture was filtered and the filtrate washed with water (2

x 5 mL) and brine (5 mL). The combined extract was dried with MgSO4 and

evaporated to obtain silyl enol ether 4.8 as a colorless liquid. 1H NMR matched

literature values.

1H NMR (600 MHz, CDCl3) δ 5.50 (s, 1H), 4.87 (s, 1H), 3.75 (d, J = 17.2 Hz,

3H), 0.23 (s, 9H).

249


Et2O (50 mL) and piperidine (6.2 mL, 0.063 mol) were added to a RBF. The

reaction mixture was cooled with -25 °C with an acetone bath and dry ice chips.

AsCl3 (1.2 mL, 14 mol) was added as an Et2O solution (8.3 mL) over 30 min. The

reaction mixture was stirred for an additional 15 min at -20 °C. Methyl pyruvate

(2.0 g, 0.20 mol) was added as an Et2O solution (5.5 mL) and warmed gradually

to rt and left to stand overnight. The reaction mixture was filtered through a pad

of Celite® and the filtrate was evaporated. The crude enamine was purified using

a kugelrohr apparatus (100 °C, 8 torr) to obtain 4.11 as a pale yellow oil (1.1 g,

33%). 1H NMR matched literature values.

1H NMR (600 MHz, CDCl3) δ 5.12 (s, 1H), 4.55 (s, 1H), 3.80 (s, 3H), 2.85 –

2.75 (m, 7H), 1.6-1.9 (m, 5H)


250

Zinc powder (48 mg, 0.73 mmol) and THF (1.0 mL) were added to a scintillation

vial. The zinc was activated (by addition of cat 1,2-dibromoethane, heating to

reflux for 1 min with vigorous stirring, cooling to rt, addition of cat TMSCl, heating

to reflux for 1 min with vigorous stirring, and cooling to rt). The activated zinc

solution was cooled with an ice-water bath and ethyl-2-(bromomethyl)acrylate

(0.10 g, 0.52 mmol) was added dropwise to the reaction mixture. CuCN·2LiCl (1

M solution in THF, 0.57 mL, 0.57 mmol) was added to a separate scintillation vial

and cooled using a dry ice/acetone bath (at -78 °C). The organozinc solution

was syringed away from the residual zinc powder and added dropwise to the

CuCN·2LiCl solution. The reaction mixture was warmed gradually to -30 °C.

Cyclohexenone 4.1 (58 mg, 0.26 mmol) was added as a THF solution (0.5 mL)

and the reaction mixture was stirred for 1 h (at -30 °C). The reaction progress

was monitored by TLC. The reaction mixture was quenched with a saturated

NaHCO3 solution (5.0 mL), extracted with EtOAc (3 x 2.5 mL), the combined

extract washed with brine (1.0 mL), dried with MgSO4, and evaporated. The

crude material was purified using flash chromatography (hexanes/EtOAC = 1/1)

to obtain compound 4.33 and 4.1 (as a 1.3:1 mixture).


1H NMR (600 MHz, CDCl3) δ 6.29 (t, J = 2.7 Hz, 1H), 5.84 (dt, J = 10.0, 3.5

Hz, 1H), 5.65 (t, J = 2.4 Hz, 1H), 5.61 (d, J = 10.1 Hz, 1H), 4.11 (s,

6H), 2.94 – 2.81 (os, 2H), 2.25 – 2.14 (m, 1H), 1.80 – 1.77 (m, 1H),

1.65 (t, J = 4.5 Hz, 1H), 1.41 (s, 3H).

251


BrZn OEt

O

O b) CuBr•SMe2, thenTMSClc) Cyclohexenone

a)

O

OO

O OHO

O

O

OEt

4.1 4.35

4.29

HO

H

H






(0.15 g, 0.78 mmol) was added dropwise to the reaction mixture and stirred for 5

min. CuBr·SMe2 (0.18 g, 0.86 mmol) and THF (1.0 mL) were added to a

separate scintillation vial and cooled using a dry ice/acetone bath (at -78 °C).

The organozinc solution was syringed away from the residual zinc powder and

added dropwise to the CuBr·SMe2 solution followed by addition of TMSCl (0.11

mL, 0.86 mmol). The reaction mixture was warmed gradually to -30 °C. The

organocopper solution was then recooled with a dry ice/acetone bath (at -78 °C)

and cyclohexenone 4.1 (66 mg, 0.29 mmol) was added as a THF solution (0.5

mL) and the reaction mixture was stirred for 1 h (at -78 °C). The reaction

progress was monitored by TLC. The reaction mixture was quenched with a

saturated NaHCO3 solution (5.0 mL). The mixture was extracted with EtOAc (3 x

2.5 mL) and the combined extract washed with brine (1.0 mL), dried with MgSO4,

252

and evaporated. The crude material was purified using flash chromatography

(hexanes/EtOAC = 1/1) to obtain compound 4.35.


1H NMR (600 MHz, CDCl3) δ 6.17 (s, 1H), 5.50 (s, 1H), 4.23 – 4.21 (os, 2H),

4.18 (q, J = 14.3, 7.1 Hz, 2H), 3.90 (t, J = 5.6 Hz, 2H), 3.83 – 3.78

(os, 2H), 2.32 (dd, J = 13.9, 6.7 Hz, 1H), 2.23 (dd, J = 13.8, 7.0 Hz,

1H), 2.07 – 2.02 (os, 4H), 1.85 – 1.79 (os, 2H), 1.70 – 1.62 (os,

2H), 1.41 – 1.23 (os, 5H), 1.01 – 0.92 (m, 1H)








min. CuBr·SMe2 (0.18 g, 0.86 mmol) and THF (1.0 mL) were added to a

separate scintillation vial and cooled using a dry ice/acetone bath (at -78 °C).

The organozinc solution was syringed away from the residual zinc powder and

added dropwise to the CuBr·SMe2 solution followed by addition of TMSCl (0.11

253

mL, 0.86 mmol). The reaction mixture was warmed gradually to -30 °C. The

organocopper solution was then recooled with a dry ice/acetone bath (at -78 °C).

2,6-lutidine (0.10 mL, 0.86 mmol) and cyclohexenone (28 mg, 0.29 mmol) were

added and the reaction mixture was stirred for 30 min (at -78 °C). The reaction


saturated NaHCO3 solution (5.0 mL). The mixture was extracted with CH2Cl2 (3 x

2.5 mL) and the combined extract washed with brine (1.0 mL), dried with

Na2SO4, and evaporated. The crude material was purified using flash

chromatography (hexanes/EtOAC = 1/1) to obtain compound 4.36.


1H NMR (600 MHz, CDCl3) δ 6.17 (s, 1H), 5.75 (dt, J = 9.4, 3.4 Hz, 1H), 5.65

(d, J = 10.1 Hz, 1H), 5.55 (s, 1H), 4.19 (q, J = 7.2 Hz, 2H), 2.58 (dd,

J = 33.3, 13.3 Hz, 2H), 2.05 – 1.86 (os, 2H), 1.75 – 1.63 (os, 2H),

1.63 – 1.53 (os, 2H), 1.30 (t, J = 7.1 Hz, 3H), 0.08 (s, 9H).


Methyl ester 4.36 (0.062 g, 0.29 mmol) and THF (1.0 mL) were added to a

scintillation vial which was then cooled with a dry-ice/acetone bath (at -78 °C).

TBAF (1.0 M solution in THF, 0.35 mL, 0.35 mmol) was added dropwise. After

15 min, the reaction mixture was quenched with a saturated NaHCO3 solution

254

(1.0 mL). The mixture was extracted with CH2Cl2 (3 x 1.0 mL) and the combined

extract washed with brine (1.0 mL), dried with Na2SO4, and evaporated to obtain

the crude methyl ester. The crude material was purified using flash

chromatography (hexanes/EtOAC = 1/1) to obtain compound 4.31 (10 mg, 15%

over two steps).


1H NMR (600 MHz, CDCl3) δ 6.21 (s, 1H), 5.52 (s, 1H), 4.20 (q, J = 7.1 Hz,

2H), 2.43 – 2.33 (os, 3H), 2.26 (ddd, J = 20.9, 14.1, 6.4 Hz, 2H),

2.07 – 1.97 (os, 3H), 1.91 (d, J = 13.2 Hz, 1H), 1.64 (q, J = 25.4,

12.6 Hz, 1H), 1.38 – 1.31 (os, 2H), 1.30 (t, J = 7.1 Hz, 3H).


CuBr•SMe2 (0.10g, 0.49 mmol) in 2:1 THF/DMS (5.5 mL) was added to a RBF

and cooled with a dry-ice/acetone bath (-78 °C ) and titrated vinylmagnesium

bromide (0.91 M, 4.3 mL, 3.9 mmol) was added dropwise. The reaction mixture

turned dark red. After stirring for 10 min, cyclohexenone 4.1 in THF (0.5 mL) was

added dropwise to the reaction mixture. After 1 h, the reaction was complete and

quenched by pouring the reaction mixture into a vigorously stirring solution of

10% NH4OH. The reaction mixture was filtered through Celite®. The Celite® pad

255

was washed with Et2O (3 x 5.0 mL). The aqueous layer was extracted with Et2O

(3 x 5.0 mL) and the combined extract dried with MgSO4 and evaporated. The

mixtures of diastereomers 4.37a and 4.37b was purified by flash chromatography

(hexanes/EtOAc = 75/25) to obtain 0.26 g and 0.051 g of 4.37a and 4.37b

respectively (70%).

TLC Rf = 0.44 and 0.35 (hexanes/EtOAc = 60/40) [KMnO4]

Data corresponding to maJor diastereomer 4.37a (Rf = 0.44)

1H NMR (600 MHz, C6D6) δ 5.37 (qd, J = 16.9, 10.3, 6.5 Hz, 1H), 4.81 (dd, J

= 10.2, 0.9 Hz, 1H), 4.73 (dd, J = 17.2, 1.1 Hz, 1H), 4.04 (dd, J =

7.8, 3.0 Hz, 3H), 4.00 (dd, J = 7.8, 3.1 Hz, 3H), 2.08 (d, J = 12.7

Hz, 1H), 1.76 (os, 4H)1.46 (t, J = 12.8 Hz, 1H), 1.29 – 1.21 (os,

2H), 1.07 (d, J = 12.8 Hz, 1H), 0.69 (qd, J = 12.7, 3.4 Hz, 1H), 0.58

(qd, J = 12.7, 3.4 Hz, 1H).

Data corresponding to minor diastereomer 4.37b (Rf = 0.35)

1H NMR (600 MHz, C6D6) δ 5.32 (qd, J = 16.5, 10.7, 5.6 Hz, 1H), 4.90 –

4.81 (os, 2H), 4.02 (dd, J = 7.7, 2.6 Hz, 3H), 3.99 (dd, J = 7.7, 2.6

Hz, 3H), 2.26 – 2.20 (m, 1H), 2.08 (d, J = 13.8 Hz, 1H), 1.78 – 1.72

(os, 4H), 1.30 (dd, J = 12.2, 5.8 Hz, 1H), 1.13 – 1.02 (os, 2H), 0.97

(ddd, J = 16.1, 12.2, 4.3 Hz, 1H), 0.93 – 0.87 (m, 1H).

256


O

OO O

H

H

NMO•H2OOsO4

Me2CO/H2O2:1

O

OO O

OH

35%

OH

4.37 4.39

H

H

Alkene 4.37 (6 mg, 0.02 mmol) and THF/water mixture (2:1) (1.0 mL) were added

to a scintillation vial. OsO4 (1 g/25 mL in water) (5 µL, 0.7 µmol) and NMO·H2O

(0.35 mg, 0.03 mmol) were added and the reaction mixture was stirred overnight.

TLC confirmed the alkene starting material had been consumed. Na2SO3 (8.5

mg, 0.06 mmol) was added to the vigorously stirring reaction mixture and the

reaction mixture stirred for 30 min. The mixture was extracted with EtOAc (3 x


and evaporated. The crude material was purified using flash chromatography to

obtain diol 4.39, 2.4 mg (35%).


1H NMR (600 MHz, C6D6) δ 4.11 (d, J = 7.8 Hz, 3H), 4.09 (d, J = 7.8 Hz,

3H), 3.70 – 3.48 (os, 3H), 2.32 – 2.27 (os, 2H), 2.25 – 2.20 (m, 1H),

2.13 – 2.07 (m, 1H), 1.93 – 1.86 (m, 1H), 1.77 (s, 1H), 1.64 (dd, J =

29.1, 15.9 Hz, 1H), 1.57 (s, 1H), 1.56 – 1.50 (m, 1H), 1.49 – 1.33

(os, 4H)

257


Alkene 4.37b (0.23 g, 0.89 mmol), NMO·H2O (0.36 g, 2.7 mmol), and CH2Cl2 (10

mL) were added to a RBF and the mixture cooled with a dry ice/acetone bath.

The reaction was sparged with ozone containing oxygen and monitored by TLC

until the starting material (alkene 4.37b) was consumed. The reaction mixture

was warmed to rt and quenched with a solution of 1:1 saturated

NaHCO3/Na2S2O3. The mixture was extracted with CH2Cl2 (3 x 5.0 mL) and the

combined extract washed with brine (5.0 mL), dried with Na2SO4, and

evaporated. The crude aldehyde 4.40 was used in the next step without further

purification.


1H NMR (600 MHz, C6D6) δ 8.90 (s, 1H), 3.92 (s, 6H), 2.16 (d, J = 14.6 Hz,

1H), 1.78 – 1.73 (m, 2H), 1.71 (s, 3H), 1.50 (dd, J = 14.5, 7.2 Hz,

1H), 1.35 (d, J = 13.0 Hz, 1H), 1.16 (dd, J = 12.4, 5.4 Hz, 1H), 0.84

– 0.80 (m, 1H), 0.79 – 0.64 (os, 2H)

LiNTMS2 (1.0 M in THF, 1.1 mL, 1.1 mmol) and THF (5.0 mL) were added to a

RBF and the reaction mixture was cooled with a dry-ice/bath (at -78 °C).

258

Phosphonate 4.47 (0.33 g, 1.1 mmol) in a THF solution (0.5 mL) was added to a

RBF and stirred for 15 min. Aldehyde 4.40 was added as a THF solution (0.5

mL) and the reaction mixture was stirred for 1 h. The reaction mixture was

quenched with a solution of 1:1 saturated NaHCO3/Na2S2O3 and extracted with

Et2O (3 x 5.0 mL) and the combined extract washed with brine (5.0 mL), dried

with MgSO4, and evaporated. The crude material was purified using flash

chromatography to obtain silyl enol ether 4.48 (0.19 g, 48% over two steps).

TLC Rf = 0.35 (hexanes/EtOAc = 1/1, 0.1% NEt3) [KMnO4]

1H NMR (600 MHz, C6D6) δ 5.13 (d, J = 9.6 Hz, 1H), 4.03 (dd, J = 7.9, 3.0,

Hz, 3H), 3.98 (dd, J = 7.9, 3.0 Hz, 3H), 3.39 – 3.25 (os, 1H), 2.28

(dd, J = 12.7, 2.2 Hz, 1H), 1.74 (s, 1H), 1.56 – 1.49 (m, 1H), 1.45 (t,

J = 12.7 Hz, 1H), 1.35 (dd, J = 12.5, 4.8 Hz, 1H), 1.15 – 1.08 (m,

1H), 1.02 (t, J = 7.9 Hz, 2H), 0.75 (dd, J = 20.8, 11.6 Hz, 1H), 0.69

(q, J = 7.9 Hz, 1H).


Silyl enol ether 4.48 (0.16 g, 0.36 mmol), NEt3 (0.05 mL, 0.36 mmol), and MeOH

(5.0 mL) were added to a RBF and stirred at rt for 6 h. Reaction progress was

monitored by TLC. The reaction mixture was quenched with a solution of

saturated NaHCO3 and extracted with CH2Cl2 (3 x 5.0 mL) and the combined

259

extract washed with brine (5.0 mL), dried with Na2SO4, and evaporated. The

crude material was purified using flash chromatography (hexanes/EtOAc = 45/55,

0.1% NEt3) to obtain compound 4.3 (0.10 g, 83%).


1H NMR (600 MHz, C6D6) δ 4.00 (dd, J = 7.9, 3.0 Hz, 3H), 3.97 (dd, J = 7.9,

3.0 Hz, 3H), 3.24 (s, 3H), 2.24 (dd, J = 17.7, 7.3 Hz, 1H), 2.12 (dd,

J = 17.7, 5.7 Hz, 1H), 1.98 (ddd, J = 12.7, 3.8, 2.3 Hz, 1H), 1.74 (s,

3H), 1.31 – 1.20 (os, 4H), 1.03 (ddd, J = 12.8, 5.6, 3.2 Hz, 1H), 0.60

– 0.44 (os, 2H)

13C NMR (125 MHz, C6D6) δ 205.9, 191.6, 161.7, 109.2, 68.7, 68.7, 52.2,

49.8, 48.2, 45.3, 34.9, 34.8, 31.1, 26.7, 24.1

Synthesis of Compound 4.4774-76

Boric acid (82 mg, 1.3 mmol), L-tartaric acid (20 g, 0.13 mol), and HPLC grade

MeOH (300 mL) were added in a RBF and stirred overnight. Most of the MeOH

260

was evaporated off. Methyl ester 4.50 was recovered in quantitative yields and

used without further purification.

1H NMR (600 MHz, CDCl3) δ 3.66 (s, 2H), 3.87 (s, 6H), 4.56 (s, 2H)

Dimethyl tartrate 4.50 (7.5 g, 0.042 mol) and Et2O (60 mL) were added to a RBF

and the reaction mixture cooled with an ice-water bath (at °C). Periodic acid (11

g, 0.046 mol) was added in portions over 1h. The reaction mixture was gradually

warmed to rt and stirring was continued for 1h (at rt). The reaction mixture was

filtered through a pad of Celite®, and evaporated (with 45 torr pump). The crude

reaction mixture was purified using a kugelrohr apparatus (150 °C, 45 torr) to

obtain 4.51 as a clear liquid (3.6 g, 49% over two steps). Methyl glyoxalate 4.51

was used without further purification.

Methyl glyoxalate (0.78 g, 9.0 mmol), benzene (1.0 mL), dimethyl phosphite (0.82

mL, 9.0 mmol), and p-TsOH (2.5 mg, 0.013 mmol) were added in a RBF fitted

with a Dean-Stark trap and condenser. The reaction mixture was brought to

reflux. Reaction progress was monitored by TLC. After 2 h, heat was removed

and the benzene evaporated. The crude material was purified using flash

chromatography to yield phospohonate 4.52 (0.51 g, 29%).

TLC Rf = 0.38 (acetone/hexanes = 60/40) [KMnO4]

1H NMR (600 MHz, CDCl3) δ 4.59 (d, J = 16.0 Hz, 1H), 3.90 (s, 3H), 3.87

(dd, J = 10.7, 7.6 Hz, 6H).

261

Phosphonate 4.52 (0.74 g, 3.8 mmol), CH2Cl2 (10 mL), TESCl (0.76 mL, 4.5

mmol), NEt3 (0.57 mL, 4.1 mmol), and DMAP (46 mg, 0.38 mmol) were added to

a RBF and the cloudy, white reaction mixture stirred. After a 1 h, the reaction

mixture became clear. Reaction progress was monitored by TLC. The reaction

mixture was quenched with a saturated solution of NaHCO3 and extracted with

CH2Cl2 (3 x 10 mL) and the combined extract washed with brine (10 mL), dried


chromatography (hexanes/EtOAc = 25/75) to obtain phosphonate 4.47 (1.0 g,

86%).

TLC Rf = 0.63 (MeOH/ CH2Cl2 = 10/90)

1H NMR (600 MHz, C6D6) δ 4.66 (d, J = 18.1 Hz, 1H), 3.85 (dd, J = 10.5, 7.6

Hz, 6H), 3.82 (s, 3H), 0.98 (t, J = 7.9 Hz, 9H), 0.66 (q, J = 7.9 Hz,

6H).


Zinc powder (0.11 mg, 1.7 mmol) and THF (1.0 mL) were added to a scintillation




262



min. CuBr·SMe2 (0.26 g, 1.2 mmol) and THF (1.0 mL) were added to a separate

scintillation vial and cooled using a dry ice/acetone bath (at -78 °C). The

organozinc solution was syringed away from the residual zinc powder and added

dropwise to the CuBr·SMe2 solution followed by addition of TMSCl (0.16 mL, 1.2

mmol). The reaction mixture was warmed gradually to -30 °C. The

organocopper solution was then recooled with a dry ice/acetone bath (at -78 °C).

Cyclohexenone 4.56 (50 mg, 0.45 mmol) was added and the reaction mixture

was stirred for 1 h (at -78 °C). The reaction progress was monitored by TLC.

The reaction mixture was quenched with a saturated NH4Cl solution (5.0 mL).

The mixture was extracted with CH2Cl2 (3 x 2.5 mL) and the combined extract

washed with brine (1.0 mL), dried with Na2SO4, and evaporated. The crude

material was purified using flash chromatography to obtain compound B1 (43

mg, 42%).


1H NMR (500 MHz, CDCl3) δ 6.21 (s, 1H), 5.53 (s, 1H), 4.20 (q, J = 13.8, 6.9

Hz, 2H), 2.49 – 2.36 (os, 2H), 2.36 – 2.16 (os, 3H), 2.00 – 1.80 (os,

2H), 1.68 – 1.58 (m, 1H), 1.43 – 1.21 (m, 1H), 1.30 (t, J = 7.1 Hz,

3H), 1.08 (d, J = 6.7 Hz, 2H), 1.02 (d, J = 6.4 Hz, 1H).

Alkene B1 (43 mg, 0.19 mmol), NMO·H2O (0.78 mg, 0.57 mmol), and CH2Cl2 (10

mL) were added to a RBF and the mixture cooled with an ice-water bath (at 0

263

°C). The reaction was sparged with ozone containing oxygen and monitored by

TLC until the starting material (alkene B1) was consumed. The reaction mixture

was quenched with a solution of 1:1 saturated NaHCO3/Na2S2O3. The mixture

was extracted with CH2Cl2 (3 x 5.0 mL) and the combined extract washed with

brine (5.0 mL), dried with Na2SO4, and evaporated. The crude material was

purified using flash chromatography (hexanes/EtOAC = 1/1) to obtain compound

4.55 as a mixture of diastereomers (48 mg, 78%).


1H NMR (600 MHz, CDCl3) δ 4.29 (q, J = 7.1 Hz, 2H), 2.91 – 2.77 (os, 1.5H),

2.71 (dt, J = 11.5, 5.7 Hz, 0.5H), 2.49 – 2.40 (os, 1.5H), 2.35 – 2.27

(m, 0.5H), 2.22 (dd, J = 14.0, 5.9 Hz, 0.5H), 2.11 – 2.03 (m, 0.5H),

2.01 – 1.85 (os, 1.5H), 1.66 – 1.53 (m, 1H), 1.45 (ddd, J = 24.4,

12.8, 2.9 Hz, 0.5H), 1.34 (t, J = 7.1 Hz, 3H), 1.07 – 0.97 (os, 3H).


O TiCl4,CH2Cl2

-78 to -40 °C

O

68%

TMS

4.56 4.57a

H HO

4.57b

H

HH

Cyclohexenone 4.56 (0.85 g, 7.7 mmol) and CH2Cl2 (20 mL) were added to a

RBF and cooled with a dry ice/acetone bath (at -78 °C). TiCl4 (1.7 mL, 0.015

mol) was added dropwise to the vigorously stirring reaction mixture. After

complete addition of the TiCl4, the reaction mixture was stirred for an additional

264

30 min (at -78 °C). Allyltrimethylsilane (1.5 mL, 9.4 mmol) was added as a

CH2Cl2 solution (5.0 mL) into the reaction mixture with a syringe pump. The

reaction mixture was stirred for 1 h at -78 °C and then warmed to -40 °C and

stirred for an additional 1 h. Reaction progress was monitored by TLC. The

reaction mixture was quenched with water and extracted with CH2Cl2 (3 x 20 mL)

and the combined extract washed with brine (20 mL), dried with Na2SO4, and

evaporated (with 120 torr pump). The crude material was purified using flash

chromatography (hexanes/EtOAc = 97/3) to obtain cyclohexenone 4.57a and

4.57b (0.80 g, 68%).

TLC Rf = 0.26 (4.57a) and 0.33 (4.57b) (hexanes/EtOAc = 95/5)

[KMnO4]

Data corresponding to compound 4.57a

1H NMR (600 MHz, CDCl3) δ 5.75 (dt, J = 16.2, 7.3 Hz, 1H), 5.04 (s, 1H),

5.02 (d, J = 5.2 Hz, 1H), 2.42 (d, J = 13.1 Hz, 1H), 2.33 (dp, J =

12.4, 6.2 Hz, 1H), 2.14 – 2.05 (os, 3H), 2.01 (t, J = 13.1 Hz, 1H),

1.90 (d, J = 13.0 Hz, 1H), 1.85 – 1.76 (m, 1H), 1.44 – 1.29 (os, 2H),

1.01 (d, J = 6.5 Hz, 3H).

Data corresponding to compound 4.57b

TLC Rf = 0.26 (4.57a) and 0.33 (4.57b) (hexanes/EtOAc = 95/5)

[KMnO4]

1H NMR (600 MHz, CDCl3) δ 5.72 (dt, J = 17.4, 7.1 Hz, 1H), 5.04 (s, 1H),

5.01 (d, J = 7.4 Hz, 1H), 2.47 – 2.38 (os, 2H), 2.25 (dd, J = 13.9,

6.4 Hz, 1H), 2.14 – 2.07 (m, 1H), 2.06 – 1.99 (os, 2H), 1.91 (dt, J =

265

19.0, 6.1 Hz, 1H), 1.83 (ddd, J = 13.6, 9.6, 4.3 Hz, 1H), 1.69 – 1.58

(os, 2H), 1.07 (d, J = 6.8 Hz, 3H).


Alkene 4.57 (0.50 g, 3.3 mmol) and 3:1 acetone/water mixture (11 mL) were

added to a scintillation vial. OsO4 (1 g/25 mL in water) (1.5 mL, 0.16 mol) and

NMO·H2O (1.3 mg, 9.9 mmol) were added and the reaction mixture was stirred

overnight. TLC confirmed the alkene starting material (4.57) had been

consumed. NaIO4 (0.35 g, 1.6 mol) was added and the reaction mixture was

stirred for 15 min. The reaction mixture was filtered through a cotton plug and

Na2SO3 was added to the filtrate and stirred for 5 min. The mixture was extracted

with CH2Cl2 (3 x 10 mL) and the combined extract washed with brine (10 mL),

dried with Na2SO4, and evaporated. The crude material was purified using flash

chromatography to obtain compound 4.58 (2.2 mg, 39%).

TLC Rf = 0.28 (hexanes/ EtOAc = 60/40) [KMnO4]

1H NMR (600 MHz, CDCl3) δ 9.75 (s, 1H), 2.50 – 2.40 (os, 3H), 2.38 – 2.29

(os, 2H), 2.13 – 2.06 (os, 2H), 1.96 – 1.91 (m, 1H), 1.48 (ddd, J =

24.5, 12.9, 3.1 Hz, 1H), 1.40 (ddd, J = 26.1, 12.9, 3.1 Hz, 1H), 1.03

(d, J = 6.5 Hz, 3H)

266


Alkene 4.57 (0.50 g, 3.3 mmol) and 3:1 acetone/water mixture (80.0 mL) were

added to a scintillation vial. OsO4 (1 g/25 mL in water) (1.5 mL, 0.16 mol) and

NMO·H2O (1.3 mg, 9.9 mmol) were added and the reaction mixture was stirred

for 5 h. TLC confirmed the alkene starting material had been consumed. The

reaction mixture was quenched with a saturated solution of NaHSO3 and

extracted with Et2O (3 x 50 mL) and the combined extract washed with brine (50

mL), dried with MgSO4, and evaporated (with 120 torr pump). The crude diol

(4.59) was carried forward without further purification (0.57 g, 93%).

Diol 4.59 (0.57 g, 3.0 mmol) and CH2Cl2 (40 mL) were added into a RBF and

cooled with an ice-water bath. Imidazole (0.42 g, 6.1 mmol) and TBSCl (0.51 g,

3.4 mmol) were added to the reaction mixture. The reaction progress was

monitored by TLC and was complete after 3 h. The reaction mixture was

quenched with a saturated solution of NaHCO3 (50 mL) and extracted with

CH2Cl2 (3 x 50 mL) and the extract washed with brine (50 mL), dried with

Na2SO4, and evaporated. The crude material was purified using flash

chromatography (hexanes/EtOAc = 75/25) to obtain the TBS protected

compound as a mixture of diastereomers (0.11 g, 12%).

267

The TBS protected compound (33 mg, 0.11 mmol), CH2Cl2 (1.0 mL), NMO·H2O

(23 mg, 0.17 mmol), and 4Å MS were added into a RBF. After stirring for 5 min,

TPAP (2 mg, 6 µmol) was added and the reaction mixture was stirred overnight.

The reaction mixture was filtered through a pad of Celite®, evaporated, and

purified by column chromatography to obtain diketone 4.60 (16 mg, 49%).


1H NMR (600 MHz, CDCl3) δ 4.13 (s, 2H), 2.72 (hept, J = 5.9 Hz, 1H), 2.50

– 2.41 (os, 4H), 2.20 (dd, J = 13.9, 5.8 Hz, 1H), 1.97 (td, J = 10.5,

5.5 Hz, 1H), 1.93 – 1.86 (m, 1H), 1.65 – 1.59 (m, 1H), 1.59 – 1.52

(m, 1H), 1.06 (d, J = 6.7 Hz, 3H), 0.92 (s, 9H), 0.08 (s, 6H).


K2CO3MeOH

O

O OH

O

87%

4.58 4.61

Aldehyde 4.58 (0.10 g, 0.65 mmol), K2CO3 (81 mg, 0.58 mmol), and MeOH (13

mL) were added to a scintillation vial and stirred for 1 h. The reaction progress


NaHCO3 solution (10 mL). The mixture was extracted with EtOAc (3 x 10 mL)

and the combined extract washed with brine (10 mL), dried with MgSO4, and


obtain compound 4.61 as a mixture of diastereomers (87 mg, 87%).

268


Data corresponding to maJor diastereomer

1H NMR (600 MHz, CDCl3) δ 3.90 (d, J = 8.6 Hz, 1H), 2.35 – 2.28 (m, 1H),

2.26 – 2.19 (os, 3H), 1.66 – 1.54 (os, 6H), 1.06 (s, 3H)

Synthesis of Compound 4.62a and 4.62b

Using K2CO3 as the base

Ketone 4.60 (16 mg, 0.05 mmol), K2CO3 (0.7 mg, 0.05 mmol) and MeOH (0.5

mL) were added into a scintillation vial and stirred overnight. The reaction

mixture was quenched with a saturated NH4Cl solution (0.5 mL). The mixture

was extracted with CH2Cl2 (3 x 0.5 mL) and the extract washed with brine (0.5

mL), dried with Na2SO4, and evaporated. The crude NMR show a ratio of 11:1 of

the two diastereomers 4.62a and 4.62b. The crude material was purified using

flash chromatography to obtain compound 4.62a and 4.62b (9 mg and 6 mg

respectively, 93%).

TLC Rf = 0.37 (4.62a) and 0.34 (4.62b) respectively (hexanes/EtOAc =

75/25) [Anisaldehyde]

Data corresponding to Compound 4.62a

1H NMR (600 MHz, C6D6) δ 3.19 (s, 2H), 2.14 – 2.08 (m, 2H), 1.99 (qt, J =

18.4, 2.8 Hz, 1H), 1.74 (dt, J = 5.9, 2.9 Hz, 1H), 1.69 (dt, J = 14.1,

269

2.6 Hz, 1H), 1.63 (s, 1H), 1.62 – 1.55 (m, 1H), 1.51 (dt, J = 14.1,

3.2 Hz, 1H), 1.29 – 1.23 (m, 3H), 1.07 (s, 1H), 1.06 – 1.02 (m, 9H),

0.88 (s, 1H), -0.03 (d, J = 11.2, 6H).

13C NMR (125 MHz, CDCl3) δ 215.0, 77.3, 77.0, 76.7, 73.2, 68.9, 50.5, 43.28,

41.0, 27.2, 26.8, 25.8, 24.5, 18.2, 13.7

Data corresponding to Compound 4.62b

1H NMR (600 MHz, CDCl3) δ 3.34 (d, J = 9.5 Hz, 1H), 3.25 (d, J = 9.6 Hz,

1H), 2.28 (s, 1H), 2.24 – 2.10 (os, 4H), 1.85 – 1.78 (os, 2H), 1.73

(dt, J = 14.4, 3.2 Hz, 1H), 1.63 (qd, J = 6.1, 3.1 Hz, 1H), 1.27 (ddd,

J = 13.8, 11.7, 5.9 Hz, 1H), 0.97 (s, 3H), 0.88 (s, 9H), 0.04 (d, J =

4.7 Hz, 6H).

Using LDA as the base

Diisopropylamine (1.4 mL, 10 mmol) and THF (4.0 mL) were added to a RBF and


(2.30 M in hexanes) (3.5 mL, 9.1 mmol). The reaction mixture was stirred at 0 °C

for 10 min and then cooled with a dry ice/acetone bath. Diketone 4.60 (1.0 g, 9.1

mmol) as a THF solution (1.0 mL) was added dropwise to the freshly prepared

LDA solution at -78 °C and the resulting mixture was allowed to stir for 30 min.

The reaction mixture was warmed gradually to rt. The reaction mixture was

quenched with a saturated NaHCO3 solution. The mixture was extracted with

270

CH2Cl2 (3 x 20 mL) and the combined extract washed with brine (20 mL), dried


chromatography to obtain compound 4.62a and 4.62b as a mixture of

diastereomers 1:37 (19 mg combined, 95%).

TLC Rf = 0.37 (4.62a) and 0.34 (4.62b) respectively (hexanes/EtOAc =

75/25) [Anisaldehyde]

Data matched that from the K2CO3 experiments listed above.


Alcohol 4.61 (10 mg, 0.65 mmol), CH2Cl2 (1.0 mL), NMO·H2O (13 mg, 0.97

mmol), and 4Å MS were added into a RBF. After stirring for 5 min, TPAP (1 mg,

3 µg) was added and the reaction mixture was stirred overnight. The reaction

mixture was filtered through a pad of Celite®, evaporated, and purified by column

chromatography (hexanes/EtOAc = 60/40) to obtain diketone 4.60 (9.6 mg, 97%).


1H NMR (600 MHz, CDCl3) δ 2.65 – 2.61 (m, 1H), 2.55 (d, J = 21.0 Hz, 2H),

2.39 (d, J = 20.2 Hz, 2H), 1.91 (s, 4H), 1.11 (s, 3H).

13C NMR (125 MHz, CDCl3) δ 62.6, 43.9, 30.0, 27.5, 24.7, 12.1

271


O

OO O BrMg O

OO HO

THF, -78 °C

H97%

4.1 4.65

Cyclohexenone 4.1 (0.60 g, 2.7 mmol) and THF (5.0 mL) were added into a RBF

cooled with a dry ice/acetone bath. Allylmagnesium bromide (0.6 M in Et2O

solution, 8.9 mL, 5.4 mmol) was added dropwise with a syringe pump. TLC after

5 min showed reaction completion. The reaction mixture was quenched with a

saturated NaHCO3 solution (20 mL). The mixture was extracted with Et2O (3 x

20 mL) and the combined extract washed with brine (20 mL), dried with MgSO4,

and evaporated. The crude material was purified using flash chromatography to

obtain compound 4.65 as a white solid (0.63 mg, 97%).


1H NMR (600 MHz, C6D6) δ 5.43 – 5.34 (m, 1H), 5.32 (ddd, J = 10.0, 4.3, 3.1

Hz, 1H), 4.98 (d, J = 10.0 Hz, 1H), 4.89 (d, J = 10.2 Hz, 1H), 4.80

(dd, J = 17.1, 1.2 Hz, 1H), 4.23 – 4.17 (os, 6H), 2.07 – 2.02 (m,

1H), 1.90 (dd, J = 14.1, 6.7 Hz, 1H), 1.77 (s, 3H), 1.54 – 1.47 (m,

1H), 1.33 – 1.26 (m, 1H), 1.12 – 1.03 (os, 2H), 0.92 – 0.85 (m, 2H).

272


KH (30% in mineral oil, 0.41 g, 0.010 mol) was weighed into a scintillation vial

and washed with THF (3 x 0.5 mL). KH was brought up in fresh THF (1.5 mL)

and the reaction mixture was cooled with an ice-water bath. 18-crown-6 (1.1 g,

4.4 mmol) was added and the reaction mixture was stirred for 5 min. Alkene 4.65

(0.55 g, 2.7 mmol) in a THF solution (0.5 mL) was added dropwise. Reaction

progress was monitored by TLC, completion was observed after 3 h. The

reaction mixture was quenched by slow, careful addition of the reaction mixture

to a vigorously stirring solution of saturated NaHCO3 solution (5.0 mL). The

mixture was extracted with CH2Cl2 (3 x 5.0 mL) and the combined extract


material was purified using flash chromatography (hexanes/EtOAc = 75/25), to



1H NMR (600 MHz, C6D6) δ 5.43 (ddt, J = 17.2, 10.1, 7.2 Hz, 1H), 4.95 (dd,

J = 10.1, 0.7 Hz, 1H), 4.88 (dd, J = 17.0, 1.5 Hz, 1H), 4.06 (dd, J =

7.9, 3.1 Hz, 3H), 4.02 (dd, J = 7.9, 3.1 Hz, 3H), 2.02 (ddd, J = 12.6,

3.7, 2.2 Hz, 1H), 1.76 (s, 3H), 1.61 (tq, J = 13.8, 6.9 Hz, 2H), 1.30 –

1.25 (os, 2H), 1.24 – 1.19 (m, 1H), 1.15 – 1.06 (os, 2H), 0.62 – 0.47

(os, 2H)

273


• Synthesis of diol B2

Alkene 4.66 (0.10 g, 0.38 mmol), K2CO3 (16 mg, 0.11 mmol), and 3:1

acetone/water mixture (12 mL) were added into a RBF. OsO4 (1 g/25 mL in

water) (3.5 µL, 5.6 µmol) and NMO·H2O (46 mg, 0.34 mmol) were added and the

reaction mixture was stirred overnight. TLC confirmed the alkene starting

material had been consumed. Na2SO3 was added and the reaction mixture was

stirred for 30 min. The reaction mixture was extracted with EtOAc (3 x 50 mL)

and the combined extract washed with brine (20 mL), dried with MgSO4, and

evaporated. The crude diol B2 was obtained a mixture of diastereomers, 84 mg

(84%) and used without further purification.

Data corresponding to compound B2

TLC Rf = 0.15 (EtOAc = 100) [KMnO4]


2.8 Hz, 3H), 3.32 – 3.27 (m, 0.36H), 3.23 – 3.18 (m, 0.43H), 3.12 –

3.07 (m, 0.75H), 2.99 – 2.92 (m, 0.62H), 2.17 (d, J = 13.4 Hz,

0.27H), 2.12 (d, J = 12.9 Hz, 0.33H), 1.76 (s, 3H), 1.56 – 1.45 (os,

274

1.23H), 1.40 – 1.23 (os, 6.35H), 1.15 – 1.08 (os, 1.83H), 1.00 –

0.86 (os, 1.58H), 0.84 – 0.79 (m, 0.49H), 0.76 – 0.71 (m, 0.40H),

0.65 – 0.59 (os, 1.30H), 0.57 – 0.48 (os, 0.94H)

• Synthesis of compound B3

Diol B1 (0.24 g, 0.80 mmol), imidazole (0.16 g, 2.4 mmol) and CH2Cl2 (16 mL)

were added into a RBF. TBSCl (0.18 g, 1.2 mmol) was added to the vigorously

stirring reaction mixture. Reaction progress was monitored by TLC (Rf = 0.80,

100% EtOAc). The reaction mixture was quenched with a saturated NaHCO3

solution (20 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL) and the

combined extract washed with brine (10 mL), dried with Na2SO4, and evaporated.

The crude material was purified using flash chromatography to obtain compound

B3 as a white solid (0.21 mg, 63%).




3.0 Hz, 3H), 3.50 (d, J = 44.6 Hz, 1H), 3.34 (td, J = 9.3, 3.9 Hz, 1H),

3.25 – 3.20 (m, 1H), 2.25 (dddd, J = 31.3, 12.6, 3.6, 2.1 Hz, 1H),

2.09 (d, J = 26.2 Hz, 1H), 1.75 (s, 3H), 1.72 – 1.63 (m, 1H), 1.51 –

275

1.34 (os, 3H), 1.29 – 0.95 (os, 3H), 0.92 (s, 9H), 0.76 – 0.58 (os,

2H), 0.01 (s, 6H).

• Synthesis of compound 4.67

O

OO O

OH

OTBS

H

H

NMO•H2OTPAP, 4Å MS

CH2Cl2

O

OO O

O

OTBS

H

H

78%

B2 4.67

TBS protected compound B2 (0.18 g, 0.11 mmol), CH2Cl2 (2.0 mL), NMO·H2O

(88 mg, 0.65 mmol), and 4Å MS (0.22 g) were added into a RBF. After stirring

for 5 min, TPAP (7.6 mg, 22 µmol) was added and the reaction mixture was

stirred overnight. The reaction mixture was filtered through a pad of Celite®,

evaporated, and purified by column chromatography to obtain diketone 4.67

(0.14 g, 78%).

Data corresponding to compound 4.67



3.1 Hz, 3H), 3.83 (d, J = 2.0 Hz, 2H), 2.08 (ddd, J = 12.6, 3.8, 2.2

Hz, 1H), 1.96 (ddd, J = 22.5, 16.9, 6.4 Hz, 2H), 1.87 – 1.83 (m, 1H),

1.74 (s, 3H), 1.43 – 1.35 (os, 2H), 1.31 (dd, J = 12.8, 5.1 Hz, 1H),

1.14 – 1.07 (m, 1H), 0.94 (s, 9H), 0.69 – 0.55 (os, 2H), -0.01 (s,

6H).

276


Compound 4.67 (25 mg, 61 µmol) and THF (0.5 mL) were added into a

scintillation vial and the reaction mixture was cooled with a dry ice/acetone bath.

TBAF (1.0 M solution in THF, 67 µL, 67 µmol) was added dropwise. The

reaction mixture was held at -78 °C for 30 then warmed gradually to rt. Reaction

progress was monitored by TLC. After stirring at rt for 1.5 h, the reaction was

complete by TLC. The reaction mixture was quenched with a saturated NaHCO3

solution (1.0 mL). The mixture was extracted with EtOAc (3 x 10 mL) and the

combined extract washed with brine (1.0 mL), dried with MgSO4, and evaporated.

The crude material was purified using flash chromatography to obtain compound

B4 as a white solid (7.4 mg, 41%).


TLC Rf = 0.44 (MeOH/EtOAc = 5/95) [Anisaldehyde]

1H NMR (600 MHz, C6D6) δ 4.26 (s, 2H), 4.01 (dd, J = 7.9, 3.1 Hz, 3H), 3.97

(dd, J = 7.9, 3.1 Hz, 3H), 3.29 (s, 3H), 2.05 (ddd, J = 12.7, 3.7, 2.3

Hz, 1H), 1.83 – 1.72 (m, 4H), 1.54 (s, 3H), 1.33 (dd, J = 26.5, 13.3

Hz, 3H), 1.22 (dd, J = 12.6, 5.0 Hz, 1H), 1.08 – 1.00 (m, 1H), 0.61 –

0.49 (m, 2H)

Ketone alcohol B4 (1.6 mg, 5.4 µmol), K2CO3 (1.5 mg, 11 µmol), and MeOH (0.5

mL) were added into a RBF and stirred for 1 h. Reaction progress was

277

monitored by TLC. The reaction mixture was quenched with a saturated

NaHCO3 solution (1.0 mL). The mixture was extracted with CH2Cl2 (3 x 0.5 mL)

and the combined extract washed with brine (1.0 mL), dried with Na2SO4, and


obtain compound 4.69 as a white solid (1.6 mg, quantitative yield).


TLC Rf = 0.39 (CH2Cl2 /EtOAc = 80/20) [Anisaldehyde]

1H NMR (600 MHz, C6D6) δ 3.99 (qd, J = 7.9, 3.1 Hz, 6H), 3.29 (s, 2H), 2.05

(ddd, J = 12.7, 3.7, 2.3 Hz, 1H), 1.83 – 1.72 (m, 1H), 1.75 (s, 3H),

1.71 – 1.65 (m, 1H), 1.54 (s, 2H), 1.33 (dd, J = 26.5, 13.3 Hz, 2H),

1.22 (dd, J = 12.6, 5.0 Hz, 1H), 1.08 – 1.00 (m, 1H), 0.55 (os, 2H).


Diol 4.70 (42 mg, 0.14 mmol) and CH2Cl2 (0.5 mL) were added into a RBF and

cooled with an ice-water bath. DIPEA (75 µL, 0.42 mmol) was added dropwise

and the reaction mixture was stirred for 5 min. MOMCl (13 µL, 0.78 mmol) was

added dropwise and the reaction progress was monitored by TLC. After 30 min

at 0 °C, the reaction mixture warmed gradually to rt and stirred for an additional 2

h. The reaction mixture was quenched with a saturated NaHCO3 solution (1.0

mL). The mixture was extracted with CH2Cl2 (3 x 0.5 mL) and the combined

278

extract washed with brine (1.0 mL), dried with Na2SO4, and evaporated. The

crude material was purified using flash chromatography to obtain the MOM-

protected alcohol intermediate as a mixture of diastereomers (28 mg, 58%).

TLC Rf = 0.31 (EtOAc) [Anisaldehyde]

The MOM-protected alcohol (6.4 mg, 19 µmol), CH2Cl2 (0.5 mL), NMO·H2O (3.8

mg, 2.8 µmol), and 4Å MS (25 mg) were added into a RBF. After stirring for 5

min, TPAP (0.3 mg, 0.97 µmol) was added and the reaction mixture was stirred

for 2 h. The reaction mixture was filtered through a pad of Celite®, evaporated

and purified by column chromatography to obtain diketone 4.71 (6.4 mg, 47%).

TLC Rf = 0.23 (MeOH/ CH2Cl2 = 5/95) [Anisaldehyde]


(dd, J = 7.9, 3.1 Hz, 3H), 3.70 (d, J = 1.7 Hz, 2H), 3.08 (d, J = 3.8

Hz, 3H), 2.04 (ddd, J = 12.7, 3.5, 2.3 Hz, 1H), 1.90 – 1.77 (os, 3H),

1.76 (s, 3H), 1.40 – 1.30 (os, 2H), 1.27 (dd, J = 13.0, 5.1 Hz, 1H),

1.09 – 1.04 (m, 1H), 0.65 – 0.50 (os, 2H)


279

Magnesium (0.428 g, 18 mmol), one crystal of I2 and THF (5.0 mL) were added

into a RBF and the reaction flask was cooled with an ice-water bath. Allyl

chloride B5 (1.8 g, 8.8 mmol) was added dropwise as a THF solution (1.5 mL)

with a syringe pump. The reaction mixture progressed from cloudy to clear.

Cyclohexenone 4.1 (0.50 g, 2.2 mmol) and THF (2.0 mL) were added to a

separate RBF and cooled with a dry ice/acetone bath. The Grignard solution

was carefully syringed away from the unreacted magnesium and added dropwise

to the stirring, cooled cyclohexenone reaction mixture. The reaction mixture was

quenched with a saturated NaHCO3 solution (10 mL). The mixture was extracted

with EtOAc (3 x 20 mL) and the combined extract washed with brine (25 mL),

dried with MgSO4, and evaporated. The crude material was purified using flash

chromatography to obtain compound 4.73 (0.74 g, 85%) as a mixture of

diastereomers (ratio of 1:2)

TLC Rf = 0.23 and 0.39 (MeOH/ EtOAc = 10/90) [KMnO4]

1H NMR (600 MHz, C6D6) δ 7.31 – 7.19 (os, 2H), 7.11 – 6.98 (os, 3H), 5.44

– 5.21 (os, 3H), 5.05 (s, 0.5H), 4.95 (s, 1H), 4.78 (s, 0.5H), 4.71 (s,

1H), 4.32 – 4.07 (os, 12H), 3.73 – 3.58 (os, 3H), 3.54 (s, 1H), 3.41

(s, 0.5H), 2.39 (d, J = 12.9 Hz, 0.5H), 2.22 – 2.06 (os, 2.5H), 1.78

(s, 3H), 1.77 (s, 1.5H), 1.63 – 1.54 (os, 1.5H), 1.53 – 1.45 (m,

280

0.5H), 1.41 (d, J = 18.8 Hz, 1H), 1.32 (d, J = 11.8 Hz, 0.5H), 1.27 –

1.20 (os, 2H), 1.17 (dd, J = 13.5, 6.0 Hz, 0.5H), 1.14 – 1.07 (m,

1H), 0.81 (ddd, J = 24.9, 13.4, 5.8 Hz, 0.5H)


Allylic alcohol 4.73 (25 mg, 64 mmol), 18-crown-6 (0.10 g, 39 mmol), and THF

(6.5 mL) were added into a RBF and cooled with an ice-water bath. KOtBu (1.0

M in THF, 0.19 mL, 19 mmol) were added dropwise. The reaction mixture was

warmed gradually to rt and stirred for an additional 3 h. Reaction progress was


NaHCO3 solution (10 mL). The mixture was extracted with Et2O (3 x 10 mL) and

the combined extract washed with brine (10 mL), dried with MgSO4, and


obtain compound 4.74 (6 mg, 23%).


1H NMR (600 MHz, C6D6) δ 7.23 (dd, J = 56.3, 7.5 Hz, 4H), 7.08 (t, J = 7.4

Hz, 1H), 5.06 (s, 1H), 4.74 (s, 1H), 4.29 (s, 2H), 4.06 (dd, J = 7.9,

3.1 Hz, 3H), 4.02 (dd, J = 7.9, 3.1 Hz, 3H), 3.67 (d, J = 4.2 Hz, 2H),

2.11 (ddd, J = 12.6, 3.7, 2.2 Hz, 1H), 1.82 (dd, J = 13.8, 7.0 Hz,

281

1H), 1.76 (s, 3H), 1.78 – 1.67 (os, 2H), 1.43 (m, 1H), 1.34 – 1.23

(m, 3H), 1.13 – 1.08 (m, 1H), 0.54 (dddd, J = 28.1, 25.2, 13.1, 3.3

Hz, 2H).


Alkene 4.74 (5.7 mg, 15 µmol), NMO·H2O (6.0 mg, 44 µmol), and 3:1

acetone/water solution (0.5 mL) were added into a scintillation vial. OsO4 (1 g/25

mL in water) (5 µL, 0.7 µmol) was added to the stirring reaction mixture.

Reaction progress was monitored by TLC. After 3 h, NaIO4 (16 mg, 74 µmol)

was added to the reaction mixture and after 5 min, the diol intermediate was

completely consumed. The reaction mixture was filtered through a cotton plug

and Na2SO3 was added to the filtrate and stirred for 5 min. The mixture was

extracted with CH2Cl2 (3 x 0.5 mL) and the combined extract washed with brine

(0.5 mL), dried with Na2SO4, and evaporated. The crude material was purified

using flash chromatography to obtain compound 4.75 (2.2 mg, 39%).


1H NMR (600 MHz, C6D6) δ 7.34 – 7.28 (os, 4H), 7.19 (m, 1H), 4.30 (d, J =

1.8 Hz, 2H), 4.13 (dd, J = 7.8, 3.1 Hz, 3H), 4.09 (dd, J = 7.8, 3.1

Hz, 3H), 3.68 (d, J = 2.2 Hz, 2H), 2.17 – 2.13 (m, 1H), 2.05 (ddd, J

= 22.8, 17.0, 6.3 Hz, 3H), 1.94 (dd, J = 14.0, 7.1 Hz, 1H), 1.86 (s,

282

3H), 1.65 (s, 1H), 1.48 – 1.33 (m, 5H), 1.24 – 1.13 (m, 2H), 0.74 –

0.60 (os, 2H)


N

O

OO O

OMe

MeMgClTHF

0 C rt

89%

O

OO O

4.78 4.79

Amide 4.78 (1.0 g, 3.5 mmol) and THF (20 mL) were added into a RBF and

cooled with an ice-water bath. Methylmagnesium chloride (3.0 M in THF, 3.5 mL,

11 mmol) was added dropwise with a syringe pump. The reaction mixture

warmed gradually to rt and stirred overnight. The reaction mixture was quenched

with a saturated NaHCO3 solution (50 mL). The mixture was extracted with

EtOAc (3 x 25 mL) and the combined extract washed with brine (20 mL), dried


chromatography to obtain compound 4.79 as a white solid (0.75 g, 89%). An

analytical sample of ketone 4.79 could be prepared by recrystallization using

toluene/hexanes (5/1).

MP 48-52 °C


1H NMR (600 MHz, C6D6) δ 5.41 – 5.30 (m, 1H), 4.84 (d, J = 9.3 Hz, 1H),

4.78 (dd, J = 17.1, 1.5 Hz, 1H), 3.87 (dd, J = 8.2, 3.5 Hz, 3H), 3.71

(dd, J = 8.2, 3.5 Hz, 3H), 1.76 (dd, J = 11.7, 2.7 Hz, 1H), 1.68 (s,

283

3H), 1.62 – 1.55 (m, 1H), 1.45 (s, 3H), 1.44 – 1.31 (os, 2H), 0.84 –

0.77 (m, 1H)

13C NMR (125 MHz, C6D6) δ 208.5, 137.3, 115.8, 109.0, 69.2, 51.2, 35.2,

33.6, 31.99, 3.1, 23.9


O

OO O

O

cat Grubbs2nd Gen.

57%

4.79

O

OO O

O

4.80

To a RBF was added CH2Cl2 (10 mL). The CH2Cl2 was degassed by refluxing

under a constant stream of argon for 30 min. After the CH2Cl2 cooled to rt, the

methyl ketone 4.79 (0.1 g, 0.42 mmol) was added followed by the addition of the

methyl vinyl ketone (84 µL, 1.0 mmol). Grubbs 2nd Generation catalyst was

added to the reaction mixture and heated to reflux. The heating was maintained

for 1 h. The progress of the reaction was monitored by TLC. After 1 h, the

reaction mixture was cooled to rt and most of the CH2Cl2 was evaporated and the

crude material, a brown oil, was purified by flash chromatography to obtain

compound 4.80 as a tan solid (68 mg, 57%). The starting alkene (4.79) was also

recovered (26 mg, 26%).


1H NMR (600 MHz, C6D6) δ 6.10 (dt, J = 15.9, 6.6 Hz, 1H), 5.73 (d, J = 15.9

Hz, 1H), 3.84 (dd, J = 8.2, 3.5 Hz, 3H), 3.69 (dd, J = 8.2, 3.5 Hz,

284

3H), 1.85 (s, 3H), 1.67 (s, 3H), 1.63 (dd, J = 11.4, 2.7 Hz, 1H), 1.46

– 1.37 (m, 1H), 1.42 (s, 3H), 1.36 – 1.23 (os, 2H), 0.74 – 0.69 (m,

1H)


Diketone 4.80 (10 mg, 0.35 mmol), K2CO3 (25 mg, 0.18 mmol), and MeOH (0.5

mL) were added to a scintillation vial and stirred for 1 h. The reaction progress


NaHCO3 solution (10 mL). The mixture was extracted with EtOAc (3 x 0.5 mL)

and the combined extract washed with brine (0.5 mL), dried with MgSO4, and





3.0 Hz, 3H), 2.00 (ddd, J = 12.6, 3.9, 2.2 Hz, 1H), 1.76 – 1.66 (os,

5H), 1.65 – 1.59 (m, 1H), 1.58 – 1.52 (os, 4H), 1.37 – 1.27 (os, 3H),

1.13 – 1.06 (m, 1H), 0.67 – 0.58 (m, 1H), 0.56 – 0.47 (m, 1H).

13C NMR (125 MHz, C6D6) δ 206.6, 204.4, 109.3, 68.7, 49.9, 49.4, 48.5, 35.3,

34.91, 31.3, 29.8, 26.9, 24.2

285


In a RBF was added CH2Cl2 (10 mL). The CH2Cl2 was degassed by refluxing

under a constant stream of argon for 30 min. After the CH2Cl2 cooled to rt, the

methyl ketone 4.79 (0.1 g, 0.42 mmol) was added followed by the addition of the

crotonaldehyde (84 µL, 1.0 mmol). Grubbs 2nd Generation catalyst was added to

the reaction mixture. The progress of the reaction was monitored by TLC. After

1 h, most of the CH2Cl2 was evaporated and the crude material, brown oil was

purified by flash chromatography to obtain compound 4.83 as a tan solid (73 mg,

65%). The starting alkene (4.79) was also recovered (13 mg, 13%). An

analytical sample of aldehyde 4.83 could be prepared by recrystallization using

MTBE/EtOH (1/1).

MP 76-80 °C


1H NMR (600 MHz, C6D6) δ 9.27 (s, 1H), 5.72 – 5.68 (os, 2H), 3.82 (dd, J =

8.1, 3.4 Hz, 3H), 3.67 (dd, J = 8.1, 3.4 Hz, 3H), 1.68 (s, 3H), 1.55

(d, J = 8.7 Hz, 1H), 1.37 (s, 3H), 1.41 – 1.31 (m, 1H), 1.25 – 1.16

(os, 2H), 0.66 – 0.59 (m, 1H)

13C NMR (125 MHz, C6D6) δ 207.7, 192.1, 154.2, 133.6, 109.1, 69.0, 51.2,

35.1, 33.6, 30.4, 24.9, 23.9

286

Synthesis of Compound 4.84 and 4.85

Compound 4.83 (10 mg, 0.35 mmol), K2CO3 (25 mg, 0.18 mmol), and MeOH (0.5

mL) were added to a scintillation vial and stirred overnight. The reaction


saturated NaHCO3 solution (10 mL). The mixture was extracted with EtOAc (3 x


and evaporated. 1H NMR of the crude material showed no starting aldehyde

(4.83) and a 1:1.5 ratio of bicyclo[2.2.2]octane product 4.85 to the cyclohexenone

product 6.84. The desired product (4.85) could be obtained by being crystallized

from benzene obtain a white solid (2.7 mg, 27%).



1H NMR (600 MHz, CDCl3) δ 4.37 (dd, J = 8.2, 2.9 Hz, 3H), 4.23 (dd, J =

8.2, 2.9 Hz, 3H), 4.20 – 3.19 (m, 1H), 1.98 (d, J = 18.2 Hz, 1H),

1.77 (s, 3H), 1.69 (d, J = 18.2 Hz, 1H), 1.42 (s, 1H), 0.93 (t, J =

12.1 Hz, 1H), 0.81 (t, J = 10.2 Hz, 1H), 0.74 – 0.69 (m, 1H), 0.66 (d,

J = 14.1 Hz, 1H), 0.53 (ddd, J = 13.7, 11.0, 7.6 Hz, 1H), 0.44 (d, J =

3.4 Hz, 1H).

287

13C NMR (125 MHz, C6D6) δ 209.4, 109.5, 68.4, 67.8, 52.2, 44.6, 38.1, 37.5,

26.7, 25.0, 24.1, 21.1

288

Spectra of Compounds from Chapter 4 Figure 4.1 – 1H NMR of Compound 4.6 (500 MHz, CDCl3)

289


290


291


292


293


294


295

Figure 4.8 – 1H NMR of Compound 4.37a (600 MHz, C6D6)

296

Figure 4.9 – 1H NMR of Compound 4.37b (600 MHz, C6D6)

297


298


299


300


301


302


303


304

Figure 4.17 – 1H NMR of Compound B1 (500 MHz, CDCl3)

305


306

Figure 4.19 – 1H NMR of Compound 4.57a (600 MHz, CDCl3)

307

Figure 4.20 – 1H NMR of Compound 4.57b (600 MHz, CDCl3)

308


309


310


311

Figure 4.24 – 1H NMR of Compound 4.62a (600 MHz, C6D6)

312

Figure 4.25 – 13C NMR of Compound 4.62a (125 MHz, CDCl3)

313

Figure 4.26 – 1H NMR of Compound 4.62b (600 MHz, CDCl3)

314


315


316


317


318

Figure 4.31 – 1H NMR of Compound B2 (600 MHz, C6D6)

319


320


321


322


323


324


325


326


327


328


329


330


331


332


333


334


335


336

A.1 Experimental – Reactions in Chapter 5


THF (75 mL) and n-BuLi (3.35 M in THF, 12 mL, 40 mmol) were added into a

RBF. The reaction flask was cooled with a dry ice/acetone bath. Nitrile 5.28 (7.0

g, 41 mmol) in THF solution (100 mL) was added dropwise to the cooled n-BuLi

solution. The reaction mixture was stirred for 30 min and then warmed gradually

by moving the reaction flask to an ice-water bath. The reaction mixture was

stirred for an additional 10 min and then cooled again with a dry ice/acetone

bath. Homoallyl iodide (8.3 g, 46 mmol) in THF solution (10 mL) was added

dropwise to the reaction mixture. After stirring for 30 min at -78 °C, the reaction

mixture was allowed to warm gradually to 5 °C over 2.5 h. The reaction mixture

was moved to an ice-water bath and the CeCl3 mixture was added rapidly

through a cannula.

[To prepare the CeCl3 mixture: CeCl3 (15 g, 62 mmol) and THF (100 mL) were

added into a RBF and stirred for 2 h. The CeCl3 solution was cooled with an ice-

337

water bath and methylmagnesium chloride (2.78 M in THF, 21 mL, 58 mmol) was

added dropwise and stirred for 2.5 h.]

The reaction mixture was stirred for 1 h at 0 °C, and then quenched with a

saturated NaHCO3 solution and water. The mixture was extracted with EtOAc (3

x 200 mL) and the combined extract washed with brine (200 mL), dried with

MgSO4, and evaporated. The imine (5.29), THF (210 mL), water (11 mL), and

acetic acid (11 mL, 0.17 mol) were added into a RBF. The reaction progress was

monitored by TLC (hexanes/EtOAc = 10/90). After 2 h, the imide had completely

converted to the ketone. The reaction mixture was quenched with a saturated

NaHCO3 solution and water. The mixture was extracted with EtOAc (2 x 200 mL)


evaporated to obtain a pale yellow/orange oil. The crude product was purified

using flash chromatography (hexanes/EtOAc = 75/25) to obtain compound 5.1,

6.5 g (65%).


Analytical data matched the previous compound (4.70) isolated from the

Grignard reaction.


338

Alkene 5.1 (0.10 g, 0.42 mmol), NMO·H2O (0.17 g, 1.3 mmol), and CH2Cl2 (20

mL) were added to a RBF and the mixture cooled with an ice-water bath. The

reaction was sparged with ozone containing oxygen and monitored by TLC

(hexanes/EtOAc = 75/25) until the starting material (alkene 5.1) was consumed.

The reaction mixture was warmed to rt and quenched with a solution of 1:1

saturated NaHCO3/Na2S2O3. The mixture was extracted with CH2Cl2 (3 x 10 mL)


evaporated. The crude aldehyde C1 was used in the next step without further

purification (81 mg, 80%).

Data corresponding to compound C1



(dd, J = 8.2, 3.5 Hz, 3H), 1.69 (dd, J = 11.5, 3.0 Hz, 1H), 1.67 (s,

3H), 1.44 – 1.38 (m, 1H), 1.37 (s, 3H), 1.33 – 1.21 (os, 2H), 1.05 –

0.96 (m, 1H).

Aldehyde C1 (81 mg, 0.34 mmol), CH2Cl2 (25 mL), and DBU (31 µL, 0.21 mmol),

were added into a RBF and stirred overnight. Reaction progress was monitored

by TLC (100% EtOAc). NEt3 (0.52 mL, 3.8 mmol) and MsCl (97 µL, 1.3 mmol)

were added to the reaction mixture. Reaction was complete after 5 min. The

reaction mixture was quenched with a saturated NaHCO3 solution. The mixture

was extracted with CH2Cl2 (3 x 25 mL) and the combined extract washed with

brine (25 mL), dried with Na2SO4, and evaporated. The crude product was

339

purified using flash chromatography (hexanes/EtOAc = 50/50) to obtain

compound 5.1 (55 mg, 59%).


1H NMR matched the previous compound (3.10) isolated from the olefin

metathesis reaction.


Aldehyde 5.2 (0.50 g, 1.9 mmol) was dissolved in dioxane (30 mL). To the

aldehyde solution was added a Na2CO3 (0.30 g, 2.8 mmol) solution in water (10

mL). The reaction mixture was stirred at rt for 3 h. A Celite® pad was prepared

and the reaction mixture was filtered and the pad washed with dioxane (3 x 10

mL). The filtrate was evaporated to obtain a thick, brown oil. To the brown oil

was added benzene dropwise until crystallization began. The solid was filtered

and washed with benzene (3 x 0.25 mL) to obtain compound 5.4 as a white solid

(0.32 g, 63%).

1H NMR matched the previous compound (4.85) isolated from the K2CO3/MeOH

reaction conditions.

340


Imidazole (0.16 g, 2.3 mmol), DMAP (12 mg, 0.09 mmol), and DMF (1.0 mL)

were added into a RBF. TESCl was added dropwise to the vigorously stirring

reaction mixture. Alcohol 5.2 (25 mg, 0.09 mmol) was dissolved in DMF (0.25

mL) and added to the reaction mixture and stirred for 3 h. Reaction progress

was monitored by TLC (hexanes/EtOAc = 40/60). The reaction mixture was

quenched with a saturated NaHCO3 solution. The mixture was extracted with

EtOAc (3 x 10 mL) and the combined extract washed with brine (10 mL), dried

with MgSO4, and evaporated. The crude product was purified using flash

chromatography (hexanes/EtOAc = 75/25) to obtain compound 5.29 as a white

solid (33 mg, 93%).

TLC Rf = 0.32 (hexanes/EtOAc = 75/25) [CAM]


2.7 Hz, 3H), 3.77 (d, J = 7.4 Hz, 1H), 2.12 (dt, J = 18.2, 2.4 Hz, 1H),

1.81 – 1.76 (dt, J = 18.2, 2.4 Hz, 1H), 1.76 (s, 3H), 1.53 (s, 1H),

1.32 (dd, J = 14.0, 7.6 Hz, 1H), 1.25 (d, J = 14.0 Hz, 1H), 1.04 –

0.97 (m, 1H), 0.94 – 0.87 (m, 1H), 0.84 (t, J = 8.0 Hz, 9H), 0.78 (dt,

J = 12.8, 9.4 Hz, 1H), 0.63 (ddd, J = 13.8, 11.0, 7.7 Hz, 1H), 0.44

(qd, J = 7.9, 2.2 Hz, 6H).

341


O

OH

OO

O

Boc2ODMAPCH2Cl2

O

OBoc

OO

O

88%

5.305.4

Boc2O (0.21 mL, 0.93 mmol) was dissolved in CH2Cl2 (5.0 mL). To the reaction

mixture were added NEt3 (0.13 mL, 0.93 mmol), DMAP (1.0 mg, 9.32 µmol), and

ketone 5.4 (50 mg, 0.19 mmol). The reaction mixture was stirred for 1 h and the

reaction progress monitored by TLC (hexanes/EtOAc = 40/60). The reaction

mixture was quenched with a saturated NaHCO3 solution. The mixture was

extracted with EtOAc (3 x 20 mL) and the combined extract washed with brine

(20 mL), dried with MgSO4, and evaporated. The crude product was purified

using flash chromatography (hexanes/EtOAc = 75/25) to obtain compound 5.30

as a white solid (63 mg, 88%).



Hz, 3H), 4.26 (dd, J = 8.3, 2.7 Hz, 3H), 1.96 (dt, J = 18.5, 2.4 Hz,

1H), 1.72 (s, 3H), 1.67 (dt, J = 18.6, 3.2 Hz, 1H), 1.56 (dd, J = 14.8,

8.3 Hz, 1H), 1.36 (s, 1H), 1.30 (d, J = 14.8 Hz, 1H), 1.24 (s, 9H),

0.92 (ddd, J = 13.1, 10.6, 2.2 Hz, 1H), 0.76 (t, J = 10.4 Hz, 1H),

0.63 (dd, J = 20.5, 10.4 Hz, 1H), 0.54 (ddd, J = 13.6, 11.0, 7.5 Hz,

1H).

13C NMR (125 MHz, C6D6) δ 207.9, 152.5, 109.4, 82.3, 73.0, 67.2, 50.4, 44.3,

37.33, 34.8, 27.3, 26.2, 24.4, 23.7, 21.0

342


CDI (91 mg, 0.56 mmol) was weighed out into a RBF in a glove box. The CDI

was dissolved in CH2Cl2 (6.0 mL). NEt3 (0.13 mL, 0.93 mmol) was added to the

CDI solution. Alcohol 5.4 (50 mg, 0.19 mmol) was dissolved in CH2Cl2 (0.25 mL)

and added to the reaction mixture and stirred for 30 min. Reaction progress was


NaHCO3 solution. The mixture was extracted with CH2Cl2 (3 x 10 mL) and the


The crude product was purified using flash chromatography (100% EtOAc) to

obtain compound 5.32 as a white solid (68 mg, 79%).

TLC Rf = 0.32 (100% EtOAc) [Anisaldehyde]

1H NMR (500 MHz, C6D6) δ 7.94 (s, 1H), 6.84 (d, J = 9.3 Hz, 2H), 4.79 (d, J

= 7.9 Hz, 1H), 4.08 (dd, J = 8.2, 2.7 Hz, 3H), 4.01 (dd, J = 8.2, 2.7

Hz, 3H), 1.67 (s, 3H), 1.61 (s, 2H), 1.33 (dd, J = 15.5, 8.9 Hz,1H),

1.26 (s, 1H), 0.91 (t, J = 7.2 Hz, 1H), 0.86 (d, J = 14.1 Hz, 1H), 0.73

(t, J = 13.5 Hz, 1H), 0.59 (ddd, J = 13.4, 9.6, 2.6 Hz, 1H), 0.45 –

0.41 (m, 1H).

343


Ketone 5.31 (10 mg, 0.027 mmol) and KCN·18-crown-6 complex (27 mg, 0.083

mmol) was dissolved in acetonitrile. The reaction mixture was stirred overnight

and reaction progress was monitored by TLC (100% EtOAc). The reaction

mixture was evaporated and purified by flash chromatography (MeOH/CH2Cl2 =

5/95) to obtain compound 5.33 as a white solid (4.5 mg, 45%)


Rf = 0.26 (MeOH/CH2Cl2 = 5/95) [Anisaldehyde]


3H), 4.27 (d, J = 8.2 Hz, 3H), 1.97 (d, J = 18.8 Hz, 1H), 1.78 (s,

3H), 1.72 (d, J = 18.6 Hz, 1H), 1.56 (dd, J = 14.8, 8.2 Hz, 1H), 1.38

(s, 2H), 1.31 (d, J = 15.0 Hz, 1H), 0.95 (t, J = 12.4 Hz, 1H), 0.80 (t,

J = 12.4 Hz, 1H), 0.73 – 0.64 (m, 1H), 0.55 (ddd, J = 13.7, 11.0, 7.5

Hz, 1H).

13C NMR (125 MHz, C6D6) δ 207.7, 109.6, 75.8, 75.1, 67.3, 50.5, 44.5, 37.56,

35.1, 26.4, 26.3, 24.3, 23.8, 21.2

344


O

OBoc

OO

O

OBoc

OO

O

OH

Me3Si [Ce]

-78 C -30 °C

TMS

73%

5.30 5.36

CeCl3 was brought up in THF (5.0 mL) and vigorously stirred for 1 h. In a

separate RBF were added THF (5.0 mL) and n-BuLi (3.33 M in THF, 0.32 mL,

1.1 mmol). The n-BuLi solution was cooled with a dry ice/acetone bath and

TMS-acetylene (0.15 mL, 1.1 mmol) was added dropwise and stirred for 1 h.

The CeCl3 was cannulated into the reaction mixture and stirred for an additional 1

h. Ketone 5.30 (0.20 g, 0.54 mmol) in a THF solution (0.5 ml) was cooled with a

dry ice/acetone bath and cannulated over to the organocerium reaction mixture.

The reaction mixture was allowed to stir for an additional 30 min and then

gradually warmed up to -30 °C and stirred for 2 h. Reaction progress was

monitored by TLC (hexanes/EtOAc = 40/60). The reaction mixture was

quenched with a saturated NaHCO3 solution and extracted with EtOAc (3 x 20

mL). The extract was washed with brine (20 mL), dried with MgSO4, and

evaporated. The crude product was purified using flash chromatography

(hexanes/EtOAc = 75/25) to obtain compound 5.36 as a white solid (0.20 g,

79%).



345


Hz, 3H), 4.51 (dd, J = 8.4, 3.1 Hz, 3H), 2.69 (s, 1H), 2.28 – 2.19 (m,

1H), 1.73 (s, 3H), 1.64 – 1.54 (os, 3H), 1.51 – 1.43 (m, 1H), 1.35 –

1.27 (os, 2H), 1.22 (s, 9H), 0.83 (t, J = 10.0 Hz, 1H), 0.52 (ddd, J =

13.6, 10.6, 7.1 Hz, 1H), 0.09 (s, 9H)

13C NMR (125 MHz, C6D6) δ 152.3, 110.9, 109.0, 89.7, 82.8, 74.9, 72.4, 68.4,

48.6, 43.4, 39.8, 35.3, 27.5, 24.3, 23.9, 23.2, 22.5, -0.6


OBoc

OO

O

OH

TMS

TBAFTHF0 C

85%

OBoc

OO

O

OH

5.36 5.37

Compound 5.36 (32 mg, 69 µmol) was dissolved in THF (0.5 mL) and cooled with

an ice-water bath. TBAF (1.0 M in THF, 0.14 mL, 0.14 mmol) was added

dropwise to the reaction mixture and stirred for 15 min. Reaction progress was

monitored by TLC (hexanes/EtOAc = 60/40). The reaction mixture was

quenched with a saturated NaHCO3 solution and extracted with EtOAc (3 x 1.0

mL). The extract was washed with brine (2.0 mL), dried with MgSO4, and



85%).


346



Hz, 3H), 4.43 (dd, J = 8.4, 3.1 Hz, 3H), 2.68 (s, 1H), 2.13 (dd, J =

13.7, 4.4 Hz, 1H), 1.90 (s, 1H), 1.72 (s, 3H), 1.57 (t, J = 14.6 Hz,

2H), 1.42 – 1.35 (m, 1H), 1.34 – 1.25 (os, 3H), 1.22 (s, 9H), 0.75 (t,

J = 10.9 Hz, 1H), 0.43 (ddd, J = 13.4, 10.6, 6.6 Hz, 1H)


Toluene (15 mL), quinoline (15 µL, 0.13 mmol), Pd on BaSO4 (5 mg), and alkyne

5.37 (10 mg, 25 µmol) were added into a RBF. The reaction mixture was put

under a hydrogen atmosphere and stirred vigorously. The reaction progress was

monitored by 1H NMR until all the alkyne was reacted. The hydrogen balloon

was removed and the reaction mixture was filtered through a pad of Celite® and

evaporated. The crude material was purified by flash chromatography to obtain

alkene 5.40 as a white solid (7.7 mg, 78%).


1H NMR (600 MHz, C6D6) δ 5.64 – 5.46 (os, 2H), 4.86 (dd, J = 10.2, 2.4 Hz,

1H), 4.69 (dd, J = 9.3, 3.2 Hz, 1H), 4.33 (dd, J = 8.4, 3.0 Hz, 3H),

4.27 (dd, J = 8.4, 3.0 Hz, 3H), 3.02 (d, J = 1.2 Hz, 1H), 1.82 (ddt, J

= 14.5, 9.3, 2.7 Hz, 1H), 1.69 (s, 3H), 1.50 (dt, J = 14.3, 3.1 Hz,

347

1H), 1.42 (dt, J = 14.3, 2.4 Hz, 1H), 1.31 (ddd, J = 14.1, 5.8, 3.0 Hz,

1H), 1.26 – 1.21 (os, 10H), 0.93 – 0.84 (m, 1H), 0.83 – 0.77 (m,

1H), 0.77 – 0.69 (m, 1H), 0.53 (ddd, J = 14.0, 10.7, 5.5 Hz, 1H).


Alkene 5.40 (1.5 mg, 3.8 µmol), NMO·H2O (1.5 mg, 11 µmol), and CH2Cl2 (13

mL) were added to a RBF and the mixture cooled with an ice-water bath. The

reaction was sparged with ozone containing oxygen and monitored by TLC

(CH2Cl2/EtOAc = 95/5) until the starting material (alkene 5.40) was consumed.

The reaction mixture was quenched with a solution of 1:1 saturated

NaHCO3/Na2S2O3. The mixture was extracted with CH2Cl2 (3 x 10 mL) and the


The crude material was purified by flash chromatography to obtain alkene 5.41

(1.0 mg, 67%).



(dd, J = 8.4, 2.8 Hz, 3H), 4.08 (dd, J = 8.4, 2.8 Hz, 3H), 1.87 (ddt, J

= 12.5, 9.2, 2.9 Hz, 1H), 1.72 (s, 1H), 1.66 (s, 3H), 1.44 – 1.39 (os,

2H), 1.25 (s, 9H), 1.04 – 1.00 (os, 2H), 0.96 (d, J = 8.9 Hz, 2H),

0.72 (t, J = 9.8 Hz, 1H), 0.48 – 0.43 (m, 1H).

348


CeCl3 (1.5 g, 6.0 mmol) was brought up in THF (13 mL) and vigorously stirred for

2 h. In a separate RBF were added THF (2.5 mL) and n-BuLi (3.13 M in THF,

1.9 mL, 6.0 mmol). The n-BuLi solution was cooled with a dry ice/acetone bath

and TMS-acetylene (0.86 mL, 6.1 mmol) was added dropwise and stirred for 30

min. The CeCl3 was cannulated into the reaction mixture and stirred for an

additional 1 h. Ketone 5.4 (0.33 g, 1.2 mmol) in a THF solution (1.0 ml) was

cooled with a dry ice/acetone bath and cannulated over to the organocerium

reaction mixture. The reaction mixture was allowed to stir for an additional 30

min and then gradually warmed up to -30 °C and stirred for 2 h. Reaction

progress was monitored by TLC (hexanes/EtOAc = 40/60). The reaction mixture

was quenched with a saturated NaHCO3 solution and extracted with EtOAc (3 x

20 mL). The extract was washed with brine (20 mL), dried with MgSO4, and



76%).


MP 158-162 °C

349


3.1 Hz, 3H), 3.23 (td, J = 9.2, 5.0 Hz, 1H), 2.09 (s, 1H), 2.04 (d, J =

9.2 Hz, 1H), 1.94 (dt, J = 14.0, 2.6 Hz, 1H), 1.78 (s, 3H), 1.60 –

1.52 (m, 1H), 1.49 (d, J = 14.2 Hz, 1H), 1.29 – 1.22 (os, 2H), 1.12 –

1.04 (os, 1H), 1.01 (ddt, J = 13.5, 4.9, 2.5 Hz, 1H), 0.81 – 0.70 (os,

2H), 0.15 (s, 9H)

13C NMR (125 MHz, C6D6) δ 110.7, 109.1, 91.1, 72.8, 70.5, 68.6, 48.9, 43.7,

39.48, 38.4, 24.4, 24.1, 23.9, 22.1, -0.4


Compound 5.45 (0.28 g, 0.76 mmol), K2CO3 (0.11 g, 0.76 mmol), and MeOH (25

mL) were added into a RBF and stirred for 2 h. The reaction progress was

monitored by TLC. The reaction mixture was evaporated and brought up in

water (25 mL) and extracted with EtOAc (3 x 20 mL). The extract was washed

with brine (20 mL), dried with MgSO4, and evaporated. The crude product,

compound 5.46, was obtained as a white solid (0.34 g, 76%) and used without

further purification.


350


3.1 Hz, 3H), 3.19 (td, J = 9.1, 4.9 Hz, 1H), 2.03 (s, 1H), 1.96 (d, J =

9.1 Hz, 1H), 1.93 (s, 1H), 1.84 – 1.78 (os, 4H), 1.56 – 1.49 (os, 2H),

1.42 (d, J = 13.1 Hz, 1H), 1.23 (s, 1H), 1.10 – 1.06 (m, 1H), 1.02 –

0.94 (m, 2H), 0.72 – 0.66 (os, 2H)

13C NMR (125 MHz, CDCl3) δ 108.2, 87.6, 75.9, 72.8, 70.7, 68.2, 49.1, 43.7,

39.0, 38.3, 24.2, 23.7, 23.5, 22.1


Diol 5.46 (0.19 g, 0.64 mmol) was suspended in toluene (15 mL) and

dibutyldimethoxytin (160 µL, 0.70 mmol) was added. The flask was fitted with a

Dean-Stark trap and the vigorously stirring reaction mixture was heated to reflux

and 12 mL of toluene was distilled off. TBAI (0.36 g, 0.98 mmol) and PMBBr

(110 µL, 0.75 mmol) were added to the reaction mixture. The reaction mixture

was heated with an oil bath (set at 80 °C) for 6 h. Reaction progress was


NaHCO3 solution and filtered through a pad of Celite®. The filtrate was extracted

with CH2Cl2 (2 x 20 mL). The combined extract was dried with Na2SO4, and


351


81%).



2H), 4.57 (dd, J = 8.4, 2.9 Hz, 3H), 4.54 (dd, J = 8.4, 2.9 Hz, 3H),

4.01 – 3.92 (os, 2H), 3.68 (d, J = 10.4 Hz, 1H), 3.25 (s, 3H), 3.22

(dd, J = 8.1, 1.9 Hz, 1H), 2.27 – 2.21 (m, 1H), 1.93 (s, 1H), 1.89 (d,

J = 13.7 Hz, 1H), 1.78 (s, 3H), 1.46 (ddd, J = 13.6, 10.8, 3.1 Hz,

1H), 1.37 (os, 2H), 1.27 (d, J = 12.4 Hz, 1H), 1.15 – 1.08 (m, 1H),

0.85 (t, J = 10.0 Hz, 1H), 0.58 (ddd, J = 13.4, 10.8, 6.2 Hz, 1H)


OPMB

OO

O

OH

5.47

cat PPTSTHF/H2O

(MeO)2CMe2PPTS

K2CO3MeOH

OPMB

HOHOOAc

OH

C2

OPMB

OH

OO AcO

C3

OPMB

OH

OO HO

5.48

92%overthreesteps

Compound 5.47 (42 mg, 0.10 mmol) and PPTS (2.0 mg, 7.9 µmol) and 1/1

THF/water (1 mL) were added to a RBF and stirred for 6 h. Reaction progress

was monitored by TLC (hexanes/EtOAc = 50/50). The reaction mixture was

quenched with a saturated NaHCO3 solution and extracted with EtOAc (3 x 1.0

352

mL). The combined extract was dried with MgSO4, and evaporated. The crude

product C2 was obtained and carried forward without further purification.



Compound C2, PPTS (5 mg, 20 µmol), and 2,2-dimethoxypropane (25 µL, 40

µmol) were dissolved in CH2Cl2 (500 µL) and stirred for 1 h. Reaction progress

was monitored by TLC (100% EtOAc). The reaction mixture was evaporated and

the crude compound (C3) was carried forward without further purification.


The crude residue (C3) was dissolved in MeOH (500 µL) and K2CO3 was added

(50 mg, 0.36 mmol) and the reaction mixture was stirred vigorously. Reaction

progress was monitored by TLC. The reaction mixture was quenched with water

and extracted with EtOAc (3 x 0.5 mL). The combined extract was dried with

MgSO4, and evaporated. The crude product 5.48 was obtained as a white solid

could be carried forward without further purification (40 mg, 92%).



2H), 4.79 (s, 1H), 4.57 (d, J = 10.3 Hz, 1H), 4.47 (d, J = 12.4 Hz,

1H), 4.31 (d, J = 11.8 Hz, 1H), 4.24 (d, J = 10.3 Hz, 1H), 4.19 (dd, J

= 12.0, 4.6 Hz, 1H), 4.11 (dd, J = 11.9, 6.5 Hz, 1H), 4.01 (dd, J =

8.4, 3.6 Hz, 1H), 3.80 (s, 3H), 3.67 (d, J = 11.7 Hz, 1H), 3.63 (d, J =

12.4 Hz, 1H), 3.36 (s, 1H), 2.58 (s, 1H), 2.31 (dt, J = 13.7, 2.9 Hz,

1H), 2.13 (dt, J = 13.7, 2.5 Hz, 1H), 2.00 – 1.92 (os, 2H), 1.89 (ddd,

353

J = 15.7, 10.8, 4.8 Hz, 1H), 1.85 – 1.81 (m, 1H), 1.75 – 1.65 (os,

2H), 1.46 – 1.39 (os, 4H), 1.35 (s, 3H)


Compound 5.48 (40 mg, 0.093 mmol) was dissolved in CH2Cl2 (1.0 mL). DMP

(36 mg, 0.84 mmol) was added and the mixture stirred for 5 min. Reaction

progress was monitored by TLC. The reaction mixture was purified by flash

chromatography to obtain lactol 5.49 as a white solid as a 4:1 mixture of

diastereomers (40 mg, quantitative yield).



2H), 5.11 (d, J = 13.0 Hz, 2H), 4.37 (dd, J = 16.5, 11.7 Hz, 2H),

4.13 (d, J = 12.6 Hz, 1H), 3.99 (dd, J = 12.6, 2.8 Hz, 1H), 3.95 (d, J

= 8.3 Hz, 1H), 3.87 (dd, J = 11.4, 4.3 Hz, 2H), 3.32 (s, 3H), 2.72

(dd, J = 14.0, 10.2 Hz, 1H), 2.45 (dd, J = 12.9, 3.8 Hz, 1H), 2.30 (d,

J = 12.8 Hz, 1H), 2.20 – 2.15 (m, 1H), 2.14 (s, 1H), 1.76 (s, 1H),

1.65 (dt, J = 10.7, 8.0 Hz, 1H), 1.60 (d, J = 15.4 Hz, 1H), 1.56 (s,

3H), 1.50 (dd, J = 13.7, 8.4 Hz, 1H), 1.38 (s, 3H), 1.37 – 1.30 (m,

1H).

354


Compound 5.49 (18 mg, 0.042 mmol), as a mixture of diastereomers, acetic

anhydride (8.0 µL, 0.084 mmol), and DMAP (15 mg, 0.13 mmol) were dissolved

in CH2Cl2 (0.5 mL). Reaction progress was monitored by TLC. After 1.5 h, the

reaction mixture was purified by flash chromatography to obtain compound 5.54

as a mixture of diastereomers (20 mg, quantitative yield).

TLC Rf = 0.21 and 0.28 (hexanes/EtOAc = 70/30) [Anisaldehyde]

1H NMR (500 MHz, CDCl3) δ 7.26 – 7.22 (os, 2H), 6.87 (s,2H), 5.00 (d, J =

12.0 Hz, 1H), 4.79 (d, J = 12.0 Hz, 1H), 4.68 (dd, J = 15.4, 10.9 Hz,

2H), 4.52 (dd, J = 16.4, 11.0 Hz, 2H), 3.92 (dd, J = 12.0, 1.8 Hz,

1H), 3.90 – 3.83 (os, 2H), 3.80 (s, 3H), 3.08 (d, J = 11.3 Hz, 1H),

2.94 (s, 1H), 2.40 (d, J = 13.2 Hz, 1H), 2.15 (t, J = 10.9 Hz, 1H),

2.06 (s, 3H), 1.93 (d, J = 14.1 Hz, 1H), 1.89 – 1.82 (os, 2H), 1.65

(ddd, J = 13.7, 10.6, 7.1 Hz, 1H), 1.55 (s, 3H), 1.51 – 1.45 (os, 4H),

1.42 – 1.34 (os, 4H)

355


Compound 5.54 (5.0 mg, 1.1 µmol), silyl enol ether 5.55 (8.0 g, 5.5 µmol), and

CH2Cl2 (0.25 mL) were added into a scintillation vial. The reaction flask was

cooled with a dry ice/acetone bath. SnCl4 was added to the reaction mixture.

The reaction mixture was warmed gradually to rt. The reaction progress was

monitored by TLC. The reaction mixture was quenched with water and extracted

with EtOAc (3 x 0.25 mL). The combined extract was dried with MgSO4, and

evaporated. The crude mixture was purified by flash chromatography and

compound 5.56 was isolated.

1H NMR (500 MHz, CDCl3) δ 9.58 (s, 1H), 7.01 (d, J = 8.6 Hz, 2H), 6.81 (d, J

= 8.6 Hz, 2H), 3.79 (s, 3H), 2.72 (s, 2H), 1.04 (s, 6H).


MeOH (35 mL), pyridine (0.56 mL, 7.0 mmol), Pd on BaSO4 (15 mg, 7 µmol), and

alkyne 5.46 (0.21 g, 0.70 mmol) were added into a RBF. The reaction mixture

356

was placed under a hydrogen atmosphere and vigorously stirred. The reaction

progress was monitored by 1H NMR until all the alkyne was reacted (30 min).

The hydrogen balloon was removed and the reaction mixture was filtered through

a pad of Celite®, and evaporated. The filtrate was evaporated and redissolved in

EtOAc (25 mL) and washed with 10% CuSO4 solution (2 x 50 mL), to remove the

pyridine, and brine (25 mL). The extract was dried with MgSO4, and evaporated.

The crude product 5.57 was obtained as a white solid which could be carried

forward without further purification (0.20 g, 98%).

1H NMR (600 MHz, C6D6) δ 6.01 (dd, J = 17.2, 10.8 Hz, 1H), 5.19 (d, J =

17.1 Hz, 1H), 5.11 (t, J = 13.0 Hz, 1H), 4.26 (dd, J = 8.4, 3.1 Hz,

3H), 4.17 (dd, J = 8.3, 3.1 Hz, 3H), 3.63 – 3.55 (m, 1H), 2.88 (d, J =

9.8 Hz, 1H), 2.27 (s, 1H), 2.18 – 2.08 (m, 1H), 1.74 (s, 1H), 1.67

(dt, J = 14.4, 2.3 Hz, 1H), 1.41 – 1.24 (os, 9H).


Diol 5.57 (0.44 g, 1.5 mmol) was dissolved in THF (10 mL) and the solution was

cooled with an ice-water bath. NaH (60% dispersion, 0.18 g, 4.5 mmol) was

added to the vigorously stirring solution of diol. After 30 min, the reaction mixture

was warmed to rt and BnBr (0.35 mL, 3.0 mmol) was added dropwise and the

reaction mixture was stirred overnight. The reaction mixture was cooled with an

357

ice-water bath, carefully quenched with a saturated NaHCO3 solution, and

extracted with EtOAc (3 x 15 mL). The combined extract was dried with MgSO4,

evaporated, and purified using flash chromatography (hexanes/EtOAc = 67/33) to

obtain compound 5.58 as a white solid (0.52 g, 92%).


1H NMR (600 MHz, C6D6) δ 7.12 (d, J = 7.3 Hz, 2H), 7.07 (t, J = 7.3 Hz, 2H),

7.04 – 7.01 (m, 1H), 5.66 (dd, J = 16.8, 2.3 Hz, 1H), 5.57 (ddd, J =

16.8, 10.4, 1.5 Hz, 1H), 4.93 (dd, J = 10.4, 2.3 Hz, 1H), 4.40 – 4.36

(os, 4H), 4.29 (dd, J = 8.3, 3.0 Hz, 3H), 4.04 (d, J = 10.9 Hz, 1H),

3.76 (d, J = 10.9 Hz, 1H), 3.08 (dd, J = 9.0, 3.9 Hz, 1H), 1.73 (s,

3H), 1.67 – 1.63 (m, 1H), 1.53 (dt, J = 14.2, 2.8 Hz, 1H), 1.39 –

1.32 (os, 2H), 1.28 (d, J = 14.4 Hz, 1H), 0.99 – 0.89 (os, 2H), 0.82

(dd, J = 18.7, 10.7 Hz, 1H), 0.68 – 0.59 (m, 1H)


(MeO)2CH2PPTS

OBn

OH

OO HO

C4

DMPCH2Cl2

OBn

O

OO

HO

C5

cat PPTS,THF/H2Othen LiOH

OBn

OO

OMe

OH

OBn

OH

HOHO HO

5.58 5.67

Ac2O, DMAPCH2Cl2

OBn

O

OO

AcO

5.59

64%over 4steps

358

Compound 5.58 (0.45 g, 1.2 mmol) and PPTS (4.4 mg, 23 µmol) were dissolved

in a 4/1 solution of THF/water (40 mL). Reaction progress was monitored by

TLC. After 2 h, the reaction mixture was poured into a solution of LiOH (0.1 g,

2.3 mmol) in water (10 mL). Reaction progress was again monitored by TLC.

After 1 h, the reaction mixture was quenched with a saturated NaHCO3 solution,

and extracted with CH2Cl2 (3 x 30 mL). The combined extract was dried with

Na2SO4, and evaporated. Tetraol 5.67 was used without further purification.



1H NMR (600 MHz, CDCl3) δ 7.39 – 7.30 (os, 5H), 6.22 (dd, J = 16.9, 10.9

Hz, 1H), 5.38 (dd, J = 17.0, 1.3 Hz, 1H), 5.00 (dd, J = 10.9, 1.3 Hz,

1H), 4.76 (bs, 1H), 4.64 (d, J = 10.6 Hz, 1H), 4.34 (d, J = 10.6 Hz,

1H), 3.98 – 3.89 (os, 6H), 3.30 (bs, 3H), 1.94 – 1.83 (os, 5H), 1.69

– 1.63 (m, 1H), 1.61 – 1.53 (os, 2H), 1.48 (t, J = 7.1 Hz, 2H)

13C NMR (125 MHz, CDCl3) δ 143.5, 136.9, 128.7, 128.1, 128.0, 109.7, 78.9,

70.3, 64.0, 49.4, 48.1, 46.5, 33.7, 24.5, 24.3, 21.5

The tetraol (5.67) was redissolved in CH2Cl2 (5.0 mL). PPTS (5 mg, 20 µmol)

and 2,2-dimethoxypropane (0.14 mL, 1.2 mmol) were added. The reaction

mixture was stirred overnight. Reaction progress was monitored by TLC. The

reaction mixture was quenched with a saturated NaHCO3 solution, and extracted

with CH2Cl2 (3 x 30 mL). The combined extract was dried with Na2SO4,

evaporated, and purified by flash chromatography (CH2Cl2/EtOAc = 85/15) to

obtain compound C4 as a white solid (0.33 g, 70% over 2 steps).

359



1H NMR (500 MHz, CDCl3) δ 7.39 – 7.29 (os, 5H), 6.15 (dd, J = 16.9, 10.8

Hz, 1H), 5.41 (d, J = 17.0 Hz, 1H), 5.08 (d, J = 10.8 Hz, 1H), 4.68

(d, J = 10.7 Hz, 1H), 4.34 (d, J = 10.7 Hz, 1H), 4.22 (dd, J = 16.2,

12.7 Hz, 2H), 4.05 (d, J = 11.5 Hz, 1H), 4.00 – 3.95 (m, 1H), 3.90

(d, J = 11.9 Hz, 1H), 3.70 (d, J = 12.5 Hz, 1H), 3.45 (d, J = 11.4 Hz,

1H), 2.12 – 2.04 (m, 1H), 1.92 (s, 1H), 1.89 – 1.80 (os, 3H), 1.79 –

1.72 (os, 2H), 1.48 (bs, 2H), 1.33 (s, 3H), 1.31 (s, 3H)

13C NMR (125 MHz, CDCl3) δ 143.1, 136.6, 128.7, 128.2, 128.1, 110.8,

98.60, 78.4, 76.7, 70.3, 63.4, 63.2, 61.9, 47.4, 46.6, 45.9, 34.2,

26.8, 24.5, 24.3, 21.6, 21.6

Compound C4 (0.20 g, 0.50 mmol) was dissolved in CH2Cl2 (10 mL). DMP (0.23

g, 0.55 mmol) was added and stirred for 45 min. Reaction progress was

monitored by TLC. The reaction mixture was evaporated (removing a majority of

the CH2Cl2) and the slurry was purified by flash chromatography (hexanes/EtOAc

= 80/20) to obtain lactol C5 as a white solid (0.20 g, quantitative yield).



1H NMR (600 MHz, CDCl3) δ 7.36 (d, J = 4.4 Hz, 4H), 7.30 (dq, J = 8.7, 4.2

Hz, 1H), 6.21 (dd, J = 16.8, 10.6 Hz, 1H), 5.34 (dd, J = 16.8, 1.7

Hz, 1H), 4.98 (dd, J = 10.6, 1.7 Hz, 1H), 4.78 (d, J = 10.7 Hz, 1H),

4.67 (d, J = 12.6 Hz, 1H), 4.28 – 4.22 (os, 2H), 4.16 (d, J = 12.6 Hz,

360

1H), 3.95 – 3.90 (os, 2H), 3.76 (dd, J = 12.7, 2.8 Hz, 1H), 3.70 (d, J

= 12.3 Hz, 1H), 2.12 (dd, J = 28.5, 13.3 Hz, 2H), 2.02 (s, 1H), 1.94

(s, 2H), 1.79 (dd, J = 13.2, 5.3 Hz, 1H), 1.71 (d, J = 12.3 Hz, 1H),

1.61 – 1.55 (os, 2H), 1.41 (s, 3H), 1.35 (s, 3H)

13C NMR (125 MHz, CDCl3) δ 145.0, 136.7, 128.9, 128.3, 127.9, 111.8,

102.4, 97.5, 82.9, 78.9, 70.2, 66.2, 62.6, 48.8, 46.1, 40.4, 34.9,

28.1, 25.3, 24.93, 23.9, 19.2

Compound C5 (0.20 g, 0.50 mmol), acetic anhydride (57 µL, 0.60 mmol), and

DMAP (61 mg, 0.50 mmol) were dissolved in CH2Cl2 (10 mL). Reaction progress

was monitored by TLC. After 6 h, the reaction mixture was evaporated and

purified by flash chromatography to obtain compound 5.59 as a mixture of

diastereomers (20 g, 91% over 2 steps).



1H NMR (600 MHz, CDCl3) δ 7.37 (d, J = 7.4 Hz, 2H), 7.34 (t, J = 7.6 Hz,

2H), 7.24 (t, J = 7.2 Hz, 1H), 6.31 (dd, J = 16.9, 10.9 Hz, 1H), 6.04

(s, 1H), 5.46 (dd, J = 16.9, 1.7 Hz, 1H), 5.06 (dd, J = 10.9, 1.8 Hz,

1H), 4.74 (d, J = 12.2 Hz, 1H), 4.33 – 4.26 (os, 2H), 3.94 – 3.87 (os,

4H), 2.23 – 2.14 (os, 2H), 2.05 (s, 3H), 1.97 (s, 1H), 1.88 – 1.82

(os, 2H), 1.82 – 1.77 (m, 1H), 1.76 – 1.71 (m, 1H), 1.64 – 1.58 (m,

1H), 1.56 (s, 1H), 1.38 (s, 3H), 1.34 (s, 3H)

361


Compound 5.59 (3.7 mg, 8.4 µmol) and trimethylsilane (6.7 µL, 42 µmol) were

dissolved in CH2Cl2 (0.5 mL). The reaction mixture was cooled with a dry

ice/acetone bath and SnCl4 was added dropwise. Reaction progress was

monitored by TLC (hexanes/EtOAc = 75/25). After 30 min, the reaction mixture

warmed to -40 °C and stirred for 15 min. The reaction mixture was quenched

with a saturated NaHCO3 solution, and extracted with CH2Cl2 (3 x 3 mL). The

combined extract was dried with Na2SO4, evaporated, and purified by flash

chromatography (hexanes/EtOAc = 90/10) to obtain compound 5.60 as a white

solid (1.5 mg, 37%).



1H NMR (600 MHz, CDCl3) δ 7.36 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 7.6 Hz,

2H), 7.24 (t, J = 7.3 Hz, 1H), 6.42 (dd, J = 16.8, 10.7 Hz, 1H), 5.82

(ddt, J = 17.0, 10.0, 6.9 Hz, 1H), 5.52 (dd, J = 16.8, 2.1 Hz, 1H),

5.14 – 5.07 (os, 2H), 5.00 (dd, J = 10.7, 2.1 Hz, 1H), 4.73 (d, J =

12.2 Hz, 1H), 4.31 (d, J = 12.1 Hz, 1H), 4.23 (dd, J = 12.3, 2.5 Hz,

1H), 4.11 (dd, J = 9.4, 5.9 Hz, 1H), 3.96 (d, J = 12.2 Hz, 1H), 3.90

(t, J = 4.6 Hz, 1H), 3.82 (dd, J = 12.1, 2.4 Hz, 1H), 3.65 (d, J = 12.2

362

Hz, 1H), 2.40 – 2.33 (m, 1H), 2.23 – 2.16 (os, 2H), 2.13 (d, J = 12.9

Hz, 1H), 1.93 (s, 1H), 1.83 (s, 2H), 1.74 (dd, J = 13.5, 5.8 Hz, 1H),

1.72 – 1.67 (m, 1H), 1.60 – 1.55 (m, 1H), 1.54 (s, 3H), 1.52 – 1.47

(m, 1H), 1.36 (s, 3H), 1.34 (s, 3H).


OBn

O

OO

SnBu3

60%

OBn

O

OO

OAc

SnCl4, CH2Cl2-78 C rt

5.59 5.61

Compound 5.59 (52 mg, 0.12 mmol) and tributyl(3-methyl-2-butenyl)tin (0.10 mL,

3.0 mmol) were dissolved in CH2Cl2 (0.5 mL). The reaction mixture was cooled

with a dry ice/acetone bath and SnCl4 (21 µL, 0.18 mmol) was added dropwise.

Reaction progress was monitored by TLC (hexanes/EtOAc = 75/25). After 30

min, the reaction mixture was quenched with a saturated NaHCO3 solution, and

extracted with CH2Cl2 (3 x 5 mL). The combined extract was dried with Na2SO4,

evaporated, and purified by flash chromatography (hexanes/EtOAc = 90/10) to

obtain compound 5.61 as a white solid (53 mg, 60%).



1H NMR (500 MHz, CDCl3) δ 7.40 – 7.30 (os, 4H), 7.25 – 7.21 (m, 1H), 6.22

(dd, J = 16.8, 10.8 Hz, 1H), 5.87 (dd, J = 17.6, 10.8 Hz, 1H), 5.70

(dd, J = 16.8, 1.8 Hz, 1H), 5.25 (s, 1H), 5.13 (dt, J = 9.4, 4.7 Hz,

363

1H), 5.05 (td, J = 10.9, 1.3 Hz, 2H), 4.74 (d, J = 12.2 Hz, 1H), 4.28

(d, J = 12.2 Hz, 1H), 4.18 (d, J = 12.7 Hz, 1H), 3.94 (d, J = 12.7 Hz,

1H), 3.89 – 3.84 (os, 3H), 2.18 – 2.08 (os, 2H), 1.95 (s, 1H), 1.84

(s, 2H), 1.80 – 1.72 (os, 2H), 1.61 – 1.47 (os, 3H), 1.38 (s, 3H),

1.33 (s, 3H), 1.32 (s, 3H), 1.24 (s, 3H)


OBn

OH

OO

OO

1. O3, NMO•H2OCH2Cl2, -78 C

2. Swern

76%

OBn

OH

OO HO

5.65 5.66

Alkene 5.65 (50 mg, 0.12 mmol), NMO·H2O (50 mg, 0.37 µmol), and CH2Cl2 (20



until the starting material (alkene 5.65) was consumed. The reaction mixture was

quenched with a solution of 1:1 saturated NaHCO3/Na2S2O3. The mixture was

extracted with CH2Cl2 (3 x 10 mL) and the combined extract washed with brine

(20 mL), dried with Na2SO4, and evaporated. The crude lactol was carried

forward without further purification


CH2Cl2 (1.0 mL) was added to the RBF followed by DMSO (0.18 mL, 2.5 mmol).


364

addition of oxalyl chloride (0.11 mL, 1.2 mmol). The reaction mixture was stirred

at -78 °C for 30 min. A solution of the crude lactol in CH2Cl2 (0.5 mL) was added

dropwise and the reaction mixture was stirred for 1 h at -78 °C. NEt3 (0.70 mL,

4.9 mmol) was added and the reaction mixture was stirred for an additional 30

min and then gradually warmed by moving the reaction flask to an ice-water bath.

After 30 min at 0 °C, the reaction was quenched with saturated NaHCO3. The

mixture was extracted with CH2Cl2 (3 x 2.0 mL) and the combined extract


material was purified using flash chromatography to obtain lactone 5.66 (38 mg,

76%).


1H NMR (600 MHz, CDCl3) δ 7.38 – 7.28 (os, 5H), 4.79 (d, J = 12.9 Hz, 1H),

4.66 (d, J = 10.8 Hz, 2H), 4.38 (d, J = 10.6 Hz, 1H), 4.15 – 3.99 (os,

4H), 3.95 (d, J = 11.6 Hz, 1H), 3.70 (d, J = 11.7 Hz, 1H), 3.08 –

3.01 (m, 1H), 1.97 (d, J = 8.7 Hz, 2H), 1.78 – 1.72 (m, 1H), 1.63 (d,

J = 14.1 Hz, 1H), 1.47 (d, J = 12.4 Hz, 1H), 1.38 (s, 3H), 1.36 (s,

3H), 1.33 – 1.24 (os, 3H)

13C NMR (125 MHz, CDCl3) δ 170.8, 136.3, 128.8, 128.4, 128.4, 97.6, 77.8,

76.3, 72.0, 70.2, 68.4, 63.9, 41.5, 37.9, 36.9, 32.7, 23.8, 23.1, 22.6

365

Synthesis of Compound 5.64 (from acetonide 5.66)

Compound 5.66 (4.0 mg, 9.9 µmol) and 1 small crystal of p-TsOH were dissolved

in a solution of 4:1 THF/water (0.5 mL). The reaction mixture was heated in an

oil bath set at 70 °C and heated for 4 h. Reaction progress was monitored by

TLC. The reaction was quenched with water. The mixture was extracted with

EtOAc (3 x 1.0 mL) and the combined extract washed with brine (2.0 mL), dried


chromatography to obtain diol 5.64 (2.5 mg, 69%).



4.57 (d, J = 11.9 Hz, 1H), 4.40 – 4.34 (os, 2H), 4.24 (d, J = 10.6 Hz,

1H), 4.15 (s, 1H), 4.00 (d, J = 10.9 Hz, 1H), 3.93 (d, J = 11.8 Hz,

2H), 3.85 (d, J = 10.9 Hz, 1H), 3.03 (ddd, J = 14.1, 4.2, 2.4 Hz, 1H),

2.49 (bs, 1H), 2.19 (bs, 1H), 1.97 (s, 1H), 1.95 – 1.90 (m, 1H), 1.80

– 1.72 (os, 2H), 1.68 (d, J = 14.1 Hz, 1H), 1.60 – 1.54 (m, 1H), 1.44

– 1.32 (os, 2H)

13C NMR (125 MHz, CDCl3) δ 171.1, 137.2, 128.8, 128.2, 127.9, 79.5, 76.5,

70.8, 70.5, 66.6, 65.4, 43.2, 41.9, 38.2, 32.8, 24.1, 23.4, 23.3

366

Synthesis of Compound 5.64 (from tetraol 5.67)

1. O3, NMO•H2OCH2Cl2, -78 C

2. I2, CaCO310:1 MeOH/H2O

OBn

OHHO

HOO

O

OBn

OH

HOHO HO

62%over 2 steps

5.67 5.64

Alkene 5.67 (0.10 g, 0.27 mmol), NMO·H2O (0.19 g, 1.4 mmol), and CH2Cl2 (10



until the starting material (alkene 5.67) was consumed. The reaction mixture was

quenched with a solution of 1:1 saturated NaHCO3/Na2S2O3. The mixture was

extracted with CH2Cl2 (3 x 10 mL) and the combined extract washed with brine

(20 mL), dried with Na2SO4, and evaporated. The crude lactol was carried

forward without further purification.

The lactol intermediate was dissolved in MeOH (10 mL). CaCO3 (0.26 g, 2.6

mmol) was dissolved in water (1.0 mL) and added to the lactol solution. I2 (0.37

g, 1.6 mmol) was added and the reaction flask kept in the dark. The reaction

mixture was heated with an oil bath set at 80 °C for 5 h. Na2SO3 was added until

the reaction mixture turned from brown to colorless. Water was added until all

the solid had dissolved. The reaction mixture was quenched with saturated

NaHCO3, extracted with EtOAc (3 x 10 mL), the combined extract washed with

brine (10 mL), dried with MgSO4, and evaporated. The crude material was

purified using flash chromatography to obtain diol 5.64 (62 mg, 62% over 2

steps).

367


1H NMR matched compound 5.64 isolated from the deprotection of the acetonide

(see reaction above).


Compound 5.64 (15 mg, 0.041 mmol) was dissolved in CH2Cl2 (0.5 mL). DMP

(52 mg, 0.12 mmol) was added and the mixture stirred for 5 min. Reaction

progress was monitored by TLC. The reaction mixture was quenched with 10%

Na2S2O3 solution and extracted with CH2Cl2. The extract was washed with brine

(0.5 mL), and evaporated to obtain lactol aldehdye 5.68 (14 mg, 95%).


1H NMR (500 MHz, CDCl3) δ 9.67 (s, 1H), 7.38 – 7.30 (os, 5H), 4.82 (d, J =

11.1 Hz, 1H), 4.68 (d, J = 11.2 Hz, 1H), 4.37 (d, J = 11.1 Hz, 1H),

4.22 (d, J = 11.2 Hz, 1H), 3.81 (d, J = 9.2 Hz, 1H), 3.08 (bs, 1H),

2.85 (d, J = 15.0 Hz, 1H), 2.07 – 2.03 (os, 2H), 1.86 – 1.79 (os, 2H),

1.76 (d, J = 14.4 Hz, 1H).

368


Imidazole (0.13 g, 1.9 mmol) and TESCl (34 µL, 0.20 mmol) were dissolved in

CH2Cl2 (1.0 mL). The reaction mixture was cooled with an ice-water bath. Triol

5.64 (67 mg, 0.19 mmol) was dissolved in CH2Cl2 (1.0 mL) and added to the

reaction mixture. Reaction progress was monitored by TLC. After 10 min, the

reaction mixture was quenched with NaHCO3 and extracted with CH2Cl2 (3 x 0.5

mL). The combined extract was dried with Na2SO4, evaporated, and purified by

flash chromatography to obtain 5.77 and 5.78 (26 mg and 15 mg respectively,

25% and 17%)


TLC Rf = 0.33 (CH2Cl2/EtOAc = 90/10) [Anisaldehdye]


4.63 (d, J = 10.4 Hz, 1H), 4.37 (d, J = 10.4 Hz, 1H), 4.32 (d, J = 7.4

Hz, 1H), 4.20 (s, 1H), 4.10 – 3.99 (os, 2H), 3.96 (d, J = 12.0 Hz,

1H), 3.92 (d, J = 10.0 Hz, 1H), 3.81 (d, J = 10.0 Hz, 1H), 3.05 (d, J

= 12.4 Hz, 1H), 2.22 (t, J = 6.3 Hz, 1H), 1.99 – 1.87 (os, 2H), 1.75 –

1.60 (os, 4H), 1.47 – 1.36 (os, 2H), 0.99 (t, J = 7.9 Hz, 9H), 0.90 –

0.88 (os, 3H), 0.65 (q, J = 7.9 Hz, 6H)

369




4.68 (d, J = 10.8 Hz, 1H), 4.26 (d, J = 11.5 Hz, 2H), 4.22 (d, J = 7.4

Hz, 1H), 4.07 (d, J = 9.5 Hz, 1H), 4.03 – 3.98 (os, 2H), 3.96 – 3.86

(os, J = 10.3 Hz, 2H), 3.01 (d, J = 14.0 Hz, 1H), 2.17 (s, 3H), 2.12

(s, 1H), 1.98 (s, 1H), 1.88 (d, J = 14.5 Hz, 1H), 1.85 – 1.81 (m, 1H),

1.79 (dd, J = 13.3, 6.0 Hz, 1H), 1.69 (d, J = 14.0 Hz, 1H), 1.65 –

1.58 (m, 1H), 1.45 – 1.39 (m, 1H), 1.39 – 1.33 (m, 1H), 0.89 (t, J =

8.0 Hz, 9H), 0.52 (q, J = 8.0 Hz, 6H)


A mixture of compounds 5.77 and 5.78 (6.6 mg, 0.014 mmol) was dissolved in

CH2Cl2 (0.5 mL). DMP (6.5 mg, 0.015 mmol) was added and stirred for 30 min.

Reaction progress was monitored by TLC. The reaction mixture was purified by

chromatography to obtain compounds 5.79 and 5.80 (2.4 mg and 1.9 mg

respectively, 36% and 29%)



370

1H NMR (600 MHz, CDCl3) δ 9.81 (s, 1H), 7.42 – 7.28 (os, 5H), 4.96 (d, J =

12.1 Hz, 1H), 4.85 (d, J = 12.1 Hz, 1H), 4.75 (d, J = 10.6 Hz, 1H),

4.30 (dd, J = 10.0, 4.9 Hz, 2H), 4.23 (dd, J = 15.8, 8.5 Hz, 2H), 3.95

(s, 1H), 3.10 (d, J = 14.1 Hz, 1H), 2.01 – 1.95 (os, 2H), 1.78 (dd, J

= 13.3, 8.1 Hz, 1H), 1.64 (d, J = 14.2 Hz, 1H), 1.42 – 1.28 (os, 4H),

0.86 (t, J = 8.0 Hz, 9H), 0.47 (q, J = 8.0 Hz, 6H)




4.71 (dd, J = 14.8, 11.2 Hz, 2H), 4.48 (d, J = 10.8 Hz, 1H), 4.29 (d,

J = 11.6 Hz, 1H), 3.93 (d, J = 7.5 Hz, 1H), 3.86 (d, J = 10.4 Hz, 1H),

3.51 (d, J = 10.4 Hz, 1H), 2.84 (ddd, J = 13.7, 4.9, 2.4 Hz, 1H), 2.72

(d, J = 5.9 Hz, 1H), 2.02 (s, 1H), 1.98 – 1.92 (m, 1H), 1.82 (d, J =

10.0 Hz, 1H), 1.70 (d, J = 13.7 Hz, 1H), 1.51 – 1.40 (os, 3H), 0.94

(t, J = 8.0 Hz, 9H), 0.56 (q, J = 8.0 Hz, 6H)

371

Spectra of Compounds From Chapter 5 Figure 5.1 – 1H NMR of Compound C1 (600 MHz, C6D6)

372


373


374


375


376


377


378


379


380


381


382


383


384


385


386


387


388


389


390


391


392


393


394


395


396

Figure 5.26 – 1H NMR of Compound C4 (500 MHz, CDCl3)

397

Figure 5.27 – 13C NMR of Compound C4 (125 MHz, CDCl3)

398

Figure 5.28 – 1H NMR of Compound C5 (600 MHz, CDCl3)

399

Figure 5.29 – 13C NMR of Compound C5 (125 MHz, CDCl3)

400


401


402


403


404


405


406


407


408


409


410


411


412

REFERENCES

(1) Corey, E. Pure Applied Chemistry 1967, 14, 19.

(2) Hoffmann, R. American Scientist 1991, 79, 11.

(3) Custar, D. W.; Zabawa, T. P.; Scheidt, K. A. Journal of the American Chemical Society 2007, 130, 804.

(4) Nicolaou, K.; Vourloumis, D.; Winssinger, N.; Baran, P. S. Angewandte Chemie International Edition 2000, 39, 44.

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