methodological studies of α

METHODOLOGICAL STUDIES OF α-HALOGENATED CARBONYLS AND THE

SYNTHETIC INVESTIGATION OF DIHYDRORESORCYLIDE

by

KRISTINA CLAIRE PROBASCO

MICHAEL P. JENNINGS, COMMITTEE CHAIR

KEVIN H. SHAUGHNESSY

TIMOTHY S. SNOWDEN

JOHN M. RIMOLDI

PAUL A. RUPAR

A DISSERTATION

Submitted in partial fulfillment of the requirements

for the Doctor of Philosophy

in the Department of Chemistry

and Biochemistry

in the Graduate School of

The University of Alabama

TUSCALOOSA, ALABAMA

2020

Copyright Kristina Claire Probasco 2020

ALL RIGHTS RESERVED

ii

ABSTRACT

The research presented herein consisted of projects with focuses on metal enolates and

silane chemistry, and their uses in methodology and total synthesis. The projects were divided

into three distinct chapters.

The first chapter covers the development of highly functionalized pyran motifs that are

commonly found in classes of natural products such as Bryostatins via an intramolecular Heck

reaction with a novel palladium enolate transfer. A bromoethoxy pentanoate compound was

synthesized through several steps and was then subjected to catalytic reactions with conditions

found in literature where many variations were changed in attempts to obtain the desired six-

membered ring.

The second chapter consists of the total synthesis of Dihydroresorcylide via a novel

palladium enolate ring closure. This structure has been synthesized twice before, however both

syntheses undergo a ring closing metathesis to create the macrocycle. The macrocyclization

attempts were based on literature published by Buchwald and Hartwig.

The third project studies the halogenation of a trialkylsilyl bond through what is believed

to be a bromonium ion intermediate followed by an SN2 like elimination according to work

published by Tamao and company. Majority of the halogenations proceeded in good yields and

with complete inversion of stereochemistry.

iii

LIST OF ABBREVIATIONS AND SYMBOLS

9-BBN 9-borabicyclo[3.3.1.]nonane

Ac2O acetic anhydride

BF3•OEt2 boron trifluoride diethyl etherate

Bn benzyl

CSA camphorsufonic acid

DBA dibenzylideneacetone

DCM dichloromethane

DIBAL-H diisobutyl aluminum hydride

DIAD diisopropyl azodicarboxylate

DIPEA diisopropyl ethyl amine

DMAP 4-dimethyl amino pyridine

DME dimethoxyethane

DMF N,N-dimethylformamide

DMP Dess-Martin periodinane

DMSO dimethyl sulfoxide

dr diastereomeric ratio

E- entgegen (opposite, trans-)

equiv equivalents

EWG electron withdrawing group

iv

GC(II) Grubbs’ generation (II) catalyst

HMPA hexamethylphosphoramide

HRMS high resolution mass spectroscopy

Hz hertz

IR infrared

Ipc2BOCH3 (−)-diisopinocampheylmethoxy borane

J coupling constant

KHMDS potassium hexamethyl disilazideLDA

LDA lithium diisopropylamide

LiHMDS or

LHMDS

lithium bis(trimethylsilyl)amide

M molar

mCPBA meta-chloroperoxybenzoic acid

MHz megahertz

mmol millimole

mol mole

MEM methoxy ethoxy methyl

MOM methoxy methyl

MTBE methyl tert-butyl ether

NA not applicable

nBuLi n-butyllithium

ND not determined

NEt3 triethylamine

v

NMR nuclear magnetic resonance

NOE nuclear Overhauser enhancement

NR no reaction

o- ortho-

-OTf trifluoromethane sulfonate (triflate)

p- para-

PTSA (TsOH) p-toluenesulfonic acid

Py (pyr) pyridine

(R)- rectus (clockwise)

rt room temperature

(S)- sinister (counterclockwise)

TBAF tetra-n-butyl ammonium fluoride

TBS tert-butyldimethylsilyl

TEA Triethylamine

TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy free radical

TES triethylsilyl

TFA trifluoroacetic acid

THF tetrahydrofuran

THP tetrahydropyran

TMS trimethylsilyl

TMSOTf trimethylsilyl trifluoromethanesulfonate

TPS triphenylsilyl

Z- zuzammen (together, cis-)

vi

ACKNOWLEDGEMENTS

The first person I want to thank is my wonderful husband, Michael Probasco. We have

had a lot of the craziness of life happen, but you are always there being steady and helping me to

take everything in stride. You have helped me grow as a person and as a chemist over these last

few years and I cannot express my gratitude enough. Without you my days would be sullen. You

keep me laughing and help me to remain motivated. I love you more than I could accurately

express and I am so proud to be your wife.

My growth as a synthetic chemist comes from the help of several people. I wish to show

appreciation to my doctoral advisor, Dr. Michael P. Jennings, for giving me encouragement and

advice to help me improve my laboratory skills. My committee members also deserve thanks for

their investment in me along with their knowledgeable research suggestions. Thank you to Dr.

Michael P. Jennings, Dr. Timothy S. Snowden, Dr. Kevin H. Shaughnessy, Dr. Paul A. Rupar,

and John M. Rimoldi. Gratitude should also be given to Dr. Ken Belmore for assistance with

NMR experiments and Qiaoli Liang for completing mass spec analysis in a timely manner. Also,

a special thank you to Dr. Douglas Masterson, Dr. David Rankin, and Robin Wilson for seeing

something in me that I didn’t see in myself and encouraging me to persevere.

I want to state my upmost appreciation to my family, Karen Morris, Otis Morris, Jesse

Mejia, and the Lee Morris family. Thank you for supporting me and never giving up on me. I

appreciate the countless vent sessions and the understanding when I don’t call. I would not be

where I am without your love.

vii

Finally, I want to express my gratitude to the people I call friends. Shelby Dickerson and

Megan Roark, you both have been there for me from undergraduate studies to now. Both of you

are incredible and I will never be able to convey how much you have kept me calm and centered

these last several years. Thank you to Cameron Massey for the long random lab talks and

keeping my husband occupied with video games when I have been too busy.

viii

CONTENTS

ABSTRACT ....................................................................................................................... ii

LIST OF ABBREVIATIONS AND SYMBOLS .............................................................. iii

ACKNOWLEDGEMENTS ............................................................................................... vi

LIST OF TABLES ............................................................................................................. xi

LIST OF FIGURES ......................................................................................................... xiii

LIST OF SCHEMES..........................................................................................................xv

LIST OF NMRS .............................................................................................................. xvii

CHAPTER 1: PALLADIUM ENOLATE TRANSFER VIA AN

INTRAMOLECULAR HECK REACTION .......................................................................1

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

1.2 Palladium Enolates.........................................................................................................2

1.3 The Heck Reaction .........................................................................................................4

1.4 Synthesis of Ethyl (E)-5-(2-bromoacetoxy)-5-phenylpent-2-enoate and the

Attempts to Undergo an Intramolecular Heck Reaction ....................................................11

1.5 Conclusion ...................................................................................................................22

1.6 Supporting Information for Chapter 1 .........................................................................22

ix

1.7 References for Chapter 1 .............................................................................................27

CHAPTER 2: TOTAL SYNTHESIS OF DIHYDRORESORCYLIDE ...........................42

2.1 Introduction ..................................................................................................................42

2.2 Isolation and Structural Elucidation, Biological Properties and Reactions, and

Synthesis of Dihydroresorcylide ........................................................................................43

2.3 Retrosynthetic Analysis ...............................................................................................48

2.4 Total Synthesis of Dihydroresorcylide: Aromatic Synthon .........................................49

2.5 Total Synthesis of Dihydroresorcylide: Aliphatic Synthon .........................................54

2.6 Total Synthesis of Dihydroresorcylide: Combining Synthons ....................................56

2.7 Future Works ...............................................................................................................59

2.8 Conclusion ...................................................................................................................60

2.9 Supporting Information for Chapter 2 .........................................................................61

2.10 References for Chapter 2 ...........................................................................................69

CHAPTER 3: STEREOSELECTIVE HALO-SUCCINIMIDE FACILITATED α-

HALOGENATIONS OF SUBSTITUTED α-TRIALKYLSILYL-ß-SUBSTITUTED

-α,ß-UNSATURATED ESTERS ......................................................................................92

3.1 Introduction ..................................................................................................................92

3.2 The Generation of α-Trialkylsilyl-α, β-Unsaturated Esters .........................................94

3.3 The Halogenation Reaction ..........................................................................................96

3.4 (Z)-α-Halogen-α, β-Unsaturated Esters Compound Library ......................................100

3.5 Future Works .............................................................................................................105

x

3.6 Conclusion .................................................................................................................105

3.7 Supporting Information for Chapter 3 .......................................................................105

3.8 References for Chapter 3 ...........................................................................................112

xi

LIST OF TABLES

Table 1.1 Base Study with Pd(OAc)2 ................................................................................14

Table 1.2 Base study with PdCl2 and PPh3 .......................................................................16

Table 1.3 Base Study with PdCl2 and P(o-tolyl)3..............................................................16

Table 1.4 Solvent Study ....................................................................................................17

Table 1.5 Pd2(dba)3 Studies ...............................................................................................18

Table 1.6 Frank Glorius and Ionic Heck Conditions ........................................................19

Table 1.7 Chloroacetoxy Intramolecular Heck Attempts ..................................................20

Table 1.8 Studies with Compound 1.19 ............................................................................22

Table 1.9 Studies with Compounds 1.20 ..........................................................................22

Table 2.1 Triflate Coupling Experiments ..........................................................................50

Table 2.2 Triflate Coupling with Silyl Enol Ether ............................................................52

Table 2.3 Bromobenzene and Ethyl Bromobenzoate Coupling ........................................52

Table 2.4 Pd Enolate Macrocycle Formation ....................................................................59

Table 2.5 Silyl Enol Ether Conversion..............................................................................59

Table 3.1 Vinyl Silane Compound Library .......................................................................96

xii

Table 3.2 Solvent Dependence Studies .............................................................................97

Table 3.3 Bromination Compound Library .....................................................................101

Table 3.4 Chlorination Compound Library .....................................................................104

xiv

LIST OF FIGURES

Figure 1.1 Pyran Motif .................................................................................................................. 1

Figure 1.2 Bryostatin and Exiguolide ........................................................................................... 1

Figure 1.3 General Pd Enolate ...................................................................................................... 2

Figure 1.4 Formation of Metal Enolate ......................................................................................... 3

Figure 1.5 Metal Enolate Coordination......................................................................................... 3

Figure 1.6 Relative Stability of Pd Enolates ................................................................................. 4

Figure 1.7 Genaralized Mizoroki-Heck Reaction ......................................................................... 5

Figure 1.8 Cis/Trans Isomerization ............................................................................................... 8

Figure 1.9 Example of 6-Endo Cylization .................................................................................. 10

Figure 1.10 6-Exo Cyclization .................................................................................................... 10

Figure 1.11 Products Isolated Under Base Study With Pd(OAc)2 .............................................. 15

Figure 1.12 Product Isolated with Stoichiometric PdCl2 Catalyst .............................................. 18

Figure 1.13 Reference Heck Reaction ........................................................................................ 19

Figure 2.1 Resorcylic Acid Backbone of RALs ......................................................................... 42

Figure 2.2 Dihydroresorcylide .................................................................................................... 43

xiv

Figure 2.3 Culvularin .................................................................................................................. 44

Figure 2.4 Retrosynthetic Analysis of 2013 Synthesis ............................................................... 45

Figure 2.5 Weinreb Amides Utilized for Synthesis .................................................................... 46

Figure 2.6 Hydrogen Bound 2.24................................................................................................ 50

Figure 2.7 Side Product Formed From 2.26................................................................................ 51

Figure 2.8 Silyl Enol Ether Formation ........................................................................................ 51

Figure 2.9 Coupling with Silyl Enol Ether ................................................................................. 52

Figure 3.1 Example Reaction Studied by Tamao ....................................................................... 93

Figure 3.2 Versatility of Vinyl Silanes ....................................................................................... 94

Figure 3.3 General Halogenation Reaction ................................................................................. 94

Figure 3.4 Copper Facilitated Silyl Ketene Acetal Formation .................................................... 95

Figure 3.5 Sample Halogenation for Optimization ..................................................................... 97

Figure 3.6 Key NOE Interactions for 3.3a ................................................................................ 101

Figure 3.7 Key NOE Interactions for 3.3d................................................................................ 103

Figure 3.8 TES Bromination ..................................................................................................... 105

xv

LIST OF SCHEMES

Scheme 1.1 Generalized Catalytic Cycle of Heck Reaction ......................................................... 6

Scheme 1.2 Preactivation of Pd Catalyst ....................................................................................... 6

Scheme 1.3 Synthesis of ethyl (Z)-2-(2-oxo-6-phenylthetrahydro-4H-pyran-4-ylidene)acetate 12

Scheme 1.4 Proposed Catalytic Cycle for Intramolecular Heck Cyclization .............................. 13

Scheme 1.5 Synthesis of 4-methylene-6-phenyltetrahydro-2H-pyran-2-one .............................. 21

Scheme 2.1 Total Synthesis of Dihydroresorcylide Published in 2013 ...................................... 46

Scheme 2.2 Total Synthesis of Dihydroresorcylide Published in 2017 ...................................... 47

Scheme 2.3 Retrosynthetic Analysis of 2.1 ................................................................................. 49

Scheme 2.4 Synthetic Pathway 1 of Aromatic Synthon .............................................................. 50



Scheme 2.7 Grignard Method of Synthetic Pathway 1 for Aliphatic Formation ........................ 55

Scheme 2.8 Oxidation Method of Synthetic Pathway 1 for Aliphatic Formation....................... 55

Scheme 2.9 Combination Method of Synthetic Pathway 1 for Aliphatic Formation .................. 55

Scheme 2.10 Synthetic Pathway 2 for Aliphatic Formation ....................................................... 56

xvi

Scheme 2.11 Synthesis of Dihydroresorcylide Via Pathway 2 ................................................... 57

Scheme 2.12 Synthesis of Dihydroresocylide Via Pathway 3 .................................................... 60

Scheme 3.1 Hypothesized Mechanism of Bromination .............................................................. 99

Scheme 3.2 Possible Mechanism of 3.3d .................................................................................. 103

xvii

LIST OF NMRS

The 1H NMR Spectrum (360 MHz, CDCl3) of Compound 1.3 ................................................... 34



The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 1.13 ................................................. 37












xviii


The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 2.35 ................................................ 81


The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 2.20 ................................................ 83

The 1H NMR Spectrum (360 MHz, CDCl3) of Compound 2.20, A ............................................ 84








The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.2a ............................................... 115

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.2b ............................................... 116

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.2c ............................................... 117

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.2d ............................................... 118

The 1H NMR Spectrum (360 MHz, CDCl3) of Compound 3.2e ............................................... 119

The 1H NMR Spectrum (360 MHz, CDCl3) of Compound 3.2f ................................................ 120

xix

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.2g ............................................... 121

The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.2g .............................................. 122

The 1H NMR Spectrum (360 MHz, CDCl3) of Compound 3.2h ............................................... 123

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.2i ................................................ 124

The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.2i ............................................... 125


The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.3a .............................................. 127



The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.3c .............................................. 130

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.3d ............................................... 131

The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.3d .............................................. 132

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.3e ............................................... 133

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.3f ................................................ 134

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.3g ............................................... 135

The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.3g .............................................. 136

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.3h ............................................... 137

The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.3h .............................................. 138

xx



The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.4b .............................................. 141


The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.4c .............................................. 143

1

CHAPTER 1: PALLADIUM ENOLATE TRANSFER VIA AN INTRAMOLECULAR HECK

REACTION

1.1 Introduction

Development of highly functionalized small molecules to serve as intermediates in synthesis

of natural products, or other biologically active macromolecules, is desirable. The pyran motif

shown in Figure 1.1 is exhibited in the class of biological compounds called Bryostatin and (-)

Exiguolide (Figure 1.2) and will be the focus of this research.1, 2

Pd enolates (Figure 1.3) have been utilized to undergo various transformations3, 4 and often

an enolate intermediate is proposed with both intermolecular and intramolecular Heck reaction

2

takes place.5, 6 However, a Pd enolate transfer is novel when introduced into an intramolecular

Heck reaction.

The following research examines the ability to perform a Pd enolate transfer via an

intramolecular Heck reaction with halogenated acetoxy α, β unsaturated esters and their olefin

analogs.

1.2 Palladium Enolates

Pd enolates have found their way into use for several decades. It has been reported that there

are three known ways to create a metal enolate as shown in Figure 1.4.7 The first way, A,

involves a metal anion displacement which is frequently shown through a transmetallation of a

variety of transition metals such as silver, or copper.8, 9 In part B, allyl coordination is visible by

removal of a halide on the Pd complex, for example, a PdCl2 has shown to undergo this

transformation.10 The final way, C, focuses on silyl enolates. Silyl enolate, similar to transition

metals, experience alteration through transmetallation.11 Upon formation of the metal enolate

complex, there are now four ways in which the Pd would coordinate.

3

Figure 1.5 details the ways in which Pd enolate coordination can occur.12 Carbon

coordination as shown in A, is the first method of coordination.13 2. B, exhibits the formation of

an oxoallyl species.8, 14 3. The formation of the oxygen coordinated enolate is shown in C.15 D

exhibits bridging as the final potential species in enolate coordination.16 The bonding to the

metal center can be influenced by a variety of factors.

According to Culkin and Hartwig, the coordination of the metal enolate is dependent on a

variety of factors from electronics to ligands. After performing NMR studies, the ketones with α-

4

methyl or methylene hydrogens and a bidentate phosphine ligand were all bound to the carbon

whereas α-methine protons were oxygen bound. Figure 1.6 summarizes the bonding and stability

of these interactions. Electronically, the carbon is favored when there is a phosphine trans on the

metal complex while oxygen is favored when there is an aryl ligand in the trans position.17

Pd enolates have been studied and are utilized in many different processes from initiation of

homocoupling,18 enantioselective Michael reactions,19 intramolecular ring formations,20, 21

formation of quaternary centers,22, 23 and synthesis.3, 4 The usefulness of these groups has

expanded organometallic coupling like that of the Heck reaction.

Olefins containing carbonyls have been found to produce a Pd enolate during a Heck

reaction under various conditions.6, 24, 25 However, despite all the research over these topics, a Pd

enolate has not been generated first and then treated to form a second enolate from the olefin.

The development of the intermolecular and intramolecular Heck reaction will be discussed in the

following section.

1.3 The Heck Reaction

The Mizoroki-Heck reaction, or Heck reaction, was founded by Tsutomu Mizoroki and

Richard Heck. The catalytic process involves cross coupling of an unsaturated halide and various

substituted olefins as shown in Figure 1.7.26

5

The proposed catalytic cycle goes through preactivation, oxidative addition, migratory

insertion, and hydride elimination shown in Scheme 1.1. Preactivation (Scheme 1.1, A) is the

reduction of the Pd, typically a Pd(II), into an active species, Pd(0), via removal of a ligand like

phosphine with assistance of a hard nucleophile like water.27-29 Phosphines are common ligands

utilized in cross coupling reactions and it will reduce to yield a phosphine oxide, while dba,

another ligand frequented in literature, will not undergo an oxide formation.30, 31 It is believed

that the nucleophile can either perform a nucleophilic substitution with the ligand on the metal

complex (outer shell mechanism), or the species will coordinate to the metal complex and go

through a reductive elimination (inner shell mechanism). The following scheme (Scheme 1.2)

exhibits a basic example of the activation. However, it was found that an excess of ligand can

hinder this step as it will not allow for the catalyst to remain active, which has shown to halt the

coupling from occurring.32

6

Oxidative addition (Scheme 1.1, B) follows preactivation and involves the active Pd catalyst

inserting itself in a carbon-halogen bond via a concerted process where all bonds that are broken

and formed happen at the same time ultimately changing the oxidation state of the Pd.33 The

halogen reactivity is as follows: I>>OTf>Br>>Cl showing that iodine is significantly more

reactive than other halogens and chlorine is the least likely to have bond insertion transpire.34

Cis/trans isomerization will occur and although it was thought to be a simpler process, studies

7

were conducted by Arturo and workers finding that there are in fact several pathways this can go

through.

These extensive studies showed that there are multiple associative and dissociative means to

go from the less stable cis isomer to the more stable trans. Figure 1.8 illustrates the findings of

this research. It should be noted that the solvent coordination pathway shown on the right side of

the figure can occur in the same manner with a metal halide complex. After insertion cis/trans

isomerization takes place oxidative addition is complete and the rate determining migratory

insertion takes place.35

8

Unlike other cross couplings, migratory insertion is the bond forming step in the Heck

reaction shown in Scheme 1.1, C. This step can often exhibit the generation of a Pd enolate and

as discussed earlier olefin type, ligands, and cone angles all influence the connectivity at this

stage.17 There are three different pathways by way this can proceed; 1. The Pd halide complex

9

will act as a carbanion where the insertion is similar to a vinylic nucleophilic substitution.33 2.

The attack can happen with neutral or cationic catalyst systems and proceeds through a classic

electrophilic addition which is most supported by literature. 3. The insertion happens via a

concerted SN2 addition.36-38 In order for the attack and bond formation to occur, a ligand needs to

be lost and can be either neutral or ionic. Monodenate ligands tend to follow the neutral pathway

while multidentate ligands tend to be ionic.39-41

Electronics also play a role in migratory insertion. An electron rich olefin can go through

both neutral and ionic intermediates for the Pd attack. The Pd will bind to the atom with the

highest electron density. While steric effects can override the outcome of couplings, electronics

will still dominate in intermolecular Heck reactions.42-47

Intramolecular Heck reactions follow the same catalytic cycle as the previously shown in the

intermolecular cycle (Scheme 1.1), however, steric effects will be the dominating factors of

migratory insertion. During intramolecular Heck reactions, the endo cyclization is typically not

present for smaller rings (5, 6, and 7) due to sites being sterically hindered. There have been

specific examples of a 6-endo cyclization transpiring under specific circumstances; however the

process did not occur via the 6-endo ring closure, but through a sequence of 5-exo trig followed

by 3-exo trig cyclizations (Figure 1.9).48-50 6-exo trig (Figure 1.10) intramolecular Heck

reactions are most common cyclizations found.51-54 This cyclization is desirable in the formation

of the 6-exo ring crucial to the research presented herein.

10

Hydride elimination is the final step of the catalytic cycle which removes the Pd via a

concerted syn elimination to afford the final alkene.55, 56 The newly formed Pd hydride complex

must be quickly scavenged by a base to avoid readdition to the olefin which would ultimately

give the wrong stereochemistry. Bases can also influence where the elimination will occur

whether internal or terminal due to availability of proton sources.57

As shown in Scheme 1.1, the E isomer predominates as the final alkene. Again, electronics

can also influence this outcome. The more electron rich the olefin, the more likely only the E

configuration will be isolated.17

11

While the Heck reaction has been widely studied, and Pd enolates can occur throughout this

process, there is no current literature presence of a Pd enolate transfer taking place to form a six

membered exo cycle. The research conducted regarding this novel venture follows.

1.4 Synthesis of Ethyl (E)-5-(2-bromoacetoxy)-5-phenylpent-2-enoate and the Attempts to

Undergo an Intramolecular Heck Reaction

Development of the targeted ring product 1.8 required a four step, linear synthetic pathway as

shown in Scheme 1.3. In the first step benzaldehyde 1.1 underwent a Grignard reaction with an

allylmagnesium bromide 1.2 to afford the homoallylic alcohol 1.3 in high yields. Grignard

reactions undergo nucleophilic attack of the carbonyl species present and are frequently utilized in

organic synthesis due to the high yields ultimately produced.58-62 It was found that when

conducting the aforementioned reaction, if the temperature was not maintained for a certain period

of time or if the Grignard reagent was not added dropwise, there would be a decrease of yield.

However, the product did not require any purification other than longer time on the vacuum to

remove excess solvent which also proved desirable.

12

The racemic alcohol 1.3 was then reacted with ethyl acrylate 1.4 via the well-known Grubbs’

cross metathesis and after purification produced an equally beneficial yield as found in the first

step. Olefins are characterized into four types when undergoing the cross metathesis, and these

categories tend to dictate whether the yields would be a statistical distribution of homodimerized

products to cross products or a single product. Based on the information provided in the paper

published by Grubbs’ and coworkers, it was decided that the homoallylic alcohol 1.3 was a type I

olefin, where its counterpart 1.4 was a type II.63 This allowed for the statistical distribution to be

overcome and in a selective E conformer 1.5.

The newly formed vinylic ester 1.5 then underwent a nucleophilic acyl substitution with

bromoacetyl bromide 1.6. Nucleophilic substitutions are widely used and with a vast number of

reagents.64-67 However, acyl halides are some of the most reactive and can produce new carbon-

oxygen bonds with ease. When conducting the substitution, it was found that by having an excess

of pyridine the reaction took place much easier. It is believed that the base would essentially trap

the free proton released after the attack of the hydroxyl group on 1.5. The bromoethoxy pentanoate

13

1.7 was formed in moderate yields.68 Upon purification it was found that there was starting material

still present which could have potentially been avoided by increasing the equivalents of pyridine;

however, the yield consistently given was proficient enough to begin development of the novel

intramolecular Heck reaction via Pd enolates by formation of the desired exocyclic alkene 1.8.

Compound 1.7 was designed as a pivotal element in an undiscovered Heck reaction

utilizing Pd enolate transfer to enforce the desired ring closure. The proposed catalytic mechanism

shown in Scheme 1.4. An oxidative addition (Scheme 1.4, A) would take place via Pd insertion

between the carbon-bromine bond ultimately forming an initial Pd enolate species. The new Pd(II)

would form a pi complex between the olefin (Scheme 1.4, B) which would lead to a migratory

insertion with the Pd attached at the α carbon of the carbonyl creating a second Pd enolate (Scheme

14

1.4, C). This species would undergo the highly important β-hydride and reductive elimination

(Scheme 1.4, D) to form the desired alkene 1.8. This theoretical cycle would continue in this

manner until the starting material was used up. Due to the ring closure generating a compound that

is six membered, it can be assumed that the Pd would not react with the structure any further as it

would be stable.

The bromoethoxy pentanoate 1.7 underwent reactions with conditions that were similar to

that found in literature for Heck reactions both inter and intramolecularly.6, 69-71 Table 1.1 shows

that 1.8 was subjected to a series of reactions under specific conditions, where the catalyst, ligand,

and solvent were Pd(OAc)2 at 0.03 equivalents, P(o-tolyl)3 at 0.09 equivalents, and toluene

respectively. The base varied because of relative strength of the base, size, and frequency of the

material found in literature. In entry 1-3, K2CO3, K3PO4, and NaHCO3 were added into the reaction

system because these are shown to be utilized a great deal when researching desirable conditions

and they are noncoordinating with the catalyst. Both entries 4 and 5 exploited the bulkiness of the

two amines TEA and Hunig’s base. Despite the use of literature-based circumstances, a series of

unwanted products were isolated.

Entry Catalyst (0.03 eq) Ligand (0.09 eq) Base (5.0 eq) Solvent Product

1 Pd(OAc)2 P(o-tol)3 K2CO3 Toluene 1.7, 1.14

2 Pd(OAc)2 P(o-tol)3 K3PO4 Toluene 1.7, 1.14

3 Pd(OAc)2 P(o-tol)3 NaHCO3 Toluene 1.7, 1.14

4 Pd(OAc)2 P(o-tol)3 TEA Toluene 1.13, 1.14

5 Pd(OAc)2 P(o-tol)3 Hunig’s Toluene 1.13, 1.14

Table 1.1 Base Study with Pd(OAc)2

Compound 1.13 (Figure 1.10) was the material collected when the amine bases were

introduced. The acetyl group formation was caused by the fact that there are β hydrogens present

on the base which allowed for a β hydrogen elimination to occur readily. Therefore, it was decided

15

to steer away from these types of hydrogen sources. While the salt like bases in entries 1-3 did not

show any adverse results, it was found that an SN2 type reaction between the acetate group of

Pd(OAc)2 and the bromoethoxy pentanoate 1.7 giving rise to 1.14 (Figure 1.11). Due to the side

reactions taking place with the catalyst and bases, it was decided to change the catalyst to Pd(Cl)2.

Table 1.2 shows a second series of base studies conducted and a change of ligand to PPh3

occurred. It was thought that potentially the methyl group on P(o-tolyl)3 pushed the cone angle

larger which could have affected coordination to the catalyst. The bases in entries 1-3 were chosen

because of the lack of additional hydrogens available to cause unfavorable side reactions.

NaH2PO4 was chosen in entry 4 despite having an available hydrogen because the hydride source

is not on the ß-phosphine thus rendering the ß-hydride elimination not possible. Entry 5 utilized

imidazole, which would be an amine base source that would not cause the β-hydride elimination

previously illustrated because of the hydride sources already being on sp2 carbon centers. The

material recovered was starting material 1.7 with a negligible amount of what appeared to be

desired product. However, recovery of the compound proved futile and it was reasoned that an

increase in catalyst loading may help improve the yield and allow for isolation of the questionable

species.

16


1 Pd(Cl)2 PPh3 K3PO4 Toluene 1.7

2 Pd(Cl)2 PPh3 K2PO4 Toluene 1.7

3 Pd(Cl)2 PPh3 K2CO3 Toluene 1.7

4 Pd(Cl)2 PPh3 NaH2PO4 Toluene 1.7

5 Pd(Cl)2 PPh3 Imidazole Toluene 1.7

Table 1.2. Base Study with PdCl2 and PPh3

In Table 1.3 the catalyst remained Pd(Cl)2, however the equivalents was increased to 0.09

and the ligand was changed back to P(o-tolyl)3 since there was so significant improvements

concerning PPh3. Entries 1-3 were potassium and sodium species chosen yet again for the inability

to coordinate to the catalyst or give up hydrogens for unfavorable reactions. NaOH, as shown in

entry 4, was utilized because of the strong basicity exhibited by the compound in solution. It was

thought that the system could benefit from a stronger base in order to help regenerate the Pd

catalyst drive the reaction to completion. Entry 5 lists pyridine as a base of choice despite having

β hydrogens. However, these hydrogens are not likely to be removed due an unfavorable formation

of an alkyne species. All entries, except for 4, produced arguably similar results as the previous

study where potential product was formed but in incredibly small amounts. Entry 4 underwent a

nucleophilic substitution and was reduced back to compound 1.5. It was then decided to set base

studies aside and focus on solvent effects.


1 Pd(Cl)2 P(o-tol)3 K2CO3 Toluene 1.7

2 Pd(Cl)2 P(o-tol)3 K3PO4 Toluene 1.7

3 Pd(Cl)2 P(o-tol)3 NaHCO3 Toluene 1.7

4 Pd(Cl)2 P(o-tol)3 NaOH Toluene 1.7

5 Pd(Cl)2 P(o-tol)3 Pyridine Toluene 1.7

Table 1.3. Base Study with PdCl2 and P(o-tolyl)3

17

Under conditions including Pd(Cl)2, PPh3, and K2CO3, solvent studies were conducted as

shown in Table 1.4. Solvents with boiling points of 110 oC or higher were targeted for this study

as it was believed that the energy barrier to obtain the potential product was too high. Entries 1

and 2 are similar to each other with xylene having the higher boiling point. Both toluene and xylene

are not coordinating solvents which allows the reaction to continue without solvent interference.

These two entries exhibited the same results as shown from the previous table. The remaining three

entries can all coordinate with the catalyst and could slow the reaction down, however the higher

boiling point of each of these would compensate for that. Unfortunately, all three materials

ultimately removed the acetyl group giving rise to compound 1.5.


1 Pd(Cl)2 PPh3 K2CO3 Toluene 1.7

2 Pd(Cl)2 PPh3 K2CO3 Xylene 1.7

3 Pd(Cl)2 PPh3 K2CO3 DMSO 1.7

4 Pd(Cl)2 PPh3 K2CO3 ETG 1.7

Table 1.4. Solvent Study

Due to the inability to increase the yield to one that would allow for isolation of what was

thought to be the desired compound it was decided that a stoichiometric equivalent of Pd(Cl)2

would be tested. This caused a significant shift of the observed methylene, which is what the

exocyclic alkene 1.8 would have produced. However, upon further studies it was discovered that

this was in fact caused by a halide displacement from a bromine to a chlorine because of the

catalyst as shown in compound 1.15 (Figure 1.12). With this information in hand, the decision to

move away from a Pd(II) species and begin studies with a Pd(0) catalyst.

18

Shown in Table 1.5, the Pd(0) catalyst that was employed was Pd2(dba)3. This was a bulkier

catalyst and was already in the active state making the compound air sensitive which meant great

care was taken to complete set up. The ligand of choice was for entries 1-3 was PPh3 and toluene

was the solvent system due to lack of decomposition on the starting material. K2CO3, DIPEA, and

pyridine were the bases that were studied. Due to the change in the catalyst, the β-hydride

elimination to form an acetyl side product did not occur as it had previously. All three entries

provided either starting material, compound 1.5, or a mixture of both. In entry 4, P(o-tolyl)3 was

exchanged with PPh3 to see if any positive results could be discerned and unfortunately this was

not the case.


1 Pd2(dba)3 PPh3 K2CO3 Toluene 1.7

2 Pd2(dba)3 PPh3 Hunig’s Toluene 1.7

3 Pd2(dba)3 PPh3 Pyridine Toluene 1.7

4 Pd2(dba)3 P(o-Tol)3 Hunig’s Toluene 1.7

Table 1.5. Pd2(dba)3 Studies

Frank Glorius and coworkers published work concerning similar compounds. Due to this

literature material, the conditions listed were followed exactly (see Table 1.6) in an attempt to

obtain any usable products.72 Again, only compound 1.5 was recovered. Entry 2 shows the

conditions found in literature for conducting an ionic Heck reaction, which follows the same

pathway as that of a neutral Heck reaction but tends to be more reactive with pi complexes.73 The

19

only material recovered after experiment was starting material 1.5 and pure silver pellets. At this

point, the technique of setting up these reactions came into question.

Catalyst Equiv. Ligand Equiv. Base Equiv. Solvent Product

1 Pd(PPh3)2Cl2 0.05 P(o-Tol)3 0.09 Hunig’s 1.5 Acetonitrile 1.7

2 Pd(TFA)2 0.1 P(o-Tol)3 0.09 Ag2CO3 2 1,4-dioxane 1.7

Table 1.6. Frank Glorius and Ionic Heck Conditions

A reference Heck reaction shown in Figure 1.13 was conducted using iodobenzene 1.16

and ethyl acrylate 1.4. After purification the iodoester 1.17 was successfully isolated and in

moderate yields. Because of the positive outcome, it was concluded that technique was not the

hindering the formation of the exocyclic alkene 1.8. The question arose if the Pd insertion between

the carbon-bromine bond was occurring due to the inability to recover any material other than that

of starting material or compound 1.5.

With that question in mind, the chloroethoxy pentanoate analog was synthesized. The

theory is that potentially the bromine atom was too large to allow the insertion, therefore with a

smaller atom the Pd catalyst could successfully insert for the oxidative addition. The synthetic

pathway remained the same with the exchange of bromoacetyl bromide 1.6 for chloroacetyl

chloride. Table 1.7 shows ligand studied conducted where monodentate phosphine ligands were

compared to a bidentate phosphine ligand. Bidentate ligands tend to be useful as they force the

20

bite angle of a catalyst to be set parameters, often times driving the cycle forward. Unfortunately,

none of entries 1-3 yielded any material other than starting material or compound 1.5. Entry 4

shows the conditions for the published article by Frank Glorius and coworkers, which also proved

to be futile.


1 Pd2(dba)3 0.03 PPh3 0.09 Hunig’s 5 Toluene 1.5, 1.15

2 Pd2(dba)3 0.03 P(o-tol)3 0.09 Hunig’s 5 Toluene 1.5, 1.15

3 Pd2(dba)3 0.03 DPPE 0.09 Hunig’s 5 Toluene 1.5, 1.15

4 Pd(PPh3)2Cl2 0.05 P(o-tol)3 0.09 DIPEA 1.5 Acetonitrile 1.5, 1.15

Table 1.7. Chloroacetoxy Intramolecular Heck Attempts

Another theory arose believing that the ester group may not be allowing the reaction to

progress as desired either due to size, location, or possible coordination of the Pd. Further analogs

1.19 and 1.20 were developed and tested with this in mind.

The synthetic pathway to create analogs 1.19 and 1.20 is shown in Scheme 1.5. This

method is very similar to the generation of the original bromoethoxy penanoate (1.7) compound.

In the first step, benzaldehyde 1.1 underwent a Grignard reaction with allylmagnesium bromide

1.2 which again was successful with high yields and did not need purification. In the previous

synthetic strategy (Scheme 3), the second portion would be to conduct a cross metathesis; however,

the formation of the ester 1.5 would not be necessary for either analog. Therefore, the second step

consisted of reacting either bromoacetyl bromide or chloroacetyl chloride with 1.3 via a

nucleophilic substitution to afford both analogs. The yields of the substitutions were comparable

to the previous experiments.

21

The proposed catalytic cycle of derivatives 1.19 and 1.20 would be similar to that of the

original except the only Pd enolate to be formed would be during the oxidative addition when the

Pd insertion of the carbon-bromine bond occurred. While this would change the scope of the

project because the Pd enolate transfer would not be present, the information gathered could give

insight to assist in the understanding of the difficulties presented with compound 1.7.

Analog 1.19 underwent a series of experiments similar to that of the bromo and

chloroethoxy pentanoate shown in Table 1.8. In entries 1-2 monodentate ligands were compared

to determine if the cone angle would have a substantial effect on the products recovered. Bidentate

ligand, DPPE, was utilized shown in entry 3. All three ligand choices did not have any desirable

impact and removal of the acetyl group to afford compound 3 was the only recoverable product.

Due to those results, it was decided to attempt the reaction with a lower amount of base. Hunig’s

base was decreased from a total of five equivalents to two. However, compound 1.3 continued to

22

be the only isolated product. The final entry was a repeat of Frank Glorius’s publication which

returned starting material and no product formation of any kind was detected.


1 Pd2(dba)3 0.03 PPh3 0.09 Hunig’s 5 Toluene 1.3

2 Pd2(dba)3 0.03 P(o-tol)3 0.09 Hunig’s 5 Toluene 1.3

3 Pd2(dba)3 0.03 DPPE 0.09 Hunig’s 5 Toluene 1.3


5 Pd(PPh3)2Cl2 0.05 P(o-tol)3 0.09 Hunig’s 1.5 Acetonitrile 1.3, 1.19

Table 1.8. Studies with Compound 1.19

Moving on to the second analog 1.20, Table 1.9 showcases the ligand studies that were

completed. Both monodentate and bidentate ligands were utilized in the course of the work.

Unfortunately, only compound 1.3 or starting material was observed.


1 Pd2(dba)3 0.03 PPh3 0.09 Hunig’s 5 Toluene 1.3


3 Pd2(dba)3 0.03 DPPE 0.09 Hunig’s 5 Toluene 1.3, 1.20

Table 1.9. Studies with Compound 1.20

1.5 Conclusion

This chapter focused on the formation and transfer of Pd enolates to generate a new six

membered exo-cycle via an intramolecular Heck reaction. This research did not afford any

desirable products, but it did give insight into the nature of catalytic cross coupling reactions.

Despite changing the catalyst, base, and ligand in the system, as well as creating derivates of the

coupling material, no products of value were discernible.

1.6 Supporting Information for Chapter 1

23

General Procedure: All of the reactions were performed under Ar in flame-dried glassware. All

starting materials, solvents, reagents, and catalysts were commercially available and used

without further purification. The NMR spectra were recorded with either a 360 or 500 MHz

Bruker spectrometer. 1H and 13C NMR spectra were obtained using CDCl3 as the solvent with

chloroform (CHCl3 1H: δ = 7.26 ppm, CDCl3

13C: δ = 77.0 ppm) as the internal standard.

Column chromatography was performed using 60-200 µm silica gel. Analytical thin layer

chromatography was performed on silica coated glass plates with F-254 indicator. Visualization

was accomplished by UV light (254 nm) and KMnO4.

Synthesis of 1-phenylbut-3-en-1-ol (1.3): To a flame dried and purged RBF, a solution of 1.1

(9.4 mmol, 0.96 mL, 1.0 eq.) in anhydrous THF (1.0 M, 10 mL) was added. The mixture was

cooled to -78 oC where 1.2 (1.0 M, 10.4 mL, 1.1 eq.) was added dropwise. The reaction stirred

overnight allowing the temperature to raise to RT. It was then carefully quenched with DI water

and extracted three times with 10 mL of diethyl ether. All the organic layers were combined and

dried with MgSO4 and concentrated. There was no purification needed. Yield: 1.3 g, 90% as

light-yellow oil. 1H NMR (360 MHz, CDCl3) δ 7.34 (m, 5H), 5.82 (td, J = 17.2, 7.3 Hz, 1H),

5.17 (m, 2H), 4.73 (m, 1H), 2.52 (m, 2H).

Synthesis of ethyl (E)-5-hydroxy-5-phenylpent-2-enoate (1.5): Homoallylic alcohol 1.3 (0.68

mmol, 0.10 g, 1.0 eq.) was dissolved in DCM (0.2 M, 2.3 mL) and added to a flame dried and

purged flask. The acrylate 1.4 (3.4 mmol, 0.36 mL, 5.0 eq.) was added dropwise followed by

addition of the Grubbs’ (II) catalyst (0.03 mmol, 0.03 g, 0.05 eq.). The mixture was stirred

overnight at RT and then concentrated. Purification took place via column chromatography in

20% EtOAc and hexanes to afford the desired 1.5. Rf: 0.7; Yield: 0.11 g, 74% as dark brown oil.

24

1H NMR (360 MHz, CDCl3) δ 7.33 (m, 6H), 6.94 (m, 1H), 5.91 (dt, J = 15.7, 1.4 Hz, 1H), 4.83

(m, 1H), 4.03 (dd, J = 5.8, 2.8 Hz, 2H), 2.66 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H).

Synthesis of ethyl (E)-5-(2-bromoacetoxy)-5-phenylpent-2-enoate (1.7): To a flame dried and

purged flask, a solution of 1.5 (0.45 mmol, 0.10 g, 1.0 eq) and DCM (0.3 M, 1.5 mL) was added.

The reaction was cooled to 0 oC where pyridine (0.91 mmol, 0.07 mL, 2.0 eq.) was added,

followed by compound 1.6 (0.91 mmol, 0.07 mL, 2.0 eq) dropwise. The mixture stirred

overnight raising the temperature to RT where is was then quenched with saturated NH4Cl and

extracted three times with 10 mL of DCM. The organic layers were combined and washed with

10 mL of saturated CuSO4. The solution was then dried with MgSO4 and concentrated.

Purification took place via column chromatography in 5% EtOAc in hexanes to afford the

desired 1.7. Rf: 0.2; Yield: 0.09 g, 57% as dark brown oil. 1H NMR (360 MHz, CDCl3) δ 7.33

(m, 5H), 6.82 (dt, J = 15.5, 7.3 Hz, 1H), 5.87 (ddd, 2H), 4.03 (dd, J = 5.8, 2.9 Hz, 2H), 3.81 (s,

2H), 2.74 (m, 2H), 0.88 (m, 3H).

Ethyl (E)-5-acetoxy-5-phenylpent-2-enoate (1.13) (Table 1.1, Entry 4): Purified from 5%

EtOAc in hexanes. Rf: 0.2; Yield: 0.008 g, 20% as a yellow oil.

Ethyl (E)-5-(2-acetoxyacetoxy)-5-phenylpent-2-enoate (1.14) (Table 1.1, Entry 1): Purified

from 5% EtOAc in hexanes. Rf: 0.2; Yield: 0.01 g, 20% as a yellow oil.

Ethyl (E)-5-(2-chloroacetoxy)-5-phenylpent-2-enoate (1.15) (Table 1.4, Entry 1): Purified

from 20% EtOAc in hexanes. Rf: 0.2; Yield: 0.03 g, 50% as a yellow oil.

Synthesis of ethyl cinnamate (1.17): To a flame dried and purged flask, acrylate 1.4 (1.0 mmol,

0.11 mL, 1.0 eq.) and iodobenzene 1.16 (1.2 mmol, 0.14 mL, 1.2 eq.) were added to anhydrous

toluene (0.05 M, 20 mL). Pd2(dba)3 (0.03 mmol, 0.03 g, 0.03 eq.) and PPh3 (0.09 mmol, 0.02 g,

0.09 eq.) were sequentially added followed by Hunig’s base (5.0 mmol, 0.87 mL, 5.0 eq.). The

25

reaction was refluxed overnight where the material was filtered and concentrated. The desired

1.17 was visible by 1H NMR. 1H NMR (500 MHz, CDCl3) δ 7.53 (m, 6H), 6.45 (d, J = 16.0 Hz,

1H), 4.28 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H).

Synthesis of ethyl (E)-5-(2-chloroacetoxy)-5-phenylpent-2-enoate (1.15): To a flame dried

and purged flask, a solution of 1.5 (0.45 mmol, 0.10 g, 1.0 eq) and DCM (0.3 M 1.5 mL) was

added. The reaction was cooled to 0 oC where pyridine (0.91 mmol, 0.07 mL, 2.0 eq.) was added,

followed by compound chloroacetyl chloride (0.91 mmol, 2.0 eq) dropwise. The mixture stirred

overnight raising the temperature to RT where is was then quenched with saturated NH4Cl and

extracted three times with 10 mL of DCM. The organic layers were combined and washed with

10 mL of saturated CuSO4. The solution was then dried with MgSO4 and concentrated.

Purification took place via column chromatography in 20% EtOAc in hexanes to afford the

desired 1.15. Rf: 0.6: Yield: 0.05 g, 39% as light brown oil. 1H NMR (500 MHz, CDCl3) δ 7.36

(m, 5H), 6.82 (dt, J = 15.5, 7.3 Hz, 1H), 5.88 (m, 2H), 4.18 (q, 2H), 4.06 (m, 2H), 2.76 (m, 2H),

1.27 (dd, J = 12.2, 5.1 Hz, 3H).

Synthesis of 1-phenylbut-3-en-1-yl 2-bromoacetate (1.19) and 1-phenylbut-3-en-1-yl 2-

chloroacetate (1.20): To a flame dried and purged flask, a solution of 1.3 (00.68 mmol, 0.10 g,

1.0 eq) and DCM (0.3 M, 2.3 mL) was added. The reaction was cooled to 0 oC where pyridine

(1.3 mmol, 0.11 mL, 2.0 eq.) was added, followed by bromoacetyl bromide or chloroacetyl

chloride (1.3 mmol, 0.10 mL, 2.0 eq) dropwise. The mixture stirred overnight raising the

temperature to RT where is was then quenched with saturated NH4Cl and extracted three times

with 10 mL of DCM. The organic layers were combined and washed with 10 mL of saturated

CuSO4. The solution was then dried with MgSO4 and concentrated. Purification took place via

column chromatography in 20% EtOAc in hexanes to afford the desired 1.19 and 1.20. Rf: 0.6

26

and 0.7 respectively: Yield: 0.07g, 39% as light brown oil. 1H NMR (500 MHz, CDCl3) 1.19 δ

7.34 (m, 5H), 5.84 (dd, J = 7.8, 5.9 Hz, 1H), 5.71 (ddt, J = 17.1, 10.2, 7.0 Hz, 1H), 5.07 (m, 2H),

3.84 (s, 2H), 2.63 (m, 2H). 1H NMR (500 MHz, CDCl3) 1.20 δ 7.34 (m, 5H), 5.88 (dd, J = 7.8,

5.9 Hz, 1H), 5.70 (ddt, J = 17.2, 10.2, 7.0 Hz, 1H), 5.09 (ddd, J = 9.5, 5.5, 1.2 Hz, 2H), 4.07 (dd,

2H), 2.63 (m, 2H).

27

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35. Casado, A. L.; Espinet, P., On the Configuration Resulting from Oxidative Addition of

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36. Ozawa, F.; Kubo, A.; Hayashi, T., Catalytic asymmetric arylation of 2,3-dihydrofuran

with aryl triflates. J. Am. Chem. Soc. 1991, 113, 1417-1419.

37. Cabri, W.; Candiani, I.; DeBernardinis, S.; Francalanci, F.; Penco, S.; Santo, R., Heck

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5796-5800.

38. Sato, Y.; Nukui, S.; Sodeoka, M.; Shibasaki, M., Asymmetric heck reaction of alkenyl

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39. Sato, Y.; Sodeoka, M.; Shibasaki, M., On the role of silver salts in asymmetric Heck-

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Chem. Lett. 1990, 1953-1954.

40. Cabri, W.; Candiani, I.; DeBernardinis, S.; Francalanci, F.; Penco, S.; Santo, R., Heck

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5796-5800.

41. Ozawa, F.; Kubo, A.; Hayashi, T., Catalytic asymmetric arylation of 2,3-dihydrofuran

with aryl triflates. J. Am. Chem. Soc. 1991, 113, 1417-1419.

42. Grigg, R.; Sridharan, V.; Sukirthalingam, S., Alkylpalladium(II) species. Reactive

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43. Meyer, F. E.; Parsons, P. J.; De Meijere, A., Palladium-catalyzed polycyclization of

dienynes: surprisingly facile formation of tetracyclic systems containing a three-membered ring.

J. Org. Chem. 1991, 56, 6487-6488.

44. Grigg, R.; Dorrity, M. J.; Malone, J. F.; Sridharan, V.; Sukirthalingam, S., Palladium-

catalyzed polycyclization-anion capture processes. Tetrahedron Lett. 1990, 31, 1343-1346.

45. Zhang, Y.; Negishi, E., Metal-promoted cyclization. 25. Palladium-catalyzed cascade

carbometalation of alkynes and alkenes as an efficient route to cyclic and polycyclic structures.

J. Am. Chem. Soc. 1989, 111, 3454-3456.

46. Carpenter, N. E.; Kucera, D. J.; Overman, L. E., Palladium-catalyzed polyene

cyclizations of trienyl triflates. J. Org. Chem. 1989, 54, 5846-5848.

47. Liu, C.-H.; Cheng, C.-H.; Cheng, M.-C.; Peng, S.-M., Palladium-Catalyzed Addition of

Alkyne to Norbornene Derivatives. Unusual Ring Formation and Expansion Reactions.

Organometallics 1994, 13, 1832-1839.

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48. Rawal, V. H.; Michoud, C., An unexpected Heck reaction. Inversion of olefin geometry

facilitated by the apparent intramolecular carbamate chelation of the σ-palladium intermediate. J.

Org. Chem. 1993, 58, 5583-5584.

49. Owczarczyk, Z.; Lamaty, F.; Vawter, E. J.; Negishi, E., Apparent endo-mode cyclic

carbopalladation with inversion of alkene configuration via exo-mode cyclization-

cyclopropanation rearrangement. J. Am. Chem. Soc. 1992, 114, 10091-10092.

50. Albeniz, A. C.; Espinet, P.; Lin, Y.-S., Cyclization versus Pd-H Elimination-Readdition:

Skeletal Rearrangement of the Products of Pd-C6F5 Addition to 1,4-Pentadienes. J. Am. Chem.

Soc. 1996, 118, 7145-7152.

51. Tietze, L. F.; Modi, A., Regioselective silane-terminated intramolecular Heck reaction

with alkenyl triflates and alkenyl iodides. Eur. J. Org. Chem. 2000, 1959-1964.

52. Nagasawa, K.; Zako, Y.; Ishihara, H.; Shimizu, I., Stereoselective synthesis of 1α-

hydroxyvitamin D3 A-ring synthons by palladium-catalyzed cyclization. Tetrahedron Lett. 1991,

32, 4937-4940.

53. Maruyama, O.; Yoshidomi, M.; Fujiwara, Y.; Taniguchi, H., Palladium(II)-copper(II)-

catalyzed synthesis of mono- and dialkenyl-substituted five-membered aromatic heterocycles.

Chem. Lett. 1979, 1229-1230.

54. Shue, R. S., Catalytic coupling of aromatics and olefins by homogeneous palladium(II)

compounds under oxygen. J. Chem. Soc. D. 1971, 1510-1511.

55. Albert, K.; Gisdakis, P.; Roesch, N., On C-C Coupling by Carbene-Stabilized Palladium

Catalysts: A Density Functional Study of the Heck Reaction. Organometallics 1998, 17, 1608-

1616.

56. Deeth, R. J.; Smith, A.; Hii, K. K.; Brown, J. M., The Heck olefination reaction; a DFT

study of the elimination pathway. Tetrahedron Lett. 1998, 39, 3229-3232.

57. Spencer, A., Stereochemical course of the palladium-catalyzed arylation of disubstituted

activated alkenes with benzoyl chloride. J. Organomet. Chem. 1982, 240, 209-216.

58. De Joarder, D.; Jennings, M. P., Convergent synthesis of (+)-xestodecalactone A via a

Pd-catalyzed α-arylation reaction. Tetrahedron Lett. 2013, 54, 3990-3992.

59. De Joarder, D.; Jennings, M. P., Umpolung Pd-Catalyzed α-Arylation Reactions in

Natural Product Synthesis: Syntheses of (+)-Xestodecalactone A, (-)-Curvularin, (+)-12-

Oxocurvularin and (-)-Citreofuran. Eur. J. Org. Chem. 2015, 2015, 3303-3313.

60. Hu, N.; Dong, C.; Zhang, C.; Liang, G., Total Synthesis of (-)-Indoxamycins A and B.

Angew. Chem., Int. Ed. 2019, 58, 6659-6662.

32

61. Carrick, J. D.; Jennings, M. P., An Efficient Formal Synthesis of (-)-Clavosolide A

Featuring a "Mismatched" Stereoselective Oxocarbenium Reduction. Org. Lett. 2009, 11, 769-

772.

62. Lee, S.-M.; Lee, W.-G.; Kim, Y.-C.; Ko, H., Synthesis and biological evaluation of α,β-

unsaturated lactones as potent immunosuppressive agents. Bioorg. Med. Chem. Lett. 2011, 21,

5726-5729.

63. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H., A General Model for

Selectivity in Olefin Cross Metathesis. J. Am. Chem. Soc. 2003, 125, 11360-11370.

64. Kim, D. W.; Song, C. E.; Chi, D. Y., Significantly Enhanced Reactivities of the

Nucleophilic Substitution Reactions in Ionic Liquid. J. Org. Chem. 2003, 68, 4281-4285.

65. Ju, Y.; Kumar, D.; Varma, R. S., Revisiting Nucleophilic Substitution Reactions:

Microwave-Assisted Synthesis of Azides, Thiocyanates, and Sulfones in an Aqueous Medium. J.

Org. Chem. 2006, 71, 6697-6700.

66. Jadhav, V. H.; Kim, J. G.; Jeong, H. J.; Kim, D. W., Nucleophilic Hydroxylation in

Water Media Promoted by a Hexa-Ethylene Glycol-Bridged Dicationic Ionic Liquid. J. Org.

Chem. 2015, 80, 7275-7280.

67. Zhao, X.; Zhuang, W.; Fang, D.; Xue, X.; Zhou, J., A Highly Efficient Conversion of

Primary or Secondary Alcohols into Fluorides with n-Perfluorobutanesulfonyl Fluoride-

Tetrabutylammonium Triphenyldifluorosilicate. Synlett 2009, 2009, 779-782.

68. Sawant, K. B.; Jennings, M. P., Efficient Total Syntheses and Structural Verification of

Both Diospongins A and B via a Common δ-Lactone Intermediate. J. Org. Chem. 2006, 71,

7911-7914.

69. Samanta, S.; Mohapatra, H.; Jana, R.; Ray, J. K., Pd(0) catalyzed intramolecular Heck

reaction: a versatile route for the synthesis of 2-aryl substituted 5-, 6-, and 7-membered O-

containing heterocycles. Tetrahedron Lett. 2008, 49, 7153-7156.

70. Jimenez, F.; Fernandez, A.; Boulifa, E.; Mansour, A. I.; Alvarez-Manzaneda, R.;

Chahboun, R.; Alvarez-Manzaneda, E., Diastereoselective Intramolecular Heck Reaction

Assisted by an Acetate Group: Synthesis of the Decahydrobenzofluorene Derivative

Dasyscyphin E. J. Org. Chem. 2017, 82, 9550-9559.

71. Zhou, W.; An, G.; Zhang, G.; Han, J.; Pan, Y., Ligand-free palladium-catalyzed

intramolecular Heck reaction of secondary benzylic bromides. Org. Biomol. Chem. 2011, 9,

5833-5837.

72. Glorius, F., Palladium-catalyzed Heck-type reaction of 2-chloro acetamides with olefins.

Tetrahedron Lett. 2003, 44, 5751-5754.

33

73. Rousee, K.; Bouillon, J.-P.; Couve-Bonnaire, S.; Pannecoucke, X., Stereospecific

Synthesis of Tri- and Tetrasubstituted α-Fluoroacrylates by Mizoroki-Heck Reaction. Org. Lett.

2016, 18, 540-543.

1.01.5

2.02.5

3.03.5

4.04.5

5.05.5

6.06.5

7.07.5

8.08.5

9.09.5

10.010.5

11.0f1 (ppm

)

2.04

1.30

2.07

1.00

6.63

2.462.482.502.522.522.532.532.532.57

4.704.734.75

5.14

5.205.765.785.815.835.867.267.267.277.277.287.297.307.307.337.347.367.377.42

The 1H NMR Spectrum (360 MHz, CDCl3) of Compound 1.334

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

10.5f1 (ppm

)

7.10

2.25

2.35

1.06

1.13

1.00

6.31

0.870.890.91

2.622.622.642.642.662.662.682.68

4.024.034.044.044.824.834.834.845.895.895.905.935.945.946.906.94

7.287.297.297.317.317.327.337.347.357.367.377.37


0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.5

f1 (ppm)

8.06

2.06

2.002.04

2.03

1.00

5.20

0.860.870.880.880.890.900.91

2.682.702.722.742.762.81

3.814.024.034.034.04

5.855.855.865.875.88

5.906.786.826.84

7.267.287.307.307.317.327.327.337.347.357.37


0.00.5

1.01.5

2.02.5

3.03.5

4.04.5

5.05.5

6.06.5

7.07.5

8.08.5

f1 (ppm)

3.87

1.55

1.81

1.75

0.17

1.76

1.00

5.49

0.20

1.241.281.301.301.312.102.742.792.802.802.822.824.094.094.174.184.194.194.204.214.225.855.855.865.865.875.885.885.885.896.836.846.866.877.287.327.337.347.347.347.357.357.367.377.377.387.387.397.397.397.487.50


0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

10.5f1 (ppm

)

3.10

2.06

1.00

7.40

1.341.361.37

4.264.284.294.30

6.446.47

7.397.397.407.407.537.537.547.557.697.72


38

1.01.5

2.02.5

3.03.5

4.04.5

5.05.5

6.06.5

7.07.5

8.08.5

9.09.5

10.010.5

f1 (ppm)

3.66

2.13

2.062.05

1.97

1.00

5.08

1.251.261.271.29

2.722.732.742.762.772.842.864.034.064.074.104.154.174.184.20

5.855.855.855.885.88

5.916.796.806.82

6.837.317.327.327.337.337.347.347.367.367.377.377.387.397.39


39

1.01.5

2.02.5

3.03.5

4.04.5

5.05.5

6.06.5

7.07.5

8.08.5

9.09.5

10.010.5

11.0f1 (ppm

)

2.16

1.89

2.05

1.001.00

5.19

2.582.592.602.602.612.622.632.632.632.672.672.672.69

2.70

3.84

5.065.075.075.09

5.125.675.695.705.725.74

5.847.287.297.307.307.317.317.317.317.327.327.327.337.347.347.347.357.367.367.367.377.377.387.38


1.01.5

2.02.5

3.03.5

4.04.5

5.05.5

6.06.5

7.07.5

8.08.5

9.09.5

10.010.5

11.0f1 (ppm

)

2.09

2.01

2.03

1.001.00

4.96

2.582.582.592.612.612.612.622.632.632.672.692.702.702.722.73

4.034.064.074.10

5.075.085.095.125.665.685.695.715.73

5.887.297.307.307.317.327.327.337.337.347.357.357.367.367.377.377.387.38


42

CHAPTER 2: TOTAL SYNTHESIS OF DIHYDRORESORCYLIDE

2.1. Introduction

As discussed in a previous chapter, Pd enolates have been extensively studied and are a

focus of this research. These intermediates allow for various reactions such as, Michael

reactions,1 homocoupling,2 and intramolecular ring formations,3 to occur and are even found in a

couple of examples of total synthesis.4, 5 Despite being widely utilized, the ring closure of natural

product macrocycles via Pd enolates remains an unutilized method in synthesis especially in

resorcylic acid lactones (RALs).

A class of compounds called RALs are divided into three types based on the backbone

present as shown in Figure 2.1 and are predominately found in strains of fungi. The first RAL,

Radicicol, was isolated in 1953 by Delmotte and company.6 Since then, a large quantity of these

compounds has been discovered and been found to have various biological properties ranging

from cancer cell inhibitors to antiviral activity.7, 8

43

RAL synthesis utilizes a variety of methods to obtain the desired compounds, but

formation of the macrocycle moiety is widely conducted through RCM.9-11 For example, the

Jennings’ group has previously created one of these compounds called Ponchonin J with a key

reaction being an oxocarbenium allylation.12 The purpose of this research is to synthesize

Dihydroresorclide, 2.1, shown in (Figure 2.2) via a Pd enolate ring closure rather than RCM.

2.2 Isolation and Structural Elucidation, Biological Properties and Reactions, and

Synthesis of Dihydroresorcylide

Dihydroresorcylide 2.1 has been isolated twice from two different fungal strains. The first

was in 2008, Poling and company examine Acremonium zeae, a protective endophyte found in

maize, and several new compounds were found including 2.1.13 After a series of extractions with

EtOAc and MeOH, a final extraction with acetonitrile afforded the new material. At first, the

thought was that the recovered species was that of Culvularin, 2.2, (Figure 2.3), but upon closer

inspection of the 1H NMR data, chemical shifts not consistent with Culvularin 2.2 were present.

Based on this information, more spectroscopic techniques like 13C NMR, HMBC, and mass

spectrometry were performed. The stereochemistry was also determined to be (S), though this

has come under scrutiny and will be discussed further. The material was isolated a second time

in 2016 from fungus Gliomastix sp found in a sponge giving rise to the mindset that 2.1 could be

44

common among fungal strains.14, 15 The compound was then subjected to biological testing and a

variety of biotransformations.

Poling subjected 2.1 to antifungal and leaf-wound puncture assays to determine if the

material was part of a protective endophyte relationship. Based on results of the assays,

Dihydroresorcylide 2.1 did not exhibit any fungistatic behavior against at least two samples, but

it did prove to be phytotoxic in the leaf-puncture wound assay producing “elongated lesions”

averaging 1.37 mm. This led to the thought that the product was facilitating the spread of the

endophyte into the maize tissues.15 Work conducted by Zhan and coworkers, published in 2010

and 2011, examined if the natural product could undergo biotransformations with a halogenase

and a glycolytransferase. These experiments were successful as the aromatic ring was

chlorinated at the green positions, and a glucose moiety was coupled with the hydroxy at the red

position shown in Figure 2.2.16, 17 In 2017, Dihydroresorcylide was tested as a PTP1B inhibitor.18

A PTP1B inhibitor changes the sensitivity to insulin and is a promising method of treating type 2

diabetes.19 Based on the bioassays conducted, the (R) isomer of 2.1 was a highly selective

inhibitors compared to the (S) counterpart. This means that the stereochemistry does matter.

Molecular docking studies were conducted to attempt to understand why there is selectivity.

Based on the modeling, the (R) isomer has the ability to have hydrogen-bonding, pi-pi stacking,

and hydrophobic interactions that the (S) does not. In addition to the biological testing, the

natural product has been synthesized twice by other groups.

45

The first total synthesis occurred in 2013 and the retrosynthesis published had three main

cuts being an esterification, carbonylation, and an RCM (Figure 2.4).20 Based on Scheme 2.1, the

synthesis was conducted via nine steps. The first step began with orcinol monohydrate 2.3 which

underwent a series of three steps to give 2.4. 2.4 was then saponified to yield 2.5 which was then

subjected to successful Mitsunobu esterification with (R)-hept-6-en-2-ol. The new ester 2.6 then

underwent a carbonylation. The carbonylation with a Weinreb amide (Figure 2.5, 2.10) proved

difficult so the amide was changed to 2.11 which overcame the difficulty to afford 2.7. The

material was diluted significantly in DCM and reacted with GC(II) for an efficacious RCM to

give the macrocycle 2.8. The macrocycle 2.8 was subjected to a hydrogenation and with the

removal of the alkene, the demethylation of both methoxy groups was attempted. It was found

that reagents such as BBr3 would not properly remove the groups, and after several attempts AlI3

in benzene worked the best to give the desired 2.1. The second synthesis was not conducted

until 2017.

47

The next synthesis of Dihydroresorcylide 2.1 was fulfilled to determine if the (S)

configuration reported by Poling and company was actually accurate.18 Scheme 2.2 shows the

synthetic pathway that was followed. The process is close to the previously published method

(Scheme 2.1), however a bis-MOM protected carboxylic acid 2.12 was utilized due to an easier

ability to perform the final deprotection. The acid 2.12 was treated with 2-(trimethylsilyl)ethanol

under Mitsunobu conditions to give the ester 2.13. The carbonylation with 2.13 and the Weinreb

amide 2.11 was successful leading to a saponification of the ester to yield 2.15. With the new

carboxylic acid in hand, a second Mitsunobu reaction was conducted with (S)-hept-6-en-2-ol to

afford the diene 2.16 in the desired (R) configuration. An RCM with GC(II) was performed

48

followed by subsequent hydrogenation to give 2.18. The MOM deprotection was fruitful and

yielded (R)-Dihydrorescorcylide 2.1. With the material synthesized it was now time to discover

which configuration was the correct one.

It was noted that both (R) and (S) have identical NMR data so the difference came down

to the optical rotation of the two. Upon previous synthesis, the rotation was opposite what was

published in 2008 for the (S), After generating the (R) isomer, optical rotation was examined and

determined to be identical to the literature value thus confirming the stereochemistry to be the

(R) conformer which aligns with other work published by Poling and coworkers in 2008.13

Dihydroresorcylide 2.1 has been isolated, extensively studied, and synthesized twice. This

research discussed within, aims at obtaining either isomer of the RAL through a Pd enolate ring

closure.

2.3 Retrosynthetic Analysis

Dihydroresorcylide 2.1 can be broken down into several substructures as exhibited in the

retrosynthesis in Scheme 2.3. The first of two major cuts could occur at the benzyl methylene to

break open the macrocycle. The second major cut could occur at the oxygen of the ester breaking

the piece into two components that would be the focus of the synthesis; an aromatic synthon A

and an aliphatic synthon B. Both A and B would undergo their own transformations before being

joined together. For instance, the two hydroxy groups attached to the phenyl ring would need to

be protected over the course of the synthetic approach and it is feasible to do this with methoxy

groups, or the aliphatic chain would be created through a cross metathesis of two olefins with

one containing an alcohol and the other a ketone. Once the formation of the two synthons are

complete, they could be combined through an esterification reaction and the macrocycle could be

created by way of a Pd enolate ring closure. This type of ring closure is novel to total synthesis

49

and is the focus of this research. Completion of each synthon is discussed at length in the

following sections.

2.4 Total Synthesis of Dihydroresorcylide: Aromatic Synthon

The development of the aromatic synthon A occurred through three different pathways.

The first method, shown in Scheme 2.4, took place in two steps based on work published in the

Jennings group.21 The first step involved reacting 2.24 under Mitsunobu conditions to yield 2.25.

It should be noted that despite there being two hydroxy functionalities, that only one was

protected. This is due to the strong hydrogen bonding exhibited by the hydroxy in proximity to

the carbonyl (Figure 2.6).

50

Compound 2.25 then underwent conversion of the remaining hydroxyl to a triflate 2.26.

This was completed without much difficulty. Before development of the aliphatic piece,

preliminary studies were conducted to verify that the triflate functionality would indeed couple

with an aliphatic ketone via a Pd enolate shown in Table 2.1.

Entry Ketone Catalyst Equiv. Ligand Equiv. Base (1.3 eq.) Solvent

1 2-Butanone Pd2(dba)3 0.015 BINAP 0.036 NatOBu THF

2 2-Pentanone Pd2(dba)3 0.015 BINAP 0.036 NatOBu THF

3 2-Hexanone Pd2(dba)3 0.015 BINAP 0.036 NatOBu THF

4 2-Pentanone Pd(OAc)2 0.03 PPh3 0.06 NatOBu THF

5 2-Pentanone Pd(OAc)2 0.03 P(o-tol)3 0.06 NatOBu THF

6 2-Pentanone Pd(OAc)2 0.03 PPh3 0.06 K2CO3 THF

7 2-Pentanone Pd(OAc)2 0.03 P(t-Bu)3 0.06 K2CO3 THF

8 2-Pentanone Pd2(dba)3 0.03 P(t-Bu)3 0.06 K2CO3 THF

9 2-Pentanone Pd(OAc)2 0.03 PPh3 0.06 LHMDS THF (2, 4, 6)

10 2-Pentanone Pd(OAc)2 0.03 PPh3 0.06 LDA THF (2, 4, 6)

Table 2.1 Triflate Coupling Experiments

In entries 1-3, butanone, pentanone, and hexanone were utilized to determine if the size

of the carbon chain would have a negative effect on the coupling where the conditions were

51

based on literature published by Buchwald.22 However, the only material recovered was starting

material 2.26. Entries 4-7 change the catalyst from a Pd(0) to a Pd(II) and examined

monodentate ligands with various salt bases.23-25 Unfortunately, only starting material 2.26 was

only recovered again. Entry 8 utilized a Pd(0) catalyst with a monodentate ligand, and again

there were no promising results. Entries 9-10 experimented with stronger lithium bases like LDA

and LHMDS where the reaction time was varied between two, four, and six hours. There was

only starting material 2.26 isolated. However, after repeating the experiments it was found that

the base was causing the ring to open forming 2.27 shown in Figure 2.7. With that information in

hand, it was decided to attempt coupling with the aliphatic ketone as a silyl enol ether.

The formation of the silyl enol ether was based on work completed by Tanabe with an

example shown in Figure 2.8.26 With the conversion complete, Table 2.2 exhibits the conditions

found in literature to attempt the coupling.27, 28 All three entries only provided starting material

2.28. Due to the inability to create a new carbon-carbon bond, it was decided that the triflate

would be replaced with a bromine.

52

Entry Catalyst Ligand Additive Solvent Product

1 Pd2(dba)3 DPPF LiOAc THF 2.26

2 Pd2(dba)3 P(t-Bu)3 Bu3SnF Toluene 2.26

3 Pd(PPh3)2Cl2 NA Bu3SnF THF 2.26

Table 2.2 Triflate Coupling with Silyl Enol Ether

Bromobenzene 2.29 and ethyl 2-bromobenzoate 2.30 with the silyl enol ether 2.28

(Figure 2.9) were chosen as pseudo compounds to attempt the new bond formation. In Table 2.3,

the conditions for these attempts were laid out. After several attempts, the ethyl 2-

bromobenzoate 2.30 did show some coupling product in low yields of about 10-20%. Despite the

low yield, this gave indication that the target reaction would work so it was concluded to change

the pathway of the aromatic portion from a triflate to a bromine.

Entry Catalyst Ligand Additive Solvent Product

1 Pd2(dba)3 P(t-Bu)3 ZnCl2 THF 2.30

2 Pd(PPh3)2Cl2 NA Bu3SnF THF 2.31

Table 2.3 Bromobenzene and Ethyl Bromobenzoate Coupling

In Scheme 2.5, 1-bromo-3,5-dimethoxybenzene 2.32 underwent a Vielsmeire-Haack

reaction to yield compound 2.33.29 It was found that purification would need to occur

53

immediately following work-up in order to avoid decomposition and gave a white powder.

Compound 2.33 was subjected to a selective demethylation using BBr3 to afford 2-bromo-6-

hydroxy-4-methoxybenzaldehyde 2.34. There was no demethylation product of the hydroxy at

the 4 position or any dihydroxy material isolated due to the ability of the hydroxy at the 6

position to hydrogen bond with the aldehyde. Compound 2.34 underwent a protection of the

hydroxy group with MOM-Cl.30 There were difficulties initially getting this reaction to proceed,

but it was found that the addition of the phase transfer catalyst TBAI allowed for the protection

to be completed in a moderate yield.12 The final step of the second aromatic synthon pathway is a

Pinnick oxidation with 2.35 to generate 2.20, A.

This final compound 2.20, A was designed to join with the aliphatic piece via an

esterification reaction. This will be discussed in a following section. After several attempts the

esterification was completed however there were difficulties getting the material completely

pure. Upon no longer having any more material to perform the esterification or subsequent

reactions, it was decided to change the synthetic pathway yet again to remove the MOM-Cl

protection all together.

54

Scheme 2.6 shows the final pathway for synthesis of the aromatic portion. The first step

involves conducting a Veilsmeire-Haack reaction on 2.32 same as the previous pathway.

However, the second step goes directly to the Pinnick oxidation to form 2.20, A. With this

material in hand, more attempts to perform the esterification are underway and development of

the aliphatic synthon will be discussed in the following section.

2.5 Total Synthesis of Dihydroresorcylide: Aliphatic Synthon

The synthesis of the aliphatic synthon B was developed through two pathways. Scheme

2.7 through 2.9 goes through the development of the first method of generation of compound

2.41. Scheme 2.7 illustrates reacting (S)-propylene oxide 2.37 with vinylmagnesium bromide to

form 2.22 in moderate to high yields with no need for purification.31

Scheme 2.8 utilizes pent-4-en-1-ol 2.38 to undergo a oxidation to form 2.39.

Unfortunately, a completely accurate yield was never obtained due to the inability to get the

material purified, however the material recovered was approximately 60-75%. With aldehyde

2.39 in hand, a Grignard reaction with methylmagnesium bromide was conducted to afford the

resulting alcohol 2.40 in an 85% yield. A final oxidation was completed with 2.40 to give hex-5-

en-2-one 2.23, however an accurate yield could not be calculated due to the inability to remove

the remaining DMP.

55

Scheme 2.9 shows the combination of compounds 2.22 and 2.23 via a cross metathesis.

Unfortunately, even though this reaction is widely known the conversion would not take place.

Both compounds tend to homodimerize based on what is known about Grubbs cross metathesis

and would need an additive to obtain the desired species 2.41.32 At this time the amount of hex-

5-en-2-one 2.23 had diminished and it was decided to purchase 2.23 as it was more cost effective

and avoided the issues with purification ultimately reducing the overall number of steps in the

synthon synthesis.

Now that commercially available material 2.23 was obtained, the synthetic pathway was

altered as shown in Scheme 2.10. The Grignard creating homoallylic alcohol 2.22 was still

conducted and was then coupled with 2.23 after an efficient additive was found. Based on

literature, phenol was the best additive because of its ability to coordinate to the metal complex

56

and slow down homodimerization.33 After several attempts with no positive results it was

decided to distill the phenol, which turned the material from brown to clear. After the distillation,

the metathesis was successful with an overall yield of 67% which lead to the final step of

generation of the aliphatic synthon.

Hydrogenation of 2.41 concluded the aliphatic piece. The hydrogenation was conducted

with Pd/C in ethanol under 1 atm of H2.34 This reaction while successful was only able to

produce a 60% yield. The reasons are not clear, but this reaction is being optimized. Synthon

piece A and B were coupled together as mentioned previously and will be discussed in the

following section.

2.6 Total Synthesis of Dihydroresorcylide: Combining Synthons

As shown in Scheme 2.11, with the aromatic synthon 2.20 in hand, it would be reacted

with the aliphatic synthon 2.21 via an esterification reaction to form the new ester 2.42. The ester

would then undergo a direct Pd enolate ring closure to generate macrocycle 2.43. The

macrocycle would be treated with a strong acid to complete the deprotection to give compound

2.44 which would be followed by a demethylation with BBr3 to give the final Dihydroresorcylide

2.1.

57

Esterification of aromatic synthon 2.20 with the aliphatic compound 2.21 was attempted

several times utilizing various reaction conditions. A Mitsunobu reaction was tried at first to

create the new ester. Both Mitsunobu conditions were similar where both used DIAD and PPh3

(2.0 and 1.1 equivalent respectively), with the exception of solvent choice where the first

endeavor was conducted under toluene and the second under THF. 21, 35 Unfortunately, these tries

resulted in only recovering of both starting materials 2.20 and 2.21. It was then decided to make

the carboxylic acid more reactive through the conversion to an acid chloride.

The next series of attempts consisted of conversion of the carboxylic acid 2.20 into an

acid chloride then followed by the treatment of the aliphatic piece 2.21. The chloride reagent first

chosen to complete the transformation was SOCl2. The aromatic portion 2.20 would be treated

with SOCl2 in either DCM or DMF and refluxed for a set amount of time where the reaction

would be quenched and concentrated. A second reflux directly followed with toluene, pyridine,

58

and 2.21.36 Again, there was no discernible ester formation detected which prompted the change

from SOCl2 to oxalyl chloride.

Two different reactions with oxalyl chloride were conducted.10, 37 The first employed

TPPO in acetonitrile, oxalyl chloride, and TEA to combine the two pieces while the second used

both DMF and DMAP as catalysts with oxalyl chloride in TEA and DCM. While both of these

processes were different, they both yielded the same results which was lack of esterified product

and only starting materials 2.20 and 2.21. Due to the inability to recover the desired compound

2.42, it was decided to forgo the acid chloride conversion for reactions with the carboxylic acid

as is.

Fischer esterification was utilized as the next attempt to join 2.20 and 2.21.38 The

materials were refluxed in THF and catalytic H2SO4 and again did not yield and promising

results other than the recovery of starting material. Therefore, the final method of creating the

new ester bond was to try a Steiglich esterification.39 The reaction was conducted several times

based on the work published by Santandrea in 2014, however the recrystallization was not

successful. With this in mind the work up was changed to allow for column purification which

led to the completion of the new ester bond to form compound 2.42. There were, however, some

difficulties with removing leftover DMAP even after column purification. Despite the slight

impurity, it was decided to take the material 2.42 and try to perform the desirable ring closure.

Generating the macrocycle 2.43 via a Pd enolate ring closure was attempted three times

based on work published by both Buchwald and Hartwig shown in Table 2.4.22, 40 All three

entries utilized Pd2(dba)3 as the catalyst of choice and LDA as a base. In entry 2, the ligand was

switched from DPPF to another bidentate ligand, BINAP, and in entry 3 the number equivalents

of base changed from 1.1 to 3.0. The only recoverable material from the reactions was starting

59

material 2.42. It was unclear if the lack of ring closure stemmed from conditions or technique, so

it was decided to create a silyl enol ether on the ketone of 2.42.

Table 2.5 exhibits the attempts taken to produce a silyl enol ether from ester 2.42.26 Entry

1 used 1.1 equivalents of LDA to 1.2 equivalents of TMSCl and 2.42 showed no isolatable

conversion. For entry 2 and 3 the LDA equivalents was increased to 2.0 and 3.0 equivalents

respectively. Neither entry 2 nor 3 converted the material completely so it was decided to

increase the amount of TMSCl to attempt the full conversion. Entries 4 and 5 use 2.0 equivalents

of LDA and 2.0 followed by 3.0 equivalents of TMSCl respectively. Again, there was no

conversion present but there was no longer any of ester 2.42 available. Due to the lack of

material, the synthetic pathway was shortened as previously mentioned as shown in Scheme

2.12.

Entry Catalyst Base Ligand Equiv. Product

1 Pd2(dba)3 LDA DPPF 1.1 2.42

2 Pd2(dba)3 LDA BINAP 1.1 2.42

3 Pd2(dba)3 LDA BINAP 3.0 2.42

Table 2.4 Pd Enolate Macrocycle Formation

Entry LDA Equiv. TMSCl Equiv. Solvent

1 1.1 1.2 THF

2 2.0 1.2 THF

3 3.0 1.2 THF

4 2.0 2.0 THF

5 2.0 3.0 THF

Table 2.5 Silyl Enol Ether Conversion

2.7 Future Works

60

Compound 2.45 and 2.21 would be joined via an esterification shown in Scheme 2.12.

This method will potentially include EDC to replace DCC in another Steiglich esterification

attempt, as well as, Mitsunobu and Yamaguchi reactions will be experimented with. Once ester

2.46 is obtained, the material will undergo the macrocyclization followed by a demethylation of

both methoxy groups to afford Dihydroresorcylide 2.1. This synthetic pathway is currently being

conducted, but it is hopeful that the work will yield positive results.

2.8 Conclusion

Dihydroresorcylide was isolated from maize and has been synthesized two times before.

However, the macrocycle formation has not gone through a Pd enolate ring closure as this is

novel to the research presented herein. The synthetic pathway of Dihydroresorcylide has changed

multiple times throughout the course of this work. The attempt to generate the natural product is

currently underway and the previous pathways will give valuable insight into the future

endeavors.

61


General Procedure: All of the reactions were performed under Ar in flame-dried glassware. All

starting materials, solvents, reagents, and catalysts were commercially available and used

without further purification. The NMR spectra were recorded with either a 360 or 500 MHz

Bruker spectrometer. 1H and 13C NMR spectra were obtained using CDCl3 as the solvent with

chloroform (CHCl3 1H: δ = 7.26 ppm, CDCl3 13C: δ = 77.0 ppm) as the internal standard.

Column chromatography was performed using 60-200 µm silica gel. Analytical thin layer

chromatography was performed on silica coated glass plates with F-254 indicator. Visualization

was accomplished by UV light (254 nm) and KMnO4.

Synthesis of 5-hydroxy-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (2.25): A

solution of 2.24 (24.0 mmol, 5.0 g, 1.0 eq.) and THF (0.2 M, 120 mL) was added to a flame

dried and purged flask and then cooled to 0 oC. MeOH (42.0 mmol, 1.82 mL, 1.75 eq.) and PPh3

(26.0 mmol, 6.87 g, 1.1 eq.) were added sequentially and the mixture stirred for five minutes.

DIAD (26.0 mmol, 5.14 mL, 1.1 eq.) was added dropwise and the reaction stirred at 0 oC for four

hours. The solution was then concentrated and purified via column chromatography in 10%

EtOAc and hexanes to afford 2.25. Rf: 0.2; Yield: 4.21 g, 79% as white solid. 1H NMR (360

MHz, CDCl3) δ 10.45 (s, 1H), 6.15 (d, J = 2.3 Hz, 1H), 6.00 (d, J = 2.3 Hz, 1H), 3.82 (s, 3H),

1.73 (s, 6H).21

Synthesis of 7-methoxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-yl

trifluoromethanesulfonate (2.26): To a flame dried and purged flask, a solution of 2.25 (11.2

mmol, 2.5 g, 1.0 eq.) in pyridine (0.15 M. 74.4 mL) was added and then the reaction was cooled

to 0 oC. Tf2O (16.7 mmol, 2.81 mL, 1.5 eq.) was then added in one portion and the mixture

stirred at 0 oC for 24 hours. The contents were then diluted with 50 mL of EtOAc where the

62

organic layer was washed with 50 mL of saturated CuSO4, followed by 50 mL of DI water, and

then underwent a final wash with 50 mL of brine. The organic material was dried with MgSO4

and the concentrated. Purification took place via column chromatography in 10% EtOAc in

hexanes to afford 2.26. Rf: 0.17; Yield: 3.72 g, 80% as a white solid. 1H NMR (500 MHz,

CDCl3) δ 6.53 (d, J = 2.3 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 3.88 (s, 3H), 1.74 (s, 6H).21

Tert-butyl 2-hydroxy-4-methoxy-6-(((trifluoromethyl)sulfonyl)oxy)benzoate (2.27) (Table

2.1, Entry 4): Purified via column chromatography in 10% EtOAc in hexanes. Rf: 0.20; Yield:

0.063g, 60% as a white solid. 1H NMR (500 MHz, CDCl3) δ 11.87 (s, 1H), 6.47 (d, J = 2.5 Hz,

1H), 6.32 (d, J = 2.2 Hz, 1H), 3.83 (s, 3H), 1.63 (s, 9H).21

Synthesis of trimethyl(non-1-en-2-yloxy)silane (2.28): nBuLi in hexanes (0.77 mmol, 0.70

mL, 1.1 eq.) and DIPA (0.77 mmol, 0.11 mL, 1.1 eq.) in THF (0.17 M, 4.0 mL) were added to a

flame dried and purged flask and cooled to -78 oC. The reaction stirred for 30 minutes

maintaining temperature and then ketone 2.28 (0.70 mmol, 0.10 g, 1.0 eq.) was added dropwise.

The mixture stirred for another 30 minutes still at -78 oC where TMSCl (10.5 mmol, 1.34 mL,

1.5 eq.) was added dropwise. The solution stirred for one and a half hours maintaining the

temperature and it was then poured over a mixture of ice and hexanes. Extraction then occurred

three times with 10 mL of hexanes. The combined organic layers were washed with brine and

dried with MgSO4 where the final solution was concentrated to afford the desired silyl enol ether

(2.28). There was no purification necessary. 1H NMR (500 MHz, CDCl3) δ 4.05 (d, J = 1.5 Hz,

2H), 2.02 (m, 2H), 1.44 (m, 2H), 1.30 (m, 10H), 0.90 (t, J = 7.0 Hz, 3H), 0.22 (s, 9H).

Ethyl 2-(2-oxohexyl)benzoate (2.31) (Table 2.3, Entry 2): Material did not undergo

purification and still contained residual solvent. Yield: 0.025 g, 20% as a yellow oil. 1H NMR

(500 MHz, CDCl3) δ 7.46 (d, J = 1.4 Hz, 1H), 7.34 (dd, J = 7.6, 1.2 Hz, 1H), 7.17 (d, J = 7.6 Hz,

63

1H), 4.30 (d, J = 7.1 Hz, 1H), 4.09 (s, 1H), 2.53 (t, J = 7.5 Hz, 2H), 1.58 (m, 2H), 1.35 (td, J =

7.2, 2.5 Hz, 5H), 0.92 (t, J = 7.3 Hz, 3H).

Synthesis of 2-bromo-4,6-dimethoxybenzaldehyde (2.33): 2.32 (23.2 mmol, 5.0 g, 1.0 eq.) was

dissolved in DMF (0.08 M, 28.9 mL) and placed into a flame dried and purged flask. The flask

was then cooled to 0 oC where POCl3 (57.8 mmol, 5.41 mL, 2.5 eq.) was added dropwise and

allowed to stir at 0 oC for ten minutes. The reaction then stirred at RT for 30 minutes followed by

heating to 100 oC for four hours. The mixture was cooled and diluted with 50 mL of DI water

and then extracted three times with 50 mL of EtOAc. The combined organic layers were dried

with MgSO4 and concentrated. Purification via column chromatography in 30% EtOAC in

hexanes was conducted to afford 2.33. Rf: 0.2; Yield: 1.86 g, 33% as a white solid. 1H NMR

(500 MHz, CDCl3) δ 10.32 (s, 1H), 6.79 (d, J = 2.2 Hz, 1H), 6.44 (d, J = 2.2 Hz, 1H), 3.88 (d, J

= 12.8 Hz, 6H).29

Synthesis of 2-bromo-6-hydroxy-4-methoxybenzaldehyde (2.34): A solution of 2.33 (0.41

mmol, 0.10 g, 1.0 eq.) in DCM (0.20 M, 1.0 mL) was added to a flame dried and purged flask

that was then cooled to 0 oC. BBr3 (0.20 mmol, 0.02 mL, 0.50 eq.) was added dropwise and the

mixture stirred for 30 minutes at 0 oC. MeOH was added dropwise and the mixture was

concentrated. The material was extracted three times with 5 mL of EtOAc and the combined

organic layers were dried with MgSO4 and concentrated to afford 2.34. There was no purification

needed. Yield: 0.58 g, 64% as a white solid. 1H NMR (500 MHz, CDCl3) δ 12.47 (s, 1H), 10.11

(s, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.37 (d, J = 2.3 Hz, 1H), 3.85 (s, 3H).29

Synthesis of 2-bromo-4-methoxy-6-(methoxymethoxy)benzaldehyde 2.35: A flame dried and

purged flask was cooled to 0 oC and to it, 2.34 (0.43 mmol, 0.10 g, 1.0 eq.), TBAI (0.09 mmol,

0.03 g, 0.2 eq.), DIPEA (3.0 eq.), and MOMCl (0.87 mmol, 0.06 mL, 2.0 eq.) in DCM (0.2 M,

64

1.0 mL), were added. The reaction temperature was raised to RT and the mixture stirred for 24

hours. The flask was then cooled to 0 oC and quenched with 5 mL of saturated NaHCO3.and 5

mL of DI water. The aqueous was extracted with DCM and the combined organic layers were

dried with MgSO4 and concentrated. Purification took place via column chromatography in 25%

EtOAc in hexanes to afford (2.35). Rf: 0.3; Yield: 0.13 g, 79% as a white solid. 1H NMR (500

MHz, CDCl3) δ 10.33 (s, 1H), 6.85 (d, J = 2.3 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 5.26 (s, 2H),

3.85 (s, 3H), 3.51 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 188.96, 164.32, 161.47, 126.56,

117.72, 113.53, 101.34, 95.13, 56.68, 55.93.

Synthesis of 2-bromo-4-methoxy-6-(methoxymethoxy)benzoic acid (2.20): A round bottom

flask was flame dried, purged, and then cooled to 0 oC. A solution of 2.35 (0.36 mmol, 0.10 g,

1.0 eq.) dissolved in t-BuOH and H2O (3:1 ratio, 2.2 mL and 0.92 mL) was added to the flask

followed by 2-methyl-2-butene (2.2 mmol, 0.23 mL, 6.0 eq.) in one portion. Two more mixtures

of t-BuOH and H2O were made (1:1 ratio, 0.92 mL) and in one NaClO2 (1.5 mmol, 0.13 g, 4.0

eq.) was dissolved and in the other NaH2PO4 (0.55 mmol, 0.07 g, 1.5 eq.). The solution of

NaClO2 was added to the system dropwise followed by the solution of NaH2PO4. The reaction

was raised to room temperature and stirred for five hours where it was then quenched with 10

mL of saturated NH4Cl. The material was then extracted with 10 mL of EtOAc three times. The

combined organic layers were then dried with MgSO4 and concentrated. Purification took place

via column chromatography in 5% MeOH in DCM to afford 2.20. Rf: 0.09; Yield 0.08 g, 80% as

a white solid. 1H NMR (500 MHz, CDCl3) δ 6.79 (d, J = 2.1 Hz, 1H), 6.70 (d, J = 2.1 Hz, 1H),

5.20 (s, 2H), 3.80 (s, 3H), 3.49 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 162.07, 156.41, 120.75,

111.67, 101.51, 95.34, 56.76, 56.06.

65

Synthesis of 2-bromo-4,6-dimethoxybenzoic acid (2.20, A): A round bottom flask was flame

dried, purged, and then cooled to 0 oC. A solution of 2.33 (0.41 mmol, 0.10 g, 1.0 eq.) dissolved

in t-BuOH and H2O (3:1 ratio, 2.2 mL and 0.92 mL) was added to the flask followed by 2-

methyl-2-butene (2.4 mmol, 0.26 mL, 6.0 eq.) in one portion. Two more mixtures of t-BuOH and

H2O were made (1:1 ratio, 0.92 mL) and in one NaClO2 (1.6 mmol, 0.15 g, 4.0 eq.) was

dissolved and in the other NaH2PO4 (0.62 mmol, 0.07 g, 1.5 eq.). The solution of NaClO2 was

added to the system dropwise followed by the solution of NaH2PO4. The reaction was raised to

room temperature and stirred for five hours where it was then quenched with 10 mL of saturated

NH4Cl. The material was then extracted with 10 mL of EtOAc three times. The combined

organic layers were then dried with MgSO4 and concentrated. Purification took place via column

chromatography in 5% MeOH in DCM to afford 2.20, A. Rf: 0.12; Yield 0.09 g, 80% as a white

solid. 1H NMR (360 MHz, CDCl3) δ 6.74 (d, J = 2.2 Hz, 1H), 6.43 (d, J = 2.1 Hz, 1H), 3.84 (d, J

= 11.9 Hz, 6H).

Synthesis of (S)-pent-4-en-2-ol (2.22): CuI (0.87 mmol, 0.16 g, 0.5 eq.) was added to a flame

dried and purged flask followed by THF (0.18 M, 10 mL). The flask was cooled to -78 oC and

vinylmagnesium bromide (1.0 M, 3.4 mL, 2.0 eq.) was added dropwise. The reaction stirred for

fifteen minutes and then (S)-propylene oxide (1.7 mmol, 0.10 g, 1.0 eq.) was added. The mixture

stirred overnight where the temperature gradually rose to RT. The temperature was lowered to 0

oC and the reaction was quenched with saturated NH4Cl. An extraction took place three time

with 10 mL of diethyl ether and the combined organic layers were dried with MgSO4 and

concentrated. Purification was not needed. Yield: 0.13 g, 90% as a yellow oil. 1H NMR (360

MHz, CDCl3) δ 5.81 (m, 1H), 5.12 (m, 2H), 3.85 (dd, J = 12.0, 6.0 Hz, 1H), 2.18 (m, 2H), 1.21

(d, J = 6.2 Hz, 3H).

66

Synthesis of pent-4-enal (2.39): To a flame dried and purged flask, 2.38 (1.2 mmol, 0.10 g, 1.0

eq.) and DMP (2.3 mmol, 0.99 g, 2.25 eq.) in DCM (0.17 M, 6.8 mL) were added at RT. The

reaction stirred for three hours and was then quenched with 3 mL of saturated NaHCO3 and 3

mL of Na2S2O3. The mixture stirred for an additional 30 minutes and was then extracted three

times with 10 mL of DCM. The combined organic layers were dried with MgSO4 and

concentrated. Purification could not be conducted and was taken on to the next step. Yield: 0.07

g, 75% as yellow oil. 1H NMR (360 MHz, CDCl3) δ 9.73 (t, J = 1.6 Hz, 1H), 5.72 (m, 2H), 4.95

(m, 4H), 2.04 (ddd, J = 8.4, 7.0, 4.2 Hz, 4H).

Synthesis of hex-5-en-2-ol (2.40): To a flame dried and purged flask, THF (0.24 M, 5.0 mL)

was added. The flask was cooled to -78 oC and methylmagnesium bromide (3.0 M, 0.80 mL, 2.0

eq.) was added dropwise. The reaction stirred for fifteen minutes and then (2.39) (1.2 mmol, 0.10

g, 1.0 eq.) was added. The mixture stirred overnight where the temperature gradually rose to RT.

The temperature was lowered to 0 oC and the reaction was quenched with saturated NH4Cl. An

extraction took place three time with 10 mL of diethyl ether and the combined organic layers

were dried with MgSO4 and concentrated. Purification was not needed. Yield: 0.10 g, 85% as a

yellow oil. 1H NMR (360 MHz, CDCl3) δ 5.79 (ddt, J = 16.9, 10.1, 6.7 Hz, 1H), 4.96 (m, 2H),

3.63 (t, J = 6.5 Hz, 1H), 2.04 (m, 2H), 1.45 (m, 3H), 1.18 (m, 2H).

Synthesis of hex-5-en-2-one (2.23): To a flame dried and purged flask, 2.40 (1.0 mmol, 0.10 g,

1.0 eq.) and DMP (1.2 mmol, 0.51 g, 1.2 eq.) in DCM (0.17 M, 6.0 mL) were added at RT. The

reaction stirred for three hours and was then quenched with 3 mL of saturated NaHCO3 and 3

mL of Na2S2O3. The mixture stirred for an additional 30 minutes and was then extracted three

times with 10 mL of DCM. The combined organic layers were dried with MgSO4 and

concentrated. Purification could not be conducted, and an accurate yield could not be obtained.

67

1H NMR (360 MHz, CDCl3) δ 5.78 (m, 1H), 5.02 (m, 2H), 2.80 (dt, J = 38.1, 7.3 Hz, 1H), 2.36

(m, 4H), 1.25 (s, 3H).

Synthesis of (R,E)-8-hydroxynon-5-en-2-one (2.41): A solution of 2.22 (1.2 mmol, 0.10 g, 1.0

eq.), 2.23 (3.5 mmol, 0.41 mL, 3.0 eq.), PhOH (0.58 mmol, 0.06 g, 0.5 eq.), and GC(II) (0.02

mmol, 0.02 g, 0.015 eq.) in DCM (0.2 M, 6.0 mL) was added to a flame dried and purged flask at

RT. The reaction stirred overnight where it was then concentrated and purified via column

chromatography in 25% EtOAc in hexanes. Rf: 0.1; Yield: 0.12 g, 66% as brown oil. 1H NMR

(360 MHz, CDCl3) δ 5.47 (m, 2H), 3.78 (ddd, J = 9.3, 7.4, 5.5 Hz, 1H), 2.51 (t, J = 7.2 Hz, 2H),

2.26 (m, 2H), 2.12 (m, 6H), 1.18 (m, 3H).

Synthesis of (R)-8-hydroxynonan-2-one (2.21): A solution of 2.41 (0.64 mmol, 0.10 g, 1.0 eq.)

in EtOH (0.06 M, 10 mL) was added to a flame dried and purged flask. The flask was then

placed under 1 atm of H2 overnight. The resulting mixture was carefully opened to air and

filtered through celite and washed with copious amounts of DCM. The material was concentrated

and purified via column chromatography in 25% EtOAc in hexanes. Rf: 0.2; Yield: 0.04 g, 42%

as yellow oil. 1H NMR (360 MHz, CDCl3) δ 3.76 (m, 1H), 2.39 (d, J = 7.4 Hz, 1H), 2.10 (s, 3H),

1.54 (dd, J = 14.7, 7.4 Hz, 2H), 1.35 (m, 6H), 1.15 (d, J = 6.2 Hz, 3H).

Synthesis of (S)-8-oxononan-2-yl 2-bromo-4-methoxy-6-(methoxymethoxy)benzoate (2.42):

To a flame dried and purged flask, 2.20 (0.34 mmol, 0.10 g, 1.0 eq.) and 2.21 (0.69 mmol, 0.11

g, 2.0 eq.) were added to DCM (0.05 M, 7.0 mL). DCC (069 mmol, 0.14 g, 2.0 eq.) and DMAP

(1.0 mmol, 0.13 g, 3.0 eq.) were sequentially added to the reaction and it stirred at RT for 18

hours. The mixture was then placed in the freezer for 5 hours and the filtrate was filtered and

purified. Purification took place via column chromatography in 30% EtOAc in hexanes, there

was residual solvent left over. Rf: 0.3; Yield: 0.12 g, 83% as white solid. 1H NMR (360 MHz,

68

CDCl3) δ 7.37 (s, 1H), 7.08 (s, 1H), 5.15 (dd, J = 12.7, 6.1 Hz, 1H), 3.91 (d, J = 3.7 Hz, 6H),

2.42 (td, J = 7.4, 2.5 Hz, 2H), 2.12 (m, 3H), 1.78 (m, 4H), 1.30 (m, 7H).

69


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Chem. Soc. 2018, 140, 2062-2066.

5. Sole, D.; Urbaneja, X.; Bonjoch, J., Synthesis of the 4-Azatricyclo[5.2.2.04,8]undecan-

10-one Core of Daphniphyllum Alkaloid Calyciphylline A Using a Pd-Catalyzed Enolate

Alkenylation. Org. Lett. 2005, 7, 5461-5464.

6. Delmotte, P.; Delmotte-Plaquee, J., A new antifungal substance of fungal origin. Nature.

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7. Jana, N.; Nanda, S., Resorcylic acid lactones (RALs) and their structural congeners:

recent advances in their biosynthesis, chemical synthesis and biology. New J. Chem. 2018, 42,

17803-17873.

8. Brase, S.; Glaser, F.; Framer, C., Chemistry of Mycotoxins. Springer: 2012; p 280 pp.

9. Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S. J., Concise

Asymmetric Syntheses of Radicicol and Monocillin I. J. Am. Chem. Soc. 2001, 123, 10903-

10908.

10. Moulin, E.; Barluenga, S.; Winssinger, N., Concise Synthesis of Pochonin A, an HSP90

Inhibitor. Org. Lett. 2005, 7, 5637-5639.

11. Geng, X.; Danishefsky, S. J., Total Synthesis of Aigialomycin D. Org. Lett. 2004, 6, 413-

416.

70

12. Martinez-Solorio, D.; Belmore, K. A.; Jennings, M. P., Synthesis of the Purported ent-

Pochonin J Structure Featuring a Stereoselective Oxocarbenium Allylation. J. Org. Chem. 2011,

76, 3898-3908.

13. Poling, S. M.; Wicklow, D. T.; Rogers, K. D.; Gloer, J. B., Acremonium zeae, a

Protective Endophyte of Maize, Produces Dihydroresorcylide and 7-

Hydroxydihydroresorcylides. J. Agric. Food Chem. 2008, 56, 3006-3009.

14. He, W.-J.; Zhou, X.-J.; Qin, X.-C.; Mai, Y.-X.; Lin, X.-P.; Liao, S.-R.; Yang, B.;

Zhang, T.; Tu, Z.-C.; Wang, J.-F.; Liu, Y., Quinone/hydroquinone meroterpenoids with

antitubercular and cytotoxic activities produced by the sponge-derived fungus Gliomastix sp.

ZSDS1-F7. Nat. Prod. Res. 2017, 31, 604-609.

15. Wicklow, D. T.; Poling, S. M.; Summerbell, R. C., Occurrence of pyrrocidine and

dihydroresorcylide production among Acremonium zeae populations from maize grown in

different regions. Can. J. Plant Pathol. 2008, 30, 425-433.

16. Zeng, J.; Zhan, J., A novel fungal flavin-dependent halogenase for natural product

biosynthesis. Chembiochem 2010, 11, 2119-2123.

17. Zeng, J.; Valiente, J.; Zhan, J., Generation of two new macrolactones through sequential

biotransformation of dihydroresorcylide. Nat. Prod. Commun. 2011, 6, 223-226.

18. Jiang, C.-S.; Zhang, L.; Gong, J.-X.; Li, J.-Y.; Yao, L.-G.; Li, J.; Guo, Y.-W., Concise

synthesis and PTP1B inhibitory activity of (R)- and (S)-dihydroresorcylide. J. Asian Nat. Prod.

Res. 2017, 19, 1204-1213.

19. Combs, A. P., Recent Advances in the Discovery of Competitive Protein Tyrosine

Phosphatase 1B Inhibitors for the Treatment of Diabetes, Obesity, and Cancer. J. Med. Chem.

2010, 53, 2333-2344.

20. Zhang, L.; Ma, W.; Xu, L.; Deng, F.; Guo, Y., Efficient total synthesis of (S)-

dihydroresorcylide, a bioactive twelve-membered macrolide. Chin. J. Chem. 2013, 31, 339-343.

21. Trotter, T. N.; Albury, A. M. M.; Jennings, M. P., Total Synthesis of 7-Deoxy-6-O-

methylfusarentin Featuring a Chelation-Controlled 1,3-Reetz-Keck-Type Allylation. J. Org.

Chem. 2012, 77, 7688-7692.

22. Palucki, M.; Buchwald, S. L., Palladium-Catalyzed α-Arylation of Ketones. J. Am. Chem.

Soc. 1997, 119, 11108-11109.

23. Barnard, C. F. J., Palladium-Catalyzed Carbonylation-A Reaction Come of Age.

Organometallics 2008, 27, 5402-5422.

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24. Cacchi, S.; Morera, E.; Ortar, G., Palladium-catalyzed carbonylation of enol triflates. A

novel method for one-carbon homologation of ketones to α,β-unsaturated carboxylic acid

derivatives. Tetrahedron Lett. 1985, 26, 1109-1112.

25. Kawatsura, M.; Hartwig, J. F., Simple, Highly Active Palladium Catalysts for Ketone and

Malonate Arylation: Dissecting the Importance of Chelation and Steric Hindrance. J. Am. Chem.

Soc. 1999, 121, 1473-1478.

26. Okabayashi, T.; Iida, A.; Takai, K.; Nawate, Y.; Misaki, T.; Tanabe, Y., Practical and

Robust Method for Regio- and Stereoselective Preparation of (E)-Ketene tert-Butyl TMS Acetals

and β-Ketoester-derived tert-Butyl (1Z,3E)-1,3-Bis(TMS)dienol Ethers. J. Org. Chem. 2007, 72,

8142-8145.

27. Carfagna, C.; Musco, A.; Sallese, G.; Santi, R.; Fiorani, T., Palladium-catalyzed

coupling reactions of aryl triflates or halides with ketene trimethylsilyl acetals. A new route to

alkyl 2-arylalkanoates. J. Org. Chem. 1991, 56, 261-263.

28. Iwama, T.; Rawal, V. H., Palladium-Catalyzed Regiocontrolled α-Arylation of

Trimethylsilyl Enol Ethers with Aryl Halides. Org. Lett. 2006, 8, 5725-5728.

29. Won, M.; Kwon, S.; Kim, T.-H., An efficient synthesis of Alternariol. J. Korean Chem.

Soc. 2015, 59, 471-474.

30. Kluge, A. F.; Untch, K. G.; Fried, J. H., Prostaglandins. X. Synthesis of prostaglandin

models and prostaglandins by conjugage addition of a functionalized organocopper reagent. J.

Amer. Chem. Soc. 1972, 94, 7827-7832.

31. De Joarder, D.; Jennings, M. P., Convergent synthesis of (+)-xestodecalactone A via a

Pd-catalyzed α-arylation reaction. Tetrahedron Lett. 2013, 54, 3990-3992.

32. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H., A General Model for

Selectivity in Olefin Cross Metathesis. J. Am. Chem. Soc. 2003, 125, 11360-11370.

33. Forman, G. S.; McConnell, A. E.; Tooze, R. P.; Van Rensburg, W. J.; Meyer, W. H.;

Kirk, M. M.; Dwyer, C. L.; Serfontein, D. W., A Convenient System for Improving the

Efficiency of First-Generation Ruthenium Olefin Metathesis Catalysts. Organometallics 2005,

24, 4528-4542.

34. De Joarder, D.; Jennings, M. P., Umpolung Pd-Catalyzed α-Arylation Reactions in

Natural Product Synthesis: Syntheses of (+)-Xestodecalactone A, (-)-Curvularin, (+)-12-

Oxocurvularin and (-)-Citreofuran. Eur. J. Org. Chem. 2015, 2015, 3303-3313.

35. Avuluri, S.; Bujaranipalli, S.; Das, S.; Yadav, J. S., Stereoselective synthesis of 5'-

hydroxyzearalenone. Tetrahedron Lett. 2018, 59, 3547-3549.

72

36. Bugarin, A.; Connell, B. T., Chiral Nickel(II) and Palladium(II) NCN-Pincer Complexes

Based on Substituted Benzene: Synthesis, Structure, and Lewis Acidity. Organometallics 2008,

27, 4357-4369.

37. Jia, M.; Jiang, L.; Niu, F.; Zhang, Y.; Sun, X., A novel and highly efficient

esterification process using triphenylphosphine oxide with oxalyl chloride. R. Soc. Open Sci.

2018, 5, 171988/1-88/12.

38. Lehman, J. W., Operational Organic Chemistry: A Problem-solving Approach to the

Laboratory Course. Pearson Prentice Hall: 2009.

39. Santandrea, J.; Bedard, A.-C.; Collins, S. K., Cu(I)-Catalyzed Macrocyclic Sonogashira-

Type Cross-Coupling. Org. Lett. 2014, 16, 3892-3895.

40. Culkin, D. A.; Hartwig, J. F., Palladium-Catalyzed α-Arylation of Carbonyl Compounds

and Nitriles. Acc. Chem. Res. 2003, 36, 234-245.

0.00.5

1.01.5

2.02.5

3.03.5

4.04.5

5.05.5

6.06.5

7.07.5

8.08.5

9.09.5

10.511.5

f1 (ppm)

6.27

3.77

1.291.27

1.00

1.73

3.82

6.006.016.156.15

10.45


73

0.00.5

1.01.5

2.02.5

3.03.5

4.04.5

5.05.5

6.06.5

7.07.5

8.08.5

9.09.5

10.511.5

f1 (ppm)

6.25

3.15

1.031.00

1.74

3.88

6.486.486.536.54


74

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.5

11.5f1 (ppm

)

9.50

3.18

1.011.04

1.00

1.63

3.83

6.316.326.476.47

11.87


75

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.5

11.5f1 (ppm

)

9.14

3.63

9.722.08

2.10

2.00

0.220.880.90

1.301.442.002.022.03

4.054.05


76

0.00.5

1.01.5

2.02.5

3.03.5

4.04.5

5.05.5

6.06.5

7.07.5

8.08.5

9.09.5

10.511.5

f1 (ppm)

9.64

13.9217.00

2.15

1.611.58

0.801.121.00

0.910.920.94

1.341.351.37

1.582.522.532.55

4.094.294.31

7.177.187.337.347.357.357.467.47


77

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.5

11.5f1 (ppm

)

6.46

1.08

1.16

1.00

3.873.89

6.446.44

6.796.79

10.32


78

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.5

11.512.5

f1 (ppm)

3.45

1.09

1.08

1.00

1.00

3.85

6.376.38

6.746.75

10.11

12.47


79

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.5

11.5f1 (ppm

)

3.30

3.41

2.29

1.121.06

1.00

3.51

3.85

5.26

6.716.716.856.85

10.33


80

1020

3040

5060

7080

90100

110120

130140

150160

170180

190200

210f1 (ppm

)55.9356.68

95.13

101.34

113.53117.72

126.56

161.47164.32

188.96

The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 2.35

81

0.00.5

1.01.5

2.02.5

3.03.5

4.04.5

5.05.5

6.06.5

7.07.5

8.08.5

9.09.5

10.511.5

f1 (ppm)

2.87

2.96

1.91

0.971.00

3.493.80

5.20

6.706.706.796.79


82

1020

3040

5060

7080

90100

110120

130140

150160

170180

190200

f1 (ppm)

56.0656.76

95.34

101.51

111.67

120.75

156.41162.07

The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 2.2083

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.5

11.5f1 (ppm

)

5.86

0.92

1.00

3.823.85

6.436.446.746.75

The 1H NMR Spectrum (360 MHz, CDCl3) of Compound 2.20, A

84

0.00.5

1.01.5

2.02.5

3.03.5

4.04.5

5.05.5

6.06.5

7.07.5

8.08.5

9.09.5

10.511.5

f1 (ppm)

3.07

2.22

0.98

1.94

1.00

1.201.22

2.132.162.182.212.252.26

3.833.843.863.88

5.115.125.155.165.775.785.795.795.805.815.815.825.825.825.835.835.845.845.855.865.865.865.885.885.895.91


85

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.5

11.5f1 (ppm

)

7.88

4.461.081.73

0.99

0.63

4.17

0.24

2.17

0.920.710.24

0.64

1.00

2.012.012.022.032.032.052.072.092.222.392.392.412.41

2.43

3.593.614.174.194.214.894.924.95

5.025.675.705.725.745.765.78

5.817.637.687.717.837.85

7.968.218.218.238.23

9.739.739.74


86

0.00.5

1.01.5

2.02.5

3.03.5

4.04.5

5.05.5

6.06.5

7.07.5

8.08.5

9.09.5

10.511.5

f1 (ppm)

2.312.90

2.05

1.05

1.90

1.00

1.181.181.381.411.431.451.48

1.552.022.032.042.05

3.613.633.65

4.924.954.964.97

5.015.735.755.765.775.785.805.815.825.835.85


87

0.00.5

1.01.5

2.02.5

3.03.5

4.04.5

5.05.5

6.06.5

7.07.5

8.08.5

9.09.5

10.511.5

f1 (ppm)

9.91

3.50

0.83

1.99

1.00

1.25

2.082.10

2.36

2.732.752.772.842.862.88

4.975.005.025.045.075.755.765.775.785.795.805.82


88

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.5

11.5f1 (ppm

)

2.54

5.562.212.13

1.00

2.09

1.161.171.181.201.22

2.042.122.182.22

2.513.763.773.773.783.793.793.815.425.445.455.465.465.475.485.505.515.54


89

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.5

11.5f1 (ppm

)

3.096.952.42

2.83

1.64

1.00

1.151.241.281.311.351.361.38

1.552.102.382.402.42

3.713.723.743.763.773.79


90

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.5

11.5f1 (ppm

)

30.26

11.88

5.32

3.75

14.92

6.54

1.52

4.81

0.76

1.00

4.73

1.321.341.361.541.561.581.601.621.66

1.912.402.422.44

3.00

3.903.91

5.125.145.165.17

6.486.486.496.507.087.37

8.218.23


91

92

CHAPTER 3: Stereoselective Halo-Succinimide Facilitated α-Halogenations of Substituted α-

Trialkylsilyl-ß-Substituted-α,ß-Unsaturated Esters

3.1 Introduction

Halogenations, specifically brominations, have been widely utilized in chemical reactions

because these atoms act as good leaving groups and help facilitate the formation of a variety of

new bonds. These take place across alkanes and benzylic carbons through a free radical

mechanism1 while alkenes and alkynes go through an electrophilic substitution2 and aromatics

undergo substitution via electrophilic aromatic substitution (EAS).3 There are several reagents

commonly used to conduct the brominations.

HBr and Br2 are some of the chemicals readily used to complete the halogenations.

However, Br2 is incredibly toxic leading to the study of other halogen sources. Transition metals

like, Fe, Pd, and Ru, have proven to be highly compatible for this addition or substitution on

complex materials.4-6 Another reagent that has proven to be useful when conducting

brominations is N-bromosuccinimide (NBS).7, 8

NBS is most known for its usefulness in the Wohl-Ziegler reaction where the halogen is

added at an allylic or benzylic position.9 It has two known mechanisms of bromine addition. The

first is a radical pathway and the second is the introduction of a bromonium ion complex.7 NBS

has been utilized with different types of compounds like vinyl silanes.

93

In 1987, Tamao et al. published work looking at the ability to substitute a vinyl trimethyl

silyl functional group with a halogen (Figure 3.1) and how that mechanism would work. Various

halogen sources such as, ICl, Br2, and NBS were utilized along with solvents like, DMF, CCl4,

and THF, which were successful in producing high yields of the desired halogenated compounds.

The mechanism was then studied to determine that the stereochemistry of the resulting alkene,

whether Z or E, and if it could be manipulated based on reaction conditions.10

In 1996, there was a compound library published that conducted halogenations under the

conditions set forth by Tamao, except these were completed with N-iodosuccinimide (NIS).11

These conditions were also implemented during the synthesis of several pharmaceutical or

natural products like Leukotriene B3, Haterumalide NA, and (S)-Jamaicamide C.12-14 There is

also material published concerning the bromination of styrene and related analogs and

dibrominations of arylethylenes.15, 16 However, there are not any current reports of brominations

concerning α-trialkylsilyl-α,ß-unsaturated esters.

Figure 3.2 shows the general structure of the aforementioned silanes and how versatile

these compounds are. Over the past several years these motifs have undergone different

transformations, often in a stereoselective manner, to increase the number of reactive sites.17-19

These small molecules have been studied concerning halogenations, however these studies

concerned addition of the halogen at the γ position and not the α shown in the research presented

within.20

94

Figure 3.3 shows the general reaction that will be discussed further. The halogenated

compounds could be used in Sonagashira, Sukuki, or Negishi coupling, all of which have had

their uses in total synthesis.21-23 The following work will discuss the novel results of this study

by using Tamao’s conditions as a guide.

3.2 The Generation of α-Trialkylsilyl-α, β-Unsaturated Esters

The formation of these highly functionalized vinyl silanes through ethyl propiolate (3.1)

have been extensively studied by the Jennings’ research group.18 They are believed to go through

a complex copper mediated cycle with the Grignard reagent to give a silyl ketene acetal

intermediate that upon work-up will selectively give the formation of the (E) silane (Figure 3.4).

95

This halogenation research began by generating a compound library of the α-trialkylsilyl-

α,ß-unsaturated esters and are shown in Table 3.1. A total of nine vinyl silanes were utilized over

the course of this project. Compounds 3.2a-3.2c were all trisubstituted α,ß-unsaturated esters

with aromatic substituents, specifically o-tolyl, phenyl, and 3-methoxy phenyl. Compound 3.2d

was tetrasubstituted with a phenyl and a methyl in the ß- position. The silane group was changed

from a TMS group to a TES for compound 3.2e. The remaining compounds (3.2f-3.2i) were all

trisubstituted with alkyl substituents and both 3.2g and 3.2i were novel. These small molecules

were then subjected to NBS to facilitate the substitution of the silane functional group.

96

3.3 The Halogenation Reaction

As previously discussed, NBS has been extensively studied for the completion of

bromine substitution. Research published by Tamao research group is of the most intriguing for

this project due to the reagent, solvent, or a combination of the both ability to alter the outcome

concerning yield and stereochemistry of the vinyl silanes studied.10 Based on the conditions set

97

forth, a sample study was conducted to optimize reaction conditions concerning the unsaturated

ester silanes. Figure 3.5 shows the model reaction which was carried out under Ar at room

temperature while stirring for 18-24 hours with vinyl silane 3.2a, 2.0 equivalents of NBS, and

the solvent of choice. The conversion percent was established by crude NMR due to the

substantial shift of the ß proton seen when comparing starting material and products. Table 3.2

lists the findings of the solvent dependence study.

Entrya Solvent Conversion* %

1b DMF 100

2c DMF 63

3 DME 75

4 THF 53

5 Ether 26

6 DCM 10

7 Toluene 10

Table 3.2. Solvent Dependence Studies. *conversion calculated via crude 1H NMR. a. All entries

utilized 3.2a due to availability. 1b was conducted with 2.0 equivalents of NBS. 2c was

conducted with 4.0 equivalents of NBS.

All entries utilized 3.2a as the vinyl silane of choice due to the availability of the

compound. Entries 1 and 2 were both conducted with the aprotic solvent DMF, however, the

equivalents of NBS was altered 2.0 equivalents and 4.0 equivalents for entry 1 and 2

98

respectively. It was interesting to discover that double the equivalents had significant impact on

the conversion which is possibly due to the increase of Br2 formation in the system. Entries 3 and

4 explore other aprotic solvents such as DME and THF, and these two entries exhibited a

decreased amount of conversion that took place in the reaction. Entries 5-7 implemented other

organic solvents of varying polarity such as diethyl ether, DCM, and toluene, all of which also

showed a substantial decrease of silane conversion. It should be noted that the conversion

percent for these entries is significantly lowered than the previous donor solvents and cannot be

determined to be accurate. This is consistent with the work published by Tamao showing that as

the polarity decreases, so did silane bond cleavage. The less electronegative or nucleophilic a

solvent, the less chance there is for it to attack the ß-carbon and ring open the bromonium ion

intermediate. All the solvents appeared to give solely the (Z) isomer of the newly formed

brominated compounds leading to the belief that the reaction was not solvent dependent

regarding stereochemistry but was dependent regarding conversion. Based on the studies by

Tamao and ourselves, we can theorize a possible mechanism (Scheme 3.1).10

99

The α,ß-alkene would act as both electrophile and nucleophile to form the bromonium

ion intermediate from NBS. DMF would then attack the ß position thus causing the bromonium

ion ring to open. From this there are two different rotamers, one with an eclipsed transition state

and one with a staggered transition state, that could be present that will undergo an elimination

with the succinimide anion to yield either inversion or retention of stereochemistry. The

mechanism presented cannot be followed by the non-donor solvents, such as DCM and toluene,

but it is likely that these go through a stabilized cationic mechanism discussed in Scheme 3.2

100

later in the chapter. A compound library of α-bromo-α,ß-unsaturated esters was generated and

discussed in the following section.

3.4 (Z)-α-Halogen-α, β-Unsaturated Esters Compound Library

The transformation of α-trialkylsilyl-α,ß-unsaturated esters into α-halogen-α,ß-

unsaturated esters took place via 2.0 equivalents of NBS in DMF. Table 3.3 shows the molecules

that were generated with the previously mentioned vinyl silanes. The yields for the compounds

ranged from 58%-90% and while most gave complete inversion of stereochemistry, which was

verified by NOE studies shown in Figure 3.6, there were a few unexpected results.

102

Compounds 3.3a and 3.3b both proceeded without any incident to give a yellow oil in

yields of 90% and 73% respectively. Compound 3.3c was the only material to have a

dibromination occur and it is theorized that the vinyl silane is an anisole analog which is a strong

ortho/para director so while the substitution of the silane is occurring so is an aromatic

substitution. It should also be noted that 3.3c was isolated in a 61% yield as a yellow powder and

was the only material to be a solid. Compounds 3.3e-3.3h proceeded to be isolated all as oils and

with inversion of stereochemistry. 3.3d gave intriguing results compared to the others.

The tetrasubstituted 3.3d was the only compound to give complete retention of

stereochemistry which was confirmed by NOE studies of both the vinyl silane, 3.2d, and the

brominated product, 3.3d, shown in Figure 3.7. 3.2d (E isomer) was confirmed to be the product

instead of 3.2d (Z isomer) by the lack of interactions between the ß-methyl and the ester. The

only interactions that occurred with the ester of 3.3d (E isomer) were from the aromatic group.

When considering the mechanism proposed, in order to have retention of stereochemistry, an

eclipsed rotation would take place which is a higher energy transition state than its staggered

counterpart. Due to this, it can be assumed that another mechanism (Scheme 3.2) took place

likely involving a hyperconjugated carbocation. This mechanism shows the silane activating the

double bond to allow the attack of the bromine on the NBS but not the subsequent attack by the

bromine as shown in Scheme 3.1. The C-Br bond would form in the α-position leaving a

stabilized tertiary carbocation in the ß-position. The carbocation would be further stabilized due

to σ orbital overlap of the silane group which is also known as the ß-silicon effect.24 Elimination

would subsequently follow leaving the halogenation to have retention of stereochemistry other

than the expected inversion.

103

The intermediate theorized to transpire in Scheme 3.2 could have rotation about the α-

carbon the give inversion of stereochemistry or a mixture of products. However, as retention was

the only product isolated regarding 3.3d, parameters like sterics must be considered. Based on

the Taft parameters it can be assumed that any rotation concerning 3.3d would lead to a higher

energy transition state making the E isomer the desired product.25 As stated earlier, it is plausible

that the solvents like DCM would undergo this type of mechanism, however at a much slower

rate than DMF.

104

Table 3.4 shows the isolation of three chlorinations (3.4a-3.4c) using NCS instead of

NBS. These reactions were also heated to 60 oC for 18-24 hours in lieu of just stirring at room

temperature. Compound 3.4a was the only one of the three to give a 1:1 ratio of the (Z) and (E)

isomers where the other two produced complete inversion. It is a possibility that the mechanisms

in Scheme 3.1 and 3.2 are competing.

Another reaction that was conducted is shown in Figure 3.8. The vinyl silane, 3.2e, was

subjected to standard conditions to give rise to 3.3b. The vinyl silane was similar to that of 3.2b

with the TMS group being changed to a TES group. Instead of giving complete inversion of

stereochemistry, it was found that a 3:1 (Z)/(E) mixture was generated. It is theorized that the

TES group was more sterically hindering so as to not allow for rotation. All of the work

conducted in this project furthers the versatility of these α-trialkylsilyl-α,ß-unsaturated esters.

105

3.5 Future Works

It is hopeful that in the future the (Z)-ß-substituted-α-trialkylsilyl-α,ß-unsaturated esters

could be studied to determine if the halogenation is both stereoselective and stereospecific. It

would also be desirable to conduct full mechanistic studies of the halogenations, especially those

that gave mixtures of isomers or complete retention of stereochemistry.

3.6 Conclusion

The formation of vinyl silanes was successful and were utilized to create α-bromo-α,ß-

unsaturated esters with both aryl and alkyl substituents in a stereoselective manner with good

yields. These small molecules have multiple reactive sites making them useful in the synthesis of

natural products and other pharmaceuticals.


All of the reactions were performed under Ar in flame-dried glassware. All starting materials,

solvents, reagents, and catalysts were commercially available and used without further

purification, with the exception of N-Bromosuccinimide, which was recrystallized in H2O. The

NMR spectra were recorded with either a 360 or 500 MHz Bruker spectrometer. 1H and 13C

NMR spectra were obtained using CDCl3 as the solvent with chloroform (CHCl3 1H: δ = 7.26

ppm, CDCl3 13C: δ = 77.0 ppm) as the internal standard. Column chromatography was performed

106

using 60-200 µm silica gel. Analytical thin layer chromatography was performed on silica coated

glass plates with F-254 indicator. Visualization was accomplished by UV light (254 nm) and

KMnO4.

General experimental procedure for the formation of -trialkylsilyl--unsaturated

esters: CuI (0.029 g, 0.15 mmol) and LiCl (0.013 g, 0.30 mmol) was placed in a 100 mL round

bottom flask (flame dried under vacuum) under Ar. Dry THF (20 mL) was added and the

mixture was stirred at rt for a period of 0.5 h until complete dissolution had occurred. The clear,

light yellow homogeneous solution was cooled to –78 C, and ethyl propiolate (0.294 g, 3.0

mmol) was added, followed by TMSOTf (3.3 eq., 1.8 mL, 9.9 mmol). After 5 minutes at –78

C, the aryl or alkyl Grignard reagent (1.2 eq., 3.6 mmol) was added dropwise via syringe, and

the solution was stirred at –78 C for 1 h and allowed to warm to rt. The reaction was quenched

with H2O and the product extracted with Et2O (3 x 25 mL), and the combined organic layers

were washed with deionized H2O followed by saturated NH4Cl. The organic layer was

separated, dried with MgSO4, and concentrated in vacuo to give the crude product, which was

then analyzed by 1H NMR spectroscopy to determine diastereoselectivity. Column

chromatography of the crude material (3% ethyl acetate in hexanes) afforded the pure vinyl

silane products.

Ethyl (E)-3-(o-tolyl)-2-(trimethylsilyl)acrylate (3.2a): Yield: 0.692 g, 88%: 1H NMR (500

MHz, CDCl3) 7.15 (m, 4H), 7.03 (s, 1H), 4.08 (q, J = 7.2 Hz, 2H), 2.31 (s, 3H), 1.09 (t, J = 7.2

Hz, 3H), 0.25 (s, 9H).18

Ethyl (E)-3-phenyl-2-(trimethylsilyl)acrylate (3.2b): Yield: 0.684 g, 92%: 1H NMR (500 MHz,

CDCl3) 7.25 (m, 5H), 6.77 (s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H), 0.19 (s,

9H).18

107

Ethyl-(E)-3-(3-methoxyphenyl)-2-(trimethylsilyl)acrylate (3.2c): Yield: 0.734 g, 88%: 1H

NMR (500 MHz, CDCl3) 7.23 (t, J = 7.8 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.89 (s, 1H), 6.83

(dd, J = 8.3, 3.0 Hz, 1H), 6.78 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.79 (s, 3H), 1.23 (t, J = 7.2 Hz,

3H), 0.24 (s, 9H).18

Ethyl-(E)-3-phenyl-2-(trimethylsilyl)but-2-enoate (3.2d): Yield: 0.668 g, 85%: 1H NMR (500

MHz, CDCl3) 7.26 (m, 5H), 3.86 (q, J = 7.2 Hz, 2H), 2.19 (s, 3H), 0.92 (t, J = 7.2 Hz, 3H), 0.28

(s, 9H).18

Ethyl-(E)-3-phenyl-2-(triethylsilyl)acrylate (3.2e): Yield: 0.722 g, 83%: 1H NMR (360 MHz,

CDCl3) 7.31 (m, 5H), 6.79 (s, 1H), 4.18 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H), 1.01 (t, J

= 7.6 Hz, 9H), 0.75 (q, J = 7.6 Hz, 6H).18

Ethyl-(E)-4-methyl-2-(trimethylsilyl)pent-2-enoate (3.2f): Yield: 0.702 g, 82%: 1H NMR (360

MHz, CDCl3) 5.89 (d, J = 9.3 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.92 (m, 1H), 1.29 (t, J = 7.0

Hz, 3H), 1.00 (d, J = 6.6 Hz, 6H), 0.13 (s, 9H).18

Ethyl (E)-3-cyclohexyl-2-(trimethylsilyl)acrylate (3.2g): Yield: 0.46 g, 60%, light yellow oil:

1H NMR (500 MHz, CDCl3) δ 5.93 (d, J = 9.3 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.63 (m, 1H),

1.68 (m, 5H), 1.30 (t, J = 7.1 Hz, 2H), 1.26 (m, 2H), 1.12 (m, 3H), 0.12 (s, 9H). 13C NMR (125

MHz, CDCl3) δ 170.6, 156.4, 133.8, 59.8, 40.3, 32.5, 25.9, 25.6, 14.4, -1.3. IR (NaCl): 2977, 2927,

1713, 1606, 1448, 1263, 1192, 855 cm-1. HRMS (EI-EBE Sector) m/z: [M]+ Calcd for C14H26O2Si

254.1696; found 254.1702. Rf = 0.50, 3% EtOAc in hexanes.

Ethyl-(E)-4-phenyl-2-(trimethylsilyl)but-2-enoate (3.2h): Yield: 0.734 g, 70%: 1H NMR (360

MHz, CDCl3) 7.27 (m, 5H), 6.30 (t, J = 7.0 Hz, 1H), 4.27 (q, J = 7.0 Hz, 2H), 3.74 (d, J = 7.0

Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H), 0.18 (s, 9H).18

108

Ethyl (E)-2-(trimethylsilyl)undec-2-enoate (3.2i): Yield: 0.56 g, 65%, yellow oil: 1H NMR (500

MHz, CDCl3) δ 6.15 (t, J = 7.3 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.35 (m, 2H), 1.43(m, 2H), 1.29

(m, 10H), 1.27 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 6.9 Hz, 3H), 0.13 (s, 9H). 13C NMR (125 MHz,

CDCl3) δ 170.6, 151.8, 135.9, 59.9, 31.9, 31.7, 29.4, 29.3, 29.2, 29.1, 22.7, 14.4, 14.1, -1.3. IR

(NaCl): 2956, 2925, 2871, 2855, 1715, 1464, 1247,1191, 1033, 840, 754. HRMS (EI-EBE Sector)

m/z: [M]+ Calcd for C16H32O2Si 284.2160; found 284.2172. Rf = 0.62, 4% EtOAc in hexanes.

General experimental procedure for the -halogenated--unsaturated esters: In a dark

room, NBS or NCS (0.80 mmol, 140 mg, 2.0 equiv.) was added to a (flame-dried under vacuum)

round-bottom flask under Ar. The flask was covered in aluminum foil and then a solution of vinyl

silane (3.2a-3.2i) (0.40 mmol, 0.10 g, 1.0 equiv.) in anhydrous DMF (1.00 mL) was added in one

portion. The mixture was stirred at rt for a minimum of 24 hours where it was then quenched with

saturated Na2CO3 (1.00 mL) and the product was extracted with CH2Cl2 (3 x 10 mL), and the

combined organic layers were washed with deionized H2O (3 x 10 mL). The organic layer was

dried with MgSO4 and concentrated in vacuo to give the crude product. Column chromatography

of the crude material (3% Et2O in pentane) afforded the pure halogenated products 3.3a-3.3h and

3.4a-3.4c in yields ranging from 58%-91%.

Ethyl (Z)-2-bromo-3-(o-tolyl)acrylate (3.3a): Yield: 0.092 g, 90%, yellow oil. 1H NMR (500

MHz, CDCl3) δ 8.29 (s, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.27 (m, 4H), 4.35 (q, J = 7.1 Hz, 2H), 2.32

(s, 3H), 1.40 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 163.1, 140.6, 137.0, 133.7, 130.1,

129.4, 128.6, 125.6, 115.7, 62.8, 19.9, 14.2. IR (NaCl): 1720, 1481, 1257, 865, 482 cm -1. HRMS

(EI-EBE Sector) m/z: [M]+ Calcd for C12H13BrO2 268.0099; found 238.0105. Rf = 0.39, 3% Et2O

in pentane.

109

Ethyl (Z)-2-bromo-3-phenylacrylate (3.3b): Yield: 0.074 g, 73%, yellow oil. 1H NMR (500

MHz, CDCl3) δ 8.22 (s, 1H), 7.86 (m, 2H), 7.43 (m, 3H), 4.36 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1

Hz, 3H).26

Ethyl (Z)-2-bromo-3-(2-bromo-3-methoxyphenyl)acrylate (3.3c): Yield: 0.060 g, 61%, yellow

solid. 1H NMR (500 MHz, CDCl3) δ 8.27 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 3.0 Hz,

1H), 6.83 (dd, J = 8.8, 3.0 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).

13C NMR (125 MHz, CDCl3) δ 162.8, 158.4, 140.4, 135.2, 133.6, 117.1, 116.7, 115.8, 114.8, 63.0,

55.6, 14.2. IR (NaCl): 1720, 1463, 1280, 1234, 908, 729. HRMS (EI-EBE Sector) m/z: [M]+ Calcd

for C12H12Br2O3 361.9153; found 361.9164. Rf = 0.29, 3% Et2O in pentane.

Ethyl (E)-2-bromo-3-phenylbut-2-enoate (3.3d): Yield: 0.075 g, 70%, clear oil. 1H NMR (500

MHz, CDCl3) δ 7.32 (m, 3H), 7.18 (m, 2H), 3.95 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H), 0.91 (t, J = 7.1

Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 164.9, 147.0, 141.2, 128.3, 128.0, 126.8, 111.1, 61.7,

25.9, 13.4. IR (NaCl): 1288, 1277, 1042, 700. HRMS (EI-EBE Sector) m/z: [M]+ Calcd for

C12H13BrO2 268.0099; found 268.0090. Rf = 0.18, 3% Et2O in pentane.

Ethyl (Z) and (E)-2-chloro-3-phenylacrylate (3.4a): Yield: 0.040 g, 89%, yellow oil. (Z)-

product: 1H NMR (500 MHz, CDCl3) δ 7.91 (s, 1H), 7.63 (d, J = 7.5, 1H), 7.43 (m, 4H), 4.36 (q,

J = 7.1 Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H); (E)-product: 1H NMR (500 MHz, CDCl3) δ 7.30(m, 5H),

7.21 (s, 1H), 4.21 (q, J = 7.2, 2H), 1.18 (t, J = 7.1, Hz, 3H).27, 28

Ethyl (Z)-2-bromo-4-methylpent-2-enoate (3.3e): Yield: 0.069 g, 67%, yellow oil. 1H NMR

(500 MHz, CDCl3) δ 7.08 (d, J = 9.3 Hz, 1H), 4.27 (q, J = 7.1 Hz, 1H), 2.86 (m, 1H), 1.33 (t, J =

7.1 Hz, 2H), 1.09 (d, J = 6.7 Hz, 3H).29

110

Ethyl (Z)-2-bromo-3-cyclohexylacrylate (3.3f): Yield: 0.083 g, 90%, yellow oil. 1H NMR (500

MHz, CDCl3) δ 7.10 (d, J = 9.2 Hz, 1H), 4.27 (q, J = 7.1 Hz, 1H), 2.57 (m, 1H), 1.72 (m, 5H),

1.33 (m, 2H), 1.33 (t, J = 7.1 Hz, 2H), 1.19 (m, 3H).29

Ethyl (Z)-2-bromo-4-phenylbut-2-enoate (3.3g): Yield: 0.082 g, 80%, yellow oil. 1H NMR (500

MHz, CDCl3) δ 7.43 (t, J = 7.3 Hz, 1H), 7.33 (m, 2H), 7.25 (m, 3H), 4.28 (q, J = 7.1 Hz, 2H), 3.70

(d, J = 7.3 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 162.4, 144.0, 137. 2,

128.8, 128.6, 126.9, 117.0, 62.5, 38.4, 14.1. IR (NaCl): 2360, 2341, 1652, 1255, 992, 799. HRMS

(EI-EBE Sector) m/z: [M]+ Calcd for C12H13BrO2 268.0099; found 268.0096. Rf = 0.42, 3% Et2O

in pentane.

Ethyl (Z)-2-bromoundec-2-enoate (3.3h): Yield: 0.059 g, 58%, yellow oil. 1H NMR (500 MHz,

CDCl3) δ 7.29 (t, J = 7.2 Hz, 1H), 4.28 (t, J = 7.1 Hz, 2H), 2.34 (m, 2H), 1.51 (m, 2H), 1.33 (t, J

= 7.1 Hz, 3H), 1.29 (m, 10H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 162.6,

146.3, 116.3, 62.3, 32.1, 31.8, 29.3, 29.3, 29.2, 27.5, 22.6, 14.2, 14.1. IR (NaCl): 2926, 1730, 1718,

1235. HRMS (EI-EBE Sector) m/z: [M]+ Calcd for C13H23BrO2 290.0881; found 290.0882. Rf =

0.45, 3% Et2O in pentane.

Ethyl (Z)-2-chloro-4-methylpent-2-enoate (3.4b): Yield: 0.068 g, 82%, yellow oil. 1H NMR

(500 MHz, CDCl3) δ 6.88 (d, J = 9.4 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.90 (m, 1H), 1.34 (t, J =

7.1 Hz, 3H), 1.08 (d, J = 6.7 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 162.8, 148.3, 122.8, 62.2,

29.1, 21.1, 14.2. IR (NaCl): 1734, 1721, 1251, 1145, 1041, 754 cm -1. HRMS (EI-EBE Sector)

m/z: [M]+ Calcd for C8H13ClO2 176.0604; found 176.0601. Rf = 0.40, 3% Et2O in pentane.

Ethyl (Z)-2-chloro-4-phenylbut-2-enoate (3.4c): Yield: 0.052 g, 80%, yellow oil. 1H NMR (500

MHz, CDCl3) δ 7.33 (m, 2H), 7.23 (m, 3H), 7.22 (t, J = 7.4 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.71

(d, J = 7.4 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 162.4, 140.2, 137.4,

111

128.8, 128.6, 126.8, 125.2, 62.30, 35.6, 14.1. IR (NaCl): 1730, 1268, 1043 cm -1. HRMS (EI-EBE

Sector) m/z: [M]+ Calcd for C12H13ClO2 224.0604; found 224.0605. Rf = 0.27, 3% Et2O in pentane.

112


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-0.50.0

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

f1 (ppm)

9.31

3.13

3.16

2.11

1.004.28

0.25

1.081.091.11

2.31

4.054.074.084.10

7.037.087.087.107.107.117.117.137.157.157.167.177.177.187.197.217.22

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.2a

115

-0.50.0

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

f1 (ppm)

9.18

3.14

2.05

1.00

5.22

0.19

1.141.161.18

4.124.144.164.18

6.777.207.217.227.227.237.237.247.257.257.267.267.277.287.297.297.30

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.2b

116

-0.50.0

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

f1 (ppm)

9.06

3.06

3.12

2.03

0.980.980.971.00

1.00

0.24

1.211.231.24

3.79

4.184.204.214.22

6.786.816.826.836.846.896.926.926.936.937.207.227.23

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.2c117

-0.50.0

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

f1 (ppm)

8.88

3.12

3.00

1.98

5.85

0.28

0.910.920.94

2.19

3.843.853.873.88

7.217.217.227.227.237.237.237.247.247.247.267.267.267.277.287.287.287.287.297.297.30

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.2d

118

-0.50.0

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

f1 (ppm)

6.23

9.23

3.06

2.04

1.00

5.32

0.730.740.760.770.991.011.031.191.211.22

4.164.174.194.20

6.797.267.267.277.277.287.287.297.297.307.317.327.327.327.327.337.347.347.35

The 1H NMR Spectrum (360 MHz, CDCl3) of Compound 3.2e

119

-0.50.0

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

f1 (ppm)

9.13

6.35

3.54

1.05

2.19

1.00

0.13

0.991.001.271.291.31

2.862.882.892.902.912.922.932.942.942.96

4.154.174.194.21

5.885.90

The 1H NMR Spectrum (360 MHz, CDCl3) of Compound 3.2f120

-0.50.0

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

f1 (ppm)

8.76

3.32

5.17

5.44

1.02

2.12

1.00

0.121.041.041.071.081.111.121.141.151.151.171.171.181.191.201.201.241.251.271.281.281.291.301.311.321.641.661.661.691.712.602.612.622.632.642.66

4.174.184.194.21

5.925.94

7.26

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.2g

121

010

2030

4050

6070

8090

100110

120130

140150

160170

180190

200210

220f1 (ppm

)

-1.28

14.37

25.5525.94

32.47

40.27

59.83

76.7577.0077.25

133.78

156.37

170.61

The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.2g

122

-0.50.0

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

f1 (ppm)

9.20

3.34

2.08

2.20

1.00

5.54

0.18

1.331.351.37

3.733.75

4.244.264.284.30

6.286.306.32

7.227.247.257.267.277.317.327.337.35

The 1H NMR Spectrum (360 MHz, CDCl3) of Compound 3.2h

123

-0.50.0

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

f1 (ppm)

8.92

3.26

14.482.33

1.97

2.12

1.00

0.13

0.860.880.891.261.271.281.301.311.43

2.332.342.362.37

4.174.184.204.21

6.146.156.17

7.26

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.2i

124

-100

1020

3040

5060

7080

90100

110120

130140

150160

170180

190200

210220

f1 (ppm)

-1.31

14.0914.37

22.6529.0529.2129.3029.3831.6531.85

59.86

76.7577.0077.25

135.91

151.80

170.52

The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.2i

125

-1.0-0.5

0.00.5

1.01.5

2.02.5

3.03.5

4.04.5

5.05.5

6.06.5

7.07.5

8.08.5

9.09.5

10.0f1 (ppm

)

3.21

3.21

2.09

3.67

1.02

1.00

1.381.401.41

2.32

4.344.364.374.39

7.227.247.257.267.287.287.297.307.317.657.67

8.29

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.3a

126

010

2030

4050

6070

8090

100110

120130

140150

160170

180190

200210

220f1 (ppm

)

14.19

19.89

62.75

76.7577.0077.25

115.73

125.55128.60129.38130.12133.71137.00140.64

163.12

The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.3a

127

-0.50.0

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

f1 (ppm)

3.23

2.06

3.02

1.97

1.00

1.381.391.41

4.344.354.364.38

7.267.427.437.437.447.847.857.857.867.868.22


128

0.00.5

1.01.5

2.02.5

3.03.5

4.04.5

5.05.5

6.06.5

7.07.5

8.08.5

9.09.5

10.0f1 (ppm

)

3.34

3.11

2.20

1.20

1.201.19

1.00

1.381.401.41

3.82

4.354.374.384.40

6.826.826.836.847.267.407.407.497.51

8.27

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.3c

129

010

2030

4050

6070

8090

100110

120130

140150

160170

180190

200210

220f1 (ppm

)

14.18

55.63

62.97

76.7577.0077.25

114.82115.83116.65117.14

133.35135.22140.39

158.40

162.78

The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.3c

130

-0.50.0

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

f1 (ppm)

3.22

2.69

2.00

1.803.13

0.890.910.92

2.32

3.933.943.963.97

7.177.187.187.197.197.267.317.317.327.327.33

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.3d131

010

2030

4050

6070

8090

100110

120130

140150

160170

180190

200210

f1 (ppm)

13.44

25.88

61.73

76.7577.0077.25

111.09

126.78128.01128.29

141.22

147.02

164.94

The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.3d132

-0.50.0

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

f1 (ppm)

6.34

3.17

1.02

2.04

1.00

1.081.091.321.331.35

2.832.842.842.852.862.862.872.88

4.254.264.274.29

7.077.097.26

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.3e

133

0.00.5

1.01.5

2.02.5

3.03.5

4.04.5

5.05.5

6.06.5

7.07.5

8.08.5

9.09.5

10.0f1 (ppm

)

3.72

5.54

5.47

1.04

2.06

1.00

1.161.191.211.321.331.341.671.671.681.701.701.701.711.741.741.762.542.552.562.562.572.572.582.592.60

4.244.264.274.29

7.097.107.26

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.3f134

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

f1 (ppm)

3.29

2.05

2.14

3.532.161.00

1.311.321.34

3.693.70

4.254.274.284.30

7.237.247.247.267.267.277.317.337.347.417.437.44

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.3g

135

010

2030

4050

6070

8090

100110

120130

140150

160170

180190

200210

220f1 (ppm

)

14.14

38.35

62.50

76.7577.0077.25

116.98

126.85128.63128.80

137.22

144.02

162.39

The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.3g

136

-0.50.0

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

f1 (ppm)

3.57

15.51

3.06

1.87

2.00

0.87

0.870.880.901.281.291.301.321.331.351.471.481.501.511.531.542.312.332.342.36

4.254.274.284.29

7.267.277.297.30

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.3h137

010

2030

4050

6070

8090

100110

120130

140150

160170

180190

200210

220f1 (ppm

)

14.0714.17

22.6427.5429.1529.3031.8232.13

62.32

76.7577.0077.25

116.26

146.31

162.57

The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.3h138

0.00.5

1.01.5

2.02.5

3.03.5

4.04.5

5.05.5

6.06.5

7.07.5

8.08.5

9.09.5

10.0f1 (ppm

)

3.70

3.28

2.10

1.66

1.015.123.000.701.150.57

1.161.181.191.371.381.391.391.401.41

4.194.204.214.234.344.354.374.38

7.217.267.287.287.297.297.307.327.327.337.337.347.347.347.397.417.417.427.427.447.617.627.637.637.847.847.857.857.91

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.4a139

-0.50.0

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

f1 (ppm)

5.67

3.71

1.13

2.00

0.92

1.071.091.321.341.35

2.862.882.882.892.902.902.912.922.922.94

4.254.274.284.29

6.876.89


140

010

2030

4050

6070

8090

100110

120130

140150

160170

180190

200210

220f1 (ppm

)

14.16

21.05

29.05

62.16

76.7577.0077.25

122.82

148.26

162.77

The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.4b

141

-0.50.0

0.51.0

1.52.0

2.53.0

3.54.0

4.55.0

5.56.0

6.57.0

7.58.0

8.59.0

9.510.0

f1 (ppm)

3.06

1.89

2.00

4.621.92

1.311.321.34

3.703.71

4.264.274.284.30

7.207.217.227.237.237.257.267.267.277.317.327.347.34

The 1H NMR Spectrum (500 MHz, CDCl3) of Compound 3.4c

142

010

2030

4050

6070

8090

100110

120130

140150

160170

180190

200210

220f1 (ppm

)

14.14

35.62

62.30

76.7577.0077.25

125.19126.82128.61128.80

137.42140.19

162.40

The 13C NMR Spectrum (500 MHz, CDCl3) of Compound 3.4c

143

methodological studies of α

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