ABSTRACT 
 
 
 
 
Title of Dissertation: PALLADIUM-CATALYZED ALLYLIC-
ARYLATION: MECHANISTIC STUDIES AND 
APPLICATION TO THE TOTAL SYNTHESIS OF 
(?)-7-DEOXYPANCRATISTATIN DERIVATIVES  
  
 Krupa H. Shukla, Doctor of Philosophy, 2009 
  
Directed By: Professor Philip DeShong 
Department of Chemistry and Biochemistry 
 
 
Palladium-catalyzed carbon-carbon bond formation is one of the most widely used 
reactions for the synthesis of biologically active substances. The DeShong group has 
demonstrated that hypervalent silicates can be employed for allyl-aryl carbon-carbon 
bond couplings in the presence of a Pd(0) catalyst. The goals of this dissertation are (1) to 
demonstrate application of palladium-catalyzed allylic-arylation coupling to the total 
synthesis of (?)-7-deoxypancratistatin and its analogues, and (2) to study the mechanism 
of allyl-aryl cross coupling reactions. 
In spite of the potent antitumor and antiviral activity of (+)-7-deoxypancratistatin, the 
use of this compound is limited in clinical applications because of its low natural 
abundance and lack of a practical scalable synthetic route. In order to test the feasibility 
of siloxane-based coupling in the synthesis of 7-deoxypancratistatin, a simplified 
analogue of (?)-7-deoxypancratistatin was synthesized. The key reaction in the synthesis 
  
involved stereoselective construction of a carbon-carbon bond between A and C rings via 
coupling of an aryl siloxane with an allylic carbonate.  
While siloxane methodology was successfully applied to the synthesis of a 
(?)-7-deoxypancratistatin analogue, application of this methodology to the natural 
product (?)-7-deoxypancratistatin proved to be a significant challenge. To understand the 
causes of the failure of the coupling reaction, a detailed mechanistic study was 
undertaken. Hammett analysis of the allyl-aryl coupling reaction demonstrated that the 
rate of the coupling reaction was enhanced by electron-withdrawing groups on the aryl 
siloxane. The positive slope of the Hammett plot indicated a charged transition state in 
which negative charge on the aryl ring was stabilized inductively. Furthermore, this study 
provided useful information regarding the nature of ligands on the palladium. Based on 
this study, a new family of Pd(0) olefin catalysts was developed.  These catalysts were 
found to be highly efficient and formed carbon-carbon bond even at ambient temperature.  
Novel Pd(0) olefin complexes were successfully employed in the synthesis of 
(?)-7-deoxypancratistatin. The key coupling reaction of allylic carbonate with aryl 
siloxane produced Hudlicky's intermediate, thus constituting formal total synthesis of the 
actual product. Though the reaction required higher catalytic loading and proceeded in 
moderate yields, the ability of the reaction to work at ambient temperature is 
advantageous for practical synthesis of the natural product. Future studies shall aim at 
optimization of the key coupling reaction and application of this methodology to the 
synthesis of pancratistatin and related derivatives. 
 
  
 
PALLADIUM-CATALYZED ALLYLIC-ARYLATION:  
MECHANISTIC STUDIES AND APPLICATION TO THE TOTAL SYNTHESIS 
OF (?)-7-DEOXYPANCRATISTATIN DERIVATIVES 
 
 
 
By 
 
 
Krupa H. Shukla 
 
 
 
 
 
Dissertation submitted to the Faculty of the Graduate School of the 
University of Maryland, College Park, in partial fulfillment 
of the requirements for the degree of 
Doctor of Philosophy 
2009 
 
 
 
 
 
 
 
 
 
 
Advisory Committee: 
Professor Philip DeShong, Chair 
Professor Jeffery Davis 
Professor Daniel Falvey 
Professor Richard Payne 
Assistant Professor Barbara Gerratana 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
? Copyright by 
Krupa H. Shukla 
2009 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ii 
 
 
 
 
If we knew what it was we were doing, it would not be called research, would it? 
? Albert Einstein 
 
 iii 
 
DEDICATION 
 
 
~ To My Loving Parents ~ 
 
 iv 
 
ACKNOWLEDGMENTS 
I extend my gratitude to my advisor, Professor Philip DeShong for guiding me 
throughout this project. Without his encouragement and guidance it would have been 
impossible for me to accomplish what I have. This research experience has been one of 
the most rewarding and challenging experiences of my life and I am indebted to him. 
The entire DeShong group has been very supportive. I am grateful to all the 
former and current members. Special acknowledgements go to Debra Boehmler, Bridget 
Duvall, William McElroy, and Ju-Hee Park who have been very generous assisting and 
teaching me important lab skills and techniques.  
I thank Yiu-Fai Lam, Yinde Wang, Noel Whittaker and Yue Li for their 
assistance obtaining spectral data. I also thank Professor Christian Wolf and his student 
Hanhui Xu at Georgetown University for their help with microwave experiments. 
Many thanks to Yomi Okunola, An-Ni Chang and Julia Khusnutdinova, my 
friends at the University of Maryland. Special thanks to Julia for suggestions that 
improved this manuscript. I also thank Vasudha and Richa, my high school friends who 
inspired me to stay focused.  I am grateful to my TA Carmen (2003-2004), who 
encouraged me to do undergraduate research and enthused me to pursue doctoral degree. 
Finally, I express my heartfelt gratitude to my lovely family who has always been 
supportive and motivating. I thank my grandparents for their blessings and my parents for 
their endless sacrifices and providing me with the best of everything. I am greatly 
thankful to my sweet brother who has always stood by me and has helped me to the best 
of his abilities. I warmly appreciate my husband for his abundant love, encouragement 
and understanding. Last, but not least, I thank God for turning my dream into reality.  
 
 v 
 
TABLE OF CONTENTS 
LIST OF TABLES ........................................................................................................ VII 
LIST OF FIGURES .....................................................................................................VIII 
LIST OF SCHEMES ....................................................................................................... X 
LIST OF ABBREVIATIONS ..................................................................................... XIV 
CHAPTER 1 
PALLADIUM-CATALYZED ALLYLIC-ARYLATION ............................................ 1 
Introduction..................................................................................................................... 1 
Allylic-Arylation............................................................................................................. 2 
Hiyama-like Coupling................................................................................................. 3 
Suzuki Coupling.......................................................................................................... 7 
Stille Coupling .......................................................................................................... 11 
Conclusion .................................................................................................................... 13 
CHAPTER 2 
TOTAL SYNTHESIS OF (?)-7-DEOXYPANCRATISTATIN ANALOGUE ......... 14 
Introduction................................................................................................................... 14 
Isolation and Biological Activity.............................................................................. 14 
Synthetic Strategies................................................................................................... 17 
(i) Michael Addition ............................................................................................. 19 
(ii) Nucleophilic Addition..................................................................................... 20 
(iii) Electrophilic Aromatic Substitution .............................................................. 21 
(iv) SN2 and SN2? Coupling................................................................................... 22 
(iv) Palladium-Catalyzed Coupling ...................................................................... 26 
(v) Photocyclization.............................................................................................. 27 
Research Goal ............................................................................................................... 28 
Results and Discussion ................................................................................................. 30 
Synthesis of Coupling Partners: Allylic Carbonate and Aryl Siloxane .................... 30 
Coupling of Allylic Carbonate with Aryl Siloxane .................................................. 31 
Generation of B ring and Installation of diol............................................................ 33 
Conclusion .................................................................................................................... 37 
Experimental Details..................................................................................................... 38 
 
 vi 
 
CHAPTER 3 
FORMAL TOTAL SYNTHESIS OF (?)-7-DEOXYPANCRATISTATIN............... 52 
Introduction................................................................................................................... 52 
Results and Discussion ................................................................................................. 54 
Synthesis of Coupling Partners: Allylic Carbonate and Aryl Siloxane .................... 54 
Coupling of Allylic Carbonate with Aryl Siloxane .................................................. 56 
Preliminary Attempts............................................................................................ 56 
Investigation of Problems ..................................................................................... 57 
Successful Coupling.............................................................................................. 63 
Conclusion .................................................................................................................... 68 
Experimental Details..................................................................................................... 69 
CHAPTER 4 
MECHANISTIC STUDIES ON PALLADIUM-CATALYZED ALLYLIC-
ARYLATION .................................................................................................................. 86 
Introduction................................................................................................................... 86 
Transmetalation......................................................................................................... 88 
Hammett Analysis..................................................................................................... 93 
Hiyama Coupling.................................................................................................. 93 
Suzuki Coupling.................................................................................................... 94 
Stille Coupling ...................................................................................................... 96 
Results and Discussion ................................................................................................. 98 
Hammett Analysis..................................................................................................... 98 
Role of Ligands....................................................................................................... 108 
Conclusion .................................................................................................................. 119 
Experimental Details................................................................................................... 120 
REFERENCES.............................................................................................................. 129 
 
 
 
 vii 
 
LIST OF TABLES 
CHAPTER 2 
Table 2.1: Reported total syntheses of the Amaryllidaceae isocarbostyrils. Adapted 
from ref 76. ................................................................................................. 18 
CHAPTER 4 
Table 4.1: Summary of Hammett studies ..................................................................... 98 
Table 4.2: Role of ligands in the allyl-aryl coupling reaction .................................... 110 
Table 4.3: Optimization of Pd(0)-olefin catalyzed allyl-aryl coupling reaction......... 116 
 
 
 
 viii 
 
LIST OF FIGURES 
CHAPTER 1 
Figure 1.1: Catalysts for coupling of allylic substrates with aryl boronic acid 
derivatives................................................................................................... 10 
CHAPTER 2 
Figure 2.1: Structure of Amaryllidaceae alkaloids ....................................................... 14 
Figure 2.2: Signaling pathways to apoptosis. Redrawn from ref 72............................. 15 
Figure 2.3: Relative stereochemistry confirmed from correlation with 1H NMR 
coupling constants ...................................................................................... 36 
CHAPTER 3 
Figure 3.1: Pd(NBD)(MAH) and Pd(COD)(NQ) complexes....................................... 62 
Figure 3.2: 1H-1H COSY of carbamate 49 (Hudlicky's intermediate).......................... 64 
CHAPTER 4 
Figure 4.1: Espinet's model for transmetalation in Stille reaction................................ 89 
Figure 4.2: Transmetalation of alkyl boranes ............................................................... 90 
Figure 4.3: Hammett analysis of the reaction of diaryl(difluoro)silanes with 
iodobenzene. Taken from ref 156............................................................... 94 
Figure 4.4: Hammett analysis of the reaction of arylboronic acid with E-bromostilbene. 
Taken from ref 157. .................................................................................... 95 
Figure 4.5: Palladacycles used in Hammett analysis of arylboronic acid with aryl 
bromides ..................................................................................................... 96 
Figure 4.6: Hammett analysis of Stille coupling reaction in absence of LiCl. Taken 
from ref 165. ............................................................................................... 97 
Figure 4.7: Hammett analysis of Stille coupling reaction in presence of LiCl. Taken 
from ref 165. ............................................................................................... 97 
 
 ix 
 
Figure 4.8: 19F NMR spectra of silicate formation (a) TBAF in THF at 29 ?C (b) 19F 
NMR spectrum of silicate complexes resulting from 1:1 mixture of TBAF 
and Triethoxyphenylsilane at 29 ?C. Insert is 19F signal at ? -121 after 
cooling to -28 ?C. ..................................................................................... 101 
Figure 4.9: Summary of relative rates of coupling reactions with siloxane derivatives
.................................................................................................................. 103 
Figure 4.10: Hammett analysis of allyl-aryl coupling reaction .................................. 104 
Figure 4.11: Donor-Acceptor model for transition-metal-olefin complexes. Redrawn 
from ref 190. ............................................................................................. 112 
Figure 4.12: Various alkenyl ligands.......................................................................... 113 
Figure 4.13: Pd(NBD)(MAH), Pd(COD)(MAH) and Pd(COD)(TCNE) complexes. 114 
Figure 4.14: Pd(COD)(NQ), Pd(COD)(BQ), Pd(COD)(DQ), Pd2(NBE)2(BQ)2 
complexes ................................................................................................. 117 
Figure 4.15: 29Si NMR spectrum of silicate formation at -28 ?C. .............................. 125 
Figure 4.16: Effect of temperature on silicate formation (19F NMR spectrum). Mixture 
of TBAF and phenyltriethoxysilane (a) 10 min, at rt. (b) 2 h 25 min, at 
-30 ?C. (c) 2 h 40 min, at rt. (d) 4 h 55 min, at -30 ?C. ............................ 127 
Figure 4.17: Effect of TBAF concentration on silicate formation (19F NMR spectrum) 
(a) 0.5 equiv. TBAF, 1.0 equiv. siloxane. (b) 1.0 equiv. TBAF, 1.0 equiv. 
siloxane. (c) 1.5 equiv. TBAF, 1.0 equiv. siloxane. (d) 2.0 equiv. TBAF, 
1.0 equiv. siloxane.................................................................................... 128 
 
 
 
 x 
 
LIST OF SCHEMES 
CHAPTER 1 
Scheme 1.1...................................................................................................................... 1 
Scheme 1.2...................................................................................................................... 2 
Scheme 1.3...................................................................................................................... 3 
Scheme 1.4...................................................................................................................... 4 
Scheme 1.5...................................................................................................................... 4 
Scheme 1.6...................................................................................................................... 5 
Scheme 1.7...................................................................................................................... 6 
Scheme 1.8...................................................................................................................... 7 
Scheme 1.9...................................................................................................................... 7 
Scheme 1.10.................................................................................................................... 8 
Scheme 1.11.................................................................................................................... 8 
Scheme 1.12.................................................................................................................... 9 
Scheme 1.13.................................................................................................................... 9 
Scheme 1.14.................................................................................................................... 9 
Scheme 1.15.................................................................................................................. 11 
Scheme 1.16.................................................................................................................. 12 
Scheme 1.17.................................................................................................................. 12 
Scheme 1.18.................................................................................................................. 13 
CHAPTER 2 
Scheme 2.1.................................................................................................................... 19 
Scheme 2.2.................................................................................................................... 20 
Scheme 2.3.................................................................................................................... 21 
 
 xi 
 
Scheme 2.4.................................................................................................................... 22 
Scheme 2.5.................................................................................................................... 23 
Scheme 2.6.................................................................................................................... 24 
Scheme 2.7.................................................................................................................... 25 
Scheme 2.8.................................................................................................................... 25 
Scheme 2.9.................................................................................................................... 26 
Scheme 2.10.................................................................................................................. 27 
Scheme 2.11.................................................................................................................. 27 
Scheme 2.12.................................................................................................................. 28 
Scheme 2.13.................................................................................................................. 28 
Scheme 2.14.................................................................................................................. 29 
Scheme 2.15.................................................................................................................. 30 
Scheme 2.16.................................................................................................................. 31 
Scheme 2.17.................................................................................................................. 31 
Scheme 2.18.................................................................................................................. 32 
Scheme 2.19.................................................................................................................. 34 
Scheme 2.20.................................................................................................................. 34 
Scheme 2.21.................................................................................................................. 35 
CHAPTER 3 
Scheme 3.1.................................................................................................................... 52 
Scheme 3.2.................................................................................................................... 52 
Scheme 3.3.................................................................................................................... 53 
Scheme 3.4.................................................................................................................... 53 
Scheme 3.5.................................................................................................................... 54 
Scheme 3.6.................................................................................................................... 55 
 
 xii 
 
Scheme 3.7.................................................................................................................... 55 
Scheme 3.8.................................................................................................................... 56 
Scheme 3.9.................................................................................................................... 57 
Scheme 3.10.................................................................................................................. 58 
Scheme 3.11.................................................................................................................. 59 
Scheme 3.12.................................................................................................................. 60 
Scheme 3.13.................................................................................................................. 60 
Scheme 3.14.................................................................................................................. 61 
Scheme 3.15.................................................................................................................. 63 
Scheme 3.16.................................................................................................................. 64 
Scheme 3.17.................................................................................................................. 66 
Scheme 3.18.................................................................................................................. 66 
Scheme 3.19.................................................................................................................. 67 
Scheme 3.20.................................................................................................................. 67 
CHAPTER 4 
Scheme 4.1.................................................................................................................... 86 
Scheme 4.2.................................................................................................................... 87 
Scheme 4.3.................................................................................................................... 88 
Scheme 4.4.................................................................................................................... 90 
Scheme 4.5.................................................................................................................... 91 
Scheme 4.6.................................................................................................................... 92 
Scheme 4.7.................................................................................................................... 93 
Scheme 4.8.................................................................................................................... 93 
Scheme 4.9.................................................................................................................... 95 
Scheme 4.10.................................................................................................................. 96 
 
 xiii 
 
Scheme 4.11.................................................................................................................. 99 
Scheme 4.12................................................................................................................ 100 
Scheme 4.13................................................................................................................ 105 
Scheme 4.14................................................................................................................ 118 
Scheme 4.15................................................................................................................ 126 
 
 
 xiv 
 
LIST OF ABBREVIATIONS 
Ac acetyl 
acac acetylacetonate 
aq. aqueous 
Ar aryl 
Bn benzyl 
BQ 1,4-benzoquinone 
Bu butyl 
Bz benzoyl 
calcd calculated 
COD 1,5-cyclooctadiene 
COSY correlation spectroscopy 
Cy cyclohexyl 
CBz carboxybenzyl 
dba dibenzylideneacetone 
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene 
DQ duroquinone 
DCN 1,4-dicyanonaphthalene 
DIPHOS 1,2-bis(diphenylphosphino)ethane 
DMAP 4-dimethylaminopyridine 
DMF N,N-dimethylformamide 
DMSO dimethyl sulfoxide 
E ester 
EDG electron-donating group 
ee enantiomeric excess 
EI electron ionization 
equiv. equivalent(s) 
Et ethyl 
Et2O diethyl ether 
ESI electrospray ionization 
EWG electron-withdrawing group 
FAB fast atom bombardment 
FT fourier transform 
Fu furyl 
GC gas chromatography 
 
 xv 
 
h hour(s) 
HMPA hexamethylphosphoramide 
HPLC high performance liquid chromatography 
HRMS high resolution mass spectrometry 
HSQC heteronuclear single quantum coherence 
Hz Hertz 
i-Pr isopropyl 
IR infrared 
J coupling constant 
L ligand 
LRMS low resolution mass spectrometry 
m meta 
M+ molecular ion 
m/z mass-to-charge ratio 
MAH maleic anhydride 
m-CPBA meta-chloroperoxybenzoic acid 
Me methyl 
MeCN acetonitrile 
MHz Megahertz 
min minute 
MOM methoxymethyl 
mp melting point 
MS mass spectrometry 
NBD norbornadiene 
NBE norbornene 
NMO N-methylmorpholine-N-oxide 
NMP N-methyl-2-pyrrolidone 
NMR nuclear magnetic resonance 
NQ 1,4-naphthoquinone 
Nu nucleophile 
o ortho 
OAc acetate 
OBz benzoate 
p para 
PEG poly(ethylene glycol) 
Ph phenyl 
PMB p-methoxybenzyl 
 
 xvi 
 
Rf retention factor 
SAR structure activity relationship 
satd saturated 
rt room temperature 
t-Bu tertiary butyl 
TBAF tetrabutylammonium fluoride 
TBAB tetrabutylammonium bromide 
TBAT tetrabutylammonium triphenyldifluorosilicate 
TBS t-butyldimethylsilyl 
TCNE tetracyanoethylene 
Tf trifluoromethanesulfonyl 
TFA trifluoroacetic acid 
TFP tri-2-furylphosphine 
THF tetrahydrofuran 
TLC thin layer chromatography 
TIPS triisopropylsilyl 
TMS trimethylsilyl 
Ts tosyl 
UV ultra violet 
 
 1 
 
CHAPTER 1 
PALLADIUM-CATALYZED ALLYLIC-ARYLATION 
INTRODUCTION 
Palladium-catalyzed carbon-carbon bond formation is one of the most 
synthetically important and versatile reactions in the chemist's repertoire.1,2 The two most 
commonly used metal derivatives used in coupling include boron (Suzuki coupling)3 and 
tin (Stille coupling)4 (Scheme 1.1). The limitations associated with boron reagents 
include synthesis of the boronic acid derivatives, homocoupling and incompatibility with 
Lewis basic functions. While Stille coupling offers functional group tolerance, it is 
limited in pharmaceutical applications due to the toxicity of tin reagents and the removal 
of the trace tin byproducts.  
Scheme 1.1 
I
OMe
Ph?SnBu3
Ph?B(OH)2
OMe
Ph
Stille Coupling
Suzuki Coupling
Pd(0)
Ph?Si(OEt)3
Hiyama-like Coupling
 
In contrast, silicon-based coupling (Hiyama coupling)5-9 offers a viable alternative 
to other coupling technologies because of the low cost, low toxicity and chemical 
stability of silicon-derived compounds.10,11 Hiyama demonstrated that the coupling of 
aryl fluorosilanes with aryl iodides and bromides proceeded in moderate to good yields. 
 
 2 
 
Recently, the DeShong group developed siloxane methodology, which utilizes 
hypervalent siloxane derivatives in the presence of a palladium catalyst to form an 
aryl-aryl carbon bond.12-16 Subsequently, an efficient cross-coupling of aryl bromides and 
chlorides with aryl siloxanes using the palladium/imidazolium catalytic system was 
reported by Lee.17 Aryl siloxanes have also been used in aqueous systems by Wolf.18 
More recently, Clarke reported the first microwave accelerated Hiyama-like coupling of 
aryl siloxanes with aryl halides.19 Not only are siloxanes less toxic than Stille reagents, 
they are also quite stable, easily prepared and purified.20,21 Recently, the use of aryl 
silanols and aryl silanolates as efficient coupling partners has emerged as reported by 
Denmark.22-25  
ALLYLIC-ARYLATION 
In addition to aryl-aryl cross-coupling reaction, organometallic reagents of 
silicon, boron and tin can be used to construct the allyl-aryl bond (Scheme 1.2). In most 
cases, allyl halides or allyl carboxylates, prepared from the corresponding alcohols, are 
used as allylating agents.  
Scheme 1.2 
Ph?SnBu3
Ph?B(OH)2
Ph
Stille Coupling
Suzuki Coupling
Pd(0)
Ph?Si(OEt)3
Hiyama-like Coupling
OR
 
 
 3 
 
Organometallic reagents are unstabilized nucleophiles (pKa > 25) and follow the 
general mechanism outlined in the Scheme 1.3.26 Allyl benzoate 1 reacts with Pd(0) to 
give the ?-allyl Pd intermediate 2, with inversion of configuration. Next, the aryl group is 
transferred from the organometallic species 3 onto the Pd via transmetalation to form the 
Pd(II) intermediate 4. Subsequent reductive elimination from the same face as the 
palladium generates 5 with overall inversion at the reaction center. Note that the ?-allyl 
Pd intermediate 4 is a meso compound. Therefore, reductive elimination could also result 
in formation of ent-5.  
Scheme 1.3 
BzO
Pd OBz
2
Pd(0)
1
Ph
Pd Ph
5
Ph-M
3
4
 
Hiyama-like Coupling 
Palladium-catalyzed coupling of allylic carbonate with aryl and vinyl 
fluorosilanes was reported by Hiyama and Hatanaka (Scheme 1.4).27 This reaction 
proceeded without fluoride ion activation; however the reaction suffered from poor 
 
 4 
 
yields. Moreover, the synthesis of fluorosilanes involves multiple steps and fluorosilanes 
are hydrolytically unstable. Subsequently, Hiyama examined the coupling reaction of 
allylic and benzylic carbonate with an organo[2-(hydroxymethyl)phenyl]dimethylsilane 
in the absence of any activator (Scheme 1.5).28 Upon treatment with a mild base (K2CO3), 
the proximal hydroxyl group gets converted to an alkoxide and coordinates to the nearby 
silicon atom to produce a five-membered penta-coordinated silicate species. In 
comparison to fluorosilanes, this tetraorganosilicon reagent is highly stable. 
Scheme 1.4 
OCO2Et
Pd2(dba)3?CHCl3
PPh3, 60 ?C, 40%
SiEtF2
 
Scheme 1.5 
Pd2(dba)3, P(2-thienyl)3
OCO2t-Bu Me
2Si
OH
CuOAc, 70 ?C, 75%
 
In an effort to extend the viability of silicon-based coupling, the DeShong group 
developed the palladium-catalyzed allylic-arylation methodology as depicted in the 
Scheme 1.6.29-34 Phenyltriethoxysilane 6 when treated with tetrabutylammonium fluoride 
(TBAF), generated in situ hypervalent species 7. This hypervalent reagent 7 reacted with 
allylic benzoate 8 to give cyclohexene 9. This methodology has been shown to efficiently 
transfer a wide variety of aryl groups to allylic esters in excellent yields (70-95%).32 
 
 5 
 
 In more complex systems such as allylic benzoate 10, there are regiochemical as 
well as a stereochemical issues (Scheme 1.6). The reaction of aryl siloxane 6 with allylic 
carbonate 10 forms two regioisomers 11 and 12 with an overall inversion of 
stereochemistry. The origin of regioselectivity and stereoselectivity can be understood 
from the mechanism shown in the Scheme 1.7. 
When allylic benzoate 10 reacts with palladium, the benzoate group is displaced 
by palladium from the opposite face (inversion) to form ?-allyl intermediate 13.  Next, 
the aryl group is transferred from the hypervalent silicate species 7 onto Pd via 
transmetalation to give ?-allyl intermediate 14. The resulting ?-allyl intermediate 14 is 
?unsymmetrical? since palladium is pushed away from the methyl group to minimize 
steric interactions. Reductive elimination therefore occurs predominantly on C1 from the 
same face (retention) as palladium to obtain 11 as the major product with a net inversion 
of configuration at the allylic carbon.  
Scheme 1.6 
OBz
OBz
Me
Me
Ph
Me
Ph
Ph
Major Minor
Ph?Si(OEt)3 TBAF
Ph Si
OEt
F
OEt
OEt
6 7
8
Pd(0) 9
10 11 12
95%
 
 
 6 
 
Scheme 1.7 
Ln
OBz
Me
MePd
Ln
MePdPhMeH
H H
Pd LnPh
Me
Ph
Me
Ph
1 3
Major Minor Pd(0)
1
3
10
13
1
3
1
3
14
11 12
Ph Si
OEt
F
OEt
OEt
7  
Recently, Pd(0) nanoparticle (generated in situ) catalyzed cross-coupling of allyl 
acetates and aryl and vinyl siloxane has been reported (Scheme 1.8).35 It is postulated that 
Pd(II) is reduced to Pd(0) by allyl acetate and TBAB (tetrabutylammonium bromide) 
stabilizes Pd(0) nanoparticles. The reaction is applicable to a variety of unactivated and 
activated allyl acetates (Baylis-Hillman acetate adducts) and organosiloxanes. This 
reaction is highly regioselective providing straight chain olefins through coupling from 
the less substituted carbon. Moreover, the nanoparticles can be recovered after reaction 
and remain appreciably active through three catalytic cycles. However, this reaction has 
not been applied to cyclic allylic substrates.  
Activated allyl acetates (Baylis-Hillman acetate adducts derived from methyl 
acrylate, acrylonitrile, acyclic and cyclic ?,?-unsaturated ketones) have also shown to 
couple with aryl siloxane in poly(ethylene glycol) (PEG) by Kabalka.36 
 
 7 
 
Scheme 1.8 
CO2Me
OAc
Si(OMe)3
PdCl2, TBAB
TBAF, THF, 65 ?C, 75%
OAc
CO2Me
Si(OMe)3
PdCl2, TBAB
TBAF, THF, 65 ?C, 80%
 
Suzuki Coupling 
The coupling of sodium tetraphenylborate with allylic acetate (Scheme 1.9) was 
demonstrated by Fiaud and Legros.37 However, the reaction was limited to the transfer of 
phenyl groups.  
Scheme 1.9 
NaBPh4
Pd(dba)2, PPh3
60 ?C, 80%
OAc Ph
 
A breakthrough in this field of boron-based coupling was achieved by 
Moreno-Ma?as who reported coupling of aryl boronic acids with allyl bromides in 
refluxing benzene using Pd(dba)2 as catalyst (58-91% yield)38 and by Hayashi who 
coupled aryl boronic acids with allyl acetates using a resin-supported palladium catalyst 
under basic conditions in water (45-99% yield).39 
A practical and stereoselective synthesis of C-arylglycosides by coupling of 
arylboronic acid and peracetylated glycols in the presence of catalytic Pd(OAc)2  was 
reported by Maddaford (Scheme 1.10).40  In this case, the regioselectivity is governed by 
 
 8 
 
the electronic effect of the oxygen functionality and is limited to this specific substrate 
apparently since the galacto analogue did not undergo coupling. 
Scheme 1.10 
PhB(OH)2
Pd(OAc)2, MeCN
rt,  82%
O
OAc
AcO
AcO
OAcO
AcO
Ph
 
Balme and co-workers have developed a novel catalytic system [PdCl2(TFP)2] 
(TFP ? tri-2-furylphosphine) of allyl acetates with a variety of aryl boronic acids in the 
presence of fluoride (Scheme 1.11).41 The reaction displays excellent regioselectivity and 
stereoselectivity as evident by the formation of a single coupling product with 
E-geometry. The reaction also works well with cyclic allyl acetates. [PdCl2(TFP)2] has 
been shown to also couple pinacol aryl and vinyl boronates to allyl acetates in moderate 
to good yields by Ortar (Scheme 1.12).42 
Scheme 1.11 
OAc B(OH)2
[PdCl2(TFP)2], KF
MeOH, rt, 86%
B(OH)2
[PdCl2(TFP)2], KF
MeOH, rt, 78%
OAc
 
 
 9 
 
Scheme 1.12 
OAc B
[PdCl2(TFP)2], KF
MeOH, rt, 82%
OO
 
Mino and co-workers reported palladium-catalyzed coupling of allylic acetates 
with boronic acids at room temperature in the presence of Pd(OAc)2 and phosphine-free 
hydrazone ligand to produce allyl benzene derivatives in good yields (Scheme 1.13).43 
Scheme 1.13 
OAc B(OH)2
+
NN NN
R
R
R
RR = (CH
2)5
Pd(OAc)2, K2CO3
DMF-H2O, rt, 94%  
Scheme 1.14 
Me
B(OH)2OAc
Bu MeBu
N
N
Pd
OAc
SbF6
?/? 100:0, E/Z>20
60 ?C, 65%, 97% ee
1, 2-dichloroethane
 
Air-tolerable allyl-aryl coupling reaction in the presence of palladium catalyst was 
reported by Sawamura recently.44 The reaction of optically active allyl acetates with 
phenylboronic acid in the presence of Pd(OAc)2, 1,10-phenanthroline and AgSbF6 gave 
 
 10 
 
coupling product in good yields. The reaction takes place with excellent ? to ? chirality 
transfer and syn-selectivity (Scheme 1.14). 
Some of the other catalysts developed for coupling of allylic substrates with 
arylboron derivatives are shown in Figure 1.1.45-47 N-Heterocyclic carbene palladium 
complex I is able to catalyze reaction of activated allyl chlorides with arylboronic acid at 
room temperature.45 Despite the presence of ?-hydrogens in the allylic substrate, the 
coupling of allylic substrates proceeded to give excellent yields of coupling products. 
N?jera introduced a thermally stable catalyst, di(2-pyridyl)methylamine-based Pd(II) 
complex II which can function in aqueous conditions.46 The coupling reaction of allylic 
substrates (allylic chlorides, allylic acetates, allylic carbonates) with arylboronic acids 
occurred in refluxing water or at room temperature in aqueous acetone to provide 
coupling products in good yields. Recently, N?jera and co-workers cross-coupled allyl 
chlorides with potassium aryltrifluoroborates using an oxime-derived palladacycle III in 
aqueous acetone at room temperature or 50 ?C.47 In comparison to toxic and pyrophoric 
phosphines, the coupling protocol employed by these catalysts (Figure 1.1) is 
user-friendly and environmentally benign.  
N N
Pd
(OAc)2
N
NHCONHCy
N
Pd
ClCl
HO Pd
N
Me
OH
2
I II III  
Figure 1.1: Catalysts for coupling of allylic substrates with aryl boronic acid derivatives 
Recently, cross-coupling of allylic alcohol with aryl and vinyl boronic acids in 
organic as well as aqueous solvents have emerged.48-51 Also, microwave assisted 
 
 11 
 
allylic-arylations have been reported.52,53 Apart from palladium-catalyzed 
allylic-arylation using boron reagents, nickel-catalyzed54,55 and rhodium-catalyzed56 
coupling reactions are also known in the literature.  
Stille Coupling 
Stille performed palladium-catalyzed reaction of allylic acetates with aryl and 
vinyl stannanes (Scheme 1.15).57 However, the reaction gave poor yields when used for 
cyclic allyl acetates. Later, Echavarren reported palladium-catalyzed cross-coupling 
reaction of allylic carbonates with organostannanes.58  
Scheme 1.15 
CO2Me
OAc
PhSnMe3 CO2Me
Ph
Pd(dba)2, PPh3
55 ?C, 47%  
In an effort to improve the yield of these couplings, the effect of polarity of the 
solvent on stereoselective coupling reaction of allyl chlorides and aryl stannane was 
reported by Kurosawa (Scheme 1.16).59 In the presence of weakly coordinating solvents 
such as benzene, acetone, CH2Cl2 or THF retention of configuration 15 was observed. 
However, nearly complete inversion 16 was observed in coordinating solvents such as 
DMSO or MeCN indicating a change of mechanism in the presence of strongly donor 
ligands on the metal. 
 
 12 
 
Fairlamb has reported a new bromosuccinimido-Pd catalyst 17 synthesized from 
Pd2(dba)3?CHCl3 for the coupling of allylic and benzylic bromides with vinyl stannanes 
(Scheme 1.17).60  
Scheme 1.16 
CO2Me
Cl
CO2Me
Ph
Pd(0)
CO2Me
Ph
SnBu3
96 4
0 100
Benzene
Acetonitrile
15 16
 
Scheme 1.17 
Pd
PPh3
PPh3
Br
N
O
OBu3Sn CO2Et
Br
17
62%
CO2Et
 
Due to high tolerance towards most functional groups, allyl-aryl Stille coupling 
reaction has been employed in the construction of a variety of ring systems in highly 
functionalized molecules.61,62 Although the Stille coupling is tolerated by many 
functional groups, the reaction suffers from several limitations. The tin (IV) derivatives 
are toxic, the removal of tin byproducts is difficult and the coupling exhibits moderate 
stereoselectivities.29 For example, the coupling of allylic benzoate 18 with hypervalent 
silicate (TBAT) resulted in the stereoselective formation of regioisomers 19 and 20. 
Moreover, high regioselectivity was observed, evident by the formation of the major 
 
 13 
 
regioisomer 19. However, coupling of allylic benzoate 18 using Stille reaction conditions 
gave mixture of several products (Scheme 1.18).  
Scheme 1.18 
O
Me
Ph O
Me
Ph
19 20
O
Me
Ph O
Me
Ph
19 20
O
Me
Ph O
Me
Ph
21 22
O
OBz
Me
TBAT
PhSnMe3
Pd(0), 65%
Pd(0), 65%
19:20 = 15:1
18
LiCl
19:20:21:22 = 15:4:1:2  
CONCLUSION 
Palladium-catalyzed cross-couplings utilizing hypervalent silicate anions have 
several advantages compared to Stille and Suzuki coupling reactions. These include mild 
reaction conditions, stability, low toxicity and ease of preparation of silicon reagents. 
Moreover, allyl-aryl cross-coupling reaction involving siloxane methodology results in 
stereospecific arylation with net inversion of configuration. The succeeding chapters will 
demonstrate how palladium-catalyzed allylic-arylation methodology involving 
hypervalent silicates has been applied to the synthesis of natural product 
7-deoxypancratistatin and its derivatives.  
 
 14 
 
CHAPTER 2 
TOTAL SYNTHESIS OF 
(?)-7-DEOXYPANCRATISTATIN ANALOGUE 
INTRODUCTION 
O
O NH
O
HO
OH
OH
OH
R
23, pancratistatin, R = OH
24, 7-deoxypancratistatin, R = H
A B
C
7
O
O NH
O
OH
OH
OH
R
25, narciclasine, R = OH
26, 7-deoxynarciclasine, R = H
A B
C
7
O
O N
OH
A B
HO
C
27, lycorine
 
Figure 2.1: Structure of Amaryllidaceae alkaloids 
Isolation and Biological Activity 
Amaryllidaceae alkaloids (Figure 2.1) have been recognized for a long time 
because of their medicinal value. Among various alkaloids isolated from Amaryllidaceae 
species, (+)-pancratistatin (23) shows the most promising biological activity. 
Pancratistatin was first isolated and extracted from the Hawaiian daffodil bulb 
Pancratium littorale (also known as Hymenocallis littorale) in a low yield of 0.014% dry 
weight.63 Since, many related analogues have been isolated including the less toxic 
analogue, (+)-7-deoxypancratistatin (24).64 This deoxygenated analogue (24) was isolated 
from the roots of the bulbs Haemanthus kalbreyeri and is eight to thirty-two times less 
toxic65 and about ten fold less potent than pancratistatin (23).66 
The U.S. National Cancer Institute identified the potent anticancer activity of 
(+)-pancratistatin (23) in early 1980s.67,68 Pancratistatin (23) was shown to inhibit growth 
 
 15 
 
of numerous cell lines including leukemia and ovarian sarcoma. Recently, Pandey and 
co-workers have shown that pancratistatin selectively induces apoptosis in various types 
of cancer cell lines (breast, colon, prostrate, neuroblastoma, melanoma and leukemia) at 
micro molar concentrations.69-71 
Apoptosis (programmed cell death) can be activated through intrinsic or extrinsic 
pathway (Figure 2.2).71,72 In intrinsic pathway, disruption of mitochondrial membrane 
followed by release of cytochrome c activates caspase-3. The extrinsic pathway is 
initiated by receptor/ligand binding that ultimately leads to an activation of caspase-3. 
Caspase-3 activates deoxyribonuclease to cause DNA fragmentation and consequently 
apoptosis. Conventional anticancer therapies (chemotherapy and radiotherapy) trigger 
intrinsic pathway by inducing DNA damage. However, these treatments carry risk of 
DNA damage and mutations in non-cancerous cells. 
Cytochrome c APAF1+
Caspase 3 Caspase 9Caspase 8
Cell Death
IAP
BCL2
Apoptotic stimulus
(chemotherapy, UV)
Death
Ligand
De
ath
Re
ce
pto
r
BID
Mitochondrion
Intrinsic
Extrinsic
 
Figure 2.2: Signaling pathways to apoptosis. Redrawn from ref 72.  
 
 16 
 
To understand the selectivity of (+)-pancratistatin (23), Pandey and co-workers 
studied the mechanism of the action of pancratistatin in human leukemia cell line.71 
These studies suggested a possible interaction between pancratistatin, caspase-3 and Fas 
receptor within the plasma membrane to induce apoptosis. It is postulated that high 
expression of Fas receptors or the presence of caspase-3 in the plasma membrane in 
leukemia cells might be responsible for the selective targeting of cancer cells. 
Additionally, an early increase in caspase-3 activity and intact mitochondrial membrane 
potential upon treatment with pancratistatin indicated involvement of an extrinsic 
pathway in apoptosis. Interestingly, DNA fragmentation did not occur prior to caspase-3 
activation, indicating that pancratistatin's target is non-genomic.  
Apart from potent antitumor activity, (+)-pancratistatin (23) and 
(+)-7-deoxypancratistatin (24) also possess antiviral activity.65 Antiviral activity was 
observed against RNA flaviviruses (Japanese encephalitis, yellow fever and dengue) and 
bunya viruses (Punta Toro and Rift Valley viruses).  
 In spite of its interesting biological profile, (+)-pancratistatin (23) and 
(+)-7-deoxypancratistatin (24) have found limited clinical application because of their 
low natural abundance and lack of practical synthetic route. Therefore, there is a need to 
design a practical scalable route for the preparation of multigram quantities of antitumor 
alkaloids (23) and (24). Several unnatural derivatives and analogues have been subjected 
to SAR (structure activity relationship) to identify the pharmacore. However, none of 
these are as potent as natural products (+)-pancratistatin (23) and 
(+)-7-deoxypancratistatin (24), indicating the necessity of the entire structure.73-76 
 
 17 
 
Synthetic Strategies 
In addition to interesting biological activity, (+)-pancratistatin (23) and 
(+)-7-deoxypancratisatin (24) natural products have drawn considerable attention because 
of their structural complexity. The structure of (23) and (24) involves a highly 
functionalized cyclohexyl ring (C ring) with six contiguous stereocenters coupled through 
a carbon-carbon bond to a flat aromatic (A ring), with a trans-fused lactam forming the B 
ring of the molecule (Figure 2.1).  
There are numerous reports towards the total syntheses of this compounds 
(Table 2.1).73-93 The first total synthesis of racemic pancratistatin (23) was reported by 
Danishefsky in 198977, followed by the first asymmetric synthesis of pancratistatin by 
Hudlicky in 1995.78 Moreover, Pettit has developed synthesis of (+)-pancratistatin from 
(+)-narciclasine because of higher natural abundance of narciclasine in plant extracts.84 
There have been attempts to synthesize simplified analogues and derivatives of 
pancratistatin as well.73-75 Despite these efforts, none of these approaches are suitable for 
commercially viable synthesis of  pancratistatin (23) and 7-deoxypancratistatin (24). The 
majority of the synthetic routes that have been reported to date are too long or low 
yielding for practical preparations of the natural product (Table 2.1). Besides a short 
10-step relay synthesis of (+)-pancratistatin from (+)-narciclasine by Pettit, only three 
other syntheses (Hudlicky, Madsen, Li) involve less than 15 steps (a number suggested 
by Hudlicky for synthetic practical applications). Though the syntheses of Hudlicky 
(entries 2, 11 and 12) and Madsen (entry 13) are comparatively short, they are rather low 
yielding. The shortest synthesis so far is that reported by Li's group (entry 9). The 
synthesis proceeds in 13 steps with 9% overall yield, however, uses expensive (+)-pinitol 
 
 18 
 
as the starting material. Based on these criteria, none of the reported strategies are 
efficient for practical applications.  
Entry Isocarbostyril Year Author no. of stepsa Yield (%) 
1 (?)-pancratistatin 1989 Danishefsky 27 0.16 
2 (+)-pancratistatin 1995 Hudlicky 14 2 
3 (+)-pancratistatin 1995 Trostb 19 8 
4 (+)-pancratistatin 1997 Haseltine 24 0.97 
5 (+)-pancratistatin 1998 Magnus 22 1.2 
6 (+)-pancratistatin 2000 Rigby 23 0.35 
7 (+)-pancratistatin 2001 Pettitc 10 3.6 
8 (?)-pancratistatin 2002 Kim 21 4 
9 (+)-pancratistatin 2006 Li 13 9 
10 (+)-7-deoxypancratistatin 1995 Keck 22 4 
11 (+)-7-deoxypancratistatin 1995 Hudlicky 12 2.6 
12 (+)-7-deoxypancratistatin 1995 Hudlicky 10 3 
13 (+)-7-deoxypancratistatin 1996 Chida 29 0.03 
14 (+)-7-deoxypancratistatin 1998 Keck 15 12 
15 (+)-7-deoxypancratistatin 2000 Plumet 21 3 
16 (+)-7-deoxypancratistatin 2006 Madsen 13 1.4 
17 (+)-7-deoxypancratistatin 2006 Madsen 15 4.3 
18 (?)-7-deoxypancratistatin 2006 Padwa 23 3 
a Number of steps and overall yield from commercially available starting material for the 
longest linear sequence. One-pot procedures are counted as one step. b Full procedures 
have not been disclosed. c Relay synthesis from (+)-narciclasine. 
Table 2.1: Reported total syntheses of the Amaryllidaceae isocarbostyrils. Adapted from 
ref 76. 
  
The most common strategy towards synthesis of pancratistatin (23) and 
7-deoxypancratistatin (24) involve formation of a bond between aromatic ring (A ring) 
and more or less functionalized cyclohexane (C ring) ring. The approaches used for 
coupling of A and C rings include Michael addition (Plumet), nucleophilic addition 
(Magnus), electrophilic aromatic substitution (Haseltine), SN2/SN2' coupling reaction 
 
 19 
 
(Hudlicky, Trost and Li), palladium-catalyzed coupling reaction (Chida) and 
photocyclization (Rigby). These synthetic strategies are discussed below. As mentioned 
earlier, these strategies are not viable for practical production of pancratistatin (23) and 
7-deoxypancratistatin (24) (vide infra). Alternatively, there are less common approaches 
where the ring C is constructed after linkage of the aromatic ring to suitable precursor of 
ring C as reported by Danishfeky77, Kim85, Keck89, 90, Madsen92 and Padwa.93  
(i) Michael Addition 
Heathcock was the first to construct ABC network based on the coupling of aryl 
ring with cyclohexyl ring.94 Aromatic anion 28 underwent 1,4-addition with 
nitrocyclohexene to give a mixture of the cis and trans aryl nitrocyclohexanes 29 
(Scheme 2.1). The cis/trans mixture was equilibrated to obtain the trans isomer, which 
was used to generate lactam 30 in three subsequent steps.   
Scheme 2.1 
OTBS
CONEt2
O2N
1.
2. HOAc
O
O
OTBS
CONEt2
O
O
O2N
OH
O
O NH
O
28 29 30
70%
 
Plumet devised synthesis of (+)-7-deoxypancratistatin (24) via ring opening of 
vinyl sulfone 32 (Scheme 2.2).91 1,4-addition of aromatic anion 31 to vinyl sulfone 32 
gave cyclohexenol 33 with the correct configuration at C10b. Epoxidation of 
cyclohexenol 33, followed by oxirane opening with concomitant intramolecular 
 
 20 
 
lactonization completed the synthesis of (+)-7-deoxypancratistatin (24). Plumet's 
synthesis is fairly long (21 steps) as well as low yielding (3%).  
Scheme 2.2 
O
O
O
OPhO2S
O
O
O
O
OPhO2S
OH96%
31
33
32
10b
-78 ?C
24
10a O
O NH
O
HO
OH
OH
OHA B
C
 
Branchaud and Friestad proposed a palladium-catalyzed intramolecular 
1,4-addition of aryl iodide on an chiral enone to construct bond between A and C 
rings.95,96 However, this route has not been extended to pancratistatin (23) and 
7-deoxypancratistatin (24) to date.  
(ii) Nucleophilic Addition 
Magnus reported the total synthesis of (+)-pancratistatin (23) via intermolecular 
coupling of an aromatic anion 34 with the cyclohexanone derivative 35 to form 10a-10b 
carbon-carbon bond (Scheme 2.3).82 Nucleophilic addition of anion 34 to the 
cyclohexanone 35 gave alcohol 36. Benzylic alcohol 36 was converted to ketone 37 in 
three steps. The treatment of ketone 37 with the chiral amide 38 in the presence of LiCl 
gave asymmetric lithium enolate, which was trapped with TIPSOTf to form silyl enol 
ether 39. Further manipulations completed the synthesis of (+)-pancratistatin (23) 
(22 steps) in a low yield of 1.2%. 
 
 21 
 
Scheme 2.3 
O
O
OMe
O
O
O
O
O
OMe
OTIPS
O
O
OMe
OH85%34
35
36
39
10a 10b
10a 10b
-78 ?C O
O
OMe
O
37
10a 10b
Ph NLi Ph
Me Me
LiCl, TIPSOTf
-78 ?C, 95%
383 Steps
O
O
O
O NH
O
HO
OH
OH
OH
OH
A B
C
7
23  
(iii) Electrophilic Aromatic Substitution 
Haseltine accomplished a formal total synthesis of (+)-pancratistatin (23) via 
Danishfesky's intermediate 42.81 The key bond between A and C rings was constructed 
using an intramolecular electrophilic aromatic substitution (Scheme 2.4). Triflation of 
alcohol 40 in the presence of 2,6-lutidine gave the expected cyclized product 41. Several 
protection and deprotection steps provided Danishfesky's lactone intermediate 42 
constituting a formal total synthesis (24 steps, 0.97% yield). It is interesting to note that 
when a donor substituent (OBn) is present on the aromatic ring (on carbon 7), the desired 
cyclized adduct was obtained in very low yield (8%). Instead, a major regioisomer arising 
from an undesired rearrangement was observed. Electrophilic aromatic substitution has 
also been applied to construct 7-deoxynarciclasine (26) analogue via epi-selenonium 
ion.97 
 
 22 
 
Scheme 2.4 
O
O O
Tf2O, LutidineO
O
OH
O
O O
O
O
73%
7 40 41
O
O O
OBn
OH
42
OBn O
Danishefsky's Intermediate
9 Steps
(+)-pancratistatin
23
 
(iv) SN2 and SN2? Coupling  
Hudlicky's Approach 
The first asymmetric synthesis of (+)-pancratistatin (23) by Hudlicky involved 
opening of aziridine ring 44 by aromatic cuprate reagent 43 (Scheme 2.5).78 The 
regioselective SN2 ring opening of aziridine 44 led to inversion at C10b, establishing the 
desired stereochemistry. Subsequent key steps included installation of trans-diol and the 
formation of lactam to complete the synthesis of (23). However, the presence of 
benzamide moiety led to lengthy manipulations to affect the lactamization and the 
functionalization of the double bond.  
To overcome problems associated with the manipulations of benzamide, the 
amide was introduced in (+)-7-deoxypancratistatin (24) as the last step after the coupling 
reaction (Scheme 2.6) in the second-generation synthesis.80,87 However, the coupling of 
cuprate 46 with aziridine 44 produced compound 45 in lower yield. The low yield might 
be due to the instability of the organolithium compound and the corresponding cuprate 
compared to the compound 43.  
 
 23 
 
Scheme 2.5 
OTBS
CONMe2
O
O
CuCNLi2
2
O
O
N
Ts
OTBS
O
O
CONMe2
O
O
NHTs-78 ?C to rt
BF3?Et2O
75%
44
45
43 10b O
O NH
O
HO
OH
OH
OH
OH
A B
C10a
23
 
To save the number of functional group interconversion steps, aziridine 48 was 
prepared where the amide carbon was also used as the protecting group of aziridine 
(Scheme 2.6).87 The ring opening of aziridine 48 by cuprate 46 produced carbamate 49. 
Similar synthetic sequence (using enantiomer of aziridine 48) was used to synthesize an 
enantiomer of 7-deoxypancratistatin.98 Hudlicky has also made considerable efforts 
towards the synthesis of analogues of pancratistatin (23) and 7-deoxypancratistatin (24) 
using a similar approach (Scheme 2.6).73-75  
Though short (10 steps), the synthesis by Hudlicky is rather low yielding (3%) 
and arduous. The key steps that reduce the yield are aziridination and aziridine 
ring-opening. The aziridine ring-opening requires extremely low temperature, thus 
making this synthesis unsuitable for practical applications. Furthermore, both coupling 
partners 46 and 48 are moderately unstable, entailing a difficulty in their preparation.  
 
 
 24 
 
Scheme 2.6 
O
O
CuCNLi2
2
O
O
N
Ts
O
O
O
O
NHTs-78 ?C to rt
BF3?Et2O
32%
44 4746
10b
O
O
O
O
NHE
49
10bO
O
CuCNLi2
2
O
O
N
E
-78 to -30 ?C
BF3?Et2O
34%
4846
2 Steps
E=CO2Me
O
O NH
O
HO
OH
OH
OHA B
C
24
10a
10a
 
Trost's Approach 
In the asymmetric synthesis of (+)-pancratistatin (23) by Trost, carbon-carbon 
bond between A and C rings was constructed by allylic substitution of the carbonate 51 
via SN2? chemistry (Scheme 2.7).79 Reaction of allylic carbonate 51 with mixed cuprate 
50 resulted in inversion of configuration to provide allylic-arylated system 52. This type 
of mixed cuprate 50 is unstable and significant optimization was required for this step. 
Due to the difficulty associated with purification of the azide, azide 52 was not isolated. 
Additionally, full procedures have not been disclosed for this synthesis.     
 
 25 
 
Scheme 2.7 
OCO2Me
N3
O
O
O
O
CuCN
OMe
O
O
O
O
N3
OMe
MgBr
51
52
50
23
0 ?C O
O NH
O
HO
OH
OH
OH
OH
A B
C
 
Li's Approach 
Li's synthetic approach towards (+)-pancratistatin (23) is outlined in the 
Scheme 2.8. Intramolecular nucleophilic opening of cyclic sulfate 53 using aryl cerium 
reagent constructed the key bond to generate 54.86 In comparison to organomagnesium 
and organolithium reagents, organocerium reagents are much milder to avoid side 
reactions. Though the synthesis represents the shortest (13 steps) and the most high 
yielding (9%) route, the starting material (+)-pinitol is relatively expensive ($1,027 per 
10 g).75 
Scheme 2.8 
N
OOR
O
O
R O
O
OMe
OS
O
O
O
t-BuLi, CeCl3
NR
HO3SO
OOR
O
O
OMe
O
O
(+)-pancratistatin72%
Br
5453   R=MOM
-78 ?C to rt 23
 
 
 26 
 
(iv) Palladium-Catalyzed Coupling 
Heck Reaction 
Ogawa synthesized (+)-7-deoxypancratistatin88 from the key intermediate 56 
produced in the synthesis of (+)-7-deoxynarciclasine.99 Intramolecular Heck reaction of 
aryl bromide 55 generated intermediate 56 (Scheme 2.9). Interestingly this Heck reaction 
proceeds via anti elimination instead of generally observed syn elimination. The desired 
stereochemistry at C10b for the synthesis of (+)-7-deoxypancratistatin (24) was achieved 
via hydrogenation of alkene 56. The synthetic route towards (24) is the longest reported 
to date (29 steps) and is also extremely low yielding (0.03%).  
Scheme 2.9 
NPMB
O
O
O NPMB
O
O
O
(+)-7-deoxypancratistatin
OR
OR
Br
OPMB
OR
OR
OPMB
TlOAc, 140 ?C, 68%
(+)-7-deoxynarciclasine
Pd(OAc)2, DIPHOS
5655
26
24
R=MOM
10b
10a
  
Suzuki Coupling 
 Hudlicky employed palladium-catalyzed Suzuki coupling to construct the bond 
between A and C rings in narciclasine (25) (Scheme 2.10).98 The reaction of arylboronic 
acid 57 with vinyl bromide 58 formed alkene 59. Analogous approach has also been used 
by Banwell to construct an enantiomer of narciclasine (25).100 
 
 27 
 
Scheme 2.10 
O
5857
O
O
B(OH)2
OMe
(+)-narciclasine
NCO
2Me
Br
O
O
O
O
OMe
O
NCO
2Me
Br
O
O
Br
Pd(PPh3)4
Na2CO3, 30%
59
25
 
Recently, Pandey and co-workers formed epi-7-deoxypancratistatin 63 via 
cross-coupling of arylboronic acid 60 with iodo enone 61 (Scheme 2.11).101 This was 
followed by intramolecular aza-Michael addition to generate cis-fused lactam ring in 63.  
Scheme 2.11 
O
O NH
OH
OH
OH
HO
O
O
O
B(OH)2
NHCBz
O
OR
OR
OR
I
Pd(0)
84%
O
OR
OR
OR
NHCBz
O
O
61
60
62 63
R=MOM
 
(v) Photocyclization 
Rigby's synthetic approach is based on a hydrogen bond controlled aryl enamide 
photocyclization (Scheme 2.12).83 Irradiation of enamide 64 at 254 nm in benzene 
established desired stereochemistry at C10b in compound 65 in 30% yield (60% based on 
recovered starting material). Further functionalization of C ring completed the synthesis 
 
 28 
 
of (+)-pancratistatin (23). This synthesis is fairly long (23 steps) and enormously low 
yielding (0.35%) as well.  
Scheme 2.12 
NPMB
OTBSO
OO
H
O
O
h?, PhH
NPMB
OTBSO
OO
H
O
O
30%
64 65
10b
10a O
O NH
O
HO
OH
OH
OH
OH
A B
C
23  
Analogous photocyclization approach was adapted in the synthesis of 
7-deoxypancratistatin analogue 68 by Pandey (Scheme 2.13).102 Irradiation of 
carbamate 66 at 280 nm gave the cyclized product 67 as single isomer.  
Scheme 2.13 
O
O NH
OH
OHHO
O
66 68
O
O NCO2Me
OR
OR
67
O
O
O NCO2Me
OR
ORRO
h?, DCN
68%
R=TBS
 
RESEARCH GOAL  
The purpose of this work is to design an efficient synthetic route to antitumor 
alkaloids pancratistatin (23) and 7-deoxypancratistatin (24) using palladium-catalyzed 
allylic-arylation coupling methodology, thus providing multi-gram quantities of these 
compounds for clinical evaluations.  
 
 29 
 
In order to test the feasibility of aryl-allyl coupling, (?)-7-deoxypancratistatin 
analogue 69 was first synthesized. The retrosynthetic approach to the synthesis of 
7-deoxypancratistatin analogue 69 is outlined in the Scheme 2.14. The trans diol in 69 
will be generated from the alkene 70 via opening of epoxide. The B ring of the alkene 70 
will be obtained from the carbamate 71 by Friedel-Crafts cyclization. The allyl-aryl bond 
between the A and C rings in carbamate 71 will be constructed from palladium-mediated 
coupling of the aryl siloxane 72 and allylic carbonate 73.  
The synthetic route to aryl siloxane 72 and allyl carbonate 73 had already been 
established in the DeShong group.34 Also, the synthesis of carbamate 71 had been 
accomplished by the coupling reaction between aryl siloxane 72 and allylic carbonate 73. 
However, the subsequent steps to form the B ring and installation of trans diol had not 
been optimized. Provided with carbamate 71, the goal of my research project was to 
optimize these subsequent steps and complete the synthesis of 7-deoxypancratistatin 
analogue 69. 
Scheme 2.14 
O
O
Si(OEt)3
+
NHCO2Et
OCO2Et
O
O NH
O
HO
OH
O
O NHCO2Et
O
O NH
O
A
C
B
A
C
A
C
BA
C
69 70 71
72
73
7-deoxypancratistatin analogue
 
 
 30 
 
RESULTS AND DISCUSSION 
Synthesis of Coupling Partners: Allylic Carbonate and Aryl 
Siloxane 
Allylic carbonate 73 was synthesized as outlined in the Scheme 2.15. The 
synthesis of carbonate 73 commenced from the commercially available 
cyclohexadiene 74. Diels-Alder reaction of cyclohexadiene 74 with the acyl nitroso 
dienophile (generated in situ) formed hydroxamate 75.103 The cleavage of N-O bond in 
hydroxamate 75 using molybdenum hexacarbonyl yielded allylic alcohol 76.104 Finally, 
acylation of 76 with ethyl chloroformate afforded allylic carbonate 73.  
Aryl siloxane 72 was synthesized as shown in the Scheme 2.16.20 The 
commercially available aryl bromide 77 underwent a Grignard reaction to generate the 
organomagnesium species which was quenched by tetraethylorthosilicate (Si(OEt)4) to 
form aryl siloxane 72. 
Scheme 2.15 
ClCO2Et, pyridine
O
N
CO2Et
NHCO2Et
OH OCO2Et
NHCO2Et
74 75
76 73
EtOCONHOH, N+ Bu4IO4- Mo(CO)6, reflux , 82 ?C
CHCl3/DMF, 71% MeCN/H2O, 62%
CH2Cl2, rt, 83%
 
 
 31 
 
Scheme 2.16 
Si(OEt)3O
O
O
O
Br
61%
77 72
(ii) Si(OEt)4, THF, -78 ?C to rt
(i) Mg(0), THF, 75 ?C
 
Coupling of Allylic Carbonate with Aryl Siloxane 
The coupling of allylic carbonate 73 with electron-rich aryl siloxane 72 in the 
presence of TBAF and Pd(dba)2 catalyst gave the allylic arylated coupling products 73 
and 79, respectively, as 1:1.6 ratio of diastereomers in 81% yield (Scheme 2.17). 
Scheme 2.17 
NHCO2Et
OCO2Et O
O
Si(OEt)3
O
O NHCO2Et
Pd LnAr
H NHCO2Et
HH
O
O
NHCO2Et
1 3
1
3
+
1
3
1
373 78
72
71
79
71:79 = 1.0:1.6
Pd(dba)2, TBAF
65 ?C, THF
81%
 
The low regioselectivity in the products is consistent with the previously proposed 
model for regioselectivity in cyclohexenyl systems. Using the model developed in our 
lab, the pi-allyl Pd complex 78 derived from allylic carbonate 73 formed on the face 
opposite from the departing carbonate. This ?symmetrical? Pd-complex 78 does not have 
substituents on the face of the ?-complex which has Pd attached. Accordingly, 
subsequent reductive elimination of the aryl group from silicon is equally probable at the 
1 and 3 positions and therefore, a modest regioselectivity was observed. The role of 
 
 32 
 
electronic factors on the regioselectivity of the coupling reaction was unknown. 
However, the results from Szab?105 indicated that the coupling reaction would favor 
carbamate 79, as observed in the experiment. Surprisingly, when benzyl carbamate (CBz) 
analogue of 73 was used as the coupling partner with the aryl siloxane 72, the yield of 
coupling products (CBz analogues of 71/79) decreased (33-50%) dramatically.  
Scheme 2.18 
NHCO2Et
OCO2Et
Si(OEt)3
NHCO2Et
NHCO2Et
+
73 67%, 80:81 = 1.0:1.7
Pd2dba3?CHCl3, TBAF
55 ?C, THF
SnBu3
B(OH)2
80 81
PdCl2TFP2, KF
rt, MeOH
80%, 80:81 = 1.0:3.0
51%, 80:81 = 1.0:1.0
Pd2(dba)3, AsPh3, LiCl
50 ?C, NMP
 
Similar allyl-aryl coupling reaction can also be accomplished via Stille29 (tin) and 
Suzuki41 (boron) reaction (Scheme 2.18). Both Stille and Suzuki reaction worked well to 
produce regioisomers 80 and 81. However, the undesired coupling product 81 was 
obtained in much greater amount in the Suzuki reaction compared to Stille and Hiyama 
coupling reaction.  
 
 33 
 
Generation of B ring and Installation of diol 
With carbamate 71 in hand, the next goal was to construct the B ring via 
Friedel-Crafts acylation. When both ethyl carbamate 71 and CBz analogue of 71 were 
subjected to Bischler-Napieralski cyclization using DMAP/Tf2O, the yield of lactam was 
very low (15-20%). Therefore, an alternative route was investigated. 
The mixture of regioisomeric carbamates 71 and 79 was subjected to 
Friedel-Crafts acylation using P2O5 and POCl3/Me3SiOSiMe3 (1:1) (Scheme 2.19).106 The 
cyclization reaction was completely regioselective where only regioisomer 71 underwent 
cyclization to form the lactam 20 in good yield (55-65%). Attempts to optimize the 
reaction conditions indicated that reaction worked well as indicated in the literature. 
However, when mixture of CBz analogues 71/79 was subjected to similar reaction 
conditions, the lactam 70 was obtained in low yield (15%) comparable to that using 
Tf2O/DMAP reagent. We decided to change the sequence of steps by forming the 
epoxide first and then perform the cyclization (Scheme 2.19). While the epoxidation of 
alkenes 71/79 proceeded in moderate yield to give epoxides 82/83, the cyclization of 
82/83 using POCl3/P2O5 showed decomposition. This route was abandoned therefore.  
Having optimized the yield of lactam 70, the next goal was to install trans diol via 
epoxidation. Previous work in DeShong group had shown that the epoxidation of the 
double bond using m-CPBA107 gave a mixture of diastereomeric epoxides 84 in low yield 
(15-30%) (Scheme 2.20). Attempts to improve the yield of epoxides using more reactive 
epoxidation reagents led to extensive decomposition of the alkene. The subsequent step 
of epoxide opening of 84 gave poor yield of diol 69 as well.  
 
 
 34 
 
Scheme 2.19 
O
O NHCO2Et
O
O
O
O NH
O
O NHCO2Et
O
NHCO2Et
O
O
71 79 +
POCl3/Me3SiOSiMe3
 P2O5, 85 ?C, 56%
70
82
83
m-CPBA, NaHCO3
40 ?C, 51%
POCl3/Me3SiOSiMe3
 P2O5, 85 ?C
O
O NH
O
O  
Scheme 2.20 
O
O NH
O
O
O
O NH
O
O
O
O NH
HO
OH
51%
15-30%
i) H2O2, HCO2H, rt
ii) NaOH, 90 ?C
< 30%
70
84
69
m-CPBA, 
NaHCO3, rt
 
A more direct method of introducing the trans diol functionality was used for the 
synthesis of diol 69 (Scheme 2.20). According to this one-pot trans-dihydroxylation, the 
 
 35 
 
reaction of alkene 70 with hydrogen peroxide in formic acid generates diastereomeric 
epoxides 84a/84b (Scheme 2.21).108 Under acidic conditions (formic acid), the epoxides 
are protonated and then opened by formic acid to generate a mixture of alcohol formates 
85a/85b. Because of trans-diaxial opening of epoxide to avoid intermediate boat 
conformation, only the desired trans relationship will be installed. Therefore, hydrolysis 
of mono-formates provides the desired diol 69 with a single stereoconfiguration. In 
principle, the stereoselectivity in the epoxidation reaction was of no consequence since 
the diaxial opening of each epoxide should be regiospecific and give only trans-diol 69. 
Scheme 2.21 
O
O NH
O
O
O NH
O
HO
OH
1. H2O2, HCOOH , rt
2. NaOH , 90 ?C
O
O NH
O
O
O NH
O
O
O
H
H O
H
H
O
H
H
Nu
Nu
O
O NH
O
OH
OHCO
O
O NH
O
OCHO
HO
NaOH
Nu = HCOOH
H2O2, HCOOH
70 69
84a
84b
85a
85b
 
 
 36 
 
Much optimization was required for the isolation of diol 69 because of difficulty 
while working with such a polar compound, which is poorly soluble in most organic 
solvents (ethyl acetate, acetone, methanol). A variety of normal or reverse-phase methods 
led to an extensive loss of product. The most efficient purification method ultimately 
involved an extraction-precipitation regime, which gave trans diol in 51% yield 
(Scheme 2.20). Attempts to acylate hydroxyl groups to improve the solubilty of diol 69 in 
organic solvents failed, presumably because of sterical interference caused by peri 
hydrogen on C10 of aromatic A ring (Figure 2.1).  
The relative stereochemistry of diol 69 was confirmed by the COSY experiment 
and by correlation to the published 1H NMR data of the benzoate of the 
7-deoxypancratistatin derivative 86 (Figure 2.3).109 The coupling constant of 2 Hz 
between H1 and H10b of 69 is diagnostic of a cis relationship between the two protons. 
Protons H4a and H10b of 69 exhibit a 13 Hz coupling constant which is indicative of a 
trans diaxial relationship. These coupling constant values are in accord with the coupling 
observed (J = 2 Hz) for protons H1 and H10b and (J = 13 Hz) for protons H4a and H10b 
respectively in 86. 
NH
OH
H4a
O
O
O
H
H10b
OH
H1
NR
OR
H4a
O
O
O
H1
H10b
OR
OR
ORH
J 1, 10b = 2 Hz
J  4a, 10b = 13 Hz
J 1, 10b = 2 Hz
J  4a, 10b = 13 Hz
69 86  
Figure 2.3: Relative stereochemistry confirmed from correlation with 1H NMR coupling 
constants 
 
 37 
 
CONCLUSION 
The synthesis of (?)-7-deoxypancratistatin analogue has been accomplished via 
palladium-catalyzed allylic-arylation. The key reaction in the synthesis involves the 
stereoselective formation of a carbon-carbon bond between the A and C rings by 
coupling of aryl siloxane with allylic carbonate. Subsequent steps include generation of B 
ring by Friedel-Crafts acylation and installation of the trans diol. The key coupling 
reaction is advantageous compared to Stille reaction because it avoids the use of toxic tin 
reagents. Additionally, the coupling is superior to the Suzuki reaction which results in 
formation of undesired regioisomer predominantly (Scheme 2.18). Our 
palladium-catalyzed allylic-arylation coupling methodology is also superior to allyl-aryl 
coupling by Hudlicky and Trost because of the ease of preparation of coupling partners, 
aryl siloxane and allyl carbonate as well as trouble-free coupling reaction.  
 
 38 
 
EXPERIMENTAL DETAILS 
General Methods 
All reactions were run under an atmosphere of argon unless otherwise noted. 
Glassware used in the reactions was dried for a minimum of 12 h in an oven at 120 ?C or 
flame dried prior to use. Tetrahydrofuran was distilled from sodium/benzophenone ketyl, 
while methylene chloride, pyridine, methanol and N-methyl-2-pyrrolidone were distilled 
from calcium hydride. Phosphorous oxychloride was distilled from P2O5.  
Thin-layer chromatography (TLC) was performed on 0.25 mm silica gel coated 
plates treated with a UV-active binder with compounds being identified by one or more 
of the following methods: UV (254 nm), vanillin/sulfuric acid charring, or KMnO4 
charring. Flash chromatography was performed using glass columns and medium 
pressure silica gel (Sorbent Technologies, 45-70 ?). 
Infrared spectra were recorded on a Nicolet 560 FT-IR spectrophotometer. 
Samples used for obtaining infrared spectra were either dissolved in carbon tetrachloride 
or taken neat. IR band positions are reported in reciprocal centimeters (cm-1) and relative 
intensities are listed as br (broad), s (strong), m (medium), or w (weak). Nuclear magnetic 
resonance (1H, 13C NMR) spectra were recorded on a 400 MHz spectrometer. Chemical 
shifts are reported in parts per million (?) and coupling (J values) are reported in hertz 
(Hz). Spin multiplicities are indicated by the following symbols: s (singlet), d (doublet), t 
(triplet), q (quartet), m (multiplet), br s (broad singlet), br d (broad doublet). Low 
resolution mass spectrometry (LRMS) and high resolution mass spectrometry (HRMS) 
were obtained on a JEOL SX-02A instrument. 
 
 39 
 
Aryl Siloxane 72 
1. Mg(0), 75 ?C
2. Si(OEt)4, rtO
O Br Si(OEt)3
O
O
61% 7277  
To 811 mg (33.8 mmol, 2.00 equiv.) of washed magnesium turnings was added 10.0 mL 
of anhydrous THF. After heating the reaction mixture at 75 ?C, 2.00 mL (16.9 mmol, 
1.00 equiv.) of the aryl bromide 77 was added dropwise under argon and reaction was 
allowed to stir for 45 min. This was followed by addition of 10.0 mL of anhydrous THF 
to the reaction mixture. After 4 h, the Grignard mixture was cannulated into 9.55 mL 
(42.3 mmol, 2.50 equiv.) of Si(OEt)4 in 20.0 mL anhydrous THF. The reaction was 
allowed to stir for 3 h under argon at room temperature. The black solution was extracted 
with 3 ? 200 mL Et2O and the organic layers were washed with 200 mL H2O. The 
combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to 
give a brown oil. Purification by column chromatography (2% EtOAc/98% hexane, Rf  = 
0.26) yielded 2.94 g (61%) of aryl siloxane 72 as a colorless oil: IR (CCl4) 2970 (s), 2926 
(m), 2885 (m), 2780 (w), 2739 (w), 1611 (w), 1479 (s), 1234 (s), 1169 (s), 1095 (s) cm-1; 
1H NMR (400 MHz, CDCl3) ? 7.16 (dd, J = 1, 8 Hz, 1H), 7.09 (d, J = 1 Hz, 1H), 6.84 (d, 
J = 8 Hz, 1H), 5.93 (s, 2H), 3.83 (q, J = 7 Hz, 6H), 1.20 (t, J = 7 Hz, 9H); 13C NMR (100 
MHz, CDCl3) ? 149.3, 147.3, 129.2, 123.6, 113.8, 108.5, 100.5, 58.6, 18.1; LRMS (FAB) 
284.4 (M+, 100), 283.4 (42), 239 (80), 161 (65); HRMS (FAB) calcd 284.1080 (M+), 
found 284.1080.  
 
 40 
 
Hydroxamate 75 
EtOCONHOH, N+Bu4IO4- O
N
CO2Et
CHCl3/DMF, 0 ?C to rt
71%
7574  
To 6.29 g (14.5 mmol, 1.40 equiv.) of NBu4+IO4- (tetrabutylammonium periodate) under 
argon was added chloroform (12.0 mL) and DMF (4.00 mL). The reaction mixture was 
cooled to 0 ?C and then 0.990 mL (104 mmol, 1.00 equiv.) of cyclohexadiene 74 was 
added. Finally, 1.09 g (104 mmol, 1.00 equiv.) of hydroxamic acid (EtOCONHOH) 
dissolved in chloroform (6.00 mL) and DMF (2.00 mL) was added via addition funnel. 
The reaction mixture was stirred at 0 ?C to room temperature for 17 h. The product was 
extracted with Et2O (4 ? 100 mL), washed with H2O (100 mL), dried over MgSO4, 
concentrated in vacuo to give the crude hydroxamate 75 as a brown oil. Flash column 
chromatography on silica gel (50% EtOAc/50% hexane, Rf = 0.49) gave 1.36 g (71%) of 
hydroxamate 75 as a light orange oil: IR (CCl4) 3062 (w), 2984 (m), 2936 (m), 2862 (w), 
1706 (s), 1380 (s), 1268 (s), 1081 (s) cm-1; 1H NMR (400 MHz, CDCl3) ? 6.55-6.46 (m, 
2H) , 4.76 (m, 1H), 4.70 (m, 1H), 4.18-4.07 (m, 2H), 2.17-2.04 (m, 2H), 1.45 (qt, J = 2, 
12 Hz, 1H), 1.33 (t, J = 12 Hz, 1H), 1.20 (dt, J = 2, 7 Hz, 3H); 13C NMR (100 MHz, 
CDCl3) ? 158.3, 132.0, 131.6, 71.0, 62.2, 49.9, 23.4, 20.6, 14.5; EI mass spectrum, m/z 
(relative intensity) 183 (M+, 98), 105 (72), 79 (92), 77 (80), 67 (65), 29 (76), 27 (65); 
HRMS (ESI) calcd for C9H14NO3 (M+H)+ 184.0974, found 184.0974. 
 
 
 41 
 
Alcohol-Carbamate 76 
O
N
CO2Et
Mo(CO)6
NHCO2Et
OH
 CH3CN/H2O, reflux
62%
7675  
To 7.71 g (42.1 mmol, 1.00 equiv.) of the hydroxamate 75 dissolved in 240 mL 
acetonitrile and 15 mL distilled water was added 12.2 g (46.3 mmol, 1.10 equiv.) of 
molybdenum hexacarbonyl (Mo(CO)6). The reaction mixture was refluxed at 82 ?C for 
66 h. The black-brown reaction mixture was vacuum filtered through Celite and the 
filtrate was concentrated in vacuo to give crude alcohol-carbamate 76 as a yellow oil. 
Flash column chromatography on silica gel (75% EtOAc/25% hexane, Rf = 0.33) gave 
4.81 g (62%) of carbamate 76 as a yellow oil: IR (CCl4) 3619 (m), 3450-3100 (br s), 
3028 (m), 2981 (s), 2940 (s), 1713 (s), 1502 (s), 1316 (s), 1231 (s), 1067 (s) cm-1; 1H 
NMR (400 MHz, CDCl3) ? 5.86 (d, J = 10 Hz, 1H), 5.73 (dd, J = 2, 10 Hz, 1H), 4.67 (br 
s, 1H), 4.16-4.07 (m, 4H), 1.88-1.80 (m, 2H), 1.72-1.63 (m, 2H), 1.53 (br s, 1H), 1.22 (t, 
J = 7 Hz, 3H); 13C NMR (100 MHz, CDCl3) ? 156.0, 132.5, 130.9, 64.5, 60.8, 46.2, 28.9, 
25.6, 14.6; EI mass spectrum, m/z (relative intensity) 185 (M+, 4), 157 (100), 141 (92), 96 
(76), 68 (87), 55 (99), 39.5 (99.5); HRMS calcd for C9H15NO3 (M+) 185.1053, found 
185.1052. 
 
 42 
 
Carbonate-Carbamate 73 
ClCO2Et
NHCO2Et
OH OCO2Et
NHCO2Et
pyridine/ CH2Cl2
rt, 83%
76 73  
To 2.84 g (15.4 mmol, 1.00 equiv.) of alcohol-carbamate 76 in 35.0 mL anhydrous 
CH2Cl2 and 1.85 mL (23.0 mmol, 1.50 equiv.) anhydrous pyridine was added 2.28 mL 
(23.0 mmol, 1.50 equiv.) of ethyl chloroformate dropwise via syringe under argon. The 
reaction was allowed to stir at room temperature for 5 days. The reaction mixture was 
extracted with CH2Cl2 (3 ? 50 mL), washed with H2O (50 mL), dried over MgSO4 and 
concentrated in vacuo. Flash chromatography on silica gel (30% EtOAc/70% hexane, Rf 
= 0.43 afforded 3.28 g (83%) of the carbonate-carbamate 73 as a yellow oil: IR (CCl4) 
3450 (m), 3042 (w), 2987 (w), 1747 (s), 1727 (s), 1502 (s), 1265 (s) cm-1; 1H NMR (400 
MHz, CDCl3) ? 5.86 (m, 2H), 5.03 (m, 1H), 4.64 (br s, 1H), 4.19-4.14 (m, 3H), 4.08 (q, J 
= 7 Hz, 2H), 1.88 (br s, 3H), 1.67-1.63 (m, 1H), 1.28 (t, J = 7 Hz, 3H), 1.21 (t, J = 7 Hz, 
3H); 13C NMR (100 MHz, CDCl3) ? 156.2, 155.0, 134.4, 128.3, 127.7, 70.3, 64.2, 61.2, 
46.6, 26.2, 25.6, 14.9, 14.5; FAB mass spectrum, m/z (relative intensity) 258 ((M+H)+, 
2), 168 (100), 90 (40), 62 (46); HRMS (FAB) calcd for C12H19O5N (M+H)+ 258.1332, 
found 258.1342. 
 
 43 
 
Carbamates 80 and 81 
NHCO2Et
OCO2Et
NHCO2Et
NHCO2Et
+
73
M
80 81
PdLn
M = Si, Sn, B
 
Hiyama-like Coupling 
The coupling reaction of carbonate 73 with PhSi(OEt)3 had been performed previously by 
Bogaczyk in the DeShong group.31 To a solution of 100 mg (0.389 mmol) of allyl 
carbonate 73 and 20 mg (0.020 mmol) Pd2(dba)3?CHCl3 in 10 mL dry THF was added 
190 ?L (0.778 mmol) PhSi(OEt)3, followed by 778 ?L (0.778 mmol, 1.0 M solution in 
THF) TBAF. The solution was degassed via a single freeze-pump-thaw cycle and then 
heated to 55 ?C. The reaction mixture was quenched after 48 h with 40 mL H2O. The 
layers were separated and the aqueous phase was extracted with 3 ? 40 mL Et2O. The 
combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification 
of the residue by flash chromatography (20 mm, 20 cm, 5% EtOAc/95% hexane) gave 48 
mg (51%) of carbamates 80:81 as a white solid. The ratio of carbamates 80 to 81 was 
1.0:1.0. The pure regioisomers were separated using preparative HPLC (3:1 
hexane:EtOAc). Carbamate 80: TLC Rf = 0.35 (3:1 hexane:EtOAc); IR (CCl4) 3447 
(w), 3029 (w), 2933 (w), 1729 (s), 1552 (s) cm-1; 1H NMR (CDCl3) ? 7.21-7.29 (m, 5H), 
5.89 (ddd, J = 2, 4, 10 Hz, 1H), 5.62 (ddd, J = 2, 4, 10 Hz, 1H), 4.80 (br s, 1H), 4.01 (q, J 
= 7 Hz, 2H), 3.78-3.83 (m, 1H), 3.29-3.33 (m, 1H), 2.14-2.24 (m, 2H), 1.87-1.92 (m, 
1H), 1.58-1.62 (m, 1H), 1.16 (t, J = 7 Hz, 3H); 13C NMR (CDCl3) ? 156.0, 142.6, 128.4 
 
 44 
 
(2C), 128.3, 127.9, 126.7, 60.6, 52.6, 48.0, 25.5, 23.0, 14.5; FAB mass spectrum m/z 
(relative intensity) 246 ((M + H), 17), 102 (100), 91 (25); HRMS (FAB) calcd for 
C15H20O2N (M+H) 246.1494, found 246.1491. Carbamate 81: TLC Rf  = 0.35 (3:1 
hexane:EtOAc); IR (CCl4) 3454 (w), 3026 (w), 2943 (w), 1728 (s), 1500 (s) cm-1; 1H 
NMR (CDCl3) ? 7.16-7.31 (m, 5H), 5.82 (d, J = 10 Hz, 1H), 5.77 (d, J = 10 Hz, 1H), 
4.63 (br s, 1H), 4.32-4.34 (m, 1H), 4.12 (q, J = 7 Hz, 2H), 3.36-3.38 (m, 1H), 2.07-2.09 
(m, 2H), 1.58-1.63 (m, 1H), 1.47-1.52 (m, 1H), 1.25 (t, J = 7 Hz, 3H); 13C NMR (CDCl3) 
? 156.0, 145.2, 133.1, 129.6, 128.4, 127.5, 126.3, 60.7, 47.0, 41.8, 31.0, 29.6, 14.6; FAB 
mass spectrum m/z (relative intensity) 246 ((M + H), 17), 157 (66), 91 (100); HRMS 
(FAB) calcd for C15H20O2N (M+H) 246.1494, found 246.1491.  
Suzuki Coupling 
To 60.2 mg (0.234 mmol, 1.00 equiv.) of allyl carbonate 73 under argon was added 13.6 
mg (0.0234 mmol, 0.100 equiv.) PdCl2TFP2. This was followed by addition of 57.1 mg 
(0.468 mmol, 2.00 equiv.) PhB(OH)2, 57.4 mg (0.936 mmol, 4.00 equiv.) KF and 4.00 
mL dry MeOH. The reaction mixture was stirred at room temperature for 24 h. The 
product was extracted with Et2O (5 ? 20 mL), washed with H2O (20 mL), dried over 
MgSO4, concentrated in vacuo to give the crude as a yellow oil. Flash column 
chromatography on silica gel (10% EtOAc/90% hexane, Rf = 0.14) gave 46.0 mg (80%) 
of carbamates 80 and 81, respectively, in a 1.0:3.0 ratio as a yellow solid. 
Stille Coupling 
To 70.4 mg (0.274 mmol, 1.00 equiv.) carbonate 73 and 201 mg (0.548 mmol, 2.00 
equiv.) PhSnBu3 in 10 mL dry NMP was added 25.2 mg (0.0822 mmol, 3.00 equiv.) 
AsPh3, 75.3 mg (0.0822 mmol, 3.00 equiv.) Pd2(dba)3 and 69.7 mg (1.64 mmol, 6.00 
 
 45 
 
equiv.) LiCl. The reaction mixture was stirred at 50 ?C for 24 h. The product was 
extracted with Et2O (5 ? 20 mL), washed with H2O (20 mL), dried over MgSO4, 
concentrated in vacuo to give the crude as a yellow oil. Flash column chromatography on 
silica gel (20% EtOAc/80% hexane, Rf = 0.33) gave 45.0 mg (67%) of carbamates 80 and 
81, respectively, in a 1.0:1.7 ratio as a yellow solid. 
Carbamates 71 and 79 
NHCO2Et
OCO2Et O
O
Si(OEt)3 O
O NHCO2Et
O
O
NHCO2Et
+
73
72
71
7971:79 = 1.0:1.6
Pd(dba)2, TBAF
65 ?C, THF
81%
 
To 338 mg (1.19 mmol, 2.00 equiv.) of aryl siloxane 72 nd 153 mg (0.595 mmol, 1.00 
equiv.) of carbonate-carbamate 73 dissolved in 15.0 mL anhydrous THF was added 1.19 
mL (1.19 mmol, 2.00 equiv.) TBAF under argon. This was followed by addition of 68.4 
mg (0.119 mmol, 0.100 equiv.) Pd(dba)2. The reaction mixture was subjected to one 
freeze pump thaw cycle and then heated at 65 ?C for 24 h. The reaction was then 
quenched by addition of 30 mL H2O. The product was extracted with 3 ? 25 and washed 
with H2O. The combined organic extracts were dried over MgSO4, filtered and 
concentrated in vacuo to give a brown oil. Flash column chromatography on silica gel 
(15% EtOAc/85% hexane, Rf = 0.20) gave 140 mg (81%) of carbamates 71 and 79, 
respectively, in a 1.0:1.6 ratio as a yellow solid. The two regioisomers were inseparable 
using column chromatography and were thus carried as mixture through the next step. 
 
 46 
 
The regioisomers however, are separable by HPLC.34 A small amount of the mixture was 
separated on preparative HPLC (25% EtOAc/75% hexane) for spectral analysis. 
Carbamate 71: mp 111-113 ?C; IR (CCl4) 3443 (w), 2930 (w),  2858 (w), 1727 (m), 
1550 (s), 1502 (m), 1485 (m), 1251 (m) cm-1; 1H NMR (400 MHz, CDCl3 ? 6.73-6.67 (m, 
3H), 5.90 (s, 2H), 5.87 (dd, J = 2, 10 Hz, 1H), 5.58 (dd, J = 2, 10 Hz, 1H)  4.72 (br s, 
1H), 4.03 (q, J = 7 Hz, 2H), 3.72 (br s, 1H), 3.22 (s, 1H), 2.25-2.10 (m, 2H), 1.91-1.88 
(m, 1H), 1.58 (sextet, J = 7 Hz, 1H) 1.18 (t, J = 7 Hz, 3H); 13C NMR (100 MHz, CDCl3) 
? 156.0, 147.6, 146.2, 136.5, 128.0, 127.9, 121.5, 108.7, 108.0, 100.9, 60.6, 52.7, 47.6, 
25.5, 22.9, 14.5; FAB mass spectrum m/z (relative intensity) 290 ((M+H)+, 21), 201 
(100), 174 (31), 135 (81), 73 (90); HRMS (FAB) calcd for C16H20O4N (M+H)+ 290.1392, 
found 290.1379. Carbamate 79: mp 90-92 ?C; IR (CCl4) 3446 (w), 3028 (w), 2943(w), 
1727 (s), 1547 (s), 1489 (s) cm-1; 1H NMR (400 MHz, CDCl3) ? 6.72 (d, J = 8 Hz, 1H), 
6.64-6.59 (m, 2H), 5.90 (m, 2H), 5.75 (m, 2H), 4.63 (br s, 1H), 4.29 (br s, 1H), 4.10 (q, J 
= 7 Hz, 2H), 3.29-3.28 (m, 1H), 2.07-2.01 (m, 2H), 1.54-1.41 (m, 2H), 1.23 (t, J = 7 Hz, 
3H); 13C NMR (100 MHz, CDCl3) ? 156.1, 147.6, 146.0, 139.2, 133.2, 129.6, 120.4, 
108.1, 108.0, 100.8, 60.7, 46.9, 41.4, 31.1, 29.5, 14.6; FAB mass spectrum m/z (relative 
intensity) 290 ((M+H)+, 46), 201 (100), 174 (24), 135 (60), 73 (48); HRMS (FAB) calcd 
for C16H20O4N (M+H)+ 290.1392, found 290.1390. 
 
 47 
 
Lactam 70 
O
O NHCO2Et
O
O
O NH
O
NHCO2Et
O
+
POCl3, P2O5
 Me3SiOSiMe3
71 79 70
85 ?C, 56%
 
To 294 mg (1.02 mmol, 1.00 equiv.) of coupling product mixture 71/79 was added P2O5 
(3.13 g, 21.6 equiv.) and then 5.00 mL (23.0 equiv.) hexamethyldisiloxane under argon. 
This was followed by dropwise addition of POCl3 (5.00 mL) via syringe. The reaction 
mixture was stirred at 85 ?C for 19 h. The purple reaction mixture was quenched with 
100 mL ice water and was stirred for 5.5 h at room temperature. The product was 
extracted with EtOAc (7 ? 75 mL), dried over MgSO4, concentrated in vacuo to give 
crude as a yellow solid. Flash column chromatography on silica gel (75% EtOAc/25% 
hexane, Rf = 0.23) gave 48 mg (56%, based on the amount of carbamate 71 in the original 
mixture) of alkene 70 as a white solid: mp >300 ?C; IR (Neat) 3185 (w), 2920 (m), 1665 
(s), 1612 (m), 1451 (s), 1254 (s), 1036 (w) cm-1; 1H NMR (400 MHz, CDCl3) ? 7.55 (s, 
1H), 6.85 (s, 1H), 6.09-6.07 (m, 2H 1H), 6.00 (s, 2H), 5.88-5.86 (m, 1H), 3.46-3.44 (m, 
1H), 2.26 (m, 2 H), 1.94-1.93 (m, 1H), 1.86-1.82 (m, 1H); 13C NMR (100 MHz, CDCl3) ? 
166.0, 151.2, 146.4, 136.6, 128.8, 123.7, 122.7, 108.7, 103.6, 101.6, 53.5, 41.1, 28.1, 
24.5; HRMS (FAB) calcd for C14H13NO3 244.0973, found 244.0974. 
 
 48 
 
Epoxides 82 and 83 
O
O NHCO2Et
O
O
O NHCO2Et
O
NHCO2Et
O
O71
+
82
83
m-CPBA, NaHCO3
CH2Cl2, 40 ?C, 51%
O
NHCO2Et
O
79
+
 
To 209 mg (0.723 mmol, 1.00 equiv.) of mixture of coupling products 71 and 79 
dissolved in anhydrous CH2Cl2 was added 243 mg (2.89 mmol, 4.00 equiv.) of sodium 
bicarbonate (NaHCO3), followed by addition of 375 mg (2.17 mmol, 3.00 equiv.) of 
m-CPBA. The reaction mixture was stirred at 40 ?C for 25 h and was quenched with 25.0 
mL of saturated NaHCO3 and 25 mL of saturated Na2S2O3 (sodium thiosulfate) solution. 
The product was extracted with 4 ? 50 mL EtOAc and washed with 50 mL water. The 
combine organic layers were dried over MgSO4 and concentrated in vacuo to give crude 
as a yellow solid. Flash chromatography on silica gel (30% EtOAc/70% hexane) yielded 
41 mg of epoxide 82 (Rf = 0.25) and 72 mg of epoxide 83 (Rf = 0.34) as white solids 
(51% combined yield): Epoxide 82: mp 178-181 ?C; IR (Neat) 3314 (m), 2979 (w), 2921 
(w), 2845 (w), 1684 (s), 1540 (s), 1473 (s), 1282 (m), 1238 (s), 1051 (s) cm-1; 1H NMR 
(400 MHz, CDCl3) ? 6.77-6.69 (m, 3H), 5.93 (s, 2H), 4.87 (br s, 1H), 3.99 (q, J = 7 Hz, 
2H), 3.60 (br s, 1H), 3.31 (m, 1H), 3.17 (d, J = 4 Hz, 1H), 2.96 (d, J = 7 Hz, 1H), 2.21-
2.16 (m, 1H), 2.06-2.00 (m, 1H), 1.69-1.65 (m, 1H), 1.46-1.38 (m, 1H) , 1.15 (t, J = 7 Hz, 
3H); 13C NMR (100 MHz, CDCl3) ? 155.7, 147.9, 146.6, 134.3, 121.4, 108.5, 108.4, 
101.0, 60.6, 56.0, 52.4, 51.9, 46.8, 22.6, 22.4, 14.5. HRMS (ESI) calcd for C16H20O5N 
(M+H)+ 306.1342, found 306.1310. Epoxide 83: mp 157-160 ?C; IR (Neat) 3295 (m), 
 
 49 
 
2988 (w), 2936 (w), 2859 (w), 1675 (s), 1531 (s), 1488 (s), 1440 (m), 1243 (s), 1042 (s) 
cm-1; 1H NMR (400 MHz, CDCl3) ? 6.76-6.65 (m, 3H), 5.93 (s, 2H), 4.91 (d, J = 8 Hz, 
1H), 4.15-4.10 (m, 3H), 3.36 (m, 1H), 3.25 (d, J = 4 Hz, 1H), 2.97 (dd, J = 6, 4 Hz, 1H), 
1.87-1.81 (m, 1H), 1.72-1.67 (m, 1H), 1.37-1.31 (m, 2H), 1.24 (t, J = 7 Hz, 3H); 13C 
NMR (100 MHz, CDCl3) ? 156.1, 147.8, 146.2, 137.1, 120.6, 108.4, 108.1, 101.0, 60.9, 
59.1, 55.0, 48.0, 40.2, 30.0, 24.6, 14.6. HRMS (ESI) calcd for C16H20O5N (M+H)+ 
306.1342, found 306.1310. 
Epoxides 84a, 84b 
O
O NH
O
O
O NH
O
O
O
O NH
O
O
rt
70 84a/b 84a/b
m-CPBA
NaHCO3, CH2Cl2
 
To a solution of the lactam 70 (59 mg, 0.24 mmol, 1.0 equiv.) in dichloromethane (2.0 
mL), was added sodium bicarbonate (41 mg, 0.48 mmol, 2.0 equiv.), followed by purified 
m-CPBA (63 mg, 0.36 mmol, 1.5 equiv.). The two phase reaction mixture was vigorously 
stirred for 24 h at room temperature, before diluting with water (2.0 mL) and stirring for 
another 30 min. The two phases were separated, and then extracted with dichloromethane 
(3 ? 5 mL). The combined organics were washed with satd. aq. sodium bicarbonate (2 ? 
3 mL), dried over MgSO4 and concentrated in vacuo. Flash chromatography on silica gel 
(gradient elution 75%-100% EtOAc/hexane) gave faster eluting 84 (3 mg, 5%) and 
slower eluting 84 (6 mg, 9%), both as white solids. Faster eluting 84: TLC Rf  = 0.37 
(80% EtOAc/20% hexane); mp >300 ?C; IR (CCl4) 2957 (w), 2930 (s), 2851 (m), 1720 
 
 50 
 
(s), 1360 (w), 1217 (w), 909 (m) cm-1; 1H NMR (400 MHz, CDCl3) ? 7.56 (s, 1H), 7.00 
(s, 1H), 6.03 (s, 2H), 3.54 (d, J = 4 Hz, 1H), 3.44 (br s, 1H), 3.29 (dd, J = 2, 2 Hz, 1H), 
3.23 (dd, J = 4, 12 Hz, 1H), 3.00 (d, J = 12 Hz, 1H), 1.95-1.90 (m, 1H), 1.65-1.59 (m, 
3H); HRMS (FAB) calcd for C14H13NO4 260.0924 (M+H), found 260.0923. Slower 
eluting 84: TLC Rf = 0.21 (80% EtOAc/20% hexane); mp >300 ?C; 1H NMR (400 MHz, 
CDCl3) ? 7.51 (s, 1H), 6.97 (s, 1H), 6.02 (s, 2H), 5.97 (br s, 1H), 3.72 (s, 1H), 3.51 (dt, J 
= 3, 12 Hz, 1H), 3.36 (t, J = 3 Hz, 1H), 3.11 (d, J = 12 Hz, 1H), 2.20-2.16 (m, 1H), 2.07-
2.02 (m, 1H), 1.69-1.59 (m, 2H). 
Diol 69 
O
O
O NH
O
O
O NH
HO
OH
1. H2O2, HCO2H, rt
2. 1M NaOH, 90 ?C
70 69
51%
 
To a solution of alkene 70 (68 mg, 0.28 mmol, 1.0 equiv.) in formic acid (1.7 mL) was 
added 0.15 mL of 30% aqueous hydrogen peroxide. This yellow solution was stirred for 
14 h at room temperature and then volatile material was removed on rotary evaporator to 
obtain 90 mg white solid.  Aqueous sodium hydroxide (1 M, 0.35 mL, pH = 9) and 2.0 
mL MeOH was then added and reaction mixture was heated at 90 ?C for 3 h. The reaction 
mixture was cooled and solvents were evaporated to obtain a light brown solid. Washing 
the crude product with copious amount of hot ethyl acetate (30 ? 30 mL) gave 60 mg 
light yellow solid. An attempt to recrystallize the crude solid using acetone/methanol 
failed because of poor solubility of the product in most organic solvents as well as water. 
 
 51 
 
Instead, white solid precipitated when the acetone/methanol solution was cooled at 0 ?C 
for a week. The solution was vacuum filtered to obtain product as a white solid. The 
filtrate was cooled at 0 ?C and the process was repeated two additional times to obtain 40 
mg (51%) of diol 69 as a white solid: mp 232-234 ?C; IR (Neat) 3356-3199 (br s),  2938 
(w), 2892 (w), 1629 (s), 1601 (s), 1469 (s), 1261 (s), 1040 (s) cm-1; 1H NMR (400 MHz, 
DMSO) ? 7.64 (s, 1H), 7.28 (s, 1H), 6.89 (s, 1H), 6.05 (d, J = 2 Hz, 2H), 4.86 (d, J = 5 
Hz, 1H), 4.81 (d, J = 4 Hz, 1H), 4.21 (m, 1H), 3.76 (m, 1H), 3.48 (ddd, J = 8, 8, 12 Hz, 
1H), 2.85 (dd, J = 2, 13 Hz, 1H), 1.79-1.74 (m, 1H), 1.65-1.60 (m, 1H), 1.53 (dd, J = 2, 
13 Hz, 1H); 13C NMR (100 MHz, DMSO) ? 163.8, 150.2, 145.6, 136.1, 124.3, 106.7, 
104.9, 101.3, 68.2, 67.3, 49.0, 40.6, 25.5, 25.3; HRMS (FAB) calcd for C14H15NO5 
(M+H)+ 278.1029, found 278.1028. 
 
 
  
 
 
 52 
 
CHAPTER 3 
FORMAL TOTAL SYNTHESIS OF 
(?)-7-DEOXYPANCRATISTATIN 
INTRODUCTION 
We have successfully applied palladium-catalyzed allylic-arylation to the 
synthesis of (?)-7-deoxypancratistatin analogue (69) (see Chapter 2) by coupling an aryl 
siloxane 72 with allylic carbonate 73 (Scheme 3.1).110 The reaction proceeds via 
formation of a ?symmetrical? ?-allyl palladium complex 78 (Scheme 3.2). In this 
instance, reductive elimination from complex 78 is equally probable onto either carbon 1 
and 3, resulting in formation of two regioisomers 71 and 79.  
Scheme 3.1 
O
O
Si(OEt)3
+
NHCO2Et
OCO2Et
O
O NH
O
HO
OH
O
O NHCO2Et
A C A
C
BA
C
697172 73
Pd(0)
TBAF
 
Scheme 3.2 
NHCO2Et
OCO2Et O
O
Si(OEt)3
O
O NHCO2Et
Pd LnAr
H NHCO2Et
HH
O
O
NHCO2Et
1 3
1
3
+
1
3
1
373 78
72
71
79
71:79 = 1.0:1.6
Pd(dba)2, TBAF
65 ?C, THF
81%
 
 
 53 
 
Having demonstrated that this coupling reaction would occur, the next goal was to 
extend siloxane methodology to the synthesis of (?)-7-deoxypancratistatin (24). As 
shown in the retrosynthesis presented in Scheme 3.3, the coupling of aryl siloxane 72 
with allylic carbonate 87 would form the desired bond between A and C rings to produce 
carbamate 49. In comparison to allyl carbonate 73 (Scheme 3.1), allyl carbonate 87 has 
large isopropylidene protected diol portion. We anticipate the coupling of allylic 
carbonate 87 will result in formation of ?unsymmetrical? ?-allyl palladium complex 88 
(Scheme 3.4). Due to steric bulk provided by isopropylidene group, palladium would 
predominantly reside toward carbon 3 in complex 88. Subsequently, reductive 
elimination would preferentially result in formation of carbamate 49, the desired 
regioisomer required for the synthesis of (24). 
Scheme 3.3 
O
O
Si(OEt)3
+
NHE
OCO2Et
O
O
O
O NH
O
HO
OH
OH
OH O
O NHE
O
O
A CA
C
BA
C
24 49 72 87  E = Ester  
Scheme 3.4 
O
O
Si(OEt)3
+
NHE
OCO2Et
O
O O
O NHE
O
O
87
Pd(0)
TBAF
72 49
O O
NHE
PdPh
Ln
88
1
3
1
3
1
3
 
 
 54 
 
RESULTS AND DISCUSSION 
Synthesis of Coupling Partners: Allylic Carbonate and Aryl 
Siloxane 
Allylic carbonate 87 was synthesized using strategy similar to that used for 
carbonate 73 (see Chapter 2) from 1,4-cyclohexadiene. Diene 93 was synthesized from 
commercially available 1,4-cyclohexadiene (89) using Yang's procedure (Scheme 3.5).111 
Dibromination of diene 89 at low temperature afforded dibromoalkene 90, which was 
dihydroxylated to obtain cis-diol 91. Protection of diol 91 with 2,2-dimethoxypropane 
gave acetonide 92. Subsequent dehydrobromination of 92 with DBU provided diene 93.  
Scheme 3.5 
Br
Br
O
O
89 90
93
Br2, CHCl3
-78 ?C, 82%
OsO4, NMO 
acetone, rt, 93%
Br
Br
OH
OH
91
p-TsOH, CH2Cl2, rt, 82%
OMe
DBU, benzene 
reflux, 49%
Br
Br
O
O
92
MeO
 
Diene 93 was used to prepare allyl carbonate 87 (Scheme 3.6) using the 
methodology developed for the model system (see Chapter 2). Diels-Alder reaction of 
diene 93 with acyl nitroso dienophile (generated in situ) provided racemic hydroxamate 
94.103 Reduction of N-O bond to generated allylic alcohol 95104 and subsequent 
protection of alcohol with chloroformate provided allylic carbonate 87.  
 
 
 55 
 
Scheme 3.6 
OH
NHE
O
O
OCO2Et
NHE
O
O
N
O
O
O
ClCO2Et, pyridine
CH2Cl2, rt
 NBu4+IO4- Mo(CO)6, MeCN/H2O 
reflux
O
O
93 94
E = CO2Me, 31%
95 87
E
H
NHO E
 CHCl3/DMF, 0 ?C to rt
E = CO2Et, 57%
E = CO2Me, 79%
E = CO2Et, 67%
E = CO2Me, 86%
E = CO2Et, 93%  
Aryl siloxane 72 was synthesized as shown in the Scheme 3.7.20 The 
commercially available aryl bromide 77 underwent a Grignard reaction to generate the 
organomagnesium species which was quenched by tetraethylorthosilicate (Si(OEt)4) to 
form aryl siloxane 72. 
Scheme 3.7 
Si(OEt)3O
O
O
O
Br
61%
77 72
(ii) Si(OEt)4, THF, -78 ?C to rt
(i) Mg(0), THF, 75 ?C
 
 
 56 
 
Coupling of Allylic Carbonate with Aryl Siloxane 
Preliminary Attempts 
It was anticipated that palladium-catalyzed coupling of allylic carbonate 87 with 
aryl siloxane 72 would yield the coupling product 49 with high regioselectivity based on 
the formation of ?unsymmetrical? ?-allyl palladium complex 88 (Scheme 3.8). However, 
repeated attempts to couple allylic carbonate 87 and aryl siloxane 72 were unsuccessful 
and no traces of carbamate 49 were detected. The use of a more active catalyst such as 
?-allyl palladium chloride dimer did not form carbamate 49, but interestingly gave arene 
ether 96.34 
Scheme 3.8 
O
O
Si(OEt)3OCO
2Et
NHE
O
O
O
O
NHE
O
O
O
O
O NHE
O
O
(allylPdCl)2, PPh3
TBAF, THF, 60 ?C
10 %
72 O O
NHE
PdPh
Ln
88
96
1
3
1
3
87
49
E = CO2Et
 
The plausible mechanism for the formation of arene ether 96 is outlined in the 
Scheme 3.9. Upon reaction of palladium with allylic carbonate 87, the carbonate 
rearranged to form carbonate 97, which underwent hydrolysis under the coupling 
conditions to give allylic alcohol 98. Alcohol 98 reacted with aryl siloxane 72 in the 
presence of palladium to generate arene ether 96. This mechanism is supported by the 
isolation of allylic alcohol 98 (18-32%) under various reaction conditions. The highly 
 
 57 
 
regioselective formation of ether 96 is in accordance with our proposed model in 
Scheme 3.4. The regiochemistry of compound 96 was confirmed using 1H-1H COSY 
experiment. The crystal structure of arene ether 96 further verified regiochemistry, 
stereochemistry as well as ether functionality.34  
Since the coupling of siloxane 72 and carbonate 87 failed under all conditions, it 
was decided that the coupling of carbonate 87 using arylboronic acid (Suzuki coupling) 
and aryl stannane (Stille coupling) would be investigated. While traces of coupled 
product (7% yield) were detected in the Stille coupling, no coupling was seen in the 
Suzuki reaction. The coupling of carbonate with aryl siloxane in the presence of Pd(dba)2 
was unsuccessful under microwave irradiation as well. 
Scheme 3.9 
OCO2Et
NHE
O
O
O
O
Si(OEt)3
NHE
O
O
EtO2CO
NHE
O
O
HO
TBAF
O
O O O
O
NHE
Pd(0) hydrolysis
Pd(0)
97 98
72
96
87
E = CO2Et
 
Investigation of Problems 
The failure of allylic carbonate 87 to undergo allylic-arylation reaction can be 
attributed to the steric bulk of isopropylidene group that blocks the ? face of the alkene, 
 
 58 
 
the face on which the palladium metal must reside (Scheme 3.8). We wanted to know if 
the steric bulk is blocking the formation of ?-allyl intermediate 99 or if it is blocking the 
subsequent transmetalation step (Scheme 3.10). To test if the ?-allyl intermediate 99 was 
formed, we decided to couple malonate anion (a soft nucleophile) with allylic 
carbonate 87. Since the Tsuji-Trost coupling26 of malonate anion with allylic carbonate 
87 will occur via the same ?-allyl intermediate 99, the success of this coupling reaction 
will infer that formation of ?-allyl intermediate 99 is possible.  
Scheme 3.10 
NHE
O
OPd
Ph
NHE
O
OPd
Ln
pi-allyl intermediate transmetalation
Ln
O O
NHE
PdPh
Ln
88
O O
NHE
PdLn
99  
Coupling of malonate anion 100 was first attempted with the model allylic 
carbonate 73 (Scheme 3.11). Unfortunately, Pd(dba)2 and Pd2(dba)3?CHCl3 catalysts 
which were used for the coupling of carbonate 73 with aryl siloxane 72 were ineffective 
(see Chapter 2), and showed predominance of starting material 73 even with 
stoichiometric catalyst loading. However, the Pd(OAc)2/PPh3 system gave diester 101 in 
56% yield. The success of this coupling reaction was not surprising. Since we had already 
demonstrated that coupling of aryl siloxane 72 with allylic carbonate 73 proceeds via 
?-allyl intermediate 102 to form carbamates 71/79 (Scheme 3.11), it was expected that 
 
 59 
 
coupling of carbonate 73 with malonate anion 100 would proceed through the same 
?-allyl intermediate 102 and generate diester 101 with equal feasibility.  
The observance of single regioisomer (101) in the coupling was consistent with 
the model developed in our group (Scheme 3.12). After the formation of ?-allyl adduct 
102, the malonate anion 100 attacked from the face opposite to the palladium (the same 
face as the leaving group) to retain the stereochemistry. However, because the carbamate 
moiety (NHE) is on the same face of attacking malonate anion 100, the nucleophile 
attacks at C1, further away from the carbamate moiety: resulting in the formation of 
regioisomer 101 with an overall retention of stereochemistry.  
Scheme 3.11 
NHE
OE
O
O NHE
NHE
NHE
EE
O
O
Si(OEt)3
O
NHE
O
Pd
Ln
E E
+
Pd(0)
56%73 (E = CO2Et) 102
100
71
79
101
 81%
72
TBAF
 
Having accomplished the coupling of malonate anion 100 with model allylic 
carbonate 73 (Scheme 3.11), we investigated whether the ?-allyl intermediate 99 
(Scheme 3.10) is formed in the coupling of more complex allylic carbonate 87 with 
malonate system. The coupling of allylic carbonate 87 with malonate anion 100 
 
 60 
 
proceeded in a good yield to give regioisomeric diesters 102 and 103 in 4.8:1.0 ratio 
(Scheme 3.13). The ratio of two regioisomers was determined from the integration of 
methyl groups of isopropylidene moiety. The major regioisomer was identified as 
diester 102 using a 1H-1H COSY experiment (see Experimental Section for details of the 
COSY analysis). 
Scheme 3.12 
NHE
EEPd
Ln
H NHE
HH
NHE
Pd
Ln
1
31
3
favored disfavored 102
E E
100
101
NHE
OE
1
3
73 (E = CO2Et)
Pd(0)
 
Scheme 3.13 
OE
NHE
O
O
E E
NHE
E E
O
O
NHE
O
O
E
E
 Pd(OAc)2, PPh3
THF, 65 ?C, 70%
102:103 = 4.8:1.0
87   (E = CO2Et) 102 103100
 
The regioselectivity of the malonate coupling reaction with allyl carbonate 102 is 
rationalized in Scheme 3.14. It was anticipated that the reaction of carbonate 87 will 
result in formation of "unsymmetrical" ?-allyl palladium complex 99 as previously 
discussed. Since palladium resides more towards C1 due to steric compression with the 
 
 61 
 
isopropylidene group, malonate anion 100 was expected to attack at C3 to produce diester 
103 as the major regioisomer. Furthermore, since the nucleophile attacks from the bottom 
face, attack further away from the carbamate moiety (NHE) would be preferred. 
However, diester 102 was observed as the predominant regioisomer. The formation of 
diester 102 suggests preferential attack of malonate anion 100 at C1 termini. This is 
attributed to possible palladium-oxygen coordination with the isopropylidene moiety 
which pushes palladium away from C1, preferring attack of nucleophile at C1.  
Scheme 3.14 
O O
NHE
Pd
Ln
99
1
3
E E
100
O O
NHE
PdLn
99
3
NHE
E E
O
O
103
1
Predicted
E E
100
Observed 1
NHE
O
O
E
E
102
3
Major
1
3
 
The success of this coupling reaction proves that the ?-allyl palladium 
intermediate 99 from the allylic carbonate 87 is formed during the Tsuji-Trost coupling. 
However, when the same reaction is conducted with aryl siloxane 72, the undesired arene 
ether 96 as well as rearrangement product 98 was obtained (Scheme 3.9). This suggests 
either transmetalation or subsequent reductive elimination must be the cause for the 
 
 62 
 
failure of coupling reaction between aryl siloxane 72 and allylic carbonate 87 
(Scheme 3.8). However, since reductive elimination of aryl systems is known to be fast 
(ary-aryl > alkyl-aryl > alkyl-alkyl)4, it was more likely that transmetalation was the root 
of the problem.  
In order to understand the failure of allyl-aryl coupling in the 
7-deoxypancratistatin (24) synthesis (Scheme 3.8) mechanistic study on the siloxane 
reaction was performed. The details of this study are reported in Chapter 4. This study 
had indicated that the best catalyst system for allyl-aryl cross-coupling reaction would 
consist of palladium bonded to sterically demanding, but weakly ?-bonding ligands. This 
set of ligand requirements is not found in most Pd(0) catalysts since Pd(0) is stabilized 
typically by strong ?-donating ligand systems (phosphines). However, some Pd(0) 
catalysts have been prepared that have these characteristics (IV112 and V113,114, 
Figure 3.1) 
O OO
Pd
Pd(NBD)(MAH)
Pd
O O
Pd(COD)(NQ)
IV V  
Figure 3.1: Pd(NBD)(MAH) and Pd(COD)(NQ) complexes 
 
 63 
 
Successful Coupling 
Pd(NBD)(MAH) IV and Pd(COD)(NQ) V were employed in the coupling 
reaction of complex allyl carbonate 87 and aryl siloxanes 72 and 6 (Scheme 3.15). The 
coupling reaction catalyzed by Pd(NBD)(MAH) IV resulted in lower yield of 
carbamate 104. However, the reaction in the presence of Pd(COD)(NQ) V worked 
reasonably well, even at ambient temperatures to give coupled products 49 and 104 in 
30-40% yield. As anticipated the coupling reaction exclusively produced regioisomers 49 
and 104, respectively. Carbamate 49 is the much desired regioisomer for the synthesis of 
natural product 7-deoxypancratistatin (24).  
Scheme 3.15 
Si(OEt)3OCO2Et
NHE
O
O
NHE
O
O
TBAF, rt or 55 ?C
30-40%
87
Pd(COD)(NQ)
O
O
Si(OEt)3
72
Pd(COD)(NQ)
O
O NHE
O
O
49
104
6
Si(OEt)3
NHE
O
O
Pd(NBD)(MAH)
104
6
TBAF, rt or 55 ?C
30-40%
TBAF, rt or 55 ?C
11-19%
E = CO2Me
 
 
 64 
 
Scheme 3.16 
NHaE
O
OO
O NHaE
O
O
O O
NHE
PdPh
Ln
88   E = CO2Me 49
1
3
1
3
O
O
Not observed
49'
1
3
Observed
Hg
HcHb
Hd
Hb
H
 
 
Figure 3.2: 1H-1H COSY of carbamate 49 (Hudlicky's intermediate) 
 
 65 
 
The observed regiochemistry is consistent with the model proposed by DeShong 
(Scheme 3.16). Due to steric bulk arising from the acetonide moiety, an ?unsymmetrical? 
palladium complex is formed where palladium resides farther from the acetonide group. 
The regioselectivity of carbamate 49 was established using 1H-1H COSY (Figure 3.2). 
Having identified the NHa proton at ? 6.18 using HSQC spectroscopy, it was possible to 
locate Hb proton adjacent to the NHa. Since Hb proton is not coupled to adjacent olefinic 
proton, the regioisomer was determined to be 49. If product 49' (Scheme 3.16) had 
formed, Hb proton would show correlation with the neighboring olefinic proton. 
The formation of carbamate 49 via palladium-catalyzed allylic-arylation 
constitutes the formal total synthesis of 7-deoxypancratistatin (24). Carbamate 49 is an 
intermediate reported in Hudlicky's synthesis of 7-deoxypancratistatin. The spectra of 49 
were identical to those reported by Hudlicky.80 
Allylic-arylation using Hudlicky's approach (Scheme 3.17) involves coupling of 
aziridine 48 with cuprate 46 via SN2 process.80,87 The yield of the key reaction is 
comparable to our palladium-catalyzed allylic-arylation using siloxane methodology. 
However, the use of extremely low temperature (-78 to -30 ?C) in Hudlicky's procedure, 
limits its application for large-scale synthesis. On other hand, our allyl-aryl coupling 
reaction can be performed at ambient temperature (Scheme 3.15), and is suitable for 
large-scale industrial production.  
Allylic-arylation approach has also been used by Trost to synthesize 
(+)-pancratistatin (23) (Scheme 3.18).79 Reaction of allylic carbonate 51 with mixed 
cuprate 50 provide allylic-arylated system 52 via SN2? reaction. However, Trost's 
synthesis used complex reaction conditions and was limited to small quantities of 
 
 66 
 
material. Moreover, preparation of mixed cuprate is arduous due to its instability, thus 
making this synthesis unsuitable for practical applications.  
Scheme 3.17 
O
O
CuCNLi2
2
O
O
N
E
O
O
O
O
NHE
BF3?Et2O, THF
-78 to -30 ?C, 34%E = CO
2Me
48 49
46 O
O NH
O
HO
OH
OH
OHA B
C
24  
Scheme 3.18 
OCO2Me
N3
O
O
O
O
CuCN
OMe
O
O
O
O
N3
OMe
MgBr
51
52
50
23
0 ?C O
O NH
O
HO
OH
OH
OH
OH
A B
C
 
According to Hudlicky's procedure, the key steps after the formation of carbamate 
include installation of trans-diol via allylic-alcohol 52 directed epoxidation and Friedel-
Crafts acylation to generate B ring (Scheme 3.19). Following Hudlicky's procedure, 
carbamate 49 was deprotected to generate allylic alcohol 105 (not isolated). The 
subsequent step of epoxidation of allyl alcohol 105 was performed in benzene as reported 
by Hudlicky. However, the poor solubility of diol 105 in benzene led to longer reaction 
times and in consequence extensive decomposition. Switching to acetonitrile as solvent 
 
 67 
 
improved solubility of the diol 105 and NMR analysis of the crude product indicated 
formation of epoxide 106. However, the yield of 106 has not been optimized. 
Nonetheless, the formation of carbamate 49 by siloxane methodology constitutes formal 
total synthesis of (?)-7-deoxypacratistatin (24). In future, this allylic-arylation approach 
shall be extended to the synthesis of pancratistatin (23) (Scheme 3.20). 
Scheme 3.19 
O
O
O
O
NHE
49  E = CO2Me
O
O
OH
OH
NHE
t-BuOOH
VO(acac)2
benzene, 80 ?C
O
O
OH
OH
NHE
O
AcOH/THF
H2O, 65 ?C
105
106
O
O NH
O
HO
OH
OH
OHBA
C
24  
Scheme 3.20 
OCO2Et
NHE
O
O
87
Pd(COD)(NQ)
O
O
Si(OEt)3
72
Pd(COD)(NQ)
O
O NHE
O
O
49
O
O
Si(OEt)3
107
OMe
O
O NHE
O
O
108
OMe
O
O NH
O
HO
OH
OH
OHBA
C
24
O
O NH
O
HO
OH
OH
OHBA
C
23
OH
 
 
 68 
 
CONCLUSION 
Palladium-catalyzed allylic-arylation involving coupling of allylic carbonate and 
aryl siloxane has been applied to produce (?)-7-deoxypancratistatin (24) via Hudlicky's 
intermediate. The key reaction involves the use of a novel Pd(0) olefin complex 
(Pd(COD)(NQ)) and results in stereospecific arylation to form single regioisomer. This is 
a first example of application of palladium-catalyzed allylic arylation to the synthesis of 
7-deoxypancratistatin (24). Though the yield for the key reaction is moderate, the ability 
of the coupling to work at ambient temperature is an advantage compared to 
allylic-arylation methodology by Hudlicky and Trost. Also, due to the ease of preparation 
of coupling partners, aryl siloxane and allyl carbonate compared to unstable aryl cuprate 
and aziridine, the siloxane coupling methodology is particularly well-suited for the 
synthesis of these materials. We believe our synthetic approach is short as well as 
efficient and thus has potential of getting commercialized. Future goals aim at 
development of olefin based palladium catalysts to optimize the key reaction with the 
goal of obtaining multigram quantities of (24) and application of this methodology to the 
synthesis of pancratistatin (23) derivatives.  
 
 69 
 
EXPERIMENTAL DETAILS 
General Methods 
All reactions were run under an atmosphere of argon unless otherwise noted. 
Glassware used in the reactions was dried for a minimum of 12 h in an oven at 120 ?C or 
flame dried prior to use. Tetrahydrofuran was distilled from sodium/benzophenone ketyl, 
while methylene chloride and pyridine were distilled from calcium hydride.  
Thin-layer chromatography (TLC) was performed on 0.25 mm silica gel coated 
plates treated with a UV-active binder with compounds being identified by one or more 
of the following methods: UV (254 nm), vanillin/sulfuric acid charring, or KMnO4 
charring. Flash chromatography was performed using glass columns and medium 
pressure silica gel (Sorbent Technologies, 45-70 ?). 
Infrared spectra were recorded on a Nicolet 560 FT-IR spectrophotometer. 
Samples used for obtaining infrared spectra were either dissolved in carbon tetrachloride 
or taken neat. IR band positions are reported in reciprocal centimeters (cm-1) and relative 
intensities are listed as br (broad), s (strong), m (medium), or w (weak). Nuclear magnetic 
resonance (1H, 13C NMR) spectra were recorded on a 400 or 500 MHz spectrometer. 
Chemical shifts are reported in parts per million (?) and coupling (J values) are reported 
in hertz (Hz). Spin multiplicities are indicated by the following symbols: s (singlet), d 
(doublet), t (triplet), q (quartet), m (multiplet), br s (broad singlet), br d (broad doublet). 
Low resolution mass spectrometry (LRMS) and high resolution mass spectrometry 
(HRMS) were obtained on a JEOL SX-02A instrument. 
 
 
 70 
 
Dibromoalkene 90 
Br
Br
89 90
 -78 ?C, 82%
Br2, CHCl3
 
The dibromoalkene 90 was prepared from 1,4-cyclohexadiene 89 according to Yang's 
procedure.111 To 15.0 mL (159 mmol, 1.00 equiv.) of 1,4-cylcohexadiene 89 dissolved in 
35.0 mL of CHCl3 at -78 ?C was added 8.15 mL (159 mmol, 1.00 equiv.) of Br2 dropwise 
over 2 h. The reaction mixture was stirred for additional 2 h, and then quenched by the 
addition of 75.0 mL 0.1 M aqueous sodium thiosulfate (Na2S2O3) solution. The product 
was extracted with 5 ? 100 mL CH2Cl2 and washed with 100 mL of Na2S2O3 solution. 
The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo 
to afford 31.0 g (82%) of dibromoalkene 90 as a white solid, mp 33-37 ?C (lit.111 34-37 
?C) which was used without further purification.  IR (CCl4) 3037 (w), 2937 (w), 2882 
(w), 2819 (w), 1660 (w), 1421 (s), 1325 (m), 1211 (s), 1187 (m), 1159 (m) cm-1; 1H NMR 
(400 MHz, CDCl3) ?? 5.65 (s, 2H), 4.50 (s, 2H), 3.17 (d, J = 19 Hz, 2H), 2.59 (d, J = 19 
Hz, 2H); 13C NMR (100 MHz, CDCl3) ? 122.3, 48.7, 31.2; LRMS (EI+) m/z 240 (M+ 25), 
161 (23), 159 (25), 79 (100), 77 (38). The spectral data was identical to the literature.111 
Dibromodiol 91 
Br
Br
Br
Br
OH
OH
90 91
OsO4, NMO
acetone, rt, 93%
 
 
 71 
 
To 16.0 g (66.9 mmol, 1.00 equiv.) of dibromoalkene 90 dissolved in 170 mL of acetone 
and 25.0 mL of H2O was added 11.8 g (100 mmol, 1.50 equiv.) of NMO under argon. 
This was followed by addition of 100 mg of OsO4. The reaction was allowed to stir for 3 
days at room temperature and was then quenched by the addition of 28.5 g of (150 mmol, 
2.24 equiv.) sodium metabisulfite. The product was extracted with 5 ? 200 mL CH2Cl2 
and washed with 200 mL H2O. The combined organic extracts were dried over MgSO4, 
filtered and concentrated in vacuo to give 17.0 g (93%) of dibromodiol 91 as a creamy 
solid, mp 103-104 ?C (lit.111 103-105 ?C), which was used without further purification. 
IR (CCl4) 3491-2953 (br s), 2951 (w), 2889 (w), 1685 (w) cm-1; 1H NMR (400 MHz, 
pyridine - d5) ? 6.11 (br s, 2H), 4.86 (ddd, J = 12, 11, 4 Hz, 1H), 4.40 (ddd, J = 12, 11, 4 
Hz, 1H), 4.26 (m, 1H), 3.98 (ddd, J = 12, 4, 3 Hz, 1H), 2.94 (ddd, J = 12, 12, 11 Hz, 1H), 
2.84 (ddd, J = 15, 4, 3 Hz, 1H), 2.71 (dddd, J = 12, 4, 4, 1 Hz, 1H), 2.15 (ddd, J = 15, 12, 
2 Hz, 1H); 13C NMR (100 MHz, pyridine - d5) ? 71.5, 70.9, 56.5, 55.6, 43.7, 42.1; LRMS 
(EI+) m/z 274 (M+, 5), 195 (90), 193 (95), 177 (78), 175 (98), 113 (28), 95 (100), 67 (94), 
55 (51). The spectral data was identical to the literature.111 
Acetonide 92 
Br
Br
OH
OH
Br
Br
O
O
91 92
 p-TsOH,  CH2Cl2, rt, 82%
2,2-dimethoxypropane
 
To 17.0 g (62.1 mmol, 1.00 equiv.) of dibromodiol 91 in 400 mL CH2Cl2 was added 87.7 
mL (621 mmol, 10.0 equiv.) of 2,2-dimethoxypropane, followed by the addition of 2.10 g 
(11.0 mmol, 0.177 equiv.) p-TsOH. The reaction was allowed to stir for 64 h. The 
 
 72 
 
reaction mixture was extracted with 3 ? 300 mL CH2Cl2 and washed with 300 mL H2O. 
The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo 
to obtain 15.9 g (82%) of acetonide 92 as a yellow oil, which was used without further 
purification. IR (CCl4) 2990 (m), 2932 (m), 2877 (m), 2827 (w), 1720 (w), 1456 (m) 
cm-1; 1H NMR (400 MHz, CDCl3) ? 4.39-4.44 (dt, J = 4, 8, Hz, 1H), 4.28 (q, J = 5 Hz, 
1H), 4.14-4.22 (m, 2H), 2.70-2.77 (m, 2H), 2.32-2.40 (m, 1H), 2.17-2.25 (m, 1H), 1.51 
(s, 3H), 1.32 (s, 3H); 13C NMR (100 MHz, CDCl3) ? 109.4, 73.0, 72.6, 51.6, 49.4, 36.5, 
35.0, 28.7, 26.5. The spectral data was identical to the literature.111 
Diene 93 
Br
Br
O
O
O
O
92 93
DBU, benzene,
reflux, 49%
 
To 16.3 g (52.0 mmol, 1.00 equiv.) of acetonide 92 in 58.0 mL benzene was added 18.7 
mL (187 mmol, 3.6 equiv.) of DBU dropwise via an addition funnel. The reaction 
mixture was heated at reflux (80 ?C) for 24 h. The HBr was removed by vacuum 
filtration and the filtrate was extracted with 3 ? 500 mL pentane and washed with 500 mL 
H2O. The combined organic extracts were dried over MgSO4, filtered and concentrated in 
vacuo to afford a yellow oil. Purification by column chromatography (60% 
CH2Cl2/pentane; Rf  = 0.22) rendered 3.87 g (49%) of diene 93 as a yellow oil. IR (CCl4) 
3049 (m), 2986 (m), 2928 (m), 2862 (m), 2792 (w), 1961 (w), 1472 (w), 1441 (m), 1383 
(m), 1351 (m), 1243 (m), 1216 (m) cm-1; 1H NMR (400 MHz, CDCl3)  ? 5.96-5.99 (m, 
2H), 5.85-5.89 (m, 2H), 4.63 (s, 2H), 1.40 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz, 
 
 73 
 
CDCl3) ? 126.7, 123.7, 104.5, 70.2, 27.8, 25.2. The spectral data was identical to the 
literature.111 
Hydroxamate 94 
N
O
O
O
 NBu4+IO4-O
O
93 94
E = CO2Me, 31%
E
H
NHO E
 CHCl3/DMF, 0 ?C to rt
E = CO2Et, 57%  
Hydroxamate (E = CO2Et): To 23.6 g (54.6 mmol, 1.40 equiv.) of NBu4+IO4- 
(tetrabutylammonium periodate) under argon was added chloroform (80.0 mL) and DMF 
(26.0 mL). The reaction mixture was cooled to 0 ?C and then 5.93 g (39.0 mmol, 1.00 
equiv.) of diene 93 was added. Finally, 4.10 g (39.0 mmol, 1.00 equiv.) of hydroxamic 
acid (HONHCO2Et) dissolved in chloroform (40.0 mL) and DMF (13.0 mL) was added 
via addition funnel. The reaction mixture was stirred at 0 ?C to room temperature for 50 
h. The product was extracted with Et2O (5 ? 100 mL), washed with H2O (100 mL), dried 
over MgSO4, concentrated in vacuo to give the crude hydroxamate 94 as a brown oil. 
Flash column chromatography on silica gel (30% EtOAc/70% hexane, Rf = 0.26) gave 
5.72 g (57%) of hydroxamate 94 as a creamy solid, mp 126-128 ?C; IR (CCl4) 2994 (m), 
2933 (m), 1717 (s), 1373 (s), 1254 (s), 1210 (s), 1081 (s) cm-1; 1H NMR (400 MHz, 
CDCl3) ? 6.47-6.38 (m, 2H), 5.06-5.03 (m, 1H), 4.90-4.87 (m, 1H), 4.55-4.49 (m, 2H), 
4.25-4.12 (m, 2H), 1.30-1.25 (m, 9H); 13C NMR (100 MHz, CDCl3) ? 158.1, 130.6, 
129.5, 111.0, 73.1, 72.6, 71.3, 62.8, 52.9, 25.6, 25.4, 14.4; EI mass spectrum, m/z 
 
 74 
 
(relative intensity) 255 (M+, 37), 240 (100), 95 (78), 85 (50), 29 (47); HRMS (EI) calcd 
for C12H17NO5 (M)+ 255.1107, found 255.1112. 
Hydroxamate (E = CO2Me): light yellow solid. mp 146-148 ?C; IR (CCl4) 3087 (w), 
2999 (m), 2985 (m), 2935 (m), 1719 (s), 1440 (s), 1379 (s), 1336 (s), 1250 (s), 1215 (s) 
cm-1; 1H NMR (400 MHz, CDCl3) ? 6.45-6.35 (m, 2H), 5.03-5.00 (m, 1H), 4.87-4.84 (m, 
1H), 4.53-4.46 (m, 2H), 3.72 (s, 3H), 1.27 (s, 3H), 1.26 (s, 3H); 13C NMR (100 MHz, 
CDCl3) ? 158.4, 130.6, 129.4, 110.9, 73.0, 72.5, 71.3, 53.6, 52.8, 25.5, 25.3; HRMS (ESI) 
calcd for C11H16O5N (M+H)+ 242.1029, found 242.1016. 
Alcohol-Carbamate 95 
N
O
O
O
Mo(CO)6, MeCN/H2O 
reflux
94
E = CO2Me, 31%
E
E = CO2Et, 57%
OH
NHE
O
O
95
E = CO2Me, 79%
E = CO2Et, 67%  
Alcohol-Carbamate (E = CO2Et): To 5.72 g (22.4 mmol, 1.00 equiv.) of the 
hydroxamate 94 dissolved in 240 mL acetonitrile and 12.0 mL distilled water was added 
7.10 g (26.9 mmol, 1.20 equiv.) of molybdenum hexacarbonyl (Mo(CO)6). The reaction 
mixture was refluxed at 82 ?C for 15 h. The black-brown reaction mixture was vacuum 
filtered through celite and the filtrate was concentrated in vacuo to give crude 
alcohol-arbamate 95 as a black solid. Flash column chromatography on silica gel (50% 
EtOAc/50% hexane, Rf = 0.44) gave 3.85 g (67%) of carbamate 95 as a white solid, mp 
124-127 ?C; IR (CCl4) 3617 (w), 3451 (w), 2988 (w), 2902 (w), 1735 (s), 1545 (m), 1210 
 
 75 
 
(m) cm-1. 1H NMR (400 MHz, CDCl3) ? 5.94-5.90 (m, 1H), 5.81-5.78 (m, 1H), 5.12 (br s, 
1H), 4.24-4.18 (m, 3H), 4.14-4.09 (m, 3H), 2.42 (br s, 1H), 1.43 (s, 3H), 1.33 (s, 3H), 
1.23 (t, J = 7 Hz, 3H); 13C NMR (100 MHz, d6- DMSO) ? 155.9, 132.6, 129.5, 107.9, 
79.8, 75.9, 69.2, 59.7, 51.5, 27.2, 25.0, 14.6; LRMS (FAB) m/z 258 (M+1+, 42), 240 (66), 
182 (70), 154 (63), 110 (100); HRMS calcd 258.1342, found 258.1341.  
Alcohol-Carbamate (E = CO2Me): white solid. mp 86-88 ?C; IR (CCl4) 3617 (m), 3449 
(m), 3414 (w), 3049 (w), 2995 (m), 2942 (m), 2909 (m), 1730 (s), 1551 (m) cm-1. 1H 
NMR (400 MHz, CDCl3) ? 5.91-5.88 (m, 1H), 5.78-5.74 (m, 1H), 5.35 (br d, J = 8Hz, 
1H), 4.21-4.18 (m, 3H), 4.08-4.06 (m, 1H), 3.65 (s, 3H), 3.12 (br s, 1H), 1.41 (s, 3H), 
1.31 (s, 3H); 13C NMR (100 MHz, CDCl3) ? 156.6, 131.1, 129.7, 109.1, 79.2, 76.8, 68.9, 
52.2, 51.1, 26.9, 24.6; HRMS (ESI) calcd for C11H18O5N (M+H)+ 244.1185, found 
244.1180. 
Carbonate-Carbamate 87 
OH
NHE
O
O
OCO2Et
NHE
O
OClCO2Et, pyridine
CH2Cl2, rt
95 87
E = CO2Me, 79%
E = CO2Et, 67%
E = CO2Me, 86%
E = CO2Et, 93%  
Carbonate-Carbamate (E = CO2Et): To 1.11 g (4.32 mmol, 1.00 equiv.) of alcohol-
carbamate 95 in 15 mL anhydrous CH2Cl2 and 0.522 mL (6.48 mmol, 1.50 equiv.) 
anhydrous pyridine was added 0.642 mL (6.48 mmol, 1.50 equiv.) of ethyl chloroformate 
dropwise via syringe under argon. The reaction was allowed to stir at room temperature 
 
 76 
 
for 5 days. The reaction mixture was extracted with CH2Cl2 (5 ? 25 mL), washed with 
H2O (25 mL), dried over MgSO4 and concentrated in vacuo. Flash chromatography on 
silica gel (75% EtOAc/25% hexane, Rf = 0.75 afforded 1.32 g (93%) of the carbonate-
carbamate 87 as a white solid, mp 82-84 ?C; IR (CCl4) 3446 (m), 2984 (m), 2933 (m), 
2912 (m), 1754 (s), 1730 (s), 1506 (s), 1370 (s), 1254 (s), 1224 (s), 1064 (s), 1040 (s) cm-
1; 1H NMR (400 MHz, CDCl3) ? 5.93-5.86 (m, 2H), 5.11 (br s, 1H), 4.93 (br s, 1H), 4.36-
4.33 (m, 1H), 4.21 (q, J = 7 Hz, 4H), 4.12 (q, J = 7 Hz, 2H), 1.44 (s, 3H), 1.33-1.29 (m, 
6H), 1.24 (t, J = 7 Hz, 3H); 13C NMR (100 MHz, CDCl3) ? 156.0, 154.3, 131.5, 127.1, 
109.3, 76.1, 75.9, 73.9, 64.4, 61.1, 50.2, 26.9, 24.9, 14.6, 14.2; LRMS (FAB) m/z 330 
(M+1+, 6), 154 (38), 136 (40), 73 (48); HRMS (FAB) calcd (M + 1)+ 330.1553, found 
330.1553. 
 Carbonate-Carbamate (E = CO2Me): creamy solid. mp 63-65 ?C. IR (CCl4) 3442 (m), 
2992 (m), 2956 (m), 2906 (m), 1751 (s), 1733 (s), 1554 (m), 1508 (s) cm-1; 1H NMR (400 
MHz, CDCl3) ? 5.86-5.80 (m, 2H), 5.21 (br s, 1H), 5.1 (s, 1H), 4.30-4.27 (m, 1H), 4.19-
4.14 (q, J = 8 Hz 4H), 1.40 (s, 3H), 1.28-1.24 (m, 6H); 13C NMR (100 MHz, CDCl3) ? 
156.4, 154.2, 131.3, 127.0, 109.2, 75.9, 75.8, 73.9, 64.3, 52.1, 50.3, 26.8, 24.7, 14.1;  
HRMS (ESI) calcd for C14H22O7N (M+H)+ 316.1396, found 316.1383. 
Arene Ether 96 
Si(OEt)3O
O
O
O
NHE
O
O
O
OE
NHE
O
O (allylPdCl)2, PPh3
TBAF, THF, 60 ?C
10%
72 9687  E = CO2Et  
 
 77 
 
To a solution of 245 mg (0.900 mmol, 2.00 equiv.) of siloxane 72 in anhydrous THF 
(10.0 mL) was added 154 mg (0.468 mmol, 1.00 equiv.) of carbonate 87, 8 mg (0.021 
mmol, 5 mol %) of (allylPdCl)2, 16.0 mg (0.063 mmol, 15 mol %) of PPh3 and 0.900 mL 
(0.900 mmol, 1 M in THF, 2.00 equiv.) of TBAF. The reaction mixture was heated to 
60 ?C and after 10 min, the color changed from yellow to amber. After 18 h, the reaction 
mixture was quenched by addition of brine (30 mL), extracted with ether (3 ? 30 mL), 
dried over MgSO4 and concentrated in vacuo. Flash chromatography on silica gel (10% 
EtOAc/90% hexane) gave 18 mg (10%) of arene ether 96 as a white solid: recrystallized 
from CH2Cl2/hexane, mp 126-127 ?C; TLC Rf = 0.27 (25% EtOAc/75% hexane); IR 
(CCl4) 3444 (m), 2963 (m), 2928 (m), 1724 (s), 1558 (m) cm-1; 1H NMR (400 MHz, 
CDCl3) ? 6.69 (d, J = 8 Hz, 1H), 6.49 (d, J = 2 Hz, 1H), 6.34 (dd, J = 2, 8 Hz, 1H), 6.08 
(dd, J = 4, 10 Hz, 1H), 6.01 (dd, J = 4, 10 Hz, 1H), 5.95 (s, 2H), 5.01 (d, J = 6 Hz, 1H), 
4.72-4.70 (m, 1H), 4.66-4.64 (m, 1H), 4.45-4.42 (m, 1H), 4.22-4.19 (m, 1H), 4.10 (q, J = 
7 Hz, 2H), 1.48 (s, 3H), 1.38 (s, 3H), 1.27 (t, J = 7 Hz, 3H); 13C NMR (400 MHz, CDCl3) 
? 156.9, 154.1, 148.8, 143.0, 129.2, 128.7, 108.6, 108.4, 101.8, 100.3, 76.1, 75.3, 73.0, 
71.7, 52.7, 28.4, 26.2, 14.5. FAB mass spectrum m/z (relative intensity) 378, 320, 240, 
180, 119, 85. X-ray crystal confirmed regiochemistry, stereochemistry as well as ether 
functionality.34 
Diester 101 
Pd(OAc)2, PPh3,
NHCO2Et
OCO2Et
NHCO2Et
CO2EtEtO2C
101
THF, 65 ?C, 56%
73
EtO2C CO2Et
100  
 
 78 
 
Sodium hydride (33 mg of 60% dispersion in oil, 0.83 mmol, 3.0 equiv.) was washed 
with 3 ? 2 mL of hexane and 2 ? 3 mL of anhydrous THF. To a suspension of the oil-free 
sodium hydride in 2 mL THF was added 0.13 mL (0.88 mmol, 3.2 equiv.) of diethyl 
malonate and stirred for 10 minutes. The diethyl malonate anion 100 was then added to a 
solution of 71 mg (0.28 mmol, 1.0 equiv.) of allyl carbonate 73 dissolved in 1 mL 
anhydrous THF. This was followed by addition of 36 mg (0.14 mmol, 0.50 equiv.) 
triphenyl phosphine and 6.2 mg (0.028 mmol, 0.10 equiv.) of palladium acetate. The 
reaction mixture was allowed to stir at 65 ?C for 22 h. The solution was filtered through 
Celite and the filtrate was extracted with 5 ? 25 mL Et2O and washed with 25 mL H2O. 
The combined organic layers were dried over MgSO4, concentrated in vacuo to give 
crude diester 101 as a brown oil. Flash column chromatography on silica gel (20% 
EtOAc/80% hexane, Rf = 0.15) gave 50 mg (56%) of diester 101 as a colorless oil; IR 
(CCl4) 3450 (w), 2987 (m), 2936 (m), 2872 (w), 1730 (s) 1502 (m), 1214 (m) cm-1; 1H 
NMR (400 MHz, CDCl3) ? 5.71 (s, 2H), 4.74 (d, J = 8 Hz, 1H), 4.21-4.11 (m, 5H), 4.06 
(q, J = 7 Hz, 2H), 3.26 (d, J = 8 Hz, 1H), 2.83-2.79 (m, 1H), 1.74-1.67 (m, 3H), 1.50-1.44 
(m, 1H), 1.25-1.17 (m, 9H); 13C NMR (100 MHz, CDCl3) ? 168.2, 168.1, 155.7, 131.5, 
128.8, 61.4, 60.7, 56.1, 44.7, 35.0, 27.7, 22.2, 14.6, 14.0; FAB mass spectrum m/z 
(relative intensity) 328 ((M+H), 9), 239 (28), 161 (100), 79 (38); HRMS (FAB) calcd for 
C16H26O6N (M+H)+ 328.1760, found 328.1773.  
The regiochemistry of carbamate 101 was established using 1H-1H COSY (400 MHz, 
CDCl3) (see page 79). NHa proton identified using HSQC spectroscopy is coupled only to 
Hb proton. Since, Hb proton is coupled to vinyl proton; the regioisomer was determined to 
be 101. (If 101' had formed, Hb would not couple to vinyl proton.) 
 
 79 
 
NHaCO2Et
CO2EtEtO2C
101
Hb NHaCO2Et
101'
Hb
EtO2C
EtO2C
Only Observed Not Observed  
COSY of Diester 101 
 
 
 80 
 
Diesters 102 and 103 
OE
NHE
O
O
E E
NHE
E E
O
O
NHE
O
O
E
E
 Pd(OAc)2, PPh3
THF, 65 ?C, 70%
102:103 = 4.8:1.0
87 102 103100
E = CO2Et
 
Sodium hydride (37.9 mg of 60% dispersion in oil, 0.948 mmol, 3.00 equiv.) was washed 
with 3 ? 3 mL of hexane and 3 ? 3 mL of anhydrous THF. To a suspension of the oil-free 
sodium hydride in 2 mL THF was added 0.152 mL (1.01 mmol, 3.20 equiv.) of diethyl 
malonate and stirred for 10 minutes. The diethyl malonate anion 100 was then added to a 
solution of 104 mg (0.316 mmol, 1.00 equiv.) of allyl carbonate 87 dissolved in 2 mL 
anhydrous THF. This was followed by addition of 41.4 mg (0.158 mmol, 0.500 equiv.) 
triphenyl phosphine and 7.09 mg (0.0316 mmol, 0.100 equiv.) of palladium acetate. The 
reaction mixture was allowed to stir at 65 ?C for 24 h. The solution was filtered through 
celite and the filtrate was extracted with 5 ? 25 mL Et2O and washed with 25 mL H2O. 
The combined organic layers were dried over MgSO4, concentrated in vacuo to give 
crude as brown oil. Flash column chromatography on silica gel (20% EtOAc/80% 
hexane, Rf = 0.29) gave 88 mg (70%) of diesters 102 and 103 (102:103 = 4.8:1.0) as light 
yellow oil; The ratio of regioisomers was determined from the 1H NMR. The major 
regioisomer was established to be 102 based on COSY (400 MHz, CDCl3). Diesters 102 
and 103 : IR (CCl4) 3439 (w), 2984 (m), 2936 (w), 2913 (w), 1737 (s) 1506 (s), 1373 (m), 
1220 (s) cm-1;  Diester 102: 1H NMR (400 MHz, CDCl3) 5.82-5.72 (m, 2H), 4.77 (br s, 
1H), 4.52 (s, 1H), 4.28 (s, 1H), 4.24-4.13 (m, 5H), 4.06 (q, J = 7 Hz, 2H), 3.45 (s, 2H), 
 
 81 
 
1.39 (s, 3H), 1.34 (s, 3H), 1.27-1.19 (m, 9H); Diesters 102 and 103: FAB mass spectrum 
m/z (relative intensity) 532 ((M+Cs)+, 75), 342 (32), 179 (22), 133 (100); HRMS (FAB) 
calcd for (M+Li)+ 406.2053, found 406.2056. 
1H NMR spectrum of diesters 102 and 103 indicated predominantly one 
regioisomer. The ratio of two regioisomers was determined from the integration of 
methyl groups of isopropylidene moiety. Diester 102 was established as the major 
regioisomer by COSY (400 MHz, CDCl3). Ha proton (NHa proton identified using HSQC 
spectroscopy) is coupled only to Hb proton. However, Hb proton is not coupled to vinyl 
proton (which is the case only for regioisomer 102). Therefore, the predominant 
regioisomer was determined to be diester 102. 
COSY of diesters 102 and 103 
 
 
 82 
 
Carbamate 104 
Si(OEt)3
NHE
O
OOCO2Et
NHE
O
O
TBAF, THF, 55 ?C
30-40%
87
Pd(COD)(NQ)
1046  
Carbamate (E = CO2Me): To 97.0 mg (0.404 mmol, 2.00 equiv.) of aryl siloxane 6 and 
66.5 mg (0.202 mmol, 1.00 equiv.) of carbonate-carbamate 87 dissolved in 4.00 mL 
anhydrous THF was added 0.404 mL (0.404 mmol, 2.00 equiv.) TBAF under argon. This 
was followed by addition of 37.6 mg (0.101 mmol, 0.500 equiv.) Pd(COD)(NQ). The 
reaction mixture was heated at 55 ?C for 24 h. The reaction was then quenched by 
addition of 25.0 mL H2O. The product was extracted with 3 ? 25 ml CH2Cl2 and washed 
with H2O. The combined organic extracts were dried over MgSO4, filtered and 
concentrated in vacuo to give a brown oil. Flash column chromatography on silica gel 
(20% EtOAc/80% hexane, Rf = 0.15) gave 24 mg (38%) of carbamate 104 as pale yellow 
solid, mp 148-150 ?C; IR (CCl4) 3469 (w), 3448 (w), 2987 (w), 1730 (s), 1507 (s), 
1246(s), 1221 (s) cm-1; 1H NMR (400 MHz, (CD3)2CO) ? 7.30-7.27 (m, 2H), 7.22-7.18 
(m, 3H), 6.22 (br d, J = 8 Hz, 1H), 5.99-5.95 (m, 1H), 5.87 (d, J = 10 Hz, 1H), 4.68 (t, J = 
5 Hz, 1H), 4.26 (m, 1H), 3.69 (q, J = 10 Hz, 1H), 3.51 (br d, J = 10 Hz, 1H), 3.38 (s, 3H), 
1.45 (s, 3H), 1.33 (s, 3H); 13C NMR (100 MHz, (CD3)2CO) ? 157.3, 142.7, 136.8, 129.3, 
129.1, 127.5, 124.8, 109.8, 77.9, 73.3, 56.7, 51.6, 47.4, 28.7, 26.5; HRMS (ESI) calcd for 
C17H22O4N (M+H)+ 304.1549, found 304.1563.  
Carbamate (E = CO2Et): light yellow solid. mp 109-112 ?C. IR (CCl4) 3469 (w), 3452 
(w), 3032 (w), 2987 (m), 2929 (w), 2876 (w), 1726 (s), 1548 (s), 1511 (s), 1381 (m), 
 
 83 
 
1246 (s), 1221(s) cm-1; 1H NMR (400 MHz, (CD3)2CO) ? 7.30-7.26 (m, 2H), 7.22-7.18 
(m, 3H), 6.23 (br d, J = 8 Hz, 1H), 5.99-5.96 (m, 1H), 5.87 (d, J = 12 Hz, 1H), 4.68 (t, J = 
4 Hz, 1H), 4.28 (dd, J =  4 Hz, J = 8 Hz, 1H), 3.81 (q, J = 4 Hz, 2H), 3.69 (dd, J = 8 Hz, J 
= 12 Hz, 1H), 3.53 (br d, J = 8 Hz, 1H), 1.45 (s, 3H), 1.33 (s, 3H), 1.01 (t, J = 8 Hz, 3H); 
13C NMR (100 MHz, (CD3)2CO) ? 156.9, 142.8, 136.8, 129.3, 129.1, 127.5, 124.9, 109.8, 
77.9, 73.4, 60.3, 56.7, 47.5, 28.7, 26.5, 15.0; HRMS (ESI) calcd for C18H24O4N (M+H)+ 
318.1705, found 318.1674. The regiochemistry of carbamate 104 was established using 
1H-1H COSY (400 MHz, (CD3)2CO) in a manner similar to carbamate 49 (page 64, 
Figure 3.2) 
COSY of carbamate 104 
 
 
 84 
 
Carbamate 49 (Hudlicky's Intermediate) 
Si(OEt)3O
O NHE
O
OOCO2Et
NHE
O
O
TBAF, THF, 55 ?C
30-40%
72 87
O
O
Pd(COD)(NQ)
49  
Carbamate (E = CO2Me): To 462 mg (1.63 mmol, 2.00 equiv.) of aryl siloxane 72 and 
256 mg (0.813 mmol, 1.00 equiv.) of carbonate-carbamate 87 dissolved in 15.0 mL 
anhydrous THF was added 1.63 mL (1.63 mmol, 2.00 equiv.) TBAF under argon. This 
was followed by addition of 152 mg (0.407 mmol, 0.500 equiv.) Pd(COD)(NQ). The 
reaction mixture was heated at 55 ?C for 24 h. The reaction was then quenched by 
addition of 30.0 mL H2O. The product was extracted with 3 ? 50 ml CH2Cl2 and washed 
with H2O. The combined organic extracts were dried over MgSO4, filtered and 
concentrated in vacuo to give brown oil. Flash column chromatography on silica gel 
(30% EtOAc/70% hexane, Rf = 0.17) gave 98 mg (35%) of carbamate 49 as pale yellow 
solid, mp 177-179 ?C ((lit.80 190-191 ?C); IR (CCl4) 3467 (w), 3442 (w), 3042 (w), 2995 
(w), 2881 (w), 1730 (s), 1504 (s), 1486 (s), 1250 (s) cm-1; 1H NMR (500 MHz, 
(CD3)2CO) ? 6.75 (d, J = 8 Hz, 1H), 6.68-6.65 (m, 2H), 6.18 (br d, J = 8 Hz, 1H), 5.97-
5.93 (m, 3H), 5.85 (d, J = 10 Hz, 1H), 4.66 (t, J = 5 Hz, 1H), 4.25-4.22 (m, 1H), 3.62 (q, 
J = 10 Hz, 1H), 3.46 (br d, J = 10 Hz, 1H), 3.42 (s, 3H), 1.45 (s, 3H), 1.33 (s, 3H); 13C 
NMR (125 MHz, (CD3)2CO) ? 157.4, 148.6, 147.4, 136.9, 136.6, 124.8, 122.5, 109.9, 
109.4, 108.8, 101.9, 77.9, 73.3, 56.9, 51.6, 47.1, 28.7, 26.6; HRMS (ESI) calcd for 
C18H22O6N (M+H)+ 348.1447, found 348.1440. 1H and 13C NMR spectra in CDCl3 are 
 
 85 
 
identical with that reported by Hudlicky.80 The regiochemistry of carbamate 49 was 
established using 1H-1H COSY (500 MHz, (CD3)2CO), provided on page 64,  Figure 3.2. 
Carbamate (E = CO2Et): light yellow solid. mp 151-153 ?C; IR (CCl4) 3467 (w), 3446 
(w), 3042 (w), 2995 (w), 2935 (w), 2874 (w), 1726 (s), 1547 (s), 1511 (s), 1486 (s), 1250 
(s) cm-1; 1H NMR (500 MHz, (CD3)2CO) ? 6.75 (d, J = 8 Hz, 1H), 6.68-6.65 (m, 2H), 
6.11 (br d, J = 8 Hz, 1H), 5.97-5.94 (m, 3H), 5.86 (d, J = 10 Hz, 1H), 4.66 (t, J = 5 Hz, 
1H), 4.25-4.22 (m, 1H), 3.86 (q, J = 5 Hz, 2H), 3.62 (q, J = 10 Hz, 1H), 3.46 (br d, J = 10 
Hz, 1H), 1.45 (s, 3H), 1.33 (s, 3H), 1.05 (t, J = 5 Hz, 3H); 13C NMR (125 MHz, 
(CD3)2CO) ? 157.0, 148.7, 147.4, 136.8, 136.7, 124.9, 122.6, 109.9, 109.5, 108.8, 102.0, 
77.9, 73.4, 60.5, 57.0, 47.3, 28.8, 26.6, 15.0; HRMS (ESI) calcd for C19H24O6N (M+H)+ 
362.1604, found 362.1563. 
 
 86 
 
CHAPTER 4 
MECHANISTIC STUDIES ON 
PALLADIUM-CATALYZED ALLYLIC-ARYLATION 
INTRODUCTION 
The DeShong group has developed palladium-catalyzed arylation of allylic esters 
via coupling of aryl siloxanes (see Chapter 1).29-34 This methodology has been shown to 
be both highly regio- and stereoselective and has been successfully applied to the 
synthesis of a (?)-7-deoxypancratistatin analogue 69 (Scheme 4.1) (see Chapter 2). 
However, repeated attempts to effect coupling between carbonate 87 and siloxane 72 for 
the synthesis of 7-deoxypancratistatin (24) were unsuccessful and no trace of the desired 
adduct 49 was detected. 
Scheme 4.1 
OE
NHE
OE
NHE
O
O
O
O
Si(OEt)3
NHE
O
O
NHE
O
O
O
O O NH
HO
O
O
OH
OH
OH
O
O NH
O
HO
OH
Pd(0), TBAF
24
69
72
73
71
49
Pd(0), TBAF
7-deoxypancratistatin analogue
7-deoxypancratistatin
87  
 
 87 
 
It was hypothesized initially that failure of allyl carbonate 87 to undergo arylation 
was the result of the steric bulk of the isopropylidene group that blocked the ?-face of the 
alkene and prevented formation of the requisite ?-allyl intermediate 99 (Scheme 4.2). 
However, the successful coupling of allylic carbonate 87 with malonate anion 100 
demonstrated that formation of ?-allyl intermediate 99 had been produced since it 
underwent Tsuji-Trost coupling. This result led us to infer that either transmetalation or 
the subsequent reductive elimination step, latter steps in the mechanism, must be 
responsible for failure of the coupling reaction between aryl siloxane 72 and allyl 
carbonate 87 (Scheme 4.3). Since both transmetalation and reductive elimination involve 
transfer of an aryl group during the catalytic cycle, we anticipated that altering 
substituents on the aryl ring would affect the relative rates of these processes. 
Accordingly, we chose to investigate the role of substituents on aryl siloxane in 
controlling the rate of the coupling reaction via Hammett analysis. 
Scheme 4.2 
OO
O NHE
O
O
O
NHE
OE
E E
NHE
E E
O
O
NHE
O
O
E
E
O
O
Si(OEt)3
F
70%
100
109
102 103
102:103 = 4.8:1.0
Pd(0)
87 (E = CO2Et)
49
O O
NHE
PdLn
99
 
 
 88 
 
Scheme 4.3 
O
O
NHE
O
O
NHE
OO
O NHE
O
Si
OEt
F
OEt
OEt
O
O
O
O
NHE
OE
Pd
Ln
Pd
LnO
O
Pd(0)
transmetalation
reductive elimination substitution/pi ? allyl formation
O O
NHE
PdLn
87
9988
49
109
 
Transmetalation 
Transmetalation of organometallic compounds with transition metal complexes is 
one of the key steps in carbon-carbon bond formation. However, mechanistic details of 
the transmetalation process are not well understood for most of these catalytic processes. 
Among many useful coupling variants, the Stille reaction is the most extensively studied 
system with regard to the mechanism of transmetalation. One of the earliest studies is that 
of palladium-catalyzed coupling of benzoyl chloride with benzyltin reagents by 
Stille.115,116 Subsequently, Farina reported a kinetic analysis of the effect of palladium 
ligands on the Stille reaction117 and Hartwig investigated the mechanism of 
transmetalation of tin amides and tin thiolates.118 More recently, Amatore and Jutand 
have studied the mechanism of Stille reaction in the presence of AsPh3 ligated palladium 
 
 89 
 
catalyst, and confirmed Farina's proposal that AsPh3 increased the efficiency of the Stille 
reaction compared to PPh3.119 An extensive kinetic study of the transmetalation reaction 
in Stille coupling has been carried out recently by Espinet, who has proposed an 
associative transmetalation model for the key step and also investigated the nature of the 
transition state (Figure 4.1).120-123 Studies on internal-coordination driven transmetalation 
are also known in literature.124-126 Transmetalation studies on palladium-catalyzed cross 
couplings of alkynyl stannanes with aryl iodides and that with metal-halides have been 
reported by Crociani127 and Lo Sterzo128, respectively. Additionally, Wendt129 and 
Clarke130 have reported studies on transmetalation of organostannanes and organozincs, 
respectively, with platinum complexes. More recently, theoretical calculations on 
transmetalation of Stille reaction have appeared.131-135 
X
Sn R2
PdLn R1 Sn R
2
?+
PdLn
X
R1?
+
?-
SE2 (cyclic) SE2 (open)
 
Figure 4.1: Espinet's model for transmetalation in Stille reaction 
Transmetalation in the Suzuki-Miyaura and Hiyama protocols have been studied 
less extensively. Transmetalation processes for cross-coupling of organoboron 
compounds in alkaline solution have been studied by Miyaura.136 Three possible 
pathways for transmetalation process have been proposed (Scheme 4.4). In Path A, the 
addition of sodium hydroxide generates tetravalent boronate anion 110 which enhances 
nucleophilicity of organic group and thus accelerates transmetalation. Alternatively, 
ligand exchange between R-Pd-X and a base R?O generates oxo palladium(II) complex 
 
 90 
 
111 in situ (Path B). The high bascity of the Pd-OR species as well as the high 
oxophilicity of boron results in enhanced reactivity of the oxo palladium complex. On the 
other hand, reaction of allyl acetate can proceed under neutral conditions since oxidative 
addition directly yields ?-allylpalladium acetate complex 111 (Path C). These three 
pathways are highly dependent on the combination of bases and organoboron reagents, as 
well as organic electrophiles.  
Scheme 4.4 
R-Pd-X
Path A
B
OH
OH
OHR'
R-Pd-R'
Path B R''O
R-Pd-OR''
110
111
Path C
R-OR'' +  Pd(0)
R'-B(OH)2
(HO)2B R'
R''O Pd R
 
R'L2Pd
O
B
H
SE2 (cyclic)
112
 
Figure 4.2: Transmetalation of alkyl boranes 
Woerpel and Soderquist studied transmetalation of primary alkyl borane 
derivatives to palladium and proposed a hydroxo bridged SE2 (cyclic) transition state 112 
(Figure 4.2 ).137,138 More recently, theoretical studies on mechanism of Suzuki-Miyaura 
 
 91 
 
reaction catalyzed by diphosphine palladium complexes have been reported. According 
to these studies arylboronic acid is activated by an external base, which attacks the 
palladium center as an boronate anion.139-144  
The use of organosilanes rather than boranes as cross-coupling partners has been 
less studied and mechanistic knowledge for Hiyma coupling is scarce. Because the Si-C 
bond is less polarized than the corresponding B-C bond, Hiyama introduced use of a 
nucleophilic fluoride source to polarize Si-C bond via formation of a reactive 
pentacoordinate silicate and enhance transmetalation.145-148 Hiyama showed that the 
stereochemistry of transmetalation can be influenced by the reaction temperature and the 
solvent used.145,147 For example, the cross-coupling reaction of aryl triflates 113 with 
chiral alkylsilanes 114 (Scheme 4.5) in THF at low temperatures proceeded with 
retention of configuration, whereas reaction at higher temperatures or in polar solvents 
(HMPA) resulted in inversion of configuration. Retention of configuration is attributed to 
fluorine-bridged SE2 (cyclic) transition state 115 in the transmetalation (Scheme 4.6). At 
higher temperature or in polar solvents, a fluorine-silicon bridge is cleaved resulting in 
SE2 (open) transition state 116 and thus inversion of configuration. Stereochemistry in 
cross-coupling of allyltrifluorosilanes with aryl triflates was shown also to be influenced 
by temperature and fluoride source.148 
Scheme 4.5 
X
F3Si
Me
X = H, OMe
OSO2CF3
Y
Y = H, 3-CHO, 4-COMe
Pd(PPh3)4
TBAF
Y
X
Me
50-100 ?C
113 114  
 
 92 
 
Scheme 4.6 
F4Si Ph
HMe
Pd(Ar)LnF
F4Si Ph
HMe Pd(Ar)(F)Ln
Ln(Ar)Pd Ph
HMe
Ph Pd(Ar)Ln
HMe
Ar Ph
HMe
Ph Ar
HMe
SE2(cyclic)
SE2(open) Inv
retention
inversion
115
116  
Recently, Sakaki reported a theoretical study of the transmetalation between 
palldium(II)-vinyl complex and vinyl silane.149 The study indicated a very large 
activation barrier for transmetalation process in the absence of fluoride anion. In the 
presence of fluoride anion, transmetalation is accelerated by the formation of a very 
strong Si-F bond and the stabilization of the transition state by hypervalent Si center 
induced by the fluoride anion. 
Denmark has also performed mechanistic studies on organosilanes via kinetic 
analysis under both fluoride-mediated and fluoride-free conditions.150,151  In an effort to 
study transmetalation process, stable transmetalation intermediates in Stille, Suzuki and 
Hiyama cross-coupling have also been isolated.152-155 
 
 93 
 
Hammett Analysis  
Hiyama Coupling 
Mechanistic studies of transmetalation of an aryl group in metal-catalyzed 
couplings of organosilanes using Hammett analysis have been reported previously 
(Scheme 4.7). For example, Hatanaka and Hiyama have shown that electron-donating 
groups (EDG) enhance the rate of transmetalation of diarylfluorosilicates with an aryl-
palladium complex (Figure 4.3).156 The negative slope is indicative of the electrophilic 
character of the transmetalation. The presence of EDG on diarylfluorosilicate 117 
increases the nucleophilicity of the aryl-silicon bonds, which aids in electrophilic attack 
of arylpalladium(II) complex 118 via a Si-Pd binulclear intermediate 119 formed by a 
fluoride bridge (Scheme 4.8). 
Scheme 4.7 
SiF2R I
R
(?3-C3H5PdCl)2
R = OMe, Me, H, F, CF3  
Scheme 4.8 
Ar Si Ar Si
F
F
Ar' PdIIFLn
PdLAr'
F
SiAr
F
Ar' PdIILn
Ar
Ar'-Ar PdoLn
117
118
119
 
 
 
 94 
 
 
Figure 4.3: Hammett analysis of the reaction of diaryl(difluoro)silanes with iodobenzene. 
Taken from ref 156. 
Suzuki Coupling 
The reactivity of various arylboronic acid for the coupling of (E)-bromostilbene in 
the presence of Pd(OAc)2/PPh3 was evaluated by competitive experiments (Scheme 
4.9).157 Arylbornic acids containing an electron-donating group (EDG) in the para 
position were found to be more reactive (? = -0.71) (Figure 4.4). EDG increases 
nucleophilicity of the aryl group, promoting transfer of aryl group to the electron 
deficient palladium. This result is analogous to the results from the Pd(OAc)2/PPh3 
catalyzed cross-coupling reaction of arylboronic acid with vinyl bromide, generated in 
situ from 1,2-dibromoethane (? = -1.26).158 On the other hand, nickel-catalyzed Suzuki 
coupling of an arylboronic acid and an aryl tosylate gave the opposite result: electron-
withdrawing groups (EWG) on the aryl boronic acid facilitated transmetalation and gave 
a slope of ? = 0.81.159 
 
 95 
 
Scheme 4.9 
B(OH)2 B(OH)2
R
R = OMe, Me, Cl, CF3
Br
Pd(OAc)2/PPh3, KOH
R
 
 
Figure 4.4: Hammett analysis of the reaction of arylboronic acid with E-bromostilbene. 
Taken from ref 157. 
Additionally, Hammett analysis has also been employed to study the mechanism 
of the reaction of aryl bromides and arylboronic acid catalyzed by palladacycles (Figure 
4.5). It was found that aryl bromides bearing EWG accelerated the rate of reaction and 
gave correlation values of ? = 0.48, ? = 0.66, and ? = 0.99 for palladacycles VI160, VII160 
and VIII161 respectively. Transmetalation processes have also been studied for the cross-
coupling of phenyl boronates with propargylic carbonates (? = 0.73)162,  ?-selective cross-
coupling of potassium allyltrifluoroborates with aryl bromides (? = -1.1)163, and 1,4-
addition of arylboronic acids to enones (? = -0.54).164 
 
 96 
 
PPh
2
Pd
N Cl
i-Pr
2 PPh2
Pd
N Cl
PCy3
i-Pr
VI VII
Pd
N
VIII
F3OCO 2
Pr-i Pr-i
 
Figure 4.5: Palladacycles used in Hammett analysis of arylboronic acid with aryl 
bromides 
Stille Coupling 
Farina studied the electronic influence of aryl stannane on the transmetalation step 
by competitive experiment of vinyl triflate with various para-substituted aryl stannanes 
(Scheme 4.10).165 In the absence of lithium chloride, EDG on the aryl stannane 
accelerated transmetalation (? = -0.89),  indicating development of positive charge in the 
transition state (Figure 4.6). However, in the presence of LiCl, the linear relationship 
could not be obtained (Figure 4.7). This indicated two mechanistically different pathways 
for the transmetalation process in the presence of salt. Farina's results are in contrast to 
that by Stille employing acid chlorides and benzylic stannanes (? = 1.2).116 
Scheme 4.10 
SnBu3 SnBu3
R
R = NMe2, OMe, Cl, CF3
Pd2dba3, AsPh3
(LiCl)
t-Bu
R
OTs
t-Bu t-Bu
 
 
 97 
 
 
Figure 4.6: Hammett analysis of Stille 
coupling reaction in absence of LiCl. Taken 
from ref 165. 
 
Figure 4.7: Hammett analysis of Stille 
coupling reaction in presence of LiCl. 
Taken from ref 165. 
 
In summary (Table 4.1), Hammett studies of cross-coupling reactions have 
indicated that transmetalation is a complex process in which the rates of coupling are 
strongly influenced by substituents on the ring as well as the catalyst and/or ligand. In 
light of the failure of our aryl-allyl coupling reaction in the 7-deoxypancratistatin (24) 
synthesis (Scheme 4.1), we chose to investigate the mechanism of the siloxane-based 
coupling reaction in detail.  
The goal of this project was to perform a Hammett study of the coupling reaction 
utilizing palladium-catalyzed siloxane derivatives. The study reported below is the first 
mechanistic investigation of an allyl-aryl coupling process involving silicon-based 
reagents. 
 
 
 98 
 
Organometallic Partner Electrophilic Partner Catalyst ?
SiF2R
I (?3-C3H5PdCl)2
B(OH)2R
Br
Pd(OAc)2/PPh3
SnBu3R Pd2dba3, AsPh3t-BuTsO
TsOB(OH)2R
-1.5
-0.71
0.81
-0.89
1.
2.
3.
4.
NiCl2(PCy3)2
 
Table 4.1: Summary of Hammett studies 
RESULTS AND DISCUSSION 
Hammett Analysis 
The proposed mechanism for the allyl-aryl coupling reaction is summarized in 
Scheme 4.11. The relative rates for each individual step of the coupling will be discussed 
below. Cyclohexenyl carbonate (120) was chosen as the coupling partner for the siloxane 
study because it was known to undergo facile allyl-aryl coupling with siloxane 
derivatives under established protocols. There is significant literature precedent for the 
rapid and reversible formation of ?-allyl palladium complexes from allylic derivatives 
with both phosphine and dibenzylideneacetone (dba) ligands.166,167 (The reversibility of 
 
 99 
 
the reaction is diminished with carbonates since the carbonate anion decomposes to 
carbon dioxide and alkoxide under the typical coupling conditions).166 
Scheme 4.11 
 
Pd
LnOCO2Et
Pd
R
Ln
Si(OEt)3
R
F
Pd
Si(OEt)3F
R
Ln
Si(OEt)3
R
TBAF
Pd(0) transmetalation
?+
???
?
120 123 124 125 126
122
fast
fast
R121
 
However, it was important to conclusively demonstrate that this step was not rate-
determining in this coupling system, and that result can be inferred from the subsequent 
Hammett analysis reported below. If formation of the ?-allyl intermediate 123 were 
rate-determining, then a correlation of rates with Hammett parameters on the siloxane 
moiety would not be observed because the siloxane would not appear in the rate equation 
for formation of the ?-allyl complex. Accordingly, the Hammett correlation observed 
(vide infra) is consistent with the formation of the ?-allyl palladium complex being a fast 
process. 
Formation of the hypercoordinate silicate 122 from the reaction of fluoride anion 
(TBAF) with the siloxane derivative 121 is not rate-determining either. This was 
demonstrated by 19F NMR spectroscopy of the reaction of TBAF and phenylsiloxane 
derivatives 121. In the key experiment, a hypercoordinate silicate species (121, R = H) 
 
 100 
 
was generated in situ by reaction with fluoride source (TBAF) (Scheme 4.12 and 
Figure 4.8). The formation of hypercoordinate silicates was observed using 19F NMR 
where the fluorine signal of TBAF (? -114)168 disappeared rapidly (10 min) at room 
temperature on addition of phenylsiloxane to give two new fluorine signals: a sharp 
singlet at  ? -121, and a broad resonance centered at ca.  ? -127, respectively, as shown in 
Figure 4.8. The signals at  ? -121 and  ? -127, respectively, are consistent with chemical 
shifts of hypercoordinate fluorosilicate species such as 122 and 127, respectively reported 
by this and other groups.169-177 Upon cooling (-29 ?C), the 19F signal at  ? -121 sharpened, 
showing silicon satellites (JSi-F = 207 Hz). Additonally, 29Si NMR also indicated coupling 
of 207 Hz at  ? -129 confirming the formation of hypervalent silicate species (see 
Experimental Section, Figure 4.15).  
Scheme 4.12 
Si(OEt)3
R
FSi(OEt)3
R
TBAF
Si(OEt)2
R
F
OEt
Si(OEt)3
R
F
122
F
2
127  
 
 101 
 
 
Figure 4.8: 19F NMR spectra of silicate formation (a) TBAF in THF at 29 ?C (b) 19F 
NMR spectrum of silicate complexes resulting from 1:1 mixture of TBAF and 
Triethoxyphenylsilane at 29 ?C. Insert is 19F signal at ? -121 after cooling to -28 ?C. 
The broad signals in the 19F NMR spectrum are consistent with formation of 
hypercoordinate complex(es) that undergo dynamic processes including ligand exchange 
and pseudorotation. The equilibrium between the various silicates is dependent on 
stoichiometry of fluoride:siloxane and other electronic factors. The 19F NMR spectra are 
also temperature dependent, indicating a dynamic process (see Experimental Section). 
Preliminary studies of silicate formation indicated that the electronic effects of the groups 
attached to the aryl ring had an effect on the relative quantities of each component, but 
additional studies have to be undertaken to determine the relative importance of each 
silicate to the overall coupling reaction. Nonetheless, the conclusion drawn from this 
JSi-F = 207 Hz 
-28 ?C 
a) TBAF at 29 ?C 
b) TBAF and Triethoxyphenylsilane (1:1) at 29 ?C 
 
 102 
 
study is that at room temperature, the siloxane reacted with fluoride ion to provide 
hypercoordinate silicates rapidly, much more rapidly than coupling occurred. 
Analogously, when TBAF (2 equiv.) was added to a mixture of phenylsiloxane (1 
equiv.) and its p-methoxy congener (1 equiv.), the signal for TBAF rapidly disappeared 
and was replaced by a series of resonances indicative of hypercoordinate silicate 
formation. This experiment conclusively demonstrated that formation of the silicate from 
the reaction of fluoride ion and the siloxane derivatives was fast and could not be the 
rate-determining step in the coupling reaction. 
We had proposed initially that either transmetalation of silicate 122 to ?-allyl 
palladium complex 123 or subsequent reductive elimination was the rate-determining 
step in the coupling reaction (Scheme 4.11). If this assumption were correct, then the rate 
of the allyl-aryl coupling should be influenced by the electronic characteristics of the 
substituent present on the aryl ring of siloxane 121, and substituents in the para-position 
would stabilize (or destabilize) transition state 124 resulting in a rate enhancement (or 
diminution). Competition experiments between phenyltriethoxysilane 6 and para-
substituted aryl siloxanes 121 (R = OMe, Me, Cl, CO2Et) were performed and the results 
are summarized in Figure 4.9. The relative rate of transmetalation was enhanced by 
electron-withdrawing groups (EWG). Electron-withdrawing groups are better at 
stabilizing the developing negative charge on the ipso-carbon in transition state 124 
through inductive effects.  
 
 103 
 
OCO2Et
Si(OEt)3
H
HSi(OEt)
3
R
R
Si(OEt)3
OMe
Si(OEt)3
Me
Si(OEt)3
H
Si(OEt)3
Cl
Si(OEt)3
CO2Et
Pd(dba)2, 55 ?C
THF, TBAF
0.42 0.72 1 3.4 4.2
Relative rate of coupling reaction
6 121 9 126
120
 
Figure 4.9: Summary of relative rates of coupling reactions with siloxane derivatives 
More importantly, the excellent correlation observed in the Hammett analysis is 
consistent with the proposal that the rate-determining step is either the transmetalation or 
reductive elimination reaction. As was noted above, if ?-allyl formation were the slow 
step, then no difference in the relative rates would have been observed since the 
substituents on the aryl ring would not be able to manifest their influence in the rate 
determining step of the coupling reaction. 
Having established the nature of the substituent effect for the siloxane coupling 
protocol, the magnitude of the stabilization that occurred in the transition state for the 
coupling was determined from the Hammett correlation. Hammett plots were obtained by 
plotting log (k/k0) against substituent parameters  ?p,  ?-, and  ?+.178 The plot of log (k/k0) 
 
 104 
 
against  ?p gave the best linear correlation to the experimental data (Figure 4.10) with 
slope ? = 1.4. The linear regression with  ?p value indicated that an inductive effect was 
chiefly responsible for stabilization of the transition state.  
The positive slope (? = 1.4) of the line indicated that coupling was sensitive to the 
electronic effects of substituents and that a significant amoung of negative charge was to 
be found on the aromatic ring in the transition state 124 (Scheme 4.11). Contrast the 
magnitude of the ? value (+1.4) with the values obtained in studies of borates and 
stannanes, respectively (described above) where |?| = 0.7-1.1 (Table 4.1). The positive 
slope of ? = 1.4 is in sharp contrast with the studies reported by Hiyama (? = -1.5)156, 
Monteiro (? = -0.71)157 and Farina (? = -0.89)165 using silicon, boron and stannane 
derivatives, respectively, in the presence of palladium catalyst, where EWG retarded the 
rates of coupling reaction (Table 4.1).  
COOEtCl
H
OMe
Me ? = 1.4
R2 = 0.95
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
-0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5
?p
lo
g(
k/k
o)
 
Figure 4.10: Hammett analysis of allyl-aryl coupling reaction 
It is noteworthy to reiterate the significance of the Hammett correlation: the 
observed substituent effects are consistent with formation of the ?-allyl complex being a 
fast and reversible reaction as was noted above and either the transmetalation or the 
 
 105 
 
reductive elimination is rate-determining (Scheme 4.11). If formation of ?-allyl complex 
were rate-determining, then the Hammett plot should have had a slope of zero because 
the aryl siloxane was not involved in that step of the mechanistic cycle.  
It is worth emphasizing that the term ?rate-determining step? in the discussion 
above is not precise. Rate-determining and product-determining have been used 
interchangably, although this is not valid in a strict interpretation.  We know that 
formation of pi-allyl intermediate 123 is fast and reversible step (Scheme 4.13). Assuming 
transmetalation and reductive elimination is irreversible, if reductive elimination is slow, 
the product-determining step is transmetalation since it is the first irreversible step. This 
may not be the rate-determining step, but it is the step that leads to selective formation of 
one coupling product over the alternative. On the other hand, if transmetalation is slower 
than reductive elimination, transmetalation is still product-determining as well as rate-
determining. In this study, relative rates of irreversible steps were measured and not the 
absolute rates. Nonetheless, regardless of which step is slow (rate-determining), 
transmetalation is the product determining step.  
Scheme 4.13 
Si(OEt)3
F
Ar1
Si(OEt)3
F
Ar2
Ar1
Ar2
transmetalation
reductive
elimination
Pd
Ln
123
Pd
Ar1
Ln
Pd
Ar2
Ln
transmetalation
reductive
elimination
 
 
 106 
 
 From the data provided it is not possible to unambiguously determine which of 
these two steps is rate-determining. For this coupling reaction, however, we propose that 
the rate-determining step is transmetalation, rather than reductive elimination, based on 
several lines of circumstantial evidence.  
First, since no coupled product 49 was obtained in the 7-deoxypancratistatin  (24) 
synthesis, it is reasonable to assume that the transmetalation had not occurred to give 
palladium complex 88 (Scheme 4.3). Although the rationale for this conclusion is 
complex, the analysis is important for the mechanistic study in question. Formation of 
pi-allyl complex 99 (Scheme 4.3) was fast and reversible; thus the experimentally 
observed rearrangement of the cyclohexenyl carbonate was observed as a byproduct in 
this coupling (see Chapter 3). If the rate-determining step was transmetalation, then a 
slow transmetalation reaction would provide greater opportunity for rearrangement and 
decomposition of the cyclohexenyl starting material without leading to coupled product. 
If, on the other hand, reductive elimination were the rate-determining step, coupled 
product, even if only trace amounts, would have been obtained since it is unlikely that 
transmetalation was reversible. Reductive elimination must result in formation of 
coupled product or reduced arene (via beta-hydride elimination followed by reductive 
elimination). No trace of either coupled product or reduced arene was observed under 
these conditions. 
A second piece of evidence supporting the conclusion that transmetalation was 
rate-determining was derived from the study of Kurosawa on the reductive elimination of 
diorganopalladium complexes.179,180 Kurosawa was able to prepare allyl-aryl palladium 
complexes (utilizing an alternative methodology) and measured the rate of reductive 
 
 107 
 
elimination at 0 ?C. If extrapolated to 55 ?C, as in our coupling protocol, the rates of 
reductive elimination would be much faster than the rate of coupling observed, thus 
suggesting that transmetalation, and not reductive elimination, is rate-determining step 
for the allyl-aryl coupling reaction reported in our study. Admittedly, the evidence is 
circumstantial, since the Kurosawa system involved different ligands on the metal center 
than our coupling protocol. 
Even more significant is that Kurosawa demonstrated that electron-deficient 
alkenes promoted, not retarded, the reductive elimination in his system. This observation 
is particularly germane to our coupling system in which the electron-deficient dba 
(dibenzylideneacetone) is a ligand on the catalyst that functions for this coupling. 
Assuming that the silicate system behaves analogously to the Kurosawa analog, we 
would anticipate that the reductive elimination step would be facilitated by the presence 
of electron-deficient ligand as was observed by Kurosawa.179-181 
As has been noted by Denmark in his mechanistic studies of analogous silanol-
based aryl-aryl coupling reactions, there is no unambiguous evidence for the 
intermediacy of a diorganopalladium (II) complex that undergoes reductive elimination to 
produce the product (Scheme 4.11).151 In the allyl-aryl system described herein, it is 
possible that ?-allyl complex 123 reacted with the activated silicate 122 via a substitution 
reaction to yield the product directly. Nonetheless, one would observe that this step 
would be rate-determining.  
Further support for our hypothesis that the rate-determining step in the coupling 
reaction is transmetalation, and not reductive elimination comes from Hartwig's lab. 
Hartwig has reported several mechanistic studies of palladium-catalyzed coupling 
 
 108 
 
reactions in which reductive elimination is the rate determining step.182-186 In each of 
these studies, however, an isolable palladium (II) complex was prepared and then 
decomposed thermally via reductive elimination to provide product. Hammett analyses of 
these systems have shown significant substituent effects, but the results are not as 
straightforward as is observed in our system. For C-S bond formation, the substituent 
effect was qualitatively similar to those observed in our study, namely faster rates with 
electron-withdrawing substituents, but there was no correlation with Hammett sigma 
values. They were able to correlate the rates of reductive elimination only with a mixed 
Hammett value that included both inductive and resonance contributions.184 Analogous 
situations were observed for C-N and C-C coupling reactions, respectively.185,186 
Role of Ligands 
The studies summarized above have established that Hammett analysis is an 
excellent method for gathering mechanistic information regarding the transition state 
(124) for the transmetalation step of the mechanism (Scheme 4.11). Furthermore, this 
Hammett methodology can be employed for investigating the roles of catalyst-ligand 
combinations in the coupling reaction. Typically, the development of an "optimized" 
catalyst system for a coupling reaction involves the empirical development of conditions 
and reagents using various ligand-metal ratios and is based on yield or turnover of 
product. The actual role that the ligand (Ln in 124, Scheme 4.11) plays in transmetalation 
cannot be assessed except in a qualitative sense: the reaction yield was high or low. 
Adding ligand or substituting a new metal may change the yield of the reaction, but does 
not provide precise mechanistic information about the rate-determining step in the 
 
 109 
 
catalytic process. However, once the relative rates for various substituents had been 
measured under standardized conditions, we were able to extend our Hammett study to 
include various catalyst-ligand combinations. In particular, we were interested in 
determining whether the rate of transmetalation could be enhanced by changing ligands 
on the palladium. Ligands with different electronic and steric properties187 might be able 
to stabilize the transition state 124 (Scheme 4.11) differently and hence affect the rate of 
transmetalation. By measuring the relative rates between two aryl siloxanes, it should be 
possible to investigate the role that electronic factors play in the coupling reaction.  
As shown in the Table 4.2, entry 1, the best catalyst for the coupling of siloxanes 
and cyclohexenyl carbonate (120) is Pd(dba)2. Changing the catalyst to either Pd2(dba)3 
or Pd2(dba)3?CHCl3 resulted in a considerable decrease in the yield of coupled product. 
Why the yield is diminished is less clear since all three of these Pd-complexes are 
thought to behave comparably as Pd(0) sources. On the other hand, the relative rates of 
p-anisoylsiloxane/phenylsiloxane (121:6) with all three catalyst systems, it was observed 
that the ratio of 0.42 ? 0.02 was maintained. The result clearly demonstrated that the rate-
determining step in the coupling reaction was identical with all three catalysts systems 
and that another step in the mechanism must be responsible for the diminished yields of 
product. The effect of various added ligands on the coupling reaction was evaluated and 
the results are summarized in the Table 4.2. 
 
 
 
 110 
 
OCO2Et
Si(OEt)3
H
H
Si(OEt)3
OMe
OMe
Pd(0), 55 ?C
Ligand
THF, TBAF
120
9 1261216  
Entry Pd (0) Source 
(10 mol %) 
Ligand 
(20 mol %) 
Relative 
Rate 
Yield 
(%)a 
1 Pd(dba)2 - 0.42 80 
2 Pd2(dba)3 - 0.42 63 
3 Pd2(dba)3?CHCl3 - 0.40 61 
4 Pd(dba)2 AsPh3 0.39 53 
5 Pd(dba)2 PPh2(C6F5) 0.42 32 
6 Pd(dba)2 PCy3 0.42 55 
7 Pd(dba)2 P(o-tolyl)3 0.43 48 
8 Pd(dba)2 PPh3 0.25 <20b 
9 Pd(dba)2 I 0.33 <20b 
10 Pd(dba)2 II - NA 
11 Pd(dba)2 III - NA 
12 Pd(dba)2 P(2-Fu)3 - NA 
13 Pd(dba)2 - 0.45 79c 
14 Pd(dba)2 - 0.39 64d 
15 Pd(OAc)2 PCy3 0.39 <20b 
16 Pd(OAc)2 AsPh3 0.44 <20b 
17 Pd(OAc)2 PPh3 - NA 
18 Pd(OAc)2 P(2-Fu)3 - NA 
19 Pd2(dba-4,4'-OMe)3 - 0.39 55 
20 Pd(dba-4,4'-CF3)2?H2O - 0.41 51 
P
t-Bu t-Bu
P
Cy Cy
P
P
128
129
130  
a Yield determined by gas chromatography using a standard. b Yield determined 
by column chromatography. c DMF was used as a solvent. d Dioxane was used 
as a solvent. Note: relative rates and yields in entry 1 are averages of three runs, 
entries 2-9, 15-16 and 19-20 are averages of two runs. P(2-Fu)3 is 
tri-2-furylphosphine (TFP). 
Table 4.2: Role of ligands in the allyl-aryl coupling reaction 
 
 
 111 
 
Strongly electron-donating ligands (PCy3 and P(o-tolyl)3, entries 6 and 7) with cone 
angles significantly greater than triphenylphosphine, gave higher yields of coupled 
products than triphenylphosphine, respectively, but did not alter the relative rate of 
arylated products. The larger cone angle of these phosphines would be expected to 
provide a ?-allyl complex with a low coordination number due to steric bulk, thus 
facilitating transfer of aryl group from the fluoride-activated siloxane. More electron-
withdrawing ligands (entries 5 and 12) significantly reduced the yields of coupled 
product also, but had no effect on the relative rates. AsPh3 (entry 4) gave a better yield of 
coupled products when compared with PPh3 (entry 8). Since, the As-Pd bond is longer 
than the P-Pd bond; the As-Pd complex might be experiencing less steric hindrance from 
phenyl groups. With stannane derivatives, Farina had also shown that AsPh3 ligand  
dissociates more readily from palladium intermediates compared to PPh3, thus enhancing 
the rate of transmetalation (>103) compared to PPh3.117 Large deviations from the relative 
rate ratios were observed for the addition of ligands such as PPh3 and the Buchwald 
ligand 128188,189 (entries 8 and 9). Unfortunately, the yields of coupling products in these 
systems were so low that it is inappropriate to draw meaningful conclusions about the 
coupling reactions. 
The study of ligand effects on allyl-aryl coupling reaction revealed that Pd(dba)2 
in absence of any phosphine ligands is the best catalytic system (Table 4.2, entry 1). It is 
known that electronic and steric properties of phosphine ligands can be tuned to achieve 
desired catalytic reactivity. We wondered if the same idea can be applied to design 
metal-olefin catalysts for our allyl-aryl coupling reaction. As seen in the Figure 4.11, the 
metal-olefin bond is described as a combination of  ?-donation from a filled olefin 
 
 112 
 
?-orbital to an empty metal orbital and ?-back donation from a filled metal orbital to an 
empty olefin ?* orbital.190,191 For an electron rich d10-configuration such as Pd0, ?-back 
donation from palladium center to olefin is important. Stronger ?-back donation results in 
stronger palladium-olefin bond, thus increasing the stability of palladium complex, but 
reducing the lability of the olefin ligand. Both the electronic and steric nature of olefins 
plays an important role in determining the binding affinity to palladium. Electron 
deficient alkenes are bound more tightly to palladium because of increased ?-back-
donation. Additionally, strained olefins such as norbornene possess high binding affinity 
to palladium because of relief of ring strain upon carbon rehybridization and reduction of 
steric hindrance.190  
C
C
M ? donation
C
C
M
pi
pi*
pi donation
 
Figure 4.11: Donor-Acceptor model for transition-metal-olefin complexes. Redrawn 
from ref 190. 
The catalytic activity as well as stability of metal-olefin complex can be tuned by 
adjusting the electronics and sterics of the olefin ligand. It is believed that for most 
transmetalations an open coordination site is required.190 We envisioned that an olefin 
ligand lacking an electron withdrawing group that can readily dissociate from palladium 
would facilitate transmetalation of the aryl group from silicon to palladium. However, 
such olefins may also reduce the stability of palladium complex. For example, palladium 
 
 113 
 
complexes such as Pd(norbornene)3, Pd(COD)2 and Pd(ethene)3 are stable only at 
extremely low temperatures.192,193 
First, effect of electronic nature of dba (dibenzylideneacetone) ligands 
(Figure 4.12) on the relative rate of allyl-aryl coupling reaction was studied (Table 4.2, 
entries 19 and 20). It was anticipated that electron donating groups (OMe) on the dba 
ligand will destabilize ?-back donation compared to more electron withdrawing groups 
(H, CF3). This would promote dissocation of dba from the palladium and faciliate 
transmetaltion. Accordingly, [Pd2(dba-4,4'-OMe)3] and [Pd(dba-4,4'-CF3)2?H2O] catalysts 
were prepared according to Fairlamb's procedure194 and a competition experiment of allyl 
carbonate 120 was performed. The change of electronic character of the dba ligands, 
respectively, did not change the relative rate; however the yield of coupled product 
decreased (entries 19 and 20, Table 4.2). In contrast to our coupling results, the Suzuki 
coupling of aryl chlorides with arylboronic acids performed by Fairlamb showed that 
electron donating groups on Pd(dba)2 increased the rate of the cross-coupling reaction, 
relatively to unsubstituted dba (131, R = H).194 Very recently, Fairlamb has reported 
palladium(0) complexes containing thienyl analogues (132, 133) of dibenzylideneacetone 
(dba) and evaluated their reactivity in oxidation addition reaction with iodobenzene.195 
O
R Rdba
R = OMe, H, CF3
131
O
132
S
O
S S
133
 
Figure 4.12: Various alkenyl ligands 
 
 114 
 
Pd2(dba)3 serve as an important precursor for the synthesis of zerovalent 
palladium complexes bearing additional ligands such as phosphines, nitrogen, sulfur as 
well as olefins.112-114,196-208 The stability of these complexes is governed by subtle 
interplay between electron-donating and electron-withdawing properties of the ligand. 
Our intial attempts involved preparation of mixed olefin complexes according to the 
procedure reported by Itoh and co-workers.112 Itoh prepared mixed olefin complexes of 
Pd(0) by a ligand substitution of Pd2dba3?CHCl3. By an appropriate combination of 
electron-donating and electron-withdrawing olefin ligands it was possible to isolate three-
coordinate mixed olefin complexes (IV, IX, X, Figure 4.13). Catalysts IV, IX and Xwere 
prepared and used in the aryl-allyl coupling reaction (Table 4.3, entries 1-3).  
O OO
Pd Pd
CN
CNNC
NC
Pd(NBD)(MAH) Pd(COD)(TCNE)
Pd
O OO
Pd(COD)(MAH)
IV XIX
 
Figure 4.13: Pd(NBD)(MAH), Pd(COD)(MAH) and Pd(COD)(TCNE) complexes 
As seen in Table 4.3, replacing olefin MAH (maleic anhydride) with TCNE 
(tetracyanoethylene), but retaining COD (cyclooctadiene) as diene, reduced the yield of 
coupled product dramatically (entries 2 and 3). On other hand, by subsituting COD 
(cyclooctadiene) with NBD (norbornadiene) but retaining MAH improved yield (entries 2 
and 4). Interestingly, the catalytic activity of Pd(NBD)(MAH) IV and Pd(COD)(MAH) 
 
 115 
 
IX does not correlate to the strain energy of NBD and COD. One would anticpate NBD 
having larger strain energy compared to COD to bind tighter to the palladium due to the 
relief of strain and thus be less labile. However, higher yields with Pd(NBD)(MAH) IV 
compared to Pd(COD)(MAH) IX suggested NBD to be more labile olefin. This result is 
constistent with that of Orchad and Weiss who showed despite higher strain energy, NBD 
bings less strongly to metal (copper or silver) compared to COD and pointed to 
significance of steric factors.209,210 
It is important to note that both Pd(NBD)(MAH) IV and Pd(COD)(MAH) IX 
catalyzed allyl-aryl coupling reaction even at ambient temperature, which is not the case 
with Pd(dba)2. This suggests that these catalysts are far more reactive than Pd(dba)2. 
However they produce lower yields compared to Pd(dba)2 (Table 4.3, entry 1). This can 
be attributed to instability of these complexes in solution compared to Pd(dba)2. During 
coupling reaction precipitation of palladium black is observed within 2-3 hrs when using 
Pd(NBD)(MAH) IV and Pd(COD)(MAH) XI, but this is not the case with Pd(dba)2. 
While the preparation of Pd(NBD)(MAH) IV was easy, the preparation of 
Pd(COD)(MAH) XI and Pd(COD)(TCNE) X was tedious and required careful handling 
due to their instability (precipitation of palladium black) when exposed to air and ambient 
temperature. This was also the case with catalysts Pd(cyclopentene)(MAH)2 and 
Pd(norbornene)MAH2 which could not be isolated due to extensive decomposition to 
palladium black.  
 
 116 
 
OCO2Et Si(OEt)3
Pd(0)
TBAF
120 6
9  
Entry Pd(0) (25 mol%) TBAF equiv. Siloxane equiv. Yield (%) 
1 Pd(dba)2 2.0 2.0 70 
2 Pd(COD)(MAH) 2.0 2.0 38 
3 Pd(COD)(TCNE) 2.0 2.0 17 
4 Pd(NBD)(MAH)a 2.0 2.0 54 
5 Pd(COD)(NQ) 2.0 2.0 48 
6 Pd(COD)(DQ) 2.0 2.0 23 
7 Pd(COD)(NQ) 2.0 2.0 41b 
8 Pd(COD)(NQ) 8.0 8.0 45 
9 Pd(COD)(BQ) 2.0 2.0 20 
10 Pd(NBE)2(BQ)2 2.0 2.0 21 
All reactions were performed at 55 ?C for 24 h. a 12 mol% of catalyst used. 
b Reaction in entry 6 was performed in DMF. 
Table 4.3: Optimization of Pd(0)-olefin catalyzed allyl-aryl coupling reaction  
 
The instability of mixed olefin complexes prepared by Itoh limited their 
application in the allyl-aryl coupling reaction. We next chose to examine Pd(0)-triolefin 
complexes containing quinones prepared from Pd2dba3?CHCl3 (Figure 4.14).113,114 These 
catalysts are stable at ambient temperature and therefore easy to prepare. When employed 
in the allyl-aryl coupling reaction, Pd(COD)NQ V gave superior yields in comparison to 
palladium complexes formed using Pd(COD)BQ XI and Pd(COD)DQ XII, indicating a 
strong electronic influence on the catalyst's performance. It is interesting to note that 
subtle changes such as inclusion of aromatic ring (NQ = naphthoquinone) in the catalyst 
dramatically improve the yield compared to BQ (benzoquinone) and DQ (duroquinone). 
 
 117 
 
Optimization of reaction conditions using Pd(COD)(NQ) V showed no improvements in 
yield. Dinuclear Pd(0) complex possessing  BQ as a bridging ligand and NBE 
(norbornene) as a monodentate ligand was also prepared114, however, this catalyst XIII 
resulted in poor yield (Table 3, entry 10).  
 
Pd
O O
O
O
Pd
O
O
Pd
Pd2(NBE)2(BQ)2Pd(COD)(NQ) Pd(COD)(DQ)
Pd
Pd(COD)(BQ)
V XI XII XIII
OO
Pd
OO
 
Figure 4.14: Pd(COD)(NQ), Pd(COD)(BQ), Pd(COD)(DQ), Pd2(NBE)2(BQ)2 complexes 
From the results summarized in Table 4.3, Pd(NBD)(MAH) IV and 
Pd(COD)(NQ) V were identified as appropriate cataysts for allyl-aryl coupling reaction 
using cyclohexenyl carbonate as substrate 120. Next, these catalysts were applied in the 
coupling of more complex carbonate 87 with aryl siloxane 6 and siloxane 72. (Scheme 
4.14). It was observed that even stoichiometric amounts of Pd(NBD)(MAH) IV gave 
worse yields (11-13%) compared to Pd(COD)(NQ) V for the coupling reaction (Scheme 
4.13). Thus, Pd(COD)(NQ) V is the best catalyst as of now for the reaction shown in the 
Scheme 4.14.  
 
 118 
 
Scheme 4.14 
Si(OEt)3OCO2Et
NHE
O
O
NHE
O
O
TBAF, rt or 55 ?C
30-40%
87
Pd(COD)(NQ)
O
O
Si(OEt)3
72
Pd(COD)(NQ)
O
O NHE
O
O
49
104
6
Si(OEt)3
NHE
O
O
Pd(NBD)(MAH)
104
6
TBAF, rt or 55 ?C
30-40%
TBAF, rt or 55 ?C
11-19%
E = CO2Me
 
Though Pd(dba)2 works well (70% yield, Table 4.3) with the simple allyl-aryl 
coupling reaction it does not function in the coupling of complex allyl carbonate 87 with 
aryl siloxane 72. This might be because electron withdrawing dba disssociates less 
readily from the palladium compared to COD, hindering transfer of aryl group to the 
palladium center. However, Pd(COD)(NQ) results in lower yields compared to Pd(dba)2 
in case of cyclohexenyl carbonate (Table 4.3) presumably because of its decompostion to 
palladium black. 
The coupling product 49 is the desired compound for the synthesis of natural 
product 7-deoxypancratistatin (24) (see Chapter 3). The moderate yield of the coupling 
reaction is one of the drawbacks of this reaction. Future goals would aim at application of 
different kinds olefin-based catalysts in palladium-catalyzed allylic arylation to optimize 
the key reaction.  
 
 119 
 
CONCLUSION 
Mechanistic studies on coupling reaction of allyl carbonate and aryl siloxane has 
offered several useful insights; 
1. On the basis of Hammett analaysis of allyl-aryl coupling of para-substituted 
siloxane derivatives with cylcohexenyl carbonate, the rate-determining step of the 
coupling reaction was identified as either transmetalation or reductive elimination. 
Furthermore, it was observed that the rate of coupling reaction was enhanced by 
electron-withdrawing substituents, indicating deveopment of  negative charge on 
the aromatic ring in the transition state of the rate-determining step. 
2. Competition studies as a function of ligand type revealed that electronic as well as 
the steric nature of phosphine ligands on the metal site dramatically affect yield of 
coupled product, but rarely affect the relative rates of the coupling reaction. This 
idea was used to explore steric and electronic nature of olefin-based palladium 
catalyst on allyl-aryl coupling reaction. 
3. A new family of catalysts for the siloxane coupling process that overcomes the 
limitations have been developed. These catalyst are more reactive than Pd(dba)2 
which is apparent from their ability to catalyze the reaction at ambient 
temperature.  
4. Tri-olefin-based Pd(0) catalyst, Pd(COD)(NQ) has been succesfully applied in the 
coupling reaction of complex allyl carbonate 87 with aryl siloxane 72 
(Scheme 4.14) to produce much needed coupling product 49 (Hudlicky's 
intermediate) for the synthesis of natural product 7-deoxypancratistatin (24).  
 
 120 
 
EXPERIMENTAL DETAILS 
General Methods 
All reactions were run under an atmosphere of argon unless otherwise noted. 
Glassware used in the reactions was dried for a minimum of 12 h in an oven at 120 ?C. 
Tetrahydrofuran was distilled from sodium/benzophenone ketyl, while methylene 
chloride, pyridine, dimethylformamide and dioxane were distilled from calcium hydride. 
PPh3, PCy3, and 2-(dicyclohexylphosphino)biphenyl were recrystallized from hexanes 
prior to use. P(o-tolyl)3 and P(2-Fu)3 were recrystallized from ethanol. AsPh3, PPh2(C6F5) 
and 2-(di-t-butylphosphino)biphenyl were used as received. [Pd2(dba-4,4'-OMe)3] and 
[Pd(dba-4,4'-CF3)2?H2O] catalysts were prepared using the procedure reported by 
Fairlamb.194 Pd(COD)(TCNE)112, Pd(COD)(MAH)112, Pd(NBD)(MAH)112  
Pd(COD)(NQ)113, Pd(COD)(BQ)113, Pd(COD)(DQ)113, Pd2(NBE)2(BQ)2114 were prepared 
as reported in the literature.  
19F NMR and 29Si NMR were recorded on a high field 500 MHz NMR 
spectrometer. 19F and 29Si chemical shifts are referenced to external standard TFA and 
TMS respectively. Gas chromatography was performed on a Hewlett Packard 5890 GC 
equipped with a flame ionization detector using a 25m methyl silicon column. 
 
 121 
 
Allyl carbonate 120 
OH
ClCO2Et, pyridine
CH2Cl2, rt, 64%
OCO2Et
120  
To 2.09 g (21.3 mmol, 1.00 equiv.) of commercially available 2-cyclohexen-1-ol in 20.0 
mL anhydrous CH2Cl2 and 2.57 mL (31.9 mmol, 1.50 equiv.) anhydrous pyridine was 
added 3.17 mL (31.9 mmol, 1.50 equiv.) of ethyl chloroformate dropwise via syringe 
under argon. The reaction was allowed to stir at room temperature for 7 days. The 
reaction mixture was extracted with CH2Cl2 (3 ? 50 mL), washed with H2O (50 mL), 
dried over MgSO4 and concentrated in vacuo. Flash chromatography on silica gel (5% 
EtOAc/95% hexane, Rf = 0.51) afforded 2.32 g (64%) of the allyl carbonate 120 as a 
colorless oil; IR (CCl4) 3042 (w), 2981 (w), 2947 (m), 2875 (w), 2838 (w), 1737 (s), 
1373 (s), 1265 (s), 1017 (s) cm-1; 1H NMR (400 MHz, CDCl3)  ? 5.97-5.93 (m, 1H), 5.77-
5.73 (m, 1H), 5.10-5.09 (m, 1H), 4.16 (q, J = 7 Hz, 2H), 2.05 (m, 1H), 2.05-1.98 (m, 1H), 
1.88-1.80 (m, 3H), 1.62 (m, 1H), 1.28 (t, J = 7 Hz, 3H); 13C NMR (100 MHz, CDCl3)  ? 
154.8, 133.2, 125.0, 71.5, 63.6, 28.2, 24.8, 18.5, 14.2. The spectral data (1H NMR) were 
identical to that reported in the literature.211 
 
 122 
 
General procedure for competition experiments for allyl-aryl coupling 
reaction (Table 4.2) 
OCO2Et
Si(OEt)3
H
H
Si(OEt)3
R
R
Pd(dba)2, 55 ?C
THF, TBAF
6 9 126
120
R = OMe, Me, Cl, CO2Et
121
 
To 121 mg (0.712 mmol, 1.00 equiv.) of allyl carbonate 120, 342 mg (1.42 mmol, 2.00 
equiv.) of aryl siloxane 6 and 383 mg (1.42 mmol, 2.00 equiv.) of p-anisoylsiloxane 121 
(R = OMe) dissolved in 4.00 mL of anhydrous THF was added 40.9 mg (0.0712 mmol, 
0.100 equiv.) of Pd(dba)2 under an atmosphere of argon. This was followed by addition 
of 2.84 mL (2.84 mmol, 4.00 equiv.) of 1 M TBAF solution in THF and the reaction 
mixture was stirred at 55 ?C for 24 h. The product was extracted with 5 ? 20 mL Et2O 
and washed with 20 mL H2O. The combined organic layers were dried over MgSO4 and 
concentrated in vacuo to give coupling products 9 (R = H) and 126 (R = OMe). The 
crude product was filtered through a short silica plug. The relative quantity of 0.44 for 
p-anisoylsiloxane 121 (R = OMe) was determined from the amount of 
methoxyphenylcyclohexene 126 (R = OMe) obtained relative to phenylcyclohexene 9 
using GC (gas chromatography). The same experimental procedure was used to 
determine relative rates of different aryl siloxanes 121. Moreover, effects of different 
catalysts, ligands and solvents on the relative rate of transmetalation were examined 
 
 123 
 
(Table 4.2), using analogous competition experiments, where yields were determined by 
GC using standard unless otherwise noted.  
Aryl siloxanes 121 
Si(OEt)3R
121
R = OMe, Me, Cl, CO2Et  
p-anisoylsiloxane (R = OMe), p-tolylsiloxane (R = Me), and p-chlorophenylsiloxane (R = 
Cl) were prepared from commercially available p-bromoansiole, p-bromotoluene and 
p-chloroiodobenzene respectively according to the procedure previously reported by 
DeShong and Manoso.20,212 p-Carboethoxyphenylsiloxane (R = CO2Et) was prepared 
from ethyl-4-iodobenozate by Masuda's procedure.213 The 1H NMR spectral data of aryl 
siloxanes 121 (R = OMe212, R = Me212, R = Cl20, R = CO2Et213) were identical to that 
reported in the literature. 
Alkene (9, 126) 
R
126  R = OMe, Me, Cl, CO2Et
9   R = H
 
The spectral data of phenylcyclohexene214 9, methoxyphenylcyclohexene.32,215 (126, 
R = OMe), methylphenylcyclohexene32,33 (126, R = Me), chlorophenylcyclohexene32,33 
(126, R = Cl) and carboethoxyphenylcyclohexene33 126 (R = CO2Et) matched to those 
previously reported in the DeShong group. 
 
 124 
 
General procedure for allyl-aryl coupling using Tri-olefin-based Pd(0) 
catalysts (Table 4.3) 
OCO2Et Si(OEt)3
Pd(0)
TBAF
120 6
9  
To 76.5 mg (0.450 mmol, 1.00 equiv.) of allyl carbonate 120, 216 mg (0.900 mmol, 2.00 
equiv.) of aryl siloxane 6 in 4.00 mL of anhydrous THF was added 41.9 mg (0.113 mmol, 
0.250 equiv.) of Pd(COD)(NQ) under an atmosphere of argon. This was followed by 
addition of 0.900 mL (0.900 mmol, 2.00 equiv.) of 1 M TBAF solution in THF and the 
reaction mixture was stirred at 55 ?C for 24 h. The product was extracted with 5 ? 25 mL 
Et2O and washed with 25 mL H2O. The combined organic layers were dried over MgSO4 
and concentrated in vacuo to give crude cyclohexene 9. Purification by column 
chromatography (100% pentane; Rf  = 0.65) rendered 37.0 mg (52%) of cyclohexene 9 as 
a colorless oil. 1H NMR (400 MHz, CDCl3)  ? 7.31-7.27 (m, 2H), 7.22-7.18 (m, 3H),   
5.89-5.86 (m, 1H), 5.72-5.69 (m, 1H), 3.41-3.38 (m, 1H), 2.08-1.99 (m, 3H), 1.74-1.71 
(m, 1H), 1.61-1.53 (m, 2H); The NMR spectrum was identical to the literature.214 
 
 125 
 
Formation of hypercoordinate silicates 
Triethoxyphenylsilane (0.18 mmol, 43 mg) was mixed with 1 M TBAF (0.18 
mmol, 0.18 mL) in 0.50 mL THF and 19F NMR spectrum was recorded after 10 minutes 
at 29 ?C. 19F spectrum indicated two major resonances at  ? -121 and -127 and two minor 
resonances at  ? -113 and -128 (see Figure 1, (b)). After 1 h, TBAF and siloxane mixture 
was cooled to -28 ?C. Upon cooling, the 19F signal at  ? -121 sharpened, showing silicon 
satellites (JSi-F = 207 Hz). 19F NMR spectrum of hypercoordinate silicates is provided in 
Chapter 4, Figure 4.8. While 19F NMR was obtained at 0.36 mM concentration, 19Si 
NMR required higher concentration (3 ? 0.36 mM) and longer time (18 h). The chemical 
shift of triplet at  ? -129 ppm indicates hypercoordinate silicate anion, JSi-F = 207 Hz. 
 
Figure 4.15: 29Si NMR spectrum of silicate formation at -28 ?C. 
JSi-F = 207 Hz 
 
 126 
 
Based on 19F and 29Si NMR, we have tentatively assigned conformationally stable 
bis-fluorosilicate derivative 135 or 136 as the hypercoordinate arylfluorosilicate which 
arises from conformationally mobile mono-fluorosilicate 134 (Scheme 4.15). The 19F and 
29Si NMR spectra and coupling constant are consistent with that of TBAT, previously 
characterized by the DeShong group. Additionally, it was observed that bis-fluorosilicate 
when reacted with allyl carbonate 120, gave coupled product in 60% yield.  
Scheme 4.15 
Si(OEt)3
F
Si(OEt)3
F
Si
OEt
OEt
F
F
Si
F
F
OEt
OEt
60%
Si
Ph
Ph
F
F
TBAT 29Si shift = ? -106
19F shift = ? -96
J Si-F = 252 Hz
Si(OEt)2
F
OEt
F
136
135
120
134
Pd(dba)2, 55 ?C
OCO2Et
F
 
 
 
 127 
 
 
 
Figure 4.16: Effect of temperature on silicate formation (19F NMR spectrum). Mixture of 
TBAF and phenyltriethoxysilane (a) 10 min, at rt. (b) 2 h 25 min, at -30 ?C. (c) 2 h 40 
min, at rt. (d) 4 h 55 min, at -30 ?C. 
 
 128 
 
 
 
Figure 4.17: Effect of TBAF concentration on silicate formation (19F NMR spectrum) (a) 
0.5 equiv. TBAF, 1.0 equiv. siloxane. (b) 1.0 equiv. TBAF, 1.0 equiv. siloxane. (c) 1.5 
equiv. TBAF, 1.0 equiv. siloxane. (d) 2.0 equiv. TBAF, 1.0 equiv. siloxane. 
 
 129 
 
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