W ‘
. ---fl

   

 

 

 

 

 

 

 

 

 

 

F‘k‘or

   

 

 

This is to certify that the
dissertation entitled

CHROMIUM AND IRON ORGANOMETALLICS IN ORGANIC
SYNTHESIS: SYNTHETIC STUDIES TOWARD TOTAL
SYNTHESIS OF TAXOL AND CHROMIUM TO IRON
TRANSFER PROCESSES

presented by

YIQIAN LIAN

has been accepted towards fulfillment
of the requirements for the

PhD. degree in Chemistry

 

 

W to W

Main? Professor’s Signature

June 28, 2006

 

Date

MSU is an Affinnative Action/Equal Opportunity Institution

 

LIBRARY
MICI".IQ;.. State
University

 

 

 

 

 

PLACE IN RETURN BOX to remove this checkout from your record.
To AVOID FINES return on or before date due.
MAY BE RECALLED with earlier due date if requested.

 

DATE DUE

DATE DUE

DATE DUE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

6/01 c:/ClRC/DateDue.p65-p.15

 

 

 

CHROMIUM AND IRON ORGANOMETALLICS 1N ORGANIC SYNTHESIS:
SYNTHETIC STUDIES TOWARD TOTAL SYNTHESIS OF TAXOL AND
CHROMIUM To IRON TRANSFER PROCESSES
By

Yiqian Lian

A DISSERTATION

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY
Department of Chemistry

2006

ABSTRACT

CHROMIUM AND IRON ORGANOMETALLICS IN ORGANIC SYNTHESIS:
SYNTHETIC STUDIES TOWARD TOTAL SYNTHESIS OF TAXOL AND
CHROMIUM TO IRON TRANSFER PROCESSES
By

Yiqian Lian

The Wulff—Kaesler reaction — a chromium-mediated intramolecular [2 + 2]
cycloaddition - of Fischer carbene complexes and the dienyne 94 has been demonstrated
to be a suitable method for the preparation of the bicyclo[3.1.1]heptanone intermediates
as A-ring synthons of taxol and taxane derivatives. A diastereoselective synthesis of taxol
A-ring synthons has also been achieved from the reaction with the chiral dienyne 110a,
which results in good syn/anti ratios in favor of the desired bicycloheptanone isomers.
The proposed mechanism suggests that asymmetric induction may originate from
chelation of the oxygen to the chromium during the reaction.

It has also been revealed that closure of the B-ring of taxol via an aldol
condensation/Grob fragmentation does not proceed as anticipated and instead results in
undesired fragmentation. A modified strategy has been designed on the basis of careful
mechanistic considerations which represents an attractive route to the ABC tricyclic core
of taxol and deserves further investigation.

The first examples of both inter- and intramolecular cyclopropanation reactions of
dienyl chromium carbene complexes under a non-CO atmosphere have also been
demonstrated. The dienyl carbene complexes can react with an electron-deficient olefin
to give dienylcyclopropanes as a mixture of trans- and cis-isomers in an intermolecular

fashion. The intramolecular cyclopropanation reaction of alkenyloxy dienyl carbene

complexes with a terminal double bond tethered to the oxygen can occur if the tether
length is appropriate. In all cases, the Diels-Alder reaction that was thought to be a
possible competitive reaction did not appear to occur.

The serendipitous finding and the subsequent development of a novel iron-
mediated thermal ortho-benzannulation of Fischer carbene complexes are also described.
It is the first time that trans,trans-a,B,y,6-unsaturated Fischer carbene complexes have
been employed successfully for the ortho-benzannulation reaction. The first examples of
the “ortho-cyclohexadienone annulation” with 6,6-disubstituted dienyl carbene
complexes have also been illustrated. This reaction also worked with a few dienyl
carbene complexes having a cis-a,B-double bond, although the scope for the cis-a,[3-
dienyl substrates has not been established.

Mechanistic studies suggest that two pathways are possible to form the dienone
iron tricarbonyl complex and the phenol product. One involves direct transfer of the
carbene ligand from Cr to Fe, and the other involves initial coordination of the iron to the
diene fragment. A tentative mechanism has been proposed for the chromium to iron
transfer processes.

Some new aspects of the ortho-benzannulation reaction under thermal conditions
in the absence of an iron source have also been illustrated under both argon and CO
atmospheres. It was surprising to find that photons were not necessary for a few cis-afi-
dienyl carbene complexes of particular structure types, and the unusual reactivity is
believed to result from the ring strain in the substrates rather than the possible extra

coordination site in the carbene complexes.

To my wife: Xiuni, and our daughter: Angela Weike

my parents: Bogui and Suying, and my sister: Danbo

iv

ACKNOWLEDGMENT

First and foremost, I would like to thank my advisor, Professor William D. Wulff,
for his support, encouragement and patience during my study at Michigan State
University. His enthusiasm about chemistry and his dedication to producing “good
science” have been and will continue to be invaluable influence and motivation for me to
strive to be an excellent synthetic chemist. I benefited a lot each time when I talked to
him about chemistry, not only because of his knowledge of chemistry, but also because of
his willingness and openness for discussion. Prof. Wulff allows and always encourages
me to explore my own ideas, which has certainly helped me grow as an independent
chemist. Above all, he is a great human being and it has been a privilege and pleasure to
work under his tutelage.

I would also like to thank my committee members, Professors Robert Maleczka,
Babak Borhan, and Mitch Smith, for their help and valuable discussions during the past
few years. Professor Maleczka is always willing to help, no matter whether it is related to
chemistry or not. Thanks are also due to Dr. Rui Huang for his X—ray structure analysis
and Dr. Dan Holmes and Kermit Johnson for their help with NMR experiments.

In the Wulff group, I learned a lot from a number of great colleagues. Among the
former group members, Dr. Hongqiao Wu taught me some useful techniques or tricks in
organic synthesis during the first two years; Dr. Yonghong Deng always encouraged me
to do my best to keep my dreams alive. I also benefited from informal discussions with

Drs. Xuejun Liu, Mike Fuertes, Manish Rawat, Jie Huang, Glenn Phillips, Andrei

Vogoushin and Billy Mitchell. Quite a few of them have become good friends of mine
and we keep in touch regularly.

Many current colleagues of course deserve special thanks. Cory Newman has
been my labmate for four years and we certainly have had a lot of excitement (as well as
frustrations) together in the lab. In addition to chemistry, we often talked about sports
both in and outside the lab. The trip to Washington, DC, for the ACS meeting with
Cory and his wife Janelle and my wife Xiuni was fun and memorable. It has also been a
pleasure to work with Keith Korthals, another wonderful down-to-earth-type
Midwestemer, in the same lab for the past five years. Zhensheng Ding, a talented person
who has a lot of interests in addition to chemistry, has provided a lot of fun in the lab. I
also wish to thank Chunrui Wu, Gang Hu, Victor Prutyanov, Kostos Rampalakos, Alex
Predeus and Aman Desai for their help and friendship. In addition, I have had the
pleasure to work with Kelsie Betsch, an undergraduate student from Augustana College
in Sioux Falls, South Dakota, during the summer of 2004.

The life has been certainly more enjoyable with some good friends around at
MSU. Kun Li, Li Gao and Xuezheng Song are such wonderful people that one would not
meet very often in a life; Chunxu (John) Zhang, a former USD labmate and friend, has
been working in East Lansing for the last three years. It is impossible to count how many
times we hung around together, but it has always been fun.

Finally, I would like to thank my parents, Bogui and Suying, who live far away
from this country but are always there to support me wherever I go and whatever I do.
My sister, a brilliant law school graduate, along with my parents, always has confidence

in me and encourages me to fulfill my goals. Of course, the biggest non-academic

Vi

achievement at MSU was meeting the lovely girl, Xiuni, who later became my wife.
Without her company during the often difficult times, I cannot imagine what my life
would have been like. I probably cannot say enough for her about her unwavering
support, understanding and love throughout these years. Our daughter Angie Weike
certainly has been our great joy, it is such a wonderful thing watching her grow each day.

This dissertation is dedicated to these important family members in my life.

vii

TABLE OF CONTENTS

LIST OF SCHEMES .................................................................................................... xii
LIST OF TABLES ...................................................................................................... xvi
LIST OF FIGURES .................................................................................................... xvii
KEY TO ABBREVIATIONS AND SYMBOLS ....................................................... xviii
CHAPTER ONE. TAXOL: ITS BIOLOGY AND CHEMISTRY .................................. 1
1.1 INTRODUCTION TO THE TAXANE DITERPENES ........................................... 2
1.2 THE DISCOVERY OF TAXOL ...................................................................... 3
1.3 BIOLOGICAL STUDY AND CLINICAL APPLICATIONS OF TAXOL ................... 7
1.3.1 The Biological Role of Taxol ....................................................... 7
1.3.2 Clinical Applications ................................................................... 9
1.4 THE SUPPLY ISSUE AND THE SEMISYNTHESIS OP TAXOL .......................... 12
1.5 TOTAL SYNTHESIS OF TAXOL .................................................................. 16
1.5.1 Completed Total Syntheses and Their Strategies ........................ 17
1.5.2 Some Other Strategies to Access ABC Tricyclic System ............ 23

1.6 STUDIES ON TAXOL ANALOGs AND STRUCTURE—ACTIVITY RELATIONS

(SARS) .................................................................................................. 24

CHAPTER TWO. SYNTHETIC STUDIES TOWARD TAXOL: UTILIZING

2.1

THE WULFF—KAESLER REACTION OF FISCHER CARBENE
COMPLEXES AND 1,6-ENYNES ....................................................... 27

FISCHER CARBENE COMPLEXES AND THE WULFF—KAESLER REACTION 27

2.1.1 Fischer Carbene Complexes: The Background ........................... 28

viii

2.2

2.3

2.4

2.5
2.6

2.7

2.1.2 The Wulff —Kaesler Reaction of Fischer Carbene Complexes and
1,6-Enynes ................................................................................. 33
THE RETROSYNTHETIC STRATEGY TOWARD THE TAXOL SKELETON AND
PREVIOUS EFFORTS ................................................................................ 36
FURTHER STUDIES ON THE THE WULFF—KAESLER REACTION .................... 44

2.3.1 Bicylo[3. 1 .l]heptanones Intermediates for the Synthesis of the

A-Ring Synthons of Taxol and Taxane Derivatives .................... 44
2.3.2 Asymmetric Induction in the Wulff —Kaesler Reaction:

Diastereoselective Formation of Taxol A-ring Synthons ............ 50
2.3.3 Mechanistic Considerations for the Asymmetric Induction ........ 52

REVISION OF THE PREVIOUSLY INCORRECTLY ASSIGNED TRICYCLIC
INTERMEDIATE ....................................................................................... 57
2.4.1 Investigations on the Hydrolysis of Enol Ethers 99 and the
Discovery of the Unexpected Fragmentation .............................. 58
2.4.2 Correction of a Previously Misinterpreted Tricyclic Structure 62
A MODIFIED STRATEGY FOR THE TOTAL SYNTHESIS OF TAXOL ............... 64
STUDIES ON CLOSURE OF THE B-RING FOR ENTRY INTO THE ABC
TRICYCLIC CORE OF TAXOL .................................................................... 66

CONCLUSIONS AND FUTURE DIRECTIONS ................................................ 70

CHAPTER THREE. AN INVESTIGATION OF THE CYCLOPROPANATION

3.1
3.2
3.3

3.4
3.5

REACTION OF DIENYL FISCHER CARBENE COMPLEXES .......... 73

BACKGROUND OF THE CYCLOPROPANATION REACTION OF FISCHER
CARBENE COMPLEXES ............................................................................. 73
INTERMOLECULAR CYCLOPROPANATION REACTIONS OF DIENYL FISCHER
CARBENE COMPLEXES ............................................................................ 76

INTRAMOLECULAR CYCLOPROPANATION REACTIONS OF DIENYL FISCHER

CARBENE COMPLEXES ............................................................................ 78
CONTROL REACTIONS UNDER 500 PSI OF CO ........................................... 80
CONCLUSIONS ........................................................................................ 82

ix

CHAPTER FOUR. A NOVEL IRON-MEDIATED THERMAL ORTHO-

4.1

4.2

4.3
4.4

4.5
4.6

4.7

4.8

BENZANNULATION REACTION OF DIENYL FISCHER CARBENE
COMPLEXES: CHROMIUM TO IRON TRANSFER PROCESSES 83

BENZANNULATION AND ORTHO-BENZANNULATION OF FISCHER CARBENE
COMPLEXES: BACKGROUND AND SYNTHETIC APPLICATIONS ................... 83

4.1.1 Benzannulation of Fischer Carbene Complexes and Their

Applications .............................................................................. 83
4.1.2 ortho-Benzannulation of Fischer Carbene Complexes and Their
Applications .............................................................................. 91
THE DISCOVERY OF A NOVEL THERMAL ORTHO-BENZANNULATION
MEDIATED BY IRON ................................................................................. 98
PREPARATION OF TRANS-a,B-DIENYL CARBENE COMPLEXES ................. 104
THE SCOPE AND LIMITATIONS OF THE REACTION .................................... 107
4.4.1 trans-a,|3-Dienyl Fischer Carbene Complexes ......................... 107
4.4.2 cis-orfi-Dienyl Fischer Carbene Complexes ............................. 109
4.4.3 Conversion of the Dienone Iron Tricarbonyl Complexes to Phenols
................................................................................................. 114
4.4.4 Control Experiments the trans, trans-Dienyl Complex 181b ...... 115
THE MECHANISTIC STUDY .................................................................... 1 17
THERMAL ORTHO-BENZANNULATION IN THE ABSENCE OF IRON ............. 127
4.6.1 Are Photons Really Necessary? ................................................ 127
4.6.2 Does Additional Coordination Contribute to the Unusual
Reactivity? ............................................................................... 13 1
MISCELLANEOUS REACTIONS ................................................................ 132
4.7.1 Other Attempted Thermal Reactions ........................................ 132
4.7.2 Diastereoselective Reduction of Dienone Complexes ............... 137
CONCLUSIONS ...................................................................................... 139

CHAPTER FIVE. EXPERIMENTAL SECTION ...................................................... 141

5.1 GENERAL INFORMATION ....................................................................... 141

5.2 EXPERIMENTAL PROCEDURES AND CHARACTERIZATION DATA FOR
CHAPTER TWO ..................................................................................... 142

5.3 EXPERIMENTAL PROCEDURES AND CHARACTERIZATION DATA FOR
CHAPTER THREE .................................................................................. 171

5.4 EXPERIMENTAL PROCEDURES AND CHARACTERIZATION DATA FOR

CHAPTER FOUR .................................................................................... 180
REFERENCES AND NOTES .................................................................................... 229
APPENDIX 1. X-RAY STRUCTURE AND CRYSTAL DATA FOR 99d-cryst ..................... 251
APPENDIX 2. X-RAY STRUCTURE AND CRYSTAL DATA FOR 254a ............................ 268
APPENDIX 3. SEM/EDS SPECTRA FOR 181a AND 254a ............................................ 278

xi

Scheme 1.1.

Scheme 1.2.

Scheme 1.3.

Scheme 1.4.

Scheme 1.5.

Scheme 1.6.

Scheme 1.7.
Scheme 1.8.
Scheme 2.1.
Scheme 2.2.
Scheme 2.3.
Scheme 2.4.
Scheme 2.5.
Scheme 2.6.
Scheme 2.7.
Scheme 2.8.
Scheme 2.9.
Scheme 2.10.
Scheme 2.11.
Scheme 2.12.

Scheme 2.13.

LIST OF SCHEMES

Potier and Greene’s Semisynthesis of Taxol .......................................... 15
Holton’s Semisynthesis of Taxol ........................................................... I6
Holton’s Approach to the Taxol Skeleton ............................................... 18
Nicholaou’s Approach to the Taxol Skeleton .......................................... 19
Danishefsky’s Approach to the Taxol Skeleton ....................................... 20
Wender’s Approach to the Taxol Skeleton .............................................. 21
Kuwajima’s Approach to the Taxol Skeleton .......................................... 22
Mukaiyama’s Approach to the Taxol Skeleton ........................................ 23
The Preparation of Fischer Carbene Complexes ...................................... 30
The Wulff-Kaesler Reaction and Its Mechanism ..................................... 34
Stereoselection in the Wulff-Kaesler Reaction ........................................ 35

Bicyclo[3.1.l]heptanone 76 from a Crossed [2 + 2] Cycloaddition ......... 35

Kim’s Initial Attempts on the ABC-Tricyclic Skeleton ........................... 36
Second Generation of Retrosynthetic Strategy ........................................ 37
Attempted Wulff-Kaesler Reaction with Dienyne 86 .............................. 37
The Reaction of Complex 63a with Dienyne 86a .................................... 38
Third Generation of Retrosynthetic Strategy ........................................... 39
Preparation of 94 and Its Reaction with Complex 63a ............................. 4O
Isomerization of the Double Bond in Bicycloheptanone 101 ................... 40
The Formation of 99d and ItS Subsequent Reaction with an Acid .......... 41
Fourth Generation of Retrosynthetic Strategy ......................................... 42

xii

Scheme 2.14.

Scheme 2.15.

Scheme 2.16.

Scheme 2.17.

Scheme 2.18.

Scheme 2.19.

Scheme 2.20.

Scheme 2.21.

Scheme 2.22.

Scheme 2.23.

Scheme 2.24.

Scheme 2.25.

Scheme 2.26.

Scheme 2.27.

Scheme 2.28.

Scheme 2.29.

Scheme 2.30.

Scheme 2.31.

Scheme 2.32.

Scheme 2.33.

Scheme 2.34.

Scheme 3.1.

The Preparation of Chiral Dienyne 110a ................................................ 43
Synthesis of Bicyclo[3.1.l]heptanone 118a with Chiral 110a ................. 43
Preparations of Substituted Carbene Complexes 63b-d .......................... 45
The Wulff-Kaesler Reaction of Complexes 63b-d with Dienyne 94 ....... 47

The Proposed Mechanism for the Wulff-Kaesler Reaction of complex 63

with Dienyne 94 ..................................................................................... 49
Diastereoselective Synthesis OfBicyclo[3.1.1]heptanones 118 ............... 51
The Effect of the Protective Groups on the Diastereoselectivity ............. 53
Chelation of Oxygen to Chromium in the Wulff-Kaesler Reaction .......... 54
Proposed Solvent Coordination in the Wulff-Kaesler Reaction .............. 55
Hydrolysis of the Enol Ethers with Weak Acids ..................................... 59
The Unexpected Fragmentation of 99c under Acidic Conditions ............. 61
The Proposed Mechanism for the Fragmentation of 99c ......................... 62

Revision of a Previously Incorrectly Assigned Structure and Identification

of a New Structure from the Reaction of 99d with HCI .......................... 63
Mechanistic Considerations for the Acid-Catalyzed Fragmentation ........ 65
Modified Strategy to Achieve the Desired Fragmentation ...................... 66
A Test of New Strategy for the Desired Fragmentation .......................... 67
Realization of the Desired Fragmentation .............................................. 68
The Formation of Aldehydes and Attempted B-ring Closure .................. 69
Proposed Manipulations of the Aldehyde Functionality for B-ring

Closure .................................................................................................. 71
A Possible Approach for the Formation of ABC Tricyclic Core ............. 72
Another Strategy for the Construction of the Taxol Skeleton ................. 72

The Cyclopropanation Reaction of Dienyl Complex 181a with 182 ....... 75

xiii

Scheme 3.2.

Scheme 3.3.

Scheme 3.4.

Scheme 3.5.

Scheme 4.1.

Scheme 4.2.

Scheme 4.3.

Scheme 4.4.

Scheme 4.5.

Scheme 4.6.

Scheme 4.7.

Scheme 4.8.

Scheme 4.9.

Scheme 4.10.

Scheme 4.11.

Scheme 4.12.

Scheme 4.13.

Scheme 4.14.

Scheme 4.15.

Scheme 4.16.

Scheme 4.17.

Scheme 4.18.

Scheme 4.19.

The Cyclopropanation Reactions of Dienyl Complexes with Methyl

Acrylate ................................................................................................ 77
Intramolecular Cyclopropanation Reactions of Dienyl Complexes ......... 79
The Cyclopropanation Reaction otTungsten Complex 192 ..................... 80
A Control Experiment with 181a under 500 psi CO ............................... 81
General Scheme of the Benzannulation Reaction .................................... 84
A Simplified Mechanism of the Benzannulation Reaction ...................... 85
Regioselectivity of the Benzannulation Reaction ................................... 86
General Scheme of the Cyclohexadienone Annulation ........................... 86
The Rationale for the Indene and Furan Formation ................................. 87
The Strategy for the ortho-Benzannulation Reaction .............................. 92
First Example of the ortho-Benzannulation Reaction ............................. 92
The Photochemical ortho-Benzannulation Reaction ................................ 93
Reported Unsuccessful Example of ortho-Benzannulation ..................... 94
The ortho-Benzannulation of Aminocarbene Complexes ....................... 94
Formation of o-Methoxy Amino Naphthalenes with Isonitriles .............. 95
First Example of Thermal ortho-Benzannulation By Merlic ................... 96
General Scheme of the Thermal Reaction Reported By Barluenga ......... 97

Therrnolysis of Pentadienyl Carbene Complex 181a under 500 psi CO... 98

Aldol Condensations with Aliphatic Aldehydes ................................... 104
Preparation of Dienyl Complexes using Aumman’s Method ................ 105
Aldol Condensation with Ketone 261 .................................................. 105
Preparation of Iodide 263 and Carbene Complex 1811‘ ......................... 106

The Iron-Mediated ortho-Benzannulation of cis-a,B-Complex 224 ....... 110

xiv

Scheme 4.20.

Scheme 4.21.

Scheme 4.22.

Scheme 4.23.

Scheme 4.24.

Scheme 4.25.

Scheme 4.26.

Scheme 4.27.

Scheme 4.28.

Scheme 4.29.

Scheme 4.30.

Scheme 4.31.

Scheme 4.32.

Scheme 4.33.

Scheme 4.34.

Scheme 4.35.

Scheme 4.36.

Scheme 4.37.

Scheme 4.38.

Attempted Preparation of the cis,trans-Complex 181f .......................... 112

Attempted Iron-Mediated Thermal ortho-Benzannulation of 237 ......... 1 13
Demetalation of Iron Tricarbonyl Complexes ...................................... 1 15
Control Experiments with 181b in the Absence of an Iron Source ........ 116
Attempted Photochemical Reaction of trans, trans-181b ...................... 117
A Related Literature Example of Cyclohexadienone Formation ........... 117

Mechanistic Considerations for the Iron-Mediated ortho-Benzannulation

............................................................................................................. 118
Preparation of Iron-Coordinated Chromium Carbene Complex 274a 119
Attempted Preparation of the Dienyl Iron Complex 275a ..................... 121
Preparation of Iron Complexed Ketene 275b ....................................... 122
Attempted Detection of Possible Intermediates .................................... 123
Attempted In-situ Detection of Possible Intermediate(s) ....................... 124
Direct Carbene Ligand Transfer from Chromium to Iron ..................... 125
Proposed Mechanism for the Iron-Mediated Thermal

ortho-Benzannulation .......................................................................... 1 26
Attempted Thermolysis of 237 without an Iron Source ........................ 129
Selective Reduction of 224 with Wilkinson’s Catalyst ......................... 131
Generation of o-Methoxy p-Alkoxy (or p-Amino) Phenols .................. 134
Attempted Preparation of the B-Methoxy Dienyl Complex 295a .......... 135
Preparation of the Amino Complex 301 and Its Thermal Reaction ....... 136

XV

Table 2.1.

Table 2.2.

Table 4.1.

Table 4.2.

Table 4.3.

Table 4.4.

Table 4.5.

Table 4.6.

Table 4.7.

Table 4.8.

Table 4.9.

Table 4.10.

Table 4.11.

Table 4.12.

Table 4.13.

LIST OF TABLES

The Wulff-Kaesler Reaction of Complex 63a and Dienyne 94 ................... 45
The Wulff—Kaesler Reaction with Chiral Dienyne 110a ............................. 50
Thermolysis under 500 psi CO with External Iron Sources ....................... 101
Optimization of the Reaction under 1 atm of Ar or CO ............................. 102
The Iron-Mediated Thermal ortho-Benzannulation ................................... 108
Thermal ortho-Benzannulation of cis-a,B-Dienyl Complex 264 ............... 11 1
The Iron-Mediated Thermolysis of Carbene Complex 227 ....................... 114

Thermolysis of the Iron-Coordiated Chromium Carbene Complex 274a .. 119

Thermolysis of the Ketene Complex 275b ................................................ 122
Thermolysis of 224 in the Absence of an Iron Source ............................... 128
Thermolysis of 227 in the Absence of an Iron Source ............................... 130
Thermal Reaction of Carbene Complex 290 ............................................. 132
Thermal Reactions of 239 in the Presence of Fe2(CO)9 ............................ 133
Attempted Conversion of Ketene Complex 294 to Phenol 237 ................. 134
Diastereoselective Reduction of the Dienone Complex 254a .................... 138

xvi

Figure 1.1.
Figure 1.2.
Figure 2.1.
Figure 2.2.
Figure 2.3.
Figure 2.4.

Figure 3.1.

Figure 3.2.

Figure 3.3.
Figure 4.1.
Figure 4.2.
Figure 4.3.

Figure 4.4.

LIST OF FIGURES

Some Examples of the Taxane Family of Diterpenoids .............................. 2
The Structure-Activity Relationships (SARS) of Taxol .............................. 25
Metal-Carbene Complexes 50 (General Structure) and 51 ......................... 27
Fischer-type Carbene Complexes .............................................................. 28
Schrock-type Carbene Complexes ............................................................ 29
X-ray Structure of the Bicyclo[3.1.l]heptanone 99d-cryst ........................ 48
Possible Products from the Reactions Involving Dienyl Complexes 178 and

Olefins 179 ............................................................................................. 74
The Carbene Complexes and Olefins Designed for Intermolecular Reaction:5
Carbene Complexes Designed for Intramolecular Reactions ..................... 78
Synthesis of Natural Products Involving Benzannulation Reaction ............ 90
Structures of VAPOL and VANOL Ligands ............................................. 91

Synthesis of Natural Products Involving ortho-Benzannulation Reaction .. 96

X-ray Structure of Dienone Iron Tricarbonyl Complex 254a .................. 100

xvii

KEY TO ABBREVIATIONS AND SYMBOLS

AC

Ar

Bn

Bz
CAN
mCPBA
DBU
DIBAL
DMF
DMSO
HMPA
hv
LAH
LDA
L-Selectride
MOM
MsCl
NMO
Red—Al
TBAF
TBS
THF
TMS

Troc

EDS
SEM

Acetyl

Aryl

Benzyl

Benzoyl

Ceric Ammonium Nitrate
meta-Chloroperoxybenzoic Acid
1,8-Diazabicyclo[5 .4.0]undec-7-ene
Diisobutylaluminum Hydride
Dimethylformamide

Dimethyl Sulfoxide
Hexamethylphosphoramide
Irradiation with Light

Lithium Aluminum Hydride

Lithium Diisopropylamide

Lithium Tri-sec-butylborohydride
Methoxymethyl

Methanesulfonyl Chloride
N-Methylmorpholine N-Oxide
Sodium Dihydrobis(2-methoxyethoxy)-aluminate .
Tetra-n-butylammonium Fluoroborate
Tert-butyldimethylsilyl (TBDMS)
Tetrahydrofuran

Trimethylsilyl
B,B,B-Trichloroethoxycarbonyl (Tcec)

Energy Dispersive Spectrometer

Scanning Electron Microscopy

xviii

CHAPTER ONE

TAXOL: ITS BIOLOGY AND CHEMISTRY

Taxol has created a great impact in the areas of clinical oncology and biomedical

research in the past few decades.1 As Goodman and Walsh wrote in their book entitled
The Story of Taxol: “Taxol is arguably the most celebrated, talked about, and
controversial natural product in recent years: Celebrated because of its efficacy as an
anti-cancer drug and because its discovery has provided powerful support for policies
concerned with biodiversity. Talked about because in the late 19805 and early 19905, the
American public was bombarded with news reports about the molecule and its host, the
slow-growing Pacific yew. Controversial because the drug and the tree became embroiled
in several sensitive political issues with broad public policy implications.”2 As a result, it

has become one of the few organic compounds, which, like benzene, aspirin and Viagra,

is recognizable by name to the average citizen.3

The approval of taxol for use as an anti-cancer drug in 1992 was the culmination
of 30 years of work, and many areas of research pertinent to taxol continued very actively
and enthusiastically around the world after that. Therefore, the discovery and
development of taxol is a complex story with many fronts,4 and a comprehensive review

of taxol is not possible here. The following description is intended to serve as a brief

 

overview of taxol, and to highlight some most important aspects of the discovery and
development, the biological studies and clinical applications as well as the chemistry,

especially the synthesis of taxol.

1.1 INTRODUCTION TO THE TAXANE DITERPENES
The taxane family of diterpenoids is a group of substances isolated from various

yew (T axus) species.5 More than 350 taxane diterpenes, or taxoids, have been isolated
and characterized, with the majority being reported over the last 15 years or so. The
search for derivatives was driven in part by the proven extraordinary anticancer activity
of taxol. Some representative examples of taxanes are illustrated in Figure 1.1, all of
which are naturally occurring compounds except Taxotere6 (2) — the semisynthetic
analog of taxol (1).

Figure 1.1. Some Examples of the Taxane Family of Diterpenoids.

R0 OOH

  
       

F‘i

 

HO‘W g g 0
OH 0 OAc
0
Ph Ph
1: Taxol, R‘ = Ph, R2 = Ac 3: 10-Deacetylbaccatin lll (10-DAB), R = H
2: Taxotere. R1 = t-BuO. R2 = H 4: Baccatin III. R =Ac

AcO 9A9 OAc AcO 9A0

 
  

 
 
 

 

  

AcO‘".

 

H OAc H OAc

5: Baccatin l 7: Taxinine

oooooooooooooooooooooooooooooooooooooooooooooooooooooo

 

 

 

 

8: Taxane ABC Skeleton and Numbering

The taxane diterpenes share the ABC tricylic carbon skeleton (8) with few
exceptions, and the numbering of the 6-8-6 membered ring system is also shown. These
compounds bear different degrees of oxygenation and some structural subgroups may be
discerned. For example, the C-ring functionality can have an elaborate 3-oxygenated
oxetane in taxol (1), a less complicated epoxide in baccatin I (5), or a simple allylic ester
in taxinine (7). Among all of the known taxanes, taxol (1) is one of the most functionally
and stereochemically complex molecules.

The taxanes are a new class of anticancer drug of which taxol is the first clinically
effective representative,7 and some members of its family exhibit multidrug resistance

reversing activity.8

1.2 THE DISCOVERY OF TAXOL

The story about the discovery of taxol begins with the state of cancer treatment
research in the mid 20th century. The successful use of penicillin in World War II
ushered in the “antibiotic era”, and many drugs such as erythromycins and tetracyclines
became available in addition to penicillins and sulfa drugs, which resulted in a significant
decease in deaths from infectious diseases of all types, including a major killer —

pneumonias.4a This changed the mortality patterns drastically such that heart disease and

cancer were then becoming the major killers. From late 19405 to early 19505, the reports
of the first few chemotherapeutic agents used for human cancer treatment, especially

nitrogen mustards as well as aminopterin and 6-mercaptopurine,9 led to heightened

interest and belief in chemical agents rather than in radiotherapy and surgery as the
techniques of choice in cancer treatment.

However, there were few major cancer research centers at that time. The Sloan-
Kettering Institute was the largest private cancer research institute, which evaluated about
3,000 compounds (synthetic and natural) for anticancer effects every year, representing
more than 75% of the total American chemotherapy screening capacity.10 This was
certainly inadequate and too slow. Furthermore, there were only a few largely non-
coordinated small research groups working on various subjects such as carcinogenesis,
etiology and treatment. These Situations indicated the necessity and urgency of the
formation of a national cancer drug screening program, and in 1953 the Congress directed
the National Cancer Institute (N CI) to organize such a program, which led to the creation
of the Cancer Chemotherapy National Service Center (CCNSC) within NC] in 1955.'1
Its early strategy was to act as a public screening facility for compounds submitted
voluntarily by institutions and companies, and all of them were synthetic compounds and
fermentation products with known structures. In 1960, the CCNSC screened more than
30,000 compounds annually — ten times of the volume of the Sloan-Kettering Institute. In
the same year, the program was extended to include natural products, from both plants

10,12

and animals, whose structures were unknown, and it was transformed from a service

into a “targeted drug development program”.”a
To get plants assessed as part of the CCNSC screening program was a challenge
since the investigation of the bioactivity of plants was essentially a new area at that time.

Although for more than a century, it was known that many plant alkaloids — nitrogen-

containing secondary metabolites — were bioactive, yet by 1952, only two percent of the

world’s plant species had been screened for their alkaloid content. '3 Even less was known
about the cytotoxic and anti-tumor possibilities of plant products.

The initial selection of plant extracts to be screened was based on rapid
availability. To obtain enough Specimens and to get the botanical information correct,
collaborations with the US. Department of Agriculture (USDA) would be important
because one of the most important functions of the USDA was in collecting, identifying,
storing and cultivating plant materials as their task of introducing beneficial plants into
American agriculture. When the joint NCI—USDA plant screening program was started in
1960, it was decided that random selection of plants for screening was the best way to
uncover compounds of hitherto unknown types of activity.2 Although selective searching
- targeting a specific family or genus — would lead to a higher number of hits, but by the
same token, it would not uncover substances possessing entirely new structures and
mechanisms of activity. The main concept lies in that diversity in morphological
characteristics would likely be mirrored by diversity in the types of chemicals that these
plants produced, which gives the best chance of finding chemical variety and with that
perhaps antitumor activity.

The plant collection agreement between the NCI and USDA resulted in many
collecting trips by USDA botanists to a variety of locations in the United States. In 1962,
as part of their sweep in the west coast, a team led by Arthur Barclay collected samples of
the bark of the Pacific yew, Taxus brevifolia, in the Gifford Pinchot National Forest in
the state of Washington.2 Initial studies from a crude extract of the bark showed
cytotoxicity against KB cells,14 and in late 1964, thirty pounds of bark samples were sent

by NCI to Wani and Wall, chemists at the Research Triangle Institute in North Carolina

who had been contracted by NCI for fractionation studies.4a Subsequently, fractions from
this extract showed cytotoxic activity against leukemia cells and inhibitory action against
a variety of tumors.

In October 1966, Wall and Wani isolated some pure crystalline needles and
named the compound “taxol” (tax- for taxus and -01 for alcohol due to the evidence for
the presence of hydroxyl group(s)).15 It took about two years for them to isolate 0.5 g of
pure compound from 12 kg of dried bark in a yield of 0.004%! The isolation Of taxol was
first presented at the annual meeting of the American Chemical Society in Miami Beach,
Florida, in 1967,16 with little being said about its structure. In 1971, Wall and Wani and
their coworkers published the structure of taxol (1) including its absolute stereochemistry
(Figure 1.1),17 along with the studies of its antileukemic and antitumor activity. Taxol
was the first compound possessing the taxane ring system that had been demonstrated to
have such activity.18 The first structure-activity data were also presented showing that
both the taxol core structure and the side chain were essential for activity.l7

Despite the fact that taxol was the most interesting of the more than 114,000
compounds obtained from about 35,000 samples of roughly 15,000 plant species that
were tested during the existence of the NCI—USDA plant program between 1960 and
1981,'9 further investigation of taxol languished for almost a decade due, primarily, to
difficulty of extraction from the natural source, problems with the murine screening
system, and a belief that taxol was simply another microtubule-destabilizing agent like
colchicines and the vinca alkaloids.20 However, the situation changed dramatically in
1979 when Susan Horwitz and coworkers at the Albert Einstein College of Medicine

reported a breakthrough discovery of the unique mechanism of action of taxol.2| It was

found that taxol stabilizes microtubules instead of destabilizing them like all other known
agents, and this mode of action breaks down cellular replication and eventually leads to

cell death.”

1.3 BIOLOGICAL STUDY AND CLINICAL APPLICATIONS OF TAXOL

1.3.1 The Biological Role of Taxol

As mentioned above, taxol does indeed act on microtubules, but with a
completely different mechanism of action.21 Microtubules are protein structures found
within cells, one of the components of the cytoskeleton. A normal microtubule has a
diameter of about 24 nm and varying length from several micrometers to possibly
millimeters. Microtubules serve as structural components within cells and are involved
in many important cellular processes including mitosis, cytokinesis, and vesicular
transport. Due to their versatility, usage and importance in the growth of cells,
microtubules have been called “the most strategic subcellular targets of anticancer
chemotherapeutics.”23

Microtubules are polymers of Ot- and B-tubulin dimers. During polymerization,
the tubulin dimer binds two molecules of guanosine 5’—triphosphate (GTP), and these
GTP-bound dimers join in a head-to-tail fashion to form protofilaments in the presence of
magnesium ions. The protofilaments then bundle in a hollow cylindrical filament.
Typically, the protofilaments arrange themselves in an imperfect helix with one turn of

the helix containing 13 tubulin dimers. From this point, the growth occurs only at the

ends of the tubule. Typically, equilibria are set up at both ends of the microtubule with

constant 1055 and gain of tubulin subunits, the rate of which is often different at the two
ends and results in a growing polarity. Worthy of mention is that the tubulin dimer is the
binding target of a number of drugs, such as colchicine and nocodazol, which inhibit the
polymerization of tubulin,.24

In general, microtubules are not static structures. After a certain period of time,
the growth and disassembly reaches equilibrium at relative concentrations of the
microtubule and free tubulin, and this concentration of tubulin is called the critical
concentration.25 It was proposed that GTP hydrolysis was an ongoing background process
and once the hydrolysis catches up to the tip of the microtubule, it begins a rapid
depolymerization and shrinkage.

Horwitz and coworkers in 1979 reported the unique mechanism of action of
taxol,21 and they discovered that taxol affects the tubulin-microtubule equilibrium by
decreasing both the critical concentration of tubulin (to almost zero mg/mL) and the
induction time for polymerization, even in the absence of GTP, MAPS (microtubule-
associated proteins) and magnesium ions, which are normally required for
polymerization. The extremely stable microtubules formed by taxol showed a shorter
average length and resistance both to cooling and to ionic calcium, which usually
depolymerize microtubules. They also found that taxol binds much more strongly, though
still reversibly, to the intact microtubule than to the tubulin dimer, and the binding site
appears to be distinct from that of other anti-microtubule agents and common MAPS.26 It
was later demonstrated that the maximum stabilization effects of taxol occur at a 1 :1 ratio

Of taxol/tubulin dimer.27 It was of interest to note that Heidemann and Gallas of Michigan

State University showed in 1980 that taxol’s microtubule activity in vitro was similar in
vivo.28

Studies have shown that taxol affects microtubules in all different phases of the
cell life cycle, and it can also disturb many cellular phenomena that are not directly
related to cell division but involved with microtubules.29 Although the molecular
mechanisms are not yet completely understood, it has been hypothesized that the
programmed cell death or apoptosis results from conflicting growth regulatory signals,

for example, from extended mitotic block, which ultimately lead to an unsuccessful

attempt to traverse the cell cycle.30

1.3.2 Clinical Applications31

After the paper on the mechanism of action by Horwitz and coworkers appreared,
publications dealing with taxol and microtubules mushroomed. Yet as far as the NCI was
concerned, the compound must be highly active in at least one tumor model, otherwise it
had little chance of progressing, whatever its mechanism of action. Preclinical studies
demonstrated that taxol was active against murine Bl6, L1210, P388, and P1534
leukemias — cancers characterized by overproduction of white blood cells.“ It was also
efficacious against a number of leukemias and solid tumors in xenografts (tissues
transferred from one species to another), including those in breast, ovary, brain, colon
and lung.32 Taxol also had a proven effect upon Walker 256 carcinoma, sarcoma 180,
and Lewis lung tumor cell lines.33 However, the formulation was problematic during the
study because the solubility of taxol in water (less than 0.01 mg/mL) and other aqueous

based systems is very low. So many attempts were made using mixed solvent approaches,

emulsions, and liposomes,34 before the Cremophor-ethanol surfactant formulation was
decided by the NCI for further development of taxol. After acceptable animal toxicology
studies were completed in 1982, an Investigational New Drug Application (INDA) was
submitted to the Food and Drug Administration (FDA) in the following year.411 In April
1984, the FDA gave approval to initiate clinical trials of taxol.

Until the filing of an INDA, a compound is tested on cell lines and animals only.
The granting of an INDA allows the NCI to begin testing a compound on humans. These
tests, called clinical trials, are sequenced into phases, each of which evaluates specific
criteria of the compound. Phase I evaluates for safety, to establish that a compound is
safe, with respect to dosage for human consumption (to determine a maximum tolerated
dose (MTD)); phase II focuses on effectiveness; and phase III aims at comparison against
standard therapies. In general the time needed to complete and the number of patients
enrolled in clinical trials increases as the phases progress.

Phase I clinical trials for taxol began in April 1984 and were conducted at seven
clinical sites.35 The trials were initially hampered by acute hypersensitivity reactions that
were believed to be caused by the use of Cremophor — a polyethoxylated castor Oil — in
the formulation but the problem was later solved by effective protocols such as
prophylactic pretreatment with antihistamines and longer infusion times.36 The main
organ toxicities, such as myelosuppresion, peripheral neuropathy and mucositis in
leukemia patients, are dose related and largely reversible. The recommended dose from
Phase I studies was generally in the range of 200-250 mg/m2 (of body surface area),

administered in about 3 L of isotonic solution over a period of 6—24 hours.37 Worthy of

10

mention is that several trials involving the co-administration of taxol and other drugs,
such as cisplatin,38 were also performed and gave favorable results.

In April 1985, Phase II clinical trials started with use of 24-hour continuous
infusion and premedication regimen. Throughout the Phase I and the early Phase II
clinical trials, taxol was in short supply and the number of studies was quite limited, so
the clinical trials (especially for Phase II) were slowed down. The discovery by the Johns
Hopkins group39 in early 1989 that taxol had important activity in refractory ovarian
cancer provided an impetus for the NCI to seriously consider the large-scale production
of taxol.40 In August 1989, the NCI issued a request for applications for a Cooperative
Research and Development Agreement (CRADA) to expand supply and clinical trials
leading to marketing of taxol. The CRADA competition was won by the Bristol-Meyers
Company (soon to become Bristol-Myers Squibb Company) who, with its only contractor
— Hauser Chemical Research and in cooperation with the NCI, did an outstanding job of
making supplies of taxol available so that broad trials in major types of cancers were able
to be conducted. For advanced ovarian cancer, taxol had a response rate of 30—35%,
which was significant since these refractory cases had not responded to standard
treatment;39’4' for metastatic breast cancer, it gave a 56% response rate with manageable
side effects;42 for non-small-cell lung cancer, the response rate was 20-50%.43 The proven
efficacy of treating these cancers eventually led to successful marketing of taxol.

The New Drug Application (N DA) for refractory ovarian cancer was approved by

the FDA in December 1992 and the Bristol—Myers Squibb Company (BMS) trademarked
Taxol® and launched it to the public in 1993. The FDA approved in April 1994 the

Supplemental NDA (SNDA) for the treatment of metastatic breast cancer and of breast

ll

cancer that recurred within 6 months of initial chemotherapy treatment. It was also
approved for a 3-hour infusion option in the treatment of metastatic ovarian and breast
cancers. Then in 1997, the FDA approved Taxol for the second-line treatment of AIDS
related Kaposi’s sarcoma, and one year later for use in combination with cisplatin for the
first-line treatment of non-small cell lung cancer in patients who are not candidates for
surgery or radiation therapy. The clinical uses of Taxol are still being expanded as
various combination therapies are being explored, for example, recent studies of Taxol
have shown promise in Alzheimer’s therapy.44 After its launching on the market in 1993,
Taxol quickly became a huge commercial success as the billion-dollar-per-year all time
best-selling cancer treatment drug, with annual sales peaking at nearly $1.6 billion in

2000, the same year generic paclitaxel entered market.“46

1.4 THE SUPPLY ISSUE AND THE SEMISYNTHESIS 0F TAXOL

Even during the first years after taxol was launched in the market for the
treatment of ovarian and breast cancers, the only method for large-scale production of
taxol was the extraction from the bark of the Pacific yew, T axus brevifolia, under good
manufacturing practice (GMP) guidelines. But the limited availability of the bark, the
low concentrations in the bark and the difficulty in large-scale production were still
problems affecting the supply of taxol. The Pacific yew, Taxus brevifolia, is a very slow-
growing conifer found principally in the understory of old-growth forests in the Pacific
Northwest from northern California to Alaska, as well as the Cascade Range in

Washington and Oregon, the western slopes of the Rockies, and the Lewis Range in

12

Montana. About 3,000 trees would need to be killed in order to obtain one kilogram of
taxol for the treatment of only about 500 patients. The killing of the slow-growing trees,
which may take 125 years to grow 9 meters high and 22 cm in diameter and yield only
3—5 pounds of bark from each tree (giving <0.5 g of taxol), caused ecological and
environmental concerns and led to the legislation of the Pacific Yew Act (HR. 3836) by
Congress in 1992.2

Alternative ways, such as biosynthesis47 and semisynthesis“, for large-scale
production of taxol were pursued. Significant work has been carried out both on the
scientific study of the biosynthetic pathways to taxol and on the important practical
application of plant tissue culture methods to its commercial production.49 It has been
recently reported by BMS and a Korean. company called Samyang Genex that the
commercial production of taxol by cell culture methods has been achieved but the details
of the process have not been released.478

When discussing the supply issue and semisynthesis of taxol, one must also
consider the taxol analog — Taxotere (2)6 — the only other taxoid drug currently in clinical
use. Taxotere, whose generic name is docetaxel, only differs in two functional groups
from taxol (Figure 1.1), and it was first synthesized by French scientists Potier and
coworkers.50 This compound has the same mechanism of action as that of taxol but its
potency is approximately twice that of taxol.51 While most of the effects of Taxotere
mirror those of taxol, it appears that the microtubules formed by Taxotere induction are
structurally different from those formed by taxol induction.” An attractive feature of

Taxotere is its increased solubility in water.53

13

The semisynthetic routes to taxol and/or Taxotere start from lO-deacetyl-baccatin
III (IO-DAB) 3, which was isolated in 1981 by Potier and coworkers from the needles of
the English yew, Taxus baccarat.54 This discovery was very significant for a number of
reasons. First, lO-DBA is present in substantial concentration and its yield was much
higher (~10 times) than that of taxol: about 1.0 g of lO—DAB per kilogram of fresh
needles, compared with the yield of 100—150 mg of taxol from a kilogram of dried bark.55
Secondly, it could be isolated easily and on a much larger scale from a very common
English yew. Thirdly, perhaps most importantly, the needles are renewable, and there is
no need to kill the trees, although the renewability of needles was not viewed as
important until late 19805, when growing requirements of the clinical trials increased the
demand for bark and concerns about saving Taxus brevifolia began to surface. Thus, in
order to synthesize taxol, the main goal is to attach the side chain at the C-13 position,
which was proved to be essential for the anticancer activity from Wall and Wani’s
original work.l7

After several preliminary attempts,50 Potier, Greene and coworkers achieved the
first successful semisynthesis of taxol with an intact side chain in 1988 (Scheme 1.1).56
Since lO-DAB has four hydroxy groups, regioselectivity could be a problem when the
side chain is installed. Of the three secondary hydroxyl groups, it was found that the two
—OH groups on C-7 and C-10 were more reactive than that on C-13.50 This is because the
—OH group on C-13 is tucked underneath the concave face of the cup- or dome-shaped
lO-DAB, which makes it sterically disfavored. The different reactivities were utilized by
sequential protection of the two alcohols with TES- and acetyl groups before the —OH

group at C-13 was reacted with the acid 10 under the influence of DPC-DMP to attach

14

the side chain. The yield was only 80% at 50% conversion, perhaps a reflection of the
hindered nature of this hydroxyl group, thus leaving much room for improvement before
this method could be considered commercially attractive. Acidic treatment of 11 provided
taxol in 89% yield. This semisynthesis of taxol from 10-DAB (3) has served as the
standard protocol for other modified procedures developed later.

Scheme 1.1. Potier and Greene’s Semisynthesis of Taxol.

HO 00H

1) TESCI, pyr.. rt (85%)

 

2) AcCl, pyr., 0 °C (85%)

 

0=<
Ph
3: 10-Deacetylbaccatin Ill (10-DAB)

 

DPC. DMAP,
Ph . OH PhMe. 73 °C
OEt (80% at 50% conv.)

 

HCI, EtOH/H20

(89%)

   

1: Taxol

Holton improved the synthesis by using a more compact B-lactam 12 in the
esterification step, which proved to be more effective and efficient and proceeded in
nearly quantitative yield.57 The lactam 12 was initially prepared by chiral resolution of
racemic material, however, Ojima subsequently reported a practical asymmetric synthesis
of this B-lactam.58 Deprotection of the C-2’ hydroxyl group in 11a could be carried out
using HF/pyridine to give taxol in >98% yield. Holton had patents issued in 1991 and

1992 that were later licensed to BMS. In 1995, BMS started the large-scale production of

15

taxol by semisynthesis following Holton’s approach, which is still the method currently
used by BMS for the commercial synthesis of taxol.47g

Scheme 1.2. Holton’s Semisynthesis of Taxol.

HO OOH

AcO 0 ores

    
   

1) TESCI. imidazole

 

HO“" o 2)A020.I.HMDS
0H6 OAc
0
Ph
3: 10-Deacetylbaccatin III (10-DAB) 9
0
JL 0
Ph NI I LDA or
pa“ "to/Q LHMDS

 

HF/pyr.

   

1: Taxol

, 11:
(~80% overall yield, lab scale)

1.5 TOTAL SYNTHESIS OF TAXOL

The total synthesis of taxol represents one of the greatest challenges to synthetic
chemistry. Taxol contains an unusual and distorted ABCD ring system with a large
number of stereocenters to be controlled; the central B-ring is an eight-membered
carbocycle which is notoriously difficult to form because of both entropic and enthalpic
factors; the A-ring includes a somewhat problematic bridgehead double bond formally
forbidden in a six-membered ring by Bredt’s rule;59 the C-ring is trans-fused with its

angular methyl group. Moreover, the high degree of oxygenation in the molecule requires

16

that each oxygen is introduced in a manner such that they can be differentially protected.
Additionally, the oxetane ring can open under acidic or nucleophilic conditions, and the
—OH group at C-7 may epimerize under basic conditions if left unprotected. All of these
considerations taken together constitute a formidable challenge to the synthesis of taxol,
but on the other hand, it should not be surprising to find that it is precisely these
challenges that have attracted the attention of some of the world’s best synthetic chemists
and that there are many hundreds of papers in the literature describing approaches to the
synthesis of taxol. Synthetic chemists like to challenge their chemical ingenuity and like
to conquer “a molecular Mount Everest”.60

An added incentive was the fear in the early 1990’s that natural supplies of taxol
would be inadequate to meet the demand for the drug, which gave hope that a synthetic
approach could overcome the problem. This concern was alleviated by the development
of semisynthetic approaches described above. Furthermore, a total synthesis would likely
take 40—50 steps and give low overall yield making it essentially impossible to be
considered for a practical process for commercialization. Nonetheless, the promise of the
preparation of new analogs and the challenge of developing new synthetic methods

continues to provide a rationale for new synthetic approaches. Studies to date have

culminated in six completed total syntheses of taxol.

1.5.1 Completed Total Syntheses and Their Strategies
The first two total syntheses of taxol were completed in 1994 by Holton61 and
Nicolaou62, respectively and essentially simultaneously. Holton actually submitted his

synthesis for publication more than a month earlier than Nicolaou, but it appeared a week

17

later. The journal of Chemistry and Industry described the two events as a “photo-finish
in the race to artificial taxol”.63 After that, four other groups reported their successful
syntheses. The following description will only highlight each of the six elegant

completed total syntheses, focusing on their strategies and key steps.

The Holton Synthesis“

Holton’s synthesis is a linear approach and in the form of AB —-> ABC —> ABCD,
which was built on his earlier synthetic studies on taxusiné4 and his discovery of the
“epoxy alcohol fragmentation” to install the AB ring system. As shown in Scheme 1.3,
this fragmentation worked well to give 14 in 93% yield from 13, which was readily
prepared from commercial available Patchino (B-patchoulene oxide). The AB-ring
synthon 14 was then converted to lactone 15, which underwent the Dieckmann
cyclization to form the C-ring. The elaboration of the oxetane D-ring was achieved
through the key intermediate 17. Holton’s total thesis Of taxol was completed in 41 steps
in ca. 2% overall yield.

Scheme 1.3. Holton’s Approach to the Taxol Skeleton

 

 

cone
Tesq
1) AcOOH ' steps
/ ‘ores . ’ o ——> _
OH 2) “(0’1")“ Tesot’ TBSO‘“
3) resort, Pyr.
13 (93%) 14
LDA. then AcOH
(93%)

Tesq OBOM Tesq OH

      

The Nicolgou SYnthe§_i_s62

Nicolaou adopted a late 8-membered ring formation with a convergent A- and C-
ring union, and the synthesis is of the form A + C -+ A—C -> ABC —P ABCD. Both A-
and C-ring precursors 18 and 20 were prepared by the Diels-Alder reaction with different
dienes and dienophiles followed by functional group manipulations. One of the key
coupling reactions was to link 18 and 20 using a Shapiro reaction via the in-situ
generated lithium species 19 (from sulfonylhydrazone 18) to form the alcohol 21 with
correct stereochemistry at C-2 (taxol skeleton numbering). The second key step was the
McMurry coupling of the bis-aldehyde 22 which proved to be troublesome, and even
after careful experimentation the best yield of 23 obtained was only 23—25%, with side
products being formed in significant amounts. The total synthesis of taxol by Nicolaou
and coworkers takes 51 steps and the overall yield is only ca. 0.03%.

Scheme 1.4. Nicholaou’s Approach to the Taxol Skeleton

OBn

 

 

NHSOzAr Li (82%)

TiCIg-(DME)

A

Zn-Cu. DME. 70 °C
(23%)

   

19

The Danishefsbl Synthesis65
The Danishefsky synthesis is of the form C —> CD —> A—CD —’ ABCD, and it is

the only synthesis to date in which the oxetane D-ring is incorporated early and
maintained throughout the synthesis. A key to this strategy was the protection of the C-4
hydroxyl group as its benzyl ether (e.g. in 25) rather than an acetate to avoid the
neighboring group participation by acetate which is a large part of the reason for the
oxetane ring’s lability in taxol.66 This synthesis makes effective use of the
enantiomerically pure Wieland-Miescher ketone 24 and all the stereochemistry of the
ABCD system derives from the chiral center of this ketone. Coupling of the aldehyde 26
with the in-situ generated lithium species 27 (from the corresponding iodide), after
treatment of TBAF, gave 28 as a single diastereomer, perhaps analogous to Nicolaou’s
similar precedent. The key cyclization to give the ABCD system was achieved by an
impressive Heck reaction of 29. Further functionalization of 30 and the completion of
the synthesis rely on a few known methods. The Danishefsky’s synthesis requires 47
steps from the Wieland-Miescher ketone and the overall yield is ca. 0.2%.

Scheme 1.5. Danishefsky’s Approach to the Taxol Skeleton

OTMS
CN

OTBS
27 Li

THF, --78 °C.
then TBAF

(74%)

Pd(PPh3)4

 

K2(CO)3. CH3CN
85 0C

 

(49%)

Meander Synthesis67

Wender utilized a linear approach in the form A —’ AB -+ ABC —> ABCD, but it
is very different from the formally similar Holton synthesis. The synthesis relies on a key
rearrangement reaction of intermediate 34 derived from verbenone 31, the oxidation
product of the abundant natural product pinene. The tricyclic intermediate 33 was readily
prepared from 31 in five steps, and was then converted to epoxide 34 which set up the
base catalyzed fragmentation to give the AB synthon 36 in 85% yield. The C-ring was
installed via an aldol condensation (37 —> 38). This synthesis, which took 37 steps from
verbenone in an overall yield of ca. 0.2%, was claimed to be the shortest reported
synthesis of taxol.

Scheme 1.6. Wender’s Approach to the Taxol Skeleton

i steps 0W5 MezcuLi. —78 °C
0 I | then AcOH, H20

“mm“ coza (97%)

 
   
 
  

 

O
31 32

  
 

TIPSOTI

 

2.6-lutidine

  
 

 

 

(85%)

    

36

DMAP. TrocCl
(62%)

AC0 0 OTroc

 

21

The Kuwajima Synthesis68

The Kuwajima synthesis uses an A + C —* A—C -* ABC —> ABCD approach. A
highly functionalized A-ring synthon 39 was brought together with the C-ring precursor
40 to form 41, which then underwent Lewis acid-catalyzed cyclization to give the ABC
tricyclic system 42. One difference of this synthesis with previous approaches is the
protection of the C-1 and C-2 hydroxyl groups late into the synthesis as a cyclic
benzylidene acetal (e.g. in 43) rather than a cyclic carbonate. Another feature of interest
was that all the stereochemistry was derived from the C-1 position of the aldehyde 39.

Scheme 1.7. Kuwajima’s Approach to the Taxol Skeleton

PhS 08"

 

 

M I
+ BnO 1) (8” 9C :
I 0\ ’6
(52%) B
39 40 Me 41

2) Pinacol. DMAP

1) TICI2(OIPI')2
(59%)

O OMOP PhS pan
steps steps
TBSO“" O OH O O HO OH
Y
Ph 43 42

The Mukaiyama Synthesis69

The Mukaiyama synthesis is unique in that the B-ring was formed first, leading to
a B —> BC -’ ABC —’ ABCD approach. Cyclization of the bromoaldehyde 44 in the
presence of Smlz gave the B-ring synthon 45 in 68% yield. The intramolecular aldol

condensation of 46 installed the C-ring, followed a few steps later by a pinacol reduction

22

(McMurry coupling) of 48 to give the ABC tricyclic system 49 in yields ranging from
42—71%, depending on which silyl protecting group was used for the C-1 hydroxyl
group.

Scheme 1.8. Mukaiyama’s Approach to the Taxol Skeleton

 

 

Br 98” OBn BnO O
Smlz, -78°C TBSO steps
. CHO : —-
i menA O, DMAP
O ’0 OPMB C4 : 2: OAc
TBS (68%) PMBO OBn
44 45

NaOMe, (79% based on
then Nat-I 61% conversion)

TiClz, LIAIH4

    
   

 

s H
(424%) PMBO‘ ban

   

47

As mentioned earlier, the total synthesis of taxol is unlikely to be used for its
commercial production, but the rich and diverse chemistry that was developed during the
process was incredibly enormous, as has been demonstrated in the six completed total

syntheses.

1.5.2 Some Other Strategies to Access the ABC Tricyclic System

Besides the completed syntheses by the six labs cited above, more than fifty
groups world-wide have published articles on their synthetic approaches.70 When
searching the literature, one has to be amazed by so many fascinating constructions and
proposed constructions that have been adumbrated and disclosed. Some of the approaches
.573

to access the ABC tricylic core are:71 Swindell’s amide fragmentation,72 Blechert and

Winkler’s74 retroaldol condensations, Shea’s75, Jenkin’s76 and Winkler’s77 intramolecular

23

Diels-Alder approaches, Blechert’s oxidative ring expansion,78 Trost’s fragmentation,79
Kishi’s Nozaki reaction,80 Paquette’s oxy-Cope approach,81 Funk’s intramolecular
Claisen rearrangement,82 Yadav’s Wittig rearrangement (ring contraction),83 Patteden’s
radical cyclization,84 Wang’s sequential anionic condensation,85 etc. Many of these may
not carry realistic prospects for maturing into comprehensive total synthesis, but the
chemistry that was developed for the various approaches to taxol is still remarkable and

enormous.

1.6 STUDIES ON TAXOL ANALOGS AND STRUCTURE—ACTIVITY

RELATIONS (SARS)

The studies on taxol derivatives and other analogs, in addition to Taxotere, have
been very active, with the main purpose of better understanding the structure-activity
relationships (SARs) and searching for a new generation of taxol-based antitumor agents
with improved physical, chemical and biological profiles. As an example of the latter, it
would be most important to have the drug delivered more selectively to the tumor cells.
Among the numerous taxol analogs, about two dozen have entered preclinical
development, four are currently in phase I clinical trials and six additional analogs are in
phase II clinical trials.478

The limited water-solubility of taxol and its initial clinical use requiring a 24-hour
infusion prompted great interest in developing more water soluble prodrugs.86 However,

clinicians found later that the infusion times could be reduced to 3 hours, and this

removed much of the initial impetus for prodrug development. At this time, therefore, no

24

prodrugs have entered the market place, but the prodrug approach continues to be of
interest as a mechanism for targeting taxol to its site of action.87

As mentioned earlier, much of the chemical work on taxol derivatives and analogs
has been carried out with a View to determining structure-activity relationships for these

I.88 Some of the work is

compounds and defining the key pharmacophore of taxo
summarized in Figure 1.2, where the key structure-activity relationships of taxol are

shown.

Figure 1.2. The Structure-Activity Relationships (SARs) of Taxol.

 

without significant loss of activity; some acyl

Acetyl or aoetoxy group may be removed
analogs have improved activity

 

 

 

 

 

 

N-acyl group required; [Reduction improves activity slightly]
some acyl analogs have \ /
improved activity

 

 

 

OH group may be esteritied. epimerized
MO 0 OH or removed without significant loss of acitivity

 

   
 

 

 

May be changed to alkenyl
or substituted phenyl;
some give improved activity

 

Oxetane ring required for activity:
0 Substitution of O with 8 reduces activity

 

 

 

 

 

 

 

Removable of acetate reduces activity slightly;
some acyl analogs have increased activity

\

[Contracted A-ring inactive] Acyloxy group essential; certain
alkenyl and substituted aromatic
[OH group helpful but not essential ] amps give improved activity

Free OH or a hydmlyzable
ester thereof required

J

 

 

 

 

 

 

 

 

 

 

It is of interest to mention that some bridged analogs of taxol were also prepared
and studied, with some showing interesting results and others proving to be inactive.89
Recent studies by the Horwitz and Kingston groups have shown that the side chain of
taxol may be not as essential for activity as was previously thought.90

Before concluding this chapter on the biology and chemistry of taxol, it should be

mentioned that although taxol was for many years unique in terms of its mechanism of

25

action, in recent years a number of other natural products have been found to promote the
assembly of tubulin into microtubules in the same way as taxol does. The most important
and familiar compounds in this class are epothilones A and B,91 discodermolide92 and
eleutherobin.93 Efforts were also directed to prepare compounds including both taxol
fragment and fragments of these compounds, such as epothilone A, to examine whether
improved activity would be achieved.94

Taxol has revolutionized the treatment options for patients with advanced forms
of breast and ovarian cancers as well as some other types of cancers. As discussed in the
previous sections, much fascinating chemistry has also been developed following
synthetic explorations pertinent to taxol, and it continues to grow.

All of the work in this thesis was either the result of efforts directly aimed at the
synthesis of taxol or the result of serendipitous findings on the way to taxol that led to
completely unanticipated areas of chemistry that were of sufficient significance to

demand investigation on their own merits.

26

CHAPTER TWO

SYNTHETIC STUDIES TOWARD TAXOL:
UTILIZING THE WULFF—KAESLER REACTION OF FISCHER

CARBENE COMPLEXES AND 1,6-ENYNES

2.1 FISCHER CARBENE COMPLEXES AND THE WULFF—KAESLER

REACTION

Transition metal carbene complexes, which have a trigonal planar carbon
connected to the metal, contain a formal double bond between the metal and the carbon.
The general structure of a metal-carbene complex is shown in 50 (Figure 2.1), where X
and Y can be alkyl, alkenyl, alkynyl, aryl, H, or heteroatom-containing (O, N, S,
halogens) groups.

Figure 2.1. Metal-Carbene Complexes 50 (General Structure) and 51

IX OMe
LnM=C\ (OC)5w=(
Y Ph
so 51

The tungsten complex 51 was the first characterized stable transition metal
carbene complex that was reported by Fischer and Massbdl in 1964.95 This report ushered
in the important, dynamic and exciting area of chemistry in metal carbene complexes,

which has attracted literally hundreds of chemists to explore the chemistry in this

27

field.""’97 The investigations have led to the discovery of numerous new complexes, novel

reactions and have resulted in a great number of applications to organic synthesis.97

2.1.1 Fischer Carbene Complexes: The Background

There are two types of metal-carbene complexes: the Fischer type”96 and the
Schrock type.98 Each represents a different formulation of the bonding of the CXY group
to the metal (a general structure shown in 50), and therefore they differ in several ways.99

The Fischer carbene complexes contain middle to late transition metals, such as
chromium, tungsten and iron, which are in low oxidation states (Figure 2.2). Due to the
electron richness of the metal, the ancillary ligands are usually good it acceptors, which
are most commonly CO and PPh3. The carbene carbon is normally stablized by an
electronegative heteroatom, for example, nitrogen, oxygen or sulfur. Fischer carbene
complexes are considered to have a singlet ground state if removed from the metal.
Consequently, the carbene ligand is regarded as a 2-e1ectron O donor through its filled spz
orbital and as a weak 1: acceptor Via back donation of electrons from a filled metal d
orbital to the empty 2p orbital of the free carbene. As a result, the carbene carbon of a
Fischer-type complex is typically electrophilic.

Figure 2.2. Fischer-type Carbene Complexes

M = Middle to Late Transiton Metal
[e.g. Cr(0). W(0). Mo(0). Fe(0)]

L = Good n: Acceptor
[e.g. CO. PPh3]

 

OMe

Example: (OC)5Cr Heteroatom on Cat—carbon
[e.g. O. N. S]

52

28

On the other hand, Shrock-type carbene complexes contain early transition metals
in high oxidation states, such as titanium(IV) and tantalum(V) (Figure 2.3), therefore,
good 0 or n: donor ligands are required (e.g. cyclopentadienyl ligand (Cp), alkyl groups
and chlorine). The substituents on the carbene carbon are usually alkyl groups and/or
hydrogen. Since Schrock carbene complexes are considered to have a triplet ground state
if removed from the metal, the carbene ligand is regarded as a dianionic ligand in its
formal oxidation state to form two covalent bonds, and as a result, the carbene carbon is
often nucleophilic.

Figure 2.3. Schrock-type Carbene Complexes

“mi-«mi M = Early Transiton Metal
L110 H ' Ie-O- TI(IV). Ta(V)]

L = Good 0 or at Donor
[e.g. Cp. Cl, Alkyl]

Example: @ H
\ H or alkyl on Cot-carbon

HSCWJE a=<

53

 

 

The Wulff research group has been interested in Fischer carbene complexes for
more than two decades, mainly focusing on their applications to organic synthesis. Thus,

the following discussion will be largely limited to the Fischer carbene complexes.

The Preparation of Fischer Carbene Complexes.

The most commonly used methods for the preparation of Fischer-type carbene
complexes are summarized in Scheme 2.1. The most extensively studied Fischer carbene
complexes are group 6 complexes with chromium and tungsten complexes as the more
common ones. Many of the alkoxy carbene complexes 56 can be conveniently prepared

from the corresponding organolithium reagent 54, where R can be an alkyl, aryl, alkenyl

29

 

or alkynyl group. Addition of the organolithium to a group 6 hexacarbonyl gives the
lithium metal acylate 55 which is then followed by alkylation with a trialkyloxonium
tetraflouroborate100 or an alkyl trifluoromethane sulfonatem'. This procedure is normally
referred to as the standard Fischer protocol. The yields of carbene complexes by this
method are usually good to excellent and most complexes are solids that can be purified
by crystallization. Alternatively, since most Fischer carbene complexes can be handled in
the presence of air, their purification can be accomplished by silica gel column
chromatography. The sensitivity of the complexes to air increases with temperature and
an inert atmosphere is normally employed for reactions carried out above room
temperature.

Scheme 2.1. The Preparation of Fischer Carbene Complexes

OH
(CO)5M=<

R
RX Cr CO
I tBuLi 1 CaK

 

 

 

 

     
  

 

 

 

 

 

RL. M16016 (c0) M=<0Li R‘OTf 1) K2[Cr(CO)sl 0
I 5 t <
u 55 R or R‘3OBF4 2) R10" R C'
or R‘308F4 61a
M 8 Cr, w, Mo
R = alkyl, alkenyl, R2.N*x- R110" 0'
aryl, alkynyl R 30351 1) hv
0 2 2) RICH _ R
NR 4 '—
(C0)5M 62
:(R HXR3
l AcCl Cr(cO)6
ll 1 CBK
OAc XR3
(co)5M=< HXR3 (CO)5M=( 1) K2[Cr(CO)sl EL
R R T R NR3
59 50 2) TMSCI 2
(or prepared directly from 55) SR ’ N 2 (when XR3 = NR32)

 

 

The lithium acylate 55 can also undergo cation exchange with
tetraalkylammonium halide to give a stable tetraalkylammonium acylate 58 which can be

easily isolated and is more reactive to a given electrophile than the corresponding lithium

30

acylate. The reaction of 58 with an acyl halide such as acetyl chloride produces an
acyloxy carbene complex of the type 59 that is often too unstable for isolation under
ambient conditions but its reactivity can be utilized in the preparation of a variety of
heteroatom stabilized complexes (e. g. 56 and 60) by substitution reactions with alcohols,
amines and thiols.102 Acyl complexes of the type 59 can also be generated by reacting the
lithium acylate 55 directly with an acyl halide; however, the yield is usually much lower
than that from the reaction from 58. Alternatively, the amino and thiol complexes of the
type 60 may be prepared by the direct treatment of the alkoxy complexes 56 with amines
and thiols.103

Perhaps the most important non-Fischer synthesis of carbene complexes of the
types 56 and 60 is by the reactions of the pentacarbonyl chromate dianion with acid
halides 61a and amides 61b, respectively.104 This approach is especially usefill for the
preparation of complexes with a quaternary carbon center next to the carbene carbon,
which usually cannot be efficiently made by the standard Fischer protocol.

In addition to these thermal methods discussed above, another approach for the
preparation of alkoxy carbene complexes 56 uses metal carbonyl and an alkyne 62 under
photochemical conditions.105 It involves the rearrangement of a metal alkyne complex to
a metal alkylidene complex which is then trapped by an alcohol. An advantage of this
method is that highly reactive anionic reagents need not be employed; however, the

reaction works well only in specific systems and has yet to be optimized for general use.

31

 

Mions with Fischer Cgrbene Complexes.

The growth in the number of useful reactions and their applications has been
exponential with time since the discovery of the first Fischer carbene complex in 1964.95
The reactions involving Fischer carbene complexes can be divided in two main
categories: reactions at the metal center and those at the carbene-carbon substituent.97
There have been a number of comprehensive reviews of this rich chemistry over the past
decades,97 and some of the major reactions are summarized below.

The two most extensively studied reactions of Fischer carbene complexes at the
metal center are cyclopropanation and benzannulation reactions.97 The cyclopropanation
reaction, a formal [2 + l] cycloaddition, is one of the first reactions of carbene complexes
to be investigated, which has been driven not only by potential synthetic applications, but
also due to the relationship of this reaction to olefin metathesis.‘06 A brief background of
the cyclopropanation will be discussed in Chapter 3.

The benzannulation reaction (DOtz-Wulff reaction) of a,B-unsaturated Fischer
carbene complexes with alkynes generates new benzene rings that have 1,4-dioxygen
substitution. This process occurs in the coordination sphere of the metal under neutral
conditions at or near ambient temperature. This reaction has evolved as a very valuable
method for the preparation of p-alkoxy phenols and quinones and is the most extensively
applied reaction of Fischer carbene complexes in organic synthesis.97 An overview of this
reaction, including its mechanistic considerations, the scope and limitations of the
reaction and its synthetic applications, will appear in Chapter 4.

In addition to the cyclopropanation and benzannulation reactions, there are many

other cycloadditions that take place at the metal center in the coordination sphere of the

32

 

metal. Among those is the formation of four-membered and five-membered rings through
the coupling of the carbene ligand with alkynes.97°’d’107

Reactions of Fischer carbene complexes can also occur at the carbene-carbon
substituent, where the metal plays the role of reactivity and selectivity auxiliary.97°’d For
example, a,[3-unsaturated alkenyl or alkynyl carbene complexes can act as dienophiles in
the Diels-Alder reaction with significant rate enhancement and better regioselectivity
over their corresponding ester analogs.108 These carbene complexes can also undergo [2
+ 2] cycloadditions with olefins (mainly for alkynyl complexes),109 or react with
nucleophiles in Michael additions.110 In addition, the a-carbon of Fischer carbene

complexes can be easily deprotonatedlll and the resulting ‘metallo-enolate’ can

participate in aldol condensations with aldehydes and ketones.”2

2.1.2 The Wulff—Kaesler Reaction of Fischer Carbene Complexes and 1,6-Enynes
The Wulff—Kaesler reaction, a chromium-mediated intramolecular [2 + 2]
cycloaddition, was first reported in 1985 for the reaction of Fischer carbene complex 63a
with 1,6-enyne 64 which gave the bicyclo[3.2.0]heptanone 65 in 45% yield (Scheme
2.2).113 The mechanistic pathway is believed to involve an alkyne insertion in the 16-
electron species 66 to generate the 711,113 -Vinyl carbene complexed intermediate 67, which
then undergoes the insertion of a CO ligand to give Vinyl-ketene complex 68 that is
trapped intramolecularly by the olefin via a [2 + 2] cycloaddition to afford the
bicyclo[3.2.0]heptanone 65. This was the first example of the chromium-mediated
intramolecular [2 + 2] cycloaddition, although similar intramolecular cycloadditions

involving metal-free ketenes with tethered olefins are well documented.”4

33

 

 

Cyclobutanones have been proven to be versatile synthetic intermediates of great value in

organic synthesis.”5

Scheme 2.2. The Wulff-Kaesler Reaction and Its Mechanism

OMe \ CH3CN 70°C
(CO)Scr=<CH3 + O ".457 ld
yie
l (E/Z= 2:1)

64

CC/em 32' H65H\[:Mo + 2] cylcloaddition

(OC)4Cr\ OMe CO insertion

‘ =<::A: \/ CH3 ocme/// CH3

(0C) Cr
66 67 3 68

 

 

Wulff and Kim further reported in 1993 that this reaction could be carried out
with 1,6-enynes having different substitution patterns,“6 and some examples are shown
in Scheme 2.3. It was observed that the solvents could have a big effect on the product
distribution. Bicycloheptanone products were formed exclusively in a polar and
coordinating solvent such as acetonitrile, while in a non-polar and non-coordinating
solvent, such as hexane, furans and cyclopentenones were formed.“7 It was also found
that metal-mediated reactions showed faster rates and improved stereoselectivities in

comparison with the corresponding metal-free cycloadditions of ketenes and alkenes.

34

 

Scheme 2.3. Stereoselection in the Wulff-Kaesler Reaction

0
OMe 1) CH3CN, 70 °C
(CO)SCr=( + \\ e H
CH3 I 2) HOAc O 33% yield
11 : 1 dr

 

 

 

63a
69 7o
OMe O
1) CH3CN, 70 °C
(CO)SCr=< + \\ ;
CH3 2) HOAc o 64% yield
63. l > 11 : 1 dr
71 72
OTBS
OMe 1) CH3CN. 70 °C
(CO)5Cr=( 4» % e o .
CH 2) HOAc 73 /0 yield
3 20 : 1 dr
63a

73

 

One of the interesting findings was that, when the olefin in the enyne (as in 75)
was disubstituted at the remote end from the alkyne, bicyclo[3.l.1]heptanone 76 was
obtained via a crossed [2 + 2] cyclization of the ketene intermediate 77.“8 The product 76
has geminal dimethyl groups on the six-membered ring which resembles the taxol A-ring.
Further functionalization, such as the incorporation of the C-ring, seemed possible, thus
plans began to be considered for the utilization ofbicyclo[3.1.1]heptanones of the type 76
as A-ring synthons of taxol and taxane derivatives (refer to Fig. 1.1).

Scheme 2.4. Bicyclo[3.1.l]heptanone 76 from a Crossed [2 + 2] Cycloaddition

OMe % 1) CH3CN. 70 °C 0
(CO)5Cr=< + e
CH3 | 2) HOAc

o
‘3' 75 7s 69%

 

Cr(CO)3

\ OMe

9 CH3
[“0

77

35

2.2 THE RETROSYNTHETIC STRATEGY TOWARD THE TAXOL SKELETON

AND PREVIOUS EFFORTS

As mentioned in Section 2.1.2, a plan was initiated to apply the Wulff—Kaesler
reaction of Fischer carbene complexes and 1,6-enynes to the construction of synthons for
the A-ring of taxol and other taxane derivatives. Dr. Kim first looked at the possibility of
using an oxy-cope rearrangement to synthesize the ABC tricyclic skeleton. As shown in
Scheme 2.5, the alcohol 80 was prepared quantitatively from the bicyclo[3.l.1]heptanone
78, but attempts to install the B-ring through anionic oxy-Cope rearrangement or
thermolysis (refluxing in xylene) did not afford the desired tricyclic compound 81.”7 In
related studies on the metal-free [2 + 2] cycloaddition, Snider reported that anionic Cope
rearrangements of molecules of the type 80 were only successful for unsubstituted allylic
alcohols generated by the addition of vinyllithium to a ketone. More highly substituted
alkenyllithium adducts (e.g. an analog of the type 80) failed to react, thus the introduction
of the C-ring could not be realized.”4" Based on these literature results as well as Kim’s
unsuccessful attempts, the strategy Of using anionic oxy-Cope rearrangements to
construct the ABC tricyclic core was abandoned.

Scheme 2.5. Kim’s Initial Attempts on the ABC-Tricyclic Skeleton

 

 

Li
OMe . . M80
OMe Anionic oxy-Cope
79 “ rearrangement
\ _ v _
, A ,
H0 or Thermolysis
O O
78 80 100% 81

A completely different strategy was then devised as shown in Scheme 2.6. It was
envisioned that rapid entry into the ABC tricyclic core of taxol be achieved by utilizing

the Wulff—Kaesler reaction of carbene complex 87 and enyne 86 which should give the

36

bicyclo[3.l.1]heptanone 85 as a suitable A—C synthon. It was considered that 85 could be
further manipulated for subsequent condensation and fragmentation into the ABC
skeleton, for example, via acid induced epoxide-ring cleavage of 83.

Scheme 2.6. Second Generation of Retrosynthetic Strategy

 

 

 

82 — 83 83a _

OR"
(OCISCI OR' / \ ""233” Swim" R-
+ 590R (I: 0%

o |
L)
37 as

The feasibility of the strategy outlined in Scheme 2.6 was then investigated.
Unfortunately, the reaction of carbene complex 63a with the cis-dienyne 86 did not give
the [2 + 2] cycloaddition product, instead, a 56% yield of the aldehyde 88 was isolated
(Scheme 2.7).119 This result was rationalized by suggesting that either the Vinyl ketene
complex 89a or 89b was generated during the reaction and underwent a [1,5] sigmatropic
hydrogen shift to form 88 rather than an intramolecular [2 + 2] cycloaddition.

Scheme 2.7. Attempted Wulff-Kaesler Reaction with Dienyne 86

 

(CO)5Cr=< + =
CH3

 

63. 86
F Ci(00)3 (OC)3Cr —
/// \ OMe / \\ OMe
| H g CH3 0" I H Cd CH3
‘ 89a 89b "‘

 

 

37

In an effort to prevent the proposed [1,5] sigmatropic shift that gave rise to 88, the
trans-dienyne 86a was then prepared. Presumably, the formation of an aldehyde Via
[1,5]-H shift would be geometrically prevented by the E-configuration of the alkene, as
shown in 91a/b in Scheme 2.8. However, an intramolecular [2 + 2] cycloaddition of
91a/b would also not be possible because it would otherwise result in the generation of a
six membered ring with a trans-double-bond. Interestingly, the cyclobutenone 90 was
isolated in 70% yield, probably resulting from the electrocyclic ring closure of the vinyl
ketene complex 91a.

Scheme 2.8. The Reaction of Complex 63a with Dienyne 86a.

CH3CN 70 °C
(CO)5CI3=<::: _ >mom

 

90 70%
/Cr(CO)3 (00130 \
eOfWWOMe
6' CH3 ii
0
91a 91b

The failure of dienyne 86 to form bicyclo[3.l.1]heptanone products upon reaction
with the chromium carbene complex 63a indicated that the strategy for the synthesis of
taxol outlined in Scheme 2.6 was not viable. A slight modification of the strategy was
suggested by the known isomerization of the bicyclo[3.l.1]heptanone 95 to
chrysanthenone 96, as shown in Scheme 2.9.120 If the same isomerization could be
effected on intermediate 93 then the original strategy could be saved since epoxidation of
92 would intersect with intermediate 84 (cf. Scheme 2.6) and the new (third generation)
retrosynthesis would descend to the isomeric exo-methylene dienyne 94 and the carbene

complex 87.

38

Scheme 2.9. Third Generation of Retrosynthetic Strategy

0 o
4 OR' / OR'
92 1:1) 0, £3 :1) ‘ ¢
0 O
o o
92
(005ch Wullt-Kaeslar 0"" R,
reactlon ‘3 O
| 0
"L0 °
94

% H2, 5% PdlCaCO3 E g

0 O
95 96 100%
chrysanthenone

 

The dienyne 94 could be conveniently synthesized in 76% yield in one pot from
the commercially available isopropenyl acetylene 97 by utilizing Brandsma’s method,m
presumably via the dipotassio derivative after treatment with the Lochmann-Schlosser
reagent (nBuLi—KOtBu)122 and subsequent transformation into the lithiated dianion by
the cation exchange with anhydrous lithium bromide (Scheme 2.10). The reaction of
dienyne 94 and carbene complex 63a afforded the desired bicyclo[3.l.1]heptanone 99a,
along with a substantial amount of the cyclobutenone 100a being formed as the side
product. The product distribution is a function of temperature with the ratio reversing
from a predominance of the cyclobutenone 100a at higher temperatures (e. g. 100 °C) to a
distribution in favor of the bicylco[3.l.l]heptanone 99a at lower temperatures (e.g. 45
°C). Further studies showed that electronic tuning of the alkoxy substituent of the
carbene moiety could control the product ratio and a more electron withdrawing group on

the oxygen led to a greater proportion of the bicycloheptanone product.”9

39

Scheme 2.10. Preparation of 94 and Its Reaction with Complex 63a

 

Br
2.2 eq.nBuLi —\=‘< \
3 _ 2.2eq.K018u [ > “—6 ] 98 \

2.2 eq. LiBr e |

97 97a
94 76%

 

oooooooooooooooooooooooooooooooooooooooooooo

o

OMe OMe

OMe
(CO)5Cr=( . S CH3“ e ‘ CH + / CH
CH3 l (0.01 M in 63:) 3 3

0 \
63a
94 99a

100a

 

 

Jiang and Fuertes also examined the exo to endo isomerization and found that the
desired endo-isomer 102 could be achieved in 70% yield upon treatment of 101 with 5%
Pd/BaCO3 under an atmosphere of hydrogen.“9 Thus, it appeared that the third
generation strategy outlined in Scheme 2.9 which incorporated dienyne 94 for providing
the endo-cyclic double bond required for epoxidation and subsequent fragmentation
offered a viable approach to the synthesis of taxol and other taxane derivatives.

Scheme 2.11. Isomerization of the Double Bond in Bicycloheptanone 101.

o 0
H2. 5% Pd/Ba003
CH3 e ‘ cH3
rt. 4 h

0 O
101 102 70%

 

When the more substituted carbene complex 63d was reacted with dienyne 94, the
bicyclo[3.l.1]heptanone 99d was obtained as anticipated (Scheme 2.12). However, very
surprisingly, after 99d was subjected to strong acidic conditions, the expected triketone
104 was not observed. Instead, an unknown compound was isolated at that time and was
later assigned to be the tricyclic compound 103.123 The spectral data appeared to support
the structure where one of the two carbonyls in the B-diketone was in the enol form. This

assignment was tentative and awaited further confirmation.I24 The proposed mechanism

40

involving intermediate 106 via an aldol condensation and subsequent Grob-type

fragmentation125 seemed to be reasonable.

Scheme 2.12. The Formation of 99d and Its Subsequent Reaction with an Acid

0
OMe
(COIsCr OMe OMe
CH ON ”T
+ \\ -—;——’ + /
o i 45 °C, 48h O \
94

 

 

 

 

 

0
O
K/O ok/O
53“ 99d 40% 100d 21%
0MB 0 0
eq. HCI ICchN ..
, a o
O O 0
103 72% 104 Not observed
I Grob Frag.
H‘ o T
Aldol Condensation \

II

 

 

 

106

If the structure of 103 were correct, this would be significant for the strategy for
the synthesis of taxol and taxanes derivatives because the tricyclic core could then be
prepared directly from bicycloheptanones of the type 93, without the need for performing
the isomerization and epoxidation steps (refer to Scheme 2.9)! Therefore, the
retrosynthetic strategy was modified such that the B-ring (e.g. in 82a) is installed by
direct aldol condensation and Grob-type fragmentation, as outlined in Scheme 2.13.
Since epoxidation would not be involved in the strategy, the oxygen functionality on the
A-ring of the ABC tricyclic core 82b could be introduced in the form of a dienyne of the

type 110.

41

Scheme 2.13. Fourth Generation of Retrosynthetic Strategy

 

0 OR
R' Wullt-Kusler
@?:$ H§ Q 0:0 :SRED Aldol Swoiu 5: OR reaction (OC)5Cr SW?
02“ O
828 107 94
0 0R R' R.Wullr-ltimlor 0R"
reaction (QC-35C!r OR' RO..,_ \
Wag? I::(> RO\ :11)RO + \
02 i
H 0
82b 108 87 110

F uertes developed an efficient way to synthesize the chiral dienynes 110 from
commercially available (S)-B-hydroxy-y-butyrolactone 111.126 Scheme 2.14 shows the
synthesis of the dienyne 110a whose alcohol is protected as a benzyl ether. Starting from
the chiral lactone 111, protection of the free alcohol with benzyl trichloroacetimidate in
the presence of catalytic amount of triflic acid gives 112 in 88% yield. Then reduction
with DIBAL followed by a Wittig reaction affords the alcohol 113 in 78% over two steps.
Swern oxidation and subsequent nucleophilic addition of TMS-ethynyl magnesium
bromide furnishes the propargylic alcohol 115, which is then subjected to another Swern
oxidation followed by Wittig methylation and removal of the TMS group to furnish the
final product 110a. The synthesis consists of 8 steps and the overall yield is 54%. Thus, a
variety of dienynes of the type 110 that differ in the O-protecting group can be prepared
using the same sequence with different protecting groups or simply by protecting group

exchange (for example, with the TIPS-analog of 110a, which can be easily deprotected).

42

Scheme 2.14. The Preparation of Chiral Dienyne 110a.

 

 

 

 

 

 

 

o o OH
£0 CI3CC(=NH)OBn f0 1) DIBAL BnOa...
cat. TtOl-l 2 Ph P=C CH )
HO BnO ) 3 ( 3 2 |
111 112 88% 113 78% (two steps)
0 OH
DMSO. (COCI)2 3,10,, TMS : McBr ano. DMSO. (COCI); ano..,,_
t T H t h. \ : \
\
then Et3N TMS then Et3N TMS
l I I
114 95% 115 116 94% (two steps)
Ph3P=CH2 Bnoh“. AgNC)3 8007.,“
_. Q Q
TMS Nal
I I
117 110a 88% (two steps)

The reaction of dienyne 110a with carbene complex 63a worked well and gave
118a in 88% yield as a mixture of syn/anti isomers (Scheme 2.15). The cyclobutenone
product was not observed and the syn to anti ratio (3.1 : 1) was good with the major
isomer being the desired one that was needed for our proposed fourth generation strategy
for the synthesis of the taxol skeleton. Fuertes then went on to make more functionalized
bicyclo[3. 1.1]heptanones with substituted carbene complexes, but his attempts at closure
of the B-ring using J iang’s conditions were unsuccessful.126

Scheme 2.15. Synthesis of Bicyclo[3. l . l ]heptanone 118a with Chiral 110a.

0M8 Bnolh‘. \ 1) CH3CN..45 °C 0 O O
(0050., < + \ (0.01 M in 63s) : +
CH3 300 CH: BnO CH3
l 2) HOAc

83a 0

 

110a 118a 88% (syn/anti = 3.1)
Based on these previous efforts, it was decided to carry out more systematic
studies on the Wulff—Kaesler reaction and, of course, to continue the progress toward the

total synthesis of taxol.

43

2.3 FURTHER STUDIES ON THE WULFF—KAESLER REACTION

2.3.1 Bicylo[3.1.1]heptanone Intermediates for the Synthesis of the A-Ring

Synthons of Taxol and Taxane Derivatives

This work begins with a look at the Wulff—Kaesler reaction of the chromium
carbene complex 63a with dienyne 94. This reaction was initially studied by Jiang and it
was found that the formation of the desired bicycloheptanone 99a was favored at a lower
temperature with an optimal temperature of 45 °C for a reaction performed at 0.01 M
concentration in 63a for 48 hours.1 ”"23 It was deemed necessary to determine if a higher
concentration of 63a could be employed and whether the reaction was complete in a
shorter time. As shown in Table 2.1, both the overall yields and the ratios of 99a/100a are
essentially the same for reactions performed at both 0.01 and 0.1 M concentrations in
complex 63a. This is significant since it means that the reaction is amenable to scale-up
and that large-scale reactions can be carried out without the use of a large amount of
solvent. Furthermore, both reactions were complete in 24 hours. The assignment of E/Z
isomers of 100a was made by the difference in chemical shift of the enol ether carbons
according to Strobel’s empirical rulem Since 99a Was obtained as a single isomer, it
could not be assigned by Strobel’s rule and was assumed to be in the E configuration

according to studies on related compounds.l '9

44

Table 2.1. The Wulff-Kaesler Reaction of Complex 63a and Dienyne 94

 

 

 

 

O
OMe \\ CH3CN. 45 °c 0M9 OMe
(COiSC’=<CH3 t 7 CH3 ’ CH3
I o \
83a
9‘ 99! (Eonly) 100. (E/Z)
Y' ld,‘V
Entry [63a], M Time, h '6 ° 99a: 100a
99a 100m 10an Total
1 0.01 48 46 24 12 82 1.3
2 0.1 48 44 23 10 77 1.3
3 0.01 24 46 20 11 77 1.5
4 0.1 24 47 22 12 81 1.4

 

A few substituted carbene complexes 63b-d were then prepared to examine the
scope of the reaction with dienyne 94 (Scheme 2.16). The complex 63b was prepared
from cyclohexyl iodide 119 in 25% yield using the standard Fischer protocol, and the low
yield in this reaction was presumably due to a competing elimination of the 2°-halide 119
under the reaction conditions.

Scheme 2.16. Preparations of Substituted Carbene Complexes 63b-d.

 

 

I OMe
1)tBuLi (OC)5Cr
3) Me308F4
119 6311 25%
OH Cl OMe
0 soc:2 0 1) K2[Cr(CO)5] (OC)5Cr
2) Me3OBF4
120 121 100% 63c 76%
OH OMe

1 E I (pelt-Cr

Q TMSCl Q OH :3 ”BU”
Net 0 2) Cr(CO)3 O
0 TMSO K/O 3) MeaoBF-i K/O
122 123 124 82% (2 steps) 63d 71%

 

 

 

45

For the tertiary alkyl carbene complex 63c, the chromate dianion method was
used to prepare it.104 This method was first reported by Semmelhack in the synthesis of
alkoxy carbene complexes from acid chlorides with disodium or dilithium
pentacarbonylchromate (Na2[Cr(CO)5] or Li2[Cr(CO)5]) that was prepared from sodium
naphthalide and trimethylaminopentacarbonyl chromium(0).104a Hegedus later developed
a similar method to prepare amino carbene complexes from amides using dipotassium
pentacarbonylchromate (K2[Cr(CO)5]) which was generated from the reduction of
Cr(CO)6 with potassium graphite (CgK).104C This potassium chromate dianion reagent has
also been applied to the synthesis of alkoxy carbene complexes from acid chlorides as
well,104d and the advantage of using potassium chromate dianion is that the only by-
product in principal is graphite which can be filtered off at the end of the reaction. The
sodium or lithium chromate dianion approach has naphthalene as the by-product which
can be problematic during the purification of the product carbene complex. Thus, the
potassium chromate dianion approach was employed in the preparation of complex 63c.
It was pleasing to find that when acid chloride 121 was treated with the in situ generated
dipotassium pentacarbonylchromate for three hours followed by methylation with
Meerwein’s salt, the carbene complex 63c was obtained in 76% yield.

The synthesis of complex 63d was originally developed by Jiang123 and the
overall yield was later improved (Scheme 2.16). The precursor iodide 124, was made
from cyclohexenone 122 in 82% yield over two steps. With careful handling of the light
sensitive iodide 124 during the preparation of the carbene complex and with the use of
Meerwein’s salt in the methylation step, the complex 63d was obtained in 71% yield,

which was a significant improvement over the original report (54% yield).123

46

The Wulff-Kaesler reactions of complexes 63b-d with dienyne 94 were then
carried out (Scheme 2.17). In each case, the reaction worked well to give the desired
bicyclo[3.l.1]heptanone 99 as the major product, but a significant amount of the
cyclobutenone 100 was obtained as a side product. The cyclobutenones were isolated as a
mixture of E and Z isomers, except for 100c which has a quaternary center next to the
enol ether. Cyclobutanone 100c was obtained as a single isomer and its stereochemistry
was not determined. It is interesting to note that most of the peaks in the 13C NMR
spectra of all three bicycloheptanones 99b-d are fairly broad, especially for those more
downfield, and as a result, it took a long time to obtain the spectra. This unusual peak
broadening is probably due to a dynamic process which is slow on the NMR scale,
presumably the result of a conformational change in the bicyclic system.

Scheme 2.17. The Wulff—Kaesler Reactions of 63b-d with Dienyne 94

O

OMe OMe
(OCIsCr \ CH3CN. 45 °c We
‘0' \ _—D \ + /
| o
\
63b 94 99b 45% 100b 41% (27:1)
0
OMG OMe
(OCIsCr \ CH3CN. 45 °c \ OMe
+ \ ______. + ,
’6 I o
\
63c 94 99c 39% 100:: 36%
o

OMe OMe

(OC)5CT \ CH30N. 45 0C ‘ H 0MB
'8' \ —. + I
E > 0
O I o \

Kxo 90 Lo

63d 94 99d 64% 100d 24% (24:1)
It was also pleasing to find that the reaction of complex 63d gave a higher overall

yield (88%) than that was reported by Jiang (61%) and that the product selectivity of 99d

47

over 100d was good. The bicycloheptanone 99d has a ketone functionality (protected as
an acetal) which was necessary for the proposed subsequent B-ring closure in the
synthesis of the ABC tricyclic skeleton of taxanes (Scheme 2.13). Very careful NMR
studies showed that the bicyclo[3.l.1]heptanone 99d actually existed as a mixture of two
isomers (~1:1 ratio), which were tentatively assigned as the two epimers shown in
Scheme 2.17. The mixture of isomers showed nearly a single set of peaks in the IH NMR
spectrum, with the only three peaks of the vinyl protons being partially overlapped and
all others showing complete overlap. Fortunately, one of the epimers, 99d-cryst, could
be recrystallized in pure form from EtOAc/hexanes and its X-ray structure clearly shows
the relative stereochemistry in this diastereomer (Figure 2.4).

Figure 2.4. X-ray Structure of the Bicyclo[3.1.l]heptanone 99d-cryst.

 

OMe
O
o
90

99d-cryst

 

 

 

 

A mechanistic proposal to account for the formation of bicycloheptanone product
99 and the cyclobutanone product 100 is presented in Scheme 2.18. The branch point in
the mechanism is the 111,113 -Vinyl carbene complex intermediate 126 which is thought to
result from alkyne insertion into the 16-electron species 125. A CO insertion in

intermediate 126 generates the vinyl ketene complex 127 which then gives the desired

48

 

bicycloheptanone 99 via a [2 + 2] cycloaddition. Alternatively, complex 126 may form
the isomeric 111,713 -vinyl carbene complex 128 where the chromium is coordinated to the
more electron poor double bond, and after insertion of a CO ligand the intermediate 129
is generated. The formation of the cyclobutanone side product 100 in these reactions is
believed to result from the electrocyclic ring closure of intermediate 129 (Scheme
2.18).”9

Scheme 2.18. The Proposed Mechanism for the Wulff-Kaesler Reaction

of Complex 63 with Dienyne 94

 

 

OMe
(CO)5Cr=<
R

63 126

(CO)4CF=<(R)M6 m Cr}
(COI4R

IsomerizatV1 26Vinsertion\
\ Cr(CO)3
CI(CO)3OM CO insertion OMe
‘x/W e \ OMe R

 

C
\9 R \Cr R (#6
(C0)4
129 128 127
o
OMe
/ %0Me
R \
R
\ o

100

In summary, the successful examples of the reaction of carbene complexes 63a-d
with dienyne 94 have further shown that the Wulff—Kaesler reaction is a feasible way to
prepare bicyclo[3.l.1]heptanones as suitable A-ring synthons for the synthesis of taxol

and taxane derivatives.

49

2.3.2 Asymmetric Induction in the Wulff—Kaesler Reaction: Diastereoselective

Formation of Taxol A-ring Synthons

As mentioned in Section 2.2, Fuertes extensively studied the Wulff—Kaesler
reaction of complex 63a with a variety of chiral dienynes of the type 110.126 In the
present work, it was decided to take a Closer look at the reactions of dienyne 110a with
different carbene complexes and to determine the diastereoselectivity of these reactions.

The reaction of carbene complex 63a and the dienyne 110a was initially carried
out at both 0.01 M and 0.1 M in 63a. After hydrolysis of the enol ether primary product
with aqueous acetic acid, it was found that the overall yield of 118a was only slightly
lower when the reaction was performed at 0.1 M than that at 0.01 M in 63a (Table 2.2).
However, the desired isomer syn-118a was obtained in essentially same yields (63% vs.
66%) since the diastereomeric ratio of syn to anti actually increased a little (3.7 vs. 3.1)
when a higher concentration of 63a was used. These results show that the reaction can be
carried out at 0.1 M in 63a without any significant effect on the yield of syn-118a. The
assignment of the syn/anti isomers was based on their 1D NOESY spectra and on an X-
ray structure of the TROC-protected analog of syn-118a that had been previously
determinedm’

Table 2.2. The Wulff—Kaesler Reaction with Chiral Dienyne 110a.

 

 

 

 

BnO. O
OM . 0
(OC)5Cr=< 9 + Q 1)CH3CN, 45 C t +
CH: | 2) HOAc Bno 0 CH3 3'10 CH3
63a
1111- syn-118a anti-118a
Y' ld,°/ ,
Entry [63a],M Time,h '6, ° syn/antl
syn-118a anti-118a Total
1 0.01 24 66 21 87 3.1
2 0.1 24 63 17 80 3.7

 

50

 

When the chiral dienyne 110a was reacted with the more substituted carbene
complexes 63b-c, the reactions worked very well (Scheme 2.19).128 As in the reaction
with complex 63a, the formation of cyclobutenones was basically completely shut
down,129 which is mechanistically interesting and synthetically important. Furthermore,
the diastereomeric ratio of syn to anti was greater than 3:1 in all three cases. The syn-
isomer was the major diastereomer which has the correct stereochemistry required for the
proposed synthesis for taxol (Scheme 2.13). Worthy of note is that for the
bicycloheptanone ll8c, which has a quaternary carbon next to the enol ether, the
hydrolysis with aqueous acetic acid did not lead to a diketone product. Instead, the enol
ether form of the product was isolated where each was a single isomer of the enol ether.
The problems with the hydrolysis of such compounds will be discussed in detail in
Section 2.4. Gratifyingly, complex 63d, which has a protected ketone group, also reacted
with 110a to efficiently give syn-118d as the major product (the hydrolysis of 118d was
not carried out).

Scheme 2.19. Diastereoselective Synthesis ofBicyclo[3.1.l]heptanones 118.

(OC)5Cr 1) CH3CN. 45 °C
2) HOAC

 

 

110a syn-1181: 62% (3. 1,1) anti-118!) 20%
Me 8110. 0MB 0 OMe
(case; 1) CH3CN, 45 °C \ \
4.
2) HOAc Bno 3'10
0
110a syn-118C 55% (34:1) anti-118C 16%
0
OMG OMe
(OCIsCr CH30N. 45 °c ‘ -
—_.BnO + 800
O
0 o
K/O K/O
63d110a syn-118d 60% (3 2,1) anti-118d 19%

51

 

It has been demonstrated in the above reactions that bicycloheptanones of the type
syn-118 can be efficiently synthesized from the chiral dienyne 110a with different
carbene complexes containing the C-ring of taxol via the Wulff—Kaesler reaction in a
diastereoselective manner. These bicycloheptanones can be used as A-ring synthons of

taxol in the proposed total synthesis of this natural product.

2.3.3 Mechanistic Considerations for the Asymmetric Induction

Perhaps the most interesting mechanistic question about the reactions of dienyne
110a is what is the source of preference for the syn isomer. Fuertes investigated the
reactions of the triphenylphosphine carbene complex 130 and dienynes of the type 110
with different protecting groups on the oxygen,126 and a few examples are shown in
Scheme 2.20. The triphenylphosphine ligand in complex 130 is more labile than a CO
ligand with the result that the reactions of complex 130 and dienynes 110 can be
performed at room temperature. However, the selectivity and yield for the reaction of
dienyne 110a are nearly unaffected by the lower temperature. The reaction of the
triphenylphosphine complex 130 (0.1 M) with dienyne 110a at room temperature gives a
syn/anti ratio of 3.2 : 1 (Scheme 2.20), whereas the pentacarbonyl complex 63a (0.1 M)
at 45 °C gives a ratio of 3.7 : 1 (Table 2.2). As can also be seen from Scheme 2.20, when
the size of the protecting group R is smaller (methyl vs. benzyl) the diastereomeric ratio
increases (4.8 V5. 3.2); when the protecting group is quite large, the selectivity is reversed
to give a ratio of l : 6.7 in favor of the formation of the anti isomer in the case of R = t-

butyl. Although these results were obtained when the triphenylphosphine complex 130

52

was employed, similar observations would be expected from the reactions with the
pentacarbonyl complex 63a.

Scheme 2.20. The Effect of the Protecting Groups on the Diastereoselectivity

 

Ron, 0 0
(0C) cr=<OMe ' Q 1) CH3CN. rt, 24 h 0
4 4, 4? +
| CH3 I 2) HOAC RO CH3 R0 CH3
ppn3 0
13° 11° syn-118 anti-118

 

[130], M dienyne R product overall yield, % syn/anti

 

0.1 1109 Me 1189 89 4.8 : 1
0.1 1103 En 118a 88 3.2 : 1
0.01 1103 Bn 1183 89 3.2 : 1
0.1 110f t-Bu 118f 88 1 26.7

 

Based on the above results and the observations of the diastereoselectivity in the
reactions of 110a with different carbene complexes, it is reasonable to believe that the
oxygen in 110 plays a special role in the course of the reaction. Specially, the data in
Scheme 2.20 suggests that a chelation of the oxygen to the chromium could occur, which
leads to the syn isomer. Furthermore, when chelation of the oxygen to the chromium
cannot take place (R = t-butyl), the anti isomer is formed.

A mechanistic scenario involving coordination of the oxygen to the chromium is
shown in Scheme 2.21. Alkyne insertion into the tetra-coordinated complex 125 can give
the two different vinyl carbene complexes 131 and 132 which have the chromium
carbonyl group bound in an n',n3-fashion to the bottom and the top of the molecule,
respectively. In the case of the chromium sitting on the bottom as in 131, when the
oxygen becomes coordinated to chromium, it may facilitate the insertion of CO to
generate the Vinyl ketene complex 133 which leads to the formation of syn-

bicyclo[3.1.1]heptanone 118 via a [2 + 2] cycloaddition which occurs on the face of the

53

ketene that is opposite to the chromium unit (anti to chromium, thus the name “[2 + 2]
anti” in Scheme 2.21). However, when the chromium carbonyl group is on the top as in
132, after the chelation of oxygen to chromium and the generation of the Vinyl ketene
complex 134, the alkene side chain is held in a position where it cannot reach the ketene
unit and thus the [2 + 2] cycloaddition will not proceed. Therefore, anti-118 cannot be
formed in this case.

Scheme 2.21. Chelation of Oxygen to Chromium in the Wulff—Kaesler Reaction

OMe — CO OMe
(OC)5Cr=( (0C)..Cr=(

R9 RI

as 125

 

R0,,

4’

110

 

00 CO

R\/oc -Cr—CO

.==== >’\\/L7fj2£\(°M°
ROCOY.» co

=h/7’A (OMe

134 \\°
[2 + 2] anti

 

syn-118 anti-118
The possibility of oxygen chelation may also explain why cyclobutenones are
seen in the reactions of dienyne 94 (Scheme 2.17) but not in the reactions of dienyne

110a (Scheme 2.19). Chelation of the oxygen to chromium in 133/134 would prevent the

54

 

free rotation about the bond between the ketene terminal carbon and its (it-carbons. This
may prevent the migration of the chromium to the 1,1-disubstituted double bond: 126 to
128 in Scheme 2.18, which in turn could prevent the formation of the cyclobutenone
product. As mentioned earlier, it would be expected that chelation of the oxygen may also
facilitate the CO insertion which should affect the branch point at intermediate 126 in
Scheme 2.18 in a manner that would disfavor cyclobutenone formation.119

However, in these experiments, syn-118 was obtained as the major isomer, not the
exclusive one. One could argue that there must be some pathway(s) where the product
can be formed without chelation. Such a mehanism is proposed in Scheme 2.22.

Scheme 2.22. Proposed Solvent Coordination in the Wulff—Kaesler Reaction

0M0 - CO 0M0
(OC)5Cr=I< ——+ (OC)4Cr=<
R' w
63 ‘us
R0...
Sb

 

 
  

OC-IC{-CO
CC CC
131

l S = solvent

 

M” r
3"“‘
135 T.S.
disfavored [2 + 2] syn [2 + 2] syn favored
[2 + 21m 0M0 O OMe A 2] anti
R0 R' R0 R'
O

syn-118 anti-118

55

 

If the oxygen on the dienyne is not coordinating to the chromium during the
reaction when intermediates are being generated that are unsaturated at chromium, then it
is certainly possible that the solvent may be coordinating to the chromium. In fact,
previous work has shown that acetonitrile can coordinate to the chromium and facilitate
CO insertion to give a vinyl ketene intermediate much more effectively than other
solvents.‘30 The solvent assisted vinyl ketene complex formation in the case of the chiral
dienyne 110 would lead to the two diastereomeric complexes 135 and 136 as shown in
Scheme 2.22. In the absence of oxygen chelation to the chromium, the situation becomes
more complex because the [2 + 2] cycloaddition can occur either syn to the metal or anti
to the metal (Scheme 2.22). Wulff and Kim suggested in an early publication that the syn
approach involving pre-coordination of the olefin to the metal was occuring in a related
metal-mediated intramolecular [2 + 2] cycloaddition due to the rate acceleration
compared with the corresponding metal free reaction.116 Nonetheless, both syn and anti [2
+ 2] cycloadditions will be considered here.

An analysis of intermediates 137 and 138 by mechanical models does not indicate
obvious close contacts that would favor one over the other. However, similar
considerations of the transition states 135 and 136 for the anti [2 + 2] cycloaddition lead
to the prediction that 135 would be disfavored by the fact that the 1,1-disubstituted alkene
is projected directly towards the ligands on the metal. Thus, if the [2 + 2] cycloaddition
occurs anti to the metal, then the anti product would be predicted to be the major product
in the absence of chelation of the oxygen substituent. If the [2 + 2] cycloaddition occurs

syn to the metal, then it is not clear whether syn or anti would be favored.

56

 

Taken together, the mechanisms proposed in Schemes 2.21 and 2.22 can explain
why both syn-118 and anti-118 are formed and why the syn-isomer is predominant when
a less bulky group (e.g. benzyl or methyl group) is on the oxygen of the dienyne 110.
Here the syn product results when the oxygen coordinates to the chromium and the anti
product results when the solvent competes with the oxygen for coordination. However,
when the oxygen in 110 is protected with the bulky t-butyl group, the chelation of oxygen
to the chromium will be unlikely and instead the coordination of the solvent should be the
dominant process. Since all the ketene complexes in Scheme 2.22 would be expected to
be in equilibrium, anti-118 should be formed predominantly when pathway (b) is
involved and the “[2 + 2] anti” cycloaddition of 136 would be favored, which is

consistent with what Fuertes has observed for the reaction with 118f (Scheme 2.20).

2.4 REVISION OF THE PREVIOUSLY INCORRECTLY ASSIGNED TRICYCLIC

INTERMEDIATE

As discussed above, it has been established that the Wulff—Kaesler reaction of
chromium carbene complexes of the type 63 with dienyne 94 worked well to provide
bicyclo[3.l.1]hepatones 99 as the desired major products (Scheme 2.17), and that the
reactions with the chiral dienyne 110a resulted in a good stereoselectivity in favor of the
syn isomer of 118 for the diastereoselective synthesis of taxol A-ring synthons (Scheme
2.19). The bicycloheptanone syn-118d actually has the required A—C ring system, thus
the next task would be to determine whether the B-ring could be closed to effect the

construction of the ABC tricyclic Skeleton of taxol.

57

Before moving on to carry out this important task, it was decided to gain further
evidence in support of the proposed tricyclic compound 103 (refer to Scheme 2.12).
Ideally, it would be great if a crystalline derivative could be prepared so that an X-ray
diffraction analysis could be carried out to confirm the structure. Since this compound is
an oil, considerable time was spent making a variety of derivatives, including acetals,
esters, enamines, alcohols, a ternary imminium salt, hydrazones and a carbazone. For
most of these attempts, crystalline products were not observed, while in a couple of cases,
solid compounds were isolated, but none gave crystals suitable for an X-ray analysis.
Thus, it was very disappointing at the time since the structure still could not be

confirmed.

2.4.1 Investigations on the Hydrolysis of Enol Ethers 99 and the Discovery of the

Unexpected Fragmentation

At the same time that crystalline derivatives of 103 were sought, investigations
were also conducted to explore the unexpected reluctance of the enol ether 118c to
undergo hydrolysis (Scheme 2.19). As demonstrated in Sections 2.2 and 2.3, the
hydrolysis of a number of the enol ethers can be conveniently achieved with aqueous
acetic acid at room temperature. For examples shown in Scheme 2.23, bicycloheptanones
99a and 99b, with either a methyl or cyclohexyl group next to the enol ether, were both
easily hydrolyzed with weak acids to form diketone 101 and 139, respectively, although
the reaction rate decreased significantly (72 h vs. 9 h) as the size of the group increased
(from methyl to cyclohexyl).I31 It was surprising to find that the hydrolysis of 99c with

weak acids failed, giving only the recovery of the starting material 99c after stirring with

58

 

aqueous acetic acid or oxalic acid for several days. It may be expected that the increased
steric bulk near the enol ether may slow the hydrolysis; however, the dramatic effect seen
on the rate of hydrolysis was surprising.

Scheme 2.23. Hydrolysis of the Enol Ethers with Weak Acids

OMe O
HOAc/ether/HZO. rt. 9 h
CH3 ; CH3
0

 

0%?

 

 

99: 101 90%
OMe O
\ HOAc/ether/Hzo. rt. 72 h
0 Or: (COZH)2/H20. rt. 72 h V 0
99b 139 89-96%
OMe 0
~ HOAc/ether/Hzo. rt
0 Or: (COZH)2/HZO. rt 0
99¢: 140

Next a strong acid (4 N aq. HCl in CH3CN) was employed to attempt to convert
the enol ether 99c to diketone 140 at room temperature. As expected, the enol ether in
99c had reacted, but to our disappointment, the desired diketone 140 was not observed.
Instead, two unexpected new compounds were isolated in significant amounts, but their
structures were not determined at that time. When 99c was treated with p-tolyl sulfonic
acid (PTSA) in wet acetone at room temperature or with oxalic acid in THF/H20 at 45
°C, similar results were observed.

The unsuccessful conversion of 99c to the corresponding diketone 140 prompted
a search for other methods for the conversion of enol ethers to ketones that do not use
strong Brensted acids. During this time, Tsuji and coworkers reported that the palladium

132

complex, PdClz(CH3CN)2, could effectively hydrolyze enol ethers. When the same

reaction conditions were applied to 993, clean conversion to 101 was observed, however,

59

enol ether 99c was unreactive to these conditions. This failure is presumably due to the
sterics surrounding the double bond that prevents the coordination of the palladium
species. Meanwhile, a search was conducted to find groups other than methyl that could
be introduced on the heteroatom of the carbene complex, in the hope that the hydrolysis
problem could be solved for dienynes of the type 99c. A number of substituents were
investigated, including MOM, TMS, TIPS, SEM, Troc, chloroethyl, bromoethyl, TMS-
ethyl, however none led to satisfactory results. In some cases, the corresponding carbene
complexes could not be formed, and in others the Wulff—Kaesler reaction was
unsuccessful, and still in others the hydrolysis of analogs of 99c failed under a variety of
methods.

After the attempts to change the oxygen substitutuent of the enol ether proved to
be fruitless, attention was then directed to the elucidation of the two structures from the
reaction of 99c under strong acidic conditions. Extensive studies by NMR and mass
spectroscopy were undertaken. One of the most striking features of the two compounds
is that neither of them has a vinyl proton peak in the 1H NMR spectrum, however, there
are peaks in the olefin region in both 13 C NMR spectra, which indicates that the exocyclic
double bond has been rearranged to a tetrasubstituted olefin. It was initially thought that
the quaternary center on the cyclohexane ring might have undergone a rearrangement, but
this was proved not to be the case after careful analysis of the Spectral data and the
finding of a literature example of a successful hydrolysis of an enol ether with a
quaternary center next to it.133 Finally after extensive analysis of several NMR
experiments, the identitities of the hydrolysis products of 99c were determined to the

rearranged diketone 141c and its hydrated form l42c, as shown in Scheme 2.24.'34 Thus,

60

the methylcyclohexyl part of 99c remained untouched in the reaction, while the bicyclic
system underwent fragmentation. Worthy of mention is that the mass spectra were
misleading for 142c which has a molecular weight of 306. The GC—MS results indicated
a molecular ion (M+) of 288, resulting from a favorable loss of H20 probably in the GC
column. Even the FAB—MS, a soft ionization method that usually gives the MH+ ion as
the base peak, had a base peak of 289 with a much lower peak of 307 (about 20% of the
intensity of 289). This is probably an unusual case for a FAB—MS spectrum, nonetheless,
it dramatically increased the difficulty in the elucidation of the structure of 142c.

Scheme 2.24. The Unexpected Fragmentation of 99c under Acidic Conditions

OMe O 0
~— 4 N aq. HCI I CH3CN
> “ HO
O O 0
99¢ ‘

141C 35% 142c 35%

9%

140 Not observed

 

How did this acid catalyzed fragmentation occur? It is believed that the
rearrangement is initiated by the protonation of the reactive exocyclic double bond to
generate cation l43c, and then the bond between the two quaternary carbons breaks to
relieve the strain in the four-membered ring and form the cation 144c (Scheme 2.25).
Subsequently, cation l44c can either undergo an elimination to form 141c or it can be
trapped by H20 to form 142c - the hydrated form of l4lc. It is also believed that l4lc

and 142c are in equilibrium under reaction conditions.

61

 

Scheme 2.25. The Proposed Mechanism for the Fragmentation of 99c

OMe O O
T 523% 2 > m
0 O O

HO-

 

 

99c 1430 H 144‘;
H20
0 Hzo“ o
+
r“ H °
[H20 144: J 145::

 

 

 

 

2.4.2 Correction of the Previously Misinterpreted Tricyclic Structure

After the two structures MR and 142c were determined, a re-examination of the
structure 103 (Scheme 2.12) was undertaken in light of this new information. As
discussed earlier, most of the data fit well with this structure, but there existed some

inconsistencies that could not be accounted for.124

Although the original structure
assignment of 103 was tentative, it seemed to be reasonable based on the data available at
that time and no better candidate had been brought forward since then.

Fortunately, by carefully comparing the data of 103 with those of the elucidated
structures l41c and 142c, it became possible to assign the structure of the compound

previously identified as 103 as the triketone 142d (Scheme 2.26). This was an astonishing

finding: the ABC tricyclic core of taxol had actually never been formed!! The molecular

62

weight of 103 is 288 which is 18 less than that of the structure 142d. As was seen with
142c, the GC—MS of 142d also gave a predominant peak for loss of H20 at m/z = 288
and only a tiny peak for the molecular ion at m/z = 306. The triketone 142d presumably
exists as a mixture of two inseparable diastereomers, and the 13'C NMR Spectrum showed
that some peaks were twinned while others were single peaks. HPLC analysis (using
chiral-AD column) Showed that there were two sets of enantiomers in a 1:1:1:1 ratio,
which is consistent with the fact that product 142d exists as a mixture of two
diastereomers (1:1). In addition, another compound that had not been recorded before
was obtained from the reaction of 63d and 94. This compound was identified as 141d and
was also isolated in a significant amount (30% yield). The same mechanism is believed to
be operating in this case as that shown in Scheme 2.25. It was shown that the two
compounds were in equilibrium under reaction conditions because when pure 141d or
142d was treated with aqueous HCl/CH3CN for 10 hours, a mixture of 141d and 142d
was obtained in each case, slightly in favor of the hydrated form 142d.
Scheme 2.26. Revision of a Previously Incorrectly Assigned Intermediate and

Identification of a New Structure from Reaction of 99d with HCl

(CO)5Cr 0M9 0"“
b + §§ CHacN %
45 °c. 47h o
8/0 | 00/0
63d 94

996

aq. HCI I CH3CN

o 0
+110
0 o
o o

141d 30% (two steps) 1426 35% (two steps)

63

 

While it is good to finally correct the wrong structure, at the same time, it was bad
news because the structure 103 contains the ABC ring system of taxol and as a result
inspired continued efforts on the taxol project in the wrong direction. Nevertheless, the
Wulff—Kaesler reaction is still a good approach for the construction of
bicyclo[3.l.1]heptanones that can serve as A-ring synthons of taxol and taxane
derivatives. Thus, a modification of the Strategy is needed which employs a different

tactic for the closure of the B-ring.

2.5 A MODIFIED STRATEGY FOR THE TOTAL SYNTHESIS OF TAXOL

As a direct consequence of the elucidation of the two structures from the reaction
of 99d under strong acidic conditions (Scheme 2.26), the retrosynthetic strategy had to be
changed. Clearly, the acid catalyzed rearrangement of the bicyclic system occurs before
the aldol reaction can take place, thus the anticipated aldol condensation of 105 and the
fragmentation of 106 actually will not be possible as formulated in Scheme 2.12. Careful
mechanistic considerations suggested that slight modifications could possibly change the
fragmentation pathway of the four-membered ring in favor of the direction that retains
the A-ring of taxol.

Under acidic conditions, there are two possible fragmentation pathways (Scheme
2.27). Upon protonation of the exo-cyclic double bond to form the carbocation 143,
either one of the two bonds can be broken to release the strain in the four-membered ring
and these are indicated as path (A) or (B). The reason why path (A) is favored in this case

is because it generates cation 144 which should be more stable than the acyliurn ion 146

64

formed via path (B). The cation 144 leads to the formation of the rearranged products
141/142. However, bond breaking through pathway (B) is required for taxol synthesis
since the A-ring of taxol is maintained, thus, a method is needed to reverse the direction
of fragmentation such that path (B) would be favored and/or that path (A) would be shut
down.

Scheme 2.27. Mechanistic Considerations for the Acid-Catalyzed Fragmentation

 

 

HO
(”We () (D
\ H3O’ PathA *
R R ' R
C) C)
H C)
99 143 144

146 141
Ill i
C)
2:ij m
H0 R

/ + o
C)

146 142

According to the above mechanistic analysis, it was anticipitated that if a
functional group was introduced to stabilize cation 146, the fragmentation could be
reversed. As shown in Scheme 2.28, a solution was envisioned converting the ketone 99
to its corresponding alcohol or a protected alcohol derivative of the type 147. Protonation
of 147 will give cation 148, for which fragmentation to 152 may be favored through path

(B) because now a much more stable oxonium ion would be formed.

65

Scheme 2.28. Modified Strategy to Achieve the Desired Fragmentation

O 0
R
OR’ ? OR'
RI!
148

 

 

H4
OMe
R
.. OR'
R H Rn
14" 149
l Panel 7 ' H20
0
R " + ,R R
o R. 0“ R" 0R'
99 152 150
m 0 1'

R 0
R
'1’ OR. HO R” 0R4
Rn
152

151

2.6 STUDIES ON CLOSURE OF THE B-RING FOR ENTRY INTO THE ABC

TRICYCLIC CORE OF TAXOL

The simple bicyclo[3.l.1]heptanone 99a was chosen to test the idea outlined in
Scheme 2.28. Addition of nBuLi to 99a was expected to give 153, however, after the
reaction mixture was warmed to room temperature from —78 °C, a mixture of at least two
inseparable isomers were isolated that did not appear to contain an —OH group as
determined by its IR spectrum. Since it was difficult to identify the compounds while
they were part of a mixture, the mixture was carried on to the next step by treatment with
4 N aqueous HCl in THF. Among the expected products were those with structures such
as 156/157 and 158 which would have been formed via the paths (A) and (B),

respectively. Alternatively, the ketone 155 Would have been also possible as it would

66

have simply resulted from hydrolysis of 153 (Scheme 2.29). However, none of these
compounds was observed, instead, diketone 159 was isolated in 60% yield over the two
steps. The formation of 159 with an exo-cyclic double bond was unexpected and
presumably resulted from the hydrolysis of 154 which had been generated in the first
step. An explanation for formation of 159 is shown in Scheme 2.29. Addition of n-
butyllithium to 99a would initially give the alkoxide 153a, which could fragment to give
the intermediate 153b to relieve the strain in the four-membered ring and give a
carbanion that is doubly stabilized by two olefins. The diketone 154 could thus be
accounted for by a proton quench of the central position of the pentadienyl anion 153b.

Scheme 2.29. A Test of New Strategy for the Desired Fragmentation

 

 

 

 

 

OMe OMe - 0M6
W nBuLi. THF \

O -78 10 25 °C OH

0
99:
153 ?
154
[41v HCI/T HF
O
H
155 157
(not observed) r
via Path A from 153 via Path 8 from 153 60% (two steps)
(not observed) (not observed)

 

if if i?

67

 

 

 

During the addition of n-butyllithium to 99a, an observation was made that was
first ignored but was then reinvestigated. In the course of slow warming of the reaction
mixture to room temperature, the TLC was checked when the temperature was around
-10 °C. The spot seen on the TLC had a different Rf value (Rf = 0.27, 10% EtOAc) from
that of the mixture isolated after warming to room temperature (presumably isomers of
154, Rf = 0.15, 10% EtOAc). This suggested that a different compound was present prior
warming to room temperature and if so this compound could be the alcohol 153. If this
was true, anion 153b must have been formed at temperatures above —10 °C. With this in
mind, it was decided to quench the reaction at a lower temperature. As Shown in Scheme
2.30, the reaction was quenched at —78 °C after stirring for an hour at this temperature to
give a mixture presumably containing the alcohol 153. The major product had the same
Rf value as the intermediate(s) that was observed at —10 °C. Attempts to isolate this
product by chromatography were unsuccessful due to partial decomposition on the silica
gel column. Instead, the mixture was treated with aqueous HCl for 3 hours and the
diketone 158 was obtained in 55% yield over two steps via the desired fragmentation
pathway presumably from 153.

Scheme 2.30. Realization of the Desired Fragmentation!

— H+ —
% nBuLi. THF ~ 4 N aq. HCl/THF 0
-78 °C. 1 h OH

— 153 _.

 

 

 

153 55%
It was later found that simply treating the ketone 9911 with LAH gave the alcohol
160 in 79% yield, which was then rearranged upon treatment with aqueous HCl to give

the aldehyde 161 in 62% yield via the desired fragmentation pathway (Scheme 2.31).

68

Similarly, the bicyclo[3.l.1]heptanone 99d was efficiently converted to the alcohol 162
and subsequently to the desired aldehyde 163, which sets the stage for the B-ring closure.
Obviously, B-ring formation could not be achieved under acidic conditions because the
aldehyde 163 was obtained under these conditions. Thus an effort was made to effect a
base mediated aldol closure. The first base examined was KOIBu, but it gave a complex
mixture that did not appear to contain any of the tricyclic compound 164. An attempt to
favor the intramolecular aldol reaction by a base involving a counterion capable of
chelation was then examined. However, when 163 was treated with Mg(0Me)2, a
Meerwein—Pondorf—Verley (MPV) reaction occurred which reduced the aldehyde to the
corresponding alcohol.135 To avoid the MPV reaction, Zr(OtBu)4 was employed, but
only a complex mixture was obtained from the reaction while all the starting material was
consumed. It may be that the formation of an eight-membered ring from an aldol
condensation could be disfavored in this system. Nonetheless, the conversion of 163 to
164 would represent a very attractive route to the ABC ring system of taxol and thus
deserves further consideration.

Scheme 2.31. The Formation of Aldehydes and Attempted B-ring Closure

OMe OMe
% LAH/THF W 4N aq. HCVTHF(1:1) 0
O H OH
99:

 

 

 

 

 

 

 

o
160 79% H 161 62%
OMe OMe O 0
‘ LAH/THF “‘ aq HCI/THF ..
o H 0H 3
o o O
K)? Co , 0 0“
o 0 o —KOtBu
991! 162 89 A 163 63 A _MC(OM9)2 164

- zqoreu),

69

2.7 CONCLUSIONS AND FUTURE DIRECTIONS

The Wulff—Kaesler reaction of Fischer carbene complexes and dienyne 94 has
been demonstrated as a suitable method for the preparation of the
bicyclo[3.l.1]heptanone intermediates as A-ring synthons of taxol and taxane derivatives.
The chiral dienyne 110a has also been employed in the reaction and results in good
syn/anti ratios in favor of the desired bicycloheptanone isomers, thus providing a
diastereoselective synthesis of taxol A-ring synthons. The asymmetric induction is
believed to originate from chelation of oxygen to chromium during the reaction and a
mechanism based on this has been proposed.

It has also been revealed that the closure of the B-ring of taxol via an aldol
condensation/Grob fragmentation does not proceed as anticipated and instead results in
undesired fragmentation. Extensive analysis of the NMR and mass spectra of the
rearranged products led to the correction of a previously misinterpreted structure of a key
triketone intermediate. A modified strategy has been designed on the basis of careful
mechanistic considerations which represents an attractive route to the ABC tricyclic core
of taxol and deserves further investigation.

Efforts in the future will certainly be directed to the construction of the ABC
tricyclic core as the utmost important task. By no means have the approaches for the
aldol condensation in the B-ring closure for 163 been exhausted. Other reagents,
including different bases, will be worth examining. In a slight modification, it might be
possible to convert the aldehyde functionality to an activated functional group, such as a
reactive carboxylic acid derivative 165 (e.g. N-acylamidazoles‘36) to examine Claisen-

type condensation, as shown in Scheme 2.32.

70

Scheme 2.32. Proposed Manipulations of the Aldehyde Functionality for Closure

of the B-ring
0 0
Reagents ? fl
/ 0 OH 0
O

0 o
Claisen ?
XR O o 0

Based on the fragmentation studies described in Section 2.4, if a strong Brensted
acid is not involved in the removal of the protecting group of the ketone on the C-ring,
the undesired fragmentation may be avoided. Thus, if the carbonyl group in the carbene
complex can be protected as a base-cleavable group in 166, the bicycloheptanone 167 can
be converted to 168 under basic conditions. The aldol condensation of 168 to give 106
might not be a problem in this case because a six-membered ring is formed (Scheme
2.33). The subsequent fragmentation of 106 would be expected to occur via the desired
pathway to give the tricyclic compound 103. The difficulty in this stategy, of course, is to
find an appropriate protecting group which can be cleaved by a base (or at least without
using strong Brensted acids) to give a carbonyl group or its equivalent. Dithianes may be
an option since there have been a couple of rare examples that they are removed with a

7
base.13

71

Scheme 2.33. A Possible Approach for the Formation of the ABC Tricyclic Core

(00,023 Viki? 3... % ‘\ E140 ::
Rx XR 0Rx XR 0 0° 02H 0 o o
166 167 168 108 103
An alternative strategy to avoid the use of strong Brensted acids is to synthesize a
bicycloheptanone of the type 173 (Scheme 2.34). Carbene complex 171 can be prepared
by a Diels—Alder reaction of 169 with 170. If the adduct 171 can be converted to
intermediate 172, it would provide an interesting substrate for the Wulff—Kaeslser
reaction, thus the conversion of intermediate 173 to 174 would be realized without using

a strong Bronsted acid (Scheme 2.34).

Scheme 2.34. Another Strategy for the Construction of the Taxol Skeleton

OM OMe OMe
e 0
, [4 + 2] (OC)sCr H (OC)50r
(OC)50r + TMSV ,,,,,,,,, , _______ -
TMS TMS
169 17a TMS TMS
171 172

O H:\ 0 OMe
.0 % “”5” 7
““0,Fa""
a 02 0
0 H TMS
175 174 173

All of the above strategies for the construction of the ABC tricyclic core of taxol
rely on nucleophilic additions for closure of the B—ring. Other strategies, for example,
utilizing ring closing metathesis (RCM) or the carbon—carbon coupling reactions, can
certainly be pursued as well. Accordingly, the structures of the carbene complexes will
need to be carefully designed and the viability of their preparations must be taken into

considerations.

72

CHAPTER THREE

AN INVESTIGATION OF THE CYCLOPROPANATION REACTION

OF DIENYL FISCHER CARBENE COMPLEXES

3.1 BACKGROUND ON THE CYCLOPROPANATION REACTION OF FISCHER

CARBENE COMPLEXES

During the studies toward the total synthesis of taxol discussed in Chapter 2, at
one point it was decided to investigate if carbene complexes of the type 176 (Fig. 3.1),
which have a double bond at the [3 and y positions to the carbene carbon, could be
prepared. These carbene complexes can be interesting substrates in the Wulff—Kaesler
reaction for the construction ofbicyclo[3.1.1]heptanone intermediates for the synthesis of
taxol since the functional group(s) on the C-ring may be further utilized for closure of the
B-ring. Because complexes 176 consist of a cyclohexenyl ring, it is reasonable to
consider that a [4 + 2] reaction could be employed in their preparation. It has been well
established that a,B-Unsaturated Fischer carbene complexes can act as potent dienophiles
in Diels-Alder reactions with 1,3-dienes, however, this reaction will give a cyclohexenyl
ring with the resultant double bond being at the undesired y and 0 positions.108 A possible
alternative approach to install the double bond in the right position in 176 would be using

a dienyl carbene complex as the electron deficient diene source in an inverse electron

73

demand Diels—Alder reaction. This type of reaction has not been reported.138 The
reactions of simple dienyl carbene complexes of the type 178 with Olefins 179 should
serve as a model system to test whether this approach to cyclohexenyl carbene complexes
of the type 177 is viable (Figure 3.1).

Figure 3.1. Possible Products from the Reactions Involving Dienyl Complexes

 

178 and Olefins 179
0M8 fl OMe 0M6 R2
(OC)SCr OR' (OC)sCr R2 [4 + 2] (OC)sCr R2 [2 + 1] OMe
R, :> / + E 1 C: _
7 — R 7 R‘ _
.. R R
R O 175 177 178 179 180 R

 

 

 

This work was undertaken with full knowledge that the reaction of Fischer
carbene complexes with alkenes can also give cyclopropanes. Thus, as shown in Figure
3.1, it was envisioned that both [4 + 2] and [2 + 1] adducts could be possibly formed
from the reactions of 178 and 179.

The cyclopropanation reaction of Fischer carbene complexes, a formal [2 + 1]
cycloaddition, is one of the first and longest studied reactions of the heteroatom-
stabilized group 6 metal carbene complexesm‘s'139 It is well known that Fischer carbene
complexes can react with olefins under the proper conditions to produce cyclopropanes,
for example, alkoxycarbene complexes readily undergo cyclopropanation under thermal
conditions with olefins bearing electron-withdrawing group(s),'40 but a high pressure of
carbon monoxide is needed for alkenes with electron-donating substituent(s).Ml
Barluenga has recently reported a diastereoselective intermolecular cyclopropanation

with unactivated simple alkyl-substituted (electronically neutral) Olefins,142 which has

further extended the scope of the reaction.

74

However, in terms of the Fischer carbene complexes being studied in this

”3 To the best of our

reaction, dienyl alkoxy complexes have received little attention.
knowledge, there is only one known example in the literature which was reported by the
Wulff group in 1990 and involves the reaction of the pentadienyl methoxy chromium
carbene complex 181a with the silyl enol ether 182 to give the dienylcyclopropane 183
144,145

under a high pressure of carbon monoxide (Scheme 3.1).

Scheme 3.1. The Cyclopropanation Reaction of Dienyl Complex 181a with 182

0TBS

 

OMe a
— Neat H ix
— 100 atm CO
1313 H3 25°C. 4 d 183 CH3

49% yield. > 95% cis

Therefore, a more extensive study of the reactions of this type of doubly
unsaturated carbene complexes with olefins was deemed to be necessary. Based on
published results of the study of cyclopropanation reactions of Fischer carbene
complexes,106 it was expected that the reactions of 178 and 179 (Fig. 3.1) would be
favored to give cyclopropanes 180, nonetheless, the importance of easy access to
complexes of the type 177 made the further search for Diels—Alder reactions of this type
worthwhile. By all means, it was considered to be an interesting “one stone, two birds”
project that was well worth the anticipated effort. Thus, the reactions of dienyl carbene

complexes with olefins were carried out in both inter- and intramolecular fashions.

75

3.2 INTERMOLECULAR CYCLOPROPANATION REACTIONS OF DIENYL

FISCHER CARBENE COMPLEXES

Simple trans, trans-dienyl carbene complexes 181a and 181b were prepared for
the examination of the intermolecular reactions with both electron-rich and electron-
deficient olefins 184-187 (Figure 3.2). It would be interesting to see if and how the
electronic properties of the olefins would affect their reactions. Complexes 181a and
181b were readily prepared by an aldol condensation of the methyl methoxy carbene
complex with crotonaldehyde and cinnamaldehyde, respectively, by a procedure
developed in the Wulff lab.112a Alternatively, complex 181b could be prepared using
Aumman’s approach for aldol reactions with non-enolizable aldehydes.l 12b":

Figure 3.2. The Carbene Complexes and Olefins Designed for Intermolecular

Reactions
OMe

(OC)SCr = ("93° 7
_ __ 1atm Ar. A

R
181: R = CH3
1811) R = Ph

 

 

0E1 510 051
T if
188 1

87

Olefins: £7 i/ COZMG
184

|
185

 

All the reactions were performed under an atmosphere of argon in a glass vessel.
When either carbene complex 181a or 181b was heated in dihydrofuran 184m 80 °C, a
complex mixture was obtained in each case which did not seem to contain cyclopropanes
or Diels—Alder adducts or any of the starting carbene complex. Further attempts with
complex 181b and ethyl vinyl ether 185 or the more electron-rich ketene diethyl acetal
186146 also failed to give any cyclopropane products or Diels—Ader products.147 The

failure of the formation of cyclopropanes was not really surprising because there have

76

been reports in the literature that the cyclopropanation reaction with electron-rich olefins
will not take place unless a pressure of carbon monoxide is employedm However, it is
not clear why the Diels—Alder reaction also failed with the three electron-rich olefins
since the diene unit in the dienyl complexes is expected to be electron deficient.

The reaction of both 181a and 181b with methyl acrylate 187, an electron-
deficient olefin, gave cylcopropane products in high yields (Scheme 3.2). Both trans- and
cis-isomers of the cyclopropanes 188 and 189 were obtained and their stereochemistry
was determined by 1D NOESY studies. While both reactions gave a moderate 1.9 : l
diastereomeric ratio in favor of the trans-isomer, the phenyl dienyl complex 181b
afforded higher overall yield than that of the pentadienyl complex 181a (95% vs. 82%).
The more stable nature of 181b under the reaction conditions may be one of reasons that
can be attributed to the higher yield in the cyclopropanation reaction. Worthy of mention
is that no [4 + 2] adducts were observed in these two reactions.

Scheme 3.2. The Cyclopropanation Reactions of Dienyl Carbene Complexes

with Methyl Acrylate

NOE

OMe 002m A
(OC)SCr il/ 187 (neat) ”@0149 MeOzc‘AfiMe
_ ~ 4" 3,,— + 4" "19 __
_ 80 °C. 1 n M9020 —\____\ {/HE
R

 

R
R NOE

181: R s CH3 188mm R = CH3 54% 188-cia 28%

181b R = Ph 189-trans R = Ph 62% 189-cl: 33%

The above results have Shown that trans, trans-dienyl chromium carbene
complexes can undergo the cyclopropanation reaction with an electron deficient olefin
under an inert atmosphere, but the reaction fails with electron rich Olefins. In all cases, no

Diels—Alder adducts were observed.

77

3.3 INTRAMOLECULAR CYCLOPROPANATION REACTIONS OF DIENYL

FISCHER CARBENE COMPLEXES

Efforts were then directed to the reactions in an intramolecular fashion. The olefin
was incorporated at the end of the alkenyloxy group with different carbon tether lengths
to the oxygen (Figure 3.3). Similarly, in addition to the cyclopropanes that were
anticipated to be produced, particular attention would be directed to the possibility of the
formation of Diels—Alder adducts. The carbene complexes l90a-d were prepared using

l”2a or Aumman’s aldol reaction for non-

either Wulff’s aldol condensation protoco
enolizable aldehydemb'c from the corresponding methyl alkenyloxy chromium carbene

complexes.148

Figure 3.3. Carbene Complexes Designed for Intramolecular Reactions.

0‘41:— Toluene

(OC)5Cr ?
— 1 atm Ar, A
R
1908-d
R = CH3. Ph
11 = 1. 2, 4

As shown in Scheme 3.3, complex 190a (R = Ph, n = 1) was heated in toluene at

 

 

80 °C under an argon atmosphere for 5 hours until all of the starting material was
consumed. It was not surprising to find that the reaction did not give any of the
cyclopropane 191a, presumably due to the short tether that would otherwise lead to a
structure suffering from the unfavorable ring strain. When the tether length was extended
to two carbons between the pendent double bond and the oxygen as in 190b (R = Me, n =
2) and 190c (R = Ph, n = 2), both reactions proceeded smoothly. Cyclopropane l91b
(when R = Me) was obtained in a moderate 58% yield and 19lc (when R = Ph) was

afforded in 73% yield, which was consistent with the observation that the pentadienyl

78

complex 181a gave a little lower yield than that of the phenyl dienyl complex 181b in
intermolecular cyclopropanations (refer to Scheme 3.2). The longer chain alkenyloxy
carbene complex 190d (R = Ph, 11 = 4) was relatively unreactive and the reaction required
heating at 120 °C for 5 hours to go to completion which produced a complex mixture of
compounds. Previous studies on the intramolecular cyclopropanation of (non-dienyl)
alkoxycarbenes showed that the optimal tether length between the carbene carbon and the
olefin was three atoms,149 and our results supported these observations. Worthy of
mention is that the intramolecular Diels—Alder adducts from the reactions of these dienyl
alkenyloxy carbene complexes 190a-d were not Observed, although DOtz reported that a
dienyl diallylamino tungsten carbene complex was able to produce the [4 + 2] adducts in

d150 and Barluenga reported two successful examples when the allyloxy dienyl

a low yiel
complexes have the a,B-double bond embedded in a four—membered ring.15 ‘

Scheme 3.3. Intramolecular Cyclopropanation Reaction of Dienyl Complexes

Toluene
(OC’SC' ——*‘P\//’\¢\Ph
80 °C 5 h

1908 _"P 191:
f/
o

(OC)5Cr Toluene O
H 80 °C. 2 him/v12
R

1901) R = Me 1911) R = Me 58%
1906 R = Ph 191C R = Ph 73%

0414: Toluene

(CO)50r --———> Complex Mixture
_ 120 °C. 5h

190d Ph
There has been one report that the reaction of a Fischer carbene complex and a

diene can be fine-tuned to give either the cyclopropanation product or the Diels—Alder

79

adducts by judicious choice of the metal (chromium vs. tungsten) in the carbene
complex.152 Thus, the tungsten carbene complex 192 was prepared to examine its
thermolysis. A little surprisingly, after the tungsten complex 192 was heated at 80 °C for
an hour, only cyclopropane 19lc was obtained in 91% yield (Scheme 3.4), with no
detectable amount of [4 + 2] adducts being observed. Apparently, the chemospecificity of
different metal complexes was not applicable in this case.

Scheme 3.4. The Cyclopropanation Reaction of Tungsten Complex 192

H
(0C) W O Toluene 0
5 _ 4f / /
— 80 °C. 1 h Ph
Ph
192

191C 91%

 

These intramolecular examples have indicated that, even though both the potential
1,3-diene unit and the dienophile are present in the dienyl complexes, the

cyclopropanation reaction products, are the only products observed.”3

3.4 CONTROL REACTIONS UNDER 500 PSI OF CO

In order to test if the presence of C0 would affect the reactions of dienyl carbene
complexes, complex 190b was heated in benzene at 80 °C under 500 psi of CO in a
Monel Parr reactor. Unfortunately no detectable amount of either the [4 + 2] or [2 + 1]
cycloaddition product was obtained. However, a new organometallic compound was
observed whose structure was not determined at that time. This compound appeared to be
stable in air and the NMR spectra suggested that it still has the intact pendent terminal

Olefin. In order to confirm that the oxygen tethered olefin was not involved in the

80

formation of this unexpected product, it was decided to examine the thermolysis of the
methoxy carbene complex 181a in the presence of C0. Complex 181a was treated to the
same conditions as those for 190b, and as expected, a similar unknown compound was
isolated. The compound was initially assigned as the chromium carbonyl cyclohexadienyl
complex 193 (n = 3 or 4) based on its NMR and IR spectra. Its unusal stability in air
suggests that a chromium tetracarbonyl complex 193b (n = 4) would be a better candidate
because it would be an l8-electron species and thus would be expected to be stable. The
molecular weights of the two possible structures 193a and 193b are 274 and 302,
respectively; however, the mass Spectrum Shows a molecular ion peak of 278, with no
peaks of 274 or 302. This was the big discrepancy in the assignment of the structure of
the unexpected metalcarbonyl complexed product. The successful elucidation of the
structure led to the serendipitous discovery and development of a novel ortho-
benzannulation reaction, which will be discussed in great detail in Chapter 4.

Scheme 3.5. A Control Experiment with 181a under 500 psi of C0

 

O
OMe . H
OMe
(OC)5CT 500 p51 CO : H3C“*
— _ benzene. 80 °C. 2h '.
CH3 Cr(CO)n
1818 1938 n = 3 7
193b n = 4 ?

81

3.5 CONCLUSIONS

In summary, the first examples of both inter- and intramolecular cyCIOpropanation
reactions of dienyl chromium carbene complexes under a non-C0 atmosphere have been
described. The results suggest that the electron density on the olefin can determine

whether the reaction will occur in an intermolecular manner. Electron-rich olefins do not

undergo cyclopropanation reactions with dienyl carbene complexes, while methyl
acrylate, an electron-deficient olefin, reacts with dienyl carbene complexes to give
dienylcyclopropanes as a mixture of trans- and cis-isomers. The intramolecular
cyclopropanation reaction of alkenyloxy dienyl carbene complexes with a terminal
double bond tethered to the oxygen can occur if the tether length is appropriate. It has
also been demonstrated that a tungsten carbene complex affords a high yield of the
cyclopropane product in an intramolecular formal [2 + 1] reaction. In all cases, the
Diels—Alder reaction which was thought to be a possible competitive reaction did not
appear to take place since no [4 + 2] adducts were observed, indicating that the strategy
outlined in Figure 3.1 for the synthesis of cyclohexenyl carbene complexes of the type
177 is not viable.

The results demonstrate that cyclopropanes which are tethered to a diene moiety
can be efficiently prepared with appropriate substrates involving dienyl carbene
cornPlexes. This type of cyclopropane, which may be difficult to prepare by other
methods, is useful in organic synthesis,154 such as metal-catalyzed ring expansions to

Synthesize medium-sized rings. '55

82

CHAPTER FOUR

A NOVEL IRON-MEDIATED THERMAL
ORTHO-BENZANNULATION OF DIENYL FISCHER CARBENE

COMPLEXES: CHROMIUM TO IRON TRANSFER PROCESSES

4. l BENZANNULATION AND ORTHO-BENZANNULATION OF FISCHER

CARBEN E COMPLEXES: BACKGROUND AND SYNTHETIC

APPLICATIONS

As mentioned in Section 2.1, the study of Fischer carbene complexes during the
past forty years has resulted in a large number of new reactions and numerous
applications in organic synthesis.97 The benzannulation reaction (Ddtz-Wulff reaction) is
one of the most thoroughly studied reactions of Fischer carbene complexes and has been

an important method for the synthesis of phenols and, by oxidation thereof, quinones.156

4- 1 - l Benzannulation of Fischer Carbene Complexes and Their Applications

The benzannulation reaction is a formal [3 + 2 + 1] reaction, where it incorporates
the Organic portion of an a,B-unsaturated carbene complex 195, an alkyne 196, and a CO

ligand to form a phenol derivative 197 (Scheme 4.1). The fragment ensemble shows how

83

the three fragments are connected in the reaction. The a,[3-unsaturated carbene complex
195 can be an aryl or alkenyl complex, and as will be discussed later in this section, the
metal is not just limited to chromium, but it is the most effective and the most commonly

used.

Scheme 4.1. General Scheme of the Benzannulation Reaction

 

OH 9
(OC) Cr OR RL R2 RL R2 C RL
5 =1»; 4 ll _. R1| H
R1 R2 R1 R5
R5 OR OR Rs
195 196 197
Fragment Ensemble

Since its first report by K. H. DOtz in 1975,'57 the benzannulation reaction has
been studied extensively, not only because of its mechanistic complexity, but also due to
its wide applications in organic synthesis.156 Thus, it is not possible to give a
comprehensive review of the reaction here, and the following description will hopefully

serve as a very brief overview of its mechanism, scope and applications.

Mechanistic Considerations and Regioselectivitv

 

The mechanism of the benzannulation reaction is still not fully understood. There
have been a few different versions proposed for the reaction that differ mainly in the
01‘ der of the steps and the nature of the intermediates.158 The generally accepted
mechanism is shown in Scheme 4.2. The first and rate-determining step of the reaction is
the dissociation of a C0 ligand to generate an unsaturated l6-electron species 198.159
Slesequent insertion of an alkyne into the chromium — carbene carbon bond generates

the n',n3-vinyl carbene complex 199. Then C0 insertion takes place to give the vinyl

ketene complex 200 which undergoes an electrocyclic ring closure (ERC) to provide the

84

cyclohexadienone complex 201. Finally, tautomerization and loss of chromium

tricarbonyl affords the p-alkoxy phenol 197.

Scheme 4.2. A Simplified Mechanism of the Benzannulation Reaction

 

 

 

 

0R RL R2 OH R
(0050i + H L
R1 R2 Rs R‘ Rs
OR
195 195 197
RL
ii 1 1
OR R2 R R2 R 0
(00) at Rs / \ OR CO / OR ERC R2 RL
4 __, ___.
_ I . 2 I
R‘ R2 RL / Rs insertion Dec \ Rs R1 Rs
Cr RL Cr(CO)3 0R Cf(CO)3
193 (CO)4 201
199 200

During the benzannulation reaction, the regiochemistry of the incorporation of an
unsymmetrical alkyne is determined by the steric differences of the acetylene
substituents,I60 and the major isomer is the one in which the sterically larger group (RL) is
incorporated adjacent to the phenol functionality. The source of regioselectivity is
believed to be from the interaction of the substituents on the alkyne with the carbon

monoxide ligands in the vinyl carbene complexes 199 and 202 (Scheme 4.3). Extensive
Hiickel calculations reveal that the substituent at the 2-position of 199 or 202 is at least
one angstrom closer to its nearest C0 ligand than that at the 1-position,161 which accounts
fol’ Why the intermediate 199 with the sterically smaller group (R5) at the 2-position is
fa"Cred as compared to the intermediate 202. Consequently, the major isomer is the
p1161101 197 that has the larger group (R1,) adjacent to the newly formed phenol

fulletionality, although it is not clear whether it is a kinetic or thermodynamic outcome.

The reaction is highly regioselective with terminal alkynes, but often gives poor

85

 

selectivity with an unsymmetrical disubstituted acetylene, in which case the lack of

regiocontrol can be overcome in intramolecular annulations in which the acetylene is

tethered to the oxygen in the carbene complex.162

Scheme 4.3. Re gioselectivity of the Benzannulation Reaction

 

RL RL
2 R' II II 2 R‘
R / 3 OR OR R / 3 0R
Rs 00 Cr Rs
R 1 i\ 2 ._ ‘ )‘ _ _. R 1 i\ 2
L Rs S RL
R1 R2
oc—CE—co OC-Cr—CO
co "co 198 00 ‘00
199 favored 202 disfavored
OH OH
R2 RL R2 R5
R1 Rs R1 RL
OR OR
197 major 203 minor

For an a,B-unsaturated carbene complex of the type 204 that is disubstituted at
the B-position with carbon substituents, the reaction with an alkyne gives a non-
tautomerizable cyclohexa-2,4-dienone 205 as the final product (Scheme 4.4).163 This
reaction is often referred to as the cyclohexadienone annulation. The [3,B-disubstituted
alkenyl and indolyl carbene complexes both work well in the reaction,"53’I64 but aryl

Carbene complexes that have carbon substituents in both ortho-positions usually do not

g i Ve cyclohexadienone products. '65

Scheme 4.4. General Scheme of the Cyclohexadienone Annulation

 

0
OR RL R3 R
(OC)5Cr R3 + I l R2 L
R‘ R2 R R‘ Rs
5 OR
204 196 205

86

 

The Scope m Limitations of the Benzannulation Reaction
The benzannulation reaction generally produces good to excellent yields of
phenols, however, it can be very sensitive to the reaction conditions and the nature of the
substrates. The reaction can form a number of side products, and those most commonly
observed include indenes (cyclopentadienes), furans and cyclobutenones.
Chemoselectivily. The indene (cyclopentadiene) side product results from a direct
cyclization of the vinyl carbene complexed intermediate 199 without the insertion of a
carbon monoxide (Scheme 4.5).166 While the product 207 is rarely seen from the reaction
with alkenyl chromium complexes, aryl carbene complexes are more likely to produce
the direct cyclization product, which in this case would be indene 208. For many
reactions, the formation of the indene products can be most detrimental in accounting for
the less than optimal yields of the desired phenol products. Since the formation of the Z-
isomer 199a is also possible upon the insertion of the alkyne, and since CO insertion
gives the vinyl ketene complex 200a which cannot cyclize to a phenol, this pathway is

thought to be the origin of the furan side-product 209. '67

Scheme 4.5. The Rationale for the Indene and F uran Formation

 

 

 

 

 

 

R1
R2 R1 R1
’ \ OR OR OR OR
/ \ Rs Rs
Cr RL RL R
Cr(CO)3 L
(CO)4 208
109 200 207
R2
\ l R2 R2 1
R0 R1 R0 1 \
R
/\ —. | R O \ 8
RL Rs otC \ RS /
/ Ru
Cr R Cr(CO)3 R0
(COM
199 2008 209

87

 

Metal Effects. The reactions with tungsten or molybdenum carbene complexes
have also been studied, and it has been shown that in general these complexes are much
less chemoselective for the formation of the phenol products than the corresponding
chromium complexes.168 One exception is that the reactions Of alkenyl carbene
complexes with terminal alkynes always give the phenol products in high yields no
matter which Of the three metals is contained in the carbene complex. Compared to

chromium complexes, molybdenum complexes are generally less stable, and while
tungsten complexes are generally more stable, their reactions suffer from alkyne

polymerization]6m”I69 which competes with the formation of the phenol product. A few

non-group 6 Fischer carbene complexes, such as iron,170 cobalt)“ and manganese'72

complexes, have also been investigated, but none provides a general method for the

synthesis of phenols.

Solvent Effects. Studies have shown that the nature of the solvent has more of an
effect on the reactions of aryl carbene complexes than on alkenyl complexeslésa’173 Non-
polar and non-coordinating solvents usually favor the formation of phenol product, while
in polar and coordinating solvents, such as DMF and acetonitrile, a number of different

Side products can be formed in significant amounts.

Concentration Effects. The concentration of the reaction can affect the
diStribution of the products but this is generally limited to the reactions with aryl carbene
c()li‘lplexes.lésa’nh’b’n“ It has been found that the phenol/indene partition is more

favorable at higher concentrations. The distribution is a function of the alkyne

cotIcentration and not of the carbene complex concentration.

88

 

Temperature Effects. There have not been extensive studies of the effect of the
temperature on the product distribution. It has been shown that in some cases the indene
side product is favored over phenol at higher temperatures. mb
Heteroatom-Stabilizing Substituents. Besides oxygen-stabilized carbene
complexes, other hetero-atom stabilized complexes have also been examined, among
which the most thoroughly studied is the more electron-rich amino complexes. As
expected, the more electron rich substituent increases the electron density on the metal
center and strengthens the back bonding from the metal to the CO ligands, which in turn
disfavors the insertion of a CO ligand and leads to a decreased amount of the phenol
product. Consequently, the formation of the indene product is favored and this is
especially true with a polar and coordinating solventm In fact, the reaction of amino
carbene complexes and alkynes in DMF has become an efficient method for the synthesis
of indenes, although the efficiency of the reaction is highly dependent on the nature of the
substituents on the nitrogen.176 One exception is the reaction of amino alkenyl carbene
complexes and terminal alkynes which gives predominantly the phenol product.177 It
should not be surprising that the reaction of amino carbene complexes can be tuned to
give more of the phenol product over the indene product by lowering the electron density
on the nitrogen by introducing an electron-withdrawing group. Successful examples Of
this include installing a carbonyl group on the nitrogen (e.g. forming a carbamate)I78 and
using an aromatic pyrrole ring.179
Stereoselectivity. There are a few reports that have examined how the

Corlfiguration of the newly formed planar center of chirality due to the creation of a

chromium tricarbonyl group complexed to an aromatic ring would be influenced by

89

 

existing stereogenic centers in the substrate(s), and in some cases high stereoselection can

be achieved while in others the stereoselection is limited or the scope has yet to be

explored. ‘80

Applications in the Synthesis of Complex Molecules

The benzannulation reaction of a,B-unsaturated carbene complexes and alkynes,
with its attractive features such as mild reaction conditions and tolerance of a wide range

of functional groups, has found applications in the synthesis Of a large number of phenol

and quinone containing complex molecules. A few examples of natural products are
‘62b‘c’lsz (+)-olivin,183 dauno-

shown in Figure 4.1: sphondin,18' deoxyfrenolicin,
188

mycinone,m°‘I84 11-deoxydaunomycinone,”35’186 landomycinone,187 fredericamycin A,

and (-)-kendomycin,189 and each of their syntheses utilizes the benzannulation reaction as

the key step.
Figure 4.1. Synthesis Of Natural Products Involving Benzannulation Reaction

     

O
H QMe OH

O I HO : : floOH
/
O OH OH o

OMe
210 Sphondin 212(+)-0|ivin

O OH

“° .00
o o 0.
OH

213 R = OH Daunomycinone
214 R= H 11-Deoxydaunomycinone 215 Landomycinone

 

OMe O OH On
Me

 

217 (-)-Kendomycin

216 Fredericamyctn A

90

 

This reaction has also been applied in the synthesis of the vaulted biaryl ligands,
VAPOL and VANOL,190 for use in asymmetric catalysis. The VAPOL and VANOL
ligands have been shown as superior ligands in the catalytic asymmetric aziridination
reaction,191 Diels-Alder reaction (VAPOL),192 and the imino aldol reaction (V APOL).193

Figure 4.2. Structures of VAPOL and VANOL Ligands

 

21a (8)-VAPOL 219 (8)-VANOL

4- l -2 ortho-Benzannulation of Fischer Carbene Complexes and Their Applications

As discussed in Section 4.1.1, the key intermediate in the benzannulation reaction
of a,B-unsaturated carbene complexes and alkynes is the vinyl ketene complex 200
(Scheme 4.2). It was then not surprising to propose that if the a,[3,y,6-unsaturated carbene
Complex 220 would undergo insertion of a carbon monoxide, the doubly unsaturated
Vinyl ketene complex 221 would be formed with the alkoxy group attached to the ketene
carbon (Scheme 4.6). Similar to 200, the ketene complex 221 might be expected to
undergo an electrocyclic ring closure to give the cyclohexadienone complex 222 which
Would tautomerize to afford the phenol 223 after the loss of chromium tricarbonyl. The
fOrlned phenol 223 has an alkoxy group in the ortho-position, thus the reaction is refered
to as the ortho-benzannulation reaction. This reaction would be a valuable compliment to

the benzannulation reaction which produces p-alkoxy phenols.

91

Scheme 4.6. The Strategy for the ortho-Benzannulation Reaction

OR OR O OH
O:
(OC)5Cr C / /C'(CO)3 R4 OR R‘ OR
R4 R1 ——> R4 R1 —. ——>
\ / \ / R3 \ R' R3 R1
R3 R2 R3 R2 R2 Cr(CO)3 R2
220 221 222 223

Inspired by the pioneering work of Hegedus who found that the photolysis of

simple chromium carbene complexes caused insertion of a carbon monoxide ligand to
form the corresponding ketene complexes)”195 Wulff and coworkers reported in 1989
that the norbomadienyl carbene complex 224, upon UV irradiation, gave the expected
phenol 225 in 18% yield (Scheme 4.7).'96 This was the first example of the ortho-
benzannulation reaction, which demonstrated that the insertion Of a CO ligand was
realized photochemically for a doubly unsaturated carbene complex of the type 220. It
was later shown by Merlic that the yield Of this reaction could be dramatically improved
197

(93 %) if the reaction was performed under an atmosphere of carbon monoxide.

Scheme 4.7. First Example of the ortho-Benzannulation Reaction
5 CT(CO)5 b OMe
/ OMe h‘U I O OH
224 225

The Sgpe and Limitations of the ortho-Benzannulation Reaction

 

The photochemical ortho-benzannulation reaction has since been explored and
developed as a synthetic method,m’198 and some examples are illustrated in Scheme 4.8.
The reaction requires that the a,B—double bond in the dienyl carbene complex has a cis-

dlSPosition. As a consequence of synthetic expediency, most of the carbene complexes

92

 

that have been examined either have the a,B-unsaturated double bond incorporated into
an aryl ring or are those that can be directly prepared from a [4 + 2] or [2 + 2]
cycloaddition onto the alkyne function of an enynyl carbene complex.'99’200 The reaction

is independent of the nature of the unsaturation that comprises the dienyl component of
the carbene complex and even substrates with aryl groups as both the a,B- and 7,6-
unsaturation are effective for this photochemical ortho-benzannulation (e.g. 227 —> 228).

Scheme 4.8. The Photochemical ortho-Benzannulation Reaction

 

 

 

Or(cO)s OMe
l , OH
O 1)nBuLI O OMe hv 0‘
2) Cr(C0)e CO, THF
3) MeOTf
228 227 92% 228 90%
Cr(CO)5 0M9
Br . 0H
(In W“ Qt” 00
/ R 2) CI’(CO)5 / R CO.THF R
3) MeOTf
229a R=Ph 230: 87% 231a 42%
229i» R=Me 230!) 90% 231!) 23%
OMe (OC)5Cr OMe Cr(CO)5 0M3
OH
g n o 06
+ -——-—> —————.
TMSO HO 0 Comp HO O
232
233 234 86% 235 78%
(OC)5Cr OMe O ”(Go’s 0 We OH
0 [“21 OMe n .
U + II ' ' '0
CO.THF O
238
233 237 69% 238 50%

However, when the dienyl carbene complex, such as complex 239, has a trans-
O" B-double bond, the reaction has been reported to fail under photochemical conditions
(Scheme 4.9).197 As alluded to in Scheme 4.6, during the reaction the a,B-double bond

rleeds to be cis disposed (e.g. in 221) in order for the cyclization to take place

93

 

Apparently, the isomerization of the trans-a,B-double bond of carbene complex 239
could not be realized under the reaction conditions.

Scheme 4.9. Reported Unsuccessful Example of the ortho-Benzannulation

0 e
(CO)5CI'

M OH OM
hv e
239 240
Merlic and coworkers also examined dienyl aminocarbene complexes and found
that the photochemical ortho-benzannulation was unsuccessful with dialkylaminocarbene
complexes with the exception of a single example.201 Similar to the methods discussed
for the optimization Of the thermal benzannulation of amino carbene complexes with
alkynes (Section 4.1.1), tuning the electron density of the substituents on nitrogen by
incorporating a relatively electron-poor carbamate into the carbene complexes (e.g. 243)
favors the formation of the ortho-amino phenol products from dienyl amino complexes,
and in some cases, giving synthetically useful yields (Scheme 4.10). However, all known
examples of this reaction are considerably slower than their corresponding alkoxy
carbene complexeszm

Scheme 4.10. The ortho-Benzannulation Of Aminocarbene Complexes

Cr(OO), NM82

OH
_+.. 06
pn co 0

0

d A hv OH
N Ot-Bu O‘

Bn

Ph co. THF O

243 244 62%

241 242

 

94

 

In a related reaction, doubly-unsaturated carbene complexes can react thermally
with isonitriles to form o-alkoxy aromatic amine derivatives (Scheme 4.11).202 This
reaction presumably proceeds via a dienyketenimine species that is analogous to 221.
Similarly, a structural requirement of the dienyl carbene complexes is a cis-a,B-double

bond. Alkenyl, aryl and furyl groups can all function as the unsaturation components,
except in the case where both the (1,6 and 7,5 unsaturated units are incorporated into aryl
groups. This reaction is different from the ortho-benzannulation in the sense that it
requires an isonitrile as the reacting partner and the intermediate does not involve a
ketene complex.

Scheme 4.11. Formation Of o-Methoxy Amino Naphthalenes with Isonitriles

 

011(30):, 0MB
OMe THF NHCHzcozEt
4‘ CNCHQCOZEI
/ Ph reflux Ph
245 246 80%
0100):; OMe
toluene NHI’B“
0M9 + CNt-Bu .____. 0C
reflux
/ O ‘0
247 248 78 %

muons in the Synthesis of Natural Products

The photochemical ortho-benzannulation to form o-phenols and, by oxidation
thereof, o-quinones has been applied in the synthesis of complex natural products. For
eXaInple, as shown in Figure 4.3, Merlic has successfully utilized the reaction in the
elegant total syntheses of calphostins A-D,203 the potent and selective inhibitors of

protein kinase C (PKC). The Wulff group has recently applied this reaction to the total

95

 

synthesis of carbazoquinocin C,204 a member Of a family of compounds possessing

neuronal cell protecting activity.

Figure 4.3. Synthesis of Natural Products Involving the ortho-Benzannulation

Reaction

249a Calphostin A: R1 = Bz. R2 = 82 Q Ma
24913 Calphostin B: R‘ = 82. R2 = H D

0R1 249c Calphostin c: R1 = 82. R2 = COz-O-OH u 6

0H 0 249d Calphostin D: R1 = H, R2 = H

   

250 Carbazoquinocin C

 

Exam les Of the Thermal ortho-Benzannulation to Form o-Alkoxv Phenols

 

It was reported by Merlic that, for the thermal reaction of complex 224, the
highest yield that could be Obtained was only 29% when the reaction was performed in
refluxing heptane (Scheme 4.12).197 When other dienyl complexes were tested under
thermal conditions, little or no benzannulation products were Observed.

Scheme 4.12. First Example of the Thermal ortho-Benzannulation By Merlic

Cr(CO)5

b b we
/
OMe heptane / O OH
O "3"" O

224 225 29%

 

Barluenga has recently reported that, in rare cases, the formation of o-methoxy
phenols could be induced thermally (Scheme 4.13).205 All the examples are strictly
litTlited to complexes of the type 251 in which the Ot,B-double bond is embedded into a
Strained four-membered ring, and the reactions give good to high yields of o-methoxy

phenols 252. It was believed that the unusual reactivity was due to the geometric

96

restraints Of the cyclobutene ring that was introduced in the starting complexes. All the
reactions were carried out under an atmosphere Of nitrogen, and it was claimed that the
reaction failed under a CO atmosphere.

Scheme 4.13. General Scheme of the Thermal Reaction Reported By Barluenga

Cr(CO)5 OMe

R30 R30
R‘jjéiMe THF. reflux pyjfiOI-i
5 5
RR6 / R2 N2 RR6 R2
R‘ \X/ R1

251 co 252

Aumman has also Observed the ortho-benzannulation products in low to moderate
yields with several similar cyclobutene-containing examples of the corresponding
tungsten carbene complexes under thermal conditions.206 Also, there has been a related
report on cis-styrenyl type chromium carbene complexes with a chalcogen—stabilized iron
cluster on the double bond, which can thermally afford both phenol and indene
products.207

From all the known examples described above, it is clear that the scope of the
thermal ortho-benzannulation is very limited, and that the cis-a,B-unsat11ration not only is
required but also has to be embedded in a strained ring. This rigid structural requirement
in the starting carbene complexes and, therefore the limited geometries in the products,
have essentially restricted its use, and as a consequence this thermal reaction has not been
of broad interest. These examples were merely viewed as exceptional cases in which the

ortho-benzannulation reaction be effected under thermal conditions.

97

 

4.2 THE DISCOVERY OF A NOVEL THERMAL ORTHO-BENZANNULATION

MEDIATED BY IRON

As discussed in Chapter 3, the cyclopropanation reaction of dienyl Fischer
carbene complexes was examined in both intermolecular and intramolecular fashions. In
the course of a control experiment for the cyclopropanation reaction, an unexpected metal
carbonyl complex was isolated from the reaction Of the trans, trans-pentadienyl carbene
complex 181a in benzene at 80 °C under 500 psi of carbon monoxide in a Monel Parr
reactor (refer to Scheme 3.5). It took quite a while to finally determine the product as the
114-dienyl iron tricarbonyl complex 254a which was isolated in 39% yield (Scheme
4.14).208 This iron complex had certainly never been expected from the thermolysis of
181a since only the chromium complex was used and no iron-containing reagent was
involved in the reaction. An organic product — the pentaene 253a — was also isolated in
~30°/o yield, resulting from dimerization Of the carbene ligand, which was not
unexpected.209

Scheme 4.14. Thermolysis of Pentadienyl Complex 181a under 500 psi of CO

 

O
OMe H
500 si CO H C OMe OMe
‘OC’SC' p = 3 / /| + “30*
_ __ benzene. 80°C. 2h H30 \ \ OMe
Fe(CO);
OH3
181a 253a ~30% 254: 39%

The product 254a was initially thought to be the cyclohexadienone chromium
tricarbonyl complex 1938 on the basis Of its NMR spectra (Scheme 3.5). If that structure
was correct, it would have a molecular weight of 278; however, the mass spectrum gave a
molecule ion of 274. This was the big problem in the assignment of the complex. Another

surprising observation was that the complex was very stable in air without any signs of

98

 

tautomerization and remained unaffected even upon treatment with strong acids, which
did not seem possible for an unsaturated 16-electron group 6 metal complex, such as
1938 (unless it was a ground-breaking discovery in organometallics!).2'0 Thus, a
tetracarbonyl structure 193b was suggested for the product which would have 18
electrons on the metal and would be expected to be stable. But again, the molecular
weight of 193b is 302 and this peak was not Observed on the mass spectrum. The
question that then came to the fore was: which metal would it be if it were not
chromium? If this product contained iron, then an iron tricarbonyl complex would fit the
high resolution mass spectrum (HRMS), and it could also easily explain the unusual
stability that was observed since this complex would be an 18-electron species. As a
confirmation, an SEM/EDS analysis211 was performed to identify which metal was
present, and the results clearly showed that the metal in the product was indeed iron and
also that the starting complex contained only chromium.212 The stereochemistry Of the
methyl group in the complex 254a was assigned as syn to the iron tricarbonyl group
based on its X-ray structure determination (Figure 4.4). Worthy of note is that the X-ray
structure was actually taken prior to the SEM/EDS studies but the electron density
difference between iron and chromium is small enough that a normal X-ray diffraction

analysis cannot distinguish between the two.

99

'_Y

 

Figure 4.4. The X-ray Structure of the Dienone Iron Tricarbonyl Complex 254a

  

0:14) 05" is”?

 

C(13) N
bill. a.-
,"///’i- l l
‘7 U016 0
\ 0(7) ' H OMe
94*, ¢ . H3C““
‘ C111) “2
‘ - (2(8) ‘Fe(CO)3
0 254a
0" 0(12i

 

 

 

Then the question was: where did iron come from? SEM/EDS analysis ruled out
the starting carbene complex 181a and the benzene solvent was distilled in glass, so the
only remaining possible origin would be from the reaction vessel. As mentioned earlier,
the reaction was performed in a Monel Parr reactor that is composed of 65% nickel, 33%
copper, and only 2% iron and the reactor did not look corroded. On the other hand, the
mechanical stirrer appeared to be quite corroded and it was suspected that iron was
leached from it.”3

After determining where iron was coming from, it was decided to pursue other
sources of iron to save the mechanical stirrer, and more importantly to be able to maintain
rigorous control over the source of the iron. As shown in Table 4.1, the introduction Of
any Of the three iron sources resulted in higher yields of the cyclohexadienone complex
254a, with diiron nonacarbonyl being superior to triiron dodecacarbonyl and
benzylideneacetone tricarbonyl214 which is known to be an effective iron tricarbonyl

transfer agent. It was not necessary to add more than one equivalent of the iron carbonyl

100

 

complexes since a slight excess (1.5 equivalents) did not make any difference. In each
case, the formation of a trace amount of the pentaene 253a was also observed.

Table 4.1. Thermolysis under 500 psi of CO with External Iron Sourcesa

 

 

 

 

 

 

 

 

 

O
(OO),cr=<o::‘\ Additive H “CM 8
._ : ch‘WO
__ 500 psi CO 5
CH3 benzene, 80 °C. 2 h "F6(CQ)3
181a 254:
Entry Additive Equiv. 254a, % yield
1 -- -- 39
2 F (CO) 1.0 58
e
3 3 '2 1.5 59
4 F (CO) (b )b 1.0 63
e a
5 3 1.5 63
6 F (CO) 1.0 89
————-—-—~ e
7 2 9 1.5 89

 

 

 

 

a) All the reactions were carried out at 0.02 M in complex 181a.

b) Benzylideneacetone iron tricarbonyl.

Since the reaction was performed under 500 psi of CO, a high pressure reactor
had to be used. For the purpose of convenience, we sought to carry out the reaction in a
glass vessel under one atmosphere of argon or carbon monoxide. Much to our delight, the
reaction worked very well and afforded the desired dienone complex 254a and the
corresponding phenol 255a (Table 4.2). In all cases, no pentaene 253a was observed
when the reaction was performed under 1 atm argon or CO, and the phenol 255a resulted
from the tautomerization of 254a followed by loss of iron tricarbonyl. It was of interest to
note that the overall yields Of 254a and 255a were only slightly higher under an
atmosphere of CO than under argon. The reaction was not very sensitive to the solvent
and THF appeared to be slightly better. The reactions in THF or benzene were fairly

clean and the separation Of the products was not a problem, however, when the reaction

101

 

was performed in acetonitrile the purification was not easy due to the presence of some
hard-to-separate impurities. As will be shown later, THF and benzene were the solvents
that would be used in determining the scope of the reaction. As was observed from the
reaction under 500 psi of CO, diiron nonacarbonyl was the better iron source under 1 atm
of argon or CO.

Table 4.2. Optimization of the Reaction under 1 atm of Ar or CO8|

OMe Additive (1 eq.) H 0 0”
(OC)SCr 1atm CO or Ar W. OMe H30 OMe
_ g H3C Q +
— solvent, T °C "

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CH3 "’i=e(CO)3
181C 25‘. 255.
Additive Solvent CO/Ar T, °c Time, h 254a, % 255a, % 9V6”?
yield, /0
CO 80 17 68 12 30
F82(CO)9 CH3CN
Ar 80 20 34 8 42
co 80 36 68 7 75
l762(CO)9 heptane
Ar 80 20 54 5 59
CO 80 24 70 8 78
F62(CO)9 benzene
Ar 80 28 58 6 64
co 80 46 61 20 81
F92(CO)9 THF
Ar 80 20 50 10 60
co 80 48 6O 7 67
Fe(CO)3(ba) benzene
Ar 80 7 18 3 21
CO 80 144 - - - < 05 < 0.55
- - - benzene
Ar 80 144 -- - 3 3
CO 60 108 69 5 74
Fe2(CO)9 heptane
CO 100 12 59 13 72

 

 

 

 

 

 

 

 

a) Unless otherwise specified, all the reactions were carried out at 0.02 M in 181a.

b) With 70% recovery of 181a.

The control experiment under argon without a source of iron did produce a small
amount of 255a (8% yield) but only after 144 hours at 80 °C (Table 4.2). After 144 hours

at 80 °C under a CO atmostphere, only a trace of 255a was observed with a 70% recovery

102

of the starting complex 181 a. Clearly, iron is playing the key role in this carbonylative
cyclization.

The temperature study was also carried out under an atmosphere of CO. Heptane
was chosen as the solvent simply because it has a high boiling point (98 °C). As can be
seen from the last two entries in Table 4.2, the reaction took 108 hours to complete at 60
°C although the overall yield (74%) was essentially the same as the reaction performed at
80 °C (75% yield); while after 12 hours at 100 °C, the reaction gave a slightly lower
overall yield (72%). Thus, with both the reaction time and the yield taken into account, it
was determined that 80 °C was the temperature that would be used in the study of the
scope of the reaction.

In summary, the first example of the iron-mediated ortho-benzannulation of a
Fischer carbene complex has been demonstrated. It is the first time that the ortho-
benzannulation reaction has been realized with a trans, trans-dienyl carbene complex.
Another feature of this novel reaction is that it is performed under thermal conditions.”5

The next phase of this study is to investigate the scope of the reaction. The
optimized reaction conditions that will be employed are shown as follows: diiron

nonacarbonyl used as the iron source, THF or benzene as the solvent, and the reaction

would be carried out under one atinosphere of CO at 80 °C.

103

 

4.3 PREPARATION OF TRANS-mfi-DIENYL CARBENE COMPLEXES

A series of trans-orfi-dienyl carbene complexes were synthesized. Most of the
carbene complexes were conveniently prepared by an aldol condenstaion of the methyl
carbene complex 256 with an unsaturated aldehyde or a ketone.112 For the reaction of the
methyl carbene complex 256 with an aldehyde, the protocol developed by Wulff was
used with slight modifications (Scheme 4.15).l 12“ The reaction involves the deprotonation
of 256 with n-BuLi, and then the addition at —78 °C of a pre-mixed solution of the Lewis
acid SnCl4 and the aldehye 257. The resulting aldol adduct is dehydrated upon treatment
with MsCl and Et3N to furnish the dienyl carbene complex 181. The reaction usually
gives moderate to good isolated yields of carbene complexes 181 along with the recovery
of some of the starting complex 256.

Scheme 4.15. Aldol Condensations with Aliphatic Aldehydes

 

 

H
O R5
R3 R4 0M8
(OC)SCr=<OMe "BU“ _ 257111.11, 1.11 A MsCl, Et3N ‘ ‘00)50' _ R5
CH . _
3 Et20.-78 °C 811014, -78 °C CHZCIZ, o C R3 R4
258 1811-. ii. 1.1)
OMe 0M9 OMe OMe
were (0050' _ (OC)5Cr (OC)50r
_ _ CH3 _
CH3 CH3
181: 52% (63%)* 1819 31% (61%) 1811 52% (72%) 1811 51% (70%)

 

" Yields in prarentheses are based on unrecovered starting material.
This aldol condensation is also effective for cinnamaldehyde, however, for the
preparation of this type Of dienyl complex with an aryl (or cinnamyl) goup in the O
112b,c

position, Aumann’s procedure using TMSCl and Et3N was employed (Scheme 4.16).

Aumann’s procedure is much simpler since it is a one-step reaction which can be

104

 

performed at room temperature and usually go to completion after 2—3 days and give

good to high yields of the products 181. However, this procedure can only be used for

non-enolizable aldehydes.

Scheme 4.16. Preparation Of Dienyl Complexes using Aumman’s Method

 

OR
OR H TMSCl/EtaN
(OC)5M=( + 0 e (00’5”
CH3 -' ether. r.t.. 2—3 days — —
Ar Ar
256M=Cr.R=Me 260: R=Ph 181bM=Cr.R=Me,Ar=Ph; 68%
258 M = W. R = Me 200!) R = CH=CHPh 1811: M = W. R = Me. Ar = Ph; 65%

1816 M = Cr, R = Et. Ar= Ph; 61%

259M=Cr.R=Et
181b M = Cr, R = Me. At = CH=CHPh; 72%

When a ketone was used in the aldol condensation, the better Lewis acid was
BF3'OEt2 and the dehydrating reagent was alumina as reported by Gilbertson and
Wulff.”2d As shown in Scheme 4.17, the reaction with trans-4-phenyl—3-buten-2-one 261
afforded 43% yield of the isolated B-methyl substituted complex 181e (51% yield based

on the recovery of 256).

Scheme 4.17. Aldol Condensation with Ketone 261

OMe

 

(OC)5Cr=(OMe i)1eq. nBuLi. £120. -78 0C : iii) A1203; (0050 — CH3
CH3 ii) 0 CH3 hexanes _

255 _ BF3-Et20. Ph
Ph 820000 1819 43%(51%)

261

The dienyl carbene complex 181f with a methyl group in the Oi-position could not

be prepared by an aldol condensation since the requisite ethyl methoxy carbene complex
and cinnamaldehyde did not give any desired product 1811’ under the reaction conditions
developed by Wulff,112a although the starting carbene complex was all consumed. Thus,
this compound was prepared by the Fischer protocol from the dienyl iodide 263. The

Synthesis of the precursor iodide 263 involves a one-pot hydroboration/iodination

105

sequence216 from 1-((E)-pent-1-en-3-ynyl)benzene 262, which was conveniently prepared
by a known procedure217 from cinnamaldehyde (Scheme 4.18). Considering all the
possible isomers that could form in the hydroboration step, it was delightful to be able to
isolate the trans,trans-iodide 263 in 24% yield which would be difficult to prepare using
other methods. The subsequent standard Fischer protocol worked well and gave the Oi-
methyl dienyl complex l81f in 62% yield.

Scheme 4.18. Preparation of Iodide 263 and Carbene Complex 1811'

H3C 0M8

\\ i) HBBrz'SMez I)=\_\ 1) “BULL '73 °C (0C)sCr
.. H c _ i —
_ u) 3 N NaOH, 3 Ph 2) Cr(CO)6. rt. “3‘3
ph then l2/ether 3) MeOTf, r.t. P"

262 263 24% 181f 62%

 

 

With trans-a,B-dienyl carbene complexes 181a-j in hand, the stage was set for an
extensive examination of the efficiency and the scope Of the novel ortho-benzannulation

reaction, which will be discussed in the following section.

106

 

4.4 THE SCOPE AND LIMITATIONS OF THE REACTION

4.4.1 trans-a,B-Dienyl Fischer Carbene Complexes

The reactions of trans-a,[3-dienyl carbene complexes 181a-j were carried out with
one equivalent of Fe2(CO)9 at 80 °C in THF or benzene under 1 atm of CO, and the
results are summarized in Table 4.3. It was delightful to find that the reaction was
effective with all the carbene complexes that were examined and gave high to excellent
overall yields of the isolated dienone complexes 254 and/or the phenols 255. In all cases,
only a single diastereomer of the dienone complex was formed and the stereochemistry of
each was assigned as syn based on the X-ray structure determination of 254a. For most Of
the substrates, THF was the optimal solvent. The reaction always gave more Of the
phenol product in the more polar and coordinating solvent THF than in benzene.
Successful substrates include those that have either an alkyl or aryl group at the 6-
position (e.g. 181a and 181b), and also dienyl complexes that are substituted at the Oi, B,
y or O position(s) all worked well. It is also interesting to note that the reaction of the
tungsten complex 181c was superior to that of the corresponding chromium complex,
giving 92% overall yield of 254b and 255b in THF. Only the phenol 255b was isolated
from the reaction of the trienyl carbene complex 18lh. It is conceivable that the
corresponding dienone complex was formed in the reaction but that it was conveted to the
phenol 255b immediately after the reaction mixture was Opened to the air.218 Worthy of
mention is that complexes 1811 and 181 j which are disubstituted at the O-carbon
efficiently reacted to give the non-tautomerizable cyclohexadienone iron tricarbonyl

complex 254i (81% yield) and the Spiro-complex 254j (85% yield), respectively. This is

107

 

the first time that an “ortho-cylcohexadienone annulation” has been realized with a 0,5-

disubstituted dienyl carbene complex.

Table 4.3. The Iron-Mediated Thermal ortho-Benzannulationa

 

 

 

 

 

OMe 0”
(OC)5Cr R2 Fe2(CO)9 (1 eq.) R5 OMe
_. R‘ r
R1 3... 1atm CO R3 R1
R R5 Solvent. 80°C R2
181 254 256
Carbene Complex 101 Dienone 254 Phenol 255 Carbene Complex 181 Dienone 254 Phenol 255
cm H O OM 0H s OMe H O OM 0“
e H M g e 1911 OM
_ ' H3C —— \1 CH3 CH
CH3 Fe(CO)3 Pb F6(CO)3
181a 254a 1811 1
THF: 81% (75:25)b THF: 80% (5844)
C6116: 78% (90:10) CgHez 87% (8317)
0 0H : OMe
OMe H .
(00):,ch WOW PhGOM S (oclsCr “our:
Ph""'© ' _ (Kym
— ‘1
p11 Fe(CO)3 \Fetcola
1810 25411 2558 1810
THF: 82% (40 80) THF: 91%(93:7)
C6:Hs 80% (58: 44) 06116: 88% (98:2)
OMe 0“ OMe OH
P11 Emcob —
181c 2540 25511 3 18"! 255b
THF: 92% (25:75) , THF: 70%
Cal-13: 75% (90:10) E C5H5: 78%
08 H 0 CB OH Me OM
(>11 05! z 6
Ph Fe(CO)3 § 5:1:«0013
181d 254d 255d , 181'
THF: 88% (23:77) 3 THF: 81%
Cal-161196 (83:37) 5 06H: 78%
OMe H O OH
(0C)5Cr CH3 Ph.*°M° Ph\:,0Mo 3 (0050:6118 0"“
Ph CH3 Fe(CO)3 CH3 5 RFqCOh
1810 254. 255. ml
THF: 75% (25:75) THF: 85%
Cal-161996 (67:33) CeHez 81%

 

 

a) Unless otherwise specified, all reactions were carried out at 0.02 M in complex 181.
b) The yields are combined yields of isolated 254 and 255; ratios in parentheses are

calculated from the integration of the NMR spectra of the crude reaction mixtures.

108

The studies demonstrate that the iron-mediated ortho-benzannulation of trans-
Oi,B-dienyl carbene complexes is broad in scope. The dienyl complex can have
substituent(s) at any position(s) of the diene unit. That trans-a,[3-dienyl complexes are
good substrates for this ortho-benzannulation greatly increases the power of the ortho-
benzannulation not only due to the fact that it can now be carried out under thermal
conditions, but also because many of the trans-substituted dienyl carbene complexes can
be easily prepared by an aldol condensation as illustrated in Section 4.3. The cis-
substituted dienyl complexes that had been previously required for the reaction can be

difficult to make unless they are locked into a ring (refer to Schemes 4.8 and 4.13).

4.4.2 cis-a,B-Dienyl Fischer Carbene Complexes

Given the effectiveness of the chromium to iron transfer in the thermal ortho-
benzannulation of trans-a,B-dienyl carbene complexes, it was deemed important to
determine if this process could be extended to the development of a thermal method for
the ortho-benzannulation of cis-dienyl complexes. The carbene complex 224 was the first
of such complexes that were tried, and gratifyingly, it was found that the reaction
afforded an 80% yield of the desired naphthol 225 when the reaction was performed
under 1 atm of carbon monoxide in the presence of Fe2(CO)9. The yield was much lower
(15%) under argon. Merlic reported that the highest yield that could be obtained under
thermal conditions was only 29% when complex 224 was heated in refluxing heptane (in
the absence of an iron source).197 Thus, the iron-mediated ortho-benzannulation of 224
was viewed as a great success since previously high yields of 225 could only be obtained

under photochemical conditions.

109

 

Scheme 4.19. The Iron-Mediated ortho-Benzannulation of cis-orfi-Complex 224

once). ' b OMe
/ b 0M8 F82(CO)9(1 8(1) t / OH

O benzene. 80 °C 0

224 225

Under 1 atm CO: 80%
Under 1 atm Ar: 15%

 

Next the cis-01,13-dienyl complex 264 was examined. Barluenga reported that
complex 264 would give the ortho-benzannulated product 265 in 72% yield when simply
heated in refluxing THF under an atmosphere of nitrogen.205 Curiously, it was also
claimed that this reaction failed when 264 was heated under an atmosphere of carbon
monoxide. In this study, when the reaction was carried out at 80 °C under an argon
atmosphere in a Schlenk flask, the best yield obtained was only 40%. Importantly,
contrary to what Barluenga claimed, it was found that the reaction actually gave a slightly
higher yield (42%) under a CO atmosphere than under an argon atmosphere, as indicated
in Table 4.4. It was also found that diiron nonacarbonyl could promote the reaction
which gave an increased 68% combined yield of the phenol 265 and the iron complexes
266a and 266b. The stereochemistry was tentatively assigned as anti for 266a and syn for
266b. These results further demonstrate that the scope Of the iron-mediated thermal

reaction could be expanded to include cis-a,B-dicnyl complexes.

110

Table 4.4. Thermal ortho-Benzannulation of cis-orfi-Dienyl Complex 264*

 

 

 

Or(CO)5 OMe OMe OMe
We 1 atm CO/Ar ‘ m0” (Dmljfgo [CD/T1650
80 .C (00:51:8/ (OC)3Fe/
284 285 266: 28811
Entry Additive CO/Ar Solvent Time, h 265, % 266a, % 266b, %
1 - - - Ar THF 10 4O - - - - - -
2 --- CO THF 72 42 -—- ---
3 Fe2(CO)9 (1 eq.) CO THF 48 49 10 9
4 Fez(CO)9 (1 eq.) CO Benzene 96 57 7 trace

 

"‘ Unless otherwise specified, all reactions were carried out at 0.02 M in 264.

Next it was decided to examine an acylic dienyl complex with a cis-a,B-double
bond. The cis,trans-iodide 267 was Obtained in a 10:1 ratio of Z/E isomers using a
procedure reported by Zhao for related compounds.”9 However, upon the application of
the standard Fischer protocol to the preparation of the cis,trans-carbene complex 1811',
none of the desired complex was isolated. These failed attempts included variations with
different methylating reagents, such as Meerwein’s salt (trimethyl oxonium
tetrafluoroborate) and methyl triflate. In addition, an attempt was made to convert the
lithium chromium acylate intermediate to the corresponding tetramethyl ammoniuim salt
and then methylation, but this also failed to give cis,trans-18lf. In all cases, a small
amount of trans, trans-carbene complex 181f (~ 5% yield) was Obtained, along with the
major product of the reaction which was determined to be the cyclopentenone 268.
Clearly, cis,trans-dienyl carbene complex 1811' that was generated from the Z-isomer was
not stable and underwent spontaneous cyclization (without the insertion of a carbon

monoxide) to give the cyclopentadiene 269 which, upon hydrolysis, afforded 268.

111

Scheme 4.20. Attempted Preparation Of the cis,trans—Complex 1811'

Ph , 0MB 0
l __ 1) 2 eq. t-BuLi (0050.,
_ > — + H3C Ph
“30 2) Cr(CO)5 H30 —
Ph

 

3) MeOTf
267 (Z/E = 10:1) trans.trans-181f ~ 5% 268 51%
\Z-isomer) /
OMe Ph OMe
(0%ch —> H3C\ 6: ,Ph
H30
cis,trans-181f 269

It is known that dienyl carbene complexes, which have an amimo group at the 0
position and which have the y,O-unsaturation and the carbene moiety cis disposed,
undergo facile cyclization to give cyclopentadiene derivatives.220 However, the carbene
complexes 224 (Scheme 4.19) and 264 (Table 4.4) also have a cis disposition of the 7,5-
unsaturation and the carbene moiety, and they are clearly stable. This suggests that the
exact geometry about the afi-double bond is important for the stability Of the complex.
Thus, dienyl complexes can undergo direct cyclization to form cyclopentadiene
derivatives at or below room temperature if the angles and lengths of the bonds on the
cis-a,[3-double bond are appropriate. In contrast, the trans,trans-carbene complex 1811‘ is
stable and, upon treatment with diiron nonacarbonyl, undergoes the ortho-benzannulation
tO give an 87% yield of the dienone complex 2541' and phenol 2551' (Table 4.3).

Since F e2(CO)9 was found to effectively promote the thermal ortho-
benzannulation of the cis-a,B-unsaturated dienyl complex 224 (Scheme 4.19), attention
was turned to the investigation of other cis-a,B-unsaturated dienyl complexes that Merlic
had reported as successful substrates in the photoinduced ortho-benzannulation (Scheme
4.8). For example, Merlic reported that complex 237 gave the o-methoxy phenol 238 in

50% yield upon photlysis (Scheme 4.8).197 Treatment of 237 with Fe2(CO)9 under

112

thermal conditions in either THF or benzene under 1 atm of CO failed to give any of the
cyclized product 238. This included an attempted reaction under 500 psi of CO in a Parr
reaction. In all cases, complex mixtures were Obtained and none of the desired 238 was
observed while all the starting material was consumed. It is still unclear at this moment
why this substrate does not undergo the iron-mediated thermal ortho-benzannulation
reaction while complex 224 does. Worthy of mention is that all the reactions were heated
at 90 °C since the consumption of 237 seemed to be slow at 80 °C.

Scheme 4.21. Attempted Iron-Mediated Thermal ortho-Benzannulation of 237

 

 

CdCOk
0 I OM, Fe2(CO>i(1eq.)
CO. 90°C
THFor benzene
237 238

A different but also undesired outcome was Observed for the iron-mediated
thermal ortho-benzannulation of the biphenyl complex 227. Merlic reported that this
complex gave a 90% yield of the o-methoxy phenol 228 under photochemical conditions
(Scheme 4.8). However, upon heating at 80 °C in the presence of Fez(CO)9, the reaction
of biphenyl carbene complex 227 was very sluggish and it took days (or even weeks) to
consume all the starting material (Table 4.5). Surprisingly, the major product of this
reaction was always the direct cyclization product 270. The o-methoxy phenol 228 was
the minor product if it was formed at all. In two cases, a small amount of the enol ether
271 was also isolated, resulting from the dimerization of the carbene ligand. The results
showed that, under all these conditions that were tried, the insertion of a carbon
monoxide was not as fast as the direct cyclization which led to the formation Of 9-

methoxy fluorene 270. Given the failure of complexes 227 and 237 to give ortho-

113

benzannulated products in the presence Of iron, no other cis-a,[3-disubstituted dienyl
complexes that are known to be photo substrates were not tested in the presence Of diiron

nonacarbonyl.

Table 4.5. The Iron-Mediated Thermolysis of Carbene Complex 227.3

Cr(CO)5

OMe OMe O
0.1., F62(C0)9(16CI-) 0“ OMe
= + o - .1.
O co, 1°C 0 O MeO O
228 270 271

227

 

 

Entry CO Solvent T, °C Time,d 228,% 270,% 271,%

 

1 1 atm benzene 8O 16 20 68 ---
2 1 atm THF 80 7 < 1 79 ---
3 1 atm CH3CN 80 5 --- 77 ---
4 1 atm toluene 130 1 < 1 80 ---
5b 500 psi benzene 80 3.6 --- l9 8

6 500 psi toluene 130 0.7 <2 50 26

 

a) Unless otherwise specified, all reactions were performed at 0.02 M in 227.

b) With 46% recovery of 227.

4.4.3 Conversion of the Dienone Iron Tricarbonyl Complexes to Phenols

The demetalation of the iron tricarbonyl complexes can be achieved efficiently to
give the corresponding o-methoxy phenols. The dienone complex 254b that has a phenyl
group on the sp3 carbon of the ring was slowly converted to the phenol 255b even on a
silica gel column. Simply stirring 254b with silica gel in CHzClz open to air for a couple
of days gave a 95% yield of 255b (Scheme 4.22). In contrast, the iron tricarbonyl
complexes that have an alkyl group on the sp3 carbon of the ring are quite robust and are

not converted to the corresponding phenols on silica gel. However, upon stirring in

114

Et3N/HzO at room temperature for 5 hours, complex 254a was converted to the phenol
255a in 91% yield. Alternatively, an 82% yield of the phenol 255a was Obtained after
254a was refluxed in pyridine for 12 hours under an argon atmosphere.221 Similarly, the
iron complex 254g was converted to 255g in 90% yield upon treatment with wet Et3N.

Scheme 4.22. Demetalation of Iron Tricarbonyl Complexes

HO OH

 

 

OMe Silica gel. CHZCIZ 2 Ph OMe
1311“ ,
air. n.2-3d
2548 “(GOP 25511 95%
O
H OH
OMe
H3C“ EtaNleO _ HacUOMe
rt. 5 11
Fe(CO)3
254: 255: 91%
H O OH

 

2 it. 20 h

"Fe CO)
2540 ( 3 2559 90%

4.4.4 Control Experiments on the trans,trans-Dienyl Complex 181b

As shown in Table 4.2, simple thermolysis of the trans, trans-pentadienyl carbene
complex 181a without an iron source failed to give the thermal ortho-benzannulation
product 255a in any Significant yield. Complex 181a has an alkyl group in the O-position,
and it was decided to run another control experiment with the trans, trans-dienyl complex
181b which has a phenyl group in the O-position (Scheme 4.23). The outcome was the
same when benzene was used as the solvent. After complex 181b was heated in benzene
at 80°C for 4 days under an atmosphere Of CO, only a trace of the phenol 255b was

observed along with an 83% recovery Of the starting material. A small amount of 255b

115

(~7% yield) was Obtained from the thermolysis of 181b under argon along with a 28%
recovery of 278b. These results are remarkably similar to those Obtained form the thermal
control of 181a. The thermolysis of 181b was also examined in THF. Only a trace of
phenol was observed under an atmosphere of either argon or CO while all the starting
material was consumed. Clearly, all the results further demonstrate that a source of iron
tricarbonyl is essential in the thermal ortho-benzannulation of trans,trans-dienyl carbene
complexes.

Scheme 4.23. Control Experiments with 181b in the Absence of an Iron Source

OMe . . OH
(0C)sCr No Fe P11 OMe
———> + 1811)
— 1 atm CO/Ar
— 80 °C. 4 d
P11
181b 2558

 

In benzene: under CO: < 1% (25513) + 83% (1811))
under Ar: ~ 7% (26513) + 28% (18113)
In THF: under CO: < 3% (255b)
under Ar: < 1% (255b)

 

 

Given that the cis-a,B-unsat11rated complexes 237 (Scheme 4.21) and 227 (Table
4.5) will only cleanly give the ortho-benzannulation product under photochemical
conditions, the question is then raised as to whether the trans-afi-unsaturated dienyl
complex 181b will only give the ortho-benzannulation product in the presence of iron. To
answer this question, a solution of 181b in THF was irradiated with a 450 W medium
pressure mercury lamp under an atmosphere of carbon monoxide for 14 h until all the
staring material was consumed. This reaction only gave a trace amount (< 5% yield) of
the ortho-benzannulated product 255b (Scheme 4.24). The failure of the photochemical
reaction of trans,trans-dienyl complex 181b is in agreement with Merlic’s report on the

unsuccessful attempt with the trans-styryl complex 239 (Scheme 4.9).

116

Scheme 4.24. Attempted Photochemical Reaction Of trans, trans-181b

OMe OH

(OC)sCr hv : Ph OMe
— _ CO. THF. 1411

Ph
181 b 2551) trace (< 5%)

 

These negative control experiments further demonstrate the uniqueness of the
iron-mediated thermal ortho-benzannulation reaction of trans-a,[3-dienyl carbene
complexes. In the absence of iron, this reaction does not work under either thermal or

photochemical conditions.

4.5 THE MECHANISTIC STUDY

SO what does the iron do in this reaction? How does this iron-assisted conversion
of the dienyl chromium carbene complex to the iron tricarbonyl cyclohexadienone
complex occur? In the only related chemistry, Franck-Neumann reported that the iron
tricarbonyl complexed diazo ester 272, upon heating at 100 °C in cumene, gave the
cyclohexadienone complex 273 in 45% yield. This suggests that an iron carbene
222

complexed intermediate could insert CO and cyclize to a dienone (Scheme 4.25).

Scheme 4.25. A Related Literature Example of Cyclohexadienone Formation

N CO Et
2 2 (OC)3Fe CO Et
/ 100 °C |\\ 2
- —Fe(CO)3 ——"
\ cumene H C -.,’
3 H
CH;
272 273 45%

With regard to how the organic fragment is transferred from chromium to iron,
there are two most likely possibilities. First, the iron tricarbonyl could become complexed

to the dienyl unit in 181 to form an r14-iron tricarbonyl complex of the type 274 followed

117

by loss of chromium (Scheme 4.26). Second, there could be a direct transmetalation to
give an iron carbene complex of the type 275 which then undergoes internal coordination
to the diene in some fashion such that the trans-a,B-double-bond is isomerized. To
distinguish between these two possibilities, it was decided to prepare both Of the
complexes 274 and 275 by independent synthesis and test the viability of each in the
formation of 254 and 255.
Scheme 4.26. Mechanistic Considerations for the Iron-Mediated
ortho-Benzannulation

P— —

OR

(OC)5CI‘
_ , 0
OR (OC)3Fe// H OR 0“
(00),,ch Fe2(CO)9 274 Ph Ph,...g Ph©/OR
__ ——’A ' a '
— °r ”Fe(cob

Ph OR 254 255

181 (OCHFex

275 P"

— ‘

 

 

Carbene complex 274a has not been previously reported and its preparation is
shown in Scheme 4.27. The known 5-phenylpent-2E,4E-dienoic acid 276223 was
converted to the corresponding methyl ester 277 which was subsequently complexed with
iron tricarbonyl to form the previously unknown dienyl iron tricarbonyl complex 278.2'4
Saponification gave unknown acid 279 and then by treatment with oxalyl chloride
afforded the unknown acid chloride 280 in 91% yield over two steps. Then the modified
chromate dianion method224 developed by Hegedus was employed to prepare the

complex 274a in 28% yield.

118

Scheme 4.27. Preparation of the Iron-Coordinated Chromium Carbene

 

 

 

 

Complex 274a
MeOH Fez(CO)9 '
PhWCOZH PhWCOZMe e Ph—//—l—\—002Me
H2804 (cat) toluene. 55 °C Fe(CO);
Ultrasonic
176 277 94% 278 79%
30% aq. KOH
MeOH.THF
OEt
(991519" 1) K2[Cr(CO)5] ' (COCI) '
2
— / = Ph—//|—\LC02CI Ph—m—COfl'l
(OC)3Fe// 2) EtOTf Fe(CO)3 benzene. rt Fe(CO);
274. 28% P" 280 99% 279 92%

With the complex 2748 in hand, its thermolysis at 80 °C in benzene was

examined under an atmosphere of argon and carbon monoxide (Table 4.6). Since iron

tricarbonyl was already installed in the complex, no external source Of iron was added to

the reaction. A 71% overall yield of 254d and 255d was Obtained when the thermolysis

was performed under argon; while under CO, the thermolysis gave a 95% overall yield.

These results indicate that the complex 2748 is a definite candidate as an intermediate in

the ortho-benzannulation of dienyl carbene complexes (Scheme 4.26).

Table 4.6. Thermolysis of the Iron-Coordinated Carbene Complex 274a.a

OEt

 

 

 

(OC)sCr H 0 OE OH
__ , 1atm CO orAr A PW“ t + Ph OEt
(OC)3Fe// ' a
ph "Fe(cO)3

2148 254d 255d
Entry Additive Solvent Temp, °C Ar/CO Time, h Yield, %
1 - - - benzene 80 Ar 2 71 (4:1)b
2 - - - benzene 80 CO 6 95 (6:1)

 

a) Both reactions were carried out at 0.02 M in 274a.

b) Ratios of 254d/255d in crude mixtures.

119

The fact that the iron tricarbonyl coordinated chromium carbene complex 274 will
thermally undergo conversion to the ortho-benzannulated product does not exclude the
possibility that the iron carbene complex 275 is an intermediate in this reaction.
However, the reactions of iron tetracarbonyl carbene complexes with alkynes normally
do not produce phenols. Furans or pyrones are more typical products from these
reaction.‘70 There has been only one report of the formation of a p-alkoxy phenol and this
was from the reaction of the phenyl (ethoxy) tetracarbonyl iron carbene complex with
dimethyl acetylenedicarboxylate.1703 In related chemistry, it has been reported that
vinylketene complexes Of iron can react with alkynes to form benzannulation
productsm‘226 However, whether o-alkoxy phenols can be generated from dienyl iron
carbene complexes of the type 275 remains unknown.

Attempts were made to generate the iron carbene complex 275a from the
corresponding acid chloride 281 with Collman’s reagent — disodium
tetracarbonylferrate.227 This approach was attempted under three different conditions (a-c
in Scheme 4.28), which included variations in the temperature, the manner of addition,
and the ethylating reagent;228 however, in all cases, none Of the desired complex 2758
was isolated. An unexpected iron complex was obtained in each case and its structure
was determined to be the diiron complex 282, which presumably resulted from the
acylation of the initial adduct from the acid chloride 281 and Na2[Fe(CO)4] with the acid
chloride 281. A couple of related diiron complexes have been reported by Watanabe and
coworkers in their efforts to synthesize a,B-unsaturated iron carbene complexes.229 The
yield from the reaction under the conditions Shown in (a) was 25%, while the yields for

(b) and (c) were not calculated.

120

Scheme 4.28. Attempted Preparation of the Dienyl Iron Complex 275a

 

 

1 N [F co ]THF 08 Ph
ph ) 82 e( )4. (OO).Fe _
WCOZCI X" _ __
2) Et3OBF4 or EtOTf _
O
281 275: Ph

(OC)3Fe .
(a) 1) Na21Fe(CO)41. THF, -78 °c to 11. 8 11; 2) £1308F4. H20 (degassed). 0 °C, 1 11.

(b) 1) Na2[Fe(CO)4]. THF. —78 °c to rt, 5 11; 2) moan. CHZCIZ, 0 °C. 1 11. (99’3“
(c) 1) Slow addition 01281 in THF to Na2[Fe(CO)4] in THF at r1 and stirred for 2 11;
2) EtOTf, ether/HMPA.-78 °c to rt.

 

 

 

 

The aldol condensation of the methyl ethoxy iron carbene complex 283 with
cinnamaldehyde should provide direct access to the dienyl iron complex 257a. It was
curious to find that there were no known examples of the aldol reaction of iron carbene
complexes in the literature. The methyl ethoxy iron carbene complex 283 was prepared
according to literature procedure (Scheme 4.29).228a It is worthy to note that iron carbene
complexes are normally prepared as their ethoxy complexes rather than methoxy analogs.
The reason for this is that the tetracarbonyl iron acylate intermedate 283a can alkylate
either on oxygen or on iron. Apparently, the more hindered ethyl substituted
electrophiles, such as ethyl fluorosulfonate, give a much higher proportion of alkylation
on oxygen than do methyl electophiles.228“‘ The aldol reaction Of 283 with
cinnamaldehyde gave the ketene complex 275b in 33% yield and none of the iron
complex 275a was isolated (Scheme 4.29). It is clear that the dienyl iron carbene
complex 275a was not stable and underwent spontaneous insertion of a carbon monoxide

to generate the previously unkown ketene complex 275b.m‘"230

121

Scheme 4.29. Preparation of the Iron Complexed Ketene 275b

O - MOOSOZF

(OO).Fe=(

2831

i

 

Fe(CO)5

 

 

 

EtOSOzF or EtOTf
EtZOIHMPA
OE, o-c OEt
OEt 1)n-BuLi.ether.-78°C (OC)4Fe ' /’
(OO),Fe=’\ e _ (ochre /
2) Cinnamaldehyde. __
CHZCIZ. -78 to 0 °c
283 27511 P“ 27511 /
33% Ph

While the carbene complex 275a is not stable and isomerizes to the ketene
complex 275b, the ketene complex 275b will in turn isomerize to the cyclohexadienone
complex 254d when heated at 80 °C in benzene. Thermolysis either under argon or under
CO gave the desired dienone complex 254d and the phenol 255d in nearly quantative
overall yields. Thus it appears that the iron-mediated ortho-benzannulation of dienyl
chromium carbene complexes could also involve the iron carbene complex 275 resulting .
from a transmetalation from the chromium complex 181 (Scheme 4.26).

Table 4.7. Thermolysis of the Ketene Complex 275b.a

0E1 O

 

0:0 , H OEt OH
1 Ar . P11 E
(093“? 8"" CO” = ”w * (firm
‘8
/ Fe(CO)3
27511 ph 254d 255d

 

Entry Additive Solvent Temp, °C Ar/CO Time, h Yield, %
1 - - - benzene 80 co 12 96 (3:1)b
2 - - - benzene 80 Ar 22 99 (8:1)

 

 

8) Both reactions were carried out at 0.02 M in 275b.

b) Ratios Of 254d/255d in crude mixtures.

Given that the experiments described above suggest that either the 114-dienyl iron

complex 274 or the nl-iron carbene complex 275 could be an intermediate in the reaction

122

(Scheme 4.26), it was decided to stop the reaction early to look for evidence of the
presence of either 274 or 275a or 275b. A sample of 181d was heated at 80 °C with one
equivalent of F 62(CO)9 for only 3 hours, but the NMR spectrum of the crude reaction
mixture showed only the starting carbene complex 181d, the dienone complex 254d and
the phenol 255d (in a ratio of about 1:10:1). NO evidence for the presence of either
complex 274a or 275b was Obtained. It was considered that a lower temperature might
help because the conversion of the intermediate 274a or 275b to the final products may
be faster than the starting material. In the event, a sample of 181d was heated at 60 °C
for 9 hours and then the reaction flask was placed in an ice-bath and the solvent was
removed on high vacuum. Unfortunately, only the starting material and the final products
were observed in the 1H NMR spectrum of the crude reaction mixture (in a ratio of about
5:20;] for 181d/254d/255d).

Scheme 4.30. Attempted Detection of Possible Intermediates

OEt OE!
OEt F62(CO)9 0:0
(00) Cr ,
(OC)5C1' ....13ET.€9....- 5 _ / or (OC)3Fe//
_ _ be1nzoéne ? (OC)3Fe//

Ph P11 /
181d 2748 275b P11
Given the failure to detect intermediates 274a and 275b in the crude reaction
mixtures that were obtained by stopping the reaction short Of completion, it was then
decided to follow the reaction by 1H NMR. Three reactions were carried out, each
having one of the three complexes 181d, 274a and 275b in toluene-d3 under an
atmosphere of carbon monoxide (Scheme 4.31). The reaction of 181d was performed in
the presence of one equivalent of diiron nonacarbonyl in an effort to detect 274a and/or

275b. The thermolysis of 274a was carried out to see if 275b could be Observed. Finally,

the thermolysis of 275b was monitored to probe for intermediates on the way to 254d.

123

For each of the three experiments, the temperature was set at 80 °C because the reaction
Of 181d seemed to be too slow at lower temperatures (e.g. 40 °C, 60 °C and 70 °C). The
lH NMR spectra were taken every 20—30 minutes for at least 3 hours or until all of the
starting material was gone. The thermolysis of 275b was complete within a half hour,
which was much faster than the reactions of 274a and 181d (about 20% and 5%
conversions, respectively, after a half hour). Unfortunately, in each case, only the starting
material and the final products 254d and 255d were observed, and none Of the possible
intermediates were detected. It is reasonable to rationalize that, for the reaction of 181d,
either or both of the complexes 274a and 275b are formed gradually in small amounts
under the reaction conditions, and that the conversion to the final products is fast,
preventing their detection. At this point, both intermediates 274a and 275b must be
considered as possible intermediates on the pathway.

Scheme 4.31. Attempted In-situ Detection of Possible Intermediates

 

F82(CO)9
OEt CO. toluene-03 061 H 0 OH
(OC)SCr so °c _ (OC)SCr . OEt Ph OEt
_ 7 v — —. Ph“" 0 +
— (OC)3Fe//
Ph Fe(cO)3
181d 274: Ph 2541! 255d
?
F82(CO)9 7
CO. toluene-da OEt
80 °c O=C ,
(OC)3Fe//
/
27511 P11

The key transformation that would be required for the formation of iron carbene
complex 275 from the chromium carbene complex 181 is the transmetalation of the latter
with an iron tetracarbonyl fragment. The transfer of the carbene ligand from group 6

Fischer carbene complexes to other metals has been an active area Of interest.209 The first

124

known example involves the reaction Of a molybdenum carbene complex with
photochemically generated F e(CO)4 to produce an iron carbene complex,231 however, to
the best Of our knowledge, there are no known examples Of the transfer of a carbene
ligand from chromium to iron.

In an effort to demonstrate that a carbene ligand can be transferred from
chromium to iron, the chromium carbene complex 284 was heated in benzene at 80 °C
under 1 atm CO with one equivalent of Fe2(CO)9. After 30 hours, the iron carbene
complex 285 was isolated in 20% yield with a 28% recovery of 284 (Scheme 4.32). A
significant amount of ethyl benzoate was also observed, presumably resulting from the
oxidation Of the unstable iron complex 285. This result demonstrates for the first time
that the direct carbene ligand transfer from chromium to iron can occur. This of course
does not mean that the dienyl complex 274 cannot be an intermediate in the reaction.

Scheme 4.32. Direct Carbene Ligand Transfer from Chromium to Iron

 

05* Fence). (1 ca) 051
(OC)5Cr=( : (OC)4Fe=( + 234
Ph 1 atm CO. benzene P"

284 80 °C. 30 h 285 20% 28%

Based on the above mechanistic studies, a tentative mechanism has been proposed
for the thermal ortho-benzannulation of trans-afi-dienyl carbene complexes (Scheme
4.33). Complex 181d could react with an Fe(CO); fragment to give 274a (path A) or
undergo transmetalation with an Fe(CO)4 fragment to give the carbene complex 275a
(path B). The resulting complex 274a may possibly go on to form the ketene complex
286 which could lose chromium to give the ketene complex 275b. Alternatively, the bi-
metallic complex 2748 could lose chromium via the formation of the nl,n3-vinyl iron

carbene complex 287 which upon CO insertion would give the vinyl ketene complex

125

275b. The conversion Of 275a to the vinyl ketene complex 275b may be a one-step
process involving simultaneous coordination of the double bond and CO insertion
(Scheme 4.29) or a two-step process involving the loss of CO to give complex 287 and
then re-incoorporation of CO.232 The isomerization of the trans-01,13-double-bond is
proposed to result from the inter conversion of the r14-vinyl ketene complex 275b (E
configuration) and the nZ-ferracyclopentenone complex 288. A related 114 to n 2
conversion has been Observed for a cobalt vinyl ketene complex.233 The 112-complex 288
should be able to undergo a loss of CO to give either the E or Z isomer of 275b,
depending on the direction of rotation of the styryl group.233 The Z—isomer of 275b, that
is complex 289, would have the geometry that would allow for the electrocyclic ring
closure (ERC) that leads to the Observed product 254d.
Scheme 4.33. Proposed Mechanism for the Iron—Mediated Thermal

ortho-Benzannulation

 

 

 

(OC)4CT
OEt CE! 1 OEt
(OC)5Cr F82(CO)9/CO (OC)5Cr 0:0
— P th A _ " T "
_ a (OC)3Fe“ / Pat" A‘ (0C)3Fe“ /
P11
181d 27“ P11 2“ p11
Fe2(cO)g/col Path 8 1 Path A2 1
OEt OEt o OEt
OEt \\
- co OC Fe _ + co O=C- + co c
(OO),Fe ( )3 \ / ____._______. / \
_ / (°C)3F°‘/ (ochre
Ph / / /
2758 287 27511 288

Ph Ph Ph
L l

 

 

OH H O _ OE!
Ph U051 phi‘woa ERC 0:5
«— .— (OC)3Pe\;
Fe(CO)3 P11
255d 254d 2119

 

 

 

126

4.6 THERMAL ORTHO-BENZANNULATION IN THE ABSENCE OF IRON

4.6.1 Are Photons Really Necessary?

As discussed in Section 4.4.2, some cis-a,[3-dienyl complexes, such as 224
(Scheme 4.19) and 264 (Table 4.4), will undergo the ortho-benzannulation reaction in the
presence of one equivalent of Fe2(CO)9. It was reported that the photochemical reaction
of 224 gave a 93% yield of the phenol 225, and that complex 224 would undergo the
same reaction under strictly thermal conditions giving 225 in 29% when the reaction was
performed in the refluxing heptane.197

In the course of the present study, it was deemed necessary to perform thermal
controls on the ortho-benzannulation Of complex 224 and the results proved to be quite
stunning. As shown in Table 4.8, the thermolysis of 224 in refluxing heptane under argon
gave a 28% yield Of 225, which is essentially the same yield reported by Merlic (29%).197
However, when the reaction was performed under an atmosphere of carbon monoxide,
the phenol product 225 was obtained in 75% yield! Apparently the reported 29% yield
was from a reaction performed under an inert atmosphere]97 The thermolysis of 224 was
then performed at 80 °C in a number of different solvents, including heptane, CH3CN,
THF and benzene. In all cases, the phenol product 225 was obtained in high to excellent
yields from the reactions performed under CO. An astonishing 92% yield was obtained
when benzene was used as the solvent! This was a truly stunning finding! Apparently, the

thermal cyclization of 224 was never optimized at least according to the published

information. However, upon consulting the Ph.D. thesis of D. Xu, it appears that the

127

proper control experiments were done.234 It was reported by Xu that the thermolysis of
224 in THF at 90 °C under 50 psi of CO gave an 80% yield Of 225.

Table 4.8. Thermolysis of 224 in the Absence of an Iron Source*

cacok

b OMe
/ b OMe N° 'Fe' : / O OH
O 1 atm Ar/CO Q

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

224 225
Entry Additive Solvent CO/Ar T 0C Time, h Yield, %
la Ar 100 1.5 28
- - - heptane
1b CO 100 1.5 75
2a ‘ _ _ he tame Ar 80 39 35
211 p CO 80 42 80
3a Ar 80 4 36
- - - CH CN
3b 3 CO 80 8 73
4a Ar 80 5 41
4b ' ‘ ' THF CO 80 16 87
5a benzene Ar 80 36 51
511 CO 80 22 92

 

 

 

 

 

 

 

* Unless otherwise specified, all reactions were carried out at 0.02 M in 224.

So why bother using a photochemical reactor? Are photons really needed for the
ortho-benzannulation Of complexes with a cis-Oi,B-double bond? As was seen for
complex 224, photons are not necessary at all. In addition, complex 264 has been shown
to afford the desired phenol in moderate yields under thermal conditions (Table 4.4).

To probe further as to whether photons are necessary, complex 237 was heated at
90 °C in either THF or benzene under 1 atm of CO, but no evidence for the ortho-
benzannulation product could be Obtained (Scheme 4.34). The reaction was also
performed in THF under 500 psi of CO and under argon, but in each case, a complex
mixture was obtained which did not appear to contain any of the expected product 238,

although Xu reported that a 12% yield of 238 was obtained after complex 237 was heated

128

at 90 °C in THF under 50 psi of CO for 48 hours.“234 It is unclear at this point why
complex 237 failed to give the ortho-benzannulation product under thermolysis, given its
structure similarity with complex 264 which gives the o-methoxy phenol 265 under
thermal conditions (Table 4.4). However, this is clearly an example of an ortho-
benzannulation reaction that requires photolysis since as descired above this reaction will
not go under thermolysis or in the presence Of Fez(CO)9 (Scheme 4.21).

Scheme 4.34. Attempted Thermolysis of 237 without an Iron Source

 

Cr(CO)5 OMe
O OMe NO ’Fe' 0 OH
' x = '0
CO or Ar. 90 °C O
THFor benzene
237 238

The thermolysis Of the biphenyl complex 227 was also examined and the results
are shown in Table 4.9. Under all of the conditions shown in the table, the major product
was either the non-CO cyclized product 270 or the alkene 271 which results from
dimerization of the carbene ligand. These results mirror those of the iron-mediated
reactions of 227 which were presented in Table 4.5. The largest difference between the
two is that the reaction in benzene at 80 °C under 1 atm of CO where the iron—mediated
reaction gives none of the dimer 271 and the thermal reaction gives a 51% yield of this
product. As mentioned earlier in this chapter, the photolysis of complex 227 gives a 90%
yield of the o-methoxy phenanthrol 228 (Scheme 4.8). Xu also reported that thermolysis
of 227 in THF at 90 °C under 50 psi of CO for 7 days gave 270 as the major product
(46% yield), along with 271 (26%) and 228 (15%). Thus, complex 227 apprears to be

another case where photolysis is required to give the ortho-benzannulated product.

129

Table 4.9. Thermolysis of 227 in the Absence of an Iron Source*

Cr(CO)5 OMe We 0
OMe No'Fe' OH OMe
#- - e - ..
O co. T°C O M80 D
227 228 270 271

Entry CO Solvent T, °C Time,d 228,% 270,% 271,%

 

 

 

1 1 atm benzene 80 12 16 26 51
2 1 atm THF 80 16 15 58 6
3 1 atm Toluene 130 0.8 < 1 82 4

4 500 psi Toluene 130 0.5 <2 50 38

 

* Unless Otherwise specified, all reactions were carried out at 0.02 M in 227.

Therefore, it does not seem that all the carbene complexes with a cis-Oi,B-double
bond can undergo the ortho-benzannulation reaction efficiently under thermal conditions.
But what makes the thermal CO insertion process so efficient for the substrate 224 (Table
4.8)? Barluenga claimed that ring strain was responsible for the unusual reactivity Of
complexes Of the type 264 (Scheme 4.13 and Table 4.4).205 Does it mean that ring strain
is the reason why complex 224 reacts thermally? Also, why then does complex 237 not
react thermally (Scheme 4.34) Since it should have the same ring strain as 264?

The oxygen in the tetrahydropyran ring in the type 264 and the unconjugated
double bond in the norbomadienyl ring in 224 can both provide an additional
coordination site for the metal during the reaction. Does this possible extra coordination
facilitate the insertion of carbon monoxide which leads to the formation Of the desired

phenol product?235’236

130

4.6.2 Does Additional Coordination Contribute to the Unusual Reactivity?

To test the idea that the non-conjugated double bond in 224 is coordinating to the
chromium during the reaction resulting an acceleration Of CO insertion, it was decided to
prepare the complex 290. After a few unsuccessful attempts to prepare the vinyl bromide
precursor to the carbene complex 290 that is required for the standard Fischer synthesis,
it was pleasing to find that Wilkinson’s catalyst — (Ph3P)3RhCl — would selectively
reduce complex 224 to give the phenylnorbomylenyl complex 290 in 91% yield (Scheme
4.35).

Scheme 4.35. Selective Reduction of 224 with Wilkinson’s Catalyst

Cr(CO)5 Cf(C0)5

P11 P RhCl. H
’ h OMe ( 3 )3 2 L b OMe
O benzene.rt O

224 290 91%

In the absence of any iron source, the thermolysis with 290 under argon only gave
a trace (~ 2% yield) of the phenol 291, and the major product of the reaction was the
indanone 292 which was isolated in 43% yield (Table 4.10). The indanone 292
presumably results from the hydrolysis of the non-CO cyclized product 293. However,
under an atmosphere of carbon monoxide, the desired phenol 291 was obtained in 78%
yield, along with 9% Of the indanone 292. Thus, in the absence of the unconjugated
double bond in 224, the ortho-benzannulation reaction still goes thermally, which
suggests that the strain Of the ring does in fact contribute to the unusual reactivity in
complexes 224 (Table 4.8) and 264 (Table 4.4). The thermolyses of 290 in the presence

Of one equivalent of Fe2(CO)o were also performed under an atmosphere of argon and

131

carbon monoxide (Entries 3 and 4), which gave results very similar to the thermal

reactions in the absence of an iron source.

Table 4.10. Thermal Reaction of the Carbene Complex 290*

Cr(CO)

b 5 b we ° b O”
0M9 THF, 80 c O OH + a

290 292 293

291

 

Entry Additive Ar/CO Time, h 291, % 292, %

 

1 - - - Ar 7 ~ 2 43
2 - - - CO 48 78 9
3 Fe2(CO)o Ar 12 10 48
4 Fe2(CO)9 CO 48 76 8

 

* Unless otherwise specified, all reactions were carried out at 0.02 M in 290.

4.7 MISCELLANEOUS REACTIONS

4.7.1 Other Attempted Thermal Reactions
Thermal Reactions of Complex 239 in the Presence of Diiron Nonacarbonyl

As shown in Table 4.11, the reaction of complex 239 in the presence of one
equivalent of Fe2(CO)9 only afforded trace amounts of the ortho-benzannulated product
240. The major product of the reactions at 80°C is the vinyl ketene complex 294.237
When the reaction was performed in THF or benzene under 1 atm CO, the ketene
complex 294 was isolated in 82% and 80% yields, respectively. When the reaction was
carried out in a Parr reactor under 500 psi CO, an 83% yield of 294 was isolated and the

phenol 240 was not detected. When the reaction temperature was raised to 100 °C, only

132

traces of both compounds were Observed; and at 130 °C, neither product was detected. So
in all cases, only trace or none of the desired 240 was observed.

Table 4.11. Thermal Reactions of 239 in the Presence of F e2(CO)9*

 

OMe OH M 0
e
(0050' 1 eq. Fe2(CO)9 OMe '
- = 00 + ..\
I/
O F6(CO)3
239 240 294

 

Entry CO Solvent T, °C Time,h 240,% 294,%
l 1 atm THF 80 72 trace 82

 

2 1 atm benzene 80 72 trace 80
3 500 psi benzene 80 24 n.d. 83
4 1 atm benzene 100 72 trace trace
5 1 atm toluene 130 7 n.d. n.d.

 

* Unless otherwise specified, all reactions were carried out at 0.02 M in 239.

The ketene complex 294 was then thermolyzed with the thought that if it were to
cyclize to the naphthol 240 then at least a two-step ortho-benzannulation of complex 239
could be achieved. Unfortunately, thermolysis at 100 °C and 130 °C under 1 atm CO only
gave a trace of the naphthol 240 was Observed in both attempts while all the starting
complex 239 was consumed (Table 4.12). The results further support the fact that the iron
tricarbonyl complexed ketene 294 is unstable at high temperatures and decomposes
instead of cyclizing to form the phenol product. It is not clear why the ketene complex
294 does not cyclize. This could be due to the failure of the double bond to isomerize, or
to the reluctance the final elecrocyclic ring closure to occur since this would result in the
disruption of the aromaticity Of the phenyl ring.238 So the presence of the phenyl ring in

the y,O-unsaturation unit may be the source for the failure of the cyclization in this case.

133

Table 4.12. Attempted Conversion of the Ketene Complex 294 to Phenol 240*

MeO | OH
\ 1 atm CO OMe
8| —---* 00
0 Fe(CO)3 solvent. T °C
294 2“)

 

Entry Solvent T, °C Time, h 240, % yield
1 benzene 100 43 trace
2 toluene 1 30 1 8 trace

 

 

* Both reactions were carried out at 0.02 M in 294.

Phenols with orthoLpara-Disubstituted Heteroatom F unctiong Grows

During the studies on the scope of the iron-mediated ortho-benzannulation, it was
decided to investigate the possibility Of generating phenols with ortho,para-disubstituted
heteroatom functional groups. As shown in Scheme 4.36, the idea was that if complexes
of the type 295 could be prepared with an oxygen or a nitrogen functionality at the [3-
position, an o-methoxy p-alkoxy (or p-amino) phenol 297 would be the eventual product.
The preparation of the carbene complexes need not to be stereoselective since both the cis
and trans isomers of 295 may undergo the ortho-benzannulation reaction.

Scheme 4.36. Generation of o-Methoxy p-Alkoxy (or p-Amino) Phenols

OMe H O OH
(OC)5Cr XRR' F°2(C°)9 OMe P11 OMe
_ --------------- . [anewo .
— *1.
Fe(Cola .
(x = o o, N) P" XRR XRR
295 298 297

Attempts were then made to prepare the [ii-methoxy dienyl complex of the type
295. As Shown in Scheme 4.37, when the cyclopentenyl ethynyl complex 298 was

dissolved in methanol at 0 °C in the presence Of a catalytic amount of sodium methoxide,

134

the cyclopentenone 299 was isolated in 75% yield and none of the desired dienyl carbene
complex 295a was obtained. Apparently, complex 295a in which the carbene carbon
moiety and the y,O-unsaturation are cis disposed did form, but this complex was not
stable and cyclized spontaneously at 0 °C to give the cyclopentadiene 300 which was
then hydrolyzed to form 299.220 This result is consistent with the earlier observation in
the attempted preparation of the acyclic cis,trans-dienyl complex 181f (Scheme 4.20).
Thus, no further efforts were made to prepare complexes of the type 295 for the iron-
mediated thermal ortho-benzannulation reaction.

Scheme 4.37. Attempted Preparation Of the B-Methoxy Dienyl Complex 295a

 

 

OMe o
(OC)5Cr
MeOH
\\ a
NaOMe (cat). 0 °C M80
298 299 75%
l MeOH l
MeO
OMe
(OC)5Cr :
OMe MeO
2959 300

Attem ted Pre aration of o-Amino Phenols

 

As discussed in Section 4.1.2, with the proper tuning of the electron density on
the nitrogen substituents, a,B,y,O-doubly unsaturated amino carbene complexes can
undergo photochemical ortho-benzannulation. Thus, it would be desirable to determine if
dialkyl amino complexes could participate in the iron-mediated ortho-benzannulation
since this would be a potential route to ortho-amino phenols. The dimethylamino dienyl

carbene complex 301 was prepared in 64% yield from the corresponding methoxy

135

complex 181b (Scheme 4.38). After heating 301 at 80 °C in THF for 42 hours, the 1H
NMR spectrum of the crude reaction mixture Showed that a significant amount of the
starting material 301 was still not consumed, along with a new compound X whose
structure has not yet been determined. After heating in benzene for 96 hours, similar
results were Obtained with a little higher ratio of X : 301 (2 : 3 vs. 1 : 2). However, when
the mixture was heated at 110 °C for 48 hours, a complicated mixture was Obtained and
neither X nor 301 was Observed. The unknown compound was initially thought to be 302
based on NMR spectra, except that one non-carbonyl carbon was not located in the 13.C
NMR spectrum. If this structure were true, it would have a molecular weight of 353,
however, the mass spectra indicates a molucule ion peak of 313. Nonetheless, the
consumption of the starting material 301 was found to be extremely sluggish at 80 °C. It
is reasonable to predict that if the electron density on the nitrogen is tuned appropriately
by the introduction Of electron withdrawing groups, at some point the ready formation of
the ortho-benzannulated product will be restored as has been Shown for amino complexes
201

in the benzannulation reaction.

Scheme 4.38. Preparation Of the Amino Complex 301 and Its Thermal Reaction

 

 

 

 

 

OMe o NMez
(OC)5Cr<—\—\ HNMe2/Et20. -78 C (omsmx
Ph Ph
178!) 301 64%
NM82 H O OH
(OC)sCr “2‘00!9 6: NMez + Ph NMe2
_ " Phw“©
— 1atm CO ,9
Ph ’F8(CO)3
301 302 303
Conditions Results
THF. 80 °C, 4211 Unknown X : 301 = 1 :2

Benzene. 80 °C. 96 11 Unknown X : 301 = 2 :3
Toluene, 110 °C. 48 h Complex mixture, NO x or 301

 

 

136

4.7.2 Diastereoselective Reduction of Dienone Complexes

AS demonstrated in earlier sections, the iron-mediated thermal ortho-
benzannulation gives dienone iron tricarbonyl complexes in significant amounts
especially for carbene complexes with an alkyl group on the 6 carbon. If the dienone
complex could be reduced to the corresponding alcohol in a diastereoselective manner,
the resulting alcohol, after removal of iron tricarbonyl, could be a useful intermediate for
further synthetic transformations including acting as a diene in the Diels-Alder reaction.

It was anticipated that the reduction would form syn-304 with high
diastereoselectivity because the reducing reagent would be expected to approach the
dienone complex of the type 254a from the top since both the iron tricarbonyl unit and
the methyl group sit on the bottom of the ring. However, when NaBH4 was used under
different conditions, the best syn/anti ratio of 304 obtained was only about 3.3 : l. The
syn isomer was believed to be the less polar compound since its hydroxy group is
sterically shielded.239 In those cases where bulkier reagents such as NaBHgCN and
NaBH(OAc)3 were used, only the starting material 254a was recovered and neither 304
or 255a was observed. More reactive reagents such as Red-Al and L-Selectride gave the
phenol 255a as either the major or the exclusive product, presumably due to the basicity
in the reaction mixture that effects the tautomerization of the dienone complex 254a.
Worthy of mention is that the pure syn-304 in CDC13 in an NMR tube was partially

converted to anti-304 at room temperature after a couple of days.

137

Table 4.13. Diastereoselective Reduction Of the Dienone Complex 254a

H O H 9“ OH OH
OMe . ? OMe H OMe
H30" Reduc‘m" H30“ + H3C‘ + H3C. : ,OMe
a '51; '5

 

 

11,
Fe(CO)3 F8(CO)3 F8(CO)3
254: syn-304 anti—304 25511
Conditions Results

 

NaBH4 / MeOH, rt, 3 h

304 ~ 60% (syn/anti = 1 : 0.7); 255a (~5%)

 

NaBH4 (in portions) / MeOH, rt, 3 h

Similar as above

 

NaBI-I4 (H20) / MeOH, 0 °C to rt, 1 h

304 (syn/anti = 1 : 0.3); 255a (trace)

 

NaBH4 / MeOH, -78 °C to rt

304 (major, syn/anti = l : 0.3), 25511 (trace)

 

NaBH4 (1 :1 acetone/AcOH)/acetone, 0 °C to rt

254a recovered; NO 304 or 2559 observed

 

NaBH3CN / MeOH, pH = 4 buffer

254a recovered; No 304 or 255a Observed

 

NaBH(OAC)3, ACOH/CHzClz, 24 h

254a recovered; No 304 or 255a observed

 

Red-Al / benzene, 50 °C, 1 h

2558 (major), 304 (trace)

 

L-Selectride, -20 °C to rt, 2 h

 

 

2558 only

 

The low selectivity with NaBH4 was certainly not expected; however, the X-ray
structure of 254a (Figure 4.4) clearly shows that the cyclohexdienone ring is in a twist-
boat-like conformation which bends away from the iron tricarbonyl unit, increasing the
otherwise less likely attacking from the bottom by NaBH4. This may explain why the

formation of anti-304 was not Shut down. Since the reduction of dienone complexes was

not a priority in this study, no further efforts were made tO Optimize this reaction.

138

 

4.8 CONCLUSIONS

Serendipity has been and continues to be an important source of great discoveries
in science. In this chapter, the serendipitous finding and the subsequent development of
the highly novel iron-mediated thermal ortho-benzannulation Of Fischer carbene
complexes are discribed. The first examples of the ortho—benzannulation reaction have
been achieved under thermal conditions in the presence of an iron source. It is the first
time that trans, trans-a,B,y,O-unsaturated Fischer carbene complexes have been employed
successfully for the ortho-benzannulation reaction, which greatly increases the power of
this reaction since many of the trans-substituted complexes can be easily prepared by an
aldol condensation of the methyl carbene complex with an aldehyde or a ketone. The cis-
substituted complexes that had been previously required for the reaction can be difficult
to make unless they are locked into a ring. The first examples of the “ortho-
cyclohexadienone annulation” with 6,6-disubstituted dienyl carbene complexes have also
been illustrated. Furthermore, these trans-(1,13—unsaturated Fischer carbene complexes
undergo thermal ortho-benzannulation only in the presence of an iron source, and they
fail both under thermal conditions in the absence of iron and under photochemical
conditions.

The iron-mediated thermal ortho-benzannulation also worked with some dienyl
carbene complexes having a cis-Oi,B-double bond but failed with others, and the scope for
the cis-a,B-dienyl substrates has not been established. It is believed that the bond lengths
and angles for both double bonds are very important in order for the electrocylic ring
closure (ERC) to occur. Otherwise, even after the ketene intermediate is formed during

the reaction, it could just decompose if the double bonds are not properly aligned or are

139

not in the proper position for ring closure to occur. In addition, since the y,O-unsaturation
and the carbene moiety are cis disposed, it becomes obvious that the insertion of a carbon
monoxide must be fast enough to compete with the direct cyclization in order to shut
down the formation of the indene product.

Mechanistic studies suggest that two pathways are possible to form the dienone
iron tricarbonyl complex and the phenol product. One involves direct transfer of the
carbene ligand from Cr to Fe, and the other involves initial coordination of the iron to the
diene fragment. A tentative mechanism has been proposed for the chromium to iron
transfer process in this iron-assisted conversion of the dienyl chromium carbene
complexes to dienone iron tricarbonyl complexes.

Some important findings were also made during the investigation of the thermal
ortho-benzannulation reaction in the absence of an iron source. It was surprising to find
that thermolysis of the norbomadienyl carbene complex 224 worked efficiently to give
the phenol product and thus no photons are necessary, which clears away the
misinformation about this particular reaction previously presented in the literature. It was
also interesting to find that, contrary to what was claimed in the literature, the reaction of
the complex 264 gave the desired o-methoxy phenol under an atmosphere of carbon
monoxide. However, the thermal reaction in the absence of an iron source only worked
well with a few cis-a,B-dienyl carbene complexes of particular structure types, and the
unusual reactivity is believed to result from the geometric restraints in the substrates

rather than any possible extra coordination Site in the carbene complexes.

140

CHAPTER FIVE

EXPERIMENTAL SECTION

5.1. GENERAL INFORMATION

Unless otherwise indicated, all common reagents and solvents were used as
obtained from commercial suppliers without further purification. Prior to use,
tetrahydrofuran and diethyl ether were distilled from Na/benzophenone; methylene
chloride was distilled from CaHz; benzene and toluene were distilled from sodium, all
under nitrogen. TLC was performed on Silicyle plastic backed TLC plates (TLP-
R10011B-323). Flash chromatography was carried out using 230-400 mesh silica gel.
Routine 1H NMR spectra were recorded on Varian 300 and 500 MHz Spectrometers with
residue chloroform-d (7.24 ppm) as an internal reference. Routine 13C NMR spectra
were recorded on Varian 75 and 125 MHz spectrometers with the central peak of the
residue chloroform-d triplet (77.0 ppm) as an internal reference. Infrared Spectra were
recorded on a Nicolet 42 F TIR spectrometer. Mass spectral data were obtained at the
Michigan State University Mass Spectrometry Facility which is supported, in part, by a
grant (DRR-OO480) from the Biotechnology Research Technology Program, National

Center for Research Resources, National Institutes of Health.

141

5.2. EXPERIMENTAL PROCEDURES AND CHARACTERIZATION DATA FOR

CHAPTER Two

I OMe
E (OC)5CT=:
119 63b

The Preparation of Carbene Complex 14b:

In a 250-mL RBF was placed 60 mL of pentane (dried with 4 A molecular sieves)
and cooled to —78 °C, tBuLi (1.7 M/pentane, 12.35 mL, 21 mmol) was added under an
argon atmosphere. In a separate 100-mL RBF, cyclohexyl iodide 119 (2.10 g, 10 mmol)
was dissolved in 40 mL of ether and then transferred via a cannula to the above tBuLi
solution at —78 °C. The mixture immediately turned milky white and was stirred for 10
min before the cooling bath was removed, and the stirring continued for an additional 0.5
h after the mixture was warmed to room temperature. Then it was cooled down back to
—78 °C and transferred into a 200-mL RBF which contained Cr(CO)5 (2.2 g, 10 mmol)
and 10 mL of ether at -—78 °C. The resulting mixture was stirred for 5 min, and then the
bath was removed and the stirring continued for an additional 1 h after it reached room
temperature. After the solvents were removed on a rotary evaporator, 20 mL of distilled
water and 5 mL of methylene chloride were added, followed by two equivalents of
Meerwein’s salt while stirring (it should become acidic with pH around 2, if not, more
Meerwein’s salt needed to be added). The mixture was stirred for about 20 min and
extracted with CHzClz until the orange-yellow color in the mixture disappeared. The
organic extract was then washed with sat. aq. NaHCO3 (30 mL) and brine (30 mL)

sequentially, dried with MgSO4 and filtered. After concentration, the orange-yellow oil

142

was subject to a silica gel chromatography using straight hexanes as the eluent to give
carbene complex 63b (0.80 g) in 25% yield as a yellow-orange solid.

Spectral data for 63h: mp 52—54 °C. R1- = 0.45 (hexanes); 1H NMR (300 MHz,
CDC13): O 1.02-1.33 (m, 1H), 1.10 (t, J = 12.9 Hz, 2H), 1.24 (t, J = 12.9 Hz, 2H), 1.66-
1.73 (m, 1H), 1.74 (s, 2H), 1.77 (s, 2H), 3.87 (t, J= 11.1 Hz, 1 H), 4.74 (s, 3H); 13C NMR
(75 MHz, CDC13): O 25.64, 25.88, 28.59, 67.93, 71.90, 216.46, 223.30, 366.17; IR
(NaCl): 2936s, 2859m, 2062s, 1919vs, 1453s, 1254s, 1232s cm'l; MS (EI) m/z (%
relative intensity): 318 (M+, 2), 290 (6), 262 (4), 234 (3), 206 (22), 179 (19), 178 (100),
143(14),133(11),131 (22), 129 (15), 81 (17), 80 (20), 52 (63), 41 (12). Anal calcd for

C13H14Cr06: C, 49.06; H, 4.43. Found: C, 48.95; H, 4.33.

02% 0% (00.50%;
120 121 83c

The Preparation of Carbene Complex 63c:
A 100-mL Schlenk flask was charged with graphite powder (0.87 g, 72.7 mmol,
19.5 eq.) and heated in an Oil bath to 160 °C under vacuum. Freshly cut potassium metal
(0.35 g, 9.0 mmol, 2.42 eq.) was rinsed in dry hexanes and dried before being added
portion-wise to the heated flask while stirring and under a continuous flow of argon.
(Note: It is important that either good stirring and/or occasional manual Shaking of the
flask is maintained throughout the heating process to ensure complete intercalation of the
potassium metal into the graphite layers. It is also desirable to Open the flask under a
flow of argon and scrape the melted potassium Off the wall of the flask and the surface of

the stir bar.) The solid mixture was kept at 160 °C with stirring under argon atmosphere

143

 

until the color of the powder turned from black to bronze, indicative of the formation of
CsK. Total heating time once the powder has turned bronze was about 35 min. The solid
was then allowed to cool to room temperature and 20 mL of dry THF was added under a
positive flow of argon. The bronze suspension was cooled to —78 °C and Cr(CO); (0.90
g, 4.1 mmol, 1.1 eq.) was added in one portion. The flask was closed under argon and
the dark suspension was allowed to warm to 0 °C and stirred at this temperature for 1.5
h, during which time the color turned from bronze-black to a thick slurry of silvery green
in a yellow-green solution. (It was ready to use immediately or could be stored in freezer
for days.)

After cooling back down to —78 °C, a solution of acid chloride 121 (0.60 g, 3.7
mmol, 1.0 eq, freshly prepared by refluxing 0.53 g of acid 120 and 2.7 g of thionyl
chloride in 10 mL Of benzene for 2 h and concentrated under reduced pressure) dissolved
in 10 ml THF was added slowly and the reaction mixture was then gradually warmed to
room temperature and stirred at this temperature for at least 3 h. The black suspension
was then filtered on a sufficiently large coarse fritted funnel packed with Celite, rinsed
with either dry THF or ether. The solvent of the filtrate was then removed on a rotary
evaporator and the residue was placed on high vacuum for a couple of minutes. The
resulting potassium acylate was dissolved in a minimum Of water and 5 ml of CHzClz,
and was then treated portion-wise with Meerwein’s reagent, Me3OBF4 (about 1.09 g, 7.4
mol, 2 eq.), until the reaction mixture was acidic (pH ~2). The mixture was stirred at
room temperature for 20-30 minutes and extracted with CH2C12 until all of the organge-
yellow color was removed from the aqueous layer. The organic extract was washed

sequentially with saturated aqueous NaHCO3 solution and brine, dried with MgSO4,

144

filtered and concentrated under reduced pressure. Silica gel column chromatography (5%
EtOAc/hexanes) afforded complex 630 (0.94 g) in 76% yield as an orange oil, which
solidified to an orange-yellow solid upon standing in a freezer at —20 °C.

Spectral data for 63c: Rf = 0.55 (10% EtOAc/hexanes); 1H NMR (500 MHz,
CDC13): O 1.11 (s, 3H), 1.24-28 (m, 1H), 1.48-1.55 (m, 5H), 1.62-1.65 (m, 2H), 1.92 (p, J
= 6.4 Hz, 2H), 4.87 (s, 3H); l3C NMR (125 MHz, CDCl3): O 22.80, 23.10, 25.79, 36.20,
62.51, 68.61, 217.12, 222.66, 374.71; IR (NaCl): 2934m, 20585, l916vs, 1453m, 12485
cm"; MS (EI) m/z (% relative intensity): 332 (M+, 0.4), 304 (4), 276 (9), 248 (5), 220
(17), 193 (13), 192 (100), 189 (13), 175 (12), 158 (30), 145 (15) 143 (38), 95 (35), 82
(16), 52 (62), 41 (1 1). Anal calcd for C14H16CrO6: C, 50.61; H, 4.85. Found: C, 50.86; H,

4.82.

OMe
' @0501
g: 0:: O
o o K/O
122

124 83d

The Preparation of Carbene Complex 63d.

TO a solution of sodium iodide (8.99 g, 60 mmol) and 2-cyclohexen-l-one 122
(4.81 g, 50 mmol) in 120 mL acetonitrile was rapidly added TMSCl (6.52g, 60 mol) at
room temperature with rigorous stirring under an argon atmosphere. The resulting
suspension (yellow precipitate and red-brown liquid) was stirred for an hour before
ethylene glycol (3.72 g, 60 mmol) was added rapidly and the mixture was stirred for 20
min. Acetonitrile was then removed on a rotary evaporator and 150 mL of pentane and

50 mL of saturated aqueous NaHCO3 solution were added. The mixture was filtered and

145

the red organic layer was washed with 50 mL of brine. dried with MgSO4 and filtered
through a plug of neutral alumina gel and rinsed with hexanes. After removal of the
volatiles, the analytically pure cyclohexyl iodide 124 (10.94 g) was obtained in 82% yield
over two steps.

Spectral data for 124:R1~ = 0.58 (20% EtOAc/hexanes); 'H NMR (500 MHz,
CDCl3): 6 1.53-1.67 (m, 3H), 1.79-1.91 (m, 2H), 2.14 (t, J= 12.6 Hz, 1H), 2.34 (dm, J=
12.6 Hz, 1H), 2.48 (dp, J = 12.6, 2.1 Hz, 1H), 3.93-3.98 (m, 4H), 4.22 (tt, J= 12.6, 4.2
Hz, 1 H). The spectral data are consistent with that reported by Jiang.123

In a 100-mL RBF was placed 30 mL pentane (dried with 4 A molecular sieve)
and cooled down to —78 °C, tBuLi ( 1.7 M/pentane, 6.6 mL, 11.1 mmol) was added under
an argon atmosphere. In a separate 50-mL RBF, cyclohexyl iodide 124 (1.42 g, 5.3
mmol) was dissolved in 20 mL of ether and transferred to the above tBuLi solution via a
cannula at —78 °C. The mixture immediately turned milky white and was stirred for 15
min. The cooling bath was then removed and the solution was Slowly warmed to room
temperature and stirred for an additional an hour at this temperature. Then the solution
was cooled down back to —78 °C and transferred via cannula into a 200 m1 RBF that
contained Cr(CO)6 (1.17 g, 5.3 mmol) in 10 mL of ether, also at —78 °C. The resultant
mixture was stirred for half hour before the cold bath was removed and stirring continued
for 1.5 hours at room temperature. After removal of the volatiles, 20 mL of distilled
water and 5 mL of methylene chloride were added, followed by two equivalents of
Meerwein’s salt (it Should become acidic with pH ~ 2, if not, more Meerwein’s salt
needed to be added). The mixture was stirred for 20 — 30 minutes and the organic layer

was separated and further extraction of the aqueous phase with CH2C12 was performed

146

until the yellow color disappeared in the organic layer. The combined organic extracts
were washed with 10 mL of sat. aq. NaHCO3 solution and 10 mL of brine sequentially,
dried with MgSO.1 and filtered. After concentration, the orange-yellow Oil was subject to
silica gel chromatography using 5-10% EtOAc/hexanes as the eluent to give carbene
complex 63d (1.42 g) in 71% yield as an orange solid.

Spectral data for 63d: mp = 47—49 °C; R1 = 0.30 (10% EtOAc/hexanes); 'H NMR
(500 MHz, CDCl;;): 0 1.07 (q, J = 12.6 Hz, 1H), 1.27 (t, J = 11.9 Hz, 1H), 1.40-1.50 (m,
1H), 1.57 (q, J= 13.5 Hz, 1 H), 1.69-1.79 (m, 4 H), 3.90-3.92 (m, 4 H), 4.21 (t, J= 11.8
Hz, 1H), 4.74 (s, 3H); 13C NMR (125 MHz, CDC13): O 23.06, 27.71, 35.30, 36.43, 64.52,
64.57, 68.16, 68.64, 108.62, 216.47, 223.38, 364.56; IR (KBr): 2958m, 2885w, 2061s,
1921vs, 1452m, 1259m, 1232m cm"; MS (EI) m/z (% relative intensity): 376 (M+, 23),
292 (27), 265 (15), 264 (56), 237 (28), 236 (100), 204(22), 176 (17), 162 (54), 160 (29),
141 (21), 99 (38), 93 (19), 80 (18), 52 (52); HRMS (EI) calcd for C15H16Cl‘03 m/z

376.0250, found 376.0250.

[‘35

94
The Preparation of Dienyne 94.
TO isopropenyl acetylene 97 (1.21 mL, 12.6 mmol) in 20 mL THF was added
nBuLi/hexanes (2.29 M, 12.1 mL, 27.7 mmol) at —78 °C under argon atmosphere,
followed by freshly prepared KOtBu solution [from KH (1.21 g, 30.1 mmol) and tBuOH

(2.05 g, 27.7 mmol) in 20 mL THF]. The yellow mixture was stirred for 30 minutes

147

before warming up to 0 °C for 15 minutes. The reaction was then brought down to —30
°C and a solution of anhydrous LiBr (2.41 g, 12.7 mmol) in 10 mL THF was added
Slowly. After 20 minutes the yellow-orange solution was cooled to -78 °C and prenyl
bromide 98 (1.46 mL, 12.6 mmol) was added dropwise over 10 minutes. The mixture
was allowed to warm to room temperature and after an hour, 15 mL of sat. aq. NHaCl and
30 mL of pentane was added. The organic phase was separated and washed sequentially
with water and brine, dried with MgSOa. Concentration gave the crude dienyne which
was further purified by column chromatography using pentane as the eluent to afford
dienyne 94 (1.28 g, 76% yield) as a clear colorless liquid.

Spectral data for 94: Rf = 0.50 (hexanes); 1H NMR (300 MHz, CDCl;): 6 1.60 (s,
3H), 1.67 (s, 3H), 2.14-2.22 (m, 4H), 2.87 (s, 1H), 5.05-5.10 (m, 1H), 5.28 (s, 1H), 5.40
(s, 1H); 13C NMR (75 MHz, CDC13): O 17.73, 25.69, 26.55, 37.11, 76.85, 84.10, 122.83,
123.12, 130.50, 132.38; IR (KBr): 3286s, 2966s, 2924s, 2856m, 2362s, 2343m, 1458m,
1377m cm'l; MS (EI) m/z (% relative intensity): 134 (M+, 7), 133 (89), 119 (19), 101
(25), 99 (100), 98 (36), 97 (97), 96 (43), 95 (58), 91 (36), 89 (29), 87 (26), 82 (23), 69
(34), 57(41), 56 (38), 50 (25); HRMS (El) calcd for C10H14 m/z 134.1096, found

134.1091.

148

General Procedure for the Synthesis of Bicycloheptanones 99 and Cyclobutenones
100: Illustrated for 99a and 100a.

O
OMe OMe
(CO),Cr=(OMe + E e ., /
CH3 CH3 CH3
1 o \
63a
94 99a 1008

A lO-mL or 100-mL flask with a threaded Teflon high-vacuum stop-cock was

 

charged with carbene complex 63a (125 mg, 0.50 mmol), dienyne 94 (74 mg, 0.55 mmol)
and 5 mL or 50 mL of CH3CN to make a 0.1 or 0.01 M solution in 63a. The solution was
deoxygenated by the freeze-thaw method (—196/25 °C, 3 cycles), back-filled with argon
at room temperature, sealed and then heated at 45 °C for 24 or 48 hours. Then the
mixture was transferred to a lOO-mL round bottom flask and acetonitrile was removed
under reduced pressure. The residue was dissolved in 20 mL CHzClz and filtered through
a pad of Celite to get rid of green chromium complexes. The yellowish residue was then
subjected to silica gel chromatography (5—10% EtOAc/hexanes) to isolate 99a and 100a.
Careful chromatography was able to provide pure samples of 99aE, 100aE and 100aZ.
The assignment of E/Z isomers of 100a was made by the difference in chemical shift of
the enol ether carbons by the method of Strobel.127 Since 99a was obtained as a Single
isomer, it could not be assigned by Strobel’s rule, presumably in the E-form according to
our study on related compounds. ‘ ‘9

Bicycloheptanone 99aE: 44—47% yield. White crystals, mp 61—62 °C. Rf = 0.35
(10% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3): 1.08 (s, 3 H), 1.10 (s, 3 H), 1.74 (s,
3 H), 2.05-2.20 (m, 2 H), 2.28-2.37 (m, 1 H), 2.46 (dd, J= 16.5, 8.0 Hz, 1 H), 2.68 (dd, J

= 4.8, 1.5 Hz, 1 H), 3.55 (s, 3 H), 4.23 (s, 1 H), 4.80 (s, 1 H), 4.87 (s, 1 H); 13C NMR

149

(125 MHz, CDCl3): 17.9, 19.2, 24.6, 25.1, 27.4, 29.7, 54.5, 63.0, 76.1, 89.7, 109.3, 150.4,

156.6, 210.2; IR (NaCl): 2953s, 17773, 16555, 12295 cm-l; MS (EI) m/z (relative
intensity) 220 (M+, 45), 205 (20), 192 (95), 177 (100), 161 (34), 145 (75), 135 (45), 110
(30), 105 (45), 91 (40), 77 (25), 69 (25), 59 (20), 55 (2); Anal calcd for C14H2002: C,
76.33; H, 9.15. Found: C, 76.47; H, 9.52.

Cyclobutenone 100aE: 20—24% yield. Colorless viscous oil. Rf = 0.32 (10%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3): 1.63 (s, 3 H), 1.70 (s, 3 H), 2.15 (s, 3 H),
2.29 (q, J= 7.5 Hz, 2 H), 2.58 (t, J= 7.5 Hz, 2 H), 3.11 (s, 2 H), 3.56 (S, 3 H), 4.85 (s, 1
H), 5.11 (t, J: 7.2 Hz, 1 H); 13C NMR (125 MHz, CDC13): 17.8, 19.0, 24.8, 25.7, 29.7,

49.2, 54.9, 87.4 (enol ether), 122.8, 133.1, 143.4, 160.9 (enol ether), 167.2, 187.4; IR

(NaCl): 2923s, 1754s, 1657s, 1227s cm-l; MS (EI) m/z (relative intensity): 220 (W, 9),
205(9), 189(12),177(15),152(9),149(13),147(13),145(35),123(19),119(22),109
(27), 108 (21), 105 (33), 91 (41), 79 (22), 77 (27), 69 (16), 65 (15) 53 (15), 43(100), 41
(65); Anal calcd for C14H2002: C, 76.33; H, 9.15. Found: C, 76.01; H, 9.48.
Cyclobutenone 100aZ: 10—12% yield, Colorless viscous oil. Rf = 0.14 (10%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3): 1.64 (s, 3 H), 1.70 (s, 3 H), 1.96 (s, 3 H),
2.27 (q, J= 7.5 Hz, 2 H), 2.68 (t, J= 7.5 Hz, 2 H), 3.10 (s, 2 H), 3.68 (s, 3 H), 4.80 (s, l
H), 5.11 (m, 1 H); 13C NMR (125 MHz, CDCl3): 17.5, 17.7, 25.1, 25.6, 31.1, 49.6, 55.2,

93.2 (enol ether), 123.2, 132.6, 141.6, 156.3 (enol ether), 168.2, 188.5; IR (NaCl): 2923s,

17613, 1653m, 1658m, 1223m, 1086m ch; MS (EI) m/z (relative intensity) 220 (M+,
55), 205 (20), 189 (20), 179 (30), 163 (15), 145 (22), 135 (22), 123 (20), 117 (10), 109
(30), 89 (65), 84 (63), 69 (100), 77 (15), 65 (10), 59 (24), 55 (27); Anal calcd for

C14HzoOz: C, 76.33; H, 9.15. Found: C, 76.30; H, 9.36.

150

 

OMe
(OC)5CT + \\
|
631) 94

Bicycloheptanone 99b and C yclobutenone I 00b.

0
OMe OMe
‘ + /
° \
9911

100b

Following the general procedure for the preparation of 99a and 100a, the reaction
of complex 63b (148 mg, 0.46 mmol) and dienyne 94 (68 mg, 0.51 mmol) in 5 mL of
CH3CN at 45 °C for 24 h gave 99bE (60 mg, 45% yield) as a white solid as a Single
isomer, 100bE (40 mg, 30% yield) as a yellowish oil, and 100bZ (15 mg, 11% yield) as a
yellowish oil.

Spectral data for 99bE: mp 61—63 °C. Rf = 0.50 (10% EtOAc/hexanes); 1H NMR
(500 MHz, CDC13): O 1.04 (s, 3H), 1.07 (S, 3H), 1.08-1.28 (m, 4H), 1.34-1.46 (m, 2H),
1.56-1.71 (m, 4H), 1.98-2.12 (m, 3H), 2.31-2.41 (m, 2H), 2.63 (dd, J= 2.4, 1.2 Hz, 1H),
3.51 (s, 3H), 4.02 (brs, 1H), 4.81 (s, 1H), 4.84 (s, 1H); 13C NMR (125 MHz, CDCl3)I O
17.72, 24.57, 25.32, 26.14, 26.41, 26.49, 30.73, 37.95, 41.41, 54.52, 62.80, 76.30, 88.07,
109.13, 151.88, 165.09, 209.50; IR (NaCl): 2934s, 2853s, 1779s, 1647s, 1451m, 1211s
cm"; MS (EI) m/z (% relative intensity): 288 (M+, 13), 260 (90), 245 (51), 217 (100), 205
(21), 204 (30), 177 (37), 176 (44), 163 (20), 144 (32), 135 (27), 131 (25), 117 (23), 104
(36), 91 (51), 83 (75), 77 (36), 55 (60), 41 (69). Anal calcd for C19H23021 C, 79.12; H,
9.78. Found: C, 79.16; H, 9.86.

Spectral data for 100bE: R1 = 0.47 (10% EtOAc/hexanes); 'H NMR (300 MHz,
CDCl3): O 1.02-1.49 (m, 8H), 1.63 (s, 3H), 1.69 (S, 3H), 1.72-1.74 (m, 2H), 2.03-2.09 (m,

1H), 2.27 (q, J: 6.9 Hz, 2 H), 2.57 (t, J= 7.5 Hz, 2H), 3.09 (S, 2H), 3.54 (s, 3H), 4.68 (S,

151

1H), 5.11 (t, J= 7.2 Hz, 1H); 13,C NMR (125 MHz, CDCl;): 6 17.75, 24.87, 25.67, 26.01,
26.16, 29.66, 30.46, 40.81, 49.26, 54.93, 85.38, 122.94, 133.04, 143.52, 166.81, 168.26,
187.16; IR (NaCl): 2928s, 2853s, 1754s, 1647s, 1451m, 12158 cm"; MS (EI) m/z (%
relative intensity): 288 (M+, 7), 260 (12), 245 (16), 217 (27), 205 (27), 177 (37), 145 (32),
105 (31), 91 (51), 83 (56), 79 (26), 69 (29), 55 (73), 41 (100). Anal calcd for C19H2302:
C, 79.12; H, 9.78. Found: C, 78.94; H, 9.77.

Spectral data for 100bZ: Rf = 0.35 (10% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3): O 1.14-1.27 (m, 8H), 1.60 (s, 3H), 1.67 (S, 3H), 1.75-1.85 (m, 2H), 2.15 (t, J=
11.5 Hz, 1H), 2.25 (q, J= 7.2 Hz, 2 H), 2.63 (t, J= 7.5 Hz, 2H), 3.09 (s, 2H), 3.61 (s,
3H), 4.89 (s, 1H), 5.09 (t, J = 7.2 Hz 1H). Compound 100bZ was easily isomerized to
100bE in CDC]; in the NMR tube, so other spectra data were not obtained. The

assignment of 100bZ was based on the 1H NMR spectrum and by comparison to the

(D
OMe OMe
\ + /
C)
\
99c

100c

related compounds that we have studied. 1 19

("We
(OC)5CT + Q
I
53c 94

Bicycloheptanone 99c and Cyclobutenone 100c.

 

Following the general procedure for the preparation of 99a and 100a, the reaction
of complex 63c (137 mg, 0.41 mmol) and dienyne 94 (61 mg, 0.45 mmol) in 5 mL of
CH3CN at 45 °C for 24 h gave yellowish oily 99cE (46 mg, 39 % yield) as a single
isomer and colorless Oily 100c (43 mg, 36% yield) as a single isomer whose

stereochemistry was not determined.

152

Spectral data for 99cE: Rf = 0.40 (10% EtOAc/hexanes); 'H NMR (300 MHz,
CDCl3): O 1.07 (s, 3H), 1.08 (S, 3H), 1.09 (s, 3H), 1.23-1.47 (m, 8H), 1.71-1.76 (m, 2H),
2.06-2.22 (m, 2H), 2.26-2.38 (m, 1H), 2.41-2.46 (m, 1H), 2.63 (dd, J = 2.4, 2.1 Hz, 1H),
3.59 (s, 3H), 4.46 (s, 1H), 4.84 (s, 1H), 4.89 (s, 1H); l3C NMR (125 MHz, CDCl3): O
17.84, 22.67, 22.73, 24.67, 25.25, 26.39, 27.33, 35.99, 36.50, 41.11, 60.48, 62.89, 77.52,
99.25, 109.76, 149.81, 165.60, 209.56; IR (NaCl): 29305, 2855s, 1779s, 1642s, 1450m,
1103m cm"; MS (EI) m/z (% relative intensity): 302 (M, 23), 247 (14), 205 (73), 191
(33), 177 (22), 163 (26), 145 (81), 139 (100), 105 (42), 97 (36), 91 (44), 55(68), 41 (45).
Anal calcd for C20H3002: C, 79.42; H, 10.00. Found: C, 79.10; H, 9.92.

Spectral data for 100c: Rf = 0.28 (10% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13): O 1.05 (s, 3H), 1.22-1.46 (m, 8H), 1.60 (s, 3H), 1.66 (S, 3H), 1.68-1.72 (m, 2H),
2.27 (q, J= 7.5 Hz, 2 H), 2.60 (t, J = 7.5 Hz, 2H), 3.12 (s, 2H), 3.59 (s, 3H), 5.06-5.10
(m, 1H), 5.09 (S, 1H); 13C NMR (125 MHz, CDCl;): 5 17.71, 22.41, 24.76, 25.68, 26.27,
30.64, 35.45, 41.02, 49.58, 61.21, 61.24, 95.02, 122.89, 133.07, 143.06, 170.67, 170.74,
188.05; IR (NaCl): 2928s, 28538, 17618, 1647s, 1449m, 1100m cm"; MS (EI) m/z (%
relative intensity): 302 (W, 31), 205 (100), 148 (54), 145 (22), 105 (18), 97 (25), 91 (24),
55 (47), 41 (27). Anal calcd for C20H3002: C, 79.42; H, 10.00. Found: C, 79.15; H,

10.14.

 

K/O

53d 94

O
OMe OMe
(CclsCr a H /°Me
+ \\ +
O
O I O \
K/O LO
9M! 1mm

Bicycloheptanone 99d and C yclobutenone 100d.

153

Following the general procedure for the preparation Of 99a and 100a, except that,
before chromatography the CHzClz solution was stirred at room temperature under CO
overnight and then filtered and concentrated. The reaction of complex 63d (376 mg, 1.0
mmol) and dienyne 94 (174 mg, 1.3 mmol) in 10 mL of CH3CN at 45 °C for 40 h gave
99d (212 mg, 64 % yield), 100dE (58 mg, 17 % yield) and 100dZ (24 mg, 7 % yield), all
of which are colorless oils. Compound 99d existed as a mixture of two inseparable
isomers, tentatively assigned as two epimers, in about 1:1 ratio based on the integrations
of the relative vinyl proton peaks, the only three partially overlapping peaks of the two
isomers (singlets at 4.07(br), 4.78, 4.84, and 4.13(br), 4.80, 4.86 ppm, respectively).
Recrystallization in EtOAc/hexanes was able to separate some of 99d-cryst as a white
solid (~ 80 mg) and the rest still contained two isomers.

Spectral data for 99d-cryst: Rf = 0.41 (30% EtOAc/hexanes); mp = 113—1 15 °C;
1H NMR (300 MHz, CDC13): O 1.06 (s, 3H), 1.09 (s, 3H), 1.39-1.76 (m, 7H), 1.89-1.93
(m, 1H), 2.08-2.17 (m, 2H), 2.36-2.45 (m, 3H), 2.62 (dd, J= 4.5, 1.8 Hz, 1H), 3.51 (s,
3H), 3.76-3.92 (m, 4H), 4.07 (brs, 1H), 4.78 (s, 1H), 4.84 (S, 1H); l3C NMR (125 MHz,
CDC13): O 17.73, 23.27, 24.54, 25.14, 27.97, 29.25, 35.06, 35.97, 38.80, 54.56, 54.59,
62.89, 63.92, 64.00, 76.36, 88.72, 108.62, 109.34, 152.55, 163.62, 208.74; IR (NaCl):
2946s, 2876m, 1775s, 1658s, 1647s cm"; MS (EI) m/z (relative intensity): 346 (M, 5),
314 (21), 284 (32), 269 (15), 253 (16), 227 (12), 205 (100), 163 (20), 128 (20), 99 (100),
91 (26), 86 (30), 55 (53), 41 (50); Anal calcd for C21H3OO3: C, 72.80; H, 8.73. Found: C,
72.49; H, 9.00. The X-ray Structure of 99d-cryst, which clearly indicates the

stereochemistry of the hydrogen, is shown in Appendix 1.

154

Spectral data for 100dE: Rf = 0.36 (30% EtOAc/hexanes); 1H NMR (500 MHz,
CDC13): O 1.11-1.17 (m, 1H), 1.36-1.50 (m, 3H), 1.60 (s, 3H), 1.58-1.70 (m, 5H), 1.66 (s,
3H), 2.26 (q, J = 7.2 Hz, 2H), 2.55 (t, J = 7.1 Hz, 2H), 3.08 (s, 2H), 3.51 (s, 3H), 3.89-
4.00 (m, 4H), 4.67 (s, 1H), 5.08 (tm, J = 7.2 Hz, 1H); 13C NMR (125 MHz, CDC13): O
17.75, 23.09, 24.85, 25.66, 29.52, 29.88, 34.62, 37.71, 38.50, 49.36, 54.97, 64.12, 64.25,
85.60, 109.10, 122.95, 133.01, 143.14, 166.02, 167.69, 187.48; IR (NaCl): 29308, 17528,
1653s, 15598 cm".

Spectral data for 100dZ: Rf = 0.33 (30% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3): O 1.10-1.19 (m, 1H), 1.36-1.52 (m, 3H), 1.60 (8, 3H), 1.67 (s, 3H), 1.72-1.90 (m,
4H), 2.26 (q, J = 7.2 Hz, 2H), 2.47-2.55 (m, 1H), 2.62 (t, J = 7.2 Hz, 2H), 3.10 (s, 2H),
3.62 (s, 3H), 3.93-3.95 (m, 4H), 4.89 (s, 1H), 5.08 (tt, J = 7.2, 1.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3): 6 17.76, 23.18, 24.99, 25.71, 30.11, 30.81, 34.74, 37.63, 39.50,
49.78, 57.16, 64.28, 64.41, 93.79, 108.88, 123.01, 132.91, 142.02, 164.50, 169.75,

187.97; IR (NaCl): 29248, 17628, 15548 cm".

General Procedure for the Syntheis of Bicycloheptanones syn-118 and anti-118:

Illustrated for syn-118a and anti-118a.

O

OMe BnO..,__ \\ O o
(OC)SCr=< + ____. ,
BnO CH3 BnO CH3
CH3 I

0
53a
1 1 08 syn-1 1 Ba anti-1 1 88

A lO-mL or 50-mL flask with a threaded Teflon high-vacuum stop-cock was

charged with carbene complex 63a (50 mg, 0.22 mmol), dienyne 110a (53 mg, 0.22

155

mmol) and 2 or 20 mL of CH3CN to make a 0.1 or 0.01 M solution in 63a. The solution
was deoxygenated by the freeze-thaw method (—196/25 °C, 3 cycles), back-filled with
argon at room temperature, sealed and then heated at 45 °C for 24 hours. Then the
mixture was transferred to a 100-mL round bottom flask and CH3CN was removed on a
rotary evaporator. The residue was dissolved in 20 mL CHzClz and filtered through a pad
of Celite to get rid of green chromium complexes. The crude mixture was then taken up
in 5 mL THF/H20 (4:1) and oxalic acid (50 mg) was added. The hydrolysis was
monitored by TLC until the enol ether was all consumed. When the reaction was
complete the mixture was diluted with ether and washed sequentially with saturated
aqueous NaHCO3 and brine. After drying over MgSO4, the mixture was filtered and the
filtrate was concentrated to yield an oily residue which was carefully purified by silica
gel column chromatography (10—20% EtOAc/hexanes) to give syn-118a and anti-118a as
pure compounds. The assignment of the syn/anti isomers was based on their 1D NOESY
studies and the X-ray structure of the TROC-protected analog of syn-118a. '26

Spectral data for syn-118a: 63—66% yield. White solid, mp 66—67 °C. Rf = 0.25
(30% EtOAc/hexanes); 1H NMR (500 MHz, CDC13): 1.07 (s, 3 H), 1.10 (s, 3 H), 2.23 (8,
3 H), 2.30 (dd, J: 14.7, 5.4 Hz, 1 H), 2.50 (ddd, J= 14.4, 5.4, 1.2 Hz, 1 H), 2.65 (d, J=
16.8 Hz, 1H), 2.69 (d, J= 4.8 Hz, 1 H), 2.80 (d, J: 16.8 Hz, 1 H), 3.88 (d, J= 4.8 Hz, 1
H), 4.26 (d, J = 12.6 Hz, 1 H), 4.61 (d, J= 12.6 Hz, 1 H), 4.95 (8, 1 H), 5.07 (s, 1 H),
7.21-7.35 (m, 5 H); 13C NMR (125 MHz, CDC13): 17.87, 23.53, 29.89, 33.32, 36.68,
41.00, 61.07, 68.78, 71.92, 74.28, 113.87, 127.25, 127.40, 128.24, 138.06, 148.17,
203.64, 206.60; IR (NaCl): 2961m, 17888, 17208, 17058, 12678, 7368 cm]; MS (EI) m/z

(relative intensity): 312 (M+, 0.3), 254(2), 221 (49), 206(4), 179 (16), 161 (22), 137

156

(40), 133 (74), 105 (72), 91 (100), 77 (33), 65 (58), 43 (100), 41 (48); HRMS (E1) calcd
for C20H24O3 m/z 312.1725, found 312.1724. Anal calcd for C20H24O3: C, 76.89; H, 7.74.
Found: C, 76.55; H, 7.90.

Spectral data for anti-118a: 17-21% yield. Colorless viscous oil. Rf = 0.28 (30%
EtOAc/hexanes); 1H NMR (500 MHz, CDC13): 1.04 (s, 3 H), 1.14 (s, 3 H), 2.09-2.14 (m,
1 H), 2.17 (8, 3 H), 2.48-2.58 (m, 1 H), 2.64 (d, J= 6.0 Hz, 1 H), 2.69 (d, J = 2.4 Hz, 2
H), 4.03 (tt, J= 9.0, 2.4 Hz, 1 H), 4.61 (d, J = 16.0 Hz, 1 H), 4.67 (d, J= 16.0 Hz, 1 H),
4.72 (d, J = 2.4 Hz, 1 H), 5.42 (d, J = 2.4 Hz, 1 H), 7.26-7.36 (m, 5 H); l3C NMR (125
MHz, CDC13): 18.16, 23.69, 30.12, 31.83, 35.29, 40.95, 61.41, 71.62, 71.70, 73.46,
107.43, 127.47, 127.76, 128.42, 137.93, 149.30, 205.91, 206.97; IR (NaCl): 3055m,
2961m, l7728,1723s, 17038, 12858, 7348 cm'l; MS (EI) m/z (relative intensity): 312
(MI, 0.3), 297 (2), 221 (11), 204 (19), 178 (19), 161 (29), 146 (22), 133 (51), 120 (56),
109 (17), 91 (100), 65 (84), 55 (51), 43 (100); HRMS (EI) calcd for C20H24O3 m/z

312.1725, found 312.1722. Anal calcd for C20H2403: C, 76.89; H, 7.74. Found: C, 76.65;

H, 7.96.
o
OMe BnOk OMe 0 We OMe
(OC)5CT § ‘ \ 800"... I
+ ——-e BnO * BnO ”
I 0 \
530 110‘ syn-118c anti-118C 11860

Bicycloheptanones syn-118C and anti-118C and Cyclobutenone 118cc:

Following the general procedure for the preparation of syn-118a and anti-1183,
except that the acid hydrolysis was not performed, the reaction of complex 63c (83 mg,
0.25 mmol) and dienyne 110a (66 mg, 0.28 mmol) in 2.5 mL of CH3CN was carried out

at 45 °C for 24 h. The purification for this reaction was not easy and performed as

157

follows. The concentrated yellowish residue was subjected to silica gel chromatography
(10% EtOAc/hexanes) to give only one pure isomer of 118cc (16 mg, 16% yield) as a
colorless viscous oil, and the rest was presumably a mixture of isomers of 118C as well as
the other isomer of 118cc which could not be separated when the solutions of various
ratios of EtOAc/hexanes were used as the eluent. Very careful silica gel chromatography,
using EtOAc/CHzClz/hexanes (1:50:49) as the eluent, could isolate the major isomer of
syn-l 18c (56 mg, 55% yield) as a colorless viscous oil, but the remaining was still not
separable. Based on our studies on the related compound 118a and its analogs, anti-118c
was expected to have the characteristic methine proton (next to BnO- group) to appear
around 4.05 ppm as a triplet of multiplets on 1H NMR spectrum, while the corresponding
characteristic proton of syn-118c showed as a doublet at 3.89 ppm. Then the yield (16%)
of the presumed anti-1 18c was calculated from the 1H NMR spectrum of the crude
mixture by comparing the integrations of the relative methine protons after syn-118c was
isolated. The stereochemistry of syn-l 18c was assumed to be in the E configuration
(same as in the related compounds 99), and whether 118cc existed as an E or Z isomer
was not determined.

Spectral data for syn-118c: Rf = 0.33 (10% EtOAc/hexanes); 0.19 (1:50:49
EtOAc/CHZCIZ/hexanes); 1H NMR (300 MHz, CDC13): 6 1.01 (s, 3H), 1.08 (8, 3H), 1.10
(s, 3H), 1.23-1.46 (m, 8H), 1.69—1.77 (m, 2H), 2.38 (ddd, J= 49.8, 14.4, 5.5 Hz, 2H),
2.63 (d, J= 4.7Hz, 1 H), 3.60 (s, 3H), 3.89 (d, J= 5.4 Hz, 1H); 4.39 (8, 1H), 4.45 (dd, J=
76.0, 12.6Hz, 2H), 5.05 (s, 1H), 5.14 (8, 1H), 7.21-7.31 (m, 5H); 13C NMR (125 MHz,
CDC13): 6 18.00, 22.66, 22.70, 24.83, 26.39, 33.57, 35.94, 36.43, 37.08, 41.20, 60.90,

60.95, 68.75, 73.90, 76.23, 98.69, 114.85, 127.21, 128.27, 138.40, 147.88, 166.55,

158

204.17; IR (NaCl): 2928s, 28518, 17718, 16428, 14538, 10658 cm"; MS (EI) m/z (%
relative intensity): 408 (M, 0.1), 339 (3), 317 (1), 312 (3), 293(3), 221 (10), 175 (18),
161(10),149(60),127(9),105(12), 97 (15), 91 (100), 77(11), 71 (15), 69 (29), 65 (12),
55 (39), 43 (42), 41 (37). Anal calcd for C27H36O3: C, 79.37; H, 8.88. Found: C, 79.45;

H, 9.12.

Spectral data for 118cc: Rf = 0.26 (10% EtOAc/hexanes); 1H NMR (500 MHz,
CDC13): 6 1.04 (s, 3H), 1.24-1.42 (m, 8H), 1.58 (8, 3H), 1.62-1.64 (m, 2H), 1.67 (s, 3H),
2.47 (m, 2H), 3.18 (8, 2H), 3.63 (8, 3H), 4.49 (t, J= 6.4 Hz, 1H), 4.53 (dd, J= 53.7, 11.7
Hz, 2H), 5.13 (t, J = 7.0 Hz, 1H), 5.17 (s, 1H), 7.28-7.33 (m, 5H); 13C NMR (125 MHz,
CDC13): 6 17.92, 22.43, 25.81, 26.25, 31.50, 35.50, 35.56, 41.12, 48.11, 61.76, 71.73,
75.80, 95.32, 118.54, 127.70, 127.81, 128.41, 134.83, 137.88, 144.58, 167.08, 171.51,
187.10; IR (NaCl): 29268, 28558, 17618, 10928 cm'l; MS (EI) m/z (% relative intensity):
408 (M+, 0.03), 339(4), 217(1), 161 (4), 159(4), 133 (4), 105 (9), 97 (1 l), 91 (100), 69
(16), 55 (19), 41 (14). Anal calcd for C27H3603: C, 79.37; H, 8.88. Found: C, 79.00; H,

9.01.

OMe OMe O OMe
(OC)5Cr BnOh, ‘ \
7b + if _. BnO/V% ” Bn0%
O
0 I o o
K/O k/O K/O
63d

110a syn-118d anti-118d

Bicycloheptanones syn-118d and anti-118d:
Following the general procedure for the preparation of syn-118a and anti-118a,
except that, before chromatography the CHzClz solution was stirred under CO overnight

and then filtered and concentrated. The reaction of complex 63d (210 mg, 0.55 mmol)

159

and dienyne 110a (126 mg, 0.53 mmol) in 25 mL of CH3CN was performed at 47 °C for
25 h afforded syn-118d (143 mg, 60% yield) which was contaminated with trace of
inseparable impurities. All other isomers could not be separated in reasonable purities by
silica gel column chromatography using 5-15% EtOAc/hexanes as the eluent. Compound
syn-118d has a characteristic methine proton as a doublet at 3.89 ppm, but the expected
triplet of multiplets from anti-118d was not well separated in the region around 4 ppm in
both the crude mixture and eluted fractions. By carefully checking the patterns in the
NMR spectra of syn-118a and anti-118a, it was determined the two singlet peaks at 5.38
and 4.94 ppm to be from the protons of the exocyclic double bond of anti-118d and the
yield of this tentatively assigned anti-118d was calculated to be 19% by comparing the
integrations of the two peaks with those of syn-118d.

Spectral data for syn-118d: Rf = 0.45 (30% EtOAc/hexanes); 'H NMR (500 MHz,
CDC13): 6 1.10 (8, 3H), 1.08 (8, 3H), 1.40-1.45 (m, 1H), 1.50-1.52 (m, 2H), 1.54 (8, 1H),
1.58-1.64 (m, 2H), 1.66-1.69 (m, 1H), 2.21 (d, J= 12.0 Hz, 1H), 2.38 (ddd, J= 29.3, 7.1,
5.3 Hz, 2H), 2.56 (t, J: 2.2 Hz, 1H), 2.64 (d, J: 4.9 Hz, 1H), 3.53 (s, 3H), 3.85-3.87 (m,
2H), 3.89 (d, J = 5.4 Hz, 1H), 3.99-4.02 (m, 2H), 4.17-4.19 (m, 1H), 4.27 (d, J = 13.3 Hz,
1H), 4.78 (d, J = 13.3 Hz, 1H), 4.97 (s, 1H), 5.16 (s, 1H), 7.25-7.34 (m 5H); 13C NMR
(125 MHz, CDC13): 6 17.88, 22.87, 24.69, 26.95, 33.70, 35.02, 36.94, 37.60, 54.54,
54.56, 61.03, 63.76, 64.03, 68.22, 72.80, 74.64, 88.14, 108.97, 114.43, 127.22, 127.80,
128.25, 138.67, 150.76, 163.58, 203.83; IR (NaCl): 29408, 17738, 16538, 1456m, 10608
cm"; MS (EI) m/z (% relative intensity): 452 (M+, 1), 311 (23), 175 (11), 141 (24), 99

(49), 91 (100), 69 (15), 55 (20), 41 (20).

160

OMe 0

99b 139
The Hydrolysis of the Enol Ether 99b:

Method A: To a solution of 99h (14.8 mg, 0.51 mmol) in 5 mL of ether was added
2 mL of HOAc/H20 (5:2), the resultant mixture was stirred at room temperature for 3
days until TLC showed the disappearance of the starting material. The product was
extracted with methylene chloride and washed with H20. After concentration,
chromatography using 5-10% EtOAc/hexanes as the eluent gave diketone 139 (13.5 mg,
96% yield) as a colorless liquid.

Method B: To a solution of 99b (9.5 mg, 0.033 mmol) in 2 mL of THF/1120 (4:1)
was added 20 mg of oxalic acid, the resultant mixture was stirred at room temperature for
3 days until TLC showed the disappearance of the starting material. The product was
extracted with methylene chloride and washed with H20. After concentration,
chromatography using 5-10% EtOAc/hexanes as the eluent gave diketone 139 (8.0 mg,
89% yield) as a colorless liquid.

Spectral data for 139: Rf = 0.33 (10% EtOAc/hexanes); 1H NMR (300 MHz,
CDCl;,): 6 1.00 (8, 3H), 1.17 (8, 3H), 1.20-1.31 (m, 4H), 1.62-1.85 (m, 6H), 2.02-2.42 (m,
5H), 2.64 (dd, J = 2.5, 1.8 Hz, 1H), 2.77 (d, J = 9.6 Hz, 2H), 4.38 (d, J = 2.4 Hz, 1H),
4.81 (d, J= 1.5 Hz, 1H); IR (NaCl): 29328, 28558, 17758, 17138, 1451m cm"; MS (EI)
m/z (% relative intensity): 274 (M+, 16), 207 (17), 206 (100), 205 (37), 150 (11), 123

(68), 105 (12), 95 (15), 91 (13), 83 (34), 69 (83), 55 (50), 41 (65).

161

OMe O O
x HCI
—'——" + H0
0 0 0
991:

1416 142c

The Formation of Diketones 14lc and 142c.
A 25-mL RBF was charged with 99c (45 mg, 0.15 mmol) and added a solution of
0.5 mL of concentrated HCl in ~10 mL of CH3CN and 1 mL of H20. The mixture was
stirred at room temperature for 4 hours and worked up as usual. Chromatography on the
silica gel column gave diketones 14lc (~15 mg, 35% yield) and 142c (~16 mg, 35%

yield), both as colorless oils.

Spectral data for 1416: R, = 0.27 (10% EtOAc/hexanes); ‘H NMR (300 MHz,
CDC13): 6 1.18 (s, 3H), 1.28-1.56 (m, 10H), 1.80 (s, 3H), 1.80 (s, 3H), 1.81 (s, 3H), 2.00
(s, 3H), 2.38 (t, J = 6.0 Hz, 2H), 3.64 (t, J = 6.0 Hz, 2H), 3.56 (s, 3H); 13C NMR (75
MHz, CDC13): 6 21.47, 22.38, 22.94, 22.99, 25.24, 25.90, 27.65, 33.32, 33.99, 34.91,
48.36, 129.06, 131.64, 141.52, 155.39, 190.28, 212.29; IR (NaCl): 2911s, 2849s, 1709s,
1655m, 1456m cm"; MS (EI) m/z (% relative intensity): 288 (M, 4), 192 (14), 191 (92),
164 (39), 163 (31), 149 (11), 136 (12), 121 (21), 105 (11), 97 (100), 91 (13), 79 (9), 77
(8), 67 (17), 55 (71), 41 (25). HRMS calcd for C19H2302 m/z 288.2089, meas 288.2090.

Spectral data for 142c: Rf = 0.05 (10% EtOAc/hexanes); 0.25 (30%
EtOAc/hexanes). 1H NMR (300 MHz, CDC13): 6 1.16 (8, 3H), 1.17 (8, 3H), 1.19 (8, 3H),
1.23-1.60 (m, 8H), 1.1.68-1.78 (m, 1H), 1.82 (s, 3H), 1.96-2.05 (m, 3H), 2.32-2.50 (m,
3H), 3.50 (s, 2H), 5.15 (s, 1H); 13C NMR (75 MHz, CDC13): 6 21.62, 22.98, 24.73, 24.79,
25.25, 25.83, 28.48, 32.52, 33.62, 34.88, 48.35, 54.64, 72.51, 130.57, 158.88, 201.90,
212.15; IR (NaCl): 3470br, 2928s, 2851m, 1707s, 1636m, 1379m cm"; FAB-MS m/z:

307 (MH+), 289 (MH+—18).

162

OMe

(C0)50r 0 0
§ CH3CN HCI
+ t 4; +
0 H0
K/O O 0

63d 94 141 d 142d

 

The Formation of Triketones 141d and 142d.

A 50-mL flask with a threaded Teflon high-vacuum stop-cock was charged with
carbene complex 63d (0.376 g, 1.0 mmol), dienyne 94 (0.174 g, 1.3 mmol) and 10 mL of
CH3CN. The solution was deoxygenated by the freeze-thaw method (—196/25 °C, 3
cycles), back-filled with argon at room temperature, sealed and then heated at 45 °C for
47 hours. The flask was then opened and added ~6.0 mL of cone. HCl and 15 mL of H20.
The resulting yellow-green solution was stirred at room temperature for 4 h. The volatiles
were removed on a rotary evaporator and the aqueous solution was extracted with
CH2Cl2. The organic extract was washed with sat. aq. NaHC03 and brine sequentially,
dried with MgS04 and concentrated. Purification by silica gel chromatography (10%,
then 30%, 50% EtOAc/hexanes) gave 141d (0.085 g, 30% yield) and 142d (0.106 g, 35%
yield), both as yellowish oils. Triketone 142d existed as an inseparable mixture of two
diastereomers (four enantiomers) and the '3C NMR spectrum showed some doublet-type
peaks while others were singlets. The HPLC results (using chiral-AD column) showed
that there were four enantiomers in a 1:1:1 :1 ratio.

Spectral data for 141d: Rf = 0.35 (50% EtOAc/hexanes); 1H NMR (500 MHz,
CDC13): 6 1.62-1.72 (m, 2H), 1.76 (8, 3H), 1.80 (s, 3H), 1.93 (8, 3H), 1.95-2.02 (m, 1H),
2.07-2.14 (m, 1H), 2.20-2.25 (m, 2H), 2.30-2.35 (m, 1H), 2.32 (t, J = 6.0 Hz, 2H), 2.40-

2.49 (m, 1H), 2.56 (t, J = 6.0 Hz, 2H), 2.92-3.02 (m, 1H), 3.4 (s, 2H); 13(3 NMR (75

163

MHz, CDCl3): 6 21.29, 22.18, 22.63, 24.48, 27.17, 27.22, 32.93, 38.02, 40.61, 42.32,
49.42, 128.31, 130.98, 142.24, 156.23, 189.66, 207.90, 209.98; MS (EI) m/z (% relative
intensity): 288 (M+, 13), 191 (59), 163 (52), 151 (32), 123 (24), 97 (49), 69 (65), 57 (65),
55 (65), 41 (100) ; HRMS (EI) calcd for C13H2403 m/z 288.1725, meas 288.1729.
Spectral data for 142d: Rf = 0.12 (50% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13): 6 1.14 (8, 3H), 1.18 (s, 3H), 1.65-1.76 (m, 3H), 1.87 (8, 3H), 1.98-2.16 (m, 3H),
2.29-2.53 (m, 7H), 2.95-3.02 (m, 1H), 3.34 (d, J= 17.1 Hz, 1H), 3.47 (d, J= 17.1 Hz,
1H), 5.02 (s, 1H); 13C NMR (125 MHz, CDC13): 6 21.66, 24.62, 24.63, 24.71, 27.41,
28.26, 32.51, 37.69, 40.85, 42.59, 50.01, 54.61, 72.49, 130.06, 159.99, 201.83, 207.56,
210.94 (There are some doublet-type peaks due to the existence of two inseparable
diastereomers); IR (KBr): 3465br, 2968m, 17188, 16318, 1379m cm"; MS (EI) m/z (%
relative intensity): 306 (M+, 2), 288 (M48, 15), 248 (66), 191 (19), 164 (18), 163 (15),
151 (100), 150 (15), 149 (25), 124 (43), 123 (39), 121 (22), 97 (63), 96 (20), 69 (46), 67
(23), 59 (25), 55 (31); Anal calcd for C13H2604: C, 70.56; H, 8.55. Found: C, 70.54; H,
8.23. The results of HPLC analysis using the chiral-AD column (40% isopropyl
alcohol/hexanes, 1 mL/min) showed 4 well-separated peaks in a 1:1:1:1 ratio with

retention times of 7.63, 11.28, 15.03 and 23.05 minutes, respectively.

When the purified 141d (~10 mg) in 4 N aqueous HCl (1.5 mL) and CH3CN (1.0
mL) was stirred at room temperature for 10 hours, both 141d and 142d were observed
from the 1H NMR spectrum of the crude mixture in a ratio of 4 : 5 in favor of the
formation of 142d. When the purified 142d was treated with the same conditions, very

similar results were observed with a 141d/142d ratio of 3 : 4.

164

 

OMe
% nBuLi. THF HCI o
-711 °c. 1 h
0 0
99:

158
The Preparation of Diketone 158:

A flame dried 25-mL RBF was charged under argon with 99a (40.0 mg, 0.12
mmol) in 3 mL of THF and cooled to —78 °C. In a separate 10-mL RBF, nBuLi (2.5 M,
0.11 mL, 0.27 mmol) was dissolved in 5 mL of THF at —78 °C and was transferred
slowly via a cannula to the flask containing 99a. The resulting mixture was stirred at —78
°C for an hour and subsequently quenched with glacial acetic acid (48 mg, 0.8 mmol).
The mixture was then allowed to warm to room temperature. After usual workup, the
major compound was isolated as by silica gel chromatography (partially hydrolyzed to
158) and then treated with a solution of 3 mL of 4 N HCl and 2 mL of THF for 4 hours.
The product was extracted with ether (3 x 5 mL), washed sequentially with sat. NaHC03
aqueous solution and brine, dried with anhydrous Na2804. Chromatography with 10%
EtOAc/hexanes gave diketone 158 (26.2 mg) in 55% yield as a colorless oil.

Spectral data for 158: Rf = 0.14 (10% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13): 6 0.85 (t, J = 7.5 Hz, 3H), 0.92 (s, 3H), 0.93 (s, 3H), 1.21—1.29 (m, 2H), 1.43-
1.53 (m, 2H), 1.48 (s, 3H), 1.64-1.81 (m, 2H), 1.92-2.09 (m, 2H), 2.14 (8, 3H), 2.31-2.51
(m, 2H), 2.59 (dd, J: 5.1, 3.3 Hz, 111), 3.11 (s, 2H); 13C NMR (125 MHz, CDCl3): 6
13.88, 20.42, 21.87, 22.36, 22.83, 25.74, 27.13, 29.22, 31.16, 37.36, 43.56, 44.37, 57.03,
130.30, 130.81, 207.44, 214.46; IR (KBr): 29598, 29308, 17078 cm"; MS (EI) m/z (%

relative intensity): 264 (M+, 33), 246 (23), 231 (21), 221 (16), 206 (14), 191 (27), 161

165

(43),151(25),147(120,137(43),135(16),121(100),119(20),109(13),107(20),105

(28), 93 (16), 91 (22), 85 (34), 77 (16), 57 (54).

OMe
W nBuLi. THF HCI O

0 ~78 to 25 °C

 

11

159
The Formation of Diketone 159:

A flame dried 25-mL RBF was charged under an argon atmosphere with 99a (51
mg, 0.23 mmol) in 5 mL of THF and cooled to —78 °C. In a separate 10-mL RBF, nBuLi
(2.5 M, 0.14 mL, 0.35 mmol) was dissolved in 5 mL of THF at —78 °C and was
transferred slowly via a cannula to the flask containing 99a. The resulting mixture was
stirred at —78 °C for an hour, and warmed up slowly to room temperature over three
hours and then stirred at room temperature for another an hour. After usual workup, the
crude mixture was treated with a solution of 3 mL of 4 N HCl and 2 mL of THF for an
hour. The product was extracted with ether (3 x 5 mL), washed sequentially with sat.
NaHC03 aqueous solution and brine, dried with anhydrous Na2S04. Silica gel column
chromatography with 10% EtOAc/hexanes gave diketone 159 (36.5 mg) in 60% yield as
a colorless oil.

Spectral data for 159: Rf = 0.10 (10% EtOAc/hexanes); lH NMR (300 MHz,
CDC13): 6 0.86 (t, J = 7.5 Hz, 3H), 0.87 (8, 3H), 0.97 (8, 3H), 1.22-1.30 (m, 2H), 1.44-
1.54 (m, 2H), 1.56-1.70 (m, 2H), 2.08 (8, 3H), 2.10-2.14 (m 2H), 2.40 (td, J= 7.2, 5.7 Hz,
2H), 2.50-2.59 (m, 4H), 4.59 (s, 1H), 4.72 (s, 1H); 13C NMR (125 MHz, CDC13): 6 13.88,

22.32, 23.41, 25.64, 25.66, 26.12, 30.06, 30.25, 36.76, 42.98, 44.80, 50.30, 53.74, 110.00,

166

146.82, 208.16, 213.56; IR (KBr): 2957s, 2926s, 2853m, 1709s cm'l; MS (EI) m/z (%
relative intensity): 264 (M+, 23), 246 (19), 231 (24), 206 (14), 191 (30), 161 (79), 138
(47), 137 (27), 121 (100), 119 (27), 107 (18), 95 (13), 91 (18), 85 (35), 84 (24), 79 (13),

77 (13), 57 (66).

OMe OMe
o H OH 0
991 160 H 161

The Formation of Aldehyde 161.

A solution of 99a (16.5 mg, 0.075 mmol) in 2 mL of THF was added LAH (1.0
M, 0.225 mL, 0.225 mmol) at room temperature and stirred for 6 hours. The reaction
mixture was quenched with H20 and extracted with ether. The organic extracts were
washed with sat. aqueous NIIaCl solution and brine sequentially, dried with anhydrous
Na2804 and concentrated. Purification by silica gel column (5—10% EtOAc/hexanes)
gave alcohol 160 (13.1 mg, 79% yield) as a color less oil which solidified in freezer at
-20 °C.

Spectral data for 160: Rf = 0.22 (10% EtOAc/hexanes); 1H NMR (300 MHz,
CD2C12): 6 0.74 (8, 3H), 1.36 (8, 3H), 1.59 (8, 3H), 1.87-1.98 (m, 4H), 2.30-2.39 (m, 1H),
2.48-2.57 (m, 1H), 3.57 (s, 3H), 4.18 (8, 1H), 4.19 (s, 1H), 4.69 (d, J= 0.9 Hz, 1H), 4.70
(d, J = 0.9 Hz, 1H); l3C NMR (75 MHz, CD2C12): 6 18.23, 23.38, 23.90, 25.07, 26.36,
41.96, 45.84, 54.81, 57.52, 72.58, 91.16, 106.91, 152.35, 157.34.

To a solution of 160 (10.8 mg, 0.049 mmol) in 1 mL of THF was added 1 mL of 4
N HC1, and the mixture was stirred for 10 hours. The organic product was extracted with

ether, washed with brine and dried with anhydrous Na2SO4. After removal of the

167

solvents, the residue was purified by silica gel chromatography (10% EtOAc/hexanes) to
give aldehyde 161 (6.3 mg, 62%) as a colorless oil.

Spectral data for 161: Rf = 0.40 (30% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13): 6 0.95 (8, 3H), 1.08 (s, 3H), 1.50 (s, 3H), 1.71-1.91 (m, 2H), 2.05-2.11 (m, 2H),
2.15 (8, 3H), 2.22 (dt, J = 9.9, 3.0 Hz, 1H), 3.17 (s, 2H), 9.84 (d, J = 3.0 Hz, 1H); 13C
NMR (125 MHz, CDC13): 6 19.66, 20.43, 23.17, 27.09, 29.40, 30.44, 36.63, 43.25, 57.13,
130.29, 131.37, 206.17, 206.54; IR (KBr): 2932m, 17218 cm"; MS (EI) m/z (% relative
intensity): 208 (M, 57), 190 (38), 175 (29), 162 (59), 147 (55), 137 (65), 121 (87), 107

(100), 95 (94), 91 (66), 81 (62), 67 (36), 55 (26).

The Formation of Aldehyde 163.

Following the procedure for the preparation of 160, the reaction of 99d (121 mg,
0.35 mmol) with LAH (1.0 M, 1.05 mL, 1.05 mmol) in 10 mL THF after 4 h afforded
alcohol 162 (108 mg) in 89% yield.

Spectral data for 162: Rf = 0.30 (30% EtOAc/hexanes); 1H NMR (300 MHz,
CD2C12): 6 0.72 (s, 3H), 1.36 (s, 3H), 1.42-1.47 (m, 5H), 1.63-1.71 (m, 3H), 1.83-1.98
(m, 4H), 2.24-2.36 (m, 2H), 2.51-2.63 (m, 1H), 3.54 (8, 3H), 3.74-3.88 (m, 4H), 4.09 (s,
1H), 4.25 (d, J = 2.1 Hz, 1H), 4.66-4.68 (m, 1H), 4.71-4.72 (m, 1H); 13C NMR (125
MHz, CD2C12): 6 23.43, 23.82, 23.85, 25.43, 26.31, 29.32, 35.33, 36.46, 38.50, 42.33,

45.79, 54.95, 57.55, 64.15, 64.35, 75.57, 89.79, 106.88, 109.20, 153.91, 162.71.

168

Following the procedure for the preparation of 161, the reaction of 162 (108 mg,
0.31 mmol) with 4 mL of 4 N HCl in 4 mL of THF after 1 h gave aldehyde 163 (57 mg)
in 63% yield. Aldehyde 163 existed as a mixture of two inseparable isomers as
evidenced with a few doublet-type peaks in the 13C NMR spectrum.

Spectral data for 163: Rf = 0.16 (30% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13): 6 0.92 (s, 3H), 1.04 (d, J= 3.3 Hz, 3H), 1.43 (d, J= 2.1 Hz, 3H), 1.63-1.89 (m,
4H), 2.04-2.09 (m, 4H), 2.20 (dt, J = 10.2, 3.0 Hz, 1H), 2.29-2.41 (m, 3H), 2.52 (dd, J =
14.4, 11.4 Hz, 1H), 2.91-2.99 (m, 1H), 3.13-3.32 (m, 2H), 9.82 (d, J= 3.0 Hz, 1H); 13C
NMR (125 MHz, CDC13): 6 19.68, 20.33, 23.18, 25.00, 27.06, 27.87, 30.38, 36.41, 40.68,
40.69, 42.99, 49.90, 57.00, 129.33, 131.62, 206.12, 207.85, 209.84 (There are a few
doublet-type peaks due to the existence of two inseparable isomers); IR (KBr): 2940m,

2871m, 1715s em".

0 O
Mg(0Me)2
/ 0 ,CH2 0
O H0
163 163:

The Formation of Alcohol 163a.

To a solution of 163 (42.0 mg, 0.14 mmol) in 10 mL of THF was added
Mg(0Me)2/Me0H (2.0 M, 0.7 mL, 1.4 mmol) and the mixture was heated at 60 °C for 32
h, before 10 mL of ether was added and the mixture was quenched with 5 mL of H20.
The organic layer was separated and the aqueous phase was further extracted with ether.

The combined organic extracts were washed with sat. aqueous NH4C1 and brine

169

sequentially, dried with anhydrous Na2804 and concentrated. Purification by silica gel
column (30-50% EtOAc/hexanes) gave alcohol 163a (17.0 mg) in 40% yield.

Spectral data for 163a: Rf = 0.17 (50% EtOAc/hexanes); 1H NMR (500 MHz,
CDC13): 6 0.80 (d, J = 2.5 Hz, 3H), 0.98 (d, J = 6.0 Hz, 3H), 1.46 (d, J = 2.0 Hz, 3H),
1.51-1.53 (m, 3H), 1.74-1.78 (m, 2H), 1.89-1.94 (m, 1H), 2.07-2.13 (m, 4H), 2.30-2.43
(m, 3H), 2.56 (dd, J= 15, 11.5 Hz, 1H), 2.95-3.01 (m, 1H), 3.16-3.33 (m, 2H), 3.53 (dd,
J = 10.5, 7.0 Hz, 1H), 3.82 (ddd, J = 10.5, 3.0, 1.5 Hz, 1H); 13C NMR (125 MHz,
CDC13): 6 20.43, 21.82, 22.40, 25.06, 27.32, 27.91, 31.03, 36.44, 40.92, 41.17, 43.03,
46.79, 49.82, 64.15, 129.61, 131.86, 208.58, 210.05; IR (KBr): 3420br, 2938m, 17118
cm"; MS (EI) m/z (% relative intensity): 292 (M+, 1), 274 (1), 234 (2), 206 (2), 177 (4),
152(12),149(14),135(16),123(15),121 (59),109(31), 107(58), 97 (100), 93 (43), 91

(24), 81 (27), 69 (52), 55 (32), 41 (69).

170

5.3. EXPERIMENTAL PROCEDURES AND CHARACTERIZATION DATA FOR

 

CHAPTER THREE
(CO-2M6
0M6 H OMe MeO c OMe
(case, I 187 «A; + 2 \A/
— : M6026 "— H ‘—
CH3 CH3 CH3
181a 1884111173 1884:]:

The Preparation of Cyclopropanes 188-trans and 188-cis.

TO a 10-mL flask with a threaded Teflon high-vacuum stop-cock was added
carbene complex 181a240 (47 mg, 0.15 mmol) and 2 mL of methyl acrylate 187. The
solution was deoxygenated by the freeze-thaw method (—196/25 °C, 3 cycles), back-filled
with argon at room temperature, sealed and heated at 80 °C for an hour. The mixture was
then cooled down to room temperature and transferred to a 50-mL round bottom flask
and concentrated under reduced pressure. The residue was subjected to silica gel column
chromatography (5—10% EtOAc/hexanes) tO give cyclopropanes 188-trans (16.5 mg,
54% yield) and 188-cis (8.4 mg, 28% yield), both as colorless Oils. The assignment Of
trans- and cis-isomers was based on the NOE results shown below.

Spectral data for 188-trans: Rf = 0.27 (10% EtOAc/hexanes). 1H NMR (300
MHz, CDCl3): 6 1.42-1.52 (m, 2H), 1.74 (dd, J= 6.9, 1.5 Hz, 3H), 2.12 (dd, J= 9.3, 7.2
Hz, 1H), 3.29 (s, 3H), 3.65 (8, 3H), 5.51 (d, J = 15.0 Hz, 1H), 5.63-5.75 (m, 1H), 6.03-
6.11 (m, 1H), 6.31 (dd, J= 15.6, 10.5 Hz, 1H); 13C NMR (125 MHz, CDC13): 6 18.13,

21.57, 29.48, 51.84, 55.62, 68.24, 124.43, 129.37, 130.83, 131.45, 171.04; IR (NaCl):

2954m, 17308, 1439m, 1167m cm-l; MS (EI) m/z (relative intensity): 196 (M+, 78), 181

(100), 168 (18), 149 (11), 137 (61), 136 (65), 12 (77), 105 (30), 91 (19), 77 (21), 65 (10).

171

Spectral data for 188-cis: Rf = 0.15 (10% EtOAc/hexanes). lH NMR (300 MHz,
CDC13): 6 1.50 (dd, J = 8.4, 6.0 Hz, 1H), 1.73 (dd, J = 6.6, 1.2 Hz, 3H), 1.78-1.92 (m,
2H), 3.25 (s, 3H), 3.68 (8, 3H), 5.32 (d, J= 15.3 Hz, 1H), 5.64-5.75 (m, 1H), 5.98-6.17
(m, 1H), 6.20 (dd, J= 15.0, 10.5 Hz, 1H); l3C NMR (125 MHz, CDC13): 6 18.13, 19.54,

29.24, 51.97, 56.01, 67.65, 128.80, 130.12, 130.28, 130.62, 169.76; IR (NaCl): 2928m,

17388, 1439m, 1167m cm-l; MS (EI) m/z (relative intensity): 196 (M+, 63), 181 (95), 168

(20), 149 (10), 137 (100), 121 (79), 109 (26), 105 (42), 91 (34), 77 (41), 65 (15).

 

NOE 0.7%
fl MeOZCWOMe
H. G ,OMe s. '-.
s‘ ‘=. H *—
MeOZC 1 b”/_\=‘\
— CH
N E 1. °/ 3
1884mm 1884:];
C02Me
OMe
(0C )5Cr Ir 1 87 Fifi-(OMe M602C¥A{OM6
— : M8020 a... + H ",—
Ph Ph Ph
181., 189-trans 139.“,

The Preparation of Cyclopropanes 189-trans and 189-cis.

Following the procedure described above for the preparation Of 188, the reaction
Of carbene complex 181b240 (73 mg, 0.2 mmol) and 2 mL Of methyl acrylate gave
cyclopropanes 189-trans (32 mg, 62% yield) and 189-cis ( 17 mg, 33% yield), both as
colorless Oils. The assignment of trans- and cis-isomers was based on the NOE results

shown below.

172

Spectral data for 189-trans: Rf = 0.24 (10% EtOAc/hexanes). 1H NMR (300
MHz, CDC13): 6 1.49-1.59 (m, 2H), 2.19 (dd, J = 9.3, 7.5 Hz, 1H), 3.34 (8, 3H), 3.68 (s,
3H), 5.79 (d, J= 15.6 Hz, 1H), 6.48-6.57 (m, 2H), 6.81 (dd, J= 15.6, 10.5 Hz, 1H), 7.19-
7.38 (m, 5H); l3C NMR (125 MHz, CDC13): 6 22.00, 29.82, 51.87, 55.78, 68.40, 126.32,

127.45, 128.22, 128.29, 128.58, 131.21, 131.96, 137.29, 170.99; IR (NaCl): 3024m,

2951m, 1728s, 1439m, 1375m, 1165m cmd; MS (EI) m/z (relative intensity): 258 (M+,
100), 199 (70), 198 (60), 183 (16), 167 (57), 155 (28), 141 (15), 128 (17), 115 (17), 91
(34), 77 (10).

Spectral data for 189-cis: R, = 0.12 (10% Et20/hexanes). ‘H NMR (300 MHz,
CDC13): 6 1.20-1.25 (m, 1H), 1.86-2.00 (m, 2H), 3.32 (s, 3H), 3.71 (s, 3H), 5.54 (d, J=
15.0 Hz, 1H), 6.39-6.57 (m, 2H), 6.76 (dd, J= 15.6, 10.5 Hz, 1H), 7.20-7.38 (m, SH); 13(2
NMR (125 MHz, CDC13): 6 19.77, 29.70, 52.02, 56.64, 67.76, 126.36, 127.63, 127.66,

128.63, 130.42, 132.45, 132.68, 137.12, 169.54; IR (NaCl): 2951m, 1734s, 1437m,

1167m ch; MS (EI) m/z (relative intensity): 258 (M+, 100), 199 (79), 198 (57), 167

(55), 155 (37), 1541 (18), 121 (15), 115 (19), 91 (34), 77 (11).

NOE 1.2%

m MeOzc‘A’OMe

H‘A’OMe

. ., H "'—
MeO2C ”'1 bH/~L_\
NOE 1.9% P“
Ph
189-trans 189-cl:

173

of of

(CO),Cr=( (0050K

194. 190. Ph

 

The Preparation of Carbene Complex 190a.
This compound was prepared by Aumann’s method for related compounds.”2b A

24' (98 mg, 0.355 mmol) in 8 mL Of ether was treated with

solution Of 194a
cinnamaldehye (47 mg, 0.355 mmol), TMSCl (135 1.1L, 1.065 mmol) and Et3N (198 11L,
1.42 mmol) and stirred at room temperature for 27 hours. The dark red mixture was
filtered through a short pad Of Celite and concentrated. The residue was subjected tO
silica gel chromatography (hexanes as the eluent) tO afford 190a (51 mg, 37% yield) as a
red solid.

Spectral data for 190a: R, = 0.14 (hexanes); 0.45 (10% Et20/hexanes). 'H NMR

(300 MHz, CDC13): 6 5.42-5.54 (m, 4H), 6.14-6.27 (m, 1H), 6.79-6.85 (m, 2H), 7.04-7.09

(m, 1H), 7.33-7.50 (m, 6H); IR (NaCl): 2054s, 1923vs em".

OH OH

(CO)5Cr=< —" (CO’SC'H

1941) 190b CH3

The Preparation of Carbene Complex 190b.
Following a literature procesure for related compounds,l ‘28 the reaction of 194b24'
(0.50 g, 1.72 mmol) and crotonaldehyde (0.285 mL, 3.42 mmol) afforded 190b (0.15 g,

27% yield) as a red solid, along with recovered l94b (0.23 g, 46%). The yield based on

unrecovered starting material was 50%.

174

Spectral data for 190b: Rf = 0.20 (hexanes). lH NMR (300 MHz, CDC13): 6 1.89
(d, J = 6.9 Hz, 3H), 2.72 (q, J = 6.6 Hz, 2H), 4.97 (t, J = 6.6 Hz, 2H), 5.14-5.23 (m, 2H),
5.83-5.96 (m, 1H), 6.06-6.15 (m, 1H), 6.25-6.36 (m, 1H), 6.60 (dd, J = 14.7, 10.8 Hz,

1H), 7.21 (d,J= 14.7 Hz, 1H).

,fl .54

(0C)5Cr:< —. (00),,ch

194b 1901: P“
The Preparation of Carbene Complex 190c.

Following the procedure described above for the preparation Of 190a, the reaction
of 194152“ (290 mg, 1.0 mmol) and cinnamaldehyde (132 mg, 1.0 mmol) with TMSCl
(0.38 mL, 3.0 mmol) and Et3N (0.56 mL, 4.0 mmol) in 10 mL Of ether after 36 hours
afforded 190c (242 mg, 60% yield) as a red solid.

Spectral data for 190c: Rf = 0.12 (hexanes). 1H NMR (300 MHz, CDC13): 6 2.76
(q, J = 6.6 Hz, 2H), 5.02 (t, J = 6.6 Hz, 2H), 5.18-5.27 (m, 2H), 5.89-5.98 (m, 1H), 6.76-
6.81 (m, 2H), 7.00-7.05 (m, 1H), 7.31-7.49 (m, 6H); 13C NMR (125 MHz, CDC13): 6
33.97, 78.58, 118.14, 127.01, 127.37, 128.91, 129.59, 131.06, 133.45, 136.09, 142.87,

145.00, 216.78, 224.50, 329.42.

175

/ f/J
of/J °
(CO)5Cr=< ——’ (coherH
194d 190d — Ph

The Preparation of Carbene Complexes 194d and 190d.

A solution Of methyl pentacarbonylchromium tetramethylammonium salt (0.62 g,
2 mmol) in CH2C12 (20 mL) was added freshly prepared 5-hexenyl triflate242 and stirred
at room temperature for 30 minutes. The reaction was quenched with saturated NaHC03
aqueous solution. The organic layer was separated and the aqueous phase was further
extracted with CH2C12. The combined organic extracts were washed with brine and dried
with MgSOa, filtered and concentrated. Purification by chromatography with hexanes
gave 194d (0.62g, 96% yield) as an orange Oil.

Spectral data for 194d: R, = 0.20 (hexanes). lH NMR (300 MHz, CDC13): 6 1.60
(p, J = 7.5 Hz, 2H), 1.93-2.03 (m, 2H), 2.14 (q, J = 7.5 Hz, 2H), 2.92 (s, 3H), 4.89 (brs,
2H), 4.96-5.07 (m, 2H), 5.73-5.87 (m, 1H).

Following the procedure described above for the preparation Of 1903, the reaction
Of 194d (290 mg, 0.91 mmol) and cinnamaldehyde (120 mg, 0.91 mmol) with TMSCl
(0.35 mL, 2.74 mmol) and Et3N (0.51 mL, 3.65 mmol) in 10 mL Of ether after 3 days
afforded 190d (250 mg, 64% yield) as a red Oil.

Spectral data for 190d: Rf = 0.09 (hexanes). 1H NMR (300 MHz, CDC13): 6 1.64
(q, J = 7.5 Hz, 2H), 1.97-2.07 (m, 2H), 2.18 (q, J = 7.5 Hz, 2H), 4.97 (t, J = 6.6 Hz, 2H),
5.02-5.10 (m, 2H), 5.77-5.90 (m, 1H), 6.72-6.85 (m, 2H), 7.02-7.07 (m, 1H), 7.31-7.49
(m, 6H); l3C NMR (125 MHz, CDC13): 6 25.32, 29.03, 33.25, 79.85, 115.24, 127.08,

127.38, 128.92, 129.57, 131.29, 136.18, 138.04, 142.88, 144.82, 216.89, 224.53, 329.67.

176

fl .54

O
(OC)SW=( (OCRWH

194c-W 192
The Preparation of Tungsten Carbene Complex 192.

Following the procedure described above for 194d, the reaction Of the methyl
pentacarbonyltungsten tetramethylammonium salt (0.882 g, 2 mmol) and 3-butenyl
triflate after 30 minutes afforded l94c-W (0.763 g, 90% yield) as an orange Oil.

Spectral data for 194c-W: Rf = 0.23 (hexanes). 1H NMR (300 MHz, CDC13): 6
2.70 (q, J = 6.6 Hz, 2H), 2.86 (s, 3H), 4.82 (brs, 2H), 5.15-5.22 (m, 2H), 5.79-5.92 (m,
1H); 13C NMR (125 MHz, CDC13): 6 33.39, 52.22, 83.31, 118.44, 132.71,|197.24,
203.43, 330.92.

Following the procedure described above for the preparation Of 190a, the reaction
Of l94c-W (371 mg, 0.88 mmol) and cinnamaldehyde (111 11L, 0.88 mmol) with TMSCl
(335 11L, 2.64 mmol) and Et3N (491 11L, 3.53 mmol) in 10 mL Of ether after 3 days
afforded 192 (210 mg, 45% yield) as a dark red solid.

Spectral data for 192: Rf = 0.08 (hexanes). 1H NMR (300 MHz, CDC13): 6 2.73
(q, J = 6.6 Hz, 2H), 4.84 (t, J = 6.6 Hz, 2H), 5.17-5.26 (m, 2H), 5.85-5.98 (m, 1H), 6.80
(dd, J = 15, 11.1 Hz, 1H), 6.94-7.11 (m, 2H), 7.33-7.51 (m, 6H); 13C NMR (125 MHz,
CDC13): 6 33.73, 81.30, 118.08, 127.28, 127.42, 128.99, 129.65, 133.47, 134.95, 136.33,

144.84, 147.09, 197.63, 203.93, 303.38.

177

,fl

0
(00150 __. 9
"WM
— _ CH3

1906 CH3 1916
The Preparation of Cyclopropane l9lh.

TO a 25-mL flask with a threaded Teflon high-vacuum stop-cock was added
carbene complex 190b (109 mg, 0.34 mmol) and 7 mL of toluene. The solution was
deoxygenated by the freeze-thaw method (-196/25 °C, 3 cycles), back-filled with argon at
room temperature, sealed and heated at 80 0C for 2 hours. The mixture was then cooled
down to room temperature and transferred tO a 50-mL round bottom flask and
concentrated under reduced pressure. Purification by silica gel column chromatography
(0—5% Bt0Ac/hexanes) afforded l9lb (29.5 mg, 58 % yield) as a colorless Oil.

Spectral data for 191b: Rf = 0.37 (10% EtOAc/hexanes). 1H NMR (300 MHz,
CDCl;): 6 0.77 (ddd, J= 9.0, 6.3, 0.9 Hz, 1H), 1.12 (t, J= 6.0 Hz, 1H), 1.48 (dt, J: 8.7,
5.1 Hz, 1H), 1.71 (dd, J= 6.2, 1.4 Hz, 3H), 1.91 (ddd, J = 12.0, 7.2, 2.2 Hz, 1H), 2.05-
2.15 (m, 1H), 3.56 (td, J = 9.6, 7.2 Hz, 1H), 4.09 (td, J = 9.0, 2.4 Hz, 1H), 5.51 (d, J =
15.0 Hz, 1H), 5.56-5.68 (m, 1H), 5.98-6.07 (m, 1H), 6.27 (dd, J= 15.0, 10.5 Hz, 1H); 13(2
NMR (125 MHz, CDC13): 6 16.42, 18.11, 23.99, 28.75, 66.70, 68.27, 127.65, 127.95,

129.66, 130.92; MS (EI) m/z (relative intensity): 150 (M+, 100), 135 (38), 107 (19).

.H

0
0C Cr _.
( )5 H 9%9M P h

190c Ph 191c

The Preparation of Cyclopropane l9lc.

178

Following the procedure described above for the preparation Of 191b, the reaction
of 190c (200 mg, 0.49 mmol) in 10 mL Of toluene after heating at 80 0C for 6 hours
affored l9lc (76 mg, 73% yield) as a colorless Oil.

Spectral data for l9lc: Rf = 0.36 (10% EtOAc/hexanes). lH NMR (300 MHz,
CDC13): 6 0.84-0.89 (m, 1H), 1.21 (t, J= 6.0 Hz, 1H), 1.54-1.60 (m, 1H), 1.91-1.99 (m,
1H), 2.09-2.21 (m, 1H), 3.61 (td, J= 9.3, 6.9 Hz, 1H), 4.14 (td, J= 9.0, 2.7 Hz, 1H), 5.76
(d, J= 15.3 Hz, 1H), 6.45-6.54 (m, 2H), 6.77 (dd, J= 15.3, 10.5 Hz, 1H), 7.14-7.37 (m,
5H); 13C NMR (125 MHz, CDC13): 6 14.24, 26.65, 28.77, 66.91, 68.56, 126.18, 127.15,

127.49, 128.53, 128.57, 130.66, 133.54, 137.54; IR (NaCl): 3025m, 2928m, 2874m,

1638m, 1595m, 1063m, 988s ch; MS (EI) m/z (relative intensity): 212 (M+, 100), 197

(15), 183(10),157(12), 141 (16), 128(36),115(14), 91 (13), 77 (11).

,H

E :0
(00sz ___. .
_ WM Ph

192 P“ 1911:

The Preparation of Cyclopropane l9lc from Tungsten Complex 192.

Following the procedure described above for the preparation Of 193b, the reaction
Of the tungsten carbene complex 192 (84.0 mg, 0.15 mmol) in 3 mL Of toluene after
heating at 80 °C for an hour gave l9lc (30.1 mg, 91%) as a colorless Oil. The spectral

data were consistent with those Obtained from the reaction wtih 190c as described above.

179

5.4. EXPERIMENTAL PROCEDURES AND CHARACTERIZATION DATA FOR

CHAPTER FOUR

Cr(CO)5

’ b OMe ’ 500M;
0 Q

224 225
The Thermolysis of Complex 224 in the Presence or Absence of F e2(C0)9.

General Procedure: A 25-mL flask with a threaded Teflon high-vacuum stop-
cock was flushed with nitrogen for 10 minutes before it was charged with the carbene
complex 224 (40.2 mg, 0.1 mmol), one equiv of Fe2(C0)9 (36.4 mg, 0.1 mmol), and 5
mL Of the solvent. The mixture was degassed by the freeze-thaw method (-196/25 °C, 3
cycles), back-filled with 1 atm C0 or argon at room temperature, sealed and heated at 80
°C until the red color disappeared, indicating all the starting carbene complex was
consumed. The mixture was then allowed to cool to room temperature and transferred to
a 100-mL round bottom flask and concentrated under reduced pressure. The residue was
subjected to silica gel chromatography (5—10% EtOAc/hexanes) tO furnish the phenol
225 as a white solid.

Following the general procedure described above, when benzene was used as the
solvent and in the presence of 1 atm C0, after 24 h, the reaction gave the phenol 225
(19.0 mg, 80% yield). The same reaction under 1 atm argon for 24 h afforded 15% yield
Of 225 (3.6 mg).

Spectral data for 225: Rf = 0.20 (10% EtOAc/hexanes); ]H NMR (300 MHz,

CDCl;): 6 2.33 (d, 1H, J = 6.6 Hz), 2.41 (d, 1H, J = 6.6 Hz), 3.96 (s, 3H), 4.36 (s, 1H),

180

4.44 (s, 1H), 5.98 (s, 1H), 6.89-6.97 (m, 2H), 7.26-7.36 (m, 2H), 7.79 (d, 1H, J= 8.1 Hz),
8.07 (d, 1H, J = 8.1 Hz); 13C NMR (125 MHz, CDC13) 6 47.74, 49.20, 61.86, 71.52,
121.38,122.48, 122.72, 123.70, 124.71, 126.05, 138.70,139.71, 141.07, 141.47, 142.99,

144.34. The spectral data are consistent with the reported data for this compound.197

For the reactions that were carried out in the absence of Fe2(C0)9, the general

procedure described above was followed except that none Of the iron source was added.

(1) When the reaction was performed in acetonitrile without any iron source in
the presence of 1 atm C0 for 8 h, a 73% yield Of 225 was Obtained. The same
reaction under 1 atm argon for 4 h gave 225 in 36% yield.

(2) When the reaction was performed in THF without any iron source in the
presence Of 1 atm C0 for 16 h, an 87% yield Of 225 was Obtained. The same
reaction under 1 atm argon for 5 h gave 225 in 41% yield.

(3) When the reaction was performed in benzene without any iron source in the
presence Of 1 atm C0 for 22 h, a 92% yield Of 225 was Obtained. The same
reaction under 1 atm argon for 36 h gave 225 in 51% yield.

(4) When the reaction was performed in heptane without any iron source in the
presence Of 1 atm C0 for 42 h, an 80% yield Of 225 was obtained. The same
reaction under 1 atm argon for 39 h gave 225 in 35% yield.

(5) When the same reactions as in (4) were performed except that the reaction
temperature was at 100 °C, under 1 atm C0 after 1.5 h, a 75% yield of 225
was Obtained, while under 1 atm argon after 1.5 h 225 was isolated in 28%

yield.

181

Cr(CO)5 OMe OMe
(‘8 ——' «H + + Phh
O O 0 M90 0
227 228 270 271
The Thermolysis of Complex 227 in the Presence or Absence of Fe2(C0)9.

General Procedure (I) — for reactions performed under 1 atm C 0: A 25 -mL flask
with a threaded Teflon high-vacuum stop-cock was flushed with nitrogen for 10 minutes
before it was charged with the carbene complex 227 (77.7 mg, 0.2 mmol), one equiv Of
Fe2(C0)9 (72.8 mg, 0.2 mmol), and 10 mL Of the solvent. The mixture was degassed by
the freeze-thaw method (—196/25 °C, 3 cycles), back-filled with 1 atm CO at room
temperature, sealed and heated at 80 °C or 130 °C until the red color disappeared,
indicating all the starting carbene complex was consumed. The mixture was then allowed
to cool tO room temperature and transferred to a 100-mL round bottom flask and
concentrated under reduced pressure. The residue was subjected to silica gel
chromatography (5—10% Et0Ac/hexanes) to give the first eluted 9-methoxy fluorene 270
as the major isomer, followed by the enol ether 271 that was contaminated by a small
amount Of 270, and the third eluted phenol product 228 (in the cases that 228 and 271
were also formed).

Following the general procedure (I) described above, when benzene was used as
the solvent and at 80 °C, after 16 d, the reaction gave 271 (9.0 mg, 20%) and 270 (26.6
mg, 68%); when THF was used as the solvent and at 80 °C, after 7 d, the reaction gave
270 (30.9 mg, 79%), along with a trace (< 1%) Of 228; when acetonitrile was used as the

solvent and at 80 °C, after 5 d, the reaction gave 270 (30.0 mg, 77%); when toluene was

182

used and at 130 °C, after 1 d, the reaction gave 270 (31.4 mg, 80%) and only trace (< 1%)
Of 228 was Observed.

For the reactions that were carried out in the absence Of F e2(C0)9, the general
procedure (I) described above was followed except that none Of the iron source was
added. When the reaction was performed in benzene without any iron source at 80 °C for
12 d, 228 (7.0 mg, 16%), 270 (10.0 mg, 26%) and 271 (20.2 mg, 26%) were Obtained;
when the reaction was performed in THF without any iron source at 80 0C for 16 d, 228
(6.7 mg, 15%) and 270 (22.8 mg, 58%) were Obtained, along with trace Of 271 (~ 3%);
when the reaction was performed in toluene without any iron source at 130 °C for 20 h,
270 (32.0 mg, 82%) was Obtained, along with traces of 228 (< 1%) and 271 (~ 2%).

Spectral data for 228: Rf = 0.18 (10% Et0Ac/hexanes); 1H NMR (300 MHz,
CDC13): 6 3.99 (8, 3H), 6.19 (s, 1H), 7.50-7.65 (m, 4H), 7.99 (d, 1H, J = 7.8 Hz), 8.28
(dd, 1H, J = 6.3, 3.6 Hz), 8.61-8.64 (m, 2H); IR (NaCl) 3394 br, 29248, 2855ms, 1628s,
14538 cm". The spectral data are consistent with the reported data for this compound.197

Spectral data for 270: Rf = 0.34 (10% Et0Ac/hexane8); 1H NMR (300 MHz,
CDC13): 6 3.04 (8, 3H), 5.59 (s, 1H), 7.30 (td, 2H, J = 7.5, 1.2 Hz), 7.38 (t, 2H, J= 7.5
Hz), 7.60 (d, 2H, J = 7.2 Hz), 7.66 (d, 2H, J = 7.2 Hz); MS (EI) m/z (% relative intensity)
196 (M+, 100), 195 (75), 181 (31), 165 (87), 152 (21). The spectral data are consistent
with the reported data for this compound.243

Spectral data for 271: Rf = 0.32 (10% Et0Ac/hexanes); 1H NMR (300 MHz,
CDCl;): 6 2.86 (s, 6H), 7.22-7.40 (m, 14H), 7.46 (d, 4H, J = 4.5 Hz); 13C NMR (125

MHz, CDC13) 6 56.52, 125.18, 126.99, 127.03, 127.80, 128.32, 128.58, 130.19, 130.50,

183

 

[mm

132.10, 141.77, 141.80. MS (EI) m/z (% relative intensity) 392 (M+, 45), 345 (28), 317

(32), 302 (18), 195 (11), 181 (80), 165 (40), 152 (65), 151 (100), 127(8), 77(5), 69(7).

General Procedure (11) — for reactions performed under 500 psi C 0: A Monel
Paar pressure reactor equipped with a magnetically driven mechanical stirrer was flushed
with carbon monoxide for a few minutes before it was charged with the carbene complex
227 (77.7 mg, 0.2 mmol), one equiv Of Fe2(C0)9 (72.8 mg, 0.2 mmol), and 10 mL of
benzene or toluene. Then the reactor was further flushed with C0 for another 2 minutes
and filled with 500 psi C0 and heated at 80 or 130 °C with stirring for 0.5—3.6 days. The
mixture was transferred tO a 100-mL round bottom flask and concentrated on a rotary
evaporator. The yields Of 228, 270 and 271 (and unreacted 227) were calculated from the
NMR spectra Of the crude mixture using triphenylmethane as the internal standard.

Following the general procedure (II) described above, when benzene was used as
the solvent, the reaction at 80 °C for 3.6 d gave 270 (19%) and 271 (4%), along with a
46% recovery of 227; when toluene was used as the solvent, the reaction at 130 °C for 12
h gave 228 (< 2%), 270 (50%) and 271 (13%); when no iron source was added and
toluene was used as the solvent, the reaction at 130 °C for 17 h gave 228 (< 2%), 270

(50%) and 271 (19%);

CT(CO)5

l OMe

 

237

Attempted Thermolysis of Complex 237 in the Presence or Absence of Fe2(C0)9.

184

l-'

Following the general procedure (I) described above for the thermolysis of 227
under 1 atm C0, the reaction conditions that were tried for 237 included: (1) with one
equiv Of Fe2(C0)9 in THF at 80 °C for 24 h and 90 °C for 48 h; (2) with one equiv of
Fe2(C0)9 in benzene at 90 °C for 41 h; (3) without any iron source in THF at 80 °C for
24 h and 90 °C for 48 h; (4) without any iron source in THF at 90 °C for 36 h; (5) without
any iron source in benzene at 90 °C for 41 h; (6) without any iron source in THF under 1
atm argon at 65 °C for 60 h. In each Of the above cases, all the starting carbene complex
237 was consumed, and a very complex mixture was Observed and none Of the desired
238 was isolated.

Following the general procedure (11) described above for the thermolysis of 227
under 500 psi C0, the reaction conditions that were tested for 237 included: (1) with one
equiv of Fe2(C0)9 in benzene at 90 °C for 16 h; (2) without any iron source in THF at 90
°C for 22 h. In each Of the two cases, all the starting carbene complex 237 was consumed,

and a very complex mixture was Observed and none Of the desired 238 was isolated.

The Preparation of Carbene Complexes 181(a—j).

lm’c and trans, trans-

Carbene complexes trans, trans-18mm, trans, trans-181c
1816245 are known in the literature. Aldehydes 257a, 257g, 2571, 260a, and ketone 261

are commercially available; aldehydes 2573'246 and 260b247 can be readily prepared

according to the literature procedures.

185

General Procedure for the Preparation of Complexes (trans,trans-181a, trans-181g,

trans-181i and trans-181 j): Illustrated for trans,trans-l8la.

OMe
OMe H
(0C)5Cr=( + O _ (0C)sCr
CH3 — ‘-
CH3 — CH
259 257: 181: 3

Carbene Complex trans, trans-I 81a. This procedure is similar tO one that has
been reported for this compound.112m The methyl(methoxy)carbene complex 256248 (0.25
g, 1 mmol) was dissolved in 30 mL Of anhydrous ether and deprotonated with one
equivalent of n-BuLi (2.5 M in hexanes, 0.4 mL) under argon at —78 °C for 20-30 min.
In a separate flask under argon, a solution Of crotonaldehyde 257a (0.41 mL, 5 mmol) in
10 mL Of CH2C12 was cooled to —78 °C and treated with SnCla (0.58 mL, 5 mmol) for 20-
30 min. Then the solution Of the enolate Of complex 256 was transferred via cannula tO
the flask with the aldehyde/SnC14 complex. The mixture was stirred at —78 °C for two
hours before it was quenched by the rapid addition to 50 mL Of water. The organic layer
was separated and washed with brine (30 mL) and dried over anhydrous Na2804. The
solvent was removed on a rotary evaporator and the residue was subjected to silica gel
chromatography by first elution with pentane to remove the unreacted 256 (46 mg, 18.4%
recovery) and subsequent elution with ether/CH2Cl2/hexanes (1:1:3) to give the aldol
adduct. The aldol adduct, after removal Of the solvent, was dissolved in ~ 50 mL Of
CH2C12 and cooled to 0 °C, then MsCl (0.16 mL, 2 mmol) and Et3N (0.31 mL, 2.2 mmol)
were added. When the dehydration reaction was complete as indicated by TLC (usually
5-10 min), it was quenched by saturated aqueous NaHC03 solution (20 mL). The organic
layer was separated and the aqueous phase was further extracted with ether (2 x 15 mL).

The combined organic layer was washed sequentially with aqueous NaHC03 (30 mL)

186

solution and brine (30 mL), dried over anhydrous Na2804 and concentrated. The residue
was chromatographed on silica gel with hexanes to afford the carbene complex 181a (156
mg, 52% yield) as a red solid. The yield based on unrecovered 256 was 63%.

Spectral data for trans, trans-181a: Rf = 0.24 (hexanes); mp 51—52 °C; 1H NMR
(300 MHz, CDC13): 6 1.89 (d, 3H, J = 6.0 Hz), 4.70 (s, 3H), 6.06-6.15 (m, 1H), 6.25-6.35
(m, 1H), 6.10 (dd, 1H, J = 14.7, 11.1 Hz), 7.24 (d, 1H, J = 14.7 Hz); l3C NMR (125
MHz, CDC13) 6 19.40, 66.05, 130.69, 131.99, 141.46, 144.83, 216.84, 224.32, 332.68; IR
(NaCl) 2056vs, 1921vs br, 15728 cm"; MS (EI) m/z (% relative intensity) 302 (M+, 1),
274(2), 246(1), 218 (1), 190(10), 162 (15), 147(14), 130(20), 117(7), 91 (5), 52 (100).

Anal calcd for C12H10Cr06: C, 47.69; H, 3.34. Found: C, 47.69; H, 3.44.

0C Cr
M3513 —‘ ’5 it)

2579 1819

Carbene Complex trans-1 81 g. Following the procedure described above for the
preparation Of 181a, the reaction Of 256 (250 mg, 1 mmol) and 257g (0.57 mL, 5 mmol)
afforded 181g (105 mg, 31% yield) as a red solid, along with recovered 256 (124 mg,
50% recovery). The yield based on unrecovered 256 was 61%.

Spectral data for trans-181g: Rf = 0.24 (hexanes); mp 69—70 °C; 1H NMR (300
MHz, CDCl;) 6 1.60-1.72 (m, 4H), 2.18-2.24 (m, 4H), 4.69 (s, 3H), 6.35 (t, 1H, J = 3.6
Hz), 6.65 (d, 1H, J= 15.3 Hz), 7.26 (d, 1H, J= 15.3 Hz); 13C NMR (125 MHz, CDC13) 6
21.89, 21.96, 24.03, 27.35, 66.02, 135.36, 135.59, 137.20, 145.20, 217.01, 224.34,
332.43; IR (NaCl) 2056vs, 1919vs br, 15708 cm’l; MS (EI) m/z (% relative intensity)

342 (M+, 1), 314 (3), 286 (2), 258 (3), 230 (18), 202 (46), 200 (34), 170 (14), 168 (21),

187

160 (44), 129 (14), 91 (20), 77 (15), 52 (100). Anal calcd for C.5H,,CrO,: C, 52.64; H,

4.12. Found: C, 52.37; H, 3.97.

H OMe

OMe
(0C)5Cr==( + Gig“ ——- (°C)scr:<=\_<cl13
CH _
3 CH3

256 2571 1811 CH3

Carbene Complex trans-1817'. Following the procedure described above for the
preparation Of 181a (except that two equivalents Of aldehyde/SnC14 was used), the
reaction of 256 (1.0 g, 4 mmol) and 257i (0.77 mL, 8 mmol) afforded 181i (0.66 g, 52%
yield) as a red solid, along with recovered 256 (0.25 g, 25% recovery). The yield based
on unrecovered 256 was 70%.

Spectral data for trans-181i: Rf = 0.19 (hexanes); mp 67—68 °C; 1H NMR (300
MHz, CDC13): 1.92 (s, 6H), 4.67 (s, 3H), 5.94 (dt, J = 11.4, 1.2 Hz, 1H), 7.03 (dd, J =
14.4, 11.4 Hz, 1H), 7.20 (d, J = 14.4 Hz, 1H); 13C NMR (125 MHz, CDCl;): 19.4, 27.3,
65.8, 124.9, 130.2, 141.0, 153.2, 217.1, 224.4, 331.4; IR (cm-1): 2056vs, 1919vs br,
1561m; MS (EI) m/z (relative intensity) 316 (M+, 2), 288 (7), 260 (1), 232 (3), 204 (24),
176 (32), 161 (49), 160 (33), 144 (41), 131 (38), 109 (13), 91 (31), 79 (29), 77 (26), 52

(100); Anal. Calcd for C13H12Cr06: C, 49.38; H, 3.82. Found: C, 49.72; H, 3.91.

(OC)5Cr=(:M: °£O__. (“km—”6:6

269 257] 181]
Carbene Complex trans-I81]. Following the procedure described above for the
preparation Of 181a (except that 2.9 equivalents of aldehyde/SnC14 was used), the

reaction Of 256 (0.685 g, 2.74 mmol) and 257j246 (1.70 g, 8 mmol) afforded 1811' (0.50 g,

188

51% yield) as a red solid along with recovered 256 (0.20 g, 29% recovery). The yield
based on unrecovered 256 was 72%.

Spectral data for trans-181i: Rf = 0.24 (hexanes); mp 60—61 °C; IH NMR (300
MHz, CDC13) 6 1.60 (brs, 6H), 2.24-2.26 (m, 2H), 2.39-2.41 (m, 2H), 4.67 (s, 3H), 5.88
(d,1H, J=11.7 Hz), 7.09 (dd, 1H, J=14.1,11.7 Hz), 7.25 (d, 1H,J = 14.1 Hz); l3C
NMR (125 MHz, CDC13) 6 26.47, 28.12, 28.65, 30.34, 38.47, 65.75, 121.77, 129.16,
141.36, 161.61, 217.09, 224.40, 331.00; IR (NaCl) 2056s, 1919vs br, 1559m cm"; MS
(EI) m/z (% relative intensity) 356 (M, 1), 328 (5), 300 (3), 272 (3), 244 (35), 216 (35),
214 (52), 184 (41), 161 (43), 160 (66), 121 (40), 91 (63), 77 (30), 52 (77), 51 (100). Anal

calcd for C16H16Cr06: C, 53.94; H, 4.53. Found: C, 54.09; H, 4.60.

OMe

OMe H
(OC),Cr==( 4 Qt (OC)5Cr
CH3 — _
Ph —

253 290: 1916 P“
The Preparation of Carbene Complex tranerans-181b.

This compound was prepared by Aumann’s method for related compounds.l ”b A
solution of 256 (1.25 g, 5 mmol) in 30 mL Of ether was treated (with cinnamaldehye 260a
(0.66 g, 5 mmol), TMSCl (1.91 mL, 15 mmol) and RN (2.80 mL, 20 mmol) and stirred
at room temperature for 3 days. The dark red mixture was filtered through a short pad Of
Celite and concentrated. The residue was subjected to silica gel chromatography (hexanes
as the e1uent)tO afford 181b (1.24 g, 68% yield) as a red solid.

Spectral data for trans, trans-181b: Rf = 0.10 (hexanes); mp = 87—88 °C; IH
NMR (300 MHz, CDCl;) 6 4.74 (s, 3H), 6.75-6.85 (m, 2H), 7.02-7.07 (m, 1H), 7.31-7.41

(m, 3H), 7.43-7.50 (m, 3H); 13C NMR (125 MHz, CDCl3) 6 66.11, 127.01, 127.39,

189

 

128.90, 129.59, 131.01, 136.11, 142.85, 145.04, 216.80, 224.48, 331.42; IR (NaCl)
2054vs, 1917vs br, 15618 cm‘l; MS (EI) m/z (% relative intensity) 364 (M, 1), 336 (1),
308(1), 280(1), 252(5), 224 (13), 205 (100), 172(9), 128 (15), 115 (18), 77 (13), 73

(53), 51 (52). Anal calcd for C17H12Cr06: C, 56.05; H, 3.32. Found: C, 56.32; H, 3.55.

CC C
(OC)5Cr=<:M: _. ( )5 r

2601) 131 1‘! Ph

The Preparation of Carbene Complex traneranerans-lSlh.

Following the procedure described above for the preparation Of 181b, the reaction
of 256 (0.49 g, 1.96 mmol) and 2606247 (0.31 g, 1.96 mmol) with TMSCl (0.75 mL, 5.88
mmol) and Et3N (1.10 mL, 7.84 mmol) in 10 mL Of ether afforde l81h (0.55 g, 72%
yield) as a red solid.

Spectral data for trans,trans,trans-278h: Rf = 0.10 (hexanes); mp 180 °C (dec).
lH NMR (300 MHz, CDC13) 6 4.72 (s, 3H), 6.36 (dd, 1H, J= 14.1, 11.4 Hz), 6.71 (d, 1H,
J = 11.4 Hz), 6.76 (d, 1H, J: 12.0 Hz), 6.83-6.95 (m, 2H), 7.26-7.38 (m, 4H), 7.41-7.44
(m, 2H); 13C NMR (125 MHz, CDC13) 6 65.98, 127.03, 128.36, 128.55, 128.83, 131.26,
131.30, 136.45, 137.83, 142.41, 145.55, 216.87, 224.56, 330.42; IR (NaCl) 2054vs,
1921vs br cm"'; MS (EI) m/z (% relative intensity) 390 (M, 1), 362 (1), 334 (2), 306(1),
278 (21), 250 (63), 218 (29), 198 (23), 167 (29), 165 (26), 152 (18), 149 (29), 129 (18),
128 (18), 115 (10), 103 (50), 77 (33), 52 (87), 51(100). Anal calcd for C19H14Cr06: C,

58.47; H, 3.62. Found: C, 58.10; H, 3.84.

190

 

NOE

OMe
OMe CH3 fl
(OC)50r=< , o=(__\ (cotter cu, H
CH3

H _
H
256 261 L; P“
”CE 1816

The Preparation of Carbene Complex transports-1816

This compound was prepared by a procedure published for related compounds.l ”d
To a solution of the methyl(methoxy)carbene complex 256 (0.25 g, 1 mmol) in 30 mL of
ether under argon was added n-BuLi (2.5 M in pentane, 0.4 mL, 1 mol) at —78 °C and
stirred for 20 minutes. In a separtate flask, trans-4-phenyl-3-buten-2-one 261 (1.46 g, 10
mmol) in 50 mL of ether under argon was treated with BF3°0Et2 (1.27 mL, 10 mol) at
0 °C and stirred for 20 minutes. The solution Of the enolate Of complex 256 was
transferred via cannula to the flask with the 261/BF3'0Et2 complex at 0 °C. The mixture
was then allowed to warm tO room temperature and stirred for an hour before it was
poured into an Erlenmeyer flask with 25 mL Of buffer solution (pH = 7). The organic
layer was separated and the aqueous phase was further extracted with ether (30 mL). The
combined organic layers were washed sequentially with H20 (30 mL) and brine (30 mL),
dried over anhydrous Na2S04 and concentrated. The residue was dissolved in 25 mL Of
hexanes and A1203 (Activated, Brockmann I, 2.0 g, 5.0 equivalents by weight) was added
and stirred vigorously until TLC showed no aldol adduct was left. The mixture was then
filtered and concentrated. Purification by silica gel chromatography afforded 181c (0.161
g, 43% yield) as a dark red solid, along with recovered 256 (0.040 g, 16% recovery). The

yield based on unrecovered starting material was 51%. The stereochemistry Of l8le was

confirmed by an NOE study as shown above.

191

Spectral data for trans,trans-181e: Rf = 0.13 (hexanes); mp 110—111 °C; lH
NMR (300 MHz, CDC13) 6 2.06 (s, 3H), 4.76 (s, 3H), 6.76 (d, 1H, J = 16.2 Hz), 6.98 (d,
1H, J = 16.2 Hz), 7.29-7.50 (m, 6H); 13C NMR (125 MHz, CDC13) 6 15.51, 66.28,
127.13, 128.85, 128.91, 132.40, 134.59, 136.42, 137.11, 143.57, 216.69, 224.28, 337.66;
IR (NaCl) 2053s, 1921vs br, 1536m cm"; MS (EI) m/z (% relative intensity) 378 (M+,
0.3), 350 (0.2), 322 (1), 294 (0.5), 266 (6), 238 (29), 187 (22), 186 (33), 171 (32), 153
(31), 141 (34), 128 (100), 115 (31), 91 (18), 77 (15), 51 (49). Anal calcd for ClsHtaCr06:

C, 57.15; H, 3.73. Found: C, 57.41; H, 3.90.

H30 ' OMe
OC) Cr
_ “3° — Ph H30 _
Ph
262 P"

263 1911
The Preparation of Carbene Complex tranerans-181f.

The vinyl iodide trans, trans-263, the precursor to 181f, was prepared using the
one-pot hydroboration/iodination249 sequence as follows. To a solution of 1-((E)-pent-1-
en-3-ynyl)benzene 262250 (0.67 g, 4.7 mmol) in 5 mL Of CH2C12 at 0 °C, HBBr2-SMe2
(1 M in CH2C12, 4.7 mL, 4.7 mmol) was added dropwise. After the addition was complete,
the cold bath was removed and the mixture was allowed to warm to room temperature
and stirred for 3 hours. Then the volatiles were removed on a rotary evaporator and the
crude borane was added at 0 °C tO an aqueous NaOH solution (3N, 8 mL, 5 equivalents)
with rapid stirring. After the mixture had been stirred for 30 minutes at 0 °C, 5 mL of
ether was added, followed by dropwise addition Of 12 (1.31g, 5.2 mmol) in 15 mL Of
ether. The reaction mixture was stirred at 0 °C for 30 minutes, followed by warming to

room temperature and stirring for an additional 30 minutes. Excess 12 was then destroyed

192

with a few drops of saturated aqueous Na2S203 solution. The ether layer was separated
and the aqueous layer was extracted with ether (3 x 10 mL). The combined organic
phase was dried over anhydrous Na2SO4 and concentrated on a rotary evaporator. The
residue was subjected to silica gel chromatography (hexanes as the eluent) to give
trans,trans-263 (300 mg, 24% yield) as a white solid that was contaminated with a small
amount Of inseparable impurities, but appeared to be one regioisomer. Some starting
enyne was also recovered (106 mg, 16%). The stereochemistry was assigned based on
halogen-metal exchange with n-BuLi followed by protonation. The resulting trans,cis-l-
phenylpenta-1,3-diene has NMR data consistent with published data for this
compound?“

Spectral data for trans,trans-263: Rf = 0.26 (hexanes); 1H NMR (300 MHz,
CDC13) 6 2.59 (d, 3H, J= 1.2 Hz), 6.48 (d, 1H, J= 15.0 Hz), 6.83 (dd, 1H, J= 15.0, 10.8
Hz), 6.93 (dd, 1H, J = 10.8, 1.5 Hz), 7.24-7.40 (m, 5H); 13C NMR (125 MHz, CDC13) 6
28.26, 97.56, 123.61, 126.49, 127.93, 128.68, 132.78, 136.79, 140.73; MS (EI) m/z (%
relative intensity) 270 (M, 100), 143 (61), 128 (17), 115 (13). Reliable elemental
analysis data were not Obtained due to the small amount Of inseparable impurities.

TO a solution Of trans, trans-263 (160 mg, 0.60 mmol) in 15 mL Of ether at —78 0C
was added t-BuLi (1.7 M in pentane, 0.71 mL, 1.2 mmol) dropwise. The mixture was
then stirred at —78 °C for 2 hours before it was transfered via cannula to Cr(C0)(, (159
mg, 0.72 mmol) in 15 mL Of ether at room temperature. The solution was stirred for 3
hours and then cooled to 0 °C. MeOTf (0.12 ml, 1.08 mmol) was added and solution was
warmed to room temperature and stirred for 1 hour. The reaction was quenched with

aqueous NaHCO; (10 mL) solution and the organic layer was washed with brine ( 15

193

 

mL), dried over anhydrous Na2S04 and concentrated. The residue was chromatographed
on silica gel with hexanes to give the carbene complex 1811' as a red solid, contaminated
with small amount Of impurities. Recrystallication from hexanes at low temperature (—78
°C) afforded pure 1811' (140 mg, 62% yield).

Spectral data for trans,trans-l8lf: Rf = 0.10 (hexanes); mp 114—1 15 °C; 1H NMR
(300 MHz, CDC13) 6 1.96 (s, 3H), 4.66 (s, 3H), 6.89-7.11 (m, 3H), 7.28-7.38 (m, 3H),
7.47-7.50 (m, 211); 13C NMR (125 MHz, CDC13) 6 14.16, 66.39, 123.76, 127.13, 128.82,
128.85, 136.63, 138.23, 139.84, 150.52, 216.76, 223.82, 346.90; IR (NaCl) 2053s,
1917vs, 1904vs cm"; MS (EI) m/z (% relative intensity) 378 (W, 0.4), 350 (0.4), 322
(6), 294(3), 266 (10), 238 (17), 206 (18), 195 (22), 193 (21), 180 (13), 179 (11), 167
(13), 165 (13), 141 (17), 128 (27), 115 (25), 91 (29), 77 (14), 52 (100). Anal calcd for

C13H14C1‘O62 C, 57.15; H, 3..73 Found: C, 57.05; H, 3..67

”Fe(con

OMe H O
(OC)sCr _ 500psi CO Hacm‘me + moi/0W
— H30 \ \ OMe ..
CH3
181a 2536 254.
The Thermolysis of trans,trans-181a under 500 psi CO.

A Monel Paar pressure reactor equipped with a magnetically driven mechanical
stirrer was flushed with carbon monoxide for a few minutes before it was charged with
the carbene complex 181a (30.2 mg, 0.1 mmol) and 5 mL Of benzene. Then the reactor
was further flushed with C0 for another 2 minutes and filled with 500 psi C0 and heated
at 80 °C with stirring for 2 hours. The mixture was transfered to a 100-mL round bottom

flask and concentrated on a rotary evaporator. The residue was purified by silica gel

194

 

chromatography to give 253a (~6.6 mg, 30%) as a yellowish oil (~l.4:1 mixture of
isomers) and 254a (10.9 mg, 39%) as a yellowish solid.

Spectral data for 253a: Rf = 0.54 (10% EtOAC/hexanes); 1H NMR (300 MHz,
CDC13) 1.76-1.80 (m, 6H), 3.59 (s, 3.5H, major isomer), 3.67 (8, 2.5H, minor isomer),
5.72-5.82 (m, 2H), 6.10-6.22 (m, 3H), 6.27-6.46 (m, 3H). This compound was very
unstable and other spectral data were not obtained.252

Spectral data for 254a: Rf = 0.14 (10% EtOAC/hexanes); mp 98—99 °C; 1H NMR
(300 MHz, CDC13) 6 1.26 (d, 3H, J= 6.6 Hz), 2.30 (q, 1H, J= 6.6 Hz), 2.78 (dt, 1H, J=
6.6, 2.1 Hz), 3.59 (s, 3H), 5.35 (m, 1H), 6.00 (dd, 1H, J = 4.8, 2.1 Hz); 13C NMR (125
MHz, CDC13) 6 16.80, 37.67, 56.95, 61.20, 78.88, 85.37, 110.63, 194.44, 209.60; IR
(NaCl) 2054vs, 1981vs br, 16768 cm‘l; MS (EI) m/z (% relative intensity) 278 (M+, 3),
250 (8), 222 (47), 194 (25), 179 (100), 164 (26), 162 (23), 134 (20), 95 (22), 83 (17), 56
(53), 41 (18); HRMS-FAB (NBA as the matrix) calcd for CanFe05 (MH+) m/z
278.9956, meas 278.9943. Anal calcd for CtthoFe05: C, 47.52; H, 3.64. Found: C,
47.34; H, 3.58. The stereochemistry was assigned as syn based on the X-ray structure
determination (Appendix 2).

The presence of iron in 254a was confirmed by SEM/EDS. The analysis was
performed using a JEOL J SM-3 5C scanning electron microscope (SEM) equipped with a
Noran energy dispersive spectrometer (EDS). Data were acquired using a 20 kV
accelerating voltage and an accumulation time of 60 seconds. The carbene complex 181a
was also subjected to an SEM/EDS analysis which revealed the presence of chromium

and the absence of iron. The two spectra are shown in Appendix 3.

195

For the reactions in the presence of an external source of iron under 500 psi C 0,
the procedure described above was followed except that one or 1.5 equivalents (as shown
in Table 4.1 in the text) of an iron source was also added.

When one equiv of Fe3(C0)12 was present the reaction gave 254a in 58% yield.
The same reaction with 1.5 equiv Fe3(C0)12 afforded a 59% yield of 254a.

When one equiv of benzylideneacetone iron tricarbonyl (Fe(C0)3(ba)) was
present the reaction gave 254a in 63% yield. The same reaction with 1.5 equiv
Fe(C0)3(ba) afforded a 63% yield of 254a as well.

When one equiv of Fe2(C0)9 was present the reaction gave 254a in 89% yield.
The same reaction with 1.5 equiv Fe2(C0)9 afforded the exactly same 89% yield of 254a.

In each of the above cases, a trace amount (< 5%) of the pentaene 253a was

observed.

General Procedure for the Iron Mediated Carbonylative Cyclization of Carbene
Complexes 181 and the Preparation of Iron Tricarbonyl Cyclohexadienone

Complexes 254 and Phenols 255: Illustrated for trans,trans-Carbene Complex 181 a.

5;:Fa(CO)3

OH
(OCWRCW—r ”30%/0M9 H3660“!
255a

1813

Trans, trans-Carbene Complex I81a. A 25-mL flask with a threaded Teflon high-
vacuum stop-cock was flushed with nitrogen for 10 minutes before it was charged with

the carbene complex 181a (60.4 mg, 0.2 mmol), Fe2(C0)9 (72.8 mg, 0.2 mmol), and 10

196

mL of the solvent (THF or benzene in most cases). The mixture was degassed by the
freeze-thaw method (—196/25 °C, 3 cycles), back-filled with 1 atm C0 (or argon in some
cases for the optimization with 181a in Table 4.2 in the text) at room temperature, sealed
and heated at 80 °C until the red color disappeared, indicating all the starting carbene
complex was consumed. The mixture was then allowed to cool to room temperature and
transferred to a 100-mL round bottom flask and concentrated under reduced pressure.
The residue was subjected to silica gel chromatography (5—10% Et0Ac/hexanes) to
furnish the dienone complex 254a and the phenol 255a.

Following the general procedure described above, when THF was used the
solvent, after 36 hours, the reaction afforded 254a (33.9 mg, 61% yield) as a yellowish
solid and 255a (5.5 mg, 20% yield) as a white solid.

Spectral data for 255a: Rf = 0.26 (10% EtOAC/hexanes); 1H NMR (300 MHz,
CDC13) 6 2.23 (8, 3H), 3.85 (s, 3H), 6.69-6.74 (m, 3H); IR (NaCl) 35268 cm". The

spectral data agree with the data reported in the literature.253

For the optimization of the reaction of I81a (Table 4.2 in the text), each was
performed on half of the scale that the general procedure indicates.

(1) When benzene was used as the solvent without any iron source and in the

presence of 1 atm C0, no detectable amount of 255a (< 0.5%) was obsereved

after 144 hours. In the presence of 1 atm argon a small amount of 255a (8%)

was obtained after 144 hours.

197

(2) When the reaction was performed in benzene in the presence of Fe2(CO)9 and
1 atm C0 for 18 hours, 254a (70%) and 255a (8%) were obtained. The same
reaction under 1 atm argon gave 254a (58%) and 255a (6%) after 28 hours.

(3) When the reaction was performed in heptane in the presence of F e2(C0)9 and
1 atm C0 for 36 hours, 254a (68%) and 255a (7%) were obtained. The same
reaction under 1 atm argon gave 254a (54%) and 255a (5%) afier 20 hours.

(4) When the reaction was performed in THF in the presence of Fe2(C0)9 and 1
atm C0 for 36 hours, 254a (61%) and 255a (20%) were obtained. The same
reaction under 1 atm argon gave 254a (50%) and 255a (10%) after 20 hours.

(5) When the reaction was performed in CH3CN in the presence of F e2(C0)9 and
1 atm C0 for 17 hours, 254a (68%) and 255a (12%) were obtained. The same
reaction under 1 atm argon gave 254a (34%) and 255a (8%) after 20 hours.

(6) When the reaction was performed in benzene in the presence of Fe(C0)3(ba)
(benzylidineacetone iron tricarbonyl)254 (1 equiv) and 1 atm C0 for 48 hours,
254a (60%) and 255a (7%) were obtained. The same reaction under 1 atm

argon gave 254a (18%) and 255a (3%) after 7 hours.

OMe H O OH
(OC)sCr OMe P11 OMe
_ _. Ph *
Ph $Fe(CO)3
1 81 b 2541) 255b

Trans,trans-Chromium Carbene Complex 181 b. A solution of the chromium
carbene complex 181b (0.2 mmol) in THF was reacted with Fe2(C0)9 according to the
general procedure described above for 20 hours. Purification afforded 254b (5.1 mg,

7.5% yield) as a yellowish solid and 255b (29.7 mg, 74.3% yield) as a yellowish Oil

198

which solidified in freezer. During silica gel chromatography the complex 254b was
slowly converted to 255b such that only 255b could be isolated in the pure form while
254b was always contaminated with a small amount of 255b. The dienone complex
254b could be converted to 255b in high yield (96-98%) simply by stirring with silica gel
in CH2C12 in open air for a couple of days (this gives a total of 81% yield of 255b). If the
crude mixture was stirred under the same conditions until the conversion of 254b to 255b
was complete (2—3 d), a 78% yield of 255b was obtained after chromatography. The
same reaction in benzene for 45 h gave 254b in 5% yield and 255b in 70% yield.

Spectral data for 254b: Rf = 0.10 (10% EtOAC/hexanes); 1H NMR (300 MHz,
CDC13) 6 3.10 (dm, 1H, J= 6.6 Hz), 3.55 (s, 1H), 3.58 (8, 3H), 5.50 (m, 1H), 6.07 (dd,
1H, J = 4.8, 2.1 Hz) 7.28-7.41 (m, 5H); 13‘C NMR (125 MHz, CDC13) 6 46.70, 53.68,
61.30, 78.97, 85.53, 111.08, 127.13, 128.13, 128.64, 136.57, 191.68, 209.26; IR (NaCl)
2054vs, 1983vs br, 16828 cm"; MS (EI) m/z (% relative intensity) 340 (M+, 0.7), 312
(2), 284 (41) 256 (37), 226 (87), 208 (34), 200 (21), 18 (20), 157 (35), 141 (42), 129
(100), 127 (53), 115 (37), 84 (24), 77 (13), 57 (27), 56 (62), 51 (11).

Spectral data for 255b: Rf = 0.18 (10% Et0Ac/hexane8); 1H NMR (300 MHz,
CDC13) 6 3.92 (s, 3H), 5.85 (s, 1H), 6.84-6.98 (m, 3H), 7.29-7.34 (m, 1H), 7.42 (t, 2H, J
= 7.5 Hz), 7.59-7.62 (m, 2H); 13C NMR (125 MHz, CDC13) 6 56.14, 109.59, 119.66,
122.68, 127.10, 127.66, 128.18, 129.16, 137.67, 142.75, 146.78; IR (NaCl) 3509br,
2938m, 1590m, 1474s, 14338, 12698 cm'l; MS (EI) m/z (% relative intensity) 200 (M+,
100), 185 (30), 157 (11). Anal calcd for C13H1202: C, 77.98; H, 6.04. Found: C, 77.60;

H, 5.92.

199'

 

For the control experiments in the absence of Fe2(C0)9: following the general
procedure described above, the reaction of 181b (0.2 mmol) in benzene under 1 atm
argon for 96 h without any iron source gave 255b (~ 7%) along with a 28% recovery of
181b. The same reaction under 1 atm C0 for 96 h gave trace (< 1%) of 255b along with a
83% recovery of 181b.

The reaction of 181b (0.2 mmol) in THF under 1 atm argon for 96 h without any
iron source gave trace (< 1%) of 255b. The same reaction under 1 atm C0 for 96 h gave
trace (< 3%) of 255b.

For the reactions under photochemical conditions: A solution of 181b (182 mg,
0.5 mmol) in 125 mL of dry THF in a quartz photoreactor was purged with nitrogen for
15 min and then with C0 for another 15 min. The solution was photolyzed with a 450 W
medium pressure mercury lamp for 14 h while slowly sparging with CO. The resulting
yellowish solution was allowed to stand over night under 1 atm C0 before it was
concentrated. Purification by silica gel column chromatography (5—10% Et0Ac/hexanes)

afforded only a small amount of 255b (~ 3 mg, 4.3% yield).

OMe H

O
(oc)5w OMe OH
Ph Q Ph flow;
__ —————. .4.
254b

1.
P6 Fe(CO)a
181c 2556

Trans, trans-Tungsten Carbene Complex 181c. A solution of the tungsten carbene
complex 181c in THF was reacted with was reacted with Fe2(C0)9 for 72 h following the
general procedure described above. Purification gave 254b (7.0 mg, 10% yield) as a
yellowish solid and 255b (32.7 mg, 82% yield) as a yellowish oil which solidified in

freezer. The same reaction in benzene for 24 h gave 254b in 30% yield and 255b in 45%

200

 

yield. Spectral data for 254b and 255b matched those obtained from the reaction of the

chromium complex 181b.

(3E1 Pi C) (DE! (DH
(0&5ch Ph,.* Ph . : ,OEl
_ ——. +
254d

pr. item):
1816 255d

Trans, trans-Chromium Carbene Complex I81d. A solution of the ethoxy carbene
complex 181d in THF was reacted with Fe2(CO)9 for 24 h following the general
procedure described above. Purification afforded 254d (11.0 mg, 16% yield) as a
yellowish solid and 255d (30.0 mg, 70% yield) as a yellowish oil which solidified in
freezer. During the silica gel chromatography, 254d was slowly converted to 255d such
that only 255d could be isolated in the pure form while 254d was contaminated with a
small amount of 255d. The same reaction in benzene after 36 h gave 254d in 20% yield
and 255d in 61% yield.

Spectral data for 254d: Rf = 0.12 (10% EtOAc/hexanes); 'H NMR (300 MHz,
CDC13) a 1.21 (t, 3H, J = 6.9 Hz), 3.08-3.12 (m, 1H), 3.14-3.22 (m, 1H), 3.56 (s, 1H),
4.33-4.43 (m, 1H), 5.50 (ddd, 1H, J = 6.6, 4.8, 0.9 Hz), 6.08 (dd, 1H, J = 4.8, 2.1 Hz),
7.27-7.41 (m, 5H); 13C NMR (125 MHz, CDC13) a 15.36, 46.74, 53.62, 70.07, 79.02,
85.78, 110.37, 127.08, 128.09, 128.64, 136.61, 191.75, 209.42; IR (NaCl) 2054s, 1987vs,
l682m cm"; MS (EI) m/z (% relative intensity) 354 (M+, 0.3), 326 (1), 298 (54), 270
(65), 226 (100), 214 (11), 208 (28), 185 (15), 164 (39), 152 (24), 133 (41), 128 (43), 78
(27), 56 (41).

Spectral data for 255d: Rf = 0.25 (10% EtOAc/hexanes); 1H NMR (300 MHz,

CDCl3) 6 1.47 (t, 3H, J = 7.2 Hz), 4.16 (q, 2 H, J = 7.2 Hz), 5.93 (s, 1H), 6.83-6.98 (m,

201

3H), 7.29-7.35 (m, 1H), 7.39-7.45 (m, 2H), 7.59-7.63 (m, 2H); 13C NMR (125 MHz,
CDCl;) 6 14.992, 64.74, 110.52,119.60, 122.57, 127.03, 127.60, 128.14, 129.15, 137.78,
142.92, 146.02; IR (NaCl) 35151», 2980m, 1470s, 1437m cm"'; MS (EI) m/z (% relative
intensity) 214 (M, 80), 186 (100), 157 (10), 139 (12), 128 (36), 115 (19), 102 (12), 77

(23). Anal calcd for C14H1402: C, 78.48; H, 6.59. Found: C, 78.46; H, 6.45.

— _ ph ortwcoh CH3

181° 254. 2550

Trans,trans-Chromium Carbene Complex 181c. A solution of the carbene
complex l8le in benzene was reacted with Fe2(CO)9 for 36 h following the general
procedure described above. Purification afforded 254e (34.9 mg, 49% yield) as a
yellowish solid and 255e (17.2 mg, 40% yield) as a yellowish oil which solidified in
freezer. During the silica gel chromatography, 2546 was slowly converted to 255e such
that only 255e could be isolated in the pure form while 254e was contaminated with a
small amount of 255e. The same reaction in THF after 36 h gave 254e in 16% yield and
255e in 59% yield.

Spectral data for 254e: Rf = 0.12 (10% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13) 6 2.72 (s, 3H), 3.10 (dd, 1H, J= 2.4, 1.5 Hz), 3.56 (s, 1H), 3.57 (s, 3H), 5.98 (d,
1H, J= 2.4 Hz), 7.27-7.40 (m, 5H); 13C NMR (125 MHz, CDC13) 6 21.36, 46.63, 56.96,
61.16, 85.80, 96.83, 108.16, 127.04, 128.08, 128.63, 136.66, 192.25, 209.33; IR (NaCl)

2050vs, 1979vs br, 1684s cm‘l; MS (EI) m/z (% relative intensity) 354 (M, 0.2), 326

202

 

 

(0.5), 298 (22), 270 (42), 240 (100), 222 (18), 184 (10), 165 (21), 127 (30), 84 (13), 56
(35).

Spectral data for 255e: Rf = 0.22 (10% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13) 6 2.31 (s, 3H), 3.90 (s, 3H), 5.66 (s, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.27-7.32 (m,
1H), 7.37-7.43 (m, 2H), 7.56-7.59 (m, 2H); 13C NMR (125 MHz, CDC13) 6 21.13, 56.13,
110.61, 122.83, 127.02, 127.24, 128.16, 129.04, 129.12, 137.84, 140.44, 146.56; IR
(NaCl) 3517br,2940m,1601m,1503s, 1487s cm ;MS (EI) m/z (% relative intensity)
214 (M+, 100), 199 (45), 184 (47), 153 (12), 128 (25), 115 (13). Anal calcd for

C|4H14Ozz C, 78.48; H, 6.59. Found: C, 78.12; H, 6.67.

(“Roma/1;”. —. Pb H‘OMe ”16:0,“
H3O — 31:61:26“ CH
181f 2551

Trans,trans-Chromium Carbene Complex 1811'. A solution of the carbene
complex 1811' in benzene was reacted with Fe2(CO)9 for 10 h following the general
procedure described above. Purification gave 254f (51.1 mg, 72% yield) as a yellowish
solid and 2551' (6.4 mg, 15% yield) as a yellowish oil which solidified in freezer. During
silica gel chromatography, 254f was slowly converted to 255f. Thus only 2551' could be
isolated in the pure form while 254f was contaminated with a small amount of 255f. The
same reaction in THF for 36 h gave 44% yield of 254f and 36% yield of 255f.

Spectral data for 254f: Rf = 0.15 (10% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13) 6 2.38 (s, 3H), 2.94 (d, 1H, J= 6.3 Hz), 3.52 (s, 1H), 3.61 (s, 3H), 5.47 (d, 1H, J

= 6.3 Hz), 7.27-7.38 (m, 5H); l3c NMR (125 MHz, CDC13) 6 16.24, 46.58, 49.71, 61.43,

80.26, 103.10, 111.75, 127.01, 128.08, 128.61, 136.87, 192.75, 209.47; IR (NaCl)

203

 

2051vs, 1979vs br, 1682s cm’l; MS (EI) m/z (% relative intensity) 354 (M+, 0.3), 326
(1), 298 (41), 270 (44), 240 (100), 222(31),184(14),l78(14),166(22), 153(11),141

(16), 128 (21), 115 (20), 56 (21).

 

Spectral data for 255f: Rf = 0.18 (10% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13) 6 2.33 (s, 3H), 3.83 (s, 3H), 5.86 (s, 1H), 6.60 (d, 1H, J= 8.1 Hz), 7.01 (d, 1H, J
= 8.1 Hz), 7.28-7.34 (m, 1H), 7.39-7.44 (m, 2H), 7.56-7.59 (m, 2H); ”C NMR (125

MHz, CDC13) 6 15.84, 60.61, 122.10, 125.40, 126.31, 127.03, 128.29, 129.02, 129.79, r-

 

137.64, 145.63, 146.00; IR (NaCl) 3497br, 2940m, 1601m, 1487m, 1462m, 14125 cm’l;
MS (EI) m/z (% relative intensity) 214 (M+, 100), 200 (26), 199 (10), 141(3), 115(3).

Anal calcd for C14H1402: C, 78.48; H, 6.59. Found: C, 78.22; H, 6.34.

OMe H 0 OH
(OC)5Cr “0M8 I We
__ ——-p ‘9' +
"Fe(c0)3
1819 2549 2559

Trans-Chromium Carbene Complex 181g. A solution of the carbene complex
181g in benzene was reacted with Fe2(CO)9 for 24 h following the general procedure
described above. Purification afforded 254g (54.5 mg, 86% yield) as a yellowish fluffy
solid and 255g (~ 0.7 mg, 2% yield) as a white solid. The same reaction in THF for 72 h
gave 85% yield of 254g and 6% yield of 255g.

Spectral data for 254g: Rf = 0.10 (10% EtOAc/hexanes); mp 154—155 °C; lH
NMR (300 MHz, CDC13) 6 1.15-1.58 (m, 4H), 1.77-1.99 (m, 3H), 2.14-2.24 (m, 2H),
3.56 (s, 3H), 5.09 (d, 1H, J = 4.5 Hz), 5.91 (d, 1H, J = 4.5 Hz); 13C NMR (125 MHz,
CDC13) 6 24.84, 25.23, 28.49, 34.94, 43.92, 61.00, 75.66, 79.98, 82.30, 109.21, 194.87,

210.42; IR (NaCl) 2056s, 1989vs br, 1669s cm"; MS (EI) m/z (% relative intensity) 318

204

(M+, 2), 290 (3), 262 (46), 234 (36), 219 (100), 200 (24), 177 (11), 115 (13), 91 (14), 77
(11), 55 (18). Anal calcd for C14H14Fe05: C, 52.86; H, 4.44. Found: C, 52.98; H, 4.54.
Spectral data for 255g: Rf = 0.35 (10% EtOAc/hexanes); mp = 92—93 °C; 1H
NMR (300 MHz, CDC13) 6 1.72-1.77 (m, 4H), 2.66-2.70 (m, 4H), 3.83 (s, 3H), 5.63 (s,
1H), 6.56 (d, 1H, J= 8.1 Hz), 6.65 (d, 1H, J= 8.1 Hz); 13C NMR (125 MHz, CDC13) 6
22.59, 22.97, 23.06, 29.05, 56.15, 108.08, 119.42, 123.63, 130.80, 142.98, 143.75; IR

(NaCl) 3407br, 2924m, 1495m, 12715, 1090m cm"l; MS (EI) m/z (% relative intensity)

 

178 (M+, 100), 163 (20), 150 (35), 146 (32), 145 (52), 135 (56), 117 (47), 115 (43), 107
(43), 91 (43), 77 (41), 55 (24), 39 (42). Anal calcd for CuHMOz: C, 74.13; H, 7.92.

Found: C, 74.18; H, 8.28.

OMe OH
(OC)5Cf
__ PhVUOMe
181h Ph 2551:

Trans, trans, trans-Carbene Complex 1 81 h. A solution of the carbene complex
181h in benzene was reacted with Fe2(CO)9 for 8 h following the general procedure
described above. Purification afforded 255b (33.2 mg, 73% yield) as a yellowish solid.
The same reaction in THF for 10 h gave a 70% yield of 255b.

Spectral data for 255b: Rf = 0.14 (10% EtOAc/hexanes); mp 72-73 °C; 1H NMR
(300 MHz, CDC13) 6 3.89 (s, 3H), 5.96 (s, 1H), 6.75 (dd, 1H, J= 8.1, 1.8 Hz), 6.83 (t,
1H, J = 8.1 Hz), 7.14-7.24 (m, 3H), 7.30-7.45 (m, 3H), 7.51-7.54 (m, 2H); 13C NMR
(125 MHz, CDC13) 6 56.10, 109.40, 118.80, 119.53, 122.97, 123.73, 126.55, 127.37,
128.57, 129.38, 137.88, 143.48, 146.73; IR (NaCl) 3507br, 3023m, 2939m, 1588m,

1476s, 12653 cm’l; MS (EI) m/z (% relative intensity) 226 (M+, 100), 211 (11), 194 (12),

205

193 (24), 165 (66), 152 (20), 115 (15), 82 (21), 76 (26), 63 (12). Anal calcd for

C15H1402: C, 79.62; H, 6.24. Found: C, 79.42; H, 6.37.

C)

CMMe }1(;
(Donor 3 . OMe
— —~ 6

CH3 $F8(C0)3
1811 2541

T rans-Chromium Carbene Complex 1 81 i. A solution of the carbene complex 1811 t.-

‘1 "' J .' -

in THF was reacted with F e2(CO)9 for 48 h following the general procedure described

 

above. Purification afforded 2541 (47.5 mg, 81% yield) as a yellowish solid. The same
reaction in benzene for 72 h gave a 76% yield of 2541.

Spectral data for 2541: Rf = 0.22 (10% EtOAc/hexanes); mp 34—35 °C; 1H NMR
(300 MHz, CDC13): 0.91 (s, 3H), 1.26 (s, 3H), 2.87 (dd, J = 6.6, 2.1 Hz, 1H), 3.59 (s,
3H), 5.23 (dd, J= 6.6, 4.8 Hz, 1H), 5.99 (dd, J= 4.8, 2.1 Hz, 1H); 13C NMR (125 MHz,
CDC13): 25.8, 33.7, 41.4, 61.2, 63.3, 77.8, 85.1, 108.9, 197.2, 209.6; IR (cm'l): 2054vs,
1981vs br, 1678s; MS (EI) m/z (relative intensity) 292 (M+, 4), 264 (11), 236 (56), 208
(32), 193 (100), 178 (90), 176 (31), 162 (33), 121 (15), 109 (19), 96 (15), 84 (20), 81
(18), 79 (15), 56 (28); Anal. Calcd for CleleeOS: C, 49.35; H, 4.14. Found: C, 49.37;

H, 4.05.

OMe O
(0050 NaOMe
"' 3

"Fe CO)
181] 254] ( 3

Trans-Chromium Carbene Complex 1811'. A solution of the carbene complex

181j in THF was reacted with Fe2(CO)9 for 24 h following the general procedure

206

described above. Purification afforded 254j (56.6 mg, 85% yield) as a yellow oil. The
same reaction in benzene for 72 h gave an 81% yield of 254j.

Spectral data for 254j: Rf = 0.24 (10% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13) 6 1.03-1.07 (m, 1H), 1.22-1.28 (m, 1H), 1.31-1.45 (m, 5H), 1.53-1.54 (m, 1H),
1.75 (dt, 1H, J= 13.2, 4.2 Hz), 1.92 (td, 1H, J= 13.2, 4.2 Hz), 3.18 (dd, 1H, J= 6.6, 5.0
Hz), 3.59 (s, 3H), 5.28 (dd, 1H, J = 6.6, 5.0 Hz), 5.98 (dd, 1H, J = 5.0, 2.4 Hz); 13C
NMR (125 MHz, CDC13) 6 21.09, 21.61, 25.61, 32.83, 43.09, 44.57, 59.22, 61.18, 77.43,
85.18, 109.01, 196.79, 209.61; IR (NaCl) 2932m, 2054vs, 1979vs br, 1680s cm"; MS
(EI) m/z (% relative intensity) 332 (M, 2), 304 (11), 276 (100), 248 (62), 233 (95), 228
(16), 216 (27), 177 (70), 95 (31), 91 (26), 56 (75), 41 (20). Anal calcd for C|5H16Fe05:

C, 54.24; H, 4.86. Found: C, 54.64; H, 4.93.

H O OMe OH
1’I=e(00)3
254a 255a

Demetalation of the Iron Tricarbonyl Complex 254a.

The iron tricarbonyl complexes of the type 254 not having a phenyl group on the
sp3-ring carbon are quite robust and are not converted to the phenols 255 on silica gel. A
25-mL round bottom flask was charged with 254a (27.8 mg, 0.1 mmol), 5 mL of Et3N
and 0.5 mL of H20. This mixture was stirred at room temperature under argon for 5
hours. Then Et3N was removed on a rotary evaporator and 10 mL of ether was added
followed by 10 mL of saturated aqueous NH4C1 solution. The organic phase was
separated and the aqueous layer was further extracted with ether (2x10 mL). The

combined ether layer was dried over NaZSO4 and concentrated. The residue was loaded

207

 

onto a silica gel chromatography to afford 255a (12.5 mg, 91% yield) as a white solid.
Alternatively, when a solution of 254a (19.5 mg, 0.07 mmol) in 5 mL of pyridine was

refluxed under argon for 12 hours, phenol 255a was obtained in 82% yield (7.9 mg).

9

gFe(CO)3

o
2 2559
Demetalation of the Iron Tricarbonyl Complex 254g.
Following the procedure described above for the demetalation of 2542, after

stirring with Et3N/I-120 for 20 h, the complex 254g (31.8 mg, 0.1 mmol) was converted to

the phenol 255g (16.0 mg, 90% yield) as a white solid.

Cr(CO)5 OMe OMe OMe
(OCH-'6 (OC)3Fe
264 . 255 266: 2551:
The Thermolysis of Complex 264 in the Presence or Absence of Fe2(CO)9.
General Procedure: A 25-mL flask with a threaded Teflon high-vacuum stop-
cock was charged with the carbene complex 264205 (40.1 mg, 0.1 mmol), Fez(CO)9 (36.4
mg, 0.1 mmol), and 5 mL of THF or benzene. The mixture was degassed by the freeze-
thaw method (—196/25 °C, 3 cycles), back-filled with 1 atm CO or argon at room
temperature, sealed and heated at 80 °C until the red color disappeared, indicating all the
starting carbene complex was consumed. The mixture was then allowed to cool to room

temperature and transferred to a 100-mL round bottom flask and concentrated under

208

2" ". J-T

 

reduced pressure. The residue was subjected to silica gel chromatography (5—10%
EtOAc/hexanes) to furnish the phenol 265 and the iron complexes 266a and 266b.

Following the general procedure described above, when the reaction was
performed in THF under 1 atm CO for 48 h, 265 (12.0 mg, 49%), 266a (4.0 mg, 10%)
and 266b (3.6 mg, 9%) were obtained. The stereochemistry was tentatively assigned as
anti for 266a (presumably less polar) and syn for 266b. During the silica gel
chromatography, 266a/b were slowly converted to 265 such that only 265 could be
isolated in the pure form while 266a/b were contaminated with a small amount of 72. The
same reaction in benzene for 96 h gave 265 (13.9 mg, 57%) and 266a (2.6 mg, 7%) along
with trace (< 2%) of 266b.

Spectral data for 265: Rf = 0.14 (10% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13) 6 1.41-1.60 (m, 2H), 1.81-1.91 (m, 1H), 2.02-2.14 (m, 3H), 2.68 (t, 2H, J = 7.5
Hz), 2.83 (t, 2H, J = 7.5 Hz), 3.55 (q, 1H, J = 5.1 Hz), 3.68-3.85 (m, 2H), 3.97 (s, 3H),
5.17 (d, 1H, J = 5.1 Hz), 5.35 (s, 1H); 13C NMR (125 MHz, CDC13) 6 19.61, 22.85,
26.18, 29.01, 29.55, 41.64, 57.87, 61.40, 72.91, 126.13, 132.44, 132.62, 132.76, 140.38,
140.84. The spectral data are consistent with the reported data for this compound.205

Spectral data for 26621: Rf = 0.20 (30% EtOAc/hexanes); lH NMR (300 MHz,
CDC13) 6 1.72-2.09 (m, 9H), 2.20-2.25 (m, 1H), 2.57 (td, 1H, J: 4.8, 0.9 Hz), 3.67-3.71
(m, 1H), 3.76 (s, 3H), 3.89-3.92 (m, 1H), 4.08-4.14 (m, 1H), 5.65 (d, 1H, J= 2.4 Hz); 13C
NMR (125 MHz, CDC13) 6 19.37, 22.83, 25.03, 26.65, 30.56, 45.34, 49.92, 59.05, 62.01,
74.13, 77.49, 99.60, 101.50, 112.97, 184.23, 209.72; IR (NaCl) 20418, 1970vs, 1669m
cm"; MS (EI) m/z (% relative intensity) 386 (M, 1), 358 (2), 330 (31), 302 (3), 272

(100), 257 (17), 246 (11), 240 (38), 231(14),149(11),115(17), 91 (16), 56 (22).

209

Spectral data for 266b: Rf = 0.08 (30% EtOAc/hexanes); 'H NMR (300 MHz,
CDC13) 6 2.03 (m, 9H), 2.17-2.22 (m, 1H), 2.47-2.50 (m, 1H), 3.57 (td, 1H, J = 4.5, 3.3
Hz), 3.71 (s, 3H), 3.77-3.81 (m, 1H), 4.05-4.10 (m, 1H), 5.15 (d, 1H, J = 3.0 Hz); ”C
NMR (125 MHz, CDC13) 6 20.62, 25.17, 26.22, 26.59, 30.71, 41.82, 50.11, 59.03, 61.39,
64.14, 71.71, 71.96, 103.78, 109.80, 185.97, 210.27; IR (NaCl) 20415, 1968vs, 1669m
cm"; MS (EI) m/z (% relative intensity) 386 (M+, 1), 358 (1), 330 (29), 302 (2), 272 (75),
246 (14), 240 (28), 231 (20), 149 (18), 121 (21), 111 (21), 97 (27), 95 (22), 83 (31), 71

(76), 69 (47), 57 (100), 43 (34).

For the reactions that were carried out in the absence of Fe2(C0)9, the general
procedure described above was followed except that none of the iron source was added.
When THF was used as the solvent under 1 atm of argon without any iron source, after
10 h, the reaction gave 265 (9.8 mg, 40%) as a white solid. The same reaction under 1

atm CO afforded 265 in 42% yield (10.3 mg).

H “30 O
Ox ——’ 1>=\.=\ -———’ H3Cfiph
Ph Ph
2608 267 (Z/E = 10 : 1) 268

Preparation of Dienyl Iodide cis,trans-267 and its Conversion to Cyclopentenone 268
via the cis,trans-Carbene Complex 181f.

The iodide cis,trans-267 was prepared by a procedure reported by Zhao for
related compounds.255 To a stirred suspension of (ethyl)triphenylphosphonium iodide
(3.36 g, 8.0 mmol) in 40 mL THF was added n-BuLi (1.6 M in hexane, 5.0 mL, 8.0

mol) at room temperature. After the disappearance of the solid material, the solution

210

was transferred via cannula to a flask with iodine (1.83 g, 7.2 mmol) in 80 mL of THF at
—78 °C. The resulting suspension was vigorously stirred for 5 minutes and warmed to
—20 °C, then sodium bis(trimethylsi1yl)amide (1M in THF, 6.8 mL, 6.8 mmol) was added
to produce a red solution and the mixture was stirred for 5 minutes. T rans-
cinnamaldehyde 260a (0.85 mL, 6.7 mmol) was added and the solution was stirred for 10
minutes. The reaction was quenched with saturated aqueous NHaCl solution (100 mL)
and diluted with ether (100 mL). The mixture was filtered through a short pad of Celite.
The organic layer was separated and the aqeous phase was further extracted with ether (2
x 50 mL). The combined organic layers were washed sequentially with saturated
aqueous NH4C1 solution (100 mL), H20 (100 mL) and brine (100 mL) and then dried
with anhydrous MgSO4 and concentrated. Silica gel chromatography (hexanes as the
eluent) afforded cis,trans-267 (1.17 g, 65% yield) as a white solid (Z/E = 10:1). The
stereochemistry was assigned based on halogen-metal exchange with n-BuLi followed by
protonation. The resulting mixture of trans, trans-l-phenylpenta-l,3-diene and trans,cis-
1-phenylpenta-1,3-diene have NMR data consistent with published data for these two

compounds.” 1

Spectral data for cis,trans-267: Rf = 0.26 (hexanes); 1H NMR (500 MHz, CDC13)
6 2627-2630 (m, 3H), 6.48 (dq, 1H, J = 5.7, 0.3 Hz), 6.67 (d, 1H, J = 9.3 Hz), 6.80 (dd,
1H, J = 9.3, 5.7 Hz) 7.22-7.25 (m, 1H), 7.30-7.33 (m, 2H), 7.42-7.44 (m, 2H); 13C NMR
(125 MHz, CDC13) 6 34.12, 102.51, 126.59, 127.94, 128.65, 131.04, 134.27, 134.39,
136.99; MS (EI) m/z (% relative intensity) 270 (W, 100), 143 (70), 141 (25), 128 (68),

127(17), 115 (25). Anal calcd for CHHHI: C, 48.91; H, 4.10. Found: C, 48.88; H, 4.11.

211

 

p1

 

To a solution of cis,trans-267 (0.37 g, 1.37 mmol, Z/E = 10:1) in 30 mL of THF
was added two equivalents of t-BuLi (1.7 M in pentane, 1.61 mL, 2.74 mmol) dropwise
at -78 °C. The mixture was stirred for 2 hours at this temperature before it was
transferred via cannula to a solution of Cr(CO)6 (0.33 g, 1.51 mmol) in 30 mL of THF at
room temperature and stirred for 2 hours. Then MeOTf (0.28 mL, 2.47 mmol) was added
at 0 °C and stirred for 30 minutes. The reaction was quenched with saturated aqueous
NaHCO; solution (20 mL) and extracted with ether (3 x 30 mL). The combined ether
extracts were washed with brine (30 mL), dried over anhydrous Na2S04 and concentrated
on a rotary evaporator. The residue was subjected to silica gel chromatography (0-10%
EtOAc/hexanes) to afford cyclopentenone 268 (120 mg, 51% yield) as a colorless oil,
along with a small amount of carbene complex trans, trans-1811' (from the small amount
of the minor E-isomer of the starting material).

Spectral data for 268: Rf = 0.16 (10% EtOAc/hexanes); lH NMR (300 MHz,
CDC13) 6 1.82 (d (showing additional splitting, 3H), J = 2.4 Hz), 2.64 (dm, 1H, J = 18.9
Hz), 3.08 (dm (m shows 8 lines), 1H, J = 18.9 Hz), 3.54 (dd, 1H, J = 6.9, 2.4 Hz), 7.10-
7.43 (m, 6H); 13C NMR (125 MHz, CDC13) 6 10.41, 36.38, 50.98, 126.74, 127.53,
128.68, 139.76, 141.04, 157.04, 208.93; IR (NaCl) 3029m, 2923m, 17058, 1638m,
1495m cm"; MS (EI) m/z (% relative intensity) 172 (M, 100), 129(11), 1128 (20),
115(5), 104 (6), 103 (6). The 1H NMR data of 268 are consistent with those reported for

(1.256

this compoun The proton on the methylene that is trans to the phenyl group of 268

shows a particularly characteristic 8-1ine pattern.256

212

 

 

OEt
' ' (OC)5Cr
PthozH —> Ph—m—COZMe Ph—m—COZCI _ ,

‘75 278 280

 

 

274: P"

The Preparation of Carbene Complex 274a.

A solution of 176257 (1.75 g, 10 mmol) in 20 mL methanol was added 0.5 mL of
concentrated H2S04, and the mixture was exposed to ultrasound for 4 h. The reaction was
worked up by adding 25 mL of water and the product was extracted with CH2C12 (3 x 25
mL). The combined organic extracts were washed successively with 10% NaHCO;
aqueous solution and brine, dried with anhydrous MgS04 and concentrated to give
analytically pure ester 277 (1.76 g, 94%).

Spectral data for 277: Rf = 0.30 (10% EtOAc/hexanes); lH NMR (300 MHz,
CDC13) 6 3.75 (s, 3H), 5.97 (d, 1H, J = 15.3 Hz), 6.85-6.87 (m, 2H), 7.28-7.36 (m, 3H),
7.39-7.47 (m, 3H). The spectral data are consistent with the reported data for this

compound.258

To a dry 100 mL flask under argon was added 277 (1.74 g, 9.25 mmol), Fe2(CO)9
(3.54 g, 9.72 mmol) and degassed toluene (20 mL). The mixture was heated at 55 °C for
15 h before it was filtered through a short pad of Celite. After the removal of the solvent,
the residue was subject to silica gel column (5% EtOAc/hexanes) to give 278 (1.67 g,
54%) as a yellow solid, along with recovery of 277 (0.52 g, 30%). The yield based on
unrecovered 277 was 79%.

Spectral data for 278: R. = 0.26 (10% EtOAc/hexanes); mp 115-116 °C; 1H NMR
(300 MHz, CDCl;) 6 1.32 (dm, 1H, J= 7.2 Hz), 2.35 (dm, 1H, J= 8.7 Hz), 3.67 (s, 3H),
5.88-5.96 (m, 2H), 7.17-7.28 (m, 5H); 13C NMR (125 MHz, CDC13)6 45.47, 51.65,

82.35, 83.10, 126.23, 127.07, 128.75, 138.56, 172.48, 208.82 (hr); IR (NaCl) 2054s,

213

L h—

 

1987vs, 1713m cm"; MS (EI) m/z (% relative intensity) 328 (M+, 2), 300 (6), 272 (21),
244 (50), 214(31),186(29),184(65),128(100),127(62),115(12), 81 (11), 77 (12), 57
(40), 56 (50). Anal calcd for C15H12Fe05: C, 54.91; H, 3.69. Found: C, 55.06; H, 3.79.

A solution of 278 (0.60 g, 1.83 mmol) in 10 mL of CH3OH under argon was
added 10 mL of 30% KOH aqueous solution and 10 mL of THF. The mixture was stirred
at room temperature for 8 h before it was acidified with 10% HCl solution to a pH of
about 2 with external cooling. Extraction with ether (3 x 30 mL) followed by drying with
NaZSOa, and concentration gave a yellow solid. The product was purified by dissolving it
in a 30% NaOH solution, washing several times with ether, and then acidifying with 10%
HCl solution. The organic layer was separated and the aqueous phase was further
extracted with ether (3 x 20 mL). The combined organic phase was dried with Na2S04,
and concentrated to give a pure yellow crystalline solid 279 in 92% yield (0.53 g).

Spectral data for 279: mp 195 °C (dec); 1H NMR (300 MHz, CDC13 with drops of
DMSO-d6) 6 1.18 (dm, 1H, J= 7.5 Hz), 2.20 (dm, 1H, J = 8.7), 5.74-5.81 (m, 2H), 6.99-
7.27 (m, 5H), acid OH not observed; 13C NMR (125 MHz, CDC13) 6 46.20, 62.00, 81.98,
83.33, 125.92, 126.62, 128.39, 138.46, 173.45, 209.26 (hr); IR (NaCl) 2002s, 1975vs,
1669s cm"; MS (EI) m/z (% relative intensity) 314 (M+, 1), 286 (1), 258 (2), 230 (8), 184
(9), 174 (11), 135 (20), 129 (89), 128 (100), 117 (40), 115 (47), 107 (38), 105 (22), 97
(26), 95 (18), 91 (49), 77 (35), 69 (22), 55 (20).

To a stirred solution of 279 (0.50 g, 1.59 mmol) in 10 mL benzene at room
temperature as added oxalyl chloride (0.63 mL, 7.16 mmol), and the mixture was stirred
under argon for 5 h. The volatiles were removed on a rotary evaporator to give crude

acid chloride 280 (0.55 g, 99%) which was used directly for the next step.

214

 

 

Spectral data for 280: 1H NMR (300 MHz, CDC13 with drops of DMSO-d6) 6 1.55
(d, 1H, J = 6.9 Hz), 2.62 (d, 1H, J = 8.7 Hz), 5.90-5.99 (m, 2H), 7.22-7.38 (m, 5H).

To a 100-mL Schlenk flask was added graphite powder (0.37 g, 30.81 mmol, 19.5
equiv), and the flask was then placed in an oil bath and heated to 160 °C under vacuum.
During this time of heating, the freshly cut potassium metal (0.15 g, 3.84 mmol, 2.43
equiv) was rinsed in dry hexane and added portion-wise to the heated flask while stirring
and under a continuous flow of argon. (Note: It is important that either good stirring
and/or occasional manual shaking of the flask is maintained throughout the heating
process to ensure complete intercalation of the potassium metal into the graphite layers.
It is also desirable to open the flask under a flow of argon and scrape the melted
potassium off the wall of the flask and the surface of the stir bar.) The solid mixture was
kept at 160 °C with stirring under argon atmosphere until the color of the powder turned
from black to bronze, indicative of the formation of CsK. Total heating time once the
powder had turned bronze was about 35 min. The solid was then allowed to cool to
room temperature and 15 mL of dry THF was added under a positive flow of argon. The
bronze suspension was cooled to —78 °C and chromium hexacarbonyl (0.38 g, 1.74
mmol, 1.1 equiv) was added in one portion. The flask was closed under argon and the
dark suspension was allowed to warm to 0 °C where it was stirred for 1.5 h, during
which time the color turned from bronze-black to a thick slurry of silvery green in a
yellow-green solution. (It was ready to use immediately or could be stored in freezer for
days.)

After cooling back down to —78 °C, a solution of 280 (0.55g, 1.58 mmol, 1 equiv)

in 10 ml of THF was added slowly and the reaction mixture was then gradually warmed

215

 

 

to room temperature and stirred at this temperature for at least 3 h. The black suspension
was then filtered on a sufficiently large coarse fritted funnel packed with Celite, rinsing
with either dry THF or ether. The solvent of the filtrate was then removed on a rotavopor
and the residue was placed on high vaccuum for 20 min. The resulting potassium acylate
was dissolved 20 ml of CH2C12, and the mixture was cooled to 0 °C. EtOTf (0.31 mL,
2.37 mmol, 1.5 equiv) was added slowly and the solution was stirred for 30 min before
being quenched with sat. NaHCO; solution (20 mL). The organic layer was separated and
the aqueous phase was further extracted with CHzClz until all the red color was removed.
The combined organic extract was washed with brine and dried with Na2S04 and
concentrated under reduced pressure. Silica gel column chromatography using 0-5%
EtOAc/hexanes as the eluent afforded 274a (0.23 g, 28%) as a dark red solid.

Spectral data for 274a: Rf = 0.06 (hexanes); mp 115 °C (dec); 1H NMR (300
MHz, CDCl;;) 6 1.59 (t, 3H, J = 7.2 Hz), 2.81 (d, 1H, J = 8.4 Hz), 2.84 (d, 1H, J= 9.99
Hz), 4.80-4.97 (m, 2H), 5.75 (ddd, 1H, J = 8.4, 5.1, 1.0 Hz), 5.90 (dd, 1H, J= 9.9, 5.1
Hz), 7.20-7.29 (m, 5H); 13C NMR (125 MHz, CDC13) 6 14.72, 63.32, 73.16, 76.04,
77.41, 82.60, 126.46, 127.54, 128.98, 137.92, 209.04 (br), 216.84, 223.65, 335.19; IR
(NaCl) 2066s, 2045vs, 2000s, 1923vs cm"; MS (EI) m/z (% relative intensity) 518 (M+,
l), 503 (3), 490 (3), 462 (2), 434 (8), 429 (11), 415 (3), 406 (13), 401 (3), 382 (5), 378
(21), 355 (19), 350 (9), 338 (16), 322 (18), 294 (78), 281 (21), 270 (29), 266 (21), 265
(80), 250 (70), 227 (23), 221 (27), 207 (19), 197 (22), 193 (20), 192 (20), 184 (22), 157
(13), 147 (35), 142 (20), 141 (53), 129 (42), 128 (43), 115 (47), 109 (28), 108 (30), 107
(26), 105 (20), 97 (25), 91 (15), 83 (41), 80 (30), 69 (39), 57 (51), 55 (47), 52 (100), 43

(38). Anal calcd for C21H14CrFe09: C, 48.68; H, 2.72. Found: C, 48.88; H, 2.91.

216

 

 

0

El 0
(OC)50r H OH
_ , 05' Ph OEt
I/, ——————————«> Ph“ [Ill] +
(OC)3F8 / $
P” 254d

’r
F6(CO)3
2742 255d

The Thermolysis of Complex 274a.

A 25-mL flask with a threaded Teflon high-vacuum stop-cock was flushed with
nitrogen for 10 minutes before it was charged with the carbene complex 274a (51.8 mg,
0.1 mmol) and 5 mL of benzene. The mixture was degassed by the freeze-thaw method
(—196/25 °C, 3 cycles), back-filled with 1 atm argon at room temperature, sealed and
heated at 80 °C until the red color disappeared (2 h), indicating all the starting carbene
complex was consumed. The mixture was then allowed to cool to room temperature and
transferred to a 50-mL round bottom flask and concentrated under reduced pressure. The
residue was subjected to silica gel chromatography (5—10% EtOAc/hexanes) to furnish
the dienone complex 254d (9.9 mg, 28%) and the phenol 255d (9.2 mg, 43%). The same
reaction under 1 atm CO for 6 h gave 254d (12.4 mg, 35%) and 255d (12.9 mg, 60%).

Their spectral data are identical with those from the reaction of 181d.

0E1
0E1 O=C I

(00),Fe=( ———- (OC)3Fe//

283
275b Ph

The Preparation of the Ketene Complex 275b.
To a solution of 283228a (0.54 g, 2.25 mmol) in 30 mL of ether at —78 °C was
added nBuLi (2.5 M in hexanes, 0.9 mL, 2.25 mmol), and the resulting yellow mixture

was stirred for 15 min. Cinnamaldehyde (0.57 mL, 4.50 mmol) was then added to the

217

above solution and stirred for 10 min at —78 °C before the cold bath was replaced by an
ice bath and continued stirring for an hour. The solvent was removed on a rotary
evaporator and the product was purified by silica gel column chromatography (0—5%
EtOAc/hexanes) to afford 275b (0.26g, 33%) as a yellow solid.

Spectral data for 275b: Rf = 0.24 (10% EtOAc/hexanes); mp 77—78 °C; lH NMR
(300 MHz, CDC13) 6 1.30 (t, 3H, J= 6.9 Hz), 2.82 (dd, 1H, J= 10.2, 8.4 Hz), 3.72-3.96
(m, 2H), 5.98 (d, 1H, J: 8.4 Hz), 6.49 (dd, 1H, J= 15.6, 10.2 Hz), 6.65 (d, 1H, J= 15.6
Hz), 7.24-7.39 (m, 5H); l3C NMR (125 MHz, CDC13) 6 14.76, 53.46, 65.38, 87.63,
95.87, 126.28, 128.08, 128.81, 129.30, 132.49, 136.50, 207.36 (br), 235.35; IR (NaCl)
2056s, 1987vs, 17463 cm"; MS (EI) m/z (% relative intensity) 354 (M+, 1), 326 (3), 298
(14), 270 (89), 258 (5), 242 (66), 228 (63), 226 (95), 214 (42), 198 (25), 196 (31), 184
(53), 172 (15), 157 (82), 146 (33), 141 (27), 133 (100), 129 (65), 128 (65), 115 (40), 110
(45), 91 (23), 81 (47), 77 (37), 57 (39), 56 (51). Anal calcd for C17H14Fe05: C, 57.66; H,

3.98. Found: C, 57.88; H, 4.11.

_ OEt H o OH
O-C/’ 05‘ Ph OEt
(oclsFe / _. Ph “““ O +
"a
/ Fe(CO)3
275b ph 254d 255d

The Thermolysis of Complex 275b.

A 25-mL flask with a threaded Teflon high-vacuum stop-cock was flushed with
nitrogen for 10 minutes before it was charged with the carbene complex 275b (35.4 mg,
0.1 mmol) and 5 mL of benzene. The mixture was degassed by the freeze-thaw method
(—196/25 °C, 3 cycles), back-filled with 1 atm argon at room temperature, sealed and

heated at 80 °C until the red color disappeared (22 h), indicating all the starting carbene

218

complex was consumed. The mixture was then allowed to cool to room temperature and
transferred to a 50-mL round bottom flask and concentrated under reduced pressure. The
residue was subjected to silica gel chromatography (5—10% EtOAc/hexanes) to furnish
the dienone complex 254d (18.8 mg, 53%) and the phenol 255d (9.8 mg, 46%). The same
reaction under 1 atm CO for 12 h gave 254d (10.4 mg, 29%) and 255d (14.3 mg, 67%).

Their spectral data are identical with those from the reaction of 181d.

Ph Na2[Fe(CO)4]
WCOZCI :

 

281

 

The Reaction of Acid Chloride 281 with Na2[Fe(CO)4].

Under an atmosphere of argon, a solution of disodium tetracarbonylferrate ,—
dioxane complex (1:1.5), NazFe(CO)4°1.5C4H302 (1.08 g, 3.1 mmol), in 20 mL of THF
at —78 °C was added slowly a solution of 281 (0.60 g, 3.1 mmol) in 15 mL of THF. The
mixture was then gradually warmed to room temperature and stirred for 6 h. The solvent
was removed in vacuo and the flask was backfilled with argon, and about 1.0 g of
Et3OBF4 was added before 20 mL of degassed ice-cold water was added with rapid
stirring. Then ether (10 mL) was added and more Et3OBF4 was added until the solution

259 The organic layer was separated and the aqueous phase was

turned acidic (pH ~ 2).
further extracted with either until all the red color disappeared. The combined organic

extract was washed with brine and dried with Na2804 and concentrated. The residue was

219

 

subjected to silica gel chromatography (0—10% EtOAc/hexanes) to furnish the iron
complex 282 (0.23 g, 25%) as a red solid.

Spectral data for 282: Rf = 0.25 (10% EtOAc/hexanes); mp 220 °C (dec); 1H
NMR (300 MHz, CDC13) 6 3.23 (t, 1H, J = 9.3 Hz), 6.12 (d, 1H, J = 15.3 Hz), 6.24 (d,
1H, J= 9.0 Hz), 6.49 (dd, 1H, J= 15.3, 10.2 Hz), 6.72 (d, 1H, J= 15.6 Hz), 6.90 (dd, 1H,
J= 15.6, 11.4 Hz), 7.10 (d, 1H, J= 15.3 Hz), 7.21-7.25 (m, 1H), 7.31 (t, 2H, J= 7.5 Hz),
7.36-7.41 (m, 5H), 7.48-7.51 (m, 2H), 7.60 (dd, 1H, J= 15.6, 11.4 Hz); 13C NMR (125
MHz, CDC13) 6 62.94, 89.90, 114.37, 125.42, 126.21, 127.58, 127.77, 128.73, 129.02,
130.18, 131.11, 131.24, 135.32, 137.11, 145.08, 150.17, 176.70, 203.08, 210.96, 211.86;
IR (NaCl) 2060vs, 2010vs, 1966vs, 1618m, 1568s cm‘l; MS (FAB, NBA) m/z 594 (M+),
566 (M-CO), 538 (M-2CO), 510 (M-3CO), 482 (M-3CO), 454 (M-SCO), 426 (M-6CO).

Anal calcd for ngngFezOg: C, 56.60; H, 3.05. Found: C, 56.99; H, 3.15.

 

OEt OEt
(OC)50r=< (OC)4Fe=<
Ph Ph

284 285
Direct Carbene Ligand Transfer from Chromium Complex 284.

A 25-mL flask with a threaded Teflon high-vacuum stop-cock was flushed with
nitrogen for 10 minutes before it was charged with the carbene complex 284 (65.2 mg,
0.2 mmol), Fe2(CO)9 (72.8 mg, 0.2 mmol), and 10 mL of benzene. The mixture was
degassed by the freeze-thaw method (—196/25 °C, 3 cycles), back-filled with 1 atm CO at
room temperature, sealed and heated at 80 °C for 30 h. The mixture was then allowed to
cool to room temperature and transferred to a 50-mL round bottom flask and

concentrated under reduced pressure. The residue was subjected to silica gel

220

I

chromatography (5—10% EtOAc/hexanes) to furnish the iron carbene complex 285 (12.1
mg, 28%) along with a recovery of 284 (18.0 mg, 28%). A significant amount (about
37% yield, calculated from the NMR spectrum of the crude mixture) of ethyl benzoate

was also observed.

Spectral data for 285: Rf = 0.30 (hexanes); 1H NMR (300 MHz, CDC13) 6 1.65 (t,
3H, J = 7.2 Hz), 5.14 (q, 2H, J = 7.2 Hz), 7.34-7.44 (m, 5H); l3C NMR (125 MHz,
CDC13) 6 14.74, 77.84, 125.99, 127.71, 131.26, 154.33, 200.00, 213.30, 323.04; IR

(NaCl) 20525, 1935vs cm". The spectral data are consistent with the reported data.228a

CT(CO)5 Cf(CO)5
25... 2%...
224 290

The Preparation of Carbene Complex 290.
A solution of 224 (1.21 g, 3.0 mmol) in 50 mL of degassed benzene was added

 

(Ph3P)3RhCl (0.42 g, 0.45 mmol) under at atmosphere of hydrogen and stirred at room
temperature for 8 h. The mixture was then passed through a short pad of alumina and
concentrated. The residue was then subjected to silica gel column chromatography (0—5%
EtOAc/hexanes) to afford 290 (1.10 g, 91%) as a red solid.

Spectral data for 290: Rf = 0.13 (hexanes); mp 89—90 °C; 1H NMR (300 MHz,
CDC13) 6 1.37 (dm, 1H, J= 8.7 Hz), 1.44-1.50 (m, 1H), 1.82-1.97 (m, 4H), 3.22 (s, 1H),
3.42 (s, 1H), 4.29 (s, 3H), 7.05-7.09 (m, 2H), 7.22-7.31 (m, 3H); 13C NMR (125 MHz,
CDC13) 6 25.72, 27.15, 46.84, 47.63, 49.15, 65.42, 127.39, 127.73, 128.54, 134.50,

138.51, 216.26, 223.96, 352.49 (one aromatic/vinyl carbon not located); IR (NaCl)

221

2060s, 1929vs cm—l; MS (EI) m/z (% relative intensity) 404 (M+, 1), 376 (1), 348 (1), 320
(15), 292 (5), 264 946), 232 (24), 221 (25), 204 (50), 193 (18), 153 (14), 117 (24), 91

(11), 52 (100). Anal calcd for ConmCrO6: C, 59.41; H, 3.99. Found: C, 59.40; H, 4.07.

Cr(CO)5
fix ion/16 __. Lima; + g l EEO
21100 291292
The Thermolysis of Complex 290 in the Absence or Presence of Fez(CO)9.

A 25-mL flask with a threaded Teflon high-vacuum stop-cock was charged with
the carbene complex 290 (40.4 mg, 0.1 mmol) and 5 mL of THF. The mixture was
degassed by the freeze-thaw method (—196/25 °C, 3 cycles), back-filled with 1 atm CO at
room temperature, sealed and heated at 80 °C until the red color disappeared (48 h),
indicating all the starting carbene complex was consumed. The mixture was then allowed
to cool to room temperature and transferred to a 50-mL round bottom flask and
concentrated under reduced pressure. The residue was subjected to silica gel
chromatography (0—5% EtOAc/hexanes) to furnish the phenol 291 (18.8 mg, 78%) that
was contaminated with a small amount of 292, and the ketone 292 ( 1.7 mg, 9%) as a
white solid. The same reaction under 1 atm argon for 7 h gave 291 (~ 2%) and 292
(43%).

When the thermolysis of 290 was carried out in the presence of Fe2(CO)9, the
above procedure was followed except that one equivalent of the iron source was added.
The reaction with Fe2(CO)9 under 1 atm CD for 48 h gave 291 (76%) and 292 (8%),

while the same thermolysis with Fe2(CO)o under 1 atm argon for 12 h gave 291 (10%)

and 292 (48%).

222

 

Spectral data for 291: Rf = 0.18 (10% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13) 6 1.11-1.26 (m, 2H), 1.577-1.62 (m, 1H), 1.80-1.84 (m, 1H), 1.93-2.03 (m, 2H),
3.77 (s, 1H), 3.87 (5, 1H), 3.97 (s, 3H), 6.00 (s, 1H), 7.31-7.39 (m, 2H), 7.79-7.82 (m,
1H), 8.10-8.13 (m, 1H); 13C NMR (125 MHz, CDC13) 6 26.62, 27.81, 40.76, 42.25,
49.68, 61.41, 122.43, 122.78, 123.29, 123.83, 124.72, 124.98, 136.64, 137.06, 137.25,
140.60; IR (NaCl) 3442 br, 29635, 2869m, 1587m, 14605, 13565, 13025 cm"; MS (EI)
m/z (% relative intensity) 240 (M+, 63), 212 (100), 197 (66), 169 (19), 168 (18), 151 (23),
139(19),115(15), 76 (10), 75 (11).

Spectral data for 292: Rf = 0.22 (10% EtOAc/hexanes); mp 57—58 °C; lH NMR
(300 MHz, CDC13) 6 0.58-0.65 (m, 1H), 1.01-1.09 (m, 1H), 1.20-1.37 (m, 2H), 1.65 (dt,
1H, J= 9.9, 1.5 Hz), 1.78-1.82 (m, 1H), 2.64 (t, 1H, J= 4.2 Hz), 2.72 (t, 1H, J= 4.2 Hz),
2.94 (ddd, 1H, J= 8.1, 5.4, 1.8 Hz), 3.66 (dd, 1H, J= 8.4, 5.1 Hz), 7.31-7.38 (m, 2H),
7.55 (td, 1H, J = 7.8, 1.2 Hz), 7.67 (d, 1H, J = 7.5 Hz); 13C NMR (125 MHz, CDC13) 6
24.15, 24.92, 40.21, 40.23, 43.08, 47.76, 55.22, 123.58, 126.75, 127.57, 134.53, 138.56,
156.22, 208.86; IR (NaCl) 2957m, 2874w, 17115, 1603m cm'l; MS (EI) m/z (% relative
intensity) 198 (M+, 10), 132 (100), 130 (20), 115 (11), 91 (4), 77 (6), 67 (5). Anal calcd

for CMHMO: C, 84.81; H, 7.12. Found: C, 84.69; H, 7.50.

OMe
0H
MeO
- — 0o + . I \
//
O F8(CO)3
239 240 294

The Thermolysis of 239 and the Formation of Complex 294.
A 25-mL flask with a threaded Teflon high-vacuum stop-cock was flushed with

nitrogen for 10 minutes before it was charged with the carbene complex 239 (67.6 mg,

223

 

 

 

 

0.2 mmol), Fe2(CO)9 (72.8 mg, 0.2 mmol), and 10 mL of THF. The mixture was
degassed by the freeze-thaw method (—196/25 °C, 3 cycles), back-filled with 1 atm of CO
at room temperature, sealed and heated at 80 °C until the red color disappeared (72 h),
indicating all the starting carbene complex was consumed. The mixture was then allowed
to cool to room temperature and transferred to a 100-mL round bottom flask and
concentrated under reduced pressure. The residue was subjected to silica gel
chromatography (5—10% EtOAc/hexanes) to furnish the ketene complex 294 (51.5 mg,
82%) as a yellow solid, with trace of 240 observed from the NMR spectra of the crude
mixture.

The same reaction in benzene for 72 h gave 294 (50.2 mg, 80%) and trace of 240.
When the reaction was performed at 100 °C in benzene for 72 h, a messy mixture was
obtained and only traces of 294 and 240 were observed; when the reaction temperature
was at 130 °C in toluene for 7 h, a messy mixture was obtained and none of 294 and 240
were observed.

When the reaction that was performed under 500 psi of CO, the following
procedure was used. A Monel Paar pressure reactor equipped with a magnetically driven
mechanical stirrer was flushed with carbon monoxide for a few minutes before it was
charged with the carbene complex 239 (67.6 mg, 0.2 mmol), Fe2(CO)9 (72.8 mg, 0.2
mmol), and 10 mL of THF. Then the reactor was further flushed with CC for another 2
minutes and filled with 500 psi CO and heated at 80 °C with stirring for 24 hours. The
mixture was transfered to a 100-mL round bottom flask and concentrated on a rotary
evaporator. Purification with silica gel chromatography (5—10% EtOAc/hexanes) gave

the ketene complex 294 (51.9 mg, 83%) and none of 240 was detected.

224

 

 

Spectral data for 294: Rf = 0.22 (10% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13) 6 2.93 (d, 1H, J = 8.7 Hz), 3.64 (s, 3H), 6.46 (d, 1H, J= 8.7 Hz), 7.23-7.34 (m,
5H); 13C NMR (125 MHz, CDC13) 6 51.00, 56.50, 86.02, 96.56, 126.73, 127.38, 129.12,
138.45, 207.02 (hr), 234.79; IR (NaCl) 2060vs, 1985vs br, 17405 cm‘l; MS (EI) m/z (%
relative intensity) 314 (M, 1), 286 (10), 258 (6), 230 (13), 202 (43), 162 (28), 159 (93),
148 (98), 133 (100), 131 (85), 115 (44), 103 (67), 84 (24), 77 (47), 56 (51), 51 (18). Anal

calcd for C14H10Fe05: C, 53.54; H, 3.21. Found: C, 53.40; H, 3.35.

OMe O

(OC)SCr
. ___. 66

MeO
298 299

The Formation of 299 from Carbene Complex 298.

To a freshly prepared MeONa/MeOH solution (0.02 M, 7 mL) at 0 °C was added
the carbene complex 298205 (230 mg, 0.7 mmol) and the mixture was stirred for 10 min
(the color of the solution turned from red to red-orange). An ice-cold sat. NaHCO3
aqueous solution (10 mL) was then added and the product was extracted by ether (3 x 10
mL), dried by Na2S04 and concentrated. (During the extraction and concentration, the
red-orange color became lighter and the greenish solid covered the inner wall of the flask
afier removal of the solvent on a rotary evaporator.) Purification on the silica gel column
(lo-20% EtOAc/hexanes) afforded 299 (80 mg, 75%) as a colorless liquid.

Spectral data for 299: Rf = 0.10 (30% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13) 6 1.21-1.35 (m, 1H), 1.53-1.67 (m, 3H), 1.80-1.95 (m, 2H), 2.82 (t, 1H, J= 7.5
Hz), 3.13 (t, 1H, J= 7.5 Hz), 3.79 (s, 3H), 5.23 (s, 1H); 13C NMR (125 MHz, CDC13) 6

23.64, 28.45, 29.03, 45.68, 50.90, 58.76, 104.80, 192.04, 208.35; IR (NaCl) 2946m,

225

 

 

1694s, 1591s, 1360m em“; MS (EI) m/z (% relative intensity) 152 (MI, 51), 127 (14),

124 (100), 121 (35), 111 (55), 69 (28).

NMe;

OMe
(OCISCT (OC)SCr A
_ ——> _ ———> unknown X
Ph 301 Ph

181b
The Preparation of Amino Carbene Complex 301 and Its Thermolysis.

A solution of 181b (0.38 g, 1.04 mmol) in 10 mL of ether at —78 °C under an
atmosphere of argon was added freshly prepared MezNH/ether solution (2.0 M, 0.74 mL,
1.47 mmol) via syringe. The color of the mixture changed immediately from red to
orange-yellow and the solution was stirred for 5 min before the volatiles were removed.
Purification on the silica gel column (10% EtOAc/hexanes) afforded 301 (0.25 g, 64%)
as a orange-yellow oil which solidified in the freezer to form a yellow solid.

Spectral data for 301: Rf = 0.08 (10% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13) 6 3.40 (s, 3H), 3.86 (s, 3H), 5.71 (dd, 1H, J= 15.9, 10.2 Hz), 6.60(d, 1H, J= 15.6
Hz), 6.69-6.81 (m, 2H), 7.20-7.24 (m, 1H), 7.31 (t, 2H, J = 7.2 Hz), 7.40 (d, 2H, J = 7.2
Hz); 13C NMR (125 MHz, CDC13) 6 45.85, 51.02, 122.54, 126.44, 127.73, 127.90,
128.67, 134.52, 136.78, 140.72, 217.43, 223.56, 269.33; IR (NaCl) 2053vs, 19725,
1908vs br, 1537m cm"; MS (EI) m/z (% relative intensity) 377 (M+, 1), 349 ( 12), 321
(9), 293 (3), 265 (26), 237 (52), 201 (46), 194 (19), 159 (33), 157 (98), 128 (100), 115
(27), 95 (40), 86 (40), 77 (31), 57 (66), 52 (87), 43 (67), 41 (55).

A 25-mL flask with a threaded Teflon high-vacuum stop-cock was flushed with
nitrogen for 10 minutes before it was charged with the carbene complex 301 (89.0 mg,

0.236 mmol), Fe2(CO)9 (85.9 mg, 0.236 mmol), and 12 mL of THF. The mixture was

226

 

degassed by the freeze-thaw method (—196/25 °C, 3 cycles), back-filled with 1 atm CO at
room temperature, sealed and heated at 80 °C for 42 h. The mixture was then allowed to
cool to room temperature and transferred to a 100-mL round bottom flask and
concentrated under reduced pressure. The residue was subjected to silica gel
chromatography (5—10% EtOAc/hexanes) to furnish a very polar unknown compound X
(18.0 mg) as a yellowish oil, the structure of which has not been fully characterized. And
some of the starting complex 30] (36 mg, 40%) was recovered. The NMR spectrum of
the crude mixture indicated that the ratio of X/301 = 1 : 2.

The same reaction in benzene for 96 h resulted in a ratio of X/301 = 2 : 3. And the
reaction in toluene at 110 °C for 48 h gave a messy complex that did not appear to
contain X and no starting complex 301 was recovered.

Spectral data for X: Rf = 0.07 (30% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13) 6 1.44 (d, 1H, J = 3.6 Hz), 2.34 (d, 1H, J = 5.7 Hz), 2.99 (s, 3H), 3.17 (s, 3H),
6.00 (d, 1H, J = 4.5 Hz), 6.17 (s, 1H), 7.21-7.31 (m, 5H); 13C NMR (125 MHz, CDC13) 6
35.99, 37.10, 45.85, 61.98, 82.61, 83.54, 126.21, 126.99, 128.79, 138.91, 170.54, 209.16
(br); IR (NaCl) 2041vs, 1975vs br, 1624s cm‘l; MS (EI) m/z (% relative intensity) 313
(M, 8), 285 (32), 257 (100), 213 (7), 201 (14), 185 (64), 157 (45), 128 (94), 84 (14), 77

(14), 56 (84).

H 0 9H 0H
. OMe H ’ OMe H OMe 0”
H3Cw 0 (4301:“. H301" @ + H3C\©/OM8
2. ‘3. ‘1.

‘Fe(CO)s Fe(CO)3 Fe(CO)3
254a syn-304 anti-304 255a

Reduction of 254a for the Preparation of Complex 304.

227

 

 

 

A typical procedure: A solution of 254a (67.2 mg, 0.24 mmol) in 15 mL of
methanol was treated with NaBH.; (92 mg, 2.42 mmol) for 3 h. The reaction was then
quenched with 3 mL of H20 and stirred for 5 min. The products were extracted with ether
(3 x 10 mL) and the organic extracts were washed with brine and dried with Na2S04.
After removal of the solvent, the residue was subjected to silica gel column
chromatography (IO—20% EtOAc/hexanes) to afford syn-304 (24 mg, 36%) and anti-304
(17 mg, 25%), along with a trace (< 5%) of 255a was seen on the NMR spectrum of the
crude mixture.

Spectral data for syn-304: Rf = 0.20 (20% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13) 6 1.03 (d, 3H, J= 7.8 Hz), 1.97 (tt, 1H, J= 7.2, 1.2 Hz), 2.27 (d, 1H, J= 3.0 Hz),
2.54 (dt, 1H, J= 6.6, 1.5 Hz), 3.50 (s, 3H), 3.98 (dd, 1H, J = 7.2, 2.7 Hz), 4.99-5.03 (m,
1H), 5.26 (dd, 1H, J= 4.5, 1.2 Hz); l3C NMR (125 MHz, CDC13) 6 15.13, 34.45, 56.73,
64.14, 70.32, 74.32, 75.74, 121.89, 212.19; IR (NaCl) 3465w br, 2039vs, 1966vs cm"1;
MS (EI) m/z (% relative intensity) 252 (M+—CO, 2), 224 (9), 196 (4), 181 (18), 178 (86),
166 (11), 148 (14), 122 (89), 129 (25), 91 (78), 77 (52), 57 (82), 56 (77), 43 (100).

Spectral data for anti-304: Rf = 0.09 (20% EtOAc/hexanes); 1H NMR (300 MHz,
CDC13) 6 1.14 (d, 3H, J= 6.9 Hz), 1.65-1.71 (m, 1H), 2.00 (d, 1H, J = 4.2 Hz), 2.38 (dt,
1H, J= 6.3, 1.5 Hz), 3.47 (s, 3H), 3.98-4.01 (m, 1H), 5.19-5.23 (m, 1H), 5.37 (dt, 1H, J=
4.8, 1.5 Hz); l3C NMR (125 MHz, CDC13) 6 20.64, 36.96, 56.58, 57.93, 75.96, 77.70,

78.71, 116.32, 211.84; IR (NaCl) 3397s br, 2041vs, 1960vs cm"l.

228

 

 

 

REFERENCES AND NOTES

 

' Taxol® is a registered trademark of Bristol-Myers Squibb Company. The approved
generic name is paclitaxel. The chemical compound will be referred to as taxol thereafter
as named by Wani and Wall in his original paper in 1971 (Ref. 17). No infiingement of
the BMS trademark is intended or implied by this usage.

2 Goodman, J .; Walsh, V. The Story of T axol: Nature and Politics in the Pursuit of an
Anti-cancer Drug; Cambridge University Press: New York, 2001.

3 Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem. Int. Ed. Engl. 1994, 33, 15.

4 For detailed accounts of the history of the development of Taxol, see: (a) Suffness, M.;
Wall, M. E. In T axol: Science and Applications; Suffness, M., Ed.; CRC Press: Baca
Raton, FL, 1995. (b) Wall, M. E.; Wani, M. C. In T axane Anticancer Agents: Basic
Science and Current Status; Georg, G. 1., Chen, T. T., Ojima, I., Vyas, D. M., Eds.; ACS
Symposium Series 583; American Chemical Society: Washington, DC, 1994. (c) Ref. 2.

5 For a review on taxane diterpenoids, see: (a) Baloglu, E.; Kingston, D. G. I. J. Nat.
Prod. 1999, 62, 1448. (b) Kingston, D. G. 1.; Molinero, A. A.; Rimoldi, J. M. In Progress
in the Chemistry of Organic Natural Products; Herz, W., Kirby, G. W., Moore, R. E.,
Steglich, W., Tamm, C., Eds; Springer-Verlag: New York, 1993.

6 Taxotere® is a registered trademark of Rhone-Poulenc, and it is marketed in the US. by
Sanofi-aventis. Its generic name is docetaxel.

7 For bioactivity of other taxanes, see: (a) Rose, W. C. In T axol: Science and
Applications; Suffness, M., Ed.; CRC Press: Baca Raton, FL, 1995. (b) Kingston, D. G. I.
Pharmacol. T her. 1991, 52, 1. (c) Appendino, G. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1995; pp 237-268. (d) Appendino,
G. In The Chemistry and Pharmacology of T axol and its Derivatives; Farina, V., Ed.;
Elsevier Science: New York, 1995; pp 7-53.

8 (a) Kobayashi, J .; Ogiwara, A.; Hosoyama, H.; Shigemori, H.; Yoshida, N.; Sasaki, T.;
Li, Y.; Iwasaki, S.; Naito, M.; Tsuruo, T. Tetrahedron 1994, 50, 7401. (b) Morita, H.;
Wei, L.; Gouda, A.; Takeya, K.; Itokawa, H.; Fukaya, H.; Shigemori, H.; Kobayashi, J.
Tetrahedron 1997, 53, 4621.

9 (a) Goodman, L. S.; Wintrobe, M. M.; Dameshek, W.; Goodman, M. J .; Gilman, A.;
McLennan, M. T. J. Am. Med. Assoc. 1946, 132,126. (b) Farber, 8.; Diamond, L. K.;
Mercer, R. D.; Sylvester, R. F., Jr.; Wolff, J. A. N. Engl. J. Med. 1948, 238, 787. (c)
Burchenal, J. H.; Murphy, M. L.; Ellison, R. R.; Sykes, M. P.; Tan, T. C.; Leone, L. A.;
Kamofsky, D. A.; Craver, L. F.; Dargeon, H. W.; Rhoads, C. P. Blood 1953, 8, 965.

229

 

 

 

 

‘0 Zubrod, C. G.; Shepartz, S.; Leiter, J.; Endicott, K. M.; Carrese, L. M.; Baker, C. G.
Cancer Chemother. Rep. 1966, 50, 349.

11 (a) Schepartz, S. A. Cancer Treat. Rep. 1976, 60, 975. (b) Suffness, M. Gann Monogr.
Cancer Res. 1989, 36, 21.

'2 McCracken, R. J. Cancer Treat. Rep. 1976, 60, 973.

‘3 William, J. J .; Schubert, B. G. Economic Botany 1955, 9, 141.

'4 Wall, M. E.; Wani, M. C.; Taylor, H. L. Cancer Treat. Rep. 1976, 60, 1011.
'5 Wall, M. 13.; Wani, M. C. Cancer Res. 1995, 55, 753.

'6 Wall, M. E.; Wani, M. C. The American Chemical Society 153rd National Meeting,
Paper M-006, Miami Beach, FL, 1967.

‘7 Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A. T. J. Am. Chem. Soc.
1971, 93, 2325.

‘8 Miller, R. w. J. Nat. Prod. 1980, 43, 425.

'9 (a) Suffness, M.; Douros, J. J. Nat. Prod. 1982, 45, 1. (b) Borman, 5. Chem. Eng. News
1991,69,]1.

2" Fuchs, D. A.; Johnson, R. K. Cancer Treat. Rep. 1978, 62, 1219.

2' Schiff, P. 13.; Fant, J.; Horwitz, s. B. Nature 1979, 277, 665.

22 The promotion of microtubule assembly and inhibition of its disassembly results in
blocking a cell's ability to break down the mitotic spindle during mitosis (cell division).
With the spindle still in place the cell cannot divide into daughter cells, eventually
leading to cell death.

23 Rowinsky, E. K.; Donehower, R. C. Pharmacol. T her. 1991, 52, 35.

24 (a) Lee, V. D.; Huang, B. Plant Cell 1990, 2, 1051. (b) Wilson, L. Life Sci. 1975, 17,
303. (c) Bai, R.; Pettit, G. R.; Hamel, E. J. Biol. Chem. 1990, 265, 17141.

25 Purich, D. L.; Kristofferson, D. Adv. Protein Chem. 1984,36, 133.

26 (a) Humar, N. J. Biol. Chem. 1981, 256, 10435. (b) Vallee, R. B. J. Cell Biol. 1982,
435. (c) Vallee, R. B.; Collins, C. A. Methods Enzymol. 1986, 134, 116.

27 Schiff, P. B.; Horwitz, S. B. Biochemistry 1981, 20, 3247.

230

 

28 Heidemann, S. R.; Gallas, P. T. Developmental Biol. 1980, 80, 489.

29 (a) Keller, H. U.; Zimmerman, A. Invasion Metathesis 1986, 6, 33. (b) Komiya, Y.;
Tashiro, T. Cell Motil. Cytoskeleton 1988, 11, 151. (c) Rainey, W. E.; Kramer, R. E.;
Mason, J. 1.; Shay, J. W. J. Cell Physiol. 1985, 123, 17. (d) Mattson, M. P. Brain Res.
1992, 582, 107.

3" (a) Ucker, D. s. New Biol. 1991, 3, 103. (b) Colombel, M.; Olsson, C. A.; Ng, P. Y.;
Buttyan, R. Cancer Res. 1992, 52, 4313. (c) Lee, S.; Christakos, S.; Small, M. B. Curr.
Opin. Cell Biol. 1993, 5, 286. (d) Jordon, M. A.; Wilson, L. In Taxane Anticancer
Agents: Basic Science and Current Status; Georg, G. 1., Chen, T. T., Ojima, I., Vyas, D.
M., Eds; ACS Symposium Series 583; American Chemical Society: Washington, DC,
1994. pp138-153.

3 ' For reviews on clinical usage of Taxol, see: (a) Rowinsky, E. K.; Cazenave, L. A.;
Donehower, R. C. J. Natl. Cancer Inst. 1990, 82, 1247. (b) Rowinsky, E. K.;
Donehowever, R. C. idbd. 1991, 83, 1778. (c) Rowinsky, E. K.; Onetto, N.; Canetta, R.
M.; Arbuck, S. G. Semin. Oncol. 1992, 19, 646. (d) Arbuck, S. G.; Christian, M. C.;
Fisherman, J. S.; Cazenave, L. S.; Sarosy, G.; Suffness, M.; Adams, J.; Canetta, R.; Kole,
K. E.; Friedman, M. A. Monogr. Natl. Cancer Inst. 1993, 15, 11. (e) Goldspiel, B. R.
Pharmacotherapy 1997, 17, 1108-1258.

32 (a) Riondel, J .; Jacrot, M.; Picot, F .; Beriel, H.; Mouriquand, C.; Potier, P. Cancer
Chemother. Pharmacol. 1986, 1 7, 137. (b) Jacrot, M.; Riondel, J .; Picot, F.; Leroux, D.;
Mouriquand, H.; Beriel, P.; Potier, P. Seances Acad. Sci. Ser. 3 1983, 247, 597.

33 National Cancer Institute Clinical Brochure: Taxol (NSCI 25 9973), National Cancer
Institute, Division of Cancer Treatment, Bethesda, MD, 1983, 6-12.

34 Adam, J. D.; Flora, K. F .; Goldspiel, B. R.; Wilson, J. W.; Arbuck, S. G.; Finley, R.
Monogr. Natl. Cancer Inst. 1993, 15, 141.

35 For details of clinical studies (including phase I) with Taxol, see: (a) Ref. 31. (b)
Arbuck, S. G.; Blaylock, B. A. In Taxol: Science and Applications; Suffness, M., Ed.;
CRC Press: Baca Raton, FL, 1995.

36 (a) Weiss, R. B.; Donehower, R. C.; Wiemik, P. H.; Ohnuma, T.; Gralla, R. J .; Trump,
D. L.; Baker, J. R., Jr.; Van Echo, D. A.; Von Hoff, D. D.; Leyland-Jones, B. J. Clin.
Oncol. 1990, 8, 1263. (b) Brown, T.; Havlin, K.; Weiss, 0.; Cagnola, J.; Koeller, J .;
Kuhn, J.; Rizzo,J.; Craig, J.; Phillips, J.; Von Hoff, D. J. Clin. Oncol. 1991, 9, 1261. (c)
Onetto, N.; Canetta, R.; Winograd, B.; Catane, R.; Dougan, M.; Grechko, J .; Burroughs,
J.; Rozencweig, M. J. Natl. Cancer Inst, Monographs 1993, 131.

231

 

37 Rowinsky, E. K.; Eisenhauer, E. A.; Chaudhry, V.; Arbuck, S. G.; Donehower, R. C.
Semin. Oncol. 1993, 20, 1.

38 Cisplatin, discovered to be highly active against cancers in 1965 by Professor Barnett
Rosenberg of Michigan State University, had been the major anticancer drug before
Taxol was used, along with its later-introduced analog carboplatin, and both are still
widely used. For related information, see: Chem. Eng. News 2005, 83, (June 20, Issue
25).

39 McGuire, W. P.; Rowinsky, E. K.; Rosenheim, N. B.; Grumbine, F. C.; Ettinger, D. S.;
Armstrong, D. K.; Donehower, R. C. Ann. Inter. Med. 1989, 111, 273.

40 From 1969 to 1990, a period of over 20 years, the total production of Taxol by NCI
contractors was 3.7 kg, most of which was produced in the last 5 years of that period.
(See: Ref. 4a)

41 (a) Thigpen, T.; Blessing, J .; Ball, H.; Hummel, S.; Barret, R. Proc. Annu. Meet. Am.
Soc. Clin. Oncol. 1990, 9 (Abstract 604). (b) 02015, R. F. Curr. Probl. Cancer 1992, 16,
63.

42 Holmes, F. A.; Walters, R. S.; Theriault, R. L.; Forman, A. D.; Newton, L. K.; Raber,
M. N.; Buzdar, A. U.; Frye, D. H.; Hortobagyi, G. N. J. Natl. Cancer Inst. 1991, 83,
1797.

43 a) Murphey, W. K.; Winn, R. J.; Fossella, F. V.; Shin, D. M.; Hynes, H. E.; Gross, H.
M.; Davila, E.; Leimert, J. T.; Dhingra, H. M.; Raber, M. N.; Krakoff, I. H.; Hong, W. K.
Proc. Annu. Meet. Am. Soc. Clin. Oncol. 1992, II, 294 (Abstract 985). b) Chang, A.;
Kim, K.; Glick, J .; Anderson, T.; Karp, D.; Johnson, D. ibid. 1992, 11, 293 (Abstract
981)

44 Trojanowski, J.; Lee, V. M. Y. Am. J. Pathology 2005, 1 6 7, 1183.
‘5 Chem. Eng. News 2002, 80, 13 (June 10, issue 23); 2005, 83, (June 20, Issue 25).

46 (a) A typical treatment regimen for a 165-lb patient suffering from breast cancer
involves repeated infilsion of a 300-mg dose every three weeks for three months. The
cost of the 1.2 g of Taxol required for this course of treatment was approximately
$10,000 in 2002. (b) Testicular cancer survivor Lance Armstrong, who is most famous
for winning the Tour de France a record seven consecutive times from 1999 to2005, was
cured with three BMS drugs (including Taxol) in 1996.

47 For recent biosynthesis studies, see: (a) Walker, K.; Long, R.; Croteau, R. Proc. Natl.
Acad. Sci. USA 2002, 99, 9166. (b) Jennewein, S.; Wildung, M. R.; Chan, M.; Walker,
K.; Croteau, R. Proc. Nat. Acad. Sci. USA 2004, 101, 9149-9154. (c) Loncaric, C.;
Mern'weather, E.; Walker, K. D. Chemistry and Biology 2006, 13, 309-317. For reviews,

232

 

see: (d) Walker, K.; Croteau, R. Recent Adv. Phytochem. 1999, 33, 31. (e) Floss, H. G.;
Mocek, U. In T axol: Science and Applications; Suffness, M., Ed.; CRC Press: Baca
Raton, FL, 1995. (i) Takeya, K. In Taxus: The Genus Taxus; Itokawa, H., Lee, K.-H.,
Eds; Taylor and Francis: London, 2003, chap. 5. (g) Kingston, D. G. I. In Anticancer
Agents from Natural Products; Cragg, G. M., Kingston, D. G. I., Newman, D. J ., Eds;
CRC Press LLC: Boca Raton, FL, 2005; pp 89-122. (h) Rohr, J. Angew. Chem, Int. Ed.
Engl. 1997, 36, 2190.

48 For reviews, see: (a) Wuts, P. G. M. Curr. Opin. Drug Disc. Devel. 1998, I. 329. (b)
Holton, R. A.; Biediger, R. J .; Boatman, P. D. In T axol: Science and Applications;
Suffness, M., Ed.; CRC Press: Baca Raton, FL, 1995.

49 For Taxol production by plant tissue culture methods, see: (a) Zhong, J .-J . J. Biosci.
Bioeng. 2002, 94, 591. (b) Tabata, H. Adv. Biochem. Eng./Biotechnol. 2004, 7, 1.

5° Gueritte-Voegelein, F.; Senilh, V.; David, B.; Guenard, D.; Potier, P. Tetrahedron
1986, 42, 4451.

51 (a) Barasoain, 1.; Des Ines, D.; Duz, F.; Andreia, J. M.; Peyrot, V.; Leynadier, D.;
Garcia, R; Briand, C.; De Suusa, G.; Rahmani, R. Proc. Am. Assoc. Cancer Res. 1991,
32, 329. (b) Ringel, 1.; Horwitz, S. B. J. Natl. Cancer Inst. 1991, 83, 288.

52 Fromes, V.; Guonon, P.; Bissery, M. C.; Fellous, A. Proc. Am. Assoc. Cancer Res.
1992, 33, 511.

53 Joel, 5. P. Chemistry and Industry 1994 (March 7), 172.

54 10-DAB is present in a number of Taxus species, including T axus brevifolia and Taxus
wallichiana, a species growing in the Himalayan region.

55 (a) Senilh, V.; Gueritte, F.; Guenard, D.; Colin, M.; Potier, P. Comptes rendus del’
Academie des Sciences de Paris, Serie II 1984, 299, 1039. (b) Bissery, M.-C.; Lavelle, F.
In Cancer Therapeutics: Experimental and Clinical Agents; Teicher, B. A., Ed.; Humana
Press: Totowa, NJ; 1997, pp 175-193.

56 (a) Denis, J. N.; Greene, A. E.; Guenard, D.; Gueritte-Voegelein, F.; Mangatal, L.;
Potier, P. J. Am. Chem. Soc. 1988, 110, 5917. (b) Mangatal, L.; Adeline, M. T.; Guenard,
D.; Gueritte-Voegelein, F.; Potier, P. Tetrahedron 1989, 45, 4177.

57 (a) Holton, R. A. European Patent Application 4009 71, 1990; US Patent 5015744,
1991. (b) Holton, R. A. European Patent Application 4283 76, 1991; US Patent 5175315,
1992. (c) Holton, R. A.; Biediger, R. J .; Boatman, P. D. In T axol: Science and
Applications; Suffness, M., Ed.; CRC Press: Baca Raton, FL, 1995.

233

 

58 (a) Ojima, 1.; Habus, 1.; Zhao, M.; Georg, G.; Jayasinghe, L. R. J. Org. Chem. 1991,
56, 1681. (b) Ojima, 1.; Habus, 1.; Zhao, M.; Zucco, M.; Park, Y.-H.; Sun, C. M.;
Brigaud, T. Tetrahedron 1992, 48, 6985.

59 (a) Bredt, J .; Thouet, H.; Schnitz, J. Liebigs Ann. 1924, 43 7, 1. (b) For a review, see:
K. J. Shea, K. J. Tetrahedron 1980, 36, 1683.

6" Nicolaou, K. C.; Guy, R. K.; Potier, P. Scientific American 1996, 274, 84.

6' (a) Holton, R. A.; Somoza, C.; Kim, H. B.; Liang, F .; Biediger, R. J.; Boatman, D.;
Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.;
Zhang, R; Murthi, K. K.; Gentile, L. S.; Liu, J. H. J. Am. Chem. Soc. 1994, 116, 1597.
(b) Holton, R. A.; Kim, H. B.; Somoza, C.; Liang, F.; Biediger, R. J .; Boatman, D.;
Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.;
Zhang, R; Murthi, K. K.; Gentile, L. S.; Liu, J. H. J. Am. Chem. Soc. 1994, 116, 1599.

62 (a) Nicolaou, K. C.; Zang, Z.; Liu, J. J .; Ueno, H.; Nantermet, P. G.; Guy, R. K.;
Claiborne, C. F.; Renaud, J .; Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J. Nature
1994, 367,630. (b) Nicolaou, K. C.; Nantermet, P. G.; Ueno, H.; Guy, R. K.;
Coulandouros, E. A.; Sorensen, E. J. J. Am. Chem Soc. 1995, I 1 7, 624. (c) Nicolaou, K.
C.; Liu, J. J.; Yang, H.; Ueno, H.; Sorensen, E. J.; Claiborne, C. F.; Guy, R. K.; Hwang,
C. K.; Nakada, M.; Nantermet, P. G. J. Am. Chem Soc. 1995, I 1 7, 634. (d) Nicolaou, K.
C.; Yang, Z.; Liu, J. J .; Nantermet, P. G.; Claiborne, C. F .; Renaud, J.; Guy, R. K.;
Shibayama, K. J. Am. Chem Soc. 1995, I I 7, 645. (e) Nicolaou, K. C.; Ueno, H.; Liu, J.

J .; Nantermet, P. G.; Yang, Z.; Renaud, J .; Paulvannan, K.; Chadha, R. J. Am. Chem. Soc.
1995, 117, 653.

63 Anon. Chemistry and Industry 1994 (February 21), 125.

64 Holton, R. A.; Juo, R. R.; Kim, H. B.; Williams, A. D; Harusawa, S.; Lowenthal, R.
E.; Yogai, S. J. Am. Chem. Soc. 1988, 110, 6558.

65 Danishefsky, S. J.; Masters, J. J.; Young, W. B.; Link, J. T.; Snyder, L. B.; Magee, T.
V.; Jung, D. K.; Isaacs, R. C. A.; Bommann, W. G.; Alaimo, C. A.; Coburn, C. A.; Di
Grandi, M. J. J. Am. Chem. Soc. 1996, 118, 2843.

66 (a) Samaranayake, G.; Magri, N. F .; Jitrangsri, C.; Kingston, D. G. I. J. Org. Chem.
1991, 56, 5114. (b) Chen, S.; Huang, S.; Wei, J.; Farina, V. Tetrahedron 1993, 49, 2805.

67 (a) Wender, P. A.; Badham, N. F .; Conway, S. P.; Floreancig, P. E.; Glass, T. E.;
Granicher, C.; Houze, J. B.; Jéinichen, J .; Lee, D.; Marquess, D. G.; McGrane, P. L.;
Meng, W.; Mucciaro, T. P.; Miihlebach, M.; Natchus, M. G.; Paulsen, H.; Rawlins, D. B.;
Satkofsky, J .; Shuker, A. J .; Sutton, J. C.; Taylor, R. E.; Tomooka, K. J. Am. Chem. Soc.
1997, 119, 2755. (b). Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.;
Glass, T. E.; Houze, J. B.; Krauss, N. E.; Lee, D.; Marquess, D. G.; McGrane, P. L.;

234

 

Meng, W.; Natchus, M. G.; Shuker, A. J .; Sutton, J. C.; Taylor, R. E. J. Am. Chem. Soc.
1997, 119, 2757.

68 (a) Morihira, K.; Hara, R.; Kawahara, S.; Nishimori, T.; Nakamura, N.; Kusama, H.;
Kuwajima, I. J. Am. Chem. Soc. 1998, 120, 12980. (b) Kusama, H.; Hara, R.; Kawahara,
S.; Nishimori, T.; Kashima, H.; Nakamura, N.; Morihira, K.; Kuwajima, I. J. Am. Chem.
Soc. 2000, 122, 3811.

69 Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura, T.; Ohkawa, N.; Sakoh,
H.; Nishimura, K.; Tani, Y.; Hasegawa, M.; Yamada, K.; Saitoh, K. Chem. Eur. J. 1999,
5, 121 and references therein.

70 Wender, P. A.; Natchus, M. G.; Shuker, A. J. In Taxol: Science and Applications;
Suffness, M., Ed.; CRC Press: Baca Raton, FL, 1995.

71 For an excellent review on the synthetic efforts through the middle of 1991 , see:
Swindell, C. S. Org. Prep. Proceed. Int. 1991, 23, 465.

72 (a) Swindell, C. 5.; deSolms, 5. J.; Springer, J. P. Tetrahedron Lett. 1984,25, 3797. (b)
Swindell, C. S.; deSolms, S. J. ibid. 1984, 25, 3801. (c) Swindell, C. S.; Patel, B. P.;
deSolms, S. J .; Springer, J. P. J. Org. Chem. 1987, 52, 2346. (d) Swindell, C. S.; Patel, B.
P. Tetrahedron Lett. 1987, 28, 5275. (e) ) Swindell, C. S.; Patel, B. P. J. Org. Chem.
1990, 55, 3.

_ 73 Neh, H.; Blechert, S.; Schnick, W.; Jansen, M. Angew. Chem. Int. Ed. Engl. 1984, 23,
905.

74 (a) Winkler, J. D.; Subrahmanyam, D.; Hsung, R. P. Tetrahedron 1992,48, 7049;
corrigendum: ibid. 1993, 49, 291. (b) Winkler, J. D.; Lee, C.-S.; Rubo, L.; Muller, C. L.;
Squattrito, P. J. J Org. Chem. 1989, 54, 4491.

75 Jackson, R. W.; Higby, R. (3.; Gilman, J. W.; Shea, K. J. Tetrahedron 1992, 48, 7013.

76 Bonnert, R. V.; Jenkins, P. R. J. Chem. Soc. Perkin Trans. 1 1989, 413 and references
therein.

77 Winkler, J. D.; Kim, H. S.; Kim, 8. Tetradedron Lett. 1995,36, 687.
7" Blechert, 5.; Muller, R.; Beitzel, M. Tetrahedron 1992, 48,6953.
79 Trost, B. M.; Hiemstra, H. J. Am. Chem. Soc. 1982, 104,886.

80 (a) Kress, M. H.; Ruel, R.; Milller, W.; Kishi, Y. Tetrahedron Lett. 1993, 34, 5999;
1993, 34, 6003.

235

 

 

 

 

 

8‘ Paquette, L. A.; Zhao, M.; Montgomery, F .; Zeng, Q.; Wang, T. Z.; Elmore, S.;
Combrink, K.; Wang, H.-L.; Bailey, S.; Su, Z. In Current Trends in Organic Synthesis;
Scolastico, C., Nicotra, F., Eds; Kluwer Academic/Plenum Publishers: New York, 1999.

pp 25-34.
82 Funk, R. L.; Daily, W. J.; Parvez, M. J. Org. Chem. 1988, 53, 4141.
83 Yadav, J. S.; Ravishankar, R. Tetrahedron Lett. 1991, 32, 2629.

84 Hitchcock, S. A.; Pattenden, G. Tetrahedron Lett. 1992, 33, 4843; corrigendum: ibid. .
1992, 33, 7448.

 

85 Wang, Z.; Warder, S. E.; Perrier, H.; Grimm, E. L.; Bernstein, M. A.; Ball, R. G. J.
Org. Chem. 1993, 58, 2931.

 

86 A prodrug is a pharmacological substance (drug) which is administered in an inactive
(or significantly less active) form. Once administered, the prodrug is metabolized in the

body in vivo into the active compound.

87 For an overview of prodrugs for Taxol, see: Kingston, D. G. 1.; Jagtap, P. G.; Yuan, H.;
Samala, L. In Progress in the Chemistry of Organic Natural Products; Herz, W., F alk,
H., Kirby, G. W., Eds; Springer-Verlag Wien: New York, 2002.

88 For reviews, see: (a) Zefirova, O. N.; Nurieva, E. V.; Ryzhov, A. N.; Zyk, N. V.;
Zefirov, N, S. Russ. J. Org. Chem. 2005, 41, 315. (b) Kingston, D. G. I. J. Nat. Prod.
2000, 63, 726.

89 (a) Ojima, 1.; Lin, S.; Inoue, T.; Miller, M. L.; Borella, C. P.; Geng, X.; Walsh, J. J. J.
Am. Chem. Soc. 2000, 122, 5343. (b) Ganesh, T.; Guza, R. C.; Bane, S.; Ravindra, R.;
Shanker, N.; Lakdawala, A. S.; Snyder, J. P.; Kingston, D. G. 1. Proc. Natl. Acad. Sci.
USA 2004, 101, 10006. (c) Boge, T. C.; Wu, Z.-J.; Himes, R. H.; Vander Velde, D. G.;
Georg, G. I. Bioorg. Med Chem. Lett. 1999, 9, 3047. (d) Yuan, H.; Kingston, D. G. I.

Tetrahedron 1999, 55, 9707.

 

9° He, L.; Jagtap, P. 0.; Kingston, D. o. 1.; Shen, H.-J.; Orr, o. A.; Horwitz, s. B.
Biochemistry 2000, 39, 3972.

9' (a) Bollag, D. M.; McQueney, P. A.; Zhu, J.; Hensens, O.; Koupal, L.; Liesch, J .;
Goetz, M.; Lazarides, E.; Woods, C. M. Cancer Res. 1995, 55, 2325. (b) Koalski, R. J.;
Giannakakou, P.; Hamel, E. J. Biol. Chem. 1997, 272, 2534.

92 Ter Harr, E.; Kowalski, R. J.; Hamel, B; Lin, C. M.; Longley, R. E.; Gunasekera, S. P.;
Rosenkranz, H. S.; Day, B. W. Biochemistry 1996, 35, 243.

236

 

93 Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.; Casazza, A. M.; Carboni, J .;
F airchild, C. R. .1. Am. Chem. Chem. 1997, 119, 8744.

94 (a) Ojima, 1.; Chakravarty, S.; Tadashi, 1.; Lin, S.; He, L.; Horwitz, S. B.; Kuduk, S. B.;
Danishefsky, S. J. Proc. Natl. Acad. Sci. USA 1999, 96, 4256. (b) Ojima, 1.; Lin, S.;
Inoue, T.; Miller, M. L.; Borella, C. P.; Geng, X.; Walsh, J. J. J. Am. Chem. Soc. 2000,
122, 5343,

95 Fischer, E. O.; Maasb61, A. Angew. Chem, Int. Ed. Engl. 1964, 3, 580.

96 D6tz, K. H.; Fischer, H.; Hofmann, P.; Kreissl, F. R.; Schubert, U.; Weiss, K.
Transition Metal Carbene Complexes, Verlag Chemie: Weinheim; Deerfield Beach,
Florida; 1983.

97 For reviews on the chemistry of Fischer carbene complexes and their synthetic
applications, see: (a) D6tz, K. H. Angew. Chem, Int. Ed. Engl. 1984, 23, 587. (b) Wulff,
W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press:
Greenwich, CT, 1989; Vol. 1. pp 209-393. (c) Wulff, W. D. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, 1., Eds; Pergamon Press: Oxford, UK, 1991; Vol 5. (d)
Wulff, W. D. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G.
A., Wilkinson, G., Eds; Pergamon Press: Oxford, UK, 1995; Vol. 12, pp 469-547. (e)
Hegedus, L. S. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G.
A., Wilkinson, G., Eds; Pergamon Press: Oxford, 1995; Vol. 12, pp 549-576. (1) Doyle,
M. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A.,
Wilkinson, G., Eds; Pergamon Press: Oxford, 1995; Vol. 12, pp 387-420. (g) Harvey, D.
F.; Sigano. D. M. Chem. Rev. 1996, 96, 271. (h) de Meijere, A.; Schirmer, H.; Duetsch,
M. Angew. Chem, Int. Ed. 2000, 39, 3964. (i) D6tz, K. H.; Tomuschat, P. Chem. Soc.
Rev. 1999, 28, 187. (j) Hemdon, J. W. Coord. Chem. Rev. 1999, I81, 177. (k) Metal
Carbenes in Organic Synthesis; D6rwald, F. 2., Ed.; Wiley-VCH: New York, 1999. (1)
Metal Carbenes in Organic Synthesis. Topics in Organometallic Chemistry, 13; D6tz, K.
H., Ed.; Springer-Verlag: Berlin, Heidelberg. 2004. (m) Barluenga, J .; Femandez-
Rodriguez, M. A.; Aguilar, E. J. Organomet. Chem. 2005, 690, 539.

9" Schrock, R. R. J. Am. Chem. Soc. 1974, 96, 6796.

99 For an introduction to the metal carbene complexes, see: (a) Crabtree, R. H. The
Organometallic Chemistry of the Transition Metals, 3rd Ed.; John Wiley & Sons, Inc:
New York, 2001. (b) Spessard, G. O.; Miessler, G. L. Organometallic Chemistry;
Prentice Hall: Upper Saddle River, New Jersey, 1996.

“’0 Aumann, R.; Fischer, E. 0. Chem. Ber. 1968, 101,954.

'0' (a) Harvey, D. F.; Brown, M. F. Tetrahedron Lett. 1990, 31,2529. (b) Alkyl

fluorosulfonates were used before, see: Casey, C. P.; Cyr, C. R.; Boggs, R. A. Synth.
Inorg. Met. Org. Chem. 1973, 3, 249.

237

 

 

 

 

'02 Connor, J. A.; Jones, E. M. J Chem. Soc. A 1971, 3368.
'03 Ref. 96, p 153.

104 (a) Semmelhack, M. F.; Lee, G. R. Organometallics 1987, 6, 1839. (b) Imwinkeried,
R. ; Hegedus, L. S. Organometallics 1988, 7, 702. (c) Schwindt, M. A.; Lejon, T.;
Hegedus, L. S. Organometallics 1990, 9, 2814. (d) Bueno, A. B.; Moser, W. H.;
Hegedus, L. S. J. Org. Chem. 1998, 63, 1462.

'05 (a) D6tz, K. H.; Sturm, W.; Alt, H. G. Organometallics 1987, 6, 1424. (b) Alt, H. G.;
Englhardt, H. F.; Steinlein, E.; Rogers, R. D. J. Orgnomet. Chem. 1988, 344, 321. (c)
Parlier, A.; Rudler, H. J. Chem. Soc, Chem. Commun. 1986, 514.

'06 For reviews, see: (a) Ref. 97(g); (b) Brookhart, M.; Studabaker, W. B. Chem. Rev.
1987, 87, 411. (c) Doyle, M. P. Chem. Rev. 1986, 86, 919.

107 For a review for the preparation of 5-membered carbocyclic rings, see: Hemdon, J. W.
Tetrahedron 2000, 56, 1257.

‘08 (a) Wulff, w. D.; Yang, D. C. J Am. Chem. Soc. 1983, 105, 6726. (b) Wulff, w. D.;
Bauta, W. E.; Kaesler, R. W.; Lankford, P. J .; Miller, R. A.; Murray, C. K.; Yang, D. C.
J. Am. Chem. Soc. 1990, 112, 3642 and references therein. (c) Anderson, B. A.; Wulff,
W. D.; Powers, T. S.; Tribbitt, S.; Rheingold, A. L. J. Am. Chem. Soc. 1992, 114, 10784.
(d) Wulff, W. D.; Powers, T. S. J. Org. Chem. 1993, 58, 2381. (e) Powers, T. S.; Jiang,
W.; Su, J.; Wulff, W. D. J. Am. Chem. Soc. 1997, 119, 6438.

'09 a) Faron, K. L.; Wulff, W. D. J. Am. Chem. Soc. 1988, 110, 8727. (b) Wulff, W. D.;
Faron, K. L.; Su, J.; Springer, J. P.; Rheingold, A. L. J. Chem. Soc., Perkin Trans. 1
1999, 197 and references therein.

“0 (a) Fischer, E. o.; Kalder, H. J. J Orgnomet. Chem. 1977, 13, 57. (b) Pipoh, R.; van
Eldik, R.; Henkel, G. Organometallics 1993, 12, 2236 and references therein.

m For example, the pKal value of a-protons in methyl(methoxycarbene)pentacarbonyl
chromium(0) is about 8, see: Casey, C. R; Anderson, R. L. J. Am. Chem. Soc. 1974, 96,
1230.

“2 (a) Wang, H.; Hsung, R. P.; Wulff, w. D. Tetrahedron Lett. 1998,39, 1849. (b)
Aumann, R.; Heinen, H. Chem. Ber. 1987, 120, 537. (c) D6tz, K. H.; Noack, R.; Harms,
K. Tetrahedron 1990, 46, 1235. (d) Wulff, W. D.; Gilbertson, S. R. J. Am. Chem. Soc.
1985, 107, 503.

“3 Wulff, w. D.; Kaesler, R. w. Organometallics 1985, 4, 1461-1463.

238

 

“4 (a) Snider, B. B. Chem. Rev. 1988,88, 793. (b) Chen, L. Y.; Ghosez, L. Tetrahedron.-
Aymmetry 1991, 2, 1181. (c) Xu, S. L.; Xia, H. J.; Moore, H. W. J. Org. Chem. 1991, 56,
6094. (d) Baeckstrom, R; Li, L.; Polec, 1.; Unelius, C. R.; Wimalasiri, W. R. J. Org.
Chem. 1991, 56, 3358. (e) Snider, B. B.; Allentoff, A. J. J. Org. Chem. 1991, 56, 321. (1)
Lee, S. Y.; Kulkarni, Y. S.; Burbaum, B. W.; Johnston, M. I.; Snider, B. B. J. Org. Chem.
1988, 53, 1848. (g) Snider, B. B.; Walner, M. Tetrahedron 1989, 45, 3171.

”5 Bellus, D.; Ernst, o. Angew. Chem, Int. Ed. Engl. 1988,27, 797.

“6 Kim, 0. K.; Wulff, w. D.; Jiang, w. J Org. Chem. 1993,58, 5571-5573.

”7 Kim, O. K. Ph.D. Thesis, The University of Chicago, 1990.

”8 For a related metal-free crossed [2 + 2] cycloaddition, 866 RBf- 20(3), (e), (t) and (8)-
”9 Jiang, W.; Fuertes, M. J.; Wulff, w. D. Tetrahedron 2000,56, 2183.

120(a)Kn11tarni, Y. 5.; Snider, B. B. J Org. Chem. 1985, 50, 2809. (b) Widmark, 6. Acta
Chem. Scand. 1955, 9, 941.

12' Klusener, P. A.; Kulik, W.; Brandsma, L. J Org. Chem. 1987, 52, 5261.

”2 (a) Lochmann, L; Pospisil, J.; Lim, D. Tetrahedron Lett. 1966, 257. (b) Schlosser, M.
J. Organomet. Chem. 1967, 8, 9.

123 Jiang, W. phi). Thesis, The University of Chicago, 1996.

124 There existed some inconsistencies in the spectra that were not very convincing for the

proposed tricyclic structure. For example, the 13 C NMR spectrum showed three carbons
above 200 ppm which better fit the triketone structure, while DEPT spectrum showed six
quaternary carbons above 70 ppm that indicated the B-diketone should be in the enol
form. Furthermore, the exchangeable proton at 5 ppm to be assigned from the B-hydroxy
group was not very reasonal since it is expected to be above 10 ppm.

125 (a) Grob, C. A. Angew. Chem, Int. Ed. Engl. 1969, 8, 535. (b) For a recent synthetic
application of the Grob fragmentaion, see: Molander, G. A.; Huerou, Y. L.; Brown, G. A.
J. Org. Chem. 2001, 66, 4511.

‘26 Fuertes, M. J. Ph.D. Thesis, The University of Chicago, 2001.

127 Strobel, M. P.; Andrieu, C. G.; Paquer, D.; Vazeux, M.; Parm, C. C. Nouv. J. Chim.
1980, 4, 101.

'28 The reaction of 63b and 110a was performed by Fuertes (see Ref. 126).

239

 

'29 When complex 63c was used in the reaction, the cyclobutenone product 118cc was

isolated in 16% yield as a single isomer, whose stereochemistry was not determined.
0

(”Me
31101.... /

118cc

‘30 Chan, K. S.; Peterson, G. A.; Brandvold, T. A.; Faron, K. L.; Challener, C. A.;
Hyldahl, C.; Wulff, W. D. J. Organomet. Chem. 1987, 334, 9.

131 Jiang also carried out the hydrolysis of 99a and obtained very similar results, see: Ref
123.

'32 Aoyama, H.; Tokunaga, M.; Hiraiwa, S.-I.; Shirogane, Y.; Obora, Y.; Tsuji, Y. Org.
Lett. 2004, 6, 509.

‘33 Wijkens, P.; Vermeer, P. J. Organomet. Chem. 1986, 301, 247.

134 Similar fragmentation for a related compound has been reported, see: (a) Kulkarni, Y.
S.; Niwa, M.; Ron, E.; Snider, B. B. J. Org. Chem. 1987, 52, 1568. (b) Hebrault, D.;
Uguen, D. Tetrahedron Lett. 1998, 39, 6699.

‘35 The corresponding alcohol 163a was formed in ~ 40% yield.
0

’CH2 0
C)
163:

'36 For an introduction to N-acylimidazoles, see: (a) Fife, T. H. Acc. Chem. Res. 1993, 26,
325 and reference therein. (b) Zaramella, S.; Stromberg, R.; Yeheskiely, E. Eur. J. Org.
Chem. 2002, 2633. '

137 Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.; John
Wiley & Sons, Inc: New York, 1999.

'38 For an inverse electron demand [4 + 2] reaction involving pyranylidene carbene
complexes , see: Wang, S. L. B.; Wulff, W. D. J. Am. Chem. Soc. 1990, 112, 4550.

139 For recent examples of diastereo- and enantioselective cyclopropanation with Fischer
carbene complexes, see: (a) Barluenga, J .; Suarez-Sobrino, A. L.; Tomas, M.; Garcia-
Granda, S.; Santiago-Garcia, R. J. Am. Chem. Soc. 2001, 123, 10494. (b) Barluenga, J.;
Bernad, P., Jr.; Concellon, J. M. J. Org. Chem. 1997, 62, 6870.

240

 

‘40 (a) Fischer, E. 0.; Dotz, K. H. Chem. Ber. 1970, 103, 1273. (b) D'o’tz, K. H.; Fischer,
E. 0. Chem. Ber. 1972, 105, 1356. (c) Wienand, A.; Reissig, H.-U. Tetrahedron Lett.
1988, 29, 2315. (d) Hemdon, J. W.; Turner, S. U. Tetrahedron Lett. 1989, 30, 4771. (e)
Harvey, D. F .; Brown, M. F. Tetrahedron Lett. 1990, 31 , 2529. (f) Wienand, A.; Reissig,
H.-U. Organometallics 1990, 9, 3133. (g) Hemdon, J. W.; Turner, S. U. J. Org. Chem.
1991, 56, 286. (h) Wienand, A.; Reissig, H.-U. Chem. Ber. 1991, 124, 957.

‘4' (a) Fischer, E. o.; Dotz, K. H. Chem. Ber. 1972, 105, 3966. (b) Dorrer, B.; Fischer, E.
O.; Kalbfus, W. J. Organomet. Chem. 1974, 81, C20. (c) Wulff, W. D.; Yang, D. C.;
Murray, C. K. Pure Appl. Chem. 1988, 60, 137.

'42 Barluenga, J .; Lopez, S.; Trabanco, A. A.; Fernandez-Acebes, A.; F lérez, J. J. Am.
Chem. Soc. 2000, 122, 8145.

'43 For a review on dienyl carbene complexes (1-metalla-1,3,5-hexatrienes), see:
Aumann, R. Eur. J. Org. Chem. 2000, 17.

”4 Murray, C. K.; Yang, D. C.;Wu1ff,W. D. J Am. Chem. Soc. 1990, 112, 5660.

'45 An example of cyclopropanation with acyloxy dienyl carbene complex has also been
reported, see: Ref. 144.

'46 (a) Zheng, Q.-H.; Su, J. Synth. Commun. 1999, 3467. (b) Nandanan, E.; Jang, S.-Y.;
Moro, S.; Kim, H. O.; Siddiqui, M. A.; Russ, P.; Marquez, V. E.; Busson, R.; Herdewijn,
P.; Karden, T. K.; Boyer, J. L.; Jacobson, K. A. J. Med. Chem. 2000, 43, 829. (c)
Venneri, P. C.; Warkentin, J. Can. J. Chem. 2000, 78, 1194.

”7 In the case when 181b was treated with ethyl enol ether 185, about 20% of ketone A

was obtained, presumably hydrolyzed from the metathesis product B. This type of

metathesis is well documented in the literature, for an example, see: Ref. 141(c).
0 OMe

Ph Ph

”8 For the preparation of methyl alkenyloxy chromium carbene complexes, see: (a)
Stiderberg, B. C.; Hegedus, L. S.; Sierra, M. A. J. Am. Chem. Soc. 1990, 112, 4364. (b)
Christoffers, J.; D6tz, K. H. Organometallics 1994, I 3, 4189. (c) Xu, Y.-C.; Wulff, W. D.
J. Org. Chem. 1987, 52, 3263.

'49 S6derberg, B. C.; Hegedus, L. S. Organometallics 1990, 9, 313.

'50 Dotz, K. H.; Noack, R.; Harms, K. Tetrahedron 1990, 46, 1235.

'51 Barluenga, J .; Aznar, F .; Palomero, M. A. J. Org. Chem. 2003, 68, 537.

241

 

‘52 Wulff, w. D.; Yang, D. C.; Murray, C. K. J Am. Chem. Soc. 1988, 110, 2653.

'53 Intramolecular cyclopropanation with acyloxycarbene complexes has been reported,
see: Barluenga, J .; Aznar, F.; Gutierrez, 1.; Martin, J. A. Org. Lett. 2002, 4, 2719.

‘54 For applications of cyclopropanes in organic synthesis, see: (a) Reissig, H.-U. Top.
Curr. Chem. 1988, I44, 73. (b) Reissig, H.-U. In The Chemistry of the Cyclopropyl
Group; Patai, S.; Rappoport, A., Eds; John Wiley and Sons: New York, 1987; Chapter 8.

'55 For examples, see: (a) Taber, D. F.; Joshi, P. V.; Kanal, K. J Org. Chem. 2004, 69,
2268. (b) Zuo, G.; Louie, J. Angew. Chem, Int. Ed. 2004, 43, 2777.

'56 For reviews on the benzannulation reaction: see: (a) Ref. 97. (b) Waters, M. L.;
Wulff, W. D. Org. Reactions in press.

‘57 Dotz, K. H. Angew. Chem, Int. Ed. Engl. 1975, 14,587.

'58 For discussions on the mechanistic issues, see: (a) Waters, M. L.; Bos, M. E.; Wulff,
W. D., J. Am. Chem. Soc., 1999, 121, 6403, and references therein. (b) Barluenga, J .;
Aznar, F.; Gutierrez, 1.; Martin, A.; Garcia-Granda, S.; Llorca-Baragano, M. J. Am.
Chem. Soc. 2000, 122, 1314 and references therein. (c) Ref. 97.

'59 Fischer, H.; Mfihlemeier, J.; Mark], R.; D6tz, K, H. Chem. Ber. 1932, 115, 1355-

‘6" (a) Wulff, w. D.; Tang, P.-C.; McCallum, J. 5. J Am. Chem. Soc. 1981, 103, 7677.
(b) D6tz, K, H.; Mfihlemeier, J .; Schubert, U.; Orama, O. J. Organomet. Chem. 1983,
24 7, 187. (c)Wu1ff, W. D.; Chan, K.-S.; Tang, P.-C. J. Org. Chem. 1984, 49, 2293. (d)
Yamashita, A.; Toy, A. Tetrahedron Lett. 1986, 27, 3471.

‘6‘ Hoffman, P.; H'a'mmerle, M.; Unfried, (3. New J Chem. 1991, 15, 769.

‘62 (a) Gross, M. F.; Finn, M. o. J Am. Chem. Soc. 1994, 116, 10921. (b) Semmelhack,
M. F.; Bozell, J. J .; Keller, L.; Sato, T.; Spiess, E. J .; Wulff, W. D.; Zack, A. Tetrahedron
1985, 41, 5803. (c) Semmelhack, M. F .; Bozell, J. J .; Sato, T.; Spiess, E. J .; Wulff, W.;
Zack, A. J. Am. Chem. Soc. 1982, 104, 5850.

' ‘63 (a) Tang, P.-C.; Wulff, w. D. J Am. Chem. Soc. 1984, 106, 1132. (b) Wulff, w. D.;
Gilbertson, S. R. J. Am. Chem. Soc. 1985, 107, 503. (C) Gilbertson, S. R.; Wulff, W. D.
Synlett 1989, 47.

‘64 Bauta, W. E.; Wulff, W. D.; Pavkovic, S. F .; Zaluzec, E. J. J. Org. Chem. 1989, 54,
3249.

242

 

‘65 (a) D6tz, K, H.; Dietz, R.; Kappenstein, C.; Neugebauer, D.; Schubert, U. Chem. Ber.
1979, 112, 3682. (b) Quinn, J. F.; Bos, M. E.; Wulff, W. D. Org. Lett. 1999, 1, 161.

‘66 (a) Dem, K, H. J Organomet. Chem. 1977, 140, 177. (b) Yamashita, A. Tetrahedron
Lett. 1986,27, 5915.

'67 McCallum, J. S.; Kunng, R.-A.; Gilbertson, S. R.; Wulff, W. D. Organometallics
1988, 7, 2346.

‘68 (a) Wulff, w. D.; Bax, B. M.; Brandvold, T. A.; Chan, K. 5.; Gilbert, A. M.; Hsung,
R. R; Mitchell, J.; Clardy, J. Organometallics 1994,13, 102. (b) Foley, H. C.; Strubinger,
L. M.; Targos, T. S.; Geoffroy, G. L. J. Am. Chem. Soc. 1983, 105, 3064. (c) D6tz, K, H.;
Larbig, H. J. Organomet. Chem. 1991, 405, C38. (d) D6tz, K, H.; Larbig, H. Bull. Soc.
Chim. Fr. 1992, 129, 579.

‘69 Katz, T. J.; Lee, 5. J. J Am. Chem. Soc. 1980, 102,422.

'70 (a) Ur-Rahman, A.; Schnatter, W. F. K.; Manolache, N. J. Am. Chem. Soc. 1993, 115,
9848. (b) Semmelhack, M. F.; Park, T. Organometallics 1986, 5, 2550. (c) Semmelhack,
S. F .; Tamura, R.; Schnatter, W.; Springer, J. J. Am. Chem. Soc. 1984, 106, 5363.

17‘ Wulff, w. D.; Gilbertson, s. R.; Springer, J. P. J Am. Chem. Soc. 1986, 108,520.

172 (a) Balzer, B. L.; Cazanoue, M.; Sabat, M.; Finn, M. G. Organometallics 1992, 11,
1759. (b) Balzer, B. L.; Cazanoue, M.; Finn, M. G. J. Am. Chem. Soc. 1992, 114, 8735.

'73 (a) Chan, K. S.; Peterson, G. A.; Brandvold, T. A.; Faron, K. L.; Challener, C. A.;
Hyldahl, C.; Wulff, W. D. J. Organomet. Chem. 1987, 334, 9. (b) Bos, M. E.; Wulff, W.
D.; Miller, R. A.; Chamberlin, S.; Brandvold, T. A. J. Am. Chem. Soc. 1991, 113, 9293.
(c) Wulff, W. D.; Tang, P.-C.; Chan, K. S.; McCallum, J. S.; Yang, D. C.; Gilbertson, S.
R. Tetrahedron 1985, 41 , 5813.

‘74 Gross, M. F.; Finn, M. G. J Am. Chem. Soc. 1994, 116, 10921.

‘75 Liptak, V.; Wulff, W. D. unpublished results.

”6 Yamashita, A. Tetrahedron Lett. 1986, 27, 5915.

'77 (a) Wulff, W. D.; Gilbert, A. M.; Hsung, R. P.; Rahm, A. J. Org. Chem. 1995, 60,
4566. (b) Barluenga, J .; Aznar, F .; Gutierrez, 1.; Martin, A.; Garcia-Granda, S.; Llorca-
Baragano, M. A. J. Am. Chem. Soc. 2000, 122, 1314.

”8 (a) Dotz, K. H.; Grotjahn, D.; Harms, K. Angew. Chem, Int. Ed Engl. 1989,28, 1384.

(b) Grotjahn, D. B.; Kroll, F. E. K.; Schafer, T.; Harms, K.; D6tz, K. H. Organometallics
1992, 11, 298.

243

 

 

 

 

”9 Merino, 1.; Hegedus, L. s. Organometallics 1995, 14, 2522.

180 (a) Wulff, w, 1), Organometallics 1998, 1 7, 3116, and references therein. (b) Hsung,
R. P.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1994, 116, 6449. (c) Hsung, R.
P.; Wulff, W. D.; Challener, C. A. Synthesis 1996, 773. (d) D6tz, K. H.; Stinner, C.
Tetrahedron: Asymmetry 1997, 8, 1751.

‘8' Wulff, W. D.; McCallum, J. S.; Kunng, F. A. J. Am. Chem. Soc. 1988, 110, 7419.

'82 Xu, Y.-C.; Kohlman, D. T.; Liang, s. X.; Erikkson, C. Org. Lett. 1999, 1, 1599.

‘83 The total synthesis has been finishied in our group, but yet to be published. For
preliminary synthetic studies, see: Liptak, V. P; Wulff, W. D. Tetrahedron 2000, 56,
10229.

'84 Wulff, w. D.; Tang, P.-C. J Am. Chem. Soc. 1984, 106, 434.

‘35 (a) Dotz, K, H.; Popall, M.; Miller, G. J Organomet. Chem. 1987, 334, 57. (b) Dotz,
K, H.; Popall, M. Angew. Chem, Int. Ed. Engl. 1987, 26, 1158. (c) D6tz, K, H.; Popall,
M. Chem. Ber. 1988, 121, 665.

“‘6 Wulff, w. D.; Xu, Y.-C. J Am. Chem. Soc. 1988, 110, 2312.

'87 Roush, w. R.; Neitz, R. J. J Org. Chem. 2004, 69, 4906.

'88 (a) Boger, D. L.; Jacobson, I. C. Tetrahedron Lett. 1989, 30, 2037. (b) Boger, D. L.;
Jacobson, I. C. J. Org. Chem. 1990, 55, 1919. (c) Boger, D. L.; Jacobson, I. C. J. Org.
Chem. 1991, 56, 2115. (d) Boger, D. L.; Hitter, O.; Mbiya, K.; Zhang, M. J Am. Chem.
Soc. 1995, 117, 11839.

189 The synthesis of the major portion of (-)-kendomycin has been reported: White, J. D.;
Srnits, H. Org. Lett, 2005, 7, 235.

'90 Bao, J.; Wulff, W. D.; Dominy, J. B.; Fumo, M. J.; Grant, E. B.; Rob, A. C.;
Whitcomb, M. C.; Yeung, S.-M.; Ostrander, R. L.; Rheingold, A. L. J. Am. Chem. Soc.
1996, 118, 3392.

'9' (a) Antilla, J. C.;Wu1ff,W. D. J Am. Chem. Soc. 1999, 121, 5099. (b) Antilla, J. C.;
Wulff, w. D. Angew. Chem, Int. Ed 2000, 39,4518.

‘92 (a) Bao, J.; Wulff, w. D.; Rheingold, A. L. J Am. Chem. Soc. 1993, 115, 3814. (b)
Heller, D. P.; Goldberg, D. R.; Wulff, W. D. J. Am. Chem. Soc. 1997, 119, 10551.

'93 xue, 5.; Yu, 5.; Deng, Y.; Wulff, w. D. Angew. Chem. Int. Ed. 2001, 40, 2271.

244

 

 

‘94 (a) McGuire, M. A.; Hegedus, L. 5. J. Am. Chem. Soc. 1982, 104, 5538. (b) Hegedus,

L. S.; deWeck, G.; D’Andreas, S. J. Am. Chem. Soc. 1988, 110, 2122. (c) Hegedus, L. S.;
Schwindt, M. A.; De Lombaer, S.; Imwinkelried, R. J. Am. Chem. Soc. 1990, 112, 2264.

(d) SGderberg, B. C.; Hegedus, L. S.; Sierra, M. A. J. Am. Chem. Soc. 1990, 112, 4364.

'95 For reviews of photochemistry of Fischer carbene complexes, see: (a) Ref. 1e. (b)
Hegedus, L. S. Tetrahedron 1997, 53, 4105.

'96 (a) Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L- 8'9 Ed;
JAI Press: Greenwich, CT, 1989; Vol. 1, p 336. (b) Yang, D. C. Ph-D. ThCSiSr UHiVETSitY
of Chicago, 1986, p 28.

‘97 Merlic, C. A.; Xu, D. J Am. Chem. Soc. 1991, 113, 7418.

'93 Merlic, C. A.; Roberts, w. M. Tetrahedron Lett. 1993,34, 7379.

199 For [4 + 2] cycloaddition of alkynyl carbene complexes with 1,3-dienes, see: Wulff,
W. D.; Yang, D. C. J. Am. Chem. Soc. 1984, 106, 7565.

200 For [2 + 2] cycloaddition of alkynyl carbene complexes with alkenes, see: (a) Faron,
K. L.; Wulff, W. D. J. Am. Chem. Soc. 1988, 110, 8727. (b) Wulff, W. D.; Faron, K. L.;
Su, J.; Springer, J. P.; Rheingold, A. L. J. Chem. Soc., Perkin Trans. 1 1999, 197.

2‘“ Merlic, C. A.; Xu, D.; Gladstone, B. G. J org. Chem. 1993,58, 538.

202 (a) Merlic, C. A.; Burns, E. E.; Xu, D.; Chen, 8. Y. J Am. Chem. Soc. 1992, 114,
8722. (b) Merlic, C. A.; Burns, E. E. Tetrahedron Lett. 1993, 34, 5401.

203 (a) Merlic, C. A.; Aldrich, C. C.; Albaneze-Walker, J .; Saghatelian, A. J. Am. Chem.
Soc. 2000, 122, 3224. (b) Merlic, C. A.; Aldrich, C. C.; Albaneze-Walker, J.; Saghatelian,
A.; Mammen, J. J Org. Chem. 2001, 66, 1297.

20“ Manish, R.; Wulff, w. D. Org. Lett. 2004, 6,329.

205 (a) Barluenga, J .; Aznar, F .; Palomero, M. A. J. Org. Chem. 2003, 68, 537. (b)
Barluenga, J .; Aznar, F .; Palomero, M. A. Barluenga, S. Org. Lett. 1999, I, 541.

206 Wu, H.-P.; Aumann, R.; Fr6hlich, R.; Wibbeling, B. Eur. J. Org. Chem. 2000, 1183.

207 Mathur, P.; Ghosh, S.; Sarkar, A.; Rheingold, A. L.; Guzei, I. A. Tetrahedron 2000,
5 6, 4995.

245

 

208 For organo-iron chemistry including 114-dienyl complexes, see: The Organic
Chemistry of Iron, Vols. 1 and 2; Koerner von Gustorf, E. A., Grevels, F.-W., Fischler, 1.,
Eds; Academic Press: New York; 1978 (Vol. 1) and 1981 (Vol. 2).

209 Gomez-Gallego, M.; Mancheno, M. J .; Sierra, M. A. Acc. Chem. Res. 2005, 38, 44
and references therein.

2'0 For electron figurations of metals in organometallic complexes, see: (a) Crabtree, R.
H. The Organometallic Chemistry of the Transition Metals, 3rd Ed.; John Wiley & Sons,
Inc: New York, 2001. (b) Spessard, G. O.; Miessler, G. L. Organometallic Chemistry;
Prentice Hall: Upper Saddle River, New Jersey, 1996.

2” For an introduction to SEM/EDS analysis, see: Flegler, S. L.; Heckman, J. W.;
Klomparens, K. L. Scanning and Transmission Electron Microscopy: An Introduction;
Oxford University Press: New York, 1993. _«

2‘2 The SEM/EDS analysis results of both 254a and 181a are included in Appendix 3.

2” It was known a long time ago that iron could be converted to iron carbonyl at high
temperature in the presence of carbon monoxide, see: (a) Hieber, W. A. Z. Anorg.
Allegem. Chem. 1940, 245, 295. (b) Handbook of Organometallic Compounds; Hagihara,
N., Kumada, M., Okawara, R., Eds; W. A. Benjamin, Inc.: New York, 1968; p 886.

2” (a) Howell, J. A. 5.; Johnson, B. F. G.; Josty, o. L.; Lewis, J. J Orgnomet. Chem.
1972, 39, 329. (b) Barton, D. H. R.; Gunatilaka, A. A. L.; Nakanishi, T.; Patin, H.;
Widdowson, D. A.; Worth, B. R. J. Chem. Soc., Perkin I 1976, 821.

215 A preliminary communication has been published, see: Lian, Y.; Wulff, W. D. J. Am.
Chem. Soc. 2005, 127, 17162.

2‘6 (a) Brown, H. C.; Campbell, J. B., Jr. J Org. Chem. 1980, 45, 389. (b) Brown, H. C.;
Chandrasekharan, J. J. Org. Chem. 1983, 48, 644.

2‘7 (a) Wang, z.-x.; Gao, G.-A.; Shi, Y. J Org. Chem. 1999, 64, 7646. (b) Corey, E. J.;
Fuchs, P. L. Tetrahedron Lett. 1972, 3769.

2'8 It was observed that the reaction mixture turned from clear yellowish solution to gray
suspension immediately after the mixture was opened to air, suggesting the loss of iron
tricarbonyl from the complex.

2'9 Chen, J.; Wang, T.; Zhao, K. Tetrahedron Lett. 1994, 35, 2827.
220 (a) Aumann, R.; F r6hlich, R.; Prigge, J .; Meyer, O. Organometallics 1999, 18, 1369.

(b) Wu, H.-P.; Aumann, R.; Fr6hlich, R.; Wibbeling, B. Eur. J. Org. Chem. 2000, 1183.
(c) Duetsch, M.; Stein, F.; Lackmann, R.; Pohl, E.; Herbst-Irmer, R.; de Meijere, A.

246

 

Chem. Ber. 1992, 125, 2051. ((1) Wu, Y.-T.; Schirmer, H.; Noltemeyer, M.; de Meijere,
A. Eur. J. Org. Chem. 2001, 2501. (e) For a related microreview, see: Aumann, R. Eur. J.
Org. Chem. 2000, 17.

22‘ Demetalation by FeCl3 or Ce(N 114)2(NO3)6 is not effective. For other possible
methods, see: Franck-Neumann, M.; Geoffroy, P.; Gassmann, D. Synlett 2002, 2054.

222 Franck-Neumann, M.; Geoffroy, P.; Winling, A. Synlett 1995, 341.
2” Crombie, L.; Crombic, w. M. L. J. Chem. Soc., Perkin Trans. 1 1994, 1267.
224 (a) Semmelhack, M. F.; Lee, G. R. Organometallics 1987, 6, 1839. (b) Schwindt, M.

A.; Lejon, T.; Hegedus, L. S. Organometallics 1990, 9, 2814. (c) Bueno, A. B.; Moser,
W. H.; Hegedus, L. S. J Org. Chem. 1998, 63, 1462.

l. .

225 (a) Darbasie, N. D.; Schnatter, W. F. K.; Warner, K. F.; Manolache, N. Tetrahedron
Lett. 2006, 47, 963. (b) Morris, K. G.; Saberi, S. P.; Salter, M. M.; Thomas, S. E.; Ward,
M. F .; Slawin, A. M. Z.; Williams, D. J. Tetrahedron 1993, 49, 5617. (c) Benyunes, S.
A.; Gibson, S. E.; Peplow, M. A. Tetrahedron: Asymmetry 1997, 8, 1535.

226 (a) For a comprehensive review of vinylketene transition metal complexes, see:

Gibson, S. E.; Peplow, M. A. Adv. Organomet. Chem. 1999, 44, 275. (b) For a related
reaction of vinylketene cobalt(I) complexes and alkynes, see: Huffman, M. A.;
Liebeskind, L. S. J Am. Chem. Soc. 1990, 112, 8617.

”7 Collman, J. P. Acc. Chem. Res. 1975, 8, 342.

m (a) Semmelhack, M. F.; Tamura, R. J Am. Chem. Soc. 1983, 105, 4099. (b) Chen, J.-
B.; Lei, G.-X.; Yin, J.-G. Acta Chimica Sinica 1989, 4 7, 1105.

229 (a) Mitsudo, T.; Ishihara, A.; Kadokura, M.; Watanabe, Y. Organometallics 1986, 5,
238. (b) Mitsudo, T.; Watanabe, H.; Sasaki,T.; Takegami, Y.; Watanabe, Y.
Organometallics 1989, 8, 368.

230 (a) Alcock, N. W.; Richards, C. J .; Thomas, S. E. Organometallics 1991, 10, 231. (b)
For a related isolated chromium(0) vinylketene complex, see: Anderson, B. A.; Wulff, W.
D.; Rheingold, A. L. J Am. Chem. Soc. 1990, 112, 8615.

23‘ (a) Fischer, E. 0.; Beck, H. J. Angew. Chem, Int. Ed. 1970, 9, 72. (b) Fischer, E. 0.;
Beck, H. J.; Kreiter, C. G.; Lynch, J.; Mueller, J.; Winkler, E. Chem. Ber. 1972, 105, 162.

232 (a) Alcock, N. W.; Richards, C. J.; Thomas, 5. E. Organometallics 1991, 10,231. (b)

Mitsdo, T.; Watanabe, H.; Sasaki, T.; Takegami, Y.; Watanabe, Y. Organometallics
1989, 8, 368.

247

 

233 Huffman, M. A.; Liebeskind, L.; Pennington, W. T. Organometallics 1992, 11, 255.
234 Xu, D. Ph.D. Thesis, Universisty of California, Los Angeles, 1991.

235 For an n2,n4-norbomadienyl iron dicarbonyl ketene complex, see: (a) Park, J.; Kang,
S.; Whang, D.; Kim, K. Organometallics 1991, 10, 3413. (b) Park, J .; Kang, S.; Whang,
D.; Kim, K. Organometallics 1992, 11, 1738.

236 There are examples of carbonyl-vinylketene coupling by addition 0f donor ligands,
see: (a) Mitsudo, T.-A.; Sasaki, T.; Watanabe, Y.; Takegami, Y. J Chem. Soc., Chem.
Commun. 1978, 252. (b) Mayr, A.; Asaro, M. F.; Glines, T. J. J. Am. Chem. Soc. 1987,
109, 2215.

237 An ethoxy analog of 294 has very recently reported, see: Ref 225(a).

238 For reactions of vinylketene iron complexes with alkynes, see: Refs. 225 and 226.
23" Kuhn, D. F.; Lillya, C. P. J Am. Chem. Soc. 1972, 94, 1682.

240 For the preparation of 181a and 181b, see: Ref. 215; or Section 5.4 in the text.

2‘“ S6derberg, B. C.; Hegedus, L. 5.; Sierra, M. A. J Am. Chem. Soc. 1990, 112, 4364.
242 Stang, P. J .; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85.

243 Wright, B. B; Platz, M. s. J Am. Chem. Soc. 1984, 106, 4175.

244 (a) Ref. 112a; (b) Anderson, R. L. Ph. D. Thesis, University of Wisconisn, 1974, p.
60.

245 For the preparation of ethoxy carbene complex, see: Ref. 112b.
24" Corey, E. J.; Enders, D.; Bock, M. G. Tetrahedron Lett. 1976, 7.
247 Reid, M.; Rowe, D. J .; Taylor, R. J. K. Chem. Commun. 2003, 2284.

248 Hegedus, L. S.; McGuire, M. A.; Schultze, L. M. Org. Synth. Coll. Vol. VIII, 1993,
216.

249 Brown, H. C.; Campbell, 1. B., Jr. J Org. Chem. 1980, 45, 389. (b) Brown, H. C.;
Chandrasekharan, J. J. Org. Chem. 1983, 48, 644.

25" (a) Wang, z.-x.; Gao, G.-A.; Shi, Y. J Org. Chem. 1999, 64, 7646. (b) Corey, E. J.;
Fuchs, P. L. Tetrahedron Lett. 1972, 3769.

248

 

 

 

25' (a) Chen, J.; Che, C.-M. Angew. Chem. Int. Ed. 2004, 43, 4950. (b) Chinkov, N.;
Majumdar, S.; Marek, I. J. Am. Chem. Soc. 2003, 125, 13258.

252 For an analog of 60a, see: Sierra, M. A.; del Amo, J. C.; Mancheno, M. J .;
Gémez-Gallego, M. J Am. Chem. Soc. 2001, 123, 851.

253 Lai, C.-H.; Shen, Y.-L.; Wang, M.-N.; Rao, N. S. K.; Liao, C.-C. J Org. Chem.
2002, 6 7, 6493.

254 Howell, J. A. S.; Johnson, B. F. G.; Josty, P. L.; Lewis, J. J Organometal.
Chem. 1972, 39, 329.

2” Chen J.; Wang, T.; Zhao, K. Tetrahedron Lett. 1994, 35, 2827.

256 Khand,1. U.; Pauson, P. L. J Chem. Res. (S) 1977, 9.

257 Crombic, L.; Crombic, W. M. L. J Chem. Soc., Perkin Trans. 1 1994, 1267.

25“ Drew, J.; Letellier, M.; Morand, P.; Szabo, A. G. J Org. Chem. 1987, 52, 4047.

259 The (anticipated) ethylation followed the literature procedure for the preparation of
iron carbene complexes, see: Ref. 228(b).

249

 

 

 

APPENDICES

250

APPENDIX 1

X-RAY STRUCTURE AND CRYSTAL DATA FOR 99d-cryst

251

Ema
rats. a w
E: V - l

5.30
S: 22“.!
gr ram $6

$30

       

RF

is 3

ORTEP Diagram of 99d-cryst

252

 

 

99d-cryst

 

 

 

X-ray Structure of 99d-cryst (Displayed in Chem Draw®)

253

X-ray Crystallographic Data for 99d-cryst

Table 1.

Crystal data and structure refinement for

l-[2'—(1",4"-Dioxa-spiro[4.5]dec—7"-yl)-2'-methoxy—vinyl]
-7,7-dimethyl-2-methylene-bicyclo[3.1.1]heptan-6—one

 

Identification code
Empirical formula
Formula weight
Temperature
Wavelength

Crystal system
Space group

Unit cell dimensions

Volume

Z

Density (calculated)
Absorption coefficient

F(000)

Crystal size

Theta range for data collection
Index ranges

Reflections collected / unique
Completeness to theta = 28.33
Refinement method

Data / restraints / parameters
Goodness-of—fit on FA2

Final R indices [I>23igma(I)]

shelxl

C21 H30 04
346.45
293(2) K
0.71073 A
monoclinic

P 2(l)/c

II

a 24.575(5) A
b 8.6136(17) A
c = 18.4l6(4) A
alpha 90 deg.
beta 95.55(3)
gamma 90 deg.

deg.

3880.0(13) A“3
8

1.186 Mg/m“3

0.080 mmA-l

1504

0.6 x 0.3 x 0.3 mm

1.67 to 28.33 deg.

-23<=l<=23

-32<=h<=3l, -ll<=k<=ll,

45301 / 9406 [R(int) = 0.2185]
97.0%

Full-matrix least-squares on F“2
9406 / O / 512

0.935

wR2 = 0.1225

R1 = 0.0748,

254

R indices (all data) R1 = 0.2663, wR2 = 0.1734
Extinction coefficient 0.0023(3)

Largest diff. peak and hole 0.241 and -0.l93 e.A“—3

Table 2. Atomic coordinates ( x 10“4), equivalent isotropic
displacement parameters (A“2 x 10“3), and occupancies for
l—[2'-(l",4"-Dioxa-spiro[4.5]dec—7"-yl)-2'-methoxy—vinyl]
-7,7—dimethyl-2-methylene-bicyclo[3.1.1]heptan—6-one

 

 

x y z U(eq) Occ.
C(l) 1076(1) 5731(4) 4109(2) 45(1) 1
C(2) 1383(2) 4311(4) 4407(2) 43(1) 1
C(3) 1932(2) 4660(4) 4809(2) 50(1) 1
C(4) 1948(2) 6197(4) 5226(2) 56(1) 1
C(5) 1543(2) 7340(5) 4840(2) 53(1) 1
C(6) 1505(2) 7010(4) 4030(2) 52(1) 1
C(7) 950(2) 6749(5) 4803(2) 56(1) 1
C(8) 1191(2) 2883(5) 4326(2) 65(1) 1
0(9) 1685(1) 7634(3) 3520(1) 79(1) 1
C(10) 765(2) 5873(5) 5458(2) 69(1) 1
C(11) 545(2) 8050(6) 4586(3) 102(2) 1
C(1') 622(2) 5460(5) 3520(2) 58(1) 1
C(2') 688(2) 4994(4) 2847(2) 52(1) 1
0(3') 268(1) 4729(4) 2313(1) 76(1) 1
C(4') -270(2) 4929(10) 2502(3) 152(3) 1
0(1") 1799(1) 1110(3) 1696(1) 50(1) 1
C(2") 1958(2) 94(4) 2281(2) 52(1) 1
C(3") 2287(2) 1098(4) 2835(2) 70(1) 1
0(4") 2214(1) 2638(3) 2582(1) 41(1) 1
C(5") 1792(1) 2636(4) 1988(2) 36(1) 1
C(6") 1249(1) 2999(4) 2270(2) 36(1) 1
C(7") 1223(1) 4668(4) 2545(2) 38(1) 1
C(8") 1343(2) 5788(4) 1929(2) 49(1) 1
C(9") 1897(2) 5431(4) 1683(2) 53(1) 1
C(10") 1934(2) 3777(4) 1420(2) 47(1) 1
C(21) 3921(1) 6564(4) 2318(2) 29(1) 1
C(22) 3910(1) 4848(4) 2526(2) 34(1) 1
C(23) 3413(2) 4379(4) 2899(2) 49(1) 1
C(24) 3200(2) 5667(4) 3377(2) 50(1) 1
C(25) 3341(1) 7257(4) 3087(2) 41(1) 1
C(26) 3327(1) 7183(4) 2261(2) 33(1) 1
C(27) 3969(1) 7514(4) 3068(2) 35(1) 1
C(28) 4296(2) 3857(4) 2395(2) 42(1) 1
0(29) 3030(1) 7699(2) 1761(1) 40(1) 1
C(30) 4366(2) 6868(5) 3680(2) 49(1) 1
C(31) 4085(2) 9238(4) 2952(2) 46(1) 1
C(21') 4279(1) 6995(3) 1743(2) 29(1) 1

255

 

C(22' 4190(1) 6579(3) 1045 28(1) 1
0(2 4511(1) 7012(2) 508 35(1) 1
C(24' 4981(1) 7919(4) 712 46(1) 1
0(21" 3733(1) 1517(3) -69 49(1) 1
C(22" 3700(4) 421(6) 471 129(2) 1
C(23") 3361(2) 1043(5) 1017 65(1) 1
0(24") 3191(1) 2526(2) 748 44(1) 1
C(25") 3512(1) 2942(4) 171 34(1) 1
C(26") 3966(1) 4022(3) 455 31(1) 1
C(27") 3738(1) 5541(3) 729 27(1) 1
C(28" 3361(1) 6292(4) 117 33(1) 1
C(29" 2910(1) 5195(4) -182 38(1) 1
C(30" 3140(1) 3659(4) —429 35(1) 1
U(eq) is defined as one third of the trace of the orthogonalized

Uij tensor.

 

Table 3. Bond lengths [A] and angles [deg] for
1-[2'-(1",4"-Dioxa-spiro[4.5]dec—7"—yl)-2'-methoxy-Vinyl]
-7,7-dimethy1-2-methylene-bicyclo[3.1.1]heptan-6-one

C(l)---C(1') 1.498(5)
C(1 ---C(2) 1.513(5)
C(1 --—C(6) 1.542(5)
C( --~C(7) 1.604(5)
C( ---C(8) 1.321(5)
C( ---C(3) 1.503(5 )
C( ---C(4) 1.530(5)
C( ---H(3A) 0.9700
C( ---H(38) 0.9700
C( -—-C(5) 1.525(5)
C( ---H(4A) 0.9700
C( ---H(4B) 0.9700
C( ---C(6) 1.513(5)
C(5 ---C(7) 1.540(5)
C(5 ---H(5) 0.9800
C(6 ---O(9) 1.203(4)
C(7)---C(1l) 1.526(5)
C(7)-—-C(10) 1.528(5)
C(8)---H(8A) 0.9300
C(8)---H(88) 0.9300
C( 0)--H(10A) 0.9600
C( --H(1OB) 0.9600
C( --H(10C) 0.9600
C( --H(11A) 0.9600
C( -—H(118) 0.9600
C( )--H(11C) 0.9600
C(l')--C(2') 1.327(4)
C(1')--H(1') 0.9300
C(2')--O(3') 1.375(4)
(C(2')--C(7") 1.503(5)

256

0(3' )--C(4')
C(4' )"H(4'A)
C(4')-"%{(4'B)
C(4')--H(4' C)
0(13')--C(2 ")
O(1")__C( 5")
C(2")--C(3")
C(2")--H(2"A)
C(2" )--H(2"B)

C(3" )--O(4")
C(3")-41(3"A)
C(3" )--H(3"B)

0(4")--C(5")
C(5")--C(10")
C(5" )--C(6" )
C(6")--C(7")
C (6") --H (6"A)
C(6")--H(6"B)
C(7" )--C(8" )
C(7" )--H(7" )
C(8")‘-C(9" )
C (8' )--H (8"A)
C(8" )--H(8"B)
C(9")--C(10")
C(9") ___H(9 HA)
C(9")--H(9"B)
C(10") -H(10D)
C(10") -H(10E)
C(21)--C(21' )
C(21)--C(22)
C(21)--C(26)
C(21)--C(27)
C(22)--C(28)
C(22)--C(23)
C(23)--C(24)
C(23)--H(23A)
C(23)--H(23B)
C(24)--C(25)
C(24)--H(24A)
C(24)--H(24B)
C(25)~ C(26)
C(25)- C(27)
(2 5) H(25)
C(26)-:O(29)
C(27)--C(30)
C(27)—-C(31)
C(28)--H(28A)
(2 8)- H(288)
C(30)- H(30A)
(3 0)- -H(3OB)
0)--H(30C)
1)

(3

C(3 --H(31A)
C(3 l)--H(3lB)
C(31)--H(31C)
C(2 1')- Q ')
C(21')-H(21' )
C(2 2') -O(23' )

O<DCDF4C>OFACDFJC)O)4F4FJH‘O<DF4C)C>HIAF4CDC>O)4

.411(5)
.9600
.9600
.9600
.414(4)
.421(4)
.511(5)
.9700
.9700
.412(4)
.9700
.9700
.434(3)
.501(4)
.509(4)
.528(4)
.9700
.9700
.539(4)
.9800
.508(5)
.9700
.9700
.511(5)
.9700
.9700
.9700

0.9700

OOOOOOOOl—‘l—‘r—‘Ol—‘r—‘OOHOOD—‘l—Jr—‘t—Jl—JHH

.204(3)
.523(4)
.531(4)
.9300
.9300
.9600
.9600
.9600
.9600
.9600
.9600
1.333(4)
0.9300
1.375(3)

257

 

 

 

C(22')-C(27")
O(2 3') -C(2 ')
C(24')-H(24C)
C(2 4') -H(24D)
C(24')-H(24E)
0(21") -C(22")

O(21") -C(25")
C(22")-C (23")
C(22")"H (22A)

M22")- (228)
C(23") -O(24")

C(23") -H(23C)
C(23")-H (23D)
O(24")-C(25")
C(25") -C(30")
C(25")-C (26")
C(26")-C (27")
C(26")-H (26A)
C(26")-H (26B)
C(27") -C(28")
C(27")-H (27")
C(28") -C(29")
C(28")-H(28C)
C(28")-H(280)
C(29")-C(30")
C(29")-H(29A)
C(29")-H(29B)
C(30")-H(30D)
C(30")-H(3OE)

1')--C(1)---C(2)
l')--C(l)---C(6)
2)---C(l)---C(6)
1')--C(1>---C(7)
2)---C<1)-——C(7)
6)---C(1)---C(7)
8)---C(2)---C(3)
8)---C(2)---C(l)

3)---C(2)*—-C(l)
2)---C(3)---C(4)
2)---C(3)---H(3A)

00000033000OOEOOOOOOOOOOOOOO

4)---C(3)---H(3A)
2)‘-—C(3)-——H(3B)
4)---C(3)---H(3 8)
3A)--C(3)---H(3 B)
5)--~C(4)*--C(3)
5)---C(4)---H(4A)
3)---C(4)---H(4A)
5)---C(4)---H(4B)
3)---C(4)---H(4B)
4A)--C(4)---H(4B)
6)’--C(5)---C(4)
6)---C(5)---C(7)
4)---C(5)-—-C(7)
6)---C(5)'--H(5)
4)---C(5)---H(5)
7)---C(5)---H(5)

OOOOD—‘OOO—‘OHOOHHHHOOD—‘OOl—‘F—‘I—‘OOOF—‘H

116.
120.
106.
118.
106.

82.
122.
123.
114.
113.
108.
108.
108.
108.
107.
109.
109.
109.
109.
109.
108.
108.

85.
112.
115.
115.
115.

258

.500(4)
.416(3)
.9600
.9600
.9600
.380(5)
.430(3)
.468(6)
.9700
.9700
.419(4)
.9700
.9700
.429(3)
.496(4)
.507(4)
.529(4)
.9700
.9700
.530(4)
.9800
.518(4)
.9700
.9700
.526(4)
.9700
.9700
.9700
.9700

wwbbwwwwww

(.11)

www

mmmwQNNQQQQOQOOQWLDHDQQWWKOCDOW

 

 

 

0(9 )---C(6)‘--C(5)
0(9 )---C(6)-—-C(l)
C(5)---C(6)---C(1)
C(ll)‘-C(7) -~-C(10)
C(ll)--C(7)---C(5)
C(10)--C(7)---C(5)
C(ll)--C(7)---C(l)
C(lO)-—C(7)---C(l)
C(5)---C(7)---C(l)
C(2)---C(8)---H(8A)
C(2)---C(8)---H(BB)
H(8A)--C(8)---H(8B)
C(7)---C(10)--H(10A)
C(7)---C(lO)--H(IOB)
H(lOA) -C(lO)--H(lOB)

C7)---C(lO)--H(10C)
lOA)-C(lO)--H(10C)
lOB)-C(lO)--H(10C)

7)---C1)--H(11A)
7)---C ll)--H(llB)
llA)-C ll)--H(llB)
7)---C l)--H(11C)

(1

(

(

(1

llA)-C(ll)--H(11C)

llB)-C(ll)--H(11C)

2')—-C(l ')--C(1)

2')--C(l' )--H(l' )

1)---C(1')--H(l')

1')--C(2')--O(3')
(
(
(

OOOOOOZEZEOZZOOOOOOOOOZEZEOZEOOCCZCO

1')--C 2')--C(7")
3')--C 2')--C(7")
2')--O 3')--C(4' )
3')--C(4')--H(4 A)
3')“C(4')--H(4 B)
4'A) -C(4')--H(4' B)
3')--C(4')-‘H(4 C)
4'A) -C(4')--H(4' C)
4'B) -C(4')--H(4 C)
2")-:O(1" )--C(5")
l")- C(2")-‘C(3 ")
l")- -C(2" )--H(2"A)
3") -C(2")--H(2"A)
1")--C(2" )--H(2"B)
3" )- -C(2" )--H(2"B)
H(2"A) -C(2")--H(2"B)
O(4")--C(3" )--C(2")
O(4")__C(3")__H(3 HA)
C(2")--C(3")--H(3"A)
0(4")--C(3" )--H(3"B)
C(2" )--C(3")--H(3"B)
H(3"A) -C(3" )'-H(3"B)
C(3" )--O(4")‘-C(5")
0(1" )--C(5" )--O(4")
O(l")--C(5")*-C(10")
0(4" )--C(5")--C(10")
0(1" )--C(5")--C(6")
0(4 ")—-C(5" )--C(6")
C(10")-C(5")--C(6")

133.
134.

91.
109.
111.
118.
111.
117.

87.
120.
120.
120.
109.
109.
109.
109.
109.
109.
109.
109.
109.
109.
109.
109.
124.
117.
117.
124.
126.
109.
117.
109.
109.
109.
109.
109.
109.
107.
104.
110.
110.
110.
110.
108.
105.
110.
110.
110.
110.
108.
108.
104.
109.
109.
111.
109.
112.

AAA/‘AAI-‘AA
wwwwbbwwb
vvvvvvvvv

w

wwww

AAA’.‘

LION

NOWUWNNmf-J\lmChGChCDKDCDCDCDCDmNU'IUWUWUWLDU'l-bP-‘bUTONONkOUWUWU‘UWU‘U‘U'ILfiUWUTUTUWOOOCDObxii-4bHAKD
LA)

wmwwwmw

259

 

 

5" )--C(6 ")-*C(7 ")
5" )--C(6")--H(6"A
7")-—C(6")--H(6 "A
5")--C(6")--H(6"B
7")-—C(6")--H(6"B
6"A) -C(6")--H(6"B
'>--c<7")——c<6")
')‘-C(7" )--C(8")
)——C(7 ")--C(8")
)--C(7")--H(7")
)--C(7")--H(7")
)*-C(7")--H(7 ")
)

)

)

)

)

)
)
)
)

2
2
6
2
6'
8|
9" --C(8")--C(7")
9v __C(8u)__H(8 HA)
7' -C(8" )--H(8 "A)
9' —-C(8")--H(8"B)
7" )--C(8")--H(8"B)
8"A)‘ C(8")"H(8"B)
8" )--C(9")--C(10")
")--C(9 ")*-H(9 "A)
10") -C(9")--H(9"A)
8")--C(9")--H(9"B)
10") -C(9")--H(9"B)
"A) -C(9")--H(9"B)
5" )--C(10") -C(9")
5" )--C(10")-H(10D)
9")--C(10") -H(1OD)
5" )- -C(10") -H(10E)
9" )--C(lO")-H(10E)
lOD)- C(10")-H(10E)
21' )-C (2 l)--C(22)
21' )-C (21)--C(26)
22)--C(21)--C 6)

C(
C(
C(
C(
C(
H(
C(
C(
C(
C(
C(
C(
C(
C(
C(
C(
C(
H(
C(
C(8
C(
C(
C(
H(9
C(
C(
C(
C(
C(
H(
C(
C(
C(
C(2 ') C(2l)--C 7)
C(
C(
C(
C(
C(
C(
C(
C(
C(
C(
H(
C(
C(
C(
C(
C(
H(
C(
C(
C(
C(
C(
C(

(2
(2
22)--C(21)--C(27)
26)--C(21)--C(27)
28)--C(22)--C(23)
28)--C(22)--C(21)
23)‘-C(22)- C(2 1)
22)--C(2 3) :CQ 4)
22)--C(23)- H(23A)
24)--C(23)- H(23A)
22)--C(2 3)--H(23B)
24)--C(23)--H(23B)
23A)- C(2 3)--H(238)
25)--C(24)--C(23)
25)--C(24)--H(24A)
23)-:C(24)--H(24A)
25)- 4)--H(24B)
23)--C(24)--H(24B)
24A)- C(2 4)--H(24B)
26)--C(2 5) CQ 4)
26)- :C(25) :C(27)
24)- C(2 5) C(27)
26)-:C(25) Q 5)
24)- -C(25)- Q 5)
27)--C(25)- -H(2 5)

112.
109.
109.
109.
109.
107.
111.
113.
109.
107.
107.
107.
109.
109.
109.
109.
109.
108.
112.
109.
109.
109.
109.
107.
111.
109.
109.
109.
109.
108.
116.
119.
108.
119.
106.

82.
122.
123.
113.
113.
108.
108.
108.
108.
107.
110.
109.
109.
109.
109.
108.
109.

84.
113.
115.
115.
115.

L0

mum

AAA
v

(A) LA) U)

AAAAAAAAAA

UJLAJUJWNNUJUJLDU)

wwwmoomr—onmmmw\Icnoooooo\lxommqwr—INebowwwwmommmmommmmmmq\qur—thommmmr—a
LU

260

)))))))))

)))))))))

120.0

120.0

120.0

109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5

)))))))))))))))

124.5(3)

117.8

117.8

124.7(3)

125.5(3)

109.7(3)

117.9(2)

109.5
109.5
109.5
109.5
109.5
109.5

)))))))

(((((((

108.3(3)

108.7(4)
110.0
110.0
110.0
110.0
108.3
104.9(4)
110.8
110.8
110.8
110.8
108.8

))))))))))))))))))))))))))))))))

)' ' '

(((((((((((((((((((((((((((((((((((((((((((((((((((((((((

)))))))))))))))))))))))))))))))))

(((((((((((((((((((((((((((((((((((((((((((((((((((((((((

)))))))))))

))))))))))))))))))))))))))))))

' ' ) """"

"""
"""

"""""

(((((((((((((((((((((((((((((((((((((((((((((((((((((((((

O
O

C

C
C

C

C
C

C

H

261

C(25" )- C(26") -C(27" ) 111.1(3)
C(25" ) -C(26") -H(26A) 109.4
C(27" )- C(26")-H(26A) 109.4
C(25")-C(26") -H(26B) 109.4
C(27") -C(26") -H(26B) 109.4
H(26A)- C(26")-H(26B) 108.0
C(22')-C(27") -C(26") 110.9(2)
C(22')-C(27")-C(28") 114.0(3)
C(26")-C(27")-C(28" ) 109.5(2)
C(22')-C(27")-H(27" ) 107.4
C(26")-C(27")-H(27" ) 107.4
C(28")-C(27")-H(27" ) 107.4
C(29") -C(28") -C(27' ) 111.8(3)
C(29")-C(28")-H(28C) 109.2
C(27") -C(28")-H(28C) 109.2
C(29")-C(28")-H(28D) 109.2
C(27")-C(28")-H (280) 109.2
H(28C) -C(28")-H (28D) 107.9
C(28")-C(29") -C(30") 111.7(3)
C(28")-C(29")-H (29A) 109.3
C(30") -C(29")-H (29A) 109.3
C(28")-C(29")-H(29B) 109.3
C(30")-C(29")-H(29B) 109.3
H(29A) -C(29")-H(29B) 107.9
C(25") -C(30") -C(29") 110.7(3)
C(25") -C(30")-H(3OD) 109.5
C(29")-C(30") -H(300) 109.5
C(25")-C(30")-H(30E) 109.5
C(29") -C(30 ") -H(30E) 109.5
H(30D) -C(3O ")-H(30E) 108.1

 

Symmetry transformations used to generate equivalent atoms:

Table 4. Anisotropic displacement parameters (A“2 x 10“3) for
l-[2'-(1",4"-Dioxa-spiro[4.5]dec-7"-yl)-2'—methoxy—vinyl]
—7,7-dimethyl-2-methylene-bicyclo[3.1.1]heptan-6-one

 

 

U11 U22 U33 U23 U13 U12
0(1) 45(2) 54(3) 36(2) -4(2) 0(2) 3(2)
C(2) 49(2) 49(3) 34(2) 3(2) 11(2) -10(2)
C(3) 48(3) 55(3) 47(2) 13(2) 4(2) -2(2)
C(4) 58(3) 64(3) 43(3) 10(2) -5(2) —19(2)
C(5) 74(3) 44(3) 40(2) 0(2) —2(2) -8(2)
C(6) 73(3) 45(3) 38(2) 5(2) -1(2) 6(2)
C(7) 66(3) 62(3) 37(2) —10(2) -3(2) 16(2)
C(8) 78(3) 61(3) 54(3) 0(2) 2(3) —13(3)
0(9) 136(3) 55(2) 45(2) 11(2) 2(2) —22(2)
C(10) 56(3) 104(4) 47(3) —27(3) 7(2) —12(3)

262

))))))))))))))))))))))))))))))))))))))))

((((((((((((((((((((((((((((((((((((((((

))))))))))))))))))))))))))))))))))))))))

((((((((((((((((((((((((((((((((((((((((

))))))))))))))))))))))))))))))))))))))))

((((((((((((((((((((((((((((((((((((((((

))))))))))))))))))))))))))))))))))))))))

((((((((((((((((((((((((((((((((((((((((

))))))))))))))))))))))))))))))))))))))))

((((((((((((((((((((((((((((((((((((((((

))))))))))))))))))))))))))))))))))))))))

((((((((((((((((((((((((((((((((((((((((

5434799619910052571056692288959754462191
3444466943347753344433435522345485433434
l 2

l! I l v n u n n n n n n n 01234567890112341234567890
1123412345678912222222223322222222222223

((((((((((((((((((((((((((((((((((((((((

CCCOCOCCOCCCCCCCCCCCCCCOCCCCOCOCCOCCCCCC

 

The anisotropic displacement factor exponent takes the form:

1

U12

+ 2 h k a* b*

[ h“2 a*“2 U11 + ...

-2 pi“2

263

Table 5. Hydrogen coordinates ( x lOA4), isotropic displacement
parameters (A“2 x 10‘3), and occupancies for
1-[2'-(1",4"-Dioxa-spiro[4.5]dec-7"—yl)-2'-methoxy—viny1]
-7,7-dimethyl-2-methylene-bicyclo[3.1.1]heptan-6-one

 

 

x y z U(eq) Occ.
H(3A) 2204 4688 4461 53(11) 1
H(3B) 2029 3825 5150 56(11) 1
H(4A) 1855 6019 5719 49(10) 1
H(4B) 2314 6628 5253 57(11) 1
H(5) 1597 8431 4979 71(12) 1
H(8A) 1396 2049 4520 78(15) 1
H(BB) 849 2712 4074 62(13) 1
H(lOA) 699 6599 5835 95(15) 1
H(lOB) 1045 5156 5638 94(17) 1
H(lOC) 435 5314 5311 111(18) 1
H(llA) 477 8636 5012 94(15) 1
H(llB) 208 7612 4371 180(30) 1
H(llC) 694 8722 4240 74(16) 1
H(l') 266 5630 3635 67(12) 1
H(4'A) -525 4699 2088 170(20) 1
H(4'B) —319 5984 2652 180(30) 1
H(4'C) -332 4242 2896 130(30) 1
H(2"A) 2178 -752 2122 70(13) 1
H(2"B) 1640 -334 2484 89(15) 1
H(3"A) 2156 984 3313 130(20) 1
H(3"B) 2671 812 2869 113(19) 1
H(6"A) 1190 2291 2665 34(9) 1
H(6"B) 959 2836 1882 31(8) 1
H(7") 1515 4796 2943 32(8) 1
H(8"A) 1064 5678 1522 54(11) 1
H(8"B) 1335 6851 2102 65(12) 1
H(9"A) 2175 5603 2086 58(11) 1
H(9"B) 1968 6134 1292 54(11) 1
H(lOD) 1687 3639 981 47(10) 1
H(lOE) 2303 3575 1298 53(11) 1
H(23A) 3504 3476 3201 47(10) 1
H(238) 3123 4083 2530 46(10) 1
H(24A) 2806 5574 3377 51(10) 1
H(24B) 3362 5553 3875 71(12) 1
H(25) 3142 8130 3278 39(9) 1
H(28A) 4269 2823 2533 77(14) 1
H(288) 4596 4189 2164 53(11) 1
H(30A) 4363 7516 4103 57(11) 1
H(BOB) 4728 6846 3525 51(11) 1
H(3OC) 4258 5833 3796 59(12) 1
H(31A) 4108 9768 3413 88(14) 1
H(318) 3794 9680 2631 77(13) 1
H(31C) 4424 9349 2739 88(15) 1
H(Zl') 4586 7596 1881 9(7) 1
H(24C) 5165 8150 288 67(12) 1
H(24D) 5223 7353 1057 52(11) 1
H(24E) 4875 8870 931 62(12) 1

264

H(22A) 4063 181 698 380(70) 1
H(2ZB) 3539 -527 263 260(40) l
H(23C) 3049 378 1066 160(20) 1
H(23D) 3572 1134 1489 124(19) 1
H(26A) 4196 4243 69 25(8) 1
H(26B) 4189 3520 850 39(9) 1
H(27") 3513 5280 1123 17(7) 1
H(28C) 3199 7220 302 37(9) 1
H(28D) 3575 6599 -275 17(7) 1
H(29A) 2698 5683 -591 42(9) 1
H(29B) 2667 4996 193 38(9) 1
H(3OD) 2842 2952 -573 29(8) 1
H(30E) 3341 3836 -850 47(10) 1

 

Table 6. Torsion angles [deg] for
1-[2'-(l",4"—Dioxa—spiro[4.5]dec-7"-yl)-2'-methoxy-vinyl]
-7,7-dimethyl-2-methylene-bicyclo[3.1.1]heptan-6-one

 

C(6) C(1) C(2) C(3) 22.9(4)
C(6) C(1) C(2) C(8) -157.0(3)
C(7) C(1) C(2) C(3) -64.1(4)
C(7) C(1) C(2) C(8) 115.9(4)
C(1') C(1) C(2) C(3) 161.6(3)
C(1') C(1) C(2) C(8) -18.4(5)
C(1) C(2) C(3) C(4) 34.1(4)
C(8) C(2) C(3) C(4) -l45.9(4)
C(2) C(3) C(4) C(5) -29.7(4)
C(3) C(4) C(5) C(6) -3l.5(4)
C(3) C(4) C(5) C(7) 61.4(4)
C(4) C(5) (3(6) C(1) 84.6(3)
C(4) C(5) C(6) 0(9) -103.8(5)
C(7) C(5) C(6) C(1) -27.5(3)
C(7) C(5) C(6) 0(9) 144.1(5)
C(2) C(1) C(6) C(5) -78.4(3)
C(2) C(1) C(6) 0(9) 110.1(5)
C(7) C(1) C(6) C(5) 26.5(3)
C(7) C(1) C(6) 0(9) -145.0(5)
C(1') C(1) C(6) C(5) 145.1(3)
C(1') C(1) C(6) 0(9) -26.4(6)
C(4) C(5) C(7) C(1) -81.6(3)
C(4) C(5) C(7) C(10) 38.2(5)
C(4) C(5) C(7) C(11) 166.3(3)
C(6) C(5) C(7) C(1) 26.4(3)
C(6) C(5) C(7) C(10) 146.1(4)
C(6) C(5) C(7) C(11) -85.8(4)
C(2) C(1) C(7) C(5) 79.5(3)
C(2) C(1) C(7) C(10) -41.8(4)
C(2) C(1) C(7) C(11) -168.7(4)
C(6) C(1) C(7) C(5) -26.0(3)
C(6) C(1) C(7) C(10) -147.3(4)
C(6) C(1) C(7) C(11) 85.8(4)

265

VVVVV
. c n n I- Q Q C c ‘ " - ‘

.vvvvvvvvvvvvv

= C c c CO

‘
vvvvvvvvvvvvv

000000000000nooonnonnnoononoonoonno
6533733333333:CCECB’GQSSSECGZCSCSSGCCC

\Jm

OOOOOOOOOOOOOOOOOOOOO
n>n>m>k>m)m>m)m)m>m>m)m>n3m>m>n>m>m>m>n)m)
\JN!A~4PQFJ\JA~Q.b(prhoFJG)\JO)H

(.3

V

v

v

AAAAAAAAAAA

C)C)()C)()F)C)C)C)O O Otfi<fi

O
H‘H’H’Q)RJH‘K)R)F‘F‘F‘F‘F‘H‘H‘H‘

0(

C(
C(
C(
C(
C(
C(

F)

()()C)O 0(n(1()C)C)C)O
§E§§§SS§Q§NSA

0(3')
0(3')
C(2")
C(3")
0(4n)
5")
5")
5")
5")
C(5")
C(5")
C(6")
C(6")
C(6")
C(7")

C(
C(
C(
C(

C(10")
C(10")
C(10")

C(22)
C(22)
C(22)

NNNNNNNMNN
OWONQONGUWUTDLQ

C(5")
0(4n)
C(6")

C(10")

0(1")
C(6")

C(10")

C(7")
C(7")
C(7")
C(6")
C(8")
C(6")
C(8")
C(2')
C(8")
C(9")
C(9")
(

C 10")

C(9")
C(9")
C(9")
C(5")

C(28)
C(28)
C(28)
C(23)
C(23)
C(23)
C(24)
C(24)
C(25)
C(26)
C(27)

)

-l47
91
-35
-69

63.

162
179

-0.
-1.
178.
-25.
9.

9.
32.
-86.
149.
-25.
94.
-142.
-176.
67.
-53.
121.
-115.
-58.
64.
-178.
56.
177.
-58.
58.
176.
-69.
52.
-55.

20.
157.
-115.
-159.
~22.
64.
147.
-33.
27.
33.
-59.
109.
-137.
-84.
28.
19.
-116.
138.
-147.
76.
-28.

.2(3)
.6(4)
.3(5)
.0(5)
6(5)
.3(4)
.2(4)

0
\)\l

V

war-)Lommaooooqmt—‘momoommr—‘q
.b.b(b.b(b.b.b.u.b.b(»(»(».A-b u)u)u)U1U1®-U7

vvvvvvvvvvvvvvvvvvvvvvvvv

400.12.
.51..)

1(4

N
.5

omwmdNUWUmebmeI—‘OOWCDNWH
Nww-bbUWNUJA-bbbbbLUWAwwwnb

)))))))))))))))))))))))))))))))))))))))))))))))

((((((((((((((((((((((((((((((((((((((((<((((((

36935263210148113507325737915219951487219369058
67467112960369784283260139798502874419769545953
4386289443784726667. 71 11391306751625757556755
1.1. _ 11.1. .11 l _l__ll_lll_l_1_l_
_ _ _ _ . _ _ _ _
00111100011155522237443451064067776688289909995
33332233333322222222222222322322222222222232222
CCCCCCCCCCCCCCCCCCOCCCCOCOCCOCCCCCCCCCCCCCCCCCC

))))))))))))))))))))))))))))))))
"""""""""""""

((<((((((((((((((((((((((((((((((((((((((((((((

)))))))))))))))))))))))))))))

"""""""""""

(((((((((((((((((((((((((((((((((((((((((((((((

(((((((((((((((((((((((((((((((((((((((((((((((

267

Symmetry transformations used to generate equivalent atoms:

 

APPENDIX 2

X-RAY STRUCTURE AND CRYSTAL DATA FOR 254a

268

.
R
$//\

0(14) @3 Q
C(13)

 

 

 

 

 

0(12)
0
I.lfi/OMe
H380
2Fe(CO)3
254a
ORTEP Diagram of 2543

269

X-ray Crystallographic Data for 2543

Table 1.

wa72604

Crystal data and structure refinement for

 

Identification code
Empirical formula
Formula weight
Temperature
Wavelength

Crystal system
Space group

Unit cell dimensions

Volume

Z

Density (calculated)
Absorption coefficient
F(OOO)

Crystal size

Theta range for data collection

Index ranges
Reflections collected / unique

Completeness to theta = 28.32

wa72604

C11 H10 Fe 05
278.04

173(2) K
0.71073 A
Monoclinic

P2(1)/c

a 12.152(2) A

b 7.3323(15) A

c 13.315(3) A

alpha 90 deg.

beta 108.59(3) deg.

gamma 90 deg.

1124.5(4) AA3

4

1.642 Mg/m“3

1.347 mmA-l

568

0.25 x 0.1 x 0.05 mm
1.77 to 28.32 deg.
-16<=h<=l6,

—9<=k<=9, ~17<=l<=17

12943 / 2711 [R(int) = 0.0523]

97.0%

270

Refinement method

Data / restraints / parameters
Goodness-of-fit on FAZ

Final R indices [I>251gma(I)]
R indices (all data)

Largest diff. peak and hole

Full-matrix least-squares on FAZ

2711 / 0 / 194

0.746
R1 = 0.0344, wR2 = 0.0904
R1 = 0.0623, wR2 = 0.1091

0.413 and -0.304 e.A“-3

271

 

 

Table 2. Atomic coordinates ( x 10A4), equivalent isotropic
displacement parameters (A“2 x 10‘3), and occupancies for
wa72604

x y z U(eq) Occ.
Fe 2142(1) 540(1) 969(1) 20(1) 1
C(1) 3847(2) 152(4) 1076(2) 27(1) 1
C(2) 3607(2) 2030(4) 1081(2) 23(1) 1
C(3) 3179(2) 2675(3) 1905(2) 20(1) 1
C(4) 3651(2) 1888(3) 2983(2) 22(1) 1
C(5) 4044(2) -81(4) 3019(2) 26(1) 1
C(6) 3645(2) -865(4) 1907(2) 26(1) 1
0(7) 2833(2) 4480(2) 1812(2) 27(1) 1
C(8) 1858(3) 4870(4) 2172(3) 35(1) 1
0(9) 3718(2) 2768(3) 3779(1) 34(1) 1
C(10) 3645(3) -1203(5) 3808(3) 34(1) 1
C(11) 1259(2) 2130(4) 8(2) 30(1) 1
0(12) 721(2) 3145(3) -603(2) 48(1) 1
C(13) 1636(2) -1365(4) 89(2) 29(1) 1
0(14) 1312(2) -2577(3) -459(2) 46(1) 1
C(15) 1239(2) 195(4) 1787(2) 26(1) 1
0(16) 646(2) -17(3) 2293(2) 41(1) 1

 

U(eq) is defined as one third of the trace of the orthogonalized

Uij tensor.

272

 

273

Table 3. Bond lengths [A] and angles [deg] for
wf072604
Fe-C(15) 1.794(3)
Fe-C(13) 1.801(3)
Fe-C(11) 1.809(3)
Fe-C(1) 2.051(3)
Fe-C(2) 2.053(2)
Fe-C(6) 2.122(3)
Fe-C(3) 2.142(2)
C(1)-C(2) 1.408(4)
C(1)-C(6) 1.420(4)
C(2)-C(3) 1.436(3)
C(3)-0(7) 1.382(3)
C(3)—C(4) 1.482(3)
C(4)-0(9) 1.221(3)
C(4)-C(5) 1.516(4)
C(5)-C(6) 1.516(4)
C(5)-C(10) 1.530(4)
C(7)-C(8) 1.442(4)
C(11)-C(12) 1.142(3)
C(13)-C(14) 1.138(3)
C(15)-C(16) 1.143(3)
C(15)-Fe-C(13) 97.90(12)
C(15)-Fe-C(11) 100.38(12)
C(13)-Fe—C(11) 92.13(13)
C(15)-Fe-C(1) 137.62(12)
C(13)-Fe-C(1) 93.76(12)

C(11)-Fe-C(1)
C(15)-Fe-C(2)
C(l3)-Fe-C(2)
C(11)-Fe-C(2)
C(1)-Fe-C(2)
C(15)-Fe-C(6)
C(13)-Fe-C(6)
C(11)-Fe-C(6)
C(1)-Fe-C(6)
C(2)-Fe-C(6)
C(15)-Fe—C(3)
C(13)-Fe-C(3)
C(11)-Fe-C(3)
C(1)-Fe-C(3)
C(2)-Fe-C(3)
C(6)-Fe-C(3)

(3(2)-C(1)-C(6)

C(2)-C(3)-C(4)

O(7)-C(3)-Fe

119.

135.

124

90.

40.

98.

93.

159.

39

69.

96.

163.

92.

70.

39.

77

115.

70.

72.

116.

69.

73.

114.

118.

119.

122.

66.

104.

122.

80(12)

66(11)

.64(11)

78(11)
13(11)
78(11)
31(12)

15(11)

.73(11)

64(11)
31(10)
91(10)
69(11)
57(10)

97(9)

.06(10)

0(2)
02(15)

83(15)

0(12)-C(ll)-Fe
O(14)-C(13)-Fe

O(l6)-C(15)-Fe

122.

115.

109.

111.

113.

118.

67.

109.

114.

178.

179.

178.

 

Symmetry transformations used to generate equivalent atoms:

 

 

Table 4. Anisotropic displacement parameters (A“2 x 1023) for
wa72604
011 022 033 023 013 012
Fe 20(1) 21(1) 20(1) -2(1) 7(1) -2(1)
C(1) 20(1) 35(2) 27(1) -6(1) 11(1) -1(1)
C(2) 20(1) 29(1) 21(1) -1(1) 7(1) -7(1)
C(3) 20(1) 22(1) 19(1) -l(1) 6(1) -4(1)
C(4) 18(1) 26(1) 21(1) 1(1) 5(1) -3(1)
C(5) 18(1) 31(1) 27(1) 5(1) 5(1) 1(1)
C(6) 24(1) 23(1) 32(1) 0(1) 10(1) 3(1)
0(7) 32(1) 19(1) 31(1) 1(1) 11(1) -2(1)
C(8) 38(2) 26(2) 45(2) -2(1) 17(1) 7(1)

275

C(10)

C(11)

C(12)

C(13)

C(14)

C(15)

C(16)

39(1)

32(2)

28(1)

45(1)

28(1)

44(1)

22(1)

34(1)

42(1)

38(2)

30(1)

45(1)

33(2)

44(1)

26(1)

58(1)

51(1)
25(1)

38(1)

-2(1)

12(1)

15(1)

 

The anisotropic displacement factor exponent takes the form:

-2 pi“2

[ h“2 a*“2 011 + ...

276

+ 2 h k a* b* 012 ]

Table 5. Hydrogen coordinates ( x 1024), isotropic displacement

parameters (A“2 x 10“3), and occupancies for

 

 

wa72604
x y z U(eq) Occ.
H(l) 4020(30) -320(40) 460(20) 28(8) 1
H(2) 3640(20) 2810(40) 550(20) 21(7) 1
H(S) 4860(30) 0(40) 3270(20) 19(7) 1
H(6) 3630(20) —2190(40) 1890(20) 21(7) 1
H(8A) 1760(30) 6130(50) 2090(30) 41(9) 1
H(8B) 2020(30) 4550(50) 2900(30) 47(10) 1
H(BC) 1090(40) 4100(60) 1870(40) 90(15) 1
H(lOA) 2750(30) -1150(40) 3600(20) 31(8) 1
H(lOB) 4020(30) -790(50) 4500(30) 55(11) 1
H(lOC) 3830(30) -2380(50) 3780(30) 48(10) 1

 

277

APPENDIX 3

SEM/EDS SPECTRA FOR 181a AND 254a

278

SEM/EDS Spectra for Chromium Complex 181a

I hermo NUHAN

 

 

 

 

 

279

SEM/EDS Spectra for Iron Complex 254a

Thermo NORAN

 

 

 

 

 

280

02845 31 AA

\\\\

293

\\

\\\

\

‘

\\\\\\

M \

\