PROGRESS TOWARD THE TOTAL SYNTHESIS OF PACLITAXEL (TAXOL®)
DISSERTATION
Presented in Partial Fulfillment of the Requirements for
the Degree Doctor of Philosophy in the Graduate
School of The Ohio State University
By
Matthew M. Kreilein, M.S.
* * * * *
The Ohio State University
2005
Dissertation Committee: Approved by
Professor Leo A. Paquette, Advisor
Professor David J. Hart
Professor T.V. RajanBabu ______Advisor Professor Pui-Kai Li Chemistry Graduate Program
ABSTRACT
Described herein is the continuation of efforts focused towards the synthesis of Taxol utilizing a route that is amenable to novel analog formation from advanced Taxol precursors. Elaboration of (1S)-(+)-10-camphorsulfonic
acid to a highly functionalized taxane skeleton has been achieved in a total of
twenty-two synthetic operations. Highlighting the brevity and efficiency of this
series is the fact that only five operations thus far are protecting group
manipulations, which tend to significantly increase the length and complexity of a
synthetic route.
Entry to a completed D-ring has been made by prevous researchers in a
six-step sequence. After the revelation that formation of the densly
functionalized A-ring in the presence of a completed D-ring was not possible, the
focus became one of elaboration of the A-ring using the very useful diosphenol
intermediate 3.1.
Two areas of research have been explored and are described. First, the
route to the bridge-migrated taxane 1.85 was reviewed and problems existing in
the key alkenyl iodide coupling, dihydroxylation, C2 oxygenation, and bridge
migration were investigated and resolved.
ii With an efficient synthesis of 1.85 in hand, attention was focused on completion of the A-ring beginning with routes originating from 1.85. It was quickly realized that use of the diosphenol intermediate 3.1 would be
advantageous, the optimization of its synthesis was explored and realized.
A-Ring completion from 3.1 was attempted to no avail via early functionalization of the northern sector utilizing various methods. Attention was then focused on the southern sector in an attempt to bring about C14 deoxygenation at an early stage. Again, progress was halted and a new route had to be envisioned. Protection of C1 was employed to stave off undesired retro-aldol fragmentation of the A-ring; however, deoxygenation was again thwarted.
The final approach explored has given rise to an oxygenation strategy that has allowed for the synthesis of the C12 ketone 3.49. With this ketone, arrival at the A-ring might be realized through four more transformations. At that point, the route would be at a point utilized in previous Taxol syntheses and arrival at 1.1 would be imminent providing a new method of entry into natural and unnatural taxanes.
iii
To Mom, Mike, Michael, and Dad
iv
ACKNOWLEDGMENTS
I would first like to thank my advisor, Professor Leo Paquette. It has been
a pleasure working with you on this project, sharing ideas, inspiration, and
excitement. It has been a pleasure and an honor to be a member of this great
research group that you have molded. Thank you for the opportunity.
I would also like to thank Professors David Hart and T.V. RajanBabu for serving as dissertation committee members, instructors, and true colleagues
throughout my time here at OSU. Thank you for all your time and hard work.
Very special thanks to the members of Team Taxol that I have worked
with in the past: Drs. Ruslan Arbit, Nancy Brennan, Xin Guo, John Hofferberth,
and Ho Yin Lo. Your help on this project was invaluable.
Thank you to Rebecca Martin and Donna Rothe. Without your efforts, this
whole group would collapse.
I must thank the entire Paquette research group for all your help and for
being the best colleagues that I think I’ll ever have. Another special thank you to
Ryan & Elizabeth Hartung and Dave & Tammy Hilmey for being great friends of
mine here at OSU and for allowing me to have some surrogate pets, Ginger and
Mr. Bojangles, the last few years I was here. In addition, Ryan and Dave
v proofread this entire document. I know what a chore it was for you guys to read
the entire Taxol saga over again. Thank you.
I would like to thank my true lab mates: Dr. Dean Clyne, Dr. Jiyoung
Chang, Xiaowen Peng, Brandon Shetuni, Dr. Feng Geng, Peter Selvaraj,
Zhenjiao Tian (a.k.a. ZT and Mom-dude), Dr Adam Preston, and Dr. Marshall
Stepanian for putting up with my moodiness, occasional anger, routine cursing, my music, and off-color humor over the years. You all have earned and extra medal for surviving in an enclosed space with me.
I have the best family in the world. The extended family is to big to go into great detail about, but they all deserve a big thank you for all their support.
Grandpa, you were a great man, who instilled the importance of education in
your children and grandchildren, I thank you for that, and hope to embody you
when the day comes with my family. Alex and Maxwell, stay in school. It is hard
work, but you will never feel better about working hard than the day you get to
write something like this.
Finally, I have saved the best for last. There are four people who never
faltered in their support of me at any point in my life, and I’m sure never will. This
entire body of work is as much theirs as it is mine. Mom, Mike, Michael, and
Dad, I cannot possibly begin to put into words what I owe you. All I can do is say
that I appreciate the education you have given me, the many sacrifices you have
made for me, and the support and love you have given me throughout my life.
From the bottom of my heart, thank you.
vi
VITA
May 21, 1977...... Born – Cincinnati, Ohio
May 1999...... B.A. Chemistry, Saint Louis University
November 2001...... M.S. Chemistry, The Ohio State University
September 1999 – September 2000...... University Fellow The Ohio State University
October 2000 – October 2002 ...... Dept. of Education GAANN Fellow The Ohio State University
November 2002 – March 2004 ...... Graduate Teaching and Research Fellow The Ohio State University
March 2004 – present...... Lubrizol Industrial Fellow The Ohio State University
PUBLICATIONS
Research Publications
1. “1,4-Dioxene” Electronic Encyclopedia of Reagents for Organic Synthesis, Paquette, L.A. Ed.-in-Chief. John Wiley and Sons.
FIELDS OF STUDY
Major Field: Chemistry
vii
TABLE OF CONTENTS
Abstract ...... ii
Dedication ...... iv
Acknowledgments ...... v
Vita ...... vii
List of Tables ...... xii
List of Figures...... xiii
List of Schemes...... xvii
List of Abbreviations ...... xxi
Chapters:
1. Background...... 1
1.1 Introduction ...... 1
1.2 History of the Yew Tree...... 2
1.3 Isolation and Structural Determination of Taxol ...... 3
1.4 Overview of the Biological Activity of Taxol...... 8
1.5 Review of Prior Total Syntheses of Taxol ...... 15
1.5.1 Syntheses Based on the Coupling of A-Ring and C/D-Ring Precursors ...... 17
1.5.2 Syntheses of Taxol Based on Initial B-Ring Formation...... 21
viii
1.6 Taxane Synthesis in the Paquette Group: Motivation and Precedent ...... 24
1.6.1 Examination of the Oxy-Cope Rearrangement: Proof of Concept ...... 29
1.6.2 Synthesis and Utility of Early-oxygenated Substrates ...... 31
1.7 Development of a New Approach to Taxol...... 35
2. Synthesis and Functionalization of the B, C, and D-Rings...... 38
2.1 Synthesis of Coupling Partners and Formation of the Pretaxane Core...... 38
2.1.1 Synthesis of Coupling Partners 1.90 and 1.91 ...... 38
2.1.2 Alkenyl Iodide Coupling – Problems and Solution ...... 41
2.2 Further Functionalization of the B-Ring En Route to Bridge Migration ...... 45
2.2.1 C-Ring Closure and Hydride Shift Reaction ...... 45
2.3 Formation of a Bridge Migrated Taxane...... 50
2.3.1 Original Conditions for Bridge Migration Precursor Formation...... 50
2.3.2 Second Generation Route to 1.85 ...... 52
2.4 Additional Insight into Bridge Migration and Pretaxane Chemistry...... 53
2.5 Completion of a D-Ring Synthesis and Development of the Requirement for Initial A-Ring Completion ...... 55
2.5.1 First Generation D-Ring Synthesis ...... 56
2.5.2 Second Generation D-Ring Synthesis...... 57
ix 3. A-Ring Functionalization...... 59
3.1 Early A-Ring Functionalization and Failure of the Eastward Strategy...... 59
3.2 Synthetic Challenges Resident in the A-Ring...... 60
3.2.1 A-Ring Completion in Taxusin ...... 61
3.2.2 C14 Ketone Reduction and Retro-aldol Fragmentation...... 63
3.3 A-Ring Elaboration from the Bridge Migrated Product ...... 65
3.3.1 A-Ring Completion Based on Reduction and Elimination...... 65
3.3.2 A-Ring Completion Based on Intramolecular Reduction...... 67
3.4 Optimization of the Synthesis of the Diosphenol...... 69
3.5 A-Ring Completion Based on Functionalization of the Northern Sector ...... 80
3.5.1 Basic Plan and Strategic Considerations...... 80
3.5.2 Northern Sector Strategies – Bromination and Selenation ...... 81
3.5.3 Northern Sector Strategies – Palladium and Hypervalent Iodine Oxidation...... 84
3.6 A-Ring Completion Based on Early C14 Deoxygenation ...... 89
3.6.1 C14 Reduction and Xanthate Formation ...... 89
3.6.2 Xanthate Reduction Attempts...... 93
3.7 A-Ring Functionalization Employing C1 Protection...... 95
3.7.1 Alternate Diosphenol Protection ...... 96
3.7.2 C1-C14 Diol Protection Attempts...... 98
x 3.7.3 Successful C1 Dimethylsilyl Protection ...... 100
3.7.4 A-Ring Elaboration Plans With C1 Protection Secured ...... 102
3.8 Miscellaneous Diosphenol and A-Ring Functionalization...... 107
3.9 Oxygenation Strategy to a Completed A-Ring and Current Work...... 110
3.9.1 Initial Plan and Strategy Development ...... 110
3.9.2 Epoxidation Exploration and Optimization...... 114
3.9.3 Oxirane Opening and C12 Hydroxyl Group Oxidation...... 119
4. Conclusion and Future Work ...... 123
4.1 Observations on the Chemistry of Diosphenols and Their Derivatives...... 123
4.1.1 Reactions Involving the Enol ...... 124
4.1.2 Reactions of the Ketone ...... 126
4.2 Final Conclusions and Future Work ...... 127
5. Experimental Details...... 129
List of References...... 182
Appendices:
Appendix A: 1H NMR Data...... 193
xi
LIST OF TABLES
Table Page
3.1 Results of Early Diosphenol Optimization ...... 75
3.2 Results of Selenation of C12...... 82
3.3 Oxidation of Silylated Diosphenols with Palladium and IBX ...... 85
3.4 Results of Xanthate Formation Attempts...... 92
3.5 Results of Reduction of 3.36 ...... 93
3.6 Allylation of Diosphenol Substrates...... 97
3.7 Attempts at Protection of the C1-C14 Diol ...... 99
3.8 Meerwein-Ponndorf-Verley Reductions Attempted ...... 100
3.9 Protection of the C1 Hydroxyl Group in Diosphenol Systems...... 101
3.10 Attempted Reduction of C1 Protected Species ...... 107
xii
LIST OF FIGURES
Figure Page
1.1 Structure of Taxol...... 5
1.2 Structures Utilized in the First Semi-synthesis of Taxol ...... 6
1.3 DNA Damage Model with Taxol Interaction in the Process...... 10
1.4 Diagram of Microtubule Assembly with Taxol Interaction Illustrated...... 13
1.5 Key Structural Features of the Baccatin Nucleus of Taxol...... 16
1.6 Key Structure Activity Relationships in Taxol ...... 25
1.7 Novel Taxol Analogs Slated for Synthesis ...... 27
2.1 X-ray Crystal Structure of 2.11...... 47
2.2 X-ray Crystal Structure of 2.12...... 47
2.3 “Two Pronged” Approach to Taxol ...... 56
3.1 Migration Product 1.85 and Target Completed A-ring 1.84...... 61
3.2 Utility of Diosphenol 3.1 ...... 69
3.3 HMBC Correlations Present in 3.47 ...... 116
3.4 HMBC Correlations Present in 3.53-Z and 3.53-E ...... 117
3.5 1H NMR Spectrum of Z- (top) and E-olefin (bottom) ...... 119
3.6 HMBC Correlations Present in 3.49 ...... 121
xiii 4.1 Reactivity Profile in Our Diosphenol Intermediate...... 123
4.2 C12 and Enol Oxygen Reactivity in Diosphenols ...... 124
4.3 Epoxidation Reactions on Diosphenols...... 125
4.4 Ketone Reactivity in Diosphenols...... 126
A.1 1H NMR Spectrum of 2.1...... 194
A.2 1H NMR Spectrum of 2.3...... 195
A.3 1H NMR Spectrum of 2.4...... 196
A.4 1H NMR Spectrum of 1.90...... 197
A.5 1H NMR Spectrum of 2.5...... 198
A.6 1H NMR Spectrum of 2.6...... 199
A.7 1H NMR Spectrum of 2.7...... 200
A.8 1H NMR Spectrum of 1.91...... 201
A.9 1H NMR Spectrum of 1.89...... 202
A.10 1H NMR Spectrum of 1.88...... 203
A.11 1H NMR Spectrum of 2.9...... 204
A.12 1H NMR Spectrum of 2.10...... 205
A.13 1H NMR Spectrum of intermediate alcohol...... 206
A.14 1H NMR Spectrum of 1.87...... 207
A.15 1H NMR Spectrum of 2.11...... 208
A.16 1H NMR Spectrum of 2.12...... 209
A.17 1H NMR Spectrum of 2.19...... 210
A.18 1H NMR Spectrum of 2.20...... 211
A.19 1H NMR Spectrum of 2.25...... 212
xiv A.20 1H NMR Spectrum of intermediate hydroxy epoxide ...... 213
A.21 1H NMR Spectrum of 2.24...... 214
A.22 1H NMR Spectrum of 1.85...... 215
A.23 1H NMR Spectrum of 3.1...... 216
A.24 1H NMR Spectrum of 3.15...... 217
A.25 1H NMR Spectrum of 3.21...... 218
A.26 1H NMR Spectrum of 3.23...... 219
A.27 1H NMR Spectrum of 3.24...... 220
A.28 1H NMR Spectrum of 3.25...... 221
A.29 1H NMR Spectrum of 3.30...... 222
A.30 1H NMR Spectrum of 3.31...... 223
A.31 1H NMR Spectrum of 3.32...... 224
A.32 1H NMR Spectrum of 3.33...... 225
A.33 1H NMR Spectrum of 3.34...... 226
A.34 1H NMR Spectrum of 3.36...... 227
A.35 1H NMR Spectrum of 3.38...... 228
A.36 1H NMR Spectrum of 3.39...... 229
A.37 1H NMR Spectrum of 3.40...... 230
A.38 1H NMR Spectrum of 3.41...... 231
A.39 1H NMR Spectrum of 3.42...... 232
A.40 1H NMR Spectrum of 3.44...... 233
A.41 1H NMR Spectrum of 3.47...... 234
A.42 1H NMR Spectrum of 3.53-Z ...... 235
xv A.43 1H NMR Spectrum of 3.53-E ...... 236
A.44 1H NMR Spectrum of 3.48...... 237
A.45 1H NMR Spectrum of 3.49...... 238
xvi
LIST OF SCHEMES
Scheme Page
1.1 The Nicolaou Approach to Taxol...... 17
1.2 The Danishefsky Approach to Taxol ...... 19
1.3 The Kuwajima Approach to Taxol ...... 20
1.4 The Holton Approach to Taxol ...... 22
1.5 Wender’s Pinene Path to Taxol...... 23
1.6 The Mukaiyama Approach to Taxol...... 24
1.7 General Retrosynthesis of Taxol...... 28
1.8 Early Evidence of the Potential of the Oxy-Cope Rearrangement ...... 30
1.9 Coupling and Oxy-Cope With an Advanced C/D-Ring Precursor...... 31
1.10 Successful Synthesis of a C10 Oxygenated Substrate ...... 32
1.11 Sensitivity of the Oxy-Cope Reaction...... 33
1.12 Problems with Other C2 Oxygenated Precursors...... 34
1.13 Current Retrosynthetic Analysis of Taxol ...... 36
2.1 Synthesis of Camphor-derived Coupling Partner 1.90 ...... 39
2.2 Synthesis of Alkenyl Iodide Coupling Partner 1.91...... 40
2.3 Original Coupling Reaction Conditions and Problems Encountered...... 41
xvii 2.4 Optimized Alkenyl Iodide Coupling and Oxy-Cope Rearrangement ...... 42
2.5 Formation of A/B-Ring Pretaxane Core...... 44
2.6 C-ring Closure and Hydride Shift of Aldol Product ...... 46
2.7 Utility of Hydride Shift in 1-Deoxypaclitaxel Precursor Synthesis ...... 48
2.8 Formation of Diketone by B-ring Functionalization...... 49
2.9 Original Steps for B-ring Functionalization and Bridge Migration ...... 51
2.10 New Sequence for Arrival at a Bridge Migrated Taxane ...... 53
2.11 Actual Bridge Migration Products Formed from 2.24...... 54
2.12 First Generation Synthesis of the Oxetane Ring ...... 57
2.13 Second Generation D-ring Synthesis...... 58
3.1 Successful and Attempted Formation of A-ring Diosphenols...... 60
3.2 A-ring Elaboration in the Synthesis of Taxusin...... 62
3.3 Undesired Retro-aldol A-ring Cleavage...... 65
3.4 A-ring Elaboration from Bridge Migrated Product...... 65
3.5 Reduction of Bridge Migrated Compound ...... 67
3.6 Hydrosilylation Chemistry for C14 Reduction...... 68
3.7 Oxidation State Control in Taxusin Diosphenol Synthesis ...... 71
3.8 Probable Mechanism of Diosphenol Formation ...... 73
3.9 Result of Low Temperature Oxidation of 1.85...... 77
3.10 Diosphenol Formation Attempts Using Selenium Oxidation...... 78
xviii 3.11 Optimized Synthesis of Diosphenol 3.1...... 78
3.12 A-ring Completion Based on Northern Sector Functionalization...... 81
3.13 Bromination of Diosphenol Type Substrates ...... 84
3.14 A-ring Functionalization Based on Tsuji’s Palladium Chemistry ...... 86
3.15 Alternative Application of Tsuji Palladium Chemistry ...... 87
3.16 Tsuji Palladium Chemistry With O-Acylated Starting Material ...... 88
3.17 General C14 Deoxygenation Strategy...... 89
3.18 Functionalization of the A-ring en route to C14 Deoxygenation...... 90
3.19 Reduction of Allylated Functionalized Diosphenol...... 98
3.20 Plan for A-ring Advancement from 3.42 ...... 103
3.21 A-Ring Functionalization Avoiding Potential Loss of C1 Protection...... 104
3.22 Taxusin-like Approach to the A-Ring...... 105
3.23 Epoxide Route to a Completed A-Ring ...... 106
3.24 Exploratory Diosphenol and A-Ring Functionalization ...... 109
3.25 Additional A-Ring Functionalization Attempts ...... 110
3.26 Early Oxygenation Strategy to a Completed A-Ring ...... 111
3.27 Initial Epoxidation of the A-Ring ...... 112
3.28 Plan for Arrival at the A-Ring Using an Epoxidation Strategy...... 113
3.29 A-Ring Completion via Epoxidation of the Brominated Analog...... 114
xix 3.30 Epoxidation of A-Ring with Possible Payne Rearrangement...... 115
3.31 Interesting Reaction in lieu of Desired A-Ring Epoxidation ...... 118
3.32 Arrival at an A-Ring Precursor from 3.47 ...... 120
xx
LIST OF ABBREVIATIONS
α alpha
[α] specific rotation
Ac acetyl
All allyl
br broad (IR and NMR)
β beta
n-Bu normal-butyl t-Bu tert-butyl
Bz benzoyl
°C degrees Celsius
calcd calculated
CSA (1S)-(+)-10-camphorsulfonic acid
δ chemical shift in parts per million downfield from tetramethylsilane d doublet (spectra); day(s)
DMAP 4-(N,N-dimethylamino)pyridine
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
xxi EI electron impact (MS) eq equivalent
ES electrospray (MS)
Et ethyl
FAB fast atom bombardment (MS)
γ gamma g gram(s) h hour(s)
HRMS high-resolution mass spectrometry
IR infrared
J coupling constant in Hz (NMR) k kilo
KHMDS potassium hexamethyldisilazide
L liter(s)
LDA lithium diisopropylamide m milli; multiplet (NMR)
μ micro
M molarity (concentration in moles per liter)
Me methyl
MHz megahertz min minute(s) mol mole(s)
Ms methanesulfonyl
xxii MS mass spectrometry; molecular sieves m/z mass to charge ratio (MS)
NaHMDS sodium hexamethyldisilazide
NMO 4-methylmorpholine-N-oxide
NMR nuclear magnetic reasonance p para
Ph phenyl
PMB p-methoxybenzyl
PMP p-methoxyphenyl ppm parts per million py pyridine q quartet (NMR) rt room temperature s singlet (NMR); second(s) t tertiary (tert) t triplet (NMR)
TBAF tetrabutylammonium fluoride
TBS t-butyldimethylsilyl
TES triethylsilyl
Tf trifluoromethanesulfonyl
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethylsilyl
xxiii
CHAPTER 1
BACKGROUND
1.1 Introduction
“One of the few organic compounds, which, like benzene and
aspirin, is recognizable by name to the average citizen.”1
Rarely does a single molecule or scientific theory revolutionize an entire
field of science. The subject of this dissertation, Taxol®, is one of those rarities.2
Since its discovery in 1962, it has had an enormous impact on the fields of organic synthesis, cell biology, chemotherapy, and medicinal chemistry. Its effects have even been felt in the environmental and political community as well.
Its structure, function, and derivatization have been heavily researched since its discovery. There have been six successful syntheses described, and an entirely new mechanism of cellular interaction has been uncovered.
Despite this large body of research, new discoveries dealing with Taxol regularly emerge and continue to be notable and interesting scientific pursuits.
One area that enjoys almost endless possibilities is the formation of new derivatives of Taxol. Derivatization of a biologically active natural product serves
1 two purposes. First, the structure activity relationships (SARs) present in the
molecule can be ascertained. Secondly, new derivatives have the potential to be
even more effective than the parent natural product. With the dense functionality
present in Taxol, there are infinite derivatives to be explored. This dissertation will discuss the efforts in the Paquette group towards the successful total synthesis of Taxol using a route that will also allow for the formation of novel derivatives that cannot be obtained from highly advanced natural precursors, the traditional method used for this purpose.3 An enormous body of literature dealing
with almost every aspect of Taxol is readily available.4-7 Therefore, only a brief
introduction will be presented at this time. Additional information can be gained from the works referenced.
1.2 History of the Yew Tree
Taxol and its congeners, as we know them today, are diterpenes isolated from several species of yew tree within the genus Taxus. However, evidence dating as far back as 50,000 years ago reveals the interaction of man with the yew tree.8 A complete recount of this history is not feasible; however, a cursory
review is appropriate within the context of the difficulties in the procurement of
large supplies of Taxol.
There is evidence that the yew tree was used and cultivated by ancient
Egyptians, Celts, Romans, Greeks, and numerous other European and Asian civilizations. It has been used in the manufacture of weapons, ships, tools, and musical instruments to name a few. While day-to-day uses have varied
2 according to particular needs, one use has been consistent throughout the ages.
The yew tree was unanimously regarded as a symbol of strength, longevity, healing, and death. It has been used in ancient funeral ceremonies, and its extracts have been used repeatedly throughout history as medicines and poisons. In the Celtic tree alphabet, the yew is a chieftain tree and is known as the death tree. Its presence has been especially noted in European history. The
English yew was commonly used for the construction of the English longbow, which shaped history at the battle of Agincourt. Three English monarchs were reportedly killed with yew bows. References to the yew and its toxicity have appeared in the works of authors such as Shakespeare, Chaucer, Wordsworth,
Tennyson, Yeats, and T.S. Eliot. Its numerous uses in the ancient world were, in a way, its Achilles heel. Numerous cultures utilized the yew tree to such an extent that over time the supply of yew trees in Europe was decimated to the point that rationing was necessary. Despite its harvesting to the brink of extinction in Europe, the yew’s persistence reflects its appropriate choice as a tree that represents strength and longevity. With a colorful history such as this, it is not surprising that the yew tree’s utility and scarcity would appear again in recent history, but this time with an unprecedented impact.
1.3 Isolation and Structural Determination of Taxol
In 1950, a decree signed by President Truman established a collaborative program between the National Institute of Health (NIH) and US Department of
Agriculture (USDA) to find plants that could be utilized as a starting material for
3 the synthesis of cortisone.6,7 In 1955, there were only six anti-cancer drugs
approved for use in the United States, all of which were synthetically prepared.
Because of this limited library of chemotherapeutic agents, thousands of samples
were also screened by the National Cancer Institute (NCI), and a joint NCI-USDA
program evolved in 1960 due to promising biological activity present in several
samples and the need for anti-cancer drugs. The work done during this joint
NCI-USDA program led to the discovery of Taxol.
The modern story of Taxol began in 1962 in the Gifford Pinchot National
Forest in Washington State when Dr. Arthur Barclay, a USDA botanist, collected
samples of the twigs, leaves, fruit, and stembark of the Pacific yew tree, Taxus
brevifolia. Barclay noted, in later years, that the Pacific yew tree was chosen
“because it was there.” The material was sent to the Wisconsin Alumni Research
Foundation where its crude extracts were subjected to a KB in vitro screen and
were found to have biological activity. Due to this activity, additional samples
were collected and sent to the lab of Dr. Monroe Wall at the Research Triangle
Institute in North Carolina in 1964. Over the next seven years, research on the
isolation and structural determination of the cytotoxic component was conducted.
Recurring demands for more stembark, the component of the tree shown to have
the highest concentration of Taxol, were the first indication of what would
become severe supply problems. A pure sample of Taxol was isolated in 1966,
and after extensive 1H NMR studies and X-ray crystallographic studies of degradation products, the structure of Taxol (1.1 in Figure 1.1) and early SAR data were published in 1971.9
4 16 17 O 15 OAc 18 12 11 O Ph NH O H 10 13 9 A B 19 2' 14 1 Ph 3'1' O 2 3 8 OH HO C 7 OH H 4 BzO 5 6 AcO C13 Ester Side Chain D 20 O
Baccatin Nucleus 1.1
Figure 1.1 Structure of Taxol
The structure of Taxol is comprised of the “baccatin nucleus” and the “C13 ester side chain” as shown. Analysis of the degradation products revealed that both the side chain and baccatin nucleus are responsible for its biological activity.
Taxol was an especially interesting candidate as it had a positive response in testing on the slow-growing B16 melanoma line. The importance of this positive result lies in the fact that the vast majority of cancer deaths were from slow- growing tumors. In order to understand its biological activity fully, additional supplies of Taxol were required and this led to the supply problems that plagued the development of Taxol for decades.
At the time, the yield of Taxol from extraction of the dried bark of the yew tree varied, but an “accepted” standard was 0.01%. The bark could only be collected in the summer and early fall months when the sap of the yew tree was flowing. Due to the overall rarity of the tree and unforeseen circumstances such
5 as extremely dry summers, barely enough Taxol was isolated from the natural source to provide the material to progress through Phase I and II clinical trials.
Supply issues were temporarily alleviated when Bristol-Myers (now Bristol-
Myers Squibb) was awarded a Cooperative Research and Development
Agreement for the commercialization of Taxol. By 1992 production capacity of the drug was 130 kg/year due to massive collection efforts by the Bristol-Myers affiliate Hauser Chemical Research. While the short-term need for clinical trials was met, the environmental impact of collection efforts forced evaluation of alternative sources of the drug. The answer to the supply problem was eventually solved after the observation that the needles of the European yew,
Taxus baccata, contained 10-deacetylbaccatin-III (10-DAB, 1.2 in Figure 1.2).
The Potier-Greene semi-synthesis of Taxol was developed using 10-DAB as a precursor. It could be converted into baccatin-III (1.3) and after C7 protection, the requisite side chain (1.4) could be attached to the baccatin nucleus.10
OR O O H 10 Ph NH O 13 HO OH HO 7 Ph OH BzO H OEE AcO O 1.4 1.2 R = H 1.3 R = Ac
Figure 1.2 Structures Utilized in the First Semi-synthesis of Taxol
6 Unlike the stembark of the Pacific yew, the needles of the European yew
were a renewable resource. In addition, the yield of 10-DAB from the European
yew needles was able to produce 0.5-1.0 g of Taxol/kg of fresh needles, whereas
the yield of Taxol from the Pacific yew was 100-150 mg of Taxol/kg of dried
bark.7 The supply problems associated with Taxol were solved; however, it and other yew tree harvesting had stripped the yew tree in massive quantities. It has
been estimated that 4 million pounds of dried yew bark was used in the
development of Taxol. With a modest yield of 10 lbs of dry bark per yew tree, this equates to 400,000 yew trees.8
With a renewable precursor of Taxol secured, the drug progressed, albeit
slowly through the clinical trial process.5-7 Two serious disadvantages to the drug
candidacy of Taxol were its extremely low water solubility (<0.01 mg/kg) and
relatively low potency. Administration of the drug was achieved using a
formulation of Cremophor EL (polyethoxylated castor oil) and ethanol. While it
allowed for successful infusion of the drug, Cremophor EL itself was known to
cause hypersensitivity reactions. During the Phase I clinical trial of Taxol, seven
of the 95 participants experienced serious cardiac-related side effects and one
trial participant died from his reaction to the drug and its formulation. The
hypersensitivity reactions were eventually staved off by premedication and
special care in treating patients with cardiac problems.
Numerous additional hurdles were associated with the clinical trials of
Taxol; however, the drug slowly progressed through Phase III clinical trials and
was approved for the treatment of refractory ovarian cancer in 1992 and
7 metastatic breast cancer in 1994. Since approval, Taxol has also become accepted as a treatment of several other forms of cancer such as non-small cell lung cancer and Kaposi’s sarcoma both as a single agent and in combination with other treatments.11 Taxol, like the yew tree, survived against unfavorable odds to become one of the best selling and well-known drugs of all time with sales reaching into the billions annually.
1.4 Overview of the Biological Activity of Taxol
The efficient manufacture of new healthy cells to replace dead or unhealthy cells requires numerous processes to be carried out with precision.
Equally important to living organisms is the regulation of the cellular processes and for steps to be taken should any one of the complex processes in cellular function go awry. In healthy cells, this task is accomplished via feedback and regulation networks present inside the cell. Should cell damage occur through either external or internal mutations of normal cellular structures and functions, elements present within the cell determine the extent of the damage and activate pathways to cope with this damage. Damage to the DNA of a cell is a serious threat to its function and on a larger scale, of the organism itself. Low-level DNA damage is quite common, and cells have mechanisms that can identify and repair the damage before it can interfere with normal cellular function or be passed onto later generations. More severe DNA damage can also be detected; however, in such cases, destruction of the entire cell is ultimately a safer alternative than attempts to repair the damage.
8 More severe problems arise when the genetic information that encodes
the cellular mechanisms that detect DNA irregularities is itself damaged. This
type of damage can interrupt or shut down the detection of DNA damage and the
proliferation of defective cells proceeds giving rise to new cells that have the
potential to become cancerous.
While it is a simplified example, the DNA damage model shown in Figure
1.3 is detailed enough to illustrate the key elements of the DNA damage cycle
and the interaction of Taxol and the cellular processes that result from this
interaction in the cell’s life cycle.12
Damage to DNA is detected by kinases of the phosphatidylinositol 3- kinase-like (PIKK) family, namely ATM (ataxia telangiectasia related), ATR (ATM
and Rad3 related), and DNA-PK (DNA dependent protein kinase). Downstream
proteins are phosphorylated by ATM, ATR, or DNA-PK and the cell cycle is
delayed at a “DNA damage checkpoint”, which slows or halts the cell’s growth in
order to mount the appropriate response and to prevent the cell from progressing along its life cycle, which would cause additional defective copies to be manufactured.
9 DNA Damage Damage Detected by Sensing Proteins (ATM/ATR and/or DNA-PK)
Cell Cycle Delay: Checkpoint Activation
Activation of Activation of 'Removal' Pathway 'Repair' Pathway
Removal Mediation DNA Repair p53/Mdm-2 cdk Bcl-2/Bax Complex cdk Inhibition Activation Interruption by p21
Apoptosis: Growth Arrest 'Recovery' of Binds Bcl-2 Caspase Cascade Cell Cycle Progression Promotes Microtubule Assembly: Taxol Mitotic Arrest (G2/M Block)
Figure 1.3 DNA Damage Model with Taxol Interaction in the Process12
At the checkpoints, cellular processes that repair the damaged DNA are activated as well as processes with the ultimate goal of defective cell destruction.
In the case of minor DNA damage, repair is completed before the removal pathway has progressed past the point where recovery of a live functioning cell is not possible.
The removal pathway contains a very important element, the tumor suppressor protein p53. During normal cellular functioning, p53 is kept at low levels due to degradation by Mdm-2. When the DNA damage cycle is initiated,
10 the interaction of Mdm-2 and p53 is interrupted and p53 will initiate removal of the cell via one of two possible pathways, growth arrest and apoptosis.
Growth arrest is triggered by inhibition of cdk (cyclin-dependent kinase), which is activated in the “repair” pathway, by up-regulation of the cdk inhibitor p21. The end result of this branch of the “removal” pathway is a cell that is alive yet genetically dead. At this stage, the cell is no longer a risk to the organism.
Cells can also be sent down a pathway resulting in apoptosis, which is programmed cell death. It can be triggered by a number of interactions involving p53. In the biology of Taxol, the important element is the protein Bcl-2, which is targeted by p53.
The function of Bcl-2 is to prevent a cell from engaging in apoptosis. One of the methods by which this is achieved is through binding with the protein Bax, which functions as a promoter of apoptosis. When bound to Bcl-2, Bax cannot begin apoptosis. However, in the presence of p53 brought about by the interruption of the Mdm-2/p53 interaction, the Bcl-2/Bax heterodimer is disrupted and Bax forms homodimers, which initiate apoptosis and the cell is destroyed.
Cancerous cells are characterized by unregulated cell growth. One approach to tumor growth suppression is to subvert the cell’s DNA damage mechanism and initiate growth arrest or apoptosis directly. The effect of Taxol on cells is still under intense investigation, but it is clear that Taxol intervenes in at least two of the later steps in the removal pathway.
The first biological activity associated with Taxol was the observation that
Taxol promotes the formation of stabilized microtubules.13,14 This method of
11 cancer suppression was unprecedented at the time of its discovery as other
chemotherapeutic methods dealt with the prevention of microtubule assembly.
Microtubules are extremely important in cell division by mitosis. They assist in
organelle formation, chromosomal separation, and reorganization of cellular
material. Proper microtubule structure and function depends on maintenance of
a dynamic equilibrium between the microtubule and its building block, the αβ- tubulin heterodimer. As illustrated in Figure 1.4, Taxol binds to β-tubulin once it has been incorporated to the αβ-tubulin heterodimer. This interaction disrupts
the delicate equilibrium and allows for the formation of stabilized microtubules.
The microtubules suffer from a modified structure at this point and growth of the
cell is halted at the Gap 2/Metaphase (G2/M) transition. Cells that have
undergone growth arrest due to the interaction of Taxol exit mitosis prematurely
and can re-enter the cell cycle and the DNA synthesis (S-phase) phase of the
cellular cycle without achieving reorganization of the genetic material. As a result
of the DNA synthesis, the cell suffers from polyploidy and dies. If the mitotic
block is prolonged, the cell is more susceptible to DNA fragmentation and dies as
a result of that fragmentation.
12 Normal microtubule 13 protofilaments 24 nm diameter
Nucleation Center
Normal polymerization MAP, Mg2+, GTP, Ca2+, 0 °C
α-tubulin
αβ-tubulin β-tubulin heterodimer
Taxol-promoted polymerization
Taxol
Stabilized microtubule 12 protofilaments 22 nm diameter
Figure 1.4 Diagram of Microtubule Assembly with Taxol Interaction Illustrated15
This polymerization model does not take into account or explain several observations noted for Taxol treated cells. One example is that by itself, the
Taxol-stabilized microtubules will eventually dissociate according to the equilibrium; however, in the presence of Microtubule Assembly Proteins (MAP), the equilibrium is biased towards the polymerized form and cell death occurs.
13 Taxol, as far as the evidence suggests, does not cause an overexpression of
MAP, but the effect of Taxol on MAP has not yet been ascertained.16 The unanswered areas of tubulin/Taxol interaction exposes the relative youth of this model of cellular destruction, and it is certain that more discoveries will uncover new elements to this story.
Recent data have also revealed insight into the second mechanism of the cellular processes that occur in the presence of Taxol. There is evidence indicating that apoptosis can be initiated by Taxol without mitotic arrest, and this may also play a key role in its cytotoxicity.
The exact details of this process are still a mystery; however, it has been shown that Taxol can also selectively bind to Bcl-2. As shown in Figure 1.3, Bcl-
2 binds to Bax and halts the apoptotic cycle initiated by the Bax homodimer.
When Bcl-2 is bound to another element present in the system such as Taxol, the Bax homodimer can be formed and apoptosis progresses.
Due to the complexities of these and other unknown cellular processes in which Taxol can participate, the development of more potent anti-tumor drugs has not yielded many successes. It seems that most of the SAR information ascertained regarding Taxol is due to direct modification of Taxol and analysis of these analogs.3,5,17,18 Therefore, synthetic routes capable of producing novel
analogs of Taxol are still a necessity.
14 1.5 Review of Prior Total Syntheses of Taxol
The decision to attempt the synthesis of a natural product is one that is usually not taken lightly. The successful synthesis of a natural product can vary in difficulty from compound to compound; however, all syntheses and unsuccessful synthetic attempts consume large amounts of money and manpower, and require dedication, creativity, and teamwork. While the potential pitfalls can be numerous and significant, the knowledge of the molecule and methodology used to build such structures far outweigh the costs in dollars and man-hours.
The structural features resident in Taxol make any successful synthesis a monumental achievement. Attachment of the C13 ester side chain is a trivial event, and therefore, the difficulty in a synthesis of Taxol resides in the construction of the baccatin nucleus of the molecule. As illustrated in Figure 1.5, the baccatin nucleus of Taxol contains a unique tricyclo[9.3.102,8]pentadecene core endowed with nine chiral centers, three of which are of a quaternary nature.
The C11-C12 double bond is a technical violation of “Bredt’s Rule” and the rings are rigidified by their neighbors and by the steric constraints of the dense functionality present in twelve of the fifteen core carbons. Of the fifteen baccatin core carbons, eight are oxygenated, which requires not only technology for their installation but also for their protection during steps that they will be exposed to.
Additional complications arise from the need to use transformations that will not affect the esters, oxetane, ketone, and any free hydroxyl groups resident in an intermediate. Obviously, any successful synthesis of Taxol represents a
15 monumental achievement, and a review of their salient details is warranted within
the context of how the synthesis explored in this dissertation is unique and useful
to the synthetic community.
OAc Key Features of the Baccatin Nucleus: 11 O H 12 A 9 - Anti-Bredt A/B-ring 14 1 B - Functionalization at all but 3 carbons HO 3 OH HO C 7 - 9 chiral centers, 3 of which are quaternary BzOH - 8 of 15 carbons oxygenated AcO D - 3 esters of 2 different types of esters 20 O - Ketone, oxetane, and free hydroxyl groups 1.3
Figure 1.5 Key Structural Features of the Baccatin Nucleus of Taxol
To date, six successful syntheses of Taxol have been reported in the literature. Taking every possible one and two-bond disconnections into account, the taxane core can be disconnected in 153 ways.19 Seventeen of these are
one-bond disconnections and the remaining 126 are two-bond strategies. The
126 two-bond disconnections contain only 26 ways to produce two fragments,
and only five of the two-fragment approaches utilize pieces of approximately
equal molecular weight. With all these possibilities at hand, it is curious that the
six syntheses can be classified as being members of two primary types. The first
type involves the construction of highly functionalized A and C/D-ring precursors
which are coupled first in an intermolecular manner then in an intramolecular fashion to construct the B-ring. The other syntheses rely on the initial formation
16 of a B-ring with varying degrees of functionalization and are brought to completion by the attachment of the A-ring and/or C-ring precursors.
1.5.1 Syntheses Based on the Coupling of A-Ring and C/D-Ring Precursors
Three of the six completed total syntheses involve the synthesis of A and
C/D-ring precursors, which are then coupled together to form the central B-ring.
The first synthesis described to use this strategy and the second synthesis of
Taxol to appear was reported by K.C. Nicolaou in early 1994.20-24
O O OAc OEt CN + + O Cl OH OH 1.5 1.6 1.7 1.8
TBDPSO TBSO TBDPS OTBS OBn O OBn
+ 1 2 OHC O NNHSO2Ar H O Ar = 2,4,6-triisopropylphenyl O OH O 1.9 1.10 1.11 O HO OH OBn 10 O OBn
9 Taxol
H O O H O O O O O O O 1.12 O 1.13
Scheme 1.1 The Nicolaou Approach to Taxol
17 The Nicolaou approach to Taxol (Scheme 1.1) involved a Shapiro
coupling for C1-C2 bond formation and a McMurry coupling for formation of the
C9-C10 bond present in the B-ring. Shapiro coupling partners 1.9 and 1.10 were
both synthesized using a Diels-Alder cyclization between 1.5 with 1.6 and 1.7
with 1.8 and were realized after additional functionalization of the adducts.
Several attempts at the Shapiro coupling with varying types of functional groups
present on the partners were investigated. After several iterations, the
substrates 1.9 and 1.10 were found to give 1.11 in good yield and as a single
diastereomer. The Shapiro product, 1.11, was also functionalized in numerous
ways as conditions for the McMurry coupling were screened. Ultimately, the
McMurry coupling of 1.12 to give 1.13 suffered from the need to resolve the
products and a low yield that could not be optimized beyond the 34% yield
reported. Despite the significant number of steps that needed to be achieved in
progressing from 1.13 to the target, this strategy did result in a successful total
synthesis of Taxol, and the McMurry coupling again proved its utility in the
formation of difficult ring systems.
In the approach executed by Danishefsky (Scheme 1.2), the C1-C2 bond
was again formed via a key coupling step.25 The northern portion of the B-ring
was formed using a construction of the C10-C11 bond. The A-ring component,
1.16, was formed after functionalization of readily available diketone 1.14.
Enantiomerically enriched Wieland-Miescher ketone 1.15 was used to form the
C/D-ring component 1.17. After optimization on model systems, alkenyllithium coupling to give 1.18 proceeded smoothly. In this instance, the coupling was
18 achieved using a fully formed oxetane D-ring, giving insight into the stability of
such a system. The sensitivity of the D-ring seems to arise when a free hydroxyl
group or sensitive ester group is present at C4. After additional functionalization, vinyl triflate 1.19 was formed and an intramolecular Heck coupling reaction using palladium allowed for formation of the C10-C11 bond. Additional functional group interconversions led to another successful synthesis of Taxol.
O O
O 1.14 O 1.15
MeO OMe MeO OMe CN CN OTBS OTBS OTMS OTMS + 1 H 2 O O Li H H 1.16 O OBn OH OBn 1.17 1.18 OTBS OTf 10 OTBS 11 Taxol O O H O H O OBn O OBn O O 1.19 O 1.20
Scheme 1.2 The Danishefsky Approach to Taxol
19 O O Br CO2Et OTHP 1.21 1.22
PhS PhS 10 9 (BnO)2HC CH(OBn)2 + TIPSO TIPSO Br 3 O HO CHO 1.24 2 B O 1.23 Me 1.25
OH OH OH OH
TBSO HO Taxol
O O O O O OH Ph 1.26 Ph 1.27
Scheme 1.3 The Kuwajima Approach to Taxol
The final synthesis to use a double coupling strategy for B-ring completion was initially reported in 1998 by Kuwajima with full details published in 2000.26,27
The A-ring precursor 1.23 was readily formed after a Claisen-type condensation with 1.21, which was readily formed starting from a protected propargylic alcohol.
The C-ring precursor 1.24 was formed in six steps from 2-bromocyclohexenone.
Chelation-controlled addition mediated by Mg(II) was used to form the C2-C3 bond as one diastereomer, and the resulting diol was protected as a methyl boronic ester to give 1.25. A screen of several Lewis acids resulted in the use of
20 a Ti(IV) species to form the C9-C10 bond of the B-ring. Functionalization of the
adduct brought about cyclopropane 1.26, which was opened using SmI2 to yield
1.27, which has the requisite synthetic handles for C/D-ring completion. Further functionalization of the C and D-ring led to arrival at the target.
1.5.2 Syntheses of Taxol Based on Initial B-Ring Formation
The three remaining syntheses of Taxol fall, roughly, into a second category that involve rapid formation of a B-ring followed by functionalization of the C and D-rings.
The synthesis of Taxol by the Holton group, which was also the first synthesis of Taxol reported, used a rearrangement to form the A and B-rings in a very efficient manner.28,29 The epoxy-alcohol fragmentation substrate 1.28 was
readily derived from β-patchoulene and upon rearrangement and subsequent protection, gave the A/B-ring precursor 1.29 as illustrated in Scheme 1.4. The magnesium enolate of 1.29 was coupled with 4-pentenal and further functionalized to give lactone 1.30. A Dieckmann condensation using 1.30 formed the six-membered C-ring and in a rather creative use of the lactone functionality, utilized the resident lactone oxygen to form the C7 hydroxyl group present in 1.31. Further functionalization of 1.31 brought the synthesis to the D- ring precursor 1.32, which was carried to the final target.
21 OTES OTES CO2Me
12 3 TBSO 8 TBSO 8 13 O OTES OH O O 1.28 1.29 O H O O O 1.30 OTES OTES OH OBOM
TBSO 8 TBSO 8 Taxol
O H CO2Me O H OTMS O HO O OH O O 1.31 1.32
Scheme 1.4 The Holton Approach to Taxol
The approach to Taxol employed by Wender is illustrated in Scheme 1.5 and also used an epoxy-alcohol fragmentation on pinene-derived substrate 1.33 to give the A/B-ring precursor 1.34.30-37 The C-ring was installed using aldol chemistry between then ketone and aldehyde resident in 1.35. The exo-olefin present in 1.36 was functionalized to the bromo diol present in 1.37, which was used to install the D-ring and complete the pinene-based synthesis of Taxol.
22 O O O AcO O O 12 O 10 2 H OH OBOM TIPSO TIPSO OTBS O OTBS HO OBz 1.33 1.34 1.35
AcO O AcO O OH OTroc
Taxol Br TIPSO OBOM TIPSO OH HO OBz O O OH 1.36 O 1.37
Scheme 1.5 Wender’s Pinene Path to Taxol
One final B-ring based approach is somewhat unique in the fact that it
begins with the formation of a B-ring without an A or C/D-ring precursor
attached.38 The approach used by Mukaiyama began with L-serine to give
aldehyde 1.39 shown in Scheme 1.6. A SmI2-mediated coupling using the
bromide in 1.39 gave, after additional functionalization, the B-ring precursor 1.40.
Lithiation of 1.41 was followed by addition to 1.40 and the C-ring was closed vial aldol chemistry to give 1.42. The B/C-ring component 1.42 was treated with lithiated homoallyl iodide and further functionalized to yield 1.43. The C11-C12 bond was formed using a McMurry coupling and was followed by final A-ring functionalization and D-ring formation to yield Taxol.
23 BnO O OTES NH2 Br OBn OBn TBSO HO OH CHO + O O O O Br 1.38 TBS PMB PMBO OBn 1.39 1.40 1.41
BnO O O BnO O O TBSO O + O Taxol I H H O OBn TBSO OBn 1.42 1.43
Scheme 1.6 The Mukaiyama Approach to Taxol
1.6 Taxane Synthesis in the Paquette Group: Motivation and Precedent
Our plan for a synthesis of Taxol in the Paquette group is the result of having two related yet different goals. Taxol presents a difficult structure and is a complex synthetic target. The six previous syntheses are excellent examples of the creativity of synthetic chemists, and each is a great achievement in its own right. Our first goal is to develop the shortest overall synthesis of Taxol. This will require transformations that accomplish multiple tasks at once and efficient synthetic planning.
While it is noble to desire a short synthesis, it is also necessary that a synthesis, short or long, have a utility to it that is not present in the syntheses that have been previously reported. This is where the second goal of our route becomes important. Thousands of analogs of Taxol have been isolated from
24 related species of Taxus, and numerous others have been created in the
laboratory setting. A small sampling of SAR data is presented in Figure 1.6, and a wealth of SAR data for the modifications illustrated and numerous others is available.3-5,15,17,18,39,40 However, the data reported deal with modification of the
structural features present on the periphery of the molecule. Derivatization of
free hydroxyl groups, esters, amides, oxetanes, etc. is a fairly straightforward
process. It is surprising that there is a startling lack of analog formation with
respect to the core structures present in Taxol.
acetyl or acetoxy group may be removed without significant loss of activity N-acyl group required reduction improves activity slightly O OAc O phenyl group or Ph NH O H may be esterified, a close analog required epimerized, or removed Ph O OH without significant loss free 2'-hydroxyl HO of activity OH BzO H group or hydrolyzable AcO ester thereof required oxetane required O for activity helpful but not required removal reduced benzyloxy group activity slightly essential; certain substituted groups have improved activity
Figure 1.6 Key Structure Activity Relationships in Taxol15
The lack of core structure analog formation is key to the second goal of
our synthesis of Taxol. Numerous questions with regard to the SAR of Taxol
have been answered, but many remain unanswered. While the necessity of the
25 oxetane is established, is there an effect on the activity due to the
stereochemistry of that oxetane? Only the synthesis of the D-ring invertomer
1.47 can answer this. Very little data regarding A-ring modification exist;
therefore, will double bond migration or replacement and removal of the C18
methyl group be deleterious to the biological activity? A-ring modifications
illustrated in analogs such as 1.44 and 1.46 can be introduced and these molecules tested for activity. Taxol contains an A, B, C, D-ring system as shown.
What effect will manifest itself if the ring size is modified? The synthesis of the
C-nor isomer, 1.49, and the D-homo compound 1.48 would prove not only if these compounds are stable but also if they possess any biological activity. With questions such as these in mind, it is our ultimate goal to develop the shortest route to Taxol that contains an inherent ability for the formation of unique analogs of Taxol that cannot be derived from chemical modification of either Taxol or baccatin-III in order to answer these and other questions. The structures in
Figure 1.7 represent Taxol analogs that have not yet been reported in the
literature, with the exception of 1-deoxypaclitaxel (1.45), which has only recently been isolated from the yew and was proven to be less stable and biologically active than the parent.3 These molecules, complex in their own right, constitute
the second goal of our synthetic route development.
26 OAc OAc OAc X 18 12 O O O H H H 12 1 RO OH RO OH RO OH HO H HO BzO H BzO H BzO H AcO AcO AcO O O O 1.44 X = H, F, CN, Ar 1.45 1.46
OAc OAc OAc O O O H H H
RO OH RO OH RO HO HO HO OH BzO H BzO H BzO H AcO AcO AcO O O O 1.47 1.48 1.49
Figure 1.7 Novel Taxol Analogs Slated for Synthesis
In order to reach such lofty goals, a strategy aimed at the synthesis of
Taxol must be designed that contains the potential for modification so that these analogs can be constructed by modification at later steps in the route. An approach illustrating the necessary elements is presented in Scheme 1.7.
The final stages of the synthesis will start with an intermediate like 1.50 that contains and unfunctionalized A-ring framework and an oxetane ring precursor. Modification of 1.50 will install the A and D-ring and will bring about
Taxol. Taxane 1.50 can be formed using an α-ketol rearrangement of 1.51, which can be obtained after functionalization of 1.52. The taxane precursor 1.52 is the product of an anion-accelerated oxy-Cope rearrangement using allylic alcohol 1.53. The oxy-Cope substrate is the product of a metal-mediated coupling between camphor-derived coupling partner 1.54 and the C/D-ring
27 precursor 1.55. The ability for modification leading to analogs is built into this
approach. The C/D-ring precursor 1.55 can be modified to accommodate numerous ring sizes and the stereochemistry can be modified for installation of novel analogs of the C and D-rings. The camphor-derived coupling partner 1.54 can be synthesized with various functional groups at what will become C1 and
C2 in the target. The advanced taxane 1.50 can be modified in the A and D-rings using the synthetic handles that can be installed along the synthesis.
OPG OPG O O OPG 1.1 14 1 14 OPG 1 2 HO HO O H O H BzO BzO X X 1.50 1.51 X = oxetane precursor OPG O OPG OPG M H OH + Y 1 2 Y 1 1 O R Y R R H 22 1.52 1.53 1.54 1.55 Y = C/D-ring precursor
Scheme 1.7 General Retrosynthesis of Taxol
A full review of previous efforts in the Paquette group is beyond the scope of this document and not relevant to the overall work presented later. However, a discussion of the successes and problems encountered in the significant body
28 of prior research is pertinent, as it has provided information that has shaped the
current route under investigation.
1.6.1 Examination of the Oxy-Cope Rearrangement: Proof of Concept
Once it was realized that an oxy-Cope rearrangement would serve as a
novel way to assemble a pre-taxane structure, its properties and potential were
researched in great detail.41 Initially, the use of the oxy-Cope rearrangement as
a useful step in the synthesis of Taxol was done in a conspicuous manner.
Studies commenced with simple camphor-derived and C/D-ring precursor
coupling partners like those illustrated in Scheme 1.8 and was presented as a
methodology study of [3,3]-sigmatropy in bicyclic ketones.42-44 The early substrates were simplified examples synthesized and rearranged by the coupling
of known 1.56 with cycloalkenyl dichlorocerate nucleophiles such as 1.57. Only
the endo addition product 1.58 was formed due to steric shielding of the exo face
by the geminal dimethyl bridge present in 1.56. Deprotonation of the allylic alcohol led to the formation of an “endo-chair” transition state 1.59 and the result was the formation of enolate 1.60, which was quenched in situ with methyl iodide to give the bridgehead olefin 1.61.
29 Cl Ce 2 KHMDS, + OH 18-C-6, THF; MeI O SS 1.56 S 1.57 1.58 S
O- O
O- H H
S S S S S S 1.61 1.59 1.60
Scheme 1.8 Early Evidence of the Potential of the Oxy-Cope Rearrangement
As a proof of concept, the early coupling reaction was successful at the
synthesis of numerous bi- and tri-cyclic ring systems, and proved that this would be a viable route to taxanes due to the reaction progressing via the desired transition state. As a strategy for the synthesis of Taxol, the system suffered from a lack of potential for C/D-ring elaboration. The potential for completion of the C/D-ring of Taxol was increased through the use of more elaborate and highly functionalized C/D-ring precursors.12,45-55 These advanced precursors
yielded several taxanes with synthetic handles for C/D-ring synthesis in place,
yet several problems halted forward progress. The early coupling reactions utilized a camphor component that was unfunctionalized at C10. Attempts at installation of the C10 oxygen yielded oxidation at C8 instead. An example of
30 this is illustrated in Scheme 1.9. In addition, the substrates lacked the requisite
C2 oxygen and were sometimes epimeric at C3.
O OH O OH H OBn KHMDS, H 18-C-6; 1.56 O + O2, PhH OBn BnO O CeCl2 1.62 O OO 1.64 1.63
Scheme 1.9 Coupling and Oxy-Cope With an Advanced C/D-Ring Precursor
1.6.2 Synthesis and Utility of Early-oxygenated Substrates
The oxygenation of C2 and C10 were problems inherent in the use of 1.56 as a coupling partner. The C10 oxygenation problem was resolved via a straightforward process illustrated in Scheme 1.10. Enolization of 1.56 followed by epoxidation, epoxide opening, and protecting group installation provides numerous structures of type 1.66. The coupling partner 1.67 contains the requisite C10 oxygen and the advanced C/D-ring precursor 1.68 contains necessary synthetic handles for D-ring elaboration. The use of C10 oxygenated substrates also simplified the coupling as a simple vinyllithium could be employed instead of the previously used cerium derivatives, which are more difficult to synthesize and handle. Further investigation of the chemistry of 1.69
31 led to the formation of 1.70 via C-ring closure promoted by an intramolecular aldol reaction.
OH OPG LDA, TMSCl; protecting epoxidation; group installation O TBAF O O 1.56 1.65 1.66 I OMOM OMOM PMBO O
+ O O O HO O TBSO H 1.67 1.68 O O OPMB 1.69 OMOM O OH NaOH, MeOH HO TBSO H O OPMB 1.70 O
Scheme 1.10 Successful Synthesis of a C10 Oxygenated Substrate
Strategies using similar substrates were pursued in earnest for a number of years, and ultimately, a revision of strategy was necessary as oxygenation of
C2 with the required stereochemistry continued to be problematic. A strategy was devised using a substrate that was oxygenated at what will become the C2 position.
The synthesis of camphor partners with a C2 oxygen or C2 oxygen precursors led to new information regarding the potential for an even more rapid 32 method for the synthesis of a fully-functionalized taxane skeleton. While several
promising camphor-derived and C/D-ring precursors were synthesized and
coupled, new difficulties emerged using such partners. The results from the
experiments presented in Scheme 1.11 show the sensitivity of the oxy-Cope
rearrangement to the substituents present on the camphor-derived coupling
partner.
OMOM O OMOM OMOM OTBS OH H H OTBS O I H SPh O H SPh PhS O 1.71 H OBn BnO 1.73 1.74 BnO OTBS O 1.72 OMOM OMOM OMOM O- OH H OTBS O O O O O O BnO OBn OTBS 1.75 TMS TMS 1.76 TMS 1.77 OMOM O OH
OTBS O OBn 1.78 TMS
Scheme 1.11 Sensitivity of the Oxy-Cope Reaction
The camphor partner 1.71 was coupled with iodide 1.72, which contains a fully formed oxetane ring, to yield oxy-Cope precursor 1.73. Deprotonation of
1.73 was followed by successful oxy-Cope rearrangement to yield 1.74. In a 33 similar manner, the “short-SEM” containing partner 1.75 was coupled with 1.72 to
give 1.76. Deprotonation of 1.76 was expected to yield an oxy-Cope product
similar to 1.74; however, upon treating 1.76 with KHMDS, an unexpected
rearrangement took place, which opened the oxetane ring and provided 1.78 via
1.77.55
OPMB OPMB OH I + O OTES O O 1.80 1.79 TMS TMS OTES 1.81 OPMB OPMB O OH H OTES O OH HO H O H O TMS TMS 1.83 1.82
Scheme 1.12 Problems with Other C2 Oxygenated Precursors
Simplification of the C/D-ring precursor led to moderate success using a
C2 oxygenated coupling partner. As illustrated in Scheme 1.12, the “short-SEM” camphor derivative 1.79 was smoothly coupled with vinyl iodide 1.80 to give allylic alcohol 1.81. After significant effort, delicate conditions were developed to yield bridgehead olefin 1.82. Upon dihydroxylation of 1.82, an unexpected and irreversible transannular ketalization reaction ensued to yield 1.83.12 Evidence
34 gained from energy-minimized calculations revealed that the concave nature of
1.83 imposes several conformational biases in the system. One that presumably leads to the ketalization deals with the orientation of the “short-SEM” moiety and the C1 hydroxyl group. Due to the concave nature of thes system, the C2 short-
SEM protected hydroxyl group occupies the available space “outside” of the cavity formed by the curvature of the molecule. This, in turn, forces the C1 hydroxyl group to position itself inside the cavity to a significant degree. When the molecule adopts this conformation, the C1 hydroxyl group is positioned in close proximity to the C9 ketone. This allows for rapid ketalization of the molecule to occur, and due to the close proximity of the hydroxyl group to the ketone, the ketalization is irreversible.
1.7 Development of a New Approach to Taxol
The previous successes and problems provided information regarding what was necessary in a new approach to Taxol. The rapid assembly of a taxane precursor via an oxy-Cope rearrangement was to be utilized as it presents an efficient method for pretaxane synthesis. The difficulties presented in using a fully functionalized C/D-ring precursor could be alleviated through the use of a more simplified coupling partner provided that a handle for oxetane synthesis and aldol ring closure were present. Problems with the early oxygenation of C2 were apparent, and it was clear that a synthesis would have to be devised that would allow for installation of the C2 oxygen later in the route.
35 Prior research that led to the preliminary synthesis of a bridge-migrated
compound and its incorporation into the current synthetic route is illustrated in the
retrosynthesis illustrated in Scheme 1.13.
O OAc OPMB OPMB O O O Ph NH O H D-ring A-ring functionalization O functionalization Ph O OH OTBS OTBS HO HO HO OH H H O H BzO BzO BzO AcO O O 1.1 O 1.84 1.85 Common Intermediate Common Intermediate for D-ring Analogs for A-ring Analogs
OPMB OPMB OPMB O O O α-Ketol OTBS Intramolecular Rearrangement Aldol O Dihydroxylation H OTBS HO O O H H H H BzO O O O 1.87 1.88 1.86
Anionic OPMB Endoselective OPMB I Oxy-Cope OH Addition via Lithiation + O OTBS 1.90 1.89 1.91 OTBS
Scheme 1.13 Current Retrosynthetic Analysis of Taxol
Taxol can be realized after D-ring functionalization of the completed A-ring
substrate 1.84, which can be reduced for attachment of the ester side chain.
Compound 1.84 serves as a common intermediate for D-ring analog formation and can be derived from taxane 1.85. The bridge-migrated compound 1.85, a
common intermediate for A-ring analog formation, is brought about after α-ketol
rearrangement of 1.86, which is realized after C-ring closure via an
intramolecular aldol reaction using 1.87. The aldol substrate 1.87 is the product
of B-ring functionalization of 1.88, which is arrived at after anion-accelerated oxy-
36 Cope rearrangement of 1.89. The oxy-Cope substrate, 1.89, is the product of endo-selective addition of lithiated 1.91 to the camphor-derived coupling partner
1.90.
While taxane 1.85 was known, the route suffered from several problems,
and therefore, the task at hand was two-fold. First, a better, more-refined, and
higher yielding route to 1.85 had to be secured so that sufficient quantities of
1.85 could be obtained for arrival at Taxol. Second, methods for the completion
of the A and D-ring had to be evaluated.
37
CHAPTER 2
SYNTHESIS AND FUNCTIONALIZATION OF THE B, C, AND D-RINGS
Prior research had developed a working route to bridge-migrated
compound 1.85; however, the route suffered from several problems.12,56-58
Several steps required investigation as they were not amenable to large scale, suffered from low yield, low starting material recovery, and in some cases, the recovered material was isolated with stereochemistry that was not useable. As the synthesis progressed, new conditions were developed, and steps were carried out in a faster manner and on larger scale. This resulted in a new synthesis of 1.85 that is now amenable to large scale and greatly facilitates arrival at Taxol.59
2.1 Synthesis of Coupling Partners and Formation of the Pretaxane Core
2.1.1 Synthesis of Coupling Partners 1.90 and 1.91
Formation of camphor derivative 1.90 and alkenyl iodide 1.91 was accomplished on large scale and in high yield as shown in Schemes 2.1 and 2.2.
The synthesis of camphor-derived component 1.90 commenced by refluxing CSA
38 in SOCl2 to obtain sulfonyl chloride 2.1 in 90% yield. The next step involves
treatment of 2.1 with CH2N2 followed by pyrolysis of the intermediate episulfone
2.2 to deliver the known β,γ-unsaturated ketone 2.3.44 Pyrolysis of 2.2 was reported to occur at 90-95 °C and was followed by distillation to yield 2.3.
However, when this protocol was employed, ketone 2.3 was delivered in less than 30% yield. It was found that pyrolysis of 2.2 was actually occurring during solvent removal at a much lower temperature than reported. This led to a revision of the conditions that involved pyrolysis and purification by column chromatography to deliver 2.3 in a moderate 50% yield. α-Hydroxy ketone 2.4 was delivered in 70% yield using a modified Rubottom oxidation via epoxidation of the silyl enol ether of 2.3 with DMDO followed by treatment with TBAF.60,61
Conversion of 2.4 to 1.90 was accomplished via protection of the free hydroxyl as a PMB ether under mildly acidic conditions in 96% yield.62,63
Δ SOCl2, CH2N2, Et3N, 40-60 °C 90% 0 °C, Et2O 50% O O O from 2.1 O SO3H SO2Cl O2S 2.1 2.2 2.3 LDA, TMSCl, THF, -78 °C; OH PMB-imid, CSA (cat), OPMB DMDO, acetone, 0 °C; CH2Cl2, 0 °C TBAF, EtOAc, rt O 96% O 70% (three steps) 2.4 1.90
Scheme 2.1 Synthesis of Camphor-derived Coupling Partner 1.90
39 Br O 1. LiAlH4, Et2O, rt Br Br Br + LDA, THF, 2. TBSCl, DBU (cat.), OTBS Ot-Bu Ot-Bu -78 °C, 67% Et3N, CH2Cl2 O 82% (two steps) 2.6 2.5 O I + - t-BuLi, THF, -78 °C; Ph3P CH2I I DMF, -78 °C H OTBS NaHMDS, -78 °C OTBS 70% 2.7 88% 1.91
Scheme 2.2 Synthesis of Alkenyl Iodide Coupling Partner 1.91
Target alkenyl iodide 1.91 can be readily obtained via a five-step sequence from commercially available starting materials. Enolization of t-butyl
acetate was followed by addition of 2,3-dibromopropene to give known alkenyl bromide 2.5 as shown in Scheme 2.2.64 Reduction of the ester moiety was
accomplished using LiAlH4 and was followed by protection of the free hydroxyl
group as a TBS ether without purification of the intermediate alcohol to give the
bromide 2.6. In our case, protection using the more commonly employed
TBSCl/imidazole combination led to significant quantities of silyl impurities in the product. The protocol developed by Kim for the selective protection of primary alcohols using TBSCl and catalytic DBU provided 2.6 without this impurity.65
Formation of the α,β-unsaturated aldehyde 2.7 was accomplished via lithiation of
2.6 followed by nucleophilic attack on DMF. Formation of unsaturated iodide
1.91 was accomplished using the iodo-olefination protocol developed by Stork, which provided the Z-iodo olefin as the only diastereomer detectible by 1H NMR analysis.66 Iodide 1.91 was, as expected, sensitive to light and heat, and was
40 best used immediately after its preparation; however, it is possible to store 1.91
for 2-3 days provided it remains frozen in benzene.
With 1.90 and 1.91 secured, the coupling reaction between the two to
yield 1.89 was the next priority. Significant difficulties had been observed in this
reaction in the past and needed to be solved so that the supply of material was
not wasted due to unwanted side reactions.
2.1.2 Alkenyl Iodide Coupling – Problems and Solution
Previous reaction conditions did yield desired 1.89, but there were two
main areas of concern. First, 1.89 was only isolated in roughly 50% yield.
Secondly, the starting material recovered consisted of a 1:1 mixture of epimers at
C10 (Taxol numbering), as well as a portion of material that had undergone a
variant of a Curtin rearrangement to form 2.8 as illustrated in Scheme 2.3.67,68
All four compounds had similar Rf values making purification of the reaction
mixture very tedious.
I OPMB OH 1.91, t-BuLi, + 1.89 + OPMB OTBS Et2O, -78 °C; + PMP 1.91 O then 1.90 O O 1.90 2.8 PMP OPMB O
O- O
Scheme 2.3 Original Coupling Reaction Conditions and Problems Encountered
41 It was obvious that enolization of 1.90 was the problem; however, it was
not clear if the problem resulted from a lack of reactivity of lithiated 1.91 or if the
lithium halogen exchange between 1.91 and t-BuLi was slow and deprotonation
of 1.90 ensued. Evidence in the literature also suggested that using ether as the
solvent could cause degradation of t-BuLi. Performing the reaction in THF with
addition of 1.90 at -78 °C via a cooled addition funnel did not resolve the
problems encountered. These issues were solved by employing a different
method of reagent addition illustrated in Scheme 2.4.
KHMDS, 18-C-6, I OPMB 1.90 and 1.91, OPMB THF, -78 to -40 °C; THF, -78 °C; OH + 10% MeI in THF, -78 °C OTBS then t-BuLi O 65-75% 1.91 65% 1.90 1.89 OTBS OPMB OPMB - H3CI OPMB O O O- H OTBS H OTBS OTBS H H 1.88
Scheme 2.4 Optimized Alkenyl Iodide Coupling and Oxy-Cope Rearrangement
When 2 eq of t-BuLi was added to a THF solution of 1.90 and 1.91 at -78
°C, smooth formation of 1.89 was observed in 65% yield with no observable epimerization or Curtin rearrangement product. The reaction could also be carried out on up to 20 g of 1.90, which greatly improved the throughput of
42 material. Previously investigated reaction conditions for the anion-accelerated
oxy-Cope reaction yielded 1.88 on up to a 10 g scale with yields in the 65-75%
range using KHMDS and 18-C-6 followed by quenching of the resulting enolate
with MeI. The desired E-olefin was isolated as the major product and is arrived
at via the endo-chair transition state shown.
2.1.3 B-Ring Dihydroxylation – Problems and Solution
With the key oxy-Cope reaction conditions performing well, the B-ring
needed to be functionalized before C-ring closure and further elaboration towards
1.85. The first step in functionalization of the B-ring is dihydroxylation to install
the C1 and C14 hydroxyl groups. It became evident that a new set of conditions
was needed as those previously reported only gave the desired diol in 30% yield
with several other complications. First, a significant amount of material (~30%)
was dihydroxylated at the exo-olefin present in 1.88. Secondly, only partial
conversion of the starting material was observed even after a 48 h reaction time.
The longer stir time also promoted ketalization of the resulting diol similar to that
observed in 1.83 (Scheme 1.12). It was later observed that the ketalization in
this system was reversible and did not lead to difficulty in later functionalization.
The significant obstacles encountered led to the realization that the reaction was not acceptable in terms of throughput and arrival at Taxol.
A large number of reaction conditions involving various solvent systems,
OsO4 loads, additives, and reaction times and temperatures were screened by
several members on the project. After a significant period of investigation, a
43 protocol employing 0.4 eq of OsO4, 2.0 eq of NMO, and 1.3 eq of MeSO2NH2 in a
10:1 acetone:water mixture with a 30 min reaction time provided good consumption of 1.88. While conversion of 1.88 was high (80%), the yield of 2.9
was still as low as in the original procedure. It was realized that the problem with isolation of the material was due to the protocol used to decompose the
intermediate osmate ester.
OPMB OPMB O OsO4, NMO, O MeSO2NH2, H OTBS OTBS 10:1 acetone:H2O, HO then H2S (g) H H 64% (78% conversion) HO 1.88 2.9
OPMB OPMB phosgene, py, O Swern O CH2Cl2, -78 °C; oxidation OH O CSA, 81% MeOH:CH2Cl2, 0 °C O (three steps) O O H O H H O 2.10 O 1.87
Scheme 2.5 Formation of A/B-ring Pretaxane Core
Several commonly used aqueous solutions including Na2S2O3 and
NaHSO3 were screened with numerous variations in concentration, reaction time,
and temperature. It became evident that no aqueous reagent was going to be
efficient at breaking up the extremely hindered osmate ester. In light of this
observation, destruction of the osmate ester was attempted using H2S gas generated by the action of concentrated HCl on solid FeS. After a few trials, we
44 were delighted to observe smooth breakup of the osmate ester in 15 min at 0 °C.
The breakup of the intermediate could be observed by TLC and the resulting
purification and removal of osmium containing impurities was simplified as well.
The new reaction conditions provided 2.9 in up to 75% yield as shown in
Scheme 2.5. The diol functionality in 2.9 was protected as the carbonate with
phosgene and pyridine, and the pendant aldehyde, required for C-ring closure,
was installed by deprotection of the TBS ether using CSA and subsequent Swern
oxidation of the primary alcohol to yield 1.87.69 The three-step sequence from
2.9 to 1.87 proved to be incredibly efficient as it could be performed on multigram
scale and purification by column chromatography was only necessary after the
final oxidation step.
2.2 Further Functionalization of the B-Ring En Route to Bridge Migration
2.2.1 C-Ring Closure and Hydride Shift Reaction
In order to arrive at a bridge-migrated taxane, C-ring closure had to be achieved and followed by additional B-ring functionalization. The C-ring closure was accomplished using a previously optimized condition of NaOH in a
THF:MeOH solvent system and provided aldol ring closure as well as concomitant removal of the C1/C14 carbonate. At this point in time, a unique course of reactivity was observed. As illustrated in Scheme 2.6, the “back ketone” product 2.11 was isolated along with the “front ketone” 2.12, in a 6:1 ratio respectively. It was discovered that 2.11, the expected product, could give rise to
2.12 via a transannular hydride shift across the B-ring.12
45
OPMB OPMB OPMB O NaOH O OH OH OH O THF:MeOH H + H 97% O HO HO O H H HO H O H O 1.87 2.11 2.12 2.11:2.12 6:1 KOt-Bu PhH 100% 2.11:2.12 0:100
OPMB OPMB O OH OH OH via H H HO HO O H O H H - Ot-Bu
Scheme 2.6 C-ring Closure and Hydride Shift of Aldol Product
The process at work was further investigated and it was found that the position of the ketone could be regulated by the use of different solvent systems.
Specifically, the “front ketone” is favored in non-polar solvents, while the “back ketone” is favored in polar solvent systems.70 The complete conversion of 2.11 to 2.12 could be achieved by treatment of the crude aldol reaction products with
KOt-Bu in benzene. The x-ray crystal structures of 2.11 and 2.12, illustrated in
Figures 2.1 and 2.2 respectively, show the location of the shifting hydrogen atom and its close proximity to the carbonyl carbons.
46
Figure 2.1 X-ray Crystal Structure of 2.11
Figure 2.2 X-ray Crystal Structure of 2.12
47 Quite serendipitously, this reaction became one of the most useful
processes in this synthetic pathway as well as in a route aimed at the synthesis
of 1-deoxypaclitaxel.71,72 In order to arrive at the deoxy compound, a method for
reduction of the C1 ketone had to be developed. Traditional reduction methods
were unsuccessful while the transannular hydride shift proved useful as
illustrated in Scheme 2.7.
PMP PMP O O O OH O O OBz OBz EtAlCl2 OBz H HO HO O H HO BzO O H HO H BzO BzO 2.13 "Al" 2.14
PMP OH O OH O O O OTBS OTBS EtAlCl2 OTBS HO H HO HO H O H AcO AcO O H AcO 2.16 2.17 2.15
Scheme 2.7 Utility of Hydride Shift in 1-Deoxypaclitaxel Precursor Synthesis
The original observation was the hydride shift of 2.13 to give 2.14 with the requisite α-disposed hydroxyl at C1. Either conformational or steric factors prevented leaving group installation on 2.14. However, later work revealed the hydride shift of 2.15 in a similar manner to give 2.16, which was converted to its
48 corresponding mesylate and migrated to give 2.17, a strategy employed in the
synthesis of Taxusin, which also contains a bridgehead hydrogen.73,74
The hydride shift served several other purposes in this synthetic route as
well. Further functionalization of the B-ring was carried out as illustrated in
Scheme 2.8, beginning with protection of 2.12 as its C7 TBS ether to give 2.18.
Protection of C7 over C9 was possible at this point as the steric demands placed
on C9 by the C10 PMB ether and the newly installed C7 TBS ether prevented its
participation in protection chemistry. In aldol product 2.11, this inherent
selectivity does not exist and C1 is protected along with C7.12,70 This suggests
that while a crowded area of the molecule, the southern region is still accessible.
This is further corroborated by the fact that the C2 and C7 benzoate esters in
2.13 were installed in a single step with no selectivity.71
OPMB OPMB OH TBSOTf, OH OH OTBS 10 9 2,6-lutidine, NaOH 1 7 CH Cl , -78 °C MeOH:THF HO 2 2 HO O H 81% O H 94% 2.12 2.18 OPMB OPMB O O OTBS OTBS Swern oxidation HO HO HO H 82% O H 2.19 2.20
Scheme 2.8 Formation of Diketone by B-ring Functionalization
49 At this point, oxidation of the C9 hydroxyl group was pursued in order to
install the C9 ketone present in Taxol. The steric environment that provided
selective protection of C7 now prevented oxidation of C9 by traditional means.
This problem was rectified by again utilizing the transannular hydride shift
chemistry. By treating 2.18 with NaOH using a mixed polar solvent system of
MeOH:THF brought about a hydride shift to give 2.19 in high yield. With this C9 ketone and C1 hydroxyl arrangement, Swern oxidation of C1 in 2.19 formed diketone 2.20 in good yield although an extended reaction time of 3 h and warming to -50 °C was necessary.
2.3 Formation of a Bridge Migrated Taxane
2.3.1 Original Conditions for Bridge Migration Precursor Formation
Before migration could be carried out, installation of the C2 benzoate ester had to be accomplished since it was theorized that C2 would be inaccessible once the bridge was migrated. Previous research had provided the route illustrated in Scheme 2.9 as a method for functionalization of the B-ring and bridge migration. Diketone 2.20 was taken to its benzyl enol ether 2.21, which was subsequently treated with buffered m-CPBA to yield diepoxide 2.22 with high selectivity for the α-orientation of both epoxides. Originally, this was a tested bridge migration substrate; however, migration with concomitant epoxide opening was not possible. The diepoxide was then functionalized to yield 2.24 after enol epoxide opening in 2.22 to give the C2 carbinol 2.23, which was protected as its
50 benzoate ester. Subsequent studies revealed that 2.24 could in fact be migrated to give 1.85 using Al(Ot-Bu)3 in benzene.
OPMB OPMB O m-CPBA O KOt-Bu, OTBS NaHCO OTBS CSA 2.20 3 BnBr, DMF, 1 2 CH Cl , 0 °C CH Cl HO 2 2 HO 2 2 0 °C, 88% 4 70% 90% BnO H BnO O H 2.21 2.22 O OPMB OPMB O O OPMB BzCl, Et3N, O OTBS OTBS DMAP, Al(Ot-Bu)3 DMF:CH Cl PhH, 50 °C OTBS HO 2 2 HO HO O H 80% O H 70% O H HO BzO BzO O O O 2.23 2.24 1.85
Scheme 2.9 Original Steps for B-ring Functionalization and Bridge Migration
The cursory coverage of the route from 2.20 to 1.85 does not do justice to the more than one year of work that went into the determination of a suitable substrate for the bridge migration reaction. Bridge migration in this system was, at best, a fickle reaction. For example, replacement of the epoxide in 2.24 by an exo-olefin prevents migration. In addition, the identity and configuration of the elements present at C9/C10 greatly affects the ability of the system to migrate. A full review of the research towards 1.85 is not possible here and the reader is referred to the pertinent publications.12,56,57,75,76
51 2.3.2 Second Generation Route to 1.85
It was observed in previous research that α-hydroxylation of 2.20 could be
carried out to install the C2 hydroxyl group without recourse to the enol epoxide
methodology.12 Optimization of the conditions led to a new route to 1.85 as
illustrated in Scheme 2.10. After formation of 2.25 using KOt-Bu and the Davis
reagent, epoxidation using buffered m-CPBA provided 2.23.77-79 Higher
temperatures used in the epoxidation reaction led to mixtures of the α and β
disposed epoxides. Lower temperatures favored the desired α-epoxide, but
reaction times of several days were required for total consumption of 2.25.
Experimentation found that higher loads of m-CPBA at -25 °C led to selective formation of 2.23 and only required an 8 h reaction time. Protection of the C2 hydroxyl in 2.23 was then carried out using a more aggressive condition that eliminated the need to purify the starting alcohol. With the synthesis of 2.24 completed, bridge migration was the next task at hand in order to obtain 1.85.
52 OPMB OPMB KOt-Bu O O Davis reagent OTBS m-CPBA, OTBS 2.20 THF, 0 °C 1 NaHCO , HO 2 3 HO 4 83% O H CH2Cl2, -25 °C O H HO HO O 2.25 2.23
OPMB O OPMB O OTBS BzCl, py, Al(Ot-Bu)3 DMAP, CH2Cl2 PhH, 50 °C OTBS HO HO 80% (two steps) O H 70% O H BzO BzO O 2.24 O 1.85
Scheme 2.10 New Sequence for Arrival at a Bridge Migrated Taxane
2.4 Additional Insight into Bridge Migration and Pretaxane Chemistry
It was quickly observed that use of the previously reported conditions for arrival at 1.85 was not possible. Originally, the migration was carried out on small scale by heating the starting material to 50 °C overnight. With A-ring chemistry progressing, the need for larger quantities of material was apparent.
Treatment of 2.24 with freshly purchased Al(Ot-Bu)3 overnight at 50 °C was
disastrous. The significantly older reagent previously used was less active than
the new reagent and required overnight stirring. When treated with highly active
reagent, rearrangement was observed; however, as shown in Scheme 2.11, the
major compound isolated was 2.26, which lacked the B-ring benzoate ester.
Investigation into the reaction conditions revealed that after 3 h, 2.26 began to
form in small quantity. With this in mind, the reaction was repeated with a shorter
53 stir time and while recovered 2.24 was present, the benzoate-deprotected species 2.26 was not observed.
OPMB OPMB O OPMB O O O
Al(Ot-Bu)3 + 2.24 OTBS + OTBS OTBS PhH HO HO O H O H HO BzO HO BzO H 1.85 O 2.26 O 2.27 O 8 h, 50 °C 0% 50% 10% 3-5 h, 50 °C 70% 0% 20%
Scheme 2.11 Actual Bridge Migration Products Formed from 2.24
A second observation was made lending information to the complexity of this reaction. It had been observed in previous substrates that migration of the ethylene bridge present in the starting material was possible and in some cases provided a more thermodynamically favored product. In the case of 2.24, the presence of this product was not reported; however, 1H NMR analysis of the
recovered starting material showed that what appeared to be a single compound
using TLC was actually a 1:1 mixture of 2.24 and 2.27, and that the ethylene
migration was occurring as illustrated in Scheme 2.11. If complete consumption
of 2.24 was allowed, a ratio of 1.85:2.26 of 3:1 was observed. It is possible to stop the reaction as soon as the formation of 2.27 is observed, obtain 1.85 in
high yield based on recovered 2.24, and resubmit the isolated starting material
(~50%) to the reaction conditions. While this decreases the formation of
54 undesired 2.27, the cost in solvent, reagent, and time is a significant factor.
Since it is hard to tell percent conversion and therefore percent formation of 2.26 from TLC analysis, the ratios of 1.85:2.27 vary quite a bit from 10:1 to 3:1; however, with the current protocol in use (50 °C, 2-3 h) a 1.85:2.27 ratio of 5:1 is observed with 80% consumption of 2.24 representing a 70% yield of 1.85.
Thanks to improvements in the alkenyllithium coupling, dihydroxylation of
1.88, installation of the C2 benzoate ester, formation of the epoxide precursor to the D-ring, and yield of the desired bridge migration product, material supply at this stage was no longer a looming problem, and attention was shifted to the completion of the A and D-rings of Taxol.
2.5 Completion of a D-Ring Synthesis and Development of the Requirement
for Initial A-Ring Completion
With a reliable synthesis of 1.85 in hand, a “two-pronged” strategy for completion of Taxol was adopted. As illustrated in Figure 2.3, two routes are available en route to the target. The “eastward” route involves installation of the
D-ring followed by A-ring completion, and the “westward” route begins with completion of the A-ring followed by D-ring elaboration. The routes were explored simultaneously and a successful D-ring synthesis as well as new information regarding what would be required for arrival at the target was garnered from these efforts.80
55 OPMB O OPMB "Westward" route "Eastward" route O (A-ring installation) OTBS (D-ring installation) OPMB HO O O O H OTBS BzO HO O OTBS H HO BzO O H A-ring BzO O D-ring PO Functionalization Elaboration O
TAXOL
Figure 2.3 “Two Pronged” Approach to Taxol
2.5.1 First Generation D-Ring Synthesis
The initial synthesis of the D-ring utilized taxane 1.85 and began with
opening of the epoxide using TMSOTf followed by immediate deprotection of the
TMS ether to yield allylic alcohol 2.28 as illustrated in Scheme 2.12.58 Initially,
dihydroxylation to yield triol 2.31 was not possible and epoxidation followed by a titanium-mediated rearrangement provided allylic alcohol 2.30, which was smoothly dihydroxylated to give triol 2.31. Protection of the primary hydroxyl followed by mesylate formation and deprotection gave 2.32. Treating the mesylate with Al(Ot-Bu)3 in benzene promoted oxetane ring closure to give 2.33.
56 OTBS OTBS OTBS TMSOTf; m-CPBA Cp2TiCl2 1.85 H CSA H Zn, ZnCl2 H O OH OH OH 2.28 2.29 2.30 OPMB O OsO4 OTBS TMSCl; OTBS Al(Ot-Bu)3 H MsCl; H OTBS CSA O HO OH OH BzO H OH OH OH OMs HO 2.32 2.31 2.33 O
Scheme 2.12 First Generation Synthesis of the Oxetane Ring
2.5.2 Second Generation D-Ring Synthesis
While this route did deliver the desired oxetane, it was quite cumbersome to execute and suffered from poor conversion and yield in the final ring closure event. In order to shorten the route and provide 2.33 in a more efficient manner, a new route was investigated and resulted in a shortened overall synthesis from
1.85 to 2.33 to a total of six steps.
57 CSA OTBS OsO4 OTBS 1.85 TMEDA MeCN/DMSO H H OH OH OH OH 2.28 2.31 OPMB OTBS O TMSCl; Al(Oi-Pr) H 3 MsCl; i-PrOH OTBS OH HF•py OH OMs O HO BzO H 2.32 HO 2.33 O
Scheme 2.13 Second Generation D-ring Synthesis
Shown in Scheme 2.13, the route again began with allylic alcohol formation; however, it required only one synthetic operation to deliver the desired product. Conditions for dihydroxylation were explored in more detail and formation of triol 2.31 from 2.28 was achieved using OsO4 and added TMEDA. A similar three-step sequence employed in the first generation approach provided
2.32, which was closed to 2.33 in a higher yielding and cleaner manner using
81 Al(Oi-Pr)3 in i-PrOH. With a six-step sequence in hand, it seemed as if D-ring installation followed by A-ring completion would be the most efficient way to complete the synthesis of Taxol; however, problems with the functionalization of the A-ring with a D-ring in place would prove to thwart the “eastward” strategy.
58
CHAPTER 3
A-RING FUNCTIONALIZATION
Completion of the A-ring has been the most challenging aspect of the synthesis thus far. The challenge it presents has occupied the career of two graduate students and will likely be a continuing pursuit. The required transformations are not difficult on paper, but in the laboratory, they have proven to be quite formidable. Nonetheless, new information about a fascinating reactivity pattern and molecular framework continues to be revealed.
3.1 Early A-Ring Functionalization and Failure of the Eastward Strategy
Efforts aimed at the synthesis of the A-ring were underway when both the first-generation and second-generation syntheses of the D-ring were completed.
With the improved six-step sequence in hand, studies began on functionalization of the A-ring with a D-ring in place. Earlier A-ring chemistry had provided a very useful intermediate, diosphenol 3.1, as shown in Scheme 3.1 via deprotonation of 1.85 followed by reaction with molecular oxygen (specific details to follow).
59 OPMB OPMB O O Base HO OTBS O2 OTBS O HO O HO BzO H BzO H 1.85 O 3.1 O
OPMB OPMB O O Base OTBS X OTBS O HO -O HO BzO H BzO H RO RO O O R = H, PGs R = H, PGs
Scheme 3.1 Successful and Attempted Formation of A-Ring Diosphenols
Surprisingly, attempts to form an A-ring diosphenol with the oxetane in
place were unsuccessful. In fact, attempts at enolate formation in substrates with
completed oxetanes led to decomposition in all cases. Protection of the C4
hydroxyl group did not lead to any improvement in the stability of A-ring anions in
oxetane containing cases.82 From these data, we easily drew the conclusion that
A-ring functionalization would have to precede installation of the D-ring.
3.2 Synthetic Challenges Resident in the A-Ring
At first glance, moving from 1.85 to 1.84 involves only four basic synthetic operations outlined in Figure 3.1: 1) C14 methylene formation from the C14 ketone, 2) installation of the C13 hydroxyl or ketone for hydroxyl formation, 3)
60 installation of the C11-C12 double bond, and 4) installation of the C18 methyl
group.
This required series of transformations was accomplished in the Paquette
synthesis of Taxusin.74 However, the route illustrated in Scheme 3.2 is not
suitable for our purposes here since one of our goals is to develop the shortest synthesis of Taxol known to date. Parts of the route do offer us strategies that can be used to install the required elements present in 1.84.
OPMB OPMB 18 12 O 1. C14 methylene formation O 11 13 2. C13 oxygenation O 14 OTBS OTBS 3. C11-C12 double bond formation O HO HO BzO H 4. C18 methyl group installation BzO H 1.85 O 1.84 O
Figure 3.1 Migration Product 1.85 and Target Completed A-Ring 1.84
3.2.1 A-Ring Completion in Taxusin
Beginning with A-ring ketone 3.2, diosphenol formation is achieved by α- hydroxylation with Davis’ oxaziridine followed by further oxidation with molecular oxygen. Reduction to the C14 hydroxyl is followed by protection as the benzoate ester to give 3.4. Standard selenation followed by oxidative elimination installs the C11-C12 double bond in 3.5. The C14 methylene in 3.6 is installed through cleavage of the C14-O bond using SmI2, and additional functionalization of 3.5
provides C11-C12 synthetic handles. The C18 methyl group is installed via
methyllithium addition to the ketone resident in 3.7, which is installed after 61 deprotection and oxidation of 3.6. Further functionalization after C18 methyl
group installation provides the ketone necessary for samarium diiodide cleavage
of the C12-O bond in 3.8. Elimination to form the C11-C12 double bond is
achieved using thionyl chloride and reduction with DIBALH provides the hydroxyl group in 3.9 with the required stereochemistry present in the target. Final
deprotection and acetylation of the free hydroxyl groups provides Taxusin (3.10).
O 12 O 11 1. KHMDS, Davis oxazir., 1. LHMDS, PhSeBr 13 14 1 HO 18-C-6; O2 2. H2O2 H H O H 2. LAH, Et2O, rt RO BzCl, py, R = H, 3.3 3.2 OMOM DMAP R = Bz, 3.4 PMP O OH 1. SmI2 O O 1. LAH 2. OsO , py 2. SEMCl O 4 O 3. p-CH3OC6H4CH(OCH3)2 3. DDQ SEMO RO H H 4. TPAP H 3.5 3.6 3.7 OAc HO OH OAc 1. MeLi H3C 1. SmI 1. LiBF O 2 4 2. TBAF 2. SOCl2, py HO 2. Ac2O, py AcO H H H 3. TPAP 3. DIBALH H 3.8 3.9 3.10 OAc
Scheme 3.2 A-Ring Elaboration in the Synthesis of Taxusin
From migration product 3.2, 18 synthetic operations are used to complete the A-ring of Taxusin. In order to accomplish a total synthesis of Taxol that is the shortest on record, this is not an acceptable number of steps. Our A-ring
62 precursor, 1.85, is realized in 18 steps from CSA, and the route used to reach it
installs the taxane framework, numerous hydroxyl groups, and several synthetic
handles for further elaboration to the target. It is not in line with our goals to
spend an equal number of steps on final A-ring elaboration. However, the
Taxusin synthesis does provide us with information that we can use to achieve a completed A-ring. First, it illustrates that the C11-C12 double bond can be installed through at least two avenues. Elimination of a leaving group at C11 or
C12 both serve as entries into installing this functionality. Second, cleavage of the C-O bonds at C14 and C12 was accomplished with SmI2 and this strategy
may be useful to us as well. It should also be noted that the C11-C12 double
bond can be dihydroxylated as well and that epoxidation and other methods may
be useful for functionalization of C11-C12. The reductions used in the Taxusin
A-ring give α-disposed hydroxyl groups and selenation of 3.4 occurs from the top
face of the molecule suggesting that it is more accessible on steric grounds,
which bodes well for installation of C13 with the proper stereochemistry via
reduction. With this information in mind, A-ring completion began and we would
quickly learn that the completion of the A-ring from 1.85 was going to be a more challenging approach than anticipated.
3.2.2 C14 Ketone Reduction and Retro-aldol Fragmentation
Perhaps one of the most interesting hurdles faced was the retro-aldol ring cleavage that was experienced in early synthetic studies of the A-ring. Reduction of C14 proved to be a challenging task in its own right.12 The solvent used for
63 the reduction was crucial to its success. Reduction with fast-acting reagents
such as DIBALH and LAH were unsuccessful. Some conversion was noticed
with NaBH4; however, it was found that the reduction needed to be carried out in
EtOH rather than the more commonly employed MeOH. A review of the literature revealed that the lifetime of NaBH4 is greatly increased when EtOH is
used as the solvent. In Brown’s pioneering work in the borohydride area, he
determined the percent hydrogen evolution when NaBH4 was dissolved in
various solvents at 60 °C. It was found that in MeOH, 99% evolution is achieved
in only 24 min while in EtOH, 90% evolution is achieved in 14.5 h.83 In our system, this slower decomposition in EtOH allowed for the reagent to persist and reduce the very hindered C14 ketone. While a successful reduction was achieved, it resulted in retro-aldol A-ring cleavage that became a constant concern in A-ring functionalization.
As illustrated in Scheme 3.3, when 3.1 is reduced to the C14 hydroxyl compound 3.11, tautomerization to the keto form is immediately realized. Once in this form, retro-aldol ring opening involving the C1 hydroxyl gives 3.12. Due to this unwanted reaction, the first starting point for A-ring elaboration was the migration product 1.85.
64 NaBH , EtOH 3.1 4 HO 14 1 O HO CeCl3•7H2O O O HO HO O O H H 3.11 3.12
Scheme 3.3 Undesired Retro-aldol A-Ring Cleavage
3.3 A-Ring Elaboration from the Bridge Migrated Product
3.3.1 A-Ring Completion Based on Reduction and Elimination
Several other methods for functionalization of 1.85 were underway and investigation into the reduction of C14 from 1.85 was pursued as well. As illustrated in Scheme 3.4, the hope was to reduce the C14 ketone in 1.85, install a suitable leaving group, and finally eliminate the leaving group to form a C13-
C14 double bond. Through use of this handle, entry into a completed A-ring would be made via hydroboration/oxidation to install the C13 hydroxyl group as it was perceived as the least hindered of the A-ring carbons.
1. Reduction Hydroboration 13 HO 14 2. Leaving Group O HO 3. Elimination HO HO 1.85
Scheme 3.4 A-Ring Elaboration from Bridge Migrated Product
65 Reduction of 1.85 proved to be a challenging task. As illustrated in
Scheme 3.5, several reducing agents were used to bring about reduction to 3.13.
Reduction with DIBALH in toluene, which when used as the solvent is reported to
make the reagent effectively “smaller”, yielded no product. When NaBH4 was used in EtOH at room temperature, slight formation of 3.13 as an inseparable mixture of diastereomers at C14 was observed on small scale. On scale-up, the quantity of NaBH4 required was so large that significant decomposition was
observed. Low temperature reduction with NaBH4 in EtOH on small scale yielded 3.13. Again, on scale up the quantity of reducing agent required led to
significant decomposition. A modest quantity of 3.13 was obtained through the
trial reactions and an attempt was made to bring about elimination using
thiocarbonyldiimidazole; however, formation of the intermediate was not
observed.
66 OPMB OPMB O O See Table 14 OTBS OTBS O HO HO HO BzO H BzO H O O 1.85 3.13
Conditions (Amt. of 1.85) Result DIBALH, toluene, -78 °C to rt No Reaction
NaBH4, EtOH, rt (5 mg) 3.13 (mixture of diastereomers)
NaBH4, EtOH, rt (20 mg) 3 compounds (neither 3.13)
NaBH4, EtOH, 0 °C (4.1 mg) 3.13
NaBH4, EtOH, 0 °C (20 mg) 3.13 (gross xs of NaBH4, messy reaction)
OPMB OPMB O O Im2C=S Δ X OTBS 1,2-Cl2C6H4, OTBS HO HO HO H BzO H BzO O O 3.13 3.14
Scheme 3.5 Reduction of Bridge Migrated Compound
3.3.2 A-Ring Completion Based on Intramolecular Reduction
With intermolecular reductions performing poorly, recourse was made to an intramolecular reduction strategy through hydrosilylation chemistry.84-87 This method, illustrated in Scheme 3.6, provides not only reduction of C14 but also concomitant protection of the C14 and C1 diol present in a substrate of type 3.13.
Protection of the diol in this manner would allow for functionalization of other
areas of the molecule if necessary.
67 Me2SiHCl, Conditions 14 1 X DMAP, CH2Cl2, O HO 0 °C, quant. O O O O H Si 1.85 Si 3.15 3.16
Et3SiH (Ph3P)3RhCl X toluene Conditions 3.15 + H PtCl , THF, rt = 3.15 3.13 2 6 O (Ph3P)3RhCl, N2, CH2Cl2 = 3.17 O HO Si (Ph3P)3RhCl, Ar, CH2Cl2 = 3.15 Et SiH, (Ph P) RhCl, toluene = 3.15 3 3 3 3.17
Scheme 3.6 Hydrosilylation Chemistry for C14 Reduction
Installation of the dimethylhydrosilane proceeded without event to give
3.15, which was treated with Wilkinson’s catalyst in CH2Cl2 in an effort to form
3.16. A new compound was isolated; however, it proved to be the silanol 3.17.
While not the desired compound, this did show us that a reaction with the silicon
was occurring, but that oxygen present in the solvent was trapping the reactive
intermediate. Degassing of the solvent with argon as well as changing the
conditions to one involving Et3SiH returned only starting 3.15. Reaction of 3.15
with H2PtCl6 performed in an identical manner. In addition, an attempt to treat
1.85 with Et3SiH and Wilkinson’s catalyst also returned only starting material.
With the problems encountered in the reduction and functionalization of
1.85 at C14, it was decided to employ the diosphenol intermediate 3.1. It has, as
illustrated in Figure 3.2, three main reactive sites each with different properties.
68 The C14 ketone is naturally electrophilic and can be reduced. If protection of C1
or the enol can be achieved, reduction of C14 can be used without retro-aldol
fragmentation. Deprotonation of the enol provides nucleophilic centers at C12
and the enol oxygen. All of the areas of reactivity can be utilized in various
combinations to give a large number of possible routes to a completed A-ring.
However, the first task at hand was the improvement of the synthesis of 3.1 itself.
3.1
OPMB OPMB OPMB O O O HO δ+ O O OTBS OTBS OTBS HO HO O H O H O HO BzO BzO BzO H O O O Electrophilic Nucleophilic Nucleophilic at C14 at C12 at enol OH
Figure 3.2 Utility of Diosphenol 3.1
3.4 Optimization of the Synthesis of the Diosphenol
Initially, the synthesis of 3.1 was a poor-performing reaction. Yields were in the 40% range based on recovered starting material and overall conversion was low, making any effort to amass a supply of material very difficult. In addition, the reaction performed more poorly, with yields in the 30% range, on scale-up above 10-20 mg. Each time the synthesis was brought to this point,
69 attempts were made to optimize the formation of 3.1 with little success on a
number of occasions.
Literature precedent with regard to diosphenols is, for our purposes, rich
yet lacking. A significant number of diosphenol syntheses are in the literature; however, most utilize robust substrates such as steroids and start from the corresponding α-hydroxy ketone, α,β-epoxy ketone, α,α-dibromo ketone, or other substrate functionalized in a manner not applicable here.88-103 For our purposes,
it would be beneficial if the diosphenol formation could arise from the ketone
directly. As illustrated in Scheme 3.2 in the completion of the A-ring of Taxusin,
the formation of diosphenols on taxanes from the ketone is possible. In fact, the
oxidation state was controlled by temperature manipulation as illustrated in
Scheme 3.7. Deprotonation of Taxusin substrates of type 3.18 with KHMDS
formed the α-hydroxy ketone 3.19 when the reaction was quenched at -78 °C.
When the reaction was warmed to room temperature, the α-hydroxy ketone 3.19 advanced through a process of autooxidation to form the diosphenol 3.20. In the
Taxusin case, the formation of the diosphenol was a high yielding reaction giving the product reliably. This was not true in our system. Complicating matters even more was the fact that under our reaction conditions, no side-products were ever isolated. This is most likely attributed to any side-products that were formed being either too polar for isolation or having been decomposed to non-isolable materials.
70 KHMDS HO Davis oxazir. -78 °C O H 3.19 13 14
O H KHMDS 3.18 HO Davis oxazir. -78 °C to rt O H 3.20
Scheme 3.7 Oxidation State Control in Taxusin Diosphenol Synthesis
Oxidation of acidic carbons to the alcohol level is quite common and can be achieved in numerous ways. The subsequent autooxidation of α-peroxy or α- hydroperoxy substrates that is observed in this system has been severely limited to tertiary and stabilized carbons.104-106 Even more limited has been the
oxidation of secondary carbons due to a number of side reactions that can occur,
most notably fragmentation of the carbonyl-methylene bond via Doering
fragmentation and fragmentation to form diketones.107-109
Mechanistically speaking, a complex series of events must occur in order
to bring about hydroxylation followed by autooxidation. Several pathways can
exist; however, it seems that most evidence points to a series of events
illustrated in Scheme 3.8. It is generally accepted that the first step in the
sequence is formation of the enolate R- followed by single electron transfer to
give R•, the reactive radical intermediate. The intermediate R• is then subjected
to reaction with oxygen to give the peroxide radical ROO•. At this stage, two
71 reaction pathways can operate. In pathway a, the sequence is propagated by
single electron transfer to give the peroxy anion and R•, which continues the
sequence. Hydrogen abstraction alpha to the carbonyl, either from base or an
intramolecular process, ejects hydroxide anion and gives the diketone, which
tautomerizes to 3.1. In pathway b, the peroxy radical ROO• undergoes hydrogen
shift to give the hydroperoxide species containing a radical alpha to the carbonyl.
Fragmentation at this point delivers the diketone, which again tautomerizes to 3.1
and the hydroxy radical, which undergoes single electron transfer with R- delivering R•, which again propagates the reaction. A large number of other processes can operate including the formation of a dioxetane intermediate that can fragment in numerous ways by radical-based and other processes. In our case, fragmentation of the A-ring is a known process and is likely operating in our low yielding reaction.
72 OO OO
Base
O HO -O HO O HO O HO R- R•
O H R• a O -OH R- b a O HO O H 3.1 O O HO b O O HO ROO• R- R• HO O
HO - O OH OH
Scheme 3.8 Probable Mechanism of Diosphenol Formation
As mentioned before, no side-products could be isolated from the reaction mixture. Undesired reaction products can be useful in determining what step should be taken to optimize the reaction. With our absence of these useful side- products, it was obvious that improvement to the synthesis of 3.1 was going to have to come about via a trial and error process.
The first series of optimization attempts focused on altering the reaction temperature, method of addition, and solvent used (see Table 3.1). The original reaction conditions employed addition of 2 eq of KHMDS to an O2-saturated
solution of starting material in THF at -15 °C. This method provided, at most, a
50% yield of the desired product with similarly low conversion. However, yields
in the 30-35% range were also encountered. The first modification dealt with the
73 addition method of KHMDS. A “titrative” strategy was employed where 0.5 eq of
KHMDS was added to an O2 saturated solution of starting material and was
followed by TLC analysis of the reaction mixture. Through this method, it was
possible to optimize the consumption of the starting material. While this
increased the reaction conversion such that all of the starting material was consumed, yields were still in the 35% range. In the reverse sense, enolization with 2 eq of KHMDS was employed and the solution was then saturated with O2.
Again, low yields resulted. The final manipulation with regard to addition
methodology was carried out by addition of 2 eq of KHMDS followed by “titrative” addition of O2 in which O2 was bubbled through the solution for short bursts and
TLC analysis performed after each O2 addition. Yields were again low and in the
40% range. In addition, maximum consumption of the starting material was
observed, in this sequence, after the first addition of O2, which proved that
trapping the enolate with O2 was instantaneous and controlling this portion of the sequence would be all but impossible.
With controlled addition of base, the yield had not improved so temperature manipulation was attempted. Since a short “burst” of O2 led to
completion of the reaction event as mentioned above, it was theorized that
deprotonation followed by reaction of the enolate with oxygen would be an
extraordinarily fast process even at low temperatures. Therefore, the reaction
was carried out several times in THF at -78 °C. In the event, consumption of
starting material was not increased, still ending up in the 50% range, and the
yield of material was still averaging 40-50%. Finally, recourse was made to
74 solvent variation, and the solvent was changed from THF to toluene, as literature references showed that oxidation of THF by O2 to a butenolide structure was possible in strong base.110 While this would not explain the low yield, it would perhaps explain the low consumption of starting material. Carrying out the reaction in toluene at both -78 °C and -15 °C again gave low yield and modest conversion of starting material to product, in the 40% and 65% range respectively.
OPMB OPMB O O See Table HO OTBS OTBS O HO O HO BzO H BzO H O O 1.85 3.1
Condition Yield (Avg)
Titrative addition of KHMDS, O2 satd. THF soln., -15 °C 35-45%
Titrative addition of O2 to enolate, THF, -15 °C 40%
2 eq KHMDS, O2 satd. THF soln., -78 °C 40-50%
2 eq KHMDS, O2 satd. THF soln., -15 °C 30-40%
2 eq KHMDS, O2 satd. toluene soln., -15 °C 30-40%
2 eq KHMDS, O2 satd. toluene soln., -78 °C 40%
Table 3.1 Results of Early Diosphenol Optimization
Perhaps the two most perplexing aspects of this reaction sequence were that no side-products were isolated; therefore, leads pointing to what conditions to vary in the reaction were hard to come by. Second, was the unreliability of the
75 reaction under various conditions. Since the scale of the reaction was limited to
10-20 mg, numerous runs had to be carried out in order to amass useable
quantities of material. Some runs would give rise to yields in the 60% range and
be followed by runs that gave yields as low as 25%. With this amount of
unreliability present, it was decided that formation of 3.1 should be carried out
through a different reaction protocol.
Since it had been employed in the aforementioned Taxusin synthesis,
oxidation using Davis’ oxaziridine was employed in this system for diosphenol
formation. As mentioned in Scheme 3.7, hydroxylation versus diosphenol
formation could be controlled by quenching the reaction mixture at low or high
temperature. If diosphenol formation was not high-yielding and reliable using the
Davis reagent, it was theorized that the reaction could be stopped at the α-
hydroxy ketone and further oxidation could be utilized. As illustrated in Scheme
3.9, the system was treated with either KHMDS or KOt-Bu at -78 °C and then
reacted with the Davis reagent.111,112 In our case, quenching of the reaction at -
78 °C resulted only in formation of the diosphenol. Curiously, no α-hydroxylated
product from 1.85 could be isolated. This suggested to us that our system, for some reason, has an “abnormal” predisposition to further oxidation to 3.1 from
1.85 when an oxidant is introduced. While formation of the diosphenol was the desired result, the yields in both cases were again poor. Consumption of the starting material was complete; however, the yield of end-product was only 50%, and it was severely contaminated with the decomposition products of the oxaziridine reagent.
76
OPMB KHMDS, Davis OPMB O O oxaziridine, -78 °C HO OTBS or OTBS HO KOt-Bu, Davis HO O H O H BzO oxaziridine, -78 °C BzO 1.85 O 3.1 O OPMB O HO X OTBS O HO BzO H O
Scheme 3.9 Result of Low Temperature Oxidation of 1.85
With anionic oxidation conditions providing undesirable results, a new protocol was employed using oxidation with SeO2, a procedure outlined in the literature for diosphenol syntheses.113 Several conditions were employed using
dioxane and t-BuOH as solvents at their reflux temperatures. The reaction
performed better in refluxing dioxane than in t-BuOH; however, a mixture of
products resulted in low yield. As illustrated in Scheme 3.10, diosphenol
formation was also accompanied by formation of 3.21, the corresponding α,β-
unsaturated ketone of 1.85. Unfortunately, the products were formed in low yield
(50% combined); however, this was the first observed formation of 3.21 and it
opens up another avenue towards completion of the A-ring if the reaction were to
be optimized at a later time.
77 OPMB OPMB O 12 O SeO2 1.85 HO + 13 dioxane or t-BuOH OTBS OTBS Δ O HO O HO BzO H BzO H 3.1 O 3.21 O 30% 20%
Scheme 3.10 Diosphenol Formation Attempts Using Selenium Oxidation
Recourse was made to one final type of condition found in the literature.
There are several reports in the literature that are concerned with enolization by
KOt-Bu followed by oxidation with O2. While most substrates were very stable
steroids with little or no sensitive functional groups, the conditions were explored
in our system. The same protocol employed with KHMDS above was employed
with KOt-Bu in t-BuOH at room temperature. At this temperature, only
decomposition was observed. Since cooling t-BuOH to low temperature is not
possible, the reaction solvent was changed to THF as shown in Scheme 3.11.
OPMB OPMB O KOt-Bu, O2, O THF, -78 °C HO OTBS 82% yield OTBS O HO 73% conversion O HO BzO H BzO H O O 1.85 3.1
Scheme 3.11 Optimized Synthesis of Diosphenol 3.1
78 To our delight and surprise, this proved to be the “magic bullet” for
formation of this intermediate. While conversion of starting material stayed in the
60-70% range, the yield of material was increased to over 80%! In addition, the
reaction was scaled up to 100 mg and no loss of yield was observed. This
advance represented a monumental improvement in the synthetic route, and
solved material supply issues that had plagued A-ring elaboration for more than a
year.
An exact explanation for this result is not known, but it seems that KOt-Bu
compared to KHMDS provides the right combination of deprotonating power and
gentle touch necessary for this transformation. A similar phenomenon was
observed earlier in this route with regard to the synthesis of 2.25 from 2.20
(Scheme 2.10). In that particular α-hydroxylation of a ketone in the B-ring, oxidation with KHMDS and the Davis reagent performed poorly. Changing the base to the now employed KOt-Bu, provided the product in over 80% yield, which also allowed for the sequence to the bridge migrated compound to be shortened by two steps as enol ether formation followed by epoxidation and epoxide
opening could be eliminated from the sequence. With this new synthesis of 3.1, more reactions and routes could be examined and knowledge of the A-ring and diosphenols in general was greatly expanded.
79 3.5 A-Ring Completion Based on Functionalization of the Northern Sector
3.5.1 Basic Plan and Strategic Considerations
One avenue explored towards A-ring completion from 3.1 involved
installation of the C11-C12 double bond and C18 methyl group. The general
strategy is outlined in Scheme 3.12 and begins with formation of intermediate
3.22, which could be formed via elimination of a C12 group if reactivity occurred as the keto tautomer. With a substrate like 3.22 in hand, two avenues for completion exist. The first relies upon deoxygenation of C14, and the second upon installation of the C18 methyl group, which would then be followed by deoxygenation at C14. This series of events was advantageous to us as no reports of retro-aldol type chemistry had been described in taxanes containing the C11-C12 double bond. Selectivity in 3.22 was based on the fact that reduction of the C14 ketone would be preferred to the conjugated ketone present at C13.
80 12 X 11 1. C12 functionalization HO O 14 2. C11-C12 double bond O HO formation O HO 3.1 3.22 X = H, halogen
X 1. C14 deoxygenation C14 O O reduction 2. C18 installation HO HO HO 3.22 X 1. C14 reduction C18 installation O O 2. C14 deoxygenation O HO HO
Scheme 3.12 A-Ring Completion Based on Northern Sector Functionalization
3.5.2 Northern Sector Strategies – Bromination and Selenation
The obvious first choice for a series similar to the one illustrated in
Scheme 3.12 was to install a selenium atom at C12 and follow that with oxidative elimination to form the double bond.114 Selenation/elimination was used in
Taxusin and it seemed that this would be a useful strategy here as well. In order
to replicate this strategy here, several methods were used to attempt selenium
installation.
81 PhSe see table HO HO
O HO O HO 3.1 3.23
Condition Result
PhSeBr, Et3N, THF, 0 °C Decomposition
PhSeCl, Et3N, THF, 0 °C No reaction
PhSeCl, Et3N, THF, rt No reaction LHMDS, PhSeBr, THF, 0 °C Decomposition 5 eq LHMDS, 10 eq PhSeCl, THF, 0 °C 61% 3 eq LHMDS, 5 eq PhSeCl, THF, 0 °C 40% 3 eq LHMDS, 3 eq PhSeCl, THF, 0 °C 53% 2 eq LHMDS, 2 eq PhSeCl, THF, 0 °C 53% 1.5 eq LHMDS, 1.5 eq PhSeCl, THF, 0 °C 55% 1.5 eq LHMDS, 1.5 eq PhSeCl, THF, -40 °C 83% 1.5 eq LHMDS, 1.5 eq PhSeCl, THF, -78 °C 85%, 82% larger scale
Table 3.2 Results of Selenation of C12
As illustrated in Table 3.2, conditions for the formation of 3.23 were realized. The more reactive selenating reagent, PhSeBr, proved to be too harsh
for our system, and success was achieved using PhSeCl, a gentler selenating
reagent. Experimentation with the reaction conditions demonstrated that the
process was somewhat sensitive to the equivalents of base and PhSeCl, but
more sensitive to the reaction temperature. Optimization of the conditions
delivered the product in 82% yield at -78 °C on larger quantities of material.
82 In order to generate 3.22, the selenated product 3.23 was treated with
H2O2 at 0 °C and room temperature. No formation of 3.22 was observed, and a different strategy was employed. Literature precedent showed that bromination
of the enolic carbon as well as methylation of the enol oxygen of diosphenols is a facile process.115 A series of conditions were screened and diosphenol 3.1 was
converted to the bromo derivative 3.24 in good yield using py·HBr3 as shown in
Scheme 3.13. The original conditions did not employ pyridine as an additive;
however, in our case it was necessary as opening of the C-ring epoxide was
observed if it was not used. After bromination was accomplished, two strategies
emerged as potential routes to a completed A-ring. It was theorized that
selenation of 3.24 (Scheme 3.13) would occur from the β-face of the molecule,
which would give a phenylseleno moiety with the orientation used in the Taxusin
synthesis that led to double bond formation. Second, double bromination of 3.1
could be followed by dehydrohalogenation to give another A-ring alkenyl
bromide, which could be used as a synthetic handle for methyl group installation
via palladium chemistry, a strategy employed in the Kuwajima synthesis of Taxol
as a method for an A-ring precursor synthesis.27 Attempts to install these groups
in this manner were unsuccessful, presumably due to the steric demands present in the system.
83 12 Br py·HBr , py, HO 3 HO CH2Cl2, 0 °C O HO 71% O HO 3.1 3.24
Br PhSe Br Br LHMDS [O] HO O O PhSeCl X O HO O HO O HO 3.24
Br Br Br Br py·HBr3, py elimination HO X O O O HO O HO O HO 3.24
Scheme 3.13 Bromination of Diosphenol Type Substrates
3.5.3 Northern Sector Strategies – Palladium and Hypervalent Iodine Oxidation
Two other strategies that were pursued en route to 3.22 were based on the use of palladium and hypervalent iodine chemistry to oxidize a silylated diosphenol structure of type 3.22. A report was found that detailed the oxidation of a diosphenol, in a less strained system, via Saegusa oxidation of the corresponding silyl enol ether.116 In addition, research from the Nicolaou group
reported the oxidation of silyl enol ethers to α,β-unsaturated ketones using IBX.
The pursuit of these strategies was executed first by the synthesis of the
requisite starting silylated diosphenols. In earlier research conducted by Dr.
Hofferberth, diosphenol 3.1 was silylated with chlorodimethylsilane (DMSCl) to
give 3.25 as shown in Table 3.3 below. While 3.25 was stable to purification and
84 isolable as a pure compound, the corresponding trimethylsilyl compound 3.26 was not; however, it was subjected to the oxidation without attempts at purification by chromatography on silica gel.
DMSCl, DMAP, 3.1 H Si O 13 Et3N, CH2Cl2, 0 °C 82% O HO 3.25
TMSCl, Et3N, CH2Cl2 taken to 3.1 TMSO or oxidations TMSOTf, 2,6-lutidine, O HO without isolation CH2Cl2, -78 °C 3.26
Reactant Condition Result 3.25 IBX:NMO (1:1), DMSO, rt, 12 h Decomp 3.26 no workup of 3.26, IBX:NMO (1:1), DMSO, rt 12 h N/R 3.26 aq workup of 3.26, IBX:NMO (1:1), DMSO, rt, 12h N/R 3.26 Pd(OAc)2, 1,4-benzoquinone, CH3CN, rt N/R (TMSOTf) 3.26 Pd(OAc)2, 1,4-benzoquinone, CH3CN, rt N/R (TMSCl) 3.26 Pd(OAc)2, 1,4-benzoquinone, CH3CN, Δ Decomp (TMSOTf) 3.26 Pd(OAc)2, 1,4-benzoquinone, CH3CN, Δ Decomp (TMSCl)
Table 3.3 Oxidation of Silylated Diosphenols with Palladium and IBX
85 Another strategy employed as a possible route to a compound similar to
3.22 is adapted from the synthesis of ingenol reported by Winkler and was used
to install an α,β-unsaturated-α-methyl ketone structural motif.117 The series of
transformations necessary was reported by the Tsuji group and employs
Pd(OAc)2-catalyzed decarboxylation-dehydrogenation and is illustrated as a
general plan in Scheme 3.14.118
O
12 11 AllOC(O)CN AllO K2CO3 HO HO MeI O HO O HO 3.1 3.27 O AllO Pd-dppe O O MeCN O HO O HO 3.28 3.29
Scheme 3.14 A-Ring Functionalization Based on Tsuji’s Palladium Chemistry
The sequence was to commence with acylation using allyl cyanoformate,
which as opposed to its commercially available precursor, allyl chloroformate, is know to be selective for C-acylation over O-acylation.119-122 Methylation of 3.27
could then be carried out under very mild conditions, and then followed by palladium catalyzed decarboxylation-dehydrogenation to give 3.29. In practice,
3.1 was treated with LHMDS and allyl cyanoformate, and significant decomposition was observed. The only product isolated in minute yield was one
86 that seemed to suffer from the loss of the benzoyl ester, most likely from the
generation of –CN. While HRMS and NMR data were inconclusive as to the
product’s exact structure, it was apparent that this methodology would not be useful and that modifications had to be made.
12 11 AllOC(O)Cl Et3N HO AllO O 13 Base DMAP O HO O O HO 3.1 3.30 O O AllO AllO K2CO3 Pd-dppe O O O MeI MeCN O HO O HO O HO 3.28 3.29
Scheme 3.15 Alternative Application of Tsuji Palladium Chemistry
Literature precedent demonstrated that a similar series of transformations
could be carried out using the commercially available allyl chloroformate as
shown in Scheme 3.15. The product with allyl chloroformate would be the O-
acylated product, which could be rearranged to the C-acylated product. After
methylation, treatment with palladium would then give 3.29. A search of rearrangement conditions was made, and most involved very strong conditions that could not be tolerated in this system. A gentler condition was found as a
123 possibility that employed Et3N and DMAP. As illustrated in Scheme 3.16,
treatment of 3.1 with allyl chloroformate using either DMAP or LHMDS as a base
87 gave 3.30 very smoothly and in good yield. Attempts were then made at rearrangement of 3.30 using Et3N and DMAP; however, only starting O-acylated material was recovered. It was also noted in the Tsuji procedure that treatment of the O-acylated product could still be used in conjunction with palladium to bring about the elimination to yield 3.29.118 The O-acylated product 3.30 was treated with Pd(OAc)2 at room temperature and at reflux. At room temperature, only starting diosphenol 3.1 was isolated. This was also the case for the
Saegusa oxidations carried out at room temperature. The recovery of starting material suggests that activation of the carbonate and silyl enol ether is occurring, and that β-elimination in the hindered system may be the problematic step. Performing the reactions at reflux returned baseline material in the silylated examples and returned starting 3.1 when 3.30 was employed.
O allyl 12 AllO 11 chloroformate Et3N HO AllO O O 13 DMAP DMAP X O HO 80% O O HO O HO 3.1 3.30
Pd(OAc)2 MeCN dppe Δ or rt X O O HO 3.29
Scheme 3.16 Tsuji Palladium Chemistry With O-Acylated Starting Material
88 3.6 A-Ring Completion Based on Early C14 Deoxygenation
3.6.1 C14 Reduction and Xanthate Formation
With the unsuccessful installation of the C11-C12 double bond early in A-
ring chemistry, it was decided to attempt reduction and removal of the C14
hydroxyl group from 3.1. It was expected that the extra sp3-hybridized carbon
would allow extra conformational mobility thereby allowing double bond
installation to occur. The general strategy is outlined in Scheme 3.17 and was to
begin with protection of the enol oxygen to stave off the retro-aldol reaction
observed when 3.1 was reduced. This would be followed by reduction to the C14
alcohol and then by further reduction, most likely via a xanthate, to give the C14
methylene compound.
X 12 X X protection reduction HO 14 PGO PGO HO HO O HO O HO X = H, Br
X X X xanthate reduction PGO PGO PGO formation HO HO O HO HO S SMe
Scheme 3.17 General C14 Deoxygenation Strategy
Although deoxygenation is the goal, a very delicate balance of a desired hydroxyl group at C14 and a methylene unit at C14 was evident. With the
89 presence of a hydroxyl group, enolization of the C13 carbonyl involving C14
should be discouraged thereby allowing for selective functionalization of C12 in a
manner that would be useful for double bond formation. Although this dichotomy
exists, it was apparent that methodology for C14 deoxygenation was a necessity, and a sequence for its removal was explored without worrying about possible complications and/or advantages that might materialize later in the route.
NaBH4, CH2N2 CeCl ·7H O, X 12 X 3 2 SiO2, Et2O 10:1 EtOH:THF, 0 °C HO 14 MeO 3.1 rt, 98% 3.31 60% conv., 80% yield O HO 3.24 0 °C, 95% O HO 3.32 77% conv., 76% yield 3.1 X = H 3.31 X = H 3.24 X = Br 3.32 X = Br
X X xanthate MeO MeO formation HO HO see text O HO 3.33 X = H S SMe 3.34 X = Br 3.35 X = H 3.36 X = Br
Scheme 3.18 Functionalization of the A-Ring en route to C14 Deoxygenation
The necessary protection step was accomplished using a condition for
methylation of diosphenols with CH2N2 that was reported by Harmata along with the bromination of diosphenols. This protection strategy was carried out on both
3.1 and the brominated derivative 3.24 as shown in Scheme 3.18.115
Methylation with CH2N2 was unsuccessful when no additive was present in the 90 system. Attempts with HBF4 did not yield any protected material, and it was then found that silica gel was sufficiently activating to promote the formation of 3.31 and 3.32. It was during this sequence that the reactivity profile of diosphenols became quite interesting. Methylation of 3.1 required stirring at room temperature, while the reaction with 3.24 was complete at 0 °C. The reduction of
3.31 and 3.32 was accomplished using Luche reduction in EtOH, and consumption of starting material was noticeably better with 3.32. This is perhaps due to the electronegativity of the C12 bromine atom. If it were to pull electron density out of the system, the C14 carbon would become more electrophilic in
3.32 than in 3.31. With a route to the C14 alcohol compounds secured, conditions for xanthate formation were explored on both 3.33 and 3.34. Again, the reactivity in the brominated compound 3.34, when compared to the unfunctionalized compound 3.33, was markedly different.
Several conditions were screened to form the xanthate of 3.34. Trace amounts of the desired xanthate were observed using KH in CS2 at room temperature. Attempts were made to use phase transfer methodology employing
NaOH and Bu4NHSO4 in the presence of CS2; however, no product was isolated.
Heating improved product formation and the structure was identified. Attempts to
optimize led to the condition illustrated in Table 3.4 utilizing KH and 18-crown-6
at room temperature with CS2 as the solvent followed by a quench with excess
MeI. Conversion was acceptable at 83%, but the yield stayed moderately low at
60%. Optimization of the yield was not undertaken at this time; instead,
quantities of material were amassed for reduction attempts. In contrast,
91 formation of xanthate 3.35 from 3.33 was not possible under a number of conditions. The conditions originally explored on 3.34 were unsuccessful as were conditions employing NaH and an NaH/imidazole combination.
Br KH, 18-C-6, Br CS2, rt, 12 h; MeO MeO MeI, rt, 3 h HO HO 60% yield O HO 3.34 83% conversion S SMe 3.36
see table MeO MeO
HO HO O HO 3.33 S SMe 3.35
Conditions Result
NaH, imid., CS2; MeI; AIBN, Bu3SnH No Reaction KH, 40 °C, 4 h; MeI, 40 °C, 3 h No Reaction
KH, imid., CS2, rt, 12 h; MeI, 3 h No Reaction
KH, 18-C-6, CS2, DMF; MeI, 3 h Decomposition
KH, 18-C-6, CS2; MeI 3 h No Reaction
NaH, CS2, 12 h; MeI, 3 h No reaction
NaH, imid., CS2, 12 h; MeI, 3 h Decomposition
NaH, imid., CS2, THF, rt, 12 h; MeI, 3 h No Reaction
Table 3.4 Results of Xanthate Formation Attempts
92 3.6.2 Xanthate Reduction Attempts
While xanthate 3.35 could not be realized, efforts were made to reduce the xanthate present in 3.36. In our analysis, this was an even more attractive substrate as the bromine resident at C12 could potentially serve as a synthetic handle for double bond installation. The reactions illustrated in Table 3.5 were carried out with the hope that 3.37 would be obtained.
Br Br see table MeO MeO
O OH OH S 3.37 SMe 3.36
Condition Result
n-Bu3SnH, AIBN, toluene, 50-80 °C Decomposition
n-Bu3SnH, Et3B, THF, 0 °C, 1 h Decomposition
n-Bu3P-BH2, AIBN, PhH, Δ Decomposition
n-Bu3P-BH2, AIBN, PhH, 60 °C, 3 d Slow Decomp
n-Bu3P-BH2, AIBN, PhH, hν then heat to 70 Decomposition
n-Bu3P-BH2, Et3B, THF, O2, 0 °C to rt No Reaction
hν, HMPA:H2O (95:5), 1.5 h, 2357 Å, quartz tube Decomposition
hν, HMPA:H2O (95:5), 30 min, 2357 Å, quartz tube Decomposition
hν, HMPA:H2O (95:5), 5 min, 2357 Å, quartz tube Decomposition ® hν, HMPA:H2O (95:5), 15 min, 2357 Å, Vicor tube Decomposition RaNi, EtOH, rt Decomposition
Table 3.5 Results of Reduction of 3.36
93 Xanthate reduction was initially attempted under the standard Barton
deoxygenation protocol involving n-Bu3SnH as the reducing hydride and AIBN as the initiation source.124 At the elevated temperature required to activate AIBN,
decomposition of the starting material was observed. The initiation was then carried out with Et3B so that the reaction could be executed at low temperature.
Again, decomposition was observed. A series of reductions was attempted using
a phosphine borane, specifically n-Bu3P-BH2, a reagent reported by Barton to reduce xanthate functionalities in the presence of halogens.125 This was an
attractive alternative as tin seemed to be a detrimental reagent to our system,
and we attributed this result to the alkenyl bromide moiety present at C12-C13 in
3.36. All of the conditions utilizing heat to activate the reaction again resulted in decomposition. At times, it was slow to occur, but no useable material was isolated out of any of the reaction mixtures. Photochemical reduction was attempted through the employment of a phosphoramide radical, which could be generated by irradiation of HMPA. Runs at varying times were carried out using a quartz reaction vessel, but again, decomposition was observed even at the shortened reaction time of 5 min. Changing to a reaction tube made of
Vicorglass, which allows 50% of the light to pass through, again led to decomposition of the starting material in a rapid manner. One final reaction was carried out using RaNi in EtOH, in the hope that cleavage of the xanthate would occur. As with the previous attempts, no useable compounds were isolated from the reaction mixture.
94 3.7 A-Ring Functionalization Employing C1 Protection
Thus far, strategies focused on installation of the double bond were unsuccessful as were those that focused on deoxygenation of C14. It was decided to attempt these two key steps with a different order of events. It was anticipated that installation of the double bond would be possible with a hydroxyl group at C14 and that deoxygenation of C14 after that point would be possible as it had been accomplished in the Taxusin synthesis. Execution of this strategy would require using the ketone at C13 as a synthetic handle with the C14 hydroxyl group in place to direct enolization to C12. This would require unmasking of the protected enol at C13 and could potentially lead to retro-aldol chemistry. In order to avoid this undesired result, protection of C1 had to be employed, and protection of the A-ring enol had to be carried out using a group that would be easier to remove than the methyl enol ether, which could potentially require a very acidic condition that the rest of the molecule would not tolerate.
Early attempts to protect the diol resident in 3.33 under fairly mild conditions were previously attempted by Dr. Hofferberth and were unsuccessful.12 Since the brominated derivative 3.34 was easier to functionalize at the C14 hydroxyl group, diol protections were employed using this substrate in order to stave off retro-aldol chemistry that could potentially occur when the C13 ketone was unmasked. Protection of a C1-C2 diol was employed in previous
Taxol syntheses, and it was envisioned that it would be possible in our case at
C1 and C14.
95 3.7.1 Alternate Diosphenol Protection
In order to increase potential avenues in the reaction sequence, a
substrate protected at C13 with a different group was developed. The list of
potential protecting groups was rather long, but limited to groups that could be
orthogonally removed and were tolerant of basic and oxidative conditions. It was
decided that the two best candidates were a benzyl and an allyl group. An
allylated diosphenol became the first priority as the allyl group could potentially
be installed using known vinyldiazomethane (VDAM) with the same protocol
used to install the methyl group and since the precursor to VDAM,
allylnitrosourea, was available in our laboratory.
Allylation was attempted on both 3.1 and 3.24 as illustrated in Table 3.6.
Using the same procedure for the synthesis of CH2N2, VDAM was synthesized and reacted with 3.1. To our surprise, allylation of 3.1 using VDAM did not occur even after stirring the reaction mixture for 24 h at room temperature. A literature search revealed that allylation of benzoic acid at room temperature proceeded with only 50% conversion after 36 h validating our assumption that VDAM lacks the reactivity inherent in its explosive congener, CH2N2. Additional conditions
were screened that involved deprotonation of the enol oxygen, some of which led
to decomposition while others returned only starting material. A quite gentle
condition employing K2CO3 and allyl bromide in refluxing acetone was found in
the literature and was carried out with only a solvent modification.126 This
protocol did bring about formation of 3.38, albeit in low yield and with poor conversion. Substitution of allyl iodide for allyl bromide led to a very messy
96 reaction when at room temperature; however, mixing of the reagents at 0 °C
followed by warming to room temperature and changing the solvent to DMF
improved the yield and conversion of the reaction. In an identical procedure, the
selenated derivative 3.23 was allylated to give 3.39. The protocol with THF at 50
°C was employed for 3.24, but the reaction was quite low yielding. Success was swiftly realized by carrying out the reaction at room temperature in DMF.
X X see table HO O
O HO O HO 3.1 X = H 3.38 X = H 3.23 X = SePh 3.39 X = SePh 3.24 X = Br 3.40 X = Br
Substrate Condition Result
3.1 VDAM, SiO2, Et2O, rt No Reaction 3.1 KOt-Bu, allyl bromide, TBAI, THF, 0 °C to rt Decomposition 3.1 LHMDS, allyl bromide, THF, 0 °C No Reaction 3.1 KHMDS, allyl bromide, TBAI, 0 °C Decomposition 3.1 imidazole, allyl iodide, THF, rt to 50 °C No Reaction 3.1 K2CO3, allyl bromide, THF, rt No Reaction
3.1 K2CO3, allyl bromide, THF, 50 °C, 8 h 3.38 (44%) 3.1 K2CO3, allyl iodide, THF, rt 3.38 (messy)
3.1 K2CO3, allyl iodide, DMF, 0 °C to rt 3.38 (76%) 3.23 K2CO3, allyl iodide, DMF, rt 3.39 (80%)
3.24 K2CO3, allyl iodide, THF, 50 °C 3.40 (40%) 3.24 K2CO3, allyl iodide, DMF, rt 3.40 (75%)
Table 3.6 Allylation of Diosphenol Substrates
97 3.7.2 C1-C14 Diol Protection Attempts
With a new protecting group in place, reduction of 3.40 proceeded to give
3.41 in moderate yield as illustrated in Scheme 3.19. With the C1-C14 diol in
place in 3.41 and the previously known compound 3.33, attempts at protection
were carried out. Hopefully, the bromine present in 3.41 would activate the C14
hydroxyl group and allow for a reaction to occur at this hindered position.
Br Br NaBH4, CeCl3·7H2O, AllO AllO 14 1 EtOH, 0 °C, 50% O HO HO HO 3.40 3.41
Scheme 3.19 Reduction of Allylated Functionalized Diosphenol
Diol protections on 3.33 were carried out using conditions from Nicolaou,
Danishefsky, and Mukaiyama to protect the C1-C2 diol in their syntheses of
Taxol.23,25,38 In addition, protection as the cyclic boronic ester, used by Kuwajima
to protect the C1-C2 diol, was attempted.27 The boronic ester is a particularly
attractive protecting group as it is installed using a simple procedure and can be removed by treatment with H2O2 or simply by exchanging the diol oxygens of the
substrate with pinacol.
The advantage to diol protection is obvious; two sensitive functional
groups can be masked in one operation and subsequently unmasked in another
single-step process. The C14 hydroxyl group was known to be difficult to
98 access. In fact, an analog of Taxol with a β-hydroxyl group at C14 is known and
can be formed by deprotonation of the Taxol A-ring followed by treatment with
O2, which approaches the molecule from the less hindered top face.
Functionalization of the C14 α-hydroxy A-ring was achieved in the Taxusin
synthesis most likely due to “flattening” of the A-ring when the bridgehead olefin was installed. In our case, the A-ring does not have this conformational bias due to the bridgehead double bond, thus allowing the entire structure to curve further blocking of the bottom region of the molecule. It seems that this conformational bias is what thwarted our efforts to protect the C1-C14 diol in 3.33 and 3.41. As
shown in Table 3.7, attempted diol protection led to decomposition.
X X see table PGO 14 1 PGO
HO HO O O R 3.33 X = H, PG = Me R = BPh, C=O 3.41 X = Br, PG = All
Substrate Condition Result
3.33 PhB(OH)2, CH2Cl2, rt No Reaction
3.33 KH (30% in oil), phosgene, Et2O:HMPA, rt No Reaction
3.33 KH (dry), phosgene, Et2O:HMPA, rt No Reaction
3.41 PhB(OH)2, CH2Cl2, rt No Reaction
3.41 phosgene, py, CH2Cl2, 0 °C No Reaction 3.41 KH, 18-C-6, phosgene, THF, rt Decomposition
Table 3.7 Attempts at Protection of the C1-C14 Diol
99 Since the C1-C14 diol could not be functionalized as configured in 3.33
and 3.41, reduction of the C14 ketone was attempted using a Meerwein-
Ponndorf-Verley reduction in the hope that the β-hydroxyl group at C14 would be
the thermodynamic product. The compounds shown in Table 3.8 were subjected
to MPV reductions using Al(Oi-Pr)3 at various temperatures. As illustrated, at lower temperatures, no reaction was observed and when increased to the reflux temperature of toluene, decomposition ensued. Even the more reactive brominated compound 3.40 proved to resist MPV reduction.
X X see table AllO 14 1 AllO
O HO HO HO 3.38 X = H 3.40 X = Br
Substrate Condition Result
3.38 Al(Oi-Pr)3, i-PrOH, tol, 50 °C No Reaction
3.38 Al(Oi-Pr)3, i-PrOH, tol, 80 °C No Reaction
3.38 Al(Oi-Pr)3, i-PrOH, tol, Δ Decomposition
3.40 Al(Oi-Pr)3, i-PrOH, Δ No Reaction
Table 3.8 Meerwein-Ponndorf-Verley Reductions Attempted
3.7.3 Successful C1 Dimethylsilyl Protection
At this point, a revision of strategy was needed as it became clear that protection of the C1 hydroxyl group would not be possible if it was incorporated
100 as a diol protection with C14. Therefore, protection of C1 was explored on its
own. Since the enol oxygen of the diosphenol system proved to be more reactive than the C1 hydroxyl group, protection of C1 would have to be carried out on a protected diosphenol species. Methylation and allylation of the brominated and selenated diosphenols were known and each would serve as good substrates for C1 hydroxyl group protection. It was decided to pursue the allylated derivative since removal of the protecting group remained a concern.
Initially, protection was attempted as the TES ether and as the SEM ether.
see table AllO 1 AllO
O HO O O 3.38 SiH
3.42
Condition Result
TESOTf, 2,6-lutidine, CH2Cl2, -78 °C to rt No Reaction SEMCl, DMAP, DMF, rt No Reaction
DMSCl, DMAP, Et3N, CH2Cl2, 0 °C to rt No Reaction
DMSCl, imidazole, CH2Cl2, 0 °C to rt No Reaction DMSCl, imidazole, DMF, 0 °C to rt No Reaction DMSCl, py, rt 3.42 (quant.)
Table 3.9 Protection of the C1 Hydroxyl Group in Diosphenol Systems
As illustrated in Table 3.9, neither of these conditions could bring about a
protected species. Protection of the system to give 3.42 in quantitative yield was
101 finally achieved using chlorodimethylsilane, which was reported by Farina to
protect the C1 hydroxyl group in his studies on taxanes.127 In his research,
Farina also noticed the difficulty in protecting the C1 hydroxyl group, and in their
studies, the DMS group was the only group that could be successfully
installed.128
3.7.4 A-Ring Elaboration Plans With C1 Protection Secured
With C1 hydroxyl group protection secured, the alternatives for completion
were analyzed with the first option illustrated in Scheme 3.20. As concerns the known protected compound 3.42, reduction could be carried out to give the C14 hydroxyl compound. At this point, two strategies were available. The first alternative (path A in Scheme 3.20) took the C14 hydroxyl compound and focused on double bond installation by unmasking the C13 ketone followed by selenium installation and oxidation. The precursor 3.43 could then be obtained by deoxygenation of the C14 hydroxyl group. This is a rather short route to an advanced A-ring and appeared to be very promising. The second strategy (path
B in Scheme 3.20) began with deprotection of the enol ether followed by deoxygenation of C14. The newly formed C13 ketone could be subjected to selenation followed by deoxygenation to give 3.43, a protected A-ring precursor.
The only caveat noticed in this path was installation of the phenylseleno moiety at C12. In the first case, enolization of C13 involving C12 should be preferred as the C14 hydroxyl group should disfavor removal of the C14 carbinol proton. In the second case, selective enolization involving C12 could not be anticipated
102 since C14 also contains acidic hydrogens that could be removed with strong
base. However, a danger in both sequences is the deprotonation step as a
whole. Earlier work optimizing the synthesis of diosphenol 3.1 from 1.85 was
attempted by first protecting C1 as the DMS ether followed by deprotonation and
trapping with O2. In the event, removal of the DMS ether was observed upon addition of base, which was a significant concern and warranted an alternative strategy.
12 Reduction 11 1. Deallylation 3.42 AllO O 14 1 2. Deoxygenation O HO O path B SiH SiH
1. Selenation 2. Oxidative path A Elimination
1. Deallylation 2. Selenation/Elimination O 3. Deoxygenation O SiH
3.43
Scheme 3.20 Plan for A-Ring Advancement from 3.42
The second route to 3.43 begins with diosphenol 3.1 as shown in Scheme
3.21. Selenation to give known 3.23 can be followed by allylation to give known
3.39. Protection of the C1 hydroxyl could be attempted using the same condition
103 used to protect 3.38 and could then be followed by one of two reaction paths.
Both start with reduction to give the C14 hydroxyl group followed by deprotection
of the allyl enol ether. From that point, the next two steps are identical but could be approached using a different order of events. Initial oxidative elimination to install the double bond could be followed by deoxygenation of C14 and vice versa. The initial selenium elimination skirts the possibility of participation of the selenium in any radical deoxygenation chemistry and was seen as the favored alternative.
1. LHMDS, PhSeCl, 12 PhSe THF, 0 °C, 67% DMSCl, py, rt HO 14 1 AllO 2. AllI, K2CO3, O HO DMF, rt, 80% O HO 3.1 3.39
PhSe 1. Reduction 1. Reduction 2. Deallylation or 2. Deallylation AllO O 3. Elimination 3. Deoxygenation O O 4. Deoxygenation 4. Elimination O SiH preferred SiH 3.43
Scheme 3.21 A-Ring Functionalization Avoiding Potential Loss of C1 Protection
Both of these strategies lead to 3.43, which can be used to form the completed A-ring according to two general strategies. The first, outlined in
Scheme 3.22, is the strategy used to form the A-ring in the Paquette synthesis of
Taxusin.74 From 3.43, reduction followed by protection and dihydroxylation gives
104 the diol, which can be oxidized at C12 and treated with MeLi. With the methyl
group in place, C13 deprotection and oxidation can be followed by SmI2 deoxygenation and elimination to reinstall the bridgehead double bond, bringing the synthesis to a nearly completed A-ring protected at the C1 hydroxyl group.
Removing the DMS ether completes the route to 1.84.
HO OH 12 11 1. Reduction 1. Oxidation O 1 2. Protection 2. MeLi addition 14 PGO O 3. Dihydroxylation O SiH SiH
3.43 OH OH 1. C13 deprotection H C 3 2. C13 oxidation O PGO 3. SmI2 deoxygenation O 4. Elimination HO SiH 5. C1 Deprotection 1.84
Scheme 3.22 Taxusin-like Approach to the A-Ring
A second approach that was envisioned was one based on epoxidation of
the double bond in 3.43. Again, two sequences illustrated in Scheme 3.23 are
evident. The first (path A in Scheme 3.23) is a four-step sequence that begins
with epoxidation and MeLi addition to install a bridgehead hydroxyl group and the
C18 methyl group. After elimination to form the double bond and deprotection of
the C1 hydroxyl group, the target compound, 1.84 is delivered. The second seven-step approach (path B in Scheme 3.23) begins with reduction of the C13
105 ketone followed by protection. While these two steps and the subsequent re- oxidation of C13 lengthen the overall sequence, the prospect of MeLi addition to the C13 ketone is removed. After protection, epoxidation followed by MeLi addition, a two-step sequence identical to that presented in the first route, and the required C13 oxidation, 1.84 is obtained.
OH 12 11 1. Epoxidation O O 14 1 2. MeLi addition O path A O SiH SiH 1. Elimination 3.43 2. Deprotection O 3. Oxidation in HO path B 1. Reduction OH 2. Protection 3. Epoxidation PGO 4. MeLi addition O path B SiH
Scheme 3.23 Epoxide Route to a Completed A-Ring
With the significant number of completion options available, proceeding along these routes became the priority. Since 3.39 was already known, it was advanced as illustrated in Table 3.10 to the protected derivative 3.44 in good yield. At this point, reduction of the C14 ketone was the next priority. Luche reduction failed to deliver the necessary C14 hydroxyl group. It was immediately theorized that the C14 ketone had become more crowded with the installation of the DMS ether at the C1 hydroxyl group. Reduction was also not possible with 106 LiBH4 even when activated with MeOH and EtOH. Reduction with DIBALH did not deliver the C14 hydroxyl group most likely due to its steric demands.
Reduction with LiAlH4 and BH3 were also employed, but the only action on the system was decomposition with LAH at room temperature.
PhSe PhSe PhSe DMSCl, py, see table AllO AllO AllO rt, 70% O HO O O HO O 3.39 SiH SiH
3.44
Condition Result
NaBH4, CeCl3·7H2O, EtOH:THF, 0 °C No Reaction
NaBH4 (gross excess), CeCl3·7H2O, EtOH:THF, 0 No Reaction
NaBH4, CeCl3·7H2O, EtOH:THF, 0 °C to rt No Reaction
LiBH4, THF, 0 °C No Reaction
LiBH4, THF, MeOH, 0 °C No Reaction
LiBH4, THF:EtOH, rt No Reaction DIBALH, toluene, 0 °C No Reaction DIBALH, toluene, rt No Reaction
BH3·THF, THF, 0 °C No Reaction
BH3·THF, THF, rt No Reaction
LiAlH4, THF, 0 °C No Reaction
LiAlH4, THF, rt Decomposition
Table 3.10 Attempted Reduction of C1 Protected Species
3.8 Miscellaneous Diosphenol and A-Ring Functionalization
Upon initial formation of diosphenol 3.1, we were quite excited about the potential for A-ring completion. As illustrated earlier, it provides a number of 107 synthetic handles for functionalization. The drawback of employing a diosphenol
in a complex natural product is that very little literature precedent regarding their
use exists. This meant that in addition to trying to finish the A-ring of the
molecule, we had to determine what we could do to functionalize such a system.
In addition, since the A-ring of Taxol had never been made on a complete taxane
skeleton, we were charged with the task of determining what transformations in
the A-ring could be carried out.
While the oxidation of 1.85 to form 3.1 with SeO2 did not constitute a
reliable procedure, a transformation with a tiny quantity of 3.21 was attempted to bring about bridgehead bromination. It was hoped that allylic bromination using
NBS in refluxing CCl4 would allow this transformation to occur. A result such as
this would open another possible route to the completed A-ring. In practice,
decomposition in less than 30 min was observed.
An early concern for us early in the A-ring functionalization problem was our inability to protect the C1-C14 diol. Focusing on carbonate and cyclic boronic ester protections, we then wondered if a cyclic derivative could be employed that would allow for the free hydroxyl groups to be connected through a longer tether.
As shown in Scheme 3.24, C1-C14 diol 3.33 was treated with KH and CS2 and
quenched with a doubly-activated electrophile. As in the other cases of C1-C14 diol protection, no reaction was observed.
108 Br 12 11 NBS, CCl4 13 Δ X O HO O HO 3.21
KH, CS2, rt; MeO 14 1 X MeO Ph2SiCl2 HO HO O O 3.33 SiPh2 S S
Scheme 3.24 Exploratory Diosphenol and A-Ring Functionalization
While the installation of a phenylseleno group and bromine atom at C12
was very helpful to opening up avenues of A-ring completion, the installation of
other functional groups needed to be pursued. In the original diosphenol syntheses carried out by Dr. Hofferberth, attempts were made at quenching the diosphenol with formaldehyde to install a hydroxymethyl group at C12.12 This was conducted with the harsher reagent, KHMDS. It was decided that attempts should be made using KOt-Bu in light of the improvements it made in our route as a whole. In addition, reports in the literature were found that dealt with the functionalization of ketones using hypervalent iodine reagents.129,130 Diosphenol
3.1 was subjected to the literature conditions in the hope that reactions would
occur through the keto tautomer thereby installing additional C12 functionalization and manipulation of the C13 ketone. As illustrated in Scheme
3.25, neither series of reactions gave rise to useable compounds.
109 X 12 12 see table or HO HO
O HO O HO O HO 1.85 3.1 X = CH2OH or CN
Starting Material Condition Result
1.85 KOt-Bu, O2, -78 °C; H2CO, -78 °C to rt Decomposition
1.85 KOt-Bu, O2, -78 °C; H2CO , -78 °C 3.1 (trace) 3.1 LHMDS, MeOC(O)CN, THF, 0 °C No Reaction 3.1 LHMDS, TsCN, THF, 0 °C to rt No Reaction 3.1 KHMDS, TsCN, THF, 0 °C to rt No Reaction
TsO HO NaNO PhI(OH)OTs HO 2 HO MeCN, rt and Δ H2O OHO O HO 12 X HO X OHO 3.1 PhI(OAc)2 HO NaOH, MeOH MeO MeO O HO
Scheme 3.25 Additional A-Ring Functionalization Attempts
3.9 Oxygenation Strategy to a Completed A-Ring and Current Work
3.9.1 Initial Plan and Strategy Development
The latest strategy to be considered for a route to a completed A-ring cannot be characterized as focusing on either the northern or southern portion of the molecule. It involves transformations in whatever sequence is necessary for
110 arrival at the target. The work being done at this time follows along this line and
is currently evolving into a very promising strategy for A-ring completion. As
illustrated in Scheme 3.26, the approach began with 3.33, which was to be either dihydroxylated with OsO4 or epoxidized using m-CPBA. It was anticipated that the enol epoxide could be hydrolyzed to ketone 3.45 under mild conditions or that it would occur spontaneously. Our initial intention was to protect the C1-C14 diol in 3.45; however, the gathered evidence suggested that this would not be possible. Nonetheless, intermediate 3.45 still appeared to be an attractive compound to us. Upon treatment with OsO4, compound 3.45 was not observed
OsO4 or m-CPBA; HO 12 work up MeO O 13 14 or HO HO mild hydrolysis HO HO 3.33 3.45
via HO O HO or MeO MeO HO HO HO HO
Scheme 3.26 Early Oxygenation Strategy to a Completed A-Ring
In an attempt to arrive at 3.45 through epoxidation, 3.33 was treated with
buffered m-CPBA. The reaction did deliver a new compound which was isolated
with a mass corresponding to 3.46 in Scheme 3.27. A clean 1H NMR spectrum
of 3.46 was obtained; however, quantities were too small to obtain 13C NMR
111 data. The 1H NMR spectrum showed the basic structural features for 3.46, but
was not definitive. The reaction was repeated on larger scale; however, the
identical compound could not be isolated. It seemed as if the epoxidation was
occurring and that upon addition of NaOH to quench the excess m-CPBA, the
epoxide was opened to give 3.46.
HO 12 m-CPBA, NaHCO3 MeO MeO 13 14 CH2Cl2, 0 °C HO HO HO then aq. NaOH HO HO 3.33 3.46
Scheme 3.27 Initial Epoxidation of the A-Ring
Taking this reaction as a lead, investigation into epoxidation of the A-ring
was made. Modification of the reaction with m-CPBA did not yield an A-ring epoxide, and transformations using dimethyldioxirane were explored. Initial results indicated yields were very low providing A-ring epoxide 3.47 in the 20-
30% range. Consumption of all the starting material was an issue as well.
Approximately 50% of the starting material subjected to the reaction conditions was recovered. As illustrated in Scheme 3.28, the epoxide 3.47 provides entry
into a route that could yield the completed A-ring in six steps. After opening of
the epoxide with MeOH and PPTS, the C13 acetal-containing compound 3.48 needs to be selectively oxidized to give the C12 ketone 3.49. With a C12 ketone in hand, the C18 methyl group can be installed via formation of an alkenyl triflate
112 followed by methyl group installation through palladium chemistry to give 3.50.
The desired A-ring 1.84 can then be obtained after hydrolysis of the C13 acetal and removal of the C14 hydroxyl group by either xanthate formation and reduction or SmI2-mediated deoxygenation.
O HO O 12 11 MeOH, PPTS, MeO [O] MeO MeO 14 CH2Cl2, 0 °C MeO MeO HO HO HO HO HO HO 3.47 3.48 3.49
1. alkenyl MeO 1. hydrolysis O triflate MeO 2. deoxygenation 2. methylation HO HO HO 3.50 1.84
Scheme 3.28 Plan for Arrival at the A-Ring Using an Epoxidation Strategy
An analogous route was also constructed beginning with 3.34, the brominated analog of 3.47. The plan, as illustrated in Scheme 3.29, begins with epoxidation of 3.34 to give 3.51. It was hoped that the bromo epoxide 3.51
would undergo spontaneous oxidation to 3.49 upon treatment with MeOH and
PPTS or under even milder conditions. Following the steps outlined in Scheme
3.28, the target compound 1.84 in principle can be realized.
113 Br O 12 11 epoxidation Br MeOH MeO MeO 14 PPTS HO HO HO HO 3.34 3.51
O MeO O MeO HO HO as Scheme 3.28 HO 3.49 1.84
Scheme 3.29 A-Ring Completion via Epoxidation of the Brominated Analog
3.9.2 Epoxidation Exploration and Optimization
The first route to be explored began with 3.33, and the first task at hand was to optimize the epoxidation reaction as it had been occurring in only 21% yield and ~50% conversion of starting material. The first modification was the use of methyl(trifluoromethyl)dioxirane, described in the literature to react 1000
times faster than DMDO.60 Several variations in the equivalents of Oxone®,
NaHCO3, and trifluoroacetone were explored. In all cases, the yield of 3.47 was
just as low as with the original DMDO condition; however, the reaction occurred
much faster. Eventually, yields in the 50% range were realized when the
reaction mixture was made more dilute. One issue that had to be clarified was
the orientation of the epoxide resident in 3.47. As illustrated in Scheme 3.30, it
is possible that the epoxide may have undergone a Payne rearrangement to give
the C13-C14 oxirane. While it may seem to be a detriment to the route, a
strategy was developed to deal with this situation should it have occurred. In
114 fact, the strategy may very well be employed in the future if it proves to be
needed. Beginning with oxirane 3.47a, oxidation of the C12 hydroxyl group
followed by alkenyl triflate formation and methyl group installation would give rise
to 3.52. Opening of the methyl enol epoxide could be followed by deoxygenation
with SmI2 to arrive at 1.84.
HO 12 O 11 DMDO, NaHCO3, Payne MeO MeO MeO 14 acetone, 0 °C, 45% rearrangement? HO O HO HO HO HO 3.33 3.47 3.47a
1. oxidation 1. Epoxide opening 3.47a MeO 1.84 2. triflate formation 2. SmI reduction O 2 3. methylation HO 3.52
Scheme 3.30 Epoxidation of A-Ring with Possible Payne Rearrangement
In order to verify the presence of 3.47 or 3.47a, a significant amount of
NMR data was analyzed. The HMBC, COSY, and HMQC data acquired proved that it was the C12-C13 oxirane. In our systems, we quite often observe the coupling between the carbinol and hydroxyl protons in COSY spectra. This coupling provided the exact signal responsible for each of these two protons.
Using the HMBC data, it was possible to observe the correlations illustrated in
Figure 3.3.
115 OPMB H H O O MeO H H OTBS HO HO H HBzO O
Figure 3.3 HMBC Correlations Present in 3.47
With the location of the A-ring epoxide known, epoxidation of the bromine-
containing derivative 3.34 was attempted. No reaction was observed with
DMDO, and this result was attributed to either the steric constraints of the
bromine atom or the electronic deactivation of the double bond due to the
bromine. Again, recourse was made to the more reactive trifluorinated
derivative. In this event, a new compound was isolated and elucidating its
structure proved to be a challenge. It was then realized that epoxidation had not occurred. Instead, as illustrated in Scheme 3.31, oxidative cleavage of the PMB ether had occurred. The long-range correlations illustrated in Figure 3.4, along with additional spectral data, assisted in the determination of the product.131
116 O H C H
CO2Me H H O Br O MeO OTBS HO HO H BzO O
Figure 3.4 HMBC Correlations Present in 3.53-Z and 3.53-E
In addition, the initial major product of the ring cleavage was the Z-configured olefin 3.53-Z. However, upon standing at room temperature for one week, rearrangement occurred to give predominantly the E-configured olefin, 3.53-E.
The top 1H NMR spectrum in Figure 3.5, shows the aldehyde proton for 3.53-Z
as being more intense and downfield than that of 3.53-E, which can be seen
emerging from the baseline. In contrast, in the bottom 1H NMR spectrum, it can
be seen that the aldehyde proton of 3.53-E has now overtaken the downfield
proton of 3.53-Z in intensity. This interesting transformation will be investigated
further by other researchers in the Paquette group; however, it illustrates the
delicate and sometimes fickle reactivity profile inherent in this system.
117 F C O Br 3 O H3C O Br MeO X MeO
HO HO HO HO 3.34 3.51
instead... O O H C H C
CO2Me
O CO2Me O Br O Br O 20 °C MeO MeO OTBS 7 days OTBS HO HO HO H HO H BzO BzO O O 3.53-Z 3.53-E
Scheme 3.31 Interesting Reaction in lieu of Desired A-Ring Epoxidation
One area of concern in the routes above was the selectivity of oxidation of
C12 versus C14 once oxirane opening was achieved. To alleviate this potential problem, epoxidation of the diosphenols was examined before reduction of C14 had taken place. Interestingly, compounds 3.31 and 3.32 resisted epoxidation most likely due to the electronics present when C14 is a ketone. This meant that we would have to rely on internal selectivity present in the system, if any did exist. It was anticipated that the C12 hydroxyl group would be more available for oxidation instead of the C14 hydroxyl group. While C12 is obstructed by the gem-dimethyl bridge, C14 lies underneath the “taxane plane”. It was hoped that the significantly larger taxane ring system would prevent any oxidant from interacting with the C14 hydroxyl group.
118
PPM 9.880 9.870 9.860 9.850 9.840 9.830 9.820 9.810 9.800 9.790 9.780 9.770 9.760 9.750 9.740 9.730 9.720 9.710
Figure 3.5 1H NMR Spectrum of 3.53-Z (top) and 3.53-E (bottom)
3.9.3 Oxirane Opening and C12 Hydroxyl Group Oxidation
While the yield of epoxide formation was fairly low, epoxide opening to give 3.48 became the next task undertaken. It was expected that mild acidification of 3.47 with a gentle nucleophile such as MeOH would open the epoxide and provide the ketone in a single ring opening and hydrolysis event.
Initially, 3.47 was treated with CSA in MeOH at 0 °C. This condition proved to be too harsh and led to decomposition. Recourse was made to PPTS in MeOH, and instead of obtaining the C13 ketone, the dimethyl acetal was isolated, albeit, in
119 low (27%) yield as shown in Scheme 3.32. At this point, a few attempts have
been made to “soften” the conditions of the reaction with little success. An
attempt was made to bring about the oxirane opening using a much milder acid catalyst, namely silica gel, but no reaction was observed. In addition, temperature lowering seems to be an unusable strategy as well. At 0 °C, the reaction progresses very slowly, often taking several hours to observe 50% conversion. This prolonged reaction time may be what is, in fact, lowering the yield of the reaction.
PPTS, MeOH, HO TPAP, NMO, O 12 MeO 11 CH2Cl2, 0 °C CH2Cl2:MeCN (1:1) MeO 14 27% yield MeO 4 Å MS, rt HO HO 76% conversion HO HO 45% yield 3.47 3.48 42% conversion
O TfO MeO alkenyl MeO methyl group MeO triflate installation MeO MeO MeO HO HO HO formation HO HO HO 3.49 3.54 3.54
hydrolysis deoxygenation O O
HO HO HO 3.50 1.84
Scheme 3.32 Arrival at an A-Ring Precursor from 3.47
120 It was decided that while these steps are low yielding, additional forward transformations should be attempted. Should the forward progress continue, this would serve as a route worthy of optimization. If efforts are expended on optimization, it may result in significant effort exhausted towards a goal that will not pan out in the end. With the desired A-ring diol in hand, oxidation was first attempted using TPAP in CH2Cl2 with NMO·H2O as the oxidant. Again we were delighted to observe a new compound on the TLC plate. While conversion was again low (42%) and the yield was equally undesirable (45%), extensive analysis of the structural data confirmed that an oxidation did occur, and that it occurred selectively at C12. The long-range correlation data proved this as illustrated in
Figure 3.6.
OPMB O H O MeO H H MeO OTBS HO HO H HBzO O
Figure 3.6 HMBC Correlations Present in 3.49
The oxidation of C12 over C14 proved the selectivity that we were relying on in order to functionalize the northern sector over the southern sector. This now presents us with the opportunity to install an alkenyl triflate involving the
121 bridgehead and C12. Enolization of ketones to form bridgehead enolates in
taxanes have been used in previous syntheses and is the proposed method for
completion in our system as well. Scheme 3.32 above shows the final steps to
be pursued for A-ring completion. From 3.49, alkenyl triflate formation followed
by methyl group installation will provide 3.50, which can be hydrolyzed to give
1.84. Should any D-ring chemistry interfere with the ketone at C13 in 1.84, the
dimethyl acetal protecting group could be carried through the route and unmasked at a later time. However, since a completed A-ring with a C13 ketone
has been carried through in previous Taxol syntheses, this should not prove to
be a problem in our case either.
This sequence, should it provide 1.84, would represent the first de novo
synthesis of the Taxol A-ring while it exists in the taxane framework. While the
Taxusin synthesis installed the A-ring while resident in the taxane framework, it
was not complicated by the C1 hydroxyl group that provided formidable chemical
challenges along our route. This sequence would also involve only ten synthetic
transformations, making it a relatively rapid installation and removal of several
functional groups in a very confined space.
122
CHAPTER 4
CONCLUSION AND FUTURE WORK
4.1 Observations on the Chemistry of Diosphenols and Their Derivatives
While this cannot be considered an all encompassing review, the A-ring
chemistry applied to this system has definitely shed some light on the reactivity of diosphenols. As mentioned earlier, there is little information in the literature
dealing with reactions of these systems. This is quite surprising considering the
reactivity present in these masked α-diketones. Presented again in Figure 4.1 is
the reactivity profile that we have considered for our diosphenol intermediate.
OPMB OPMB OPMB O O O HO δ+ O O OTBS OTBS OTBS HO HO O H O HO O H BzO BzO H BzO O O O Electrophilic Nucleophilic Nucleophilic at C14 at C12 at enol OH
Figure 4.1 Reactivity Profile in Our Diosphenol Intermediate
123 4.1.1 Reactions Involving the Enol
In all the diosphenol systems encountered, the reactivity of enol oxygen proved to be consistent throughout. While it could be argued that the steric factors surrounding the only other hydroxyl group, the C1 hydroxyl, preclude it from participation in reactions, the fact that it can be functionalized using DMSCl when no options are available seem to make this point moot.
With deprotonation or an active reagent, the electrophilicity of C12 can be exploited. This was shown to be the case as the system could be selenated and brominated with relative ease. Once functionalization of C12 was achieved, further functionalization of C12 could not be realized; however, this might be due to the steric constraints present in this system; therefore, no conclusion can be made in that regard. The transformations in Figure 4.2 illustrate the enol and
C12 reactivity observed.
12 • Can be functionalized at enol OH (CH2N2, allyl iodide, Me2SiHCl) HO • C12 can be functionalized (py•HBr , PhSeCl) O HO 3 3.1
X • Can be functionalized at enol OH (CH2N2, allyl iodide, Me2SiHCl) HO • C12 cannot be functionalized further O HO X = Br, SePh
Figure 4.2 C12 and Enol Oxygen Reactivity in Diosphenols
124 The epoxidation reactions show a very interesting reactivity pattern as illustrated in Figure 4.3 below. In unfunctionalized diosphenols, it seems the ketone portion in the system plays an important role. Epoxidation of 3.31 could not be achieved using either DMDO or MTFMDO; however, when the ketone portion is reduced to give 3.33, epoxidation can be achieved using either reagent. It seems that the ketone is electron-withdrawing enough to prevent reactions involving the enol double bond. In the brominated cases, the incorporation of the bromine seems to be important as well. Epoxidation of the enol could not be achieved using either 3.32 or 3.34. While a steric argument can be employed here, it is possible that the bromine atom may be sufficiently electron-withdrawing to deactivate the system.
MeO MeO
O HO HO HO 3.31 3.33 no epoxidation observed epoxidation observed with DMDO or MTFMDO with DMDO or MTFMDO
Br Br
MeO MeO
O HO HO HO 3.32 3.34 no epoxidation observed no epoxidation observed with DMDO or MTFMDO with DMDO or MTFMDO
Figure 4.3 Epoxidation Reactions on Diosphenols
125 4.1.2 Reactions of the Ketone
The reactivity of the C14 ketone in our system again shows some
predictable patterns of behavior. As shown in Figure 4.4, reduction of the C14
ketone proceeded with more material conversion in the brominated case, 3.32,
than in the unfunctionalized example 3.31. In addition, deprotonation of the resulting free alcohol in 3.33 followed by xanthate formation could not be achieved. In 3.34, forcing conditions are required; however, xanthate formation is smooth and reliable. Again, this increased reactivity in 3.32 and 3.34 could be attributed to the electron withdrawing effect brought into the system by the bromine atom.
Br
MeO MeO
O HO O HO 3.31 3.32 C14 reduction possible C14 reduction proceeds with better conversion
Br
MeO MeO
HO HO HO HO 3.33 3.34 xanthate formation not possible xanthate formation smooth and reliable
Figure 4.4 Ketone Reactivity in Diosphenols
126 While the results of our diosphenol reactions provide a good lead to an overall pattern of diosphenol reactivity, it is important to keep in mind that this system in particular may be very sensitive to steric factors. These factors almost certainly affect the observations that have been made. However, the leads here could certainly serve as starting points for the exploration and further synthetic exploitation of this useful system.
4.2 Final Conclusions and Future Work
The route presented here is a very attractive route to numerous types of taxanes as well as Taxol itself. In twenty-two synthetic operations, a side chain has been synthesized and attached to a suitably prepared camphor-derived couping partner, and that product has been taken to our bridge migrated compound, 1.85, a compound that possesses the requisite synthetic handles for both A- and D-ring elaboration. With such a densely functionalized structure, it is equally amazing that out of the twenty-two total operations required to arrive at
1.85, only six are either a protection or deprotection step, and reduction of the total to five could be argued since the benzoyl protecting group is actually in the target. With a six-step D-ring installation secured and the potential for A-ring elaboration in only ten steps, this route is certainly in contention as the most efficient route to all manner of taxanes.
At the conclusion of this document, the project is at a thrilling point. Only a few more steps are needed to complete the A-ring of this challenging molecule.
However, the prospect that its completion will not be by the author is
127 disappointing. While its completion may require the hands of another researcher,
work to expedite and provide as much information to that person is and will be
carried out. Several tasks are slated for exploration and completion. First, the
epoxidation, oxirane opening, and C12 oxidation reactions will undergo
optimization so that the stockpile of material will not have to be expended by the
incoming colleague. Second, and most importantly, any opportunity to advance
the synthesis will be embraced. Progress on this molecule has always come
about in this manner, which is that when time is taken to perfect the route, efforts
are always focused forward. This will provide two important things to this project,
further information that can be used to complete the synthesis of Taxol and
additional steps to make that job easier. Taxol is well within the reach of the
Paquette group. It is certain that the work of future team members, when coupled to the work before and contained within this document will result in a truly amazing synthesis of one of Nature’s most amazing molecules.
128
CHAPTER 5
EXPERIMENTAL DETAILS
All reagents were used as shipped unless otherwise indicated. Benzene and toluene were distilled from sodium metal before use. Ether and THF were dried using sodium/benzophenone ketyl. Pyridine, Et3N, CH2Cl2, DMSO, and DMF
1 13 were dried by distillation from CaH2. H and C NMR data were acquired on
Bruker Avance or Aspect series spectrometers at the frequencies indicated using dueterated solvents as shipped from Cambridge Isotope Labs using the residual
H peak as a reference. IR data were acquired on a Perkin-Elmer 1600 series
FTIR. HRMS data were obtained either at the laboratory of Dr. Chris Hadad or at the Campus Chemical Instrumentation Center, both at The Ohio State University.
Optical rotation data were recorded on a Perkin-Elmer model 241 polarimeter.
129 (1S,4R)-10-camphorsulfonyl chloride (2.1)44,132-134
A dry roundbottomed flask was charged with SOCl2 (193 mL, 2.64
mol, 2.1 eq), CSA (290 g, 0.857 mol), and a magnetic stir bar. The
O mixture was stirred and heated to a vigorous reflux, which was SO2Cl maintained for 3 h. The heating mantle was removed and the reaction mixture was cooled to room temperature, poured over ice, and a brown precipitate formed immediately. The precipitate was filtered by vacuum and the solid dissolved in CH2Cl2 and transferred to a separatory funnel. The aqueous layer
was removed and the organic layer was dried over MgSO4. After removal of the
drying agent via filtration, the solvent and residual SOCl2 were removed under
reduced pressure. The resulting solid was placed under high vacuum overnight
to remove any residual solvent to yield 282 g (90%)of 2.1 as an off-white solid:
1 mp 67-68 °C; IR (neat, cm-1) 1740, 1370, 1170; H NMR (CDCl3, 300 MHz) δ
4.30 (d, J = 14.8 Hz, 1H), 3.72 (d, J = 14.8 Hz, 1H), 2.51-2.38 (m, 2H), 2.17-2.04
(m, 2H), 1.98 (d, J = 18.8 Hz, 1H), 1.81-1.72 (m, 1H), 1.52-1.44 (m, 1H), 1.13 (s,
13 3H), 0.92 (s, 3H); C NMR (CDCl3, 75 MHz) ppm 212.7, 64.2, 59.6, 48.1, 42.7,
42.2, 26.8, 25.2, 19.7, 19.6; MS m/z (relative intensity): 252 (M+2, 33% M), 250
(M, 2), 215 (M-Cl, 2), 151 (M-SO2Cl, 32), 123 (151-CO, 53), 109 (123-CH2, 93),
α 25 81 (100) ;[ ]D +32.1 (c 1.00, CHCl3).
130 (1S,4R)-7,7-dimethyl-1-vinyl-bicyclo[2.2.1]heptan-2-one (2.3)44,135
A 1000 mL Erlenmeyer flask containing 60 mL of 30% aqueous KOH
and 200 mL of anhydrous Et2O was cooled to 0 °C. To this solution
O was added N-nitrosomethylurea (20.6 g, 200 mmol, 1.4 eq) in
portions over a period of 20 min. Once the entire portion of nitroso compound
had dissolved, the ether layer was decanted into a 500 mL Erlenmeyer flask
containing a layer of KOH pellets, and the solution was placed in a freezer to dry
for 15 min. While the CH2N2 solution was cooled in the freezer, a 1000 mL three-
necked round bottom flask was fitted with a reflux condenser containing a KOH
drying tube and a magnetic stir bar. To the flask was added Et3N (20.0 mL, 144 mmol, 1.0 eq), and the flask was cooled to 0 °C. The previously prepared solution of CH2N2 in Et2O (~200 mL) was poured into the flask via a plastic
funnel. A solution of 2.1 in 200 mL of Et2O (36.0 g, 104 mmol) was added in ~25
mL portions waiting sufficient time between additions to allow N2 evolution to cease. Once all of the sulfonyl chloride had been added, the reaction mixture was stirred for an additional 10 min at 0 °C. The ice bath was removed and the flask was warmed to room temperature to allow excess CH2N2 to evaporate. The
+ - solid Et3NH Cl was removed by vacuum filtration through a plug of diatomaceous earth and rinsed with Et2O. The filtrate was concentrated under
reduced pressure to yield a thick orange oil. Pyrolysis of the intermediate
episulfone was achieved upon further warming to 60 to 70 °C on a rotary
evaporator. The crude β,γ-unsaturated ketone was purified by column
chromatography on silica gel (10:1 hexanes:EtOAc) to yield 11.9 g (50%) of 2.3
131 44 -1 as a waxy solid: m.p. 62-64 °C (lit 64-65 °C); IR (nujol, cm ) νmax 1747, 1640;
1 H NMR (250 MHz, CDCl3,) δ 5.76 (dd, J = 17.6, 11.1 Hz 1H), 5.33 (dd, J = 11.1,
1.7 Hz, 1H), 5.16 (dd, J = 17.6, 1.7 Hz, 1H), 2.40 (ddd, J = 18.3, 4.6, 2.2 Hz, 1H),
2.11-1.81 (m, 4H), 1.48-1.32 (m, 2H), 0.88 (s, 3H), 0.87 (s, 3H); 13C NMR (62
MHz, CDCl3,) ppm 217.1, 131 .9, 118.8, 63.9, 48.3, 43.4, 43.2, 26.7, 25.7, 19.9,
α 21 19.1; [ ]D .+16.4 (c 2.15, MeOH).
(1S,3R,4S)-3-hydroxy-7,7-dimethyl-1-vinylbicyclo[2.2.1]heptan-2-one (2.4)50
To a dry 1000 mL roundbottomed flask containing i-Pr2NH (20 mL, OH 141 mmol, 1.1 eq) in 500 mL of THF at 0 °C was added n-BuLi (88
O mL of a 1.6 M solution in hexanes, 140 mmol). The LDA solution
was stirred for 30 min at 0 °C and cooled to -78 °C. A solution of 2.3 (20 g, 121
mmol) in 100 mL of THF was added in one portion and stirred at -78 °C for 1 h.
The resulting enolate was quenched with TMSCl (10 mL, 159 mmol, 1.3 eq) and
stirred for 1.5 h at -78 °C at which point 20 mL of Et3N was added and the
reaction mixture was warmed to room temperature and concentrated under
reduced pressure. The resulting yellow oil was dissolved in ~200 mL of hexanes
and transferred to a separatory funnel. The organic layer was washed with a
saturated NaHCO3 solution and brine, dried over Na2SO4, filtered to remove
drying agent, and concentrated under reduced pressure to yield the silyl enol
ether as a yellow oil, which was used immediately or the next morning if stored in
a freezer overnight. The previously prepared silyl enol ether was dissolved in
800 mL of acetone in a 3000 mL Morton flask fitted with an addition funnel and a 132 mechanical overhead stirrer. To the solution was added NaHCO3 (104 g, 1.22
mmol, 10 eq), and the mixture was cooled to 0 °C with stirring. A solution of
® Oxone (228 g, 366 mmol, 3 eq) in 600 mL of H2O was added via addition funnel
over a period of 30 min. The mixture was stirred for 1 h and rapidly transferred to
a separatory funnel while still cold. The aqueous layer was quickly extracted with
EtOAc (3 x 200 mL) and the combined organic fractions were passed through a
plug of silica to remove excess DMDO in order to prevent epoxidation of the
olefin. The filtrate was transferred to a 2000 mL roundbottomed flask fitted with a
magnetic stir bar. The solution was treated with TBAF (20 Ml of a 1.0 M solution
in THF, 20 mmol. 0.16 eq) and the solution was stirred overnight. The solvent
was removed under reduced pressure and the crude hydroxy ketone was purified
by column chromatography on silica gel (5:1 hexanes:EtOAc) to yield 12.8 g
-1 (70%) of 2.4 as a viscous yellow oil: IR (CCl4, cm ) 3460, 3085, 1751, 1641,
1480, 1470, 1454, 1393, 1373, 1310, 1133, 1110, 1086, 1045, 994, 968, 920; 1H
NMR (300 MHz, C6D6) δ 5.90 (dd, J = 17.7, 11.2 Hz, 1H), 5.25 (dd, J = 11.2, 1.7
Hz, 1H), 5.14 (dd J = 17.7, 1.7 Hz, 1H), 3.55 (s, 1H), 3.45 (br s, 1H [OH]), 1.91
(d, J = 4.7 Hz, 1H), 1.57 (m, 2H), 1.25-1.08 (m, 1H), 1.11 (s, 3H), 0.93 (m, 1H),
13 0.63 (s, 3H); C NMR (75 MHz, CDCl3) ppm 217.5, 132.5, 118.5, 77.8, 63.2,
50.0, 48.6, 25.0 (2C), 21.6, 20.3; EI MS mlz (M+) calcd 180.1150, obsd 180.1154.
Anal. Calcd for C11H16O2: C, 73.30; H, 8.95. Found: C, 73.03; H, 8.94;
133 (1S,3R,4S)-3-(4-methoxybenzyloxy)-7,7-dimethyl-1-vinylbicyclo[2.2.1]heptan-2-one
(1.90)52
A solution of 2.4 (29.1 g, 161 mmol) and p- OPMB methoxybenzytrichloroacetimidate (91.0 g, 323 mmol, 2 eq) in
O 500 mL of dry CH2Cl2 was cooled with stirring to 0 °C in a 1000
mL roundbottomed flask. To this solution was added CSA (3.8 g, 16.1 mmol, 0.1
eq) and the mixture was allowed to warm to room temperature overnight. The
reaction mixture was quenched with a saturated NaHCO3 solution and
transferred to a separatory funnel. The aqueous layer was extracted with 3 x 100
mL of CH2Cl2, and the combined organic extracts were washed with water and
brine, dried over MgSO4, and freed of solvent under reduced pressure. The
resulting product was purified by column chromatography on silica gel (10:1
hexanes:EtOAc) to yield 46.3 g of 1.90 (96%) as a viscous yellow oil: IR (neat,
-1 1 cm ) 1760, 1620, 1520; H NMR (300 MHz, CDCl3) δ 7.29 (d, J = 10.5 Hz, 2H),
7.26 (d, J = 10.6 Hz, 2H), 5.87 (dd, J = 17.7, 11.1 Hz, 1H), 5.39 (dd, J = 11.1, 1.6
Hz, 1H), 5.23 (dd, J = 17.1, 1.6 Hz, 1H), 4.80 (d, J = 11.5 Hz, 1H), 4.62 (d, J =
11.5 Hz, 1H), 3.79 (s, 3H), 3.50 (s, 1H), 2.14 (d, J = 4.2 Hz, 1H), 2.00 (m, 2H),
13 1.46 (m, 2H), 1.13 (s, 3H), 0.90 (s, 3H); C NMR (75 MHz, CDCl3) ppm 216.1,
159.2, 131.8, 130.1, 129.3, 119.0, 113.7, 83.2, 72.4, 63.5, 55.2, 48.4, 48.2, 25.1,
+ α 25 24.7, 21.4, 20.1; MS m/z (M ) calcd 300.1725, obsd 300.1772; [ ]D -78.8 (c 2.1,
CHCl3). Anal. Calcd for C19H24O3: C, 75.97; H, 8.05. Found: C, 75.94; H, 8.10.
134 t-butyl 4-bromopent-4-enoate (2.5)64,136
Br A solution of i-Pr2NH (15.4 mL, 110 mmol, 1.1 eq) in 100 mL of Ot-Bu THF was cooled to 0 ° C and to this solution was added n-BuLi O (67 mL of a 1.42 M solution in hexanes, 1.0 eq). The base was allowed to form
for 1 h at 0 °C, and the mixture was cooled to -78 °C. A solution of t-BuOAc
(13.5 mL, 100 mmol, 1.0 eq) in 50 mL of THF was added and the reaction was
stirred at -78 °C for 1 h. To the reaction was added 2,3-dibromopropene (13.0
mL of tech (80%) grade reagent, 100 mmol, 1.0 eq), and the reaction was stirred for an additional 2 h at -78 °C. The reaction flask was taken out of the cold bath and placed on a rotary evaporator, and solvent and volatiles were removed under
reduced pressure. The remaining liquid was transferred to a separatory funnel,
diluted with 200 mL of H2O, and extracted with EtOAc. The combined organic
extracts were washed with brine, dried over MgSO4, filtered, and freed of solvent under reduced pressure. The resulting oil was transferred to a distillation pot and
placed under high vacuum at room temperature for 1 h to remove traces of
solvent. The product was distilled from the residue to yield 15.7 g (67%) of 2.5
as a clear liquid: b.p. 70 °C at 0.75 mmHg (lit137 b.p. 45.5-47.5 °C at 0.09 mmHg;
IR (neat, cm-1) 3010, 1730, 1630, 1160; 1H NMR (200 MHz, CDCl3) δ 5.59 (d, J =
1.2 Hz, 1H), 5.38 (d, J = 1.2 Hz, 1H), 2.67 (t, J = 7.5 Hz, 2H), 2.43 (t, J = 7.5 Hz,
13 2H), 1.40 (s, 9H); C NMR (CDCl3) ppm 170.8, 132.5, 117.1, 80.4, 36.8, 34.1,
+ 28.0; MS m/z: 221-219 (M -CH3), 180-178, 163-161, 135-133, 99.
135 1-t-butyldimethylsiloxy-4-bromo-4-pentene (2.6)12,56,57
A solution of 2.5 (16.7 g, 70.9 mmol) in 30 mL of dry Et2O Br OTBS was added dropwise to a slurry of LiAlH4 (2.96 g, 78.0 mmol,
1.1 eq) in 100 mL of dry Et2O so that a gentle reflux was maintained. The
reaction mixture was stirred for 3 h and carefully quenched with a solution of 3
mL of 1 M NaOH and 9 mL of water (1 mL of 1 M NaOH and 3 mL of H2O per
gram of LiAlH4 used). The solution was stirred until it appeared white in color.
The precipitated material was filtered, the filtrate was concentrated under
reduced pressure and the resulting oil was placed under high vacuum for 15 min.
The residue was dissolved in 100 mL of dry CH2Cl2. To the solution was added
dry Et3N (9.8 mL, 70.9 mmol, 1.0 eq), DBU (2.1 mL, 14.2 mmol, 0.2 eq), and
TBSCl (11.8 g, 78.0 mmol, 1.1 eq). The reaction mixture was stirred overnight,
diluted with CH2Cl2 (100 mL), and transferred to a separatory funnel. The
organic layer was washed with 1 M HCl, a saturated aqueous solution of
NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, and freed
of solvent under reduced pressure. The residue was purified by column
chromatography on silica gel (2% EtOAc in hexanes) to give 16.17 g (82%) of 2.6 as a clear oil: IR (neat, cm-1) 2955, 2929, 2858, 1256, 1206, 1104, 836; 1H NMR
(300 MHz, CDCl3) δ 5.57 (s, 1H), 5.40 (s, 1H), 3.64 (t, J = 6.1 Hz, 2H), 2.52 (t, J =
7.2 Hz, 2H), 1.75 (tt, J = 7.2, 6.1 Hz, 2H), 0.90 (s, 9H), 0.05 (s, 6H); 13C NMR (75
MHz, CDCl3) ppm 140.5, 128.2, 62.6, 31.0, 26.1 (3C), 24.5, 18.7, -5.1 (2C); EI
HRMS m/z (M+) calcd 278.0701 obsd 278.0672, (M+H)+ calcd 277.0623, obsd
277.0618.
136 5-(t-butyldimethylsilyloxy)-2-methylenepentanal (2.7)12,56,57
O A solution of 2.6 (10.0 g, 35.8 mmol, 1.0 eq) in 300 mL of
H OTBS THF was cooled to -78 ˚C and to the solution was added t-
BuLi (54 mL of a 1.42 M solution in pentane, 76.1 mmol, 2 eq) in one portion.
The resulting mixture was stirred for 30 min and neat dry DMF (27.7 mL, 358
mmol, 10 eq) was added at a rate of 0.5 mL/min. The reaction mixture was
stirred for 3 h at -78 °C and quenched by the addition of 200 mL of a saturated
aqueous NH4Cl solution. The aqueous layer was extracted with ether (3 × 200
mL), and the combined organic extracts were washed with water and brine, dried
over MgSO4, and filtered to remove drying agent. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (10:1 hexanes:EtOAc) to give 8.18 g (70%) of 2.7 as a yellow oil: 1H
NMR (300 MHz, CDCl3) δ 9.51 (s, 1H), 5.57 (s, 1H), 5.40 (s, 1H), 3.64 (t, J = 6.1
Hz, 2H), 2.52 (t, J = 7.2 Hz, 2H), 1.75 (tt, J = 7.2, 6.1 Hz, 2H), 0.90 (s, 9H), 0.05
13 (s, 6H); C NMR (75 MHz, CDCl3) ppm 194.8, 140.5, 128.2, 62.6, 31.0, 26.1
(3C), 24.5, 18.7, -5.1 (2C).
(Z)-1-iodo-3-methylene-6-t-butyldimethylsiloxy-1-hexene (1.91)12,56,57
+ - I A suspension of Ph3P CH2I I (9.00 g, 17.1 mmol, 1.3 eq) in 50
OTBS mL of THF was cooled to 0 °C and to the suspension was added NaHMDS (21.6 mL of 0.79 M solution in THF, 17.1 mmol, 1.3 eq), and the ylide was stirred at 0 °C for 1 h. The solution was cooled to -78 °C and a solution
of 2.6 (3.00 g, 13.1 mmol) in 20 mL of THF was added via cannula. The reaction
137 mixture was stirred for 3 h, warmed to -30 °C, and quenched by the addition of a
saturated NH4Cl solution. The reaction mixture was transferred to a separatory
funnel, extracted with ether (3 x 50 mL), and washed with brine. The organic
extracts were dried over MgSO4, filtered, and concentrated under reduced
pressure. The resulting oil was purified by column chromatography on silica gel
(1% EtOAc in hexanes) to yield 4.08 g (88%) of 1.91 as a yellow oil, which was either used immediately or dissolved in benzene and frozen in a commercial
1 freezer for use the next day: H NMR (300 MHz, C6D6) δ 6.58 (d, J = 8.5 Hz,
1H), 6.26 (d, J = 8.5 Hz, 1H), 5.19 (s, 1H), 5.05 (s, 1H), 3.53 (t, J = 7.8 Hz, 2H),
2.19 (t, J = 7.8 Hz, 2H), 1.55-1.71 (m, 2H), 0.80 (s, 9H), 0.00 (s, 6H). Additional
spectral data not obtained as the species was too fleeting.
(1S,2S,3R,4S,Z)-2-(6-(t-butyldimethylsilyloxy)-3-methylenehexen-1-yl)-3-(4-
methoxybenzyloxy)-7,7-dimethyl-1-vinylbicyclo[2.2.1]heptan-2-ol
(1.89)12,56,57
To a solution of 1.90 (13.3 g, 44 mmol) and 1.91 (15.6 g, OPMB ° OH 44 mmol) in 500 mL of dry Et2O at -78 C was added t-
BuLi (60 mL of a 1.5 M solution in pentane, 88 mmol, 2
eq). The reaction mixture was stirred for 30 min, OTBS
quenched by the addition of saturated aqueous NH4Cl and transferred to a
separatory funnel. The aqueous layer was extracted with Et2O (3 x 150 mL), and
the combined organic extracts were washed with brine, dried over MgSO4,
filtered to remove drying agent, and concentrated under reduced pressure. The
138 resulting oil was purified by column chromatography on silica gel (30:1
hexanes:EtOAc) to yield 15.2 g (65%) of 1.89 as a yellow oil: IR (neat, cm-1)
3511, 2935, 2852, 1608, 1507, 1457, 1248, 1169, 1095, 1060, 1000, 827, 770;
1 H NMR (300 MHz, C6D6) δ 7.23 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H),
6.55 (dd, J = 17.8, 11.0 Hz, 1H), 5.80 (d, J = 12.6 Hz, 1H), 5.68 (d, J = 12.6 Hz,
1H), 5.35 (dd, J = 11.0, 2.2 Hz, 1H), 5.18 (s, 1H), 5.09 (dd, J = 17.8, 2.2 Hz, 1H),
4.96 (s, 1H), 4.38 (dd, J = 18.6, 10.8 Hz, 2H), 3.67 (s, 1H), 3.58 (t, J = 6.3 Hz,
2H), 3.52 (s, 1H), 3.33 (s, 3H), 2.26 (t, J = 9.6 Hz, 2H), 1.92 (d, J = 4.6 Hz, 1H),
1.78-1.60 (m, 3H), 1.58 (s, 3H), 1.48-1.44 (m, 1H), 0.99 (s, 9H), 0.96-0.91 (m,
13 2H), 0.84 (s, 3H), 0.07 (s, 6H); C NMR (75 MHz, C6D6) ppm 160.1, 146.9,
137.1, 136.1, 131.3, 130.3, 129.8 (2C), 117.3, 114.6 (2C), 114.0, 88.4, 83.2,
71.7, 63.3, 60.5, 55.2, 50.6, 49.1, 34.5, 32.1, 26.5, 26.0, 24.7, 23.2, 22.9, 18.9
(3C), -4.8 (2C); EI HRMS m/z (M+) calcd 526.3478, obsd 526.3455; (M+H)+ calcd
α 22 527.3556, obsd 527.3517; [ ]D -105.4 (c 1.06, CHCl3).
(2R,4R,5S,E)-5-(5-(t-butyldimethylsilyloxy)pent-1-en-2-yl)-2-(4-
methoxybenzyloxy)-4,11,11-trimethylbicyclo[6.2.1]undec-7-en-3-one
(1.88)12,56,57
A dry 1000 mL roundbottomed flask containing 18- OPMB O crown-6/CH3CN complex (26.6 g, 101 mmol, 3.5 eq) H OTBS was placed under high vacuum overnight with stirring. H
The flask was flushed with N2 and a solution
containing 1.89 (15.2 g, 28.8 mmol) in 600 mL of dry THF was added. The
139 solution was cooled to -78 °C, treated with KHMDS (210 mL of a 0.41 M solution
in toluene, 86.4 mmol, 3 eq), warmed to -40 °C for 30 min, and cooled to -78 °C.
A solution containing dry MeI (18 mL, 288 mmol, 10 eq) in 180 mL of dry THF
was added and the solution was stirred at -78 °C for 3 h. The reaction mixture
was quenched with brine and the aqueous layer was extracted with ether (3 ×
250 mL). The combined organic layers were dried over MgSO4, filtered, and freed of solvent under reduced pressure. The residue was purified by column chromatography on silica gel (2% EtOAc in hexanes) to give 11.6 g of 1.88 (74%) as a cloudy yellow oil: IR (neat, cm-1) 3076, 2954, 2856, 1710, 1613, 1514,
1470, 1390, 1302, 1249, 1172, 1104, 1039, 1006, 893, 776, 712; 1H NMR (300
MHz, CDCl3) δ 7.22 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 5.32 (dd, J =
11.7, 4.6 Hz, 1H), 4.92 (s, 1H), 4.87 (s, 1H), 4.52 (d, J = 12.0 Hz, 1H), 4.01 (d, J
= 12.0 Hz, 1H), 3.79 (s, 3H), 3.68 (dd, J = 6.5, 3.8 Hz, 2H), 3.61 (d, J = 1.6 Hz,
1H), 2.72 (dd, J = 8.2, 3.6 Hz, 1H), 2.70-2.10 (m, 8H), 1.85-1.65 (m, 2H), 1.61-
1.45 (m, 2H), 1.22 (s, 3H), 1.06 (s, 3H), 1.03 (d, J = 7.2 Hz, 3H), 0.91 (s, 9H),
13 0.07 (s, 6H); C NMR (75 MHz, CDCl3) ppm 212.0, 159.2, 150.8, 148.4, 130.9,
129.2 (2C), 122.9, 113.9 (2C), 111.9, 89.8, 71.2, 63.6, 55.5, 54.9, 53.3, 45.9,
45.7, 32.2, 30.5, 30.4, 26.8, 26.3, 26.2 (3C), 26.1, 23.8, 20.5, 18.6, -5.0 (2C);
FAB LRMS m/z (M+) calcd 540.36, obsd 540.36; (M+H)+ calcd 541.37, obsd
α 22 541.38; [ ]D -21.2 (c 1.68, CHCl3).
140 (1S,2R,4R,5S,7S,8S)-5-(5-(t-butyldimethylsilyloxy)pent-1-en-2-yl)-7,8-
dihydroxy-2-(4-methoxybenzyloxy)-4,11,11-trimethylbicyclo[6.2.1]undecan-
3-one (2.9)12,56,57
A portion of 1.88 (5.00 g, 9.24 mmol) was dissolved in OPMB O 300 mL of a vigorously stirred 10:1 acetone:H2O OTBS HO solution. To the solution was added NMO (1.10 g, HO H
9.24 mmol), MeSO2NH2 (2.64 g, 27.7 mmol, 3 eq), and solid OsO4 (900 mg, 3.70 mmol, 0.4 eq) sequentially. The reaction mixture was
stirred for 15 min at room temperature and cooled to 0 °C. Once cooled,
gaseous H2S, generated from the action of conc. HCl on FeS, was bubbled
through the solution until the osmate ester was no longer visible on TLC (heavy
dark circle at baseline of TLC plate). The solution was filtered through a plug of
diatomaceous earth, diluted with 100 mL of H2O and transferred to a separatory
funnel. The aqueous layer was extracted with 3 x 200 mL portions of EtOAc, and
the combined organic extracts were washed with brine, dried over MgSO4,
filtered to remove drying agent, and concentrated under reduced pressure. The
crude oil was purified by column chromatography on silica gel (4:1
hexanes:EtOAc) to yield 1.1 g of recovered 1.88 (78% conversion) and 2.33 g of
2.9 (64% based on recovered 1.88) as a yellow-brown oil: IR (neat, cm-1) 3416,
2935, 2857, 1700. 1612, 1514, 1378, 1303, 1251, 1211, 1173, 1097, 1030, 1013,
1 910, 836, 776, 733; H NMR (300 MHz, CDCl3) δ 7.22 (d, J = 8.6 H, 2H), 6.85 (d,
J = 8.6 Hz, 2H), 4.98 (s, 1H), 4.91 (s, 1H), 4.45 (d, J = 11.5, 1H), 4.09 (d, J =
11.5 Hz, 1H), 3.88 (s, 1H), 3.79 (s, 3H), 3.65 -3.57 (m, 3H), 3.35 (s, 1H), 2.89 (s,
141 1H), 2.76-2.70 (m, 1H), 2.68-2.35 (m, 3H), 2.14-2.01 (m, 3H), 1.95-1.80 (m, 3H),
1.70-1.56 (m, 3H), 1.09 (s, 3H), 1.04 (s, 3H), 1.00 (d, J = 6.7 Hz, 3H), 0.89 (s,
13 9H), 0.05 (s, 6H); C NMR (75 MHz, CDCl3) ppm 213.1, 159.4, 149.4, 130.2,
129.4 (2C), 113.9 (2C), 111.9, 90.6, 83.1, 71.2, 69.3, 62.6, 56.4, 55.4, 50.2, 48.4,
37.0, 34.9, 32.8, 32.0, 31.7, 30.1, 28.6, 26.2 (3C), 18.5, 17.0, 9.7, -5.1 (2C ); FAB
+ α 22 LRMS m/z (M+H) calcd 575.38, obsd 575.35; [ ]D +175.7 (c 0.94, CHCl3).
Carbonate 2.10 & Aldehyde 1.8712,56,57
OPMB To a solution of 2.9 (4.66 g, 8.11 mmol) in 500 mL of O
R CH2Cl2 at -78 °C was added pyridine (7.0 mL, 81.1 mmol, O O H 10 eq) followed by phosgene (21 mL of a 1.93 M solution O 2.10 R = OTBS in toluene, 40.5 mmol, 5 eq), and the reaction mixture was 1.87 R = (=O) stirred at -78 °C for 30 min. The reaction mixture was quenched with 200 mL of
H2O and warmed to room temperature. The aqueous layer was extracted with 3
x 100 mL of CH2Cl2, and the organic fractions were combined, washed with
brine, dried over MgSO4, filtered, and concentrated under reduced pressure.
The resulting crude 2.10 was placed under high vacuum for 1 h to remove residual solvent, dissolved in 300 mL of both MeOH and CH2Cl2, and cooled to 0
°C. To the solution was added CSA (1.88 g, 8.11 mmol) and the reaction mixture
was stirred for 1 h at 0 °C, quenched with 200 mL of H2O, and transferred to a
separatory funnel. The aqueous layer was extracted with 3 x 100 mL of CH2Cl2,
and the combined organic extracts were washed with brine and dried over
MgSO4. The drying agent was removed by filtration, and the product was freed
142 of solvent under reduced pressure. The crude alcohol was placed under high
vacuum overnight to remove traces of solvent. In a separate vessel, a solution of
(COCl)2 (2.8 mL, 32.4 mmol, 4 eq) in 100 mL of dry CH2Cl2 was cooled to -78 °C
and to this flask was added a solution of dry DMSO (4.6 mL, 4.9 mmol, 8 eq) in
100 mL of dry CH2Cl2, and the mixture was stirred at -78 °C for 10 min. A
solution of the crude alcohol in 100 mL of dry CH2Cl2 was added via cannula and
the reaction mixture was stirred for 1 h. Neat Et3N (11 mL, 81.1 mmol, 10 eq)
was added, and the solution was stirred for 20 min at -78 °C, warmed to room temperature over 1 h, quenched with 100 mL of H2O, and transferred to a
separatory funnel. The aqueous layer was extracted with CH2Cl2, and the
combined organic fractions were washed with brine, dried over MgSO4, filtered to
remove drying agent, and concentrated under reduced pressure. The oil thus
obtained was purified by column chromatography on silica gel (4:1 to 2:1
hexanes:EtOAc) to yield 3.93 g of 1.87 (81% for three steps) as a colorless oil.
For 2.10: IR (neat, cm-1) 2960, 2945, 2860, 1805, 1704, 1611, 1510, 1462, 1245,
1 1195, 1063, 835, 760; H NMR (300 MHz, CDCl3) δ 7.21 (d, J = 8.7 Hz, 2H), 6.86
(d, J = 8.7 Hz, 2H), 5.04 (s, 1H), 4.88 (s, 1H), 4.46 (dd, J = 12.5, 3.5 Hz, 1H),
4.38 (d, J = 11.3 Hz, 1H), 4.06 (d, J = 11.3 Hz, 1H), 3.93 (s, 1H), 3.79 (s, 3H),
3.66-3.57 (m, 2H), 2.69-2.57 (m, 3H), 2.34 (dd, J = 6.7, 1.9 Hz, 1H), 2.26-2.00
(m, 5H), 1.85-1.56 (m, 5H), 1.17 (s, 6H), 1.01 (d, J = 6.7 Hz, 3H), 0.90 (s, 9H),
13 0.05 (s, 6H); C NMR (75 MHz, CDCl3) ppm 212.4, 159.4, 152.9, 148.1, 129.4
(3C), 113.8 (2C), 112.1, 93.8, 89.5, 76.8, 70.9, 62.1, 55.2, 54.5, 49.2, 48.8, 34.9,
31.7, 31.6, 31.4, 29.3, 28.5, 27.9, 25.9 (3C), 18.3, 15.9, 8.3, -5.3 (2C); FAB
143 LRMS m/z (M+) calcd 600.35, obsd 600.28; (M+H)+ calcd 601.35, obsd 601.27;
α 22 [ ]D +28.2 (c 3.2, CHCl3).
For intermediate alcohol: IR (neat, cm-1) 3520, 2938, 1797, 1700, 1611, 1509,
1 1462, 1392, 1245, 1194, 1058, 907, 829, 768, 730; H NMR (300 MHz, C6D6) δ
7.19 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.04 (s, 1H), 4.87 (s, 1H), 4.43
(dd, J = 9.0, 3.9 Hz, 1H), 4.42 (d, J = 11.5 Hz, 1H), 4.09 (d, J = 11.5 Hz, 1H),
3.91 (s, 1H), 3.79 (s, 3H), 3.63 (dt, J = 6.1, 1.7 Hz, 2H), 2.67-2.55 (m, 3H), 2.33-
1.92 (m, 5H), 1.84-1.55 (m, 5H), 1.16 (s, 6H), 0.99 (d, J = 6.7 Hz, 3H), OH not
13 present; C NMR (75 MHz, CDCl3) ppm 212.6, 159.6, 153.2, 148.3, 129.9 (2C),
129.5, 114.1 (2C), 112.3, 94.1, 89.0, 77.0, 71.0, 62.2, 55.5, 54.6, 49.4, 48.9,
35.2, 31.9, 31.6, 31.4, 29.6, 28.6, 28.2, 16.1, 8.5; EI HRMS m/z (M+) calcd
+ α 22 486.2617, obsd 486.2617; (M+H) calcd 487.2695, obsd 487.2707; [ ]D +40.8 (c
2.7, CHCl3)
For 1.87: IR (neat, cm-1) 2980, 2940, 1801, 1721, 1705, 1612, 1509, 1465, 1396,
1 1360, 1247, 1193, 1061, 1030, 820, 752; H NMR (300 MHz, CDCl3) δ 9.80 (s,
1H), 7.21 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.01 (s, 1H), 4.94 (s, 1H),
4.45 (dd, J = 12.3, 3.4 Hz, 1H), 4.42 (d, J = 11.5 Hz, 1H), 4.11 (d, J = 11.6 Hz,
1H), 3.95 (s, 1H), 3.81 (s, 3H), 2.69-2.62 (m, 4H), 2.36-2.14 (m, 6H), 1.82-1.77
(m, 2H), 1.65-1.55 (m, 1H), 1.19 (s, 6H), 1.01 (d, J = 6.7 Hz, 3H); 13C NMR (75
MHz, CDCl3) ppm 212.4, 200.8, 159.7, 153.1, 147.2, 129.8 (2C), 129.5, 114.1
(2C), 112.3, 94.0, 89.2, 76.9, 71.1, 55.5, 54.6, 49.5, 48.8, 42.5, 36.3, 31.6, 29.6,
28.7, 28.3, 27.2, 16.1, 8.7; EI HRMS m/z (M+) calcd 484.2461, obsd 484.2452;
α 22 [ ]D +40.0 (c 0.6, CHCl3).
144 Tricycles 2.11 & 2.1212,56,57
OPMB OPMB A solution of 1.87 (3.0 g, 6.20 mmol) in O OH OH OH 100 mL of MeOH and 20 mL of THF was + HO HO treated with NaOH (62 mL of an HO H O H 2.11 2.12 aqueous 0.5 M solution, 30.9 mmol. 5
eq), and stirred at room temperature overnight. The reaction was quenched with a saturated NH4Cl solution and transferred to a separatory funnel. The aqueous
layer was extracted with 3 x 500 mL of benzene, and the organic fractions were
dried over MgSO4 and filtered to remove drying agent. Care must be taken so
that the concentration in benzene is 4 mM in benzene with respect to starting
1.87. The total volume of benzene and crude aldol product were stirred at room
temperature, treated with KOt-Bu (730 mg, 6.51 mmol, 1.05 eq), and the reaction
is monitored by TLC until complete (~30 min), quenched with a pH 8 buffer of
NH4Cl/NH4OH, and stirred for 10 min. The aqueous layer was removed from the
reaction vessel via a pipette and MgSO4 was added portion wise and stirred in
the flask until the solution was dry. The drying agent was removed by filtration
and solvent was removed under reduced pressure to give 5.51 g (97%) of 2.12
as a white foam.
For 2.11: mp 155-156 ˚C; IR (neat, cm-1) 3431, 2938, 1691, 1642, 1612, 1549,
1 1513, 1462, 1248, 1093, 1031, 822, 756; H NMR (300 MHz, CDCl3) δ 7.29 (d, J
= 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.99 (s, 1H), 4.86 (s, 1H), 4.51 (d, J =
12.1 Hz, 1H), 4.41 (d, J = 2.9, 1H), 4.18-4.11 (m, 2H), 3.85-3.83 (m, 1H), 3.80 (s,
3H), 3.14 (s, 1H), 2.77-2.65 (m, 3H), 2.54-2.40 (m, 2H), 2.20-1.37 (m, 9H), 1.08
145 13 (s, 6H), 1.00 (s, 3H); C NMR (75 MHz, CDCl3) ppm 213.4, 159.1, 145.9, 131.5,
129.0 (2C), 113.9 (2C), 111.1, 86.1, 83.6, 75.8, 71.1, 69.4, 59.6, 56.4, 55.5, 49.4,
38.6, 34.5, 33.8, 32.4, 32.2, 29.9, 26.2, 17.3, 9.8; ES HRMS m/z (M+Na)+ calcd
α 22 481.2566, obsd 481.2572; [ ]D -153.7 (c 0.35, CHCl3).
For 2.12: mp 158-160 ˚C; IR (neat, cm-1) 3406, 2943, 1681, 1644, 1613, 1514,
1462, 1396, 1303, 1250, 1174, 1089, 1035, 994, 898, 823, 756; 1H NMR (300
MHz, CDCl3) δ 7.23 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 4.97 (s, 1H),
4.89 (s, 1H), 4.67 (d, J = 10.7 Hz, 1H), 4.63 (s, 1H), 4.43 (d, J = 10.9 Hz, 1H),
4.39 (s, 1H), 4.03 (dd, J = 11.1, 4.5 Hz, 1H), 3.80 (s, 3H), 3.75 (dd, J = 9.5, 1.8
Hz, 1H), 3.54 (d, J = 9.1 Hz, 1H), 3.08 (s, 1H), 2.93-2.86 (m, 1H), 2.77-2.60 (m,
3H), 2.58-2.45 (m, 1H), 2.41-2.34 (m, 1H), 2.24-1.99 (m, 3H), 1.88-1.82 (m, 1H),
1.80-1.65 (m, 1H), 1.60-1.46 (m, 1H), 1.14 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H); 13C
NMR (75 MHz, CDCl3) ppm 217.2, 159.8, 146.8, 129.8 (2C), 129.1, 114.3 (2C),
110.1, 87.7, 83.0, 77.6, 73.7, 73.6, 55.5, 50.3, 48.9, 44.7, 44.2, 39.7, 34.4, 31.4,
31.0, 30.4, 25.8, 19.3, 12.5; EI HRMS m/z (M+H)+ calcd 457.2590, obsd
α 22 457.2545; [ ]D -37.6 (c 1.54, CHCl3).
146 C7 Protected C1-C14 Diol 2.1912,56,57
A solution of 2.12 (4.5 g, 9.82 mmol) and dry 2,6-lutidine OPMB O OTBS (5.7 mL, 49.1 mmol, 5 eq) in 250 mL of dry CH2Cl2 was
HO cooled to -78 °C. To the solution was added TBSOTf (4.4 HO H mL, 19.6 mmol, 2 eq), and the reaction mixture was stirred at -78 °C for 2 h, quenched via the addition of a saturated NaHCO3 solution,
warmed to room temperature, and the mixture was transferred to a separatory
funnel. The aqueous layer was extracted with 3 x 100 mL of CH2Cl2, and the
combined organic extracts were washed with brine, dried over MgSO4, filtered to
remove drying agent, and concentrated under reduced pressure. The resulting
oil was purified by column chromatography on silica gel (4:1 hexanes:EtOAc) to
give 4.52 g (81%) of 2.18 as a clear oil. The oil was dissolved in a mixture of 125
mL of MeOH and 20 mL of THF and treated with NaOH (80 mL of a 0.5 M
aqueous NaOH solution, 39.5 mmol, 5 eq) and stirred for 30 min. The solution
was diluted with 100 mL of water and extracted with 3 x 200 mL of EtOAc. The
combined organic extracts were washed with brine and dried over MgSO4. The solution was filtered to remove drying agent and concentrated under reduced pressure to yield 4.23 g (94%) of 2.19 as a white crystalline solid: mp 145-146
˚C; IR (neat, cm-1) 3440, 2954, 2856, 1697, 1513, 1464, 1248, 1113, 1047, 834;
1 H NMR (500 MHz, CDCl3) δ 7.34 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H),
5.05 (s, 1H), 4.98 (s, 1H), 4.55-4.52 (m, 1H), 4.51 (d, J = 11.0 Hz, 1H), 4.41 (d, J
= 3.1 Hz, 1H), 4.17 (d, J = 11.0 Hz, 1H), 3.84 (s, 5H), 2.96 (d, J = 12.3 Hz, 1H),
2.72 (s, 1H), 2.70-2.62 (m, 1H), 2.62-2.59 (m, 1H), 2.50-2.49 (m, 1H), 2.32-2.29
147 (m, 1H), 2.20-2.11 (m, 2H), 2.05-2.01 (m, 2H), 1.90-1.85 (m, 1H), 1.72-1.65 (m,
2H), 1.11 (s, 6H), 1.01 (s, 3H), 0.87 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H); 13C NMR
(75 MHz, CDCl3) ppm 211.7, 158.7, 145.7, 131.2, 128.4, 113.5, 110.1, 87.1,
85.4, 77.0, 72.2, 71.9, 60.5, 56.4, 55.2, 48.4, 37.0, 34.3, 32.5, 32.3, 31.1, 31.0,
26.2, 25.7, 18.5, 17.2, 9.9, -2.2, -3.0; ES HRMS m/z (M+Na)+ calcd 595.3431,
α 20 obsd 595.3426; [ ]D -30.8 (c 0.83, CHCl3).
Diketone 2.2012,56,57
OPMB A solution of (COCl)2 (6.4 mL, 73.9 mmol, 10 eq) in 230 O OTBS mL of dry CH2Cl2 was cooled to -78 °C, and a solution of HO O H dry DMSO (10.5 mL, 147 mmol, 20 eq) in 230 mL of
CH2Cl2 was added, and the reaction mixture was stirred at -78 °C for 20 min. A
solution of 2.20 (4.23 g in 210 ml of CH2Cl2, 7.39 mmol) was added via cannula
and the reaction was stirred at -78 °C for 1 h, warmed to -50 °C for 3 h, and
cooled to -78 °C. Dry Et3N (31.0 mL, 222 mmol, 30 eq) was added, and the reaction was stirred at -78 °C for 20 min and warmed to room temperature over the period of 1 h. The solution was diluted with water, transferred to a separatory funnel, and the aqueous layer was extracted with 3 x 100 mL of CH2Cl2. The organic extracts were combined, transferred to a separatory funnel, washed with brine, dried over MgSO4, filtered to remove drying agent, and concentrated under reduced pressure. The oil was purified by column chromatography on silica gel
(6:1 hexanes:EtOAc) to yield 3.46 g (82%) of 2.20 as a white solid: mp 150 - 151
˚C; IR (neat, cm-1) 3488, 2955, 1705, 1680, 1609, 1509, 1462, 1245, 1112, 890;
148 1 H NMR (300 MHz, CDCl3) δ 7.26 (d, J = 8.1 Hz, 2H), 6.83 (d, J = 8.1 Hz, 2H),
4.99 (s, 1H), 4.68 (s, 1H), 4.62 (dd, J = 11.4, 4.1 Hz, 1H), 4.58 (d, J = 2.5 Hz,
1H), 4.33 (d, 10.8 Hz, 1H), 4.15 (d, J = 10.8 Hz, 1H), 3.78 (s, 3H), 3.30 (d, J =
10.2 Hz, 1H), 3.09 (s, 1H), 2.88 (dd, J = 15.0, 2.5 Hz, 1H), 2.78 (d, J = 12.0 Hz,
1H), 2.63-2.60 (m, 2H), 2.49 (d, J = 13.0 Hz, 1H), 2.24-2.09 (m, 5H), 1.66-1.65
(m, 1H), 1.13 (s, 3H), 1.06 (s, 3H), 1.01 (s, 3H), 0.85 (s, 9H), 0.07 (s, 3H), 0.01
13 (s, 3H); C NMR (75 MHz, CDCl3) ppm 214.9, 210.9, 158.7, 144.2, 130.8, 128.4,
113.4, 100.1, 87.4, 85.2, 76.9, 71.4, 59.6, 55.1, 54.2, 49.6, 43.9, 37.0, 34.0, 31.9,
31.5, 30.1, 26.3, 25.6, 18.6, 18.5, 9.1, -2.3, -2.5; ES HRMS m/z (M+Na)+ calcd
α 20 593.3274, obsd 593.3269; [ ]D -25.8 (c 0.08, CHCl3).
α-Hydroxy Ketone 2.2512,56,57
To a flask containing 2.20 (2.00 g, 3.50 mmol) in 250 mL of dry THF at 0 °C was
OPMB added sublimed KOt-Bu (786 mg, 7.00 mmol, 2 eq). The O OTBS solution was stirred at 0 °C for 30 min, and to the solution HO O H HO was added 1.83 g of Davis’ oxaziridine (1.83 g, 7.00 mmol, 2 eq). The progress of the reaction was monitored by TLC until complete (~1 h).
The mixture was quenched with a saturated NH4Cl solution and 1.0 mL of Me2S, stirred for 30 min while warming to room temperature, and transferred to a separatory funnel. The aqueous layer was extracted with EtOAc (3 x 100 mL), and the combined organic extracts were washed with 100 mL of 1.0 M HCl and brine, dried over MgSO4, filtered, and concentrated under reduced pressure.
The resulting oil was purified by column chromatography on silica gel (4:1
149 hexanes:EtOAc) to yield 1.70 g (83%) of 2.25 as an oil: IR (neat, cm-1) 3400,
2955, 2858, 1704, 1614, 1514, 1463, 1332, 1249, 1165, 1121, 906, 835, 780,
1 731; H NMR (500 MHz, CDCl3) δ 7.33 (d, J = 8.0 Hz, 2H), 6.91(d, J = 8.6 Hz,
2H), 5.14 (s, 1H), 5.09 (s, 1H), 4.60 (dd, J = 11.3, 4.3 Hz, 1H), 4.51 (s, 1H), 4.50
(d, J = 10.2 Hz, 1H), 4.42 (d, J = 2.9 Hz, 1H), 4.20 (d, J = 10.8 Hz, 1H), 3.85 (s,
3H), 3.81 (d, J = 9.0 Hz, 1H), 3.29 (s, 1H), 3.12-3.10 (m, 1H), 3.02 (s, 1H), 2.82-
2.79 (m, 1H), 2.54-2.50 (m, 1H), 2.49-2.45 (m, 1H), 2.23-2.11 (m, 3H), 2.04-2.00
(m, 1H), 1.78-1.70 (m, 1H), 1.28 (s, 3H), 1.21 (s, 3H), 1.13 (s, 3H), 0.91 (s, 9H),
13 0.13 (s, 3H), 0.11 (s, 3H); C NMR (75 MHz, CDCl3) ppm 212.5, 211.4, 158.9,
139.3, 130.9, 128.5 (2C), 113.8, 113.6 (2C), 88.7, 86.3, 76.9, 72.1, 60.3, 56.1,
55.2, 50.3, 43.5, 34.7, 33.3, 31.8, 31.7, 26.3, 26.2 (3C), 25.8, 19.0, 18.5, 11.1, -
+ α 21 2.4, -2.9; ES HRMS m/z (M+Na) calcd 609.3218, obsd 609.3204; [ ]D +0.8 (c
0.89, CHCl3);
Epoxyisotaxane 2.2412,56,57
A 100 mL roundbottomed flask was charged with 60 mL of OPMB O OTBS dry CH2Cl2, 2.2 (1.70 g, 2.90 mmol), NaHCO3 (1.95 g,
HO 23.2 mmol, 8 eq), and a magnetic stir bar. The solution O H BzO O was cooled to -25 °C with vigorous stirring, and to the solution was added purified m-CPBA (2.00 g, 11.6 mmol, 4 eq) . The reaction mixture was stirred overnight at -25 °C, quenched by the addition of 10 mL of a
10% aqueous solution of Na2S2O3, and transferred to a separatory funnel. The
aqueous layer was extracted with 3 x 50 mL of CH2Cl2, and the combined
150 organic extracts were washed with brine, dried over MgSO4, filtered to remove
drying agent, and concentrated under reduced pressure. The crude epoxide was
dissolved in dry pyridine (18 mL) and treated sequentially with DMAP (354 mg,
2.90 mmol, 1 eq) and distilled BzCl (2.3 mL, 19.7 mmol, 7 eq). The reaction progress was monitored by TLC. Upon completion (~ 1 h), the mixture was quenched by the addition of a saturated NaHCO3 solution and transferred to a
separatory funnel. The aqueous layer was extracted with CH2Cl2, and the
combined organic fractions were washed with brine, dried over MgSO4, filtered to
remove drying agent, and concentrated under reduced pressure and high
vacuum to remove traces of pyridine. The oil was purified by column
chromatography on silica gel (5:1 hexanes:EtOAc) to yield 1.53 g (80% over two
steps) of 2.24 as an oil.
For intermediate hydroxy epoxide: mp 177-179 ˚C; IR (neat, cm-1) 3424, 2942,
1 1701, 1507, 1466, 1384, 1249, 1114, 1025, 831; H NMR (300 MHz, CDCl3) δ
7.27 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.58 (dd, J = 11.1, 4.1 Hz, 1 H),
4.45 (s, 1H), 4.43 (d, J = 7.5 Hz, 1H), 4.18-4.14 (m, 1H), 4.11 (d, J =7.1 Hz, 1H),
4.07 (d, J = 2.5 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 1H), 3.68 (dd, J = 4.6, 1.5 Hz, 1H),
3.18 (d, J = 4.7 Hz, 1H), 3.09-3.06 (m, 1H), 2.80-2.71 (m, 2H), 2.58 (d, J = 4.7
Hz, 1H), 2.22-2.11 (m, 2H), 2.10-2.04 (m, 2H), 1.89-1.84 (m, 1H), 1.36-1.34 (m,
1H), 1.33 (s, 3H), 1.15 (s, 3H), 1.02 (s, 3H), 0.86 (s, 9H), 0.09 (s, 3H), 0.07 (s,
13 3H); C NMR (75 MHz, CDCl3) ppm 211.0, 209.9, 158.9, 130.7, 128.4, 113.6,
88.5, 85.9, 76.9, 76.1, 72.1, 60.6, 60.0, 55.9, 55.2, 53.2, 50.1, 38.4, 34.3, 34.0,
151 31.9, 30.1, 26.1, 25.8, 18.8, 18.4, 11.2, -2.35, -3.06; ES HRMS m/z (M+Na)+
α 20 calcd 625.3173, obsd 625.3167; [ ]D -16 (c 0.64, CHCl3).
For 2.24: IR (neat, cm-1) 3448, 2942, 1730, 1706, 1513, 1250, 1123, 834; 1H
NMR (500 MHz, CDCl3) δ 7.67-7.62 (m, 2H), 7.54-7.52 (m, 2H), 7.42 (s, 1H),
7.36 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 5.66 (d, J = 2.3 Hz, 1H), 4.65
(dd, J = 11.4, 4.3 Hz, 1H), 4.57 (d, J = 10.7 Hz, 1H), 4.51 (d, J = 3.5 Hz, 1H),
4.28 (s, 1H), 4.20 (d, J = 10.7 Hz, 1H), 3.86 (s, 3H), 3.79 (d, J = 4.3 Hz, 1H), 3.60
(s, 1H), 3.31 (d, J = 12.7 Hz, 1H), 2.98-2.88 (m, 1H), 2.75-2.70 (m, 1H), 2.65 (d, J
= 4.9 Hz, 1H), 2.34-2.27 (m, 2H), 2.17-2.12 (m, 2H), 1.94-1.86 (m, 1H), 1.50-1.47
(m, 1H), 1.26 (s, 3H), 1.25 (s, 6H), 0.89 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H); 13C
NMR (75 MHz, CDCl3) ppm 209.5, 205.7, 165.2, 158.9, 133.3, 130.8, 130.1,
129.7, 128.6, 128.4, 113.6, 89.7, 86.4, 76.1, 75.7, 72.5, 60.8, 58.0, 57.7, 55.2,
53.7, 50.3, 38.3, 35.7, 34.2, 33.1, 30.1, 26.4, 25.9, 18.8, 18.2, 11.0, -2.47, -3.53;
+ α 20 ES HRMS m/z (M+Na) calcd 729.3435, obsd 729.3435; [ ]D +2.4 (c 0.013,
CHCl3).
Taxane 1.8512,56,57
OPMB A dry 100 mL roundbottomed flask with a magnetic stir O bar was placed in a dry box and to the flask was added OTBS O HO BzO H Al(Ot-Bu)3 (70 mg, 0.285 mmol, 2 eq). The reagent was O dissolved in 40 mL of dry benzene and to the flask was added a solution of 2.24 (100 mg, 0.142 mmol) in 10 mL of dry benzene. The mixture was warmed to 50 °C, kept at this temperature until complete (~3 h),
152 cooled to room temperature, and quenched with 3 mL of 3% aqueous HCl. The
solution was transferred to a separatory funnel, and the aqueous layer was
extracted with 3 x 25 mL of benzene. The combined organic extracts were
washed with brine, dried over MgSO4, filtered to remove drying agent, and
concentrated under reduced pressure. The crude product was purified by
column chromatography on silica gel (6:1 hexanes:EtOAc) to yield 70 mg (75%)
of 1.85 as a clear oil: IR (film, cm-1) 3494, 2954, 1723, 1514, 1464, 1251, 1111,
1 835; H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.3 Hz,
1H), 7.50 (t, J = 7.6 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H),
5.64 (d, J = 6.3 Hz, 1H), 4.77 (d, J = 4.3 Hz, 1H), 4.59 (d, J =10.7 Hz, 1H), 4.55
(dd, J = 9.2, 7.2 Hz, 1H), 4.13 (s, 1H), 4.06 (d, J = 10.7 Hz, 1H), 3.86 (s, 3H),
3.41 (d, J = 6.3 Hz, 1H), 2.86-2.83 (m, 2H), 2.80 (d, J = 3.3 Hz, 1H), 2.63 (d, J =
3.3 Hz, 1H), 2.49-2.41 (m, 1H), 2.29-2.21 (m, 2H), 2.12-2.05 (m, 1H), 1.97-1.93
(m, 1H), 1.76 (s, 3H), 1.77-1.71 (m, 1H), 1.15 (s, 3H), 1.07-1.04 (m, 1H), 1.02 (s,
13 3H), 0.94 (s, 9H), 15 (s, 3H), 0.04 (s, 3H); C NMR (75 MHz, CDCl3) ppm 211.8,
209.4, 165.1, 159.4, 133.5, 129.6, 129.5, 128.7, 128.4, 113.8, 84.3, 84.0, 73.3,
71.8, 70.5, 57.5, 56.5, 55.2, 54.3, 52.2, 43.1, 42.0, 38.1, 30.9, 27.7, 27.3, 26.7,
25.9, 23.0, 18.2, 12.1, -1.79, -4.18; ES HRMS m/z (M+Na)+ calcd 729.3429 obsd
α 20 729.3492; [ ]D +60.7 (c 0.27, CHCl3).
153 Diosphenol 3.112
A solution of 100 mg (0.707 mmol) of 1.85 was OPMB O dissolved in 10 mL of dry THF and cooled to -78 °C. HO OTBS O HO To the solution was added sublimed KOt-Bu (32 mg, BzO H O 1.41 mmol, 2 eq) and the solution was stirred for 15 min at -78 °C. A balloon of O2 was bubbled through the solution for 5 min, and
the reaction mixture was quenched with 3 mL of saturated NH4Cl solution, diluted
with EtOAc (5 mL) and H2O (3 mL), and transferred to a separatory funnel. The
procedure was repeated five additional times and the aqueous layer was drawn off and extracted with 3 x 25 mL of EtOAc. The combined organic fractions were washed with brine, dried over MgSO4, and freed of solvent under reduced
pressure. The resulting oil was purified by column chromatography on silica gel
(5:1 hexanes:EtOAc) to yield 164 mg of recovered 1.85 (73% conversion) and
365 mg (82%) of 3.1 as a clear oil: IR (neat, cm-1) 3424, 2956, 1728, 1682,
1614, 1514, 1464, 1393, 1252, 1113, 1026, 836, 776, 712; 1H NMR (500 MHz,
CDCl3) δ 8.08 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.8 Hz,
2H), 7.40 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 6.34 (d, J = 6.5 Hz, 1H),
6.11 (s, 1H), 5.56 (d, J = 3.8 Hz, 1H), 4.68 (d, J = 10.8 Hz, 1H), 4.55 (s, 1H), 2.24
(dd, J = 10.5, 5.6 Hz, 1H), 4.17 (d, J = 10.8 Hz, 1H), 3.87 (s, 3H), 3.69 (d, J = 3.7
Hz, 1H), 3.51 (s, 1H), 3.26 (d, J = 6.3 Hz, 1H), 2.88 (d, J = 4.3 Hz, 1H), 2.43 (d, J
= 4.4 Hz, 1H), 2.09-2.05 (m, 1H), 1.79-1.67 (m, 1H), 1.58-1.54 (m, 1H), 1.52-1.48
(m, 1H), 1.48 (s, 3H), 1.23 (s, 3H), 1.14 (s, 3H), 0.90 (s, 9H), 0.12 (s, 3H), 0.08
13 (s, 3H); C NMR (125 MHz, C6D6) ppm 208.3, 190.0, 165.3, 159.8, 149.1, 134.0
154 (2C), 130.4, 130.3, 129.7 (2C), 129.5, 129.2 (2C), 120.9, 114.3 (2C), 84.2, 81.1,
74.4, 73.2, 79.2, 58.3, 58.2, 55.7, 54.7, 53.4, 41.6, 39.7, 32.8, 30.2, 29.7, 26.3
(3C), 20.7, 18.6, 11.6, -1.8, -3.6; ; EI HRMS m/z (M+) calcd 721.3403, obsd
α 22 721.3414; [ ]D +17.2 (c 0.59, CHCl3)
C1 DMS Protected Taxane 3.15
OPMB In a 25 mL pear-shaped flask was added 1.85 (10 O
mg, 0.014 mmol), Et3N (20 μL, 0.14 mmol, 10 eq), OTBS O O H DMAP (8.7 mg, 0.07 mmol, 5 eq), and 700 μL of HMe2Si BzO O CH2Cl2. The mixture was cooled to 0 °C under an atmosphere of N2, and in one
portion was added Me2SiHCl (8 μL, 0.07 mmol, 5 eq). The reaction mixture was
stirred for 30 min and concentrated under reduced pressure to leave a residue
that was purified by column chromatography on silica gel (10:1 hexanes:EtOAc)
to give 10 mg (100%) of 3.15 as a cloudy oil: IR (film, cm-1) 2955, 2856, 2159
(w), 1721 (s), 1613 (w), 1514, 1464, 1386 (w), 1360 (w), 1252 (s), 1117 (s),
1 1026, 925, 835 (s), 773, 709; H NMR (500 MHz, C6D6) δ -0.04 (s, 3H), 0.00 (s,
3H), 0.05 (d, J = 2.6 Hz, 3H), 0.15 (d, J = 2.5 Hz, 3H), 0.56-0.60 (m, 1H), 0.70 (s,
3H), 0.96 (s, 9H), 1.16 (s, 3H), 1.37-1.41 (m, 1H), 1.65-1.70 (m, 1H), 1.76-1.78
(m, 1H), 1.83 (s, 3H), 1.96-2.00 (m, 1H), 2.02-2.05 (m, 1H), 2.20-2.22 (m, 1H),
2.38 (d, J = 3.6 Hz, 1H), 2.49 (dd, J = 17.3, 6.4 Hz, 1H), 2.80-2.86 (m, 1H), 2.88
(d, J = 3.5 Hz, 1H), 3.26 (s, 3H), 3.54 (d, J = 6.0 Hz, 1H), 3.96 (d, J = 10.1 Hz,
1H), 4.63 (dd, J = 9.2, 7.2 Hz, 1H), 4.69 (d, J = 10.1 Hz, 1H), 4.72 (d, J = 4.2 Hz,
1H), 5.18-5.19 (m, 1H), 5.97 (d, J = 6.0 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 7.05-
155 7.13 (m, 3H), 7.49 (d, J = 8.6 Hz, 2H), 8.17 (dd, J = 8.0, 1.6 Hz, 2H); 13C NMR
(125 MHz, C6D6) ppm -4.2, -1.7, 1.3, 2.0, 18.6, 23.2, 26.3 (3C), 26.8, 27.8, 28.0,
30.2, 32.5, 39.8, 42.7, 45.0, 53.0, 54.6, 54.8, 56.6, 57.5, 70.9, 72.1, 74.0, 85.0,
89.1, 114.1 (2C), 128.7 (2C), 130.3 (2C), 130.4 (2C), 130.5, 130.6, 133.4, 160.1,
+ 165.0, 208.4, 209.5; ES HRMS m/z (C42H60O9Si2Na ) calcd 787.3668, obsd
α 22 787.3626; [ ]D +12.8 (c 0.33, CHCl3).
A-Ring α,β-Unsaturated Taxane 3.21
A 5 mL conical flask was fitted with a reflux condenser OPMB O and in it was placed 1.85 (10 mg, 0.0141 mmol), 2 mL of OTBS O HO dry dioxane, and a stir bar. To this solution was added BzO H O SeO2 (8 mg, 0.0707, 5 eq) and the reaction mixture was heated to reflux for 12 h, cooled to room temperature, and filtered through Celite.
Silica gel was added and the mixture was stirred for 3 h to eliminate any intermediate selenium compounds. The solution was concentrated under reduced pressure and the adsorbed material was purified by column chromatography on silica gel (10:1 to 2:1 hexanes:EtOAc gradient) to give 2 mg
of 3.1 and 3 mg of 3.21 as oils (50% total yield): IR (neat, cm-1) 2924, 2854,
1725, 1681 (m), 1613 (w), 1514 (m), 1436 (m), 1360 (w), 1252, 1175 (w), 1111,
1 1026 (m), 835 (m), 775 (w), 714 (m); H NMR (500 MHz, CDCl3) δ 8.05 (d, J =
7.1 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.9, 7.7 Hz, 2H), 7.39 (d, J = 8.6
Hz, 2H), 7.12 (dd, J = 9.9, 5.6 Hz, 1H), 6.96 (dd, J = 6.8, 1.9 Hz, 2H), 6.51 (dd, J
= 9.9, 1.3 Hz, 1H), 5.65 (d, J = 5.1 Hz, 1H), 4.67 (d, J = 10.8 Hz, 1H), 4.44 (d, J =
156 1.3 Hz, 1H), 4.31 (dd, J = 9.7, 6.5 Hz, 1H), 4.13 (d, J = 10.7 Hz, 1H), 3.87 (s,
3H), 3.20 (d, J = 5.1 Hz, 1H), 3.17 (, J = 5.5 Hz, 1H), 2.80 (d, J = 3.9 Hz, 1H),
2.52 (d, J = 4.0 Hz, 1H), 2.20-2.00 (m, 1H), 1.80-1.75 (m, 1H), 1.75-1.65 (m, 1H),
1.65 (s, 3H), 1.60-1.50 (m, 1H), 1.30-1.20 (m, 1H), 1.19 (s, 3H), 1.09 (s, 3H),
13 0.92 (s, 9H), 0.12 (s, 3H), 0.05 (s, 3H); C NMR (125 MHz, CDCl3) ppm 208.2,
199.0, 165.5, 153.1, 133.9, 130.3 (2C), 130.1, 129.9 (2C), 129.8, 129.1 (2C),
114.4 (2C), 82.9, 81.5, 73.7, 72.7, 57.7, 57.4, 56.4, 55.7, 53.7, 41.4, 41.0, 30.3,
30.1, 29.3, 28.5, 26.3 (3C), 21.5, 18.7, 14.5, 12.4, -1.7, -3.7; ES HRMS m/z
+ α 22 (C40H52O9SiNa ) calcd 727.3273, obsd 727.3247; [ ]D +32.2 (c 0.29, CHCl3).
Selenodiosphenol 3.23
OPMB A solution of 3.1 (200 mg, 0.277 mmol) in 28 mL of PhSe O ° HO THF was cooled to -78 C in a 50 mL conical flask. OTBS O HO μ BzO H LHMDS (416 L of 1.0 M in THF, 0.416 mmol, 1.5 O eq) was added and the reaction mixture was stirred for 15 min. Neat PhSeCl (79 mg, 0.416 mmol, 1.5 eq) was added and the reaction mixture was stirred for 30 min, quenched with saturated NH4Cl solution,
and transferred to a separatory funnel. The aqueous layer was extracted with 3 x
25 mL of CH2Cl2, and the combined organic extracts were dried over MgSO4,
filtered to remove drying agent, and concentrated under reduced pressure. The
resulting dark orange residue was purified by column chromatography on silica
gel (neat hexane to elute non-polar substances, then 5:1 hexanes:EtOAc) to give
200 mg (82%) of 3.23 as an orange oil: IR (film, cm-1) 2960 (s), 2361, 1734,
157 1 1669, 1616, 1515, 1457, 1259 (s), 1113 (s), 803; H NMR (500 MHz, C6D6) δ
8.15 (d, J = 7.6 Hz, 2H), 7.49 (dd, J = 7.6, 1.9 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H),
7.06 (d, J = 7.4 Hz, 1H), 7.00 (t, J = 7.4 Hz, 1H), 6.85-6.90 (m, 2H), 6.79 (d, J =
8.6 Hz, 2H), 5.90 (d, J = 2.7 Hz, 1H), 5.12 (s, 1H), 4.64 (d, J = 9.3 Hz, 1H), 4.37
(dd, J = 10.9, 4.9 Hz, 1H), 4.19 (d, J = 2.5 Hz, 1H), 3.86 (d, J = 9.5 Hz, 1H), 3.58
(s, 1H), 3.54 (s, 1H), 3.30 (s, 3H), 3.29 (s, 1H), 2.94 (d, J = 4.9 Hz, 1H), 1.95 (d, J
= 5.2 Hz, 1H), 1.60-1.82 (m, 3H), 1.48 (s, 3H), 1.43 (s, 3H), 1.10-1.18 (m, 1H),
13 0.98 (s, 3H), 0.90 ( s, 9H), 0.11 (s, 3H), 0.03 (s, 3H); C NMR (125 MHz, CDCl3) ppm 207.8, 192.7, 164.7, 158.9, 148.0, 135.1 (2C), 130.3, 130.1, 130.0, 129.9
(2C), 129.8 (2C), 129.3, 128.9 (2C), 129.7 (2C), 128.4 (2C), 113.4, 88.6, 83.2,
79.7, 75.3, 72.0, 71.8, 60.7, 58.1, 55.3, 52.6, 50.2, 42.1, 37.7, 30.2, 29.7, 28.9,
26.7, 26.2, 25.9 (3C), 19.7, 18.2, -2.4, -3.1; ES HRMS m/z (M+Na)+ calcd
α 19 899.2700, obsd 899.2763; [ ]D -28.5 (c 1.2, CHCl3).
Bromodiosphenol 3.24
OPMB A solution of 3.1 (107 mg, 0.148 mmol) and pyridine Br O μ HO (24 L, 0.297 mmol, 2 eq) in 10 mL of CH2Cl2 was OTBS O HO ° BzO H cooled to 0 C. To the solution was added solid O py·HBr3 (47 mg, 0.148 mmol, 1 eq), and the solution
was stirred for 1 h, quenched with saturated NaHCO3 solution, and diluted with
CH2Cl2 and H2O. The solution was transferred to a separatory funnel, and the aqueous layer was extracted with 3 x 25 mL of CH2Cl2. The combined organic
fractions were washed with brine, dried over MgSO4, filtered, and concentrated
158 under reduced pressure and high vacuum. The resulting yellow oil was purified
by column chromatography on silica gel (5:1 hexanes:EtOAc) to yield 84 mg
(71%) of 3.24 as a clear oil: IR (neat, cm-1) 3405, 2961 (s), 2358 (w), 1731 (s),
1 1613, 1514, 1454, 1260 (s), 1089 (s), 910, 835, 711; H NMR (500 MHz, CDCl3)
δ 8.08 (d, J = 7.2 Hz, 2H), 7.61-7.65 (m, 1H), 7.52 (dd, J = 3.8, 1.6 Hz, 2H), 7.43
(d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 6.75 (s, 1H), 5.49 (d, J = 2.9 Hz,
1H), 5.02 (d, J = 0.9 Hz, 1H), 4.68 (d, J = 10.4 Hz, 1H), 4.33 (d, J = 10.5 Hz, 1H),
4.19-4.21 (m, 1H), 4.17 (d, J = 7.1 Hz, 1H), 3.87 (s, 3H), 3.72 (d, J = 2.8 Hz, 1H),
3.41 (s, 1H), 3.58 (s, 1H), 3.00 (d, , J = 4.4 Hz, 1H), 2.37 (d, , J = 4.8 Hz, 1H),
2.09-2.12 (m, 1H), 1.70-1.85 (m, 2H), 1.37 (s, 3H), 1.29 (s, 3H), 1.16 (s, 3H),
13 0.88 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H); C NMR (75 MHz, CDCl3) ppm 207.3,
192.3, 164.7, 148.5, 133.6, 130.1 (2C), 129.8, 129.4 (2C), 129.0, 128.8 (2C),
128.6, 121.3, 113.7 (2C), 82.6, 80.1, 75.3, 72.7, 72.0, 62.7, 58.8, 58.0, 55.3,
52.7, 42.5, 38.1, 35.0, 30.0, 29.1, 26.0 (3C), 19.6, 18.2, 10.5, -2.4, -4.2; ES
+ α 20 HRMS m/z (M+Na) calcd 821.2327, obsd 821.2376; [ ]D -41.3 (c 0.12, CHCl3).
Enol DMS Protected Disophenol 3.2512
OPMB A 25 mL conical flask containing a solution of 3.1 O (10 mg, 0.014 mmol), DMAP (10 mg, 0.082 H Si O OTBS O HO mmol, 6 eq), and Et N (20 μL, 0.140 mmol, 10 BzO H 3 O eq) in 1 mL of CH2Cl2 was cooled to 0 °C, and to
the solution was added Me2SiHCl (8 μL, 0.070 mmol, 5 eq). The mixture was
stirred for 10 min and placed under high vacuum to remove volatiles. The
159 residue was purified by column chromatography on silica gel (10:1
hexanes:EtOAc) to give 8.4 mg (82%) of 3.25 as a clear oil: IR (neat, cm-1) 2955,
2856, 2159 (w), 1721 (s), 1613 (w), 1514, 1464, 1386 (w), 1360 (w), 1252 (s),
1 1117 (s), 1026, 925, 835 (s), 773, 709; H NMR (500 MHz, C6D6) δ 8.17 (dd, J =
8.0, 1.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.05-7.13 (m, 3H), 6.85 (d, J = 8.6 Hz,
2H), 5.97 (d, J = 6.0 Hz, 1H), 5.18-5.19 (m, 1H), 4.72 (d, J = 4.2 Hz, 1H), 4.69 (d,
J = 10.1 Hz, 1H), 4.63 (dd, J = 9.2, 7.2 Hz, 1H), 3.96 (d, J = 10.1 Hz, 1H), 3.54
(d, J = 6.0 Hz, 1H), 3.26 (s, 3H), 2.88 (d, J = 3.5 Hz, 1H), 2.80-2.86 (m, 1H), 2.49
(dd, J = 17.3, 6.4 Hz, 1H), 2.38 (d, J = 3.6 Hz, 1H), 2.20-2.22 (m, 1H), 2.02-2.05
(m, 1H), 1.96-2.00 (m, 1H), 1.83 (s, 3H), 1.76-1.78 (m, 1H), 1.65-1.70 (m, 1H),
1.37-1.41 (m, 1H), 1.16 (s, 3H), 0.96 (s, 9H), 0.70 (s, 3H), 0.56-0.60 (m, 1H),
0.15 (d, J = 2.5 Hz, 3H), 0.05 (d, J = 2.6 Hz, 3H), 0.00 (s, 3H), -0.04 (s, 3H); 13C
NMR (125 MHz, C6D6) ppm 209.5, 208.4, 165.0, 160.1, 133.4, 130.6, 130.5,
130.4 (2C), 130.3 (2C), 128.7 (2C), 114.1 (2C), 89.1, 85.0, 74.0, 72.1, 70.9, 57.5,
56.6, 54.8, 54.6, 53.0, 45.0, 42.7, 39.8, 32.5, 30.2, 28.0, 27.8, 26.8, 26.3 (3C),
23.2, 18.6, 2.0, 1.3, -1.7-4.2; ES HRMS m/z (M+Na)+ calcd 787.3668, obsd
α 22 787.3626; [ ]D +12.8 (c 0.33, CHCl3).
160 O-Acylated Diosphenol 3.30
A 10 mL conical flask was charged with 1 mL OPMB O of CH2Cl2, allyl chloroformate (10 μL, 0.083 AllO O OTBS O O HO mmol, 10 eq), and DMAP (20 mg, 0.167 mmol, BzO H O 20 eq), and a cloudy white solution resulted.
To this solution was added 3.1 (6 mg, 0.008 mmol) in 500 μL of CH2Cl2 via cannula, and the reaction mixture was stirred at room temperature for 2 h and quenched with saturated NH4Cl solution. The aqueous layer was extracted with
CH2Cl2 (3 x 25 mL), and the combined organic extracts were washed with brine,
dried over MgSO4, filtered, and concentrated under reduced pressure to give a yellow residue. The oil was purified by column chromatography on silica gel
(10:1 to 2:1 hexanes:EtOAc) to give 5.3 mg (80%) of 3.30 as an oil: IR (neat, cm-
1) 3507, 2924 (s), 2854 (s), 2359 (w), 2342 (w), 2280 (w), 1769 (s), 1727 (s),
1616, 1514, 1463, 1362, 1252 (s), 1111 (s), 1026 (s), 876, 835, 776, 712, 668;
1 H NMR (500 MHz, C6D6) δ 8.20 (d, J = 7.1 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H),
7.10-6.98 (m, 3H), 6.85 (d, J = 8.7 Hz, 2H), 6.37 (d, J = 6.4 Hz, 1H), 5.92 (d, J =
5.0 Hz, 1H), 5.67-5.60 (m, 2H), 5.10 (dd, J = 10.5, 1.1 Hz, 1H), 4.93 (dd, J =
10.4, 1.1 Hz, 1H), 4.74 (d, J = 10.2 Hz, 1H), 4.45-4.35 (m, 3H), 4.06 (d, J = 10.2
Hz, 1H), 3.78 (s, 1H), 3.34 (d, J = 4.9 Hz, 1H), 3.29 (s, 3H), 3.11 (d, J = 1.5 Hz,
1H), 2.92 (d, J = 4.1 Hz, 1H), 2.17 (d, J = 4.1 Hz, 1H), 1.91-1.85 (m, 1H), 1.74 (s,
3H), 1.55-1.45 (m, 1H), 1.40-1.28 (m, 4H), 1.15-1.05 (m, 4H), 0.93 (s, 9H), -0.02
13 (s, 3H), -0.03 (s, 3H); C NMR (125 MHz, C6D6) ppm 207.0, 192.9, 165.1, 160.1,
153.0, 146.1, 139.6, 133.5, 130.4, 130.1, 130.0 (2C), 130.0 (2C), 129.0 (2C),
161 128.6 (2C), 119.3, 114.3, 83.1, 82.0, 73.8, 73.2, 72.8, 69.7, 65.5, 57.3, 57.0,
54.8, 53.1, 41.5, 41.3, 30.2, 30.0, 29.0, 26.2 (3C), 21.2, 18.5, 1.4, -2.0, -4.0; ES
+ α 20 HRMS m/z (M+Na) calcd 827.3433, obsd 827.3436; [ ]D +25.2 (c 0.08, CHCl3)
Methylated Diosphenol 3.3112
To a solution of 100 mg of 3.1 in 10 mL of dry Et2O OPMB O at room temperature was added 100 mg of SiO2 MeO OTBS and 5 mL of an ethereal CH2N2 solution (prepared O HO BzO H O as for 2.3 using 600 mg of KOH, 3 mL of H2O, 5 mL of Et2O, and 500 mg of N-nitrosomethylurea). The reaction mixture was stirred at
room temperature for 1 h and freed of solvent under house vacuum. The
remaining silica gel was slurried in 5 mL of Et2O and filtered off through a plug of
silica gel (~1 in high in a pipette), which was rinsed with 40 mL of Et2O and 10 mL of CH2Cl2 to ensure that all the material had been eluted. Solvent evaporation yielded 100 mg (98%) of 3.31 as a cloudy oil: IR (neat, cm-1) 3491,
2929, 1728, 1694, 1634, 1515, 1456, 1361, 1252, 1112, 1027, 836, 776, 712; 1H
NMR (500 MHz, CDCl3) δ 8.04 (d, J = 7.1 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.51
(t, J = 7.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 6.97 (d, J = 8.6 Hz, 2H), 5.84 (d, J =
6.1 Hz, 1H), 5.64 (d, J = 5.4 Hz, 1H), 4.71 (d, J = 10.9 Hz, 1H), 4.38 (s, 1H), 4.32
(dd, J = 9.6, 6.8 Hz, 1H), 4.13 (d, J = 10.9 Hz, 1H), 3.88 (s, 1H), 3.86 (s, 3H),
3.77 (s, 3H), 3.21 (d, J = 5.4 Hz, 1H), 3.19 (d, J = 6.2 Hz, 1H), 2.73 (d, J = 3.6
Hz, 1H), 2.54 (d, J = 3.6 Hz, 1H), 2.16-2.09 (m, 1H), 1.93-1.87 (m, 1H), 1.73-1.67
(m, 4H), 1.16 (s, 3H), 1.11 (s, 3H), 1.10-1.05 (m, 1H), 0.93 (s, 9H), 0.13 (s, 3H),
162 13 0.08 (s, 3H); C NMR (125 MHz, CDCl3) ppm 208.6, 194.5, 166.0, 159.9, 152.0,
134.0, 130.3 (2C), 130.2 (2C), 129.5, 129.2, 129.8 (2C), 119.5, 114.4 (2C), 85.3,
82.3, 74.0, 72.7, 72.1, 57.4, 56.2, 55.7, 55.6, 55.0, 54.0, 41.9, 40.8, 30.4, 28.0,
26.3 (3C), 22.0, 18.6, 12.7, -1.7, -3.7; EI HRMS m/z (M+) calcd 757.3378, obsd
α 22 757.3364; [ ]D +23.0 (c 0.37, CHCl3).
Methylated Bromodiosphenol 3.32
A 25 mL round-bottomed flask was charged with OPMB Br O 3.1 (59 mg, 0.082 mmol) and pyridine (26 μL, 0.164 MeO OTBS O HO mmol, 4.0 eq) in 1 mL of CH2Cl2. The solution was BzO H O cooled to 0 °C and py·HBr3 (24 mg, 0.074 mmol,
0.9 eq) was added, and the reaction mixture was stirred for 1 h, quenched with
saturated NaHCO3 solution, and transferred to a separatory funnel. The aqueous layer was extracted with 3 x 10 mL of CH2Cl2. The combined organic
extracts were washed with brine, dried over MgSO4, filtered, concentrated under
reduced pressure, and placed under high vacuum for 1 h. The crude product was dissolved in 5 mL of Et2O and cooled to 0 °C. Silica gel (100 mg) was added followed by 5 mL of a previously prepared CH2N2 solution (as prepared for
3.31 above). The reaction mixture was stirred for 1 h and freed of solvent under
house vacuum. The resulting oil was purified by flash chromatography on silica
gel (10:1 to 5:2 hexanes:EtOAc) to give 56 mg (95%) of 3.32 as a white foam.
The target can also be synthesized from 3.24 by applying the methylation procedure as described: mp 94-97 °C; IR (neat, cm-1) 3494 (w), 2961 (s), 1732
163 (s), 1688 (s), 1613, 1514 (s), 1463, 1398, 1259 (s), 1112 (s), 909, 799, 711; 1H
NMR (500 MHz, CDCl3) δ 8.09 (d, J = 7.1 Hz, 2H), 7.64 (dd, J = 5.6, 7.4 Hz, 1H),
7.52 (dd, J = 7.7, 7.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H),
5.49 (d, J = 3.0 Hz, 1H), 5.05 (d, J = 0.9 Hz, 1H), 4.68 (d, J = 10.5 Hz, 1H), 4.32
(d, J = 10.4 Hz, 1H), 4.21 (dd, J = 10.6, 5.4 Hz, 1H), 4.13 (s, 3H), 3.87 (s, 3H),
3.83 (d, J = 2.9 Hz, 1H), 3.57 (s, 1H), 3.67 (s, 1H), 3.02 (d, J = 4.7 Hz, 1H), 2.34
(d, J = 4.7 Hz, 1H), 2.07-2.04 (m, 1H), 1.86-1.60 (m, 2H), 1.38 (s, 3H), 1.36-1.29
(m, 1H), 1.27 (s, 3H), 1.11 (s, 3H), 0.90 (s, 9H), 0.12 (s, 3H),0.11 (s, 3H); 13C
NMR (125 MHz, CDCl3) ppm , 207.5, 192.7, 165.3, 159.8, 153.1, 135.6, 134.0,
130.6 (2C), 130.4, 130.1, 129.8 (2C), 129.2 (2C), 114.2, 82.7, 81.5, 75.9, 73.1,
72.4, 63.8, 60.5, 59.4, 58.5, 55.7, 52.4, 42.7, 38.7, 35.8, 30.6, 29.5, 26.3 (3C),
19.9, 18.7, 10.8, -1.9, -3.7; ES HRMS m/z (M+Na)+ calcd 835.2483, obsd
α 21 835.2522; [ ]D -45.8 (c 0.52, CHCl3).
C14 Reduced Methylated Diosphenol 3.3312
A solution of 3.31 (148 mg, 0.201 mmol) in 13 mL OPMB O of absolute EtOH and 1.3 mL of dry THF was MeO OTBS prepared at room temperature. To this solution HO HO BzO H O was added CeCl3·7H2O (150 mg, 0.403 mmol, 2
eq) and once dissolved, the solution was cooled to 0 °C. To this mixture was added NaBH4 (15 mg, 0.403 mmol, 2 eq). The reaction mixture was stirred for 30 min treated with a second portion of NaBH4 (15 mg, 0.403 mmol, 2 eq), stirred for
2 h at 0 °C, and carefully quenched with 3 mL of saturated NH4Cl solution. The
164 mixture was diluted with 5 mL of CH2Cl2 and transferred to a separatory funnel.
The aqueous layer was extracted with CH2Cl2 (3 x 10 mL), and the combined
organic extracts were washed with brine, dried over MgSO4, filtered, and freed of
solvent under reduced pressure. The resulting oil was purified by column
chromatography on silica gel (6:1 to 3:1 hexanes:EtOAc) to yield 59 mg of 3.31
(60% conversion) and 79 mg (89%) of 3.33 as a cloudy oil: IR (neat, cm-1) 3425,
2953, 1732, 1718, 1652, 1558, 1516, 1456, 1251, 1109, 834; 1H NMR (500 MHz,
C6D6) δ 8.20 (d, J = 7.6 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.04 (t, J = 7.2 Hz, 1H),
6.95 (t, J = 7.8 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 5.92 (d, J = 2.1 Hz, 1H), 5.19 (d,
J = 12.8 Hz, 1H), 4.99 (s, 1H), 4.95 (d, J = 10.5 Hz, 1H), 5.59 (d, J = 4.4 Hz, 1H),
4.56 (s, 1H), 4.41 (d, J = 12.6 Hz, 1H), 4.36 (d, J = 10.5 Hz, 1H), 4.14 (dd, J =
11.2, 4.5 Hz, 1H), 3.30 (s, 3H), 3.26 (s, 3H), 3.19-3.15 (m, 2H), 2.76 (s, 1H), 1.93
(d, J = 4.5 Hz, 1H), 1.78-1.73 (m, 1H), 1.65-1.63 (m, 1H), 1.57 (s, 3H), 1.43 (s,
3H), 1.40-1.34 (m, 1H), 1.12 (s, 3H), 0.91 (s, 9H), 0.89-0.86 (m, 1H), 0.02 (s,
13 3H), 0.00 (s, 3H); C NMR (125 MHz, C6D6) ppm 208.0, 164.6, 159.9, 158.0,
133.4, 131.3 (2C), 130.4, 130.1 (2C), 129.4 (2C), 129.1 (2C), 128.6, 114.3, 98.9,
86.4, 77.4, 76.5, 74.5, 73.7, 73.1, 60.7, 60.5, 54.9, 54.8, 54.3, 53.8, 40.6, 36.5,
30.7, 29.9, 26.2 (3C), 20.2, 18.6, 11.0, -2.1, -3.6; ES HRMS m/z (M+Na)+ calcd
α 20 759.3535, obsd 759.3507; [ ]D -43.6 (c 0.32, CHCl3).
165 C14 Reduced Methylated Bromodiosphenol 3.34
A solution of 3.32 (46 mg, 0.056 mmol) in a mixture OPMB Br O of 5 mL of absolute EtOH and 500 μL of dry THF MeO OTBS HO HO was prepared at room temperature, and to the BzO H
O solution was added CeCl3·7H2O (53 mg, 0.142
mmol, 2.5 eq). The flask was cooled to 0 °C, NaBH4 (4.5 mg, 0.112 mmol, 2 eq)
was added, and the mixture was stirred for 30 min. Another 4.5 mg portion of
NaBH4 (4.5 mg, 0.112 mmol, 2 eq) was added and stirring was continued for 1 h.
The reaction mixture was quenched with saturated NH4Cl solution and
transferred to a separatory funnel. The aqueous layer was extracted with 3 x 50
mL of CH2Cl2, and the combined organic fractions were dried over MgSO4,
filtered, concentrated under reduced pressure. The resulting oil was purified by
column chromatography on silica gel (5:1 hexanes:EtOAc) to give 10 mg of 3.32
(77% conversion) and 27 mg (76%) of 3.34 as a cloudy oil: IR (neat, cm-1) 3382
(br,s), 2961, 2856, 1731, 1645, 1514, 1463 (w), 1260 (s), 1097 (s), 802 (s); 1H
NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.52
(dd, J = 5.7, 7.7 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 5.51
(d, J = 2.4 Hz, 1H), 5.42 (d, J = 10.3 Hz, 1H), 5.05 (s, 1H), 4.65 (d, J = 10.6 Hz,
1H), 4.46 (d, J = 2.1 Hz, 1H), 4.41 (d, J = 10.5 Hz, 1H), 4.35 (d, J = 10.7 Hz, 1H),
4.20 (dd, J = 0.3, 2.9 Hz, 1H), 4.00 (s, 3H), 3.86 (s, 3H), 3.32 (d, J = 4.2 Hz, 1H),
3.19 (s, 1H), 2.63 (s, 1H), 2.56 (d, J = 4.4 Hz, 1H), 2.10-2.01 (m, 2H), 1.75-1.70
(m, 1H), 1.32-1.29 (m, 1H), 1.28 (s, 3H), 1.24 (s, 3H), 1.23 (s, 3H), 0.88 (s, 9H),
13 0.11 (s, 6H); C NMR (125 MHz, CDCl3) ppm 208.1, 164.9, 159.6, 153.7, 134.1,
166 131.0, 130.5 (2C), 129.5 (2C), 129.3 (2C), 114.1 (2C), 108.3, 83.0, 75.9, 74.1,
73.2, 72.9, 61.6, 61.2, 59.8, 58.6, 55.7, 54.5, 41.9, 36.7, 36.5, 30.7, 29.6, 26.3,
26.0 (3C), 19.9, 18.6, 10.6, 1.4, -2.1, -3.8; ES HRMS m/z (M+Na)+ calcd
α 22 837.2640, obsd 837.2662; [ ]D -39.7 (c 0.03, CHCl3).
A-Ring Xanthate 3.36
A 25 mL round-bottomed flask was charged with OPMB Br O 18-crown-6/CH3CN complex (133 mg, 0.436 mmol, MeO OTBS HO O H 10 eq) and a stir bar, and placed under high S BzO SMe O vacuum for 1 h. The flask was flushed with N2, and a solution of 3.34 (35 mg, 0.043 mmol) in 5 mL of CS2 was added via syringe. To
this solution was added dry KH (18 mg, 0.436 mmol, 10 eq), and the mixture was
stirred overnight, treated with MeI (300 μL, 4.36 mmol, 100 eq), stirred for 2 h,
quenched by slow addition of saturated NH4Cl solution and transferred to a
separatory funnel. The aqueous layer was extracted with 3 x 10 mL of Et2O, and the combined organic extracts were dried over MgSO4, filtered, and concentrated
under reduce pressure to give a yellow oil. The residue was purified by column
chromatography on silica gel to return 6 mg of 3.34 (83% conversion) and 19 mg
(60%) of 3.36 as a yellow oil: IR (neat, cm-1) 2922 (s), 1725 (s), 1514, 1464,
1 1259 (s), 1199 (s), 1063 (s), 835 (s); H NMR (500 MHz, C6D6) δ 8.33 (d, J = 6.9
Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.13-6.98 (m, 3H), 6.85 (d, J = 8.6 Hz, 2H),
6.72 (s, 1H), 5.91 (d, J = 3.6 Hz, 1H), 5.27 (s, 1H), 4.97 (d, J = 10.3 Hz, 1H), 4.60
(d, J = 10.4 Hz, 1H), 4.36 (dd, J = 4.9, 11.1 Hz, 1H), 4.17 (d, J = 3.4 Hz, 1H),
167 3.81 (s, 1H), 3.51 (s, 3H), 3.42 (s, 1H), 3.30 (s, 3H), 2.57 (d, J = 5.1 Hz, 1H), 2.33
(s, 3H), 2.05-1.99 (m, 2H), 1.87 (d, J = 5.0 Hz, 1H), 1.73-1.69 (m, 1H), 1.56 (s,
3H), 1.49 (s, 3H), 1.49-1.40 (m, 1H), 1.14 (s, 3H), 0.90 (s, 9H), 0.07 (s, 3H), 0.00
13 (s, 3H); C NMR (125 MHz, C6D6) ppm 221.6, 207.9, 165.4, 159.9, 150.8, 133.2
(2C), 131.1 (2C), 130.8, 130.4 (2C), 129.7 (2C), 127.5, 115.0, 114.2, 84.3, 82.4,
78.9, 76.9, 73.1, 72.2, 61.2, 60.8, 59.1, 54.8, 50.5, 43.5, 38.2, 36.9, 32.4, 31.3,
30.2, 26.3 (3C), 20.1, 18.7, 14.4, 11.6, -2.1, -3.5; ES HRMS m/z (M+Na)+ calcd
α 20 927.2238, obsd 927.2298; [ ]D -41.3 (c 0.63, CHCl3).
Allylated Diosphenol 3.38
A solution of 3.1 (100 mg, 0.139 mmol) and K2CO3 OPMB O (95 mg, 0.694 mmol, 5 eq) in 20 mL of dry DMF was AllO OTBS ° O HO cooled to 0 C. To the solution was added neat allyl BzO H O iodide (40 μL, 0.416 mmol, 3 eq) and the reaction mixture was warmed to room temperature, stirred for 1 h, and treated with 10% aqueous NaHSO3 solution until the solution was clear (~5 mL). The solution was
diluted with EtOAc, transferred to a separatory funnel, and extracted with EtOAc
(3 x 25 mL). The organic fractions were combined, washed with brine, dried over
MgSO4, filtered, concentrated under reduced pressure, and the resulting oil was purified by column chromatography on silica gel (5% to 20% EtOAc in hexanes) to give 80 mg (76%) of 3.38 as a cloudy oil: IR (neat, cm-1) 3434 (w), 2926,
2855, 1724, 1608 (w), 1510, 1462 (w), 1361 (w), 1248, 1182, 1111, 1040, 830,
1 775 (w), 710 (w); H NMR (500 MHz, CDCl3) δ 8.02 (d, , J = 7.2 Hz, 2H), 7.61 (t,
168 J = 7.4 Hz, 1H), 7.49 (dd, J = 7.8, 7.7 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 6.95 (d, J
= 8.6 Hz, 2H), 6.09-6.03 (m, 1H), 5.82 (d, J = 6.2 Hz, 1H), 5.62 (d, J = 5.4 Hz,
1H), 5.43 (dd, J = 17.2, 1.2 Hz, 1H), 5.36 (dd, J = 10.5, 1.0 Hz, 1H), 4.68 (d, J =
11.0 Hz, 1H), 4.41-4.29 (m, 2H), 4.19-4.08 (m, 1H), 3.87 (s, 1H), 3.84 (s, 3H),
3.17 (d, J = 5.3 Hz, 1H), 3.14 (d, J = 5.7 Hz, 1H), 2.74 (d, J = 5.7 Hz, 1H), 2.51
(d, J = 3.6 Hz, 1H), 2.20-2.05 (m, 1H), 1.91-1.81 (m, 1H), 1.75-1.70 (m, 1H), 1.64
(s, 3H), 1.13 (s, 3H), 1.09 (s, 3H), 1.08-1.03 (m, 1H), 0.91 (s, 3H), 0.11 (s, 3H),
13 0.09 (s, 9H), 0.06 (s, 3H); C NMR (125 MHz, CDCl3) ppm 208.2, 194.1, 165.1,
159.5, 156.3, 150.5, 143.7, 133.5, 132.1, 129.9 (2C), 129.8 (2C), 129.1 (2C),
128.7 (2C), 120.6, 119.0, 113.9, 84.6, 81.4, 73.5, 72.3, 71.7, 69.6, 57.0, 55.3,
41.7, 41.5, 40.3, 31.9, 31.0, 27.7, 25.9 (3C), 22.7, 21.6, 18.2, 14.1, 12.3, -2.1, -
4.1; ES HRMS m/z (M+Na)+ calcd 783.3535, obsd 783.3517.
Allylated Selenodiosphenol 3.39
To a solution of 3.23 (200 mg, 0.228 mmol) in 15 OPMB PhSe O mL of dry DMF was added K2CO3 (95 mg, 0.685 AllO OTBS mmol, 3 eq) followed by distilled allyl iodide (20 μL, O HO BzO H O 0.228 mmol, 1 eq). The reaction mixture was stirred for 1 h at room temperature, quenched by the addition of 10% NaHSO3 solution until a white color developed (~5 mL), diluted with EtOAc, and transferred to a separatory funnel. The aqueous layer was extracted with EtOAc (3 x 25 mL), and the organic extracts were combined, washed with brine, dried over MgSO4,
filtered, and freed of solvent under reduced pressure. The crude oil was purified
169 by column chromatography on silica gel (5% EtOAc in hexanes) to give 178 mg
(80%) of 3.39 as a viscous oil: IR (film, cm-1) 2952, 2927, 2855, 1729, 1670,
1613 (w), 1560 (w), 1513, 1463 (w), 1397 (w), 1360 (w), 1302 (m), 1250, 1211
(w), 1174 (w), 1115, 1066 (m), 1026 (m), 926 (w), 835, 775 (w), 741 (w), 710 (w),
1 693 (w), 670 (w); H NMR (500 MHz, C6D6) δ 8.40 (d, J = 7.3 Hz, 2H), 7.79-7.63
(m, 2H), 7.42 (d, J = 8.5 Hz, 2H), 7.18 (t, J = 7.3 Hz, 2H), 7.12 (t, J = 7.9 Hz, 2H),
7.07-7.06 (m, 2H), 6.95 (d, J = 9.1 Hz, 2H), 6.34-6.10 (m, 1H), 6.03 (d, J = 1.8
Hz, 1H), 5.62 (dd, J = 17, 1.5 Hz, 1H), 5.51 (dd, J = 13.7, 5.6 Hz, 1H), 5.25 (dd, J
= 10.4, 1.3 Hz, 1H), 5.06 (dd, J = 12.5, 5.2 Hz, 1H), 4.63 (d, J = 9.4 Hz, 1H), 4.51
(dd, J = 11.3, 4.8 Hz, 1H), 4.48 (d, J = 2.5 Hz, 1H), 4.10 (s, 1H), 3.79 (s, 1H),
3.68 (d, J = 9.4 Hz, 1H), 3.44 (s, 3H), 3.09 (dd, J = 5.0, 1.3 Hz, 1H), 2.04 (d, J =
5.4 Hz, 1H), 2.03-2.01 (m, 1H), 1.99-1.83 (m, 1H), 1.61 (s, 3H), 1.59 (s, 3H), 1.20
13 (s, 3H), 1.16-0.97 (m, 12H), 0.21 (s, 3H), 0.12 (s, 3H); C NMR (125 MHz, C6D6) ppm 207.5, 191.5, 164.6, 159.5, 150.5, 145.2, 135.6, 134.3, 133.0 (2C), 130.6
(2C), 130.3, 130.1, 129.9, 129.2, 128.7 (2C), 128.3 (2C), 128.0, 127.9, 127.8,
127.7, 127.6, 127.3, 126.3, 117.4, 113.6, 82.8, 80.8, 73.0, 72.3, 59.4, 58.1, 57.3,
54.6, 51.4, 42.5, 38.0, 36.0, 30.6, 29.0, 25.9, 19.9, 18.2 (3C), 10.5, -2.4, -4.1; ES
+ α 18 HRMS m/z (M+Na) calcd 939.3013, obsd 939.2986; [ ]D +55.7 (c 0.28, CHCl3).
170 Allylated Bromodiosphenol 3.40
OPMB To a solution of 3.24 (24 mg, 0.0300 mmol) in 4 mL Br O AllO of dry DMF was added K2CO3 (20 mg, 0.150 mmol, OTBS O HO μ BzO H 5 eq) followed by distilled allyl iodide (13 L, 0.150 O mmol, 5 eq). The reaction mixture was stirred at room temperature for 2 h, quenched by the addition of 10% NaHSO3 solution until clear (~2 mL), and transferred to a separatory funnel. The aqueous layer was extracted with EtOAc (3 x 10 mL), and the combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting yellow oil was purified by column chromatography on
silica gel (5% to 20% EtOAc in hexanes) to yield 19 mg (75%) of 3.40 as an oil:
IR (neat, cm-1) 3492 (w), 2926, 2855, 1731, 1688, 1607, 1511, 1463, 1361 (w),
1249, 1181, 1113, 1066 (w), 1026 (w), 928 (w), 832 774 (w), 710 (w); 1H NMR
(500 MHz, CDCl3) δ 8.06 (d, J = 7.4 Hz, 2H), 7.61 (dd , J = 7.2, 7.2 Hz, 1H), 7.49
(dd, J = 7.7, 7.7 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 6.21-
6.13 (m, 1H), 5.53 (dd, J = 17.1, 1.1 Hz, 1H), 5.46 (d, J = 2.9 Hz, 1H), 5.33 (dd, J
= 13.2, 3.2 Hz, 1H), 5.05 (m, 2H), 4.69 (dd, J = 12.4, 5.5 Hz, 1H), 4.65 (d, J =
10.5 Hz, 1H), 4.30 (d, J = 2.5 Hz, 1H), 4.18 (dd, J = 10.7, 4.9 Hz, 1H), 3.84 (s,
3H), 3.81 (d, J = 2.8 Hz, 1H), 3.64 (s, 1H), 3.56 (s, 1H), 3.00 (d, J = 3.9 Hz, 1H),
2.31 (d, J = 4.8 Hz, 1H), 2.07-2.00 (m, 1H), 1.88-1.73 (m, 1H), 1.35 (s, 3H), 1.33-
1.27 (m, 1H), 1.25 (s, 3H), 1.10 (s, 3H), 0.91 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H);
13 C NMR (125 MHz, CDCl3) ppm 207.1, 192.5, 164.8, 159.4, 151.9, 135.5, 133.5,
133.4, 130.2, 130.0 (2C), 129.4 (2C), 129.1 (2C), 128.8 (2C), 118.4, 113.8, 82.3,
171 81.1, 75.5, 73.4, 72.7, 72.0, 63.5, 59.0, 58.1, 55.3, 52.1, 42.3, 38.3, 35.4, 30.2,
29.1, 25.9 (3C), 19.5, 18.2, 10.4, -2.4, -4.1; ES HRMS m/z (M+Na)+ calcd
861.2640, obsd 861.2608.
C14 Reduced Allylated Bromodiosphenol 3.41
A solution of 3.40 (9 mg, 0.0107 mmol) and OPMB Br O CeCl3·7H2O (20 mg, 0.0536 mmol, 5 eq) in 2 mL of AllO OTBS ° HO HO EtOH at 0 C was treated with NaBH4 (4 mg, 0.107 BzO H O mmol, 10 eq) and stirred for 3 h. The reaction
mixture was quenched with saturated NH4Cl solution, diluted with CH2Cl2, and transferred to a separatory funnel. The aqueous layer was extracted with CH2Cl2
(3 x 10 mL), and the combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting
oil was purified by column chromatography on silica gel (5% to 20% EtOAc in
hexanes) to yield 4 mg (50%) of 3.41 as a clear oil: IR (film, cm-1) 3376, 2925,
1 1728, 1511, 1463, 1250, 1181 (w), 1109, 830; H NMR (500 MHz, CDCl3) δ 8.05
(dd, J = 8.0, 0.91 Hz, 2H), 7.62 (dd, J = 7.5 Hz, 1H), 7.49 (dd, J = 7.8, 7.5 Hz,
1H), 7.39 (d, , J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.16-6.09 (m, 1H), 5.48-
5.41 (m, 3H), 5.30 (dd, J = 10.4, 1.1 Hz, 1H), 5.03 (d, J = 1.0 Hz, 1H), 4.81-4.75
(m, 1H), 4.62 (d, J = 10.6 Hz, 1H), 4.46 (d, J = 2.1 Hz, 1H), 4.35-4.24 (m, 2H),
4.20 (dd, J = 7.7, 3.2 Hz, 1H), 3.84 (s, 3H), 3.30 (dd, J = 4.1, 1.8 Hz, 1H), 3.17 (s,
1H), 2.59 (s, 1H), 2.54 (d, J = 4.3 Hz, 1H), 2.12-1.98 (m, 2H), 1.76-1.64 (m, 1H),
1.28 (s, 3H), 1.26 (s, 3H), 1.21 (s, 3H), 0.91-0.87 (m, 1H), 0.85 (s, 9H), 0.09 (s,
172 13 6H); C NMR (125 MHz, CDCl3) ppm 207.8, 164.5, 159.1, 156.3, 152.3, 143.7,
134.2, 133.7, 130.6 (2C), 130.1 (2C), 129.1 (2C), 128.9 (2C), 118.7, 113.9,
113.7, 108.8, 75.5, 72.8, 72.4, 71.3, 68.7, 60.8, 59.3, 55.3, 54.2, 41.6, 36.2, 31.0,
29.7, 25.9 (3C), 22.7, 19.4, 18.2, 14.1, 10.2, -2.5, -4.2; ES HRMS m/z (M+Na)+
α 21 calcd 863.2797, obsd 863.2833; [ ]D -9.52 (c 0.42, CHCl3).
Allylated DMS Protected Diosphenol 3.42
OPMB A 5 mL pear-shaped flask was charged with 3.38 O AllO (12 mg, 0.0158 mmol) in 2 mL of dry pyridine. In OTBS O O H μ DMS BzO one portion was added DMSCl (35 L, 0.315 mmol, O 20 eq), and the reaction mixture was stirred for 2 h,
quenched with saturated NaHCO3 solution, and transferred to a separatory
funnel. The aqueous layer was extracted with CH2Cl2 (3 x 10 mL), and the organic extracts were combined, washed with brine, and dried over MgSO4. The solution was concentrated under reduced pressure and high vacuum to yield 12 mg (100%) of 3.42 as an oil: IR (neat, cm-1) 3417, 2925, 2855, 1724, 1628,
1513, 1463, 1359 (w), 1251, 1180 (w), 1109, 1026 (w), 897 (w), 835, 774, 711;
1 H NMR (500 MHz, C6D6) δ 8.33 (d, J = 7.0 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H),
7.25-7.10 (m, 3H), 6.96 (d, J = 8.6 Hz, 2H), 6.19 (d, J = 5.4 Hz, 1H), 6.03-5.97
(m, 1H), 5.77 (d, J = 6.1 Hz, 1H), 5.43 (dd, J = 17.2, 1.5 Hz, 1H), 5.31 (m, 1H),
5.18 (dd, J = 10.8, 1.3 Hz, 1H), 5.02 (d, J = 10.4 Hz, 1H), 4.64 (dd, J = 9.4, 6.9
Hz, 1H), 4.61 (s, 1H), 4.36 (d, J = 10.5 Hz, 1H), 4.21 (dd, J = 12.5, 5.5 Hz, 1H),
4.08 (dd, J = 12.5 5.2 Hz, 1H), 3.52 (d, J = 5.4 Hz, 1H), 3.40 (s, 3H), 3.35 (d, J =
173 4.8 Hz, 1H), 3.19 (d, J = 3.8 Hz, 1H), 2.56 (d, J = 3.8 Hz, 1H), 2.09-1.98 (m, 1H),
1.95 (s, 3H), 1.84-1.78 (m, 1H), 1.53-1.49 (m, 1H), 1.39 (s, 3H), 1.11 (s, 3H),
1.09 (s, 9H), 0.26 (d, J = 2.5 Hz, 3H), 0.22 (d, J = 2.6 Hz, 3H),0.12 (s, 6H); 13C
NMR (125 MHz, C6D6) ppm 207.4, 192.3, 164.8, 159.9, 151.4, 133.1, 132.8,
130.4, 130.3, 130.2, 130.0 (2C), 129.9 (2C), 128.5 (2C), 128.3 (2C), 119.5,
117.7, 114.0, 86.8, 85.8, 74.1, 72.5, 71.7, 69.3, 56.8, 55.1, 54.9, 54.6, 53.7, 42.6,
41.9, 31.2, 30.0, 27.8, 27.0, 25.9 (3C), 22.1, 18.3, 12.9, 1.7, 1.0, -2.3, -4.4; ES
+ α 19 HRMS (M+Na) calcd 841.3774, obsd 841.3778; [ ]D +9.4 (c 0.39, CHCl3).
Allylated DMS Protected Selenodiosphenol 3.44
OPMB The C1 alcohol 3.42 (100 mg, 0.109 mmol) was PhSe O AllO dissolved in 5.4 mL of dry pyridine at room OTBS O O H temperature. To this solution was added Me SiHCl DMS BzO 2 O (242 μL, 2.18 mmol, 20 eq), the reaction mixture was stirred for 1 h and carefully quenched by addition of 3 mL of saturated
NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (3 x 10 mL),
and the combined organic fractions were washed with brine, dried over MgSO4,
filtered, concentrated under reduced pressure, and placed under high vacuum to
remove pyridine. The residue was purified by column chromatography on silica
gel (5% EtOAc in hexanes) to give 96 mg (90%) of 3.44 as a clear oil: IR (film,
cm-1) 2952, 2928, 2856, 1727, 1682, 1613 (w), 1576 (w), 1513, 1463 (w), 1451
(w), 1250, 1188 (w), 1153 (w), 1111, 1026, 899 836, 711; 1H NMR (500 MHz,
C6D6) δ 8.48 (d, , J = 8.3, 1.6 Hz, 2H), 7.67 (dd, J = 5.6, 2.0 Hz, 2H), 7.45 (d, J =
174 8.6 Hz, 2H), 7.25-7.14 (m, 6H), 7.10-7.06 (m, 3H), 6.92 (d, J = 8.3 Hz, 2H), 6.35-
6.36 (m, 1H), 6.06 (d, J = 2.9 Hz, 1H), 5.61 (dq, J = 17.2, 1.5 Hz, 1H), 5.50-5.47
(m, 1H), 5.45 (dt, , J = 5.9, 1.5 Hz, 1H), 5.24 (dq, , J = 10.7, 1.6 Hz, 1H), 5.15 (d,
, J = 1.1 Hz, 1H), 5.04 (ddt, J = 12.5, 5.4, 1.5 Hz, 1H), 4.68 (d, J = 9.5 Hz, 1H),
4.53 (dd, J = 11.1, 4.9 Hz, 1H), 4.48 (d, J = 2.4 Hz, 1H), 3.79 (s, 1H), 3.77 (s,
1H), 3.43 (s, 3H), 3.42 (s, 1H), 3.21 (dd, J = 4.8, 1.5 Hz, 1H), 2.09 (d, J = 5.0 Hz,
1H), 1.99-1.91 (m, 1H), 1.90-1.83 (m, 1H), 1.86 (s, 1H), 1.65 (s, 1H), 1.55 (s,
3H), 1.53-1.50 (m, 4H), 1.19 (s, 3H), 1.09 (dt, J = 13.5, 4.0 Hz, 1H), 1.05 (s, 9H),
0.95 (s, 3H), 0.31 (d, J = 2.5 Hz, 3H), 0.21 (s, 3H), 0.14 (s, 3H), 0.08 (d, J = 2.6
13 Hz, 3H); C NMR (125 MHz, C6D6) ppm 209.8, 207.5, 205.6, 190.9, 164.6,
163.7, 159.6, 151.2, 143.4, 135.5, 134.4, 133.1, 130.9, 130.6, 130.1, 129.8 (2C),
129.3 (2C), 129.1 (2C), 128.9 (2C), 126.6, 117.4, 113.9, 113.6, 89.6, 87.3, 85.1,
84.2, 83.2, 75.6, 75.1, 73.1, 72.3, 71.8, 71.1, 65.8, 61.8, 59.0, 58.1, 57.6, 57.1,
54.6, 51.5, 49.6, 44.1, 38.6, 35.5, 33.5, 31.2, 30.3, 25.9 (3C), 20.5, 18.1, 10.7,
+ α 18 1.5, -2.4, -4.2; ES HRMS m/z (M+Na) calcd 997.3252, obsd 997.3225; [ ]D
+42.1 (c 0.48, CHCl3).
A-Ring Epoxide 3.47
A 50 mL round-bottomed flask containing 3.33 (155 OPMB O O mg, 0.210 mmol), NaHCO (265 mg, 3.15 mmol, 15 MeO 3 OTBS HO HO eq), 10.5 mL of acetone, and 10.5 mL of H2O was BzO H O cooled to 0 °C with vigorous stirring. To this
solution was added Oxone® (645 mg, 1.05 mmol, 5 eq), and the reaction mixture
175 was stirred for 2 h, filtered through a plug of silica gel, and the filtrate was
transferred to a separatory funnel. The aqueous layer was extracted with 3 x 10
mL of EtOAc, and the combined organic fractions were washed with brine, dried
over MgSO4, filtered, and concentrated under reduced pressure. The resulting
oil was purified by column chromatography on silica gel (5:1 hexanes:EtOAc) to
yield 20 mg of 3.33, and 62 mg (45%) of 3.47 as a cloudy oil: IR (neat, cm-1)
3378, 2953, 2928, 2856, 1728, 1611, 1513, 1463, 1387, 1251, 1109, 1026, 833,
1 775, 711; H NMR (500 MHz, C6D6) δ 8.29 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.6
Hz, 2H), 7.21 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.8 Hz, 2H), 6.95 (d, J = 8.2 Hz,
2H), 5.98 (d, J = 1.9 Hz, 1H), 5.72 (d, J = 13.3 Hz, 1H), 4.96 (d, J = 10.6 Hz, 1H),
4.56 (s, 1H), 4.44 (d, J = 13.3 Hz, 1H), 4.38 (d, J = 10.6 Hz, 1H), 4.19 (dd, J =
11.4, 4.7 Hz, 1H), 4.08 (s, 1H), 3.84 (s, 3H), 3.70 (s, 1H), 3,45 (s 3H), 3.43 (s,
1H), 3.27 (d, J = 4.7 Hz, 1H), 3.13 (s, 1H), 2.98 (s, 1H), 2.35 (t, J = 13.7 Hz, 1H),
2.12 (d, J = 4.7 Hz, 1H), 1.80-1.78 (m, 1H), 1.77 (s, 3H), 1.63 (s, 1H), 1.59 (s,
1H), 1.52 (s, 1H), 1.44-1.40 (m, 1H), 1,38 (s 1H), 1.00 (s, 3H), 0.96-0.88 (m, 1H),
13 0.10 (s, 3H), 0.09 (s, 3H); C NMR (125 MHz, C6D6) ppm 206.5, 164.3, 159.6,
133.4, 130.7, 130.1 (2C), 129.7, 129.4 (2C), 129.1 (2C), 128.8 (2C), 113.9, 84.8,
84.0, 77.8, 76.0, 73.1, 73.0, 67.4, 61.3, 60.6, 59.8, 57.7, 54.5, 53.5, 51.5, 39.3,
37.9, 35.2, 30.2, 29.4, 25.9 (3C), 21.3, 20.3, 18.2, 13.4, 10.6, -2.4, -4.0; ES
+ α 18 HRMS m/z (M+Na) calcd 775.3484, obsd 775.3496; [ ]D .-22.1 (c 0.10, CHCl3).
176 PMB Cleaved Products 3.53-Z and 3.53-E (Z & E isomers)
A solution of 3.34 (26 mg, 0.0319 mmol), OHC
CO2Me NaHCO3 (40 mg, 0.479 mmol, 15 eq), and O ® Br O Oxone (196 mg, 0.319 mmol, 10 eq) in 1.6 MeO OTBS mL of CH3CN and 800 μL of H2O was cooled HO HO BzO H O to 0 °C. To the solution was added
trifluoroacetone (9 μL, 0.0957 mmol, 3 eq) and the reaction mixture was stirred
for 3 h, and the reaction mixture was filtered through a plug of silica gel. The filtrate was concentrated under reduced pressure, and the resulting oil was purified by column chromatography on silica gel (5% EtOAc in hexanes) to return
13 mg of 3.4 (50% conversion) and 6 mg of 3.53-Z (46%) as a cloudy oil.
For 3.53-Z: IR (neat, cm-1) 3382, 2953, 2926, 2855, 2360, 2343, 1728, 1682,
1 1451, 1252, 1178, 1111, 832; H NMR (500 MHz, C6D6) δ 9.93 (d, , J = 8.1 Hz,
1H), 8.27 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 7.3 Hz, 1H), 7.11 (d, J = 7.8 Hz, 2H),
6.64 (dd, J = 8.0, 1.5 Hz, 1H), 6.36 (d, J = 12.2 Hz, 1H), 5.94 (d, J = 2.3 Hz, 1H),
5.89 (d, J = 12.2 Hz, 1H), 5.73 (d, J = 13 Hz, 1H), 5.23 (d, J = 1.2 Hz, 1H), 4.72
(d, J = 2.1 Hz, 1H), 4.67 (d, J = 14.4 Hz, 1H), 4.40 (d, J = 13 Hz, 1H), 4.37 (d, J =
14.4 Hz, 1H), 4.28 (dd, J = 11.3, 4.8 Hz, 1H), 3.80 (s, 3H), 3.41 (s, 3H), 3.37 (s,
1H), 3.18 (dd, J = 4.2, 1.9 Hz, 1H), 2.75 (s, 1H), 2.11 (t, J = 13.8 Hz, 1H), 2.04 (d,
J = 4.4 Hz, 1H), 1.73-1.66 (m, 1H), 1.56 (s, 3H), 1.46 (s, 3H), 1.44-1.37 (m, 1H),
1.18 (s, 3H), 1.06-1.01 (m, 1H), 1.00 (s, 9H), 0.89 (dt, J = 13, 3.1 Hz, 1H), 0.14
13 (s, 3H), 0.08 (s, 3H); C NMR (125 MHz, C6D6) ppm 207.0, 189.9, 164.6, 164.2,
154.9, 154.2, 138.4, 133.4 (2C), 130.0 (2C), 129.4 (2C), 128.9 (2C), 126.5,
177 125.1, 106.7, 83.3, 76.9, 75.8, 73.7, 72.9, 70.6, 61.8, 60.6, 59.8, 57.5, 53.6, 51.3,
41.7, 36.4, 35.9, 30.2, 29.0, 25.9 (3C), 20.1, 18.2, 13.9, 10.4, -2.6, -4.3; ES
+ α 21 HRMS m/z (M+Na) calcd 869.2538, obsd 869.2512; [ ]D -3.2 (c 0.06, CHCl3).
1 For 3.53-E: H NMR (500 MHz, C6D6) δ 9.81 (d, J = 7.0 Hz, 1H), 8.15 (m, 2H),
8.08 (d, J = 16 Hz, 1H), 7.07 (m, 1H), 6.98 (m, 2H), 6.56 (dd, J = 16, 0.5 Hz, 1H),
6.49 (brd, J = 7 Hz, 1H), 5.82 (d, J = 2.5 Hz, 1H), 5.62 (d, J = 13 Hz, 1H), 5.12 (d,
J = 1.5 Hz, 1H), 4.65 (brdd, J = 13.5, 1.5 Hz, 1H), 4.59 (d, J = 2.5 Hz, 1H), 4.26
(dd, J = 13, 2 Hz, 1H), 4.17 (dd, J = 11, 4.5 Hz, 1H), 4.11 (dd, J = 13.5, 1.5 Hz,
1H), 3.68 (s, 3H), 3.39 (s, 3H), 3.23 (brdd, J = 2, 1.5 Hz, 1H), 3.05 (dd, J = 4.5, 2
Hz, 1H), 2.60 (s, 1H), 1.99 (brdddd, J = 14, 13.5, 4, 2 Hz, 1H), 1.91 (d, J = 4.5
Hz, 1H), 1.58 (dddd, J = 12.5, 4.5, 4, 4 Hz, 1H), 1.47 (s, 3H), 1.33 (s, 3H), 1.28
(dddd, J = 14, 12.5, 11, 3 Hz, 1H), 1.03 (s, 3H), 0.88 (s, 9H), 0.77 (ddd, J = 13.5,
13 4, 3 Hz, 1H), -0.02 (s, 3H), -0.05 (s, 3H); C NMR (100 MHz, C6D6) ppm 207.3,
189.0, 166.1, 164.4, 154.5, 148.5, 136.2, 133.6, 131.7, 130.2 (2C), 129.1 (2C),
125.3, 106.6, 83.7, 77.1, 76.0, 73.8, 73.0, 70.8, 61.9, 60.8, 59.9, 57.8, 53.8, 51.5,
41.9, 36.6, 36.1, 30.3, 29.2, 26,1 (3C), 20.1, 18.5, 10.6, -2.4, -3.9; ES HRMS m/z
(M+Na)+ calcd 869.2538 and 871.2571, obsd 869.2512 and 871.2518.
178 A-Ring Diol 3.48
A solution of 3.47 (51 mg, 0.0677 mmol) in 6.7 mL OPMB HO O MeO of MeOH was cooled to 0 °C and PPTS (9 mg, MeO OTBS HO HO 0.0339 mmol, 0.5 eq) was added. The reaction BzO H O mixture was stirred for 3 h, quenched with saturated
NH4Cl solution, diluted with CH2Cl2, and transferred to a separatory funnel. The
aqueous layer was extracted with 3 x 25 mL of CH2Cl2, and the combined
organic extracts were washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure to give an oil, which was purified by
column chromatography on silica gel, to give 12 mg of 3.47 and 11 mg (27%) of
3.48 as an oil: IR (neat, cm-1) 3429, 2928, 2856, 1727, 1611, 1512, 1463, 1251,
1 1100, 1110, 1069, 1036, 990, 922, 832, 756, 712; H NMR (500 MHz, C6D6) δ
8.34 (d, J = 7.1 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 7.5 Hz, 1H), 7.11
(d, J = 7.5 Hz, 2H), 6.95 (d, J = 8.2 Hz, 2H), 6.03 (d, J = 2.3 Hz, 1H), 5.23 (d, J =
12.9 Hz, 1H), 4.98 (s, J = 11.0 Hz, 1H), 4.89 (s, 1H), 4.69 (s, 1H), 4.64 (d, J =
10.6 Hz, 1H), 4.39 (dd, J = 11.4, 4.7 Hz, 1H), 4.28 (d, J = 13.3 Hz, 1H), 3.47 (s,
1H), 3.41 (s, 3H), 3.36 (s, 3H), 3.29 (dd, J = 4.5, 1.7 Hz, 1H), 3.28 (s, 1H), 3.20
(s, 3H), 3.09 (s, 1H), 2.12-2.06 (m, 1H), 2.05 (d, J = 4.7 Hz, 1H), 1.89-1.80 (m,
1H), 1.64 (s, 3H), 1.62 (s, 3H), 1.61-1.58 (m, 1H, obstructed by singlet at 1.62),
1.40 (s, 3H), 1.04 (s, 9H), 1.02-0.97 (m, 1H), 0.14 (s, 3H), 0.12 (s, 3H); 13C NMR
(125 MHz, C6D6) ppm 207.8, 164.4, 159.6, 133.2, 130.9 (2C), 130.1 (2C), 129.9
(2C), 129.2, 128.8 (2C), 113.9, 98.7, 86.9, 80.1, 78.9, 75.7, 72.7, 72.1, 62.7,
61.2, 60.2, 54.5, 53.2, 50.2, 48.5, 40.1, 38.9, 35.6, 30.4, 25.8 (3C), 22.9, 21.0,
179 18.2, 14.1, 10.8, -2.5, -4.0; ES HRMS m/z (M+Na)+ calcd 807.3746, obsd
α 18 807.3719; [ ]D -31.4 (c 0.4, CHCl3).
A-Ring Ketone 3.49
A solution containing 3.48 (21 mg, 0.0268 mmol), OPMB O O MeO NMO·H2O (7 mg, 0.0535, 2 eq), and 4 Å molecular MeO OTBS HO HO sieves (100 mg) in 2.7 mL of CH2Cl2 was treated BzO H O with TPAP (2.4 mg, 0.00669 mmol, 0.25 eq) at room
temperature. The reaction mixture was stirred overnight, and filitered through a
plug of silica gel (eluent CH2Cl2). The filtrate was concentrated under reduced pressure, and the oil was purified by column chromatography on silica gel (5% to
25% EtOAc in hexanes) to give 12 mg of 3.48 (42% conversion) and 4 mg (45%) of 3.49 as a cloudy oil: IR (neat, cm-1) 3397, 2953, 2929, 2360, 2342, 1731,
1702, 1514, 1456, 1251, 1098, 1049, 1033, 832, 716, 711; 1H NMR (500 MHz,
C6D6) δ 8.31 (d, , J = 7.1 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 7.18 (t, J = 7.6 Hz,
1H), 7.09 (t, J = 7.8 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.12 (d, J = 2.6 Hz, 1H),
5.58 (d, J = 2.0 Hz, 1H), 5.46 (d, J = 13.5 Hz, 1H), 5.10 (d, J = 10.1 Hz, 1H), 4.65
(d, J = 10.3 Hz, 1H), 4.53 (d, J = 13.4 Hz, 1H), 4.35 (dd, J = 11.2, 4.7 Hz, 1H),
3.93 (s, 3H), 3.41 (s, 3H), 3.40 (s, 1H), 3.27 (s, 3H), 3.22 (d, J = 4.4 Hz, 1H), 3.06
(s, 1H), 2.85 (d, J = 1.5 Hz, 1H), 2.46 (t, J = 13.2 Hz, 1H), 2.07 (d, J = 4.5 Hz,
1H), 1.80-1.74 (m, 2H), 1.71 (s, 3H), 1.56 (s, 3H), 1.37 (s, 3H), 1.00 (s, 9H), 0.94-
13 0.87 (m, 1H), 0.22 (s, 3H), 0.11 (s, 3H); C NMR (125 MHz, C6D6) ppm 206.3,
203.9, 164.2, 159.7, 133.3, 130.8, 130.1 (2C), 129.6, 129.4, 128.8 (2C), 128.1
180 (2C), 113.9 (2C), 98.5, 82.7, 81.9, 78.1, 74.2, 73.1, 72.5, 64.2, 61.9, 60.9, 54.5,
53.7, 52.6, 51.4, 42.3, 38.5, 34.2, 30.0, 25.9 (3C), 20.2, 18.2, 10.7, -2.7, -4.4; ES
+ α 21 HRMS m/z (M+Na) calcd 805.3590, obsd 805.3566; [ ]D -30.0 (c 0.14, CHCl3).
181
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192
APPENDIX A: 1H NMR DATA
193
0.0
2.999 2.999
3.031 3.031
1.0
1.063 1.063
1.043 1.043
1.028 1.028
1.007 1.007
1.160 1.160 2.0
0.941 0.941 1.197 1.197 3.0
2.1 0.988 0.988
4.0 1.000 1.000 H NMR Spectrum of 5.0 1 O Cl 2 SO 6.0 Figure A.1 7.0 8.0 8.0 PPM 194 2.3 H NMR Spectrum of 1 O Figure A.2
195 2.4 H NMR Spectrum of 1 OH O Figure A.3
196 1.90 H NMR Spectrum of 1 OPMB O Figure A.4
197 2.5 H NMR Spectrum of 1 -Bu t O O Figure A.5 Br
198 6.7493 0.0 0.4
0.8 10.725 1.2
1.6 2.0164 2.0
2.4 2.0017 2.8 2.6
3.2 2.1690 3.6 4.0 4.4 (ppm) 4.8 H NMR Spectrum of 1 5.2
OTBS 0.9326 1.0000 5.6 6.0 Figure A.6 6.4 Br 6.8 7.2 7.6 8.0 8.4 8.8
9.2 Integral
199 2.7 H NMR Spectrum of 1 OTBS Figure A.7 O H
200 1.91 H NMR Spectrum of 1 OTBS Figure A.8 I
201 1.89 H NMR Spectrum of 1 OTBS OPMB OH Figure A.9
202 1.88 H NMR Spectrum of 1 OTBS O H H OPMB Figure A.10 Figure A.10
203 2.9 H NMR Spectrum of 1 OTBS O H OPMB Figure A.11 Figure A.11 HO HO
204 2.10 H NMR Spectrum of OTBS 1 O H OPMB Figure A.12 O O O
205 OH O H NMR Spectrum of intermediate alcohol intermediate of H NMR Spectrum 1 H OPMB O O O Figure A.13
206 1.87 O H H NMR Spectrum of 1 O H OPMB O Figure A.14 Figure A.14 O O
207 2.11 H NMR Spectrum of 1 OH O H OPMB Figure A.15 Figure A.15 HO HO
208 0.0 0.4
0.8
3.0620 2.8841 2.9704
1.2 1.1579
1.6
1.0833 1.1507
2.0 2.1734
1.0938 1.0203
2.4
1.0921
1.7430 1.0128
2.8 0.8634 2.12
3.2 0.9652
3.6
1.1135
3.1464
0.9496 4.0 0.9648 4.4
(ppm)
0.9883 1.0000 4.8
H NMR Spectrum of 0.9508 1 OH 5.2 OH 5.6 H OPMB 6.0 O Figure A.16 Figure A.16 6.4 HO
6.8
2.0305 2.2185 7.2 7.6 8.0 8.4 8.8
9.2 Integral
209 2.19 H NMR Spectrum of 1 OTBS O H OPMB Figure A.17 Figure A.17 HO HO
210 2.20 H NMR Spectrum of 1 OTBS O H OPMB Figure A.18 Figure A.18 O HO
211 2.25 H NMR Spectrum of 1 OTBS O H OPMB HO Figure A.19 Figure A.19 O HO
212 ediate hydroxy epoxide ediate OTBS O O H OPMB H NMR Spectrum of interm HO 1 O HO Figure A.20 Figure A.20
213 2.24 H NMR Spectrum of 1 OTBS O O H OPMB BzO Figure A.21 Figure A.21 O HO
214 1.85 H NMR Spectrum of 1 OTBS O OPMB O H Figure A.22 Figure A.22 BzO HO O
215
4.0329 4.9991 0.0
0.4
14.372 0.8
4.3576
4.3965
5.8031 1.2
4.5196
2.0242
2.7547 1.6 1.6168
2.0 1.0919
2.4 0.9533 2.8
3.1 0.9693
3.2
1.0392
1.1583 3.6 4.1399
4.0
1.2482 1.0041
4.4 1.0431 0.8865 (ppm) 4.8 H NMR Spectrum of 1 OTBS
5.2
O 0.9499 OPMB O 5.6 H
6.0 0.5797
Figure A.23 Figure A.23 BzO HO 1.0000 O 6.4
HO 6.8 2.4056
7.2
2.5523
2.5300 0.9873
7.6 2.3283 8.0 8.4 8.8
9.2 Integral
216 3.15 H NMR Spectrum of OTBS 1 O OPMB O H O BzO Figure A.24 Figure A.24 O Si 2 HMe
217 3.21 H NMR Spectrum of 1 OTBS O OPMB O H Figure A.25 Figure A.25 BzO HO O
218
1.6603 2.8775
0.0 2.8207 33.120
0.4
2.8014
0.8
10.258
1.5429
3.5214 1.6037
1.2
4.2268 3.0613
1.6 1.8509
1.0099 1.2195 2.0 2.4
2.8 1.0137 3.23
3.2 0.9110 2.7682
0.9940 1.0387
3.6 1.1091
4.0
1.0847 1.6873
4.4 1.0190 (ppm) 4.8 H NMR Spectrum of
OTBS
1 0.9812 5.2 O OPMB O 5.6
H 1.0000 6.0 BzO HO Figure A.26 Figure A.26 O
6.4 PhSe 2.3027
HO 6.8
2.9110
2.9237 1.3954
7.2 2.7953 2.0934 7.6
8.0 2.0111 8.4 8.8
9.2 Integral
219
0.0 22.291 2.6090 0.4
0.8 12.901
2.1365
3.3858
3.0013 1.2 7.4367 3.6602
1.6
2.7957 1.1931
2.0 0.8576 1.1408 2.4
2.8 1.0423 3.24
3.2
1.0347 1.0807
3.6
1.0861 4.7706
4.0
1.8595 1.0662 4.4
(ppm) 1.3287 4.8
H NMR Spectrum of OTBS 0.9763 1
5.2
O 1.0000 OPMB O 5.6 H 6.0 BzO HO Figure A.27 Figure A.27 O 6.4 Br
HO 6.8 3.0411
7.2
2.1416
3.0083 1.4533 7.6
8.0 2.1072 8.4 8.8
9.2 Integral
220 3.25 OTBS H NMR Spectrum of 1 O OPMB O H BzO HO O Figure A.28 Figure A.28 O Si H
221 7.0404
0.0 11.956
0.4
1.5117 0.8
12.537 4.4539
1.2 6.9371 3.5896
1.6
3.7299 1.6014
2.0 1.9605 1.3978 2.4
2.8
1.1542 1.1291 3.30
3.2 4.0797 1.2014
3.6
1.1158
1.2577 4.0 6.1196 4.4 OTBS
(ppm) 1.3082
4.8 O 1.8910 H NMR Spectrum of
1 1.9025 OPMB O 5.2
H 1.6861 5.6
BzO
HO O 1.0451 6.0
Figure A.29 Figure A.29 O 1.0000
6.4 O
2.8796 6.8 AllO 4.8131
7.2 2.6216 7.6
8.0 2.1840 8.4 8.8
9.2 Integral
222
3.2011 0.0 3.3162 0.4
0.8
12.865
3.5174 3.8542
1.2 5.2207
3.9327 1.6 1.5854
2.0 1.4312
2.4
1.2408 0.9085 2.8
3.31 1.9866 3.2
3.6
2.9988 3.9196
4.0
1.2872
1.1992 1.0224 4.4
(ppm) 1.2117 4.8 OTBS H NMR Spectrum of 1 O 5.2
OPMB O 1.0000 5.6
H 0.9599 6.0 BzO HO Figure A.30 Figure A.30 O 6.4
6.8 MeO 2.0444
7.2
2.0895
2.6728
1.4198
7.6 2.2681 8.0 8.4 8.8
9.2 Integral
223
0.0 28.548 0.4
0.8
9.4357
2.5330
3.1131
1.1426
2.3413 1.2 3.7964 3.4341
1.6
1.1199
1.8828
1.9068 2.0 1.1029 2.4
2.8 0.9820 3.32
3.2
1.0012
1.0197 3.6
1.1859 3.7293
4.0
3.1362
1.1037 1.0408 4.4
(ppm) 1.0183 4.8
OTBS
H NMR Spectrum of 0.9702 1
O 5.2 1.0000 OPMB O 5.6 H 6.0 BzO HO Figure A.31 Figure A.31 O 6.4 Br
6.8
MeO 2.4907
7.2
2.0241
2.7006 1.2991 7.6
8.0 1.9834 8.4 8.8
9.2 Integral
224
2.9614 2.8724
0.0 6.0884
0.4
2.0333 0.8
8.9280
1.4117 3.0203
1.2
3.3464
2.9641
1.2767
1.6
1.2753 1.0578 2.0
2.4 1.0411 2.8
3.33 2.2515
2.9763 3.2 3.0250 0.8090 3.6
4.0
1.0821
1.0182 1.1213
4.4 2.0505 (ppm)
4.8
OTBS 1.0145 0.9916 H NMR Spectrum of
1 1.0732 O 5.2 OPMB O 5.6
H 1.0000 6.0 BzO HO Figure A.32 Figure A.32
HO 6.4
2.0813 6.8
MeO 2.0969 1.3550
7.2 1.9390 7.6
8.0 2.0562 8.4 8.8
9.2 Integral
225
0.0 24.395
0.4
9.2657 0.8
5.8405 3.6266 1.2
1.6
1.7170 1.1273
2.0 2.0297
2.4 1.1471 2.8
3.34 0.9661
3.2 0.9904
3.6
3.1489 2.9350
4.0
1.4745
1.0066
0.9825 1.0146 4.4
(ppm) 1.0479 4.8
OTBS
H NMR Spectrum of 0.9956 1
O 5.2
0.8210 1.0000 OPMB O 5.6 H 6.0 BzO HO Figure A.33 Figure A.33 HO 6.4 Br
6.8
MeO 1.9937
7.2
1.9852
2.0774
1.0444
7.6 1.9723 8.0 8.4 8.8
9.2 Integral
226
3.1871
3.0929 0.0 7.6018 0.4
0.8 12.219 3.9126
1.2
3.9144 3.2154
1.6 1.4060
1.1862 2.0307
2.0 2.9212
2.4 1.0734 2.8 3.36
3.2 3.1724
1.0020 2.8554
3.6 0.8891
4.0
1.0365 1.1070
4.4 1.0828 (ppm) 4.8
OTBS 1.0946 H NMR Spectrum of
1 O 1.0581 5.2 OPMB O 5.6
H 1.0000 6.0 BzO HO Figure A.34 Figure A.34 SMe O
6.4
Br
S 0.9291
2.0326 6.8 MeO 2.5726
7.2 2.0462 7.6
8.0 1.9349 8.4 8.8
9.2 Integral
227
1.5230 0.0 3.6664
0.4
11.585 0.8
2.9173 2.3283
1.2 10.976
1.6 1.3423
2.0 0.7615
2.4 0.7578 0.8588
2.8 0.8996 3.38 3.2
3.6
1.7264 0.5660
4.0
2.0541 0.9400 4.4
(ppm) 0.5189 4.8 OTBS H NMR Spectrum of 1
5.2 O
0.7076 0.5845
OPMB O 0.4385 5.6
H
0.4223 0.3922 6.0 BzO HO Figure A.35 Figure A.35 O 6.4
AllO 6.8 1.0656
7.2
0.9505
1.0883 0.5682
7.6 1.0000 8.0 8.4 8.8
9.2 Integral
228
0.0
3.0156 2.9937 0.4
0.8
11.547
3.5975 3.3212
1.2 7.0235
1.6
1.4077 2.3331 2.0 2.4
2.8 0.9999 3.39
3.2
3.2058
1.0279 3.6 1.0688
4.0 1.0384
1.0776 4.4
0.9847 1.0111 (ppm) 4.8
OTBS H NMR Spectrum of
1.0943 1
0.9813
1.0251 5.2 O 1.0866
OPMB O 1.0767 5.6
H 1.0223 6.0 BzO HO
Figure A.36 Figure A.36 1.0000 O 6.4 PhSe
AllO 6.8
3.1804
2.3491 1.4080
7.2
2.0753 1.9655 7.6
8.0 1.9206 8.4 8.8
9.2 Integral
229
3.4107 0.0 3.3343
0.4
11.246 0.8
3.6625
3.9069
1.2 3.6782
3.8297 2.9955
1.6
2.6984 1.3114
2.0 1.1500 2.4
2.8 1.0687 3.40
3.2
1.1077
1.0977
3.6
1.1220 3.4458
4.0
1.1453 1.0839 4.4
(ppm) 2.2163 4.8
OTBS H NMR Spectrum of 2.1797 1
5.2 O
1.2572
1.1110 1.0495 OPMB O 5.6 H
6.0 BzO 1.0000 HO Figure A.37 Figure A.37 O 6.4 Br
AllO 6.8 2.2963
7.2
2.2481
2.2625 1.0790
7.6 2.2017 8.0 8.4 8.8
9.2 Integral
230 4.9806 0.0
0.4
8.2094 0.8 2.2838
2.7478
2.8427
3.7997 1.2 7.3061
5.0233
1.6
1.8671 1.4890
2.0 1.4451
2.4
1.0188 0.9404 2.8
3.41 0.9101
3.2 0.9108
3.6 2.5989
4.0
2.2956
1.2554
2.1917
0.9109 4.4
0.9865 (ppm) 1.6536 4.8
OTBS H NMR Spectrum of 0.9277 1
5.2 O 1.1927
1.3643 1.4205 OPMB O 5.6 H
6.0 1.0000 BzO HO Figure A.38 Figure A.38 6.4 HO Br
AllO 6.8 1.9131
7.2
1.7805
1.9063 1.0059
7.6 1.8108 8.0 8.4 8.8
9.2 Integral
231
0.0 5.9620
2.8319
2.9504 2.1663
0.4 1.4047
0.8
3.8197
9.8991 3.2295
1.2 5.3111
1.6
1.7932
2.9531 1.5836 2.0
2.4 1.0327 2.8
3.42 0.9861
3.2
1.0178
3.0135 1.0789 3.6
4.0 1.1634
1.1820 1.1107
4.4 2.0909 (ppm) 4.8
OTBS H NMR Spectrum of
1.1213
1 1.1098
5.2 O 1.0093 1.1697 OPMB O 5.6
H 1.0526 1.1669
6.0 O BzO 1.0000 Figure A.39 Figure A.39 O 6.4 DMS
AllO 6.8
2.1554
2.1121 1.4303
7.2 2.1294 7.6
8.0 2.0223 8.4 8.8
9.2 Integral
232
0.0
2.9738 2.9686 0.4
0.8
10.118
3.7811 3.0356
1.2
3.5130 3.2028
1.6
1.4824 2.2941 2.0 2.4
2.8 0.9850 3.44
3.2 3.0587
3.6 1.0170 1.0235
4.0 1.0017
0.9962 4.4
1.0171 1.0158 (ppm) 4.8
OTBS H NMR Spectrum of
1.0547 1
0.9970
1.0304 5.2 O 1.0594
OPMB O 1.1037 5.6
H 0.9987 6.0 O BzO
Figure A.40 Figure A.40 1.0000 O 6.4 DMS PhSe
AllO 6.8
2.2531
3.0887
2.3444 1.3883
7.2
2.1560 2.0594 7.6
8.0 1.9944 8.4 8.8
9.2 Integral
233 6.2960 0.4
0.8
14.369 0.9427
1.2
4.1396
4.7010
3.2310 1.0292
1.6 3.0225
2.0
1.3016 0.9807 2.4
2.8
1.0213
1.0076
1.0313 3.2
0.9439 3.0479 3.47
3.6 1.0422
3.9599
1.0222 4.0
1.0000
1.2275
1.2462
4.4 0.9890
4.8 (ppm) 0.9874 OTBS H NMR Spectrum of 5.2 1 O
5.6 1.1280
OPMB O H 1.0156 6.0 BzO HO Figure A.41 Figure A.41 6.4 O HO
6.8 2.6594
MeO
2.7533 1.5784
7.2 2.0521 7.6
8.0 2.6469 8.4 8.8
9.2 Integral
234
3.9112 0.0 3.5529
0.6
2.3631
13.060
1.1181 3.1368
1.2
7.2362
4.1553
2.9616 0.6627
1.8
1.4243 1.6833
2.4 1.1969
3.0
Z
1.3107
1.1987
3.2553 0.4544 3.53-
3.6
3.6583
1.3505 4.2
4.6096
1.1036 1.1533 4.8
(ppm) 1.1286 5.4 H NMR Spectrum of
1 1.2367
1.0107 1.1728
6.0
1.0016 1.1060 6.6
Figure A.42 Figure A.42
3.4277 2.3761 7.2 Me 2 7.8 CO
OTBS 2.5047 8.4 O O O 9.0 H OHC BzO HO 9.6
HO
Br 1.0000
10.2 MeO Integral
235 E 3.53- Me 2 CO H NMR Spectrum of 1 OTBS O O O H OHC BzO HO Figure A.43 Figure A.43 HO Br MeO
236
0.0 3.4992 3.0874 0.4
0.8
4.0188 11.510
1.2
6.3843
4.5680
3.6932 1.6
1.6507 2.5073 2.0 2.4
2.8 1.0523
3.48
3.1976
2.1910 3.2
3.2008
3.3024 1.1587
3.6
1.3807
4.0
1.2108 1.2207
4.4
1.0667 (ppm) 1.0242
4.8 1.0329 OTBS 1.0640 H NMR Spectrum of
1 1.0298 5.2 O OPMB O 5.6
H 1.0000 6.0 BzO HO Figure A.44 Figure A.44 6.4 HO HO
MeO MeO 6.8
2.2386
2.2926 1.2754
7.2 2.1705 7.6
8.0 2.1775 8.4 8.8
9.2 Integral
237
0.0 2.8244 2.7662 0.4
0.8 1.1948 9.2325
1.2
3.4428 3.2561
1.6 3.7416
1.7554
1.2515 2.0
1.1547 2.4
0.9693 2.8 0.9275
3.49
1.0672
2.7370 3.2 3.8780
3.6 2.7832
4.0 1.0465
4.4 1.0486
(ppm) 1.0341 4.8 OTBS H NMR Spectrum of
1 1.0450
5.2 O
1.0605 OPMB O 1.0721 5.6 H
6.0 1.0000 BzO HO Figure A.45 Figure A.45 O 6.4 HO
MeO MeO 6.8
2.3760
2.0879 1.2151
7.2 1.9964 7.6
8.0 2.0177 8.4 8.8
9.2 Integral
238