Synthesis and Reactions of Unsymmetrical Oxabicyclic Alkenes

561 Pages·2011·34.44 MB·English

Synthesis and Reactions of Unsymmetrical Oxabicyclic
Alkenes: Studies toward the Total Synthesis of Phorbol
and Prostratin
by
Robert Alan Webster
A thesis submitted in conformity with the requirements
for the degree of Doctor of Philosophy
Graduate Department of Chemistry
University of Toronto
© Copyright by Robert Alan Webster 2011
Synthesis and Reactions of Unsymmetrical Oxabicyclic Alkenes:
Studies toward the Total Synthesis of Phorbol and Prostratin
Robert Alan Webster
Doctor of Philosophy
Department of Chemistry
University of Toronto
2011
Abstract
Chapter 1 details our investigation into the Diels-Alder reaction between arynes and chiral furans
and pyrroles for the synthesis of unsymmetrical [2.2.1] oxabicyclic and azabicyclic scaffolds as
single enantiomers. It was discovered that the diastereoselectivity of the aryne Diels-Alder
reaction was sensitive to conformational effects that could be exploited to obtain both high yields
and dr. Stereoselective synthesis using arynes is an overlooked field, and this contribution
represents one of only three such examples in the literature.
The desymmetrization of meso [2.2.1] oxabicyclic systems by intramolecular cyclization/ring-
opening was studied, and a cationic Rh/t-Bu-Josiphos catalyst was developed that delivered
polyclic dihydronaphthalene products in excellent yield and ee. These catalyst conditions were
used for the ring-opening of an enantiomerically pure unsymmetrical oxabicyclic alkene, which
led to the discovery that ring-opening proceeded with complete reagent control. A
regiodivergent resolution was designed that gave pairs of enantiomerically enriched
dihydronaphthalenes from unsymmetrical racemic starting materials.
In chapter 3, the scope of the regiodivergent resolution was expanded to include the ring-opening
of remotely-substituted oxabicyclic alkenes and furan-hetaryne Diels-Alder adducts. The utility
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of the method was demonstrated by using it to synthesize two important API molecules from a
single racemic precursor.
Finally, chapter 4 describes our lab’s efforts toward the total synthesis of the natural products
phorbol and prostratin that features the ring-opening of an unsymmetrical [3.2.1] oxabicycle as
the key step. Advanced intermediates (requiring >30 linear steps) were synthesized on gram-
scale. The entire carbon framework was successfully installed, and our efforts to complete the
synthesis are discussed.
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Acknowledgments
I would like to thank my supervisor Prof. Mark Lautens: I am truly grateful for your continuing
support, guidance and kindness. You have been an excellent mentor, and I have learned more
from you than I ever would have expected. You taught me to make lemonade from lemons, and
if I’m really lucky: cherry pie.
My sincerest thanks to: Dr. Alistair Boyer, David Candito and Dr. Laurie Joyce for proofreading
parts of this thesis and for their friendships during my time in Toronto.
I have had the chance to collaborate with a number of people over the years: Dr. Alistair Boyer,
Shabnam Yazdi, Nick Nguyen, Dr. Christian Böing; thank you all. I feel endebted to have
worked with such talented and motivated people. I would also like to acknowledge my Ph.D.
committee: professors Andrei Yudin, Rob Batey and Mark Taylor, for taking the time to read this
thesis, for their help over the past six years.
I would like to thank my parents: Bob and Maureen, for their love and enthusiasm, and for
bailing me out a few times when I needed to pay tuition.
Without Jisun Kim I don’t think I would have made it. Thank you for giving me a reason to stay
happy.
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Table of Contents
Acknowledgments .......................................................................................................................... iv
Table of Contents ............................................................................................................................ v
List of Tables ............................................................................................................................... viii
List of Schemes ............................................................................................................................... x
List of Figures .............................................................................................................................. xix
List of Abbreviations .................................................................................................................... xx
Chapter 1 ....................................................................................................................................... 1
1 Stereoselective Cycloaddition Reactions of Arynes .............................................................. 1
1.1 Introduction ......................................................................................................................... 1
1.1.1 Stereoselective Reactions of Arynes: An Underexplored Field ............................. 1
1.1.2 Reactivity and Properties of Arynes ....................................................................... 2
1.1.3 Methods of Aryne Generation ................................................................................ 8
1.1.4 Aryne Cycloadditions ........................................................................................... 15
1.1.5 Transition Metal-Catalyzed Reactions of Arynes ................................................. 29
1.2 Previous Work in the Lautens Group ................................................................................ 35
1.2.1 Diels-Alder Reactions of Arynes with Acyclic Dienes ........................................ 35
1.2.2 The First Diastereoselective Aryne Diels-Alder Reaction .................................... 38
1.3 Results and Discussion ..................................................................................................... 40
1.3.1 Project Objectives ................................................................................................. 40
1.3.2 Preliminary Results ............................................................................................... 41
1.3.3 Investigation of Conformational Effects ............................................................... 44
1.3.4 Synthetic Applications of the Methodology ......................................................... 52
1.3.5 Toward Catalytic Asymmetric Aryne Diels-Alder Reactions .............................. 56
1.4 Summary and Conclusions ............................................................................................... 60
1.5 Experimental Procedures .................................................................................................. 61
Chapter 2 ..................................................................................................................................... 93
2 Rhodium-Catalyzed Ring-Opening Reactions of Bridgehead-Substituted
Oxabenzonorbornadienes ...................................................................................................... 93
2.1 Introduction: Ring-Opening Reactions of Oxabicyclic Alkenes ...................................... 93
2.1.1 Nickel-Catalyzed Asymmetric Ring-Opening ...................................................... 96
2.1.2 Palladium-Catalyzed Asymmetric Ring-Opening .............................................. 101
2.1.3 Copper-Catalyzed Asymmetric Ring-Opening ................................................... 109
2.1.4 Rhodium-Catalyzed Asymmetric Ring-Opening ................................................ 112
2.1.5 Asymmetric Ring-Opening with Other Metal Catalysts ..................................... 124
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2.2 Desymmetrization of meso Bridgehead-Substituted Oxabicyclic Alkenes via an
Intramolecular Cyclization .............................................................................................. 125
2.2.1 Background ......................................................................................................... 125
2.2.2 Initial Results ...................................................................................................... 127
2.2.3 Successful Desymmetrization using a Cationic Rh Catalyst .............................. 131
2.2.4 Rh-Catalyzed Arylative/Alkylative Asymmetric Ring-Opening ........................ 134
2.3 Regioselective Reactions of Chiral Oxabicycles using a Chiral Catalyst ....................... 138
2.3.1 Ring-Opening of an Optically Pure Oxabicyclic Alkene: Substrate vs. Reagent
Control ................................................................................................................ 138
2.3.2 Parallel Kinetic Resolutions: An Overview ........................................................ 140
2.3.3 Rh-Catalyzed Regiodivergent Resolution of Unsymmetrical Oxabicycles ........ 145
2.3.4 Regiodivergent Cyclizations of Unsymmetrical Oxabicycles ............................ 151
2.4 Summary and Conclusions ............................................................................................. 153
2.5 Experimental Procedures ................................................................................................ 154
Chapter 3 ................................................................................................................................... 192
3 Overriding Electronic Bias in Ring-Opening Reactions of Unsymmetrical
Oxabicyclic Alkenes ............................................................................................................. 192
3.1 Introduction ..................................................................................................................... 192
3.1.1 Previous Work in the Lautens Group .................................................................. 193
3.2 Results and Discussion ................................................................................................... 196
3.2.1 The Total Synthesis of Rotigotine and (S)-8-OH-DPAT from a Common
Racemic Precursor .............................................................................................. 196
3.2.2 Ring-Opening of Heteroaryne-Furan Diels-Alder Adducts ................................ 213
3.2.3 Regiodivergent Ring-Opening with Boronic Acid Nucleophiles ....................... 223
3.2.4 Summary and Conclusions ................................................................................. 226
3.3 Experimental Procedures ................................................................................................ 228
Chapter 4 ................................................................................................................................... 269
4 Studies Directed Toward the Total Synthesis of Phorbol and Prostratin....................... 269
4.1 Background and Previous Synthetic Studies .................................................................. 269
4.1.1 Introduction ......................................................................................................... 269
4.1.2 Tiglianes and Related Diterpenes: Biosynthesis and Biological Activity .......... 270
4.1.3 Synthetic Approaches to Phorbol ........................................................................ 273
4.1.4 Formal Synthesis of Phorbol by Cha .................................................................. 279
4.1.5 Wender’s Total Synthesis of Phorbol ................................................................. 280
4.1.6 Practical Semi-Synthesis of Prostratin by Wender ............................................. 282
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4.2 Previous Efforts in the Lautens Group Directed Toward the Total Synthesis of
Phorbol ............................................................................................................................ 283
4.2.1 Current Synthetic Route ...................................................................................... 283
4.2.2 Domino Cyclopropanation/Cope Rearrangement ............................................... 284
4.2.3 Synthesis of the AB Ring System using an Anionic Ring Opening/Ring
Closing Reaction ................................................................................................. 285
4.2.4 Introduction of Ring C by Conjugate Addition of an Organocuprate Reagent
to a Vinyl Oxirane ............................................................................................... 288
4.2.5 Synthesis of Ring C by Ring Closing Metathesis ............................................... 290
4.3 Optimization and Scale-Up of the Synthetic Route ........................................................ 292
4.3.1 Objectives ........................................................................................................... 292
4.3.2 Synthesis of Davies’ Cyclopropanation/Cope Rearrangement Precursors ......... 292
4.3.3 Scale-up of Domino Cyclopropanation/Cope Rearrangement ........................... 294
4.3.4 Optimization of the Krapcho Decarboxylation Step ........................................... 296
4.3.5 Large Scale Synthesis of the AB Ring System ................................................... 297
4.3.6 Gram-Scale Synthesis of the Tigliane ABC Ring System .................................. 299
4.3.7 Endgame Progress ............................................................................................... 305
4.3.8 Summary and Conclusions ................................................................................. 311
4.4 Experimental Procedures ................................................................................................ 313
Appendix ..................................................................................................................................... 342
Copyright Acknowledgements .................................................................................................... 538
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List of Tables
Table 1.1 Regioselectivity of Diels-Alder Reactions between 3-Substituted Aryne and 2-
Substituted Furan Partners ............................................................................................................ 18
Table 1.2 Effect of Diene Electronics on Indolyne Diels-Alder Regioselectivity ....................... 20
Table 1.3 Screening of Benzyne Generation Methods ................................................................. 37
Table 1.4 Scope of Benzyne Diels-Alder Reaction with Acyclic Dienes .................................... 38
Table 1.5 Optimization of Diastereoselectivity in the Acyclic ADA reaction ............................. 39
Table 1.6 Screening of Alternate Chiral Auxiliaries .................................................................... 42
Table 1.7 Screening of Lewis Acid Additives ............................................................................. 44
Table 1.8 Obtaining Opposite Facial Selectivity: Conformational Control with the Auxiliary in
the 3-Position ................................................................................................................................ 49
Table 1.9 Effect of Chiral Transition Metal Catalyst Additives in the ADA Reaction ............... 59
Table 2.1 Selected Attempts to Ring-Open Oxabicycle 2.146 .................................................. 129
Table 2.2 Rh-Catalyzed Regiodivergent Resolution of Bridgehead-Substituted Unsymmetrical
Oxabenzonorbornadienes: Effect of Bridgehead Substituent ..................................................... 147
Table 2.3 Rh-Catalyzed Regiodivergent Resolution of Bridgehead-Substituted Unsymmetrical
Oxabenzonorbornadienes: Effect of a Remote Substituent ........................................................ 148
Table 3.1 Regioselective Methanolysis of Oxabicycles: Electronic Effects .............................. 194
Table 3.2 Effect of Additive and Temperature on the Rh-Catalyzed Regiodivergent Ring-
Opening of an Oxabicycle with a Remote Substitutent .............................................................. 199
Table 3.3 Attempted Direct Deoxygenation of Benzylic Alcohol 3.022 ................................... 202
Table 3.4 Attempted Synthesis of LY 274600 by C-S Coupling ............................................... 208
Table 3.5 Nucleophile Scope of the Rh-Catalyzed Regiodivergent Ring-Opening of Remotely-
Substituted Racemic Oxabicycle 3.015 ...................................................................................... 209
Table 3.6 Initial Screen of Catalyst Conditions for Hetaryne-Fused Oxabicycle Ring-Opening
..................................................................................................................................................... 215
Table 3.7 Effect of Aryl Substitution on the Regiodivergent Ring-Opening of Dihydro-
epoxyisoquinolines ..................................................................................................................... 219
Table 3.8 Development of Regiodivergent Resolution Conditions for the Addition of Boronic
Acid Nucleophiles ....................................................................................................................... 225
Table 4.1 Optimization of Ring C Formation by RCM ............................................................. 291
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Table 4.2 Large-Scale Domino Cyclopropanation/Cope Rearrangement .................................. 295
Table 4.3 Desilylation of TBS Enol Ether 4.079 ....................................................................... 296
Table 4.4 Optimization of the Krapcho Decarboxylation of Keto-ester 4.084 .......................... 297
Table 4.5 Initial Screen of Acetonide Deprotection Conditions for Ketone 4.113 .................... 303

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List of Schemes
Scheme 1.1 Stoermer and Kahlert’s Proposal of an Aryne Reactive Intermediate ........................ 2
Scheme 1.2 Roberts’ Isotopic Labeling Experiment ...................................................................... 2
Scheme 1.3 Steric/Electronic Model for Regioselectivity in Nucleophilic Addition to Arynes .... 6
Scheme 1.4 Regioselectivity in Nucleophilic Addition to Indolynes ............................................. 7
Scheme 1.5 Distortion Model for Regioselective Nucleophilic Addition to Arynes ..................... 7
Scheme 1.6 General Strategies for Aryne Formation ..................................................................... 8
Scheme 1.7 Mechanism of Aryne Formation via ortho-Deprotonation/Elimination ..................... 9
Scheme 1.8 Deprotonation of Aryl Fluorides to Form Arynes .................................................... 10
Scheme 1.9 Substituted Aryne Synthesis by Regioselective Deprotonation/Elimination ........... 10
Scheme 1.10 Collum’s Demonstration of Solvent Dependant Halide Elimination ..................... 11
Scheme 1.11 Wolthuis’ Benzyne Formation via Lithium-Halogen Exchange ............................ 12
Scheme 1.12 Knochel’s Magnesium Halide Exchange Protocol ................................................. 12
Scheme 1.13 Aryne Generation via Lanthanide-Halogen Exchange ........................................... 13
Scheme 1.14 Friedman’s Protocol for Isolation of BDC as a Benzyne Precursor ....................... 13
Scheme 1.15 Generation and Decomposition of BDC in situ as a Benzyne Precursor ................ 14
Scheme 1.16 Kobayashi’s o-Silyl Triflate Benzyne Precursor .................................................... 14
Scheme 1.17 Epibatidine Analogue Synthesis using o-Silyl Triflate Pyridyne Precursors ......... 15
Scheme 1.18 Kitamura’s o-Silyl Phenyliodonium Triflate Benzyne Precursor ........................... 15
Scheme 1.19 Diels-Alder Reaction of Benzyne with Benzene and Naphthalene ........................ 16
Scheme 1.20 Diels-Alder Reactions of Benzyne with Selected Heterocyclic Dienes ................. 17
Scheme 1.21 Gribble’s Concerted Asynchronous Diels-Alder Model ........................................ 19
Scheme 1.22 Strain-Induced Regioselectivity in Aryne Diels-Alder Reactions .......................... 19
Scheme 1.23 Martin’s Total Synthesis of Vineomycinone B Methyl Ester ............................... 21
2
Scheme 1.24 Aryne Diels-Alder Reactions of Styrenyl Alkenes ................................................. 22
Scheme 1.25 Reaction of an Acyclic Diene via [4 + 2], [2 + 2] and Ene Reaction Pathways ..... 22
Scheme 1.26 Danheiser’s Intramolecular Aryne [4 + 2] Cycloaddition of Enynes/Dienes ......... 23
Scheme 1.27 Non-Stereospecific Aryne [2 + 2] Cycloaddition ................................................... 24
Scheme 1.28 Stereospecific Aryne [2 + 2] Cycloaddition ........................................................... 24
Scheme 1.29 Mechanistic Proposals to Explain Stereospecific Aryne [2 + 2] Cycloadditions ... 25
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