SFU Thesis Template Files

206 Pages·2015·4.55 MB·English

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Chlorine as an Auxiliary in Asymmetric Aldol
Reactions and
Photocatalytic Fluorination of C-H Bonds
by
Shira D. Bogner
B.Sc., Wilfrid Laurier University 2009
Thesis Submitted in Partial Fulfillment of the
Requirements for the Degree of
Doctor of Philosophy
in the
Department of Chemistry
Faculty of Science
 Shira Bogner 2015
SIMON FRASER UNIVERSITY
Spring 2015
Approval
Name: Shira D. Bogner
Degree: Doctor of Philosophy (Chemistry)
Title: Chlorine as an Auxiliary in Asymmetric Aldol
Reactions and Photocatalytic Fluorination of C-H
Bonds
Examining Committee: Chair: Dr. Michael Eikerling
Professor
Dr. Robert A. Britton
Senior Supervisor
Associate Professor
Dr. Robert N. Young
Supervisor
Professor
Dr. Tim Storr
Supervisor
Associate Professor
Dr. Peter D. Wilson
Internal Examiner
Associate Professor
Department of Chemistry
Dr. Glenn Sammis
External Examiner
Associate Professor
Department of Chemistry
University of British Columbia

Date Defended/Approved: January 20th, 2015

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Partial Copyright Licence

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Abstract
Organohalides are ubiquitous in organic chemistry, with broad utility ranging from their
use as building blocks in multistep syntheses, to fluoropharmaceuticals that can
oftentimes provide more favourable properties to drug molecules. In this regard, two
new synthetic methods have been developed that involve the use or preparation of
organohalides: chlorine as an auxiliary for asymmetric aldol reactions, and the
photocatalytic fluorination of C-H bonds.
The aldol reaction is an important carbon-carbon bond forming reaction in organic
chemistry, the product of which is a β-hydroxyketone, which is a functionality often
encountered in drugs and natural products. As many pharmaceuticals, agrochemicals
and bioactive compounds have increased activity as single enantiomers, asymmetric
variants of aldol reactions are sought. Herein, an auxiliary strategy is demonstrated for
the stereoselective addition of lithium enolates to aldehydes in which the auxiliary itself is
not chiral, but a single chlorine atom introduced via organocatalytic asymmetric α-
chlorination. The stereodirecting influence of the chloromethine is then exploited prior to
its removal by radical reduction. This strategy is demonstrated in the synthesis of
various optically enriched β-hydroxyketones (92-99% ee), as well as the natural products
(+)-dihydroyashabushiketol and (+)-solistatin.
Fluorination reactions are essential to modern medicinal chemistry, and can provide a
means to block site-selective metabolic degradation of drugs and access radiotracers for
positron emission tomography imaging. Despite current sophistication in fluorination
reagents and processes, the fluorination of unactivated C-H bonds remains a significant
challenge. Reported herein is a convenient and economic process for direct fluorination
of C-H bonds that exploits the hydrogen abstracting ability of a decatungstate
photocatalyst in combination with the mild fluorine atom transfer reagent N-
fluorobenzenesulfonimide. This operationally straightforward reaction provides direct
access to a wide range of fluorinated organic molecules, including structurally complex
natural products, acyl fluorides, and fluorinated amino acid derivatives.
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Keywords: organic synthesis; halogens; asymmetric aldol reaction; photocatalysis;
radical fluorination
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Dedication
To my parents Ruth and David Halperin, who have been nothing but extremely loving
and supportive throughout all these years, and for showing me the values and work ethic
that has made this achievement possible.
To my wonderul husband Darren, who was a constant source of compassion,
encouragement, and support, especially when I needed it most. He was always willing
to drive me to and from Burnaby Mountain on a Sunday afternoon, which cut hours off
my commute time. Having Darren and his tremendously encouraging family in my life
these last few years has given me the support to complete my graduate studies.
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Acknowledgements
I would first like to thank my senior supervisor Dr. Robert Britton, whose continual
optimism and encouragement, even when faced with negative results, has allowed me
and the lab to thrive beyond belief. I am extremely thankful for Rob’s patience with me
throughout my graduate studies, especially during the construction of this thesis.
I would like to thank my supervisory committee: Dr. Robert Young and Dr. Tim Storr, for
their ideas and feedback over the years. I would also like to thank my internal examiner,
Dr. Peter Wilson, and external examiner Dr. Glenn Sammis for their participation on my
examining committee.
I would like to thank Dr. Regine Gries, who never hesitated when I needed help with GC.
Additionally, much of this synthetic work could not have been possible without
assistance from the staff responsible for the NMR facilities; Dr. Andrew Lewis and Colin
Zhang. I would also like to thank the wonderful graduate secretaries at SFU, especially
Lynn Wood and Nathalie Fournier.
I would like to acknowledge all the colleagues I have had the pleasure of working with in
over these last five years. From the Britton lab: Dr. Baldip Kang, Dr. Jeffrey Mowat, Dr.
James Senior, Jarod Moore, Hope Fan, Vijay Dhand, Jason Draper, Michael Holmes,
Milan Bergeron-Brlek (crystal structure), Steve Hur, Matt Taron, Abhi Bagai, Daniel
Kwon, Chris Adamson, Dr. Matt Nodwell, Lee Belding, Ajay Naidu and Robby Zhai. Last
but not least, Stanley Chang, who was with me from day one, and was always available
for a cup of coffee and a good conversation (or just me ranting and complaining).
Additionally, former members of the Wilson group: Dr. Pat Chen and Matthew Campbell,
who were always willing to help a fellow synthetic chemist. I would also like to thank
Amir Asadirad (Branda lab) for his help with the blacklight bulbs, specifically, sourcing
them from the Williams lab (thank you!) and assistance with obtaining emission spectra.
I would also like to thank Michael Jones (Storr lab), for being an amazing friend and ally,
and proving that you can make good friends in Vancouver.
For financial support, I would like to acknowledge NSERC (CGS-M and PGS-D), Dupont
Scholarship, Pacific Century Graduate Scholarship, and SFU for Graduate Fellowships.
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Table of Contents
Approval .............................................................................................................................ii
Partial Copyright Licence .................................................................................................. iii
Abstract .............................................................................................................................iv
Dedication .........................................................................................................................vi
Acknowledgements .......................................................................................................... vii
Table of Contents ............................................................................................................ viii
List of Tables ..................................................................................................................... x
List of Figures................................................................................................................... xii
List of Schemes ............................................................................................................... xiv
List of Abbreviations and Acronyms ................................................................................ xvi
Chapter 1. Introduction: Halogens in Organic Synthesis ........................................ 1
1.1. Organic Synthesis .................................................................................................... 1
1.2. Chemistry and Reactivity of Carbon-Halogen Bonds ............................................... 4
1.3. Organochlorides in Synthesis................................................................................... 5
1.4. Chapter 2 Overview................................................................................................ 10
1.5. Halogenated Molecules as Pharmaceuticals ......................................................... 11
1.6. Chapter 3 Overview................................................................................................ 13
Chapter 2. Chlorine as an Auxiliary for Asymmetric Aldol Reactions, ................. 14
2.1. Introduction: Asymmetric Aldol Reactions .............................................................. 14
2.1.1. Background: Catalytic Asymmetric Acetate Aldol Reactions .................... 16
2.1.2. Background: Chiral Auxiliaries in Acetate Aldol Reactions ....................... 19
2.1.3. Background: Stereoselective Additions to α-Substituted Aldehydes ........ 20
2.1.4. Background: Preparation of Enantioenriched α-Chloroaldehydes ............ 23
2.2. Previous Work in the Britton Lab ............................................................................ 25
2.3. Radical Dehalogenating Reagents ......................................................................... 27
2.3.1. Other Dehalogenation Methodologies ...................................................... 28
2.4. Proposal: Chlorine as an Auxiliary in Asymmetric Aldol Reactions ........................ 29
2.5. Results ................................................................................................................... 29
2.5.1. Synthesis of α-Chloroaldehydes and β-Ketochlorohydrins ....................... 29
2.5.2. Elaboration to Enantioenriched Aldol Adduct ............................................ 33
2.5.3. Total Synthesis of Natural Products .......................................................... 37
Diarylheptanoids .................................................................................................... 37
Solistatin ................................................................................................................. 42
2.6. Conclusion ............................................................................................................. 51
2.7. Experimental .......................................................................................................... 52
2.7.1. General ..................................................................................................... 52
2.7.2. Preparation and Experimental Data for New Compounds ........................ 54
Chapter 3. Photocatalytic Fluorination of Unactivated C-H Bonds, ...................... 96
3.1. Introduction: Fluorination of C-H Bonds ................................................................. 96
3.1.1. Fluorine in Medicinal Chemistry ................................................................ 97
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3.1.2. 18F and PET ............................................................................................ 100
3.1.3. 19F NMR Spectroscopy ........................................................................... 102
3.2. Methods of C-F Bond Formation .......................................................................... 103
3.2.1. Nucleophilic F- Sources ........................................................................... 103
3.2.2. Electrophilic F+ Sources .......................................................................... 104
3.2.3. Decarboxylative Fluorinations ................................................................. 104
3.2.4. sp2-Adjacent C-H Fluorination ................................................................. 106
3.2.5. Unactivated C-(sp3)-H Fluorination ......................................................... 107
3.2.6. Alkyl Radicals from C-H Bonds: Decatungstate Photocatalysis .............. 109
3.3. Results: Fluorination of Unactivated C-H Bonds .................................................. 112
3.3.1. Aliphatic and Benzylic Fluorinations ....................................................... 112
3.3.2. Benzylic and Allylic Fluorinations ............................................................ 118
3.3.3. Aldehydic Fluorination ............................................................................. 122
Acyl Fluorides from Aldehydes: Previous Work ................................................... 122
Acyl Fluorides from Aldehydes: Results .............................................................. 122
3.3.4. Fluorination of Amino Acids .................................................................... 123
Synthesis of Fluorinated Amino Acids: Previous Work ........................................ 123
Synthesis of Fluorinated Amino Acids: Results ................................................... 126
3.3.5. Fluorination in Flow ................................................................................. 131
3.3.6. Mechanistic Insight ................................................................................. 133
3.3.7. Current State in the Field ........................................................................ 137
3.4. Conclusion ........................................................................................................... 138
3.5. Experimental ........................................................................................................ 139
3.5.1. General ................................................................................................... 139
3.5.2. Characterization of Compounds Described in This Chapter ................... 140
Chapter 4. Conclusion ............................................................................................ 163
4.1. Chlorine as an Auxiliary in Asymmetric Aldol Reactions ...................................... 163
4.2. Future Work.......................................................................................................... 164
4.3. Photocatalytic Fluorination of C-H Bonds ............................................................. 165
4.4. Future Work.......................................................................................................... 166
References ................................................................................................................ 168

Appendix A. Absorbance, Emission and NMR Spectra ......................................... 183
Appendix B. X-Ray Structure of 6-Bromocamphor ................................................ 186

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List of Tables
Table 1.1. Industrial Processes for the Carbonylation of Methanol ............................ 3
Table 1.2. Properties of Various Halogens vs. Hydrogen ........................................... 5
Table 1.3. Metal Insertion into Carbon-Chlorine Bonds and Subsequent
Reactions ................................................................................................... 8
Table 2.1. Properties of Radical Reducing Agents ................................................... 27
Table 2.2. Synthesis of α-Chloroaldehydesa ............................................................ 30
Table 2.3. Synthesis of β-Ketochlorohydrins. ........................................................... 31
Table 2.4. Preliminary Dechlorination Experiments. ................................................. 34
Table 2.5. Radical Dechlorination of Various β-Ketochlorohydrins.a ........................ 35
Table 2.6. Comparison of Spectral Data for 91 and 93 With Known
Compounds ............................................................................................. 37
Table 2.7. Optimization of the Synthesis of Ketone 102 ........................................... 40
Table 2.8. Aldol Additions of Chloroaldehyde 103 .................................................... 42
Table 2.9. Aldol Additions of Methylacetoacetate with α-Chloroaldehydes .............. 46
Table 2.10. Deuterium Quenching Experiments ......................................................... 47
Table 2.11. Reactions of Dioxinone 122 with Chloroaldehydes. ................................ 49
Table 2.12. Reactions of Silyl Enol Ether 126 with α-Chloroaldehydes ...................... 50
Table 3.1. Decarboxylative Fluorinations ............................................................... 105
Table 3.2. Bond Dissocation Energies of Electrophilic Fluorinating Agents ........... 106
Table 3.3. Benzylic Fluorination. ............................................................................ 107
Table 3.4. Examples of C-H Fluorination ................................................................ 108
Table 3.5. Decatungstate Photocatalyzed Reactions. ............................................ 110
Table 3.6. Fluorination of Bornyl Acetate. .............................................................. 113
Table 3.7. Fluorination of Cyclic Substrates. .......................................................... 116
Table 3.8. Aliphatic Ester Fluorination .................................................................... 118
Table 3.9. Benzylic Fluorinations ............................................................................ 120
Table 3.10. Allylic Fluorinations ................................................................................ 121
Table 3.11. Acyl Fluorides from Aldeydes. ............................................................... 122
Table 3.12. Optimization of the Fluorination of l-Leucine ......................................... 128
Table 3.13. Fluorination of Amino Acids ................................................................... 131
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