I. An Improved Procedure for Alkene Ozonolysis. II. Exploring a New Structural Paradigm for ...

231 Pages·2013·1.55 MB·English

by  Charles Edward Schiaffo

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Student Research Projects, Dissertations, and
Chemistry, Department of
Theses - Chemistry Department
2011
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Charles Edward Schiaffo
University of Nebraska-Lincoln
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I. An Improved Procedure for Alkene Ozonolysis.
II. Exploring a New Structural Paradigm for Peroxide Antimalarials.

By

Charles E. Schiaffo

A DISSERTATION

Presented to the Faculty of
The Graduate College at the University of Nebraska
In Partial Fulfillment of Requirements
For the Degree of Doctor of Philosophy

Major: Chemistry

Under the Supervision of Professor Patrick H. Dussault

Lincoln, Nebraska

June, 2011
I. An Improved Procedure for Alkene Ozonolysis.
II. Exploring a New Structural Paradigm for Peroxide Antimalarials.

Charles E. Schiaffo, Ph.D.
University of Nebraska-Lincoln, 2011

Advisor: Patrick H. Dussault
The use of ozone for the transformation of alkenes to carbonyls has been well
established. The reaction of ozone with alkenes in this fashion generates either a 1,2,4-
trioxolane (ozonide) or a hydroperoxyacetal, either of which must undergo a separate
reduction step to provide the desired carbonyl compound. There is considerable interest
in being able to perform a reductive ozonolysis to directly provide the carbonyl. Previous
reports from the Dussault lab have shown that amine N-oxides are able to perform a
reductive ozonolysis. In the course of efforts to expand this reaction to other oxyanions it
was realized that water was also able to efficiently perform a net reductive ozonolysis via
nucleophilic capture of the carbonyl oxide. This transformation was investigated for a
variety of substrates and was shown to offer a useful alternative to conventional
ozonolysis conditions.
Malaria is a global health epidemic that affects between 300-500 million people
annually, with the most deadly strain being P. falciparum. The current treatment for
malaria is artemisinin combination therapy, but the development of artemisinin-resistant
strains of malaria has spurred the need for the development of new treatments. 1,2,4-
Trioxolanes exhibit high efficacy against malaria, but concerns remain about their
thermal and serum stability. Our analysis of the likely mechanism of action of ozonides
guided our development of structurally related 3-alkoxy-1,2-dioxolanes as a potential
treatment for malaria. This class of compounds has shown to possess high levels of
activity against P. falciparum in vitro. The synthesis of these dioxolanes required the
development of new synthetic routes, which will be discussed in detail, as will efforts to
optimize the activity of 3-alkoxy-1,2-dioxolanes. In addition, the synthesis and
evaluation of 1,2,4-trioxepanes as potential antimalarials was explored.
In the course of our investigation into the synthesis of 3-alkoxy-1,2-dioxolanes,
we found Re (VII) oxide to be an effective catalyst for the transetherification of 3-alkoxy-
1,2-dioxolanes. Re (VII) oxide was briefly explored as a catalyst for allylation or

etherification reactions that involve stabilized carbocations as intermediates.
iii
Acknowledgements

First, I would like to thank my advisor, Professor Patrick Dussault for his help and
guidance. I am grateful for all the time he spent helping me and his patience. I believe
that he has helped me become a better scientist.
I would like to thank the members of my committee: Prof. Takacs, Prof. Du, Prof.
Nickerson, Prof. Redepenning, and Prof. Choe. I am indebted to the help that Joe
Dumais and Sara Basiaga provided on the NMR and the other small instruments.
Without the help of Sergio Wittlin and Matthias Rottman, who performed the
antimalarial screening, and Tony Lloyd, from EHS who helped with the shipments, I
would have no biological data and I thank them. I also thank Prof. Jonathan Vennerstrom
and Yuxiang Dong at the University of Nebraska-Medical Center for there guidance on
medicinal chemistry.
I would like to thank Chris Schwartz, Chunping Xu, Roman Schepin, and
Prasanta Ghorai for helping me during my first year. I thank Brad Johnson for
challenging me and for the lively white board discussions that we would have. I am also
grateful for all of the current group members who have helped me.
I am fortunate for having parents who have been supportive of me through this
journey. They never doubted me and provided encouragement at all the right times.
Finally, I would like to thank my fiancée Van Nguyen Mai for her help, support, and
guidance. She has been a true pillar of stability for me during this journey.
iv
Chapter 1: Improved procedure for alkene ozonolysis..................................................1
Section 1.............................................................................................................................2
Section 1.1 Mechanism of ozonolysis.............................................................................2
Section 1.2 Issues with O in synthesis............................................................................3
3
Section 1.3 Reductive ozonolysis using N-Oxides..........................................................4
Section 1.4 Reductive ozonolysis using water.................................................................5
Section 2.............................................................................................................................6
Section 2.1 Rationale ......................................................................................................6
Section 2.2 Initial phase transfer studies..........................................................................7
Section 2.3 Anhydrous tetrabutyl ammonium salts.........................................................8
Section 2.4 Water as a trap..............................................................................................9
Section 2.5 Substrate scope............................................................................................13
Section 2.6 Conclusions.................................................................................................15
Section 2.7 Experimentals.............................................................................................15
Section 3 References........................................................................................................25
Chapter 2: 3-Alkoxy-1,2-dioxolanes as potential antimalarials ................................28
Section 1...........................................................................................................................29
Section 1.1 Malaria........................................................................................................29
Section 1.2 Antimalarial treatments...............................................................................30
Section 1.3 Artemisinin as a treatment for malaria........................................................31
Section 1.4 Mechanism of Fe-mediated artemisinin degradation..................................31
Section 1.5 Artemisinin mechanism of action against malaria......................................33
Section 1.6 Vennerstrom’s ozonides..............................................................................34
v
Section 1.7 Rationale for 3-alkoxy-1,2-dioxolanes.......................................................36
Section 2.............................................................................................................................38
Section 2.1 Previous synthesis of 1,2-dioxolanes..........................................................38
Singlet oxygen.........................................................................................................38
DePuy ring expansion..............................................................................................40
Thermolysis..............................................................................................................41
Conjugate addition to α-β-unsaturated carbonyls....................................................42
Ozonolysis of enol ethers.........................................................................................42
Radical cyclization...................................................................................................43
Electrophilic cyclization..........................................................................................45
Section 2.2 Reactions of 1,2-dioxolan-3-ols and 3-alkoxy-1,2-dioxolanes...................47
Acid-mediated etherification...................................................................................47
Base-mediated etherification...................................................................................48
Allylation of 3-alkoxy-1,2-dioxolanes.....................................................................49
Section 3.............................................................................................................................50
Section 3.1 Early work on 3-alkoxy-1,2-dioxolanes.....................................................50
Section 3.2 Synthesis of 3-alkoxy-1,2-dioxolanes.........................................................51
Section 3.3 Antimalarial results.....................................................................................56
Section 4.............................................................................................................................58
Section 4.1 Rationale for new series..............................................................................58
Section 4.2 Incorporation of spirocycle at C5/5’...........................................................59
Section 4.3 Effect of ring size at C5/5’..........................................................................63
Section 4.4 Improved leaving group..............................................................................64
vi
Section 4.5 Spirocyclic 3-alkoxy-1,2-dioxolanes..........................................................69
Section 4.6 Future directions.........................................................................................72
Section 5.............................................................................................................................74
Section 5.1 Esters...........................................................................................................74
Rationale..................................................................................................................74
Synthesis..................................................................................................................75
Antimalarial results and analysis.............................................................................77
Section 5.2 Alcohols......................................................................................................78
Rationale..................................................................................................................78
Synthesis..................................................................................................................78
Antimalarial results and analysis.............................................................................79
Section 5.3 Derivatized alcohol.....................................................................................80
Rationale..................................................................................................................80
Synthesis and antimalarial results............................................................................81
Section 5.4 Other functional groups..............................................................................81
Rationale..................................................................................................................81
Synthesis and antimalarial results............................................................................82
Section 5.5 Animal studies............................................................................................82
Section 5.6 Stability of 3-alkoxy-1,2-dioxolanes..........................................................83
Section 5.7 Future work.................................................................................................83
Section 6 Experimentals....................................................................................................86
Section 7 References........................................................................................................163
Chapter 3: 1,2,4-Trioxepanes as potential antimalarials .........................................173
vii
Section 1 Previous synthesises.......................................................................................174
Acid displacement..................................................................................................174
Cobalt-mediated peroxidation................................................................................175
Oxetane opening....................................................................................................179
Thiol-Olefin-Co-Oxygenation...............................................................................180
Singlet oxygen.......................................................................................................181
Electrophilic cyclization........................................................................................182
Ozonolysis..............................................................................................................183
Section 2 Rationale........................................................................................................184
Section 3 Results and discussion...................................................................................185
Section 4 Antimalarial results........................................................................................189
Section 5 Experimentals................................................................................................190
Section 6 References......................................................................................................200
Chapter 4: Re (VII) oxide as a catalyst for the generation of stabilized
carbocations....................................................................................................................202
Section 1 Previous work................................................................................................203
Isomerization of allylic alcohols by rhenium.........................................................203
Utilization in Prins cyclization...............................................................................205
Section 2 Hypothesis......................................................................................................206
Section 3 Etherification/acetalization of 3-alkoxy-1,2-dioxolanes................................206
Section 4 Etherification of lactols..................................................................................208
Section 5 Allylation.......................................................................................................209
Section 6 Stabilized carbocations..................................................................................210
viii
Section 7 Conclusions....................................................................................................212
Section 8 Experimentals................................................................................................213
Section 9 References......................................................................................................220