Stereoselective Synthesis and Biological Assessment of Simplified Analogs of Peloruside A

503 Pages·2012·8.62 MB·English

ETH Library
Stereoselective synthesis and
biological assessment of simplified
analogs of peloruside A
Doctoral Thesis
Author(s):
Wullschleger, Christoph Werner
Publication date:
2012
Permanent link:
https://doi.org/10.3929/ethz-a-007342696
Rights / license:
In Copyright - Non-Commercial Use Permitted
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Diss. ETH No. 20376

Stereoselective Synthesis and Biological Assessment
of Simplified Analogs of Peloruside A

A dissertation submitted to
ETH ZURICH

for the degree of
Doctor of Sciences

presented by

Christoph Werner Wullschleger
MSc ETH in Chemistry

born on December 28th, 1982

Citizen of
Vordemwald AG, Switzerland

accepted on the recommendation of

Prof. Dr. Karl-Heinz Altmann, examiner
Prof. Dr. Hans-Jürg Borschberg, co-examiner

2012

Acknowledgements
I would like to express my deep gratitude to my supervisor and mentor Prof. Dr.
Karl-Heinz Altmann. I had the chance to work in his team and laboratories with an
excellent infrastructure. I am grateful not only for the endowed confidence and
freedom in the realization of my research and my own ideas, but also for his constant
support, competent guidance and advice when my ideas failed. I will never forget his
encouraging words and patience when the progress of my project stagnated. Thank
you very much!
I am grateful to Prof. Dr. Hans-Jürg Borschberg for accepting the co-examination of
this Ph. D. thesis as well as for his advice and corrections. I was fortunate having had
the chance to work in his labs during my Master thesis, where I could benefit a lot
from his knowledge about chemistry. Actually, his enthusiasm inspired me to do a
Ph. D. in organic chemistry.
Special thanks go to our collaboration partners Prof. Dr. Jürg Gertsch from the
University of Bern, and Dr. José Fernando Díaz, Dr. Isabel Barasoain, Benet Pera Gresely
and Chiara Trigili from the Centro de Investigaciones Biológicas, Madrid, who
realized the biological assessment of my target compounds.
Especially, I want to thank Kurt Hauenstein for his invaluable help and skillful
experience, whenever his expertise was needed. Thank you very much, Kurt!
The years in the lab during my Ph. D. thesis would not have been that enjoyable
without great lab-mates in H496. I am grateful for having had the chance to work
with such lovely and passionate scientists, namely Bastien Castagner, Carolin Schwehm,
Claudio Bomio, Didier Zurwerra, Evgeny Prusov, Florian Glaus, Jürg Gertsch, Keisuke
Suzuki, Leo Betschart, Stefan Raduner, and Tao Chen.
I will always be indebted to Didier Zurwerra, with whom I shared more than three
and a half wonderful years in the lab. I am very grateful for his helpful suggestions
during my Ph. D. work and his always amenable behavior toward my own chemistry
problems. His warm-hearted, sociable character did not make it hard to get along
with him and I will always have fond memories of our business trips to Geneva and
Siena, as well as of our culinary delights, which has ended in a very good friendship.
I am looking forward to further adventures we will definitely experience together.
Thank you for all, Didi!
I want to thank my (one and only) master student Claudio Bomio, with whom I not
only shared the dedication and enthusiasm for our project, but also the sense of
humor; we always understood each other and hopefully will in future. I will never
forget the discussions about chemistry or geography in the canteen or the table
soccer matches. I hope we keep in touch.
Special thanks go to our NMR specialists Dr. Bernhard Pfeiffer and Fabienne Gaugaz
for the invaluable help and support during measuring the target compounds. I am
really grateful that you managed to measure respectable 13C-NMR spectra even with
only 0.3 mg of the final compound in hand! Furthermore I want to thank Benny and
Max Friedel Pillong (from the Schneider group) for their help in modeling the target
structures.
Many thanks also go to Philipp Gersbach (and Sascha Kopp as a former group
member) for their exceptional IT support, Räff Schiess and Oliver Horlacher for MS
maintenance. I would also like to express my gratitude to all other members of the
Altmann group not mentioned before for useful discussions, support and the creation
of a pleasant working atmosphere: Ana Catarina Viegas Lopes Simão, Anna Schlegel,
Christian Neuhaus, Jun Li, Manuel Johannes, Marc Liniger, Michel Jordi, as well as to all
former members of the group. I have pleasing memories of the past years and I will
never forget the walks to the Selecta machine with Claudio, Didi, Leo and Florian, the
numerous SOLA runnings, which were followed by a delicious dinner or the exciting
table-soccer matches. It was always a pleasure to spend the ski-weekends or just
some hours after work together in the bistro. Thank you all for your help!
Appreciation also goes to our former and current apprentices Patrick Stamm and
Tizian Herzog, to the team members of the HCI-Shop, to the MS-service team (Louis
Bertschi, Oswald Greter, Rolf Häfliger, and Xiangyang Zhang), to the members of the
former Pharma-Shop and to our always helpful secretary Sylvia Peleg.
To my dear friends I will always be indebted for their friendship! Thank you all
for your mental support and encouraging words when my motivation was low and
for the great time we have had together so far. I am really looking forward to
experiencing more together in future! Thank you all: Adrian, Alain, Andrea, Christoph,
Dani, Daniela, Flavia, Fränzi, Iris, Katja, Luc, Marc, Martina, Mathis, Olivier, Paola,
Patrick, Päsche, Philipp, Rahel, Reto, Sascha, Silvan, Simon, Stefan, Stephi, Thomi. Special
thanks go to my former flat-mates Christoph, Päsche and Stephi with whom I shared
many wonderful years in our apartment in Oerlikon.
To my dear sisters Andrea and Marina I am deeply grateful for their love and their
help in all aspects of life – especially during the advent season when I, as usually,
could not find enough time for finding appropriate Christmas presents.
Zu guter Letzt möchte ich mich bei meinen lieben Eltern Karin und Werner ganz
herzlich für Ihre Liebe, moralische wie auch finanzielle Unterstützung während all
den Jahren bedanken; ohne eure grosszügige Hilfe hätte ich weder den Skisport in
meiner Jugendzeit so intensiv ausleben, noch das Studium in so kurzer Zeit
absolvieren können. Ich verdanke euch viel und konnte immer auf euch zählen, was
ich euch nie vergessen werde!
Finally, I would like to thank you, Francesca, for the good time we always have
together. Your support and patience with me was invaluable and I would not have
achieved this work without your help and backup. When I felt unmotivated your
fantastic cookery could always cheer me up. Thank you for all; I will never forget
that!
„Bewerte deine Erfolge daran, was du aufgeben musstest, um sie zu erzielen“
Dalai Lama
To my beloved family
List of Publications

B. Pfeiffer, C. N. Kuzniewski, C. Wullschleger, K.-H. Altmann
„Macrolide-Based Microtubule-Stabilizing Agents – Chemistry and Structure-
Activity Relationships“
Top. Curr. Chem. 2009, 286, 1–72.

C. W. Wullschleger, J. Gertsch, K.-H. Altmann
„Stereoselective Synthesis of a Monocyclic Peloruside A Analogue“
Org. Lett. 2010, 12, 1120–1123.

D. Zurwerra, C. W. Wullschleger, K.-H. Altmann
„Treasures from the Sea: Discovery and Total Synthesis of Ammosamides“
Angew. Chem. Int. Ed. 2010, 49, 6936–6938; Angew. Chem. 2010, 122, 7090–7092.
List of Oral Presentations

Stereoselective Synthesis of Simplified Structural Analogs of Peloruside A
Doktorandentag – Spring Session 2010, Institute of Pharmaceutical Sciences, ETH
Zürich

Stereoselective Syntheses of Simplified Structural Analogs of Peloruside A
Swiss Chemical Society – Fall Meeting 2010, Organic Chemistry, ETH Zürich

List of Poster Presentations

Stereoselective Synthesis of a Monocyclic Peloruside A Analog
Swiss Chemical Society – Fall Meeting 2009, Organic Chemistry, ETH Lausanne

Stereoselective Synthesis of a Monocyclic Peloruside A Analog
Scholarship Fund of the Swiss Chemical Industry – Fall Session 2009, ETH Zürich

Stereoselective Synthesis of a Monocyclic Peloruside A Analog
III EWDSy – Third European Workshop in Drug Synthesis, Siena Italy, 2010