Epothilones and Thailanstatin AA disser

423 Pages·2016·24.29 MB·English

UC San Diego
UC San Diego Electronic Theses and Dissertations
Title
Synthesis of Natural and Designed Antitumor Agents: Epothilones and Thailanstatin A
Permalink
https://escholarship.org/uc/item/5h39h8j1
Author
Rhoades, Derek
Publication Date
2016

Peer reviewed|Thesis/dissertation
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University of California
UNIVERSITY OF CALIFORNIA, SAN DIEGO

Synthesis of Natural and Designed Antitumor Agents:
Epothilones and Thailanstatin A

A dissertation submitted in partial satisfaction of the

requirements for the degree

Doctor of Philosophy

in

Chemistry

by

Derek James Rhoades

Committee in charge:
Professor K.C. Nicolaou, Chair
Professor Charles L. Perrin, Co-Chair
Professor Neal K. Devaraj
Professor William H. Gerwick
Professor Nathan C. Gianneschi
Professor Teresa Helston

2016
©
Derek James Rhoades, 2016
All rights reserved.
The dissertation of Derek James Rhoades is approved, and it is acceptable for quality and
form for publication on microfilm and electronically:

Co-chair

Chair

University of California, San Diego
2016
iii
DEDICATION

This work is dedicated to my beautiful wife, Amanda, and to our future together.

iv
EPIGRAPH

You aren’t going to have good ideas, unless you have lots of ideas, and some sort of
principle of selection.

–Linus Pauling

v
TABLE OF CONTENTS
Signature Page....................................................................................................................iii
Dedication...........................................................................................................................iv
Epigraph...............................................................................................................................v
Table of Contents................................................................................................................vi
List of Abbreviations............................................................................................................x
List of Figures..................................................................................................................xvii
List of Schemes.................................................................................................................xix
List of Tables.....................................................................................................................xxi
List of Spectra..................................................................................................................xxii
List of NCI-60 Results.....................................................................................................xxix
Acknowledgements..........................................................................................................xxx
Vita................................................................................................................................xxxii
Abstract..........................................................................................................................xxxv
Chapter 1: Synthesis and Biological Evaluation of Novel Epothilone B Analogues......1
A. Introduction........................................................................................................2
1. Isolation................................................................................................2
2. Biosynthesis and Fermentation.............................................................5
3. Mechanism of Action, Clinical Candidates, Potent Analogues,
and Structure-Activity Relationships.....................................................7
B. Synthesis of Epothilone B Side Chain Analogues............................................14
1. Molecular Design...........................................................................14
2. Synthesis of Vinyl Iodide 1.33........................................................16
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3. Synthesis of Pyrazolyl Stannanes and Epothilone B Side Chain
Analogues 1.34–1.43 via Stille
Coupling.........................................................................................17
C. Biological Evaluation.......................................................................................22
1. NCI-60 Cytotoxicity Results..........................................................22
2. Further Cytotoxicity Studies and
Tubulin Assembly Induction Assay...............................................23
D. Structure-Activity Relationships and Conclusions...........................................24
1. Structure-Activity Relationships....................................................24
2. Conclusions....................................................................................25
E. Synthesis of Novel Aziridinyl Epothilone Analogues......................................26
1. Background and Initial Explorations..............................................26
2. Attemped Stille Coupling Approach..............................................30
3. Historical Inspirations and New
Synthetic Route Development........................................................31
4. Synthesis of Analogue Library.......................................................35
5. Extension of Synthetic Route to Secondary (Free –NH)
Aziridine Motif...............................................................................39
6. Synthesis of N-heterocyclic phosphonates.....................................40
F. Biological Evaluation.......................................................................................43
1. Cytotoxicity Studies and
Tubulin Assembly Induction Assay...............................................43
G. Structure-Activity Relationships and Conclusions...........................................45
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1. Structure-Activity Relationships....................................................45
2. Conclusions....................................................................................46
H. Experimental Section.......................................................................................48
1. General Procedures........................................................................48
2. Preparation of Compounds.............................................................49
3. List of Spectra..............................................................................159
4. NCI-60 One Dose Screening Results
for Analogues 1.34 and 1.35.........................................................270
5. NCI-60 5-Dose Screening Results
for Analogues 1.37–1.43..............................................................272
6. NCI-60 Dose-Response Curves for 1.37–1.43.............................279
I. References......................................................................................................286
Chapter 2: Total Synthesis of Thailanstatin A.............................................................293
A. Introduction....................................................................................................294
1. Isolation........................................................................................294
2. Biosynthesis and Fermentation....................................................296
3. Mechanism of Action and Clinical Relevance..............................297
B. Total Synthesis of Thailanstatin A..................................................................300
1. Retrosynthetic Analysis...............................................................300
2. Biosynthetic Inspiration...............................................................301
3. Synthesis of Western Fragment....................................................302

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4. Discovery of a Diastereodivergent Route for Accessing
Highly Functionalized Tetrahydropyrans via a Novel
Oxa–Michael/Hydrogenation Sequence.......................................306
5. Synthesis of Eastern Fragment.....................................................307
6. Completion of the Total Synthesis of Thailanstatin A..................309
C. Future Directions & Conclusions...................................................................310
1. Future Directions..........................................................................310
2. Conclusions..................................................................................311
D. Experimental Section.....................................................................................312
1. General Procedures......................................................................312
2. Preparation of Compounds...........................................................313
3. Comparison of Spectral Data of Natural and
Synthetic Thailanstatin A.............................................................344
4. List of Spectra..............................................................................348
5. X-Ray derived ORTEP of 2.46.....................................................382
E. References......................................................................................................383

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