Synthetic studies on guaipyridine alkaloids

167 Pages·2016·3.46 MB·English

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WWU Graduate School Collection WWU Graduate and Undergraduate Scholarship
2014
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Patrick M. M. (Patrick Michael McPhee) Shelton
Western Washington University
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Shelton, Patrick M. M. (Patrick Michael McPhee), "Synthetic studies on guaipyridine alkaloids" (2014).
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Synthetic Studies on Guaipyridine Alkaloids

By
Patrick Michael McPhee Shelton

Accepted in Partial Completion
of the Requirements for the Degree
Master of Science

Kathleen L. Kitto, Dean of the Graduate School

ADVISORY COMMITTEE

Chair, Dr. James R. Vyvyan

Dr. Gregory W. O’Neil

Dr. Tommaso A. Vannelli
MASTER’S THESIS

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Signature: Patrick Shelton

Date: March 6, 2014
Synthetic Studies on Guaipyridine Alkaloids

A Thesis
Presented to
The Faculty of
Western Washington University

In Partial Fulfillment
of the Requirements for the Degree
Master of Science

by
Patrick Michael McPhee Shelton
March 2014
Abstract
The guaipyridines are a class of naturally occurring alkaloids isolated from plants
native to the Pacific Islands and Southeast Asia. One member of this family, cananodine, has
displayed potent in vitro cytotoxic effects against two different types of hepatocellular
carcinoma cell lines. More recently discovered guaipyridne compounds, rupestines A-M,
share structural similarities to cananodine and might possess similar anti-cancer properties.
The potential medical benefits and the rare and interesting structure of the guaipyridines
make them desirable and challenging synthetic targets. Two distinct synthetic routes were
developed to access the guaipyridine core, and in doing so the total synthesis of cananodine
and its diastereomers was accomplished.
The initial route (epoxide-opening route) had previously been explored by the
Vyvyan group (see Meyer, Ligon thesis; Yarbrough unpublished results) although room for
improved efficiency and the final stereoselective hydrogenation reaction left significant work
to be completed on this project. The critical Suzuki-Miyaura cross-coupling step involving a
dienyl boronate ester and pyridyl triflate produced lower than desired yields, thus numerous
combinations of coupling partners and reaction conditions were explored to improve the
performance of this reaction. Once optimized conditions were developed, the sequence was
continued and both enantiomers of the key 7-exo cyclization precursor was successfully
isolated after base-promoted epoxide-opening. Exhaustive hydrogenation and reduction
efforts of the remaining 1,1-disubstituted alkene provided a ~1:1 diastereomeric mixture of
cananodine and its C5 epimer.
The second route (intramolecular Heck cross-coupling route) to the guaipyridine
skeleton is new to the Vyvyan lab and hinges on two key reaction steps. After preparation of
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picolyl bromide and tert-butyl hexenoate precursors, an alkylation reaction provided the
carbon-backbone compound in satisfactory yields. Subsequent phenol deprotection and
functionalization allowed for intramolecular Heck coupling between the 1,1-disubstituted
side-chain alkene and a newly formed pyridyl triflate group provided the cyclized
guaipyridine core compound in good yields.

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Acknowledgements

Research Advisor: Dr. James R. Vyvyan
Thesis Committee Members: Dr. Gregory W. O’Neil
Dr. Tommaso A. Vannelli

Financial Supporters: National Institutes of Health
WWU Fund for the Enhancement of
Graduate Research
Ross Travel Grant

Instrument Technicians and Support: Charles F. Wandler
Dr. Hla Win-Piazza
Erin Macri
Colin Hansen

Former Research Group Members: Jennifer Meyer, Toby Ligon, Loagan
Yarbrough, Mikhail Konev, Thomas Eivers

Professor Donald Craig (Imperial College, London)
Dr. John D. Gilbertson Research Group
Western Washington University Department of Chemistry

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TABLE OF CONTENTS

Abstract ......................................................................................................... iv
Acknowledgments ........................................................................................ vi
List of Tables and Figures ........................................................................... ix
List of Abbreviations .................................................................................... x

1. Introduction
1.1. Hepatocellular Carcinoma.................................................................. 1
1.2. Sorafenib and small molecule treatment of HCC. ............................. 2
1.3. Natural products as cancer fighting agents ........................................ 6
1.4. Discovery of (-)-cananodine and the rupestine natural products ..... 11
1.5. Previous guaipyiridne syntheses ...................................................... 15
1.6. Total synthesis of cananodine by Craig & Henry ............................ 19

2. Total Synthesis of Cananodine via Epoxide-Opening Route
2.1. Original synthetic strategy ............................................................... 21
2.2. Previous work by Meyer, Ligon and Yarbrough ............................. 24
2.3. Suzuki-Miyaura cross-coupling optimization
2.3.1. Preparation of coupling partners .............................................. 30
2.3.2. Coupling optimization .............................................................. 32
2.4. Synthetic route continuation
2.4.1. Preparation of the guaipyridine core ........................................ 37
2.4.2. Terminal alkene hydrogenation and reduction reactions ......... 39
2.4.3. Attempted diastereomer separation .......................................... 45
2.5. Progress toward the syntheses of rupestines B-D ............................ 48

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3. Access to the Guaipyridine Core via Intramolecular Heck Reaction
3.1. The Heck cross-coupling reaction
3.1.1. History of the Heck coupling reaction .................................... 55
3.1.2. Intramolecular Heck reaction model studies ........................... 59
3.2. Initial synthetic plan ......................................................................... 61
3.3. Preparation of precursors and the bromide elimination reaction ..... 64
3.4. Intramolecular Heck reactions ......................................................... 68
3.5. Attempted hydrogenation and reduction reactions .......................... 70
3.6. Attempted reductive-Heck reactions ................................................ 72

4. Conclusions ............................................................................................ 75

5. Experimental Section ............................................................................. 77

References .................................................................................................. 151

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List of Tables and Figures

Figure 1. Inhibition interactions between sorafenib and B-Raf ................................................. 6

Figure 2. Cytotoxic constituents of C. odorata fruit extract ..................................................... 12

Figure 3. Hypothesized interactions between cananodine and B-Raf .................................... 13

Figure 4. Rupestines A-D, F-M ......................................................................................................... 14

Figure 5. Compounds from Büchi and Van der Gen isolations and syntheses .................... 16

Figure 6. AD mix stereoselectivity mnemonic ............................................................................. 23

Figure 7. Compounds used in Suzuki coupling optimization ................................................... 32

Table 1. Suzuki Coupling Optimization Reactions ...................................................................... 36

Figure 8. Proposed directed hydrogenation of 2.32 ..................................................................... 40

Figure 9. Wilkinson’s hydrogenation crude gas chromatogram .............................................. 42

Figure 10. Attempted HPLC separation of diastereomers ......................................................... 45

Table 2. Cananodine 1H NMR Comparison ................................................................................... 47

Table 3. Cananodine 13C NMR Comparison ................................................................................. 47

Figure 11. General Heck reaction catalytic cycle ......................................................................... 56

Table 4. Survey of Heck Pd Catalysts and Bases ......................................................................... 69

Table 5. Reductive Heck Coupling Conditions ............................................................................. 74

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