Studies directed towards the natural product nominine

188 Pages·2013·6.78 MB·English

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UNIVERSITY OF SOUTHAMPTON

FACULTY OF NATURAL & ENVIRONMENTAL SCIENCES

Department of Chemistry

Studies Directed Towards the Natural Product Nominine

by

Wendy Yee Lee Goh

Thesis for the degree of Doctor of Philosophy

April 2013

UNIVERSITY OF SOUTHAMPTON
ABSTRACT
FACULTY OF NATURAL & ENVIRONMENTAL SCIENCES
DEPARTMENT OF CHEMISTRY
Doctor of Philosophy
STUDIES DIRECTED TOWARDS THE NATURAL PRODUCT NOMININE
by Wendy Yee Lee Goh

Natural product synthesis is a highly regarded and essential aspect of organic chemistry. Its
challenging nature requires a wide spectrum of reactions to be performed with a broad set
of skills being developed throughout each project. This thesis describes studies towards the
total synthesis of nominine, an indole diterpenoid which exhibits antiinsectant properties.
Synthesis of this natural product could provide entry into this family of indole diterpenoids
allowing several natural products to be accessed.

Chapter 1 introduces this natural product and its proposed synthetic route. Two total
syntheses, by Bonjoch and Nicolaou published after this project had ceased, are also
presented.

Chapter 2 discusses the methods of constructing key intermediate enone 1.1 and describes
its successful efficient synthesis on a multigram scale. The synthesis of natural products
dehydrofukinone and fukinone using this key intermediate follows in chapter 3.

Chapter 4 details the challenges and successes of the investigations towards the total
synthesis of nominine. Future work for its completion and other possible related indole
diterpenoids are described in chapter 5. A conclusion to the project and a chapter
containing experimental details conclude this thesis.

Contents
DECLARATION OF AUTHORSHIP ............................................................................... i
ACKNOWLEDGEMENTS............................................................................................. iv
ABBREVIATIONS .......................................................................................................... v
Chapter 1. Introduction ............................................................................................... 1
1.1. Natural products and their syntheses ............................................................................ 1
1.2. Nominine....................................................................................................................... 3
1.3. Proposed synthetic route to nominine ........................................................................... 4
1.4. 1st Total synthesis of ent-anominine by Bonjoch et al. ................................................. 6
1.5. 2nd Total synthesis of anominine by Nicolaou et al. ................................................... 11
1.6. Conclusion to chapter 1............................................................................................... 13
1.7. References for Chapter 1............................................................................................. 14
Chapter 2. Bicyclic enone intermediate 1.1 ................................................................ 17
2.1. Literature review ......................................................................................................... 18
2.2. Formation of bicyclic enone intermediate 1.1 ............................................................. 26
2.2.1. Route 1: 1,4-addition & trapping of enolate method .......................................... 27
2.2.2. Route 1A: With 4-chlorobutanone/4-chlorobutenone. ........................................ 29
2.2.3. Route 1B: With trimethylsilyl-3-buten-2-one. .................................................... 33
2.2.4. Route 2 – Use of ethyl 3-Methyl-1-oxo-2-cyclohexene-2-carboxylate (2.59) .... 38
2.2.5. Route 3 – Use of Wieland-Miescher Ketone ...................................................... 41
2.2.6. Large scale synthesis of enone 1.1 ...................................................................... 48
2.3. Conclusion to chapter 2............................................................................................... 50
2.4. References for Chapter 2............................................................................................. 51
Chapter 3. Total synthesis of dehydrofukinone and fukinone .................................... 55
3.1. Introduction ................................................................................................................. 55
3.2. Review of published syntheses of dehydrofukinone and fukinone ............................. 56
3.2.1. Previous syntheses of dehydrofukinone .............................................................. 56
3.2.2. Previous syntheses of fukinone ........................................................................... 60
3.3. Synthesis of dehydrofukinone ..................................................................................... 66
3.4. Synthesis of fukinone .................................................................................................. 68
3.5. Conclusion to chapter 3 ............................................................................................... 73
3.6. References for Chapter 3. ............................................................................................ 75
Chapter 4. Studies towards total synthesis of nominine ............................................. 77
4.1. 1,4-Addition reactions. ................................................................................................ 77
4.1.1. Model studies using 3-methyl-cyclohexenone and Grignard reagents: Trapping
enolate with MeI .................................................................................................................. 79
4.1.2. Model studies using 3-methyl-cyclohexenone and Grignard reagents: Trapping
enolate with TBDMSCl/TMSCl .......................................................................................... 81
4.1.3. Model studies using 3-methyl-cyclohexenone and Gilman’s reagents................ 83
4.1.4. Investigations of 1,4-addition reactions with enone 1.1 ...................................... 85
4.1.5. Conclusion to chapter 4.1 .................................................................................... 88
4.2. Synthesis of hydroxy bicyclic enone 1.3 ..................................................................... 89
4.2.1. Kishi’s method ..................................................................................................... 89
4.2.2. Dienol ether intermediate .................................................................................... 96
4.2.3. Conclusion to chapter 4.2 .................................................................................. 102
4.3. Investigating the reactions of hydroxy enone 1.3 ...................................................... 103
4.3.1. Modified-Reformatsky reaction ........................................................................ 103
4.3.2. Hydrocyanation reaction .................................................................................... 108
4.3.3. Conclusion to chapter 4.3 .................................................................................. 119
4.4. Conclusion to Chapter 4 ............................................................................................ 120
4.5. References for Chapter 4 ........................................................................................... 121
Chapter 5. Future work towards the total synthesis of nominine and beyond ...........125
5.1. Towards the total synthesis of nominine ................................................................... 125
5.2. Beyond nominine ....................................................................................................... 127
5.3. References for Chapter 5........................................................................................... 129
Chapter 6. Conclusion ............................................................................................. 131
Chapter 7. Experimental Section ............................................................................. 133
7.1. General Experimental ............................................................................................... 133
7.2. Experimental details .................................................................................................. 134

DECLARATION OF AUTHORSHIP

I, Wendy Yee Lee Goh,
declare that the thesis entitled
“Studies Directed Towards the Natural Product Nominine”
and the work presented in the thesis are both my own, and have been generated by me as the
result of my own original research. I confirm that:
 this work was done wholly or mainly while in candidature for a research degree at this
University;

 where I have consulted the published work of others, this is always clearly attributed;

 where I have quoted from work of others, the source is always given. With the
exception of such quotations, this thesis is entirely my own work;

 I have acknowledged all main sources of help;

 None of this work has been published before submission.

Signed:

Date:

i