Asymmetric synthesis of (+)-altholactone, a styryllactone from various goniothalamus species [Elektronische Ressource] / vorgelegt von Julien Barbion

Asymmetric Synthesis of (+)-Altholactone,
a Styryllactone from Various
Goniothalamus Species





Von der Fakultät für Mathematik, Informatik und Naturwissenschaften
der Rheinisch-Westfälischen Technischen Hochschule Aachen
zur Erlangung des akademischen Grades eines
Doktors der Naturwissenschaften
genehmigte Dissertation






Vorgelegt von

Diplom-Chemiker


Julien Barbion

Aus Le Plessis-Bouchard, Frankreich





Berichter: Universitätsprofessor Dr. Dieter Enders
Universitätsprofessor Dr. Hans-Joachim Gais



Tag der mündlichen Prüfung: 27.10.2006




Diese Dissertation ist auf den Internetseiten der Hochschulbibliohtek online verfügbar.

The work presented in this thesis was carried out at the Institute of Organic
Chemistry of RWTH Aachen University between November 2003 and October 2006
under the supervision of Prof. Dr. Dieter Enders.



I would like to thank Prof. Dieter Enders for the interesting research theme, the
constant support and the useful discussions, as well as the ideal working
atmosphere.



Moreover, I would like to thank Prof. Dr. Hans-Joachim Gais for his kind assumption
of the co-reference.



Parts of this work have already been published:


“Total Synthesis of (+)-Altholactone, a Styryllactone from Various Goniothalamus
Species”
D. Enders, J. Barbion, Chem. Eur. J., submitted.

ACKNOWLEDGEMENTS


Firstly, I would like to express my appreciation to Prof. Dr. Dieter Enders for giving
me the great opportunity to carry out my PhD in his research group and for his
encouragement throughout the course of this work.

I am grateful to Dr. J. Runsink for the NOE-measurements, and to Kamila Hennig,
Sabine Drehsen and Desiree Gilliam for measurement of chromatography, analytic
and preparative HPLC.

I would like to thank my labmates Dr. Michael Backes and Alexander Jonas for their
suggestions, their invaluable help and the kind and great ambiance in the lab.
I also would like to thank all members of AK-Enders for their kindness and generous
assistance throughout this work which made my time in Germany a great and rich
experience. And last, but not least, I would like to thank Benjamin Katrinyok for his
engaged participation in this project during his 6 weeks placement in the lab.

Special thanks go to Dr. Marie-Isabelle Lannou, Dr. Sylvie Dhulut, Dr. Sharon Chow
and Dr. Marianna Vrettou for their patience, their generous help for the correction of
my publication and this manuscript and for the good time in Aachen.

I gratefully acknowledge Dr. Wolfgang Bettray and Karin Risse for their administrative
assistance of my life in Germany.

I am especially grateful to the Deutsche Forschungsgemeinschaft (Graduiertenkolleg
440, SFB 380) for financial support which enabled me to undertake this study.

Finally, I thank my parents and all my friends for their loving care and unquestioning
support.

THANKS !!!


Julien Barbion
















«La science ne sert guère qu'à nous donner une idée de l'étendue de notre
ignorance»

Félicité Robert de Lamennais
French writer (1783-1854)

























My family and all my friends
Contents
Contents


1. Introduction 1
1.1 Natural products in the bioactive compounds research 1
1.2 The art and science of constructing the molecules of nature 2
1.3 Structure-Activity Relationship 5
1.4 Styryllactones and (+)-altholactone 5
1.4.1 General remarks about the styryllactones and (+)-altholactone 5
1.4.1.1 Introduction 5
1.4.1.2 Isolation and structural elucidation 7
1.4.1.3 Classification of styryllactones 8
1.4.1.4 Bioactivity of styryllactones 9
1.4.1.5 (+)-Altholactone (8) 9
1.4.2 Previous asymmetric syntheses of (+)-altholactone (8) 10
1.4.2.1 Chiral pool based strategies 10
1.4.2.2 Asymmetric synthesis by Mukai et al. 11
1.4.2.3 Asymmetric synthesis by O’Doherty et al. 12
1.4.2.4 Asymmetric synthesis by Yadav et al. 14
1.4.3 Previous work on the synthesis of styryllactones in our group 15
1.4.3.1 Asymmetric synthesis of (S)-goniothalamin by Enders et al. 15
1.4.3.2 Attempts towards the synthesis of (+)-goniotriol by Enders et al. 17

2. Objectives 21

3. Results and discussion 22
3.1 Asymmetric total synthesis of (+)-altholactone (8) 22
3.1.1 First retrosynthetic concept 22
3.1.1.1 The 2,2-dimethyl-1,3-dioxan-5-one-SAMP/RAMP-hydrazone
method 23
3.1.1.2 Alkylation and Michael addition on RAMP-hydrazone (R)-28 26
3.1.1.3 Aldol reaction with benzaldehyde 30
3.1.1.4 Reduction of the aldol product 32
3.1.1.5 Deprotection of the acetonide protected 1,3-diol 33

i Contents
3.1.1.6 Choice of a new primary alcohol protecting group 35
3.1.1.7 RAMP-directed alkylation and aldol reaction with benzaldehyde 37
3.1.1.8 New attempts of deprotection of the acetonide protected 1,3-diol 38
3.1.1.9 Study of the reduction of the aldol product carbonyl moiety 40
3.1.1.10 Improvement of the reduction reaction 41
3.1.1.11 Oxidation/cyclisation sequence 44
3.1.2 New retrosynthetic concept 50
3.1.2.1 Protection of the secondary alcohol as its benzyl ether 51
3.1.2.2 Cleavage of the acetonide and TBS protecting groups 52
3.1.2.3 Acetal protection of triol 65 52
3.1.2.4 Acetonide displacement 56
3.1.2.5 Arrangements for the oxidation/cyclisation sequence 58
3.1.2.6 Oxidation/in situ cyclisation sequence 58
3.1.2.7 Dehydrogenation of δ-lactone 74 59
3.1.2.8 Arrangements for the SN2 ring-closure 61
3.1.2.9 SN2 ring-closure and synthesis of (+)-altholactone (8) 61
3.2 Asymmetric total synthesis of (+)-goniodiol (78) 63
3.2.1 Presentation of the target molecule 63
3.2.2 Retrosynthetic concept 63
3.2.3 Deoxygenation of the δ-lactone 77 64

4. Research summary 65
4.1 Asymmetric total synthesis of (+)-altholactone (8) 65
4.1.1 Alkylation and aldol reaction of the RAMP-dioxanone hydrazone 65
4.1.2 Reduction of the carbonyl moiety of the aldol product 66
4.1.3 Oxidation/in situ cyclisation sequence 67
4.1.4 Stereoselective total synthesis of (+)-altholactone (8) 68
4.2 Asymmetric total synthesis of (+)-goniodiol (78) 70

5. Outlook 71
_5.1 Asymmetric total synthesis of ( )-altholactone (8) 71
5.2 Asynthesis of (+)-goniodiol (78) 72
5.2.1 Strategy using a tosylate group 72

ii