Vers la première synthèse totale d’ellagitannins C-arylglucosidiques : une approche biomimétique, Towards the first total synthesis of C-arylglucosidic ellagitannins : a biomimetic approach

N° d’ordre : 4019

THÈSE en Co-Tutelle

PRÉSENTÉE A

L’UNIVERSITÉ BORDEAUX 1

ÉCOLE DOCTORALE DES SCIENCES CHIMIQUES

par Anna Natangelo

POUR OBTENIR LE GRADE DE


DOCTEUR
SPÉCIALITÉ : CHIMIE ORGANIQUE

Vers la première synthèse totale d’ellagitannins C-arylglucosidiques.
Une approche biomimétique.
Directeur de thèse : Stéphane QUIDEAU

Soutenue le : 6 avril 2010

Après avis de :
MM. Piero PUCCI Professeur, CEINGE biotecnologie avanzate Rapporteur
Alessandro PEZZELLA Directeur de Recherche, Université de Naples

Devant la commission d’examen formée de :
MM. Piero PUCCI CEINGE Biotecnologie Avanzate Président du jury
Alessandro PEZZELLA Directeur de Recherche, Université de Naples Rapporteur
Stéphane QUIDEAU Professeur, Universitè de Bordeaux Directeur de thèse
Stefano MANFREDINI Professeur, Universitè de Ferrara Co-directeur de thèse
Stefan CHAISSANG Maître de Conférences, Université de Toulouse Membre invité


Université Bordeaux 1
Les Sciences et les Technologies au service de l’Homme et de l’environnement
Università degli Studi di Ferrara


DOTTORATO DI RICERCA IN CoTUTELA
con l’UNIVERSITA’ DI BORDEAUX I
in

Scienze Farmaceutiche

CICLO XXII
COORDINATORE Prof. Stefano Manfredini


Towards the first total synthesis of C-arylglucosidic ellagitannins.
A biomimetic approach.
Settore Scientifico Disciplinare CHIM/09

Sostenuto il 6 Aprile 2010
In seguito alla valutazione di:
Piero PUCCI Professore, Università di Napoli Controrelatore
Alessandro PEZZELLA Ricercatore, Università di Napoli Controrel
Stefan CHAISSANG Ricercatore, Université de Toulouse Referee Doctor Europeus
Piet HERDEWIJN Professore, Università di Leuven Referee Doctor Europeus

Davanti alla commissione costituita da:
Piero PUCCI Professore, Università di Napoli Presidente della Commissione
Alessandro PEZZELLA Ricercatore, Università di Napoli Esaminatore
Stéphane QUIDEAU Professore, Università di Bordeaux Correlatore di tesi
Stefano MANFREDINI versità di Ferrara Rel tesi
Stefan CHAISSANG Ricercatore, Université de Toulouse Esaminatore

Dottorando Tutore
Dott. Natangelo Anna Prof. Manfredini Stefano

_______________________________ _____________________________
(firma) (firma)
Prof. Quideau Stéphane

_____________________________ (firma)


Anni 2007/2010
Institut des Sciences Moléculaires (ISM, UMR-CNRS 5255) 3
Institut Européen de Chimie et Biologie (IECB), 2 rue Robert Escarpit, 33607 Pessac, France

Facoltà di Scienze Farmaceutiche, Università degli Studi di Ferrara, via Fossato di Mortara 14-19, 44100 Ferrara, Italia





This study was supported in part by grants from the French-Italian University
(Bando VINCI 2008 cap. III)






The structure, known but not yet accessible by synthesis,
is to the chemist what the unclimbed mountain,
the unchartered sea, the untilled field,
the unreached planet, are to other men.
R.B. Woodward


Wonder is the beginning of all science.
Aristotele, Metaphysics, I,2,982b


Nothing great in the world has been accomplished without passion.
F. Hegel
Contents
List of Abbreviations and Acronyms..................................................................... 11
General Introduction .............................................................................................. 13
Chapter 1 : Ellagitannins Structural Description and Total Synthesis ....... 16
1.1 Ellagitannins : a class of bioactive plant polyphenols.................................... 17
1.1.1 Ellagitannins structural properties........................................................................ 18
1.1.2 Hydrolyzable tannins classification basisd on their structural properties........... 19
1.2 C-Glucosidic ellagitannins : A special subclass of ellagitannins................... 23
1.3 Biological activity of C-glucosidic ellagitannins ............................................. 29
1.4 Ellagitannins Total Synthesis........................................................................... 31
1.5 HHDP-formation via oxidative biaryl coupling (Method A) ........................ 36
1.5.1 Total synthesis of tellimagrandin I and II (4,6-HHDP) ....................................... 36
1.5.2 Total synthesis of sanguiine H-5 (2,3-HHDP)...................................................... 38
1.5.3 Total synthesis of pedunculagin (2,3,4,6-HHDP)................................................. 39
1.5.4 Ullmann Coupling.................................................................................................. 40
1.5.5 Total synthesis of corilagin (3,6-HHDP)............................................................... 43
1.5.6 The strategy of Spring for the synthesis of sanguiin-H5...................................... 45
1.5.7 PIFA mediated oxidative coupling attempts.......................................................... 46
1.6 Enantiomerically pure Ellagitannins via double esterification of
hexahydroxydiphenic acid (Method B) ........................................................... 47
1.6.A Enantioselective synthesis of a group (S)-HHDP ................................................ 48
1.6.B Kinetic resolution................................................................................................... 50
1.6.1 Total synthesis of strictinin (4,6-HHDP)............................................................... 51
1.6.2 Total synthesis of gemine D, hippomanin A and 1,3-di-O-galloyl-4,6-O-(S)-
hydroxydiphenoyl- -D-glucopyranoside (4,6-HHDP)................................................... 53
1.6.3 Total synthesis of praecoxin B, pterocarinin C, pariin M and mahtabin A (2,3-
HHDP)............................................................................................................................. 54
1.6.4 Khanbabee’s pedunculagin (2,3,4,6-HHDP) total synthesis................................ 57
1.7 Hemisynthesis of a C-arylglucosidic ellagitannin .......................................... 58
Chapter 2 : Retrosynthetic Analysis and Precursors Synthesis ................... 59
2.1 Retrosynthetic analysis ..................................................................................... 61
2.2 Synthesis of intermediate D.............................................................................. 64
2.2.1 Synthesis of polyhydroxylated intermediate D ..................................................... 64 3
2.2.2. Synthesis of sugar E.............................................................................................. 65
2.2.3. “Biomimetic” approach to the D synthesis: esterification of the sugar E with 3
gallic acid......................................................................................................................... 67
2.2.4 Synthesis of completely protected galloyl units F ................................................ 69 0
2.2.5 Preparation of intermediates D ............................................................................ 70 0Contents
2.2.6 Preparation of the itermediates D via orthogonal deprotection of precursors D3 0
.......................................................................................................................................... 71
2.2.7 Synthesis of para-protected galloyl units F .......................................................... 73 2
2.2.8 Preparation of intermediates D ............................................................................ 74 2
2.2.9 Protection of F units ............................................................................................. 75 2
2.2.10 Preparation of intermediates D ......................................................................... 76 2’
2.2.11 Preparation of the intermediates D via orthogonal deprotection of D ........... 77 2 2’
2.3 Synthesis of inetrmediates B 78
2.4 Intermediates B via Biarylic oxidative coupling ............................................ 79
2.4.1. o-chloranil mediated intramolecular biarylic oxidative coupling ....................... 79
2.4.2 o-chloranil mediated oxidative coupling of 135b.................................................. 84
2.4.3 o-chloranil mediated oxidative coupling of 135d 86
2.4.4 Cu(II)-amine complex promoted intramolecular biarylic oxidative coupling..... 87
2.4.5 Cu(II)-amine complex mediate oxidative coupling of 149b ................................. 90
2.5 Intermediates B via acetylation of a racemic unit (±)-HHDP....................... 92
Chapter 3 : C-arylglucosidation Step.............................................................. 99
3.1 The key step of C-arylglucosidation 100
3.2 Our approach to C-arylglucosidation............................................................ 102
3.3 First C-arylglucosidation attempts: Tanaka’s conditions .................... 105
3.3.1 C