the use of the crossed aldol mukaiyama reaction - Rero Doc

186 Pages·2008·6.95 MB·English

THE USE OF THE CROSSED ALDOL MUKAIYAMA REACTION
FOR THE PREPARATION OF ADVANCED INTERMEDIATES FOR
THE SYNTHESIS OF RHAZINILAM ANALOGUES

Thesis presented to the Faculté de Science,
Institut de chimie of Université de Neuchâtel for the award of degree of
Doctor of Science

By

Ana-Maria Buciumas

Thesis accepted by the jury:

Prof. Reinhard NEIER – University of Neuchâtel
Prof. Robert DESCHENAUX – University of Neuchâtel
Prof. Philippe RENAUD – University of Bern
Prof. Thomas WARD – University of Basel

University of Neuchâtel

2008

Acknowledgment

This PhD work was accomplished from August 2003 to April 2008 in the Laboratory of synthetic
organic chemistry, Institute of Chemistry, University of Neuchâtel under the guidance of Prof.
Reinhard NEIER. Special thanks go to him for the opportunity that he gave to me to work in his
group on a wonderful topic, for his advices for being a better chemist, but also for life, for giving
me the independence to apply my ideas (not always the best, but always very fruitful for my
experience), to guide me to learn more during the seminars and conferences.

I sincerely acknowledge Prof. Philippe Renaud, Prof. Thomas Ward and Prof. Robert
Deschenaux for being the jury experts of my thesis, for taking their time to correct my manuscript
and giving me an interesting discussion and a wonderful remembrance from my exam.

I thank the group members: Dr. Olivier Vallat (uff, working with a girl…who is not able to
understand “3 grains of DMAP”…), Dr. Vallinayagam Ramakrishnan (Valli – for sharing all our
good and bad times of the four years working together), Dr. François Loiseau, “not yet, but almost
Dr.” Beat Herzog, Dr. Valeria Blangy, Dr. Sébastien Lanaspèze, Dr. Sabine Gacond, Dr. Sylvain
Burger, Damien Thevent (a wonderful colleague and friend, but a frightful Poker player), Inga
Zaitseva, Vsevolov Khlebnikov, Gurba Patrice (also a very good friend).

I thank Mrs. Jocelyne Tissot for all administrative help she made, Mr. Maurice Binggeli and Mrs.
Claire Rosset, Mr. Heinz Bursian, Julien Furrer, Jean-Denis Bernard, Armelle Vallat for their
analytical services and to Mr. Pierre Tissot for all his help in informatics problems.

My special thanks for making my life at Neuchatel very enjoyable go to my friends Claudia and
Iulian and to their little princes Ania, Sabina, Cristina and Adrian, Mustapha, Julieta, Olha,
Magdalina, Yolanda, Mona and Julien, Dalila, Cristi and their angel Amalia, Florin, Gabi and to
my best friend from the first year of University till today, Corina.

My greatest thanks go to my parents, Maria and Neculai, to my brother, Nicu, and to my
grandparents for all their support and wishes.

To Marc

Key words:

Rhazinilam, Rhazinilam analogues, Crossed Aldol Mukaiyama reaction, Stereoselectivity
of the Mukaiyama reaction.
Resume

L’étude des précédents exemples de synthèse totale du rhazinilam et de ses analogues,
nous a conduit à élaborer notre propre approche basée sur une réaction d’aldolisation
croisée de Mukaiyama comme étape clé. La voie de synthèse est décrite (en partie) ci-
dessous :

OTMS
NO2 2steps NO2 O NO2 PPh3 NO2Boc2O/DMAP NO2
Mukaiyamarc. HO THF/1%H2O HO
O O
N3 N3 O O HN O N O
Boc
La détermination de la diastéréosélectivité des reactions concernées est realizée par
analyse des structures par diffractométrie de rayons-X.
Les étapes suivantes ont été étudiées sur un modèle simplifié. Le composé 1 est obtenu
par N-acylation du 1H-pyrrole-2(5H)-one suivie de la déprotection de la fonction alcool.
L’oxydation controlée de la fonction alcool de 1 en aldéhyde suivie d’une réaction de
Wittig permet d’obtenir le composé 2.

F
O F
TBDPSO O
O
F F
NH O F TBDPSO N O TBAF HO N O C2H5O N O
O
O O O
1 2

La méthodologie envisagée pour aboutir à la synthèse des analogues du rhazinilam est
la suivante : on forme le cycle à six chaînons par une réaction d’addition de Michael
suivie de la réduction du groupement nitro et, enfin, une réaction de lactamisation
permet de former le cycle à neuf chaînons.

O O
NO2 NO2 HN
C2H5O C2H5O
O
O O O
N
N N
O O
O
O O