The Nazarov Cyclization

367 Pages·2014·19.59 MB·English

NAZAROV CYCLIZATION OF FULLY SUBSTITUTED DIENONES:
CATALYTIC DIASTEREOSPECIFIC AND ENANTIOSELECTIVE CONSTRUCTION
OF VICINAL ALL-CARBON ATOM QUATERNARY STEREOCENTERS

A DISSERTATION SUBMITTED TO THE GRADUATE DIVISION OF THE
UNIVERSITY OF HAWAIʻI AT MĀNOA IN PARTIAL FULFILLMENT OF THE
REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
IN
CHEMISTRY

MAY 2014

By
Anaïs Jolit

Dissertation Committee:
Marcus Tius, Chairperson
Thomas Hemscheidt
Philip Williams
William Chain
Joe Ramos
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Pour Papi Guguss et Mamie Raymonde

I wish you were here today

“Life is not easy for any of us. We must have perseverance and above all confidence in ourselves. We
must believe that we are gifted for something, and that this thing, at whatever cost, must be attained”

“La vie n’est facile pour aucun de nous. Mais, quoi, il faut avoir de la persévérance, et surtout de la
confiance en soi. Il faut croire que l’on est doué pour quelque chose, et que, cette chose, il faut l’atteindre
coûte que coûte”

Marie Curie
As quoted in Madame Curie: A Biography (1937) by Eve Curie Labouisse, p.69

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ACKNOWLEDGEMENTS

First and foremost, I would like to express my sincere gratitude to Professor Marcus A.
Tius for giving me the opportunity to do research in his group. I greatly appreciate your
encouragement, guidance and support during my six-year Ph.D. Thanks to your mentorship I
have gained valuable experience and knowledge that I will carry with me through the years.

I would like to express my gratitude to my committee members, Professor Thomas
Hemscheidt, Professor Philip Williams, Professor William Chain and Professor Joe Ramos for
their constructive research and career advices. I also want to acknowledge Wes Yoshida and
Glorina Cueva who make the life of so many graduate students easier by helping with data
analysis and supplies.

I would like to particularly thank Dr. Stephen Jackson, Dr. Craig Stewart and Dr. Patrick
Walleser who have been wonderful to me over the years. You guys have been such great
mentors and more importantly such good friends. Thanks for your genuine support, your
professional and personal advices and more importantly, for all the great time we spent
together drinking beers and debating about life and chemistry on the lanai or at Varsity. I stand
here today thanks to you and I will always be grateful for it.

I would like to thank all the Tius group members, past and present, who made this
whole experience worthwhile and memorable. I have been extremely fortunate to meet Dr.
Danielle McActee and Dr. Saleta Vasquez during my time in the Tius group. You ladies brought
some fun and sun in the lab and I wish you the best in life. Also, thank you to Will Bow, Ashok
Basak, Naoyuki Shimada, Go Ogawa, Gideon Berger, Darryl Dixon, Jon Congmon, Kei Kitamura,
Paolo Larini for being such good and fun co-workers.

Of course, none of this adventure would have been possible without the love and
encouragements of my family. Dad, mom, Clémence, Marthe, thank you for your unconditional
support, you have always been there for me even if I was so far away from you. I finally made it!
I hope you are proud of me and I can’t wait to be closer to home. To my boyfriend
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Dr. Francois Paquay: Thank you so much for your understanding and the joy you bring around
you, and more particularly for feeding me and dealing with my crazy mood swings over the last
months.

My Ph.D has not only been a working experience but more importantly a life experience.
I went through a lot of ups and downs, not only related to work and I would like to stress out
how important my friends were in these moments. I would like to thank from my whole heart
the people who have been here for me during the last six years. The whole French team
composed of Maitre Truchot, Mel Bee, Miss Annick, Max, Tom and Julia and off course Mister
Christophe Berini. Big Mahalo to you all, for the fun, the wine, the food, the “aperos”, the
camping trips,… Also thank you to Mario Hoyos, Felix and Sandra, Brant Jones and Benny the
Dog, Brant Landers, Ron and Barbora. I also want to congratulate my partners in crime who
made it to the final line: Marina Chong and Paul Beaumont who started their Ph.D. with me in
2008. And just for Paul: “Follow the light, you’re almost there!”

I finally want to acknowledge the little things that help you release the tension or anger
that builds during those long hours in the lab. Thanks to my yoga teacher Shelley Choy for
making me “breathe” and relax. Thanks to the beautiful island of Oahu for delivering such a
wonderful playground to escape from the “windowless” lab. I will miss the warm weather and
my “surf lunch” breaks! Off course, I have to recognize the great sponsor of this six-year of great
labor, the Kona Brewery, for its endless supplies.

Mahalo nui loa, aloha mai e.

Anaïs Jolit

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ABSTRACT

Vicinal all-carbon atom quaternary stereocenters are found in many complex natural
products. However the direct construction of such motifs remains a difficult challenge in organic
synthesis. Only a few methods for catalytic asymmetric synthesis that have been reported
recently address this synthetic problem. One new approach is to take advantage of an orbital
symmetry controlled process. The Nazarov reaction is a 4π electrocyclization that has the
potential to form two vicinal quaternary centers within a five-membered ring with good
diastereocontrol in one step. This thesis describes the development of the first catalytic enantio-
and diastereospecific Nazarov cyclization of fully substituted dienones to form vicinal all-carbon
atom quaternary stereocenters.

Chapter 1 will introduce the Nazarov cyclization. Presentation of the reaction
mechanism will be followed by a discussion that emphasizes the influence of substituents of the
dienones on the outcome of the cyclization. Recent advances in the field will be reviewed and
will mainly focus on the development of new catalytic and asymmetric Nazarov cyclizations.

Chapter 2 describes the first catalytic diastereospecific Nazarov cyclization of fully
substituted dienones that generate vicinal all-carbon atom quaternary centers. The discussion
will describe the careful design of the Nazarov substrate and the selection of reaction
conditions. The scope and limitations of the methodology will also be presented.

The α-hydroxycyclopentenones that can be prepared by means of the method described
in Chapter 2 bear two contiguous quaternary carbons within a five-membered ring. Such
compressed systems are in general very difficult to modify. We were able to carry out a number
of diastereo- and regiospecific transformations of these cyclic products. This work will be
presented in Chapter 3.

In Chapter 4, we describe the first organocatalytic asymmetric Nazarov cyclization of
fully substituted dienones using a BINOL-derived N-triflylphosphoramide catalyst. The substrate
and catalyst have been carefully designed leading to the formation of the cyclopentenone
products having vicinal all-carbon atom quaternary stereocenters in high optical purity and as
single diastereoisomers. A variety of dienones were able to undergo asymmetric cyclization and
will be discussed in the scope and limitations of the reaction.
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TABLE OF CONTENTS

ACKNOWLEDGEMENTS .................................................................................................................... v
ABSTRACT ....................................................................................................................................... vii
LIST OF TABLES ................................................................................................................................ xi
LIST OF FIGURES ............................................................................................................................ xiii
LIST OF SCHEMES ...........................................................................................................................xiv
LIST OF ABBREVIATIONS .............................................................................................................. xviii

CHAPTER 1 : The Nazarov Cyclization ............................................................................................. 1
1. The Traditional Nazarov Reaction ............................................................................................ 1
1.1. Synthetic scope and limitations of the Nazarov cyclization ............................................ 2
1.2. Substituents on divinyl ketone: Influence on reactivity and regioselectivity .................. 4
1.2.1. Steric influence of α-substituents on divinyl ketone ............................................... 4
1.2.2. Stereoelectronic influence of α- and β-substituents on divinyl ketone .................. 5
1.2.3. Steric effects of β-substituents at the internal position .......................................... 9
2. Exploiting the pentadienyl cation .......................................................................................... 12
2.1. The interrupted Nazarov reaction ................................................................................. 12
2.2. The Nazarov cyclization/Wagner-Meerwein rearrangement sequence........................ 15
3. Progress towards the catalytic asymmetric Nazarov cyclization ........................................... 19
3.1. Catalytic Nazarov cyclizations via polarization of the divinyl ketone ............................ 19
3.2. Asymmetric Nazarov cyclizations ................................................................................... 23
3.1.1. Asymmetry transfer ............................................................................................... 24
3.1.2. Chiral auxiliaries ..................................................................................................... 25
3.1.3. Catalytic asymmetric Nazarov cyclizations ............................................................ 27
4. New directions in the Nazarov cyclization in the Tius group ................................................. 31
5. References ............................................................................................................................. 32

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CHAPTER 2 : Diastereospecific Nazarov Cyclization of Fully Substituted Dienones: Generation
of Vicinal All-Carbon-Atom Quaternary Stereocenters. .............................................................. 37
1. Introduction ........................................................................................................................... 37
1.1. Background .................................................................................................................... 37
1.2. Project objectives ........................................................................................................... 41
2. Substrate synthesis ................................................................................................................ 43
2.1. Retrosynthetic approach ............................................................................................... 43
2.2. Synthesis of trisubstituted α,β-unsaturated carboxylic acid 20b .................................. 43
2.3. Synthesis of α,β-disubstituted acrylates 21 ................................................................... 46
2.4. Synthesis of dienones 19 via copper-mediated coupling .............................................. 48
3. Optimization of the Nazarov cyclization ................................................................................ 51
4. Mechanism ............................................................................................................................. 53
5. Scope of the reaction ............................................................................................................. 54
5.1. Preparation of left-hand side synthons ......................................................................... 55
5.2. Synthesis of SEM enol ether right-hand side synthons ................................................. 57
5.3. Synthesis of fully substituted dienones for the Nazarov cyclization study ................... 59
5.4. Scope of the diastereospecific Nazarov cyclization of fully substituted dienones ........ 65
6. Limitations of the Nazarov cyclization of fully substituted dienones .................................... 67
7. Conclusion .............................................................................................................................. 70
8. References ............................................................................................................................. 71

CHAPTER 3 : Stereo- and Regiospecific Modifications of a Highly Congested Cyclopentenone 75
1. Introduction ........................................................................................................................... 75
2. Protection of highly congested hydroxycylopentenone 1 ..................................................... 76
3. 1,2-Addition to highly congested cyclopentenone 6e,f ......................................................... 77
3.1. Stereoselective 1,2-hydride addition to cyclopentenone 6a ......................................... 78
3.2. Stereoselective 1,2-carbon addition to cyclopentenones 6a,f ...................................... 79
4. Cross-coupling reaction at C2 ................................................................................................ 81
5. Stereoselective formation of quaternary stereocenter at C3 by electrophilic addition ....... 84
5.1. Attempts towards formation of all-carbon atom quaternary stereocenter at C3 ........ 84
5.2. Stereoselective formation of quaternary stereocenter at C3 bearing a heteroatom ... 86
6. γ-Carbon atom functionalization ........................................................................................... 90
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7. Conclusion .............................................................................................................................. 94
8. References ............................................................................................................................. 96

CHAPTER 4 : Catalytic Enantioselective Nazarov Cyclization: Vicinal All-Carbon Atom
Quaternary Stereocenters ............................................................................................................ 97
1. Introduction ........................................................................................................................... 97
1.1. Background .................................................................................................................... 97
1.2. Primary results and objectives ..................................................................................... 101
2. Syntheses of catalysts 7 and dienone substrates 15 ........................................................... 106
2.1. Preparation of catalysts 7 ............................................................................................ 106
2.2. Preparation of dienone substrates 15 ......................................................................... 108
3. Optimization of the catalytic asymmetric Nazarov cyclization of dienones 8 ..................... 115
3.1. Optimization of the dienone substrate 8 ..................................................................... 115
3.2. Optimization of catalyst 15 .......................................................................................... 120
3.3. Optimization of the reaction conditions ...................................................................... 123
4. Preparation of substrates for the reaction scope of the catalytic asymmetric Nazarov
reaction ........................................................................................................................................ 129
5. Scope of the catalytic asymmetric Nazarov cyclization of fully substituted dienones ........ 131
6. Limitations of the methodology........................................................................................... 135
7. Proposed mechanism ........................................................................................................... 139
8. Conclusion ............................................................................................................................ 140
9. References ........................................................................................................................... 142

CONCLUSION ................................................................................................................................ 145

APPENDIX: Progress towards the total synthesis of rocaglamide ................................. 149
EXPERIMENTAL SECTION ................................................................................................. 161
EXPERIMENTAL SECTION Chapter 2 ............................................................................... 163
EXPERIMENTAL SECTION Chapter 3 ............................................................................... 250
EXPERIMENTAL SECTION Chapter 4 ............................................................................... 273

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