Cinchona alkaloids and BINOL derivatives

227 Pages·2014·16.2 MB·English

Alma Mater Studiorum – Università di Bologna

DOTTORATO DI RICERCA IN

CHIMICA

Ciclo XVI

Settore Concorsuale di afferenza: 03/C1

Settore Scientifico disciplinare: CHIM/06

Cinchona alkaloids and BINOL derivatives
as privileged catalysts or ligands in asymmetric synthesis.

Presentata da: Enrico Paradisi .

Coordinatore Dottorato Relatore

Prof. Aldo Roda_______________ Prof. Paolo Righi .

Correlatore

Dr. Giorgio Bencivenni

Esame finale anno 2014

I
Abstract

During the last fifteen years organocatalysis emerged as a powerful tool for the
enantioselective functionalization of the most different organic molecules. Both C-C and C-
heteroatom bonds can be formed in an enantioselective fashion using many types of
catalyst and the field is always growing. Many kind of chiral catalysts have emerged as
privileged, but among them Proline, cinchona alkaloids, BINOL, and their derivatives
showed to be particularly useful chiral scaffolds.
This thesis, after a short presentation of many organocatalysts and activation modes,
focuses mainly on cinchona alkaloid derived primary amines and BINOL derived chiral
Brønsted acids, describing their properties and applications.
Then, in the experimental part these compounds are used for the catalysis of new
transformations.
The enantioselective Friedel-Crafts alkylation of cyclic enones with naphthols using
cinchona alkaloid derived primary amines as catalysts is presented and discussed. The
results of this work were very good and this resulted also in a publication.
The same catalysts are then used to accomplish the enantioselective addition of indoles to
cyclic enones. Many catalysts in combination with many acids as co-catalysts were tried
and the reaction was fully studied. Selective N-alkylation was obtained in many cases, in
combination with quite good to good enantioselectivities. Also other kind of catalysis were
tried for this reaction, and considered all, the results obtained are interesting.
Another aza-Michael reaction between OH-free hydroxylamines and nitrostyrene using
cinchona alkaloid derived thioureas is briefly discussed.
Then our attention focused on Brønsted acid catalyzed transformations.
With this regard, the Prins cyclization, a reaction never accomplished in an
enantioselective fashion up to date, is presented and developed. The results obtained are
promising.
In the last part of this thesis the work carried out abroad is presented.
In Prof. Rueping laboratories, an enantioselective Nazarov cyclization using cooperative
catalysis and the enantioselective desymmetrization of meso-hydrobenzoin catalyzed by
Brønsted acid were studied.

II
III
Table of contents

Abstract II
Table of contents IV
Foreword VIII

Section 1: INTRODUCTION 1

1) Asymmetric organocatalysis 2

2) Activation modes and privileged catalysts 6
2.1) Covalent catalysis 6
2.1.1) Primary and secondary amines 6
2.1.2) N-Heterocyclic Carbenes (NHCs) 14
2.2.3) Other covalent catalysts 16
2.2) Non-covalent catalysis 18
2.2.1) Phase-transfer and Brønsted base catalysis 18
2.2.2) Hydrogen-bonding catalysis 20
2.2.3) Chiral Brønsted acids 22
2.3) Dual activations 23
2.3.1) Bifunctional and cooperative organocatalysis 23

3) Cinchona alkaloids in organocatalysis 26
3.1) A brief history 26
3.2) Cinchona alkaloids: properties and applications 30
3.3) Cinchona alkaloid derived primary amines and thioureas 33
3.3.1) Catalysts sintheses 33
3.3.2) Cinchona alkaloid derived primary amines 34
3.3.2.1) Asymmetric Counteranion Directed Catalysis 38
3.3.3) Cinchona alkaloid based thioureas 39
3.3.3.1) Some theory 41
IV
4) BINOL derived Chiral Phosphoric Acids in asymmetric catalysis 44
4.1) BINOL: a history of successes 44
4.2) Chiral Phosphoric Acids 49
4.2.1) Some theory 58
4.2.2 Catalysts synthesis 65

Section 2: The projects and their aims 68

5) The enantioselective Friedel-Crafts alkylation/acetalization
cascade of naphthols with α,β-unsaturated cyclic ketones 69
5.1) historical background and organocatalysis 69
5.1.1) Naphthols in organocatalytic Friedel-Crafts reactions 73
5.2) project discussion 75
5.2.1) Conclusion and future challenges 91
5.3) Experimental section 91

6) Aza-Michael additions to electron poor double bonds 107
6.1) introduction 107
6.2) The aza-Michael reaction of indoles with enones 113
6.2.1) part I: iminium ion catalyzed enantioselective addition of 3-methyl
indole to cyclohexenone 113
6.2.2) part II: iminium ion catalysis on other substrates 124
6.2.3) part III: Brønsted acid catalysis 127
6.2.4) part IV: miscellaneous 129
6.2.5) EXPERIMENTAL SECTION 132
6.3) The aza-Michael reaction (part V):
addition of OH-free hydroxylamines to nitroalkenes 137
6.3.1 EXPERIMENTAL SECTION

V
7) The Prins cyclization 146
7.1) introduction 146
7.2) The enantioselective Prins cyclization: the concept and the
attempts 157
7.3) EXPERIMENTAL SECTION 170

Projects carried out abroad 174

8) The Nazarov cyclization of electron-rich arenes 175
8.1) introduction 175
8.1.1) Nazarov cyclization and phosphoric acid triflimides 179
8.2) The enantioselective Nazarov Cyclization on aryl vinyl
ketones:
In-catalysis 181
8.2.1) Cu-catalyzed Nazarov cyclization 190
8.2.2) Miscellaneous 193
8.3) EXPERIMENTAL SECTION 194

9) Desymmetrization of meso compounds 197
9.1) introduction 197
9.2) Enanatioselective Brønsted acid catalyzed
desymmetrization of
meso-Hydrobenzoin 201
9.2.1) Thiourea catalyzed desymmetrization of meso diols using enol
ethers 205
9.3) EXPERIMENTAL SECTION 208

Post scriptum 211

Acknowledgements 213

VI
VII
Foreword

Nature is almost perfect. It took billions of years, but in the end life grew up not only
effective and strong, but also elegant, complex, fascinating. And it’s somehow surprising
how the existence of complex creatures like living beings is fundamentally based on
chemistry, made of chemistry. The functioning of living beings (or Life) is in the end
nothing else than an ensemble of complex and intricate network of chemical interactions
and reactions between more or less complex molecules. All of these complex chemical
mechanisms are expressed by following the instructions encoded in a molecular manual,
DNA, made with a surprisingly low Basis Set: four nitrogen bases derived from
enantiopure deoxyribose. These bases combine to give two long molecules, which as well
are paired, due to complementary interactions, to give a double helix. This double helix is
screwed on itself, in a clockwise direction. The reason why the helix is forced to screw only
in one direction lays basically on the enantiopurity of deoxyribose. Helicity is a kind of
chirality, and DNA is enantiopure. Since that, the information encoded and expressed by
DNA is chiral, and every molecule, every process, every interaction occurring in organisms
is therefore chiral, enantiopure. So, Nature is chiral. The reason why it happened, and
how, is nowadays object of big debate, but actually, despite the huge amount of work on it,
it’s still not known, and perhaps it will never be. But that’s a fact we have to deal with:
Nature is chiral, and complex, and elegant. As I told, almost perfect.

Driven by the need of making progress, grow and create welfare, humans developed,
especially in the last two centuries, a fairly good expertise in the production of many types
of chemicals, useful for their needs. Many of these chemicals are available in nature, but
not in enough amount, and many others are unavailable, so their synthesis is necessary.
Some of these molecules are not chiral, but many others are, and we have to consider this
fact, especially in the synthesis of molecules that have to interact directly with our body,
which, as seen, is chiral. Specifically, this is the case of pharmaceuticals, which have to
improve our health conditions, and pesticides, which have to be toxic for pests, but not for
everything else. While an enantiomer could have a good (or no) effect on our body or on
the environment, the other could be just useless, or harmful, and so it must not be
produced, or at least is must not be released in the environment or introduced in our
bodies.

Hence, the importance for humans of producing enantiomerically pure molecules.
Unfortunately, our technology is far away from Nature’s perfection and the synthetic
methodologies we developed are mostly scarcely effective and not enantioselective. So
how can we do?

 Since Nature is chiral, the most conceptually simple way to produce
enantioenriched compounds is starting from natural molecules, the so-called Chiral
Pool. There are a lot these molecules readily available, but unfortunately most of
the times it's difficult to obtain the products that we need directly from them. Often,
what we need is fairly different from the structures available in Nature, and thus the
synthetic elaboration becomes long, complicated, and there is always the possibility
that we, with one of ours clumsy, not enantiospecific, achiral reaction, destroy the
chirality created by nature.
 The second most conceptually simple way to produce enantioenriched compounds
is the direct use of Nature’s catalysts to perform our reactions. The use of enzymes,
or directly microorganisms for industrial application is sometimes possible, and due
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