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University of Groningen
Rhodium-catalyzed boronic acid additionsJagt, Roelof Bauke
Christiaan
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Citation for published version (APA):Jagt, R. B. C. (2006).
Rhodium-catalyzed boronic acid additions: a combinatorial approach
tohomogeneous asymmetric catalysis. s.n.
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Rhodium-Catalyzed Boronic Acid Additions A Combinatorial
Approach to
Homogeneous Asymmetric Catalysis
Richard B. C. Jagt
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R. B. C. Jagt, “Rhodium-Catalyzed Boronic Acid Additions; A
Combinatorial Approach to Homogeneous Asymmetric Catalysis”, Ph.D.
Thesis, University of Groningen, The Netherlands, 2006.
ISBN: 90-367-2710-3
ISBN: 90-367-2711-1 (electronic version)
The work described in this thesis was carried out at the
Department of Organic and Molecular Inorganic Chemistry, Stratingh
Institute, University of Groningen, The Netherlands.
Financial support was received from DSM Pharmaceutical Products,
the Ministry of Economic Affairs, and the Chemical Sciences
division of the Netherlands Organization for Scientific Research
(NWO/CW), administered through the NWO/CW Combichem program.
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RIJKSUNIVERSITEIT GRONINGEN
Rhodium-Catalyzed Boronic Acid Additions A Combinatorial
Approach to
Homogeneous Asymmetric Catalysis
Proefschrift
ter verkrijging van het doctoraat in de
Wiskunde en Natuurwetenschappen
aan de Rijksuniversiteit Groningen
op gezag van de
Rector Magnificus, dr. F. Zwarts,
in het openbaar te verdedigen op
vrijdag 8 september 2006
om 14.45 uur
door
Roelof Bauke Christiaan Jagt
geboren op 19 oktober 1977
te Emmen
-
Promotores: Prof. Dr. B. L. Feringa
Prof. Dr. Ir. A. J. Minnaard
Beoordelingscommissie: Prof. Dr. J. B. F. N. Engberts
Prof. Dr. J. N. H. Reek
Prof. Dr. J. G. de Vries
ISBN: 90-367-2710-3
-
Voor mijn ouders.
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04_Contents.doc
Contents
Chapter 1 Introduction
1.1 The Impact of Molecular Chirality
1.2 The Preparation of Enantiopure Molecules
1.3 Asymmetric Conjugate Addition Reactions
1.4 1,2-Arylations Using Organometallic Reagents
1.5 A Ligand Library Approach to Asymmetric Catalysis
1.6 Aims and Outline of this Thesis
1.7 References and Notes
1
1
2
3
6
12
16
17
Chapter 2 Enantioselective Synthesis of 2-Aryl-4-piperidones
2.1 Introduction
2.2 Results and Discussion
2.2.1 Preliminary Studies
2.2.2 Scope of the Reaction
2.3 Further Developments
2.4 Conclusions
2.5 Experimental Section
2.6 References and Notes
25
26
29
29
32
33
34
35
41
Chapter 3 Tandem Conjugate Addition/Protonation:
Enantioselective Synthesis of α-Amino Acids
3.1 Introduction
3.2 Results and Discussion
45
46
52
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04_Contents.doc
Contents
3.3 Conclusions
3.4 Experimental Section
3.5 References and Notes
56
57
58
Chapter 4 Enantioselective Synthesis of Diarylmethanols
4.1 Introduction
4.2 Results and Discussion
4.2.1 Preliminary Studies and Mechanistic Considerations
4.2.2 Ligand Library Approach
4.2.3 Scope of the Reaction
4.3 Further Developments
4.4 Conclusions
4.5 Experimental Section
4.6 References and Notes
63
64
66
66
69
75
77
78
78
84
Chapter 5 Enantioselective Synthesis of N-protected
Diarylmethylamines
5.1 Introduction
5.2 Results and Discussion
5.2.1 Preliminary Studies
5.2.2 Screening of a Primary Ligand Library
5.2.3 Introduction of the N,N-Dimethylsulfamoyl Protecting
Group
5.2.4 Screening of a Secondary Ligand Library
5.2.5 Scope of the Reaction
5.2.6 Removal of the N,N-Dimethylsulfamoyl Group
5.3 Conclusions
5.4 Experimental Section
5.5 References and Notes
89
90
92
92
92
95
97
99
101
101
102
110
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04_Contents.doc
Rhodium-Catalyzed Boronic Acid Additions
Chapter 6 An Entry to Diversity in 3-Aryl- and
3-Alkenyl-3-hydroxyoxindoles
6.1 Introduction
6.2 Results and Discussion
6.2.1 The Synthesis of Racemic
3-Substituted-3-hydroxyoxindoles
6.2.2 Enantioselective Synthesis of
3-Phenyl-3-hyroxyoxindoles
6.3 Further Developments
6.4 Conclusions
6.5 Experimental Section
6.6 References and Notes
113
114
117
117
119
124
124
125
130
Chapter 7 Enantioselective Synthesis of Trifluoromethyl
Substituted Tertiary Alcohols
7.1 Introduction
7.2 Results and Discussion
7.3 Conclusions
7.4 Experimental Section
7.5 References and Notes
135
136
137
139
140
143
Summary
147
Samenvatting
153
Acknowledgements 159
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04b_Emptypage.doc
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1
05_Chapter 1.doc
Chapter 1 Introduction
1.1 The Impact of Molecular Chirality
Chirality1 is an important aspect of the most fundamental
processes of life.2 The sugars that
constitute DNA and RNA possess a uniform stereochemical
configuration. The proteins
encoded by these oligonucleotides, crucial for the chemical
transformations in cells, consist
of chiral α-amino acids that occur exclusively in the
L-configuration. Without this chiral
homogeneity, the biomachinery that makes up all known living
organisms would not be
able to function. Even in the most elementary forms of life,
such as bacteria,3 a myriad of
different chiral molecules are involved in complex signaling
pathways. Receptor proteins
on the cell membrane or within the cytoplasm or cell nucleus can
specifically bind to one
enantiomer of a chiral “messenger” molecule and initiate a
corresponding cellular response.
These diastereomeric interactions are the key to modern drug
development.4
The interactions between biological systems and synthetic chiral
molecules has a huge
impact on contemporary everyday life and applications range from
flavors, fragrances, and
food additives to agrochemicals and life-saving drugs.
Homochirality in drugs is as old as
the first therapeutic agents isolated from natural sources, such
as quinine and morphine.
However, as products of synthetic chemistry, until recently
chiral drugs were manufactured
as racemates. The assumption that only one enantiomer of a drug
has biological activity and
the other serves as “isomeric ballast”4 has turned out to be a
rather dangerous one. The two
enantiomers of a compound most frequently bind to different
receptors, and therefore have
completely different physiological effects. The presence of the
“wrong” enantiomer has, in
some cases, been known to cause serious side-effects. This has
resulted in severe
restrictions5 to the production of bioactive molecules and at
present time “single-
-
Chapter 1
2
05_Chapter 1.doc
enantiomer drugs have a commanding presence in the global
pharmaceutical landscape”.6
The development of efficient methodologies for the synthesis of
the individual enantiomers
of an asymmetric target compound is, therefore, of continuous
interest to scientists in both
industry and academia.
1.2 The Preparation of Enantiopure Molecules
Routes to single enantiomers of small molecules can be
classified into three groups:
1) chiral pool technology, 2) resolution of racemic mixtures,
and 3) asymmetric synthesis.
The former is the most straightforward route to enantiopure
compounds and starts from
homochiral biomolecules which are provided by natural processes
such as agriculture or
fermentation. However, the lack of availability of both
enantiomers for most naturally
occurring compounds severely limits the scope of this
methodology and many chiral
building blocks can only be obtained by synthetic
procedures.7
The “classical” resolution of racemic mixtures by diastereomeric
crystallisation, to date,
often constitutes the industrial method of choice to obtain
large quantities of enantiopure
compounds.8 However, unless it can be recycled, half of the
racemic starting material (the
“unwanted” enantiomer) is a waste-product. This intrinsic
property of classical resolutions
poses a major disadvantage from an atom-economy point of view.9
The same disadvantage
applies to chemical or enzymatic kinetic resolutions, involving
a reaction in which one of
the two enantiomers reacts more rapidly than the other based on
a difference in transition
state Gibbs energy. Although in certain cases, (dynamic) kinetic
resolution can lead to
complete conversion of the starting material by in situ
racemization, generally one
enantiomer reacts whereas the other remains intact.
The remaining option for the preparation of enantiopure
molecules involves the
introduction of chirality to a prochiral substrate by asymmetric
induction.10 This may
involve the use of stoichiometric amounts of chiral reagent or a
chiral auxiliary followed by
the subsequent diastereoselective introduction of a stereogenic
center. However, the use of
equimolar amounts of valuable chiral auxiliary materials makes
these approaches rather
-
Introduction
3
05_Chapter 1.doc
unappealing. A far more attractive form of stereoselective
synthesis involves the
application of asymmetric catalysts. A relatively small amount
of enantiopure catalyst can,
in an ideal scenario, produce large quantities of enantiopure
product. Although powerful
biocatalytic methods exist, employing enzymes or antibodies as
catalysts,11 their
biomolecular homochirality often poses a problem when the
“non-natural” enantiomer of
the product is desired. Recently, directed evolution methods
have resulted in enzymes
which produce the unnatural enantiomers in excess.12
Alternatively, chemical catalysts can
be adapted to provide the desired enantiomer of the product by
choosing the appropriate
enantiomer of the ligand. Although asymmetric organocatalysis –
based on the use of small
organic molecules as catalysts − is an emerging field,13 in the
last decades considerable
progress has been made in the development of highly active
metal-catalyzed asymmetric
transformations based on enantiopure ligands complexed to a
(transition) metal core.14 The
pioneering work of Knowles, Noyori, and Sharpless on
chirally-catalyzed hydrogenation
and oxidation reactions, for which they received the 2001 Nobel
prize in chemistry,15 has
opened the field of homogeneous asymmetric catalysis. Asymmetric
reductions and
oxidations have been developed to an extent that they are in
some cases used for industrial
production of enantiomerically enriched compounds. However, in
catalytic asymmetric
carbon-carbon bond forming reactions high catalytic activity and
enantioselectivity are less
well established.
1.3 Asymmetric Conjugate Addition Reactions
The asymmetric conjugate addition (ACA) of organometallic
reagents to electron-deficient
alkenes constitutes an important approach for enantioselective
carbon-carbon bond
formation.16 In recent years, numerous chiral catalysts have
been introduced for this
asymmetric reaction.17 A breakthrough in the field was achieved
by our group in 1996 with
the introduction of chiral monodentate phosphoramidite L1, which
proved to be a highly
efficient ligand in the copper-catalyzed ACA of dialkylzinc
reagents to enones (e.g.
Scheme 1.1, reaction a).18,19 Phosphoramidites comprise a class
of cost-effective and easily
tunable ligands that have since proven useful in a host of
different reactions (vide infra).
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Chapter 1
4
05_Chapter 1.doc
Although the highly enantioselective copper-catalyzed conjugate
addition of diphenylzinc,
using the same catalyst, has been reported for
2-cyclohexenone,20 the lack of readily
available diarylzinc reagents severely limits this method. A
more convenient reaction for
the formation of sp2-sp3 carbon-carbon bonds, introducing a
stereogenic centre, is the
complementary rhodium-catalyzed ACA of boronic acids pioneered
by Miyaura and
Hayashi in 1998 (e.g. Scheme 1.1, reaction b).21 Excellent
enantioselectivities have been
achieved in the addition of aryl and alkenyl groups to a broad
range of both cyclic and
acyclic α,β-unsaturated enones employing BINAP as a chiral
ligand.
O 0.5 mol% Cu(OTf)21 mol% L1
toluene, -30 oC
Et2Zn (1.2 equiv)
O
>98% ee
OO
P N
(S,R,R)-L1
a)
b)
O 3 mol% Rh(acac)(eth)23 mol% BINAP
dioxane/H2O : 10/1, 100 oC
PhB(OH)2 (3 equiv)
O
PPh2PPh2
(S)-BINAP97% ee
Scheme 1.1 Two complementary ACA reactions
Since its introduction, this reaction has received increasing
attention.22,23 Rhodium-
catalyzed conjugate additions of arylstannane,24 arylsilicon,25
aryltitanium,26 and
alkenylzirconium27 reagents have also been reported. However,
from a practical point of
view, boronic acids remain the most interesting arylating
reagents because they are shelf
stable, readily available, and compatible with a large variety
of functional groups.28 The
chiral ligands employed in the rhodium-catalyzed addition of
arylboronic acids are mostly
bidentate and comprise biaryl bis-phosphines,21a,29
ferrocenyl-based bis-phosphines,29c
bis-β-naphthol (BINOL) based diphosphonites,30
amidomonophosphines,31 N-heterocyclic
carbenes,32 a P-chiral phosphine,33 and dienes.34 Some other
bis-phosphine ligands,
although efficient in the rhodium-catalyzed hydrogenation, fail
to induce high reactivity
-
Introduction
5
05_Chapter 1.doc
and/or selectivity in the rhodium-catalyzed conjugate addition
to enones.22,29a,c Recently, it
was shown by our group that monodentate phosphoramidite L2 is an
exceptionally efficient
ligand for the rhodium-catalyzed ACA of arylboronic acids to
enones (Scheme 1.2).35
Enantioselectivities comparable to those obtained with BINAP
have been achieved, while
the reaction rate is greatly enhanced. Employing L2 as a ligand,
using 1 mol% of catalyst,
>99% conversion was reached within 5 min at 100 oC. Miyaura
and co-workers confirmed
the successful use of phosphoramidites in this reaction.36
O 3 mol% Rh(acac)(eth)27.5 mol% (S)-L2
dioxane/H2O : 10/1, 100 oC
ArB(OH)2 (3 equiv)
O
OO
P
(S)-L2
N
Up to 98% ee
R
Scheme 1.2 Rhodium/phosphoramidite-catalyzed ACA of arylboronic
acids
The mechanism for the rhodium-catalyzed addition of boronic
acids (Scheme 1.3) has been
investigated by Hayashi et al.37 and all intermediates were
identified by NMR. In order to
displace the acetylacetonate (acac), and to generate the
catalytically active hydroxy species,
the presence of water and high temperatures are needed (step A).
It was shown that, starting
from the hydroxy species, the reaction is faster than when the
“precatalyst” prepared from
Rh(acac)(C2H4)2 and BINAP was used. A phenyl-rhodium complex and
B(OH)3 are formed
after transmetallation of the phenyl group from boron to rhodium
(step B). After
coordination of the substrate (step C), insertion of 1 into the
phenyl-rhodium bond gives an
oxa-π-allyl species (step D). Hydrolysis of this species gives
the desired phenylated product
2 and regenerates the catalytically active hydroxy species (step
E). As water is involved in
forming the active hydroxy species and acts as a proton donor
facilitating the
transmetallation, its presence is essential in order to complete
the catalytic cycle. A major
drawback of the use of water, in combination with high
temperature, is hydrolysis of
phenylboronic acid to benzene (step F). For this reason, the
arylboronic acid is often added
in excess (3-5 equiv) compared to the enone.22
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Chapter 1
6
05_Chapter 1.doc
Rh PhP*
P*
RhP*
P*
BPh B(OH)2
B(OH)3
FH2O C
R'
OB(OH)3
+
Ph-H
1
Rh OHP*
P*Rh(acac)(eth)2
+ 2P*A
H2O
R'
O
2Ph H2O
R'
O
Ph
Rh
P*
P*
Ph R'
O
DE
R
R
R
R
Scheme 1.3 Proposed catalytic cycle for the rhodium-catalyzed
asymmetric conjugate addition reaction
Inspired by the catalytic cycle proposed by Hayashi et al.,37 it
was recently found that the
use of a [Rh(OH)(cod)]2 (cod = 1,5-cyclooctadiene) or
[RhCl(cod)]2/KOH catalyst
precursor allows the reaction to be carried out at room
temperature with only 1.5 equiv of
boronic acid.38
1.4 1,2-Arylations Using Organometallic Reagents
Over the past 20 years, enantioselective formation of chiral
diarylmethanols and
diarylmethylamines has attracted a great deal of interest.39
Enantiopure derivatives of these
compounds are important intermediates for the synthesis of
biologically active molecules.40
In 1998, Miyaura and co-workers demonstrated the
rhodium-catalyzed addition of
arylboronic acids to aromatic aldehydes under conditions similar
to those used for their
conjugate addition to enones.41,42 In an asymmetric version of
this reaction, employing
MeO-MOP as chiral ligand, 41% ee was achieved for the addition
of phenylboronic acid to
-
Introduction
7
05_Chapter 1.doc
1-naphthaldehyde (Scheme 1.4, reaction a). An attempt by Frost
et al. to improve the
enantioselectivity of this reaction by using sparteine or
bis-oxazolines as ligands remained
unsuccessful (
-
Chapter 1
8
05_Chapter 1.doc
reaction. Hayashi et al. reported excellent enantioselectivities
in the addition of
arylboroxines to a range of N-tosyl- and N-nosyl-benzaldimines
(Scheme 1.5) employing
L5 and L6, respectively.50
O
NPPh2
L4
Ph
Ph
Ph
Ph
L5NHBoc
L6
NPPh2
PPh2
(R,R)-DeguPHOS
Bn
Figure 1.1 Ligands reported in the 1,2-addition of arylboronic
acids to benzaldimines
NPG
HR1
ArB(OH)2 (2 equiv)
[RhCl(C2H4)2]2 (3 mol%)
L5 or L6 (3 mol%)
KOH/H2O
dioxane, 60 oC, 6 h
HNPG
R1
R2
PG = S (Tosyl)
S NO2 (Nosyl)
PG = Tosyl: L5, 95-99% eePG = Nosyl: L6, 95-99% ee
O
O
O
O
Scheme 1.5 Arylboronic acid addition to N-tosyl and N-nosyl
protected benzaldimines
Next to the rhodium-catalyzed arylation of aldehydes and imines,
a successful alternative
for such reactions can be found in the addition of diarylzinc
reagents employing in situ
formed complexes of zinc with chiral aminoalcohols and diols as
catalysts.51 In contrast to
the addition of dialkylzinc reagents, however, addition of
diphenylzinc to aldehydes also
proceeds quite efficiently without the presence of a catalyst.
This background reaction
makes it difficult to achieve high enantioselectivities. In
1997, Dosa and Fu reported the
first enantioselective catalytic addition of diphenylzinc to
aldehydes employing axially
chiral ferrocene-based ligand L7 (Figure 1.2).52 The addition of
diphenylzinc to
p-chlorobenzaldehyde provided the product alcohol with an
enantioselectivity of 57% ee.
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Introduction
9
05_Chapter 1.doc
In 1999, Pu et al. reported high ee values in the addition of
diphenylzinc to aldehydes using
L8a as a ligand (Scheme 1.6).53 This chiral binaphthol was also
previously employed as a
highly enantioselective catalyst in the addition of
dialkylzinc.54 Interestingly, the authors
observed that when 20 mol% L8a was pretreated with 40 mol% of
diethylzinc, the resulting
chiral PhZnEt complex facilitated the addition of diphenylzinc
with a considerable increase
in enantioselectivity.55
FeN
MeMeMe
MeMe
L7
OHO
Ph
Ph
Figure 1.2 Ferrocene ligand employed by Dosa and Fu
Cl
CHO+ Ph2Zn
OHOH
Ar
Ar
OC6H13
C6H13O
F
C6H13O
F
L8a
L8b
Ar =
Cl
Ph
OH
20 mol% L840 mol% Et2Zn
Et2O, RT, 10 h:
CH2Cl2, RT, 5 h:
86% yield, 94% ee
92% yield, 95% ee
Ar =
Scheme 1.6 Addition of diphenylzinc to aldehydes using
diethylzinc as an additive
The use of fluorinated binaphthol-type ligands, resulting in an
enhanced reaction rate, was
reported by Pu in 2000.56 Various aromatic aldehydes were
converted with diphenylzinc in
the presence of 20 mol% of (S)-L8b in dichloromethane. After 5 h
at room temperature the
products were formed with good enantioselectivities in high
yields. In 1999 Bolm and
Muñiz reported ferrocene-based ligands L9 and L10 (Figure 1.3)
in the addition of
diphenylzinc to aldehydes.57 The addition of diphenylzinc to
p-chlorobenzaldehyde and
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Chapter 1
10
05_Chapter 1.doc
ferrocenecarboxaldehyde, employing ligand L9, proceeded with 90%
and >96% ee,
respectively. However, the enantioselectivity for the reaction
of other aromatic or aliphatic
aldehydes was considerably lower (3-75%) due to the background
reaction. Also here, the
use of a mixture of diphenyl- and diethylzinc (in a 1 : 2 ratio)
significantly increased the
enantioselectivity.58 For the addition of diphenylzinc to
p-chlorobenzaldehyde an ee of 99%
was achieved. Using a similar procedure, L9 catalyzed the
reaction of diphenylzinc with a
range of aldehydes with very high enantioselectivity. This
methodology has been adapted
by Bolm and Bräse to the addition of diphenylzinc to imines
(Scheme 1.7).59 The addition
of diphenylzinc to a range of in situ formed N-formylimines with
different electronic and
steric modifications proceeded with high
enantioselectivities.
FeN
O
CPh2OH FeN
O
PhCPh2OH
L9 L10
Figure 1.3 Ferrocene ligands employed by Bolm and Muñiz
SO2Tol
HN H
O
R
N H
O
R
ZnEt2/ZnPh2
ZnEt2/ZnPh2 H
(Rp,S)-L11 (10 mol%)
HN H
O
ROH
N
Ph
Ph
(Rp,S)-L11Up to 97% ee
Scheme 1.7 Catalytic asymmetric phenyl transfer reaction onto
N-formylimines
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Introduction
11
05_Chapter 1.doc
Several alternative systems for the addition of mixtures of
diphenylzinc and diethylzinc to
aldehydes have been reported.60 Triphenylborane was recently
found to be an interesting
alternative to diphenylzinc as a phenyl source.61 It is
commercially available in bulk
quantities and rather inexpensive compared to diphenylzinc. All
these methods are,
however, limited to the addition of phenyl groups. More general
systems that facilitate the
addition of a range of aryl groups, as is the case for the
addition of arylboronic acids, are
limited. Recently, however, Bolm et al.62 reported an excellent
hybrid method in which the
aryl transfer reagent was generated by mixing arylboronic acids
with an excess of
diethylzinc (Scheme 1.8).63 Subsequently, a multigram scale
application was described.64
Employing ligand L9, the addition of different aryls to a range
of benzaldehydes proceeded
with enantioselectivities from 31 to 95% ee. The presence of
catalytic amounts of a
dimethylpolyethyleneglycol (DiMPEG, Mw = 2000 g mol-1) further
improved the
enantioselectivities.65
CHOR
ArB(OH)2Et2Zn (7.2 equiv)
10 mol% L910 mol% DiMPEG
10 oC, 12 h
ROH
Ar
Scheme 1.8 Use of in situ generated zinc reagents from
diethylzinc and arylboronic acids
High enantioselectivities in the arylation of benzaldehydes,
using a mixture of arylboronic
acids and diethylzinc, have recently also been achieved using
chiral binaphthol
dicarboxamides,66 hydroxy oxazolines,67 ferrocene based
silanols,68 aminonaphtholes,69 a
camphor-derived γ-amino thiol,70 and β-amino alcohol-based
catalysts.63b,71 In addition to
boronic acids, also their boroxine trimers have been used
successfully in combination with
diethylzinc.72 All of these methods, however, are dependent on
the use of an excess of
rather expensive and reactive diethylzinc. From a practical and
industrial point of view, the
development of a direct catalytic addition of boronic acids to
aldehydes with high
enantioselectivity is more desirable.
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Chapter 1
12
05_Chapter 1.doc
1.5 A Ligand Library Approach to Asymmetric Catalysis
The identification of suitable asymmetric catalysts still poses
one of the most challenging
endeavours of contemporary organic chemistry.14 Current
mechanistic knowledge is not
sufficient to “design” catalysts which will induce high
enantioselectivity. All
stereoselective syntheses are based on the principle that the
products are formed via
diastereomeric transition states with a difference in Gibbs
energy of activation (∆∆G‡).1b
Seemingly insignificant variations in the catalyst or substrate
structure and reaction
conditions, corresponding to minute differences in transition
state energy (∆∆G‡ ≅ 1-2
kcal/mol), can cause significant changes in ee. Moreover, the
degree of structural
recognition that is a prerequisite for selective catalysts also
renders them highly substrate
dependent. In many asymmetric reactions the ligand structure
must be optimized for each
substrate class.
The relationship between ligand structure and the chemical and
physical properties of
derived complexes is a central theme in many branches of
chemistry. In essence, the
problems involved with developing asymmetric catalysts are
similar to those encountered
by medicinal chemists when developing a new drug that is
required to undergo selective
diastereomeric interactions with a specific receptor protein.
Conventional drug
development, until recently, involved the laborious process of
synthesizing and evaluating
hundreds to thousands of organic compounds in a one-at-a-time
fashion in an attempt to
enhance biological activity and selectivity. In the 1990s
pressure within the pharmaceutical
industry to speed up the drug discovery process, combined with
the increasing political and
social pressure on drug prices, have resulted in a
paradigm-shift in the field.
“Combinatorial chemistry”73 became the new standard in drug
development, dramatically
cutting the time and costs associated with serial drug
discovery. The basic principle of this
new philosophy is the parallel synthesis of a library of
compounds, followed by high-
throughput screening in order to identify the most promising
leads (Scheme 1.9). More
focussed libraries can subsequently be tested in order to
optimize the results. In contrast to
the “classical” iterative serial approach, different compounds
with a modular build-up are
generated simultaneously, in a systematic manner, under
identical reaction conditions, so
-
Introduction
13
05_Chapter 1.doc
that the products of all possible combinations of a set of
building blocks are obtained.
Although combinatorial chemistry was initially met with
resistance from the chemical
community because of its “black-box” character, its practice is
now widespread in chemical
biology and medicinal chemistry as a tool to systematically
investigate structural
requirements that are beyond rational design. Mechanistic
insight remains very important,
as it helps in the selection of suitable parameters.
Design
TraditionalSynthesis
ParallelSynthesis
ParallelScreening
SerialScreening
Scheme 1.9 Serial and parallel approaches to synthesis and
screening
Also in the field of asymmetric homogeneous catalysis,
scientists have recognized the
power of the combinatorial chemistry approach. Currently, the
development of efficient
catalysts for asymmetric catalysis is still largely empirical
and often a result of knowledge-
based intuition or serendipity. Divergent ligand synthesis
strategies, in which several
analogues of a promising ligand-type are prepared, appears to be
an especially fruitful
strategy in this area. However, the synthetic procedures for
chiral ligands are often lengthy
and unsuitable for such an approach. Due to limited time and
resources usually only a small
set of possibilities can be explored in a serial fashion. There
is a clear need for a more
methodical approach in which the structure of the catalyst is
systematically varied.
The parallel synthesis of chiral ligands with a modular
build-up,74 coupled to high-
throughput screening,75 may effectively address the problems
involved with the
optimization of asymmetric catalysts.76 Such a diversity-based
approach will also allow for
the identification of an optimal catalyst for each particular
substrate, or class of substrates,
thus overcoming the problem of generality that arises when only
a small number of chiral
catalysts are available. Although in combinatorial approaches,
focussed on biological
activity, it is quite common to use libraries of mixtures of
compounds, such strategies are
problematic in studies related to the identification of
homochiral catalysts.77 Due to the
-
Chapter 1
14
05_Chapter 1.doc
extreme sensitivity of reaction rate and selectivity to small
structural variations, the
examination of mixtures of catalysts can give rise to misleading
conclusions (i.e. two
effective catalysts that afford high ee values, but with
opposite configurations, will give a
perception of low selectivity). Even though it was recently
shown that catalysts derived
from mixtures of two different monodentate ligands can give
superior results to their
respective homocombinations,78 it is still preferable to employ
parallel reactions in which
one ligand is produced per vial. This strategy offers the
advantage that each ligand structure
is available spatially addressable and pure. Impressive results
have been obtained with
solid-phase bound libraries,79 however, in general the
translation of this chemistry to
solution phase can be quite problematic. Parallel synthesis of
asymmetric catalysts is,
therefore, mostly performed in solution phase.
Chiral ligands, employed in a parallel synthesis/screening
approach, require a modular
build-up with easily connectable components. From an industrial
perspective, where
successful catalytic procedures will be subject to scale-up, the
ligands should also be cost-
effective when produced in larger quantities.76d After a seminal
report of Gilbertson et al.
on the synthesis of modular ligand libraries of
phosphane-containing polypeptides for
asymmetric hydrogenation,80 several reports have appeared
concerning the parallel
synthesis of ligand libraries for asymmetric catalysis.76 Amino
acid building blocks81 have
proven a popular choice in initial explorations at the interface
of combinatorial chemistry
and asymmetric catalysis.82 Recently, Lefort et al. reported the
automated parallel synthesis
and in situ screening of libraries of monodentate
phosphoramidite ligands in rhodium-
catalyzed hydrogenation reactions.83 This ligand class has been
proven to be highly
successful in a wide variety of metal-catalyzed enantioselective
reactions, including:
1) rhodium-catalyzed hydrogenations84 and conjugate additions of
trifluoroborates85 and
boronic acids,35 2) a palladium-catalyzed intramolecular Heck
coupling,86 3) copper-
catalyzed ring-opening of oxabicyclic alkenes,87
desymmetrization of epoxides,88 conjugate
additions of diorganozinc reagents,19,20 and allylic
alkylations,89 and 4) iridium-catalyzed
allylic substitutions.90 A different member of the ligand family
is required for most of these
reaction-types and often for each individual substrate
class.
-
Introduction
15
05_Chapter 1.doc
The protocol of Lefort et al.83 allows for the parallel
preparation of a solution phase library
of phosphoramidites in a 96-well format in one day and their
subsequent in situ parallel
screening (Scheme 1.10). Other monodentate ligands, such as
phosphites and phosphinites,
should also be highly suitable for a similar approach. Their
automated parallel synthesis
has, however, yet to be reported.
PO
OCl
HN(R1)R2
*
PO
ON(R1)R2*
Et3N
Orbital Shaker
Parallel
Filtration
Metal
Precursors
Prochiral
SubstratesSolution Phase Library
96-Well Microplate
Et3N HCl- ( )
Crude Phosphoramidite
96-well Oleophobic Filterplate
Parallel
Reactor
OO
P ClPO
OCl* =
R3
R3R4
R4
, OOP Cl
R3
R3
Scheme 1.10 Protocol for the synthesis of a phosphoramidite
library
Phosphochloridites can be readily prepared from the
corresponding diols and an excess of
PCl3. With the help of a liquid handling robot, stock solutions
of the phosphorchloridites,
amines, and triethylamine were dispensed directly into a 96-well
oleophobic filterplate. The
vials were vortexed for 2 h, after which parallel filtration
into a 96-well titerplate − in order
to remove the precipitated Et3N·HCl salt − gave the liquid phase
ligand library. The ligand
stock solutions can be transfered to a parallel reactor for in
situ complexation to a
(transition) metal. The methodology offers the possibility to
test multiple metals and
substrates concurrently. Duursma et al. recently used this
technology in order to screen a
library of phosphoramidites in the rhodium-catalyzed conjugate
addition of
-
Chapter 1
16
05_Chapter 1.doc
vinyltrifluoroborates to cyclic and acyclic enones, effectively
testing 96 ligands on two
substrates in one run.85b It was shown that the method results
in quick discovery of leads for
effective enantioselective catalysts. Considering the broad
range of asymmetric reactions
that are catalyzed by monodentate phosphorus ligands,91 and the
recently introduced
possibility of using combinations of monodentate ligands,78 the
methodology at hand has an
enormous potential in the efficient development of highly
enantioselective catalysts that
have currently remained elusive.
1.6 Aims and Outline of this Thesis
As described in §1.3, the rhodium-catalyzed conjugate addition
of boronic acids is a highly
convenient method for the simultaneous construction of sp2-sp3
carbon-carbon bonds and
stereogenic centers. Monodentate phosphoramidite ligands lead to
highly enantioselective
catalysts in this reaction. In part, the aim of this thesis is
to expand the scope of this
reaction with more challenging substrates, leading to useful
chiral products. In Chapter 2
the enantioselective synthesis of 2-aryl-4-piperidones by
rhodium/phosphoramidite-
catalyzed conjugate addition of arylboronic acids is described.
This class of piperidones are
important intermediates in the preparation of both naturally
occurring alkaloids and a range
of synthetic drugs. Chapter 3 describes an investigation into
the feasibility of a selective
rhodium/phosphoramidite-catalyzed addition of arylboronic acids
to dehydroalanine
derivatives. In this “tandem-reaction” the introduction of an
aryl-substituent at the
β-position by conjugate addition needs to proceed with
concomitant control of the chirality
at the α-center. The products are unnatural α-amino acids, which
are increasingly important
in the fields of drug discovery and protein engineering.
It becomes apparent in §1.4 that catalysts for the conjugate
addition of arylboronic acids to
alkenes are often also suitable for their 1,2-addition to
benzaldehydes and N-protected
benzaldimines. The products of such reactions are important
building blocks for a range of
organic compounds with pharmaceutical properties. The powerful
method of parallel
synthesis and in situ screening of phosphoramidite ligands, as
described in §1.5, offers the
potential to find the most efficient catalyst for both of these
substrate classes. The second
-
Introduction
17
05_Chapter 1.doc
aim of this thesis is the development of new
rhodium/phosphoramidite-catalysts for the 1,2-
addition of arylboronic acids to aldehydes and imines. In
Chapter 4 the enantioselective
synthesis of diarylmethanols through the
rhodium/phosphoramidite-catalyzed addition of
arylboronic acids to aldehydes is described. Chapter 5 describes
the asymmetric synthesis
of N-protected diarylmethylamines from their corresponding
imines. In addition, the
possibility of using activated ketones as substrates for this
reaction has been investigated. In
Chapter 6 the synthesis of 3-aryl-3-hydroxyoxindoles through
1,2-addition of arylboronic
acids to isatins will be described. Finally, in Chapter 7 the
addition of arylboronic acids to
2,2,2-trifluoroacetophenones is discussed.
1.7 References and Notes
1. Chirality (Greek, handedness, derived from the word stem
χειρ~, ch[e]ir~, hand~) is a “dissymmetry” property important in
several branches of science. An object or a system is called chiral
if it differs from its mirror image. The term chirality was coined
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Chapter 1
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2005, 70, 1095; (b) A. L. Braga, D. S. Lüdtke, P. H. Schneider, F.
Vargas, A. Schneider, L. A. Wessjohann, M. W. Paixão Tetrahedron
Lett. 2005, 46, 7827 and references cited in these articles.
64. J. Rudolph, F. Schmidt, C. Bolm, Synthesis 2005, 840.
65. For further studies on the effect of additives in this
reaction, see: (a) J. Rudolph, N. Hermanns, C. Bolm, J. Org. Chem.
2004, 69, 3997; (b) J. Rudolph, M. Lormann, C. Bolm, S. Dahmen,
Adv. Synth. Catal. 2005, 347, 1361.
66. K. Ito, Y. Tomita, T. Katsuki, Tetrahedron Lett. 2005, 46,
6083.
67. C. Bolm, F. Schmidt, L. Zani, Tetrahedron: Asymmetry 2005,
16, 2299.
68. S. Özçubukçu, F. Schmidt, C. Bolm, Org. Lett. 2005, 7,
1407.
69. J.-X. Ji, J. Wu, T. T.-L. Au-Yeung, C.-W. Yip, R. K. Haynes,
A. S. C. Chan, J. Org. Chem. 2005, 70, 1093.
70. P.-Y. Wu, H.-L. Wu, B.-J. Uang, J. Org. Chem. 2006, 71,
833.
71. A. L. Braga, D. S. Lüdtke, F. Vargas, M. W. Paixão, Chem.
Commun. 2005, 2512.
72. X. Wu, X. Liu, G. Zhao, Tetrahedron: Asymmetry 2005, 16,
2299.
73. For a brief history of combinatorial chemistry, see: K. C.
Nicolaou, R. Hanko, W. Hartwig, In Handbook of Combinatorial
Chemistry, Vol. 1, K. C. Nicolaou, R. Hanko, W. Hartwig (Eds.),
Wiley-VCH: Weinheim, 2002, 3.
74. (a) B. Jandeleit, D. Schaefer, T. S. Powers, H. W. Turner,
W. H. Weinberg, Angew. Chem. Int. Ed. 1999, 38, 2494. (b) M. T.
Reetz, Angew. Chem. Int. Ed. 2001, 40, 284.
75. (a) A. Duursma, A. J. Minnaard, B. L. Feringa, Tetrahedron
2002, 58, 5773. (b) M. T. Reetz, Angew. Chem. Int. Ed. 2002, 41,
1335.
76. For reviews on the field of catalyst development by
combinatorial chemistry in general, see reference 74a and: (a) A.
H. Hoveyda, Chem. Biol. 1998, 5, R187; (b) B. Archibald, O.
Brümmer, M. Devenney, S. Gorer, B. Jandeleit, T. Uno, W. H.
-
Introduction
23
05_Chapter 1.doc
Weinberg, T. Weskamp, In Handbook of Combinatorial Chemistry,
Vol. 2, K. C. Nicolaou, R. Hanko, W. Hartwig (Eds.), Wiley-VCH:
Weinheim, 2002, 885. For reviews on the field of asymmetric
catalyst development by combinatorial chemistry, see: (c) A. H.
Hoveyda, In Handbook of Combinatorial Chemistry, Vol. 2, K. C.
Nicolaou, R. Hanko, W. Hartwig (Eds.), Wiley-VCH: Weinheim, 2002,
991; (d) J. G. de Vries, A. H. M. de Vries, Eur. J. Org. Chem.
2003, 799; (e) C. Gennari, U. Piarulli, Chem. Rev. 2003, 103,
3071.
77. There are exceptions, see: (a) C. Hinderling, P. Chen,
Angew. Chem. Int. Ed. 1999, 38, 2253; (b) P. Krattiger, C.
McCarthy, A. Pfaltz, H. Wennemers, Angew. Chem. Int. Ed. 2003, 42,
1722.
78. For selected examples, see: (a) D. Peña, A. J. Minnaard, J.
A. F. Boogers, A. H. M. de Vries, J. G. de Vries, B. L. Feringa,
Org. Biomol. Chem. 2003, 1, 1087; (b) M. T. Reetz, T. Sell, A.
Meiswinkel, G. Mehler, Angew. Chem. Int. Ed. 2003, 42, 790; (c) C.
Monti, C. Gennari, U. Piarulli, J. G. de Vries, A. H. M. de Vries,
L. Lefort, Chem. Eur. J. 2005, 11, 6701; (d) R. Hoen, J. A. F.
Boogers, H. Bernsmann, A. J. Minnaard, A. Meetsma, T. D.
Tiemersma-Wegman, A. H. M. de Vries, J. G. de Vries, B. L. Feringa,
Angew. Chem. Int. Ed. 2005, 44, 4209.
79. N. E. Leadbeater, M. Marco, Chem. Rev. 2002, 102, 3217.
80. S. R. Gilbertson, X. Wang, Tetrahedron Lett. 1996, 37,
6475.
81. G. Liu, J. A. Ellmann, J. Org. Chem. 1995, 60, 7712.
82. (a) B. M. Cole, K. D. Schimizu, C. A. Krueger, J. P. A.
Harrity, M. L. Snapper, A. H. Hoveyda, Angew. Chem. Int. Ed. 1996,
35, 1668. (b) K. D. Shimizu, B. M. Cole, C. A. Krueger, K. W.
Kuntz, M. L. Snapper, A. H. Hoveyda, Angew. Chem. Int. Ed. 1997,
36, 1704. (c) M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc. 1998,
120, 4901. (d) M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc.
1998, 120, 5315. (e) C. Gennari, S. Ceccarelli, U. Piarulli, C. A.
G. N. Montalbetti, R. F. W. Jackson, J. Org. Chem. 1998, 63, 5312.
(f) A. J. Brouwer, H. J. van der Linden, R. M. J. Liskamp, J. Org.
Chem. 2000, 65, 1750. (g) I. Chataigner, C. Gennari, U. Piarulli,
S. Ceccarelli, Angew. Chem. Int. Ed. 2000, 39, 916.
83. (a) L. Lefort, J. A. F. Boogers, A. H. M. de Vries, J. G. de
Vries, Org. Lett. 2004, 6, 1733. (b) M. van den Berg, D. Peña, A.
J. Minnaard, B. L. Feringa, L. Lefort, J. A. F. Boogers, A. H. M.
de Vries, J. G. de Vries, Chim. Oggi 2004, 22, detachable insert:
Chiral Catalysis-Asymmetric Hydrogenation, 18. (c) J. G. de Vries,
L. Lefort, Chem. Eur. J. 2006, 12, 4722.
84. (a) M. van den Berg, A. J. Minnaard, E. P. Schudde, J. van
Esch, A. H. M. de Vries, J. G. de Vries, B. L. Feringa, J. Am.
Chem. Soc. 2000, 122, 11539. (b) D. Peña, A. J. Minnaard, J. G. de
Vries, B. L. Feringa, J. Am. Chem. Soc. 2002, 124, 14552. (c) M.
van den Berg, A. J. Minnaard, R. M. Haak, M. Leeman, E. P. Schudde,
A. Meetsma, B. L. Feringa, A. H. M. de Vries, C. E. P. Maljaars, C.
E. Willans, D. Hyett, J. A. F.
-
Chapter 1
24
05_Chapter 1.doc
Boogers, H. J. W. Henderickx, J. G. de Vries, Adv. Synth. Catal.
2003, 345, 308. (d) L. Panella, B. L. Feringa, J. G. de Vries, A.
J. Minnaard, Org. Lett. 2005, 7, 4177. (e) L. Panella, A. Marco
Aleixandre, G. J. Kruidhof, J. Robertus, B. L. Feringa, J. G. de
Vries, A. J. Minnaard, J. Org. Chem. 2006, 71, 2026.
85. (a) A. Duursma, J.-G. Boiteau, L. Lefort, J. A. F. Boogers,
A. H. M. de Vries, J. G. de Vries, A. J. Minnaard, B. L. Feringa,
J. Org. Chem. 2004, 69, 8045. (b) A. Duursma, L. Lefort, J. A. F.
Boogers, A. H. M. de Vries, J. G. de Vries, A. J. Minnaard, B. L.
Feringa, Org. Biomol. Chem. 2004, 2, 1682.
86. (a) R. Imbos, A. J. Minnaard, B. L. Feringa, J. Am. Chem.
Soc. 2002, 124, 184. (b) R. Imbos, A. J. Minnaard, B. L. Feringa,
J. Chem. Soc., Dalton Trans. 2003, 2017.
87. F. Bertozzi, M. Pineschi, F. Macchia, L. A. Arnold, A. J.
Minnaard, B. L. Feringa, Org. Lett. 2002, 4, 2703.
88. F. Del Moro, P. Crotti, V. Di Bussolo, F. Macchia, M.
Pineschi, Org. Lett. 2003, 5, 1971.
89. (a) H. Malda, A. W. van Zijl, L. A. Arnold, B. L. Feringa,
Org. Lett. 2001, 3, 1169. (b) A. W. van Zijl, L. A. Arnold, A. J.
Minnaard, B. L. Feringa, Adv. Synth. Catal. 2004, 346, 413.
90. For iridium-catalyzed allylic alkylation reactions, see: (a)
B. Bartels, C. Garcia-Yebra, G. Helmchen, Eur. J. Org. Chem. 2003,
1097. For iridium-catalyzed allylic amination reactions, see: (b)
T. Ohmura, J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 15164; (c)
G. Lipowsky, G. Helmchen, Chem. Commun. 2004, 116. For
iridium-catalyzed allylic etherification reactions, see: (d) F.
Lopez, T. Ohmura, J. F. Hartwig, J. Am. Chem. Soc. 2003, 125,
3426.
91. See references 17, 19, 35, 84-90, and: (a) R. Imbos,
Catalytic Asymmetric Conjugate Additions and Heck Reactions, Ph.D.
Thesis, University of Groningen, 2002, 1-24. (b) A. Duursma,
Asymmetric Catalysis with Chiral Monodentate Phosphoramidite
Ligands, Ph.D. Thesis, University of Groningen, 2002, 6-17.
-
06_Chapter_2.doc
Chapter 2 Enantioselective Synthesis of 2-Aryl-4-piperidones
NCO2Bn
O
NCO2Bn
ORh(acac)(C2H4)2 (3 mol%)phosphoramidite (7.5 mol%)
(ArBO)31,4-dioxane/H2O, 100 ºC
R
Up to 99% eeHigh yields
Piperidones are important intermediates in the preparation of
natural occurring alkaloids
and synthetic pharmacophores. In this chapter the highly
enantioselective synthesis of
2-aryl-4-piperidones by rhodium/phosphoramidite-catalyzed
conjugate addition of
arylboroxines to 2,3-dihydro-4-pyridones is described.1 A
variety of products with
sterically and electronically different R-substituents have been
obtained in high isolated
yield and with excellent ee’s up to 99%.
Part of this chapter has been published: R. B. C. Jagt, J. G. de
Vries, B. L. Feringa, A. J.
Minnaard, “Enantioselective Synthesis of 2-Aryl-4-piperidones
via Rhodium/
Phosphoramidite-Catalyzed Conjugate Addition of Arylboroxines”,
Org. Lett. 2005, 7,
2433.
-
26
06_Chapter_2.doc
Chapter 2
2.1 Introduction
The piperidine ring system (1, Figure 2.1) is a frequently
encountered heterocyclic unit in
natural compounds and drug candidates.2 Naturally occurring
piperidine alkaloids (e.g.
2-11) and their synthetic analogues are of great interest to the
pharmaceutical industry.
NH
NH
CO2H NH
piperidine 1 pipecolic acid 2 coniine 3
NH
HO
Me (CH2)7CO2H
carpamic acid 4
NH
HN O
OHN
NH
Cl
Cl
NH
OH
DKP593A 5 histrionicotoxin 6
NH
N
NH
N
N NCH3
HOO OH
O OH
H3C
anabasine 8 anabasamine 9 rohitukine 11
NC2H5
O
O
O
campedine 10
OHHO O
NCH3
morphine 7
Figure 2.1 Naturally occurring piperidine alkaloids
Considering the extensive range of biological activities these
compounds exhibit, it is not
surprising that (according to an assertion of Watson et al.)
between 1988 and 1998
thousands of piperidine-derived compounds were mentioned in
clinical and preclinical
studies.3 Piperidones serve an important role en route to
substituted piperidines4 and can
also be found as a part of more complex biologically active
compounds.5 Therefore the
development of short, enantioselective routes to substituted
piperidones is a major goal.6
-
27
06_Chapter_2.doc
Enantioselective Synthesis of 2-Aryl-4-piperidones
Although few naturally occurring piperidine alkaloids contain
the arylpiperidine moiety
(8-11), the structural unit is an integral part of many
polycyclic alkaloids (e.g. morphine, 7).
Simple synthetic arylpiperidines have received increasing
attention due to their biological
activities, often resembling those of more complicated natural
alkaloids. Many 3-aryl- and
4-arylpiperidines are potent opioid receptor antagonists and can
be regarded as structurally
simplified forms of morphine.7 2-Arylpiperidines are of
noteworthy interest as being
integrated in biologically active benzo[a]- and
indolo[2,3-a]quinolizidine compounds.8
Recent biological studies of 2-arylpiperidines show a range of
biological activities for this
class of structures, revealing their potential use in the
treatment of mental and
cardiovascular diseases.9 An excellent example is found in a
class of antidepressants, which
have a common structural pattern based on a 2-arylpiperidine
moiety (Figure 2.2).10, 11
NH
Ph
HNAr
12
N
NR2
Me
F NR2O13
Figure 2.2 A class of antidepressants with a 2-arylpiperidine
moiety
Compound 13, developed by Glaxo Group Ltd., UK, is particularly
useful for the treatment
or prevention of depressive states and/or anxiety. It owes its
unique pharmacological
properties to a strong affinity with the NK1 tachykinin
receptor, one of three tachykinin
receptors identified (tachykinins are a family of peptide
neurotransmitters).11 As a
consequence of the significance of 2-arylpiperidines, the
development of efficient methods
for their enantioselective synthesis is an important objective.
However, most of the existing
methods rely on the use of a stoichiometric amount of chiral
reagents.12
Dihydropyridones of the type 14 (Figure 2.3) are versatile
synthetic building blocks: they
are easy to prepare, air-stable, and their functionality allows
a variety of chemical
transformations.13 Short, stereocontrolled synthesis of
piperidine, indolizidine, quinolizine,
and cis- and trans-decahydroquinoline alkaloids have been
reported using 2,3-dihydro-4-
pyridones as chiral building blocks.14 An attractive catalytic
route toward enantiopure
-
28
06_Chapter_2.doc
Chapter 2
2-substituted piperidones is based on the enantioselective
conjugate addition to readily
available N-protected 2,3-dihydro-4-pyridones (14).15 Until
recently, however, no suitable
procedures have been developed.16,17,18
N
O
PG 1,4-addition or reduction
[2 + 2] photocycloaddition
1,2-addition
enolate alkylationor acetoxylation
14
Figure 2.3 Versatile 2,3-dihydro-4-pyridone building block (PG =
Protecting Group)
Very few catalytic enantioselective routes for the synthesis of
2-substituted piperidines
have been reported.19 Recently, our group reported the synthesis
of 2-alkyl-4-piperidones
with high enantiomeric excess applying the copper-catalyzed
conjugate addition of
dialkylzinc reagents to 14 employing phosphoramidite ligand L1
(Scheme 2.1).17 It was
noted that this type of substrate is less reactive towards
1,4-addition than cyclic enones, e.g.
2-cyclohexenone.
N
O
PGN
O
PGR
Cu(OTf)2 (5 mol%)
L1 (10 mol%)
R2Zn
PG = CO2Bn
PG = CO2Ph
PG = CO2Me
PG = CO2Et
PG = CO2tBu
PG = p-Tosyl14
R = Me, R = Et,
R = iPr, R = Bu 15
Up to 97% ee
Up to 87% yield
OO
P N
Ph
PhL1
14a: 14e: 14c: 14d: 14e: 14f:
Scheme 2.1 Catalytic enantioselective addition of zinc reagents
to N-substituted
2,3-dihydro-4-pyridones
Although highly enantioselective 1,4-addition of diphenylzinc,
using the same catalyst, has
been reported for 2-cyclohexenone,20 the lack of readily
available diarylzinc reagents
severely limits this method. A more convenient method for the
introduction of aryl and
alkenyl moieties is the asymmetric rhodium-catalyzed conjugate
addition of boronic acids
-
29
06_Chapter_2.doc
Enantioselective Synthesis of 2-Aryl-4-piperidones
pioneered by Hayashi and Miyaura.21,22 Recently we have
demonstrated that rhodium-
catalyzed conjugate additions of arylboronic acids to enones can
be achieved with high
efficiency and excellent enantioselectivities employing
monodentate phosphoramidite L2
(Figure 2.4).23
OO P N
L2
Figure 2.4 Chiral monodentate phosphoramidite ligand L2
During our studies, Hayashi et al. reported the enantioselective
addition of arylzinc
chlorides to 2,3-dihydro-4-pyridones with excellent
enantioselectivities.24 In that study, it
was confirmed that this type of substrate is less reactive
toward 1,4-addition compared to
enones. The rhodium/BINAP-catalyzed conjugate addition of
phenylboronic acid failed to
proceed to full conversion, although the enantioselectivity was
excellent. We envisioned
that introduction of aryl groups in N-protected
2,3-dihydro-4-pyridones, using the
rhodium/phosphoramidite-catalyzed conjugate addition of
arylboronic acids, could provide
a pathway to 2-substituted 4-piperidones that is complementary
to our work with
dialkylzinc reagents.
2.2 Results and Discussion
2.2.1 Preliminary Studies
Substrate 14a was prepared in three steps from 4-piperidone
monohydrate hydrochloride
and benzyl chloroformate (Scheme 2.2, route a), following a
literature procedure of Park
et al.15a for the synthesis of ethyl
3,4-dihydro-4-oxo-1-(2H)-pyridinecarboxylate. The
desired product was obtained as a white solid in an overall
yield of 64%. The alternative
one-pot procedure of Comins et al. (Scheme 2.2, route b)15b
starting from
4-methoxypyridine suffered from low reproducibility, providing
14a in 10% to 63% yield.
-
30
06_Chapter_2.doc
Chapter 2
N
OMe
NH
O 1) ClCO2Bn, NaOH
H2O, Et2O
2) Br2, (HOCH2)2
. HClNCO2Bn
OOBr 1) DBU, Me2SO, 85 oC
2) 3M HCl, MeOH NCO2Bn
O
a)
b)1) K(i-PrO)3BH, THF, i-PrOH
2) ClCO2Bn
3) 3M HClNCO2Bn
O
14a
14a
10-63% yield
64% overall yield
(3 steps)
Scheme 2.2 Preparation of 14a according to a) Park and b)
Comins
Initial screening of the conjugate addition of phenylboronic
acid to 14a was performed
under standard conditions in a mixture of 1,4-dioxane/water
(10/1) at 100 oC with a catalyst
generated from 3 mol% Rh(acac)(C2H4)2 and 7.5 mol% L2. As in the
report of Hayashi,
with 3 equiv of phenylboronic acid, the reaction did not go to
completion according to 1H-NMR (Table 2.1, entry 1). The
enantioselectivity was, however, excellent (96% ee).
Water acts as a proton donor and facilitates the
transmetallation, therefore the use of water
is essential in order to complete the catalytic cycle (see
Chapter 1, §1.3). A drawback of the
use of water, especially in combination with high temperature,
is the hydrolysis of
phenylboronic acid to benzene. The arylboronic acid is therefore
commonly added in
excess (3-5 equiv) compared to the enone. Milder conditions can
be provided by generating
phenylboronic acid in situ from phenylboroxine ((PhBO)3) and one
equiv of water with
respect to boron (entries 2-6). Phenylboronic acid exists in
equilibrium with its trimeric
species and is released in the course of the reaction (Figure
2.5). Hayashi has demonstrated
that the use of arylboroxines has a beneficial effect on both
conversion and
enantioselectivity in the conjugate addition to highly
deactivated 1-alkenylphosphonates.25
Dehydration of arylboronic acids results in the corresponding
boroxines in quantitative
yield by azeotropic removal of water from their xylene solution
or heating neat in vacuo at
145 oC.26 The use of boroxines did not immediately improve the
conversion, but did
improve the enantioselectivity to an excellent ee of 99%. Upon
slow addition of water,
-
31
06_Chapter_2.doc
Enantioselective Synthesis of 2-Aryl-4-piperidones
thereby preventing premature hydrolysis of the boroxine, the
reaction could be driven to
84% conversion using 1 equiv of boroxine (entry 4) and to full
conversion using 3 equiv of
the reagent (entry 6), retaining 99% ee.
Table 2.1 Optimization of the reaction conditions for the
rhodium-catalyzed conjugate
addition to 14a
N
O
CO2Bn
Rh(acac)(C2H4)2 (3 mol%)
(R)-L2 (7.5 mol%)
"PhB"
1,4-dioxane/H2O, 100 oCN
O
CO2Bn
14a 15a
entry “PhB” (equiv) condition a conv. (%) b ee (%)c
1 PhB(OH)2 (3.0) A 80 96
2 (PhBO)3 (1.0) B 60 99
3 (PhBO)3 (3.0) B 75 99
4 (PhBO)3 (1.0) C 84 99
5 (PhBO)3 (2.0) C 92 99
6 (PhBO)3 (3.0) C >99 99
a All reactions were performed on 0.2 mmol scale with 3 mol%
Rh(acac)(C2H4)2 and 7.5 mol% (R)-L at 100 ºC for
2 h. Condition A: 0.55 mL of 1,4-dioxane/H2O (10/1). Condition
B: 0.5 mL of 1,4-dioxane, 1 equiv of H2O to
boron. Condition C: 0.5 mL of 1,4-dioxane, slow addition of
water by syringe pump. b Determined by 1H NMR. c
Determined by chiral HPLC.
Ph BOH
OHB
O BO
BOPh
Ph
Ph
-3 H2O
+3 H2O
Figure 2.5 Equilibrium between phenylboronic acid and
phenylboroxine
-
32
06_Chapter_2.doc
Chapter 2
2.2.2 Scope of the Reaction
With these optimized conditions in hand, the scope of the
asymmetric conjugate addition of
arylboroxines to 14a was investigated. High ee values could be
obtained with a variety of
sterically and electronically diverse arylboroxines (Table 2.2,
entries 1-9). Meta- and para-
tolyl groups could be introduced with high yield and high
enantioselectivity (entries 3
and 4).
Table 2.2 Scope of arylboroxines in the rhodium-catalyzed
asymmetric 1,4-addition to 14a
NCO2Bn
O
NCO2Bn
ORh(acac)(C2H4)2 (3 mol%)
(R)-L2 (7.5 mol%)
(ArBO)3 (3 equiv)
1,4-dioxane, 100 oC
slow addition of H2O14a 15R
entrya Ar product yield (%)b ee (%)c,d
1 Ph 15a 86 e 99 (R)
2 o-(Me)C6H4 15b 82 e 24 (R)
3 m-(Me)C6H4 15c 92 e 98 (R)
4 p-(Me)C6H4 15d 86 e 95 (R)
5 p-(MeO)C6H4 15e 85 e 96 (R)
6 m,p-(MeO)2C6H3 15f 86 e 98 (R)
7 p-(F)C6H4 15g 71 94 (R)
8 p-(F),o-(Me)C6H3 15h 75 47 (R)
9 p-(Cl)C6H4 15i 55 96 (R)
a All reactions were performed in duplicate with both
enantiomers of the ligand on 0.2 mmol scale with 3 mol%
Rh(acac)(C2H4)2 and 7.5 mol% L2 at 100 ºC for 2 h. b Isolated
yield. c Determined by chiral HPLC. d The absolute
configuration was established by comparison of the optical
rotation with literature values or by analogy (see
experimental section). e Thin layer chromatography shows a
spot-to-spot conversion in 2 h.
-
33
06_Chapter_2.doc
Enantioselective Synthesis of 2-Aryl-4-piperidones
A dramatic drop in enantioselectivity was observed for the
introduction of more sterically
demanding ortho-substituted aryl groups (entry 2 and 8),
illustrating a possible limitation of
the catalytic method. Products with one or two electron-donating
substituents on the aryl
were obtained in high yield with high enantioselectivity
(entries 5 and 6). However,
electron-withdrawing chloro and fluoro groups resulted in slower
reaction, leading to
incomplete conversions (entries 7, 8, 9). Despite this
observation, the enantioselectivity is
largely independent of the electronic nature of the
substituents. All para- and meta-
substituted products were obtained with excellent ee values
between 94 and 98%.
NCO2Bn
O
NH
O
Rh(acac)(C2H4)2 (3 mol%)
(S)-L2 (7.5 mol%)1,4-dioxane, 100 oC
slow addition of H2O
14a (S)-16
1)
(PhBO)3
(3equiv)
+2) 10 mol% Pd/C
H2 (Ca. 1 atm)
MeOH, 20 oC, 4h79% yield, 99% ee
(2 steps)
0.5 g
Scheme 2.3 Conjugate addition on a 0.5 gram scale and subsequent
deprotection
To show the applicability of this reaction for synthesis on a
laboratory scale, it was
performed on a 0.5 gram (2.2 mmol) scale (Scheme 2.3). After
flash chromatography, the
product was isolated in 86% yield with 99% ee. Subsequent
removal of the
benzyloxycarbonyl group by hydrogenation using palladium on
carbon, according to a
literature procedure,24 afforded piperidone (S)-16 in 92%
isolated yield and 79% overall
yield over the two steps.
2.3 Further Developments
Cationic palladium(II) complexes show relative high rates for
transmetallation of
organoboron compounds, a process which is generally slow for
transition metals.27 This has
stimulated research toward their use in conjugate addition
reactions where the
-
34
06_Chapter_2.doc
Chapter 2
transmetallation is a critical step. Miyaura et al. reported
both palladium-based catalyst-
systems that are able to transfer arylboronic acids28 and the
asymmetric palladium-
catalyzed conjugate addition of aryltrifluoroborates.29 The
asymmetric conjugate addition
of arylboronic acids had, however, been elusive. Shortly after
publication of our results
regarding this arylation,30 Gini et al. developed a
Pd(O2CCF3)2/Me-DuPHOS (Figure 2.6)
catalyst for the efficient and highly enantioselective addition
of arylboronic acids to a
variety of α,β-unsaturated enones in a THF/H2O (10/1)
mixture.31
NCO2Bn
O
NCO2Bn
O
14a (R)-15a
60% yield, 99% ee
Pd(OCCF3)2 (5 mol%)
PP
(R,R)-Me-DuPHOS (5.5 mol%)
THF/H2O: 10/1, 70 oC, 22 h
PhB(OH)2 (3 equiv)
(R,R)-Me-DuPHOS
Figure 2.6 Palladium-catalyzed asymmetric conjugate addition of
phenylboronic acid
Addition of phenylboronic acid to 14a with this system at 70 oC
proceeds with essentially
complete enantioselectivity (>99% ee). Although full
conversion of the starting material
was reached within 22 h, 15a was obtained in a relatively low
yield of 60%.
2.4 Conclusions
In summary, we have shown that conjugate addition of
arylboroxines with a rhodium/
phosphoramidite catalyst can be used to prepare
2-aryl-4-piperidones in high isolated yield
(82–92%) and with excellent enantioselectivity (up to 99%
ee).
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35
06_Chapter_2.doc
Enantioselective Synthesis of 2-Aryl-4-piperidones
2.5 Experimental Section
General remarks. All air- and moisture-sensitive manipulations
were carried out under a
dry nitrogen atmosphere using standard Schlenk techniques.
1,4-Dioxane was distilled from
sodium before use. 1H-NMR and 13C-NMR spectra were recorded on a
Varian 300
(300 and 75 MHz, respectively) in CDCl3 unless stated otherwise.
Mass spectra (HRMS)
were recorded on an AEI MS-902. Optical rotations were measured
on a Schmidt and
Haensch Polartronic MH8. Rh(acac)(C2H4)2 was purchased from
Strem and used without
further purification. All other chemicals were purchased from
Acros and used as received.
Flash chromatography was performed using silica gel 60 Å (Merck,
230-400 mesh).
Phosphoramidite ligands (S)-L2 and (R)-L2 were prepared from the
corresponding
H8-bis-β-naphthol, PCl3, and diethylamine according to a
previously reported procedure.23
All arylboroxines were prepared according to a modified
literature procedure from the
corresponding arylboronic acids by heating in vacuo overnight at
145 °C in a drying
pistol.25
Benzyl 3,4-dihydro-4-oxo-1-(2H)-pyridinecarboxylate (14a). This
compound was
synthesized from 4-piperidone monohydrate hydrochloride and
benzyl
chloroformate following the literature procedure for ethyl
3,4-dihydro-4-oxo-1-
(2H)-pyridinecarboxylate.15a The product was obtained as a white
solid in 64%
yield. 1H NMR δ = 7.85 (bs, 1H), 7.40-7.37 (m, 5H), 5.35 (bs,
1H), 5.27 (s, 2H), 4.05 (t, J = 7.3 Hz, 2H), 2.56 (t, J = 7.3 Hz,
2H); 13C NMR δ = 193.2, 152.5, 143.3,
134.8, 128.7, 128.4, 107.7, 69.0, 42.5, 35.6. Physical and
spectral data were in full
agreement with the literature.24
General Procedure for the rhodium/phosphoramidite-catalyzed
asymmetric conjugate
addition to 2,3-dihydro-4-pyridones (15). In a flame dried
Schlenk tube flushed with
nitrogen, 1.55 mg (6.0 µmol, 3 mol%) of Rh(acac)(C2H4)2 and 5.93
mg (15.0 µmol, 7.5
mol%) of phosphoramidite L2 were dissolved in 0.5 mL of
1,4-dioxane. After stirring for
15 min at room temperature, 46.2 mg (0.2 mmol) of substrate 1
and 0.6 mmol of the
arylboroxine were added and the resulting mixture was stirred at
reflux conditions with
N
O
CO2Bn
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36
06_Chapter_2.doc
Chapter 2
N
O
CO2Bn
slow addition of a 20 vol% solution of water in 1,4-dioxane by
syringe pump (0.1 mL/h)
during 2 h. The reaction mixture was subsequently cooled to RT,
diluted with 2 mL of
ether, and passed through a pad of silica gel. The solvent was
removed in vacuo. Reactions
were performed in duplicate, using both enantiomers of the
ligand. Enantioselectivity did
not differ more than 1% between duplos.
(S)- and (R)-Benzyl-4-oxo-2-phenylpiperidine-1-carboxylate
(15a). The crude product
was purified by flash column chromatography (n-pentane/Et2O:
1/2) to
give (R)-15a, in the case of the (R)-L2 ligand, as a white solid
in 86%
isolated yield with 99% ee (Table 2.2, entry 1). The ee was
determined on
a Chiralcel OD-H column with n-heptane/2-propanol: 90/10, flow =
0.5
mL/min. Retention times: 27.3 min [(S)-enantiomer], 29.8 min
[(R)-enantiomer]. 1H NMR
δ = 7.36 (m, 7H), 7.29-7.24 (m, 3H), 5.84 (bs, 1H), 5.25 (d, J =
12.3 Hz, 1H), 5.2 (d, J =
12.3 Hz, 1H), 2.86 (dd, J = 15.5, 7.0 Hz, 1H), 2.57-2.50 (m,
1H), 2.37 (d, J = 15.8 Hz, 1H); 13C NMR δ = 207.0, 155.3, 139.6,
136.2, 128.7, 128.5, 128.1, 127.9, 127.6, 126.6, 67.7,
54.5, 44.1, 40.4, 38.8. Physical and spectral properties were in
full agreement with the
literature.16
(S)- and (R)-Benzyl-4-oxo-2-o-tolylpiperidine-1-carboxylate
(15b). The crude product
was purified by flash chromatography (n-pentane/Et2O: 1/2) to
give (R)-
15b, in the case of the (R)-L2 ligand, as a clear oil in 82%
isolated yield
with 24% ee (Table 2.2, entry 2). The ee was determined on a
Chiralcel
OJ column with n-heptane/2-propanol: 90/10, flow = 1.0
mL/min.
Retention times: 14.7 min [(S)-enantiomer], 23.5 min
[(R)-enantiomer]. 1H NMR δ = 7.35-
7.29 (m, 3H), 7.23-7.18 (m, 6H), 5.75 (bs, 1H), 5.18 (d, J =
12.0 Hz, 1H), 5.14 (d, J = 12.2
Hz, 1H), 4.28 (bs, 1H), 3.25 (bs, 1H), 2.86 (dd, J = 15.6, 5.5
Hz, 1H), 2.80 (dd, J = 15.4,
5.5 Hz, 1H), 2.58-2.46 (m, 1H), 2.46 (d, J = 17.1 Hz, 1H), 2.26
(s, 3H); 13C NMR δ =
207.8, 155.1, 138.6, 136.4, 136.1, 128.5, 128.1, 127.9, 127.8,
126.2, 126.1, 67.7, 52.8, 44.7,
40.8, 38.9, 19.2. Physical and spectral properties were in full
agreement with the
literature.16
N
O
CO2Bn
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37
06_Chapter_2.doc
Enantioselective Synthesis of 2-Aryl-4-piperidones
N
O
CO2Bn
N
O
CO2Bn
N
O
CO2BnO
(S)- and (R)-Benzyl-4-oxo-2-m-tolylpiperidine-1-carboxylate.
(15c). The crude product
was purified by flash chromatography (n-pentane/Et2O: 1/2) to
give
(R)-15c, in the case of the (R)-L2 ligand, as a clear oil in 92%
isolated
yield with 98% ee (Table 2.2, entry 3). The ee was determined on
a
Chiralcel OD-H column with n-heptane/2-propanol: 90/10, flow =
0.5
mL/min. Retention times: 25.1 min [(S)-enantiomer], 29.0 min
[(R)-enantiomer]. The
absolute configuration was assigned by analogy. [α]D = +90.9° (c
= 0.52, CHCl3, 98% ee); 1H NMR δ = 7.02-7.39 (m, 5H), 7.14-7.21 (m,
1H), 6.95-7.03 (m, 3H), 5.75 (bs, 1H), 5.21
(d, J = 12.5 Hz, 1H), 5.14 (d, J = 12.5 Hz, 1H), 4.23 (m, 1H),
3.15 (m, 1H), 2.94 (d, J =
15.4 Hz, 1H), 2.79 (dd, J = 15.4, 7.0 Hz, 1H), 2.49 (m, 1H),
2.32 (m, 1H), 2.26 (s, 3H); 13C
NMR δ = 207.3, 155.4, 139.6, 138.5, 136.2, 128.6, 128.4, 128.2,
127.9, 127.3, 123.6, 67.7,
54.5, 44.1, 40.5, 38.9, 29.6, 21.4; HRMS calcd for C20H21NO3
323.1521 found 323.1517.
(S)- and (R)-Benzyl-4-oxo-2-p-tolylpiperidine-1-carboxylate
(15d). The crude product
was purified by flash chromatography (n-pentane/Et2O: 1/2) to
give
(R)-15d, in the case of the (R)-L2 ligand, as a clear oil in 86%
isolated
yield with 95% ee (Table 2.2, entry 4). The ee was determined on
a
Chiralcel OJ column with n-heptane/2-propanol: 90/10, flow =
1.0
mL/min. Retention times: 27.3 min [(S)-enantiomer], 30.8 min
[(R)-enantiomer]. The
absolute configuration was assigned by analogy. [α]D = +81.3° (c
= 0.64, CHCl3, 95% ee);
1H NMR δ = 7.28-7.42 (m, 5H), 7.07-7.20 (m, 4H), 5.82 (bs, 1H),
5.26 (d, J = 12.2 Hz,
1H), 5.19 (d, J = 12.2 Hz, 1H), 4.25 (m, 1H), 3.18 (m, 1H), 2.98
(td, J = 15.6, 3.2, 1.2
Hz,1H), 2.83 (dd, J = 15.4, 6.6 Hz , 1H), 2.51 (m, 2H), 2.33 (s,
3H); 13C NMR δ = 207.3,
155.4, 137.4, 136.5, 136.2, 129.4, 128.5, 128.2, 127.9, 126.6,
67.7, 54.3, 44.1, 40.5, 38.8,
20.9; HRMS calcd for C20H21NO3 323.1521 found 323.1515.
(S)- and
(R)-Benzyl-2-(4-methoxyphenyl)-4-oxopiperidine-1-carboxylate (15e).
The
crude product was purified by flash chromatography
(n-pentane/Et2O:
1/2) to give (R)-15e, using the (R)-L2 ligand, as a clear oil in
85%
isolated yield with 96% ee (Table 2.2, entry 5). The ee was
determined on a Chiralcel OD-H column with
n-heptane/2-propanol:
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38
06_Chapter_2.doc
Chapter 2
N
O
CO2BnO
O
N
O
CO2BnF
90/10, flow = 0.5 mL/min. Retention times: 35.8 min
[(S)-enantiomer], 39.9 min [(R)-
enanti