Construction of adjacent quarternary and tertiary stereocenters
via a organocatalytic transformation of Morita-Baylis-Hillman
carbonates
H
O
O
R
H
O
-
O
R
R
3
+
N
P
h
C
H
O
O
O
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R
3
+
N
P
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H
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+
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P
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-
O
E
H
H
R
B
A
A
1
)
2
)
3
)
1
2
Construction of Adjacent Quaternary and Tertiary Stereocenters
via an Organocatalytic Transformation of Morita-Baylis-Hillman
Carbonates
O
H
R
E
W
G
+
R
*
O
H
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)
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C
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A
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-
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Dirk Jan van Steenis
Report Research project, master Molecular Design Synthesis and
Catalysis (MDSC)
What is organocatalysis?
“Organocatalysis is the acceleration of a chemical
transformation through addition of a sub-stoichiometric amount of
an organic compound which does not contain a metal atom”
- Peter I. Dalko and Lionel Moisan
“Catalytic reactions mediated by small organic molecule in
absence of metals or metal ions.”
- Carlos F. Barbas, III
“ A field of chemistry that pays my mortgage and has gotten me
many free dinners.”
- David W. C. Macmillan
A part of this report has been submitted for publication:
Dirk Jan V. C. van Steenis, Tommaso Marcelli, Martin Lutz,
Anthony L. Spek, Jan H. van Maarseveen, Henk Hiemstra*. 2006.
Table of Contents
4Summary
5List of abbreviations
7Chapter 1; Introduction
71.1 Organocatalysis
91.2 Cinchona Alkaloids
121.2.1 Bi-functional cinchona alkaloids
141.3 Morita-Baylis-Hillman (MBH) Reaction
151.3.1 The Morita-Baylis-Hillman mechanism
161.3.2 Morita-Baylis-Hillman Adducts
191.4 Dynamic Kinetic Asymmetric Transformation (DYKAT) of
Morita-Baylis-Hillman Adducts
211.5 Functionalization of Morita-Baylis-Hillman Adducts via a
Tandem SN2’-SN2’ Mechanism
251.6 All-carbon Quaternary Stereocenters
Chapter 2; Allylic Nucleophilic Substitution of
Morita-Baylis-27Hillman Carbonates
272.1 Goal
292.2 Catalyst Synthesis
322.3 Preliminary Experiments and Optimization
352.4 Results
352.4.1 Substrate scope
382.4.2X-Ray analysis
2.4.3Mechanistic considerations40
412.5 Conclusions
43Samenvatting
44Acknowledgements
45Chapter 3 Experimental
References70
Summary
Organocatalysis, catalytic transformations with small organic
molecules, has found renewed interest in both academia and
industry. Although it was already known for a century that organic
compounds could catalyze asymmetric reactions, it is only since
half a decade that the potential of organocatalysis is understood
and is starting to be fully explored. In the treatment of diseases,
one enantiomer of a medicine is usually more potent, and in the
worst scenario, the opposite enantiomer can cause serious side
effects or even death. Therefore, the demand from both
pharmaceutical and chemical industry for new reliable asymmetric
transformations of molecular skeletons is higher then ever.
Nowadays, the construction of (highly) functionalized asymmetric
skeletons still suffers from drawbacks, especially when there is a
quaternary stereocenter involved in the target molecule.
Organocatalysis gained popularity in a relatively short time span,
because it has led to a large assortment of new asymmetric
demanding transformations in the last five years. In some cases,
organocatalysts meet the selectivity and efficiency levels of
established metal catalyzed organic reactions. Since
organocatalysis has a hidden potential, it could provide a solution
for challenging alterations in the future. Moreover,
organocatalysis can serve as a green alternative for transition
metal catalyzed reactions. During this master research project in
organocatalysis we found that the organocatalyst β-isocupreidine
(β-ICPD) effectively catalyzes a one-step asymmetric transformation
of Morita-Baylis-Hillman carbonates. This transformation led to new
molecular assemblies with vicinal quaternary and tertiary
stereocenters. We observed high chemo-, diastereo-, and
enantioselectivities with this reaction catalyzed by
β-isocupreidine, in addition the chemical yields of these
transformations are excellent. This one-step organocatalytic
allylic alkylation is the first, out of six reactions reported, in
which the reaction mechanism can not be only explained in terms of
a conjugate addition and thereby leading to adjacent quaternary and
tertiary stereocenters.
List of abbreviations
H2O: water
CDCl3:
deutero-chloroform
CHCl3: chloroform
DCM: dichloromethaneCH2Cl2:
dichloromethaneEtOAc:
ethyl acetate
EI:
electron impact
Et2O:
diethyl ether
FAB:
fast atom bombardment
1H NMR:
proton1 nuclear magnetic resonance
13C NMR:
carbon13 nuclear magnetic resonance
HRMS:
high resolution mass spectroscopy
J: coupling constant
Hz:
hertz
IR:
infra red
FTIR:
Fourier transform infra red
UV: ultraviolet
K2CO3:
potassium carbonate
MD3OD:
deutero-methanol
MeOH:
methanol
MgSO4:
magnesium sulfate
MHz:
megahertz
MS:
mass spectrometer
nm:
nanometer
PE:
petroleum ether
HCl: hydrochloric acid
KOH: potassium hydroxide
H3PO4: phosphoric acid
N2: nitrogen gas
DBU:
2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidine
DABCO: 1,4-diaza-bicyclo[2.2.2]octane
DMAP: N,N-dimethylpyridin-4-amine
CO2: carbon dioxide
TLC: thin layer chromatography
Boc2O: tert-butoxycarbonyl anhydride
THF:
tetrahydrofuran
DMSO: dimethylsulfoxide
ee: enantiomeric excess
dr:
diastereomeric ratio
h: hours
min:
minutes
Pd: palladium
Boc: tert-butylcarbonate
OAc: acetate
BINAP:2-(diphenylphosphino)-1-(2-(diphenylphosphino)naphthalen-1-yl)naphthalene
NH3: ammoniac
UV:
ultra violet
AAA:
asymmetric allylic alkylation
DYKAT:
dynamic kinetic asymmetric transformation
KAT
kinetic asymmetric transformation
MBH
Morita-Baylis-Hillman
Å:
Angström
Eq.:
equivalent
KBr:
potassium bromide
Mp:
melting point
H:
proton
λ:
Lambda
HPLC:
high performance liquid chromatography
s:
singlet
d:
doublet
m:
multiplet
dd:
double doublet
t:
triplet
mmol:
millimoles
M:
molarity
Chapter 1; Introduction
1.1 Organocatalysis
Less then a decade ago it was generally accepted that highly
efficient asymmetric transformations where only restricted to
chiral organometallic complexes and enzymes. Indeed, the levels of
regio- and enantioselectivity achieved nowadays by these catalyst
systems is impressive. The number of organic reactions reported in
the last decades catalyzed by these complexes has enormously
contributed to our quality of life. The oil, chemical and
pharmaceutical industry and even our economy, are extensively
relying on these ways of influencing molecular properties.
Nevertheless, the need for new and reliable asymmetric
transformations is high. The amount of new chiral drugs introduced
on the market is higher then ever and subsequently the demand for
new efficient asymmetric transformations. Nature is chiral and does
everything with tremendous (asymmetric) efficiency, moreover, in
multiple reactions catalyzed by nature, there is no metal involved.
Apparently nature does not always need metals for challenging
transformations. Scientists nowadays use nature as an inspiration
source and try to mimic these reactions in the lab. The concept of
organocatalysis can be seen as a blackboard example of this. In
recent years asymmetric organocatalysis, is regaining interest and
can be considered as a rapidly expanding research field. In
addition, organocatalysis has proven in the last years to be a
valuable alternative in respect to the traditional asymmetric
catalytic methods, a few examples are given below;
· Cheap catalyst sources with respect to organometallic
catalysts
· No toxic transition metals in the product (catalyst
leaching).
· Environmentally friendly
· Usually less demanding reaction conditions
Evidence has been found that this metal free type of catalysis
has played a important-role in the formation of essential
key-building blocks for life. The natural amino acids, L-alanine
and L-isovaline which can catalyze for instance certain Aldol
reactions, have been found in an enantiomeric excess (ee) of 15 %
on meteorites1b. Although the first asymmetric transformation with
a small organic molecule was reported in 1912, by Bredig and Fiske,
it is no more then a few years ago that the potential of
organocatalysis has been understood by the scientific community.
List and Barbas reported in 2000 a breakthrough in organocatalysis
and “pulled the trigger”. They reported that simple proline
catalyzes an aldol reaction in good enantiomeric excesses. Since
then, organocatalysis is starting to get the attention it deserves
and has become a mature concept in the field of
(homogenous)catalysis and in some cases organocatalysts meet the
selectivity and efficiency levels of established metal catalyzed
organic reactions. During the ninety years of absence, only a few
scientists understood the potential of metal free catalysis. In the
sixties, Pracejus applied cinchona alkaloids in the asymmetric
conversion of ketenes to (S)-methyl hydratropate. The seventies
brought an other milestone, Hajos and Parrish reported a L-proline
catalyzed Robinson annulation in excellent enantioselectivities.
Moreover, Wiechert reported an organocatalyic aldol reactions in
good enantioselectivities. In the eighties, Wynberg and co-workers
reported various 1,2 and 1,4 additions catalyzed by cinchona
alkaloids. Besides these notable reports, the field of
organocatalysis has been remarkably overlooked. In respect to the
traditional transition metal based catalysts, organocatalysts are
often inexpensive, environmentally friendly and the reactions can
usually be performed under aerobic reaction conditions. Different
from enzymes, organocatalysts do not require buffer conditions, and
therefore have less solubility problems and have a broad substrate
scope. Moreover, organocatalysts can usually simply be separated
from reaction mixtures without considerable catalyst leaching and
recovered via extraction. An other interesting and attractive
feature of organocatalysts is that they usually possess an
excellent functional group tolerance. These characteristics can
make them practically and interesting counterparts of traditional
homogenous catalysts and enzymes, therefore it is justified to
continue further exploration of organocatalysis.
N
N
O
O
S
O
O
F
F
F
N
N
O
N
The vast majority of (asymmetric) organic reactions can be
explained by a nucleophile and electrophile mechanism.
Organocatalysts can be divided into several subclasses namely;
Lewis bases, Lewis acids, Brønsted bases and Brønsted acids1d. The
majority of the organocatalyst published to date works via an Lewis
base mechanism (Fig. 1). For simplicity reasons, only the Lewis
base and the Brønsted acid mechanism are taken into account in this
report. The simplified Lewis base mechanism can be best described
by the following steps; the Lewis base (B), for instance a cinchona
alkaloid, starts the catalytic cycle via a nucleophilic addition
to, or deprotonation of, the substrate (S). The resulting chiral
intermediate undergoes a reaction and the newly formed product (P)
is separated from the catalyst. The catalyst is now regenerated and
available for a new catalytic cycle. Many organocatalytic reactions
described in literature cannot simply be explained by a single
Lewis base mechanism. Often there is a second mechanism involved,
usually a Brønsted acid mechanism. This type of organocatalysis is
called bi-functional organocatalysis. Cinchona bi-functional
organocatalysis was first introduced by Wynberg and coworkers7d.
They proposed that both a base and an acid can be crucial in
activation and orientating the reaction partners, an elegant
example being the asymmetric addition of aryl-thiols to conjugated
cycloalkenones7c. In a bi-functional catalyzed reaction, the
organocatalyst bears besides a Lewis base, typical a nitrogen or
phosphorus atom, also a Brønsted acid functionality. These facts
have been only recently understood and are only since the last
years frequently applied, although it was already known in the
eighties. Especially, activation and orientation through thio-urea
hydrogen bonding is emerging. Other widely applied Brønsted acids
functionalities in organocatalysis are urea and alcohol functional
groups. Similar to enzyme catalysis, there is now also hydrogen
bonding involved in the transition state. This kind of hydrogen
bonding usually makes the electrophile more electron deficient and
therefore more prone to nucleophilic attack. Besides activation,
the hydrogen bonding motive holds the electrophile also in a kind
of a conformational lock (orientation). Via this conformational
lock higher enantioselectivities can be obtained. Brønsted acid
activation through thio-ureas has been applied in asymmetric
reactions such as the Michael (conjugate) addition, (aza)-Henry,
Strecker and Friedel-Craft alkylations.
1.2 Cinchona Alkaloids
For practical and economical considerations, an important
prerequisite for an organocatalyst is that both enantiomers of the
catalyst are readily available. Now, there is access to both
enantiomers of a product with usually similar ranges of asymmetric
induction. Cinchona alkaloids are a natural class of compounds that
exhibit this unique feature and makes them highly attractive
candidates for asymmetric catalysis. Quinine (QN) / Quinidine (QD),
and Cinchonine (CN) / Cinchonidine (CD) (Fig. 2), are two pairs of
so called pseudoenantiomers. These pseudoenatiomers are not
enantiomers, because they are not mirror images.
N
N
O
N
H
2
N
N
O
N
H
S
N
H
F
3
C
C
F
3
They are called pseudoenantiomers because they are “almost
enantiomeric pairs”. To date there are more then twenty different
cinchona alkaloid producing plants known, by far the most important
is the “Cinchona pubescens”. To date, more then thirty different
kinds of cinchona alkaloids have been isolated and characterised.
The tree bark of the Cinchona pubescens can contain over 50 % of
the main four cinchona alkaloids which can be easily gathered, via
extraction. The cinchona alkaloids family forms a unique class of
natural compounds and has found widespread application, such as in
the pharmaceutical, chemical and beverage industry and are produced
on a multi-ton scale (aprox. 700 t/year) and therefore readily
available. Already three-hundred years ago, quinine (QN) received
attention because of its biological activity although the structure
was not understood yet. Quinine (QN) was officially isolated and
reported by Pelletier in 1820 In the past decades quinine (QN) has
been extensively studied and used for the treatment of malaria.
However, alternatives for the treatment of malaria have been
developed due to side effects of quinine. Nowadays cinchona
alkaloids are mainly used by the chemical and beverage industry.
Quinine (QN) is used by the soft drink industry for the typical
bitter flavour. The chemical compositions of cinchona alkaloids
differ, but usually they bear two key characteristics; they all
have an aromatic quinoline part and usually a basic quinuclidine
moiety in the molecular skeleton (Fig.2). The pseudoenantiomers,
quinine (QN) / quinidine (QD) have an additional functionality;
they bear at the 6’-position of the aromatic quinoline part a
methoxy-group. This functionality gives a handgrip for further
functionalization. A milestone achieved by making use of the chiral
properties of cinchona alkaloids, was the resolution of racemic
C
N
P
h
C
O
O
E
t
C
N
tartaric acid. Pasteur, achieved the separation of the
enantiomeric pair by using the cinchona alkaloid derivatives
quinicine and cinchonicine (Fig. 3). The first asymmetric reaction
catalyzed by a cinchona alkaloid was reported in 1912 by Bredig and
Fiske2. The asymmetric addition of hydrogen cyanide to benzaldehyde
was reported in an
C
O
O
M
e
P
h
C
O
O
E
t
C
N
B
r
enantiomeric excess (ee) of 20 %. Further development of
cinchona alkaloids in asymmetric catalysis was reported in 1960 by
Pracejus in the asymmetric conversion of ketenes4. An other
cinchona alkaloid pioneer, Wynberg, expanded the reactions
catalyzed by cinchona alkaloids to various 1,2 and 1,4 additions.7
In the last two decades cinchona alkaloids are recognized as a
privileged class of chiral auxiliaries and have found a variety of
applications in asymmetric synthesis.
1.2.1 Bi-functional cinchona alkaloids
C
O
O
M
e
C
O
O
E
t
P
h
C
N
O
2
N
C
O
O
M
e
P
h
C
O
O
E
t
C
N
In order to enlarge to scope of chemical transformations
catalyzed by cinchona alkaloids, many efforts have been put into
the modification of these natural compounds. In the past two
decades modified cinchona alkaloids have led to excellent results
in various research fields. In phase transfer catalysis (PTC),
quaternary ammonium ions derived from cinchona alkaloids have
played an important role. The quinuclidine nitrogen atom can
perfectly undergo transformation into a quaternary ammonium ion and
could serve as a phase transfer catalyst. Cinchona alkaloids have
played a key role in asymmetric dihydroxylation reactions,
C9-dimerized Cinchona alkaloids have successfully been applied as
chiral ligands in the Sharpless asymmetric dihydroxylation (AD). To
stress the importance of these ligands; various analogues of these
dimers are now commercially available. Barry K. Sharpless received
the Nobel prize in chemistry in 2001 for his contribution to
asymmetric synthesis. The cinchona dihydroxylation ligands formed a
substantial part of his work. Other alterations, different than at
the C9 position of the cinchona alkaloid, usually occur at the
C6’-position of quinine (QN) and quinidine (QD). When this position
is changed from a methoxy into a Brønsted acid functionality, these
organocatalysts become bi-functional (Fig. 4) as discussed in
paragraph 1.1. These types of organocatalysts are often referred to
as cupreines and cupreidines. In 1999, Hatakeyama proved for the
first time that when a C6’ methoxy is transformed into a C6’-OH
Brønsted acid function, high enantioselectivities could be obtained
via this moiety. Since then bi-functional cinchona organocatalysts
are fully explored. In the past few years several bi-functional
modified quini(di)ne catalysts have been published A broad spectrum
of reactions are catalyzed with excellent (enantio)selectivities.
The reactions published in the past few years have been performed
with surprisingly simple and accessible organocatalysts. Besides
unmodified cinchona alkaloids, three different kind of successful
catalysts classes for the creation of chiral skeletons can be
distinguished in literature namely;
1) Quinidine derived oxaza-twistanes (i.e.
β-isocupreidine)11
2) C6’ hydroxyl and C9 alkylated cupreidine catalysts15
3) a C6 or C9 thiourea equipped quini(di)ne 16
C
O
O
M
e
C
O
O
E
t
C
N
C
l
C
O
O
M
e
P
h
C
O
O
E
t
C
N
C
O
O
M
e
P
h
C
O
O
E
t
C
N
O
C
N
O
O
Constrained oxaza-twistanes (Fig. 5), are a class of catalysts
whose the synthesis has been mainly explored by the group of
Hofmann. These compounds posses special characteristics, due to the
extra constrained ring between C9 and C3, in respect to other
cinchona alkaloids. Especially β-isocupreidine, (IUPAC name; 3R,
8R, 9S-10, 11- Dihydro-3,9-epoxy-6’-hydroxycinchonane), derived in
one step from quinidine, has proven to be a excellent catalyst in
various reactions. The β-isocupreidine quinuclidine nitrogen atom
owes, due to the extra cycle, more basic and nucleophilic
character. Moreover, β-isocupreidine has less conformations due to
the extra ring. β-Isocupreidine has been successfully applied to
multiple reactions such as the asymmetric Morita-Baylis-Hillman
reaction(see later) and the asymmetric aza-MBH reaction between the
strongly activated Michael acceptor
1,1,1,3,3,3-hexa-fluoroisopropyl acrylate and aryl-imines.
β-isocupreidine has also been applied in the construction of
quaternary stereocenters51f. The enantio-complementary catalyst of
β-Isocupreidine has recently been synthesized. Although the
synthesis involves 19 steps, now there is access to both
enantiomers of a product. A second superior catalyst class has been
introduced by Deng and co-workers. C6’ hydroxyl and C9 alkylated
cupreidine catalysts, again easily accessible, gave excellent
levels of enantio- and diastereo-discrimination in a broad
compilation of conjugate additions. In this elegant collection of
papers published by Deng, it is demonstrated how various
1,3-dicarbonyl, 1,3-nitro-carbonyl and 1,3 cyano-carbonyl
pronucleophiles can react with simple Michael-acceptors. These
catalysts reported by Deng, can also simultaneously construct
adjacent quaternary and tertiary stereocenters, which is a
tremendous challenge in synthetic organic chemistry. These reported
asymmetric reactions elegantly show how via organocatalysis highly
functionalised skeletons are accessible with relatively simple
catalysts. (Fig. 6) The third expanding catalyst category is
thiourea modified quinidines15. Two versions have been published
recently, the C6´ 9e and C9 thiourea equipped quinidine. Although
the catalyst synthesis requires additional steps compared to the
catalysts of Deng, they have important advantages. Due to the
electron deficient thio-urea moiety of the catalyst, high levels of
enantiodiscrimination can be achieved like in a fundamental
reaction like the Henry reaction. The organocatalytic Henry
reaction, a reaction between an aldehyde and typical
nitro-(m)ethane, has recently been elucidated in high
enantioselectivities9e, 15. The catalyst of choice was a C6’
thiourea equipped quinidine with a the C9 carbon a benzyl
protective group (fig 6,C6’ THQD). In these two papers dealing with
cinchona catalyzed Henry reaction, it is verified that the C6’
thiourea moiety is a stronger hydrogen donor compared to the C6’
hydroxyl donor (BnCPD).
1.3 Morita-Baylis-Hillman (MBH) Reaction
O
C
O
O
M
e
O
O
B
r
O
C
O
O
M
e
O
O
The Morita-Baylis-Hillman reaction was first described in 1968
by Morita; he observed a phosphine-derivative catalyzed addition of
an aldehyde to an acrylate, yielding densely funtionalised
β-hydroxy-α-methylene esters (Fig. 7). He named the reaction the
“Carbinol Addition”. In 1972 the reaction was reinvented and
patented by two chemists at the Celanese Corporation in New York,
Anthony Baylis and Melville E. D. Hillman. The yield described by
Morita was poor but Baylis and Hillman found that if
1,4-DiAzaBiCyclo[2.2.2]Octane (DABCO) was used instead of the
phosphine derivative, the yield was roughly three times higher.
After its discovery, the Morita-Baylis-Hillman reaction was almost
“forgotten” for a decade, partly due to the slow reaction rate
(typically days). However, the Morita-Baylis-Hillman is recognized
now as an important carbon-carbon bond forming reaction like the
aldol, Grignard, Friedel-Crafts, Heck and Suzuki reaction. The MBH
reaction has become a well-established reaction due to fact that it
meets several important standards; the MBH reaction generates
multiple functional groups and thereby it provides a simple and
atom economic carbon-carbon bond forming process. Moreover, the MBH
reaction encloses an immense synthetic potential, almost every
aldehyde and activated olefin undergoes the MBH reaction.
Supporting evidence for this statement can be found with a simple
search in literature. The amount of papers dealing with MBH
chemistry is impressive. Up to now the MBH reaction emerged to an
important classic “text book” organic reaction but still faces
major challenges, illustrative features being the selective
formation of the tertiary stereocenter and rate. Recently, Verkade
and co-workers have made an impressive step forward. A highly
active two catalyst combination, relying on a proazaphosphatrane
organocatalyst and titanium-tetra-chloride was reported. Although
the products are obtained racemic and the catalysts are
air-sensitive, the methodology presented tolerates a broad
substrate scope. For more then a decade the selective formation of
the tertiary stereocenter has become an enormous challenge.
Selective formation of this stereocenter would provide a route to
optically enriched β-hydroxy-α-methylene esters, ketones, nitriles
etc. The first breakthrough in the asymmetric MBH reaction was
reported in 1999 by Hatakeyama and coworkers17. They used
β-isocupreidine (Fig. 5) to catalyze the asymmetric MBH reaction
between aldehydes and the strongly activated Michael acceptor,
1,1,1,3,3,3-hexa-fluoroisopropyl acrylate. Manifold chiral
catalysts have been tried, including Brønsted acids and derivatized
binaphthtyls. So far high enantioselectivities have not been
reported with simple acceptors such as methyl acrylate and
acrylonitrile. A recent trend in the asymmetric (aza)-MBH reaction
is the use of catalysts combinations. Usually DABCO and a chiral
thiourea are used.
1.3.1 The Morita-Baylis-Hillman mechanism
The Morita-Baylis-Hillman reaction involves a three component,
nucleophilic amine or phosphine mediated addition of an aldehyde to
an activated olefin. The commonly accepted mechanism involves in
the first step 1) a reversible conjugate (Michael-type) addition of
the nucleophilic catalyst to activated olefin (acrylate). The
resulting zwitterionic enolate (1)(Fig. 8) can subsequently undergo
two pathways; elimination of the catalyst or an aldol-like
nucleophilic attack on the aldehyde 2) giving the second
zwitterionic intermediate (2). Third, the second zwitterionic
intermediate can undergo now again two reaction pathways. Reaction
pathway 3) yielding the product, comprises an elimination and
transfer of a proton. The other pathway is the elimination of
benzaldehyde end thereby the intermediate is returning into the
first zwitterionic species (1). Direct evidence for this reaction
mechanism was never presented; it was only based on assumptions.
Only direct evidence for the zwitterionic species (1) was presented
by Drewes and co-workers it was assumed that the rate limiting step
(RLS) of the MBH reaction is the elimination/transfer of a proton
step 3) since a species like (1) could be isolated and analysed by
X-ray crystallography. In 2004, the groups of Coelho and Eberlin,
did a fundamental study, by electrospray ionization (ESI),
detecting the intermediates in the MBH reaction. They confirmed the
generally assumed MBH reaction mechanism. In 2005 the group of
Aggarwal and co-workers, published a study towards the kinetics and
mechanism of the MBH reaction in a-protic solvents. Interesting
results have been reported. During the MBH reaction when an excess
of starting materials are present, the RLS is the
elimination/transfer of the proton in step (3). When significant
amounts of products are present, the RLS is 2. This is due to
hydrogen bond donor capabilities of the product (Fig. 8,
intermediate A), the product can promote, via hydrogen bonding,
elimination and hydrogen transfer of step 3. This effect can be
described as autocatalysis.
O
C
O
O
M
e
O
O
O
2
N
O
C
O
O
M
e
O
O
C
l
1.3.2 Morita-Baylis-Hillman Adducts
Nowadays the Morita-Baylis-Hillman chemistry can be divided into
three major research domains namely;
1) Improvement of rate, yield and elucidation of the reaction
mechanism
2) Selective formation of the tertiary stereocenter
3) Chemical development of a various transformations of MBH
adducts
O
C
O
O
M
e
O
O
O
C
O
O
M
e
O
O
Key developments of first two domains have been shortly
overviewed in paragraph 1.3 and 1.3.1, the third, transformations
of MBH products, will be discussed shortly in the following text.
So far, in the literature many papers appeared where MBH adducts
are used to obtain compounds with certain molecular properties.
Therefore various efficient transformations of MBH products have
been reported and methodologies have been developed. MBH adducts
have proven to be important intermediates in various applications,
such as total synthesis. As discussed before the MBH reaction
relies on an atom economic process, yielding three functionalities
is close proximity. These three functionalities, an alcohol, an
alkene and an electron withdrawing group (usually an ester), are
essential key functional groups in organic chemistry today. In
principle, these key functionalities are susceptible of stereo-,
chemo- and enantioselective transformations and therefore MBH
adducts posses an enormous synthetic potential all together. Upon
modification of MBH alcohols/adducts various known organic
compounds classes can be obtained like; (γ-butyro-) lactones,
β-lactams, quinolines, indolizines, methylene-dioxanones,
pyrrolidines, coumarins, naphthalenes and derivatives thereof.
Moreover, MBH adducts undergo (perfectly) a tremendous scope of
classic reactions such as: asymmetric dihydroxylation (AD),
epoxidation, ring-closing metathesis, aldol condensations,
aminohydroxylation, radical cyclizations, Heck, Friedel-Craft and
hydrogenation. Many other reductions and photochemical reactions
also have been reported25. In figure (Fig. 9), a small selection of
successfully applied alterations is presented.
Especially, for the construction of highly functionalized
molecular skeletons, like natural compounds, MBH adducts can be
interesting building blocks. MBH adducts have been often used
multifarious in total synthesis, examples being (-)-mycestericin E
by Hatakeyama et al. (Fig. 10), Pinnatoxin A by Kishi et al.(Fig.
11) and Salinosporamide A by Corey et al.(Fig12).
O
H
C
O
O
M
e
B
r
O
H
C
O
O
M
e
O
H
C
O
O
M
e
O
H
C
O
O
M
e
O
2
N
O
H
C
O
O
M
e
C
l
O
H
C
N
1.4 Dynamic kinetic Asymmetric transformation (DYKAT) of
Morita-Baylis-Hillman adducts
O
H
C
O
O
M
e
Since the creation of highly optically enriched
β-hydroxy-α-methylene esters (and ketones, nitriles etc.) still
remains a barrier till to date, Trost and co-workers have
introduced in 2000 an alternative strategy, the so called “dynamic
kinetic asymmetric transformation” (DYKAT) of Morita-Baylis-Hillman
adducts. This deracemization reaction procedure forms one out of
the at least five enantiodiscrimination mechanisms in the famous
palladium catalyzed asymmetric allylic alkylation (AAA). This
strategy consists of a palladium catalyzed dynamic kinetic
asymmetric transformation (DYKAT) of racemic Morita-Baylis-Hillman
carbonates as depicted in figure 13. Dynamic kinetic asymmetric
transformation refers to the conversion of chiral racemic
substrates having the potential of being completely converted to
one single enantiomer of the product. The DYKAT mechanism can be
explained by the next illustrative example. In the first of step of
a DYKAT reaction, the oxidative addition of a chiral palladium
complex to the olefin occurs. Subsequently ionization of the
leaving group happens and a diastereomeric complex is formed. Next,
there are two possible options for the formation of a
diastereomeric complex. Usually one diastereomeric complex is more
favoured for nucleophilic attack (oxygen nucleophile), followed by
decomplexation leading to the product. The second diastereomeric
complex usually does not react or in much slower rates. In a DYKAT
reaction inter conversion of this “slow reacting”
diastereo-complex/π-allyl-intermediate to the “fast reacting”
diastereo-complex π-allyl-intermediate happens and subsequently
reacts. So the theoretically yield in a DYKAT reaction can be 100%
compared to 50% yield in a kinetic asymmetric transformation (KAT).
A KAT reaction, also known as a kinetic resolution, refers to the
transformation of one single enantiomer of racemic starting
material into the product. The remaining other enantiomer of a
substrate does not react or does it in slower rates. Since the
introduction, the DYKAT of MBH-adducts has been frequently used by
Trost et al. to overcome difficult key steps in the total synthesis
of natural and biological active compounds. A whole array of
compounds has been synthesized via this methodology, examples being
the total synthesis of (+)-Hippospongic acid A(Fig. 15), morphine,
codeine38b (Fig. 14), and Furaquinocin’s A, B, and E (Fig. 16).
N
O
H
R
N
N
N
R
O
H
Q
u
i
n
i
n
e
(
Q
N
)
C
i
n
c
h
o
n
i
d
i
n
e
(
C
D
)
R
=
O
M
e
R
=
H
Q
u
i
n
i
d
i
n
e
(
Q
D
)
C
i
n
c
h
o
n
i
n
e
(
C
N
)
1
1
8
9
3
4
6
´
6
´
1
8
9
3
4
*
*
H
N
N
R
O
Q
u
i
n
i
c
i
n
e
C
i
n
c
h
o
n
i
c
i
n
e
R
=
O
M
e
R
=
H
B
S
B
P
B
P
S
N
O
H
N
O
R
L
e
w
i
s
B
a
s
e
B
r
ø
n
s
t
e
d
a
c
i
d
9
6
´
N
O
H
N
O
9
6
´
3
N
O
H
9
6
´
O
N
N
O
B
M
P
O
M
e
C
O
O
M
e
O
B
n
N
O
B
M
P
C
O
O
M
e
O
B
n
M
e
O
H
H
N
O
C
l
O
M
e
O
H
O
1.5Functionalization of Morita-Baylis-Hillman adducts via a
tandem SN2’-SN2’ mechanism
N
N
R
1
R
2
1
8
9
3
6
´
4
B
n
C
P
D
R
1
=
O
H
P
H
N
C
P
D
R
1
=
O
H
C
6
´
T
h
Q
D
R
1
=
s
c
C
9
T
h
Q
D
R
1
=
H
R
2
=
B
n
R
2
=
P
h
n
R
2
=
B
n
R
2
=
s
c
s
c
=
R
1
H
N
H
N
S
C
F
3
C
F
3
C
O
2
-
O
O
O
H
H
+
H
N
O
O
O
H
O
H
H
H
O
O
O
T
B
S
O
O
O
T
E
S
O
H
H
H
N
H
A
l
l
o
c
O
C
O
2
t
B
u
M
s
O
As shown before, simple Morita-Baylis-Hillman adducts possess a
huge synthetic potential25. As a result, in recent years a lot of
papers have been published dealing with the (enantioselective)
modification of the β-position, the alcohol functionality of MBH
adducts. A number of strategies have been developed in the recent
years focusing on two different targets. One is the expansion of
synthetic methodologies in order to obtain various MBH adducts. The
other is the development of a highly enantioselective route for
obtaining MBH-alcohols, because the direct and highly
enantioselective Morita-Baylis-Hillman reaction between a simple
aldehyde and an activated olefin has proven to be a daunting
challenge. In both processes, usually the MBH-alcohol is
transformed into a leaving group. First the MBH reaction is
performed without a chiral catalyst. Once the product is obtained,
the MBH alcohol is transformed in typically an acetate or carbonate
moiety. Now these MBH-adducts are prone to a tandem SN2’-SN2’
mechanism. This mechanism, which is comparable with the DYKAT
transformations of MBH adducts, includes several steps. The first
step is usually an attack of a nucleophilic (chiral) nitrogen or
phosporus atom on the vinylic moiety of the MBH adduct occurs, with
subsequent ionization of the leaving group. Once the leaving group
has deprotonated the pro-nucleophile, the intermediate (zwitterion)
is prone to nucleophilic attack, finally leading to the product. In
the last five years a lot of papers appeared making use of this
mechanism. The mechanism can be described as an allylic
substitution reaction or, when carbon/nitrogen nucleophiles are
used, an allylic alkylation or aminaton. In 2002, Kim and
co-workers published an organocatalytic methodology which relies on
this tandem SN2’-SN2’ mechanism (Fig. 17),. MBH-acetates (racemic)
are transformed into MBH-alcohols with optical purities of 54-92%
ee and in yields of 25-42%. The process involves a successive
SN2’-SN2’ attack of a quinidine derived Sharpless asymmetric
dihydroxylation ligand, (DHQD)2PHAL, to the vinyl moiety, followed
by attack of a hydroxy anion, leading to the product. The first
step of the process occurs via a kinetic resolution step,
(DHQD)2PHAL reacts faster with one enantiomer of the starting
material. Since the obtained enantioselectivities obtained can not
be only explained by a kinetic resolution step, the author proposed
that during the
C
6
H
1
4
C
O
O
R
C
6
H
1
4
O
C
O
O
H
O
H
O
H
H
2
N
O
H
O
O
second step there is additional asymmetric induction.
Supplementary, Kim and co-workers reported in 2002 similar
N
O
H
N
O
reactions relying on again SN2’-SN2’ mechanism. MBH-acetates
were reacted with a sub-
O
B
o
c
C
O
O
M
e
R
C
O
O
E
t
C
N
R
'
+
stoichiometric amount of DABCO and various pro-nucleophiles.
N
N
R
1
R
2
1
8
9
3
6
´
4
1
B
n
C
P
D
R
1
=
O
H
2
P
H
N
C
P
D
R
1
=
O
H
3
C
P
D
R
1
=
O
H
R
2
=
B
n
R
2
=
P
h
n
R
2
=
O
H
R
4
N
O
2
R
3
R
1
R
2
+
N
O
2
R
4
R
1
R
3
R
2
C
a
t
1
,
2
,
3
When pro-nucleophiles, such as tosylamide, methyl-sulfonamide,
phthalimide, benzotriazole were used, the allylic substitution
(amination) products were obtained in moderate yields (40-91%).
Similar work was in that year reported by Orena and co-workers. In
this elegant paper is shown the sensitivity of the MBH-adducts
towards bases. When N-p-toluenesulfonimide derived MBH where
reacted with a sub-stoichiometric amount of DABCO in DCM, the
allylic substitution products (Fig. 19, compound a) were obtained
via the tandem SN2’-SN2’ mechanism. On the other hand when DABCO
was replaced by DBU, the SN2’-SN2’ mechanism does not occur. Now, a
SN2’-decarboxylation mechanism occurs leading to product b, as
depicted in figure 19. The author proposed that the results can be
explained by the
E
W
G
O
H
R
R
B
a
k
e
r
´
s
Y
e
a
s
t
E
p
o
x
i
d
a
t
i
o
n
D
i
h
y
d
r
o
x
y
l
a
t
i
o
n
O
H
O
E
W
G
R
O
O
H
O
H
C
O
M
e
C
9
H
1
9
O
H
O
H
H
O
L
a
c
t
a
m
i
z
a
t
i
o
n
N
O
H
O
P
h
H
y
d
r
o
g
e
n
a
t
i
o
n
N
H
O
R
=
m
-
n
i
t
r
o
-
p
h
e
n
y
l
A
m
i
n
o
h
y
d
r
o
x
y
l
a
t
i
o
n
R
E
W
G
O
H
O
H
N
H
T
s
higher basicity (less nucleophilic) of DBU compared to DABCO.
DABCO favours a nucleophilic SN2’-attack to the double bond instead
of deprotonation of the N-p-toluenesulfonimide. MBH adduct.
Basavaiah co-workers reported a similar methodology in order
R
E
W
G
O
M
o
c
+
N
u
H
R
E
W
G
R
E
W
G
o
r
N
u
N
u
P
d
*
to obtain enantiomerically enriched Morita-Baylis-Hillman
adducts. Again the methodology relies on a allylic substitution
tandem mechanism (Fig. 20). First the organocatalyst (quinidine)
replaces the bromo atom, resulting in a chiral-intermediate,
similar of kind intermediate as reported by Kim. Subsequently, the
chiral intermediate is prone to attack by the pro-nucleophile,
ultimately leading to the product. Unfortunately, the results
obtained by Basavaiah are rather poor with yields up to 47% and
enantioselectivities up to 40 % ee.
N
N
O
M
e
O
H
9
6
´
K
B
r
-
H
3
P
O
4
1
0
0
o
C
,
5
d
N
N
O
M
e
O
H
H
N
N
O
M
e
O
H
1
,
2
-
h
y
d
r
o
g
e
n
s
h
i
f
t
c
y
c
l
i
z
a
t
i
o
n
d
e
m
e
t
h
y
l
a
t
i
o
n
N
N
O
6
1
%
(
2
)
O
H
(
1
)
In 2004 the groups of Krische and Lu independently reported the
first metal free organocatalytic allylic alkylation relying on the
tandem SN2’-SN2’ mechanism in excellent yields and
regioselectivity’s. The group of Krische reported the highly
regioselective formation of γ-butenolides. Various γ-butenolides
where created through a phosphine catalyzed substitution of
MBH-acetates. The diastereo-selectivity ratios obtained in this
reaction were excellent, up to 20:1. The regioselectivities were
good, in general higher than 9:1. In addition, the reported yields
were excellent, up to 94%. The group of Krische reported as well a
phosphine catalyzed allylic amination and dynamic kinetic
resolution and of MBH acetates. A protocol for the amination of
several MBH-adducts by 4,5-dichlorophthalimide and phthalimide is
presented. Besides racemic aminations, there is as well a chiral
example shown, commercially available Cl-OMe-BIPHEP promotes the
amination of MBH acetates with phthalimide in 56% ee. Lu and
co-workers have described a β-IC catalyzed nucleophilic
O
O
O
E
t
O
O
B
e
t
a
-
I
C
T
o
l
u
e
n
e
,
r
t
,
1
2
h
O
O
E
t
N
u
+
O
O
E
t
N
u
substitution of tert-butylcarbonate by various carbon, anime,
oxygen and phosphorus nucleophiles (Fig. 21). The tandem SN2-SN2’
nucleophilic substitutions occurs in high regioselectivities and
excellent yields. However, in general the enantioselectivities
obtained are moderate. This methodology shows a great tolerance
towards various nucleophiles including; nitrogen, phosphorus,
sulphur, oxygen and carbon. The proposed mechanism includes (Fig.
22), first the addition of the nucleophilic chiral amine to
β-methylene functionality (vinyl moiety). After the organocatalyst
is added to the α-methylene function, a cascade of steps occurs.
First the activating group leaves the starting material, leading to
CO2 and tert-butoxide. Sub sequentially, deprotonation of the
pronucleophile by the tert-butoxide anion leads to a SN2’ attack of
the pronucleophile on the chiral intermediate. During the attack of
the pronucleophile, the organocatalyst is displaced from the
intermediate giving the product and the regenerated catalyst. Lu
and co-workers found that β-isocupreiidine was the catalyst leading
to the highest enantioselectivities and reactivity’s. In the report
there is one asymmetric example shown with a 1,3-di-carbonyl carbon
pro-nucleophile producing the expected product in a moderate
enantioselection (51% ee), high SN2-SN2’ ratio (chemoselectivity)
and high yield.
N
N
O
N
H
N
H
S
F
3
C
C
F
3
6
´
N
N
O
N
H
N
H
S
F
3
C
C
F
3
6
´
N
N
O
O
S
O
O
C
F
3
6
´
N
N
O
O
H
6
´
N
N
O
N
P
h
P
h
6
´
N
N
O
N
H
2
D
M
A
P
1
0
m
o
l
%
,
D
C
M
,
r
e
f
l
u
x
6
h
P
h
-
N
-
(
O
T
f
)
2
,
1
.
1
e
q
.
P
d
(
O
A
c
)
2
,
1
0
m
o
l
%
H
N
=
C
P
h
2
,
1
.
1
e
q
.
(
+
/
-
)
B
I
N
A
P
,
1
0
m
o
l
%
C
e
s
i
u
m
c
a
r
b
o
n
a
t
e
1
.
5
e
q
.
,
T
H
F
,
r
e
f
l
u
x
1
8
h
T
H
F
/
H
2
O
c
i
t
r
i
c
a
c
i
d
3
,
5
-
C
F
3
P
h
N
C
S
,
1
.
0
5
e
q
.
T
H
F
,
2
0
m
i
n
.
(
2
)
(
3
)
(
4
)
(
5
)
(
6
)
4
7
%
7
6
%
8
1
%
6
9
%
1.6 All-carbon Quaternary stereocenters
Synthetic chemists nowadays can create almost every tertiary
stereocenter with excellent levels of enantiocontrol and chemical
yields. Various methodologies/series of tailor made ligands have
been developed and are used commonly in organic synthesis. However,
catalytic enantioselective C-C bond formation of all-carbon
quaternary stereocenters, i.e. carbon stereocenters bearing four
different carbon substituents, still represents a tremendous
challenge for synthetic organic chemists. Moreover, when a carbon
stereocenter is situated near a vicinal tertiary or quaternary
stereocenter, the construction of these features become even more
problematic. The difficulty for the construction of these motives
arises often from steric hindrance and a limited amount of reliable
reactions. Frequently used quaternary C-C bond formation reactions
are; cycloadditions like Diels-Alder, Pd-allylations reactions and
Michael additions, also known as conjugate additions. Nevertheless,
the assembly of quaternary stereocenters still remains a
considerably underdeveloped research area even though they are
common motives in natural and pharmaceutical compounds. To overcome
these difficulties, additional research is needed in the future to
have access to complex molecular skeletons in an economic and
straightforward manner. An alternative strategy in order to obtain
quaternary stereocenters can be completed by organocatalysis1. As a
matter of fact, in the last years a number of organocatalyzed
formations of these assemblies have been reported. A variety of
organocatalysts like proline and cinchona derivatives effectively
catalyzes the formation of quaternary stereocenters. An outstanding
example of these assemblies is the cinchona catalyzed Michael
addition reported by Deng and co-workers in 200550c. The addition
of various pro-chiral tri-substituted carbon nucleophiles to
nitro-olefins was reported in high enantioselectivities (up to
>99 % ee) and diastereoselectivities (up to >98:2 %) (Fig.
23). The organocatalysts of choice were simple cupreidine derived
catalysts. To stress the challenge of simultaneous arrangements of
vicinal quaternary and tertiary stereocenters; to date only six
examples have been reported. Interestingly, five of them are
organocatalytic.
O
B
o
c
+
(
9
)
b
-
I
C
,
2
0
m
o
l
%
1
e
q
1
.
2
e
q
T
o
l
u
e
e
n
0
.
0
5
M
1
2
h
,
r
t
*
*
C
O
O
E
t
P
h
C
O
O
M
e
C
O
O
M
e
(
1
1
)
C
N
(
1
0
)
P
h
*
C
O
O
E
t
C
N
C
N
(
1
0
)
C
O
O
E
t
Chapter 2 Allylic Nucleophilic Substitution of
Morita-Baylis-
Hillman Carbonates
2.1 Goal
O
B
o
c
O
O
M
e
(
9
)
O
H
O
E
t
O
O
B
o
c
O
O
E
t
1
)
D
A
B
C
O
5
0
m
o
l
%
M
e
O
H
0
.
7
5
e
q
.
,
4
d
+
2
)
(
B
o
c
)
2
O
1
.
1
e
q
.
D
M
A
P
5
m
o
l
%
D
C
M
,
1
h
.
(
7
)
3
4
%
Enantioselective organocatalysis has revealed a extraordinary
number of new methodologies in only half a decade1Although
organocatalysis only recently found renewed interest, the hidden
potential of organocatalysis does not require further explanation
by a simple look a the literature of the past years. Since there is
still a vast request for new complex chiral skeletons and many
problems chemists have to deal with, are still unsolved,
organocatalysis can serve as a real alternative in organic
chemistry in academia and industry. The palladium catalyzed
asymmetric allylic alkylation (AAA)38, mainly developed by Trost
and co-workers, is one of the most prominent and frequently used
asymmetric transition metal catalyzed reactions. As mentioned
before in paragraph 1.4, the AAA has a wide scope and allows access
to an incredible amount of asymmetric skeletons. The
organocatalytic AAA, the dynamic kinetic asymmetric transformation
(DYKAT) of Morita-Baylis-Hillman adducts, described by Lu et al.48,
is the first procedure tolerating a variety of carbon, oxygen,
nitrogen and phosporus nucleophiles in excellent
regioselectivities. In fact, Lu and co-workers are the first who
established an organocatalytic allylic alkylation with carbon
nucleophiles, when dimethyl malonate was used a ee of 51% was
obtained. This enantioselectivity is moderate, leaving room for
improvement. During this master research project we wanted to
contribute, and further explore the potent and exciting research
area of organocatalysis. We became interested in the
organocatalytic allylic nucleophilic substitution of MBH adducts
for the reasons described before, and wanted to investigate the
further potential of this reaction. Since Lu and co-workers have
shown that 1,3-di-carbonyl entities easily can act as
pro-nucleophiles, we were interested whereas via C-C bond forming
process also quartenary stereocenters could be constructed. We
wanted to expand the organocatalytic allylic substitution by using
chiral trisubstituted carbon nucleophiles yielding in one step
vicinal quaternary and tertiary stereocenters (paragraph 1.6)
assembled MBH-adducts. In literature chiral trisubstituted carbon
nucleophiles, like ethyl-phenyl-cyanoacetate, are used frequently
to construct all-carbon or heteroatom quaternary stereocenters.
MBH-adducts are, as discussed before in paragraph 1.3, valuable
synthons in various syntheses making this procedure even more
attractive. Moreover, we wanted to construct a β-isocupreidine
catalyst with a C6’ thiourea motive. This thiourea motive,
discussed in paragraph 1.2.1, is a much better hydrogen bond donor
compared to a C6’ hydroxyl group and therefore it can lead to
higher enantioselectivities in the organocatalytic allylic
nucleophilic substitution with carbon nucleophiles.
2.2 Catalyst synthesis
O
B
o
c
+
(
7
)
b
-
I
C
,
2
0
m
o
l
%
O
M
e
O
O
M
e
O
1
e
q
1
.
2
e
q
T
o
l
u
e
e
n
0
.
0
5
M
1
2
h
,
r
t
O
M
e
O
O
M
e
O
C
O
O
E
t
C
O
O
E
t
(
8
)
R
1
E
W
G
L
G
R
1
*
E
W
G
N
u
R
1
E
W
G
R
1
E
W
G
X
R
3
P
d
[
P
d
]
X
R
3
N
u
L
G
(
X
=
P
,
N
)
P
d
-
c
a
t
a
l
y
z
e
d
a
l
l
y
l
i
c
s
u
b
s
t
i
t
u
t
i
o
n
O
r
g
a
n
o
c
a
t
a
l
y
t
i
c
a
l
l
y
l
i
c
s
u
b
s
t
i
t
u
t
i
o
n
N
N
O
(
2
a
)
O
M
e
N
O
R
N
O
P
h
O
B
o
c
C
O
O
M
e
P
h
*
C
O
O
M
e
2
a
,
b
-
I
Q
D
(
2
0
m
o
l
%
)
t
o
l
u
e
n
e
,
r
t
P
h
C
O
O
E
t
b
-
I
C
P
D
b
-
I
Q
D
C
N
1
a
R
=
H
R
=
M
e
<
5
%
c
o
n
v
a
f
t
e
r
1
4
d
P
h
O
B
o
c
C
N
P
h
*
C
N
2
a
,
b
-
I
C
P
D
(
2
0
m
o
l
%
)
t
o
l
u
e
n
e
,
-
2
0
º
C
,
4
8
h
P
h
C
O
O
E
t
C
N
1
4
9
5
%
y
i
e
l
d
,
<
2
%
e
e
6
'
3
a
1
5
To confirm the results described by Lu et al., we first started
the synthesis of the catalyst β-isocupreidine. To date, the most
convenient and high yielding synthesis of β-isocupreidine (2) was
reported by Hoffman11 and Hatakeyama et al.17 β-Isocupreidine is
formed in one step from quinidine (1) under highly acidic
conditions. This process comprises a acid-induced
cyclo-isomerization via a carbocation mechanism (Fig. 24). First,
the vinyl moiety is protonated by HBr, leading to a secondary
carbocation. This is followed by a 1,2-hydrogen shift, because a
tertiary carbocation is more stable then a secondary. Next, attack
of the C9 hydroxyl group on the tertiary carbocation takes place,
leading to cyclization to an oxo-aza-twistane. In addition, in situ
demethylation occurs, leading to a bi-functional catalyst. Similar
work-up procedures were used as described by Hatakeyama and
co-workers, although for an analytically pure batch of
β-isocupreidine, the compound was subjected to re-crystallization
and after purification, the batch was once again subjected to
column chromatography. The obtained yield was similar to what is
described by Hatakeyama et al. (61% yield). This reaction suffers
unfortunately from side-product formation, a plausible option is
likely to be cyclization via the secondary carbocation
intermediate. Next, we started the synthesis of the β-isocupreidine
catalyst, equipped with a strong Brøndsted acid thiourea-moiety
(Fig. 26). We envisaged to synthesize the target structure,
starting from β-isocupreidine via a similar strategy as reported by
Hiemstra et al.15. The next envisioned steps included, in chronical
order, a C6’OH triflation, a palladium catalyzed Buchwald amination
of the triflate and subsequent hydrolysis. Once the synthesis of
C6’-NH2 functionality was achieved, we envisioned to react the
C6’NH2 with 3,5-bis-trifluorophenyl-isothiocyanate, yielding the
target structure. We started our synthesis from pure
β-isocupreidine and performed the triflation step of the C6’
hydroxyl group with N-phenyl-bis(trifluormethane sulfonimide)
catalyzed by a
R
1
O
B
o
c
C
O
O
M
e
R
*
C
O
O
M
e
b
-
I
C
P
D
(
2
0
m
o
l
%
)
t
o
l
u
e
n
e
*
E
t
O
O
C
C
N
9
a
-
f
R
2
E
t
O
O
C
C
N
R
2
+
1
0
a
-
b
1
1
a
-
f
R
1
P
h
(
9
a
)
2
-
M
e
C
6
H
4
(
9
b
)
3
-
C
l
C
6
H
4
(
9
c
)
4
-
N
O
2
C
6
H
4
(
9
d
)
2
-
n
a
p
h
t
y
l
(
9
e
)
3
-
B
r
C
6
H
4
(
9
f
)
R
2
P
h
(
1
0
a
)
M
e
(
1
0
b
)
catalytic amount (10 mol%) of DMAP. The
(
R
)
C
O
O
R
b
-
I
C
P
D
(
2
0
m
o
l
%
)
t
o
l
u
e
n
e
,
7
2
h
,
-
2
0
º
C
(
R
)
P
h
C
O
O
E
t
9
f
C
N
+
1
0
a
1
1
f
(
2
e
q
u
i
v
.
)
(
1
e
q
u
i
v
.
)
(
S
)
O
B
o
c
C
O
O
M
e
9
f
+
B
r
B
r
8
0
%
e
e
9
0
%
e
e
reaction was stirred for 6h in DCM at reflux. Flash
chromatography afforded (3) as a pure compound in 47% yield. Next,
we subjected (3) to a palladium catalyzed Buchwald amination in
THF. The reaction went smoothly overnight at reflux conditions and
the crude reaction mixture was subjected to flash chromatography.
Compound (4) was obtained as pure compound in 76 % yield. The
C6´-NH2 was obtained via hydrolysis of the imine with citric acid.
The reaction went without problems and compound (5) was obtained as
a single product in 81% yield. The final step of the synthesis
includes a nucleophilic addition of the free amine to the
electrophile 3,5-bis-trifluoro-phenyl-isothiocyanate. The
substrates were stirred in THF and were allowed to react for 20
min. During the reaction, the product precipitated from the
reaction mixture as a white solid. Compound (6) was obtained as a
single product in 69% yield. Meanwhile, the synthesis of the
catalyst was reported by Deng et al. The results reported by Deng
matched with our results and observations. In order to examine the
bi-functional character of β-isocupreidine (2), which was shown to
be fundamental in the direct Baylis-Hillman reaction, we have
decided the synthesize β-isoquinidine (2a). This organocatalyst has
a identical molecular skeleton as (2) but now the bi-functional
character is removed from the catalyst. The synthesis of the
catalyst was accomplished by using sodium hydride and methyl
iodide.
Ph
(R)
Nu
COOMe
P
h
O
B
o
c
C
O
O
M
e
P
h
*
C
O
O
M
e
b
-
I
C
P
D
(
2
0
m
o
l
%
)
t
o
l
u
e
n
e
,
r
t
,
4
8
h
.
*
+
O
O
O
E
t
O
C
O
O
E
t
1
2
1
3
2.3 Preliminary experiments and optimization
H
C
O
O
M
e
B
r
+
O
H
Q
D
(
N
R
3
)
D
C
M
,
r
t
,
2
4
h
H
C
O
O
M
e
N
+
R
3
B
r
-
O
M
e
O
O
P
h
C
O
O
M
e
N
H
T
s
P
h
C
O
O
M
e
N
H
T
s
a
b
In order to check the results reported by Lu; we first wanted to
start a reaction with dimethyl malonate and Morita-Baylis-Hillman
carbonate (7). Therefore we needed to synthesize the MBH carbonate.
Since the synthesis of the MBH carbonate was not reported by Lu, we
had planned to synthesize the MBH alcohol via an adapted procedure
of Aggarwal et al56. and subsequently the Boc protection via
procedure Trost et al. (Fig. 28)
P
h
O
C
O
O
M
e
N
H
T
s
O
P
h
*
O
A
c
C
O
O
M
e
(
D
H
Q
D
)
2
P
H
A
L
T
H
F
/
H
2
O
P
h
C
O
O
M
e
N
R
3
N
a
H
C
O
3
P
h
O
A
c
C
O
O
M
e
P
h
O
H
C
O
O
M
e
The procedure of Aggarwal represents a simple neat MBH reaction
between benzaldehyde and ethyl acrylate, catalyzed by 50 mol%
DABCO. 0.75 eq. of methanol was added as an additive to the
reaction mixture, because of the hydrogen bond donor capabilities
to zwitterionic species 2 (paragraph 1.3.1) of methanol, resulting
in rate enhancement. The MBH alcohol was obtained after
flash-chromatography in a yield of 83% (6.4 g.). Next, the Boc
protection was performed of the MBH alcohol with Boc-anhydride.
Catalytic amount of DMAP (5 mol%) was used and the reaction was
left stirring for 1h, the reaction mixture was purified by flash
chromatography, yielding compound (7) as a colourless oil in 42%
yield. The yield was somewhat disappointing, probably due to a
short reaction time (concluded from other experiments) or by attack
of DMAP on the product and consequent liberation of the Boc
activating group. Subsequently, we repeated the experiment (Fig.
29) reported by Lu to confirm the level of enantioselection and
yield. The reaction was performed at a 0.1 mmol scale of MBH
carbonate and was left stirring overnight, a drop of the reaction
mixture was filtered to remove the catalysts, the filtrate was
analyzed by chiral HPLC. And indeed, the results reported by Lu et
al. were reproducible, the level of enantioselection was 53% and
the chemoselectivity was 97%. Next, we examined the role of the
acrylate function in the carbonate. We made a MBH carbonate like
(7) but
O
H
C
O
O
E
t
employed with a methyl ester instead of an ethyl ester electron
withdrawing group. Carbonate (9) was synthesized in a similar way
as (7), although higher in a higher yield, the compound (9) was
obtained in a yield of 67% over two steps. The catalysis experiment
was repeated with carbonate (9), and HPLC analysis revealed that
the level of enantiodiscrimination was changed slightly; we
observed an ee of 63% instead of 51% in case of (7). We found that
the enantioselection process shows a concentration effect. We found
an optimum at 0.05 M, a similar concentration as used by Lu and
co-workers. A decrease or increase in concentration of the reaction
mixture gave lower levels of asymmetric induction. Employment of
diisopropyl malonate as pronucleophile gave slightly lower levels
of asymmetric induction, 58% ee. Subsequently, we investigated the
Brønsted acid functionality of the catalyst in the organocatalytic
allylic alkylation. The thiourea derived β-isocupreidine catalyst
(6) was tested in a catalysis experiment under similar conditions
as β-isocupreidine itself. The reaction went to completion within
24 h, and had a lower level of asymmetric induction, 41% ee.
Employment of other solvents (increased polarity) resulted in lower
levels of asymmetric induction and disordered product formation.
These results where in comparison as described by Lu, toluene
remains the solvent of choice. We decided to lower the catalyst
loading of (6) to 10 mol%, leading to a decreased polarity of the
reaction medium. We where delighted to observe a significant higher
ee of 58%. This result supports the idea that the enantioselection
process of the organocatalytic allylic alkylation is favoured by an
apolar reaction medium. Hence, we lowered the reaction temperature.
The reaction with 10 mol% of (6) at -20 ºC gave almost no
asymmetric induction, 14 % ee. Interestingly, β-isocupreidine (2),
gave 72% ee., although the reaction rate was not practical and did
not go to completion after almost a week. These findings may
suggest a reversed temperature dependency of Brønsted acid
activation. After we had confirmed the results reported by Lu et
al. and examined the role of the thiourea Brønsted acid moiety, we
started to investigate the
O
C
O
O
E
t
O
O
chiral compound ethyl-phenyl-cyanoacetate (10) as
pro-nucleophile in the organocatalytic allylic alkylation.
Employment of this chiral nucleophile should theoretically result
in four different compounds, two diastereoisomers with their
corresponding enantiomers. These four compounds complicate analysis
by chiral HPLC, a prerequisite for enantiomeric excess
determination being baseline separation. Therefore, we started
first an experiment, by using 1 eq of carbonate (9) and 1 eq. of
pro-nucleophile (10) catalyzed by the a-chiral catalyst DABCO (50
mol%). Fortunately, the reaction went to completion in less then 30
min. Removal of the catalyst by a short filtration over silica and
analysis of the mixture by chiral HPLC revealed that the 4
different
C
O
O
E
t
M
e
O
O
M
e
O
O
compounds were separable. Next we started a similar catalysis
experiment as in the case for dimethyl malonate, but we replaced
dimethyl malonate by (10). To our delight the reaction went to
completion in 18h. (Fig. 30) Analysis of the crude reaction mixture
revealed an enantiomeric excess of the main diastereoisomer of 68%.
For the
N
O
O
R
R
=
H
,
M
o
r
p
h
i
n
e
R
=
C
H
3
,
C
o
d
e
i
n
e
determination of the diastereomeric ratio we used 1H-NMR and we
observed a ratio of 3:1. Lowering the reaction temperature to
-20ºC, gave an improvement of both diastereo- and
enantioselectivity, dr 4:1 and 84% ee. However the reaction rate
was not practical roughly 30% conversion in 72h. Moreover, there
was an other serious drawback; we could not separate the remaining
amount of pro-nucleophile (10) from the product (11) by column
chromatography. Consequently, we started two similar experiments at
-20ºC; one experiment (a) with one equivalent carbonate (9) and 5
equivalents pro-nucleophile (10) and one experiment (b) with
reversed ratios of the starting substrates, 5:1 respectively. We
were delighted to observe a strong rate enhancement in both cases,
experiment (b) went to completion after 22h. The levels of
diastereomeric and enantiomeric control were similar for this
experiment compared to earlier experiments. There was an important
additional advantage observed in experiment (b), we could isolate
the product after column chromatography. For further experiments we
decided to make a compromise between reaction rate, atom economy
and stereo chemical considerations of the organocatalytic allylic
alkylation. We fixed the amount of substrate for further
experiments, two equivalents of carbonate (9) and one equivalent of
pro-nucleophile (10). During the optimization of the
organocatalytic allylic alkylation we found that complete removal
of Boc-anhydride is essential for obtaining high enantiomeric
excesses. This is most likely explainable in terms of Boc
protection of the catalyst, catalyst poisoning.
2.4 Results
2.4.1 Substrate scope
M
e
O
O
C
O
O
O
O
M
e
O
O
H
[
s
c
]
R
3
R
2
R
1
[
s
c
]
=
A
=
R
1
=
O
H
,
R
2
=
C
H
3
,
R
3
=
C
H
2
O
H
B
=
R
1
=
O
H
,
R
2
=
C
H
2
O
H
,
R
3
=
C
H
3
E
=
[
s
c
]
=
O
H
We decided to continue our examinations with the employment of
different electrophile and pro-nucleophile reaction partners.
Therefore we needed first to synthesize various
Morita-Baylis-Hillman carbonates (as depicted in table one) via the
procedures of Aggarwal and Trost. The synthesis of the
MBH-substrates went without significant problems and generally in
moderate to good yields (47-83%). The pro-nucleophiles were
commercially avaiable. All the reactions were performed as
discussed in the end of paragraph 2.3. namely; two equivalents of
carbonate, one equivalent of pro-nucleophile, 20 mol%
β-isocupreidine and at a concentration of 0.05 M. In general, what
be can be concluded from table 1 is that compounds 11a-f were
obtained in high yields and good enantioselectivities. A closer
look at the table reveals the sensitivity of the pro-nucleophile
with respect to the selected carbonate substrate, hindered
substrates (10b and 10d, entries 2 and 4) required higher
temperatures to obtain satisfying reaction rates; fortunately, the
level of enantioselection was not negatively affected. A low
enantiomeric excess and diastereomeric excess was observed for
substrate 9d, possibly due to its high reactivity towards conjugate
addition possibly, the electron withdrawing p-nitro group
interferes with the hydroxyl functionality of the catalyst.
Entry
Product
T [ºC]
t [h]
Yield [%]b
drc
ee [%]d
1
COOMe
PhCOOEt
CN
11a
-20
48
94
4:1
83
2
COOMe
PhCOOEt
CN
11b
0
96
95
4:1
79
3
COOMe
MeCOOEt
CN
Cl
11c
-20
72
95
1.4:1
80
4
COOMe
PhCOOEt
CN
O
2
N
11d
-20
48
95
1.1:1
16
5
COOMe
PhCOOEt
CN
11e
20
24
66e
4:1
85
6
COOMe
COOEt
Br
Ph
CN
11f
-20
72
95f
3:1
80
a Conditions: 0.6 mmol 9, 0.3 mmol 10, 0.06 mmol β-ICPD in 6 mL
toluene.
b Isolated yield (mixture of diastereomers).
c Determined by 1H-NMR analysis of the crude reaction
mixture.
d ee of the major diastereoisomer determined by chiral HPLC.
e Compound 11e was obtained as a pure diasteromer.
f Reaction performed on 9.0 mmol of 9f
An important prerequisite of an asymmetric methodology is the
possibility to upgrade the optical purity, if the levels of
enantioselection are not excellent. Since some adducts were
obtained as crystalline solids after chromatography, we run a
reaction on a gram scale with the aim to upgrade the optical purity
of the product via recrystallization. Hence, compound 9f (3.3 g,
9.0 mmol) was reacted with cyanoacetate 10a (0.78 mL, 4.5 mmol) to
afford, after column chromatography, adduct 11f in 80% ee and 95%
yield (entry 7). A single recrystallization from cyclohexane
afforded compound 11f (59% yield, calculated on cyanoacetate 10a)
with 98% ee as a pure diastereomer. In addition, a larger scale
reaction between compound 9a (0.88 g, 6.0 mmol) and 10a (0.52 mL,
3.0 mmol) yielded adduct 11f after column chromatography in 86% ee
and 95% yield. A single recrystallization from cyclohexane afforded
compound 11f (63% yield, calculated on cyanoacetate 10a) with 99%
ee as a pure diastereomer. Instead of employment of a prochiral
trisubstituted cyanoacetate as pro-nucleophiles, we investigated
the use of prochiral trisubstituted 1,3-dicarbonyl moieties. We
decided to use ethyl 2-oxocyclohexanecarboxylate as reaction
partner (Fig. 31). The mixture was allowed to react for 48 h at
room temperature and the reaction was performed under similar
conditions as used in table 1 (Fig. 31). Analysis of the crude
reaction mixture revealed full conversion of the pronucleophile,
yielding the
C
O
O
M
e
C
O
O
E
t
O
postulated product. We were glad to observe an excellent
diastereomeric ratio of >98:2 however the enantiomeric excess
was moderate: 61% ee. Purification by column chromatography
afforded 13 as a single diastereoisomer. Nevertheless, we were not
able to determine the yield since the resulting compound 13 was not
stable. The compound was prone to decomposition in CDCl3.
Employment of ethyl 2-methyl-3-oxobutanoate as pro-nucleophile gave
immediately disappointing results and we were not able to isolate a
pure compound.
C
6
H
1
4
C
O
O
R
C
6
H
1
4
O
C
O
O
H
O
H
O
H
H
2
N
O
H
O
O
2.4.2X-Ray analysis
O
H
R
E
W
G
+
R
*
O
H
E
W
G
B
a
s
e
M
e
O
O
C
O
O
H
C
O
O
E
t
N
N
O
N
H
S
N
H
F
3
C
C
F
3
N
N
O
N
H
2
Since we could crystallize two products in pure form, we
submitted the crystals for X-ray analysis. From these crystals we
could assign unambiguously, the absolute and relative configuration
of compound 11f. (Fig. 32) Both stereocenters have the R
configuration. From compound 11a it was only possible to assign the
relative configuration. The absolute configuration of compound 11a
could not be reliably determined because of the lack of a heavy
atom. The relative configuration of this compound was analogous to
compound 11f, (Fig. 34). During column chromatography of the
reaction mixture of compound 11f, we could recover the excess of
the starting material used. Interestingly, HPLC analysis of the
recovered starting material (9f) gave evidence for a kinetic
resolution effect. Compound 9f was isolated in 90% ee.
Recrystallization afforded enantiopure crystals (47% yield based on
10a). X-Ray analysis revealed the absolute configuration, S (Fig.
35). From this result we can conclude that the catalyst has a
preference for a MBH-carbonate bearing the R configuration. As
suggested by Kim and coworkers,42 who observed a similar effect,
this can be explained in terms of a kinetic resolution in the first
step. This process, however, does not affect the enantioselectivity
of the second conjugate addition generating the C-C bond. To
confirm this statement we examined a catalytic experiment of 1
equivalent of 9a with 2 equivalents of 10a at room temperature
(hence reversing the reagents ratio): after 24 h, 9a was completely
converted to 11a with similar stereoselectivity (68% ee, 3:1 dr),
showing that both enantiomers of the MBH carbonate undergo Michael
addition although with different rates, followed by elimination of
the leaving group leading to the same intermediate.
N
N
O
O
S
O
O
F
F
F
N
N
O
O
H
2.4.3 Mechanistic considerations
The importance of employment of bi-functional catalysts in
organocatalysis, for obtaining high(er) enantioselectivities and
reactivities, has been shown in numerous examples. As well in the
asymmetric Morita-Baylis-Hillman reaction, the bi-functional
character of β-isocupreidine was shown to be fundamental. We
believe that the bi-functional character of the catalyst is also
essential in the organocatalytic allylic alkylation of MBH
carbonates. In order to confirm this assumption we started a
catalytic experiment with β-isoquinidine (2a) (β-IQD) as the
catalyst. Indeed, the role of the C6’-OH of β-ICPD is crucial for
obtaining high enantioselectivities. We observed a drastically
lower enantiomeric excess of 30%. Furthermore, less than 5%
conversion was observed after two weeks at room temperature,
suggesting that the C6’-OH of β-ICPD is also crucial for activation
of the system. Additional evidence was acquired via substrate 14,
featuring a cyano group, a poorer hydrogen bond acceptor, instead
of a methyl ester. We started a similar experiment as in case of
the other allylic substitution experiments (table 1) and MBH
electrophile 14 underwent the desired reaction (Fig. 36). As
result, product 15 was obtained in high yield but no asymmetric
induction was observed (Scheme 4).
N
N
O
N
O
H
C
O
O
M
e
O
H
C
N
On the basis of all these observations, we propose a tentative
hypothesis to rationalize our experimental results (Scheme 5).
First, substrate 9a undergoes a conjugate addition to form adduct A
(fig. 22, paragraph 1.5) . Subsequently, elimination of the OBoc
group, leading to the formation of CO2 and tert-butoxide anion
provides Michael acceptor (B) (fig. 22, paragraph 1.5). We believe
that this irreversible reaction step is responsible for the
observed kinetic resolution. As shown in the experiment with
β-isoquinidine, the presence of the C6’-OH in the catalyst is
required for activation of the ester prior to conjugate addition.
As already proposed by Lu, the tert-butoxide anion deprotonates
cyanoacetate 10a which, in turn, attacks the -unsaturated
intermediate (β-ICPD and MBH carbonate). Probably, an
intramolecular hydrogen bond between the phenolic OH and the ester
moiety is responsible for the face shielding conferring
stereoselectivity to the reaction; a DFT-minimized (Fig. 37)
structure B (fig. 22) is supporting this hypothesis. Elimination of
the catalyst from intermediate C liberates alkylated product 11a,
closing the catalytic cycle.
O
H
C
O
O
M
e
C
l
O
H
C
O
O
M
e
O
2
N
O
H
C
O
O
M
e
B
r
O
H
C
O
O
M
e
O
H
C
O
O
M
e
O
C
O
O
M
e
O
O
O
C
O
O
M
e
O
O
2.5 Conclusions
In conclusion, we have developed new methodology that allows
access to highly functionalized MBH adducts, featuring two vicinal
stereocenters, one of them bearing four carbon substituents. These
MBH-adducts can be created via a one step organocatalytic allylic
alkylation of MBH carbonates and are obtained in excellent yields
and chemo/enantio/ diastereo-selectivities. Moreover, this is the
first, metal free, one-step creation of vicinal quaternary and
tertiary stereocenters that is not completely explainable by a
conjugate addition mechanism. The methodology could be extended to
a broad scope of MBH aryl electrophiles, ranging from hindered to
activated substrates. The role of the pro-nucleophiles was also
investigated; compound 2a and 2b react with similar levels of
asymmetric induction. However compound 2b was obtained in a lower
diastereoselectivity, a plausible explanation being that
steric-bulk is vital for obtaining high diastereoselectivities.
Subsequently, we have shown for two examples that optically pure
compound could be obtained, making this reaction practically
executable. The crystals obtained for compounds 9f and 11f allowed
assignment of the absolute configuration. For compound 11a only the
diastereoselectivity could be determined. During our investigations
we found evidence for the reaction mechanism. The reaction occurs
most likely via two mechanisms, starting with a kinetic resolution
followed by enantioselective attack of the chiral nucleophile. In
addition, we showed that the carbonate that bears the R
configuration, preferentially reacts with the catalyst. We also
demonstrated the involvement of the OH-functionality of the
catalyst in the catalytic cycle. The carbonyl moiety is vital to
obtain highly enantiomerically enriched compounds. Future
investigations could be aimed at broadening the scope of this
transformation by employing alkyl instead of aryl electrophiles.
Further design of catalysts that catalyze this re
