Construction of Adjacent Quaternary and Tertiary Stereocenters
via an Organocatalytic Transformation of Morita-Baylis-Hillman
Carbonates
OBoc
CN
COOMe
+
R
COOEt
R'
O
N
N
R
CN
*
*
COOEt
COOMe
R'
OH
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.
2
Table of Contents
Summary ___________________________________________________________ 4
List of abbreviations __________________________________________________ 5
Chapter 1; Introduction ________________________________________________ 7
1.1 Organocatalysis _________________________________________________________ 7
1.2 Cinchona Alkaloids ______________________________________________________ 9
1.2.1 Bi-functional cinchona alkaloids ............................................................................. 12
1.3 Morita-Baylis-Hillman (MBH) Reaction ___________________________________ 14
1.3.1 The Morita-Baylis-Hillman mechanism.................................................................. 15
1.3.2 Morita-Baylis-Hillman Adducts .............................................................................. 16
1.4 Dynamic Kinetic Asymmetric Transformation (DYKAT) of Morita-Baylis-Hillman
Adducts _________________________________________________________________ 19
1.5 Functionalization of Morita-Baylis-Hillman Adducts via a Tandem SN2’-SN2’
Mechanism _______________________________________________________________ 21
1.6 All-carbon Quaternary Stereocenters ______________________________________ 25
Chapter 2; Allylic Nucleophilic Substitution of Morita-Baylis-Hillman Carbonates 27
2.1 Goal _________________________________________________________________ 27
2.2 Catalyst Synthesis ______________________________________________________ 29
2.3 Preliminary Experiments and Optimization ________________________________ 32
2.4 Results _______________________________________________________________ 35
2.4.1
2.4.2
2.4.3
Substrate scope ................................................................................................. 35
X-Ray analysis ................................................................................................. 38
Mechanistic considerations .............................................................................. 40
2.5 Conclusions __________________________________________________________ 41
Samenvatting _______________________________________________________ 43
Acknowledgements __________________________________________________ 44
Chapter 3 Experimental _______________________________________________ 45
References _________________________________________________________ 70
3
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.
4
List of abbreviations
H2O:
water
CDCl3:
deutero-chloroform
CHCl3:
chloroform
DCM:
dichloromethane
CH2Cl2:
dichloromethane
EtOAc:
ethyl acetate
EI:
electron impact
Et2O:
diethyl ether
FAB:
fast atom bombardment
1
proton1 nuclear magnetic resonance
H NMR:
13
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
C NMR:
5
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-1yl)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
6
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.1 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 Fiske2, it is
no more then a few years ago that the potential of organocatalysis has been understood by the
scientific community. List and Barbas3 reported in 2000 a breakthrough in organocatalysis
7
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 hydratropate4. The seventies brought an other
milestone, Hajos and Parrish reported a L-proline catalyzed Robinson annulation in excellent
enantioselectivities5. Moreover, Wiechert reported an organocatalyic aldol reactions in good
enantioselectivities6. In the eighties, Wynberg and co-workers reported various 1,2 and 1,4
additions catalyzed by cinchona alkaloids7. 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.
The vast majority of (asymmetric) organic reactions can be explained by a nucleophile and
electrophile mechanism. Organocatalysts can be divided into
B S
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). S
For simplicity reasons, only the Lewis base and the Brønsted
B
B P
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
P
alkaloid, starts the catalytic cycle via a nucleophilic addition to,
or deprotonation of, the substrate (S). The resulting chiral
Fig 1 Simplified Lewis base
catalytic cycle
8
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 bifunctional 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 emerging8. 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 alkylations9.
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 10. 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.
9
3
3
4
N
1
OH
OH
9
9
1
N
8
8
N
1
N
6´
6´
R
Quinine (QN)
Cinchonidine (CD)
4
R
R=OMe
R=H
Quinidine (QD)
Cinchonine (CN)
Fig 2 The four most natural occurring cinchoa alkaloids
10
They are called pseudoenantiomers because they are “almost

enantiomeric pairs”. To date there are more then twenty different
O

cinchona alkaloid producing plants known, by far the most
important is the “Cinchona pubescens”. To date, more then thirty
HN
N
different kinds of cinchona alkaloids have been isolated and
R
characterised. The tree bark of the Cinchona pubescens can
contain over 50 % of the main four cinchona alkaloids which Quinicine
Cinchonicine
can be easily gathered, via extraction. The cinchona alkaloids
family forms a unique class of natural compounds and has found
R=OMe
R=H
Fig 3 Cinchona alkaloids used by
Pasteur
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.11 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 182012 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 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 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 synthesis13.
11
1.2.1 Bi-functional cinchona alkaloids
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, 14 C9dimerized 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
OR
the Nobel prize in chemistry in 2001 for his
N
contribution to asymmetric synthesis. The cinchona
9
Lewis Base
dihydroxylation ligands formed a substantial part of N
his work. Other alterations, different than at the C9
position of the cinchona alkaloid, usually occur at the
6´
OH
Brønsted acid
C6’-position of quinine (QN) and quinidine (QD).
When this position is changed from a methoxy into a
Fig 4 Bi-functional organocatalyst
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 cupreidines15. 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 published16 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
12
3) a C6 or C9 thiourea equipped quini(di)ne 16
Constrained oxaza-twistanes (Fig. 5), are
a class of catalysts whose the synthesis
3
has been mainly explored by the group
N
of Hofmann. These compounds posses
9
9
special characteristics, due to the extra N
constrained ring between C9 and C3, in
β-isocupreidine,
N
OH
6´
respect to other cinchona alkaloids.
Especially
N
O
O
(IUPAC
6´
OH
Fig. 5 β-isocupreidine
name; 3R, 8R, 9S-10, 11- Dihydro-3,9epoxy-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 reaction17(see later) and the
asymmetric aza-MBH reaction between the strongly activated Michael acceptor 1,1,1,3,3,3hexa-fluoroisopropyl acrylate and aryl-imines18. β-isocupreidine has also been applied in the
construction of quaternary stereocenters51f. The enantio-complementary catalyst of βIsocupreidine
has
recently
been
synthesized19. Although the synthesis
3
involves 19 steps, now there is access to
R2
4
both enantiomers of a product. A second
N
9
superior
catalyst
class
has
been
introduced by Deng and co-workers. C6’
8
1
N
6´
sc =
R1
catalysts, again easily accessible, gave BnCPD
PHNCPD
excellent levels of enantio- and C6´ ThQD
C9 ThQD
diastereo-discrimination in a broad
H
N
CF3
S
R1
hydroxyl and C9 alkylated cupreidine
H
N
R1 = OH
R1 = OH
R1 = sc
R 1= H
R2 = Bn
R2 = Phn
R2 = Bn
R2 = sc
CF3
compilation of conjugate additions20. In
this
elegant
collection
of
papers
Fig 6 Some frequently used quinidine derrived
organocatalysts
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
13
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 C921 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)22.
1.3 Morita-Baylis-Hillman (MBH) Reaction
The Morita-Baylis-Hillman reaction was first
O
described in 1968 by Morita23; he observed a
phosphine-derivative catalyzed addition of an R
H
+
EWG Base
OH
R

EWG
aldehyde to an acrylate, yielding densely
funtionalised
β-hydroxy-α-methylene
esters
Fig 7 Some frequently used quinidine derrived
organocatalysts
(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. Hillman24. 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-BaylisHillman is recognized now as an important carbon-carbon bond forming reaction like the
aldol, Grignard, Friedel-Crafts, Heck and Suzuki reaction25. 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
14
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
stereocenter26 and rate. Recently, Verkade and co-workers have made an impressive step
forward27. 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-hexafluoroisopropyl acrylate. Manifold chiral catalysts have been tried28, 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 used29.
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-workers30 it was assumed that the rate limiting step
15
O
H
O-
1)
OR
H
R3+N
A
NR3
O
Ph
H
-
O
3)
OR
B
OR
1
O
Ph
R3+N
PhCHO
2)
Ph
O
H
R3+N
O
H
-
H
O
H
E
R
A
OR
2
Fig 8 Morita-Baylis-Hillman mechanism
(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 Eberlin31, 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-workers32, 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.
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
16
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
Ph
OH O
Lactamization
Baker´s Yeast
R
OH
HO
OH
R
C9H19
HO
O
N
EWG
O
OH
Epoxidation
Dihydroxylation
R
EWG
R = mnitroO phenyl
Hydrogenation
Aminohydroxylation
OH
OH
COMe
N
H
OH
R
EWG
OH
NHTs
Fig 9. Transfromations of Morita-Baylis-Hillman alcohols
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 adducts33
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 reported 25.
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
17
al.34 (Fig. 10), Pinnatoxin A by Kishi et al.35(Fig. 11) and Salinosporamide A by Corey et
al.36(Fig12).
OH
COOR
C6H14
O
O
OH
COOH
C6H14
H2N
O
OH
Fig 10 (-)-Mycestericin E
H
H
O
TESO
O
O
NHAlloc
O
O
H
O
HO
+
O
H
O
O
H
MsO
CO2tBu
HN
H
O
O
H
CO2OH
OTBS
Fig 11 Pinnatoxin A
O
BMP
COOMe
N
OBn
O
Me
O
BMP
COOMe
N
OBn
Me
OH
O
OH
O
H
N
Me
O
Cl
Fig 12 Salinosporamide A:
18
1.4 Dynamic kinetic Asymmetric transformation (DYKAT) of MoritaBaylis-Hillman adducts
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 adducts37. This deracemization reaction procedure forms one out of
the at least five enantiodiscrimination mechanisms in the famous palladium catalyzed
asymmetric allylic alkylation (AAA)38. 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
R
OMoc
EWG
+ NuH
Pd

Nu
R
Nu
EWG
or
R
EWG
DYKAT mechanism
can be explained by
the next illustrative
Fig 13 Dynamic kinetic asymmetric transformation” (DYKAT) of MoritaBaylis-Hillman adducts
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-allylintermediate 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)39. 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
19
methodology, examples being the total synthesis of (+)-Hippospongic acid A40(Fig. 15),
morphine, codeine38b (Fig. 14), and Furaquinocin’s A, B, and E41 (Fig. 16).
OR
O
MeOOC
O
N
R=H, Morphine
R=CH3, Codeine
Fig 14 R=H Morphine, R=CH3 Codeine
O
O
Fig 15 (+)-Hippospongic acid A
[sc]
R1
R2
[sc]=
MeO
OH
R3
O
A= R1=OH, R2=CH3, R3=CH2OH
B= R1=OH, R2= CH2OH, R3=CH3
E= [sc]=
OH
Fig 16 Furaquinocin’s A, B, and E
20
1.5
Functionalization of Morita-Baylis-Hillman adducts via a tandem
SN2’-SN2’ mechanism
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 MBHalcohols, 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
OAc
Ph

COOMe
(DHQD)2PHAL
THF/H2O
Ph
COOMe
NR3
OAc
OH
NaHCO3
Ph
COOMe
Ph
COOMe
Fig 17 Organocatalytic allylic substitution SN2’-SN2’ mechanism
carbon/nitrogen nucleophiles are used, an allylic alkylation or aminaton. In 2002, Kim and coworkers42 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
21
reacts faster with one enantiomer of the starting material. Since the
O
obtained enantioselectivities obtained can not be only explained by a
kinetic resolution step, the author proposed that during the second step
O
Ph
NHTs
COOMe
there is additional asymmetric induction. Supplementary, Kim and coworkers reported in 2002 similar reactions relying on again SN2’-SN2’
mechanism. MBH-acetates were reacted with a sub-stoichiometric
Fig 18 N-p-toluenesulfonimide derived MBH
adduct
amount of DABCO and various pro-nucleophiles. When pronucleophiles, such as tosylamide, methyl-sulfonamide,
phthalimide, benzotriazole were used, the allylic
Ph
NHTs
COOMe
44
year reported by Orena and co-workers . In this
NHTs
a
substitution (amination) products were obtained in
moderate yields (40-91%)43. Similar work was in that
COOMe
Ph
Fig 19 a)
product
b
SN2’-SN2’ product b) Michael
elegant paper is shown the sensitivity of the MBH-adducts towards bases. When N-ptoluenesulfonimide 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 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-ptoluenesulfonimide. MBH adduct. Basavaiah co-workers45 reported a similar methodology in
order to obtain enantiomerically enriched Morita-Baylis-Hillman adducts. Again the
methodology relies on a allylic substitution tandem mechanism (Fig. 20). First the
H
COOMe
Br
+
QD (NR3)
OH
DCM, rt, 24 h
H
COOMe
+
O
-
N R3 Br
O
OMe
Fig. 20 Basavaiah’s chiral leaving group methodology
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.
22
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-butenolides46. 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
acetates47. 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-workers48 have described a β-IC catalyzed
nucleophilic
O
O
O
O
OEt
Beta-IC
Toluene, rt, 12 h
Nu
O
O
OEt
+
OEt
Nu
Fig. 21 Organocatalytic allylic nucleophilic substitution of Morita-Baylis-Hillman carbonates
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 CO 2
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
23
expected product in a moderate enantioselection (51% ee), high SN2-SN2’ ratio
(chemoselectivity) and high yield.
OBoc O
Ph
OH
OMe
OMe Ph
O H
1a
O
OBoc
N
N
Nu
Ph
*
N
N
-ICPD
A
O
-CO2
OMe
3a
t-BuOH
t-BuO
OMe Ph
O H
O
*
N
N
C
OMe
O H
Nu
Nu
(E)
O
NuH
2a
Ph
N
N
B
Fig. 22 Mechanism of the organocatalytic allylic nucleophilic substitution of Morita-Baylis-Hillman
carbonates
24
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 chemists49. 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 organocatalysis 1. 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.50 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
organocatalytic51.
25
3
R2
4
N
9
R1
R3
R2
R4
+
R4
NO2
Cat
1,2,3
R1
R2
8
1
N
NO2
6´
R1
R3
1 BnCPD
2 PHNCPD
3 CPD
R1 = OH R2 = Bn
R1 = OH R2 = Phn
R1 = OH R2 = OH
Fig. 23 Organocatalytic Michael addition leading to vicinal quaternary and tertiary stereocenters
26
Chapter 2 Allylic Nucleophilic Substitution of Morita-BaylisHillman Carbonates
2.1 Goal
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
Pd-catalyzed allylic substitution
38
(AAA) , mainly developed by
R1
Trost and co-workers, is one of
the
most
prominent
frequently
used
transition
metal
[Pd]
EWG
Pd
and
LG
asymmetric
catalyzed R1
Nu
EWG
LG
Nu
R1
*
EWG
reactions. As mentioned before
in paragraph 1.4, the AAA has a
wide scope and allows access to
an
incredible
asymmetric
amount
of
skeletons.
The
AAA,
the
organocatalytic
XR3
(X=P,N)
R1
EWG
XR3
Organocatalytic allylic substitution
Fig. 23 Palladium versus organocatalytic allylic substitution
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
27
1,3-di-carbonyl entities easily can act as pro-nucleophiles, we were interested whereas via CC 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 ethylphenyl-cyanoacetate, are used frequently to construct all-carbon or heteroatom quaternary
stereocenters52. 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.
28
2.2 Catalyst synthesis
To confirm the results described by Lu et al., we first started the synthesis of the catalyst β-
H
OH
OH
N
9
N
KBr-H3PO4
(1) N
1,2-hydrogen shift
N
100 oC, 5 d
6´
OMe
OMe
OH
O
N
N
cyclization
N
N
61%
(2)
demethylation
OMe
OH
Fig. 24 Mechanism of β-isocupreidine synthesis
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
O
secondary carbocation. This is followed by a 1,2-hydrogen
N
shift, because a tertiary carbocation is more stable then a
secondary. Next, attack of the C9 hydroxyl group on the N
tertiary carbocation takes place, leading to cyclization to an
NH
oxo-aza-twistane. In addition, in situ demethylation occurs,
leading to a bi-functional catalyst. Similar work-up procedures
S
NH
were used as described by Hatakeyama and co-workers,
although for an analytically pure batch of β-isocupreidine, the
F3C
compound was subjected to re-crystallization and after
Fig. 25 β-IC-Th (6)
CF3
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
29
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 thioureamoiety (Fig. 26). We envisaged to synthesize the target structure, starting from βisocupreidine 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 catalytic amount (10 mol%) of DMAP. The 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
O
O
O
N
N
Ph-N-(OTf)2, 1.1 eq. N
N
6´
Pd(OAc)2, 10 mol% N
6´
DMAP 10 mol%,
DCM, reflux 6 h
OH
N
HN=CPh2,1.1 eq.
(+/-) BINAP, 10 mol%
Cesiumcarbonate 1.5 eq.,
THF, reflux 18 h
O
O S O
CF3
6´
N
Ph
(3) 47%
(2)
Ph
(4) 76%
THF/H2O
citric acid
O
O
N
3,5-CF3PhNCS,
1.05 eq.
N
6´
F3C
N
THF, 20 min.
NH
S
N
6´
NH2
NH
CF3
(6) 69%
Fig. 26 Synthesis of a β-isocupreidine equipped with C6’ thiourea moiety
(5) 81%
subjected to flash chromatography. Compound (4) was obtained as pure compound in 76 %
30
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.53 The results reported by Deng matched
with our results and observations. In order to examine the bi-functional character of βisocupreidine (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.
O
N
N
(2a)
OMe
Fig. 27 β-isoquinidine
31
2.3 Preliminary experiments and optimization
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.54 (Fig. 28)
The procedure of Aggarwal represents a simple neat MBH reaction between benzaldehyde
O
1) DABCO 50 mol%
MeOH 0.75 eq., 4 d
O
H
OEt
OEt
+
OBoc O
2) (Boc)2O 1.1 eq.
DMAP 5 mol%
DCM, 1h.
(7) 34 %
Fig. 28 Synthesis of a Morita-Baylis-Hillman Carbonate
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
O
OBoc
O
COOEt
+
MeO
C, 20 mol%
O
OMe
O
MeO
OMe
COOEt
Tolueen0.05 M
12 h, rt
1 eq
1.2 eq
(7)
Fig. 29 Organocatalytic allylic alkylation with dimethylmalonate
(8)
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
32
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 employed with a methyl
COOEt
ester instead of an ethyl ester electron withdrawing group. Carbonate (9)
CN
was synthesized in a similar way as (7), although higher in a higher yield,
(10)
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
OBoc O
gave slightly lower levels of asymmetric induction, 58% ee.
OMe
Subsequently, we investigated the Brønsted acid functionality of the
catalyst in the organocatalytic allylic alkylation. The thiourea derived
(9)
β-isocupreidine catalyst (6) was tested in a catalysis experiment under similar conditions as βisocupreidine 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, βisocupreidine (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
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
33
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 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
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
OBoc
+
1 eq
(9)
C, 20 mol%
CN
COOMe

Ph
COOEt
1.2 eq
(10)
Ph
CN
COOEt


COOMe
Tolueen0.05 M
12 h, rt
(11)
Fig. 30 Organocatalytic allyic alkylation with a pro-chiral cyano-acetate, leading to vicinal quaternary end
tertiary stereocenters
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.
34
2.4 Results
2.4.1 Substrate scope
We decided to continue our examinations with the employment of different electrophile and
pro-nucleophile reaction partners. Therefore we needed first to synthesize various MoritaBaylis-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 pnitro group interferes with the hydroxyl functionality of the catalyst.
Table 1 Substrate scope
EtOOC
OBoc
R1
R2
CN
*
COOMe
+
EtOOC
CN
R2
9a-f
10a-b
R1
Ph (9a)
2-MeC6H4 (9b)
3-ClC6H4 (9c)
4-NO2C6H4 (9d)
2-naphtyl (9e)
3-BrC6H4 (9f)
R2
Ph (10a)
Me (10b)
-ICPD (20 mol %)
toluene
R
*
COOMe
11a-f
35
Entry
Product
CN
Ph
T [ºC] t [h] Yield [%]b drc
ee [%]d
-20
48
94
4:1
83
0
96
95
4:1
79
-20
72
95
1.4:1 80
-20
48
95
1.1:1 16
20
24
66e
4:1
85
-20
72
95f
3:1
80
COOEt
1
COOMe
11a
CN
Ph
COOEt
2
COOMe
11b
CN
Me
COOEt
COOMe
3
11c
Cl
CN
Ph
COOEt
4
COOMe
11d
O2N
Ph
CN
COOEt
5
COOMe
11e
Ph
CN
COOEt
COOMe
6
11f
Br
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
36
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
O
O
OBoc
Ph
COOMe
OEt
+
COOEt

O
-ICPD (20 mol %)
Ph
COOMe
*
toluene, rt, 48 h.
12
13
Fig. 31 Organocatalytic allyic alkylation with 1-3 dicarbonyl moiety
under similar conditions as used in table 1 (Fig. 31). Analysis of the crude reaction mixture
revealed full conversion of the pronucleophile, yielding the 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.
37
2.4.2 X-Ray analysis
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
Fig. 32 ORTEP drawing of product 11f
Ph
CN
COOEt
(R)
(R)
-ICPD (20 mol %)
+
10a
9f
toluene, 72h, -20 ºC
(2 equiv.) (1 equiv.)
OBoc
(S)
COOR
COOMe
+
11f
Br
80% ee
Br
9f
90% ee
Fig. 33 Kinetic resolution effect of carbonate 9f
compound was analogous to
compound
11f,
(Fig.
During
34).
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
Fig. 34 ORTEP drawing of product 11a
38
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.
Fig. 35 ORTEP drawing recorvered starting material 9f
39
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 βisocupreidine 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).
Ph
OBoc
COOMe a-IQD (20 mol %)
Ph
toluene, rt
Ph
1a
CN
*
COOEt
COOMe
O
3a
<5% conv
after 14 d
N
N
Ph
OBoc
CN
Ph
a-ICPD (20 mol %)
Ph
toluene, -20 ºC, 48h
14
CN
*
COOEt
CN
6'
OR
R=H
-ICPD
R=Me -IQD
15
95% yield,
<2% ee
Fig. 36 Effects of the structure of catalyst and substrate
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
40
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.
nucleophile
Nu
(R)
Ph
COOMe
1.97 Å
Fig. 37 Minimized structure of the intermediate, β-ICPD and MBH carbonate (B3LYP/6-31G**//HF/321G*)
41
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 reaction in higher regioselectivity’s and enantioselectivities and thereby
improving the atom economy (less side-products). A detailed study towards the reaction
mechanism could assist in the rational design of catalysts and lead to better understanding of
this reaction. Additional research could be performed by investigating the importance of the
electron wtihdrawing group of the carbonate substrate for the nucleophilic attack of the
catalyst. If this reaction could be catalyzed with first an a-chiral base, for instance with
quinuclidine, it would provide a immense step forwards in the metal free AAA.
42
Samenvatting
Organokatalyse, katalyse met kleine organische moleculen, is in de afgelopen jaren opnieuw
in de belangstelling gekomen van de academische wereld en de chemische industrie. Hoewel
het al bijna een eeuw bekend is dat organische verbindingen asymmetrische reacties kunnen
katalyseren, het is pas sinds enkele jaren dat dit onderzoeksgebied volledig wordt verkend.
In de behandeling van ziektes is meestal èèn enantiomeer van een medicijn actiever, en kan in
het slechtste geval, het andere enantiomeer tot ernstige bijwerkingen lijden of zelfs tot de
dood. Daarom zijn de farmaceutische en chemische industrie continue opzoek naar nieuwe,
efficiënte en betrouwbare asymmetrische reacties voor de constructie van moleculaire
skeletten. De constructie van dergelijke asymmetrische, hoog gefunctionaliseerde
moleculaire skeletten laat tegenwoordig veel te wensen over, helemaal wanneer er een
quaternair stereocentrum in het molecuul is vertegenwoordigd. Organokatalyse kan hierin
waardevolle nieuwe reacties bieden en kan daarnaast als een groen alternatief dienen voor
bestaande metaal gekatalyseerde
reacties. In dit verslag rapporteren wij een nieuwe
asymmetrische èènstaps reactie van Morita-Baylis-Hillman adducten, die leiden tot
moleculaire assemblages met een aangrenzend quaternair en tertiar stereocentrum. De uit
quinidine, in èèn stap verkrijgbare organokatalysator β-isocupreidine, katalyseert effectief
deze asymmetrische omzetting in goede chemo-, diastereo- en enantioselectiviteit. De
opbrengst van deze reactie is uitstekend. Deze èèn-staps constructie van een aangrenzend
quaternair en tertiar stereocentrum is een zeldzame reactie, tot op heden zijn er slechts zes
bekend in de literatuur. Wat deze reactie uiterst uniek maakt is dat voor het eerst dit structuur
niet via een conjugaatadditie worden gemaakt, maar via een organokatalytische alkylering.
43
Acknowledgements
From April 2005- August 2006 I have performed my master research project in the research
group of Prof. Dr. Henk Hiemstra, Synthetic Organic Chemistry, University of Amsterdam. I
would like to thank first of all Henk and Jan for allowing me to perform my research project
in the group. I would like to thank all the group members during my research period, thank
you all for the great time. In particular, I would like to thank the “crazy” Italian Tommaso, for
daily supervision, endless discussions, and talks about everything…… I appreciated it a lot
that I could interfere in your PhD project about organocatalysis.
Furthermore; Prof. Dr. Reek (Joost) for being the second corrector of my project, Han Peeters
for recording the exact masses, Jan Geenevasen for daily assistance and for solving the
problems with NMR/IR machine(s), Richard for fruitful discussions, Maxim for the “fun” on
the lab and Jaap for exploiting the canteen in building D. Thanks a lot!
At last but not least, I would like to thank my mother, my sister and Federica.
44
Chapter 3 Experimental
General: All reagents were purchased from commercial suppliers (Aldrich and Acros
Organics) and used without further purification, unless otherwise stated. Ethyl 2cyanopropanoate (2b) was obtained from TCI. Solvents where obtained from Biosolve.
Heptane was obtained from Merck. Cyclohexane was obtained from Rathburn. Toluene was
distilled from sodium and stored over 4Å molecular sieves prior to use. Column
chromatography was performed using silica (0,035-0,070 mm pore diameter ca. 6 nm)
obtained from Biosolve. NMR spectra (1H and
13
C) were measured in CDCl3 on a Bruker
ARX 400 MHz spectrometer, CDCl3 was used as solvent. High-resolution mass spectra were
recorded on a JEOL JMS-SX/SX 102 A tandem mass-spectrometer. Infrared spectra were
-Isocupreidine (β-ICPD) and βisoquinidine (β-IQD) were prepared according to Hatakeyama et al.[55]
β-Isocupreidine (β-ICPD) (2)
Quinidine (1) (11.6 g, 35.8 mmol, 1 eq) was added to a solution of 85%
O
N
N
OH
H3PO4 (175 ml) and KBr (42.8 g, 330 mmol, 10 eq.). The resulting mixture
was stirred at 100 ºC for 5 days and finally cooled to 0 ºC. To the mixture
was dropped carefully an ice cold solution of KOH (25 wt %, 700 ml), the
PH was adjusted to 8 by using K2CO3 and extracted with CHCl3. The
resulting orange organic layer was washed with brine (2 × 200 ml), dried over MgSO4 and
concentrated in vacuo. Flash chromatography (MeOH-CHCl3 1-9) afforded (7.2 g, 23.2 mmol,
65%) as a off white solid. Spectroscopically pure compound was obtained by recrystallization from MeOH-H2O and an additional purification by column chromatography.
β-ICPD was obtained as a light yellow solid. (7.3 g, 23.3 mmol, 65 %) 1H NMR (CDCl3, 400
MHz) δ 8.71 (d, 1H, J=4.4 Hz), 8.00 (s, 1H), 7.97 (d, 1H, J = 8.8 Hz) 7.57 (dd, 1H, J=4.5, 1
Hz), 7.25 (dd, 1H, J=9.0, 2.5 Hz), 6.00 (s, 1H), 3.68 (d, 1H, J=13.5 Hz), 3.46 (d, 1H, J=6.0
Hz), 3.19 (dd, 1H, J=13.0, 8.5 Hz), 3.09-3.02 (m, 1H), 2.77 (d, 1H, J=14.0 Hz), 2.24 (t, 1H,
J=10 Hz), 1.93-1.84 (m, 1H), 1.81-1.64 (m, 4H), 1.30-1.25 (m, 1H), 1.05 (t, 3H, J=14.8 Hz).
C NMR (CDCl3, 400 MHz) δ 156.8, 146.8, 143.3,141.5, 131.5, 127.1, 122.5, 119.0, 105.6,
13
76.9, 72.5, 56.6, 54.0, 46.4, 32.8, 27.4, 23.2, 23.0, 7.3.
45
β-Isocupreidine derived with trifluoromethylsulfonyl group (3)
β-isocupreiidine (β-ICPD) (2) (5.0 g, 16.1 mmol) was added to a solution
O
N
N
O O
S F
O
F
F
of N-phenyl-bis(trifluormethane sulfonimide) (6.3 g, 17.7 mmol, 1.1 eq)
and 4-di-methylaminopyridine (DMAP) (0.2 g, 1.6 mmol, 10 mol %) in
CH2Cl2 (35 ml). After being stirred for 5h at reflux temperature, CH2Cl2
was removed by rotary evaporation and the reaction mixture was dissolved
in EtOAc and washed with sodiumhydrogencarbonate (5 × 75 ml). Flash
chromatography (EtOAc/MeOH/NH3 25% in H2O), 92-6-2) afforded 3 as a yellow foam. (3.4
g, 7.6 mmol, 47 %) (IR (CHCl3) cm-1: 2968, 1730, 1675, 1598, 1511, 1457, 1426, 1376,
1141, 1098, 1053, 1007, 978, 932, 912, 887, 846, 829. 1H NMR (CDCl3, 400 MHz) δ 9.01 (d,
1H, J=4.4 Hz), 8.23 (d, 1H, J=9.6 Hz), 8.04 (d, 1H, J=2.8 Hz), 7.82 (dd, 1H, J=4.4 Hz, 0.8
Hz), 7.62 (dd, 1H, J=9.2 Hz, 2.4 Hz), 5.97 (s, 1H), 3.61 (d, 1H, J=13.6 Hz), 3.49 (d, 1H,
J=6.0 Hz), 3.06 (dd, 2H, J=8.4, 4.0 Hz ), 2.74 (d, 1H , J=13.6 Hz), 2.19-2.17 (m, 1H), 1.771.66 (m, 4H), 1.60-1.54 (m, 1H), 1.34 (q, 1H, J=19.8 Hz, 12.8 Hz, 6.4 Hz), 1.04 (t, 3H,
J=15.2 Hz). 13C NMR (CDCl3, 400 MHz) δ 151.5, 147.2, 147.0, 145.1, 133.3, 129.4, 126.1,
118.8 (q, 479 Hz), 115.5, 77.6, 73.1, 56.9, 54.7, 46.7, 33.0, 27.5, 24.2, 23.5, 7.4. HRMS
(FAB, MH+) calcd. for C20H22N2O4F3S : 443.1252 observed; 443.1258.
β-Isocupreidine derived with diphenylmethamine group (4)
To a stirred solution of (3) (1.5 g, 3.39 mmol) in THF (15 ml) at 70 ºC
was added stepwise Pd(OAc)2 (76 mg, 0.34 mmol, 10 mol %), BINAP
O
N
N
(0.32 g, 0.51 mmol, 1.5 eq. with respect to Pd(OAc)2) and
cesiumcarbonate (1.65 g, 5.1 mmol, 1.5 eq. with respect to the starting
N
material). Finally, benzophenone imine (0.67 g, 3.7 mmol, 1.1 eq. with
respect to the starting material) was added and the reaction mixture was
left stirring for 24 h. The reaction mixture was allowed to cool down to
room temperature, filtered through Celite pad using DCM as the eluens. The solvents where
removed by rotary evaporation and the residue was subjected to column chromatography
(EtOAc/MeOH/NH3 (25% in H2O), 92-6-2). The eluens was remopved by rotary evaporation
yielding 4 as yellow foam.(1.25 g, 2.6 mmol, 76 %) IR (CHCl3) cm-1: 2967, 2884, 1675,
1612, 1596, 1574, 1499, 1446, 1377, 1317, 1291, 1244, 1140, 1099, 1053, 1006, 959, 909,
46
851. 1H NMR (CDCl3, 400 MHz) δ 8.76 (d, 1H, J=4.8 Hz), 7.94 (d, 1H, J=8.8 Hz), 7.78-7.76
(m, 2H), 7.65 (dd, 1H, J=4.4, 0.8 Hz), 7.51-7.47 (m, 1H), 7.43-7.39 (m, 2H), 7.25 (dd, 1H,
J=8.8, 2.0 Hz), 7.21-7.14 (m, 5H), 7.05 (d, 1H, J=2 Hz), 5.73 (s, 1H), 3.43 (d, 1H, J=13.2
Hz), 2.99 (d, 1H, J=6 Hz), 2.96-2.94 (m, 1H), 2.61 (d, 1H, J=13.6 Hz), 2.08 (m, 1H), 1.641.58 (m, 4H), 1.47-1.46 (m, 1H), 1.25 (t, 2H, J=14.4 Hz), 1.11 (dd, 1H, J=12.4, 6.4 Hz), 1.00
(t, 3H, J=14.8 Hz).
13
C NMR (CDCl3, 400 MHz) δ 169.3, 149.8, 148.6,145.1, 144.0, 139.2,
135.8, 131.0, 130.7, 129.5, 129.5, 128.5, 128.2, 128.0, 125.8, 125.0, 119.1, 111.4, 77.2, 73.1,
56.3, 55.0, 46.8, 32.7, 27.3, 24.3, 23.7, 7.3. HRMS (FAB, MH+) calcd. for C32H32N3O : 474.
2545 observed; 474.2547.
Amine (5)
To a stirred solution of (4) (1.0 g, 2.21 mmol) in THF (5 mL) was added a
O
N
N
NH2
solution of citric acid (10 mL, 10% in H2O). The reaction mixture was left
stirring for 24 h. Work-up procedures
can be found in the manuscript
published by Deng et al.53 Yellow foam. (0.55 g, 1.78 mmol, 81 %) IR
(CHCl3) cm-1: 3400, 2966, 2884, 1632, 1593, 1516, 1473, 1356, 1281, 1253,
1178, 1142, 1099, 1053, 1006, 978, 909, 854, 827.
1
H NMR (CDCl3, 400 MHz) δ 8.66 (d, 1
H, J=4.4 Hz), 7.89 (d, 1H, 8.8 Hz), 7.61 (dd, 1H, J= .4, 0.8 Hz), 7.10 (dd, 1H, J=8.8, 2.4 Hz),
7.04 (d, 1H, J=2.4 Hz), 5.86 (s, 1H), 4.14-4.08 (m, 3H), 3.56 (d, 1H, J= 13.6 Hz), 3.50 (d, 1H,
J= 6 Hz), 3.00 (dd, 2H, J=8.8, 4.0 Hz), 2.67 (d, 1H, 13.6 Hz), 2.13 (t, 1H, J=10.4 Hz), 1.791.74 (m, 1H), 1.67-1.62 (m, 3H), 1.53-1.49 (m, 1H), 1.02 (t, 3H, 14.8 Hz).
13
C NMR (CDCl3,
400 MHz) δ 146.4, 145.1, 142.9, 141.6, 131.5, 126.9, 120.9, 119.1, 102.4, 77.2, 73.1, 56.3,
54.7, 46.7, 32.9, 27.4, 24.2, 23.5, 7.4. HRMS (FAB, MH+) calcd. for C19H24N3O : 310.1919
observed; 310.1918.
47
bistrifluoro-thiourea (6)
to a stirred solution of (5) (250 mg, 0.81 mmol) in THF (10 mL) was
added 3,5-bis-trifluoromethyl-phenyl-isothiocyanate (155 μL, 0.85 mmol,
O
1.05 eq.) The reaction mixture was left stirring for 20 minutes and
N
subsequently, the reaction mixure was cooled to 0 ºC. The white
N
precipitate was filtered and dried. The residue was subjected to column
NH
S
NH
F3C
chromatography (EtOAc/MeOH/NH3 (25%in H2O)). Combined fractions
CF3
yielding (6) as a white solid. (332 mg, 0.55 mmol, 69 %) IR (CHCl3) cm1
: 3093, 2971, 2885, 1621, 1595, 1550, 1508, 1473, 1384, 1326, 1301,
1279, 1180, 1141, 1099, 1052, 1008, 977, 886, 851. 1H NMR (CD3OD, 400 MHz) δ 8.84 (d,
1H, J=4.8 Hz), 8.26 (s, 2H), 8.06-7.94 (m, 3H), 7.84 (d, 1H, J=4.4 Hz), 7.70 (s, 1H), 3.56 (s,
1H), 5.95 (s, 1H), 4.90, (s, 1H), 3.52 (d, 1H, J=6.8Hz), 3.04-3.00 (m, 2H), 2.87-2.83 (m, 1H),
2.17 (s, 3H), 1.79-1.69 (m, 4H), 1.60-1.53 (m, 1H), 1.40-1.37 (m, 1H), 1.05 (t, 3H, J=7.2 Hz).
C NMR (CDCl3, 400 MHz) δ. HRMS (FAB, MH+) calcd. for C28H27N4OF6S : 581.1810
13
observed; 581.1802. [α]D25 = 77.1 (c 1.0, CHCl3), Litrature value: [α]D25 = 76.7. Mp: 155-157
˚C.
Procedure for the preparation of the MBH-alcohols: Morita-Baylis-Hillman alcohols were
prepared according to Aggarwal et al.56 To a round bottom flask charged with MeOH (0.75
eq.) was added the arylaldehyde (1 eq.) and methyl acrylate (1.2 eq.). To the solution was then
added 1,4-diaza-bicyclo[2.2.2]octane (50 mol %) and the solution was stirred for 48-96 h. The
crude reaction mixture was purified by column chromatography. (PE/Et2O or PE/EtOAc
mixtures).
methyl 2-(hydroxy(phenyl)methyl)acrylate
1
OH
COOMe
H-NMR (CDCl3, 400 MHz): δ 7.40-7.30 (m, 5H), 6.35 (t, J=1.6 Hz,
1H), 5.88 (t, J=2.4 Hz, 1H), 5.56 (s, 1H), 3.71 (s, 3H), 3.36 (s, 1H).
C-NMR (CDCl3, 400 MHz): δ 166.7, 142.0, 141.3, 128.3, 127.7,
13
126.6, 125.9, 72.9, 51.9.
ethyl 2-(hydroxy(phenyl)methyl)acrylate
48
1
OH
COOEt
H-NMR (CDCl3, 400 MHz): δ 7.41-7.34 (m, 4 H), 7.32-7.28 (m,
1H), 6.36 (t, J=0.8 Hz, 1H), 5.84 (t, J=1.2 Hz, 1H), 5.58 (s, 3H),
4.19 (q, J=21.6, 7.2 Hz, 2H), 3.18 (bs, 1H), 1.26 (t, J=14.4 Hz, 3 H).
2-(hydroxy(phenyl)methyl)acrylonitrile
1
OH
CN
H-NMR (CDCl3, 400 MHz): δ 7.45-7.36 (m, 5H), 6.12 (s, 1H), 6.04 (s,
1H), 5.29 (s, 1H), 2.70 (bs, 1H).
13
C-NMR: (CDCl3, 400 MHz) δ 139.2,
129.7, 128.7, 128.6, 126.4, 126.2, 116.9, 73.8.
methyl 2-((3-chlorophenyl)(hydroxy)methyl)acrylate
1
OH
COOMe
H-NMR (CDCl3, 400 MHz): δ 7.38 (s, 1H), 7.28 (m, 3H), 6.37 (s,
1H), 5.87 (s, 1H), 5.52 (s, 1H), 3.74 (s, 3H), 3.33 (s, 1H). 13C-NMR
(CDCl3, 400 MHz): δ 166.6, 143.4, 141.4, 134.4, 129.7, 128.0,
126.8, 126.7, 124.8, 72.7, 52.1.
Cl
methyl 2-(hydroxy(4-nitrophenyl)methyl)acrylate
1
OH
COOMe
H-NMR (CDCl3, 400 MHz): δ 8.18 (dd, J=6.8, 2.0 Hz, 2H),
7.56 (dd, J=7.2, 1.6 Hz, 2H), 6.38 (s, 1H), 5.88 (d, J=0.8 Hz,
1H), 5.62 (s, 1H), 3.73 (s, 3H), 3.33 (s, 1H).
O2N
13
C-NMR
(CDCl3, 400 MHz): δ 166.4, 148.7, 147.5, 141.0, 127.4, 127.2,
123.6, 72.6, 52.2.
methyl 2-(hydroxy(naphthalen-5-yl)methyl)acrylate
1
OH
COOMe
H-NMR (CDCl3, 400 MHz): δ 8.03-8.01 (m, 1H), 7.90-7.87 (m,
1H), 7.83 (d, J=8.0 Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.52-7.48
(m, 3H), 6.40 (s, 1H), 6.37 (s, 1H), 5.59 (t, J=2.0, 1H), 3.80 (s,
3H), 3.11 (s, 1H).
13
C-NMR (CDCl3, 400 MHz): δ 167.4, 141.9,
136.4, 133.9, 130.9, 128.9, 128.7, 127.4, 126.3, 125.7, 125.5, 124.6, 123.9, 69.5, 52.2.
methyl 2-((3-bromophenyl)(hydroxy)methyl)acrylate
1
OH
COOMe
H-NMR (CDCl3, 400 MHz): δ 7.56 (t, J=3.2 Hz, 1H), 7.45-7.42 (m,
1H), 7.34-7.32 (m, 1H), 7.26-7.22 (m, 1H), 6.39 (s, 1H), 5.87 (s, 1H),
5.54 (s, 1H), 3.76 (s, 3H), 3.15 (s, 1H).
13
C-NMR (CDCl3, 400
MHz): δ 166.6, 143.7, 141.4, 131.0, 130.1, 129.7, 126.9, 125.3,
Br
49
122.7, 72.9, 52.2.
methyl 2-(hydroxy(o-tolyl)methyl)acrylate
1
OH
COOMe
H-NMR (CDCl3, 400 MHz): δ 7.45-7.43 (m, 1H), 7.27-7.17 (m,
3H), 6.35 (s, 1H), 5.83 (s, 1H), 5.63 (s, 1H), 3.79 (s, 3H), 2.65 (bs,
1H), 2.35 (s, 3H)
13
C-NMR (CDCl3, 400 MHz): δ 167.2, 141.7,
138.8, 135.7, 130.5 127.9, 126.3, 126.3, 126.2, 69.3, 52.1, 19.1.
General procedure for the preparation of MBH-carbonates (9a-f and 14)
To a solution of the Morita-Baylis-Hillman alcohol (1 eq.) in DCM (0.6 M) was added Boc2O
(1.05 eq.) and 4-dimethylaminopyridine (10 mol %). The solution was stirred for the indicated
time and subsequently the solvent was removed by rotary evaporation. The reaction mixture
was purified by column chromatography (PE/Et2O or PE/EtOAc). Finally, the Morita-BaylisHillman carbonate was left under high vacuum at 60 ºC to remove eventual traces of
unreacted Boc2O. The purity of all Morita-Baylis-Hillman carbonates 9a-f was confirmed by
1
H-NMR.
2-(methoxycarbonyl)-1-phenylallyl tert-butyl carbonate (9a)
Reaction time 90 min. Purified by column chromatography
O
O
(PE/Et2O 2:1) White solid. (1.36 g, 4.6 mmol, 83%). FTIR
O
(CHCl3) cm-1: 3027, 2985, 1741, 1632, 1440, 1396, 1371, 1281,
COOMe
1255, 1156, 1086, 962, 882 cm-1. 1H-NMR (CDCl3, 400 MHz): δ
7.42-7.31 (m, 5H), 6.49 (s, 1H), 6.42 (s, 1H), 5.93 (s, 1H), 3.73 (s,
3H), 1.48 (s, 9H). 13C-NMR (CDCl3, 400 MHz): δ HRMS (FAB, MH+) calcd. for C16H21O5
293.1389, observed 293.1399.
2-(methoxycarbonyl)-1-o-tolylallyl tert-butyl carbonate (9b)
Reaction time 100 min. Purified by column chromatography
O
O
(PE/Et2O 2:1). White solid (1.42 g, 4.64 mmol, 47%). FTIR
O
COOMe
(CHCl3) cm-1: 3029, 2984, 1739, 1634, 1440, 1396, 1371, 1281,
1157, 1082, 1036, 962, 881, 818 cm-1. 1H-NMR (CDCl3, 400
50
MHz): δ 7.32-7.30 (m, 1H), 7.21-7.16 (m, 4H), 6.72 (s, 1H), 6.43 (s, 1H), 5.72 (s, 1H), 3.73
(s, 3H), 2.41 (s, 3H), 1.46 (s, 9H). 13C-NMR (CDCl3, 400 MHz): δ 165.6, 152.6, 139.1, 136.4,
135.5, 130.6, 128.4, 127.1, 127.0, 126.1, 82.5, 72.7, 52.0, 27.8, 19.1. HRMS (FAB, MH+)
calcd. for C17H23O5 307.1545, observed 307.1551.
2-(methoxycarbonyl)-1-(3-chlorophenyl)allyl tert-butyl carbonate (9c)
Reaction time 60 min. Purified by column chromatography
O
O
(PE/Et2O 2:1). Light yellow solid. (4.40 g, 13.5 mmol, 68 %)
O
COOMe
FTIR (CHCl3) cm-1: 3030, 2985, 1744, 1633, 1577, 1475, 1439,
1396, 1371, 1278, 1156, 1082, 1037, 964, 883, 849, 818 cm-1. 1HNMR (CDCl3, 400 MHz): δ 7.39 (s, 1H), 7.30-7.28 (m, 3H), 6.44-
Cl
6.43 (m, 2H), 5.95 (s, 1H), 3.72 (s, 3H), 1.47 (s, 9H).
13
C-NMR
(CDCl3, 400 MHz): δ 165.2, 152.2, 139.7, 139.2, 134.4, 129.8, 128.7, 127.7, 126.3, 126.0,
83.0, 75.0, 52.1, 27.8. HRMS (FAB, MH+) calcd. for C16H20O5Cl : 327.0999 observed;
327.0997.
2-(methoxycarbonyl)-1-(4-nitrophenyl)allyl tert-butyl carbonate (9d)
Purification by column chromatography (PE/Et2O 2-1) colour
O
O
less oil. (1.42 g, 4.21 mmol, 57 %) FTIR (CHCl3) cm-1: 3030,
O
2985, 2955, 1745, 1633, 1609, 1526, 1495, 1441, 1396, 1371,
COOMe
1351, 1279, 1258, 1155, 1088, 1038, 968, 890, 851 cm-1. 1HNMR (CDCl3, 400 MHz): δ 8.21 (d, J=6.8 Hz, 2H), 7.60 (d,
O2N
J=6.8 Hz, 2H), 6.53 (s, 1H), 6.47 (s, 1H), 6.03 (s, 1H), 3.73 (s, 3H), 1.47 (s, 9H).
13
C-NMR
(CDCl3, 400 MHz): δ 165.0, 152.1, 147.8, 145.0, 138.6, 128.7, 126.9, 123.7, 83.4, 74.6, 52.2,
27.7. HRMS (FAB, MH+) calcd. for C16H20NO7 338.1240, observed 338.1237.
2-(methoxycarbonyl)-1-(naphthalen-5-yl)allyl tert-butyl carbonate (9e)
Reaction time 60 min. Purified by column chromatography
O
O
(PE/Et2O 2:1). Light yellow solid. (1.42 g, 4.1 mmol, 66 %) FTIR
O
(CHCl3) cm-1: 3022, 2985, 1740, 1635, 1513, 1439, 1396, 1371,
COOMe
1278, 1256, 1156, 1088, 968, 886, 847 cm-1. 1H-NMR (CDCl3,
400 MHz): δ 7.40-7.14 (m, 7H), 6.49 (s, 1H), 6.39 (s, 1H), 5.91
(s, 1H), 3.69 (s, 3H), 1.45 (s, 9H). 13C-NMR (CDCl3, 400 MHz):
51
δ 165.8, 152.7, 139.2, 133.9, 133.3, 131.0, 129.3, 128.8, 128.1, 126.6, 125.9, 125.2, 123.5,
82.8, 72.5, 52.2, 27.8. HRMS (FAB, MH+) calcd. for C20H23O5 343.1545, observed 343.1542.
2-(methoxycarbonyl)-1-(3-bromophenyl)allyl tert-butyl carbonate (9f)
Reaction time 60 min. Purified by column chromatography
O
O
(PE/EtOAc 4:1). White solid. (6.3 g, 17.0 mmol, 61 %).
O
Enantiomerically- enriched compound obtained after kinetic
COOMe
resolution with 2a (0.78 g, 2.1 mmol, 47 %). FTIR (CHCl3) cm-1:
3028, 2985, 2954, 1743, 1633, 1573, 1475, 1440, 1396, 1371,
Br
1278, 1255, 1194, 1156, 1085, 1037, 998, 964, 883, 847, 818 cm-
. H-NMR (CDCl3, 400 MHz): δ 7.55 (t, 1H J=3.6 Hz), 7.47-7.44 (m, 1H), 7.37-7.35 (m,
1 1
1H), 7.25-7.21 (m, 1H), 6.45 (s, 2H), 5.97 (s, 1H), 3.74 (s, 3H), 1.49 (s, 9H).
13
C-NMR
(CDCl3, 400 MHz): δ 165.2, 152.3, 139.9, 139.2, 131.7, 130.6, 130.1, 126.5, 126.3, 122.6,
83.1, 75.0, 52.2, 27.8. HRMS (FAB, MH+) calcd. for C16H20O5Br : 371.0494 observed;
371.0494. [α]D25 = +110.6 (c 0.99, CHCl3). Mp: 77 ˚C. HPLC Daicel Chiralcel AD,
heptane/2-propanol (95:5), flow 1.0 mL/min, λ=254 nm, tr(major)=5.5 min, tr(minor)=6.0 min.
tert-butyl 2-cyano-1-phenylallyl carbonate (14)
Reaction time 90 min. Purification by column chromatography
O
(Pe/EtOAc 2.5:1). Light yellow oil. (2.2 g, 8.5 mmol, 64 %). FTIR
O
O
(CHCl3) cm-1: 3028, 2985, 2231, 1745, 1456, 1396, 1371 1277, 1258,
CN
1157, 1090, 1037, 953, 883, 848 cm-1. 1H-NMR (CDCl3, 400 MHz): δ
7.44-7.41 (m, 5H), 6.13 (s, 1H), 6.11 (d, J=0.8 Hz, 1H), 6.07 (d, J=1.2
Hz, 1H), 1.51 (s, 9H).
C-NMR (CDCl3, 400 MHz): δ 152.1, 135.5, 131.7, 129.4, 129.0,
13
127.1, 123.3, 116.2, 83.6, 77.0, 27.8. HRMS (FAB, MH+) calcd. for C15H18O3N 260.1287,
observed 260.1288.
2-(ethoxycarbonyl)-1-phenylallyl tert-butyl carbonate (7)
Reaction time 90 min. Purified by column chromatography
O
O
(PE/Et2O 2:1) White solid. (2.4 g, 7.8 mmol, 53%). FTIR (CHCl3)
O
COOEt
52
cm-1: 3019, 2977, 1742, 1522, 1423, 1046, 929, 876. 1H-NMR (CDCl3, 400 MHz): δ 7.437.30 (m, 5H), 6.50 (s, 1H), 6.43 (s, 1H), 5.91 (s, 1H), 4.21-4.15 (m, 2H), 1.48 (s, 9H), 1.25 (t,
J=14.4 Hz, 3H).
13
C-NMR (CDCl3, 400 MHz): δ 164.9, 152.4, 139.9, 137.6, 128.5, 128.4,
127.7, 125.5, 82.5, 75.9, 60.9, 27.7, 14.0. HRMS (FAB, MH+) calcd. for
C22H22O4N
364.1549, observed 364.1535.
General procedure for the preparation of racemic 11a-f and 15: Racemic samples for
HPLC analysis were prepared using MBH-carbonate (9a-f or 14, 0.2 mmol) and
pronucleophile (10a-b, 0.2 mmol) in toluene (2 mL). 1,4-Diaza-bicyclo[2.2.2]octane (0.1
mmol) was added to the solution and stirring was continued for 30 min at room temperature.
The reaction mixtures were filtered over silica (Et2O) and the solvent was removed by rotary
evaporation. In order to obtain analytically pure samples, the reaction mixtures were subjected
to flash chromatography to afford racemic 11a-f and 15.
General procedure for the asymmetric allylic alkylation of MBH-carbonates (9a-f and
14): β-ICPD (20 mol %) was added to the total volume of toluene and the resulting
suspension was heated and stirred until formation of a clear solution. Subsequently, the
mixture was allowed to cool to the indicated temperature. MBH-carbonate (9a-f) was added
to the reaction mixture and the mixture was stirred until complete dissolution (~5-10 min).
Cyanoacetate (10a-b) was added in one portion and the mixture was kept at the indicated
temperature for the described reaction time. The experiments were stopped by filtration of the
reaction mixture over a short pad of silica gel and elution with Et2O. Solvents were removed
by rotary evaporation and the crude mixture was purified by column chromatography.
1-ethyl-5-methyl-2-cyano-4-methylene-2,3-diphenylpentanedioate (11a)
Ph
CN
COOEt
Amounts used: 6.0 mmol (1.75 g) 2-(methoxycarbonyl)-1phenylallyl tert-butyl carbonate (9a
COOMe
-
phenyl-cyano-acetate (10a), 6o mL toluene and 20 mol % β-ICPD
(186.2 mg). Reaction mixture was stirred for 72 h, small scale
experiment 48 h. Reaction temperature -20ºC. Purification by column chromatography
(PE/Et2O 4:1). Enantiopure crystals of the major diastereomer were obtained by crystallizing
the mixture of diastereoisomers from cyclohexane (2 mL). Transparent crystals (0.69 g, 1.9
mmol, 63%). FTIR (CHCl3) cm-1: 3029, 3011, 2954, 1742, 1718, 1631, 1497, 1450, 1234,
1196, 1154, 1094, 1034, 1005, 956, 858, 819 cm-1. 1H-NMR (CDCl3, 400 MHz): 7.76-7.40
(m, 2H), 7.59-7.57 (m, 2H), 7.44-7.32 (m, 6H), 6.39 (s, 1H), 6.06 (s, 1H), 5.47 (s, 1H), 4.1053
4.04 (m, 2H), 3.56 (s, 3H), 1.06 (t, J=14.2 Hz, 3H).
13
C-NMR (CDCl3, 400 MHz): δ 166.7,
166.6, 137.5, 136.6, 133.1, 129.7, 129.1, 128.6, 128.6, 128.2, 127.1, 118.0, 63.4, 59.3, 52.3,
49.9 13.7. HRMS (FAB, MH+) calcd. for C22H22O4N 364.1549, observed 364.1535. [α]D25 = 231.8 (c 1.01, CHCl3). Mp: 101˚C. HPLC Daicel Chiralcel OD-H, heptane/2-propanol (95:5),
flow 1.0 mL/min, λ=254 nm, tr(major)=17.4 min, tr(minor)=20.5 min.
1-ethyl 5-methyl 2-cyano-4-methylene-2-phenyl-3-o-tolylpentanedioate (11b)
Ph
CN
COOEt
Amounts used: 0.6 mmol (183.8 mg) 2-(methoxycarbonyl)-1-otolylallyl tert-butyl carbonate, 0.3 mmol (52.1 ul) ethyl-phenyl-
COOMe
cyano-acetate (10a), 6 mL toluene and 20 mol % β-ICPD (18.6 mg).
Reaction mixture was stirred for 96 h. Reaction temperature 0 ºC.
Purification by column chromatography (PE/ Et2O 4:1). Light yellow solid (109 mg, 0.29
mmol, 95%). FTIR (CHCl3) cm-1: 3028, 3010, 2953, 2250, 1742, 1721, 1629, 1495, 1450,
1440, 1392, 1369, 1333, 1237, 1195, 1140, 1095, 1033, 995, 953, 909 cm-1. 1H-NMR (CDCl3,
400 MHz, major diastereoisomer): δ 8.00 (d, J=7.6 Hz, 1H), 7.78-7.75 (m, 2H), 7.44-7.41 (m,
3H), 7.23-7.19 (m, 3H), 6.42 (s, 1H), 5.91 (s, 1H), 5.42 (s, 1H), 4.15-4.03 (m, 2H), 3.36 (s,
3H), 2.40 (s, 3H), 1.06 (t, J =14.4 Hz, 3H).
13
C-NMR (CDCl3, 400 MHz): δ 166.7, 166.5,
138.2, 137.5, 137.0, 132.6, 131.2, 130.8, 129.2, 128.8, 127.5, 127.4, 126.4, 126.1, 118.3, 63.2,
59.2, 51.9, 47.6, 19.9, 13.6. HRMS (FAB, MH+) calcd. for C23H24O4N 378.1705, observed
378.1711. HPLC Daicel Chiralcel OD-H, heptane/2-propanol (98:2), flow 0.7 mL/min, λ=254
nm, tr(minor)=20.9 min, tr(major)=42.6 min.
1-ethyl 5-methyl 3-(3-chlorophenyl)-2-cyano-2-methyl-4-methylenepentanedioate (11c)
CN
Amounts used: 0.6 mmol (193.1 mg) 2-(methoxycarbonyl)-1-(3COOEt
COOMe
chlorophenyl) allyl- tert-butyl carbonate, 0.3 mmol (52.1 ul) ethyl 2cyanopropanoate (10b), 6 mL toluene and 20 mol % β-ICPD (18.6
mg). Reaction mixture was stirred for 72 h. Reaction temperature -20
ºC. Purification by column chromatography (Toluene/EtOAc 95:5).
Cl
Yellow oil. (97 mg, 0.29 mmol, 95%). FTIR (CHCl3) cm-1: 3028,
2989, 2955, 2247, 1741, 1631, 1596, 1574, 1477, 1442, 1381, 1284, 1245, 1198, 1170, 1125,
1084, 1015, 965, 909, 856 cm-1. 1H-NMR,(CDCl3, 400 MHz, major diastereoisomer): δ 7.417.26 (m, 4H), 6.71 (s, 1H), 6.43 (s, 1H), 4.66 (s, 1H), 4.13-4.07 (m, 2H), 3.78 (s, 3H), 1.08 (t,
J=7.2 Hz, 3H).
13
C-NMR (CDCl3, 400 MHz) (major diastereoisomer) δ 168.4, 166.8, 139.6,
137.3, 134.5, 129.9, 129.2, 129.1, 128.2, 126.7, 119.2, 63.1, 52.7, 49.1, 48.9, 23.4, 13.7.
HRMS (FAB MH+,) calcd. for C17H19O4N : 336.1003 observed; 336.1008. HPLC Daicel
54
Chiralcel OD-H, heptane/2-propanol (99.5-0.5), flow 0.9 mL/min, λ=254 nm, tr(major)=31.1
min, tr(minor)=20.3 min.
1-ethyl 5-methyl 2-cyano-4-methylene-3-(4-nitrophenyl)-2-phenylpentanedioate (11d)
Ph
CN
Amounts used: 0.6 mmol (202.4 mg) 2-(methoxycarbonyl)-1COOEt
(4-nitrophenyl) allyl tert-butyl carbonate 0.3 mmol (52.1 ul)
COOMe
ethyl-phenyl-cyano-acetate(10a) , 6 mL toluene and 20 mol %
β-ICPD (18.6 mg). Reaction mixture was stirred for 48 h.
O2N
Reaction temperature -20 ºC. Purification by column
chromatography (PE/Et2O 4:1). Light yellow solid. (116 mg, 0.29 mmol, 95 %) FTIR
(CHCl3) cm-1: 3029, 2955, 1743, 1632, 1606, 1525, 1496, 1450, 1350, 1291, 1276, 1236,
1197, 1154, 1113, 1035, 1003, 961, 909, 858 cm-1. 1H-NMR (CDCl3, 400 MHz, major
diastereoisomer): δ 8.24 (dd, J=7.2, 2.0 Hz, 2H), 7.78 (d, J=8.8 Hz, 2H), 7.71 (dd, J=8.0, 1.2
Hz, 2H), 7.47-7.41 (m, 3H), 6.46 (s, 1H), 6.08 (s, 1H), 5.60 (s, 1H), 4.14-4.08 (m, 2H), 3.58
(s, 3H), 1.10 (t, J=14.4 Hz, 3H). 1H-NMR (CDCl3, 400 MHz, minor diastereoisomer): δ 7.96
(d, J=8.8 Hz, 2H), 7.46-7.34 (m, 5H), 7.10 (d, J=8.8 Hz, 2H), 6.70 (s, 1H), 6.62 (s, 1H), 5.06
(s, 1H), 4.36-4.27 (m, 2H), 3.69 (s, 3H), 1.22 (t, J=14.0 Hz, 3H).
13
C-NMR (CDCl3, 400
MHz, mixture of diastereoisomers): δ 166.3, 166,3, 166.2, 165.9, 147.8, 147.5, 144.2, 142.3,
139.0, 136.5, 132.4, 132.3, 130.8, 130.6, 129.7, 129.6, 129.4, 129.3, 129.3, 126.9, 126.6,
126.1, 123.7, 123.0, 117.5, 117.1, 63.9, 63.9, 58.5, 58.1, 52.8, 52.6, 52.4, 49.4, 13.9, 13.7.
HRMS (FAB, MH+) calcd. for C22H21O6N2 409.1400, observed 409.1409. HPLC Daicel
Chiralcel AD, heptane/2-propanol (95:5), flow 1.0 mL/min, λ=254 nm, tr(major)=46.7 min,
tr(minor)=14.8 min.
1-ethyl 5-methyl 2-cyano-4-methylene-3-(naphthalen-5-yl)-2-phenylpentanedioate (11e)
Ph
CN
Amounts used: 0.6 mmol (205.4 mg)2-(methoxycarbonyl)-1COOEt
COOMe
(naphthalen-5-yl) allyl tert-butyl carbonate, 0.3 mmol (52.1 ul)
ethyl-phenyl-cyano-acetate (10a), 6 mL toluene and 20 mol % βICPD (18.6 mg). Reaction mixture was stirred for 24 h. Reaction
temperature 20 ºC. Purification by column chromatography (PE/Et2O 5:1 and Toluene/EtOAc
99.5:0.5). Light yellow solid. Compound obtained as a single diastereoisomer. (82.7 mg, 0.20
mmol, 66%) FTIR (CHCl3) cm-1: 3029, 3012, 1743, 1718, 1631, 1512, 1496, 1450, 1440,
55
1368, 1334, 1236, 1196, 1140, 1095, 1035, 993, 967, 857 cm-1. 1H-NMR (CDCl3, 400 MHz,
major diastereoisomer) δ 8.26 (d, J=8.4 Hz, 1H), 8.18 (d, J=7.2 Hz, 1H), 7.89-7.83 (m, 4H),
7.57-7.45 (m, 6H), 6.39 (s, 1H), 6.06 (s, 1H), 5.89 (s, 1H), 4.08-3.98 (m, 2H), 3.40 (s, 3H),
0.97 (t, J=14.4, 3H). 13C-NMR (CDCl3, 400 MHz) δ 166.7, 166.4, 138.4, 135.4, 134.2, 132.4,
131.4, 131.1, 129.3, 128.9, 128.5, 127.5, 126.7, 126.7, 126.0, 124.9, 124.2, 123.7, 118.3, 63.3,
59.3, 52.0, 47.5, 13.5. HRMS (FAB, MH+) calcd. for C26H24O4N : 414.1705 observed;
414.1696. HPLC Daicel Chiralcel OD-H, heptane/2-propanol (95:5), flow 1.0 mL/min, λ=254
nm, tr(major)=37.9 min, tr(minor)=10.5 min.
1-ethyl 5-methyl 3-(3-bromophenyl)-2-cyano-4-methylene-2-phenylpentanedioate (11f)
Ph
CN
Amounts used: 9.0 mmol (3.34 g) 2-(methoxycarbonyl)-1-(3COOEt
bromophenyl)allyl tert-butyl carbonate, 4.5 mmol (780 ul) ethyl-
COOMe
phenyl-cyano-acetate (10a), 90 mL toluene and 20 mol% β-ICPD
(279.3 mg). Reaction mixture was stirred for 72 h. Reaction
temperature
Br
-20ºC.
Purification
by
column
chromatography
(PE/Et2O 4:1). Enantiopure crystals where obtained by crystallizing the mixture of
diasterioisomers from cyclohexane (2.5 mL). white/transparent crystals. (1.16 g, 2.65 mmol,
59 %) FTIR (CHCl3) cm-1: 3029, 3012, 2955, 1743, 1632, 1593, 1570, 1497, 1475, 1450,
1273, 1235, 1196, 1154, 1095, 1077, 1035, 999, 960, 857 cm-1. 1H-NMR (CDCl3, 400 MHz)
δ 7.73 (m, 3H), 7.55-7.53 (m, 1H), 7.49-7.48 (m, 1H), 7.45-7.38 (m, 3H), 7.28-7.24 (m, 1H),
6.41 (s, 1H), 6.05 (s, 1H), 5.43 (s, 1H), 4.18-4.06 (m, 2H), 3.59 (s, 3H), 1.12 (t, J=14.4 Hz,
3H). 13C-NMR (CDCl3, 400 MHz): δ 166.6, 166.4, 139.0, 136.9, 132.9, 132.8, 131.4, 130.1,
129.2, 129.2, 129.2, 128.1, 127.0, 122.6, 117.7, 63.7, 59.0, 52.3, 49.4, 13.7. HRMS (FAB,
MH+) calcd. for C22H21O4NBr 442.0654, observed 442.0642. [α]D25 = -164.0 (c 1.0, CHCl3).
Mp: 108 ˚C. HPLC Daicel Chiralcel AD, heptane/2-propanol (95:5), flow 1.0 mL/min, λ=254
nm, tr(major)=9.7 min, tr(minor)=12.5 min.
ethyl 2,4-dicyano-2,3-diphenylpent-4-enoate (15)
Ph
CN
Amounts used: 0.6 mmol (155.6 mg) tert-butyl 2-cyano-1-phenylallyl
COOEt
CN
carbonate, 0.3 mmol (52.1 ul) ethyl-phenyl-cyano-acetate, 6 mL toluene
and 20 mol % β-ICPD (18.6 mg). Reaction mixture was stirred for 48 h.
Reaction temperature -20 ºC. Purification by column chromatography
(PE/Et2O 4:1). Mixture of diastereo-isomers. Yellow oil. (96 mg, 0.29
mmol, 95%) FTIR (CHCl3) cm-1: 3067, 3026, 3012, 2986, 2929, 2250, 1744, 1619, 1497,
56
1451, 1394, 1369, 1297, 1236, 1194, 1096, 1034, 1004, 946, 909, 859 cm-1. 1H-NMR (CDCl3,
400 MHz) (mixture of diastereoisomers) δ 7.82 (dd, J=8.4, 1.6 Hz, 2H, major), 7.67 (dd,
J=8.0, 1.6 Hz, 2H, major), 7.53-7.04 (m, 16H), 6.26 (s, 1H, minor), 6.25 (s, 1H, minor), 5.93
(s, 1H, major), 5.75 (s, 1 H, major), 4.72 (s, 1H, major), 4.58 (s, 1H, minor), 4.41-4.26 (m,
2H, minor), 4.12-4.02 (m, 2H, major), 1.30 (t, J=7.2, 3H, minor), 1.05 (m, J=6.8 Hz, 3H,
major).
C-NMR (CDCl3, 400 MHz, mixture of diastereoisomers): δ 166.5, 165.9, 135.6,
13
133.1, 132.9, 132.1, 132.1, 130.9, 129.7, 129.6, 129.5, 129.3, 129.2, 129.0, 129.0, 128.6,
128.5, 126.9, 126.6, 122.9, 120.6, 117.6, 117.3, 117.0, 116.6, 64.1, 63.7, 58.4, 57.7, 55.4,
54.9, 13.8, 13.5. HRMS (FAB, MH+) calcd. for C21H19O2N2 331.1447, observed 331.1447.
HPLC Daicel Chiralcel AD, heptane/2-propanol (9:1), flow 1.0 mL/min, λ=254 nm,
tr(major)=21.6 min, tr(minor)=17.4 min.
3-ethyl 1,1-dimethyl 2-phenylbut-3-ene-1,1,3-tricarboxylate (8)
O
Prepared according procedure as described by Lu et al.,48 similar
O
MeO
OMe
COOEt
results where obtained. FTIR (CHCl3) cm-1: 3030, 3006, 2955, 1735,
1630, 1495, 1437, 1263, 1196, 1153, 1034, 954, 816. 1H-NMR
(CDCl3, 400 MHz): δ 7.28-7.20 (m, 5H), 6.33 (s, 1H), 5.75 (d, J=0.8
Hz, 1H), 4.72 (d, J=12.4 Hz, 1H), 4.21 (d, J=12.4 Hz, 1H), 4.16-
4.11(m, 2H), 3.75 (s, 3H), 3.49 (s, 3H), 1.23 (t, J=6.8 Hz, 3H).
13
C-NMR (CDCl3, 400 MHz):
δ 168.1, 167.8, 166.3, 141.0, 138.5, 128.5, 128.4, 127.4, 124.6, 56.3, 52.9, 52.6, 52.1, 46.5.
HRMS (FAB, MH+) calcd. for C17H21O6 321.1338, observed 321.1344.
Ethyl 1-(2-(methoxycarbonyl)-1-phenylallyl)-2-oxocyclohexanecarboxylate (13)
O
Amounts used: 0.6 mmol ()2-(methoxycarbonyl)-1-phenylallyl tert-
COOEt
butyl carbonate, 0.3 mmol (52.1 ul) ethyl-phenyl-cyano-acetate, 6
COOMe
mL toluene and 20 mol % β-IC (18.6 mg). Reaction mixture was
stirred for 24 h. Reaction temperature 20 ºC. Purification by column
chromatography (PE/Et2O 4-1 and Toluene/EtOAc 98-2). 1H NMR
(CDCl3, 400 MHz)(mixture of diastereoismers)(major diastereoisomer) δ 7.48 (d, 2H, J=6.8
Hz), 7.36-7.28 (m, 3H), 6.38 (s, 2H), 6.12 (s, 1H), 4.23 (q, 2H, J=21.6, 14.4, 7.2 Hz), 3.73 (s,
3H), 2.31 (m, 2H), 2.25 (m, 2H), 1.63 (m, 2H), 1.50 (m, 2H), 1.32 (t, 3H, J=14.4, 7.2 Hz).
HRMS (FAB, MH+) calcd. for C20H25O5 : 345.1702 observed; 345.1700. HPLC Daicel
Chiralcel AD, heptane/2-propanol (98-2), Flow 1.0 ml/min, UV 254 nm.
57
1
H-NMR spectrum of compound 11a
58
13
C-NMR spectrum of compound 11a
59
Chiral HPLC trace of racemic 11a
Chiral HPLC trace of compound 11a after chromatography
60
Chiral HPLC trace of compound 11a after recrystallization
61
1
H-NMR spectrum of compound 11f
62
13
C-NMR spectrum of compound 11f
63
Chiral HPLC trace of racemic 11f
Chiral HPLC trace of compound 11f after chromatography
64
Chiral HPLC trace of compound 11f after recrystalization
65
Computational Methods
Computations were carried out using the Spartan ’04 program.[57] The initial structure of
intermediate B was computed using ab initio methods (HF/3-21G*) and the output was used
as starting geometry for full optimization at the B3LYP/6-31G** level of theory.
Intermediate B
Charge = 1
Multiplicity = 1
Stoichiometry = C30H33N2O4
B3LYP/6-31G** Energy = -1573.2839293 Hartree
ATOM
1 H
2 C
3 C
4 N
5 C
6 C
7 C
8 C
9 H
10 H
11 C
12 H
13 C
14 H
15 C
16 O
17 H
18 C
19 C
20 H
21 C
22 H
23 H
24 N
25 C
26 H
27 H
28 C
29 H
30 H
31 C
32 H
Coordinates (Angstroms)
X
Y
Z
3.587610 -2.798929 -0.209392
3.977707 -1.789207 -0.203604
3.194582 -0.739082 0.232108
5.848494 -0.346249 -0.688123
3.768810 0.568007 0.251311
5.299926 -1.542895 -0.643783
5.104745 0.705355 -0.251565
3.089753 1.719181 0.713392
5.914178 -2.375264 -0.981700
6.697684 2.080251 -0.684198
3.677277 2.969011 0.630869
2.105373 1.640033 1.153452
4.993238 3.110899 0.116984
5.428024 4.103720 0.074261
5.686226 2.003195 -0.300262
3.041796 4.102797 1.021429
2.132970 3.878144 1.287395
1.753261 -0.977105 0.669100
0.721448 -0.413689 -0.351565
0.889665 0.638850 -0.572101
0.781798 -1.354690 -1.561185
0.373685 -0.909079 -2.472027
1.829496 -1.583296 -1.757142
-0.738417 -0.530099 0.256744
-1.743453 -0.823710 -0.859653
-1.611594 -0.053469 -1.618105
-2.736404 -0.712829 -0.425626
-1.497031 -2.248957 -1.402279
-1.699280 -2.258862 -2.476851
-2.181829 -2.967630 -0.943016
-0.025449 -2.598661 -1.128681
0.284346 -3.494342 -1.669086
66
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
C
C
H
H
H
O
C
H
H
C
C
H
C
O
C
H
H
H
O
C
C
C
C
C
C
H
H
H
H
H
C
H
H
C
H
H
H
0.191053
-0.737503
-0.350845
-1.769122
1.602048
1.528584
-1.190797
-0.363427
-2.017572
-1.593975
-2.830233
-2.891482
-0.564031
-0.779038
0.092377
1.137708
-0.064072
-0.203498
0.363232
-4.105859
-6.604006
-4.957461
-4.552390
-5.791863
-6.184903
-4.646006
-3.965543
-6.133641
-6.821479
-7.568192
-0.032335
-1.022589
-0.070008
1.035693
0.794391
2.019822
1.098324
-2.780020
-1.777860
-1.533590
-2.118543
-0.514754
-2.391962
0.669389
0.898267
0.276389
1.919946
2.213097
3.153882
3.006070
3.939053
5.099176
4.796798
5.666953
5.686674
3.033751
1.488454
0.194995
1.566730
0.783010
0.147777
0.909095
2.141850
0.787051
-0.369839
0.969959
-0.303159
-4.202553
-4.536296
-4.161566
-5.215067
-6.199928
-4.925667
-5.318959
0.417367
1.124726
2.114655
1.225234
1.656507
0.768683
1.109496
1.782354
1.696479
0.359021
-0.121539
-0.663687
0.330203
-0.594240
-0.578344
-0.650626
0.341290
-1.445054
1.131368
-0.054508
-0.060273
-1.173759
1.080740
1.076080
-1.184372
-2.041390
1.993706
1.966871
-2.061088
-0.059288
0.936512
0.601467
2.031984
0.510480
0.918493
0.884521
-0.577167
67
X-ray crystal structure determinations
X-ray intensities were measured on a Nonius KappaCCD diffractometer with rotating anode
and graphite monochromator ( = 0.71073 Å) at a temperature of 150(2) K up to a resolution
of (sin /)max = 0.65 Å-1. The structures of 9f and 11f were solved with Direct Methods
(SIR2004[58] for 9f and SHELXS-97[59] for 11f). The initial coordinates for 3a were taken
from the isostructural 3f. Full-matrix least-squares refinement was performed with SHELXL97[60]. Non-hydrogen atoms were refined freely with anisotropic displacement parameters.
Hydrogen atoms were located in the difference Fourier map (9f and 11f) or introduced in
geometrically optimized positions. All hydrogen atoms were refined with a riding model. In
11a the ethyl group was refined with a disorder model.
Structure drawings, geometry calculations and checking for higher symmetry were performed
with the PLATON[61] program.
Further crystallographic details are given in Table S1.
68
Table S1: Crystallographic details for 9f, 11f, and 11a
9f
11f
11a
Formula
C16H19BrO5
C22H20BrNO4
C22H21NO4
Fw
371.22
442.30
363.40
Crystal colour
colourless
colourless
colourless
Crystal size [mm3]
0.51 x 0.30 x 0.24
0.27 x 0.12 x 0.03
0.30 x 0.30 x 0.21
Crystal system
monoclinic
monoclinic
monoclinic
Space group
P21 (no. 4)
P21 (no. 4)
P21 (no. 4)
a [Å]
8.9808(1)
7.6675(1)
7.4898(1)
b [Å]
10.6947(1)
15.6520(3)
15.5364(2)
c [Å]
9.1042(1)
8.9590(2)
8.6839(1)
 [°]
110.7788(4)
109.8294(7)
107.0520(5)
V [Å3]
817.555(15)
1011.43(3)
966.08(2)
Z
2
2
2
dcalc [g/cm3]
1.508
1.452
1.249
 [mm-1]
2.534
2.059
0.086
Abs. correction method
multi-scan [62]
multi-scan[62]
multi-scan[62]
Abs. correction range
0.40-0.54
0.72-0.94
0.94-0.98
reflections (measured/unique)
24600/3744
23036/4628
24677/2308
Rint
0.0421
0.0465
0.0343
Parameters / restraints
203 / 1
255 / 1
257 / 3
R1/wR2 [I>2(I)]
0.0169/0.0412
0.0347/0.0640
0.0311/0.0782
R1/wR2 [all refl.]
0.0173/0.0414
0.0486/0.0683
0.0342/0.0805
S
1.075
1.031
1.031
Flack x parameter[63]
0.008(4)
-0.014(6)
[*]
Friedel pair coverage
99.9%
98.9%
[*]
min/max [e/Å3]
-0.30/0.18
-0.34/0.25
-0.16/0.19
[*] The absolute structure of 11a could not be determined reliably. Therefore Friedel pairs
were merged prior to the final refinement.
69
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